Drs. Neeraj Agarwal and Jeanny Aragon-Ching discuss several key abstracts to be presented at the 2024 ASCO GU Cancers Symposium, including sequencing versus upfront combination therapies for mCRPC in the BRCAAway study, updates on the CheckMate-9ER and CheckMate-214 trials in ccRCC, and a compelling real-world retrospective study in mUC of patients with FGFR2 and FGFR3 mutations. TRANSCRIPT Dr. Neeraj Agarwal: Hello, everyone, and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host of the podcast today. I am the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah’s Huntsman Cancer Institute, and editor-in-chief of ASCO Daily News. I am delighted to welcome Dr. Jeanny Aragon-Ching, a genitourinary oncologist and the clinical program director of Genitourinary Cancers at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing key posters and oral abstracts that will be featured at the 2024 ASCO Genitourinary Cancer Symposium, which is celebrating 20 years of evolution in GU oncology this year.  You will find our full disclosures in the transcript of this podcast, and disclosures of all guests on the podcast at asco.org/DNpod.  Jeanny, it’s great to have you on the podcast today to highlight some key abstracts for our listeners ahead of the GU meeting. Dr. Jeanny Aragon-Ching: Thank you so much, Neeraj. It’s an honor to be here. Dr. Neeraj Agarwal: Jeanny, as you know, this year we are celebrating the 20th anniversary of the ASCO GU Cancers Symposium, and judging from this year's abstracts, it’s clear that this meeting continues to play a major role in advancing GU cancer research. Dr. Jeanny Aragon-Ching: Indeed, Neeraj. This year's abstracts reflect the important strides we have made in GU cancers. So, let's start with the prostate cancer abstracts. What is your takeaway from Abstract 19 on BRCAAway, which will be presented by Dr. Maha Hussein, and of which you are a co-author? As our listeners know, several PARP inhibitor combinations with second-generation androgen receptor pathway inhibitors, or ARPIs, have recently been approved as first-line treatment for patients with metastatic castrate-resistant prostate cancer, or metastatic CRPC, and the question of sequencing PARP inhibitors and ARPIs instead of combining them has emerged. From that perspective, the results of the BRCAAway trial are very important. Can you tell us a little bit more about this abstract, Neeraj?  Dr. Neeraj Agarwal: I totally agree with you, Jeanny. The BRCAAway study attempts to answer the crucial questions regarding sequencing versus upfront combination of therapies in the mCRPC setting. It is a phase 2 trial of abiraterone versus olaparib versus abiraterone with olaparib in patients with mCRPC harboring homologous recombination repair mutations. Enrolled patients had mCRPC disease and no prior exposure to PARP inhibitors or ARPIs or chemotherapy in the mCRPC setting and had BRCA1 or BRCA2 or ATM mutations. As previously mentioned, these patients were randomized to 3 arms: abiraterone monotherapy at 1000 milligrams once daily, or olaparib monotherapy at 300 milligrams twice daily, or the combination of abiraterone and olaparib. The primary endpoint was progression-free survival per RECIST 1.1 or Prostate Cancer Working Group 3-based criteria or clinical assessment or death, so, whichever occurred first was deemed to be progression.   Secondary endpoints included measurable disease response rates, PSA response rate, and toxicity. This was a relatively small trial with 21 patients in the combination arm, 19 patients in the abiraterone monotherapy arm, and 21 patients in the olaparib monotherapy arm. It should be noted that 26% of patients had received docetaxel chemotherapy in the hormone-sensitive setting, and only 3% of patients had any prior exposure to an ARPI, and these were darolutamide or enzalutamide or in the non-metastatic CRPC setting.  The results are very interesting. The median progression-free survival was 39 months in the combination arm, while it was 8.4 months in the abiraterone arm and 14 months in the olaparib arm. An important finding that I would like to highlight is that crossover was also allowed in the monotherapy arms. Of the 19 patients receiving abiraterone, 8 crossed over to receive olaparib, and of the 21 patients receiving olaparib, 8 crossed over to the abiraterone arm. The median PFS from randomization was 16 months in both groups of patients who received abiraterone followed by olaparib or those who received olaparib followed by abiraterone. This is striking when compared to 39 months in patients who started therapy with the combination therapy of abiraterone with olaparib. Dr. Jeanny Aragon-Ching: Thank you so much for that wonderful summary, Neeraj. So the key message from this abstract is that combining olaparib and abiraterone upfront seems to be associated with improvement in PFS compared to just sequencing those agents. Dr. Neeraj Agarwal: Exactly, Jeanny. I would like to add that these results are even more important given that in real-world practice, only half of the patients with mCRPC receive a second-line treatment. Based on these results, upfront intensification with a combination of an ARPI plus a PARP inhibitor in the first-line mCRPC setting seems to have superior efficacy compared to sequencing of these agents. Dr. Jeanny Aragon-Ching: Thank you so much. Now, moving on to a different setting in prostate cancer, there were a couple of abstracts assessing transperineal biopsy compared to the conventional transrectal biopsy for the detection of prostate cancer. So let's start with Abstract 261. Neeraj, can you tell us a little bit more about this abstract? Dr. Neeraj Agarwal: Sure, Jeanny. So, in Abstract 261 titled "Randomized Trial of Transperineal versus Transrectal Prostate Biopsy to Prevent Infection Complications," Dr. Jim Hugh and colleagues led a multicenter randomized trial comparing these 2 approaches, so, transperineal biopsy without antibiotic prophylaxis with transrectal biopsy with targeted prophylaxis in patients with suspected prostate cancer. The primary outcome was post-biopsy infection. Among the 567 participants included in the intention-to-treat analysis, no infection was reported with the transperineal approach, while 4 were detected with the transrectal approach, with a p-value of 0.059. The rates of other complications, such as urinary retention and significant bleeding, were very low and similar in both groups. The investigators also found that detection of clinically significant cancer was similar between the 2 techniques and concluded that the transperineal approach is more likely to reduce the risk of infection without antibiotic prophylaxis. Dr. Jeanny Aragon-Ching: So the key takeaway from this abstract sounds like office-based transperineal biopsy is well-tolerated and does not compromise cancer detection, along with better antibiotic stewardship and health care cost benefits.  Moving on to Abstract 273, also comparing these two approaches, what would be your key takeaway message, Neeraj?  Dr. Neeraj Agarwal: In this Abstract 273, titled "Difference in High-Risk Prostate Cancer Detection between Transrectal and Transperineal Approaches," Dr. Semko and colleagues found that the transperineal biopsy based on MRI fusion techniques was also characterized by a higher possibility of detecting high-risk prostate cancer and other risk factors as well, such as perineural and lymphovascular invasion or the presence of cribriform pattern, compared to the conventional transrectal method. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So we can see that the transperineal approach is gaining more importance and could be associated with more benefits compared to the conventional methods.   Let's now switch gears to kidney cancer, Neeraj. Dr. Neeraj Agarwal: Sure, Jeanny. Let's start by highlighting Abstract 361, which discusses patient-reported outcomes of the LITESPARK-005 study. So what can you tell us about this abstract, Jeanny?  Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So as a reminder to our listeners, based on the LITESPARK-005 trial, it was a Phase 3 trial looking at belzutifan, which is an inhibitor of hypoxia inducible factor 2 alpha or I’ll just call HIF-2 alpha for short, was very recently approved by the FDA as a second-line treatment option for patients with advanced or metastatic clear cell renal cell carcinoma after prior progression on immune checkpoint and antiangiogenic therapies. The title of Abstract 361 is "Belzutifan versus Everolimus in Patients with Previously Treated Advanced RCC: Patient-Reported Outcomes in the Phase 3 LITESPARK-005 Study," and this will be presented by Dr. Tom Pells at the meeting. At a median follow-up of 25.7 months, the median duration of treatment with belzutifan was 7.6 months, while it was only 3.9 months with everolimus. At the time of data cutoff date for the second interim analysis, 22.6% of patients remained on belzutifan while only 5% remained on everolimus. In the quality of life questionnaires, the time of deterioration to various quality of life scores, as assessed by standardized scales, was significantly longer in patients randomized to the belzutifan arm compared to those in the everolimus arm. Also, patients in the everolimus arm had worse physical functioning scores. Dr. Neeraj Agarwal: Yes, Jeanny. In addition to the improved outcomes associated with belzutifan, patient-reported outcomes indicate better disease-specific symptoms and better quality of life among patients treated with belzutifan compared to everolimus. This is great news for patients with advanced renal cell carcinoma.  Now, Jeanny, can you please tell us about the two abstracts that reported longer follow-up of CheckMate 9ER and CheckMate 214 trials in untreated patients with advanced or metastatic renal cell carcinoma? Dr. Jeanny Aragon-Ching: Yes, Neeraj. So you are referring to Abstracts 362 and 363. Let's start with Abstract 362. This abstract reports the results after a median follow-up of 55 months in the CheckMate 9ER trial, comparing the combination of nivolumab and cabozantinib to sunitinib in patients with advanced RCC without any prior treatment, so first-line therapy. The primary endpoint was PFS per RECIST 1.1 as assessed by an independent central review. So there were key secondary outcomes including overall survival (OS), objective response rates, and safety. Consistent with prior analysis at a median follow-up time of 18.1 and 44 months, the combination of nivolumab and cabozantinib at a median follow up of 55.6 months continues to show a significant reduction in the risk of progression or death by 42% and in the risk of death by 23% compared to sunitinib.  Dr. Neeraj Agarwal: And Jeanny, what can you tell us about the efficacy results of this combination by IMDC risk categories? Dr. Jeanny Aragon-Ching: Similar to prior results in patients with intermediate to poor risk IMDC risk category, the combination treatment maintained significant efficacy and reduced the risk of progression or death by 44% and the risk of death by 27%. To put it simply, the update now shows a 15-month improvement in overall survival with the cabozantinib-nivolumab combination compared to sunitinib, which is amazing. Also, in patients with favorable IMDC risk group, which represented truly a small number of patients in the trial, there was a strong trend for improvement of outcomes as well. I would like to point out that no new safety concerns were identified. Dr. Neeraj Agarwal: So, it looks like the key message from this abstract is that with longer follow-up, the combination of nivolumab and cabozantinib maintains a meaningful long-term efficacy benefit over sunitinib, supporting its use for newly diagnosed patients with advanced or metastatic renal cell carcinoma.   Let's move on to Abstract 363, which compares nivolumab with ipilimumab to sunitinib in first-line advanced renal cell carcinoma. What would you like to tell us about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Yes, Neeraj. The title of this abstract is "Nivolumab plus Ipilimumab versus Sunitinib for the First-Line Treatment of Advanced RCC: Long-Term Follow-Up Data from the Phase 3 CheckMate 214 Trial." In this abstract, Dr. Tannir and colleagues report outcomes with the longest median follow-up in first-line advanced RCC setting for any clinical trial. So the median follow-up now is about 18 months. The primary endpoints were OS, PFS, and objective response rates, as assessed by an independent review according to RECIST 1.1 criteria in the intermediate to poor risk IMDC risk group, which is the intent-to-treat (ITT) analysis, while secondary outcomes included the same outcomes in the ITT population of patients. Although the progression-free survival was similar in both arms, the combination of nivolumab-ipilimumab reduced the risk of death by 28% compared to sunitinib in the ITT population of patients. When stratifying the results by IMDC risk groups, the combination arm of nivolumab-ipilimumab showed significant improvement in the intermediate to poor risk group, but there was no difference in the favorable risk group. But in the study, no new safety signals were identified. Dr. Neeraj Agarwal: Thank you, Jeanny, for such a comprehensive description of the results of these two studies. I'd like to add that the median overall survival of patients with metastatic renal cell carcinoma in the ITT population in the CheckMate 214 trial has now reached 53 months, which would have been unimaginable just a decade ago. This is wonderful news for our patients. So the key takeaway from these two abstracts would be that immune checkpoint inhibitor-based combinations remain the backbone of first-line advanced renal cell carcinoma treatment.  Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. This is wonderful news for all of our patients, especially for those who are being treated for first-line therapy.  Now, let's move on to the bladder cancer abstracts. We have two exciting abstracts from the UNITE database. What are your insights on Abstract 537, titled "Outcomes in Patients with Advanced Urethral Carcinoma Treated with Enfortumab Vedotin After Switch-Maintenance of Avelumab in the UNITE Study"? Dr. Neeraj Agarwal: As our listeners know, enfortumab vedotin is an antibody-drug conjugate that binds to a protein called Nectin 4 expressed on bladder cancer cells. In this abstract, Dr. Amanda Nizam and colleagues describe outcomes in 49 patients receiving third-line enfortumab vedotin after prior progression on platinum-based therapy and maintenance avelumab. At a median follow-up of 8.5 months, the median progression-free survival was 7 months and the median overall survival was 13.3 months with enfortumab vedotin in this treatment-refractory setting, the objective response rates were 54%. The message of this study is that enfortumab vedotin is an effective salvage therapy regimen for those patients who have already progressed on earlier lines of therapies, including platinum-based and immunotherapy regimens. Dr. Jeanny Aragon-Ching: Thank you, Neeraj, for that comprehensive review.  I want to focus on another patient population in the UNITE database, which is the use of fibroblast growth factor receptor (FGFR) alterations. Can you tell us more about the sequencing now of erdafitinib and enfortumab vedotin in these patients with metastatic urothelial cancer, as discussed in Abstract 616? Dr. Neeraj Agarwal: Sure, Jeanny. As a reminder, erdafitinib is a fibroblast growth factor receptor kinase inhibitor approved for patients with locally advanced or metastatic urothelial carcinoma harboring FGFR2 or FGFR3 alterations after progression on platinum-based chemotherapy. However, the optimal sequencing of therapies in these patients is unclear, especially with enfortumab vedotin being approved in the salvage therapy setting and now in the frontline therapy setting.  So in this retrospective study, all patients with metastatic urothelial carcinoma had FGFR2 or FGFR3 alterations. Dr. Cindy Jiang and colleagues report outcomes in 24 patients receiving enfortumab vedotin after erdafitinib, 15 patients receiving erdafitinib after enfortumab vedotin, and 55 patients receiving enfortumab vedotin only. This is a multicenter national study. Interestingly, patients receiving both agents had a longer overall survival in a multivariate analysis, regardless of the treatment sequencing, than patients receiving enfortumab vedotin alone or only with a hazard ratio of 0.52. The objective response rate of enfortumab vedotin in the enfortumab vedotin monotherapy arm was 49%. When these agents were sequenced, the objective response with enfortumab vedotin was 32% after erdafitinib and 67% when used before erdafitinib. Dr. Jeanny Aragon-Ching: Thank you so much, Neeraj. I think these are important real-world data results, but I would like to point out that larger and prospective studies are still needed to confirm these findings, especially regarding the outcome of erdafitinib after enfortumab vedotin, particularly when the latter is used in the first-line setting. Dr. Neeraj Agarwal: I totally agree, Jeanny. Now, let's discuss some abstracts related to disparities in the management of patients with genitourinary cancers.  Dr. Jeanny Aragon-Ching: Sure, actually, I would like to discuss 2 abstracts related to disparities in patients with prostate cancer. So the first one, Abstract 265, titled "Patient-Provider Rurality and Outcomes in Older Men with Prostate Cancer." In this study, Dr. Stabellini, Dr. Guha and the team used a SEER Medicare-linked database that included more than 75,000 patients with prostate cancer. The primary outcome was all-cause mortality, with secondary outcomes included prostate cancer-specific mortality. The investigators showed that the all-cause mortality risk was 44% higher in patients with prostate cancer from rural areas who had a provider from a non-metropolitan area compared to those who were in a metropolitan area and had a provider also from a metropolitan area. Dr. Neeraj Agarwal: Those are very important data and highlight the healthcare disparities among the rural population with prostate cancer that still exist.  So what is your key takeaway from Abstract 267, titled "Rural-Urban Disparities in Prostate Cancer Survival," which is a population-based study? Dr. Jeanny Aragon-Ching: Of course. This abstract discusses, actually, a very similar issue regarding access to healthcare among rural versus urban patients. In this study, Dr. Hu and Hashibe and colleagues and team at the Huntsman Cancer Institute assessed all-cause death and prostate cancer-related death risk in a retrospective study in which patients with prostate cancer based on rural versus urban residencies looked at 18,000 patients diagnosed with prostate cancer between 2004 and 2017. 15% lived in rural counties. Similar to the prior abstract we talked about, patients living in rural areas had about a 19% higher risk of all-cause mortality and a 21% higher risk of prostate cancer-specific mortality in comparison to patients living in urban areas. Dr. Neeraj Agarwal: So Jeanny, we can say that both of these abstracts, led by different groups of investigators, highlight that patients with prostate cancer living in rural areas have inferior survival outcomes compared to those living in urban areas, and it is time to focus on the disparities experienced by the rural population with prostate cancer.  Dr. Jeanny Aragon-Ching: Yeah, absolutely Neeraj. I concur with your thoughts.  So, any final thoughts before we wrap up the podcast today? Dr. Neeraj Agarwal: Yes, before concluding, Jeanny, I want to express my gratitude for your participation and the valuable insights you have shared today. Your contributions are always appreciated, and I sincerely thank you for taking the time to join us today.   As we bring this podcast to a close, I would like to highlight the significant advances happening in the treatment of patients with genitourinary cancers during our upcoming 2024 ASCO GU meeting. Many studies featuring practice-impacting data will be presented by investigators from around the globe. I encourage our listeners to not only participate at this event to celebrate these achievements, but to also play a role in disseminating these cutting-edge findings to practitioners worldwide. By doing so, we can collectively maximize the benefit for patients around the world.  And thank you to our listeners for joining us today. You will find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much.  Disclaimer: The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guest speakers express their own opinions, experience, and conclusions. Guest statements on the podcast do not necessarily reflect the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Find out more about today’s speakers:     Dr. Neeraj Agarwal  @neerajaiims  Dr. Jeanny Aragon-Ching    Follow ASCO on social media:     @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn       Disclosures:      Dr. Neeraj Agarwal:       Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences    Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas     Dr. Jeanny Aragon-Ching:    Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono  Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,   Speakers’ Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics. 

Drs. Eric Small, Anthony Zietman, and Eric Klein share their reflections as founders of the ASCO Genitourinary Cancers Symposium and discuss key moments in the Meeting’s development, its role in advancing GU cancer research, and major challenges ahead for the field as the Symposium celebrates its 20-year anniversary. TRANSCRIPT Dr. Eric Small: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Eric Small, your guest host of this ASCO Daily News Podcast today. I'm the co-leader of the UCSF Prostate Cancer Program and deputy director and chief scientific officer at the UCSF Helen Diller Family Comprehensive Cancer Center. This year, quite amazingly, we're celebrating the 20th anniversary of the ASCO Genitourinary Cancers Symposium, which is hosted annually in San Francisco. The Symposium has heralded some of the biggest strides in GU oncology and has the largest multidisciplinary, global audience for GU cancer research. I was honored to have a role in the development of ASCO GU two decades ago, along with my friends and colleagues, Dr. Eric Klein, emeritus professor and chair of the Glickman Urological and Kidney Institute at the Cleveland Clinic. And Dr. Anthony Zietman, a professor of radiation oncology at Harvard Medical School and the Massachusetts General Hospital. On today's episode, we'll be reflecting on key moments in the meeting's development, its role in advancing GU cancers and GU cancer research, and major challenges that lay ahead for the field. You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod. Eric and Anthony, I'm delighted to have this opportunity to catch up with you both to discuss ASCO GU, thank you for coming on the podcast today. Dr. Eric Klein: Thanks for having us. Dr. Anthony Zietman: Thanks for the invitation. Dr. Eric Small: Well, it's really exciting and it's wonderful to see the two of you. So, the ASCO GU Symposium has been a key annual event for all of us in the GU field. But to give our listeners some background, when the Symposium was first created, when we first met in San Francisco, starting on Thursday, February 17, 2005, it brought together 1,035 individuals interested in the prevention and treatment at that point of prostate cancer alone. At that time, the meeting was co-sponsored by ASCO, the American Society for Therapeutic Radiology and Oncology or ASTRO, the Society of Urologic Oncology (SUO), and the Prostate Cancer Foundation. It was actually the culmination of several years of planning. Clearly, it represented the first truly multidisciplinary scientific and educational meeting dedicated solely to prostate cancer, and we'll come back to talk about that. The meeting went back and forth between San Francisco and Florida for a few years before finally, settling permanently in San Francisco. In the last 20 years, ASCO and the Symposium's co-sponsors expanded the meeting to include all genitourinary specialties. This year, ASCO received more than 875 abstract submissions and anticipates that there will be even more attendees than last year. On a personal note, it's truly amazing to me that here we are, 20 years later, and the meeting is going stronger than we could ever have imagined. I must say that my motivation to help organize this meeting stem from two issues that were somewhat in tension with each other. First, the field of prostate cancer and prostate cancer research was just starting to take off at the time, and we really needed, as a community, a venue where across disciplines, we could talk and meet with each other. But that was in real tension, at least at ASCO, where we were relegated at the Annual Meeting to a tiny room at the far end of the convention center on the last day of ASCO, because really, that's all we could muster. And I do remember making a pitch, assuring folks that there was an unmet need, and that the field was going to take off, who knew? So, I'm wondering, and either of you can jump in (Dr. Klein, Dr. Zietman), tell us how you got involved in the first GU meeting, and what's the most salient feature of your involvement? Anthony, do you want to start? Dr. Anthony Zietman: I think it's really important to discuss the historical context at which this meeting was born. Back in the 1990s, we were incredibly polarized as specialties in GU oncology. PSA had been introduced in the late '80s, early '90s, screening was everywhere. There was a tidal wave of patients and an almost reckless race to treatment. All surgeons believed that all patients with localized early prostate cancer needed surgery and that they could do individually, a beautiful job. And all radiation oncologists believed that they could deliver morbidity-free treatment and could do it to everyone regardless of your age or stage. And there were a few, there were a few who thought maybe we didn't need to screen everyone, and maybe there was a little bit of overtreatment, maybe we've gone a little bit too far, but those voices were really suppressed in the '90s. Those voices didn't have a voice. Many of us also believed there was more morbidity to our treatment than we'd appreciated. And that was the media in which, us three, all young research physicians, probably all in our low forties were given the charge of this meeting. And the thing I most remember about it in the planning, is that we actually decided collectively to give voice to everyone, including maverick voices. It wasn't just about the party line, and it wasn't just about the North American line, there were Britts and there were Swedes, and there were Dutchmen who had very important things to say as well, and very, very different perspectives. And we also chose to give voice to young people as well as just our party elders, so to speak. I don't know which of us, if any of us, or maybe it was our society suggested but we do it all in a single room such that rad oncs and surgeons were all together, and it led to a kind of forced truthfulness, which started to break down this groupthink that we developed in our own silo. So, when I look back, I think that that context was very important and that what we sought as young program chairs was we sort of tapped in something that was latent in our field. Eric KIein, I don't know if you remember things as I did. Dr. Eric Klein: I do. And things were very siloed then. We had hired early in the mid-90s, I think, a young radiation oncologist named Pat Kupelian, who became a close collaborator and a good friend, and who really changed the narrative around treating prostate cancer at the Cleveland Clinic, which was all surgical prior to that time. And he did such high-quality work, it was hard not to pay attention. And he actually took it on himself in his early years when he wasn't very busy to sit down and go through all the patients that we had treated with prostate cancer at the Cleveland Clinic, radiation versus surgery, and had the temerity to write a manuscript that showed that there was no difference in survival, based on PSA biochemical recurrence and metastasis and that sort of thing. And that was sort of game changing. And it really clued me into the fact that for patient's sake, we needed to be talking to our colleagues. The second perspective was from the perspective of having attended a couple of Prostate Cancer Foundation meetings. And I think they really deserve credit for increasing the visibility of prostate cancer research, and funding it and recruiting really good scientists from other disciplines. When young scientists were told, and we heard this repeatedly, "Don't spend your career researching prostate cancer, it's a dead end." And PCF did a great job of having a multidisciplinary meeting, which was smaller and not so clinically focused, but also got me excited. Dr. Eric Small: I think you're right, Eric. And I think that the transdisciplinary nature, as Anthony pointed out was new, it was innovative. No one had really, really thought about it. It was at the margins in different meetings. Your comments about PCF, Prostate Cancer Foundation, resonate because we did take a page from their book in many ways although that meeting, as you point out, is much more basic research-focused. I don't know if you guys recall that first year, in fact, PCF was a co-sponsor. We actually had asked Mike Milken to give a talk and he did. And obviously, once we expanded to the broader GU cancers, it was less pertinent for PCF to be involved. But absolutely, I agree with you, Eric, they deserve credit. PCF, and the PCF involvement, was one of the things that changed. There's many things that are constant that haven't changed, even though the science clearly has evolved dramatically. And I'm wondering if you guys can comment on things that are the same. One thing that stands out for me: I had the opportunity to look through the agenda for the 2005 meeting. And right there, very prominently, was a special lunch session that we had designed for mentorship and career development for trainees and early career investigators, and that's still ongoing and others have modeled it. And I think that was one amazing feature of this. One of you, I think Anthony mentioned that we invited a lot of young people to speak and to be the path blazers, but we also did this career development piece, and it was a wonderful event. I wonder if either of you or both of you could comment on other things that you think are constants and you anticipate will always be there. Dr. Anthony Zietman: I think to me that constant is that every time I go, I hear speakers I've not heard before. Often very senior speakers, I've never heard them before. But it is the practice of GU ASCO to invite people that are outside your sphere of experience, which is very challenging. Dr. Eric Klein: Two things strike me. I think one is the international nature of the faculty. We tried very hard (and subsequent program directors have) to be very inclusive and to bring the work that was the most cutting-edge to the stage. There are lots of things that are done in Europe that started there sooner. PSMA treatment, for example, and many other ProtecT trial and many other things. And the debates on stage and how that gave the opportunity for every subspecialty to have the opportunity to share its perspective on particular case management issues and case management conferences, I think have been around forever. And maybe, the most valuable part of it all is to hear people's perspective on how to manage a particular patient. Dr. Eric Small: I think the other comment you made Anthony that resonated and still goes on, was it was a conscious decision to have a single session in one room where everyone attended. And not to do the usual small breakouts and concurrent sessions, but sort of the philosophy being, is we all need to hear the same thing, we all need to be in the same room at the same time. And it really fostered this transdisciplinary approach; it was truly educational for us. Now, it's sort of part of what we do, and part of what our patients expect of us. I think that bringing us all together into one room was really great. Dr. Anthony Zietman: But it's now so part of what we do, but it's difficult certainly for younger faculty and for residents to believe we ever did it any other way. But we did, and I don't know whether ASCO GU led that or reflected that, but that was the zeitgeist among young individuals like us. And it's really become the culture of contemporary practice. Dr. Eric Small: So, given that that's the culture now, which it is, and I think sure, we should take credit for it, at least in GU: why then is it important for people to continue to attend GU ASCO today if it's now our culture to do that? Dr. Anthony Zietman: For me, it's because we share information as equal partners in a multidisciplinary team. And our practice is so multidisciplinary and multi-modality these days that we can't exist alone, we no longer try to. Dr. Eric Klein: Nor can we. The amount of knowledge that's being generated in each subspecialty and it's spinoffs is so great. It's impossible for a busy surgeon to stay on top of that. And this is sort of one-stop shopping for everything that's really current and appropriate to know about. And again, I always look at these things from the patient perspective, and my ability to counsel patients about what their best treatment options might be, I thought more and more dependent, and I think today more and more depends on being knowledgeable about everything that's going on, and not just one narrow field that you happen to be an expert in. And that's why I think it's so important for youngsters to attend and even oldsters like us to attend to stay current. Dr. Anthony Zietman: Yeah, and also, multidisciplinary means so much more these days. It does mean oncologists and radiologists, information technologists. I mean, who knows what it'll mean in the future, but it's always expanding. Dr. Eric Small: And I think it's interesting, back when we did this, when we started it, we were worried about being able to fill one meeting with prostate cancer information - we did easily. It was not immediately clear that there was a role or room for additional GU cancers. And then there was an explosion both in kidney cancer work at first, and then bladder cancer. And now it's unbelievable how much is there. And perhaps, this meeting needs to be twice as long. So, I agree with you guys. I think that it's the best way to stay current. The other thing that I really appreciate about this meeting and others have a hard time doing it, is that it provides, as Eric indicated, for the busy clinician. It integrates sort of the important information that's coming in terms of more basic science and makes it readily available and digestible, which isn't always the case at pure science meetings and may or may not be apparent in other meetings. I, again, was looking at the preliminary agenda in 2005, we had asked Bill Nelson to talk about molecular targets or prevention, how forward-thinking. And that's continued to be the case that this is a meeting where you get that integration from the laboratory. Dr. Anthony Zietman: Well, and I would add to that, not just the integration of it, it's where now you get to hear things first. I mean, it used to be that, you went the AUA or ASTRO or ASCO to hear things. Now, everyone one wants to present it first at GU ASCO. Dr. Eric Klein: Yes, that's correct. Dr. Anthony Zietman: And I think we actually made it permissible in the early days that you could present at GU ASCO and at your specialty meeting. Dr. Eric Small: What are the challenges in the field that are going to likely shape the content of future meetings? And we've all alluded to the fact that the meeting is evolving and has done a really good job of staying current with the clinical science. But beyond that, what do you two feel are important areas that this meeting is likely to continue to address? Dr. Eric Klein: So, biomarker development has always been an important part of this meeting, and I think we need to broaden our view of what biomarkers are now, and in the AI era, digital pathology and AI-based models that predict treatment response and outcome. My hope is that they will be studied in a rigorous fashion, and that they will end up outperforming the kind of single biomarker approach that we've used in the past. And we need to understand that; we need to understand the science behind AI to a certain level, and we need to understand what questions AI can address, and how that might be useful. But I'm particularly excited about digital pathology where sampling error becomes less of an issue and the number of potential inputs you're looking at that are related to the output should increase exponentially. Dr. Anthony Zietman: And I would add on the AI side of things, as a former journal editor, when AI papers came into the journal, we actually didn't have enough people who could review them, who had the understanding to review these papers and tell us, "Is this a good paper or a bad paper?" So, we're going to need to increase our understanding of AI, Eric, as you said. So, I think that will be a push in the years to come. Also, on a very practical level, it is such a popular meeting, keeping us all under one roof and in one room, will become just difficult. But it's part of the culture of the meeting, and I think it's what people want. Dr. Eric Small: It's a good challenge to have. Dr. Eric Klein: Feeding everybody too. I recall one constant has always been really good breakfasts and lunches. Dr. Eric Small: Right, that has been a standard of ours. One of the interesting things that I think has changed, we saw glimmers of it back in 2005, but it was early on and it was, I think very early on in sort of a good understanding of social determinants of health and equitable access to healthcare and the challenges posed by incredible technology development and making sure that that doesn't increase disparities. And I think that that focus has increasingly been present in meetings and is not going to be lost. And it also speaks, one of you spoke to our international audience, that increasingly, I think this meeting is going to address urologic oncology and how we address it not only in developed countries, but in lower- and middle-income countries. And I think that will be a focus as well. I'm excited with what the future holds for ASCO GU. It has been an incredible run. I'm hoping that we'll be able to perhaps catalog some of the salient presentations that have been done at this meeting over the years, but there's no question as both of you have pointed out, this has become the venue. Well, thank you both for sharing your insights with us today on the ASCO Daily News Podcast. Really wonderful to see you both and talk with you. Dr. Eric Klein: Great to be here. Thanks. Dr. Anthony Zietman: Great to be here. Looking forward to the next 20 years. Dr. Eric Small: That's right. Dr. Anthony Zietman: If I'm still around. Dr. Eric Klein: Yeah, let's do this again in 20 years. That'd be great. Dr. Eric Small: We will. And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thank you. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use and the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today’s speakers:   Dr. Eric Small Dr. Eric Klein @EricKleinMD Dr. Anthony Zietman   Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:     Dr. Eric Small: Stock and Other Ownership Interests: Fortis, Harpoon Therapeutics, Teon Therapeutics Honoraria: Janssen Consulting or Advisory Role: Janssen Oncology, Teon Therapeutics, Fortis   Dr. Anthony Zietman: Leadership: Elsevier   Dr. Eric Klein:No relationships to disclose

Drs. John Sweetenham and Fred Locke discuss the FDA investigation on the risk of cancer from CAR T-cell therapy and share insights on the known number of cases and the potential implications on clinical research and patient care. TRANSCRIPT Dr. John Sweetenham: Hello, I’m Dr. John Sweetenham from the UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast. CAR T-cell therapies have been game changers for treating certain cancers including lymphomas and leukemias, as well as multiple myeloma, since the vast majority of patients who have received CAR-T do not have other curative options with conventional non-cellular, anti-cancer therapies. But on November 28, the U.S. Food and Drug Administration announced that it is investigating whether CAR T-cell therapy can, in rare cases, cause secondary cancers. The FDA launched the probe after receiving reports from clinical trials and other data sources of T-cell malignancies in patients who received CAR T-cell immunotherapies. Joining me to discuss the investigation and its implications for the field is Dr. Fred Locke, a medical oncologist and translational researcher and a senior member and chair in the Department of Blood and Marrow Transplant and Cellular Immunotherapy at the Moffitt Cancer Center in Tampa, Florida. Dr. Locke is an internationally renowned clinical research leader in the field of CAR T-cell therapy. You'll find our disclosures in the transcript of this episode, and disclosures of all guests on podcasts are available at asco.org/DNpod. Fred, it’s great to have you on the podcast today. Dr. Fred Locke: Thanks, John, I’m really glad to be here. Dr. John Sweetenham: So, T-cells are the backbone of CAR T-cell therapies, and there are currently 6 CAR-T products approved by the FDA. As our listeners will know, CAR T-cell therapies manipulate a patient's T-cells, enabling them to recognize and attack antigens on cancer cells and induce potential long-standing changes in the immune system. In its statement on November 28, the FDA said it determined that the risk of T-cell malignancies is applicable to all of the currently approved BCMA- and CD19-directed, genetically modified, autologous CAR T-cell immunotherapies. Fred, could you comment for us on the investigation: How many patients are reported to have developed second malignancies from CAR T-cell therapy, and whether there are likely to be more secondary cancers reported? Dr. Fred Locke: Yes, so the FDA and the reports are coming out that there are 19 cases of T-cell malignancy that we're aware of that have occurred after the current FDA-approved CAR T-cell therapies were administered for the treatment of leukemia, lymphoma, or multiple myeloma. The majority of those cases were reported through the FDA Adverse Event Reporting System. And we don't know a lot of details of those 19 cases. We think that there's probably about 13,000 to 14,000 patients who've been treated with the commercial CAR T-cell therapies. So if you kind of do some crude math, you can come up with 19 out of say, 13,500; we're at about 0.1% of patients who could have developed T-cell lymphoma after treatment with these CAR T-cell therapies. It's not entirely out of the realm of possibility that T-cell lymphoma could develop from gene-modified T-cells, and these are all the patient's own T-cells that have been modified outside of the body. But I would still posit that this is a really low incidence of T-cell lymphomas in these patients who really are without other great treatment options. Dr. John Sweetenham: Yeah, and I think that's a point that we'll return to a little bit later on in the conversation around the fact that you know, clearly, there are major benefits that have been associated with CAR T-cell therapy and hematologic malignancies so far. And of course over the years, I think that many of us have become familiar with and learned a great deal about how to manage some of the more serious side effects of CAR T-cell therapy. And you, of course, have led several pivotal national trials of anti-CD19 CAR-Ts for lymphoma. Can you comment at all on whether you've seen previous data from your own practice or others on the risk of second malignancy from CAR T-cell therapy? And can you share your insights on the data and any new emerging data that warrants our attention for the concern or risk of second malignancy? And I guess to round up that series of questions, is there anything currently in yours or others research into CAR-T to explain what's happening and why this is going on? Dr. Fred Locke: I think what may have prompted the FDA’s announcement of this is that on the same date that they came out with announcing their investigation, there was the release of the abstracts for the American Society of Hematology Annual Meeting. And within those abstracts, and unfortunately it was not selected for poster or oral abstract presentation, but discovered within those abstracts was one on a CAR+ T-cell lymphoma after ciltacabtagene autoleucel therapy for relapsed refractory multiple myeloma. And what these investigators and the company were reporting is that a patient with refractory multiple myeloma received the cilta-cel BCMA-directed CAR T-cell therapy and developed a stringent complete response, and about 5 months later developed a nasal facial plaque and PET+ cervical lymph nodes. And both the lymph nodes and the plaque were biopsied and showed a T-cell lymphoma in which 90% to 100% of the cells were positive by qPCR for the CAR construct and immunohistochemistry for the CAR protein. So this was a T-cell lymphoma growth where the cells were expressing the inserted protein, the chimeric antigen receptor protein, which is obviously not natural. And when they looked a little bit deeper at these patients, 91% of the cells have the same T-cell receptor sequence. So this was really a clonal sort of process. They did CAR integration analysis to see how the insertion of the CAR, the chimeric antigen receptor gene, could have potentially disrupted a gene within the T-cells. And what they found is that there were some dominant sort of insertions within certain genes suggesting monoclonality, but it wasn't within any sort of obvious activating genes that would be expected to lead to the T-cell lymphoma. They went on and did some additional analysis, and they showed that there was some existing TET2 mutations in the T-cells of this patient, prior to probably prior to the CAR T-cell manufacturer, and they weren't associated with clonal insertion. And I think, you know, it's possible that this patient who had a pre-existing mutation may have been susceptible to the development of a T-cell lymphoma prior to the CAR T-cell treatment. And TET2 was previously shown a number of years ago in a CLL patient treated with CD19 CAR T-cell therapy; it was shown that there was insertional mutagenesis, silencing the TET2 gene, and that associated with clonal expansion of the CAR T-cells in that patient and corresponded with remission of the CLL. However, the difference here is that that patient's T-cell clone went back down and contracted, and the patient remained in remission 5 years later with their T-cells still in the blood, but the minority of those T-cells had that that TET2 mutational insertional mutagenesis. All this is something we thought was theoretically possible, that T-cell lymphoma could develop after car T-cell therapy. And in fact, a prior trial using a different method of delivery of a CAR gene; instead of using a virus to insert the car into the into the T-cells, a transposon system called piggyBac was used. And in that trial, again, CD19 CAR trial, but in this case, it was allogeneic donor cells for patients who had relapsed after an allogeneic transplant. So it's sort of an autologous, you know, analogy, but it's using the donor cells. And in that trial, 2 out of like 10 patients developed clonal T-cell lymphoma, which was CAR+, but they weren't able to identify a clear insertional mutagenesis event in those cases. So, we've known this is possible, and it would have been great if this poster or if this abstract at ASH was presented as an oral or a poster so we could get more detail, but it's possible that that's the likely reason for the FDA’s announcement. Dr. John Sweetenham: Thanks. The bottom line, I guess, is that for now, the jury's still out on exactly what's underlying these observations, but something which I'm sure is going to be the subject of a lot of discussion during the ASH meeting this year and moving forward. I'd like to inform our listeners that ASCO released a statement on the FDA investigation, stating that the risk of T-cell malignancies due to CAR T-cell therapy appears to be very low. And we've just heard from Dr. Locke that, of the several thousand patients who've received CAR Ts, there are 19 cases so far, it's been reported, which puts us into some type of proportion. The ASCO statement goes on to say that based on available data, and while such malignancies have occurred in patients who have received CAR T-cell therapy, the causal relationship, whether these cases are spontaneous or are caused by the therapy, needs to be investigated further, and we've just heard a little about the detail of that. ASCO added that by issuing a warning but not revoking approval of these therapies, the FDA clearly believes that the current available evidence suggests the overall benefits of these products, used within their approved label, continue to outweigh the potential risks. So Fred, the risk of secondary malignancies is already included as a class warning in the U.S. prescribing information for these CAR T-cell therapies. But do you think that the CAR-T products could eventually be taken off the market, and how would your research be impacted if this were to happen? And maybe finally, how long will patients on CAR T-cell therapy need to be monitored moving forward? Dr. Fred Locke: I don't believe that CAR T-cell therapy will be taken off the market. As we've already talked about, the incidence is extraordinarily low and the causality is unclear. It would certainly impact my research, as I'm doing clinical trials with CAR T-cell therapies, but it would more importantly impact the way we treat patients. We did over 300 CAR T-cell therapy treatments last year here at Moffitt Cancer Center. We're one of the busiest programs in the world giving CAR T-cell therapy, and it is truly a transformative therapy for all the diseases that we administer these FDA-approved therapies for. For example, in diffuse large B-cell lymphoma, we participated in the ZUMA-7 clinical trial and recently reported that patients randomized to CAR T-cell therapy had improved overall survival. They were living longer than patients randomized in the second-line setting to get conventional chemotherapy and autologous transplant. This is clearly a therapy that can work. I would also add that the risk of secondary malignancies is real, but that's a risk for all cancer patients, particularly patients with hematologic malignancies, and for example, lymphoma patients who've gotten an autologous stem cell transplant are at a relatively high lifetime risk of developing a secondary myeloid malignancy, most commonly, treatment-related MDS or AML. And that risk is also present after CAR T-cell therapy. The degree of attribution of CAR-T versus the condition of chemotherapy for CAR-T versus the previous chemotherapy is all unclear, and more analysis needs to be done. But the risk of developing treatment-related MDS or leukemia is certainly higher than the small number of T-cell lymphomas reported. The other thing I want to point out is that there was an analysis of the SEER database that patients with B-cell lymphomas are at about a 5-fold higher risk of developing a T-cell lymphoma than the otherwise healthy population; and vice versa, by the way, T-cell lymphoma patients are at risk for developing B cell lymphoma. And in fact, in that SEER database, it's not a wildly different percentage chance of developing a T-cell lymphoma after a B-cell lymphoma. And this data came out before the advent of CAR T-cell therapy. So I really think we need more science to be done to understand what's happening for these patients. Will this impact the field? Well, certainly, there are treatments that are not CAR T-cell therapy that compete with CAR T-cell therapy or could; I'm a strong believer that they don't offer the same outcomes for patients, but we will certainly see people talking about this for some time. Then the other place where this could be relevant, I think, is as we look at CAR T-cell therapy for autoimmune disorders, and we're starting to see studies of that for lupus and other diseases, the risk to benefit ratio could be different in those cases. So this is something we really need to consider as we move forward with CAR T- cell therapy. Dr. John Sweetenham: Yeah, thanks, Fred. And as a major clinical investigator in the field of CAR-T at the moment, do you see any potential concerns about difficulties in getting patients onto the trials of CAR T-cell in the light of this information? Dr. Fred Locke: No, I really don't. We're not seeing hesitancy, at least in the patients who are referred in for CAR T-cell therapy. Again, it may give ammunition for those who are already predisposed to not refer patients in for CAR T-cell therapy, but I don't think it should. I think that these are low risks, and these therapies clearly have benefits to patients. And we should give their patients an opportunity to get these therapies, and I don't see it impacting our clinical trials at this point. Dr. John Sweetenham: Yeah, and your comments address what was going to be my final question to you and that is, as a referring oncologist, how would you advise a referring oncologist to talk with their patients about these data and their implications moving forward? Dr. Fred Locke: If the patient brings it up, I think the response should be that these are very few cases of very low incidence and very low risk. There are other risks to CAR T-cell therapy that are greater, and really speaking with a cell therapist who administers the treatment is probably the best way to give the patient the option to get CAR T-cell therapy if they want to, knowing all the risks and benefits. So, I would leave it up to the CAR-T treatment center to discuss those risks with the patient.   Dr. John Sweetenham: Well, thanks, Fred, for sharing your insights with us on these concerning developments in CAR T-cell therapy, and I think also for putting them into context in terms of the sort of magnitude of this problem in the context of the overall number of patients who are benefiting from this therapy right now. We truly appreciate your time, and thanks for sharing your thoughts with our listeners. Dr. Fred Locke: Thanks, John, my pleasure. Dr. John Sweetenham: And thank you to our listeners for your time today. If you value the insights you hear on ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.    Find out more about today’s speakers:      Dr. John Sweetenham Dr. Fred Locke @DrFredLocke     Follow ASCO on social media:         @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn         Disclosures:        Dr. John Sweetenham:    Consulting or Advisory Role: EMA Wellness     Dr. Fred Locke: Consulting or Advisory Role: Novartis, Celgene, Calibr, Allogene, Gerson Lehrman Group, EcoR1, Amgen, Bluebird Bio, Bristol Myers Squibb, Iovance Biotherapeutics, Legend Biotech, Cowen, Kite (Gilean), Umoja Biopharma, Takeda, Sana Biotechnology, Daiichi Sankyo/UCB Japan, Bristol-Myers Squibb/Celgene, Janssen, A2 Biotherapeutics, Mittenyi Biotec, Caribou Biosciences, Takeda, Umoja Biopharma Research Funding: Kite Pharma, Allogene, Novartis, Bluebird Bio, Bristol-Myers Squibb/Calgene Patients, Royalties, Other Intellectual Property: Double Mutant Survivin Vaccine. US010414810B2 CAR T Cells with Enhanced Metabolic Fitness; Serial Number: 62/939,727 Methods of Enhancing CAR T Cell Therapies. Serial Number: 62/892,292. Evolutionary Dynamics of Non-Hodgkin Lymphoma CAR-T cell therapy.  Serial Number: 62/879,534. Travel, Accommodations, Expenses: Kite Pharma, A2 Biotherapeutics

Drs. John Sweetenham and Lawrence Shulman discuss the challenges that oncologists will be confronting in 2024 and share insights on how to build clinician resilience and optimize the oncology workforce to provide better, safer care for patients with cancer. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from the UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast. I'm thrilled to welcome my friend and colleague, Dr. Larry Shulman, to the podcast today. Dr. Shulman is a professor of medicine, associate director of special projects, and the director of the Center for Global Medicine at the University of Pennsylvania Abramson Cancer Center. Dr. Shulman is also the immediate past chair of the Commission on Cancer, and also serves on the National Cancer Policy Forum of the National Academies of Science, Engineering, and Medicine. His acclaimed research has led to the development of models of clinical care to improve the patient experience and quality of care in the United States and internationally. His activities have also included innovations in health information technology, cancer survivorship care, and some other related areas. Today, Dr. Shulman will be sharing his valuable insights on some of the growing complexities and challenges that we'll be grappling with in oncology in 2024 and beyond, and potential solutions to address these issues. You'll find our four disclosures in the transcript of this episode, and disclosures of all guests on the podcasts are available at asco.org/DNpod. Larry, it's great to have you on the podcast today. Dr. Lawrence Shulman: Thank you so much, John. Dr. John Sweetenham: To start with Larry, as you know, the growth in the number of patients with cancer and cancer survivors in the U.S. is greatly outpacing the number of clinicians available to care for them. The American Association for Cancer Research, for example, estimates that there will be nearly 2 million new cancer cases in the U.S. alone this year and that the number will increase significantly in the years to come. The number of cancer survivors in total in the U.S. is predicted to grow to around 20.3 million by 2026. So, the question our community has been grappling with for some time now is: “How do we confront these realities and provide optimal care for patients, while at the same time building the resilience of the clinicians who need to care for them?” This is an area I know that you've focused on for a long time and you've published several papers in recent years as well as the great work that you've done as co-chair of the National Cancer Policy Forum workshop on the oncology workforce. Can you share your insights into some of these challenges? Dr. Lawrence Shulman: Sure, John. Thank you very much. As you mentioned, the number of oncologists in this country is pretty stable. There's consistent but relatively low number entering the workforce and those of us who were really in the first wave of oncologists in the 1970s are beginning to retire. A number of years ago we thought, well, we need to figure out ways to recruit more medical students and trainees into the field of oncology, but that's clearly not going to happen. And as you also mentioned, the number of cancer patients is rapidly increasing in this country, partly because of the aging population and partly because frankly we're better at treating them. The cure rates are better, and the number of survivors is going up. So, the math is pretty straightforward. We have a relatively stable number of oncology providers trying to care for a rapidly increasing number of patients and that's just not going to change. So, we need to have plan B; we need to figure out how we can better meet the needs in this country. And I think all of us who practice are feeling the strain of trying to take care of these increasing number of patients. I think there are a few things that are contributing to this as well. One—the good news is we have lots of new therapies, we have lots of genomics, which are leading us to better tailor therapies for our patients. But this is all complicated and it's a lot for us all to learn and keep abreast of and to manage on a day-to-day basis in the middle of a busy clinic. But the other thing is that I believe our care has become progressively more inefficient, making it harder every day that we go to clinic to care for the number of patients we need to. And that really has to change. For those of us who've been doing this for a long time, and I know you have as well, this has been a trend really over decades. It's gone in the wrong direction. It was a lot easier to practice a number of decades ago. Now, the requirements for documentation and pre-authorization and many other administrative tasks has just grown progressively over these years. And we need to figure out how to change that. And in addition, our electronic health records, which is where we live in clinic, have been remarkable and wonderful in many ways, but are also inefficient to use and we need to do a better job in optimizing their functionality. Dr. John Sweetenham: Great, thanks Larry. I do agree with you there and I think that in addition to the challenges of running the electronic health record and using that at the point of care, of course the other thing that many of our clinicians face now is an increasingly complex treatment landscape and a greater need for clinical decision support tools, which of course are not always at the moment quite as facile as we would like them to be. And I think partly because of that, many oncologists are feeling overburdened partly with these various administrative tasks they have, partly with frankly keeping up with their own specialty areas or if they're community-based general oncologists, just keeping up in general with the new information that's coming at them. And then add on top of all of that the emotional toll of caring for patients with cancer. And not surprisingly, perhaps I think we have started to see, certainly we have experienced an exodus of some oncologists in recent years who've decided to pursue careers outside of direct patient care and oncology. And those included some moving into other areas of academia, some going into industry, some going into various tech companies and so on. Are you concerned that we all struggle in the effort of building and support a resilient oncology workforce to meet the needs of this growing population that you mentioned? Dr. Lawrence Shulman: Yeah, I'm very concerned about that, John. And I think one way to think about this is that as you say, the practice of oncology inherently is a stressful and difficult, though quite rewarding way to spend your professional career. But we layer on top of that a lot of frustration and difficulties that really don't need to exist. And when I think about this, I think about really two buckets. There's a bucket of factors that are within our control in an individual institution or an individual practice, and I'll come back to that in a minute. The other bucket are external forces, things that are required by the government regulators, by the payers that need to be done in routine practice. We have less direct influence over those, though I think it's a profession, we need to think hard about how to influence the external factors as well. At the practice level, there are a lot of things that we can do. One has to do with optimizing our electronic health record, which does have, in most cases, the ability to have it customized by institution in a way that would make it optimal. And some of that again, is external because we're dealing with a vendor product that has some limited ability to be customized, but we need to do a better job of the technology that underlies our practice every day when we go to clinic. The other major factor in support, whether it's advanced practice providers, nurses, medical assistants, navigators, and other personnel who can in fact help to support the patients, help to support their families, and help to support the clinicians who are on the front line trying to care for these patients. And we all use the term, practicing at the top of your license and aspire to that. But I think frankly we don't do a great job in that regard, and we need to really think harder about how we do have the appropriate team around us. In addition, I would say that there are a lot of other things at the practice level that we need to think about, including the facility of ordering radiologic studies and consultations and so on, all of which are often more cumbersome than they should be. We really need to not put these obstacles in the way of our clinicians. Externally, I think we need to get the payers and to get the government CMS to understand that the current state, it's just not going to be viable going forward and they need to make some big changes. And I think one of the ways to think about this is that rather than doing something differently, you want to do a different thing. I mean, they really need to make some paradigm changes and what's required day in and day out from our clinicians. Dr. John Sweetenham: Absolutely. So, I want to pick up on something that you mentioned there, which is the role of navigators and the benefits that navigation, patient navigation, can have in several domains, but certainly it can help to reduce the burden on oncologists and strain in the system in general. But to take that a little bit further, I wonder if we could talk a little bit about how navigation can help in reducing care disparities. You were saying before we came on the podcast today, the concept of using patient navigators to reduce disparities in care is not new. It's been around for many, many years, but it seems like we almost have to keep relearning that they really help in terms of reducing various disparities which may be rural disparities, racial and ethnic and so on. There are plenty of data out there, as you've mentioned, just to quote a couple of studies, there was the ACCURE trial published a couple of years ago now, which was really a multi-pronged intervention to help Black patients overcome obstacles to completion of treatment. And it included navigation along with a number of other interventions, electronic health record flags to alert caregivers to missed appointments, providers to missed appointments, I should say. It also included physician champions to help engage the health care teams and some educational interventions as well with a significant impact on the access to care from Black patients. The Levine Cancer Institute in the Carolinas conducted a study in my own world, in aggressive large B-cell lymphoma a number of years ago, where they showed that they were able to navigate all of their patients into guideline-concordant care, which essentially eliminated the disparity in outcome between Black and White patients in their population. And then more recently, a study from the University of Maryland looked at Black men with prostate cancer and demonstrated that with the intervention from a navigator, the number of those patients who had their appropriate genetic testing was increased enormously to levels which were comparable with the White patients in their community. No clear evidence yet that that's impacted outcome, although intuitively, I think it would, but nevertheless, as you've already pointed out, there is a ton of evidence that navigation can help us to eliminate disparities. Could you talk a little bit about your own insights into that area and the work that you've done? Dr. Lawrence Shulman: Sure. A few years ago, the National Cancer Policy Forum held a workshop on navigation in cancer and we spent a couple of days in Washington going over many of the studies you've mentioned. And one of our speakers was Harold Freeman, who was a surgeon in Harlem. About 60 years ago, he showed that patient navigation could reduce disparities in cancer care in his setting. And I think the surprising and somewhat disappointing aspect of this is, well, we have a new therapy, whether it's immunotherapy or whatever that is shown to improve overall survival and outcomes. We adopt that, and we start using it. And yet here something that's relatively straightforward, patient navigation, which has been shown as you say, to improve access to care, to improve guideline-concordant diagnostics, guideline-concordant treatment, patient satisfaction, and ultimately improve outcomes and reduce disparities, but has not been embraced in the same way that new therapies have been embraced. And from my point of view, these factors are equally important. They translate in the patient outcomes ultimately just like the therapies that we choose to. And we need to really buy into that. We need to understand that this really affects our patient outcomes as much as our therapies do. So, a couple of things. One is that you've already mentioned the different ways that navigation might improve outcomes, and that's clearly the case. But there are other aspects which are really critical to a lot of conversations we've been having, and that is that navigators fill vital roles that when they're not present are often filled by the treating physician, trying to make sure that the diagnostic tests, the genomics are all done, trying to make sure that the patient is getting their radiologic studies on time, trying to make sure that the appropriate appointments are being set up. Navigators are very, very good at doing this. They're very good at bonding to the patients and helping the patients feel secure through this cancer journey. But if they're not there, either those things don't get done or the clinician, the treating physician or the advanced practice provider is doing that. And so, it has the dual effect of both burdening clinicians who really have another role in the care of the patients doing these other scheduling and navigation functions as well as improving the overall care. I will say that in my own experience, it's important to have navigators who are skilled in their areas, that understand the diseases that we're treating, that understand the patient's needs in relation to those diseases and the treatments and diagnostics that we have to offer. So, there is a real skill to navigation, but a skilled navigator really makes a huge difference to the patient. And again, not only in the very tangible ways that you mentioned, but also frankly in the psychological security of the patient. And patients will tell you this and there are surveys out there that show this, that patients who are undergoing a new diagnosis of cancer are terrified, do much better psychologically when they have a navigator at their side through this journey. But it has tremendous benefit to the clinicians as well. And why haven't we embraced navigators? I can only speculate, but one of the comments that I get from health system administrators is, “Well, they cost a lot of money, and their work is not reimbursed as part of health care reimbursement.” But there is, again, overwhelming evidence to show that the return on investment for navigators is substantial. And it's substantial because it keeps patients in your practice, it provides more efficient care at all levels. And we published out of the National Cancer Policy Forum work, an article that basically shows from a variety of different centers, including mine at Penn, that there is a tremendous ROI for having navigators. So yeah, it's a little bit of money upfront to hire them, but ultimately, it's a good thing financially as well as clinically. Dr. John Sweetenham: Yeah. So often with these kind of wraparound services that are so important to our patients showing and being able to clearly demonstrate the kind of downstream revenue from those services is difficult, but is I think probably evident to those of us who are in the clinic and see what happens. So, maybe we need some more sophisticated financial models to be able to highlight that to our leaders in the health systems, I think that the evidence is really quite clear. So, Larry, one of the disparities that you've mentioned, and perhaps we haven't focused on quite so much in this discussion, has been the issue of cancer care for rural versus urban communities. And I think it's important that we highlight the challenges that oncologists are facing in rural communities across the country in caring for patients who live many miles away from a hospital or clinical practice and where the oncologists do not have the kind of support system that you'd find in an academic center in a major city. Can you comment a little on that? Lawrence Shulman: Sure, John. This is a real problem. I and others have published on cancer survival statistics in rural settings and in small community hospitals and they are in fact inferior to larger academic cancer centers, probably for a multitude of reasons. And one of our colleagues, Dr. Otis Brawley, made the comment a number of years ago and still repeats it, that your likelihood of surviving cancer in the U.S. is more tightly linked to your ZIP code than your genetic code. And there is some truth to that. Now, there are tremendous challenges for providing cancer care in a small, rural hospital. We practice in academic medical centers; I'm a breast cancer doctor and I spend all of my time trying to stay current in breast cancer. And it's a field that's changing rapidly. It's hard for me to imagine how my colleagues who are generalists in the community are keeping up with the advances in so many different diseases. And I think frankly, it's really, really hard to do that. In addition, all of us at academic centers have weekly tumor boards. We get to ask our colleagues what their thoughts are about our difficult cases. We get a lot of input from pathologists, radiologists, and other colleagues. And frequently clinicians, physicians, oncologists, practicing in rural hospitals don't have that constituency around them for them to bounce difficult patients off of to try to figure out what the best approach might be for a patient. So, the differences are terrific, and the support is just not there. This is something that our country has not really confronted. We have a very big country geographically. Some of the areas of the country are quite rural. A patient can't be expected to travel four hours in each direction to an academic cancer center. We need to figure out how to better partner between our academic cancer centers and our community colleagues to support their care in ways that we've not done routinely up to this point. I know that the National Cancer Institute is very interested in this and trying to figure it out. But again, I think we have to feel a collective responsibility to support our colleagues in the community. They try really hard, they're working really hard, they're doing the best they can, but they just don't have the support that we have in academic cancer centers. Dr. John Sweetenham: Yeah, sure. Before we wrap up the podcast today, I'd like to circle back a little to something that you said earlier and a topic that I know that you've published about quite extensively in the past and that's the issue of health care technology. And I think we probably all agree that health care's been a little bit slow to capitalize on technology to improve our care processes and outcomes. And your research has highlighted that technology can facilitate patient-clinician interactions in a number of ways through augmented intelligence, texting, chatbots, among other things. Can you tell us a little bit about this, how you think that AI might be able to help us in the future to streamline the management of some of these medical and administrative issues that we've been talking about today? Dr. Lawrence Shulman: Sure, John. It's hard to turn the TV on or read a newspaper without an article on artificial intelligence. But the word you used is the word that I use, which is augmented intelligence. I don't think we're looking to replace clinicians with technology, but we're looking to in fact make their jobs easier, to remove some of the tasks that they don't need to do themselves as really an assistant, if you will, another assistant. We have used technology extremely poorly in the medical profession overall. I'm not quite sure why that is. But if you look at the banking industry or other industries, they've used technology tremendously well with great benefit, benefit not only for the people who are using the services, in our case, the patients, but also those who are providing the services, in our case, the clinicians. So, I think we need to do a better job. We need to have electronic health records that are in fact helping rather than sometimes hindering or making frustrating the care of the patients. We need to use artificial intelligence or augmented intelligence to interact with patients and help to manage them. We're using augmented intelligence chatbots to manage patients who are on oral chemotherapy able to do a lot of the tasks that normally the clinicians would be doing without in any way jeopardizing the safety or the well-being of the patients. The patients actually tell us that they like this, that it's just another way to feel connected to their practice in a way that's efficient and easy for them through texting rather than sometimes trying to call the practice, which can be frustrating. But there are lots of other things as well in analyzing data, bringing data forward that will help us to make the appropriate decisions. And one of the things that I often use as an example is the airline industry. And they have a remarkable safety record as we all know, thank goodness. But if you sit in the cockpit of an airplane and you look at the instruments, all the critical data is right in front of them, unencumbered and very clearly presented because they need those data to fly the plane, and they need those data to be rapidly and easily accessible. They can get all the data they need; you look at the cockpit ceiling, it's got a thousand switches on, everything they need is there, but the critical data is never hidden and always presented. I don't think that that in fact is the way our electronic health records are set up. In fact, quite the contrary. And all of us spend a fair amount of time looking for data and so on because the records are complicated, and they're used by a lot of different specialists. But we can use augmented intelligence to bring all the critical data up, just like the cockpit in an airplane, to make sure that we have what we need rapidly accessible, and we don't miss anything. We don't go looking for the genomic test and can't find them and then assume they weren't done and make a decision without critical data when in fact they were done, but the data is hidden. So, I think we have a lot of options to use technology to improve our daily lives. I think it will take away some of the frustrations that lead to burnout, and we'll also make practice not only more efficient, but frankly also much safer. I think we have to work hard on this. We could partner with that technology colleagues. We at Penn are trying to do that. I know others are trying to do it as well. And I think the patients will benefit, will all benefit. Practice will be better, safer, less frustrating, and the outcomes of the patients will be better. Dr. John Sweetenham: Yeah, thanks Larry. I think your analogy with an aircraft cockpit is so perceptive and I think that that's something if we could unclutter our electronic health records and what we're seeing in front of us in at the points of care in the clinic, I agree 100% that will be such a step forward. So, thanks for sharing that. Thanks also, Larry, for discussing some of these challenges that we're going to be confronting in the next year and beyond, as well as the potential solutions. I think one thing that is really important to remember despite these challenges is something that I mentioned in the introduction to the podcast today. So, when we are all feeling a little bit disheartened because of the challenges ahead of us, it's important to remember that in 2026 there will be an estimated 20.3 million cancer survivors in the United States, which really does underline how far we've come, certainly in the time that you and I have been practicing oncology, and really important not to lose sight of that. We had a lot of challenges, but really the achievements of the last 50 years or so are pretty remarkable. It's been a real pleasure to have you on the podcast today, so thank you again for joining us and for sharing your thoughts with us. Dr. Lawrence Shulman: Thanks so much for having me, John. Dr. John Sweetenham: And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. For more information on Dr. Shulman’s research discussed in this episode, please see the articles below: The Future of Cancer Care in the United States—Overcoming Workforce Capacity Limitations | Health Care Workforce | JAMA Oncology | JAMA Network Developing and Sustaining an Effective and Resilient Oncology Careforce: Opportunities for Action - PubMed (nih.gov) Re-envisioning the Paradigm for Oncology Electronic Health Record Documentation by Paying for What Matters for Patients, Quality, and Research | Health Care Reform | JAMA Oncology | JAMA Network Survival As a Quality Metric of Cancer Care: Use of the National Cancer Data Base to Assess Hospital Performance - PubMed (nih.gov) Establishing effective patient navigation programs in oncology - PubMed (nih.gov) Patient Navigation in Cancer: The Business Case to Support Clinical Needs Cancer Care and Cancer Survivorship Care in the United States: Will We Be Able to Care for These Patients in the Future? - PMC (nih.gov) Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Find out more about today’s speakers:      Dr. John Sweetenham  Dr. Lawrence Shulman     Follow ASCO on social media:       @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn       Disclosures:      Dr. John Sweetenham:   Consulting or Advisory Role: EMA Wellness     Dr. Lawrence Shulman: Consulting or Advisory Role: Genetech Research Funding (Inst.): Celgene, Independence Blue Cross

Drs. Cardinale Smith and Raymond Osarogiagbon discuss key research featured at the 2023 ASCO Quality Care Symposium, including the role of AI in quality measurement and solution-focused approaches addressing care delivery, financial toxicity, and clinician well-being. TRANSCRIPT Dr. Raymond Osarogiagbon: Hello. I'm Dr. Raymond Osarogiagbon, your guest host of the ASCO Daily News Podcast today. I'm the chief scientist at the Baptist Memorial Healthcare Corporation and director of the Multidisciplinary Thoracic Oncology Program and the Thoracic Oncology Research Group at the Baptist Cancer Center here in Memphis, Tennessee. I have the distinct delight of serving as co-chair of the 2023 ASCO Quality Care Symposium. And I am delighted to welcome my colleague, Dr. Cardinale Smith, who served as chair of the Symposium. Dr. Smith is a professor in the Department of Medicine and Geriatrics and Palliative Medicine at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai in New York. Today, we'll be discussing solutions and key research to advance high-value, high-quality cancer care that were featured at the Symposium. You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod. Dr. Smith, it's great to be speaking to you today. Dr. Cardinale Smith: Thank you. I'm excited to be speaking with you as well. Dr. Raymond Osarogiagbon: The Quality Care Symposium featured many novel approaches in care delivery, including innovative ways to advance health equity through supportive oncology. As a specialist in geriatrics and palliative medicine, your work has focused on supporting the needs of patients with cancer. What are the innovations in supportive oncology that you were excited about at the meeting? Dr. Cardinale Smith: I think we had several really fantastic sessions [on supportive oncology] at the meeting. One of the key things that came up around innovations in palliative care delivery was a roundtable discussion (“Innovations in Palliative Care Delivery for Structurally Marginalized Populations: A Roundtable Discussion”), and the speakers really focused on community-engaged approaches to the delivery of palliative and supportive care interventions. During the discussion, the speakers talked about utilizing the community voice and incorporating that into work to describe and enhance models of care delivery.  Dr. Manali Patel discussed her work on the transformative impact of patient navigators who focused on palliative care skills, in particular, communication, symptom discussions, and how that contributed to the improved outcomes of patients with advanced cancer. They saw reductions in mortality, lower acute care use, greater palliative care and hospice use, and lower total costs. Dr. Mao discussed a virtual mind-body fitness program to reduce unplanned hospitalizations among patients undergoing active cancer treatments. And Dr. Irwin presented her results of a randomized trial of patient-centered collaborative care for adults with serious mental illness who were newly diagnosed with cancer. I think these discussions just really centered on centering patients and focusing on supporting their care. And then finally, I was really excited to hear Dr. Deborah Mayer of UNC Lineberger Comprehensive Cancer Center, who received the Joseph Simone Quality Care Award, and she spoke about her distinguished career and how we can do better for our patients and ourselves (“Reflections on Improving Cancer Care: How Can We Do Better for Our Patients and Ourselves”). And what stood out for me was her recognition of the importance of “teaming,” and she really talked about acknowledging that before there was terminology for it. And it struck me because it remains so critically important in terms of how we advance the science and delivery of cancer. Dr. Raymond Osarogiagbon: Yeah, that Joseph Simone Award was amazing; I’ve got to tell you that Manali Patel's presentation blew me away. The video of the veterans talking about end-of-life care and the tough decisions, how they got to work, man, chills down my spine.  Dr. Cardinale Smith: Yeah, and I think what's even more incredible is that the folks who were helping to lead those conversations were not people who spent an incredible amount of time going to school to learn how to do this. They were folks from the community who were just engaging with people and conversations about their values. Dr. Raymond Osarogiagbon: What an original way to tackle the wicked problem. Just amazing. So improving clinician well-being was also a key topic at the meeting. Speakers addressed oncology workforce shortages and novel approaches for improving team-based care delivery. So, Cardi, what are your key takeaways from these sessions (“Building Clinician Well-Being Through Team-Based Care Delivery”) Dr. Cardinale Smith: Improving team-based care delivery is essential as the health care system can feel fragmented for patients, and, honestly, for us as clinicians as well. I think my takeaway [from this session] is that there has to be an organizational and systems-based approach to really improving this issue if we're going to make meaningful and impactful change. We were presented with data that shows that this really isn't a one size fits all approach, and what might work for physicians as a group does not work for APPs or nursing. And we really have to think about all of these different groups based on what they need.   Caroline Schenkel from the ASCO Center for Research and Analytics (CENTRA) presented impactful data on the state of the oncology workforce. And that data really assessed changes in the well-being of US-based ASCO physician members and compared the responses today in 2023 to a decade ago. And unfortunately, burnout and satisfaction with work life integration appears to have significantly worsened. And while that's not really surprising, it's disappointing. There were some factors that contributed to joy in work life, and that was speaking with and advising patients, as well as enhanced practice support inclusive of administrative patient care and staffing. So I do think that gives us some information that we can use to go forward to focus on strategies we should be really encouraging and leaning in towards. Dr. Raymond Osarogiagbon: I think it was Dr. Subbiah in this session who made the point – it's not just yoga, right? Don't tell people, “Go do yoga and get happy at work again.” You have to tackle the fundamental cause of the problem, which is this crazy workload and additional tangential obligations that we have that have taken over the core mission of patient care. Dr. Cardinale Smith: Absolutely. No one needs another pizza party. Dr. Raymond Osarogiagbon: Isn't that the truth? Dr. Cardinale Smith: I want to ask you some questions. I'm going to turn the tables on you now.  Dr. Raymond Osarogiagbon: Sure. Dr. Cardinale Smith: So let's talk about some emerging technologies. We had a session on artificial intelligence at the meeting that specifically focused on how AI will potentially impact quality care. Ray, tell me, what are some of your takeaways from these presentations? Dr. Raymond Osarogiagbon: Yeah, so AI, obviously, is a hot topic in this day and age. I had the privilege of chairing the session, “The Promise and the Perils of Artificial Intelligence (AI) in Oncology.” So we had a nice group of speakers. We had Danielle Bitterman from Dana-Farber telling us what AI is and what it promises to be for us. And then Andrew Hantel, who co-chaired the session with me, did a wonderful job describing for us the perils of AI. And then Julian Hong told us how AI promises to do all kinds of wonderful things in radiation oncology, so the huge promise of AI from back office to front office across this full spectrum of oncology, be it radiology, radiation oncology and so on and so forth, were covered.  And I would strongly urge that anybody who listens to this podcast should go to that session. Andrew Hantel talked about perils, for example, this AI black box. We don't really understand when [the AI black box] tells us this is the thing, this is the answer to your question, how does it arrive at that? How can we tell that the answers we're getting are correct or incorrect? And if we were wanting to validate, how do we go back, to do so is a real problem. And then one of the take-homes was, “You can call it all the things you want, but it's still fundamentally garbage in, garbage out.” So this machine learning, if the material fed into the machine is garbage, the answers you'll get back will still be garbage. And we had Dawn Hershman present a wonderful panorama of how AI is just another tool. It's not a panacea. We’ve still got the same problems. It's a new tool and we're still going to have to apply it using the same frameworks as we have always applied in all of science today.  And then there was an abstract that was presented from the UK as the young lady Bea Bakshi presented a paper, Abstract 74, “Accuracy of an AI Prediction Platform in Predicting Tumor Origin in a Real-World Study.” I would urge anybody who's interested in this to go back and watch that. Dr. Cardinale Smith: I was waiting a bit for them to talk to me about how the bots were going to take over, but I guess we're not quite there yet. And Dr. Lee Fleisher also added a lot of commentary. He was the former chief medical officer and director of the Center for Clinical Standards and Quality at the US Centers for Medicare and Medicaid Services (CMS). And he gave the keynote lecture, “Measuring and Driving Quality in the Future.” What did you think about some of what he had to add to this conversation? Dr. Raymond Osarogiagbon: Yeah, it was an interesting keynote. It was certainly one of the highlights of the program. He talked about measuring and driving quality of care in the future. And the thing that struck me was how he covered the full spectrum of the topics that we dealt with in the Symposium, including AI, which was quite remarkable.  Dr. Cardinale Smith: Yeah, I agree. I think he really did add an incredible amount to the conversation, and I think as much as we think CMS has control over so much of what we do, so much of it is controlled and regulated that in the end, they are just a body that oversees. And I think he really talked about that and hit that home.  Dr. Raymond Osarogiagbon: The one thing that struck me one of the throw away comments he made was how few physicians there were at CMS. What was it he said? Was it 30 something, 40 something on the regulatory side? Dr. Cardinale Smith: Yeah, it was less than 40, high 30s. Dr. Raymond Osarogiagbon: Surprising.   Dr. Cardinale Smith: Yeah. There aren't that many physicians that actually work there and yet they are driving so much of the decision-making.  Dr. Raymond Osarogiagbon: Yeah. Wow. So Cardi, let's talk about the session, the very beginning. I think you introduced that session on day one, “The Perfect Storm of High Cost Novel Therapeutics: Are We Leaving Patients Out? Dr. Cardinale Smith: It was an incredible way, in my opinion, to start the conference. I think that the speakers really came out strong, setting the stage on really the perfect storm. I think as we are developing more high-cost novel therapeutics, the first speaker, Haley Moss, talked about how all of these approvals are leading to these accelerated pricing of drugs and how really this is unsustainable. We continue to get new and new drugs that are working, right? I mean, we have longer life expectancies for patients with cancer.  Dr. Raymond Osarogiagbon: That's the good news, but somebody has to pay for it. Dr. Cardinale Smith: Correct. And the longer you live, the harder it is to be able to sustain this and people are going into bankruptcy for it. And then Arjun Gupta came in and talked about really thinking about these supportive care drugs and supportive care meds, and how we tend not to think about those medications, but they are medications that are not highly regulated and yet also are very costly. And I think what stood out for me most from the panel and this discussion was really the patient herself, Dr. Kelly Shanahan. She is a physician, an OBGYN who no longer practices and was diagnosed with metastatic breast cancer. And she really talked about how cancer put her into near bankruptcy and the cost implications to someone who we would consider in the top echelon of the financial spectrum.  Dr. Raymond Osarogiagbon: Yeah. You want to know what my favorite abstract was at this? It was Abstract 300, titled “Nationwide analysis of legal barriers impacting patients with cancer and caregivers.” Dr. Cardinale Smith: Okay, tell me about it. Dr. Raymond Osarogiagbon: Qasim Hussaini talked about how he had access to a unique data set of patients calling in for free legal assistance after diagnosis of their cancer. I was in awe of the uniqueness of his [and his co-authors’] approach. I don't think I've ever seen anybody tackle this problem in such an original way. I learned a lot from it, and I would definitely recommend that people go take a look at this Rapid Oral Abstract.  Dr. Cardinale Smith: Yeah. In fact, while we were sitting there in the conference, I was texting the director of oncology social work at my own institution and asking her if she heard of the organization that he worked with.   Dr. Osarogiagbon:  Yeah.  Dr. Smith: I'd like to highlight the last great session for our listeners. And it was really the last session of the conference, “Promises and Pitfalls of Liquid Biopsy Cancer Detection Tests in the Asymptomatic Population.” And I know sometimes folks don't always get to see or hear the last session. So, I would strongly encourage folks to check it out. I liked the session because it highlighted where we are in terms of thinking about diagnosing cancers among those who are asymptomatic. And it also highlighted a lot of questions that we have in terms of what we do with those results and who should be the responsible parties for that information? Does it fall to the primary care group? Does it fall to oncologists? And I think it was good to know that this is something that's top-of-mind for NCI and that they're really putting together a toolkit to think through this and to package that together for clinicians.  Dr. Raymond Osarogiagbon: I have to give you credit, Cardi. This was fabulous. The meeting was from end to end, just superb, and the attendance was record-breaking. Congratulations.  Dr. Cardinale Smith: Thank you. You are a fabulous partner. We had wonderful committee members, and the ASCO staff, as usual, is amazing. Dr. Raymond Osarogiagbon: Yes. We have to do this again in San Francisco next year.  Dr. Cardinale Smith: I'm looking forward to it.   Dr. Raymond Osarogiagbon: Thank you, Dr. Smith, for coming on the podcast to give us these highlights from the 2023 ASCO Quality Care Symposium. Our listeners will find the links to the sessions that we discussed on the transcript of this episode. Dr. Cardinale Smith: Thank you, Ray. It was my pleasure. Dr. Raymond Osarogiagbon: And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you.   Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today’s speakers:  Dr. Cardinale Smith @cardismith Dr. Raymond Osarogiagbon @ROsarogiagbon   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures: Dr. Cardinale Smith: Honraria: AstraZeneca Speakers’ Bureau: Teva Dr. Raymond Osarogiagbon: Stock and Other Ownership Interests: Lilly, Pfizer, Gillead Honoraria: Medscape, Biodesix Consulting or Advisory Role: AstraZeneca, American Cancer Society, Triptych Health Partners, Genetech/Roche, National Cancer Institute, LUNGevity Patents, Royalties, Other Intellectual Property: 2 US and 1 China patents for lymph node specimen collection kit and metho of pathologic evaluation Other Relationship: Oncobox Device, Inc.

Drs. Shaalan Beg and Priyanka Kanth discuss the readiness, logistics, and barriers to implementing universal germline multigene panel testing for colorectal cancer (CRC) following new guidelines from the National Comprehensive Cancer Network that recommend genomic testing for all individuals with CRC younger than age 50. The experts also address other areas of unmet needs as new data emerge on moderate-risk genes and their association with CRC. TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I'm the vice president of oncology at Science 37 and an adjunct associate professor at UT Southwestern Medical Center in Dallas. Last year, the National Comprehensive Cancer Network, or NCCN, updated its guidelines on colorectal cancer (CRC), recommending that all patients with colorectal cancer who receive a diagnosis before the age of 50 have multigene panel testing and that multigene testing should also be considered for patients 50 years of age and older with colorectal cancer, regardless of a personal or family history or other criteria. This represents a huge paradigm shift in the screening and care of patients with inherited cancers. And today, I'm joined by Dr. Priyanka Kanth, an associate professor of medicine and the director of the GI Cancer Prevention Program at MedStar Georgetown University Hospital in Washington, DC, to discuss new research that explores the readiness, logistics, and barriers associated with the implementation of universal germline testing in clinical practice.  You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod. Dr. Kanth, it's great to have you on the podcast today. Dr. Priyanka Kanth: Thank you, Dr. Beg. It's wonderful to be here today and discuss this very exciting topic. Dr. Shaalan Beg: As a gastroenterologist who sees patients and families with a high risk for GI cancer, including medically underserved populations, can you comment on the significance of the expanded NCCN guidelines for colorectal cancer? Dr. Priyanka Kanth: Yes, absolutely. So this is, I would say, a big change from NCCN recommending pretty much every colorectal cancer patient can undergo multigene panel testing or universal. So everyone who's younger than age 50 and has colon cancer should get multigene panel testing. But we are also expanding it to pretty much anyone who may have colorectal cancer, and we can offer multigene panel testing. So, we are broadening the pool of patients who can get tested, and this will bring in more patients from very different demographics. So I think it will expand to every arena of patients with different insurance profiles, underserved, and, as more insurance companies and Medicare/Medicaid picks up, I think this will help a lot more patients in not only following on their genetic testing, but also their family members.  Dr. Shaalan Beg: Medical oncologists are very familiar with the challenges of implementing somatic molecular testing for people who have cancer. I can only imagine that implementing universal germline testing also has significant logistical challenges and barriers. You recently published a study in JCO Precision Oncology along with your colleagues and captured some interesting perspectives from clinicians on their practice of implementing universal genomic testing for colorectal cancer. Can you tell us more about this? Dr. Priyanka Kanth: Absolutely. So I would first like to thank the lead authors and senior authors of this study. They are Linda Rodgers-Fouche and Sanjeevani Arora and Rachel Hodan, who literally wrote the study and created and did all the legwork. And as you know how hard it is to do these big survey studies, so really thank them.  The study is a cross-sectional survey of the members of this Community Collaborative Group of America, IGC, which I would say comprises a lot of genetic counselors, gastroenterologists, oncologists, and colorectal surgeons who take care of these patients. So these are highly specialized groups that work in the field of GI genetics. Roughly 300 plus members were sent the survey to get their take on how they think [multigene panel testing] can be implemented for all colorectal cancer patients.   So to give you a synopsis of the study, the majority of members who participated, 70% or more, they supported this universal germline testing for colorectal cancer patients. But interestingly, more than 50% also thought that it will require a change in their practice or how this will be delivered. So that's the major takeaway, I would say. We are all supportive but how to really deliver to the patient would be the biggest challenge or barrier for us in the future.  Dr. Shaalan Beg: So, your study reported concerns on knowledge among non-genetics providers. I would assume that includes a lot of clinicians who are the first people to be in contact with potential patients who would require testing. How can the field mitigate this problem? And what are some alternate delivery service models for increasing awareness and making the process of ordering and following up on the results more efficient for practices? Dr. Priyanka Kanth: We all know the biggest barrier I would say is resources like who's going to deliver the added pool of patients that get genetic testing. So most of the current scenario, they're all seen by genetic counselors, but we have a limited number of genetic counselors and they cannot truly deal with this big influx. So how to educate non-genetic providers would be the biggest barrier. But also implementing in the system itself, like can we do pretest counseling as the first contact with the patient to deliver to discuss like you should undergo genetic testing. So that contact, can that be done with a non-genetic provider or even by other modes like telemedicine? Or can we do something like an online chat box or something which could just not only go over all the types of testing but opens the door for the patient to ask questions. So if there are alternate modes of delivery where the pretest is taken care of, that would be one big change required.   The other part is like when the test is done, who returns the results? So where does it go and who explains the results? So at that point, we surely need more genetic and even non-genetic providers if they are comfortable. So how to educate them would be the biggest barrier. At that point, I think, we are still figuring out the biggest change is in the system and requiring a take from all the stakeholders who are part of taking care of these patients. So not only genetic counselors, but oncologists, gastroenterologists, pathologists who are taking care of this patient to be on board and have a really clear-cut flow of how these are delivered, how these results are returned, and how they are explained to family members. Dr. Shaalan Beg: The workflows and the resources that you have in a high-risk GI clinic at a center like Georgetown’s, I think it's safe to say, are much more than what typical resources a practicing provider will have in the clinic. How do you envision clinics resourcing for this type of test either through training or retraining their existing staff or by adding additional resources?  Dr. Shaalan Beg: At the community setting, it is really hard to educate essentially everyone as well. So, I feel like taking the load off the genetic counselor at the pretest level is the biggest implementation or change that can be done. And if we can remove that because not every patient is going to be positive for the gene mutation either; it does filter many patients who eventually will need returns. So at that place, how do you implement and where do you implement is the key and it is so system-based that I cannot even pinpoint. But I agree, bigger academic centers have better advantages and a knowledge base as compared to smaller community cancer centers or practices. Dr. Priyanka Kanth: Yeah, and I noticed that many of the respondents in your survey agreed with offering multigene panels, but there was variability by profession, and I was wondering if that resonated with you and that was an expected finding or not. Dr. Priyanka Kanth: Yes, and it was more so in terms of standardized multigene panel versus customized panel. So, this is fairly understandable because the genetic counselor is so well versed in offering which genes should be tested based on family history, but a non-genetic provider may not be fully equipped with the knowledge. So for example, myself, I do GI genetics, but if I have a patient with a lot of breast cancer in the family, I do defer them to a high-risk breast team. So there are nuances, too. The major difference here was also in standardized multigene panel, most of the gastroenterologists, oncologists were all for it compared to customized, which were more heavily leaned by the genetic counselor based on family history. And I can see why it's different because standardized, I would say, is much easier to implement and compared to customizing, which is based on family history or other cancer history and family. That's the major difference in the study. It comes down to education and experience and the follow-up based on what comes back from it.   Dr. Shaalan Beg: You've highlighted many factors, both from the pre-test, sort of preparing and selecting the right individuals, to ordering the right test based on the participant's risk factor profile and then optimal ways of following up on the results of these genomic tests. What are other areas of unmet needs when it comes to genomic testing for colorectal cancer? Dr. Priyanka Kanth: We know a lot about high-risk genes that are associated with colorectal cancer. We still are finding and learning about many genes, many moderate-risk genes, and their association with colorectal cancer. We don't have enough data or long-term cohort data to understand how they truly affect their lifetime risk for colorectal cancer and how do we truly surveil these patients. So that's one of the big barriers. Genetics still cannot explain all colorectal cancers. So as we get more data, we may discover more things and more genes that may be associated. But understanding these moderate-risk genes and their association with colorectal cancer would be, I think, one of the key areas to be looked into in the future. Dr. Shaalan Beg: And I would imagine as new biomarkers are identified, there will need to be a strategy to retest people who may have had genomic testing in the past. Dr. Priyanka Kanth: Absolutely. We are already encountering that in a practice. I have patients who have been tested maybe 10 years ago and just had Lynch mutation tested and were negative for that or so, and now we have so many other genes which are associated and also to understand family history changes. So, as family history changes, there might be clues to say that, “Okay, we should expand the panel or we should add these patients.” So it is a very dynamic situation. There could be a scenario in which we have a lot of patients who may need to be retested based on their current situation or even based on changing family history and the availability of genetic information. So, when I see a patient, I also tell them if we don't find anything or we are not doing anything major, we say, “Let's regroup in 3 to 5 years, let's see where we are,” or even with the risk mutation for some of the moderate-risk genes, we may change in a few years. So, revisiting that with these patients is highly useful. Dr. Shaalan Beg: So, is it safe to say that as of 2023, if we're seeing people in our clinic who have not had testing in the last 3 to 5 years, that they should have a discussion for repeat testing today? Dr. Priyanka Kanth: Yes, in terms of certain, I would say, newer polyposis genes in the GI world that have been included, some other moderate gene mutation which we have a little bit more sense of now and it has not been tested, I think that can be expanded. Five years is a safe bet. Last 2 to 3 years, maybe not so much, but you can revisit this. Also, some patients were tested for a smaller gene panel. So not 2 genes, but maybe 10 genes were included. That would probably still stand true. They may not need 70 gene panels, so it's still good to review that in the current scenario, and every few years, every 5 years, I would say.   Dr. Shaalan Beg: Whenever I think about any type of new test that has logistical challenges, has costs associated with it, and has operational demands of the clinic, I think about its disparate effect across different populations based on race, ethnicity, geography, demographics. Can you talk a little bit about how these guideline changes, what type of impact they may have, positive or not, for comprehensive genomic testing for colorectal cancer across different populations?  Dr. Priyanka Kanth: Yes, I think this is more positive than negative. This will include more patients and include more family members who were not being included, who were being missed. As we know that one of the reasons to do this multigene panel testing was the criteria, the family history criteria or the risk prediction models are not perfect. And the recent studies have shown that not every family member, every patient, is going to fit in these criteria. So we are getting more and more data in recent years that I think the much better, long-term option is to do a multi-chain panel and find it because we are missing patients. So it will increase the pool [of patients to be tested], and that will surely increase patients from all demographics. And as we do it more, there will be more buy-in from the payers and hopefully, this will decrease disparity. The problem, I think the negative part is how do we deliver it to everyone? If it is there but we are not able to deliver and that there is disparity on who gets the test and who does not, then that will create another disparity in a sense that it's there and we could have used it, but it's not being delivered. So the pros are we can include everyone, but how to include everyone is the big question. Dr. Shaalan Beg: So, Dr. Kanth, there are indeed challenges ahead in our pursuit for universal germline testing for colorectal cancer. I'd like to thank you for sharing your valuable insights with us today on the ASCO Daily News Podcast.   Dr. Priyanka Kanth: Thank you very much for having me here. It was great to talk to you, Dr. Beg. Dr. Shaalan Beg: And thank you to our listeners for your time today. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today’s speakers:   Dr. Shaalan Beg @ShaalanBeg   Dr. Priyanka Kanth @priyanka_kanth   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook  ASCO on LinkedIn    Disclosures:   Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. Priyanka Kanth:  Patents, Royalties, Other Intellectual Property: Methods and Compositions for Predicting a Colon Cancer Subtype

Drs. Diwakar Davar and Ben Boursi discuss the role of the gut microbiome in the outcome of cancer immunotherapy and the prevention of immunotherapy-related adverse events, as well as compelling research on nutritional interventions to improve response to immune checkpoint inhibitors. TRANSCRIPT   Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center.   Researchers have shown that microorganisms in the gut can impact the effectiveness of immunogenic chemotherapy for patients with cancer. Although microbial therapies for cancer are still at a very early stage of clinical development, compelling research in recent years has shown that changing the gut microbiome can help improve outcomes in patients receiving treatments for cancer enduring immune checkpoint inhibition.  My guest today is Dr. Ben Boursi, a GI medical oncologist at the Sheba Medical Center at Tel Aviv University in Israel. Dr. Boursi is also an adjunct professor at the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania. He joins me today to discuss his pivotal research on the role of the gut microbiome in mediating its effects on immunotherapy. And again, I want to highlight that we're recording this on October 9th, and as you may well know, many recent events over the last couple of days have happened in Israel, and so Dr. Boursi has joined us at a very difficult time. So, we're very grateful for him taking time out of his suddenly very busy schedule to join us at a time that is fraught for all. You'll find our disclosures in the transcript of this episode. You'll also find the disclosures of all guests on the podcast at asco.org/DNpod. Ben, it's great to have you on the podcast today. Thank you for being here at such a difficult time, sharing what will, I think, be a great episode.  Dr. Ben Boursi: Thanks for having me, Diwakar. Dr. Diwakar Davar: Ben, the gut microbiome and its role in terms of mediating effects and side effects of cancer immunotherapy has gotten a lot of interest recently. You've done some fundamental work in this space. Why don't you briefly summarize for the audience, firstly, what is the gut microbiome and what are the major themes in relation to cancer immunotherapy?  Dr. Ben Boursi: Well, the microbiome is the ecosystem of microorganisms, bacteria, phages, fungi, that are crucial for immunologic, metabolic and hormonal homeostasis of the host. In the last decade, we began to understand the central role of the gut and tumor microbiome in tumorigenesis, metastasis, treatment efficacy and toxicities, and in 2022, polymorphic microbiomes became one of the hallmarks of cancer, in addition to previous hallmarks that focused mainly at the cellular/genetic levels. The initial studies in mice models showed that therapeutic efficacy of immunotherapy depends on both the presence and composition of the microbiota (In germ-free or antibiotic treated mice, immunotherapy is ineffective), and following these studies, three observational studies in human patients showed that the gut microbiome can predict response to immunotherapy and that response to immunotherapy could be transferred to germ-free mice by fecal microbiota transplantation (FMT) from responding patients.  These studies helped us to define three main research questions regarding the possible role of microbial modulation in cancer treatment. First, can microbial modulation overcome resistance to immunotherapy, both primary and secondary resistance? And this question was the focus of the initial proof of concept studies. Second, can microbial modulation improve response to immunotherapy in treatment-naive patients? And third, can microbial modulation prevent or treat immune related adverse events? The initial positive results of clinical trials also led to additional questions. For example, can microbial modulation induce anti-tumor immune response even in non-immunogenic tumors? And it is important to note that there are many ways to modulate the microbiota, but so far, the only reliable way that showed positive results is fecal microbiota transplantation that allows the transfer of the entire microbiota both in terms of composition and relative abundance. Dr. Diwakar Davar: That’s great. Essentially with the trials that I think the data sets that you're referencing of course, are papers by Jennifer Wargo, Thomas Gajewski, and Lawrence Zitvogel, looking at the role of gut microbiota in several different cancers, primarily immune checkpoint sensitive tumors such as melanoma, non-small cell lung cancer and kidney cancer. And then the work from several different groups showing that essentially proof of concept experiments can be done to try to change this, certainly preclinically, and now we know that that can be done clinically.   So, I guess the failure rates of immunotherapy in some patients are quite high. And we know that the microbial composition can change the likelihood to respond to immunotherapy based on all these trials. And actually, even going back to 2015, we had two seminal papers that looked at the role of CTLA-4 blockade as well. But subsequently, many years after that, 7 years after 2015, and certainly 3 years after 2018, when the three observational PD-1 papers were published, there were 2 pivotal trials in PD-1 advanced or refractory melanoma. They demonstrated that changing the gut microbiome can reprogram the immune system to attack tumors. So, there were 2 separate trials, both published the same issue of Science. One trial was led by your group at Sheba, and another one's led by us, the University of Pittsburgh. Why don't you summarize both studies for our audience. Dr. Ben Boursi: So, both studies were Phase I clinical trials of FMT in metastatic melanoma patients who failed immunotherapy. Recipients were metastatic melanoma patients that progressed on at least one line of anti PD-1 and in BRAF mutated patients, BRAF inhibitors as well. Donors in the Sheba study were metastatic melanoma patients with durable complete responses to immunotherapy for at least one year, and in the Pittsburgh study, you also included patients with durable partial responses of more than two years as donors. It is important to note that each fecal transplant in both studies was composed of a single donor. Prior to transplantation, we performed a microbiome depletion phase using a combination of two antibiotics, vancomycin and neomycin. The goal of this phase was to assist in engraftment (by avoiding colonization-resistance by recipient bacteria) and to “reset” the immune system, which may remind some people of the logic behind bone marrow transplantation. In the Pittsburgh study, there was no bacterial eradication with antibiotics, mainly because of studies showing that response to immunotherapy is lower following antibiotic treatment.  Both studies performed FMT through colonoscopy. At Sheba, we also performed maintenance FMT using capsules in order to keep the donor's microbial composition. After the initial FMT, both studies reintroduced the same immunotherapy in which the patient progressed in the past. Clinically, we have seen a 30% response rate with durable, complete and partial responses, and in the Pittsburgh study, there was a 20% response rate and 40% disease control rate. Both studies showed following FMT, immune response in the gut and in the tumor, and tumors that were immune deserts prior to FMT became infiltrated with lymphocytes. Interestingly, in our study, there were no moderate to severe immune related adverse events following FMT and reintroduction of immunotherapy. And this is despite the fact that five of the patients had significant side effects during previous rounds of the same immunotherapy.  Dr. Diwakar Davar: So essentially, in these very early proof of concept studies, what I think is pretty remarkable is that obviously the sample sizes were very small, but remarkably, patients that appeared to respond, responded in a setting in which they were not expected to respond. So, the probability of a patient responding to attempt at giving PD-1 in patients who were PD-1 relapse refractory is on the order of about 7%, based on an FDA analysis by Viva et al. And here, two separate studies, two independent studies, investigators had not known that each paper was being published, remarkably similar results clearly demonstrating that this is perhaps one of the best pieces of evidence to suggest that microbiome modulation may actually truly be effective in reversing PD-1 refractoriness.  More recently, our colleague Dr. Bertrand Routy at University of Montreal has done a proof of concept trial in evaluating the use of healthy donor fecal microbiota transplant in addition to anti PD-1 monotherapy in PD-1 naive metastatic melanoma. In this study, published in Nature Medicine a few weeks ago, his group reported an objective response rate of 65%. What are your thoughts about this study? And specifically, what are your thoughts about some of the pharmacodynamic and translational results that were demonstrated?  Dr. Ben Boursi: This is a very interesting question, because in both the Sheba and the University of Pittsburgh studies we chose responding patients as donors. We thought that by using these patients, we provide beneficial bacteria that enhance responses to immunotherapy through several mechanisms (molecular mimicry, immunomodulatory bacterial metabolites, modulation of immune checkpoint expression, and much more), and here in the Routy paper, the researchers used FMT from healthy donors without any selection for specific beneficial bacteria, and they demonstrated a similar effect on overall response rate. So maybe FMT works actually through reducing colonization by deleterious bacteria? Another question that we should ask is whether we need to choose donors differently when we use microbial modulation in treatment resistant patients compared to treatment-naive patients? Moreover, a previous meta-analysis of FMT studies across indications that was conducted by the group of Dr. Nicola Segata, demonstrated that recipients with better engraftment were more likely to experience clinical benefit, and that increased engraftment was mainly observed in individuals receiving FMTs through multiple routes, colonoscopy and capsules, as well as recipients that received antibiotics prior to FMT. But in Routy’s trial, they not only used healthy donors, they performed bacterial cleansing only prior to FMT instead of bacterial eradication with antibiotics, and used FMTs through colonoscopy only, and they didn't give maintenance FMT. Of course, such an approach is much more feasible in the clinical setting and is relevant for designing future clinical trials.  Dr. Diwakar Davar: So, many differences, relatively few similarities, but I guess one interesting point is that of engraftment, which is that in your paper, our paper, and certainly in Bertrand's paper, it is very interesting that engraftment appears to be a key pharmacodynamic biomarker of microbiome modulation. And certainly, the analogy that you used earlier, which is that it's very similar to what happens in a stem cell transplant, which is that if there's no take, there's probably not going to be any effect. So that's very interesting that engraftment is emerging as a key PD biomarker of essentially the success of any kind of microbiome modulation across multiple different settings.  Now, we've heard of certainly defined microbial consortia, of cultivated species, as an alternative gut microbiome modulation strategy that balances the benefits of the ecological complexity of FMT with the scalability and practicality of probiotics. Do you think we are ready to design consortia?  Dr. Ben Boursi: So to date there are several probiotics that use a single bacteria and several microbial consortia that were evaluated in clinical trials, and as you mentioned, they may offer more tractable solutions for widespread clinical use. If we begin with the single bacteria probiotics, two phase 2 clinical trials found that administration of the butyrate producing probiotic clostridium butyricum 588 (CBM588) to immunotherapy naive patients with metastatic renal cell carcinoma led to markedly better immunotherapy responses, although the probiotic had a minimal effect on the composition of the microbiota, and the control arm of the trial responded worse than expected. In addition, in preclinical studies, probiotic strains of lactobacillus and bifidobacterium have been shown to enhance immune control of transplanted tumors and to augment anti PD-1 activity. However, a clinical trial in patients with metastatic melanoma found that the use of lactobacillus or bifidobacterium probiotics was associated with reduced microbiota diversity and worse responses to anti PD-1.  So here the conclusion is that when we try to design probiotics, we should not focus only on the composition since other factors, such as the relative abundance also matter. Too much of a beneficial bacterial species may potentially be worse than having a balanced and diverse microbiota. For example, a recent study of patients with non-small cell lung cancer receiving immunotherapy found that patients with a detectable Akkermansia muciniphila in their gut microbiota (this is a beneficial bacteria) responded well to treatment, but those with relative abundance of Akkermansia muciniphila greater than 5% responded worse than patients lacking Akkermansia, and this is due to the mucolytic effect of the bacteria. So, the use of rationally designed consortia may be better than a single probiotic strain.  And there are currently 3 main microbial consortia that are being evaluated: the SER-401, a bacterial consortium enriched with clostridium, led in a randomized controlled trial to reduced response to immunotherapy compared to placebo control in first line metastatic melanoma patients, potentially due to a confounding effect of a vancomycin pretreatment; MET4 is a 30 bacteria consortium that was shown to be safe and to alter the gut microbiota and serum metabolome of immunotherapy naive patients. Here, the initial study was underpowered to determine the effect on treatment efficacy; And finally, VE800 is an immunotherapy enhancing 11-bacterial consortium that is currently being evaluated in phase 1 and 2 clinical trials, and we are looking forward to see the results with this agent. Dr. Diwakar Davar: So I guess where we are right now is that social design is clearly difficult because of all the reasons you've mentioned. The SER-401 data and the MET4-IO trials certainly give us pause for thought. Certainly, no pharmacodynamic changes that were seen with SER-401, MET4-IO did result in pharmacodynamic shifts metagenomically, but neither trial was positive. And certainly, the VE800 trial, which has been ongoing now for several years, and the lack of publicly reported data certainly doesn't suggest that there's a huge efficacy signal. So consortias, at least at this point, certainly do not appear to be having a significant effect, though we don't know what might happen in the future. Data from multiple groups has shown that gut microbial composition influences the development of immune related adverse events (irAEs) in both PD-1 and combination PD-1 and CTLA-4 treated patients. Unsurprisingly, as a result, there have been attempts made at evaluating the role of fecal microbiota transplants to treat refractory immune related adverse events and very specifically immune checkpoint associated colitis or IMC. So, Dr. Yinghong Wang, who is the chair of the Immunotherapy Toxicity Working Group at the University of Texas MD Anderson Cancer Center has been very prominent in this space, and in a recent paper published in Science Translational Medicine, which is a follow up paper to her early work in Nature Medicine, she reported that HDFMT, healthy donor fecal transplantation, was very efficacious in feeding early refractory immune checkpoint colitis. So, what are your thoughts on this approach and how important is this space and where else might it be efficacious?  Dr. Ben Boursi: When I talked about the Sheba clinical study, I mentioned the possible role for microbiota modulation in the prevention of immunotherapy related adverse events in general, not only colitis. But the study by Dr. Yinghong showed that FMT can actually treat immune-related colitis refractory to steroids and anti-TNF. Now, this approach is probably relevant not only for immune related colitis, but also to other immune related adverse events. We can define certain bacterial species that may be associated with different immune related events. For example, streptococci can be associated with immune related arthritis. And maybe in the future we won't need to use FMT, but we will rather be able to target these specific immunogenic strains by narrow spectrum antibiotics or phages. The main challenge would be to develop microbiotic targeting interventions that reduce immune related adverse events without compromising therapeutic efficacy.   Now, is microbial modulation relevant only for toxicity from immune checkpoint inhibitors? So, the answer is ‘no’. We know mainly from animal models of hematopoietic cell transplantation, CAR T, and immune agonist antibodies that antibiotic-treated or germ-free mice have markedly reduced immunotoxicity, such as graft versus host disease, cytokine release syndromes, and more. It is also worth mentioning that microbial modulation is relevant not only for reducing toxicity from immunotherapy, but also from chemotherapy and other anticancer modalities. And the best example is the gastrointestinal toxicity of irinotecan that is mediated by the bacterial beta-glucuronidase. And here the targeting may even be a bit less complex. Dr. Diwakar Davar: So, what we take away from that is that starting with actually your paper originally, and papers to be produced, immune-related adverse events can be prevented using microbiome modulation with FMT, and Dr. Wang's data suggesting that eventually FMT can be used to eradicate highly refractive colitis, again, this is important to keep in mind that this approach is not yet FDA-approved. It's being done under IND. It's not currently something that is a certain standard of care. One interesting area of drug development is that there's a French microbiome company named MaaT Pharma where they have an agent that is a very interestingly a pooled microbiome product from multiple different donors. Again, the trials in both Israel and Pittsburgh used individual donors. This is a pooled donor construct. The lead candidate is actually graft versus host disease. The trial is the ARES trial, A-R-E-S, as in the Roman god of war. This trial is actually ongoing in Europe, and I believe there's some effort to try to see whether or not it's going to be a trial that can be done in the United States as well. So, at this point in time, again, we don't know whether or not there are any developmental approaches from a pharmaceutical company in the United States, but certainly this is definitely an area of interest.  So microbial therapies are still relatively early. It's going to be interesting to see how the advanced field of nutritional interventions provide an appealing method for modulating the gut microbiome due to the excellent safety profile, cost effectiveness and noninvasiveness. And certainly, if you are what you eat and your bacteria are what they eat, which goes down to our diet, there's enough rationale to believe that certain nutritional interventions can have an effect via the intermedial gut microbiota modulation. Holistic dietary changes and or supplementation specific nutrients such as prebiotics could therefore be utilized to specifically shape the population of beneficial microbes and shift the immune microbiota landscape. Now, we have seen in data published by several of our colleagues that in patients with cancer, high fiber intake is associated with greater microbial diversity, greater abundance in fiber fermenting microbes such as members of the Ruminococcaceae family, and these are all associated with the response to checkpoint inhibitor therapy. So, what do you think about nutritional interventions? Do you want us to briefly summarize data regarding nutritional data and where it stands in cancer at his time? And can you speculate as to how effective this might be in the context of patients with cancer? Dr. Ben Boursi: So, let's begin with diet. A growing number of clinical and preclinical studies suggest that specific dietary interventions such as a high fiber diet can not only improve response to immune checkpoint blockers, but also reduce immunotoxicity such as graft versus host disease. And there are many other diets that are being tested such as ketogenic diets and intermittent fasting. And the effects of diet may be mediated by both microbiota-dependent and microbiota-independent mechanisms. The limitation of this approach is that changes to the microbiota induced by diet are generally quite variable between patients and can depend on an individual's microbiota prior to intervention. And patient compliance is also a concern, particularly in the very strict diets.  Now, regarding high fiber diets, several large cohorts of melanoma patients from the US, Australia, and the Netherlands demonstrated how a high fiber diet modulates the microbiome and results in a better response to immunotherapy, better progression-free survival. Additional studies that were presented at AACR in 2023 showed that high fiber dietary interventions, in which patients received a fiber-enriched diet for six weeks, was feasible and that the high fiber diet resulted in a rapid shift in the gut microbiota toward fiber-responsive short chain fatty acid-producing taxa and a shift of the metabolome, with increase in the short chain fatty acid acetate, Omega-3, Omega-6, polyunsaturated fatty acid, and tryptophan metabolites. Prebiotics can also promote the growth of beneficial microbial species in the gut by providing targeted nutrition. And one example of a prebiotic that was shown to enhance immunotherapy efficacy in mouse models is castalagin, which is isolated from the camu-camu berry. Castalagin directly binds the outer membrane of ruminococci and promotes their growth, which has been shown to increase the CD8-positive T-cell activity and anti-PD-1 efficacy. Now, since prebiotics rely on the presence of beneficial taxa already in the host microbiota, symbiotics, which refers to the administration of the appropriate prebiotic and probiotic together, may prove in the future to be more effective than using either separately. Dr. Diwakar Davar: Certainly, these dietary interventions can be very exciting and certainly we do know of several colleagues who are doing these diet interventions, though compliance with any kind of dietary intervention may be a challenge that decides how effective such an approach is going to be. So microbial therapies in general are still at a relatively early stage of development. And it'll be exciting to see how they advance. What approaches are you excited about? What is on your radar?  Dr. Ben Boursi: There are many exciting works that are currently ongoing, and to emphasize just a few: there are many clinical trials in immunogenic tumors, in addition to melanoma, for example, renal cell carcinoma, and non-small cell lung cancer, that also evaluate different modulation protocols. We should remember that one size does not fit all, and different tumors have different microbiomes. We have a project in collaboration with MD Anderson in MSI-high patients with exciting initial results. Another study that was initiated at Sheba is using microbial modulation in order to improve TIL therapy (to overcome resistance to TIL and T-cell exhaustion). There are also studies that try to change the pharmaco-microbiome, for example, to eradicate bacteria that inactivates the chemotherapy agent, gemcitabine, in pancreatic cancer patients. And there are groups that try to identify recipients that will respond to microbial modulation and to generate better donor-recipient matching algorithms. There are already signatures like TOPOSCORE that was presented at ASCO 2023 that try to predict response to immunotherapies through the ratio between harmful and beneficial bacteria. Now, there’s also more basic science work, for example, bacterial engineering. There was a wonderful study from the Fischbach group in Stanford that demonstrated how Staphylococcus epidermidis engineered to express melanoma tumor antigens was able to generate a systemic tumor-specific response in mice models when applied topically; functional imaging of the microbiome, for example, FDG uptake in the colon can reflect microbial diversity and response to immunotherapy; works that characterizes other microbiomes such as the urinary and skin microbiomes, and their interaction with the gut microbiome; and studies of the nonbacterial component of the microbiome, mainly phages and fungi. But for me, the most important word should probably be collaboration, because without joining forces internationally, we won't be able to understand the human metaorganism, the variations according to geography, ethnicity, lifestyle, diets, and much more in the microbiome. And this is crucial in order to really understand the complex tumor ecological niche within the human host. Dr. Diwakar Davar: I think one of the key points that you just mentioned is collaboration. That's going to be very, very critical as we move this forward for many reasons, including the unexpected impact of geography upon the composition of the gut microbiome in work that has been published by many groups, but also including ours in a paper that we published about a year ago now.  So, Dr. Boursi, thank you for your great work in this area. Thank you for sharing your insights with us today on the ASCO Daily News Podcast. This is a very difficult time for all of you and your colleagues in Israel, and we thank you so much for taking such a great deal of time out of your busy workday to spend some time with us.  Dr. Ben Boursi: Thank you very much. Dr. Diwakar Davar: Thank you to all our listeners today. This is a very exciting area. This is an area where we are discovering more every day than we knew just up until the day prior. You will find the links to the studies that were discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take the time to rate, review, and subscribe wherever you get your podcast.  Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today’s speakers:   Dr. Diwakar Davar  Dr. Ben Boursi   Follow ASCO on social media:   @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Diwakar Davar:     Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences    Consulting or Advisory Role: Instil Bio, Vedanta Biosciences    Consulting or Advisory Role (Immediate family member): Shionogi    Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences    Research Funding (Inst.): Zucero Therapeutics    Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy       Dr. Ben Boursi: No relationships to disclose.        

Drs. Hope Rugo and Nancy Davidson discuss the next generation of endocrine therapy in hormone receptor-positive breast cancer – SERDs, SERMs, CERANs, and PROTACs – and challenges relating to the optimal sequence of therapeutic options. TRANSCRIPT Dr. Hope Rugo: Hello, I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco's Comprehensive Cancer Center. Hormone receptor-positive (HR+) breast cancer is the most common subset of this disease and breast cancer is the most common cancer diagnosed in women worldwide. Endocrine therapy (ET) is the cornerstone of management in hormone receptor-positive breast cancer and may involve suppressing estrogen production with aromatase inhibitors in the cancer cell itself, or directly blocking the estrogen receptor pathway through selective estrogen receptor modulators, such as tamoxifen, or the injectable selective estrogen receptor degrader, fulvestrant. However, despite the availability of these therapies, the largest unmet need lies in treatment of HR-positive HER-negative disease lies after progression on endocrine therapy. On today's episode, we'll be discussing the emerging generation of endocrine therapies in breast cancer, some of which were designed to overcome common mechanisms of endocrine resistance, and the challenges relating to the optimal sequence of therapeutic options. Today, I'm delighted to welcome the world-renowned breast cancer researcher, Dr. Nancy Davidson, to the podcast. She's a professor and the executive vice president for clinical affairs at the Fred Hutchinson Cancer Center and professor of medicine at the University of Washington as well as past president of ASCO and AACR. You'll find our full disclosures in the transcript of this episode and disclosures of all guests on the podcast can be found in our transcripts at asco.org/DNpod. Nancy, it's great to have you on the podcast today. Thanks so much for being here. Dr. Nancy Davidson: Thank you so much, Hope, for the opportunity. Dr. Hope Rugo:  You've done incredible work in the area of treating HR+ disease, but also in understanding some of the agents and pathways that are most important to our understanding of how we treat and really think about developing new drugs for HR+ breast cancer. The first generation of anti-estrogen drugs really included selective estrogen receptor modulators, but now we have a new generation of these anti-estrogen drugs. And there's also orally administered selective estrogen receptor degraders, so-called SERDs, that we hope someday will be an alternative with already one approved for the injectable SERD, fulvestrant. But there's a whole additional class of drugs, complete estrogen receptor antagonists, referred to as CERANs, and proteolysis targeting chimerics, PROTACs. These agents are all at various stages of development in both early and metastatic settings and really represent, I think, a confusing array of different treatments that are being studied, some of which of course are approved. Nancy, it would be great if you could tell us some about these exciting new agents, starting with our approved drugs and moving on to the agents that we're studying in clinical trials. Dr. Nancy Davidson: Hope, this is a terrific example of how basic science has really begun to inform clinical practice. For us as breast cancer practitioners, it was really easy for a long time because we only had tamoxifen. And then things like the aromatase inhibitors as a means of decreasing the estrogen ligand came into practice, as did fulvestrant, as you mentioned, a selective estrogen receptor degrader. Thanks though to a lot of understanding about estrogen receptor biology, and specifically, the discovery about a decade ago of estrogen receptor mutations, something that we didn't think exist ed for a long time, but which we now know exists in maybe a third to a half of breast cancers after exposure to aromatase inhibitors, that's led to really an explosion, this alphabet soup of possibilities that you talked about. SERMs, selective estrogen receptor modulators, tamoxifen is the classic one—something that acts as an agonist and as an antagonist, depending on the tissue. The SERDs, the selective estrogen receptor degraders, lead to estrogen receptor destruction. Fulvestrant is the classic example of this right now. But we're very excited that a second one has been FDA approved. That's elacestrant that was approved earlier this year, and it has specifically been developed to try to target those estrogen receptor mutant breast cancers because those are the ones that are particularly resistant. So that's the first of this new generation of SERDs that's coming on the market, has come on the market. As you say, a key advantage there is that it's oral, unlike  fulvestrant, which requires 2 monthly injections and is very, very inconvenient and uncomfortable for patients. Other SERDs are coming along. I think another one that is well along in clinical development is giredestrant, which is in the same family and being tested in clinical trials of the classic varieties. It's been tested in a window trial, looking at its ability to down-regulate Ki67. It's being tested against standard of care in first-line metastatic breast cancer. And there are some studies that are going to begin looking at it in the adjuvant setting as well. There are other members of this particular family, but I think that elacestrant is the one that we have at our fingertips right now, and giredestrant is one that's certainly coming along in clinical trials, and we should look forward to those results. For those who are interested in the giredestrant, the trials in question right now that are going on are persevERA, which is in stage 4 breast cancer, and lidERA, which is in the adjuvant setting. Now that's one new category, or it's an old category with a new twist. A second is these agents that are called complete estrogen receptor antagonists, CERANs, as you talked about them. The key here is that what they do is, the estrogen receptor has a couple of domains, and in particular, it has 2 different activation domains, AFT1 and AFT2. And these CERANs are complete estrogen receptor antagonists, so they block both of those domains. And the hope would be that they might end up being more effective than the other agents that we have available to us right now. So those are also in clinical trial at the present time, and we're waiting to see whether or not there's going be any value in that particular area that's going to able to go forward for us.   Another area that I think we want to talk about is the PROTACs, as you mentioned. These are proteolysis targeting chimeric entities. So, this is a kind of a complicated situation where you have a kind of bivalent situation where you have something that binds both to the estrogen receptor and then also to E3 ubiquinase. So, it leads to degradation again of the agents; that's another area for us to be watching. And then finally the SERCAs. So those are the selective estrogen receptor covalent antagonists, and what they do is they bind very specifically to a cysteine 530 that exists in the estrogen receptor but not in other steroid receptors. So that's where the selective part of this comes along. Now these are all in various stages of clinical investigation. Some of them are pretty early at this point, but I think the ones that are well established are elacestrant, giredestrant is coming along as we just talked about. Camizestrant is also coming along through the SERENA series of trials, and imlunestrant is also coming on through the EMBER series of trials. Hope, I would also be remiss if I didn't go back to an old drug that's a new drug, and that's lasofoxifene, which is also in the SERM family. Those who have been in our field for a while will remember that lasofoxifene was actually originally kind of tested in the prevention setting, where it seemed to have some activity. It came back into our interest because it has really strong activity against estrogen receptor mutant breast cancer models in the laboratory. And as a consequence of that, it's coming back into the clinic through a series of trials that are called the ELAINE trials, where we're looking to see whether or not it might also be better than fulvestrant. It too is an oral agent, so that's a real plus for us, and the first set of ELAINE trials would suggest that there's some nice activity without a lot of toxicity. So, lots going on in this field. You know, I think for all of these things, obviously, we're also working very hard to think about the toxicities. All of these, as I recall, are oral agents. So that gets rid of  1 huge toxicity, which is you don't have the need for some sort of injection. But they all do have some side effects. Frequently, [the toxicities] are like GI side effects or fatigue. In a couple of cases, there might be some concern about cardiac arrhythmias, but I think GI turns out to be one of the most important things that we have seen in some of these trials. Generally, it’s very well tolerated, though. I think another important question, which I'm sure is in your head and is in mine, is that how are we going to integrate these into what we already have? And so, I think a lot of the work right now is looking at patients who have already received an aromatase inhibitor plus a CDK4/6 inhibitor and are now going on to one of these new agents. But you might wonder, if they turn out to be effective and well-tolerated, whether they too should be perhaps combined with CDK4/6 inhibitors in place of the aromatase inhibitors or the fulvestrant that we use now. So, I think that we can imagine that those clinical trials are either in progress in some cases or will be coming on as we try to think about how to integrate these new approaches into our existing standard of care, which is already quite complicated, right? We've gone far from tamoxifen, which was good for everybody, to now a really complex algorithm about how we think about hormone therapy, both in early breast cancer and in metastatic breast cancer.  Dr. Hope Rugo: Well, that was a fabulous discussion about the new agents and our existing agents and both the exciting aspects, as well as the challenges. One question that comes up, I think a lot, and this is of course a huge question in many ways, but for ER-positive metastatic breast cancer, where these drugs are first being tested, maybe we'll talk about that first. There's one trial at SERENA-6, looking at camizestrant in patients who have developed evidence of an ESR1 mutation in circulating tumor DNA, who are on first-line therapy with an AI and a CDK4/6 inhibitor. What do you think about that study and where do you think that progress might go? Of course, that's based on data from another trial, which wasn't definitive, but suggested, had sort of a suggestion, you know, without studying the sequencing in detail that maybe you would have improved progression-free survival with that approach. Dr. Nancy Davidson: Yeah, by which you mean the idea of monitoring pre-ESR1 mutations and circulating DNA and then making therapy changes based on that? Is that what you’re talking about? Dr. Hope Rugo:  The PADA-1 trial, yes, and that led to this huge SERENA-6 trial, which of course is now accruing. Dr. Nancy Davidson: So, you know, we would love that, right? I think that obviously breast cancer for many years has been interested in trying to have circulating markers that we could use to help to guide our therapy in a more meaningful way than we have in the past. And I think that the trial that you've talked about is certainly one that's trying to make that see whether that's a possibility for us based on information like the PADA trial. I'm hopeful it's going to work out. I would say, let's see what that looks like, whether it's going to be useful or not. It seems to me in some cases, some of these trials have not been quite what we hoped for, but I don't think we necessarily had the molecular techniques or the sensitivity, nor did we necessarily have other things to move to because, you know, those two approaches require both a really good test, but also the ability to use the test to define a new therapy that's going to lead to improved patient outcomes. And I think that these are ingredients that we now have available to us at our fingertips more than we did, say, a decade or 2 decades ago. Exciting approach. Dr. Hope Rugo:  I do think there's a lot of challenges inherent in this process, monitoring blood on a regular basis and following up and then randomizing based on results. But I think [SERENA-6] is an incredibly important trial, as you have mentioned, to try and think about moving past using circulating tumor cells, which didn't work, to just change blindly to the next therapy, but more have a rational reason to change to a drug that may be more effective before the disease itself progresses. And just for our listeners, the unique aspect of trials like this in SERENA-6 is that you change therapy before you have evidence of disease progression, but only this molecular evidence of a mutation that is associated with resistance to the therapy you're on. So, it's a really important question. We'll see what happens, as you mentioned, sometimes we're not clever enough to really get around the fact that there are multiple mutations driving resistance in this setting, so we'll see how straightforward this is. The question also comes up, and I think that's a question with many of these trials now, is they're randomizing patients after a progression on an AI and CDK4/6 inhibitor to receive the novel endocrine therapy or fulvestrant. One of, I think, the concerns of treating oncologists is that then you're sort of eliminating the possibility of a targeted agent in that setting. And of course, we have new targeted agents we're studying as well, AKT inhibitors and new inhibitors of the PI3 kinase pathway. So, the newer trials are now combining, as you mentioned. There's a lot of concerns about drug-drug interactions here and how you might really combine them. And then there are triplet studies looking at CDK4/6 inhibitors, oral SERDs primarily, and pi3-kinase and CDK4/6 inhibitors. What's your thought on these and will they really help to move the needle forward? Dr. Nancy Davidson: I think that's a really interesting question, Hope, is whether or not we're going to find that combination therapies from the get-go are the way to go, or whether we're going to end up having to use maybe more serial therapies. Because not only is it a question about whether or not you can tackle all of these different resistance mechanisms simultaneously, but I think the other question is, as you say, are there negative drug-drug interactions, and are there toxicities that are intolerable? Although these are targeted in all cases and they're relatively benign in terms of side effects from the breast cancer perspective, they're not devoid of toxicity. And so, I think that's going to be another issue for us – whether they're well tolerated during the time that patients are taking them. I guess the other thing I always think about, Hope,  is that it's hard to know about value of cancer care, but you know, we are talking about agents that are not inexpensive. You know, when you think about the financial toxicity, in addition to the side effect toxicity that you and I just talked about, trying to think about what that value is going to look like is going to be very important for us. Also, as somebody who worked for a long time in the lab and in the clinic, you know, there are an infinite number of combinations that you and I could think about that are rational. And so, the question is, how are we going to pick the ones that are the most rational, if you will, the ones that seem to be the most promising, and take them forward into clinical trials? Because patients are our most precious resource. And so, we want to make sure that we are bringing forward only those things that really seem to have a very strong foundation and the opportunity to improve outcomes over time. Tough, tough question for us to try to think about, as you've talked about. The other thing is that, you know, these trials are not only for postmenopausal women, who are the majority of patients, but we also want to target them to premenopausal women. So, in those women, we're also looking at using an LHRH agonist on top of this, right, because many of these things are really at least so far designed for the postmenopausal state. So stay tuned. Lots of work going on. I think one of the interesting things will be making the leap from using these in metastatic disease at time of progression to taking them forward into the early breast cancer space. And several of the agents are now beginning to do that because of very strong preclinical and clinical data to date. Dr. Hope Rugo: So, we have new agents that we're studying in the metastatic setting, and we've seen a trend to move fairly rapidly from phase 1B trials directly into phase 3 trials, because as you pointed out so clearly, there are a number of drugs in this setting, and we don't really know not only which agent is better, but even what class of agents is better. So, as we move more quickly from phase 1B to phase 3, the question comes up about how we're going to study these agents optimally in the early-stage setting. They, I think we all thought that maybe changing based on ctDNA evidence of a mutation might be an approach, but that's complicated. A big question for you is whether or not you think that's ready for prime time as it's being marketed as such. And then the second question is really, are we better changing our whole approach upfront in high-risk disease or should we wait until after patients are exposed to their endocrine therapy and then switch as we go along; the EMBER-4 trial is looking at that switching approach? Dr. Nancy Davidson: Yeah, I think that this is obviously the billion-dollar question for many companies and for many of us as investigators. I don't know that I have a crystal ball into what the best approach might be. We know that already some of these have been abandoned. For example, amcenestrant. So, I don't even have to learn how to say it because it has been abandoned. It did go to phase 3, as you pointed out, in the advanced setting, looking at it with palbo vs letrozole plus palbo, and it didn’t really show a whole lot that the company wanted to pursue.  So, I think that sometimes these things are going to be abandoned based on the metastatic setting, which is a large trial, and that’s a trial where obviously it might be a little easier to the circulating markers, as you talked about, than maybe in the early-stage breast cancer setting.  I think that probably these early-stage trials are going to end up being big; they’re going to have be clean. I’m guessing that most companies and most investigators will want to target them towards high-risk individuals, as you talked about, for 2 reasons. One is that ethically, I think we feel more comfortable with that. These are individuals where standard therapies are maybe not serving them as well as we would like and where we have information to think that we can at least have equipoise about a new approach. And the second is that from a trial design point of view, the event rate is likely to be higher, and therefore you might get answers earlier and with a smaller clinical trial. So that's where I suspect we're going to go. But it's a challenging question, and I think that many investigators and many companies are really trying to struggle with that right now because we do have so many options. And we're not quite sure how to, first, develop these new drugs, but then really importantly, put them in the context of our existing drugs. And as you say, we're also simultaneously trying to develop superior molecular or circulating markers to guide us. So, there's so many variables that are going on right now in this field that, from my point of view, itmakes it really exciting, but it also makes it pretty complicated, both for investigators and for pharma as we try to think about how to position these going forward. But what a great problem to have, Hope, because remember when you and I started in breast cancer, pretty much all you needed to know was tamoxifen. And I think you and I also probably started at the tail end of the time when we were using androgens and progestins and agents that now have basically completely fallen out of favor. Dr. Hope Rugo: Estrogen Dr. Nancy Davidson: Estrogen, yeah, and your side effect profiles were not as good. So, it's a good problem to have. It's a nice situation when science can inform our clinical investigation, our clinical practice. Dr. Hope Rugo: Yes, I think it'll be fascinating to see where we end up at the end, but of course, the complexities of this include the fact that sometimes just the clinical trial design leads to a less than positive result because of the way the trial itself has been designed, which I think is the nice part about moving these earlier into treatment of high-risk disease, but also brings up the question of all sorts of areas we’re not really a place to discuss today, like how the statistical design is made, et cetera, that can sometimes result in poor evaluation of excellent agents. One of the questions that comes up, and you brought this up earlier, which I think is really important, is that we are in the era of combining our endocrine agents with targeted agents, and, oral agents, in a fascinating way, really bring up drug-drug interactions in a way that the injectable fulvestrant hasn't, and aromatase inhibitors were kind of quiet on the impacting metabolism, unlike tamoxifen. But we are seeing some drug-drug interactions and certainly the discussions about using these agents may include the question about whether or not you're having more diarrhea or nausea or fatigue or one drug causes photopsia, flashing lights, things like that. Keratitis is becoming a new toxicity to follow.  How are we going to figure out how to sequence these drugs and are they only going to work better all of them as a class in patients with ESR1 mutations in their tumors? Dr. Nancy Davidson: I think we don't know the answer to the second question yet. That's something that really needs to be sorted out. Even if they do, that's still a really important subset of patients, assuming that we continue to start with the aromatase inhibitors, right? That's where those things really seem to emerge right now. I don't know how we're going to figure those things out. I guess that I'm hoping that maybe a couple of agents in these classes will become kind of the lead agents. And so, we'll be able to do this work with a handful of things as opposed to a whole array of things. But we'll see. I think that even within classes, obviously, these agents are going be slightly different, probably. And so it may be that one member of a class may be slightly better from a, maybe not from an efficacy point of view, but from a toxicity point of view. And we'll just have to see how it goes. I don't think I have any magic answers about that. Dr. Hope Rugo: Yes, it'll be interesting to see whether or not the agents work in sequence too. You know, could you use a PROTAC after an oral SERD, for example, or a CERAN? That'll be fascinating to see. Dr. Nancy Davidson:  I'm hoping that preclinical modeling may help with that a little bit, though of course we all know that there are plenty of things that do well in preclinical models, GEMS and rodent models and PDXs, and sometimes those things translate nicely into clinical practice, but sometimes they don't. Dr. Hope Rugo: You mentioned, Nancy, that when we started out, that it was a fairly simple decision about what endocrine therapies, and we ran out very quickly. We're seeing some of those old classes come up with new agents. And you mentioned lasofoxifene, the oral SERM that seems to have some benefits and works in the later-line setting and also can be combined with a CDK4/6 inhibitor; [and also] has data with abemaciclib. There's also a new androgen receptor agonist, enobosarm, that's being tested as well. Do you think that these older mechanisms have a future as well? Dr. Nancy Davidson: I do. I think that because we'll be able to understand the biology better than we did in the past. A lot of our hormone therapy was pretty empiric several decades ago. But I think with better understanding of mechanisms and better understanding of what the patterns of resistance might be for a particular tumor, that we might be able to think about those things. You're right that there's a whole parallel universe right now in androgen receptor targeted therapies that we're not talking about today, both in perhaps in hormone-responsive breast cancers, but also in triple-negative breast cancers in a certain subset. And so that's an area where we probably need to be watching what our prostate cancer colleagues are doing as they develop these agents and thinking about where they might mechanistically make sense to apply in the breast cancer field. It won't be the first time that we've received insights from them because remember, prostate cancer people knew about androgen receptor mutations a really long time before we figured out that they existed in estrogen receptor as well. So, there's a nice cross talk, I think, between the prostate cancer field and the breast cancer field in that regard. Dr. Hope Rugo:  That's an excellent point. And we learn a lot from our colleagues studying other malignancies, and prostate cancer has been a big area there for us and hopefully will help us with studying these agents because there's different toxicity profiles, of course, as well. And then you mentioned the approval of elacestrant, the first oral SERD to have regulatory approval, and it's approved in patients who have ESR1 mutations in their tumors. We're also studying it in the ELEVATE trial in combination with all of the different targeted agents, the CDK4/6 inhibitors, mTOR inhibitor, everolimus, and the PI3 kinase inhibitor, alpelisib, to really try and understand how these can be optimally combined. Would you check for ESR1 mutations at diagnosis of metastatic disease, or would you do this more after progression or start of progression of disease on an aromatase inhibitor? Dr. Nancy Davidson: I tend to be a conservative, Hope, and so unless there's a clinical trial that might be able to be considered, I would tend to check it only after progression on the aromatase inhibitor. But I think some people are earlier adopters, and I suppose it's possible that they might want to know from the get-go. Having said that, I do think elacestrant has an approval after aromatase inhibitor, as I recall. So, presumably the patient would have to have that exposure before you would be able to act on the ESR1 mutation by administering the oral SERD. This is also a new area that may well change with time, right? You know, as we develop different agents, as the agents have different requirements or different indications, and as we perhaps have better tests, it may be things that we don't do routinely now will become very routine in the future. And perhaps in series like you talked about in a serial fashion. Dr. Hope Rugo: Absolutely. I think that's a really important comment about how we're going to think about treating hormone receptor positive disease and potentially, you know, we have new chemo options, of course, not part of our talk discussion today and antibody drug conjugates. So, the future is certainly challenging in terms of understanding this appropriate sequencing. We need data, but it's exciting to have these options. As you pointed out, this is this is a great problem to have, you know, too many drugs with efficacy to try and understand how to use these in the most appropriate way. And as you also pointed out, the use in young women is particularly important. Whether or not you need to suppress the ovaries with all of these new agents is going to be important to understand as well as a next step. I don't know if you have specific thoughts on that area as well. I mean, that may reduce toxicity for younger women. Dr. Nancy Davidson: I guess our approach right now has been to suppress them, but I agree with you; you wonder if you look at some of the mechanisms of action, whether that's really a requirement biologically and medically, or whether it's something that's kind of a leftover from the approval process. You know, that for the drug approval, these women were suppressed. I think we need to work that out because that's another area where certainly women could have ovaries removed. That's pretty straightforward, although it requires a surgical procedure. But otherwise use of LHRH agonists continues to be injections, right? And so, if we're trying to minimize convenience or maximize convenience and minimize toxicity for women with any stage of breast cancer, anything we can do, it seems to me to eliminate an injection is going to be a good thing. So important for us to be able to work that out as well, even though numerically it's a smaller number of women, it's obviously a very important number. population of women. Dr. Hope Rugo: Last question for you. One question that comes up and sent to me and panels all the time is, if you have done your next generation sequencing and you see an ESR1 mutation and a P13CA mutation, what do you prioritize in terms of your choice of treatment, because we have the choice of either using elacestrant or a fulvestrant in combination with an agent targeting the PI3 kinase pathway? Dr. Nancy Davidson: I don't know that there's a right answer to that medically right now. So, when I talk about it with patients, I suggest to them that it's probably not one or the other. It's kind of the question of which one to use first. So, we talk a little bit about side effect profiles. We talk a little bit about patient preference and neither of these drugs is devoid of problems, but sometimes patients have pretty strong feelings about which set of side effects seems the least unattractive to them or the possibility of having those side effects. And I know that if one isn't well tolerated, you can swap over to the other. Dr. Hope Rugo: Absolutely. I think that's a very important way to think about next therapies in our era of not really knowing what's right. And this idea of shared decision-making is so incredibly important. Nancy, thank you so much for sharing your insights and knowledge with us today. I could talk to you for hours about this. Dr. Nancy Davidson: Hope, thank you so much for the opportunity. It is an exciting area and I really enjoyed talking with you about what we know and the many things that we don't yet know, but we're working on. Dr. Hope Rugo: Indeed, it's certainly an exciting time. Thank you to our listeners for joining us today. And thanks to the ASCO Daily News Podcast for highlighting this important area. You'll find a link to all of the studies discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thanks so much.   Disclaimer:    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Follow today’s speakers:     Dr. Hope Rugo  @hoperugo  Dr. Nancy Davidson     Follow ASCO on social media:     @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:     Dr. Hope Rugo:  Consulting or Advisory Role: Napo Pharmaceuticals, Puma Biotechnology, Mylan, Eisai, Daiichi Sankyo Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Astellas Pharma, Talho Oncology, Veru, GlaxoSmithKline, Hoffmann-LaRoche AG/Genentech, Inc Travel, Accommodations, Expenses: Merck, AstraZeneca   Dr. Nancy Davidson: No Relationships to Disclose    

Drs. Lillian Siu and Melvin Chua discuss scientific innovations, disruptive technologies, and novel ways to practice oncology that were featured at the 2023 ASCO Breakthrough meeting in Yokohama, Japan, including CRISPR and gene editing, CAR T-cell and adoptive cell therapies, as well as emerging AI applications that are poised to revolutionize cancer care.   TRANSCRIPT Dr. Melvin Chua: Hello, I'm Dr. Melvin Chua, your guest host of the ASCO Daily News Podcast today. I'm a radiation oncologist and I currently practice in the Division of Radiation Oncology at the National Cancer Center in Singapore. I also served as the chair-elect of the ASCO Breakthrough Program Committee, and, on today's episode, we'll be discussing key takeaways from this year's Breakthrough meeting. The global meeting in Yokohama, Japan, brought together world-renowned experts, clinicians, med-tech, pioneers, and novel drug developers to discuss scientific innovations and disruptive technologies that are transforming cancer care today. I'm joined by Dr. Lillian Siu, the chair of the Breakthrough Program Committee. Dr. Siu is a senior medical oncologist at the Princess Margaret Cancer Centre and a professor of medicine at the University of Toronto.     You’ll find our full disclosures in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod.    Lillian, it's great to be speaking with you today.    Dr. Lillian Siu: Thanks, Dr. Chua. I'm happy to be here.    Dr. Melvin Chua: We were just at ASCO Breakthrough, and it showcased some incredible scientific innovations, and really showed us how technology innovations in precision oncology, biotech, and artificial intelligence are transforming cancer care. What are your thoughts?    Dr. Lillian Siu: Yeah, it was a really exciting meeting, Melvin. The theme of this year's Breakthrough meeting was “Shining a Light on Advances in Cancer Care.” And our Opening Session featured an illuminating keynote address by the renowned thought leader and tech trailblazer, Dr. Hiroshi or “Mickey” Mikitani, the founder and CEO of Rakuten and Rakuten Medical. In his address that was titled, “Innovative Technology and Oncology,” he spoke so passionately about innovation and really seeing around the corner to predict what is coming and taking risks. And I think that's what medicine is about, not just what we have in front of us, but to predict and forecast what's coming. I totally was inspired by his address, and I think a lot of the audience felt the same way. He also spoke to us a bit about his company's development in photoimmunotherapy using novel technology and light therapy in head and neck cancer. And I think that's also an area of new technology that we should watch in the next few years.    Dr. Melvin Chua: I totally agree with you, Lillian. And one of the quotes that he spoke about really spoke to my heart. He spoke about the 2 choices: whether to do or not to do and not to do is not an option. So, I think that was a very compelling message to a lot of our audience at the meeting.    So, on this same note, innovation is a driving force in oncology, and we saw countless examples of this throughout the Breakthrough meeting. Were there any sessions that really stood out for you?    Dr. Lillian Siu: There were so many exciting sessions. First of all, there is the “Drugging the Undruggable” session. This is a really important session because in the past we felt that certain cancer targets such as KRAS, MYC, etc., are not druggable. KRAS G12C is the poster child in this area. So, during this session we heard about many ways that we are now looking to target these so-called undruggable molecules in the cancer cell. And we talked about molecular glues, we talked about degraders, and really novel ways that are not yet reaching the clinic, called “cyclic peptides” were discussed by one of the speakers.     The other session that is very interesting also is CRISPR and gene editing. Obviously, we all know a little bit about gene editing, really trying to change or knock in some genes that are important perhaps to change the function. And one of the sessions talked about trail targeted induced mesenchymal stem cells, and perhaps this is a way to, again, deliver novel therapies and novel treatments to our patients. There were many examples of how CRISPR and gene editing can be ultimately going to the clinic to benefit our patients in terms of therapeutics.     I want to highlight another session, which is the CAR T-cell and Adoptive Cell Therapies. I think everybody knows about CAR T-cells, but in this session we talk about non CAR T-cells or newer things such as off the shelf NK cells, Natural Killer cells from cord blood. So, this way it is allogeneics, in other words, we don't have to rely on only a patient's donation of their samples, but actually get it from off the shelf from other donors. There are other ways to really use human induced pluripotent stem cells that we can armor them by transgenes and also CRISPR out any unwanted genes, for example, to enhance an effective function of T-cells. So many, many exciting ways to bring these cell therapies to the patients.     And last but not least, I want to highlight Dr. Chris Abbosh, who is one of our keynote speakers, talking about molecular and minimal residual disease and early cancer detection using circulating tumor DNA or liquid biopsy. He talked passionately about the TRACERx study, which he is instrumental in terms of leading together with Charlie Swanson in the UK. This is a study that really has uncovered a lot of science about cancer heterogeneity. And in that study, he also studied circulating tumor DNA and really shed a lot of light about clonal and subclonal dynamics over time that changes.     Dr. Melvin Chua: And just to touch on that point about innovation and how that translates to cancer care, I think it was great that we had those case-based applications in lung cancer, in breast cancer, and the virus-associated cancers. And I like how the speakers were able to bring in the Ying and the Yang, bring the West and the Eastern perspectives in these interactive sessions. I particularly enjoyed all of them. But the session on the lung case discussion where we know that there were this EGFR mutant lung cancers that are prevalent in this part of the world in Asia. I thought the interaction between the speakers was fantastic.     On the same note about therapies and we heard about novel therapeutics at this meeting as well. I wonder what your thoughts are about some of the sessions, and do you think some of these technologies were able to be brought into practice? And your thoughts on the novel therapeutic session that happened at Breakthrough, do you think this will actually impact clinical care?    Dr. Lillian Siu: Oh, for sure, Melvin. The 5 areas that were covered during the Novel Therapeutics session are really drugs already in the clinic. And for example, the first one was about antibody drug conjugates. We know there are now at least 12 antibody drug conjugates already approved by the FDA and many more likely to be approved in the near future. And the session really talked about what's next, how to improve upon ADC, for example, using better drug antibody ratio, talking about new payloads and really new formats that make perhaps ADCs even more potent in the future.     There was a session on oral immunotherapeutics. It was really how to target the innate immunity. And I think novel oral immunotherapeutics is very important because we all know PD-1, PD-L1 inhibitors have been the backbone, but we need another Breakthrough. And having oral immunotherapeutics will make it very attractive for patients because they don't have to come to the cancer center to receive the drugs.     Another part of that session was about T-cell engagers and bispecifics, really how to bring molecules to the T-cell, to the effective cells so that they are able to be phytotoxic to the tumor. We talked about also oncolytic viruses, how are the new ways to utilize this kind of natural agent to target the cancer cells. And lastly, we also talked about personalized cancer vaccine, which is obviously very timely. We all know a lot about vaccine now after the COVID pandemic and how do we use cancer vaccines to be a good therapeutic drug? I think especially important in the earlier disease stages as adjuvant therapy. Some exciting data, for example, in pancreatic cancer, as adjuvant really is groundbreaking for this whole topic of cancer vaccination.    Dr. Melvin Chua: That's great. And for me as a radiation oncologist who's not so deep in drug development, hearing all the talks at ASCO Breakthrough was really informative for me and I learned a lot. In particular, you spoke about the whole session there was oncolytic therapy and the results in glioblastoma multiforme, we know it's a deadly disease, was certainly very impressive. And so, it speaks to the whole notion that in fact, some of this stuff is in fact reaching the clinic and making a difference in deadly diseases. I think there's a lot to take in from there.    Dr. Lillian Siu: Melvin, you're so humble. I know you're a big expert in artificial intelligence and I think the whole session about AI applications in precision medicine really was not just in that session, but a whole theme that went throughout the entire meeting. So, I'm very interested to know what you think about some of the presentations around AI and disruptive technologies in precision medicine, such as next-generation multiomics, etc. What are your thoughts?    Dr. Melvin Chua: Absolutely, I agree with you. And there was so much material within the AI session, the multiomic session, as well as the keynote [address] by Dr. Maryellen Giger, which basically speaks about some of the pre-existing or historical work on artificial intelligence in radiology. And I'd like to first talk about the keynote by Dr. Maryellen Giger. It was very nice that she elegantly showed how AI was in fact already in practice in radiology, where it helped to fulfill or address a need for radiologists. Almost 20 years ago, they were able to show that using computer vision, you were able to basically facilitate the calling of abnormal mammograms. And it was inspiring to see how these early thoughts have now basically accelerated a lot of the advances that we see that are in practice today.     The other thing that was also was to see this global collaboration, the need for global collaboration in the artificial intelligence space and the radiologists are clearly leading the way. And I think part of the impetus for this effort came from an opportunity that arose during the COVID pandemic that clearly affected all facets of healthcare. That was a nice segue to the very sort of dense 1 hour session we had on precision oncology care with artificial intelligence. I think when we designed this session, we were very deliberate that we wanted to address all aspects of how AI could be applied. From real-world clinical data, we saw examples of how having good, well-annotated data sets could actually help to accelerate and facilitate liver cancer screening in Hong Kong. Then we also saw a very simple, practical application of AI in pathology, where apart from just having this tool to be able to extract features that could potentially predict outcomes of patients and predict drug responses, we saw a very practical example that applying AI in digital pathology could actually homogenize or harmonize the ways the pathologists review their cases. And so, I thought that was very neat and could speak to all our clinicians across both developed and developing countries.     We also saw very exciting stuff on the use of AI in terms of calling out mutations because we know that next-generation sequencing is pretty much a cornerstone of how we practice in oncology today. And yet we know that there are prohibitive costs that preclude this technology in certain parts of the world. And it was nice to see how AI could actually lower the cost of some of these sequencing technologies like being used in liquid biopsy.     And then finally, there was some fancy science as well that was showcased in the spectrum when we saw how industry as well as academics are thinking about integrating multiomic data sets to then be able to accelerate drug discovery, help define patients better, and so that we can think about how to look at precision oncology using targeted treatments for specific patient phenotypes. So I think this was a very nice transition to the Next-Generation Multiomic Technology session, where, again, some of these topics were touched on, ranging from liquid biopsies, and this was already covered in Dr. Abbosh’s talk, which you spoke about, and as well as the preceding day session where we heard snippets of it. And it was again reinforced by the speakers when it showcased liquid biopsies. We have heard so much about it in the last decade and we see it made approved now for use in the clinic, but yet so much remains unknown, like the discrepancies between assays, addressing the cost of assays and, importantly, how we deal with the information. So, I think we are just at the tip of the iceberg here. A lot of the clinical evidence needs to be generated in due course to address some of these questions.     At the same time, it was also nice to see some of the new technologies being applied in discovery science. So, we know that immunotherapy is a major player in oncology today, and the Breakthrough represents a forum whereby we're able to bring translational scientists to showcase their work. And we saw examples of that at this meeting where single cell technology, digital spatial technology, being able to apply that in pathology specimens and how the two are integrated to be able to review more novel science to us, to show us how immunotherapy works or doesn't work in some patients. Both of us have touched on so much content that was showcased at the Breakthrough, and I think this speaks to the impact, the learning experience we’ve had from Breakthrough and I think that’s the intended purpose of this meeting.    Dr. Lillian Siu: Yeah, I agree. It truly was a very exciting 3 days. And I particularly like the multiomics session where we see that the technology is so advanced just in a really short period of time. Over the last few years, we've been now able to go into single cell resolution where in the past I don't think we would ever dream of being able to do that. In fact, I recall in the single cell session, we can even see messenger RNA on the slide, which I thought was fascinating, something that I cannot imagine we can see by the naked eye. It really is an exciting time in oncology, Melvin, and the field is advancing with these new innovations and therapies, but at the same time, I think it's important that we do live globally and we need to work really also to help improve access to quality-assured cancer medicines and diagnostics in the low and middle income countries. What do you think about that part? Did we do a good job in addressing that in the meeting?    Dr. Melvin Chua: Absolutely, Lillian. We had a special session that was chaired by Dr. Peter Yu and the lecture was delivered by Dr. Gilberto Lopes from the University of Miami. And we know that he's a strong advocate for this. And the session title spoke to this topic very pointedly, “How Science, Technology, and Practice Can Be Enabled in Lower- and Middle-Resource Settings.” And I thought that the work that he highlighted, the whole ATOM coalition, was important. ATOM basically stands for Access to Oncology Medicines, and it was established last year by the UICC, the Union for International Cancer Control, along with global partners to improve access to anti-cancer drugs and to develop processes for ensuring quality delivery, as well as the optimal utilization of medicines in middle- and low-resource settings. And I think there's a lot more work to be done.     Some of the information they showed was very compelling to me from this part of the world. But we know that Asia isn’t very heterogeneous in terms of the resources, in terms of the culture. And I thought that the drug pricing, for example, how that should be addressed across the different countries is an important topic to pick up. And I hope his lecture only invigorates this conversation going forward.     Dr. Lillian Siu: Yeah. Thanks, Melvin. I totally agree. That was very inspiring. Breakthrough is such a one of a kind, international gathering that we are not only able to network while we're there; we also have a session to really allow attendees to leverage international cancer networks, to learn a bit about them, all the way from, for example, some of the North American groups to Asia Pacific groups to even global groups, and how we interact between pharma and academia, really transcending boundaries. And I think it is really, really important for us to now have these networks address issues such as equity and cancer care innovation, novel approaches and so much more. And I think, I am sure you're going to do a good job in making sure that gets into the agenda in our next year's meeting in 2024. Ultimately, we hope that these collaborations in cancer research will help to improve the outcomes for our patients with cancer.    Dr. Melvin Chua: Thank you again for sharing the great highlights of ASCO Breakthrough, and I'm really appreciative of your work, and your commitment to build a really robust program for this year. So, thank you.    Dr. Lillian Siu: And thank you, Dr. Chua. And you can bet that I will not miss Breakthrough 2024 in Yokohama in August next year. I will be there.    Dr. Melvin Chua: Okay, I'll hold you to that.     And thank you to our listeners for your time today. You'll find links to all of the sessions discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thank you again.    Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Find out more about today’s speakers: Dr. Lilian Siu  @lillian_siu  Dr. Melvin Chua  @DrMLChua    Follow ASCO on social media:   @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Lillian Siu:  Leadership (Immediate family member): Treadwell Therapeutics  Stock and Other Ownership Interests (Immediate family member): Agios    Consulting or Advisory Role: Merck, AstraZeneca/MedImmune, Roche, Voronoi Inc., Oncorus, GSK, Seattle Genetics, Arvinas, Navire, Janpix, Relay Therapeutics, Daiichi Sankyo/UCB Japan, Janssen, Research Funding (Institution): Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim, Bayer, Amgen, Astellas Pharma, Shattuck Labs, Symphogen, Avid, Mirati Therapeutics, Karyopharm Therapeutics, Amgen    Dr. Melvin Chua:  Leadership, Stock and Other Ownership Interests: Digital Life Line  Honoraria: Janssen Oncology, Varian  Consulting or Advisory Role: Janssen Oncology, Merck Sharp & Dohme, ImmunoSCAPE, Telix Pharmaceuticals, IQVIA, BeiGene  Speakers’ Bureau: AstraZeneca, Bayer, Pfizer, Janssen   Research Funding: PVmed, Decipher Biosciences, EVYD Technology, MVision, BeiGene, EVYD Technology, MVision, BeiGene  Patents, Royalties, Other Intellectual Property: High Sensitivity Lateral Flow Immunoassay for Detection of Analyte in Samples (10202107837T), Singapore. (Danny Jian Hang Tng, Chua Lee Kiang Melvin, Zhang Yong, Jenny Low, Ooi Eng Eong, Soo Khee Chee)       

Drs. Vamsi Velcheti, Taofeek Owonikoko, and Janakiraman Subramanian discuss their experiences navigating the cancer drug shortage in the United States, the impact on patients and clinical trial enrollment, lessons learned, and proactive strategies to mitigate future crises. TRANSCRIPT  Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I'm a professor of medicine and director of thoracic oncology at the Perlmutter Cancer Center at NYU Langone. On today's episode, we'll be discussing the impact of the shortage of cancer chemotherapy drugs across the United States. This has been affecting several thousands of patients with adult and pediatric cancers and hampering enrollment in clinical trials. Among the shortages are very commonly used drugs like cisplatin, carboplatin, methotrexate, and fludarabine. Some of these shortages have persisted since the time of the pandemic in 2020.   So today, to discuss this really troubling scenario, I have two outstanding colleagues, Dr. Janakiraman Subramanian, the director of thoracic oncology at Inova Schar Cancer Institute in Virginia, and Dr. Taofeek Owonikoko, a professor of medicine and the chief of the Division of Hematology and Oncology at the University of Pittsburgh Hillman Cancer Center in Pittsburgh.   Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available at asco.org/DNpod.  So, a recent survey by the NCCN found that 90% of the nation's largest cancer centers have experienced a shortage in carboplatin, and 70% of the centers have reported a shortage in cisplatin. These are platinum-based chemotherapies we use frequently in patients with cancer, and these are often curative intent treatments for several cancers, and these are used in several tumor types, both solid tumors and hematologic malignancies. So, the scale of the problem is immense.   Dr. Owonikoko, I’d like to hear your take on this situation and how are you dealing with this at the UPMC Cancer Center.  Dr. Taofeek Owonikoko: Yeah, thank you, Dr. Velcheti, and happy to be part of this panel. As you rightly surmised, the chemotherapy drug shortage is what we've all experienced across the length and breadth of the United States. Our cancer center here in Pittsburgh is not an exception. We've had to be proactive as well as think outside the box to be able to manage the challenge. Just like every other cancer center across the country, maybe to varying degrees, we've had to look at patients in need of chemotherapy with these standard-of-care agents such as cisplatin or carboplatin, and to some degree docetaxel, during this past episode of drug shortage that we all went through. And while we did not have to, fortunately, cancel any patient treatment, we all went through it with bated breath; not sure of where the next batch of chemotherapy drugs will come through, but I would say in the past couple of weeks, we've actually seen some improvement in drug availability.   But before then, we’ve had to have contingency plans where, on a weekly basis, we review our patient list and the drug regimens that they're going to need, and must make sure that we have enough drug on hand for those patients. And in situations where we thought we might not have enough drug; we also had a plan to use alternative regimens. We were proactive in having guiding principles that are consistent with ASCO's recommendations in terms of quality care delivery for cancer patients. So, I'm sure that this is more or less the same approach adopted by other leading cancer centers across the country.   Dr. Vamsi Velcheti: Thank you, Dr. Owonikoko. And Dr. Subramanian, you're in a community setting, a large cancer center that serves a lot of patients in the state of Virginia. So, what is the scale of the problem at your institution and how are you handling it?   Dr. Janakiraman Subramanian: First of all, Dr. Velcheti, thanks for having me here on this panel. And as you rightly said, this is a significant problem, and it is across the country like Dr. Owonikoko said. And as medical oncologists, we are not always thinking of drug shortages. Our focus is on taking care of our patients. So, this is one more issue that we need to keep in mind now as we manage our patients with cancer. When this shortage started, the biggest problem, as you know, was when we became aware of this was primarily in cisplatin and we had some of our patients who were getting curative treatment and we had to make a decision - can they get cisplatin or can they get carboplatin. And one of the things we did was to have an ethics committee that will review each patient that is being planned to receive cisplatin-based chemotherapy and come to a decision on how best we can support them.   The template for some of this was based upon some of the triage mechanisms we used during COVID, as well as the ASCO guideline document for managing this chemotherapy shortage, which was one of the blueprints we used. And they have reviewed all cases, all patients that are being planned for cisplatin or carboplatin for that matter, and we come to a decision based on that. And we also have another committee that constantly monitors drug availability on a weekly basis and tries to forecast where the next problem would be as we take care of our patients.   And particularly as a lung cancer doctor, we've had situations where we had to use carboplatin instead of cisplatin and even we also have carboplatin shortage. And so, the committee usually approves two cycles at a time, but thankfully so far we have not had a situation where we could not offer our patients the chemotherapy treatment. But we are very carefully monitoring the situation, hoping that this will improve.   The other aspect of the shortage has been in 5FU. A lot of our GI colleagues; I treat esophageal cancer patients as well, where we've had to forego the bolus 5FU and have a 10% reduction on all 5FU infusions. And we've been using some of that dose reduction to ensure that we can have 5FU available for all our patients. And that's how we've been trying to manage this shortage situation here at Inova Schar.   Dr. Vamsi Velcheti: Dr. Subramanian and Dr. Owonikoko, we are oncologists, we are treating patients, and the toughest part really is telling a patient that we don't have access to certain drugs and we have to switch treatments to perhaps another treatment regimen that may be suboptimal. And it's always a very anxiety-provoking discussion, and especially for patients with metastatic cancer, they're already under a lot of stress and it's a really difficult conversation. How do you handle that, Dr. Owonikoko?  Dr. Taofeek Owonikoko: That's a conversation we all hope we don't have to have. And fortunately, with this current crisis, I've actually not had such misfortune of having to inform a patient that we don't have drugs to treat them or that we have to switch to something inferior. But conceptually, it's possible that could have happened and that would have been very difficult. But the one thing that we did, though, as part of our mitigation strategy was actually to inform the patient ahead of time because the way we handled this was to look at our inventory on a week-by-week basis. And if there are patients where we felt maybe they will be coming in towards the end of the week and we may not have enough drugs for them, to let them know the possibility exists that we might have to switch them to something different. While we did not have to do that for any patient, yes, there are patients that we had to give that heads up to, to say, “We're having this shortage. We're doing everything we can to make sure it's available. But just in case it's not available…” I think what is most important for most patients is to be aware of that decision ahead of time, to be able to process it, and to be transparent.   The other challenge that we face was, if you have to choose between patients, what should be your guiding principles as to who gets the drug and who doesn't get it? I think it's very easy for all of us to say, “Oh, if it's curative intent, we do it. If it's not curative intent, we don't do it.” It's a little more complicated than that because if we put the equity hat on, curative intent doesn't actually mean that that life is more valuable than somebody who cannot be cured. And this is where really, I think having people with expertise in ethics of care delivery and disaster management will be very important for us to proactively anticipate that, should this become a recurrent problem in the future that we actually have a well-vetted approach, just like we did during COVID where you have to ration resources that we have those people with expertise to help us as oncologists because not all of us, at least personally I can speak for myself, that is not my area of expertise and comfort.  Dr. Vamsi Velcheti: Excellent points. Dr. Subramanian, anything to add?  Dr. Janakiraman Subramanian: Oh, absolutely. I echo what Dr. Owonikoko said. These are conversations that we would like to hopefully never have with our patients. But this is a crisis that we are facing now. And personally, I can tell you two situations where we ran into this problem. But overall, though, we never had to stop a treatment or cancel a treatment for our patient. In the first situation, we had a young man with a rare germ cell tumor in the hospital for whom cisplatin was key. He was already in the ICU and sometimes the treatment start dates are not perfect, unlike what we do in the outpatient setting, depending on how well he's doing or the treatment start dates might move by a day or so. So we basically had to hold a certain dose of cisplatin for him.   This brings the next question, which is how do we decide who gets cisplatin versus who can go for an alternative option? And I think Dr. Owonikoko made a great point where, just because it is a curative disease does not mean their life is more valuable. This is where I think trying to make that decision at an individual level, as an individual treating physician can be extremely hard. And that's why at our institution we have this ethics committee where we have oncologists, pharmacists, and ethicists that review these chemotherapy orders, particularly for cisplatin, and try to use some guiding principles that we learned from COVID as well as ASCO's guidance to decide how we assign our resources. That's one option, one way we have done it.    And then in another situation that was faced by one of my GI oncology colleagues was a patient that was originally planned to go on a clinical trial where the chemotherapy backbone was FOLFOX and because we had the 5FU shortage, we could not offer that patient clinical trial enrollment. And that was a tough conversation where they had to tell them that they could not go on a clinical trial that they were looking forward to. And this then brings the next question, which is by foregoing the bolus 5FU and by the 10% reduction in the infusional 5FU, are we providing them inferior treatment? And it's a conversation that's had at a very individual level. I don't envy my colleague who had to have that conversation. It's a challenge and we try to do our best to communicate to our patients that we are trying to provide care without trying to compromise the effectiveness of treatment for them.  Dr. Vamsi Velcheti: Thank you so much both of you. And we had the same issues here at NYU in New York City as well. It appears, you know, the degree of shortage and the drugs that are in shortage has been somewhat different at different locations across the United States. But the theme has been that we are having to ration treatments for our patients. And of course, there are some tumor types where there's really no adequate substitution, for example, GU cancers. I mean, you can't really not give them cisplatin. A lot of these are situations which have curative intent and young patients. So, it's really troubling.   And I think one of the things that really came out of this is there's been a lot of push from professional societies that actually ASCO has been spearheading and some intense discussions with CMS and legislators to kind of provide more long-term fix for these things. And I think all of us have to be more engaged in those discussions with our professional societies like ASCO to kind of help promote awareness. So if you kind of think about it, these drugs are not that expensive. These are generic drugs that we've all been using for such a long time. And the fact that we can't provide these drugs for various reasons is kind of really concerning. We spend so much money on research and more expensive drugs and not being able to manufacture these drugs within the country and kind of having to rely on complex supply chains is troubling, and I hope the situation improves very soon.    So, I know both of you are at large cancer centers that enroll patients on clinical trials. Of course, these drugs, especially carboplatin, for lung cancer, especially, are like core treatments that are used in managing cancer patients with lung cancer. So how is this affecting your clinical trial accrual? Are you prioritizing patients on clinical trials for these drugs? Have you had to make any decisions to hold clinical trial accrual for certain trials? Kind of curious to hear.  Dr. Taofeek Owonikoko: Yeah, so I can maybe weigh in a little bit on that in terms of what we've had to do for patients receiving treatment as standard of care versus those going on clinical trials. As we all recognize that when a patient goes on a clinical trial, even if they are going to receive a standard-of-care regimen as part of that trial, it still has to be administered in line with the protocol. So, during the extreme period of shortage anxiety, we actually had consideration for perhaps not putting patients on trial if we're not sure that they will be able to continue to receive the protocol-mandated treatment, whether it's a control intervention or the experimental intervention.   The good thing to come out of this is at least here at UPMC, we actually did not have any instance where we had to deny a patient clinical trial participation. But there were anxious periods when we already had patients enrolled and they were scheduled to receive a platinum-containing regimen and we were not sure whether or not we were going to have adequate supply of the drug for them while on trial. I think this really raises an important consideration going forward as we come out of this current shortage. I don't by any stretch of the imagination assume that this is going to be the last one we experience, but I think the lessons learned here, we have to also carry that forward both in the design of the trial as well as in the regulatory environment surrounding clinical trial conduct, to say, should another incidence of drug shortage are to happen, how do we actually operationalize that with respect to patients on trial, whether starting or already on trial?   I think it's much more challenging when the patient is already on the trial, they've already started. It's less challenging if you just have to make a decision about somebody starting newly on the trial. But equally important is that by not allowing new patients to go on trial is denying something that potentially could be of benefit to them, albeit it is still a trial, it's not an established treatment option yet.  Dr. Janakiraman Subramanian : I completely agree with Dr. Owonikoko. Those were very key points and issues that we face as well. In terms of my patients with lung cancer, we haven't had a problem in getting them on clinical trials. Even though we have had carboplatin shortage patients who are already on treatment, they were able to get the carboplatin. For new patients, we were still able to provide them carboplatin as well. The biggest problem for clinical trials has been primarily with my GI colleagues who have to use 5FU. And there, as I said before, we are unable to give bolus 5FU and there is a 10% reduction of the infusional 5FU. So, we can't have any of these patients go on clinical trials.    And as a result, anything that has to do with 5FU has come to a screeching halt in terms of clinical trials for our patients. And I think I echo the point of Dr. Owonikoko that by no means this is the last drug shortage we're going to be dealing with and we are here today discussing this, also because this shortage has not ended. It's been ongoing. It's one of the longest drug shortages in my memory as a medical oncologist, and that's concerning. We still see that there is some improvement, but we haven't gotten past it yet.     And therefore, as we develop clinical trials and we need to have methods to address drug shortages and how we manage patient enrollment as well as how do we manage existing patients who are already on a clinical trial and, if possible, what might be their options in that situation. We may not have all the answers, but it is definitely an issue that we need to think about in the future as we develop and implement newer clinical trials for our patients.  Dr. Vamsi Velcheti: I completely agree and great points, both of you. And we've had the same issues with clinical trials at NYU Langone as well due to the shortage. It’s been a challenge, and I think this is a problem that's so complex because of supply chain issues and the way the drugs are priced and incentives for manufacturing these drugs in the United States are not lucrative enough to actually onshore a lot of the production of these drugs.   I think at the end of the day, I think we have to come up with some creative, innovative, reimbursement structures for these generic chemotherapy drugs. I think this would require a very complex economic solution that perhaps ASCO and other organizations should kind of really foster an environment of innovation to kind of help facilitate onshoring some of the manufacturing of these key drugs within the United States. I think ASCO is already trying to do that, trying to collaborate with all the stakeholders to kind of address this problem is very critical, and I think all of us have to be engaged in some of the advocacy efforts that are ongoing to kind of address these drug shortages. And this is not a short-term problem.  So, Dr. Owonikoko and Dr. Subramanian, any final thoughts before we wrap up the podcast today?  Dr. Janakiraman Subramanian: So, Vamsi, you mentioned the whole complex supply chain and the fact that we rely primarily on overseas manufacturers to get these drugs that are off-patent but still a key backbone of our cancer treatment. I think those are all key issues that policymakers and leaders in the field have to keep in mind. As an institution at Inova, one of the key mechanisms that have helped us to sort of stay ahead of the shortage was to have this inventory management team that monitors the inventory out there. And in fact, the inventory management team does have access to what the inventory is in some of their main suppliers in terms of the drugs. And they also have an idea of how many patients are going through treatment, what is the weekly usage of a specific drug like carboplatin. And they try to forecast what is coming down the road and try to prepare for it.   And as we try to look for solutions, maybe a forecasting mechanism in a larger scale like either spearheaded by ASCO or by policymakers level that can, for the overall country, try to see where some of the inventory is for some of these critical drugs and try to prepare for it ahead of time, rather than wait till we hit the shortage and then try to find alternative suppliers to get the drug, which obviously doesn't happen quick enough. It takes months or even longer to catch up and get the inventory back to the level where we can comfortably take care of our patients.  I think that is something we should be advocating for that as well as the professional societies should take a handle on that and see if they can support something like that as well as letting the institutions know ahead of time what's coming might be very helpful.  Dr. Vamsi Velcheti: Yeah, very good point, Janakiraman, and I think that's a key takeaway here. I think we have to learn from other industries and try to– I mean this is not unique to healthcare by any means. I mean these chronic shortages due to supply chain issues, inventory management, there might be some learnings from other industries here that we probably should also focus on inventory management and improve supply chain logistics.   Dr. Owonikoko, any closing thoughts?   Dr. Taofeek Owonikoko: Yeah, I agree as well with all the points made by Dr. Subramanian and yourself. This is a chronic problem that requires a long-term strategy. I think it's both an economic problem as well as a regulatory problem. As we all know, part of the reason why we went through this current crisis is the regulatory decision by the FDA regarding safety of one of the manufacturers. So being proactive in terms of how these audits are conducted and giving people lead time I think will help avoid similar situations in the future.    It’s an economic problem. There's a reason why a lot of the big pharma companies are not producing these drugs. And if the cost of production is such that the amount of money you get paid is enough to cover your price, I think there is an economic issue there to be addressed. That is unfortunately not within the scope of what any one of us can do individually, but as advocates in terms of the structure of incentivizing new drug versus old drug, some of these newer drugs are quite expensive, but oftentimes they are used along with standard drugs that are not as expensive. So, where do we strike that balance where we do not stifle innovation but at the same time, we don't create a perverse incentive system where everybody just wants to come up with the newest, most expensive drug and nobody is interested in really producing the backbone chemotherapy and other agents that will make those new drugs work well.   So, I think we have to pay attention. We have to advocate for our patients through our different institutions and organizations, and I hope that society as a whole that we've learned a lot of lessons from this crisis and that will help us craft some long-term strategies.   Dr. Vamsi Velcheti: Thank you both Dr. Owonikoko and Dr. Subramanian for your time today to speak with me and our listeners and for sharing your insights with us on the ASCO Daily News podcast.   Dr. Taofeek Owonikoko: Thank you.   Dr. Janakiraman Subramanian: Thank you.  Dr. Vamsi Velcheti: And thank you to our listeners for your time today. If you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you so much.  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  ASCO Resources Related to Drug Shortages are available here.     Follow today’s speakers:    Dr. Vamsidhar Velcheti    @VamsiVelcheti    Dr. Janakiraman Subramanian  @RamSubraMD  Dr. Taofeek Owonikoko  @teekayowo    Follow ASCO on social media:     @ASCO on X (formerly Twitter)    ASCO on Facebook    ASCO on LinkedIn      Disclosures:     Dr. Vamsidhar Velcheti:     Honoraria: ITeos Therapeutics    Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus    Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline      Dr. Janakiraman Subramanian:  Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Daichi, G1 Therapeutics, Jazz Pharmaceuticals, Janssen Oncology, Lilly, Blueprint Medicines, Axcess, BeiGene, Cardinal Health, Takeda, OncoCyte  Speakers’ Bureau: AstraZeneca, Boehringer Ingelheim, G1 Therapeutics, Jazz Pharmaceuticals, Janssen Oncology  Research Funding (Inst.): G1 Therapeutics, Tesaro/GSK, Novartis, Genentech, Novocure, Merck   Dr. Taofeek Owonikoko:  Stocks and Other Ownership Interests: Cambium Oncology, GenCart, Coherus Biosciences  Consulting or Advisory Role: Novartis, Celgene, Abbvie, Eisai, GI Therapeutics, Takeda, Bristol-Myers Squibb, MedImmune, BerGenBio, Lilly, Amgen, AstraZeneca, PharmaMar, Boehringer Ingelheim, EMD Serono, Xcovery, Bayer, Merck, Jazz Pharmaceuticals, Zentalis, Wells Fargo, Ipsen, Roche/Genentech, Janssen, Exelixis, BeiGene, Triptych Health Partners, Daichi, Coherus Biosciences  Speakers Bureau: Abbvie  Research Funding (Inst.): Novartis, Astellas Pharma, Bayer, Regeneron, AstraZenece/MedImmune, Abbvie, G1Therapeutics, Bristol-Myers Squibb, United Therapeutics, Amgen, Loxo/Lilly, Fujifilm, Pfizer, Aeglea Biotherapeutics, Incyte, Merck, Oncorus, Ispen, GlaxoSmithKline, Calithera Biosciences, Eisai, WindMIL, Turning Point Therapeutics, Roche/Genentech, Mersana, Meryx, Boehringer Ingelheim  Patents, Royalties, Other Intellectual Property (Inst.):   Overcoming Acquired Resistance to Chemotherapy Treatments Through Suppression of STAT3  Selective Chemotherapy Treatments and Diagnostic Methods Related Thereto  DR4 Modulation and Its Implications in EGFR-Target Cancer Therapy Ref: 18089 PROV (CSP) United States Patent Application No. 62/670,210 June 26, 2018 (Co-Inventor)  Soluble FAS ligand as a biomarker of recurrence in thyroid cancer; provisional patent 61/727,519 (Inventor)  Other Relationship: Roche/Genentech, EMD Serono, Novartis  Uncompensated Relationships: Reflexion Medical           

Drs. Douglas Flora and Shaalan Beg discuss the use of artificial intelligence in oncology, its potential to revolutionize cancer care, from early detection to precision medicine, and its limitations in some aspects of care. TRANSCRIPT Dr. Shaalan Beg: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I'm the vice president of oncology at Science37 and an adjunct associate professor at the UT Southwestern Medical Center in Dallas.   On today's episode, we'll be discussing the use of artificial intelligence in oncology, its potential to revolutionize cancer care from early detection to precision medicine, and we'll also go over limitations in some aspects of care. I'm joined by Dr. Douglas Flora, the executive medical director of oncology services at St. Elizabeth Healthcare in northern Kentucky, and the founding editor-in-chief of AI in Precision Oncology, the first peer-reviewed, academic medical journal dedicated specifically to advancing the applications of AI in oncology. The journal will launch early next year.   You'll find our full disclosures in the transcript of this episode and disclosures of all guests on the podcast are available at asco.org/DNpod. Doug, it’s great to have you on the podcast today.  Dr. Douglas Flora: I'm glad to be here. Thanks for having me.  Dr. Shaalan Beg: First of all, Doug, congrats on the upcoming launch of the journal. There has been a lot of excitement on the role of AI in oncology and medicine, and also some concern over ethical implications of some of these applications. So, it's great to have you here to address some of these issues. Can you talk about how you got into this space and what motivated you to pursue this endeavor?  Dr. Douglas Flora: I think, Shaalan, I've embraced my inner nerd.  I think that’s pretty obvious. This is right along brand for me, along with my love of tech. And so, I started reading about this maybe 5, 6, 7 years ago, and I was struck by how little I understood and how much was going on in our field, and then really accelerated when I read a book that the brilliant Eric Topol wrote in 2019. I don't know if you've seen it, but everything he writes is brilliant. This was called Deep Medicine, and it touched on how we might embrace these new technologies as they're rapidly accelerating to ultimately make our care more human. And that really resonated with me. You know, I've been in clinical practice for almost 20 years now, and the same treadmill many medical oncologists are on as we run from room to room to room and wish we had more time to spend in the depths of the caves with our patients. And this technology has maybe lit me up again in my now 50-year-old age, say, wow, wouldn't it be great if we could use this stuff to provide softer, better, smarter care?  Dr. Shaalan Beg: When I think about different applications in oncology specifically, my mind goes to precision oncology. There are many challenges in the precision oncology space from the discovery of new targets, from finding people to enroll them on clinical trials, ensuring the right person is started on the right treatment at the right time. And we've been talking a lot about and we've been reading and hearing a lot about how artificial intelligence can affect various aspects of the entire spectrum of precision medicine. And I was hoping that you can help our listeners identify which one of those efforts you find are closest to impacting the care that we deliver for our patients come Monday morning in our clinics and which have the highest clinical impact in terms of maturity.  Dr. Douglas Flora: You know, I think the things that are here today, presently, the products that exist, the industry partners that have validated their instruments, it's in 2 things. One is certainly image recognition, right? Pattern doctors like dermatologists and people that read eye grounds and radiologists are seeing increasing levels of accuracy that now are starting to eclipse even specialists in chest radiology and CT or digital pathology with pixelated images now for companies like Path AI and others are publishing peer review data that suggests that the accuracy can be higher than that of a board-certified pathologist. We're all seeing stuff in USA Today and the New York Times about passing medical boards and passing the bar. I think image recognition is actually right here right now. So that's number 1.   Number 2, I think is less sexy, but more important. And that is getting rid of all the rote mechanical mundane tasks that pollute your days as a doc. And I mean specifically time spent on keyboard, pajama time, documenting the vast amounts of material we need for payers and for medical documentation. That can be corrected in hours with the right programming. And so, I think as these large language models start to make their way into clinic, we're going to give doctors back 3, 4, 6 hours a day that they currently spend documenting their care and let them pay attention to their patients again, face to face, eye to eye.  Dr. Shaalan Beg: I love the concept of pajama time. It's sort of become normalized in many folks that the time to do your charting is when you're at home and with your family or in your bedroom in your pajamas, cleaning notes and that's not normal behavior. But it has been normalized in clinical care for many reasons, some necessary and just some not maybe so much. We hear about some of the applications that are coming into electronic medical records. It's been many years since I saw this one demo which one of the vendors had placed where the doctor talks to the patient and then asks the electronic medical record to sum up the visit in a note and then voila, you have a note and you have the orders and you have the billing all tied up. It's been at least 4 years since I've seen that. And I'm not seeing the applications in the clinic or maybe something's turning around the corner because for a lot of people, AI and machine learning was just an idea. It was pie in the sky until chat GPT dropped and everybody got to put their hands on it and see what it can produce. And that's literally scratching the surface of what's possible. So, when you think about giving the doctors their pajama time back, and you think about decision support, trial matching, documentation, which one of those applications are you most excited about as an oncologist?  Dr. Douglas Flora: I'm still in the trenches.  I just finished my Wednesday clinic notes Friday afternoon at 4:30 pm, so I think medical documentation is such a burden and it's so tedious and so unnecessary to redouble the efforts again and again to copy a note that four other doctors have already written on rounds It's silly. So, I think that's going to be one of the early salvos that Hospital systems recognize because there's a higher ROI if you can give 400 doctors back two hours a day. It's also satisfying because the notes will be better. The notes will be carefully curated. They may bring in order sets for the MRI with gadolinium that you forgot you wanted to order; the digital personal assistant will get that. It will set a reminder on your calendar to call the patient back with their test results. It will order the next set of labs, and you're going in the next room, and you're going to be watching that patient in the room. And I've talked to other colleagues about this earlier today. You'll be able to see the daughter getting hives because you're watching her or the look that fleets across the husband's face when you go a little bit too far and you go out too much information when they're not quite ready for that. And I think that's the art of oncology that we're missing when we're flying in a room, and we've got our face on the screen and a keyboard, and we're buried in our own task and we're not there to be present for our patients. So, I'm hopeful that that's going be one of the easy and early wins for oncologists.  Dr. Shaalan Beg: Fantastic. And when we think about the spectrum of cancer care for the people who we care for, a lot happens before they walk into their medical oncologist's office in terms of early identification of cancer, just the diagnosis of cancer, the challenges around tissue acquisition, imaging acquisition. You mentioned a couple of the tools around radiomics, which are being implemented right now. Again, same question: Separate fact from fiction, which ones are we going to see in 2023 or 2024 in the clinical practice that we have? We've been hearing that pathologists and radiologists are going to be out of their jobs if AI takes off, right? Of course, that is a lot of hyperbole there. But how do you view that space and how do you see it impacting the overall burden of care that people receive, and the burden of care that physicians are experiencing?  Dr. Douglas Flora: I'm an eternal optimist, almost infuriating optimist to my partners and colleagues. So, I'm going to lean into this and say, burdens are going be reduced all over the place. We're going to have personal digital navigators to help our patients from the first touch so that they're going to have honest and empathetic questions answered within an hour of diagnosis. The information that they're going have at their fingertips with Chatbot 4 or Med-PALM 2 with Google that's about to be released as a medical generative AI. These are going to give sensitive and empathetic answers that don't put our patients on the cliff, you know, that they're falling off waiting for a doctor's visit 10 days down the road. So, I think the emotional burdens will be improved with better access to better information. I think that the physicians will also have access to that, giving us reassurance that we're going down the right path in terms of really complicated patients taking very, very large datasets and saying a digital twin of this patient would have been more successful with this approach and those sorts of things. And those are probably 3 to 5 years down the road but being tested heavily right now in academic settings with good data coming.  Dr. Shaalan Beg: Robotic empathy sounds like an oxymoron.    Dr. Douglas Flora: Yeah, look at the published studies.   Dr. Shaalan Beg: We've all seen the data on how a chatbot can outperform physicians in terms of empathy. I really find that to be hard to stomach. Help me out.  Dr. Douglas Flora: Yeah, we say that, and we say that to be provocative, but no, there's no substitute for a clinician laying a hand on a patient. We talked about how you need to see that fleeting glance or the hives on the daughter's chest and that you've gone too far and shared too much too soon before that family is ready for it. I have no doubt in my mind, these tools can make us more efficient at our care, but don't get me wrong. There's no chance that these will replace us in the room, giving a hug to a patient or a scared daughter. They're going to remember every word you say; I just want it to be the right words delivered carefully and I don't want us to rush it. So ultimately, as we make our care more human, these tools might actually give us time back in the room to repair that doctor-patient relationship that's been so transactional for the last 4 or 5 or 10 years. And my hope is, we're going to go back to doing what we went into oncology to do, to care deeply about the patients in our care and let the computers handle the rote mechanical stuff; let me be the doctor again and deserve that patient's attention and give it right back in return.   Dr. Shaalan Beg: And I think we're hearing a lot of themes in terms of AI helping the existing clinical enterprise and helping make that better. And it's not your deep blue versus Kasparov, one person is going to win. It's the co-pilot. It's reducing burden. It's making the work more meaningful so that the actual time that's spent with our patients is more meaningful and hopefully can help us make deeper connections.   Let's talk about challenges. What are some of the challenges that worry you? There've been many innovations that have come and gone, and health systems and hospitals have resisted change. And we all remember saying during COVID that we're never going to go back to the old ways. And here we are in 2023 and we are back to the old ways for a lot of things. So, what are the major limitations of AI, even at its... peak success that you see, which our listeners should be aware of, and which may worry you at times.  Dr. Douglas Flora: Well, you've actually spoken to why I started this journal. I want to make sure that clinicians are guiding some of those conversations to make sure that guardrails are up so that we're ethical and we are making sure that we are policing bias. It's no secret now you've seen these things – a lot of language models, a lot of the deep learning was programmed by people that look like me and did not include things that were culturally competent. You can look at data that's been published on Amazon and facial recognition software for Facebook and Instagram and others. And they can identify me out of a crowd as a middle-aged white guy, but 60% of the time they will not recognize Oprah Winfrey or Serena Williams or Michelle Obama. I mean, iconic global icons. And with darker skin, with darker features, with different facial features than my white Caucasian, Eurocentric features, these recognition softwares are not as good. And I'm worried about that for clinical trial selection and screening for that. I'm really, really worried about building databases that don't represent the patients in our charge. So bias is a big deal and that's got to be transparent. That's got to be published how you arrived at this decision. And so that would be number 1. Number 2 is probably that we don't have as much. visibility to how decisions are made, this so-called black box in AI. And that's vexing for doctors, especially conservative oncologists that need 3 published randomized phase 3, blinded, placebo-controlled trials before we move an inch. So, there must be more transparency. And that again is in publications, it's in peer review. They say we need real scientific rigor and not to belabor this, but our industry partners are well ahead of us. We're not generally inclined to believe them until we see it because I've got 150 AI companies coming to my hospital system as vendors some of them are worthy great partners and some of them are a little bit over their skis and selling more than they can actually deliver yet. So, I'd like to give that an opportunity to see the papers. There's about 300 produced a day in AI in medicine. Let's give them a forum and we'll duke it out with letters of the editor and careful review.  Dr. Shaalan Beg: I will say Doug, it is becoming hard to separate fact from fiction. There is so much information which is coming across us in medical journals and through our email, through our professional social media accounts that I sometimes worry that people will just start tuning it all out because they can't separate the high impact discoveries from the more pie in the sky ideas. So, tell us more about how we got here and how you see this curve of enthusiasm shifting maybe in the next 6 months or 1 year.  Dr. Douglas Flora: Yeah, it's a great question. And it's rapidly accelerating, isn't it? We can't escape this. It's entering our hourly lives, much like the iPhone did before, or me having to switch from my BlackBerry to a smartphone that didn't have buttons. I felt like I was adapting. And maybe this is what people felt like when Henry Ford was out there, and all the buggy drivers were getting fired. The reality is it's here and it was here 6 months ago. And maybe we're feeling that urgency and maybe it's starting to catch on in general society because the advent of generative AI is easier to understand. These aren't complicated mathematical models with stacking diagrams and high-tech stuff that's just happening in Palo Alto. It's Siri, it’s Cortana. It's my Google digital assistant notifying me that it's time to get on for my next meeting. And those things have been infiltrating our daily lives and our minds quietly for some time. About November 30th when chatbot GPT-3 came out from OpenAI and we started toying with it, you started to see the power. It can be creative, it can be funny, it can articulate your thoughts better than you can articulate them on paper immediately. English students have figured it out. People in marketing and writing legal briefs have figured it out and it's coming to medicine now. It is actually here, and this might be one instance where I think the hype is legit. and these tools will probably reshape our lives.   There have been some estimates by Accenture that 70% of jobs in medicine are going to be altered irretrievably by generative AI. And so, I think it's incumbent upon those of us that are leaders in healthcare systems to at least assemble the team that can help make sense and separate, like you said, the signal from the noise. I know we're doing that here at St. Elizabeth Healthcare. We've got a whole team being formed around this. We have 5 or 6 different products we bought. that we're using to help read mammograms and read lung nodules and read urinalyses, etc. You need a construct to do that appropriately. You need a team of people that are well read and well-studied and able to separate that fact from fiction. I think we're all going to have to work towards that in the next 6 to 12 months.  Dr. Shaalan Beg: Tell me about that construct. How did you, what is the framework that you use to evaluate opportunities as they come through the door?  Dr. Douglas Flora: It's something I think we're all struggling with. As I mentioned, we've got all of these fantastic industry partners, but you can't buy 200 products off the shelf as Epic add-ons as third-party software to solve 200 problems. So, it's interesting, you've just said this. I just shared a piece on LinkedIn that I loved. “Don’t pave the cow’s path.” It's a really thoughtful thing to say, “Before you build an AI solution, let's make sure we're solving the correct problem.” And the author of that piece on Substack said: Let's not use AI to figure out how to have more efficient meetings by capturing our minutes and transcribing them immediately. Let's first assess how many of these meetings are absolutely necessary. What's the real job to be done and why would you have 50% of your leadership team in meetings all day long and capture those in yet another form? Let's take a look first at the structure around the meetings and say, are these necessary in 2023 and are these productive?   So, my thought would be as we're starting this. We're going to get other smart people who are well-read, who are studying, who are listening to experts that do it six months ahead of us, and really doing a careful contemplative look at this as a team before we dive in with both feet. And there are absolutely tools that are going to be useful, but I think the idea, how do we figure this out without having 200 members of my medical staff coming to me saying, you've got to purchase all 200 of these products, and have a way to vet them scientifically with the same rigor you would for a journal before you put out that kind of outsource.  Dr. Shaalan Beg: Doug, thanks for coming on the podcast today and sharing your valuable insights with us on the ASCO Daily News Podcast. We'll be looking out for your journal, AI in Precision Oncology, early next year. Tell our listeners where they can learn more about your journal.  Dr. Douglas Flora: I really appreciate you guys having me. I love this topic, obviously, I'm excited about it. So, this journal will be ready for a launch in early October in a preview. And then our premier issue will come out in January. We're about to invite manuscripts in mid-August. I guess parties that are interested right now go to Doug Flora's LinkedIn page because that's where I'm sharing most of this and I'll put links in there that will lead you to Liebert's site and our formal page and I think we can probably put it in the transcript here for interested parties.   Dr. Shaalan Beg: Wonderful. Thank you very much and thank you to our listeners for your time today. Finally, if you have any insights on if you value the insights a little. And thank you to our listeners for your time today. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review and subscribe wherever you get your podcast.  Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.    Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      Find out more about today’s speakers:     Dr. Shaalan Beg   @ShaalanBeg     Dr. Douglas Flora   St. Elizabeth Healthcare     Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Shaalan Beg:   Employment: Science 37   Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine   Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals   Dr. Douglas Flora:  Honoraria: Flatiron Health   

Drs. Hope Rugo and Kristin Rojas discuss advances in the management of menopausal symptoms, fertility preservation, and bone health for women on endocrine therapy for breast cancer. TRANSCRIPT Dr. Hope Rugo: Hello. I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco's Comprehensive Cancer Center. And I'm also an associate editor of the ASCO Educational Book.   In patients with hormone receptor positive breast cancer, the most common subset of the most common cancer in women worldwide, adjuvant endocrine therapy significantly reduces the risk of recurrence and death. However, prolonged estrogen suppression associated with the use of endocrine therapy can cause life-altering menopausal symptoms, bone loss, and fertility concerns. These issues impact the use of endocrine therapy and potentially breast cancer outcome.    Today, we'll be discussing mitigation strategies to manage the side effects of endocrine therapy, which we hope will improve our patient's quality of life and adherence to treatment with Dr. Kristin Rojas, who addressed these issues in a recently published article in the 2023 ASCO Educational Book. Dr. Rojas is an assistant professor of surgery and a breast surgical oncologist and gynecologic surgeon at the University of Miami Sylvester Comprehensive Cancer Center.    Our full disclosures are available in the transcript of this episode, and disclosures of all guests on the podcast can be found in our transcripts at asco.org/DNpod.    Dr. Rojas, thank you for being on the podcast today.   Dr. Kristin Rojas: Thanks, Dr. Rugo, thank you so much for having me. Thank you to ASCO as well. It's truly an honor to be here with you today.  Dr. Hope Rugo: Your excellent article provides an updated overview of the existing approaches and a little forward thinking for improving the quality of life of breast cancer patients who are receiving estrogen deprivation therapy, a really broad term we use for all the hormone therapy we use in ovarian function suppression in the treatment of breast cancer. And then you had a very nice session education session at the ASCO Annual Meeting discussing these issues. Can you briefly discuss the educational session, your speakers and topics, and then we'll get more into the details of this important topic?   Dr. Kristin Rojas: At our educational session at ASCO this year, I chaired the session and presented on managing the sexual side effects and menopausal symptoms of estrogen suppression. And I had two wonderful colleagues with me: Dr. Matteo Lambertini, who shared guidelines regarding bone-targeted agents and managing bone health during endocrine suppression. And then we also had Dr. Terri Woodard, who is a reproductive endocrinologist from MD Anderson, who spoke on managing fertility concerns, which is a very important topic right now.   Dr. Hope Rugo: Yeah, that's great. And it was such a fabulous session. Our listeners can view it online at asco.org if you missed this session. But let's talk a little bit about what was in your article and what was discussed. First, I think the physical and psychological effects of cancer care we know are critical components of survivorship care. Can you tell me a little bit more about that and how we need to understand that as oncologists?  Dr. Kristin Rojas: So, as you know, as treatment continues to improve, our cancer outcomes are improving and the population of survivors continues to grow. So, I think that for many breast cancer patients, or having the diagnosis of breast cancer, becomes more of a chronic illness and less a life-threatening issue for some. I think that the conversation is now changing from “Will you live?” to “How will you live?” And I was thrilled to see that other big organizations, along with ASCO, are prioritizing managing these important symptoms in survivorship. Because I think that, as most patients will be on some form of estrogen suppression, managing the toxicity of these therapies, as you pointed out, probably does influence treatment adherence, which directly translates to an oncologic improvement. So, it's not just managing these soft symptoms, it actually will have a direct influence on probably overall survival along with disease-free survival.  Dr. Hope Rugo: Yeah, I think that's incredibly important and it's not just about doing the exam and finding out symptoms that might signify recurrence, it's really trying to address the effects of the treatment patients have gotten of chemo and their ongoing treatment with endocrine therapy that's so incredibly important. And now, of course, in medical oncology, we're adding on more agents which add to symptoms. That'll be the topic of next year's ASCO educational session. What do you do with the CDK4/6 inhibitors and managing those. But in more than 80% of women who are on the antiestrogen or various, I'm going to call hormone therapies, for early-stage breast cancer, vasomotor symptoms are a big issue. They're typically more severe in younger patients because of course they have estrogen and we take it away. So, how do we mitigate this problem in patients that can result in poor sleep and impact many aspects of one's psychosocial status? And these issues, not sleeping, of course, you make everything worse.  Dr. Kristin Rojas: Yeah, that's a really important point. And you're right, this is a really common symptom experienced by the majority of patients on endocrine suppression. And not only those patients, but patients with triple negative disease who are put into menopause from chemotherapy, etc., along with women with cancer of other disease sites. And so, as the director of our program at the Sylvester Comprehensive Cancer Center, the program is called MUSIC, which stands for Menopause Urogenital Sexual Health and Intimacy Clinic.    This is a very common symptom that patients often report. And one of the important things about this that I've realized is that hot flashes or vasomotor symptoms can actually have a pretty varied presentation. So, it's not just intense sweating. Sometimes these patients can present with palpitations, panic attacks, and they don't even realize that they're hot flashes. This is an effect of estrogen suppression and it's a central mechanism. So, it's probably related to hypothalamic dysregulation regarding how our body senses temperature changes, but it results in widespread flushing and sweating and those other aspects I told you about.   So, we've known for a long time that there are some behavioral modifications that can help with vasomotor symptoms or hot flashes. But now, we actually do have some pretty effective pharmacologic therapies for these patients as well, for whom behavioral modifications aren't completely helping the issue. Or, as you said, when patients are being woken up all night long with these hot flashes, it totally disrupts how their day goes and disrupts coping with their disease and all the other aspects of their treatment.   So, there's some effective treatments that we have. One of those being cognitive behavioral therapy has been shown to be helpful. The data on acupuncture is mixed, but I'm hopeful about this. And then the pharmacologic therapies we have. Traditionally or historically, clonidine, which is an alpha agonist, has been used along with gabapentin. But I think when choosing a medication to prescribe to a patient for hot flashes, you have to take into account the side effect profile. Clonidine does have some issues with blood pressure rebound, and gabapentin is really only effective in large doses, which can be very sedating for patients.    In the MUSIC Sexual Health After Cancer program, we typically stick to low dose SSRIs or SNRIs. I usually go with venlafaxine at a really low dose of 37.5 milligrams, and I can titrate up. I have patients take it at night in case they feel a little foggy when they first start it. But more recently, we've started using oxybutynin, which is an anticholinergic medication originally FDA approved for overactive bladder. I use the XL formulation, or you can do 2.5 or 5 milligrams BID. And this, in a study a few years ago, was shown to significantly reduce hot flashes and improve quality of life in a placebo-controlled trial.   So, important aspects of side effects of these medications with SSRIs or SNRIs working in the MUSIC Sexual Health After Cancer Program, sexual health concerns are often an issue, so those drugs can be libido zappers sometimes. But, the biggest side effect I've come across with oxybutynin for patients is dry mouth, and usually that resolves after a little while. So, we've had a lot of success in managing patients' hot flashes with these medications.  Dr. Hope Rugo: That's great and incredibly helpful. And I will say that as we're talking about these issues on this podcast, this is really important for all of our staff and our clinics because most of us don't have a fabulous clinic like the one you've started. But we are managing this with our staff, our APPs, and other areas that our patients are seeing. If everybody has this education, it will really help in the management of symptoms. And I just want to point out that venlafaxine was the first drug to be studied in this area really successful, but that we can use a whole host of different antidepressants. If people have side effects from one another, one may work really well, and generally low doses work well. The oxybutynin was such a very cool study. I think that's a great additional option.    In addition to hot flashes, we also see genitourinary syndrome of menopause, and that's part of what you deal with every day in your clinic, GSM. And this can be not just vaginal dryness, which is bad enough, but also increased infections, painful sex, recurrent bladder infections and also reduced libido, which is a really big issue, we just don't talk about very much. What's the most effective and safe treatment for GSM? And we use a lot of low dose vaginal estrogen and a variety of delivery mechanisms. What are the risk and benefits when patients really need something more?   Dr. Kristin Rojas: GSM, or genitourinary syndrome of menopause, is this newer umbrella term for what we used to call vaginal atrophy. And you're right, it encompasses not only dryness, but all the other changes that can happen to the vulvovaginal mucosa along with anatomic changes to the pelvic floor. This is critically important, I think, that we address these issues or these potential side effects at the time of endocrine therapy prescription because what we have found in our program is that while hot flashes might get better, these symptoms do not get better. And left untreated, they get worse.   And one of the surprising findings that we have presented earlier at another conference this year was that almost half of our patients, when they had their pelvic exam in the program, were also found to have vaginal stenosis. So narrowing and shortening of the vagina, making penetrative sex actually impossible. So it's really not just dryness, but a host of these other symptoms that go along with that. I like to break this down in a really simple way because I know that a lot of providers may be intimidated when patients might bring this up. But I think about it this way. Number 1, eliminate irritants. Number 2, moisturize. Number 3, lubricate. And 4, address the pelvic floor.   Oftentimes when patients present in the MUSIC program, they've been putting a lot of over the counter topical therapies on the vulva and the vagina using intravaginal washes. One of the biggest offenders of some of these symptoms is artificial fragrance, which we can actually develop an allergic reaction to, which manifests as burning and stinging. So these patients may also report burning and stinging in addition to dryness. These offenders can be in all kinds of products. So not only feminine washes, which I don't recommend in our program, but things like bath bombs, bubble bath, toilet paper. And so we kind of go through an inventory of everything that's touching the delicate tissues of the vulva and the vagina and try to back off those products.   The second thing is moisturization. It's important to talk to patients about the difference between moisturization, which I say is for maintenance, and lubricants, which are for PRN use sexual activity. But I tell patients, "lubricants for love." That's how I differentiate the use of these two different types of products because they have different properties. Usually after eliminating irritants, our first step is to start with a non-hormonal moisturizer because there's some really good high-tech non-hormonal moisturizers out there, specifically those containing hyaluronic acid, which pulls moisture from the environment and holds it on the skin. And by using this first—this is my personal opinion—but I think by improving the mucosa a little bit and kind of improving the dryness, maybe even the elasticity a little bit, I think that when patients do have persistent symptoms after using regularly these non-hormonal moisturizers at least three times a week, that adding in a low dose vaginal hormone at that time, instead of putting it on completely atrophic mucosa, you're putting it on kind of like a pretreated mucosa, which I think might decrease systemic absorption.   I'm so glad you brought up vaginal estrogen. I could give an entire talk just on that, so I’d be happy to do that next year for ASCO if anybody wants. But it is very controversial. Historically, there have not been studies showing an increased risk of recurrence with the use of local estrogen therapy, so estrogen in the vulva and the vagina. However, there was a recent study that came out this year that was a large analysis of breast cancer patients receiving different types of hormone therapy. And in a subset analysis of the group who got local vaginal estrogen, just in those patients on aromatase inhibitors, there was a slightly, but statistically significant–according to their analysis–increase in the risk of recurrence. I think there's some issues with this analysis because it was a large study and there's a lot of recall bias and measuring this in patients is really challenging. But I think it's still important to mention because a lot of patients are going to read about those things, these types of studies.   The way I approach it is to start with the lowest dose and I start with infrequent dosing. If patients have persistent symptoms, I start them with once a week or twice a week, which is different from the original pharmacokinetic studies of higher dose estrogens, which showed a bump in their serum estradiol when they used it every night for two weeks. So I actually do the opposite and taper them up. I'll do once a week to twice a week. And usually, patient symptoms are resolved at that point.   But I do want to point out, that's a great option for patients on tamoxifen because mechanistically, as you know, it probably doesn't matter if they have a little bump in their serum estrogen. But for the patients on aromatase inhibitors, we actually have a new kid on the block, a vaginal androgen called prasterone or DHEA. I dose this in the same way, titrate it up. But this can be really helpful for patients on aromatase inhibitors because the ALLIANCE trial showed that for those patients on AIs that their systemic estrogen levels do not increase. And so that's kind of how I manage that discussion. I do think it takes some multidisciplinary collaboration, so I always involve my medical oncology colleagues on this.    Lastly, lubricants. So, everyone seems to be really into using water-based lubricants, but I try to tell patients, unless you're depending on condoms for STD or contraception protection, silicone-based lubricants that are like preservative-free and don't have a lot of those gimmicks or additives, are great—they stay slippery for longer—and there's some really great brands out there. And then for patients who still have persistent pain with sex, we address the pelvic floor, which is either through the use of dilators, referring them to pelvic floor physical therapy, or other sexual devices that we use in the MUSIC program.  Dr. Hope Rugo: This is really helpful, and I think that for many of us in practice, we really want to get the specifics of what you use. I think this prasterone, the idea of DHEA is really very interesting and something that personally I haven't used, but we did use in the distant past before there was an FDA-approved version.   So I guess I have several questions just to ask about the details. So one is, when you prescribe this, do you find it's generally covered by insurance? And when you say low dose, do you mean just try it once a week? And then do you use the estrogen tablets, the brand names are often Yuvafem or Vagifem, we often use those twice a week. How often do you use them and do you use the estrogen ring also? What are the absolute specifics of what you're recommending to these women? And do you feel like sometimes in patients who are developing these symptoms that early use can help avoid the more severe symptoms and therefore reduce the exposure?   And lastly, just to say, that paper which was so interesting about the slightly increased risk of recurrence, I felt was so flawed in terms of what people were using and if they were taking their hormone therapy and risk of recurrence, the risk of the cancer itself, that I really felt like I couldn't make anything out of it in terms of the risk to patients. But I'm really interested in your specific recommendations.  Dr. Kristin Rojas: Thanks for asking about specifics. And I'm happy to give our treatment algorithms here, which we also discussed in our session and we listed in our EdBook manuscript. We do pelvic exams in the MUSIC program and I often find that there's very specific points in the vestibule or the opening of the vagina that are tender and have pain, specifically, what's known as the posterior fourchette, which is the kind of connection between the right and the left side towards the posterior aspect. So, I usually start with a 1% estradiol cream and have patients tap it to the outside and then bring in a dilator and have patients use not only a silicone lubricant, but put some of the estradiol cream on the dilator. And so that brings the product up to the top of the vagina for patients that have some of those anatomic changes that I discussed.   So this is 1 option, and we really don't have a lot of issues with insurance authorization for the cream, just every once in a while. We can also use a 4 microgram or a 10 microgram dose of estradiol, which is a tablet, which are newer options. This is in contrast to the old pharmacokinetic studies that use 25 micrograms. So this is much, much lower. I do run into some prior authorization issues with those because there tend to be newer versions of this. But as you mentioned, the estradiol ring, which I do think is a great option and when you calculate it out, releases a very low dose of estradiol every day. And it's good for patients who want a more low maintenance regimen. The only challenge I've had with that is it's a large rigid ring. And for patients who already have those anatomic changes, it can be really hard to place that in the vagina.   And so, just like you said, early prevention and treatment of these issues can prevent not only anatomic changes, but even potentially the need for exposure for larger doses of hormones. For all of those options, I tend to do it once or twice a week and then can move up. But we sometimes get kind of creative in how we use these options in terms of placing them on the dilator, placing them externally. For patients that have recurrent urinary tract infections, I also have them kind of tap some of the estradiol cream around the urethra as well to improve the urethral and potentially bladder microbiome and decrease risk of recurrent UTIs.  Dr. Hope Rugo: That's really interesting, and I think those specifics are incredibly helpful. We also will check, although I have to say there's no data to support it, the serum estradiol levels in patients who are using more than our minimal amount. We have plenty of studies that have shown that there really isn't systemic estrogen if people are using very low doses. But we will check sometimes, just sometimes people use these topical creams where they get premenopausal levels of estrogen, which of course we don't want. So, this is an incredibly helpful and useful discussion.    One of the other things that happens for these patients and our younger patients, which breast cancer is still increasing in small numbers in younger patients every year, and many of these patients have hormone receptor positive disease. And it just breaks your heart to see a 38-year-old who is planning to get pregnant next month with their new partner who develops a hormone receptor positive breast cancer. and we want to give people all the options they possibly can. We are strong proponents for harvesting eggs and either freezing eggs or embryos before you start treatment. And we figure we always have 2 weeks for breast cancer. We also use ovarian function suppression during chemo just for whatever help it might have.   But then after patients have finished their treatment and they're on hormone therapy, it's a really big issue for women about when they can have a child because we don't want to wait until they're 45. So, you had noted in your article that some women could take a break from endocrine therapy after 18 to 24 months to try and conceive. Can you tell me a little more about that?  Dr. Kristin Rojas: Sure. Well, this aspect of our discussion was very well presented by my colleague, Dr. Terri Woodard from MD Anderson, a reproductive endocrinologist, and she also put together the aspect of this for our manuscript. She talks about how fertility counseling and referral is probably underutilized, but definitely indicated for most of these patients who are of pregnancy age or premenopausal status. And observational data for a long time didn't show that pregnancy after treatment worsened oncologic outcomes. However, patients as well as many providers had reservations.   So, it's been very helpful that we now have a prospective, large, international trial known as the POSITIVE trial, the early results of which came out earlier this year, which showed that women, after 18 to 24 months, could interrupt endocrine therapy and did not have a worsened short-term oncologic outcome. And those are women with early-stage breast cancer. However, there is a concern that many patients do take longer to get pregnant in that age group or after treatment, potentially if they've received chemo. There is a concern about the duration of time that they're not on endocrine therapy afterwards, which might be further clarified in later analyses. So that's my takeaway from that study, which did show us that very helpful, reassuring information. But I think we're still waiting for the long-term data and it's definitely still a very important patient-centered discussion.   Dr. Hope Rugo: This is a really excellent point, and I think that one of the things of a trial like this, which is sort of a registry study, is that we're always going to speak with our feet to some degree. So, if patients have very, very high risk of recurrence and highly proliferative disease, we might not want them to stop at 18 months because their risks are so high early. So, it has to be a risk versus benefit discussion for individual patients, of course. But I think this data was incredibly reassuring.   It was interesting there were some patients who hadn't restarted their endocrine therapy. In the paper in the New England Journal, it told us that some of those patients were still trying to conceive. But one of the things that's going to be really important for these patients is to really make a big effort on the part of our clinical practices to get patients to restart their hormone therapy. It's very hard to do that, as you can imagine, in that setting.    Another area here is monitoring bone health. And I know that's not part of the MUSIC clinic per se because you're really focusing on GSM and other areas that we've just discussed, which are so incredibly important. And it's funny, bone health is silent, right? So, although some patients don't want to take aromatase inhibitors because they're worried about losing further bone density, they don't feel it. So that's, of course, a different kind of a toxicity. But we know that by suppressing ovarian function in young women, we cause a lot of bone loss, and in older women, already in menopause, that this continuous loss of bone increases the risk of fractures, which can be a huge impact on quality of life and even survival in some cases. So, we're really interested in trying to prevent bone demineralization and reducing the risk of fractures. I believe that Matteo Lambertini from Italy discussed this in your paper and that there's a lot of discussion about use of denosumab and zoledronate. I wonder if you could just comment a little bit on that in our last couple of minutes.  Dr. Kristin Rojas: Well, as you said, my colleague Dr. Lambertini put this aspect of our paper together, but he did put together a very nice summary of bisphosphonates and denosumab and separated their use by premenopausal and postmenopausal patients because the data surrounding those patient populations is slightly different or nuanced. But as you mentioned, it is important to monitor these patients' bone density. We have our standard recommendations such as a calcium-enriched diet, resistance and weight-bearing exercise, and vitamin D for patients, for those patients with a vitamin D deficiency or at risk of bone density loss. And so these pharmacologic agents can also help decrease bone mineral density loss and potentially decrease or likely decrease bone recurrences, which, as we know, influences survival. I think he provides a very nice summary of that, as you mentioned.  Dr. Hope Rugo: I think that's so incredibly important. And thank you for really emphasizing the weight-bearing exercise and checking vitamin D and making sure patients are taking vitamin D and at least some calcium. And then, of course, our institution, we work closely with our endocrinologists specializing in bone as well, when issues come up about risk of osteonecrosis of the jaw, and we require dental clearance for everybody starting medication just to make sure that we've reduced risk to the patient. And then when we're trying to think about stopping denosumab and should we bridge with zoledronate to reduce the risk of fracture, we also talk to our bone doc. So it's really important.   And in our last just 1 minute, I know you were thinking of saying something about measuring estrogen in the blood in patients who are using vaginal estrogens. Do you do that?   Dr. Kristin Rojas: Yeah, great question. I'm glad you brought that up. We actually don't routinely do this in the MUSIC program, but it is an important aspect to think about today, because I don't know about where you are, but here in South Florida we have a lot of patients who are receiving therapies outside of the FDA-approved space and these are typically marketed as bioidentical hormones, which is a marketing term. Oftentimes, they'll get either transdermal formulations or pelleted hormone therapy that can result in really high superphysiologic testosterone or estrogen levels. And so we typically, for those patients, do try to get them off those non FDA-approved therapies because the safety of those is unknown.   Dr. Hope Rugo: That's really interesting and so helpful. Yes, I know this whole idea of bioidentical hormones drives me crazy, but I think that's great that you brought that up, actually. We do measure it. Who knows? I think if you're really worried, measuring “Yeah, everybody's hot flashes went away,” it's probably worthwhile checking.   This was such a fabulous conversation. I learned so much. We really appreciate your contribution to the educational manuscript, to the educational program, and your fabulous insights with us today. Thank you so much for participating on the ASCO Daily News Podcast. I think everyone will find this very helpful.   Dr. Kristin Rojas: Thank you so much for having me.   Dr. Hope Rugo: And thank you to you, our listeners, for joining us today. You'll find a link to Dr. Rojas and her colleagues' article in the transcript of this episode and in the 2023 ASCO Educational Book, which features practice-changing oncology research and a wide range of compelling studies on quality and equitable cancer care.    Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thanks again.    Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Follow today’s speakers:   Dr. Hope Rugo  @hoperugo  Dr. Kristin Rojas  @kristinrojasmd    Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Hope Rugo:  Honoraria: Puma Biotechnology, Mylan, Samsung Bioepis, Chugai Pharma, Blueprint MedicinesConsulting or Advisory Role: Napo PharmaceuticalsResearch Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Odonate Therapeutics, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Ayala Pharmaceuticals, Astellas Pharma, Seattle Genetics, Macrogenics, Boehringer Ingelheim, Polyphor  Dr. Kristin Rojas:   Honoraria: Pacira Pharmaceuticals  Consulting or Advisory Role: Roche Diagnostics, Merck  Research Funding (Inst): Bristol Myers Squibb Foundation       

Drs. Pedro Barata and Naomi Haas discuss the emergence of clinical trials investigating triplet combinations in advanced renal cell carcinoma, factors that influence treatment decisions, strategies to personalize therapies in the frontline setting, including response-adaptive treatment strategies, and the use of biomarkers such as gene expression analysis to guide initial therapy. TRANSCRIPT Dr. Pedro Barata: Hello, I'm Dr. Pedro Barata. I'm your guest host of the ASCO Daily News Podcast today. I'm an associate professor of medicine and also a GU medical oncologist at University Hospital Seidman Cancer Center, Case Western University in Cleveland, Ohio. I'm also an associate editor for the ASCO Educational Book. Today I'm really delighted to welcome Dr. Naomi Haas, the director of the Prostate and Kidney Cancer Program at the Abramson Cancer Center and professor of medicine at the University of Pennsylvania.  Welcome, Dr. Haas. Dr. Naomi Haas: Thank you, Dr. Barata. It's a pleasure to be interviewed. Dr. Pedro Barata: Thank you. As you know, we've seen significant strides in the frontline treatment for patients with advanced clear cell renal cell carcinoma (RCC), and there are multiple doublet regimens that are now the standard of care for those patients. The goal for us to chat today is to discuss the emergence of clinical trials that are really investigating triple combinations and the factors that influence treatment decisions around triplet combinations for patients with advanced renal cell carcinoma. I want to congratulate you for the great work that you did in a recently published article in the 2023 ASCO Educational Book. So thank you for your contributions. And just before we get started, I just want to highlight that our full disclosures are available in the transcript of this episode. So, Dr. Haas, again, it’s great to have you. Thank you for taking the time. Let me get started. So, we know that there are multiple standard of care doublet regimens, all of them immunotherapy-based combos, and they usually include 1 checkpoint inhibitor or 2, such as ipilimumab plus nivolumab or a combination of an immune checkpoint inhibitor with a VEGF TKI. And we have a number of examples like that. Can you tell us about the trials that have emerged exploring triplet therapies in the first-line setting for patients with advanced RCC? Dr. Naomi Haas: Sure, and I'm going to focus just on triplet therapies that are just about ready to go. But as you know, Pedro, there are probably many different combinations that we'll see in the future. Some of the combinations that have already been conducted as clinical trials include combinations of VEGF receptor tyrosine kinase inhibitors along with immune checkpoint inhibitors. I'll highlight one which was batiraxcept plus cabozantinib and nivolumab, and it's a combination of VEGF inhibitor, immune checkpoint inhibitor, and also an AXL inhibitor. So, most of these capitalize on other vulnerabilities with renal cell carcinoma.  So, as you said, they build on the tyrosine kinase inhibitor pathway or on the immune checkpoint inhibitor pathway. Some of them are combining drugs such as CDK inhibitors. There was axitinib plus nivolumab plus palbociclib trial that is getting ready to launch. Others are combining the use of belzutifan, which is a HIF inhibitor in combination with VEGF inhibitor and immune checkpoint inhibitor. There are a couple of those that are ongoing, one of them looking at combinations with lenvatinib. And I think there are also trials getting ready to launch that are using it in combination with cabozantinib and nivolumab.  Additionally, another very interesting direction is trying to affect the gut microbiome. And there was a clinical trial presented by Dr. Monty Pal at the gut microbiome session at ASCO, which combined CBM-588, which is a probiotic, in combination with cabozantinib and nivolumab. And that showed an improvement in progression-free survival compared to the combination of cabozantinib and nivolumab alone. And previously there was work published using CBM-588 in combination with ipilimumab and nivolumab. So that's an area of high interest to patients. But most of these combinations capitalize on either vulnerabilities, signs of resistance in pathways or in adding other pathways that have previously been unaddressed in renal cell carcinoma, and are combined with pathways that we know are effective. Dr. Pedro Barata: Wow, that's a fantastic overview of some of the approaches being considered in the frontline, so thank you for that. And actually to your point, some of them we've seen some data, others more later stages of development. So with that in mind, we also know that we have on one side of the story we have how much of these combos of triplets can actually be effective and help patients. From the other perspective is about tolerability, treatment options, and patient health. They're both very important considerations.  Can you tell us a little bit about the safety profile of these triplet combos? I know we're talking about many different things. The microbiome triplet has a different safety profile than perhaps a combination with a TKI and different checkpoints, for instance. Can you tell us a little bit about what we expect from the safety profile when we start to combine these therapies in the upfront setting?  Dr. Naomi Haas: Sure. I think 2 of the very tolerable triplet regimens have been the combination of the CBM-588 in combination with ipilimumab and nivolumab. Really in those combinations, the authors at least have demonstrated that there has not been a great difference between the two study arms of either the doublet or the doublet in combination with the CBM-588 trial. And that's based on basically changing the bacterial flora of the gut. The Avera trial, which was using the AXL inhibitor in combination with cabozantinib and nivolumab, also seems to have a very tolerable safety profile. Now, this trial was not compared to sort of a standard of care arm, so it's a little bit difficult. A standard of care arm that I would have considered for this clinical trial would have been to use either cabozantinib alone or cabozantinib with nivolumab. Instead, this was more of a dose-finding protocol. So, more work needs to be done with that, but the side effects of that combination additive to what we already know seem to be just infusion reactions from the AXL inhibitor.  The trial that got the most attention so far has been COSMIC-313, which was combining cabozantinib with ipilimumab and nivolumab upfront. And of course, the concern with this triplet combination was that there was more hepatotoxicity seen and it was difficult to know whether the hepatotoxicity was from the combinations of the immune checkpoint inhibitors or the use of the cabozantinib. And although the trial showed an improvement in progression-free survival, it did not show as many complete responses as the comparator arm. And the other concern was that there was quite a bit of dropout due to toxicity. And of course, we don't have the overall survival endpoint for that trial yet. Dr. Pedro Barata: Great, thank you for that. I agree completely. We've seen many different safety profiles with these different triplets.  Let me touch base on a slightly different topic, and that has to do with what kind of strategies can we think to personalize treatment for clear cell RCC in the frontline. And this is not necessarily applicable only to triplet therapy. There are also some efforts with doublets, but the goal is, I would argue, is response adaptive treatment strategies or even the use of upfront biomarkers such as gene expression analysis, for example, to help us guide initial therapy. Can you give us an idea what your thoughts are about what is coming? What do you think the future will look like in terms of developing this like a biomarker-based approach? What kind of factors or markers we can use to select who gets what in the frontline setting? Dr. Naomi Haas: Sure. So, I’ll just highlight ahead of that that one important biomarker that we’re already using is the IMDC criteria, which I think if that algorithm had not been developed, we would be struggling a lot in renal cancer and that’s, of course, the algorithm that uses the thing such as performance status, hemoglobin, calcium, and time for the development of metastatic disease as well as the neutrophil count and the platelet count. And that has helped us divide categories of patients with clear cell renal cell carcinoma into poor risk, intermediate risk, or favorable risk categories. And that was recently validated in the immune therapy combinations that were previously been validated just in VEGF inhibitor therapies.  But the other useful, let’s start with clinical tools that I think are going to be very important are the health-related quality of life tools which primarily measure things such as functional health, as well as toxicity. And one of these is the FKSI-19 score which captures most renal disease-related symptoms, treatments, side effects, and functional well-being. And this has been implemented in some trials and are looked at over time whether the patient’s functional status improves. And patients who are responding to therapies generally will improve as far as their overall well-being. Although that can be difficult as a tool because if patients are experiencing toxicity, those signs might not be apparent. But that’s one tool that’s being used.  Now, people, both patient advocates and patients, have pointed out that it’s very hard to use a tool like this in real life to implement in clinic, but there are efforts being carried out to make these tools a little bit easier so that people can use them day-to-day. So, I can see that being implemented more often.  The others have to do with response assessments, and I think it’s very important to look at immune-related responses which kind of builds on the resist response, but it uses two dimensions of measurement as opposed to one dimension of measurement. And looking at those, we know now that patients who have what we call a deep response, so something better than a 75% shrinkage or even a 90% shrinkage in a very short period of time tend to be those patients who behave like patients who have complete responses. And both progression-free survival and overall survivals seem to be going in a very encouraging way looking at these tools so you could see that this tool could be implemented in real life with treating a patient and if they have a very deep response quickly, you can feel, the physician or the APP, could be very confident that the patient is going to do well for a long period of time. I think the tools that we’re waiting for the most, however, are as you said, the biomarker tools. And this is where we still have a lot of work to do, but one example of this is the transcriptomics which has been conducted in both the atezolizumab-based trials such as the IMmotion trials, and also to some extent with the JAVELIN trials, the avelumab and axitinib trials. And this goes back to looking at the tissues sample and looking at transcriptomics which show mRNA expression as well as some alterations in some of the important genes such as BAP1 and PRBM1.  And those tools have been implemented, especially in the IMmotion trial, there were 7 clusters identified, and two of the clusters are groups of patients whose tumors have transcriptomics that indicate that they would respond well to a VEGF inhibitor. And a couple of them also showed very good responses to immune checkpoint pathways. There were additional pathways which suggested that patients wouldn’t be responsive to either of these. And there is a trial called OPTIC that is funded by the Department of Defense (DOD) which is currently applying these transcriptomics, and then assigning patients to get either a VEGF IO therapy combination or a dual immune checkpoint inhibitor combination, based on their transcriptomics.  And I think what everybody would really like to see is, number 1, that these transcriptomics consistently bear out that there isn't irregularity in using these as predictors. So, they do need to be validated. But I think if there was a quick and easy way to do this, to assign patients to therapies based on these profiles, that would perhaps go a long way in predicting what therapy a patient should start with.  Another useful tool is the development of artificial intelligence. And there are a number of companies that are looking at these tools. We're implementing this retrospectively in the ASSURE trial, which was the adjuvant seraphinib synontib or placebo trial, for patients at high risk for RCC. And we're working with a company to identify, using AI, looking at the slides. And I think that if these kinds of techniques, which are already being used in prostate cancer, are something that can be developed, then what I could see in the future is that a patient's slide could be tested very quickly, and that that might also indicate things that perhaps we can't see under the microscope, as far as either a response to treatment or a risk. So, you could use that in the adjuvant setting to predict whether a patient might need adjuvant therapy or not. So I can see those being implemented.  And then the third is looking at cell-free DNA. And there are many different mechanisms that have been tested in other solid tumors, using either circulating tumor DNA or cell-free DNA. Now, the circulating tumor DNA seems to be a little bit more difficult to assess in metastatic kidney cancer because it doesn't have the mutational burden and doesn't seem to have as many mutations and things floating around that can be captured. However, cell-free DNA, which has the capability of measuring DNA methylation profiles, does seem to be showing some promise, and there have been some publications.  So this has also been tested in cancers of all stages and can be measured in both the plasma and in the urine. And that could be another helpful tool that needs to be validated, but that could be used to start a patient on treatment. And if the amounts of cell-free DNA went down with therapy, that could be a good indication, perhaps in advance of imaging, that a patient is doing well with therapy.  So those are some examples that I see potentially being used in the future to help direct therapy, provided that we can make these tools, that we can validate these tools, and secondly, that these tools are relatively inexpensive and that they're nimble, that they could be used right away, that it wouldn't take a long time to get the results back to help guide. Dr. Pedro Barata: For sure. I couldn't agree more. What a masterclass of all the emerging tools that are being investigated in RCC, this is fantastic.  So, I guess maybe one last question before I let you go. We have now a number of doublets, we have perhaps a triplet, if not more. If you were to guess, who do you think will be the ideal population for a triplet therapy? Some, in addition to all the tools you mentioned, maybe sarcomatoid features, etc. that might be part of the AI complement to what you mentioned earlier. But if you were to guess, do you think that 5 years from now, we're going to be offering a triplet therapy, whatever that triple therapy might be, to everybody, to certain populations? What can you tell us to help us predict what might happen in the near future to make us think about a thoughtful, shared decision-making process and try to predict who might be the ideal population for triplet therapy? Dr. Naomi Haas: So, I don't think we're going to use triplet therapy in everybody. And in fact, I hope we don't use triplet therapy in everybody because I have patients who have responded to single-agent nivolumab and remained in a continuous CR many years after they were treated that way. And I have other patients who really progressed very rapidly or relapsed very quickly after doublet therapy combinations. So, I think that what I would see in the future would be using the triplet therapy combinations in the challenging patients, the patients who we know we're not getting as far along with the doublet approach. And that's really our challenge. And I would see that perhaps some of this transcriptomics which indicates that there are subsets of renal cell carcinoma which are not going to respond well to a VEGF inhibitor or to an immune checkpoint inhibitor, that those are areas where there might be other relevant pathways where maybe the signal isn't quite as good with– maybe they have some response, but not an optimal response. And then combining another pathway into that would be a way forward to achieve a complete response in those populations.  I also want to emphasize that it may be that triplet therapy isn't the way to go, but that triplet therapy can be more of an adaptive design where a doublet therapy is started, and then the third drug, a triplet, is added at a later time. And an example of that is PDIGREE, which is the combination of ipilimumab and nivolumab. And then following imaging, patients are assigned, depending on the response, to get either cabozantinib alone, cabozantinib with nivolumab, or to continue on just nivolumab alone. And that might be a better way to address toxicity. But some of these other triplet combinations, one could also see- you could start, for example, with ipilimumab and nivolumab, and if they were having a response but you wanted to heighten the response, maybe adding the CBM-588 as an adaptive response or adding a CDK inhibitor, but sort of staggering the combination so that you spare patients some of the toxicity. So, I think all of those approaches need to be tested. Dr. Pedro Barata: That is fantastic. Dr. Haas, this is an incredible podcast. You did highlight several triplet combinations that are currently under investigation. You highlighted very, very important ongoing clinical trials. You touched base on what the future might bring as far as tools that might help us decide or optimize patient selection. We talked about adaptive designs. So really outstanding work. And also, I think this reflects the fantastic work in the manuscript that you wrote in the 2023 ASCO Educational Book.  So, thank you so much, Dr. Haas, for the incredible work that you have done and you continue to do in the GU field, and for taking the time to share your insights with us today on the ASCO Daily News Podcast. It's truly been a pleasure to chat with you today. Dr. Naomi Haas: Thank you.  Dr. Pedro Barata: Thank you again. And thank you also to our listeners for joining us today. Really happy with talking about this topic with Dr. Haas. You can also find links to the studies that we discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast.  So again, it has been a privilege to be here today with Dr. Haas. Thank you for joining us and have a good day.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today’s speakers:  Dr. Pedro Barata @PBarataMD Dr. Naomi Haas   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures:  Dr. Pedro Barata: Honoraria: UroToday Consulting or Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, AVEO, Dendreon Speakers’ Bureau (Inst): Caris Life Sciences, Bayer, Pfizer/Astellas Research Funding (Inst.):  Blueearth, AVEO, Pfizer, Merck   Dr. Naomi Haas: Consulting or Advisory Role: Pfizer, Merck Sharp & Dohme, Calithera, Eisai, Exelisis, AVEO, Roche/Genentech Expert Testimony: Lilly

Drs. Shaalan Beg and Shiraj Sen discuss notable advances in GI cancers featured at the 2023 ASCO Annual Meeting, including the PROSPECT and PRODIGE-23 trials in rectal adenocarcinoma, the MORPHEUS study in uHCC, and the NORPACT-1 trial in pancreatic head cancer. TRANSCRIPT     Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host for the podcast today. I'm the vice president of oncology at Science 37, and I'm an adjunct associate professor at UT Southwestern Medical Center. My guest today is Dr. Shiraj Sen. He is a GI medical oncologist and the director for clinical research at NEXT Oncology in Dallas.   Today, we'll be discussing practice-changing studies and other key advances in GI cancers that were featured at the 2023 ASCO Annual Meeting.   You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the podcast are available on our transcripts at asco.org/DNpod.   Shiraj, it's great to have you on the podcast today.  Dr. Shiraj Sen: Thanks so much for having me today, Shaalan.  Dr. Shaalan Beg: We saw exciting new data and great progress in GI oncology at the ASCO Annual Meeting. I was hoping we could talk about LBA2. This was the PROSPECT study that was presented during the Plenary Session. It's a randomized, phase 3 trial of neoadjuvant chemoradiation versus neoadjuvant FOLFOX chemo, followed by the selective use of chemoradiation, followed by TME or total mesorectal excision for the treatment of locally advanced rectal cancer. This is the Alliance N1048 trial. What are your thoughts on this study?  Dr. Shiraj Sen: Thanks, Shaalan. It was great to see another GI study presented in a Plenary Session, and I thought this was a great trial that really took us back to thinking about why we do chemoradiation as well as chemotherapy perioperatively in locally advanced rectal cancer. And asking the important question of is there a select patient set or subset where we might be able to safely omit the chemoradiation piece.  To me, the impressive part was this study enrolled from 2012 to 2018. In 2012, when this treatment really started enrolling, the standard of care was long-course chemoradiation for five and a half weeks, followed by surgery, followed by adjuvant chemotherapy with FOLFOX or CAPOX. During this time, a lot of the practices of these patients have shifted from that to giving total neoadjuvant therapy, where we bunch the chemotherapy and chemotherapy upfront prior to the patient undergoing surgery. And this study really asked us to take a look at both practices and ask the question of which one is better and is it possible to de-escalate care for patients who get upfront chemotherapy and omit the chemoradiation and still have similar outcomes.   I thought it was very interesting that this was done in a non-inferiority-type manner, and we can talk more about that in a few minutes as well. But taking that all into context, the fact that in this study, that the non-inferiority endpoints were met for both disease-free survival as well as overall survival in the patients who were able to omit chemoradiation, I think in the big picture sense told us that there truly might be a patient subset where—this is in patients with T2 node-negative disease or T3 node-negative or T3 node-positive disease—where we might be able to safely exclude the chemoradiation and still have similarly effective outcomes for these patients.  Dr. Shaalan Beg: Those are great points, especially when we have started to think about colon cancer and rectal cancer as many different diseases based on their location. And we know that in some instances their biology can be different as well.   Can you talk a little bit about who those patients are that were enrolled on this trial? Because when I think about the German rectal study that led to us using neoadjuvant chemoradiation, the data was really around pelvic control of disease and sphincter preservation. So how did the patients who enrolled in this trial relate to the typical person with rectal cancer who walks through your doors?   Dr. Shiraj Sen: Yeah, great point. I think we should point out the inclusion-exclusion criteria for this study. These patients were only those who were, again, T2 node-positive or T3 node-positive or negative, patients for whom chemoradiation would be indicated in the setting, and patients for whom they'd be good candidates for sphincter-sparing surgeries. So, tumors that are quite up high. These are not for individuals who have tumors requiring an APR. These are not for patients who have clinical T4 tumors. And this is not applied, again, to those high-risk patients who have 4 or more pelvic lymph nodes that are 1 cm in size or larger in the short access. And so, patients who need essentially an APR and the high-risk T4 tumors who are, I think, better suited by something like we'll talk about later in the PRODIGE study.   I think one last point that might be worth making here on the PROSPECT trial is that it was a non-inferiority trial. And in my opinion, this was really a great use of a non-inferiority study. I believe that when there's a new treatment under consideration used in a non-inferiority study, it should be because that therapy or modality of treatment is safer, more cost-effective, or could help increase access to care without compromising efficacy, and ideally maybe more than one of the above. And in this case, I think really all of those checkboxes are met.   In urban settings where we work, we think about access to radiation being quite plentiful, but when we get to more rural areas, or parts of the world where they may not have access to radiation like we may, I think this data can help drive care for a number of patients there. It can certainly be more cost-effective as it allows the omission of radiation. And certainly, from some of the PRO data that they presented, it certainly can be felt to be safer and help omit some toxicities as well.  Dr. Shaalan Beg: Yeah, you mentioned a total neoadjuvant therapy and we seem to be entering this space in rectal cancer where the decision on which modalities an individual person will need for the management of their disease and what sequence they will need is all up for debate, whether that's chemotherapy or radiation, long-form, short-form radiation. And we also heard some results at earlier ASCO meetings around the omission of surgery in people who've had complete clinical responses as well.   And you mentioned total neoadjuvant therapy and at ASCO this year we heard the results from LBA3504, which is a PRODIGE-23 trial. The investigators reported 7-year results of this phase 3 study from the UNICANCER group in France. This study is really pushing the envelope. What are your key takeaways here?   Dr. Shiraj Sen: Great point. I think this study, especially when taken in conjunction with the PROSPECT trial, highlights the fact that these patients really can have heterogeneous diseases and ones that really require careful consideration and discussion at multidisciplinary tumor boards. Unlike the patient population in the PROSPECT trial, the PRODIGE study did treat patients with higher-risk disease. So these were patients with clinical T3, T4 tumors and so higher risk, and asked the question now with more mature 7-year follow-up of, when compared to receiving the standard of care at the time, which was a chemoradiation followed by TME, followed by adjuvant FOLFOX for 12 cycles or the capecitabine, does TNT giving again now modified full FOLFIRINOX for six cycles followed by chemoradiation followed by TME and then adjuvant FOLFOX, do the improvements in both disease-free survival, overall survival, and metastatic relapse rate, do they hold up, and/or are there any differences in local control?   And again, here they demonstrate that even with longer-term follow-up, that the improvements in OFS, DFS, and metastatic relapse rate, really do hold up even with longer-term follow-up. And so, for these patients with higher risk disease, it does seem that giving induction chemotherapy with modified FOLFIRINOX before chemoradiotherapy really might be kind of best practices. The safety profile, even with longer-term follow-up was unchanged. There was not any increase in local recurrences. And again, looking at quality of life metrics there seemed to be similar or maybe improved quality of life for patients who receive the TNT approach. And now again, I think the next step is, as the presenter mentioned, investigating this even in a more tailored fashion, as was done with the PROSPECT study.  Dr. Shaalan Beg: Let's change gears and talk about liver cancer. Abstract 4010 showed the results of the MORPHEUS-liver study. This was a phase 1b/2 randomized trial of tiragolumab in combination with atezolizumab and bevacizumab for people with unresectable locally advanced or metastatic hepatocellular cancer. It's really exciting to see innovations with immune therapy changing how we've managed hepatocellular cancer in the last few years. And here, we're seeing an addition of a third agent to an already approved regimen of atezolizumab and bevacizumab. I was really curious to hear what your take-home message is from this study.   Dr. Shiraj Sen: Yeah, this was another very interesting abstract that was presented at ASCO this year. It's hard to believe that it was only 3 years ago that we first got the approval of atezo plus bev, and that it took more than a decade to really have us as a field improve on outcomes for patients with liver cancer above and beyond giving sorafenib. And here we are just 3 years later, already launching new phase 3 studies from these sorts of early-phase adaptive signal-seeking studies. The investigators as a whole should be commended for the speed at which new drug development has really progressed in liver cancers after, again, quite a lull we had in the pre-I/O days.   It's encouraging to see that in just 3 years that there's another phase 3 study now being launched in HCC on the heels of this data combining the atezo-bev backbone to the anti-TIGIT molecule tiragolumab. Now, I know there was a lot of discussion and some criticism of this study and what the real effects of adding tiragolumab to atezo-bev might be because of the underperformance of the control arm. In this study, the atezo-bev control arm, it should be noted that was only 18 patients, had a response rate of only 11%. And of course, with longer-term follow-up of the IMbrave150 study, we know that with the atezo-bev, we expect a response rate of about 30%. And so how a real-world population of individuals receiving atezo-bev would compare to those receiving tiro-atezo-bev has been discussed. But I think the only real way to answer that question would be with a large, randomized phase III study. And it's encouraging to see that one is being launched to ask that question.    Dr. Shaalan Beg: Absolutely. Let's change gears and talk about pancreatic cancer. LBA4005 explored short-course neoadjuvant FOLFIRINOX versus upfront surgery for people with resectable pancreatic head adenocarcinoma in the NORPACT-1 study. This is a multicenter randomized phase 2 trial and we're starting to see the reporting of clinical trials evaluating the sequencing of systemic therapies for resectable disease. We've heard studies for neoadjuvant therapy for borderline resectable as well as resectable trials in previous meetings. But there's a lot of discussion around the NORPACT-1 trial which may be causing some people to pause on our current understanding of treatment sequencing for resectable disease. I'm curious to hear what your take homes are.   Dr. Shiraj Sen: Thanks. Yes, I thought this was a very interesting study as well. Depending on which institution one practices in, in recent years, many have shifted their practice for individuals with resectable pancreatic cancer from administering full FOLFIRINOX or adjuvant therapy only after surgery to giving it in the neoadjuvant setting based on, again, a number of smaller studies, some that are single institution. This is one of the first studies that in a randomized fashion has asked the question in just resectable pancreatic cancer. So we're not talking about borderline resectable or other patients.    But in resectable pancreatic cancer, whether there are differences now comes if patients receive surgery first, followed by FOLFIRINOX-only adjuvant setting or essentially getting perioperative FOLFIRINOX and so neoadjuvant, followed by surgery, followed by, as tolerated, four cycles of adjuvant FOLFIRINOX. And I was a little surprised by some of the results and to me some of these data were a little intriguing.  Specifically, I think if we take a deeper look like the discussant had after the presentation, there are, I think, some unanswered questions. Specifically, half the patients were randomized to receive neoadjuvant FOLFIRINOX and half of them received upfront surgery. But in the group of individuals who received neoadjuvant FOLFIRINOX, it looked like only half of them completed neoadjuvant chemotherapy. And some answers into kind of why that was, and what it was about those patients then who were in the neoadjuvant arm, is one thing that comes to mind.    Secondly, what I thought was interesting was this study was that it was designed very well to try to take out as much heterogeneity as possible. However, in both arms, there was actually quite a substantial number of individuals who ended up receiving gemcitabine-based chemotherapy. And that's even in the patients who received neoadjuvant FOLFIRINOX, and individuals who received neoadjuvant FOLFIRINOX, only 25% post-op went on to receive adjuvant FOLFIRINOX. And 75% almost received gemcitabine-based therapy. And again, why so many patients received off-protocol adjuvant therapy is something that kind of struck me.  I think the third and final thing that really struck me was, in the patients that received neoadjuvant FOLFIRINOX, there was a higher rate of R0 resections. 56% of patients had an R0 resection compared to those who got upfront surgery, where there was only a 39% rate and similarly kind of higher levels of N0 resection. And yet, despite all of this, again, the authors did show quite clearly that there were not any significant improvements in outcomes for patients that received neoadjuvant therapy, but kind of how improved surgical endpoints do not translate to overall survival and overall endpoints; I think there are still some questions there.    However, I do agree overall that despite these limitations with the conclusions of the author, that at this time at least, it's not clear; the results don't support the widespread use of neoadjuvant FOLFIRINOX as a standard of care for resectable pancreatic cancer. Fortunately, there are studies ongoing, like the Alliance [for Clinical Trials in Oncology] study and the PREOPANC-3 study that hopefully will kind of help settle this verdict.    Dr. Shaalan Beg: Yeah, it's a stark reminder that we need better treatments. I think we've been shifting the sequencing of these treatments and slicing them in as many ways as we can. And the core challenge is in finding better systemic therapies that have been found to be effective in advanced stage as well as in curative stages like this. And one of the points that bothered me about this trial was the drop-off that they saw at the beginning when the biliary system was being drained, or they were getting biopsies because folks who went for surgery upfront didn't always require those procedures. They didn't require histologic diagnosis either. But as is standard practice, before we give systemic therapy, we require psychologic confirmation. And that may have introduced a delay of a couple of days or a couple of weeks, which could have resulted in some imbalances in how survival is measured and how folks were doing. Because, as you know, a lot of times people diagnosed with this disease can be fairly sick, and a matter of a couple of days or weeks can make a big difference in terms of treatment with those.  I'm really excited to wait and hear how the Alliance study and the PREOPANC follow-up trials pan out and as a very important cautionary note for everyone, both the folks who have adopted neoadjuvant therapy and those that have not followed the data. And kudos to the investigators for completing that trial.  Dr. Shiraj Sen: Yeah, I fully agree. I'm glad to see that these trials are being run. I think we should not take anything away from the fact that these are very challenging trials to run. I think we certainly owe a big kudos to the patients who enroll in these studies who have resectable disease, but they're still willing to go through the process of an extra consent form, an extra kind of screening process, additional testing required to go into a clinical trial. And it's only because of them that we're able to run these studies and, as a field, get some answers on how to best take care of our patients.   Dr. Shaalan Beg: Shiraj, thank you so much for coming to the podcast today and sharing your valuable insights on the ASCO Daily News Podcast.   Dr. Shiraj Sen: Thank you so much for having me, and to all of the ASCO staff for having this podcast.  Dr. Shaalan Beg: And thank you to our listeners for your time today. You'll find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.    Disclaimer:   The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Find out more about today’s speakers:   Dr. Shaalan Beg  @ShaalanBeg  Dr. Shiraj Sen  @ShirajSenMDPhD     Follow ASCO on social media:   @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn     Disclosures:    Dr. Shaalan Beg:   Consulting or Advisory Role:  Ispen, Cancer Commons, Foundation Medicine, Genmab/Seagen   Speakers’ Bureau: Sirtex   Research Funding (An Immediate Family Member): ImmuneSensor Therapeutics   Research Funding (Institution): Bristol-Myers Squibb, Tolero Pharmaceuticals, Delfi Diagnostics, Merck, Merck Serono, AstraZeneca/MedImmune     Dr. Shiraj Sen:   Employment: Roche/Genentech  Stock and Other Ownership Interests: Roche/Genentech  Research Funding (Institution): ABM Therapeutics, Zentalis Pharmaceuticals, Parthenon Therapeutics, Pyxis Oncology, Georgiamune Inc.      

Drs. Rana McKay and Jonathan Rosenberg highlight key advances in genitourinary cancers featured at the 2023 ASCO Annual Meeting, including the THOR study in mUCC, VESPER in muscle-invasive bladder cancer, CONTACT-03 in mRCC, and TALAPRO-2 in mCRPC. TRANSCRIPT  Dr. Rana McKay: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Rana McKay, your guest host for the podcast today. I'm a GU medical oncologist at the Morris Cancer Center at the University of California in San Diego and an associate professor at the University of California in San Diego School of Medicine. Joining me today is Dr. Jonathan Rosenberg, the chief of the Genitourinary Oncology Service at the Memorial Sloan Kettering Cancer Center in New York. We'll be discussing practice-changing studies and other key advances in genitourinary cancers that were featured at the 2023 ASCO Annual Meeting.   You'll find our full disclosures in the transcript of this episode, and disclosures of all guests featured on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod.  Jonathan, it's great to have you with us today. How are you?  Dr. Jonathan Rosenberg: I'm doing very well. Thanks so much for hosting today.  Dr. Rana McKay: Oh, of course. It's always fun to step back from ASCO and reflect on all the practice-changing and practice-informing studies that were presented.  Dr. Jonathan Rosenberg: Absolutely.  Dr. Rana McKay: Maybe we can dive right in with LBA4619. This is the much-talked-about THOR study of erdafitinib versus chemotherapy in patients with advanced or metastatic urothelial cancer with select FGFR alterations. What are your key takeaways from this study?  Dr. Jonathan Rosenberg: It is indeed a study we've been waiting for, for quite some time, to see the results in the confirmatory study after the accelerated approval of erdafitinib. This is half of the THOR trial. There were 2 cohorts of patients. One cohort were patients who previously received a checkpoint inhibitor randomized to chemotherapy or erdafitinib, and those data were reported at ASCO this year. The other cohort was randomized against a checkpoint inhibitor in patients who have not received a checkpoint inhibitor, and we'll see those data in a future meeting.   The bottom line for the THOR study is that FGFR3 inhibition improved overall survival compared with chemotherapy, and the chemotherapy in this study was a taxane. The overall survival was 12.1 months for erdafitinib compared to 7.8 months for chemotherapy with a hazard ratio of 0.64. This led to the DMC to stop the study and blind the data and cross people over. There was also a PFS advantage. There really weren't a lot of new toxicity signals seen; the usual suspects in terms of mucositis, hyperphosphatemia, diarrhea, dry mouth, and onycholysis.  And so, what it tells us ultimately is that in a patient who's progressed on a checkpoint inhibitor, we can feel comfortable about using erdafitinib knowing it provides a survival advantage in patients who've been previously treated for advanced urothelial cancer and have an FGFR alteration, either an FGFR2 or 3. And hopefully, we'll see more data in the future from the study, maybe not too long in the future from the other part of the study, comparing it to checkpoint inhibition.   Dr. Rana McKay: That's really exciting. I think it's exciting to see the data about the positivity of erdafitinib versus chemotherapy in this context. Looking at the phase 3 data is going to be really important. Looking at the data in the IO naive context is going to be really important. I feel like this sort of reaffirms what we've been doing in clinical practice. But how do you feel that the study is practice-changing?   Dr. Jonathan Rosenberg: I think it gives us reassurance that for these patients, erdafitinib is an appropriate option. There's no randomized data between erdafitinib and other choices, such as sacituzumab, which is also based on an accelerated approval, or enfortumab, which is based on randomized phase 3 trial. But it gives us level-1 evidence. I do wonder whether the comparison against the checkpoint inhibitor may turn out differently, but we'll see. Those data aren’t in evidence. And I do think it was interesting that the majority of patients who were enrolled on the trial were PDL-1 low. We'll see what the comparison to a checkpoint inhibitor is like and whether those patients have similar characteristics.  Dr. Rana McKay: Yeah, you're almost kind of selecting for people that were not primed to respond.   Dr. Jonathan Rosenberg: Exactly.   Dr. Rana McKay: Well, that's really exciting, I think. Moving on to localized bladder cancer, Dr. Pfister presented the results of the VESPER trial. That's LBA4507. I think this study was really important. This was a trial that explored dose-dense MVAC with methotrexate, vinblastine, doxorubicin, and cisplatin or gemcitabine-cisplatin as a perioperative chemotherapy for muscle-invasive bladder cancer. I think there's always been some discussion around these regimens and how they pair up against one another. Can you tell us about these data?   Dr. Jonathan Rosenberg: It's a very interesting study. It was designed back when it was felt that we could not give patients neoadjuvant therapy. And it was designed as either a neoadjuvant or adjuvant approach. Although, in reality, almost everybody who was enrolled in the study got neoadjuvant chemotherapy, which I think speaks to the shift in practice over the last 10 to 15 years towards neoadjuvant rather than adjuvant therapy. It's an interesting trial in that it used a duration of chemotherapy for the MVAC regimen, the dose-dense MVAC regimen that we don't usually use, which is 6 cycles. And functionally, about 40% of patients couldn't make it to 6 cycles and had to stop sooner, versus 4 cycles of q3-week gemcitabine and cisplatin.   And what the data show is that the progression-free survival for the entire intent-to-treat population didn't reach significance. But if you looked at the neoadjuvant population only, there was an improvement in progression-free survival as well as overall survival. So, it's sort of a negative positive trial. Negative for the primary endpoint, but positive for key secondary endpoints. They did a very interesting analysis looking at the number of cycles that patients received regardless of arm, but looking at it by arm. And it's clear from that analysis that the more chemotherapy they got, the better they did.   Although, the flaw in that analysis is that the healthier patients are, the more chemotherapy they're able to tolerate, and therefore that may translate to an improved overall survival irrespective of the amount of chemotherapy. And this was not necessarily a pre-specified analysis. I think some of the statisticians were clutching their chests during the report of this trial, having talked to several afterward. On the other hand, it does say to me that for a fit, younger patient, it is important to consider dose-dense MVAC instead of gemcitabine and cisplatin.   I'll also note, reading the publication from the first part of the trial, that it appears that nobody over 70 was enrolled from everything I could tell. And so, I question the validity of the tolerability of the results for the average 75-year-old that I see in my practice. Although age is not a bright line cut-off for anybody in terms of cancer treatment. But my own experience has been that dose-dense MVAC has been harder to tolerate for a lot of patients in their 70s, whereas I think we should feel quite comfortable giving it to patients in their sixties. And if you ask me how many cycles I would give, I probably wouldn't say 6, for dose-dense MVAC, I would probably say 4.   Dr. Rana McKay: Was there a predilection that there was a more aggressive disease like nodal disease or other things to prompt the 6 versus 4?  Dr. Jonathan Rosenberg: I think that they stopped primarily for toxicity reasons, but it wasn't clear to me that it was a disease-based issue. And for the neoadjuvant therapy, everyone was supposed to be clinically node-negative on entry, so that probably wouldn't have explained it.  Dr. Rana McKay: Very exciting. I know that the data were quite provocative, but I think it's always difficult to interpret these sorts of subgroup of subgroup analyses, and there's a lot of bias in why people may get more versus less. And I think trying to reduce these data to clinical practice is going to be really important, as you've stated.  Dr. Jonathan Rosenberg: Rana, I'd also like to talk about some key advances in renal cell carcinoma that were reported at ASCO. Dr. Choueiri presented data on LBA4500, the CONTACT-03 study, which really was the first study of its kind in solid tumors because it addressed a major question in the kidney cancer field and in other fields: Is there a role for immunotherapy rechallenge after progression on immunotherapy? Specifically, the study looked at the efficacy and safety of atezolizumab plus cabozantinib versus cabozantinib alone after progression with prior immune checkpoint inhibitor therapy in metastatic RCC. I'd like you to tell me what you think of this study and the results and how they may affect our practice.   Dr. Rana McKay: Absolutely. This was a critically important study looking at the role of IO post-progression on IO. It was a large phase 3 trial that enrolled patients with clear cell and non-clear cell patients. It actually allowed patients with papillary RCC, unclassified RCC, to enroll in the study, whereas most of these studies are excluding patients with non-clear cell disease. Patients had to have progressed on an immune checkpoint inhibitor given either as adjuvant first line or second line, given either as a single agent or in combination with one of the other combos, whether a VEGF or IO. And patients were randomized one-to-one to receive the combination of atezolizumab plus cabozantinib versus cabozantinib alone. And the dosing of the cabozantinib here is at 60 milligrams in the combination, which is the standard dosing of cabozantinib monotherapy. And the primary endpoints for the trial included PFS and OS.   And in essence, this trial was a completely negative study. The primary endpoint, which was centrally reviewed, rPFS, was negative. The hazard ratio there was 1.03. Overall survival was also negative with a hazard ratio of 0.94. And when you look at the subgroup analyses, there really wasn't any specific subgroup that seemed to derive any benefit, potentially those that had a prior response to an immune checkpoint inhibitor, but in essence, a negative study.   And I think these data are really informative because the discussion at ASCO was conducted by Dr. David Braun, and he actually had conducted a very highly scientific Twitter poll to help guide how to interpret the data and what people do. And from that, about 30% of individuals that completed the poll were actually layering on IO therapy, and continuing IO therapy after somebody progressed on therapy layering in a TKI while keeping the IO backbone going.   And I think what this study proves is that we really don't have any really robust data to guide doing that at the present time. And what we may end up doing is compromising the efficacy of the oral TKI or dose-compromising the oral TKI to try to maintain an ineffective IO. And so, I think at the present time these data, while negative, were truly practice-informing. There are other studies that are looking at this strategy as well. I think one of the criticisms here is that atezolizumab really has not had a great track record in renal cell carcinoma in every single context where it was tested, either alone or in combination. It has not met its primary endpoint and it's not utilized as a treatment in RCC. So, there's some discussion that could this be the fact that this is a PDL-1 inhibitor and that it's atezolizumab. And additionally, I think the thing to point out for is that in the modern era if we look at the cabozantinib control arm, cabozantinib in the refractory setting had a PFS of 10.8 months, which is pretty impressive for a later line PFS, if you will. So, there is another study currently ongoing called the TiNivo-2 study that's looking at tivozanib plus nivolumab versus tivozanib alone in a similar patient population. That trial is enrolling only clear cell patients that had progressed on prior IO. So, I think we'll have additional data, but very, I think, informative. I think this question comes up in a lot in other tumor sites as well because of the broad use of checkpoint inhibitors across hematologic and solid tumor malignancies.   Dr. Jonathan Rosenberg: I think this was the most informative negative study and the most negative trial I've seen in a while as well. But it did highlight the importance of asking these questions where people assume they know the answer already, and in fact, we often don't, and our assumptions are wrong. So, I thought that was fascinating and very well described.    Staying in the kidneys arena. I'd like to talk to you also about the phase 2 KEYNOTE-B61, that's Abstract 4518. It looked at first-line lenvatinib and pembrolizumab across non-clear cell carcinomas. Tell me what you thought of the trial and what your takeaways were.   Dr. Rana McKay: This is an important study. I think the treatment of non-clear cell RCC has lagged. I guess the advances have lagged behind clear cell RCC, and really robust phase 3 randomized studies in people with non-clear cell histologies are very limited. This was a single-arm phase 2, so I think we need to kind of take that for what it's worth, that enrolled patients who had non-clear cell RCC per investigator that had received no prior systemic therapy. So, this was a frontline study, and patients received pembrolizumab plus lenvatinib until disease progression or toxicity.   The study enrolled a very robust 158 patients, which is pretty impressive for a modern-day non-clear cell cohort. We've seen data from nivo-cabo that had gotten presented previously by Dr. Lee. That study was a single institution, about 40 patients or so if you will. The primary endpoint of this study was objective response rate, and the bulk of the patients that were enrolled were papillary RCC. As you would imagine, around 60% of patients were papillary. It did include around 18% with chromophobe RCC. And when we break things down by IMDC risk category, about 44% of patients were favorable-risk disease. I think the percentage of patients who were favorable is higher than if we were to take an all-comer metastatic RCC patient population.   But the objective response rate was pretty impressive at 49% with this combination. The CR rate was right around 5.7%. So, I think certainly a pretty solid signal of efficacy. But again, this is a single-arm phase 2 study. I think what's also really interesting, and I think we have to take subset analyses with a grain of salt if you will, but there were responses that were seen across all histologies. And the prior nivo-cabo study that I had shared with you had previously done a futility analysis for patients with chromophobe RCC, and that cohort actually closed down. And in this study, the response rate for the chromophobe patients, though it wasn't a lot of patients, 29 patients with chromophobia RCC, was around 27.6%, so I think these data are certainly informative. If you look at the waterfall plot, there were some deep responses that were certainly observed, and the bulk of patients had some degree of tumor shrinkage with very little patients that had primary PD.   Dr. Jonathan Rosenberg: It's really provocative. So, are we getting to a point where we might start thinking about randomized trials in the non-clear cell population to try to establish the best standard of care?  Dr. Rana McKay: Well, I think PAPMET2 is currently enrolling patients. That study is looking at the combination of cabozantinib with atezolizumab versus cabozantinib alone for frontline papillary. PAPMET1, which was led by Dr. Pal, I mean, these studies are really magnanimous because it takes all hands on deck to get these patients enrolled because they're few and far between. So, I definitely think we need to be moving in that direction. And I think we need to be moving away from lumping all non-clear cells into one bucket because I think what we're seeing is that, one, the biology of these tumors is very distinct and unique, and they don't all behave the same to any one given therapy. So, we really need to move away from just lumping all non-clear cells into one bucket and try to actually conduct studies for each specific subtype.    Dr. Jonathan Rosenberg: Understood and agree. Let's switch gears for a second and talk about prostate cancer. Can you talk about the data from Abstract 5004, the TALAPRO-2 study of talazoparib and enzalutamide compared to placebo and enzalutamide as a first-line treatment with metastatic CRPC that have HR homologous recombination repair gene alterations?    Dr. Rana McKay: Absolutely. So the TALAPRO-2 study is one of three studies that have looked at the combination of PARP inhibitors with an ARSI in the frontline mCRPC setting. And this trial randomized patients to talazoparib and enzalutamide versus placebo enzalutamide. And again, this was first-line mCRPC. Patients were allowed to have received prior docetaxel or prior abiraterone in the castration-sensitive setting, and the primary endpoint was overall survival.  At GU ASCO this year, we saw the top-line data from TALAPRO-2 first get presented. And what was actually presented at this meeting was the subset of patients that were HRR-mutated only. They had two cohorts: an all-comer cohort that was previously presented, and then now they're presenting the subset of the patients that were HRR-mutated. And I think what we've seen across the board is that the efficacy of PARP inhibitors kind of differs by underlying HRR mutations.     When we look at the entire population of HRR-deficient patients, the study was positive, talazoparib plus enzalutamide resulted in an improvement in rPFS compared to enzalutamide placebo. The hazard ratio there was 0.45. And then when we break things down by selected gene groups, they did this subset analysis in patients with only BRCA1, only BRCA2, only PALB2, only CDK12, ATM CHEK2 if you will. The data are most robust for those patients with a BRCA1/2 alteration with hazard ratios of 0.17, 0.19. Again, this is for rPFS.     But then, when we look at some of these other mutations, like ATM CHEK2, hazard ratios are higher, 0.76, 0.90. So, the effect size really kind of drops off for those non-BRCA1/2 altered HRR genes. But if we look across the different subgroup analyses, the interim OS data for the HR deficient, the time to PSA, time to cytotoxic chemo, all of that favored the combination versus placebo enzalutamide for patients that were HR deficient if we just lumped everybody all together.  Dr. Jonathan Rosenberg: How does this fit into the general landscape around this question with selection versus not selecting for HRR alterations?  Dr. Rana McKay: The data that were presented were for the selected patients, and I think that that's not where the controversy is. I think that the selected patients are the ones that seem to derive the most benefit. It's interesting because in looking at the data from PROpel and the final FDA label based off of the PROpel data, the label is only for BRCA1 and 2 patients and not for all comer HRR. It's even a more restricted label than olaporib monotherapy. So, I think it's going to be interesting. I don't know what the right answer is. I think it's going to be interesting to see how this is going to unfold for TALAPRO-2 and even for MAGNITUDE, if you will, like, how select is the selected population going to be. But at the present time, I think the label is what it is for olaparib plus abiraterone in those BRCA1/2 frontline. My hope is that this population is shrinking because everybody should be getting escalated in the metastatic hormone-sensitive setting, and we shouldn't be having people who are naive to an ARSI in frontline mCRPC.  Dr. Jonathan Rosenberg: Understood and agreed.   Dr. Rana Mckay: Well, thank you so much, Jonathan, for joining me today. It's really been a pleasure kind of going through all of the compelling advances in GU cancers from ASCO. I think it was a really exciting meeting, and thanks for your time. Dr. Jonathan Rosenberg: My pleasure. It's been great to talk to you today.     Dr. Rana Mckay: And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.    Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Follow today’s speakers:    Dr. Rana McKay  @DrRanaMcKay  Jonathan Rosenberg  @DrRosenbergMSK    Follow ASCO on social media:     @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:    Dr. Rana McKay:   Consulting or Advisory Role: Janssen, Novartis, Tempus, Exelxis, Pfizer, Bristol-Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion, Calithera, AstraZeneca, Myovant, Caris Life Sciences, Sorrento Therapeutics, AVEO, Seattle Genetics, Telix, Eli Lilly, Pfizer, Bayer, Tempus   Dr. Jonathan Rosenberg:   Honoraria: UpToDate, Medscape, Peerview, Research To Practice, Clinical Care Options, Physician Education Resource, MJH Life Sciences, EMD Serono, Pfizer  Consulting or Advisory Role: Lilly, Merck, Roche/Genentech, AstraZeneca/MedImmune, Bristol-Myers Squibb, Bayer, BioClin Therapeutics, QED Therapeutics, Pharmacyclics, GlaxoSmithKline, Janssen Oncology, Astellas Pharma, Boehringer Ingelheim, Pfizer/EMD Serono, Merck Therapeutics, Immunomedics, Tyra Biosciences, Infinity Pharmaceuticals, Gilead Sciences, Hengrui Pharmamedical, Alligator BioScience, Imvax  Research Funding (Institution): Genentech/Roche, Seattle Genetics, Bayer, AstraZeneca, QED Therapeutics, Astellas Pharma  Patents, Royalties, Other Intellectual Property (Institution): Predictor of platinum sensitivity      

    Drs. Diwakar Davar and Jason Luke discuss KEYNOTE-716, KEYNOTE-942, RELATIVITY-047, and other key advances in melanoma, including the promise of mRNA vaccines in melanoma and potentially other cancers, as well exciting advances in neoadjuvant therapies across malignancies featured at the 2023 ASCO Annual Meeting. TRANSCRIPT  Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh Hillman Cancer Center. I'm delighted to have my colleague and good friend Dr. Jason Luke on the podcast today to discuss some practice-changing studies and other advances in immunotherapy that were featured at the 2023 ASCO Annual Meeting. Dr. Luke is an associate professor of medicine, the director of the Cancer Immunotherapy Center, as well as the associate director of clinical research at the University of Pittsburgh's Hillman Cancer Center.     You can find both of our disclosures in the transcript of this episode, and disclosures of all guests on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod.   Jason, there was a lot of exciting data in the immunotherapy space highlighted at the Annual Meeting, and it's great to have you back on the podcast to discuss some of this work.   Dr. Jason Luke: Thanks for having me.    Dr. Diwakar Davar: So, the abstracts that we had selected have several key themes. We'll be covering some of the early advances in melanoma in the stage 2 and stage 2B/C space with KEYNOTE-716. I think this is a study that you know a little bit about seeing you are the presenting author and the principal investigator for the study, as well as the pivotal KEYNOTE-942 trial. And then going on to themes with using third-generation checkpoints, neoadjuvant therapy in non-small-cell lung cancer, and cutaneous squamous cell carcinoma.    But we'll start with KEYNOTE-716. So, this is LBA9505, the study which evaluated pembrolizumab versus placebo as adjuvant therapy in stage 2B and stage 2C melanoma patient population for which historically there was no real effective therapy other than remotely interferon. And these are the final results of the DMFS analysis from this phase 3 trial. So, Jason, what are your thoughts about this, and can you contextualize the results relative to the recent publication?   Dr. Jason Luke: Thanks. I think the important point to level set on this was just a few years ago; this was a population of patients that we didn't treat in clinic. In fact, sometimes they weren't even referred to medical oncology for evaluation. And that was despite the fact that we knew from historical data that the risk of melanoma-specific survival, death from melanoma, was just as high for this population of patients as it was for the patients with stage 3 melanoma, where obviously adjuvant immunotherapy has been a standard for quite some time. And so we launched this clinical trial, KEYNOTE-716. It was a global, randomized phase 3 study of almost 1,000 patients, randomizing patients to either get pembrolizumab or placebo. Importantly, these patients being those with deep primary lesions, stage 2B and 2C with negative sentinel lymph node evaluation.    People will recall that this study hit its primary endpoint on the first protocol-specified analysis at a year. And what we updated at ASCO this year was the final analysis of distant metastasis-free survival. Obviously, an important secondary endpoint because if patients eventually going to develop metastatic disease and pass away, it's the distant metastasis that we worry about. And what we saw in this trial with a landmark 36-month follow-up median of 39 months was that the benefit was increasing. In other words, the magnitude of the hazard ratio change was increasing over time as would be expected, such that at this analysis there was a 41% reduction in the risk of distant metastasis for patients treated with pembrolizumab versus placebo. And we saw a consistent benefit in the recurrence-free survival also out through that same period of time and importantly no change in the safety summary with of course the adverse event profile of pembrolizumab being what it is and well understood across oncology.    So I think these are very important data because they really kind of set the stage for the field. It is now the case that at least discussing adjuvant therapy for patients with stage 2B and 2C is the standard of care; it should be offered to all the patients. Of course, it's always a risk-benefit about whether or not patients want to pursue adjuvant therapy versus consideration of treatment at the time of recurrence. But in my clinic at least, many patients do prefer to try to eliminate the possibility of recurrence and distant metastasis as much as possible.    So I think these are very important data because they really level set the field for what to expect in this population of patients and then they also start to set the table for what's going to come after this. And that's going to be sort of the next step in our conversation here because the next generation of adjuvant studies in melanoma are now going to think about all of melanoma in the adjuvant setting as really one entity, starting from stage 2B going all the way through stage 4 resected. And that'll be relevant actually as we talk about the next abstract that will come in this discussion.   Dr. Diwakar Davar: Just to underscore, positive RFS data, positive DMFS data, and now this therapy has currently got regulatory approval in this investigation and is approved in the United States and certainly in Europe and Australia. One interesting point that we will probably have to contend with, and some of the listeners may be thinking about, is overall survival. So the last adjuvant study that demonstrated overall survival benefit was actually ipilimumab, and increasingly, the Illuminati in melanoma do not believe that we will ever see OS benefit in this disease going forward, even though it has to be an endpoint in all registration phase 3 trials. So, Jason, what are your thoughts about whether or not we'll have a positive OS readout, and even if we don't, why this is still a very important advance in this disease at this time?   Dr. Jason Luke: Your points are well taken. I think it's unclear, probably trending towards unlikely, that we would see an overall survival advantage in this trial given that we have not seen that in the stage 3 adjuvant studies. Now people can debate if, whether or not overall survival is the only meaningful endpoint for patients. I personally do not believe that's true. And to me, preventing recurrence has a value in and of itself, whether or not that's connected to overall survival. And part of the reason that I say that is that for an average patient, the median patient on a trial, of course, we can tell them treatment now, treatment later. It's a wash when you look at the overall study. And yet at the same time, for an individual person who's facing melanoma or cancer, generally they're not going to be the average patient; they're going to be one patient. And it's very possible they could end up with the type of recurrence that in fact is not highly treatable at that time.     So I think that's really the nuance that goes into those adjuvant discussions. The regulatory endpoints have been recurrence in melanoma for a long time. And I think it's important that patients understand the pros and the cons of each. The complexity in adjuvant therapy and neoadjuvant therapy is you don't necessarily know that you had to have it. You're only really going to know whether or not it didn't work if you recur later on. But to me and in my clinic, most patients are willing and interested to want to pursue those therapies in the perioperative setting to try to reduce the possibility of ever developing metastatic disease.    Dr. Diwakar Davar: Excellent. So I think key advance [is] positive DMFS data to add to the earlier reported RFS data and truly practice-changing.     So, moving on to the next study, LBA9503. This is the phase 2 trial of the Moderna vaccine. This is the trial that almost every medical oncologist knows intimately or has been called about by either the press or patients. So what is this study? This essentially is a phase 2 trial evaluating the personalized cancer vaccine PCV Moderna, made by Moderna, the mRNA vaccine, that is being studied in combination with anti-PD-1 pembrolizumab in the stage 3 BCD and stage 4 resected setting. And so there are really two very interesting results here because this is an update of the RFS data that was presented at AACR earlier this year, which was positive. What are your takes on the DMFS results, and maybe a quick blurb on how is this vaccine generated for those who may not be aware of this particular platform?    Dr. Jason Luke: Yeah, certainly. So this individualized neo-antigen therapy, as we're now calling it, is a technology platform that allows us to develop an individualized treatment for each patient based on their own cancer. So taking the actual tumor specimen, whole exome sequencing is performed to try to identify changes in the DNA, and then through a reasonably complex bioinformatic pipeline, those mutations that are likely to generate proteins that can be bound within class 1 MHC molecules are then identified in the computer and then synthesized with an mRNA, very similar to the way that the COVID vaccines were made. And then that becomes the actual drug.    So in the clinical trial, which was KEYNOTE-942, about 160 patients were randomized 2 to 1 to receive either pembrolizumab for a year as per standard adjuvant therapy but then with the addition of the individualized neoantigen therapy starting with dose 3 and throughout the rest of the year versus the control arm of pembrolizumab as the standard of care. As you mentioned, the recurrence-free survival were highly positive in this trial when it was first presented earlier this year, and at the updated ASCO we see the 18-month RFS in which the hazard ratio continues to be maintained. But I think most impressively is that distant metastasis-free survival, where we saw an even greater advantage for distant metastasis-free survival – hazard ratio here being 0.35. And so that's a huge advantage for distant metastasis-free survival in this population of patients.     And very interestingly in the clinical trial, when you follow the Kaplan-Meier plots, what you see over time is that they overlap almost the entire first year. And it's really at about a year, basically after the vaccine has had time to kick in and these neoantigens have been identified, that we then start to see the separation of the curve, which looks very flat over time. And so I think this is a very, very exciting kind of technology platform and very exciting results because there was minimal increase in toxicity – just at the site of the local injection – for the addition of the individualized neoantigen therapy.    And beyond that, hypothetically, this is not necessarily just a melanoma thing. So, of course, based on these phase 2 results, a phase 3 clinical trial called KEYNOTE-V940 is going to be launching later this year to compare pembrolizumab versus pembrolizumab plus this V940 individualized neoantigen therapy. And we're very, very excited in the field to see what those results will look like because the concept here is you could really, really enhance adjuvant therapy with this kind of an approach. Meanwhile, we're just about to talk in a little bit about all the exciting things happening in the neoadjuvant space as well. And with no increase in toxicity, obviously, that looks really good.    Suffice it to say that this technology is not specific to melanoma but rather could be applied almost to any cancer where we think about an adjuvant therapy platform. So I think the results are very, very exciting. It is a phase 2 study and it does have some caveats about not being the largest study and some other things, but you can't help but be impressed by the data that have been presented here so far.   Dr. Diwakar Davar: One important plug, I guess, in addition to that is that you mentioned that there's data using the platform in other diseases. And one really exciting paper that came out recently was Dr. Vinod Balachandran's paper; for those who haven't read it, it's in Nature, and really in a very provocative proof of concept study, they studied the platform, the vaccine plus checkpoint inhibitor therapy plus chemotherapy in a highly adverse tumor patient population. So these are patients with resectable pancreatic cancer who had the vaccine generated from pancreatic cancer that was resected after Whipple surgery. And extraordinarily, out of the 16 patients who had immune responses, 8 of them did not have relapse at a median follow-up of almost a year and a half, which is really quite extraordinary given the lack of really any effective drug outside of chemotherapy in that setting.     So, the point that you're making regarding the benefit of this therapy, suggesting that it could potentially be extended to not just melanoma, potentially other tumors such as highly immunogenic tumors, and potentially even nonimmunogenic tumors such as pancreatic cancer, really suggests that this is going to be a very exciting landscape. And potentially this area, adjuvant therapy and neoadjuvant therapy, like we'll talk about, is potentially an area in which other drugs and potentially combinations will be developed.    So next, we will be discussing 3 abstracts evaluating the theme of combinations, and these abstracts are 9501, 9502, and 4010. Abstract 9501 is an evaluation of the combination of fianlimab and cemiplimab anti-LAG-3 and anti-PD-1, respectively, in advanced melanoma, specifically focusing on the post-PD-1 experience in this disease by Dr. Omid Hamid. 9502 is the updated 2-year survival results from RELATIVITY-047, which evaluated nivolumab and relatlimab against nivolumab alone in frontline metastatic melanoma. And Abstract 4010 are the results from the MORPHEUS platform study, specifically looking at tiragolumab and atezolizumab in patients with advanced unresectable HCC.    But focusing on 9501 and 9502, Jason, what do you make of the combination of fianlimab and cemiplimab post-PD-1 setting?   Dr. Jason Luke: I think the data look very intriguing for this second combination of PD-1 and LAG-3 combination. When nivolumab and relatlimab, the approved LAG-3 inhibitor, kind of burst on the scene a couple of years ago, it was somewhat to the surprise of a lot of people in the community who had really come to think that while PD-1 and CTLA-4 were core molecules for therapeutics and cancer, that we just weren't ever really going to see something else come along in checkpoint blockade. And so nivo and rela got approved. We'll talk about them again in a second. But the data now coming forward for another PD-1 LAG-3 combination, again with cemiplimab PD-1 and fianlimab LAG-3, looks very, very promising.    So in Abstract 9501, they updated a phase 1 expansion cohort, phase 2 cohort looking at patients across the various different settings. And whereas in the treatment naive frontline metastatic setting they had previously described about a 63% response rate, they saw a similar level of response rate in patients who had previously gotten adjuvant anti-PD-1, had a period of time off treatment, and then were treated again. And that was reassuring because it suggested that this is still an active combination even with prior exposure to IO in the past.     Now, the thing that I found to be the most interesting about this combination was whereas with nivo and rela, at least from the RELATIVITY-047 phase 3 trial, it looked like there was less benefit in some of the high-risk population cohorts, at least for this combination in early testing for cemi and fian; like we talk about it sometimes, we saw there was a high response rate even in patients with liver metastases and some other high-risk features. And so I think this combination looks quite potent, and I'm very excited to see what the data will look like. I think it's very unlikely we'll ever actually get a randomized trial of two PD-1 LAG-3 combinations against each other. But suffice it to say that the data we've seen so far for fianlimab LAG-3 with cemiplimab PD-1 looks very intriguing. It certainly justifies the frontline metastatic phase 3 and the adjuvant phase 3 trials that are already in planning or ongoing.   Dr. Diwakar Davar: So one thing to consider is on the RELATIVITY-020 trial – the early trial that was led by Dr. Ascierto that really took a long time to read out – the response rate in patients with prior checkpoint inhibitor therapy was quite low. In fact, the data was quite surprising, as you'd mentioned that we had even seen this movement in the frontline setting because the response rate by BICR was only about 12%. So do you feel like the 2 LAG-3 inhibitors are fundamentally different? And if so, can you speculate as to why that might be? Again, with the caveat to the fact that these are very early data and we don't have enough information. And maybe we can also talk a little bit about the 2 pending trials that are ongoing in the advanced and adjuvant therapy landscapes perspective.   Dr. Jason Luke: I think we don't have enough data yet to truly understand whether or not they're really different. The trials that have been run so far are so different that it's hard to compare things back and forth. You can notice that the dose, the milligram dosage of fianlimab in terms of anti-LAG-3 is quite a bit higher, like a log fold higher almost than with relatlimab. And so there's some question of whether or not just merely more drug-blocking LAG-3 might in fact be more efficacious relative to the dose that's approved for relatlimab in melanoma. But beyond that, I think the data hold up very well for this new combination, again noting all the caveats about cross-trial comparison to, say, it looks to be at least as potent, possibly more potent than the relatlimab combination. But again, I think probably we need to see the data from randomized trials and how that fits into the landscape when the trials actually read out because there's a lot of things going on in melanoma that are likely to change between now and then.   Dr. Diwakar Davar: So just to draw people's attention, there are actually 2 ongoing pivotal phase 3 trials: fian plus cemi versus pembro in patients with advanced metastatic and locally advanced, previously untreated melanoma, as well as an adjuvant trial of the combination against pembrolizumab. Again, highly high-risk resected melanoma. These trials are ongoing. We don't have the results yet and we are looking forward to them.    Now, 9502, a 2-year RELATIVITY-047 result presented by Dr. Hussein Tawbi.    Dr. Jason Luke: So this is the study we were just alluding to before, the randomized phase 3 study of nivolumab versus nivolumab plus for relatlimab. To me, the most useful data sort of updating with this two-year survival follow-up is to show the maintenance of benefit between the 2 arms. And so, consistent with what we saw with nivolumab and ipilimumab, there seems to be a persistent delta between the arms for both progression-free and for overall survival out over that extended period of time, where we can see with that updated data now, at 2 years, that it's 52% of patients still alive on the relatlimab combo versus 42 with nivolumab. And it does seem like this is probably a higher-risk population of patients than participated in CheckMate-067.    So it's a little bit difficult to compare the landmarks except to notice that that difference between the control and experimental groups is consistent over a long period of time and that there were no new safety signals either, and so that was also reassuring. To me, the most interesting nugget of data in the abstract, though, is to look at what happened to patients after they were on the first-line treatment. So one of the big questions in our field is really “If patients get nivolumab and relatlimab upfront, what should they get after that?” Should they then get nivo plus ipi, or vice versa? And I think we don't have an answer clearly to that question just yet.    There was an important letter to the editor of the New England Journal now going on about a year ago by Alex Menzies and colleagues that suggested that the use of ipilimumab was attenuated, the utility of it, after a prior exposure to nivolumab plus relatlimab. They quoted a response rate on the order of only about 10% for patients who got an ipilimumab-containing regimen after initial LAG-3. In the data from Hussein Tawbi at ASCO, however, in a small number of patients, caveat, the response rate was more in sort of the low 20% range, 22% to 25%. And so that would be a much more meaningful and important sort of consideration. If we do have independent activity, then lining up sequential therapies and the toxicities associated with each will become increasingly important as we think about how to maximize these kinds of treatments for our patients, but important longer-term data to show that the benefit is holding up and it's safe, and some new insights into what to do after progression on one of these regimens.    Dr. Diwakar Davar: So, pivoting slightly to combinations, we are going to be discussing a combination of TIGIT plus checkpoints. So tiragolumab is the FC-active TIGIT inhibitor from Regeneron-Roche and this is currently in multiple pivotal phase 3 trials, several of which have been negative, including SKYSCRAPER-01 in non-small cell lung cancer and SKYSCRAPER-03 in small cell lung cancer. The MORPHEUS platform trial essentially is a platform study evaluating multiple different combinations, in this case in liver cancer. And so we have a very interesting Abstract 4010, which is giving us an early readout of the evaluation of tiragolumab plus atezolizumab along with bevacizumab in unresectable, locally advanced or metastatic hepatocellular carcinoma giving us a result that is a little different from what we had seen from the prior negative results of TIGIT. So Jason, what do you make of these early results in the advanced HCC setting?   Dr. Jason Luke: I think these are cautiously intriguing results to really highlight the point is the third checkpoint possibly being LAG-3, now a fourth checkpoint maybe with TIGIT, but with all the caveats that you talked about. In this study, the flow is that there's a continuously accruing control arm which in hepatocellular carcinoma is a combination of atezolizumab plus bevacizumab, and then other arms are added where you add in a third agent. In this case, it's the anti-TIGIT tiragolumab. And in an intriguing fashion, the response rate to the triplet was 42.5% compared to the doublet which was only 11%. So that's a pretty big difference in this population.     Now, it wasn't the largest study, only 58 patients, but it was a randomized clinical trial. And so I think those data really make people kind of open their eyes again. It's worth a little bit of a caveat here that HCC is an unusual cancer in that what is deemed to be unresectable and therefore amendable to systemic therapy is a moving target and that requires multidisciplinary evaluation of patients. And so I think a larger number of patients would really be needed to fully understand this. But certainly, a fourfold increase in the benefit or in terms of response rate looks quite intriguing.    I think the other piece of this is to be just cautious a little bit was when the initial data in non-small cell lung cancer in the CITYSCAPE study came forward, and they looked roughly sort of like this: There was more than a doubling in the PFS and the response rate, which is what triggered all of those phase 3 studies. So to me, this is enough to continue to be very interested in TIGIT as a therapeutic target. And there are many phase 3 trials already ongoing. And so I think, I'm cautiously optimistic that some of those actually will be positive and we could see more movement around TIGIT becoming a standard of care agent.    Dr. Diwakar Davar: To your point about TIGIT being an interesting target, recent data looking at the neoadjuvant landscape in melanoma from Merck, with Merck, also FC-active TIGIT and also some data from authors looking at that TIGIT also presented in this case at ASCO specifically from the ARC-7 study. So very interesting target. Several pivotal trials have been announced. Do you know of any trials that are ongoing in the adjuvant setting in other diseases?   Dr. Jason Luke: Well, as you alluded to, the vibostolimab data in melanoma for TIGIT in the neoadjuvant setting was interesting. And in fact, that has been enough to trigger a global, randomized phase 3 adjuvant study of pembrolizumab and vibostolimab versus pembrolizumab in melanoma. And that sort of takes us back to the beginning of our discussion here, building on the KEYNOTE-716 data. So, yes, TIGIT will be moving forward in the adjuvant space in melanoma and obviously at a static setting for several different tumor types with a PD-1 or PD-L1 backbone.   Dr. Diwakar Davar: So now pivoting towards neoadjuvant therapy and non-small cell lung cancer. The standard of care in this setting was established by the CheckMate-816 trial that essentially established nivolumab plus chemotherapy in the setting of resectable non-small cell lung carcinoma path. Response rate in this setting is approximately 21%. And we have several studies that are essentially looking at novel combinations or in this case, different PD-1 inhibitors in this setting. So Abstract 8500 essentially looked at nivolumab plus relatlimab from a NEOpredict-Lung trial. Jason, do you want to tell us a little bit about this?    Dr. Jason Luke: Yes, I think this is a very interesting study and that this is sort of our first peek at targeting LAG-3 in the context of lung cancer. So obviously we talked about LAG-3 for melanoma. Although the audience is probably aware that there have been neoadjuvant data for LAG-3 with relatlimab in melanoma that substantiated the phase 3 data for the metastatic setting. So one of the questions as we start to apply the LAG-3 in other diseases would be, “Do we see it hold up in both metastatic disease and in the neoadjuvant space?” But in this study, while there were no changes in the safety profile; it didn't impact on whether or not patients could have surgery. There really didn't look to be a big difference in this study between nivolumab and nivolumab plus relatlimab, with the major pathologic response as you alluded to right around 30% for both arms.    Now, it wasn't really the biggest study, but that's certainly quite a bit in contrast with what we've seen in melanoma, where with a PD-1 inhibitor you get again 25%-30%, but with adding on LAG-3, that pushes you up closer to 60%. So I think these were very interesting data that probably put a little bit of an eyebrow raise to say, “Well, let's see what happens in the metastatic setting in lung cancer with the addition of relatlimab LAG-3 on top of a PD-1.” I think it might not be quite so straightforward as what we saw in melanoma, but we'll look forward to those results because those phase 3 trials in metastatic lung cancer should be maturing sometime in the next year or two.   Dr. Diwakar Davar: The theme of neoadjuvant therapy non-small lung cancer, LBA100, which has again previously been discussed in an episode of this podcast by Dr. Jack West and Dr. Velcheti is KEYNOTE-671. And this is a study essentially that looked at pembrolizumab or placebo with platinum-based chemotherapy doublet and followed by resection. So again, a direct parallel to CheckMate-816. What do you make of the results that were reported by our colleagues in this setting, Jason?   Dr. Jason Luke: So not to rehash this, because our colleagues in the lung cancer group have already discussed this at length and obviously they're experts in that disease, but we'll just note that there was a threefold increase in major pathologic response, which turned into a major advantage for event-free survival. And so I think this is at least the third PD-1, PD-L1 combination regimen for neoadjuvant lung cancer that looks very, very promising. It certainly, to me, seems like neoadjuvant consideration really should be the standard of care already moving forward.   To me, what the big question that is left with is “Do we still need the adjuvant component after we give the neoadjuvant?” So, some of the trials are including neoadjuvant and adjuvant, some of them are only neoadjuvant. And I think that's going to be a really important question as we move into the future, both in terms of what is that contribution of the adjuvant component, and then again, going back to earlier in our discussion here, if there could be a major advantage to adding individualized neoantigen therapy, maybe it is important to have both. But I think that's one of the big questions we have to get teased out by the field over the next couple of years.   Dr. Diwakar Davar: And finally pivoting towards cutaneous squamous cell carcinoma. We have 2 abstracts discussing perioperative therapy. So cutaneous squamous cell carcinoma is a high-TMB tumor. The median tumor mutation burden in this disease is threefold that of melanoma. This is a disease in which checkpoint inhibitor therapy is approved as a single agent both with pembrolizumab and cemiplimab on the basis of nonrandomized phase 2 trials. And increasingly, there has been early development in the perioperative setting. The first data in this space came from our colleague Dr. Gross at MD Anderson, who reported in a small, nonrandomized phase 2 trial of 20 patients, a path CR rate with two cycles of cemiplimab at approximately 50%.    A larger multi-institutional phase 2 trial demonstrated that a longer duration of perioperative therapy of four cycles or 3 months of cemiplimab did not particularly improve the path response rates. The response rates were similar at approximately 50% as well. And what we have right now are 2 other trials. The first is the MATISSE trial, Abstract 9507 ,that evaluated nivolumab or nivolumab plus epilimumab in this disease. And the other one was the NEO-CESQ trial, or Abstract 9576, that evaluated neoadjuvant plus adjuvant therapy that's cemiplimab in the high-risk patient population. So we're starting with 9507. Jason, what do you make of the ipi and ipi-nivo data reported in this setting?   Dr. Jason Luke: So I think this is a really interesting study because I think part of the intent is the clinical aspect of how you manage patients with cutaneous squamous cell carcinoma. For those that don't do cutaneous oncology, many of these patients have the development of lesions, which can be actually quite difficult to resect in a way that's not otherwise mutilating or cosmetically quite problematic. And that was part of the impetus for this trial where, again, they looked at either monotherapy PD-1 or a PD-1 plus CTLA-4, and they saw great success. As was predicted based on the other data that you alluded to, response rates are more than 50% near 60%, with actually a substantial number of patients on the trial actually refusing to have surgery after they received their neoadjuvant therapy because they were so certain that they had had a good outcome.    So I think these data are quite reassuring in the context of all of this emerging data around cutaneous squamous cell carcinoma. We'll talk about this NEO-CESQ trial in just a second, but I think it really is emerging to be the standard of care very soon for the use of perioperative PD-1 for cutaneous squamous cell.   Dr. Diwakar Davar: What do you feel about the dose and schedule of checkpoint inhibitor therapy used here? So the dose of ipilimumab used was ipi-1 and not ipi-3, and they waited 4 weeks. So when patients only got two cycles of Q2 weekly nivo, and one cycle of ipilimumab, do you think the responses would have been deeper if they'd waited longer?   Dr. Jason Luke: I think it is possible that they might have been deeper, although I'm not totally sure about that. One of the other abstracts we're not directly mentioning here was a study in Merkel cell carcinoma which suggested that in fact, adding ipi and that also highly immuno-oncology-responsive tumor type did not add to the response rate. So I'm not totally sure about that. I think rather what would be most interesting here is sort of the sort of next generation of biomarker work.    As part of their presentation, the MATISSE trial team showed gene expression profiling that really strongly identified which patients were going to do well on the trial. And I think that's probably eventually going to be how we need to think about this. There are patients in the neoadjuvant setting who are going to do really well with anti-PD-1 alone. And then for those who aren't, that's where we probably really need to think about do we need combos, how long to give the treatment, etc. And I think we're really only on the cusp in the beginning of this, which is exciting as we think about moving into the future.    Dr. Diwakar Davar: Certainly, many combinations are being evaluated in this space and we are very excited for the data that it's about to hopefully come in the next couple of months to years.    So the NEO-CESQ – it’s quite a puzzle as to how to pronounce this acronym – and this evaluated cemiplimab in the high-risk setting. So it's worthwhile noting that Dr. Gross's first trial looked at high-risk stage 2, 3, and 4 disease. So the context of cutaneous squamous cell carcinoma that's node-positive disease and distant metastatic disease that is in one location or patients with node-positive disease invention. And his multi-institutional cemiplimab trial of four cycles evaluated included patients with stage 2, 3, and 4 disease.    So here in a study just in stage 3 and 4 diseases, Dr. Ascierto reported the results of 2 cycles of cemiplimab and importantly, these patients had both the neoadjuvant and the adjuvant portion of cemiplimab. So, Jason, you mentioned earlier that one of the key aspects that we start thinking about neoadjuvant therapy is exactly how much do you need. Do you need both the pre-surgical therapy and the post-surgical therapy? Is the presurgical therapy enough? After all, neoadjuvant response equals cure. How much benefit are you getting from post-surgical portions? So what do you make of the results that they've seen here and what is the impact? How do you think we'll be disentangling the impact of the neoadjuvant and the adjuvant portion of the immunotherapy upon response and survival?    Dr. Jason Luke: So just to leverage those comments, I think these data are reassuring because in this higher-risk group of patients, they saw excellent outcomes very similar to what Gross et al had previously reported. So that's good. To your question about how we are going to disentangle this adjuvant versus non-adjuvant question, there's a trial in melanoma called the NADINA trial which is ongoing now in which the use of the adjuvant therapy is actually risk-adapted. So after patients have an initial neoadjuvant treatment they're evaluated, and if they have had a pathologic complete response, they're actually going to stop that treatment and they're not going to give the neoadjuvant therapy. And so I think obviously it's a slightly different disease, but those kinds of data, I think, will be very meaningful to help us sort this out.    And I'm not sure whether or not in cutaneous squamous we would need a different trial than in melanoma, although I think in a different tumor, maybe like, say, lung cancer, you probably would need a dedicated study to try to look at that because I think just the responsiveness to checkpoint blockade is going to vary quite a bit once you get outside of cutaneous oncology. But to summarize, reassuring that a similar pathologic response rate, and I think this question of adjuvant or nonadjuvant, I think that's the next question we've got to answer in the field.    Dr. Diwakar Davar: We have now come to the end of our back-and-forth discussion on these very, very exciting abstracts. So Jason, thank you for highlighting these advances and for engaging in a robust discussion.    Dr. Jason Luke: Thanks for having me.    Dr. Diwakar Davar: And thank you to our listeners today for taking the time to listen to this podcast. You will find the links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear in the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.    Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Follow today’s speakers:   Dr. Diwakar Davar   @diwakardavar   Dr. Jason Luke   @jasonlukemd      Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:      Dr. Diwakar Davar:     Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences    Consulting or Advisory Role: Instil Bio, Vedanta Biosciences    Consulting or Advisory Role (Immediate family member): Shionogi    Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences    Research Funding (Inst.): Zucero Therapeutics    Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy    Dr. Jason Luke:      Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical , Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX    Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine    Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure    Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)    Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio        

Drs. John Sweetenham and Marc Braunstein discuss advances in hematologic malignancies featured at the 2023 ASCO Annual Meeting, including the potentially practice-changing SWOG-S1826 study in Hodgkin lymphoma, the promise of bispecific antibodies in B-cell malignancies, and a novel approach to deliver vital anti-myeloma medications that could improve patient quality of life and alleviate barriers to care. TRANSCRIPT   Dr. John Sweetenham: Hello, I'm John Sweetenham, the associate director for cancer network clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and the host of the ASCO Daily News Podcast.    The 2023 ASCO Annual Meeting featured some exciting new data on hematologic malignancies. I'm delighted to have Dr. Marc Braunstein return to the podcast to discuss some of these potentially practice-changing studies and new approaches in the heme space. Dr. Braunstein is a hematologist and oncologist at the NYU Perlmutter Cancer Center.    You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod.   Marc, it’s great to have you back on the podcast, and thanks for being here again.   Dr. Marc Braunstein: Thank you, John. It's great to be back.   Dr. John Sweetenham: Marc, we already mentioned that there are some potentially practice-changing studies that were reported at ASCO this year. And among those, LBA4, which was presented in the Plenary Session, was a study which explored the treatment of advanced Hodgkin lymphoma. This was the Southwest Oncology Group study S1826. Could you give us your insights on this?    Dr. Marc Braunstein: Sure, happy to discuss S1826. So as background, you know, the ECHELON-1 study, which was published in the New England Journal of Medicine in 2022 showed a 40% decrease in the risk of death at six years follow-up by adding brentuximab to AVD compared to bleomycin AVD. And that was in high risk or advanced-stage patients and that led to adoption of brentuximab for upfront use in patients with classical Hodgkin lymphoma in advanced stage.    Also of note, immune checkpoint inhibitors such as pembrolizumab or nivolumab do have activity in the relapse setting. The SWOG S1826 study was a randomized control study looking at the use of the PD-1 inhibitor nivolumab plus AVD versus brentuximab AVD in patients with advanced stage classical Hodgkin lymphoma who are at least twelve years of age. And the primary endpoint in the study was progression-free survival.     It was a large study which enrolled 976 patients and randomized them one to one to either nivo AVD or brentuximab AVD. The median age in the study was 27 and the median follow-up was 12 months. And what the study found, which could be practice-changing, was that the primary endpoint of progression-free survival was superior in the nivolumab arm with a hazard ratio of 0.8 and a one-year PFS of 94% versus 86%, favoring the nivolumab arm. And while there were side effects associated with the class of medications, for example, hypo or hyperthyroidism was more frequent in the nivolumab group, whereas peripheral neuropathy was higher in the brentuximab group, I think that these results are particularly encouraging for how we can continue to improve outcomes for patients with advanced-stage classical Hodgkin lymphoma. And this may be practice-changing in terms of whether we use upfront immune checkpoint inhibitors in combination with our standard chemotherapy backbone.    Dr. John Sweetenham: Yeah, absolutely. There are a couple of things that occur to me. One in particular which is unique about this study, and the fact that it was for patients who are 12 years and older in many respects represents a first because I can't think of another large, randomized study of this type which has attempted to align pediatric and adult care of patients with Hodgkin lymphoma. So, I think it's something of a landmark in that regard. I don't know if you'd agree with that.    Dr. Marc Braunstein: I agree, especially with the range of ages from 12 to 83. It's a pretty broad population by age, but I agree it does kind of reconcile those two groups in a disease that has a bimodal presentation and clearly shows that immune checkpoint inhibitors are both potent and well tolerated in different age groups.    Dr. John Sweetenham: The other question that I have about this study is we haven't seen so far in this study an overall survival benefit to the nivo arm, which is maybe not surprising, but in terms of the practice-changing potential of this study, do you think that will matter?   Dr. Marc Braunstein:  I think that's an excellent question, John. Initially, the ECHELON-1 study only showed progression-free survival, and then the update did show overall survival. And so if we take the lead from that study, we expect to see an overall survival benefit in the SWOG study as well with nivolumab, but it remains to be seen. But I think that the data presented thus far at the Plenary Session is compelling enough to consider using nivolumab upfront.   Dr. John Sweetenham: Yeah, I absolutely agree. And then I guess the other question that we're going to have to wait probably several years to know is what happens in terms of relapse? So, for the minority of these patients who do relapse, how salvageable, if that's the right word, are they going to be with a second- or third-line regimen? But I think that's clearly something for the future, and it's a very interesting, exciting outcome from this study.   Dr. Marc Braunstein: Absolutely.    Dr. John Sweetenham: Let's move on. Marc, again, we're still in the lymphoma world here, but looking at high-risk follicular lymphoma. And this was Abstract 7506, looking at epcoritamab plus the R2 regimen in patients with follicular lymphoma. Could you walk us through this one?    Dr. Marc Braunstein: Yeah, absolutely. Bispecific T-cell engaging antibodies are showing impressive efficacy in relapsed and refractory non-Hodgkin lymphoma. Epcoritamab is a bispecific antibody that binds to CD3 on T-cells and CD20 B-cells. And this antibody is currently approved for diffuse large B-cell lymphoma patients after two or more prior lines of treatment.    In this study presented by Merryman and colleagues, they explored the addition of epcoritamab to standard lenalidomide-rituximab. In 109 patients with relapsed or refractory follicular lymphoma who had at least one prior therapy, and, of note, the study was enriched for high-risk patients for progression, including those who had progression of disease within 24 months of their initial treatment and those patients who had been refractory to prior anti-CD20 treatment. This study enrolled 109 patients with relapsed refractory follicular lymphoma. The median age was 65 and 56% of patients had FLIPI scores on the higher end of the spectrum from three to five, and 61% had stage 4 disease. Also of note, 38% of patients had progression of disease within 24 months of their prior treatment. So at a median follow-up of 8.8 months, the overall response rate was impressive at 97%, and 82% of patients were still on treatment at that time.     Now, of course, with this mechanism of action of bispecific antibodies, there is a risk of both cytokine release syndrome and immune-related neurotoxicity. The rates of CRS were primarily low grade, there were only 2% grade 3, and of note, most occurred after the first dose. And in terms of ICANS or neurological toxicity, there were no grade 3 adverse events, and those occurred in only two patients. Finally, the estimated six months progression-free survival was 93%. So, if we cross-compare these results historically to the R-squared regimen, which was published to be about 80%, just cross comparing, so it's not exactly the same study, this clearly shows high activity on par or better with R-squared alone. Although this study was not a randomized study, I think the addition of epcoritamab certainly shows high overall response rates and we'll need randomized data to confirm the efficacy, but it's definitely encouraging in high-risk follicular lymphoma patients.   Dr. John Sweetenham: Thanks, Marc. I agree. I think these data are really enticing, in as much as the response rates are so high, but of course, it is follicular lymphoma, so we'll have to wait a while. But the thing that it does make me reflect on is that bispecific antibodies really are turning out to be remarkably effective in a range of B cell malignancies, so, it's very interesting to continue to watch this space.    I'm going to change gears now and talk about something completely different for a moment. And this was Abstract 1536. I think that many of us are in a position where we're now looking at how we deliver our clinical services, and particularly inpatient services, to patients with hematologic malignancy. And this study addressed that very specifically. Can I have your thoughts on that?   Dr. Marc Braunstein: Sure. In the context of how our therapies are improving, our approaches to how we manage patients clinically is changing too, in many ways for the better. So, various models exist for, you know, which practitioners manage oncology patients who happen to be admitted to the hospital. This abstract, which was performed by authors at a large medical center in New York, describes the use of a dedicated hematologic malignancy hospitalist for managing medicine-related issues. And the authors did comparisons of that service to a service primarily managed by oncologists. The authors compared things such as length of stay, whether the patients were discharged by noon, which is a hospital metric that's used for facilitating turnover of patients and space availability, as well as 30-day readmission rates among patients cared for by an oncology attending versus this heme malignancy hospitalist between July of 2021 and July 2022.    The outcomes showed that admissions to the heme malignancy hospitalists were, although less because that service was primarily for patients who required medicine-related issues as opposed to primarily oncologic issues, there were 95 admissions to that service versus 669 to the oncology service. There was a significantly shorter length of stay on the heme malignancies hospitalist service by about 2 to 5 days compared to the oncology hospitalist service. The rates of patients who were discharged by noon or the length of stay were similar between the two groups.    So, while this study is confounded by differences in acuity of disease between the services, using a dedicated heme malignancy hospitalist has many benefits, not just to offload the oncology-managed service, which may have a higher level of acuity, but also allow for a deviation of care for medicine-specific issues, to a hospitalist that's specifically trained in managing patients with hematologic malignancies and then dedicating the oncology specialty service to those who need acute oncologic care, such as those with leukemia or other high acuity diseases.    Dr. John Sweetenham: Thanks, Marc. I think it is really interesting to see some outcome data for this model of care. A number of centers I know are looking at an APP-led inpatient service for these types of patients, too, so it's going to be very interesting to see how further studies of these kinds of approaches continue to develop.    And on a related theme of changes in patterns of care, Abstract TPS1609 looked at home infusion and of course, this is something that really started to attract a lot more attention during the COVID-19 pandemic. But I wonder if you could walk us through some of the details of this poster.    Dr. Marc Braunstein: This study was presented as a poster proposing a prospective study looking at home infusion of the anti-CD38 monoclonal antibody daratumumab, which has a vital role in managing patients with newly diagnosed or relapsed multiple myeloma. And monoclonal antibodies have really revolutionized the care of patients with multiple myeloma, but often their infusion schedule is weekly or biweekly, and it does require relatively frequent visits to an infusion center.    So, this single-arm, open-label study is going to examine whether we can provide home administration of subcutaneous daratumumab and assess whether it improves quality of life and assess its safety. So, in this study, a visiting nurse will come and deliver the medication after patients take their pre-medications at home prior to the arrival of the infusion nurse. And then the investigators will provide quality of life questionnaires prior to and after the infusions and at the end of the study, and they'll be looking at any barriers to adherence, any barriers to the logistics of this home infusion arrangement.    And I think that this has a lot of potential not just to improve quality of life, but also to facilitate care to patients who may be frail, who may not have good caregiver support, who may have barriers in traveling to an infusion center or perhaps in places that are more resource-deprived and don't have local infusion centers. This could be a potential approach to delivering vital anti-myeloma medications at home, and I'm looking forward to seeing the results.    Dr. John Sweetenham: Yeah, I agree. I think a lot of us still have anxieties about the safety of this approach, but I think there are increasing data to suggest that home infusion is not only safe but also, as you mentioned, is a big enhancer of the quality of life of these patients. And so, very interesting to see how this plays out in prospective studies.    So, to close out, I wonder if you could walk us through Abstract 7072, a poster looking at the issue of clonal hematopoiesis.    Dr. Marc Braunstein: Clonal hematopoiesis, which is a phenomenon in which the blood cells acquire somatic mutation, is associated with both cardiovascular disease adverse outcomes as well as hematologic malignancy. It's been shown to be a precursor for diseases such as leukemia. So, this relatively small study from MD Anderson Cancer Center examined clonal hematopoiesis in 78 patients with malignancies, 70% of which had a history of cancer, and the authors described outcomes associated with clonal hematopoiesis.    So, again, 78 patients were examined, and 76% of them had a history of malignancy, and 73% had other comorbidities. And the authors demonstrated clonal hematopoiesis by the finding of specific mutations in the blood associated with clonal hematopoiesis. The authors essentially looked at outcomes such as mortality. They noted that only 20% of the patients developed a myeloid neoplasm, and that's relevant because, again, clonal hematopoiesis is a precursor for myeloid neoplasms. They also noted that most patients had died from a primary malignancy rather than a myeloid neoplasm, which is not too surprising considering that most patients with clonal hematopoiesis will not develop a hematologic malignancy, but it is a marker for the potential transformation.    And so, I think the authors conclude that clonal hematopoiesis is important for monitoring patients who are at risk for potential myeloid transformation and hematologic malignancy, but it's not necessarily the case that patients who have a background of malignancy will often develop a myeloid malignancy. I think there are many implications of clonal hematopoiesis for cancer in general in terms of the risk of secondary malignancies in those treated with adjuvant chemotherapy, in terms of how we monitor patients who actually more and more are going to have this detected as we use more next-generation sequencing and liquid biopsies.     So, I look forward to future studies that are exploring how to actually prospectively assess clonal hematopoiesis and use it for clinical stratification for things like adjuvant chemotherapy or monitoring for risks of hematologic malignancy.    Dr. John Sweetenham: Thanks, Marc. I agree. Very important for the future, especially as we gain more and more sequencing data.    So, Marc, in conclusion, I want to thank you very much for sharing your insights with us today on the ASCO Daily News Podcast. It's been great to talk with you again.    Dr. Marc Braunstein: My pleasure. Happy to be back, and I look forward to a future podcast session.  Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstracts discussed today in the transcripts of this episode. Finally, if you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Find out more about today’s speakers:   Dr. John Sweetenham   Dr. Marc Braunstein   @docbraunstein      Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn       Disclosures:   Dr. John Sweetenham:   Consulting or Advisory Role: EMA Wellness   Dr. Marc Braunstein:   Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb/Celgene, Adaptive Biotechnologies, GlaxoSmithKline, ADC Therapeutics, Janssen Oncology, Abbvie, Guidepoint Global, Epizyme, Sanofi, CTI BioPharma Corp   Speakers’ Bureau: Janssen Oncology   Research Funding (Institution): Janssen, Celgene/BMS        

Drs. Vamsi Velcheti and Jack West discuss ADAURA, KEYNOTE-671, and KEYNOTE-789 trials in NSCLC and the first pivotal study of sunvozertinib for the treatment of NSCLC with EGFR exon 20 insertion mutations. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast. I'm a professor of medicine and director of thoracic medical oncology at the Perlmutter Cancer Center at NYU Langone Health. My guest today is Dr. Jack West, a thoracic oncologist and associate professor in medical oncology at City of Hope Comprehensive Cancer Center. Today, we'll be discussing practice-changing studies and other key advances in lung cancer that were featured at the 2023 ASCO Annual Meeting.   Our full disclosures are available in the transcript of this episode and disclosures of all guests on the ASCO Daily News podcast are available at asco.org/DNpod.   Jack, there was a lot of exciting new data that emerged from the ASCO Annual Meeting, and it's great to have you back on our podcast today to talk about all the key updates in lung cancer.   Dr. Jack West: Absolutely. Thanks so much. It's always a high-energy meeting, and there was a lot to talk about in the lung cancer sessions this year for sure.  Dr. Vamsi Velcheti: Let’s begin with LBA3, the ADAURA trial. This was presented in the Plenary Session at ASCO; we've heard previously the DFS updates from previous meetings, and overall survival updates were presented at the ASCO 2023 Annual Meeting. So, Jack, what was the highlight of the presentation for you? And could you put things in context for us? We have known about the DFS data for a while now. What gets you so excited about this study?  Dr. Jack West: Well, we've actually been focused on this trial for literally 3 years, since Dr. Herbst presented it at another Plenary presentation back in the ASCO Meeting in 2020 when we saw tremendous differences in the DFS data. Again, this was a trial of patients with resected stage 1b to 3a EGFR mutation-positive non-small cell lung cancer. Nearly 700 patients were randomized to after-surgery, and for many, but not all, patients undergoing chemotherapy, it wasn't mandated. But after that, they were randomized to get adjuvant, placebo, or osimertinib for up to 3 years. And we saw huge differences in the disease-free survival from the first presentation, with a hazard ratio in the range of 0.2.   We have notably seen significant improvements in disease-free survival before with other EGFR TKIs for this population after surgery, but nothing in this range. And it's also notable that in the various other trials of other EGFR inhibitors in the postoperative setting, we've seen a DFS benefit, but that didn't translate to an improvement in overall survival. So, seeing a press release that this was associated with a significant and, in fact, highly significant by report, improvement in overall survival, as well as DFS, was really notable.   What's also, I think, particularly important as a focus of this is that in the later presentations of this work, with longer follow-up last year, we saw that the DFS curves showed a drop in the DFS starting after these patients had completed 3 years of treatment. So, really suggesting that at least some, if not many or most of these patients who had been on adjuvant osimertinib were subject to a higher risk of relapse once they completed that. So, again, making the endpoint of overall survival particularly important. It's always been to me the endpoint we should care about most in a curative setting. Although the DFS was the primary endpoint of the study and it was powered and built around specifically focusing on the DFS difference, so overall survival was reassuring, I think, when we actually saw it, but not what the trial was centered around.    And what we saw was a very dramatic improvement in overall survival with a hazard ratio of 0.49. That was essentially the same for the patients with stage 2 to 3a disease, as well as the broader population with stage 1b to 3a disease. When we look at the absolute numbers for overall survival at 5 years, there was an improvement from 73% to 85% with osimertinib, and in the population from 1b to 3a, an improvement from 78% to 88%. So, many things to comment on here. Really remarkable to see an 88% 5-year survival in the osimertinib arm that includes patients with stage 3a disease.    I would say that there's still some controversy, some questions about this, and it really centers around a few things. One is, like many global trials, this one enrolled patients from many places that did not have the same standard of care staging that we follow in the U.S. There wasn't any specification or mandate for PET scans, which would be very routine in the U.S. And brain MRIs were not mandated either. And so there were almost certainly some patients with more advanced disease that was not detected that would be a big advantage for the osimertinib arm, but really not characterized. And also, the crossover was made possible to osimertinib starting in April of 2020, but only 38.5% of the patients on the control arm actually received osimertinib at the time of relapse. And even though many of the other patients who had a relapse did get another EGFR inhibitor, I don't think there's much question that osimertinib is the preferred and optimal EGFR TKI.   And so there were a couple of important factors kind of going for this trial. One is the long, long, long duration of treatment at 3 years, though with a drop-off, I think some questions about whether even that is enough, and we might be tempted to treat beyond 3 years. And then how much did the inability of most of the patients on the control arm to get osimertinib later contribute? My personal view is that it is a troubling aspect of this trial. But also so many other trials that they're run globally in places where we arguably perpetuate these disparities by running these trials that, in part, magnify the differences between the two arms because some patients just will not have access to what is our best standard of care in the U.S., or many other parts of the world, but weren't necessarily available to many of the patients on the control arm where it was conducted. So, I think that's always a concern. It's definitely an issue of this trial, but I would not say it's unique to this one.  Dr. Vamsi Velcheti: Very good points, Jack, and I completely agree with you. I think those certainly are concerns. But on the other hand, this is a pragmatic trial and that's the real-world scenario in terms of access issues, in terms of osimertinib globally, correct, in the stage 4 setting, even though we all agree that osimertinib is the best option for patients with metastatic EGFR-mutated lung cancer, I think that's obviously a reflection of global access issues and global disparities and changes in standard of care in terms of workup as well. So, it's somewhat of a pragmatic trial in some ways and I completely agree with you, I think that may have potentially had some impact on the overall survival.  Dr. Jack West: Well, I would clarify that I don't think that this really highly significant difference in overall survival is undermined completely by this. There's no question in my mind that with the huge difference in disease-free survival that we'd already seen for 3 years, it has become our standard of care really for this population at least to offer it, if not to strongly recommend it. But I would say that most of us have been quite inclined to recommend it, perhaps with caveats. And I would say that this overall survival benefit mostly corroborates that, even if there are some concerns about how these trials are done, but it's still an impressive difference that would lead me to only cement my practice of pursuing it in this setting. I just would love to re-examine how we conduct these trials and potentially potentiate disparities that exist and don't want to have our trials be more positive by capitalizing on that.   Dr. Vamsi Velcheti: Let's move on to the next abstract, LBA100; this is the KEYNOTE-671 trial. This was featured during the meeting’s Clinical Science Symposium. This is a study of pembrolizumab or placebo plus platinum doublet followed by surgical resection and pembrolizumab or placebo for early-stage non-small cell lung cancer. Jack, what was the key message from this trial, and do you consider this as practice-changing?  Dr. Jack West: This has been an area where we've seen really dramatic evolution in our practice patterns, specifically, at least for patients who don't have a tumor harboring an EGFR mutation or ALK rearrangement. I would say that there has been some momentum toward preoperative neoadjuvant therapy, specifically based on the CheckMate-816 trial that gave chemo with nivolumab versus placebo and showed a significant improvement in the pathologic complete response rate at surgery as well as event-free survival. The overall survival looks encouraging but is still early and hasn't met the threshold for statistical significance, and that's FDA-approved.   But we still question whether there's a value to doing anything in the postoperative setting. And the CheckMate-816 trial did not include that as part of the trial. It allowed postoperative management at the judgment of the treating physician but didn't really prescribe anything. We now have the results of several trials in the last few months that have added a component in the postoperative setting in addition to three or four cycles of preoperative chemoimmunotherapy. And the first one that gave us a glimpse was the AEGEAN trial presented by Dr. John Heymach at AACR in April of this year that looked at chemo and durvalumab versus chemo placebo and then followed by a year of durvalumab versus placebo after surgery. That showed results in terms of major pathologic response and event-free survival that are significantly better with immunotherapy. Not clearly superior to what we would see with CheckMate-816.   And then even more recently, we saw a monthly Plenary presentation from ASCO with the Neotorch trial presented by Dr. Shun Lu of China. This was a Chinese trial only that presented results just for patients with stage 3 disease thus far. This included patients with stage 2 or stage 3, but what we saw is stage 3 results and that looked at chemo with toripalimab for 3 cycles versus placebo and then a year of checkpoint inhibitor or placebo. This also shows a benefit with the addition of immunotherapy, but not clear if that's better than what we can already achieve with neoadjuvant alone with the Checkmate-816 approach.   And then what we have now is a presentation and simultaneous publication by Dr. Heather Wakelee of KEYNOTE-671. And this is really almost the exact same trial design as AEGEAN. It's 4 cycles of platinum doublet chemotherapy and it is for patients with stage 2 to 3a disease. And this gave 4 cycles of chemotherapy with placebo or pembrolizumab. And then after surgery, patients would go on in the investigation arm to a year of pembrolizumab or to the additional year with placebo. And this shows a significant improvement in event-free survival with a hazard ratio of 0.58. It's most prominent in patients with high PD-L1, where the hazard ratio is 0.42. But there's still a benefit in patients with PD-L1 less than 1%, where it's 0.77. And there was a trend toward better overall survival here, hazard ratio of 0.73. It does not reach statistical significance at this early point. It's still preliminary but certainly looks encouraging. And there are also significant improvements in major pathologic response, where less than 10%, about a threefold difference from 30.2% with immunotherapy compared to 11% with placebo. And a very impressive improvement in pCR rate, which is 18.1% with the chemo and pembro compared to 4% with chemotherapy alone. Not surprisingly, when we look at event-free survival, it's best in the patients who achieve a pathologic complete response, but pembrolizumab improved outcomes in event-free survival even for those who didn't achieve a pCR.   The real question I would say is does the addition of a year of checkpoint inhibitor therapy postoperatively add to what we already achieve with those first three cycles with chemo-neo or 4 cycles with maybe one of these other options? And these trials can't answer that question because they just include them as a package deal. There's no way to tease apart right now the component of what incremental benefits you get from that. And it certainly adds a year of time coming in for every 3-week infusions. Even if you space that out, it's still a year of coming in and getting infusions, potential cumulative immune-related toxicities, and a lot of cost versus potentially being done. And I think that really is the big question at this point of do you want to recommend something when we don't really have a precedent for much benefit beyond the first 4 cycles? Perhaps. Certainly, we give maintenance pemetrexed and other immunotherapies and there can be benefit there. So, I wouldn't say you necessarily cap that. But if there is resistant disease after the first 4 cycles you've already given 3 cycles, how much benefit is there? How likely is it that you're going to eradicate the last cancer cells with more?   That said, I think many patients, and oncologists myself perhaps included, are going to be inclined to err on the side of possibly over-treating, but at least trying to give everything that is part of a widely studied, FDA-approved approach once these options become available. I just think it's going to end up as a careful discussion with each patient about whether they'd prefer to just say they're done or do that extra year and really feel that even if it comes back, they've done everything that made sense to try.  Dr. Vamsi Velcheti: Very good points, Jack. So let's move on to another abstract, which is the LBA9000. This is the KEYNOTE-789 trial. In my opinion, this is the most important negative phase 3 trial in lung cancer in a while. This is a trial looking at pemetrexed platinum with or without pembrolizumab in patients who have EGFR mutation-positive metastatic non-small cell lung cancer. So, what are your key takeaways, Jack?  Dr. Jack West: Well, I would say essentially we've been waiting to figure out what is the best treatment approach for patients with acquired resistance after osimertinib. And most of the patients had received osimertinib for their EGFR mutation-positive non-small cell. This is essentially KEYNOTE-189 being run in the EGFR mutation-positive patients after they've exhausted at least the major benefit of EGFR TKI therapy.   What we saw was a hazard ratio for progression-free survival of 0.8. It didn't quite make it across the threshold for efficacy, a significant difference. And so it missed that efficacy boundary. And overall survival, the hazard ratio is 0.84, also missing the efficacy boundary. When you look at the actual curves, they show modest separation, nothing eye-popping, certainly compared to some of the other trials we're talking about. But I wouldn't say they show no benefit. And I think that's, to me, why there's really still a role for a nuanced thought process and maybe some discussion about how negative this is. This is not, in my mind, stone-cold negative with no patients benefiting from immunotherapy. This is a trial that really suggests that there's a subset of patients who are benefiting from immunotherapy.   And we've also seen going back to subset analysis of the IMpower150 trial and also the ORIENT-31 trial with sintilimab and a bevacizumab biosimilar, another anti-VEGF inhibitor. These trials both really indicated a benefit in this population after EGFR TKI therapy of immunotherapy combined with VEGF. I think there could still be a value in there. I don't want to be a Pollyanna or too open-minded, but I think that there was at least a suggestion that this could still be a fruitful avenue. I think that this is still something we should do additional studies on that could bear fruit. I wouldn't close the door and categorically say this is just never going to translate to any benefit for any of these patients.   Dr. Vamsi Velcheti: The key thing, though, is, like in EGFR mutant patients I think in the previous studies as well, the response rates with single-agent PD-1 have been very minimal. And I think one of the things that's actually very important to highlight is in the operative setting, the early-stage setting, unfortunately, some of the trials with immunotherapy have included patients with an EGFR mutation. And now we have a treatment option for those patients within the adjuvant setting, especially osimertinib. We just heard from the ADAURA trial, which has a clear significant overall survival benefit. So I think it's really important to test for EGFR mutation in all stages. And if somebody with the early stage has an EGFR mutation, adjuvant immunotherapy, or perioperative immunotherapy may not be the best option for those patients.  Dr. Jack West: Right. I agree with that, although it is interesting that the KEYNOTE-671 trial did have some small population of patients with an EGFR mutation, and in that subset analysis, they seem to benefit from the pembrolizumab. I would not say that we should divert from ADAURA, but I'm just not as sure that our previous statement and mindset that immunotherapy just categorically doesn't work for patients with driver mutations is that simple.   First of all, there is some heterogeneity about which driver mutation, and the ALK-positive patients seem to really get no benefit. But I think there's still some questions about immunotherapy for EGFR. Certainly, patients with KRAS or BRAF V600E seem to benefit like the broader range of patients. And I would also say maybe it's different whether you're giving immunotherapy combined with chemotherapy versus as monotherapy. So that's why I'm just not that sure we really can characterize this that well yet.   The one additional point I would make about KEYNOTE-789 and the potential role of immunotherapy is that some experts in thoracic oncology and general oncologists alike may prefer to introduce chemotherapy at a time of progression, but keep the osimertinib going, maybe particularly for patients with brain metastases, whether current or a history of them, where we really feel that the osimertinib adds a critical component to CNS control. We don't want to ever give osimertinib or probably other EGFR TKIs concurrently with immunotherapy. So that's just a factor that we'd really want to consider when we're prioritizing where to fit in immunotherapy, if at all.  Dr. Vamsi Velcheti: Thank you, Jack. And let's move on to the next abstract, Abstract 9002. This is a pivotal study of results from the sunvozertinib, which is an EGFR exon 20 insertion site mutation drug. There's some very promising data. Jack, how do you feel this study is going to influence practice?  Dr. Jack West: Well, this is not an agent we have access to broadly yet, but I was quite impressed by it overall. I didn't mention it. We talked about it in the pre-ASCO discussion, and it was really one that I would mark as potentially practice-changing when we can get it. DZD 9008 or sunvozertinib is a potent inhibitor of exon 20 insertion mutations, and this was 97 patients, and the majority had had a couple of lines of prior therapy. They had to have gotten chemo, and the response rate was 60%, and it was really comparable efficacy with the different mutation subtypes.   I think that the main thing that I would want to clarify a little better in my own patient population is how well the drug is really tolerated. We talked about that there was not really much grade 3 toxicity and that's true, but diarrhea rates were 67%, even though it was grade 3 and just about 8%. But grade 2 diarrhea or grade 2 rash in patients who are on this therapy, we hope for a long time, I think is something we shouldn't minimize. And I think that particularly our mindset about toxicity needs to be different when we're talking about giving a treatment for 2 or 4 cycles and then being done with it versus something we hope we're going to be giving longitudinally. And we really don't want to minimize the potential impact on the quality of life of patients who are experiencing grade 2 rash, diarrhea, or paronychia for months and months, maybe more than a year at a time.   But that said, this is twice the response rate if not more than that of what we have already had for patients with this molecular aberration with an exon 20 insertion. So I think it's compelling and I think that it's going to be really valuable to offer to our patients. I just would like to clarify better how well patients who are actually on it are feeling when you incorporate the potentially chronic toxicity issues.  Dr. Vamsi Velcheti: Thank you, Jack. And let's move on to the last abstract. This the LUNAR study, LBA9005. This is a positive phase 3 study that looked at tumor-treating fields or TTF therapy with standard of care treatments in metastatic non-small-cell lung cancer following platinum failure. This has been talked about a lot at ASCO, and Jack I'm eager to hear your key takeaways about this study.  Dr. Jack West: Well, we knew from a press release several months ago, I think back in February, that there was a significant improvement in overall survival with the addition of tumor-treated fields. Again, this concept that electric fields can lead to antimitotic effect and potentially downstream induction of immunogenic cell death and enhanced immune response, that's at least the concept. And it's of course established, has utility in patients with glioblastoma, although kind of, I would say underutilized because it can be cumbersome. And I think that's one of the things we need to factor in is that this is not the easiest approach to pursue.   But we don't have that many therapies that improve overall survival significantly in previously treated patients with non-small cell lung cancer. So, I think there's good reason to focus on this and ask how beneficial it is. It was notable, it was pretty much an even split of patients enrolled on the trial, 276 patients total, but about half had gotten chemo but not gotten immunotherapy before. And then the other half, I would say the clear majority, had gotten immunotherapy as well as chemo and got docetaxel-based treatment.     And the overall survival benefit was significant for the intent to treat total population with a hazard ratio of 0.74 and a difference in 3-year survival of 18% favoring the addition of tumor-treating fields on the chest versus 7% in the patients who didn't. It really seemed to separate between the patients who had not had an immune checkpoint inhibitor and got tumor-treating fields with the checkpoint inhibitor where the hazard ratio is 0.63 and those who got tumor-treating fields with docetaxel where the hazard ratio was 0.81. So it really wasn't significant in this population.  Toxicity, no real surprises compared to what we already knew about tumor-treating fields. Mostly dermatitis, but I would say that one of the kind of unmeasured issues is that this is a device that people have to wear on their chest carrying a battery pack with them all day long. It's essentially all the waking day, and so I think that's at least cumbersome. I wouldn't call it prohibitive, but it's a challenge. And I think we need to really ask whether the juice is worth the squeeze, whether the benefit is that compelling. And I question that when we're talking about an agent that doesn't significantly move the needle against docetaxel alone.   Again, this is a population where in the U.S. we have ramucirumab to add to docetaxel. Not everyone does that. It's not uniform, but that has a statistically significant, though modest survival benefit associated with that. We don't do better than that with tumor treating fields. And so, I think that this is an option that merits discussion and some patients may opt for it, but I suspect that most of my patients would not find the absolute difference to be that compelling for the challenges it incurs. I don't know what your perspective is here.  Dr. Vamsi Velcheti: I completely agree, Jack. And I think the study design and just the fact that the standard of care has changed over the last 5, actually 6 years since the study has been open. And I'm not really so sure I could really make much sense of the data in terms of the standard of care combination with TTF providing more benefit. And I think there are more questions than answers here and I'm not so sure which populations would benefit the most. And I think, I hate to say this, but this is a nice proof of concept. I hate to say this because it's a phase 3 study and it's a positive phase 3 study, but it's clinical relevance with the current standard of care, I think, I'm not really sure how much of an impact this would really have.    Well, Jack, I've really enjoyed speaking with you about these key advances in lung cancer that were featured at the 2023 ASCO Annual Meeting. Our listeners will find links to all the studies discussed today in the transcript of this episode. Thank you so much, Jack, for joining us today.  Dr. Jack West: Always a pleasure. Thanks so much.  Dr. Vamsi Velcheti: And just like that, we've reached the end of another enriching episode. But remember, like all good things, this too must come to an end, but only until we meet again. We really would like your feedback on the podcast. If you enjoyed the podcast, please rate, review and subscribe wherever you get your podcasts.  Disclaimer:    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today’s speakers:   Dr. Vamsidhar Velcheti   @VamsiVelcheti   Dr. H. Jack West   @JackWestMD   Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:    Dr. Vamsidhar Velcheti:   Honoraria: ITeos Therapeutics   Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus   Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline     Dr. Jack West:   Honoraria: AstraZeneca, Genentech/Roche, Merck, Takeda, Mirati, Regneron, Amgen, Abbvie   Consulting or Advisory Role: AstraZeneca, Genentech/Roche, Merck, Takeda, Mirati Therapeutics, Regneron, Amgen, Abbvie, Summit Therapeutics   Speakers’ Bureau: Takeda, Merck, AstraZeneca        

Drs. Allison Zibelli and Arielle Heeke discuss the NATALEE trial’s novel approach to high-risk HR+ breast cancer, the potential of delaying CDK4/6 inhibitors in HR+, HER2-negative mBC to decrease toxicities and costs in the SONIA trial, and de-escalation strategies in HER2+ early-stage breast cancer. TRANSCRIPT Dr. Allison Zibelli: Hello. I'm Dr. Allison Zibelli, your guest host for the ASCO Daily News Podcast today. I'm an associate professor of medicine and a breast medical oncologist at the Sidney Kimmel Cancer Center at Jefferson Health in Philadelphia. My guest today is Dr. Arielle Heeke, a breast medical oncologist at the Levine Cancer Institute at Atrium Health in North Carolina.  Today, we'll be discussing practice-changing studies and other key advances in breast cancer that were featured at the 2023 ASCO Annual Meeting.   Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/DNpod.   Arielle, it's great to speak with you today.   Dr. Arielle Heeke: Thank you so much for having me.  Dr. Allison Zibelli: Let's start with LBA500. This was the NATALEE trial of ribociclib and endocrine therapy as adjuvant treatment in patients with hormone receptor-positive HER2-negative early breast cancer. What are your key takeaways from the study, and how do you think this changes our approach to high-risk ER-positive breast cancer?  Dr. Arielle Heeke: Yeah, this was definitely the study for which many of us were waiting to see the results. It was exciting to see the results come through so quickly. As you mentioned, the NATALEE trial was a phase 3 study that evaluated three years of adjuvant ribociclib at a dose of 400 milligrams, which is a little different than what we're used to in the metastatic space at 600 milligrams. But essentially, it randomized patients to receive this 400-milligram dose with their adjuvant aromatase inhibitor therapy versus just the standard of care adjuvant endocrine therapy in patients that are high risk with early-stage breast cancer.   What made NATALEE somewhat unique is they defined high risk a little bit more broadly than we've seen in previous studies, such as monarchE. So, what I mean by that is NATALEE enrolled patients with stage 2 and 3 early-stage breast cancer. And notably, they allowed for patients that were lymph node-negative but had some other high-risk features, such as a grade 3 tumor or a grade 2 tumor with high-risk genomics, such as oncotype or a high Ki-67. So, by broadening who was eligible, NATALEE captured more patients at risk for recurrence. Of course, we know that recurrence is not specific for patients with lymph node-positive disease. We can see recurrence even with stage 1, but certainly, we start to see more recurrence risk as patients drift into stage 2 and stage 3.   In the NATALEE study, the majority of these patients did receive prior chemotherapy, which I also think is interesting. We've kind of seen in the metastatic space that sometimes chemotherapy can augment patients' responsiveness to CDK4/6 inhibitors. But specifically in NATALEE, 88% of patients had received prior chemotherapy, and ultimately, about a third of the patients were lymph node-negative.   So, diving into some of the results with this first analysis that we saw at ASCO, with the median follow-up for invasive disease-free survival of just 27.7 months, they were able to show that the risk for invasive disease was reduced by 25.2% with the addition of ribociclib plus endocrine therapy compared to endocrine therapy alone. And this three-year invasive disease-free survival rate was 90.4% for the combination therapy compared to 87.1% for endocrine therapy alone, which is an absolute difference of 3.3%. Additionally, patients treated with ribociclib and endocrine therapy had a 26.1% reduced risk for distant disease-free survival compared with endocrine therapy alone, and this was a rate of 90.8% for ribociclib with endocrine therapy compared to 88.6% with endocrine therapy alone, which correlates to an absolute benefit of 2.2%.    They did show results for overall survival as well, but again, follow-up was just a median of 27.7 months. So, data was essentially immature to show any true overall survival benefit from this approach. And in fact, only 20% of patients had completed three years of ribociclib at this data cutoff. And as a reminder, again, NATALEE involved ribociclib for three years compared to two years, which we've seen with other studies in this space.   Also, what was encouraging from NATALEE were the readouts for toxicities. Neutropenia is definitely a concern with this class of medication, and they were able to show that rates of neutropenia were overall lower than what we've seen in the pooled data in the metastatic space. And also that problematic QTc prolongation for which we have to get EKGs baseline two weeks and four weeks. They also showed that the likelihood of having QTc prolongation on this therapy was significantly less at that 400-milligram dose compared to 600.   I think the key takeaway is yes, this drug is effective as adjuvant therapy, which is perhaps not surprising since we've seen such promising results in the metastatic space, but numerically not as striking as what we have at this point with adjuvant abemaciclib, but of course, this is a newer study. We hope to see that continued separation of the curves as we were fortunate enough to see with the abemaciclib data, but obviously we'll be looking for additional analyses from NATALEE.    And then how this will change practice, of course, we'll have to wait to see if the therapy is approved for use in the adjuvant setting for early-stage hormone receptor-positive breast cancer, but it certainly will be a nice option for patients that struggle with GI toxicity kind of at baseline. But also, if they were previously on abemaciclib and were not able to tolerate due to the GI toxicity, this would be an option for them. Also, as mentioned, it's a broader patient population, so we can consider this perhaps for a patient with lymph node-negative disease.   Although we will have to ask ourselves that just because someone meets eligibility for the NATALEE  study, and if the therapy is ultimately approved, is it appropriate to give it to all those patients? Or do we need to still kind of think of this in the setting of the highest-risk patient, not just any patient with stage 2 plus disease? There was a lot of talk at the meeting, certainly about biomarkers and potentially using ctDNA to try to find these predictors of benefit from CDK4/6 inhibitor therapy, but obviously, still a long way to go before we can use that type of technology in this space.  Dr. Allison Zibelli: Thank you. Staying on the topic of CDK4/6 inhibitors, everybody was excited about the SONIA trial, which was LBA1000, and this trial was asking if we can delay using CDK4/6 inhibitors for newly diagnosed ER-positive HER2-negative metastatic breast cancer as a way to decrease both toxicity and cost. Tell us about this study.  Dr. Arielle Heeke: The SONIA trial was such a cool study to see, and the presenter reported findings in such a thought-provoking way. Really great to see this sort of work being done because I think we all wonder deep down in our gut, if more is more, or if we do need to kind of be a little bit more thoughtful about how we introduce these therapies certainly from a patient perspective. Patients that participate at ASCO [meetings] have been saying for years how important it is to consider the toxicities in terms of side effects, but also, of course, financial toxicities. So, it was great to see the SONIA trial at center stage.   Essentially, as you mentioned, it was a study that randomized patients in the first-line setting with metastatic hormone receptor-positive breast cancer to receive either first-line CDK4/6 inhibitor therapy or second-line CDK4/6 inhibitor therapy. So basically, there was a mandated crossover, so patients that received the CDK4/6 inhibitor first-line did not receive a second line and vice versa. Patients that were randomized to receive their endocrine therapy as monotherapy first line went on to receive CDK4/6 inhibitor at second-line. And the second-line endocrine therapy was fulvestrant in both of those situations.    We kind of run into this problem with patients now where we have so many therapies available to us that we don't typically run out of treatment options, but rather we run up against treatment toxicity or ultimate failure of the human body to keep up with the demands of ongoing therapy. So, again, while it’s maybe somewhat attractive to start treatments earlier using things first-line rather than second-line or longer, just kind of post-CDK4/6 inhibitor progression, you know using this CDK4/6 inhibitor again with a different endocrine therapy backbone is probably not offering a meaningful benefit to that many patients. So this type of study is so necessary to really try to help us frame who needs those therapies sooner and longer or perhaps is there a substantial portion of patients that we don’t need to put them through that sort of toxicity.   So that’s the SONIA trial. Some things to note about the patient population, these patients were a bit older than what we’ve seen in some of our metastatic CDK4/6 inhibitor trials. There was a median age of 64 and 87% were postmenopausal. Additionally, just 40% had received prior chemotherapy. And as is true for most of our studies, 91% have received palbociclib on study with just 8% receiving ribociclib. And the choice of the CDK4/6 inhibitor was per the treating provider, and at the time of the of study globally, palbociclib was the more commonly prescribed CDK4/6 inhibitor. But over the last year or so, data has certainly emerged favoring ribociclib in the metastatic setting.   On the SONIA trial, patients were monitored for a median of 37.3 months. And looking at the primary endpoint of the second progression-free survival, which is defined as the time for random assignment to the second objective disease progression or death, for those patients who received first-line CDK4/6 inhibition, had a PFS2 of 31 months compared to 26.8 months with second-line CDK4/6 inhibitor use. And this slight difference was non-statistically significant. So the conclusion was that time to second progression was not impacted by whether or not a patient received first-line CDK4/6  inhibition or second-line CDK4/6 inhibition. Additionally, there were no differences in overall survival between the 2 arms with a median overall survival of 45.9 months with first-line CDK4/6 inhibitor use versus 53.7 months in second-line CDK4/6 inhibitor use.  And that actually equates to significant differences in time on drug. The median duration of CDK4/6 inhibitor use with first-line therapy was 24.6 months compared to 8.1 months with second-line use. And by being on therapy for an additional 16.5 months if you use CDK4/6 inhibitor first-line, this, of course, leads to increased toxicity and certainly increased financial burden. And it was estimated that for each patient that receives this therapy first-line, there is an additional $200,000 spent on getting them the CDK4/6 inhibitor first-line, whereas the results from SONIA suggested that whether you use it first-line or second-line, the outcomes are essentially exactly the same.   And then specific for the SONIA trial, by conducting the study, they saved approximately €25 million on drug expenditure during the conduct of the trial. It’s just amazing when you take it to that scale. And then lastly just to mention, they looked at quality of life assessments as well and there were no differences in the two arms whether they got first-line or second-line CDK4/6 inhibition.  Dr. Allison Zibelli: I thought this study was remarkable, and it got a long ovation when it was presented at the meeting. I'm certainly going to use this strategy and prioritize who needs upfront CDK4/6 inhibitor therapy.  I think that we have to think of not just drug toxicity for our patients, but financial toxicity. A lot of these drugs have very high copays and the number one cause of bankruptcy in the United States is medical costs. So that's something we really have to keep in mind. I also thought it was very interesting that the study was designed in cooperation with the patient advocacy group and patients themselves were very enthusiastic about this study and helped design it and helped recruit to it. So all in all, I thought this was a remarkable study.    So moving on, LBA1013 was the TORCHLIGHT study of toripalimab versus placebo in combination with nab-paclitaxel for patients with metastatic or recurrent triple-negative breast cancer. Many of us are not familiar with toripalimab. Can you tell us about the drug and how it was used in this study?  Dr. Arielle Heeke: Yes, toripalimab is essentially an immunotherapy agent. It's an IgG4K monoclonal antibody that targets PD-1. In this study, TORCHLIGHT, patients were randomized to receive toripalimab versus placebo in combination with nab-paclitaxel in newly metastatic triple-negative breast cancer. The patients on study were randomized two to one to receive drug or placebo. The drug is given on day 1 of a 3-week cycle at 240 milligrams and then patients of course also receive nab-paclitaxel on a day 1 and day 8 schedule of a 21-day cycle. They did look at outcomes on the study based on PD-L1 positivity status and they assessed for PD-L1 with an IHC assay JS311 antibody that ultimately generated a combined positive score. And PD-L1 positivity was defined as a CPS of greater than or equal to one based off of this assay. In the study population, about a third of patients were- patients' tumors were CPS negative, a third had a CPS of 1 to 10 and about a quarter had a CPS of greater than or equal to 10. And then approximately 7% of the tumors had an unknown status.   And then getting right into the results, we were provided results in the PD-L1 positive subgroup as well as the whole patient population. Looking at the primary endpoint of PFS, there were significant improvements seen in median PFS with the addition of toripalimab to nab-paclitaxel, again in the first line setting with a median PFS of 8.4 months with the addition of the immunotherapy agent versus 5.6 months with placebo. And this was statistically significant.  And then in the intent to treat population, there were some numeric improvements, in median, progression-free survival at 8.4 months with the addition of toripalimab versus 6.9 months with placebo.   We also got some results with overall survival that were quite intriguing, although this initial analysis was not designed to necessarily prove statistically significant differences in overall survival. But again, there were some promising trends. Looking first at the PD-L1 positive subgroup, the median overall survival was 32.8 months with the addition of toripalimab versus 19.5 months with placebo. Breaking it down a little bit further based on CPS values, for a CPS of 1 to 10, median overall survival was 32.8 months versus 19.5 months. And then for those very high CPS or greater than or equal to ten, median overall survival was not reached in this group versus 18.3 months with placebo. Also, looking in the intent-to-treat population, there were also improvements in overall survival with the addition of toripalimab with a median overall survival of 33.1 months with the addition of immunotherapy versus 23.5 months with nab-paclitaxel alone. So potentially, depending on next steps of this study, we would potentially have an option to add immunotherapy that is not biomarker specific, meaning we can potentially provide toripalimab to all patients regardless of their PD-L1 status.  Dr. Allison Zibelli: Very interesting new drug to look forward to. So, one of the major themes of this year's meeting was de-escalation strategies. For example, LBA506 reported the three-year invasive disease-free survival of the PHERGain trial, which looked at eliminating chemotherapy for HER2-positive patients getting neoadjuvant therapy. Tell us about the design of this study and how will it impact the care of these patients?   Dr. Arielle Heeke: The design was very complicated. I had to look at it a few times to really make sure I got my head around it. But I think once you do figure it out, you can see how there might be a path forward in clinical practice. Although I think for all of this work, it's maybe not ready yet for primetime, but certainly thought-provoking. But the PHERGain clinical trial, I feel like we've heard about this study for a little while and this concept of de-escalation really kind of started in the HER2-positive space. But this study was a randomized study of chemotherapy de-escalation and early HER2-positive breast cancer using PET/CT as a marker of response to therapies that don't involve chemotherapy.   Patients were eligible for the study if they had stage 1 to 3a HER2-positive breast cancer with no prior therapy for breast cancer, and ultimately 356 patients were enrolled in a 1 to 4 randomization scheme with the majority of patients ultimately enrolled into the experimental group, which is called Group B. So, to break down Group A and Group B, Group A essentially were patients that receive typical standard of care, which at this point is TCHP for six cycles, neoadjuvantly or prior to surgery. Once they complete those cycles they move into surgery and then Herceptin-PERJETA adjuvantly for additional twelve cycles.  I should also note that this study was conducted prior to results of the KATHERINE trial that showed benefit of switching to adjuvant T-DM1 if there's residual disease. So, patients in Group A as well as Group B did not receive T-DM1 at any point. So, again, Group A is kind of your standard of care. Group B was the “experimental arm.” And so, what they did in this arm to assess potential de-escalation strategies, patients first received Herceptin-PERJETA alone for two cycles with or without endocrine therapy, if they were also hormone receptor-positive. But after those two cycles, they underwent a PET/CT, and then if a response was garnered, they would continue with Herceptin-PERJETA and again plus or minus endocrine therapy to complete six cycles total before proceeding on with surgery. Then if they were fortunate enough to achieve complete response at the time of surgery, then they just continued with Herceptin-PERJETA maintenance, whereas if they did not achieve a complete response at the time of surgery, then they actually received TCHP 6 times adjuvantly. So, the chemotherapy was introduced after surgery.   And then going back to that PET/CT time point, if patients did not achieve a response at that check-in point, after 2 cycles of Herceptin-PERJETA, at that point they were transitioned to chemotherapy with TCHP, again, for six cycles. So, either they could kind of ride all the way through if they got that complete response at the time of surgery with Herceptin-PERJETA only, or if at surgery there was residual disease, they went on to receive TCHP after surgery, or if they did not have a response on that interim PET/CT after 2 cycles of HP then they would go on to receive TCHP neoadjuvantly.    So, looking at the results, they actually had 2 primary endpoints. The first primary endpoint was rates of a complete response at the time of surgery in patients that had a PET response. So, PET responses were actually seen in nearly 80% of all the patients treated with Herceptin-PERJETA without chemotherapy. And in those PET responders, a complete response rate at the time of surgery was seen in approximately 38% of patients. So, 37.9% of PET responders actually achieved a complete response when they went to surgery after receiving Herceptin-PERJETA alone, which is pretty amazing. I mean, we're used to seeing higher complete response rates with neoadjuvant therapy for HER2-positive disease, but again, this is a chemo-free regimen so that is encouraging for that 38% of patients that really didn't need chemotherapy.   And then the second primary endpoint, and this was what we saw basically for the first time with the 2023 ASCO Meeting, was results for the 3-year invasive disease-free survival in Group B or this experimental de-escalation group. And ultimately it was shown that the three-year invasive disease-free survival and the intent to treat group B population was 95.4%, which met its statistical endpoint, or, basically the null hypothesis was rejected. They just needed some sort of outcome that was not worse in terms of the 3-year invasive disease-free survival of 89%.   And then looking actually at the patients that kind of did the best. So, the patients that were PET responders and achieved a complete response at the time of surgery and therefore really only ever received Herceptin-PERJETA, their three-year invasive disease-free survival was 98.8%. So, really very good. Additional endpoints they looked at in Group A and Group B were favorable in terms of three-year invasive disease-free survival in Group A, and then three-year distant disease-free survival and three-year overall survival in both groups, all approximately 98%. So, very favorable.   So, ultimately, these findings reflect a potential role for a chemotherapy-free treatment approach for some patients with early-stage HER2-positive breast cancer. And this particular study, they used PET/CT to influence chemotherapy decision-making, which potentially identified 1 in 3 patients who can omit chemotherapy. With that, 80% of patients receiving the response with a PET/CT, and then of that, 80%, again, 38% actually having that complete response. And ongoing work is also being done to look at other mechanisms to assess for an opportunity to de-escalate with MRI imaging or HER2DX testing to again try to identify patients who can potentially defer chemotherapy in this setting. I did not see from the results what proportion of patients were hormone receptor-positive, which I think is also interesting when thinking about chemotherapy de-escalation, can you lean a little bit more heavily on endocrine therapy? Perhaps we'll get that data in the future.   Dr. Allison Zibelli: That's a very important point.  I would like to thank you, Dr. Heeke, for coming on the podcast today and sharing your valuable insights with us. We really appreciate it.  Dr. Arielle Heeke: Absolutely. It was a great meeting to dive into. It's always exciting to see what comes out of ASCO in the breast space. We're usually well represented there, and I hope that these studies will lead to further exploration.   Dr. Allison Zibelli: And thank you to our listeners for joining us today. You'll find links to all abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.  Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Follow today’s speakers:   Dr. Allison Zibelli   Dr. Arielle Heeke  @HeekeMD     Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:    Dr. Allison Zibelli:    None Disclosed   Dr. Arielle Heeke:   Honoraria: Merck  Consulting or Advisory Role: Jazz Pharmaceuticals, Caris Life Sciences, Amgen, Daiichi Sankyo/Astra Zeneca, Pfizer, AstraZeneca, Menarini, Genome Insight  Speakers’ Bureau: Daiichi Sankyo/Astra Zeneca      

Drs. Nathan Pennell and Nancy Lin discuss emerging data on the growing problem of prior authorization and insurance denials in cancer care, their potentially harmful impact on patient outcomes, and what can be done to fix the problem. TRANSCRIPT Dr. Nathan Pennell: Hello, I'm Dr. Nathan Pennell, your guest host for the ASCO Daily News Podcast today. I'm the co-director of the Cleveland Clinic Lung Cancer Program and vice chair of clinical research for the Taussig Cancer Institute. More importantly, today, for this podcast, I'm also the editor-in-chief for the ASCO Educational Book. On today's episode, we'll be discussing the growing problem of prior authorization and insurance denials, and how that impacts both providers and patients in their ability to access cancer care.  Joining me is Dr. Nancy Lin, a breast cancer medical oncologist at the Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School. She's addressed this problem in a recently published article in the 2023 ASCO Educational Book, and she's joining me today to highlight some emerging data on the possible harms from prior authorization and insurance denials, and what we can do to fix this problem.  Nancy, thanks so much for coming on the podcast today. Dr. Nancy Lin: Thank you for inviting me. Dr. Nathan Pennell: Some of our listeners may have noticed that we also did a podcast a number of years ago on a similar topic when we were with the Journal of Oncology Practice, and I was kind of hoping that prior authorizations would not be as big a problem, now, probably 8 or 9 years later, and unfortunately, it seems like it has gotten even worse.  Before we begin, I should mention that our disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available on our transcripts at asco.org\DNpod. So prior authorizations were, of course, originally intended as a cost control on the overuse of expensive medical care. However, in recent years, it seems like prior authorization has been extended to, more or less, all medical care, including supportive care medications and essential cancer care interventions that we need to use in almost every patient. We're also hearing more and more reports on patients who are denied coverage, and I think the doctors can sympathize with this, with their increasing peer-to-peer requests. And this is leading to patients being forced to wait to receive second-best options, impacting their out-of-pocket costs. And potentially, we all fear this is impacting patient outcomes, although we really would like to learn more about how this is really impacting their care. So, Nancy, can you talk to us a little bit about how prior auth is impacting patient access to cancer care today? Dr. Nancy Lin: Of course, we all have to acknowledge that part of the impetus for prior authorization is just the increasing cost of cancer care. There are some recent statistics that the U.S. spends over $200 billion annually on cancer care and that oncology drugs are a huge part of the overall drug cost in the nation and a large part of the oncology drug budget. So, I think we can't deny that the increasing costs of cancer care are in part driving this drive for more prior authorization. But this has costs, and there are costs in terms of direct patient costs as far as their quality of care, and also costs in terms of the health care providers and health care system.   And so we, as part of our article, actually solicited patients to provide their stories. And in fact, in our article, we have selected, with their permission, 3 patients who share their experiences. And these are experiences that, as a practicing oncologist, you'll be very familiar with. A patient wrote that she had been on capecitabine for a year, her disease is responding, and all of a sudden, on a Friday late in the day, she's told, “No, you need a prior authorization now, and you can't get your drug refilled.” And that led obviously to stress and delay and whatnot. And then another example is of a patient whose oncologist requested what sounds like next-generation sequencing, some sort of tumor panel and was denied. And the peer-to-peer here had apparently indicated that they are not aware of the data for the use of genomic testing and cancer treatment, which clearly there is a role for the use of genomic testing in cancer treatment. And in fact, we now have many articles that show that there's unequal access and, if we look at underrepresented minorities or other marginalized groups, that there is a dramatic difference in the utilization of advanced molecular testing. And then just the overall experience on patients and their families feeling like, at a time when they're sick, need to take charge of all of this paperwork and back and forth with insurers that is very stressful.   And then, from a provider or health care system standpoint, many, many hours are expended on prior authorizations for things like very new drug approvals that are maybe not on a pathway yet, or very commonly, simple things like a CAT scan for restaging of somebody who has advanced breast cancer where every scan requires prior authorization or antiemetics, or somebody receiving highly immunogenic chemotherapy and these kinds of death by a thousand cuts I think is how people in the health care experience the aspect of prior authorization.  Dr. Nathan Pennell: It's one of these things where we used to get a peer-to-peer for say, atypical reason for a PET scan, which made perfect sense, and you'd have to talk to an experienced expert to explain what you were doing and try to get a good rationale for that. And now, it's come to the point where a routine 2-month, 3-month CT scan is getting denied and having to be talking to someone who's not as experienced in this. Again, it feels still like a collection of anecdotes though in many ways. Is there any sort of published data on denials of care and prior auths and how this is impacting approvals and patient access? Dr. Nancy Lin: There are survey data, which one has to admit is not necessarily gold-standard data, but there are data from the American Medical Association, as well as a 2022 ASCO member survey. And in that ASCO member survey, over 90% of oncologists reported that they had personally experienced, in their patients, a delay in treatment related to prior authorization. Over 90% had issues getting needed diagnostic evaluations. Over 90% reported that they were, "forced to go to a second choice of therapy." And about a third of oncologists reported that they believed that the prior authorization, either delays or denial of care, led to changes or worsening of patient survival, which I think is the most concerning statistic of all.  Now, I think that one can argue that these are essentially physician self-report and what's the gold standard as far as whether there has been an impact? But I think that the fact that these reports are so prevalent means that, even if the reality is half of what has been reported, it's still a lot. And I think that  the power of these kinds of surveys is just enormous, that a high prevalence of the problems have been reported, I think, points to something even if we don't have gold standard quote data now.  Within our institution, Dana-Farber, we have done an analysis of oral medication prescribing. So, we do have gold standard and very granular data on patients that we've seen. And we've seen denials and requirements of prior authorization not only for expensive cancer medications and growth factors but also for even medicines like generic tamoxifen, which, honestly, how does that need prior authorization in this day and age? Medications like supportive care, antiemetics, and really things that ultimately, we were able to get approved 97% of the time, but [prior authorization now] introduces a delay and introduces stress. And although one may not be able to measure a so-called negative outcome from a patient recurrence standpoint, I think that there are other kinds of negative outcomes that are important, including just the experience of a cancer patient undergoing treatment, the stress of all of the denial letters and the delays that can occur as a result. Dr. Nathan Pennell: And it's not just patients. Obviously, we want to be patient-centered in our care and focus on how this impacts them. But this is also significantly impacting practitioners and cancer centers and physicians and the administrative burden of having to do the prior authorizations, which of course are not standardized in any way and vary from payer to payer and geographic area to geographic area. Is there data on how the changes in prior auth have impacted practices and physicians? Dr. Nancy Lin: Yes. In fact, there have been several surveys as well as in the practice types of studies trying to understand the staffing that is required to manage the prior authorization requests. And some of the estimates are an additional 40 hours per week per oncologist, that’s a full-time position. Some of these tasks can be carried out by non-oncology-trained providers but many of them do require either the oncologist or a nurse practitioner equivalent to be on the phone for the peer-to-peer or a full-time clinical provider and you are given a 4-hour window to do a peer-to-peer in the middle of clinic, that’s very disruptive. And I think that that’s fine if it’s every now and then for drugs that we all agree are perhaps outside of their usual indication. But if this is every CAT scan and every brain MRI and every time we prescribe an oral drug, it really does affect both clinic workflow, and just the psychology; I think it really contributes to burnout.  There was a very interesting survey actually of oncology trainees who, not even to the point where one is an attending physician, but at the trainee level indicating that this was something that was causing them a lot of distress, and in some cases, questioning the whole idea of going into medicine. And then when you think with the attrition that we’re seeing in the health care workforce, we do really have to be careful about these burnout issues because we really can’t afford to lose a lot of oncology staffing as the patient population ages and we’re seeing higher prevalence of cancer. I think it’s imperative that we take care of our oncology workforce. And I think this survey was very interesting because it went beyond the attending physician to other levels of oncology care, all of which are affected.  And there have been, as you know, many growing or nascent attempts at various residency programs to think about unionizing and what are the kinds of concerns or complaints that trainees bring up. And one of [the complaints] that  comes up a lot is, “We have to do these prior authorizations and there’s all this administrative paperwork that doesn't require an entry-level person.” I’m not saying that they should or shouldn’t do it - I’m not going to take a position on that - but the fact is that somebody has to do it in the current system, and whoever does it, it causes burnout. And I think that that is important. And the other piece of it has to do with equity and access to care because we’re coming from academic institutions. We have a staff of people who help with prior authorization. That's not true in every practice in the United States. And I really worry about not so much denial of care but even a step beyond that, which is if you are in an under-resourced office and it’s too hard to get certain things done, you don’t do them because you just don’t have the ability or you don’t have the staffing to be able to find insurance. And I think that is very concerning to me in terms of access to care, access to some of our immune-targeted therapies, and access to the optimal support of care medications. We come from very well-resourced places as far as the administrative staff, relatively speaking, and that’s just not true everywhere.  Dr. Nathan Pennell: This whole idea kind of falls under the idea of creating friction in the system to try to slow things down. I've seen data suggesting that things like peer-to-peer requests for appeals actually lead to a majority of physicians not having time or taking the time to actually do that. And that may be sometimes because they know it's indefensible and don't want to go through the process. But probably a lot of the time it's just because they don't have time to do it in their busy day and those patients then don't get their care covered. So, it's really a problem.  Now, the other thing that is really remarkable to me is, this is 2023 and everything is so technologically advanced. You can make major financial transactions electronically on your phone in just a few seconds, really complicated things. And yet this kind of [prior authorization] process really is still often done over the phone and by fax and with 100 different systems that don't talk to one another. And at the same time, oncology is becoming more and more guideline-driven where what we do actually have is really good evidence behind it. And there are even published guidelines for almost every disease and line of care about everything that we do from scan intervals to what kinds of treatment and how often and what supportive care is necessary. So, this would seem like an optimal situation for a technology solution where we tie in guidelines to what should and shouldn't be covered. What's going on out there in terms of trying to fix this? Dr. Nancy Lin: Some important questions are: Who makes the guidelines? What are the regulations as far as which guidelines insurance might adopt - their own internal guidelines or NCCN or comparable organizations? And what do you do when somebody wants to deviate from the guideline or pathway? And then finally a practical question, which is you don't really want to have a different platform and a different guideline for every insurance plan for every patient. And I think that is a little bit of even if we move to a purely electronic system, that will still be a problem.  The state of Florida had done this pilot study that tried to use or incorporate the NCCN guidelines as part of their approval or review process for prior authorization requests and at least based on the report that's published, saved $15 million in costs. And we would hope if the care was more NCCN guideline-concordant, which has been shown to improve outcomes, that would have been done without a detriment to patient outcomes. I don't think we have enough granular information to be 100% sure of that, but I would assume that that's most likely the case. I do think that some amount of guideline use could be useful.   And one of the things that we proposed in our article was the idea that one could create a sort of gold card system such that if a provider or a practice, for example, adheres to certain pre-agreed-upon guidelines or pathways more than 80% of the time, which is sort of considered good adherence and taking into account patient preference and comorbidities and whatnot, that that practice or provider could be sort of gold carded, so to speak, and actually have many of the prior authorization requirements go away so long as that is adhered to. And so that's one idea.  One of the concepts that Dario Trapani, who was the first author of our paper, put forward is that you don't necessarily need every person to be compliant with every guideline. Generally, you need for there to be compliance and that there could be different categories of treatment so that supportive care medications, pain medications for cancer-related pain, could potentially be exempt from prior authorization requirements completely. And then at the same time for other kinds of prior authorization requests, it's not enough to just change a fax form to an electronic form. That's an improvement from having faxes going back and forth by paper, but really isn't a fundamental change in the prior authorization process or vision. And so, this idea of the pathways and then only when something is deviated in some sort of major way in various categories to be determined that sort of triggers a peer-to-peer review that would both hopefully serve the purpose of reducing overuse of unnecessary or non- indicated treatments and save money. But also, in a way, I think that is less burdensome to the health care system. And I fully acknowledge that I am not a policy expert, I mostly research metastatic breast cancer, but this issue really affects us all very personally every day.   Dr. Nathan Pennell: I know you just said you're not a policy expert, but can you talk to us a little bit about what Congress and ASCO are doing to help from a legislation standpoint or a regulatory standpoint to help make this a little bit less painful? Dr. Nancy Lin: Yeah. So ASCO has endorsed the so-called “Improving Seniors Timely Access to Care Act.” And for those out there listening, particularly patients, you might say, “Well, I'm not a senior.” But it's important because how Medicare deals with issues often is then adopted by private insurers. And so starting with “Improving Seniors Timely Access to Care Act,” the intent is that it will also affect people with cancer at all age groups. But some of the provisions or the proposals are to convert to an electronic prior authorization system, to put systems in place for timely and efficient communication between providers and insurers, to ensure a process for real-time decisions that have some timeframe or timeline or deadline associated with it, to facilitate guidelines and pathway-informed decisions, and to also, importantly, be fully transparent about approvals and denials, portions that are denied, these sorts of reasons for denials, to really have transparency in that process which at the moment does not really exist. I think these are all very, very important steps with the overarching goal to promote timely and appropriate access to medications, procedures, and evaluations for oncology patients. Dr. Nathan Pennell: I'm just curious, in your opinion, do you think that there is actual inertia to try to change some of these things from a policy perspective? It can be kind of frustrating sometimes. It seems like the insurance industry has really kind of taken command of this by implementing these and we see the problems and we talk about them. But from a regulatory standpoint, it really seems like things are kind of maybe being a little bit neglected. Dr. Nancy Lin: I think that this is really something where I do think there will be some movement; maybe it's that I'm an optimist and that's what you need to be to be an oncologist.  I think that a big part is going to be really a focus on the impact on patients because although we certainly feel the impact on ourselves as providers and our staff, I don't know that that in and of itself is going to be enough to move the needle, like doctors complaining that they are having to spend too much time on the phone. I think the real impact is really related to the impact on patients. And as I said, I think that the AMA survey and the ASCO survey, those are very important because they really put the focus on [assessing] the impact on patients living with cancer.  Again, the limitations of a survey-based study are profound. And I do think that the current [White House] administration is very, very engaged in improving care for people with cancer. And in fact, part of this revised Cancer Moonshot [initiative] is not only better science around cancer and better molecular understanding of cancer but at the end of the day, if we can't get the right treatment to the right patient, it doesn't really matter how good the science is. And part of getting the right treatment to the right patient is not just training, guidelines and education. Part of it is just the practical aspect of insurance coverage as one important aspect of that. And so, I do think that there will be some movement on this because I think that it's really gotten to a point where this is not just inconvenient for doctors. I don't think that that's enough to drive anything forward personally, but I think that when you start to see impact on patients, that is really a big deal.  I was struck that one of the studies that we had identified was a study looking at over 13,000 chemotherapy requests and understanding how many were denied and why they were denied. And basically, about 11% of the requests ultimately were denied after peer-to-peer and all sorts of other appeals. And this was essentially the gold standard, so to speak. In this study was the oncologist's opinion as assessed by the so-called board certified oncologist, which is what was described in the publication employed by the insurer. We have these competing narratives and that is ultimately the problem: We have the AMA and the ASCO surveys which are survey-based asking the oncologists, and we have these data which are based on the insurer essentially as the gold standard arbiter. So it's hard to reconcile those two pieces of information because they're not really coming from the same place. And then I think you could also argue that, think about 13,000 chemotherapy requests, that means that essentially 90% were fine.  When we looked at our pathways employed at Dana-Farber where we check to make sure that our physicians are adhering to the pathways, we basically want to aim at about 80% with the idea that some patients decline a standard regimen, and we go to something else. They don't want alopecia with the idea that some patients have comorbidities, that you don't want to micromanage how oncologists are managing their patients. And honestly, in most pathway programs, we consider 80% to be pretty good. In this study, 80% were approved. And you might argue, is it worth reviewing 13,000 requests to this level of scrutiny for 90% to be approved? And again, I think that that really raises this idea of like rather than just switching a fax system to an electronic system to really rethink where's the low-hanging fruit? Where would prior authorization really serve a positive purpose? I think there are places where it could serve a positive purpose and where is it just adding unnecessary friction. Dr. Nathan Pennell: Yeah, it's a complicated picture and there are valid arguments on both sides. One of the things that is very appealing to me about the proposed legislation is requiring the payers to actually report and disclose their levels of denials and prior authorizations and this allow us to maybe take it beyond the anecdotal evidence to actually being able to document what they're doing. Because once you shine a light on things, sometimes it becomes a little bit harder to abuse the system.  Dr. Nancy Lin: Yes, I agree.  Dr. Nathan Pennell: Well, Nancy, thanks so much for coming on the podcast today to discuss this challenging problem. I know we could have talked about this for an hour or more. We really appreciate your work to highlight the impact of this problem both on providers and on patients, as well as outlining some efforts to find solutions. Dr. Nancy Lin: Great, thank you for having me. Dr. Nathan Pennell: I also want to thank our listeners for joining us today. If you value the insights you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Have a great day. Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today’s speakers: Dr. Nathan Pennell @n8pennell Dr. Nancy Lin @nlinmd   Follow ASCO on social media:     @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn     Disclosures:  Dr. Nathan Pennell:   Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron  Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi  Dr. Nancy Lin: Stock and Other Ownership Interests: Artera Inc. Consulting or Advisory Role: Seattle Genetics, Puma Biotechnology, Daichi Sankyo, Denali Therapeutics, AstraZeneca, Prelude Therapeutics, Pfizer, Olema Pharmaceuticals, Aleta Biotherapeutics, Artera, Johnson & Johnson/Janssen, Blueprint Medicines, Genentech, Pfizer, Seattle Genetics, Merck, Zion, Olema Pharmaceuticals        

Dr. Diwakar Davar and Dr. Jason Luke discuss advances in melanoma, including targeted therapy and the addition of LAG-3 inhibitors to checkpoint therapy, as well as promising checkpoint inhibitors in cutaneous squamous cell carcinoma and Merkel cell carcinoma in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar, and I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I'm delighted to welcome my colleague and friend, Dr. Jason Luke. Dr. Luke is an associate professor of medicine and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh's Hillman Cancer Center. He is a very, very well-renowned physician-scientist who has done fundamental work in developmental therapeutics and also in melanoma.  Today, we'll be discussing some key oral abstracts highlighting advances in immunotherapy in the cutaneous malignancy space that will be featured at the 2023 ASCO Annual Meeting.   You will find our full disclosures in the transcript of this episode and the disclosures of all guests on the ASCO Daily News Podcast are available in our transcripts at asco.org/DNpod.  Jason, thank you for coming on the podcast today. Dr. Jason Luke: Well, thanks so much for the opportunity. Dr. Diwakar Davar: So, we will go right ahead into the abstracts and the first one we thought we'd discuss is Abstract 9502, which is the RELATIVITY-047 study, specifically the 2-year results. This is the update. This has also been concurrently published at the New England Journal of Medicine Evidence online. And so in this publication and oral presentation, Hussein Tawbi, Georgina Long, and colleagues are talking about the nivo-rela data in the context of metastatic melanoma. So what is your take on this? What is your take on the data both presented and published and how would you contextualize this for the audience? Dr. Jason Luke: Right, so the RELATIVITY-047 study, as people will remember, randomized treatment-naive patients with metastatic melanoma to either receive nivolumab as standard treatment as a monotherapy or the combination of nivolumab and the anti-LAG-3 antibody relatlimab. And that study reported out a couple of years ago showing the improvement in progression-free survival as the primary endpoint. And at the time we saw that difference was approximately a 6-month absolute difference. And eventually, we saw there was an increase in the overall response rate also, again, approximately on the order of about a 10% change. What was interesting was that the overall survival initially was immature and that was an interesting follow-up point that we wanted to see. So I think what's important in seeing now this 2-year update of these data are the maintenance of the benefit for nivolumab plus relatlimab as compared to nivolumab alone across those measurements of progression-free survival and overall response rate.  Interestingly, the overall survival in the clinical trial actually did not meet the pre-specified threshold for statistical significance. That being said, when you look at the data presented in the Kaplan-Meier plots and you think about the difference, it really does appear that there's a clinically meaningful difference between these 2 groups. And the statistical cut point only missed by about .01. And so this is one of those areas where one wonders whether or not subsequent therapies may have impacted on the overall survival calculation because obviously, patients in this trial had not received ipilimumab or a PD-1 CTLA-4 combination. So the take-home message from me in this data set was that the benefit of nivolumab and relatlimab was sustained over time and there was no suggestion of any late toxicities that might make us concerned.   One advantage of this combination of nivolumab and relatlimab is the dramatically improved side effect profile relative to nivolumab and ipilimumab. So whereas immune-related adverse events that were serious, grade 3-4 is approximately 50% for nivolumab and ipilimumab, in the RELATIVITY-047 study, we see that the incidence of grade 3-4 toxicities for nivolumab and relatlimab is 17.2%, so that's less than half. So that's pretty attractive. And when we think about frontline management of patients, I think these data really support that nivolumab plus relatlimab is a reasonable consideration for some patients. And now I think the future question is really going to be, okay, well then who should get nivolumab and relatlimab versus who should still get nivolumab plus ipilimumab? Obviously, these data do not address that, and I think that that's probably the most important question for metastatic disease that's probably on the horizon. Dr. Diwakar Davar: Thank you, Jason, those are all fantastic points. It is interesting to note that as a result of the data, or really the lack thereof, the combination is actually not being launched in certain countries. So, for example, the German Health Authority, GBA, the Federal Joint Committee in Germany has decided against the acceptance of this agent because it does not accept event-free survival (EFS) as a patient-relevant endpoint. So it's interesting that we have an agent that is now going to be FDA-approved. It's already FDA-approved and available in the United States, but it will not be at least available in Germany and there may be other countries that decide favorably or unfavorably depending on how this OS data is viewed.   So pivoting to another LAG-3 inhibitor in this case fianlimab, we're going to discuss Abstract 9501. So Abstract 9501 essentially is describing a phase II trial that evaluated the LAG-3 inhibitor, fianlimab, along with the anti-PD-1 inhibitor, cemiplimab from Regeneron. The data is slightly different from what we have seen with RELATIVITY-047, the Opdualag combination. So Jason, how would you contextualize the fian-cemi combination in advanced melanoma in the context of what we've seen with RELATIVITY-047? If you could help us with that, please. Dr. Jason Luke: Yeah, absolutely. So before we dive into this specific abstract, it's, like you mentioned, probably useful to just put all of this in context. Targeting LAG-3 as an immunomodulatory approach has actually been in clinic for a decade approximately. And so the relatlimab phase 1 started quite a long time ago. And there was data for nivolumab and relatlimab in PD-1 refractory patients with melanoma that showed not a tremendously obvious level of activity. And so it was thought there that the only place they would see that activity was to go to a frontline randomized phase 2 and then phase 3 trial, as we just discussed.  In contrast to that, given all the data that had come forward about LAG-3 targeting with relatlimab, the group developing fianlimab took a different approach and rather treated a cohort of patients with treatment-naive melanoma to try to get an initial assessment right away of the activity as read out by overall response rate for this PD-1 plus LAG-3 combination, which is cemiplamab plus fianlimab.   And these authors have previously presented data about this combination from cohorts of patients who are treatment-naive who received this combination and described approximately a 64% overall response rate. And that's an impressive number in the treatment-naive setting. There's sort of a tension there to sort of say, well, wait a minute, the response rate in this single-arm study is 64%, but in RELATIVITY-047, the response rate was lower for the LAG-3 combination and I think that's not a fair comparison. We have to realize this is a much smaller group of patients that has the potential to have been somewhat biased towards a better cohort just because of where and when they were recruited to participate in this trial. All the same, I think that number does look impressive and suggest that this combination is active in the frontline.   Specific to this abstract, though, what the authors presented here was to update those previous data and then specifically also to focus on a cohort of patients who are allowed to have had previous treatment in the perioperative setting. So either neoadjuvant or adjuvant therapies. And in a subgroup of patients, they observed that even in the patients that had received adjuvant anti-PD-1 who went on to then progress later, they got actually a similar overall response rate at approximately 60% even in that group. And so I think that that seems like an exciting number as well. One would on first principles think that if patients got an adjuvant anti-PD-1, then a PD-1 LAG-3 combo could be less active. When and how the patients progressed or did not on that adjuvant therapy, however, I think makes a big difference. And given the relatively small sample size of patients that were included in this report, which is on the order of 20-ish patients who were in the previous PD-1 treated adjuvant cohort, I don't know that we can make super broad analyses trying to compare across the development programs.  What I would take from this abstract, however, is that it does appear that this other PD-1 LAG-3 combination cemiplamab plus fianlimab is also very active and certainly deserves to be investigated in similar clinical trial contexts as the nivolumab plus relatlimab combination that we previously discussed. And while it's not specifically stated here, that is happening, there is a frontline phase 3 trial for this combination of fianlimab and cemiplamab as well as adjuvant considerations, also ongoing. Dr. Diwakar Davar: So, thank you. We've seen a lot of LAG-3 data this last 2 months, the phase 2/3a RELATIVITY-020 trial has just been published in the JCO, I encourage people to read that. And so that was the evaluation of nivolumab and relatlimabin the post-PD-1 patient population that Jason alluded to, where the response rate that was observed was 12%. So we've seen a lot of interesting data, a lot of interesting survival data, and now a new potential combination with LAG-3 with fianlimab and cemiplamab from Regeneron. So it'll be a very interesting next couple of years as we see whether or not this new combination, how it shakes up against the established nivu-rela combination, again, albeit with the limitations of cross-trial comparisons and also how it performs against cemiplamab in this ongoing, as you alluded to, ongoing global phase 3 trial.  So, pivoting away from melanoma, now addressing the context of another cutaneous malignancy, a very high-risk one, Merkel cell carcinoma. So, Merkel cell carcinoma for those who are not necessarily treating a lot of this is a very rare and very aggressive cutaneous tumor. It's a neuroendocrine tumor of the skin. It's a cancer that's typically associated more than about 60% of the time with a cancer-causing virus, an oncogenic virus known as a Merkel Cell Polyomavirus.   And in this setting, checkpoint inhibitor therapy has been approved for the last couple of years, initially with a PDL-1 inhibitor, avelumab, and then more recently with a PD-1 inhibitor, pembrolizumab. And, at this point in time, there are three FDA-approved agents that are checkpoint inhibitors that are available for the treatment of this disease.   And CheckMate-358 was essentially a trial of nivolumab plus/minus ipilimumab in the setting of this Merkel cell carcinoma. So, Jason, what are your thoughts on how the addition of ipi did in this setting [in Abstract 9506]?  Dr. Jason Luke: Yeah, so I think this is a really interesting abstract because there's a slightly more context even than what you alluded to there. This study is an open-label, multi-cohort, but single-arm investigation where one cohort of patients received nivolumab alone and the other cohort received ipilimumab. It needs to be buttressed by a previous publication in The Lancet last year by the group at the Moffitt Cancer Center who also did a prospective study looking at nivolumab and ipilimumab. In that previous study that the Moffit group did, they got a response rate of 100%. All patients responded to the combination of nivolumab and ipilimumab in their study and that was quite provocative, suggesting that while anti-PD-1 alone has about a 50% response rate, adding ipi in that scenario then took it to 100. So these data were very much of interest because this could be a confirmatory data set to suggest for this rare tumor that perhaps a combination regimen should be preferred. Of course, one has to remember that adding ipilimumab to anti-PD-1 substantially enhances the toxicity profile. And these patients tend to be elderly that develop this kind of cancer, Merkel cell carcinoma. So that's a rather important caveat.   Just to get to the crux of what happened in this trial. As opposed to the previous Moffit trial, there actually did not appear to be a major increase in the benefit of adding ipilimumab, at least in this trial. Because again, in parallel cohorts, the NIVO monotherapy arm had a 60% response rate, which is roughly a little bit higher, but roughly in line with what we've seen previously. And the response rate to nivolumab plus ipilimumab was 58%. So, I mean basically the same. So, how can it be then, that we have this previous very high-profile publication that says 100% response? Now, we have a second publication that says adding ipi doesn't do anything - that's confusing, and I think it'll be really important to try to look at what were the differences between these two cohorts of patients. Did one of them have higher risk features, greater disease burden, et cetera? We don't really know that just yet, but trying to tease that out will be important.  This data also emphasized, though, the complexity around the dosing of ipilimumab. And in melanoma, we never really figured out what the best dose of ipilimumab was to give either alone or even in combination with a PD-1. And we don't really have time to get into all of it right away here, but there are multiple studies in melanoma that would suggest that giving ipi on an every 3-week dosing schedule is superior to giving it on a 6-week dosing schedule. In this study, they did use the 6-week dosing schedule. So, whether or not that could have made a difference, I guess, is unknown. But I would notice that in the previous Moffitt trial, they also used that six-week dosing schedule. This one's a head-scratcher for why did these data not confirm a previous data set? But for the time being, I think this emphasizes that PD-1 monotherapy really is the standard approach that should be considered for patients with metastatic Merkel cell carcinoma.  Dr. Diwakar Davar: That's great, Jason. And so, again, it's a very tough patient population. These are very rare patients. The Moffitt trial that Jason alluded to essentially was a trial that had in each arm, there were approximately 25 patients, of which 13, or between 11 to 13 patients were actually checkpoint inhibitor naive, wherein the dramatic 100% response rate was seen. And this is a trial where at least in this update, we've got about 25 patients in nivo monotherapy, I mean in 43 patients. And so, in a disease that is thought to be extraordinarily sensitive to checkpoint inhibitor immunotherapy because of the role of the virus and the high TMB that it's associated with, it is very interesting that the addition of an additional checkpoint inhibitor did not appear to improve outcomes. But as you alluded to multiple reasons, but we don't know how it's going to shake out. Next, Abstract 9507 and this is a very interesting trial known as the MATISSE trial. So, in the context of cutaneous squamous cell carcinoma, cutaneous squamous cell carcinoma is a relatively not uncommon cancer, primarily seen in older cancer patients, particularly a little bit more common in men. And in this setting, we've got checkpoint inhibitor therapy that is FDA-approved, at least two of which are FDA-approved right now, pembrolizumab and cemiplamab both were approved in the advanced cancer setting. And we do know that because of the extraordinarily high tumor mutation burden associated with cutaneous squamous cell carcinoma, checkpoint inhibitor therapy has got a very dramatic effect. Response rates are between 35% to 42% with pembrolizumab and 40% to 50% with cemiplamab, depending on whether or not one looks at the relapsed metastatic or the locally advanced patient populations.  And interestingly, much like we've seen with melanoma, we have migrated the use of this therapy early in the lines of patients, particularly in the setting of perioperative therapy. So, Jason, how would you contextualize the results of the MATISSE trial in relation to the existing and known data from several of our colleagues regarding the role of what checkpoint inhibitor therapy is doing in terms of organ preservation?  Dr. Jason Luke: Yeah, and I think this is an area of tremendous excitement. And as you were alluding to, the activity of anti-PD-1 really was transformative in this disease, which really can be a disfiguring and locally destructive disease. And with that activity for unresectable disease, last year, near the end of the year, there was a first report of a large neo-adjuvant clinical trial in cutaneous squamous which showed really outstanding results in terms of improving surgery and pathologic complete response using anti-PD-1 in that setting. And for this trial, this was a trial done in Europe; they took a similar tact of trying to think about giving anti-PD-1 or anti-PD-1 with anti-CTLA-4 with ipilimumab in that neoadjuvant period to see whether or not they could reduce the use of extensive surgery and/or radiation therapy.  The short version is they were able to do that. And so they described 40% of patients with single-agent anti-PD-1 and 53% of patients who received a combination having major pathologic response to treatment. And this was so much so that 10 of the patients who had pathologic responses actually withdrew their consent to go on to have surgery because they decided that they had had such a good effect of the immunotherapy, they weren't willing to put themselves through what was going to be a very difficult surgery. And I think that speaks to the upside potential of these checkpoint immunotherapy approaches in certain settings, specifically here in cutaneous squamous cell carcinoma. Moreover, they describe clinical response in neoadjuvant setting as 50% for PD-1 monotherapy and 61% for the combination and I really think that this is really ready for prime time.  With the study published in the New England Journal last year and these data now, I really think the field needs to start moving towards the use of perioperative anti-PD-1 with or without ipilimumab as a standard approach. And I think it's the case that even the NCCN and ASCO and various guideline societies are going to start acknowledging that this ought to be considered for most patients who are facing difficult surgical operations for continuous squamous cell carcinoma. Dr. Diwakar Davar: So, Jason, you bring up a fascinating point, which is the appearance of this in guidelines. So this is undoubtedly extraordinarily good data. It's confirmatory, the pathologic response rates in many ways paradoxically low. You'd expect something about 50% or so. But the reason it's low is because 10% of patients who actually benefited didn't undergo surgery. So really the degree of benefit is tremendous. It's about 50% to 60%. So the fascinating thing in the setting that we'd have is if one is going to try to get the drug FDA-approved, what we now have is the conventional setting in which one needs a definitive endpoint. And at least we know that pathological response rate is not a definitive endpoint in the context of melanoma or, for that matter, cutaneous squamous cell carcinoma. The only setting in which it is a regulatory endpoint is a non-small cell lung cancer or triple-negative breast cancer. But recently there’s been some very exciting data from another PD-1 inhibitor called dostarlimab in a trial done by your former colleague Dr. Luis Diaz when he demonstrated a dramatic result of dostarlimab in the context of perioperative rectal cancer where it is micro-satellite high wherein the standard of care is typically very disfiguring abdominal perineal resection.    So in the context of some of our listeners who might be thinking a little bit about how this pertains to regulatory approval, what are your thoughts about the paradigm of avoiding highly disfiguring surgery relating to what was seen in the rectal cancer discussion to what we’re now seeing with perioperative therapy in the context of cutaneous squamous cell carcinoma?  Dr. Jason Luke: I think it's a very important question. And the easy out for diseases that have a pattern of progression that is metastasis is to use event-free survival which can include both the pre-surgical and the post-surgical period in terms of looking for whether or not the cancer comes back. And that works for diseases potentially like lung cancer, like you said, maybe melanoma. In cutaneous squamous cell carcinoma, however, that's not probably going to work because this tends to be a locally invasive and less of a metastatic disease. So here then, we really need to have sort of organization across patient advocacy, dermatology, medical oncology to come up with what the most appropriate considerations are going to be for evaluating that long-term benefit because I think we need a tangible result that we can show the FDA. Everyone is really impressed by these results, and I think that next step is to craft this into a way that we have a measurable output that we can then go to them with and say bless this so that all of our patients can get this kind of treatment. Dr. Diwakar Davar: Really great discussion, Jason. And I think this is going to be an area of particular interest going forward, given both the number of trials that have been conducted in this space and also the role of the very interesting regulatory paradigm that has now been set initially at least with the rectal cancer that is microsatellite high and now potentially we will see with cutaneous squamous cell carcinoma.   And so the final abstract that we have selected for you is Abstract 9511. And this is a trial that was conducted by a mutual colleague, Dr. Ryan Sullivan, and his colleagues. And it's essentially a trial of looking at targeted therapy with or without navitoclax in BRAF mutant melanoma patients. And part of the reason to highlight this, it's very interesting preclinical data supporting the addition of navitoclax, b but also a great example of an early trial that came through the CTEP portfolio. And so Jason, can you tell us about why this is exciting and how we might contextualize the addition of navitoclax to the targeted therapy backbone?   Dr. Jason Luke: Sure. So listeners will be quite aware of targeting mutant BRAF as a therapeutic strategy across oncology that was really initially pioneered in melanoma with the development of vemurafenib as the first selective BRAF inhibitor. But the field, of course, moved eventually to BRAF and MEK combinations across essentially all settings. We know that dabrafenib and trametinib are now approved pan-cancer for anywhere we find a BRAF V600e mutation. In the context of melanoma, looking at mechanisms of resistance, we observed that they were quite heterogeneous with reactivation of elements of the mitogen-activated protein kinase pathway, the MAPK pathway. But also there were metabolic changes in the cancer cells themselves which could drive resistance and were downstream of some of those reactivation signaling points. So one of those is the induction of anti-apoptotic machinery in the cell. So activation of BCL-2 or Bcl-xL to try to save those melanoma cells when they were under stress by blockade with BRAF and MEK inhibitors. And that observation was made now about a decade ago or more. And that raised the possibility that repurposing a drug that was being used actually in the chemo malignancy space might be useful in augmenting targeted therapy. And that's where we come in with the navitoclax as a BH3-mimetic that can actually knock down those antiapoptotic proteins, BCL-2 Bcl-xL. And so that was the context for this initially phase I clinical trial of combining navitoclax with the dabrafenib and trametinib.  And those data supported the safety of doing that and moved to this study, which was a randomized phase 2 study of that triplet regiment versus the dabrafenib and trametinib alone. And so this study started quite a long time ago, before the sort of initiation or widespread use of anti-PD-1 antibodies. And so it had to kind of undergo some various iterations throughout its course but eventually has now read out. And it had two primary endpoints, with one being focused on improving the complete response rate for targeted therapy because that's been associated with long-term outcomes as well as to look at the maximum tumor shrinkage of patients within this trial and of course to look at other endpoints like response rate, progression-free survival, et cetera.  About half the patients who participated in the trial had prior immune checkpoint blockade and they were actually distributed evenly across the two arms. So we think that probably won't impact on the outcomes. And what was observed in the clinical trial was that in fact, the triplet did improve the complete response rate for targeted therapy. So navitoclax plus dabrafenib and trametinib had a complete response rate of 20% versus dabrafenib and trametinib alone being at 15%. Both of them had an overall response rate in the 80% range, with slightly higher for the triplet at 84% versus 80% for the double-edged standard therapy. There was also a suggestion that there may be a disproportionate benefit for the triplet actually in patients with smaller baseline tumors. And we know that the efficacy of targeted therapy is more pronounced in the lower-volume disease state.   And so overall, when we look at this without really adding much toxicity, I think this is an intriguing place to look at further drug development. BRAF and MEK inhibition has been a backbone therapy in Melanoma for a long time, but we really haven't been able to move past it or augment it in any real way because of the heterogeneity of treatment resistance. And here, by going after metabolic changes, we perhaps might have the opportunity to enhance our targeted therapy somewhat further. And so we'll look forward to further results investigating this regimen in subsequent clinical trials. Dr. Diwakar Davar: Fantastic discussion, Jason. So these are all great insights. As you've heard, we've now discussed a couple of key abstracts covering major topics that will be presented, major themes of the malignancy space at ASCO 2023, including the addition of a lactate inhibitor to checkpoint in both a randomized large phase 3 trial and a smaller phase 2 trial, the context of targeted-therapy in melanoma making another forerun in the post-3c setting. And two very interesting studies I have looked at, checkpoint inhibitor therapy in the context of cutaneous squamous cell carcinoma and Merkel cell carcinoma, addressing themes that are of huge importance going forward, including the role of perioperative therapy in squam and the addition of a CTLA-4 inhibitor in Merkel. These oral abstracts are all going to be presented at the 2023 ASCO Annual Meeting. We look forward to seeing you there.  So, thank you Jason for taking the time to join us and for highlighting these important advances in immunotherapy. And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. Thank you for your attention. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today’s speakers: Dr. Diwakar Davar @diwakardavar Dr. Jason Luke @jasonlukemd   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures:  Dr. Diwakar Davar:  Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences Consulting or Advisory Role: Instil Bio, Vedanta Biosciences Consulting or Advisory Role (Immediate family member): Shionogi Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences Research Funding (Inst.): Zucero Therapeutics Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy  Dr. Jason Luke:  Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical , Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof) Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio

Dr. John Sweetenham and Dr. Marc Braunstein discuss the role of maintenance therapy in high-risk multiple myeloma, advances in myelodysplastic syndromes in the COMMANDS study, the promise of bispecific antibodies in the pivotal EPCORE NHL-1 in relapsed/refractory large B-cell lymphoma, and improving outcomes for patients with chronic lymphocytic leukemia in the CAPTIVATE trial.  TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the associate director for cancer network clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast. My guest today is Dr. Marc Braunstein, a hematologist and oncologist at the NYU Perlmutter Cancer Center. Today, we'll be discussing key posters and oral abstracts highlighting advances in hematologic malignancies that will be featured at the 2023 ASCO Annual Meeting.   You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod.  Dr. John Sweetenham: So, Marc, thanks for returning to us and coming to join us on the podcast today. Dr. Marc Braunstein: Thanks for inviting me back. Dr. John Sweetenham: I'd like to start out with Abstract 8001. This is a study which is addressing the role of maintenance therapy in patients with high-risk multiple myeloma. Could you take us through this study and the key take-home points that you think are the most important ones? Dr. Marc Braunstein: Sure, absolutely. So, the first abstract that we're going to discuss is an oral abstract being presented by Dr. Nooka regarding maintenance therapy in high-risk multiple myeloma patients. Outcomes of patients with multiple myeloma are clearly improving, yet those with high-risk cytogenetic abnormalities, which represent about 10-20% of all multiple myeloma, tend to have poorer survival, and worst among these are those with what's called ultra-high-risk or double-hit multiple myeloma who have more than 1 high-risk cytogenetic abnormality. So, this study looked at maintenance therapy following stem cell transplantation in 26 high-risk patients, about 59% of whom had double hit disease, representing very high-risk disease. This was a phase II study looking at using carfilzomib, pomalidomide, and dexamethasone in high-risk multiple myeloma patients who achieved at least a partial remission following stem cell transplant. There were 26 patients enrolled. The median age was 60. Of note, about 59% of patients were Black, which is important because these patients tend to be historically underrepresented in studies. And what they found was that at study entry, about 24% of patients were in a complete remission or better, and that deepened to 79% while on the study. And the median time to best response was 2 months, which is fairly brisk. With a median follow-up of about 26 months, the 36-month progression-free survival was 63%, and the overall survival was 72%, which is impressive, again in the context of patients who have very high-risk disease. So, although it remains to be determined what the optimal regimen or duration of maintenance should be in multiple myeloma, clearly, combination therapy is effective and should be used in patients who have high-risk or ultra-high-risk multiple myeloma. Dr. John Sweetenham: Great. Thanks, Marc. So, as you say, I mean, clearly the take-home message is around the effectiveness of this type of maintenance therapy. I just have a couple of quick follow-up questions for you. The first of those is, where do you see this going next? I mean, in your opinion, what would be the next logical study with this combination or similar combinations? And then secondly, what do you see on the horizon for those patients with very high-risk myeloma, particularly the double-hit population that you just mentioned? Dr. Marc Braunstein: It's a paradigm in multiple myeloma that combination therapy tends to be more effective as long as we're able to manage the adverse events that come with additional combinations. And we've been able to succeed in that regard with quadruplet regimens, even now that we have monoclonal antibodies that tend to be better tolerated and more targeted in nature. In terms of maintenance therapy, single-agent lenalidomide has been the long-standing agent of use for the majority of patients. But we now understand that the combination of an immunomodulator like lenalidomide and a proteasome inhibitor like bortezomib or carfilzomib is more effective for patients with higher risk disease.   We also have data from various upfront studies of quadruplet regimens, such as the FORTE study, which looked at carfilzomib and lenalidomide maintenance after transplant that shows that we can improve progression-free survival in all comers with multiple myeloma following transplants. So, I think down the road we're going to be looking at more use of combination therapies and maintenance. And as far as for high-risk patients, whether that's going to be using monoclonal antibodies in maintenance or combination proteasome inhibitors and immunomodulators or even other immunotherapies like bispecific antibodies as maintenance in the future remains to be determined, but clearly, for high-risk patients, we should be using combination therapies. Dr. John Sweetenham: Thanks, Marc. Let's change gears a little now and take a look at Abstract 7003, which addresses patients with myelodysplastic syndrome. This study addresses the efficacy and safety results from a study of luspatercept versus epoetin alfa in low-risk myelodysplastic syndrome. I wonder if you could describe this study and the results to us and maybe also for the benefit of our listeners, just mention quickly the mechanism of action of the experimental agent here.  Dr. Marc Braunstein: This is an oral abstract being presented by Dr. Garcia-Manero looking at a phase 3 study, as you mentioned, called the COMMANDS study, and this is looking at an agent called luspatercept in patients with low-risk myelodysplastic syndrome (MDS). So, patients with MDS can have inferior quality of life and survival when they become transfusion dependent. An earlier study called the MEDALIST study, which was published in the New England Journal of Medicine in 2020, randomized low-risk or intermediate-risk patients with MDS who were refractory or unlikely to respond to erythropoietin stimulating agents to either luspatercept, which is an agent that binds to TGF-beta family members and helps stimulate erythropoiesis. Patients were randomized in the MEDALIST study to luspatercept or placebo. And that study showed that luspatercept could improve a degree of anemia and lead to transfusion independence in certain patients. So, the COMMANDS study is a randomized controlled study that randomized 354 patients with low-risk MDS who were transfusion dependent and naive to an erythropoietin stimulating agent to receive either luspatercept or the erythropoietin stimulating agent erythropoietin alfa with the primary endpoint of transfusion independence at some time between 12 to 24 weeks. So, patients were randomized 1:1 to receive either luspatercept or epoetin alfa, and the primary endpoint again was transfusion independence. So, 354 patients were randomized in the study and the median treatment durations were 42 weeks of luspatercept and 27 weeks of epoetin alfa. And transfusion independence occurred in greater quantity in the patients who got luspatercept. For example, in the patients who received luspatercept at 8 weeks, transfusion independence was achieved in 74 versus 51% in the epoetin alfa group. So, in terms of treatment-related adverse events, they were fairly similar between the groups and consistent with the classes -  they were reported in 30% in the luspatercept group and 17% in the erythropoietin group, with no difference in patients who progressed to acute myeloid leukemia.  So, I think when it comes to MDS in low-risk patients, it's really important to preserve their quality of life by limiting their transfusion burden. And I think this study demonstrates that luspatercept continues to be an important part of the management in these low-risk patients. And whether or not you would start a patient with low-risk transfusion-dependent MDS on an erythropoietin stimulating agent or luspatercept is really addressed by this study showing that you can achieve greater rates of improvement in anemia and transfusion independence with luspatercept.  Dr. John Sweetenham: Great. Thanks, Marc. A really interesting study. And I do have one question for you about this study, which I think will make it clear to you that I am an expert neither in myelodysplastic syndrome nor in erythropoiesis. But my question is based on the mechanism of action. Is there any rationale for combining these 2 agents in future studies?  Dr. Marc Braunstein: Yes, it would potentially make sense to use 2 synergistic mechanisms to improve erythropoiesis. We would have to see what the potential for adverse events are. I think epoetin alfa tends to be a fairly low burden in terms of its side effect profile. Luspatercept can have some potentially dose-limiting side effects, such as GI side effects, but you can make dose adjustments to both of these medications. So we may need to find the correct doses of either of them in combination. But from a theoretical standpoint, it makes sense that these could potentially be synergistic, especially in patients who are likely to respond to erythropoietin by having a baseline lower erythropoietin level. Dr. John Sweetenham: Okay, let's move on in another change of gear now. And for the rest of the podcast, we're going to be talking about some studies in lymphoid malignancy, beginning with Abstract 7535, which is a follow-up of the phase 2 CAPTIVATE study which now has significantly extended follow-up from the original report. So Marc, can you walk us through this study and the outcomes to date? Dr. Marc Braunstein: Absolutely. So this is a poster being presented by Dr. Barr and it is looking at CLL, which is a field that is really moving away from chemotherapy for newly diagnosed patients, thanks to the development of novel targeted agents. The CLL14 trial, which was published in the New England Journal of Medicine in 2019, showed that fixed-duration venetoclax plus obinutuzumab improved progression-free survival and rates of negativity of minimal residual disease, or MRD, when compared to chlorambucil and obinutuzumab. So building on the success of that study, combining a monoclonal antibody and a BCL2 inhibitor, the CAPTIVATE study is a phase II study, which examines venetoclax with ibrutinib, the BTK inhibitor, and previously untreated CLL. So it's kind of combining 2of the novel targeted therapies in a fixed duration, similar to what was done in the CLL14 study where patients received 1 year of therapy and then stopped treatment.   So in the CAPTIVATE study, 154 patients were enrolled. This was a phase 2 study that included about 56% of higher-risk patients who had unmutated IGHV, and the median time on the study was 50 months, with a CR rate of 58% at a 4-year follow-up and an overall response rate of 96%, which is quite high, especially considering that more than half of patients had high-risk disease. The progression-free survival was 79% and the overall survival rate was 98% at 4 years. And when they looked at patients who had undetectable minimal residual disease, the 4-year overall survival rate was 100%, which also suggests that MRD can help serve as a predictive marker of longer-term survival. So I think we have to also consider what the side effects are of combining these 2 agents and the most common adverse events were hematologic, which is expected based on what we know about the 2 classes. So I think the implication of the study is that giving 2 oral agents for a fixed period of treatment for 12 cycles is a rational approach that may spare patients indefinite therapy and can lead to positive outcomes, including in patients who have high-risk features with CLL.  Dr. John Sweetenham: Yeah, the other interesting observation that was made in the abstract, which I found to be really encouraging, was the fact that a number of these patients apparently have been re-treated successfully upon progression with ibrutinib again, which seems to be somewhat reassuring as well.  Dr. Marc Braunstein: That's right. There were 4 patients who started re-treatment in the study and perhaps we'll see the outcomes of that small subgroup are at the poster presentation. But I think when we discuss fixed-duration treatment, it also opens the door to potentially re-challenging patients when they relapse. We know that when we stop single-agent BTK inhibitors, which are historically given indefinitely in patients with CLL, those patients who stop, many will relapse, but you can potentially re-challenge them with the BTK inhibitor. So this study with the CAPTIVATE trial gives us some liberty to discontinue therapy, but also considering re-challenging upon relapse.   Dr. John Sweetenham: Yeah, absolutely. Moving on to aggressive B-cell lymphoma, now, the next abstract I'd like to discuss with you is Abstract 7525. I find this one particularly interesting as the continued excitement around CAR T cell therapy for relapsed aggressive lymphoma remains high at the moment. It's intriguing that t cell-engaging antibodies also have been reported, at least, to have remarkable activity in this set of diseases. So can you take us through Abstract 7525 and what they're reporting?  Dr. Marc Braunstein: Absolutely. Bispecific antibodies represent an emerging field in multiple hematologic malignancies, and this is a class of antibodies that bind to both the tumor cell as well as T-cells, and activate T-cell immunity against the tumor cell. So epcoritamab is a bispecific antibody that binds to CD3, which is expressed on T cells, and CD20, which is expressed on B cells. And Thieblemont et al published results in the Journal of Clinical Oncology last year in a phase I/2 study that looked at epcoritamab in patients with diffuse large B cell lymphoma following 2 prior lines of therapy, and this was given subcutaneously until progression of disease. In that study, at a median follow-up of about 11 months, the overall response rate was 63% with 39% complete remissions.   So the EPCORE NHL-1 study, which is being presented at this year's ASCO meeting, is presenting the updated results of that study looking at patients with diffuse large B cell lymphoma that includes a small population as well of patients with high-grade B cell lymphomas and primary mediastinal B cell lymphomas who had at least 2 prior lines of therapy. In this presentation, 157 patients were included in this study, and 61% had primary refractory disease, and actually, 39% had prior CAR T-cell therapy, of whom 75% progressed within 6 months. So these were patients who were not only refractory to treatment but also had prior T-cell therapy.   So at a median follow-up of 20 months, the overall response rate was 63% and the complete response rate was again about 39%, and the median duration of complete remission was 21 months. In terms of overall survival, the median was about 19 months, which is substantial for this group of patients who really wouldn't be expected to respond very well to conventional therapies.   As we know, T-cell-engaging therapies, such as these bispecific antibodies or CAR T-cells have the potential risk for certain immune-related adverse events, including cytokine release syndrome or icons, and a neurologic syndrome related to the therapy. And it's worth noting that the CRS in this study was predominantly low-grade. There were only 3% of patients who had grade III CRS, and 9 patients, or 6% had grade I to II icons. I think that also reflects how we're better managing those side effects and intervening earlier. So I think the results are impressive from the standpoint of the population studied, who were quite refractory to treatment and show relatively high rates of response. In fact, the median overall survival was not reached in the overall population.   So I think what we take away from this abstract is that bispecific antibodies are going to play a vital role in the relapse-refractory setting for large cell lymphoma and may also offer an alternative to patients who aren't necessarily fit for CAR T-cell therapy, which plays a vital role in patients who are both refractory to first-line therapy or relapse-refractory to subsequent disease. So these are very encouraging results, and I'm sure we'll see randomized data as well in the future, further supporting the use of bispecific antibodies like epcoritamab.  Dr. John Sweetenham: Yeah, I agree. Thanks, Marc. I think that's a great summary. And it's particularly exciting to me that the investigators were able to achieve this kind of level of response and progression-free survival with a subcutaneous treatment. It's really quite remarkable and really exciting to see that.  We're going to wind up with our final abstract today, which is looking at the utilization of circulating tumor DNA in, again, in patients with aggressive B cell lymphoma. This is Abstract 7523, so maybe you could walk us through this one, Marc.  Dr. Marc Braunstein: Absolutely. So this is a poster being presented by Dr. Herrera looking at a, I guess you could call it a biomarker in the blood using circulating tumor DNA in patients with newly diagnosed diffuse large B cell lymphoma in the POLARIX study. So the results of the phase 3 POLARIX study were published last year in the New England Journal of Medicine and showed improvement in progression-free survival with the addition of these anti-CD79b antibody polatuzumab to standard R-CHOP chemotherapy compared to R-CHOP alone. And this study actually led to the approval of first-line treatment that includes polatuzumab.   In the abstract being presented by Dr. Herrera, the investigators looked at the value of circulating tumor DNA as a potential marker to serve as a guide for prognosis and predicting longer-term responses, particularly when the blood is cleared of circulating tumor DNA. So the study involved 654 patients who had ctDNA results both at baseline and then with longitudinal assessment, and they used an assay called the CAPP-Seq assay to assess circulating tumor DNA and assess for its clearance. In the study, undetectable circulating tumor DNA was achieved in 57% of patients who got the polatuzumab R-CHP combination and 59% of the patients who got R-CHOP by cycle 5 and then 6% in the polatuzumab group at 67% in the R-CHOP group.  So the rates of circulating tumor DNA clearance were similar between the 2 arms. But what's notable is that patients in the polatuzumab arm who achieved a complete response at the end of treatment plus cleared their circulating tumor DNA had superior progression-free and overall survival compared to patients who achieved a CR but retained circulating tumor DNA in their blood.   And this has implications because it might help gauge, for example, if patients may need additional cycles to clear the circulating tumor DNA, although we still need more data to answer whether that's necessary or not. And it may help serve as a predictive marker for longer-term remission, particularly in patients who perhaps have higher risk factors at baseline. So I don't think this is necessarily ready for primetime to use in clinical practice, but it is intriguing to know that we could finally have a tumor-specific biomarker in the blood to help monitor patients and potentially predict their longer-term remissions.  Dr. John Sweetenham: Thanks, Marc. I agree. Great summary, and obviously there's still something to learn about the kinetics of the response and so on. And also, I suppose it raises the question of whether those patients who still have detectable levels should be switched at the end of therapy to some kind of preemptive second-line therapy. And these are obviously all questions for the future, but it's going to be very interesting to watch this space, I think, and see how this story develops. Dr. Marc Braunstein: Absolutely. And my colleagues in the solid tumor space are already using circulating tumor DNA, for example, in colon cancer, to help with surveillance. So perhaps this could be a tool to use to predict relapse also in patients who are on surveillance after their treatment. But again, as you alluded to, we need more data to address that.  Dr. John Sweetenham: Well, thanks so much, Marc, for sharing your insights with us today on a really interesting set of abstracts coming up at the June meeting. And thanks for joining us on the ASCO Daily News Podcast. Dr. Marc Braunstein: Thank you for inviting me.  Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstracts discussed today in a transcript of this episode. Join us again after the annual meeting for key takeaways on the late-breaking abstracts and other key advances from the ASCO Annual Meeting. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today’s speakers:  Dr. John Sweetenham Dr. Marc Braunstein @docbraunstein   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn  Disclosures: Dr. John Sweetenham:Consulting or Advisory Role: EMA Wellness Dr. Marc Braunstein:Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb/Celgene, Adaptive Biotechnologies, GlaxoSmithKline, ADC Therapeutics, Janssen Oncology, Abbvie, Guidepoint Global, Epizyme, Sanofi, CTI BioPharma Corp Speakers’ Bureau: Janssen OncologyResearch Funding (Institution): Janssen, Celgene/BMS

Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss the CLEAR study in renal cell carcinoma, a new exploratory analysis combining the TheraP and VISION trials in metastatic urothelial cancer, and compelling advances in prostate cancer and across GU oncology in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host for the ASCO Daily News Podcast today. I'm the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I'm delighted to welcome Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical director of the Genitourinary Cancers Program at the Inova Schar Cancer Institute in Virginia.   Today, we'll be discussing some key abstracts in GU oncology that will be featured at the 2023 ASCO Annual Meeting.  Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcript at asco.org\DNpod.   Jeanny, it's great to have you on the podcast today. Dr. Jeanny Aragon-Ching: Thank you so much, Dr. Agarwal, for having me. Dr. Neeraj Agarwal: Jeanny, let's begin with Abstract 4502 regarding long-term updated results on the CLEAR study. The abstract reports the final, prespecified overall survival analysis of the CLEAR trial, a four-year follow-up of lenvatinib plus pembrolizumab versus sunitinib in patients with advanced renal cell carcinoma. Dr. Jeanny Aragon-Ching: Yes, I would be happy to. So, just as a reminder, the combination of lenvatinib and pembrolizumab was initially approved by the FDA in August 2021 for first-line treatment of adult patients with advanced renal cell carcinoma. So, this was based on significant benefits that were seen in progression-free survival, which was a primary endpoint, but also showed improvement in the overall response rates compared with sunitinib in first-line advanced renal cell carcinoma.   So this abstract reports on longer-term follow-up now at a median of 49.8 months, and PFS favored the combination lenvatinib and pembrolizumab compared to sunitinib across all MSKCC risk groups, and PFS benefit versus lenvatinib and pembro compared to sunitinib was maintained with a hazard ratio of 0.47. And even overall survival was also maintained with the combination with a hazard ratio of 0.79, and the overall survival favored the combination across all risk groups. If we look at the CR rate, it was 18.3% for the combination compared to 4.8% with sunitinib, unless patients in the combination arm received subsequent anticancer therapies, and that's intuitive. And the PFS2 was also longer with the combination at 43 months compared to 26 months. Now, it is important to note that grade III or more treatment-related adverse events did occur in about 74% of the patients in the combination of lenvatinib and pembro, compared to 60.3% in patients with sunitinib. Dr. Neeraj Agarwal: Jeanny, this is good news. So the main message from the abstract is that sustained results from this combination of lenvatinib plus pembrolizumab are being seen even after a longer follow-up of more than four years.  Dr. Jeanny Aragon-Ching: Yes, I agree. So now, moving on, Neeraj, to a different setting in the RCC space, let's look at Abstract 4519, which is titled “Efficacy of First-line Immunotherapy-based Regimens in Patients with Sarcomatoid and/or Rhabdoid Metastatic Non-Clear Cell RCC: Results from the IMDC,” which will be discussed by Dr. Chris Labaki. So, Neeraj, based on this abstract, can you tell us a little bit more about the impact of these adverse pathologic risk features in non-clear cell RCC?  Dr. Neeraj Agarwal: Of course. So, using real-world patient data, the IMDC investigators compared the outcomes of patients with metastatic non-clear cell RCC who were treated with immunotherapy-based combination regimens versus those who were treated with VEGF-TKIs alone. They also assessed the impact of sarcomatoid and rhabdoid features on response to IO-based combinations versus VEGF-TKIs. Of 103 patients with metastatic non-clear cell RCC who had rhabdoid or sarcomatoid features, 32% of patients were treated with immunotherapy-based combinations.   After adjusting for confounding factors, the authors show that those treated with a combination of two immune checkpoint inhibitors or an immune checkpoint inhibitor with a VEGF-TKI combination had significantly improved overall survival, which was not reached in the immunotherapy combination group versus seven months within the VEGF-TKI group. Time to treatment failure and objective responses were also prolonged, significantly higher, and better in the immunotherapy groups compared with patients who were treated with VEGF-TKIs alone. Interestingly, if you look at those 430 patients with metastatic non-clear cell RCC who did not have sarcomatoid or rhabdoid features, they didn't seem to benefit with immunotherapy-based combinations.  Dr. Jeanny Aragon-Ching: This is an exciting update, Neeraj. What are the key takeaways from this abstract? Dr. Neeraj Agarwal: So the main takeaway is if you see a patient with advanced non-clear cell RCC who has sarcomatoid and rhabdoid features, there appears to be a rather substantial and selective benefit with IO-based combinations. And in this context, I would like to highlight the ongoing SWOG 2200 trial also known as PAPMET2 trial, which is comparing the combination of cabozantinib plus atezolizumab. So immuno-therapy-based combinations versus cabozantinib alone in advanced papillary renal cell carcinoma setting. So this trial is being led by Dr. Benjamin Maughan and Dr. Monty Pal. And I like to encourage our listeners to consider referring their patients for involvement in this federally funded trial so that we can validate the data from this retrospective study in a prospective way. So, Jeanny, let’s now move on to another important disease type which is urothelial carcinoma. There is a very recent accelerated FDA approval of the drug combination of enfortumab vedotin and pembrolizumab for cisplatin-ineligible metastatic urothelial carcinoma patients. This is Abstract 4505, which is being presented by Dr. Shilpa Gupta and colleagues. Can you please tell us more about this update? Dr. Jeanny Aragon-Ching: Yeah, absolutely. So, as you mentioned, Neeraj, the FDA just granted accelerated approval in April 2023 for this combination of enfortumab vedotin or EV, which is and ADC, antibody drug conjugate against nectin-4 and the PD-1 inhibitor pembroluzimab. So it’s a combination for patients with locally advanced or metastatic urothelial carcinoma who are considered cisplatin ineligible. So this is nearly a four-year follow-up.   So as a reminder, this was a phase 1b/2 trial that included 45 patients and it had a primary endpoint of safety and tolerability although the key secondary endpoints included confirmed overall responses, duration of response, progression-free survival, and the resist criteria was investigated via investigator and BICRs which is in a blinded independent central review. Even overall survival was a key secondary endpoint.  So, the bottom line was the confirmed overall response by BICR was 73.3%, the disease control rate was about 84%, and the CR rate was 15.6% with a PFS of close to 13 months, and a 12-month overall survival rate of 83%. However, it is important to cite that there were treatment-related adverse events including skin reactions in 66%, neuropathy occurred in 62%, and ocular disorders in 40%. And there was a little bit of pneumonitis in close to 9%, colitis, and hypothyroidism, so there are side effects to watch out for.  Dr. Neeraj Agarwal: So, Jeanny this is great. What is the key takeaway from this trial?  Dr. Jeanny Aragon-Ching: So I think the most important thing is we now have a new combination of EV and pembro which shows very promising responses and survival in part which led to the FDA accelerated approval in the cisplatin-ineligible population of patients. However, we must note that the phase 3 trial of EV302 will ultimately establish which approach is really beneficial for all of our cisplatin-ineligible patients, either a carboplatin-based chemotherapy regimen or a non-platinum-based regimen such as EV and pembro. Dr. Neeraj Agarwal: Thanks Jeanny, would you like to discuss any other study in the bladder cancer space? Dr. Jeanny Aragon-Ching: Absolutely. I think Abstract 4508 from Dr. Seth Lerner and colleagues will be very relevant to our colleagues. This abstract is SWOG S1011, which is a phase 3 surgical trial to evaluate the benefit of a standard versus an extended lymphadenectomy performed at the time of radical cystectomy for muscle-invasive bladder cancer.  Dr. Neeraj Agarwal: Yes. So this trial, as you said, is an important trial which randomized in a one-on-one fashion 618 patients with muscle-invasive bladder cancer undergoing radical cystectomy, and these patients were randomized to either standard lymph node dissection or an extended lymph node dissection. And standard lymph node dissection included, as we know, external and internal iliac and operative lymph node. The extended lymph node dissection included lymph nodes up to aortic bifurcation which included common iliac, presciatic, and presacral lymph nodes. At a median follow-up of approximately 6 years, there was no disease-free survival or overall survival benefit in patients undergoing an extended lymph node dissection compared to standard lymph node dissection. And extended lymph node dissection was also associated with greater morbidity and preoperative mortality. Dr. Jeanny Aragon-Ching: Very interesting data, Neeraj. So these results, I think, will be very useful for a lot of our surgical colleagues in both academia and the community who may still be inclined to perform extended lymphadenectomy during cystectomy. This study shows that it's actually not necessary. Dr. Neeraj Agarwal: Absolutely. So now let's move on to another disease type, which is very important - prostate cancer. There are several practice-informing abstracts that are worthwhile discussing. The first of these involves Abstract 5002, which looks at the impact of the PSA nadir as a prognostic factor after radiation therapy for localized prostate cancer, which will be presented by Dr. Praful Ravi and  colleagues. Jeannie, can you please tell us more about this abstract? Dr. Jeanny Aragon-Ching: Yeah, definitely. So this abstract, as you mentioned, Neeraj, is a prognostic impact of PSA nadir of more than or equal to 0.1 nanogram per ml within six months after completion of radiotherapy for localized prostate cancer - an individual patient data analysis of randomized trials from the ICECaP Collaborative. Basically, it refers to an attempt to evaluate early surrogate measures to predict for long term outcomes such as prostate cancer-specific survival, metastases-free survival, and overall survival. So they looked at a big registry from the ICECaP collaboration that included 10,415 patients across 16 randomized controlled trials. And those men underwent treatment for intermediate risk and high risk prostate cancer treated with either radiation therapy alone in about a quarter of patients, or they got RT with short-term ADT in about 58% of patients, and 17% of them got RT with long-term ADT.  So, after a median follow-up of ten years, what they found was, if you had a PSA nadir that is over or equal to 0.1 nanogram per ml within six months after completion of radiation therapy, it was associated with worse prostate cancer-specific survival, metastases-free survival, and overall survival. For instance, the five-year metastases-free survival for those who achieved a PSA nadir of less than 0.1 was 91% compared to those who did not, which was 79%. Therefore, they concluded that if you achieve a bad PSA of 0.1 or above within six months after you completed radiation, you had worse outcomes.  Dr. Neeraj Agarwal: Jeanny, what is the key takeaway message from this study? Dr. Jeanny Aragon-Ching: The key takeaway from this ICECaP analysis is that this information would be very important to augment a signal-seeking endpoint, especially for clinical trial development, so that we can develop further strategies to de-escalate for those who don't need systemic intensification or therapy intensification versus escalation for those who really do. Dr. Neeraj Agarwal: So, my radiation oncology colleagues need to watch out for those patients who do not achieve a PSA of less than 0.1 nanogram per ml within the first six months of finishing radiation therapy. Very interesting data.  Dr. Jeanny Aragon-Ching: Yes, absolutely. So. Neeraj another important abstract for our fellow clinicians, switching gears a little bit now, is Abstract 5011, which is titled “Do Bone Scans Overstage Disease Compared to PSMA PET?” This was an international, multicenter retrospective study with blinded, independent readers. Can you tell us more about this abstract? Dr. Neeraj Agarwal: Yes, a relatively small retrospective study, but still pertinent to our practice. So I'll summarize it. This study by Dr. Wolfgang Fendler and colleagues evaluated the ability of bone scans to detect osseous metastasis using PSMA PET scan as a reference standard. So in this multicenter retrospective study, 167 patients were included, of which 77 patients were at the initial staging of prostate cancer, 60 had biochemical recurrence after definitive therapy, and 30 patients had CRPC or castor-resistant disease.  These patients had been imaged with a bone scan and a PSMA PET scan within 100 days. And in all patients, the positive predictive value, negative predictive value and specificity for bone scan were evaluated at different time points. They had bone scan and PSMA PET scan and both were compared. And what they found was interesting. All these three values - positive predictive value, negative predictive value, and specificity for bone scan were 0.73, 0.82 and 0.82 in all patients, and in initial staging, it was even lower at 0.43 and 0.94 and 0.80.  So, without getting into too much detail regarding these numbers, I want to highlight the most important part of the study, that at the initial staging, 57% patients who had a positive bone scan had false positive bone scans. The interreader agreement for bone disease was actually moderate for bone scans and quite substantial for the PSMA PET scan.  Dr. Jeanny Aragon-Ching: So, Neeraj, what do you think is the key takeaway message here for our audience?   Dr. Neeraj Agarwal: The key takeaway message is that positive predictive value of bone scan was low in prostate cancer patients at initial staging, with the majority of positive bone scans being false positive. This suggests that a large proportion of patients which we consider to have low-volume metastatic disease by bone scan actually have localized disease. So in the newly diagnosed patients with prostate cancer, patients should ideally have a PSMA PET scan to rule out metastatic disease.   So, let's move on to another abstract I would like to discuss, which has important implications in treatment, especially now that lutetium 177 is approved, but frankly not available widely. Dr. Jeanny Aragon-Ching: Yeah, that's actually very timely. So the abstract you're referring to is 5045, which is being presented by Dr. Yu Yang Sun and colleagues entitled “Effects of Lutetium PSMA 617 on Overall Survival in TheraP Versus VISION Randomized Trials: An Exploratory Analysis.” So, Neeraj, can you tell us more about the relevance of this exploratory analysis? Dr. Neeraj Agarwal: Definitely. In this abstract, Dr. Yang Sun and colleagues assess the effect of lutetium PSMA on overall survival in two different trials, TheraP and VISION trials. So, just for our listeners' recollection, the phase 2 TheraP trial compared lutetium PSMA and cabazitaxel in patients with mCRPC who had progression on docetaxel and had significant PSMA avidity on gallium PSMA pet scan, which was defined as a minimum uptake of SUV max of 20 at least one site of disease and SUV max of more than 10 at all sites of measurable disease.  In this trial, 20 of 101 patients in the cabazitaxel arm crossed over to lutetium PSMA, and 32 of 99 patients in the lutetium PSMA arm crossed over to cabazitaxel. In the VISION trial, patients with mCRPC who previously progressed on at least one ARPI and one taxane-based therapy and had a positive gallium PSMA scan, and here, positivity was not stringently pre-specified as it was done in the context of TheraP trial. So, positive gallium pet scans were randomly assigned in two to one fashion to receive either lutetium PSMA plus best supportive care or standard of care versus standard of care.  And I'd like to highlight that the standard of care comprised ARPIs and bone protecting agents and these patients were not allowed to have cytotoxic chemotherapy such as cabazitaxel in the standard of care arm. Now, overall survival was similar in the lutetium PSMA group regardless of whether they got lutetium PSMA in the VISION trial or TheraP trial. There was no difference in overall survival with lutetium in the lutetium arms of VISION and TheraP trial with a hazard ratio of 0.92. And there was no difference in the overall survival between the lutetium PSMA and the cabazitaxel group in the TheraP trial if you use counterfactual analysis, assuming crossover had not occurred. So, quite interesting in my view. Dr. Jeanny Aragon-Ching: Yeah, thanks Neeraj for that wonderful synopsis and discussion. So, what is the key take home message then? Dr. Neeraj Agarwal: The main message in this new exploratory analysis, which combined both the TheraP and VISION trials, is that lutetium PSMA and cabazitaxel seem to be associated with similar overall survival benefit in these highly selected patients with PSMA positivity. Additionally, the difference in the observed effect of lutetium PSMA and overall survival in the TheraP and VISION trials may be actually better explained by the use of different treatments in the respective control arms of these trials. And these results, in my view, are quite pertinent for those patients and providers who do not have access to lutetium-177 therapy.  Let's go to another abstract that is currently relevant to our practice, given many patients with advanced prostate cancer who have concurrent diabetes; I'm talking about Abstract 5066. Jeanny, can you please tell us more about this abstract?  Dr. Jeanny Aragon-Ching: Certainly, Neeraj. So this abstract will be presented by Dr. Amy Shaver and colleagues. So it's also very relevant, since many men who are diagnosed with prostate cancer frequently also have a concomitant diagnosis of type 2 diabetes mellitus. So, this was a SEER-Medicare population database analysis that looked at men who were treated with either abiraterone or enzalutamide and also had concomitant diagnosis of type 2 diabetes mellitus (DM). And they were identified using ICD-9 and ICD-10 codes and they were all tied in to acute care utilization. So they looked at CMS research data codes and ER hospitalization visits six months after treatment initiation was recorded. So all in all, they took a sample of 11,163 men, of whom close to 62% were treated with abiraterone and about 38% were treated with enzalutamide.  So, of these, about 27% of them had type 2 DM, of whom 59% received abiraterone and about 41% had enzalutamide. So, the bottom line is, compared to those without diabetes mellitus, those who had type 2 diabetes had worse acute care utilization, which was 43% higher than those who got abiraterone compared to enzalutamide, and also had higher overall mortality. Therefore, the bottom line is, having type 2 diabetes mellitus, unfortunately, portends worse outcomes in men with prostate cancer, so careful attention needs to be paid to those who are starting out already with such comorbidities. So Neeraj, any final thoughts you have regarding this abstract and overall before we wrap up on the podcast today?  Dr. Neeraj Agarwal: Absolutely. So it looks like, based on this very important pertinent Abstract 5066, which talks about the impact of diabetes on our patients, I think we need to be very watchful regarding the impact of diabetes on our patients who are being treated with abiraterone or enzalutamide, especially drugs which are known to make the metabolic syndrome and diabetes worse. I think close monitoring and close attention to control of diabetes is very important. So with that, I would urge the listeners to come and join us at the Annual Meeting, not only to celebrate these successes but also to help disseminate this cutting-edge data to practitioners and maximize the benefit to our patients across the globe.   And thank you to our listeners for joining us today. You will find links to the abstracts we discussed today on the transcript of this episode. Finally, if you value the insights that you hear on our ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast.  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today’s speakers:  Dr. Neeraj Agarwal @neerajaiims Dr. Jeanny Aragon-Ching Follow ASCO on social media:   @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn     Disclosures:  Dr. Neeraj Agarwal:   Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences  Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas  Dr. Jeanny Aragon-Ching: Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant,  Exelixis, Speakers’ Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics.

Dr. Shaalan Beg and Dr. Mohamed Salem discuss novel therapies in gastrointestinal cancers, including CAR T therapy and the CodeBreak-101 trial in mCRC, new advances in uHCC in the HIMALAYA trial, and an exciting update from the NAPOLI-3 trial in pancreatic cancer, ahead of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I'm the vice president of oncology at Science 37 and an adjunct associate professor at UT Southwestern Simmons Comprehensive Cancer Center. My guest today is Dr. Mohamed Salem, a GI oncologist at the Levine Cancer Institute at Atrium Health. We'll be discussing key posters and oral abstracts in GI oncology that will be featured at the 2023 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode, and disclosures of all guests on the podcast can be found in our transcripts at asco.org/DNpod. Mohamed, thanks for coming on the podcast today.  Dr. Mohamed Salem: Thanks, Shaalan.  Dr. Shaalan Beg: There's some interesting studies in colorectal cancer that I'd like to get us started with today. Abstract 3547 is titled “A Phase I Dose-escalation Study of GCC19 CAR T: A Novel Coupled CAR Therapy for Patients with Metastatic Colorectal Cancer.” What are your thoughts on the study? Dr. Mohamed Salem: Actually, this was a very exciting study to see coming out in GI cancer, especially colorectal cancer. As you know, CAR T made its way to the treatment of lymphoma and other heme malignancies. In fact, we saw a fascinating response and outcome using that technique and that niche in the immunotherapy module. The challenge we had was that we could not replicate this in solid tumors until very recently. I'm sure you had the same thing in your clinic, too. A lot of patients with GI cancer or colorectal cancer come to you and say, "Okay, why can't I have CAR T?" And the response was, "We don't know if it's effective or if it's going to work yet." Here at our center, we had a phase 1 study, I think that was looking also at CAR T and solid tumors, particularly prostate cancer. So that I think was very exciting to see that technology is making its way to the solid tumor. I was very pleased to see this CAR T study coming out from the work of our Chinese colleagues looking into this in the CRC space.  Obviously, as you know, in colorectal cancer, we made a significant advancement, but I don't think we made enough advancement yet, and especially for refractory patients, patients with refractory disease who have underwent multiple lines of therapy. And this study actually addressed the need for those patients. So in this study, that was a phase I escalation dose, very much is we looked at about 13 patients who had metastatic CRC, they had at least two lines of therapy. So in what we say is a "refractory setting," unfortunately for those patients, we don't have large treatment options. And they used two doses, the first dose and the second dose that was a little bit higher. And the interesting part is that they were able to see very nice responses on this patient population. In the lower dose, I think the response was the PFS was about 1.9 months. But when they went up on the dose, actually the PFS was 6.3 months, which I think in the refractory setting is very meaningful.   And also the median overall survival for the first group was 13 months, which in the refractory setting is something we don't see often, and the higher dose was 18 months, which was even better. So there was a trend that higher doses are perhaps more effective or have better efficacies than lower doses, but also in terms of side effects, actually patients were relatively able to tolerate it well, and there were no surprising adverse events. So again, yes, that's 13 patients in total. So it's a very small study, but like everything else, the proof of concept sometimes is the first step and it's very important to see that data to suggest that this technology now can be utilized in solid tumors and CRC, especially now there is an unmet need for those patient populations. I'm sure you and I will see a lot of patients at the clinic with good progress status, and just looking for the next option, and I'm glad to see that. Hopefully, we can continue to build on that work.  Dr. Shaalan Beg: Another key abstract in colorectal cancer is Abstract 3513, the CodeBreak 101 study. This is a phase 1b safety efficacy trial of sotorasib plus panitumumab and chemotherapy with FOLFIRI for previously treated KRAS-G12C mutated colorectal cancer. And this is a really important study because even though KRAS-G12C represents a minority of KRAS mutated colorectal cancer, we know that this treatment can cause meaningful improvement in disease for other cancers like non-small cell lung cancer. And when sotorasib was tested as monotherapy in colorectal cancer, it saw an objective response rate of 9.7% that increased to 30% when added to panitumumab.   So in this trial, they took sotorasib plus panitumumab and added it to chemotherapy to see how it’s tolerated and what its effectiveness is going to look like. And they enrolled people who had more than one or more lines of prior therapy for metastatic disease. They treated 33 patients. The most common side effect was dermatologic, which is probably related to EGFR-based therapy, and they saw a confirmed overall response rate of 58%. Side effects are those that we look to expect with this specific regimen. I don't see any additional safety concerns here, but this can be a big step forward for KRAS-G12C-altered colorectal cancer. What do you think? Dr. Mohamed Salem: I totally agree. And again, it was very exciting to see that abstract and that result. I totally believe now, and I'm sure you would agree with me too, Shaalan, that we're moving from an era of one size fits all to a precision oncology and tailored treatment. And the fact now we have a treatment option for patients with a KRAS mutation is very exciting because before, we didn't have much that we can do about that mutation. So now it's not just a proof of concept. Now you're hitting that target with the chemotherapy and you're getting a 50% response rate. That’s something interesting also to see for this patient population and as you highlighted as safety also, and the adverse event was not high and patients were able to tolerate it, which makes it more doable for us to use it. Dr. Shaalan Beg: Yeah. And one of the challenges in the precision oncology space, which I'm sure you're experiencing in clinic as well, are the real-world applications of precision oncology and the drop-offs that happen that are preventing us from universal precision oncology - meaning the drop-offs that we see on eligible patients receiving the appropriate genomic testing, those who have genomic testing receiving the appropriate treatment. And we've seen a couple of fairly high-profile studies that are describing this in non-small cell lung cancer where the rates are not as encouraging as we would want it to be, which to me, as a physician, makes me worried that there are people out there who we don't know are carrying these mutations or have these mutations, and it hasn't been acted upon.   And related to that, there is an abstract at ASCO23, which is Abstract 3602, that looked at the real-world rates of FDA-approved targeted therapy and immunotherapy for people with metastatic colorectal cancer. They used the VA's National Precision Oncology Program data to study the prevalence of these mutations and how many of the folks ended up receiving the treatment that would be appropriate for those mutations. And this is a very exciting study. They looked at 908 metastatic colorectal cancer patients who underwent genomic profiling, 81% were colon and the rest were rectal. They found that 34% of patients harbored NRAS, KRAS, BRAF mutations, 9.6% were TMB-high, 7.7% had BRAF V600E, and 5.6% were MSI-high, which kind of puts the overall actionable variant prevalence in colon cancer at 47% and for rectal cancer at 44%.  And then they went down to see amongst those 424 eligible patients, how many ended up on appropriate therapy. And these were their numbers: for MSI-high 70%, TMB-high 47%, NRAS, KRAS, BRAF, wild-type 38%, BRAF V600E 17%. So nearly 30% of patients with MSI-high colorectal cancer did not receive immune checkpoint inhibitor therapy, and again, other aspects in terms of EGFR use, and I know that there are other challenges that may affect the use of EGFR inhibitors in colorectal cancer, but it really begs the point on aspects related to implementation science, on getting the testing and acting on those results. And I'm curious to what you're seeing that's being done on these initiatives nationally.  Dr. Mohamed Salem: I totally agree with you, Shaalan. This is a big problem we’re facing day in and day out because we struggle to find treatment options for our patients. And I think if we’re missing patient with targetable or actionable mutations and we’re not utilizing that, I don’t think that’s a good situation to be in. And I think that’s just a group effort. You have to work with the pathologist, you have to work with your team at the clinic. And as an oncologist treating this patient, we have to pay close attention to those markers. And frankly, just look for them. At least  the ones that you know are going to have therapeutic implications.  I do also think patient advocacy has a huge role here and huge opportunities that they can contribute. I am sure you are familiar with the pancreatic study that was published by our colleague Mike Pishvaian in Lancet a year or two ago. I think he named it the Know Your Tumor Type. I think that should be the way forward now, not just for pancreatic but for any cancer. Patients should ask their oncologists what my tumor is. Is it MSI-high, is it KRAS-G12C, is it BRAF? Because it will affect the treatment. I think it’s multi-layer and all of us should work in a cohesive manner to be able to not ever miss those markers which carry therapeutic potential.   Dr. Shaalan Beg: So moving on to hepatocellular carcinoma, Dr. George Lau and colleagues, they'll be sharing data from the phase 3 HIMALAYA study with hepatocellular carcinoma in the Annual Meeting that's Abstract 4004. And he looked at outcomes by occurrence of immune-related events for people who received tremelimumab and durvalumab. What are your thoughts on this study?  Dr. Mohamed Salem: This was a very interesting abstract to see. For a long time, we didn't have many treatment options in hepatocellular carcinoma. So, over the last two or three years now, I think we've made nice advancements in the therapeutic landscape. So, we have multiple options including immunotherapy which is very exciting for all of us to be able to utilize those powerful drugs in that disease. The question that comes out is who actually responds? Obviously, in HCC you don't have a lot of biomarkers like the immune therapy biomarkers like MSI-high and PDL-1, and TMB. It isn't really playing a huge role in HCC. So, as you know, the HIMALAYA study is a phase 3 study and examined the STRIDE regimen which is treme plus durva in the first line of patients with metastatic or unresectable HCC against sorafenib. And the outcome was in favor of the STRIDE regimen with improvement in OS response rate and duration of response and because of that, it became one of the standards of care for that disease. But Abstract 4004 is actually asking a very interesting question - whether immune-related adverse events can predict outcomes. Meaning like those patients who experience immune-related adverse events will likely do better compared to those patients who didn't experience immune-related adverse events or not. The idea of adverse events as a biomarker if you will, for efficacy is not new. I mean we saw that back in the renal carcinoma TKI, hypertension. People who had hypertension were more likely to have a better response. In the GI also there was some data suggesting that rash might be a biomarker in predicting response to EGFR. So the same question we’re applying here - immune-related adverse events can function as a biomarker for efficacy for the immune system.  And there are some data out there in other tumors that may be the case, but I think at least to my knowledge in the HCC or GI, this was the first study to address that question. So just to remind our audience that the HIMALAYA was a phase 3 study using the STRIDE regimen as a frontline for patients with hepatocellular carcinoma, either unresectable or metastatic disease. And they compared the STRIDE which is durva-treme compared to the standard of care at that time was sorafenib. The primary endpoint was overall survival and they had secondary endpoint duration of response, response rate, and obviously adverse event.  The study was positive, it met its primary endpoint and OS was in favor of the STRIDE regimen compared to sorafenib. But that part of the abstract now is focusing mainly on those patients who had immune therapy and whether that was a STRIDE regimen or the third arm that durva alone treatment. And they're looking at those patients who had immune-related adverse events, and those who didn't have immune-related adverse events. So basically four groups of patients, the patient who had a STRIDE regimen, about 139 patients had immune-related adverse events, and about 249 didn't have immune-related adverse events. For the cohort who had durva alone, about 64 patients had immune-related adverse events, almost 300 patients had no immune-related adverse events.  And it was very interesting that at least in the STRIDE arm, those patients who experienced immune-related adverse events, their outcome was better than those patients who did not have immune-related adverse events. It's the same trend seen on the durva alone arm, but I think the number was very small to make a statistical value out of it. But I think at least in the STRIDE arm there was a suggestive trend toward the outcome of those patients who experienced immune-related adverse events. So I think this is in a way very interesting because we're always wondering if we give the same dose at least in immunotherapy like for everyone.   What I was wondering is if it's too much, too little, or just right. It's hard to know for sure. But perhaps in my opinion and just me trying to understand why, in my theory, maybe that's just an indication of patients receiving enough drugs and effective drugs that will translate into efficacy. But at the same time, I also wanted to just put a word of caution here because we don't want to see side effects as a good thing. I think we want to make sure that us as oncologists treating these patients and patients also don't see like it's good to have a side effect. Side effects associated with especially those grade 3 or 4 can be associated with significant problems and decreased quality of life. So, definitely should be looking at those side effects and be careful interpreting those data. But I think that is very interesting and I will look for more work on that.   Dr. Shaalan Beg: Let's move on to pancreatic cancer. We heard the results of the NAPOLI-3 clinical trial at GI ASCO and this year in ASCO 2023 we will hear the results of Abstract 4006 by Dr. O'Reilly that are presenting results of the 12 and 18-month survival rates from the study that compared NALIRIFOX or nano-liposomal irinotecan, 5-fluoro/leucovorin, and oxaliplatin versus nab-paclitaxel/gemcitabine for newly diagnosed pancreatic cancer patients. I'm interested to hear what you think about that study. Dr. Mohamed Salem: Thank you, Shaalan. So this also is a very exciting abstract to see, and anyone who treats pancreatic cancer patients realizes that, unfortunately, even in 2023, we don't have a lot of treatment options. And yes, I think over the last decade we're now talking about second-line and third-line, but yet we still don't have a lot of treatment options. So, having more options is always good. But the question now is how do you sequence those chemotherapy options? Most of us obviously use FOLFIRINOX in the first line or gemcitabine and paclitaxel in the first line. Until very recently– because we didn’t have a head-to-head comparison– we couldn't tell patients for sure if one is better than the other. I think we had some assumptions, but it wasn't really proven. It was just a cross-trial comparison.  So, the fact is that now we have that phase 3 trial looking at liposomal irinotecan, 5-fluoro/leucovorin and the oxaliplatin comparing to nab-paclitaxel/gemcitabine. To me, that was actually very exciting because now, at least, I can see a triplet chemotherapy drug compared to a doublet chemotherapy drug. And as you mentioned, Shaalan, the first initial read was positive in favor of the triplet regimen compared to the doublet, which I think was an important message to give to our colleagues and all of us that if you can, obviously, the triplet comes with side effects, but if you can deliver the triplet, that's perhaps a better starting point for the treatment. But the study here, we're trying to get more read after more mature or more time-lapsing. So the initial study was initial read was positive. And I think this is good to see, too because it translates that even with a longer follow-up, we're still seeing the same benefit. So the OS rate in 12 months for the triplet was about 45% compared to 39.5% for the doublet, and the 18 months, a year and a half, was 26% compared to 19%. So, definitely, you can see an improvement in every single endpoint. OS in general was 11.1 months compared to 9.2 months, and PFS was also in favor of the triplet. So I think it's a message here to reinforce what we saw a few months ago in the initial presentation that, in fact, the triplet is associated with better outcomes if you can safely manage the toxicity and guide the patient through the process. Dr. Shaalan Beg: Well, thank you very much, Mohamed. This was a lot of fun. Thanks for sharing your valuable insights with us on the ASCO Daily News Podcast. Dr. Mohamed Salem: Thank you for having me and looking forward to the full presentation at the meeting. And please, if you haven't registered for the meeting yet, make sure you attend. It's a wonderful opportunity to learn from an expert in the field and also meet your colleagues and make new friends. I also want to take this opportunity to thank the ASCO Daily News Podcast team for taking the time, and also for our colleagues who reviewed these abstracts. This takes a lot of time and effort, and I think they're doing a wonderful job. So, thank you to all of them, and I'll see you all at ASCO.  Dr. Shaalan Beg: And thank you to our listeners for your time today. You'll find links to the abstracts discussed today in the transcript of this episode. I'll be back to cover late-breaking abstracts and other key advances in GI oncology after the annual meeting, so please join us for more key insights from ASCO 23 on the ASCO Daily News Podcast.  Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.  Disclaimer:The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today’s speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Mohamed Salem @SalemGIOncDoc   Follow ASCO on social media: @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn   Disclosures:  Dr. Shaalan Beg: Consulting or Advisory Role:  Ispen, Cancer Commons, Foundation Medicine, Genmab/Seagen Speakers’ Bureau: Sirtex Research Funding (An Immediate Family Member): ImmuneSensor Therapeutics Research Funding (Institution): Bristol-Myers Squibb, Tolero Pharmaceuticals, Delfi Diagnostics, Merck, Merck Serono, AstraZeneca/MedImmune  Dr. Mohamed Salem: Consulting or Advisory Role: Taiho Pharmaceutical, Exelixis, Bristol-Myers Squibb, Exelixis, QED Therapeutics, Novartis, Pfizer, Daiichi Sankyo/Astra Zeneca Speakers' Bureau: Genentech/Roche, Taiho Pharmaceutical, Daiichi Sankyo/Astra Zeneca, BMS, Merck

Drs. Vamsi Velcheti and Jack West discuss key abstracts in advanced SCLC and NSCLC, along with highlighting the largest known data set correlating ctDNA levels and efficacy outcomes in the EMPOWER-Lung 1 trial, in advance of the 2023 ASCO Annual Meeting. TRANSCRIPT Dr. Vamsidhar Velcheti: Hello, I am Dr. Vamsidhar Velcheti, your guest host of the ASCO Daily News Podcast today. I am a professor of medicine at NYU Grossman School of Medicine and the director of thoracic oncology at Perlmutter Cancer Center at NYU Langone Health. I am delighted to welcome Dr. Jack West, a thoracic oncologist and associate professor in medicine at the City of Hope Comprehensive Cancer Center.                                  Today, we'll be discussing key posters and oral abstracts in lung cancer that will be featured at the 2023 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode and disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/DNpod.  Jack, it's great to have you on the podcast today. Dr. Jack West: Well, thank you so much, it's my pleasure to be here.  Dr. Vamsidhar Velcheti: Let's begin with Abstract 8512. This is the follow-up of the Gronberg trial, the Danish trial of BID thoracic radiation for limited-stage small cell lung cancer. What are your key takeaways from this trial? Dr. Jack West: Well, as you noted, this has been presented before a few years ago. It's a trial for limited-stage small cell lung cancer and it directly compared chemotherapy with either 45 Gray or 60 Gray of chest radiation delivered twice daily. It's not an enormous study, it's 170 eligible patients. And years ago, we saw that the efficacy endpoints looked very promising for the patients who received a higher dose of 60 Gray on a BID schedule, which is above our standard. We generally either give 45 Gray BID or probably more commonly in the US and I think globally give maybe 60 Gray on a once-a-day schedule. But the efficacy looked quite promising and without any clear increase in the toxicity of it. And really, despite the impressive results, this hasn't changed practice. It is not a large study and I think that I would say that most of the radiation oncology world has been reserving judgment until potentially seeing a larger study.  But what's being presented at ASCO are the longer-term results that continue to look excellent. You have a progression-free survival median of 18.6 months versus 10.9 months. That's not statistically significant but has a hazard ratio of 0.76 associated with it. And the median overall survival is even more pronounced of 43.5 months favoring the 60 Gray arm compared to 22.6 months in 45 Gray on a BID schedule that has a hazard ratio of 0.69. And this is statistically significant. The authors note that they will be presenting five-year overall survival as well. And there's also just passing mention that, as was seen previously, there was no increase in toxicity, no prohibitive toxicity. So I don't think it's necessarily going to change practice because the numbers of patients, which I think are really the leading concern, hasn't changed. But these very promising results still hold up over time and I think should compel us to carefully assess this as an option to potentially increase outcomes for this challenging setting where progress is slow to come. Dr. Vamsidhar Velcheti: Yeah, I completely agree, Jack. And I think one of the things that we have seen, at least in the non-small cell setting, like the higher dose of conventional radiation is not superior to the 45 Gray, BID dosing. I think there were some studies with CALGB and the Gronberg trial, but I think at the end of the day, it comes down to patient conveniencer. It's not often feasible for patients to come in twice a day for radiation. That might be something that might limit utilization here.  Dr. Jack West: I think that's a very good point. It's just difficult when you have the potential for higher cure rates, but it is at least challenging, if not completely infeasible. But I really agree with you that that's a big part of why it's underutilized relative to the strength of the data for BID. But we have to be able to actually administer these. Dr. Vamsidhar Velcheti: So let's move on to another trial. And again, we've seen the data before. This is Abstract 8521, the CheckMate-816 trial. They reported the three-year results of the neoadjuvant nivolumab chemotherapy versus chemotherapy by definitive surgery in patients with resected non-smoker lung cancer. What is the data that's being presented at ASCO this year? Dr. Jack West: So yes, as you mentioned, we've seen data on CheckMate-816 for a few years now. It’s been published in the New England Journal of Medicine and it's FDA-approved and has become a standard of care, if not the standard of care, but there are many dimensions to this. And one of the questions has been what happens to the patients who did not undergo surgery, which was about 17% of patients on the chemoimmunotherapy arm, a full quarter of patients on the chemo arm. What happened to these folks? And that's what is being presented by Dr. Jonathan Spicer, a thoracic surgeon in Montreal who's been heavily involved with this trial. And I think that's going to be the overwhelming focus of this.  And what is reported in the abstract, and I'm sure we'll see more interesting results, is that the outcomes are superior in the patients who received chemoimmunotherapy with nivolumab, in the patients who did not undergo surgery as well as those who did. Specifically, they report on the median time before death or distant metastases, and that was 24.8 months as a median for the chemoimmunotherapy arm versus 15.6 months for the patients who receive neoadjuvant chemo alone. The hazard ratio for that's 0.63. There was also a striking difference in the three-year survival rates, 36% versus 13% also favoring chemo and nivolumab.  They also talked about the actual treatments that patients received when they didn't have surgery, and about 60% in both of those arms received radiation instead of surgery, and about half the patients also received additional systemic therapy. So we will see more. But I think it helps to address one lingering question of what happens to the patients who did not end up pursuing surgery and showing that the results were more favorable for the recipients of chemo nivolumab, even in that subset. Dr. Vamsidhar Velcheti: It's simply fascinating how the field is evolving in the perioperative space, Jack. And there are more unanswered questions here and up for debate for years with the recent agent trials we had seen at AACR. We've seen the same kind of trend even with the agent, I think it was 20%, who did not make it to surgery. A lot of them are like stage 3 patients. So it begs the question, are we kind of just being more aggressive with induction therapy? Maybe some of these patients are biologically or anatomically not bound to have surgery. I mean, it's hard to really tell. Dr. Jack West: It really is important for us to still select appropriate patients for this, rather than become overly ambitious and try to shoehorn patients who are really not ideal or appropriate candidates for surgery and anticipate or have kind of aspirational resectability if they aren't de novo great candidates for surgery. We, of course, need to remember that chemoradiation followed by consolidation durvalumab on the PACIFIC trial is not some terrible consolation prize. We've done remarkably better with this over the years, and it's a very strong option.  Dr. Vamsidhar Velcheti: Exactly. The other open question, but of course this abstract doesn't really address is, what do you do with all the patients who perhaps have major pathologic responses and what do you do after surgery? That's kind of an open question, and we probably need a better way to determine who might need adjuvant therapy or surgery. I don't know if you have any thoughts on that.  Dr. Jack West: As you say, I think that's a big question, a gaping hole in our knowledge base, but it's not addressed here. I think we are going to be struggling with that in the coming years.   Dr. Vamsidhar Velcheti: Right. So let's move on to Abstract 9002. This is a report of the first pivotal study results of DZD9008 sunvozertinib in patients with exon 20 EGFR mutation. What are your key takeaways from the study? Dr. Jack West: So I would say obviously we have a couple of agents that target EGFR exon 20 mutations, but unfortunately, neither of the agents that are commercially available is especially active. And they certainly have toxicity challenges, whether it's amivantinab or mobocertinib,  they both share some challenges and they're not as efficacious as some of the other targeted therapies we use in different molecular settings. So I would say there's still some unmet need here. And these results with sunvozertinib DZD9008 selective irreversible EGFRexon20 insertion inhibitor really got my attention as very impressive. These are patients who were heavily pretreated. The median was two prior lines of therapy. This is not de novo first line, and that's a setting where it's pretty hard to see response rates that are over 30 or 40%, but what they actually report is about 60.8% response rate and nearly 100 patients assessed. They also looked at patients who had brain metastases and 31 patients in their sample had de novo metastases and the intracranial response rate was 48.5%, so nearly half.  This is, of course, something that we hope to see as a pattern when we have a targeted therapy that's very effective for the right target, not just overall extracranial, but intracranial efficacy. And we're going to need to see the details on the tolerability because, as I mentioned, the available agents now have the dual challenge of just modest efficacy and really quite challenging, particularly GI toxicities and amivantamab has issues also with infusion reactions. So some work there and I think there's room to improve on that. This looks to me very promising and I would welcome having the opportunity to use it in my patients who have an exon20 mutation.  Dr. Vamsidhar Velcheti: Yeah, I think certainly the brain intracranial activity is perhaps going to be the differentiator here. Given that mobocertinib has limited intracranial activity, I think that's very encouraging to see. So let's move on to the next abstract, the SCARLET trial, Abstract 9006. So this is a clinical trial of sotorasib plus chemotherapy in KRAS G12C-positive patients. Can you tell us a little bit more about this study, Dr. West? Dr. Jack West: Sure. So this was a single-arm phase II trial. It's not large, it's 30 patients, but we really have yet to see results that would compel me to move sotorasib into the first-line setting. I was a little underwhelmed with the CodeBreaK 200 results that didn't beat docetaxel for survival in the second-line setting. But here it's a combination of carboplatin pemetrexed with sodorasib in the first-line setting in patients, of course, with a KRAS G12C mutation and nonsquamous histology. And the reported response rate by independent review is 88.9%, which is quite impressive. The median PFS is not reached yet. The PFS at six months is 61.2%. So I think we'll need to see the full data set, but that really impresses me as a very relevant finding. So I would love to learn more about this. And I think that if it is anything close to holding up with these response rates, close to 90%, I mean, even if it's 70 or 80%, I think that is compelling enough to really want to study this further in the first line setting and maybe a path to getting KRAS inhibitors used in the front line. Dr. Vamsidhar Velcheti: Yeah, I completely agree. And I think with all the issues around the combination with checkpoint inhibitors, especially with sotorasib high liver toxicity, so I think the only way this could move into the frontline is with combination with chemotherapy, especially in certain subsets like KEAP1 CUL drug patients, STK11/KEAP1 patients where immunotherapy historically underperforms. So it'll be interesting to see how this can evolve.  So, moving on to Abstract 9012, this is a clinical trial evaluating a often very neglected patient population. This is a retrospective study of chemo without immunotherapy in the elderly population of patients with PD-L1-positive tumors. So what is your takeaway from this study? Dr. Jack West: I would say that it really complements in my mind the presentation by Dr. Akinboro and colleagues from the FDA last year at ASCO, which was looking at the data for the trials of immunotherapy or chemoimmunotherapy in patients with high PD-L1 50% or higher. And what they found was that there was an improvement in response rate and progression-free survival and a trend, but not a significant difference in overall survival favoring chemoimmunotherapy in those patients. But they also noted that patients who were 75 or older did not seem to benefit from chemoimmunotherapy relative to immunotherapy alone. Now, that is in patients with high tumor PD-L1. This is looking specifically at patients who are 75 and older in Japan, 58 centers, and we're talking about over 1,200 patients, 1,245. And they looked at patients with any PD-L1. So the full spectrum, about 22% had PD-L1 less than 1%,31%, one to 49%, and just over a third, 34% with PD-L1 over 50%. I would presume the balance, that missing 13%, was not tested. But these are real-world data and they have strengths and limitations relative to controlled clinical trials.  But I think that there is some power in numbers and real-world data. And what they saw was that the patients who received chemoimmunotherapy had a median overall survival of 20 months. It was 19.8 months with a checkpoint inhibitor alone. And those data for both of those conditions are far better than a platinum doublet alone with a median overall survival of 12.8 months. Single-agent chemo just median overall survival of 9.5 months. And then when they looked at toxicities, saw that the grade three or higher immune-related adverse events was clearly higher in the patients who had chemoimmunotherapy, they had a greater need for steroids and a greater probability of pneumonitis than the patients over 75 who received a checkpoint inhibitor alone.  And so I would say it's not randomized data. You can only take this so far, but the fact is that it, I think, complements what we saw from the FDA. And that would help me in a situation where we need to make a nuanced decision, there's competing potential standards of care. I think this is informative along with the IPSOS trial that has been presented in some other settings and shows a benefit for in that setting was atezolizumab, I believe, first as the immunotherapy for older patients and PS2. So I think that we're seeing converging evidence to support this concept. Dr. Vamsidhar Velcheti: Yeah, and I completely agree. And I think sometimes the clinical nuances at the individual patient level, I think there are so many other factors that we can actually look at the real-world data, like, for example, tumor burden and medical tomographies. There's so many things that we need to factor into while making those decisions.  Let's move on to the next abstract. This is Abstract 9022. This is an abstract looking at correlations of ctDNA levels and efficacy outcomes in the EMPOWER-Lung 1 trial. What are your key takeaways from this study? Dr. Jack West: I would love to use ctDNA for clinical decision-making in a few years. I think it could be as pivotal as PET scans, but we don't have the data yet to show that you can use the results to improve outcomes. But this is looking at ctDNA in a different setting, as you mentioned, it's looking at the EMPOWER-Lung 1 trial, which was cemiplimab versus chemotherapy in patients with PD-L1 over 50% and did not have a driver mutation. They had ctDNA samples available from 175 patients who were pretty evenly split between chemo and checkpoint inhibitor cemiplimab. What they found was that molecular response, or particularly complete molecular response, if it was seen as in complete eradication of ctDNA at week nine, so after three cycles, was highly correlated with imaging-based response for patients who got cemiplimab. It was not correlated for the patients who got chemotherapy and, perhaps not surprisingly, the patients who had a complete molecular response that was associated with the best overall survival, an immediate overall survival of 29 months compared to the rather dismal results for patients who had no drop in their ctDNA, where the median overall survival was just eight months.  So, I think that it would be wonderful to be able to use this as a help. We know that sometimes patients have ambiguous imaging. There is the possibility of pseudoprogression and just potentially pneumonitis, making it difficult to interpret. I think that ctDNA could be helpful in that situation, but also for early feedback on who might benefit from intensification and adding chemotherapy, who we should cut our losses and switch to something else other than cemiplimab. And in the best-case scenarios, we do have a subset of patients who are doing extraordinarily well, potentially one or a couple of years later, and we just don't know if or whether to stop it and whether patients can do just as well after stopping after a prolonged period on treatment compared to staying on it. And we don't want to give this for years longer at the expense of cumulative toxicities and requiring a patient to come in for ongoing treatments month after month, year after year, for any longer than they would need.  I think that there's great potential utility for this as a concept. But again, at some point, what we'll really need is not to just apply this retrospectively, but prospectively to guide therapeutic decisions, to see if we can have patients do better by intensifying for those patients who need it or de-intensifying for patients who don't. Dr. Vamsidhar Velcheti: It's great, Jack. And I completely agree. I think those kinds of de-escalation trials are very much needed. I'm hoping that we'll get there very soon.   Thank you so much, Dr. West, for sharing your valuable insights with us today on the ASCO Daily News Podcast. We really appreciate your time. Thank you so much. Look forward to seeing you in Chicago. Dr. Jack West: Awesome. Great.  Dr. Vamsidhar Velcheti: And I'd like to thank all the listeners for joining us today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you so much.  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today’s speakers: Dr. Vamsidhar Velcheti @VamsiVelcheti Dr. H. Jack West @JackWestMD  Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures:  Dr. Vamsidhar Velcheti: Honoraria: ITeos Therapeutics Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline  Dr. Jack West: Honoraria: AstraZeneca, Genentech/Roche, Merck, Takeda, Mirati, Regneron, Amgen, Abbvie Consulting or Advisory Role: AstraZeneca, Genentech/Roche, Merck, Takeda, Mirati Therapeutics, Regneron, Amgen, Abbvie, Summit Therapeutics Speakers’ Bureau: Takeda, Merck, AstraZeneca

Dr. Allison Zibelli and Dr. Megan Kruse highlight the PALMIRA and LEONARDA-1 trials, a new standard of care in the treatment of hand-foot syndrome for patients receiving capecitabine, and other key breast cancer studies that will be featured at the 2023 ASCO Annual Meeting. TRANSCRIPT Dr. Allison Zibelli: Hello. I'm Dr. Allison Zibelli, your host for the ASCO Daily News Podcast. I'm an assistant professor of medicine and a breast medical oncologist at the Sidney Kimmel Cancer Center at Jefferson Health. My guest today is Dr. Megan Kruse, a breast medical oncologist at the Cleveland Clinic Taussig Cancer Institute. We'll be discussing key abstracts in breast cancer that will be featured at the 2023 ASCO Annual Meeting.   Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcript at asco.org/DNpod.   Megan, it's great to speak with you today.   Dr. Megan Kruse: Thank you for having me.  Dr. Allison Zibelli: Let's begin with Abstract 1001. This is the PALMIRA trial, a study of second-line endocrine therapy plus palbociclib in HER2-negative ER-positive patients. We all have patients who have progressed on a CDK4/6 inhibitor, and this trial investigated a possible treatment approach for these patients. What are your thoughts?  Dr. Megan Kruse: I think this is a really tough space to know what to do, so I'm glad that we're getting more data to help inform our treatment decisions here. And I think it's also really tough for patients to wrap their heads around letting a CDK4/6 inhibitor go when many of them have done so well with it in the first-line treatment setting. So, in this study, patients were randomized to either continue on with their CDK4/6 inhibitor in the second line, the palbociclib specifically, along with a different endocrine therapy versus just switching to a different endocrine therapy alone. And what I thought was interesting was that the progression-free survival for both arms of the study were actually pretty similar. But that if you look at six-month progression-free survival as a particular endpoint, there were more encouraging results in the patients that continued on with the maintenance palbociclib along with the alternate endocrine therapy compared to what they received in the first line. So, I think this leaves the door open for certain patients to maintain ongoing benefit from their first-line CDK4/6 inhibitor with a switch in the endocrine therapy in the second line.    The challenging thing is it's hard to know who these patients are. I didn't see anything yet in the abstract that would suggest a differential population where this approach would be more successful. But the authors do note that there are some additional biomarker analyses that are pending. So, I hope that we see some data there when the full abstract is presented to get a sense of who might be a good candidate for this approach within the hormone receptor-positive HER2-negative metastatic breast cancer population.  Dr. Allison Zibelli: Thank you for that, Megan. I am not alone in finding these patients very hard to treat once they progress on a CDK4/6 inhibitor because there really is no standard of care in this space. So, I'm hoping this will provide some additional guidance for this patient population.  Dr. Megan Kruse: Yeah, I agree. Absolutely. I think the patients in the second line are now very different biologically after they've received CDK4/6 inhibitor. So, knowing what to do in this space really challenges our historical standards of care and I think it's a big gap in knowledge.   Dr. Allison Zibelli: Next, let's talk about Abstract 1007. This was a study about fixed-dose capecitabine and metastatic breast cancer. We all know that the package insert dose for capecitabine is probably too high, and a lot of us have been tinkering with the dose and scheduling in the absence of good evidence for that approach. This study looked at the efficacy of a lower dose with a fixed schedule. How do you think this will influence clinical practice?   Dr. Megan Kruse: Yeah, I was excited to see this study. I think that has pretty immediate ramifications for what we do. And particularly with respect to the fixed-dose of capecitabine that was chosen, the authors ended up going with 1,500 milligrams twice a day, which honestly, in my practice is sort of where I end up with a lot of my patients. Even if I try to start higher based on their body weight and based on the package insert dosing, I find that I pretty much end up at 1,500 milligrams twice a day no matter what I do. So, I thought that this was a very realistic study and happy to have it as part of our collective breast cancer knowledge. The other thing that was interesting here, not only the dose that they used but also the schedule that seven days on, seven days off I think is something that we do have data and a precedent for, although it doesn't seem to be utilized from the beginning. I find myself sticking with the 14 days on and seven days off when I start patients on capecitabine for metastatic disease management.   What was great in this study was that in terms of efficacy for cancer control, both dosing and schedules, either the fixed-dose or the standard dose seemed equivalent. So, that provides a lot of reassurance, I think, for us as providers, and we can share that easily with patients. But what was notable was that the incidence of diarrhea and hand-foot syndrome, mucositis as well, were all much, much better with the fixed-dose and that more limited seven days on, seven days off schedule. To me, that's very meaningful because I think we run into a lot of treatment delays and a lot of unnecessary modifications with our patients that we start on the higher dose, that maybe will have better dose intensity over time if we started with a lower dose and a schedule that is more feasible for patients and has a better impact on their quality of life. So, I think this was a great abstract, and I'm excited to see what happens with the utilization of capecitabine. It'll be nice to see some real-world data potentially, once this is out there, of what practitioners are actually doing.    Dr. Allison Zibelli: Well, I know that in my case, I'm immediately calling the builders of our EMR to put this into our treatment pathways. I think that capecitabine is underused in the community because of the perception that it has so many side effects and that's a shame because it really has a lot of activity and it's convenient for patients. So, I'm hoping this will allow oncologists to use this drug more in the second-line setting.  Dr. Megan Kruse: Yeah, I agree. I think it's a terrific option and it's that really nice bridge from the targeted endocrine approaches that we use for patients in the first line, potentially second line, then as they transition into needing chemotherapy and becoming endocrine resistant, having an oral option is really a nice bridge there and I'd love to see patients be able to stick with it longer than potentially some do, just based strictly on toxicity. So, I love having this data out there.   Dr. Allison Zibelli: So moving on to Abstract 12005. This is a related abstract because it's addressing a common toxicity in patients that are on capecitabine, which is hand-foot syndrome. This abstract described a randomized, double-blind, placebo-controlled trial of topical diclofenac to prevent hand-foot syndrome. Could you tell us more about this? And would you consider this to be a new standard of care?  Dr. Megan Kruse: I would consider this to be a new standard of care. I think that this abstract is exciting, number one because focusing on symptom management is something that we need more data on. I think we think so much about anti-cancer efficacy of our drugs, which of course is our first priority, but those drugs only have their benefit if we can get patients to take them. So focusing on symptom management is key and it's something that we don't see a ton of abstracts on many times at our national meetings.    And the other thing that I really like about this particular abstract is that the topical diclofenac is something that's so readily accessible. I would say that a lot of my patients have this in their medicine cabinets already because we're thinking about things like joint pain and arthritis all the time. So it's something that I think, again, is immediately actionable and it's hard to know exactly what we would do with this given the last Abstract we talked about where hopefully we're running into less hand-foot syndrome. But I see them as being very complementary pieces of data because there's no reason why we couldn't use both pieces of data together and use a more fixed-dose approach to our capecitabine prescriptions, but also use the topical diclofenac as another way to decrease the incidence of hand-foot syndrome.   I don't know about you, but hand-foot syndrome is the thing that I hear the most about with capecitabine. We're always educating on diarrhea and mucositis and blood counts and fatigue, but by far and away the day-to-day toxicity that I encounter that we manage or have to take time to think about is hand-foot syndrome. So knowing that the use of the topical diclofenac decreases the incidence of hand-foot syndrome in general and particularly higher grade and more problematic, hand-foot syndrome, I think is a big step forward. Our patients are always looking for things to add to their arsenal for symptom management. So we already have a list of moisturizing lotions we talk to them about, and I see us adding this line about the topical diclofenac in there right away in June.   Dr. Allison Zibelli: I agree with you. I think that there is not enough attention paid to the side effects of our therapies and I thought this was a great abstract.    Next, let's talk about the LEONARDA Trial. Abstract 1017. This trial assessed lerociclib, a novel CDK4/6 inhibitor, in ER-positive HER2-negative metastatic breast cancer. Could you describe this trial and how do you think that this fits into the treatment landscape?  Dr. Megan Kruse: So this trial, the LEONARDA Trial, uses lerociclib in combination with fulvestrant for patients with essentially second-line treatment of HR-positive HER2-negative breast cancer, and is randomized against fulvestrant in combination with placebo. And what we saw here I think is a pretty typical trend that we see for our endocrine therapy CDK4/6 inhibitor studies where there was roughly a doubling of progression-free survival. So the progression-free survival was 11 months with the lerociclib and fulvestrant combination compared to the placebo fulvestrant combination at 5.5 months. The response rates were also higher in the CDK4/6 fulvestrant arm compared to the fulvestrant placebo arm at 26.9% versus 9.9%.   What's interesting about this particular novel CDK4/6 inhibitor is that it’s continuous dosing and it’s BID dosing from what the abstract describes. And I think then that leads to a natural comparison with our other continuous BID dosing, CDK4/6 inhibitor, which is abemaciclib. And so when I was evaluating this abstract, I think the efficacy results were pretty much what I was expecting for a CDK4/6 inhibitor with endocrine therapy. What drew my attention was more the toxicity information. And so when you look at that, you actually see a pretty high rate of both neutropenia and leukopenia for this novel CDK4/6 inhibitor. Those were at 90% all-grade neutropenia and 87% all-grade leukopenia. And I think that's higher than what we would expect in comparison to abemaciclib. So if you look at the results for the MONARCH-2 trial, we're seeing all-grade neutropenia being about 50% with abemaciclib.    So when I'm thinking about how does this new drug fit into the landscape, you would think about patients who maybe have a preference for continuous dosing rather than cycled dosing like some of our other CDK4/6 inhibitors. But in that perspective, you'd be looking for some other sort of benefit, and I think when it comes to cytopenias, this might not actually fill that mark. It does seem to have a lower incidence though of diarrhea, so that is definitely a benefit. Here, we saw that all-grade diarrhea with the lerociclib was just under 20%, and the rate of that with abemaciclib in the MONARCH-2 trial was actually 87%. So if I'm looking for a combination of lesser diarrhea, continuous dosing, this might actually have a space. But I think it's hard to know what to do with the CDK4/6 inhibitors now that we have so many options. The selection of particular agents and the sequencing of those agents is still really a challenge. So as more drugs get added to the space, it just gets a little bit murkier about what we would choose.  Dr. Allison Zibelli: I agree. I'm not sure how I would fit this into my current therapeutic plan, so we'll be looking for more data about this in the future.   Dr. Megan Kruse: Agree.   Dr. Allison Zibelli: Finally, Abstract 517 looks at treatment outcomes for patients with very small node-negative HER2-positive tumors in the SEER database. I thought this was very interesting because we've had very limited data in this patient population. I recently had two patients in my clinic with these T1a and T1b HER2-positive tumors, and up until now, we really haven't had much guidance. So what can we learn from this data?  Dr. Megan Kruse: I agree with you. Clinically, this is a big challenge, and I think it is one of the challenges that comes about with having such excellent treatment options where we don't want to leave anything on the table for patients with potentially curable disease. And there's that specter of how aggressive HER2-positive disease left untreated or appropriately untreated is in our minds and what that could mean for patients' lives. And so I think our tendency for these types of patients is to treat more aggressively sometimes than we would need to in the absence of data. And knowing that many of our trials in this space have reflected patients with larger tumors or lymph node positivity really makes it challenging. So I was really encouraged to see these results, and it's a large study. So this is a study of almost 13,000 patients with stage I HER2-positive breast cancer, specifically T1N0 HER2-positive breast cancer. And as you might expect, most of these patients, about three-quarters, were also hormone receptor-positive.   So the authors did a really nice job at breaking down the breast cancer-specific survival results at three, five, and seven years over this time frame for patients and then dividing it out into the hormone receptor-positive HER2-positive and hormone receptor-negative HER2-positive. So I think the key points to take away from this are that overall, the breast cancer-specific survival for these patients is excellent. And I think that that is probably what we have come to expect with data that we've seen from the APT study and its longer-term follow-up. What was interesting to me about this was that the use of chemotherapy over the study period from 2010 to 2019 actually increased over time, and I would suspect that APT had a lot to do with that. Coming out in 2015 and suggesting that it was possible to treat these patients with smaller tumors in a way that hopefully was meaningful without overdoing it. I wasn't really surprised to see that trend.   I think the key takeaway point here is that for patients with T1c disease, those really seem to be the ones where we see a differential benefit between the group of patients that received chemotherapy and those that did not. For the T1a and T1b patients it seemed like breast cancer-specific survival at the different endpoints was quite similar and with really, really high numbers, I mean, between 98 and 100% survival. When you get to those T1c patients, that's where you're starting to see the numbers slip a bit. And with survivals that are about 4-5% different for the arm that received chemotherapy versus those that did not, in favor, of course, of the chemotherapy. The trend was actually more statistically significant for the hormone receptor-positive HER2-positive patients, which was unexpected in my mind. That might be more of a statistical change than anything because the magnitude of difference actually was a little bit stronger for the hormone receptor-negative HER2-positive patients.   But I think in general, what this reinforces for me is that those smallest of the small HER2-positive tumors probably don't need chemotherapy. And that's what's reflected in my institutional guidelines, and I think I will continue to practice that way. That's really for the T1aN0 patients. For the T1bN0 patients, those are patients that right now I am recommending chemotherapy for. And these results made me wonder if it's really necessary because the five-year breast cancer-specific survival was nearly identical in this study. So I'd love to have some more conversations with folks about that at ASCO and really think about what this means for our national guidelines. No surprise, I think the T1cN0 patients will continue to get chemotherapy, and that is appropriate in my mind based on this information.  Dr. Allison Zibelli: It's so nice to have data on something that's been a data-free zone for so long. So I was really happy to see this abstract.    So thank you, Megan, for coming on this podcast today and sharing your insights with us. We really appreciate it.  Dr. Megan Kruse: Thank you for having me. It definitely energizes me as we approach the upcoming ASCO meeting.  Dr. Allison Zibelli: And thank you to our listeners for joining us today. You'll find links to all the abstracts discussed today in the transcripts for this episode. Finally, if you value the thoughts and insights that you hear on the ASCO Daily News Podcast, please take a minute to rate, review, and subscribe. It helps other people to find us, and you can do that wherever you get your podcasts.   Disclaimer:  The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Follow today’s speakers:  Dr. Allison Zibelli  Dr. Megan Kruse  @MeganKruseMD  Follow ASCO on social media:   @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn  Disclosures:   Dr. Allison Zibelli:   None Disclosed  Dr. Megan Kruse:  Consulting or Advisory Role: Novartis Oncology, Puma Biotechnology, Immunomedics, Eisai, Seattle Genetics, Lilly 

Dr. John Sweetenham and Dr. Neeraj Agarwal discuss advances across the spectrum of malignancies, including key studies in precision oncology and disparities in cancer care in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, now the associate director for cancer network clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast. I'm delighted to welcome Dr. Neeraj Agarwal, director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, who is editor-in-chief of the ASCO Daily News.  Today we'll be discussing some key advances across the spectrum of malignancies, as well as novel approaches in precision medicine and cancer disparities that will be featured at the 2023 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode, and disclosures of all guests on the podcast can be found on our transcripts at asco.org/DNpod.  Neeraj, it's great to have you back on the podcast today. Dr. Neeraj Agarwal: Thank you so much, John, for having me. Dr. John Sweetenham: Neeraj, let's begin by discussing some practice-changing phase 3 trials, starting with Abstract 5500, the KEYNOTE-826 study. This study reports the final overall survival results from a randomized, double-blind, phase 3 study of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer, which will be presented by Dr. Bradley Monk.  Dr. Neeraj Agarwal: I'd be happy to. The initial analysis of the KEYNOTE-826 study revealed that first-line pembrolizumab plus chemotherapy provided significant improvements in the overall survival and progression-free survival compared to placebo plus chemotherapy in patients with metastatic, persistent, or recurrent cervical cancer who had not previously received systemic chemotherapy and were not candidates for curative treatments such as surgery or radiation. In this study, patients were randomly assigned in a 1:1 ratio to receive pembrolizumab or placebo at 200 milligrams every three weeks for up to 35 cycles, along with chemotherapy with paclitaxel, plus a platinum therapy with or without bevacizumab.   From November 2018 to January 2020, 617 patients were enrolled with 308 receiving pembrolizumab plus chemotherapy and 309 patients receiving placebo plus chemotherapy. At the data cutoff of October 3, 2022, the median follow-up was 39 months. At this protocol-specified final overall survival analysis, pembrolizumab plus chemotherapy treatment continues to show a significant improvement in overall survival and progression-free survival, regardless of whether patients receive bevacizumab or not. The incidence of grade 3 or more adverse events was higher in the pembrolizumab plus chemotherapy arm than the placebo plus chemotherapy arm, with the most common adverse event being anemia, neutropenia, and hypertension. Dr. John Sweetenham: These are exciting data, Neeraj. So the main message from this trial is that pembrolizumab plus chemotherapy, with or without bevacizumab, can now be considered as standard of care for first-line treatment of persistent, recurrent, or metastatic cervical cancer. Dr. Neeraj Agarwal: Yes, I agree, John. Now, moving on to a different common type of cancer, let's discuss Abstract 1001, titled “Second-Line Endocrine Therapy with or without Palbociclib Maintenance in Patients with Hormone Receptor-Positive/HER2-Negative Advanced Breast Cancer: Results from the PALMIRA Trial,” which will be discussed by Dr. Antonio Llombart-Cussac. So, John, based on this abstract, can you please tell us about the role of palbociclib after prior progression on this drug? Dr. John Sweetenham: Yes. In this study, the authors aimed to determine if palbociclib maintenance with an alternative endocrine therapy improves the anti-tumor activity of second-line treatment in patients with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer who had disease progression to first-line treatment with palbociclib in combination with endocrine therapy. After including 198 patients in the trial with a 2:1 randomization, 136 patients received palbociclib with endocrine therapy and 62 patients received endocrine therapy alone. And at a median follow-up of 8.7 months, the primary endpoint of progression-free survival was not met with a median progression-free survival of 4.2 months in the palbociclib-containing combination versus 3.6 months in the control arm. Also, higher grade 3 to 4 adverse events were reported in patients treated in the palbociclib arm. Dr. Neeraj Agarwal: Thanks, John. So you are saying that continuing the CDK4/6 inhibitor palbociclib after prior disease progression on palbociclib, even when the primary endocrine therapy has been changed, doesn't seem to be beneficial, therefore, this practice may be discouraged in the clinical setting? Dr. John Sweetenham: Yes, that's correct. Neeraj, I think that's the conclusion from this study. Dr. Neeraj Agarwal: So, John, now let's switch gears and highlight some precision oncology studies.  Dr. John Sweetenham: Well, Abstract 3602, titled “Real World Rates of FDA-Approved Targeted Therapy and Immunotherapy Prescriptions for Metastatic Colorectal Cancer Patients in the VA's National Precision Oncology Program” will be presented by Dr. Alice Nono Djosta. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Well, comprehensive genomic profiling has the potential to guide the administration of FDA-approved biomarker-directed therapies and improve outcomes among patients with metastatic colorectal cancer. So, in this study, Abstract 3602, investigators sought to determine the rates of actionable biomarkers and prescription of associated FDA-approved therapies among veterans in the National Precision Oncology Program. Patients with metastatic colorectal cancer who had undergone comprehensive genomic profiling via tissue or liquid biopsy were included between 2019 and 2022 and had 1 of the following 5 actionable biomarker profiles including: NRAS, KRAS, BRAF wild-type, BRAF V600E mutation, MSI-high, TMB-high, NTRK fusion or rearrangements.  Prescription data for seven FDA-approved biomarker-directed therapies were extracted and rates of comprehensive genomic profiling (CGP)-directed therapy prescriptions were assessed by the investigators. A total of 908 patients with metastatic colorectal cancer underwent comprehensive genomic profiling, with 80% patients having colon adenocarcinoma and 20% with rectal adenocarcinoma. The combined rates of any actionable variants were 47% in patients with colon adenocarcinoma and 45% in patients with rectal adenocarcinoma. After including 424 eligible patients for FDA-approved biomarker therapy, only 70% patients with MSI-high, 48% patients with TMB-high, 38% patients with NRAS, KRAS, and BRAF wild-type, and only 17% of patients with BRAF V600E mutation received FDA-approved CGP-directed therapies.  Dr. John Sweetenham: Very important data, Neeraj. What's the main conclusion of this study? Dr. Neeraj Agarwal: So, in conclusion, this study found that almost 30% of patients with MSI-high metastatic colorectal cancer did not receive effective immune checkpoint inhibitors. And overall, a significant number of eligible patients did not receive FDA-approved biomarker-directed therapies. So, it is crucial that we evaluate the barriers to prescribing comprehensive genomic profiling-directed therapies in our patients with metastatic colorectal cancers.  So, John, let's move on to lung cancer, where the use of single-gene testing is still common in the community practice. Can you please tell us about Abstract 6506, titled “The Impact of Single-Gene Testing on Subsequent Comprehensive Genomic Profiling Success in Community Oncology Practice for Advanced Non–small Cell Lung Cancer”? These are results from a prospective observational reference laboratory testing program and these results will be presented by Dr. Mary Nesline. Dr. John Sweetenham: Yes, definitely. In this study, researchers aim to investigate the impact of prior single-gene testing on comprehensive genomic profiling success and therapeutic opportunities for patients with non–small cell lung cancer in community settings. They included patients who underwent at least 1 single gene testing for guideline recommending genomic variants in non–small cell lung cancer such as BRAF, EGFR, KRAS, MET exon 14 skipping mutations, ALK, RET, and ROS1 rearrangements as well as PD-L1 immunohistochemistry.  And they offered comprehensive genomic profiling either before or after receipt of a negative single gene test. Of 580 patients with non–small cell lung cancer with the comprehensive genomic profiling ordered between 2021 and 2022, around 30% of the patients had at least 1 single-gene testing ordered prior to the comprehensive testing, with a median of 5 prior single-gene tests. Compared to CGP-only cases. CGP per cases with prior negative single gene testing was canceled twice as often at tissue review, had a higher DNA extraction failure, and a lower DNA sequencing success. CGP also identified guideline-recommended variants in genes with no single-gene testing offered during the study period, such as ERBB2 mutations, or NTRK2/3 fusions, as well as variants targeted in ongoing clinical trials in 28% of patients. Dr. Neeraj Agarwal: Very interesting. So John, what is your key takeaway message from this? Dr. John Sweetenham: The main message is that in a community oncology setting, the practice of ordering single gene testing prior to comprehensive genomic profiling for patients with non–small cell lung cancer is common. Prior negative single-gene testing led to a higher rate of CGP test cancellation due to tissue insufficiency and increased CGP DNA extraction failures. The practice of single-gene testing does not align with practice guideline recommendations and may negatively impact the potential benefits of CGP testing for patients with non–small cell lung cancer.  Now, let's move on to another important abstract that our fellow clinicians should hear about. This is Abstract 1534 titled “Real-World Experience of an In-House Dihydropyrimidine Dehydrogenase Genotype Test to Guide Fluoropyrimidine Dosing at a Multi-Site Cancer Hospital” that will be presented by Dr. Jai Patel. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. Fluoropyrimidines, such as 5-fluorouracil and capecitabine, are commonly used to treat solid tumor cancers such as gastrointestinal and breast cancers. We know that severe toxicity occurs in one-third of patients, which delays the timely completion of treatments and result in prolonged hospitalization of these patients. These toxicities may be due in part to genetic variation in the DPYD gene. Five variants are known to have moderate to strong evidence according to the Clinical Pharmacogenetics Implementation Consortium. So, in this observational study, the authors describe the implementation of an in-house DPYD test and its impact on the dosing of these fluoropyrimidines, which include capecitabine and 5-fluorouracil.  From March 2020 to December 2022, 491 patients received DPYD genotyping testing, and 90% of them had gastrointestinal cancers. The median lab turnaround time was only 3 days. Pre-treatment testing was ordered in 80% of patients, and 93% of patients had results before starting cycle 1. Overall, 6% of patients were heterozygous carriers. Fluoropyrimidine dose was reduced, avoided, or discontinued in 90% of these patients. Moreover, in pre-treatment carriers, 90% of patients received an upfront dose reduction, avoidance, or they even declined chemotherapy. Dr. John Sweetenham: Thanks, Neeraj. So what do you think is the key takeaway message here? Dr. Neeraj Agarwal: So, DPYD genotype-guided dosing of fluoropyrimidine, including 5-fluorouracil and capecitabine, is logistically feasible with a rapid turnaround time and can result in treatment dose modifications for most carriers, potentially avoiding or mitigating severe toxicities, especially in those patients who received pre-treatment testing. Dr. John Sweetenham: Thanks again. Now let's transition to studies that focus on disparities in cancer care. Dr. Neeraj Agarwal: Definitely. Let's discuss Abstract 6530, titled “Impact of Free Hospital-Provided Rideshare Service on Radiation Therapy Completion Rates: A Matched Cohort Analysis.” In this study, Dr. Eric Chen and colleagues assess the potential of rideshare services in facilitating timely radiation therapy for patients facing barriers, such as limited transportation, financial constraints, and lack of adequate social support. So the authors analyzed data from about 2,900 patients who underwent radiation therapy and found that 58 of them utilized a free hospital-provided rideshare service.  These free hospital-provided rideshare service utilizers had a lower median age and were more likely to identify as Black or African American compared to those who did not utilize these services. They also had higher socioeconomic disadvantages and traveled shorter distances for treatment. Interestingly, more rideshare utilizers underwent radiation therapy with curative intent, had longer treatment course duration, and a higher number of fractions prescribed. In the matched-cohort analysis, the study found that radiation therapy completion rates were significantly higher for rideshare utilizers compared to non-rideshare utilizers, especially for patients who were undergoing radiation therapy with curative intent.  Dr. John Sweetenham: So what's the key take-home message from this abstract? Dr. Neeraj Agarwal: This study highlights the potential benefit of utilizing hospital-provided free ride-share services, particularly for patients facing barriers to timely treatment. So, using these services were associated with higher radiation therapy completion rates, especially in the curative setting.  So, John, there is another study, Abstract 1606, titled “Trends and Disparities in Oncology Telehealth after the Initial Pandemic Era” that will be presented by Dr. Michael Lee and colleagues. They evaluated whether telehealth utilization continued after the pandemic and if demographic differences in its users persist. So John, please tell us more about this abstract. Dr. John Sweetenham: Yes, the authors conducted a retrospective cohort study in 22 Kaiser Permanente Northern California hematology and oncology clinics between October 1, 2020, and June 1, 2022. The study investigated the use of office, video, and telephone visits, analyzing more than 340,000 hematology oncology visits with MD or DO providers. Of these visits, 25% were in-office, 37% were video visits, and 39% were telephone visits. Monthly telehealth visits peaked in January 2021, representing around 86% of total visits, and decreased to 69% of the total visits by June 2022. Video visits were more common for new appointments, whereas telephone visits were more common for return appointments. Moving to the post-pandemic period, telehealth visits remained popular, with video visits being the most commonly utilized. However, telehealth use varied among demographic populations. Video visits were a significantly higher proportion of all visits among individuals less than 45 years old, primary English speakers, patients with commercial insurance, non-Hispanic Whites and Asians, compared with Hispanic, Whites, and Blacks, and patients living in the deprived neighborhoods. Dr. Neeraj Agarwal: Interesting data, John. So what is the key takeaway message from this abstract? Dr. John Sweetenham: Well, overall, it's encouraging to see that even after the pandemic, telehealth continued to be widely used. However, the concerning issue is that telehealth is less utilized in patients who may need it most. The next step, in my view, will be to work on barriers to access telehealth by underprivileged populations.   And that brings our discussion to a close today. Before we wrap up the podcast, Neeraj, do you have any final thoughts to share? Dr. Neeraj Agarwal: Yes, thanks, John. I would urge our listeners to come and join us at the ASCO Annual Meeting, not only to celebrate these successes but also to help disseminate these cutting-edge data to practitioners and patients across the world. Dr. John Sweetenham: Absolutely. I'd like to thank our listeners for joining us today, and thank you, Neeraj, for sharing your insights with us as well.  You will find links to the abstracts discussed today on the transcripts of this episode. Finally, if you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.  Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Find out more about today’s speakers: Dr. John Sweetenham Dr. Neeraj Agarwal @neerajaiims Follow ASCO on social media:   @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn   Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Neeraj Agarwal:  Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences   Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas

Host Dr. John Sweetenham and guests Dr. Karen Reckamp and Dr. Harpreet Singh discuss the S2302 Pragmatica-Lung trial, a streamlined, real-world clinical trial that is poised to simplify and transform the entire clinical trials model as we know it. TRANSCRIPT Dr. John Sweetenham: Hello, I’m Dr. John Sweetenham, the associate director for cancer network clinical affairs at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast.  Today, we are going to be discussing a streamlined, real-world clinical trial from the Southwest Oncology Group (SWOG), which is S2302, also known as the Pragmatica-Lung trial. This study is poised to simplify and transform the entire clinical trials model as we know it. Joining me for this discussion is the trial’s lead investigator, Dr. Karen Reckamp. Dr. Reckamp is a clinical professor, director of the Division of Medical Oncology, and associate director for clinical research at Cedars-Sinai Samuel Oschin Cancer Center. I’m also delighted to welcome Dr. Harpreet Singh, the director of 1 of 3 divisions of oncology at the U.S. Food and Drug Administration. She will discuss the FDA’s views on streamlining clinical trials to reach more representative groups of patients and will also more broadly address some of the key questions that regulators consider when deciding on whether real-world data can substitute for randomized controlled trials. Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/DNpod. Dr. Reckamp and Dr. Singh, it’s a great pleasure to have you on the podcast today. Dr. Karen Reckamp: Thank you for having us. Dr. John Sweetenham: Dr. Reckamp, I’m going to start with you if I may and ask if you could give us some background on S2302, the Pragmatica-Lung trial for non-small cell lung cancer. Dr. Karen Reckamp: Sure. The Pragmatica-Lung trial really started with the sub-study from Lung-MAP, which was called S1800A, and it was a randomized phase 2 trial that evaluated pembrolizumab and ramucirumab versus standard of care for patients who had previously received chemotherapy and immunotherapy with advanced non-small cell lung cancer and had had disease progression. And in this phase 2 trial, we found that there was an improvement in overall survival with a hazard ratio of 0.69% and survival of 14.5 months for pembrolizumab and ramucirumab, and 11.6 months for standard of care. And with that, we had again a randomized phase 2 trial, but the study was small. And so, trying to think about how to move this to the next level to get phase 3 data, we started thinking about how to do this in a way that would reduce the timelines and potentially move this treatment to patients more quickly than standard registrational, randomized phase 3 trials. And that’s kind of where S2302 and Pragmatica-Lung started. Dr. John Sweetenham: So, can you tell us in a little more detail how the dramatically streamlined pragmatic design of this trial is going to hopefully simplify trial design and trial conduct in the future beyond non-small cell lung cancer?  Dr. Karen Reckamp: I think the important piece of this—and we have Dr. Singh here to speak to the FDA part—but this has been a partnership with the FDA and CTEP [NCI’s Cancer Therapy Evaluation Program]. Really, our goal was to try and find a way to run trials in a more streamlined way. One of our colleagues at CTEP during this process said, “If this is not making you uncomfortable, then you're not doing it right.” So, the first thing we did was kind of lean into the discomfort because for those of us who have been writing trials and putting trials together for the last 20-plus years, this is dramatically different. And we’re really looking at one question, and that is overall survival. We’re trying to validate the overall survival we saw in S1800A. And with that, we stripped away all the unnecessary data collection that comes along with other types of registrational issues that come with randomized phase 3 trials. And then, we also looked at patient burden and really opened it up. So, again, pragmatically, making this practical, allowing investigators to be empowered to treat patients how they normally would in their own practice. And so, moving forward, again, for types of trials where we have drugs whose toxicity profiles are well known, they’re used in practice but using novel combinations for a subset of patients who have limited treatment options available, this could really change the paradigm moving forward for these types of trials in multiple diseases. Dr. John Sweetenham: Yeah, thanks. And in addition to simplifying the trial design, obviously, one of the goals here is to have a study population which is more representative of the patients who are seen typically in community practice. Hopefully, we’ll overcome some of the known disparities that we see in clinical trial accrual. Could you speak just a little bit to how the study design and the organization of the study helps to achieve that? Dr. Karen Reckamp: So, I think it’s on several levels, but we are looking to allow this to be more generalizable and allow a more diverse population into this study. First, by again stripping down the eligibility criteria to only the absolute essential criteria for understanding our scientific question. And so, we don’t require imaging studies to be uploaded or presented. If the patient has progression, it’s based on the investigator's opinion. And so, we don’t need to be searching for outside scans or things like that. We don’t have tissue requirements, and we don't even actually have lab requirements. If this is a patient, you would treat your standard of care practice with the standard of care regimens; those are the labs that you do. So, it’s all based on standard of care. So, by doing this based on standard of care, it really allows almost any patient to enroll. And then we have outreach. We have our DEI group and our community practices very well engaged to make sure that we have broad reach. Having this open through NCTN [NCI’s National Clinical Trials Network] will make sure that we get this to multiple practices in far-reaching parts across the United States. Dr. John Sweetenham: Yeah, I think that’s excellent. And you’ve already alluded to the fact that the data collection requirements for the study are going to be kind of pared down to the absolute minimum and that’s going to include, I believe, toxicity reporting as well. So, can you comment a little bit on that and, specifically, what your plans are for reporting toxicity in this trial? Dr. Karen Reckamp: Yes, you’re correct. This is significantly pared down from what we’re used to doing. And so, most clinical trial offices are struggling with staffing and making sure that their patients have enough staff and that they have enough staff to get patients onto trials efficiently, and then getting the data in is always a challenge for sites. So, we have really, again, working with our partners, working with the FDA, and with CTEP, we have minimized what we are going to collect on patients. So, we’re collecting survival and vital status on patients. We are collecting the background standard information that we collect on kind of prior therapies, and we are collecting only unexpected grade 3 and higher adverse events. And so, thinking about these drugs—ramucirumab and pembrolizumab—we know how these drugs work, we know the toxicity profile, we’re using them in combinations and single agents in multiple tumor types. And so, thinking about most of the immune-related adverse events wouldn’t even be reportable because they're expected. And so, a large number of data that is normally collected would not be collected here. And, as noted, we don’t collect scans, we don't collect labs, we're not collecting con-meds, start and stop dates. A lot of that burden of data collection, but also data auditing and queries, goes away. It should be a significantly easier trial to perform by sites.  Dr. John Sweetenham: And can you just update us on the status of the trial right now? Dr. Karen Reckamp: We’re in the process of pre-activation, and so, if you're an NCTN site, you can actually go in and do some pre-training and take a look at the draft protocol. And we are anticipating approval sometime in early March. Dr. John Sweetenham: Great. Congratulations on getting this trial launched and underway because I know that the word “groundbreaking” is used a lot, but I think that, obviously, if this trial proves to be the success that it looks like it will be, then it's going to have, I think, major implications for study design in the future. And that’s going to lead me to ask a couple of questions to Dr. Singh. And the first one of those is the FDA’s decision to consider data from a simplified pragmatic trial design like this, which uses more limited clinical information, is really kind of almost revolutionary. And could you comment a little on this from the FDA perspective and how you think it’s going to influence the future of clinical trials and the future of cross-trials? Dr. Harpreet Singh: Well, thanks so much for the question, and thanks for having me. I want to push back on that just a little bit because I think, for what it’s worth, the FDA has been advocating for trial efficiencies in oncology for many years. And, of course, as you know, our current commissioner, Dr. Robert Califf, is very vested in this concept. And certainly, the idea of pragmatic trial has been there in the field of cardiology for some time.  In terms of this trial, in particular, in coming to oncology, I do think actually putting pen to paper and drafting the protocol, which we did really in cohesion with SWOG and many calls with Karen and others who were a part of this, that collaborative piece, I think, is groundbreaking because what we saw here was a great deal of discomfort, actually around everything that we were stripping down. We sensed a lot of discomfort in terms of including various, like you mentioned, safety issues, safety reporting not being perhaps as rigorous as we’re accustomed to seeing at the FDA. And certainly, investigators are accustomed to collecting other endpoints besides overall survival, like time to progression, but the real-world version of that, or time to next therapy. And so, one very difficult lesson that I’ve had to learn, and we’ve had to learn, is that you have to really learn to say no to some very interesting trial design elements that are not essential to the big question here, which is, does this combination regimen offer an improvement in survival over the control? So, while I do think the actual organizational and structural piece of this, now that it’s actually stood up, is groundbreaking, I think that the idea of pragmatic trials and incorporating clinical care into the idea of answering a clinical question as opposed to the traditional randomized clinical trial is a concept that’s been around. I’m just thrilled to see it actually occur in this very, I think, ideal setting for patients with lung cancer. Dr. John Sweetenham: Yeah, absolutely. I want to broaden the scope of what we’re discussing here just a little bit, perhaps to talk a little more about the “real world” and “real-world data.” More real-world data is being considered in regulatory decision-making. And one of the questions I have, again, from an FDA perspective, is that everyone still, I think, regards randomized controlled trials as the gold standard for evaluating efficacy if not effectiveness, of various interventions. What are the key questions that you consider when deciding whether any kind of real-world data analysis is a good substitute for a randomized controlled trial?  Dr. Harpreet Singh: Well, thank you for the question about how FDA considers real-world data when we consider this to be appropriate. There are many nuances to this. So, first of all, what is real-world data? And there’s actually a distinction between real-world data, which is just simply a source used in observational studies traditionally. But real-world data is not specifically a trial design; it’s just data. Whereas real-world evidence, which is evaluating the benefits and risks which are derived from real-world data, may come from things like electronic health records. It’s not either-or. So, for example, in a pragmatic trial, you could use a blended approach where you have some components of real-world data or real-world practice, which we may consider kind of part of real-world data, but while retaining some elements of randomized control trials. So, I think when FDA considers real-world evidence, so I’ll say that instead of data, it usually would be a source like a very high-quality registry or data obtained through a very well-designed observational study. And this would be in settings of perhaps super rare diseases in which randomization is either not feasible or, in some cases, where you may have preliminary data which suggests that randomization is not ethical. But we agree with the general idea that the gold standard is randomization.  And that’s what I love about this pragmatic trial, is that you are retaining the benefit of randomization while bringing pragmatic elements in, bringing the trial to patients and really incorporating clinical practice into the trial, as opposed to the reverse, where you’re having patients enrolled on a traditional trial where the visits are outside of routine. Dr. John Sweetenham: Thanks for drawing that distinction between real-world evidence and real-world data because I think the two expressions are sometimes used a little carelessly, as maybe I just did. But certainly, one of the things that I’ve observed over the last several years since we started to incorporate real-world data or real-world evidence into our kind of oncology lexicon is that real-world data has been used in a fairly relaxed, let’s say, way and certainly any relatively small series which has been registry based or retrospective, there’s been a tendency to use this term called real-world data, which personally, I’ve certainly seen applied to patients who are undergoing very intensive therapies such as CAR T. And certainly, when I look at the patient characteristics in those elements of so-called real-world data, it’s a long way from the real world that I’m familiar with in my own practice. And so, I do think that the term has been used very loosely. And your point about real-world evidence is an important one, I think. People are still questioning whether real-world evidence in oncology is truly valid. And I think to some extent, you’ve already answered that question.  Do you think that there are mistakes and pitfalls that investigators can avoid when they’re looking at real-world evidence? Dr. Karen Reckamp: Sure. I mean, I think the first point of clarification is, are we looking at this evidence to support use of an oncology drug in clinical practice, or are you an investigator working to bring real-world evidence to the FDA for drug approval? But either way, no matter what scenario you’re in, I think the first question you must ask yourself is, is this data fit for purpose? And what does that actually mean, ‘fit for purpose’? And I think it goes to things like, are the patients well-matched? So, there’s this very complex process, but the concept is not complex of propensity score matching, which our statisticians do for us beautifully. But this idea of are the patients in this data set that you’re looking at, this is just a collection of data, right? How relevant is it to the patient in front of you? Is there some sort of matching that’s going on in terms of patient characteristic?  After that, you have to ask yourself about this kind of array of epidemiologic biases that are inherent in non-randomized comparisons. Like, is this contemporaneous data? So, if this data set came from a group of patients who started their therapy—this goes to the idea of the index date, okay, start of therapy—has the standard of care changed? Has supportive care become increasingly better? Obviously, the answer to that is yes. And so, if you have these contemporaneous mismatches, then can you actually really rely on this real-world data or evidence, either one, as you’re applying it to your patient? So, I think if it’s for regulatory purposes, certainly you could avoid many mistakes by coming to the FDA early and often, which we always recommend. And if it’s you as a clinician, as a health care provider, looking at this collection of data, I think you do have to walk yourself through in a really basic kind of logical process of, “how well does this data apply to the scenario in which I want to use this therapy?” So, index date, selection, timing, patient characteristics, things like that. Dr. John Sweetenham: Yeah, great, thanks. And I’d like to maybe ask both of you for your comments on one final question, and this is circling back to the S2302 study. Intrinsic to the study design and the concept is that the population in this study will be truly representative of the “real world.” My two questions to both of you will be, first of all: What is the gold standard for representative? In other words, what does that really mean to have a representative population of patients with advanced non-small cell lung cancer? And secondly, do you have any safeguards in place in the course of the study designed to make sure that that study population doesn’t get skewed in some way so that it becomes unrepresentative of the real world? So, Dr. Reckamp, maybe I can start with you and ask you for your comments about that. Dr. Karen Reckamp: Thank you. I think that’s a very good question and something that we grappled with as we designed this study and really did keep coming back to that. So, I think when we talk about representation, most randomized trials don’t have broad representation. They are very specific populations that we curate in order to take as much variability out of the trial as possible so that we can investigate just the experimental arm versus standard of care or whatever we’re evaluating. And here, we’ve consciously made an effort to say we want to know how this works in a real practice and make this as generalizable as possible while still being safe. So, we have the premise of keeping patients safe as the number one goal of this trial. And then, we want to look at the survival data. So, we actually did lower the bar a bit and changed our hazard ratio. Our hazard ratio was 0.69% for the phase 2 trial. We loosened that a little bit for the phase 3 trial, knowing that the patients that are coming on to trial are not going to be perfect patients, and there may be a little more coming together of those curves. That being said, randomization is what is supposed to wash away all sins, which has been said many times as we put this trial together. And so, the randomization is really the goal, to utilize the randomization process in order to make sure that there is balance and that we are getting representation on both sides that will help us understand how the investigational arm is really doing in this population. It’s not going to be perfect, and we are allowing for performance status 2 patients. But I think we all believe that this is really important because there’s a large proportion of patients who have performance status 2 who never go on to trials, but in the real world, we treat them generally with the standard of care options that we use. So, I think this is really important for moving things forward, and will be groundbreaking in that way, too. Dr. John Sweetenham: Great, thank you. And Dr. Singh, just to add to that, will the FDA be looking at this from the perspective of making sure that the study population as a whole—accepting that randomization will hopefully cancel out some of the potential pitfalls there—but will the FDA be looking to make sure that the population as a whole is truly representative of what’s out there in the real world?  Dr. Harpreet Singh: We always look at the population. We are always hopeful that, in general, the population is reflective of the disease for which—in this case, lung cancer. I think in this case, we were very hands-on with developing the protocol, and it is our hope and it’s our expectation, and I think it very much will happen that you are going to see a very diverse and representative, more generalizable population here. I just want to add a piece to this because remember that traditional randomized clinical trials typically do have a more homogeneous patient population because a lot of this is designed around a de-risking strategy when you’re bringing new drugs to market. One of the reasons we felt so comfortable stripping away, as Karen mentioned, no lab criteria. If the clinician says, “I think you're fit for this regimen, go ahead and enroll them.” We pushed for inclusion of PS 2 patients. We, the FDA, did. So, yes, we’re going to be looking, but we do really hope that these really streamlined inclusion and exclusion criteria allow for that. And so there's other things too, like race, ethnicity, age. And so it starts with not excluding patients based on perhaps unfair or arbitrary cutoffs like labs. Not to say that performance status is arbitrary. But in this case, if the clinician deems you fit for this therapy, that is between the patient and the investigator and their judgment, which is really part of the element of real-world trials and this pragmatic element too.  I also wanted to add on this idea of diverse representation, we expect there to be a lot of extra, for lack of a better term, noise, in this trial, even though it’s randomized. And so, part of the negotiation around designing this trial was the need for an increased sample size to try to account for some of what we expect to be perhaps unequal randomization, perhaps in terms of patient characteristics on either side, perhaps patients lost to follow-up, etc. And so, when we talk about pragmatic trials, one element is that you probably often may need an increased sample size to account for the increase in heterogeneity, not only in your patient population but perhaps in monitoring as well. Dr. John Sweetenham: Well, thank you both, Dr. Reckamp and Dr. Singh, for a great discussion today and for sharing your insights on these developing trends in clinical trial design. Dr. Reckamp and Dr. Singh, we’ll be watching closely to see how the trial performs in the coming months and advances the concepts of pragmatic trial design that Dr. Singh mentioned earlier within the FDA. We obviously are very excited to see whether this change in trial conduct will enable you to meet new groups of patients and ultimately improve outcomes for them. So, thanks once again for being with us today. Dr. Harpreet Singh: Thanks so much. Dr. John Sweetenham: And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today’s speakers: Dr. John Sweetenham  Dr. Karen Reckamp  @ReckampK  Dr. Harpreet Singh  @harpreet_md Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn  Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Karen Reckamp: Consulting/Advisory Role: Amgen, Takeda, AstraZeneca, Seattle Genetics, Genentech, Blueprint Medicines, Daiichi Sankyo/Lilly, EMD Serono, Janssen Oncology, Merck KGaA, GlaxoSmithKline, Mirati Therapeutics Research Funding (Institution): Genentech/Roche, Janssen Oncology, Calithera Biosciences, Elevation Oncology, Daiichi Sankyo/AstraZeneca, Blueprint Medicines Dr. Harpreet Singh: None Disclosed

Dr. Mohamed Salem, Dr. Myriam Chalabi, and Dr. Andrea Cercek discuss pivotal neoadjuvant immunotherapy clinical trials for patients with MSI-H/dMMR colorectal cancer, focusing on the development of active therapies in the neoadjuvant setting—where patients are treated without surgery, radiation, or chemotherapy—and the importance of patient selection in finding the right target and treatment to improve outcomes. TRANSCRIPT Dr. Mohamed Salem: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host today, Dr. Mohamed Salem. I'm a GI oncologist at the Levine Cancer Institute at Atrium Health. Today, we will be discussing very promising advancements in the neoadjuvant immunotherapy for patients with MSI-H/dMMR colorectal cancer. And I'm very delighted to welcome two world-renowned oncologists whose research has tremendously helped shape the treatment landscape of colorectal cancer. Dr. Myriam Chalabi is a GI medical oncologist at the Netherlands Cancer Institute, and Dr. Andrea Cercek is a medical oncologist at Memorial Sloan Kettering in the United States.  Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/DNpod.  Dr. Chalabi and Dr. Cercek, welcome to the ASCO Daily News Podcast. Dr. Myriam Chalabi: Thank you for having me. Dr. Andrea Cercek: Thank you very much for having me. Dr. Mohamed Salem: It's a pleasure to have two world-renowned stars like you. Thank you for taking the time.  So, before we start going deep into the topic, obviously, now we are seeing emerging data in CRC using immunotherapy as the neoadjuvant approach, which actually can reduce or even eliminate some of the other treatment modalities and potentially save patients from toxicities. Both of you led what I think are landmark studies in this field. I wanted to give you the chance to tell our audience about your studies and why you think they’re important. Dr. Cercek? Dr. Andrea Cercek: Sure. Thank you so much. So, our study was a neoadjuvant study in early-stage, locally advanced rectal cancer with tumors that were mismatch repair-deficient or MSI-H. And rectal cancer normally is treated with chemotherapy, chemoradiation, and surgery. And the goal of the trial was to utilize PD-1 blockade alone in this subpopulation and evaluate the response.  Patients received six months of dostarlimab, which is a PD-1 blocking agent, and then were evaluated for response. If there was no residual disease, they were able to avoid radiation and surgery. And what we've seen thus far in the presentation at GI ASCO in 2022 was that all patients who received six months of dostarlimab had a clinical complete response, so no residual tumor, and were able to avoid chemotherapy, radiation, and surgery and are on observation. And the study is ongoing and actively accruing patients. Dr. Mohamed Salem: All of us were very excited seeing that presentation at ASCO. And when we came back to the clinic everyone was talking about it, including patients, obviously. Thank you for this, Dr. Cercek. Dr. Chalabi, you also led a similar study that was actually presented in ESMO in 2022. Can you please give us, like, a brief description of that trial? Dr. Myriam Chalabi: Yeah, sure. So, this is the NICHE trial, and actually the NICHE trial has been ongoing for quite some time now. We recently presented a larger NICHE-2 study, but basically– so what we started out by doing in NICHE is giving patients what we considered back then a window of opportunity study. We treated patients with MMR-deficient tumors, which I'll be focusing on for now, with two cycles of nivolumab and one single cycle of low-dose ipilimumab. And patients all undergo surgery within six weeks of registration within the study. And back in 2020, we published the first data of NICHE-1 showing 100% pathologic responses with 60% pathologic complete responses and decided that this should definitely be a treatment that we need to explore in a larger group of patients. And that's where NICHE-2 was born, which we presented at ESMO last year, where we treated over 100 patients with this neoadjuvant approach of two cycles nivolumab, one single cycle ipilimumab, showing 99% pathologic responses, including 95% major pathologic responses and 67% pathologic complete responses. And this was all within five and a half weeks of the first treatment with immunotherapy, so a very short treatment duration with dual checkpoint blockade. Dr. Mohamed Salem: Amazing results, too. And I know you had a standing ovation when you presented the outcome of the study. And again, congratulations to you, your investigator, and also all the patients participated. Dr. Myriam Chalabi: Thank you so much.  Dr. Mohamed Salem: I guess the first question that comes to my mind - we have two trials, obviously, now we're moving from one size fits all to precision therapy, like getting actually the right treatment for the right patient. But in the NICHE study, it was a checkpoint inhibitor, and the rectal study was a single agent. I want to start with you, Dr. Chalabi. In your opinion, when should we use single agent or double blockade immunotherapy? Dr. Myriam Chalabi: That is a great question. I'm going to start off by saying that I don't know the exact answer. I don't think we know that answer. And Dr. Cercek is going to share also her thoughts on this because we're seeing, of course, fantastic responses with monotherapy as well in Dr. Cercek's study. And we've also seen that in a study by Dr. Overman with monotherapy. So that may suffice in some patients, although what we're seeing is that you need to treat patients longer, probably to achieve that response, at least clinically. And I think that is the difference with dual checkpoint blockade, that we're giving in NICHE where we're seeing these very deep responses in just under six weeks’ time.  So, I think it may be more of a question of how long we want to treat patients for to achieve the endpoint that we're aiming for. And, of course, there may be, at some point, patients that need dual checkpoint blockade, but so far, we're seeing great responses in both of our studies. So I think we need more patients, more data to see whether we're going to see non-responders. And hopefully, the studies that are ongoing in the metastatic disease setting will give us at least a little bit of insight into what the differences are in response to mono and dual checkpoint blockade and whether we can tell which patients might benefit more from the combination. But I think there's still a lot of work to be done in that field. Dr. Mohamed Salem: I totally agree. Dr. Cercek, same question to you. What do you think?  Dr. Andrea Cercek: Dr. Chalabi answered beautifully and very comprehensively. I agree completely with what she said. It's hard to argue with the responses that we're seeing with PD-1 blockade alone. But then again, dual checkpoint inhibitors in the NICHE study with just one month of therapy had phenomenal responses as well. So I think it's a question of duration of therapy and, really importantly, what we're trying to achieve. If our goal is organ preservation, then perhaps longer duration is better. The question then becomes, can we do, should we do longer duration with dual checkpoint inhibitors versus single agent? So I think, as she concluded, I couldn't agree more that we just need more information, we need more work to do, basically to answer this question for our patients. Dr. Mohamed Salem: More to come and more studies, which is fascinating.  So, Dr. Chalabi, you created actually a new term on Twitter called ‘Chalabi Plot’. It was amazing to see such a response. But we're curious, among those patients who achieved complete response so far, did you see any relapse? Dr. Myriam Chalabi: Short answer, no.  we're waiting, of course on the disease-free survival data, the three-year DFS data for NICHE-2, and we hope to have that by the end of this year, beginning of next year. But as of now, we showed that data, and so far, we haven't seen any recurrences in, actually, any of the patients treated in NICHE-2. Dr. Mohamed Salem: Fantastic. Dr. Cercek. So I think your slide -- I remember clearly from the ASCO presentation -- was all complete response, every single patient.  Same question, did you see any relapse so far? Dr. Andrea Cercek: So far, no, we have not. Dr. Mohamed Salem: Amazing. So, Dr. Cercek, as you know, and obviously, this is metastatic disease, but in KEYNOTE-177, as you know, about 30% of patients with MSI-high tumors did not respond to checkpoint inhibitors. So that makes some of us feel nervous about using checkpoint inhibitors alone in colorectal cancer, even with MSI-high status. I was curious if you can comment on this and if there is a way we can perhaps sort out who actually is likely to respond and who is likely not going to respond. Dr. Andrea Cercek: I think that's a really important question and an excellent point. And we believe that the difference lies in the fact that in KEYNOTE-177, the patients had metastatic disease, whereas in our neoadjuvant studies that we're discussing, they have early-stage disease. And whether that has to do with the tumor differences, young tumors versus older tumors once they become metastatic, or the microenvironment, remains to be determined. But certainly, there is this pattern of incredible responses with checkpoint inhibitors in early-stage dMMR tumors. And in KEYNOTE-177, as you mentioned, about 30% of patients progressed. And I think we don't know why that is. We are seeing this, about a third of progressors repeatedly in the metastatic setting with checkpoint inhibitors. And so perhaps there is a population. But whether this is driven by genomics or something else, we don't know. Dr. Mohamed Salem: Great. So, along the same lines, especially rectal cancer, obviously, because surgical resection is a key component in the treatment paradigm, do you feel patients who achieve pathological complete response should still go under surgical resection or should go under the ‘watch and wait' approach? Dr. Andrea Cercek: In general, I'm a fan of organ preservation. I think in rectal cancer, the reasons are obvious. It's a challenging surgery. It's very toxic to the patients. It changes their lives forever. In survivorship, 30% of them require a permanent colostomy because of the location of the tumor. So there, the field of rectal cancer, in general, is moving towards non-operative management, even in the MSI-proficient patients, by trying to optimize therapy to increase clinical complete responses and therefore omit surgery. So that's the difference with rectal cancer. In colon cancer, it's a different discussion. I think for many patients, surgery is very straightforward. It's a hemicolectomy. It doesn't alter lifestyle in survivorship, so it's not as morbid as it is in rectal cancer. Of course, I think if a patient is older with MSI-deficient tumor perhaps can undergo surgery, then clinical complete responses become critical because then we can monitor them after just checkpoint blockade, and they don't need surgery.  The challenge there, and I would love to hear Dr. Chalabi's comments on this, too, is just that imaging is challenging. We have a hard time in colon cancer determining whether someone has a clinical complete response or not. It seems to be very different than in rectal cancer, where with endoscopy and with the rectal MRI, we really can't tell whether the tumor is still present or not. This remains a challenge in colon cancer. Dr. Mohamed Salem: Dr. Chalabi, I would like to hear your thoughts and also how you practice in Europe. I don't know if it's the same like here in US or different. Dr. Myriam Chalabi: I completely agree with Dr. Cercek. Well, if we look at the rectal cancer patients, I think this is fantastic. That even though this is a small population achieving this high clinical complete response rate, not having to operate or even give any chemotherapy or radiation therapy to these patients, it is extremely important both in the short term but also in terms of long-term complications and morbidity. When it comes to the colon cancer responses that we're seeing in NICHE, those are all pathologic responses, of course. And we have been evaluating also preoperatively using scans to see whether we can assess these complete responses based on imaging. That doesn't seem to be the case. We do see responses in all patients, so we see these are all very large bulky tumors that we're treating in NICHE-2. And we do see responses in almost all of these patients, but it's not close to complete responses, definitely not in all of the complete responders that we're seeing. So that makes it difficult.  And the question is, what if we would be waiting or treating longer because these bulky tumors need more time to disappear or to be cleared before you're going to see it on the imaging? So that is a question that I don't have an answer to just yet. We may be getting some more data on that with the currently ongoing trials. And as Dr. Cercek pointed out, the endoscopies when you have a right-sided colon tumor are different than doing just a sigmoidoscopy for a rectal tumor. So, we actually do have one patient who hasn’t undergone surgery, and that is actually a patient with an MMR-proficient tumor within the NICHE trial who had a complete response. And that patient has a sigmoidal tumor, and he actually had toxicities which prevented him from undergoing timely surgery and now has a complete response after two years, both endoscopically and on imaging. So, he hasn’t undergone surgery, and that is a great example of how we may be doing this in the future. It's an interesting case within the trial to follow and see how we can do it in the future. Dr. Mohamed Salem: That’s fascinating news. So, was it MMR-proficient? Dr. Myriam Chalabi: Yes, this is an MMR-proficient tumor.  Dr. Mohamed Salem Wow. Any particular biomarkers that you think he or she had to predict that? Dr. Myriam Chalabi: We have treated more patients with MMR-proficient tumors. We have 31 patients, and we have seen actually responses in 9 out of 31 patients in the MMR-proficient tumors with the same combination of two doses of nivolumab and one of ipilimumab. We previously published on half of the cohort approximately on what the possible predictive biomarkers of response could be, and that was a costimulation for CD8 and PD-1. So PD-1 positive CD8 T cells. And we're currently doing the same work for the rest of the cohort. So hopefully, we'll be able to show that soon and see whether this still stands for the completed MMR-proficient cohort. But definitely also very exciting data for the MMR-proficient. Dr. Mohamed Salem: So, this is actually a very good segue to my next question because I know all of us are looking for this. Like, obviously, we're seeing a fascinating response in those patients with MSI-high tumors, but majority of colorectal cancer, as you know, they actually have MSS-proficient tumors. Any thoughts about how we can overcome the primary resistance for this tumor to checkpoint inhibitors? So let me start with you, Dr. Cercek.  Dr. Andrea Cercek: I'm very much looking forward to Dr. Chalabi's data on this because, honestly, we have not seen such amazing responses to immunotherapy in MSS tumors. The initial studies were complete flatline, no responses at all. And here, she just described a patient that had a complete response to just a month of checkpoint inhibitors. So that's phenomenal, and hopefully, we'll learn from the responders.  We believe that there is a subpopulation of MSS colorectal cancer that is more immune sensitive, immune hot, whichever term you like to use. And it's just a matter of appropriately identifying those patients. And personally, I think the answer lies in the neoadjuvant setting in early tumors where they're treatment-naive, not exposed to chemo, not exposed to radiation, younger, have their innate microenvironment. And so, I think it's likely a combination of the above. But obviously, the ultimate goal is to find out who those patients are and then potentially treat them just like this with immunotherapy. And that would be another nice chunk of the pie where we could utilize immunotherapy for our patients. Dr. Mohamed Salem: Very true. Dr. Chalabi, especially with your experience and just showing there is a chance for those people to respond, what are your thoughts about how we can overcome this primary resistance? Dr. Myriam Chalabi: It’s great to be here with Dr. Cercek because, obviously, we have very similar interests but it’s also good to see that we think the same way because I completely agree with what she just said in terms of neoadjuvant. I think that was one of the most important things that we did here, giving this neoadjuvant treatment in non-metastatic tumors. It’s probably a very important driver in the responses that we’re seeing. So, we’ve been seeing data now a bit more in the metastatic disease setting where MSS tumors seem to be responding to new generations of checkpoint blockade. And the question is how those would do in the neoadjuvant setting that would be even different than what we’re seeing now. But there’s definitely some proof of MSS tumors that can respond to immunotherapy. The question on how to overcome the primary resistance, I think that question is for us: Who are the patients with primary resistant tumors and why are they primarily resistant? And then we can think about how to change that and how to change them into the tumors that are responding. I think these types of data will be key to understand more and know; hopefully, even you said, in the metastatic disease setting, to make these tumors more pliable in response to immunotherapy. Dr. Mohamed Salem: I agree. So, both of you are leading us toward how to choose the right patient with the right target for the right treatment. That's an amazing journey you’re taking all of us on.  So, Dr. Cercek, I have to admit that with your data, it created some problems for us in the clinic because all patients the following day came in asking for immunotherapy. We had a hard time trying to explain that maybe this is not the right treatment for them or, like, not the right platform. But I wanted to ask you, if we'll have a patient tomorrow in the clinic with localized rectal cancer and happen to have an MSI-high tumor, what would be your recommendation in terms of how to approach that patient? Dr. Andrea Cercek: I think, ideally, you would discuss clinical trials with the patient. We have opened the study now to not just rectal cancer but colon cancer and, in fact, all solid tumors that are mismatch repair-deficient. So I think at this time, the patients really should be treated on a clinical trial. As we learn more, in particular, until we are more comfortable assessing for a clinical complete response and follow-up. I think the surveillance piece will be critically important. In rectal cancer, it's well established, but it's not in the other tumor types. So my recommendation would be to enroll the patient on a trial. Dr. Mohamed Salem: Just to add to that too, obviously, as you know, there is now the cooperative group trial that’s looking at that option and we obviously encourage all centers to participate and open that study to have this option for our patients. Dr. Chalabi, so what do you guys do in Europe for these patients? Dr. Myriam Chalabi: In Europe, it's a very different situation. I would have answered this question differently by saying, well, we don't have that option of treating patients outside of clinical trials. So basically, we have to make sure that we have clinical trials for these patients. And that's something that we've had for colon cancer patients. That is still the case. And we're getting rectal cancer trials also for patients with MMR deficient tumors and have those also for MMR proficient tumors. For us and I agree completely that we should be treating patients within clinical trials, we don't have another option. But still, even if we did, I think it's important to create data within clinical trials to be able to ultimately also show why this should be standard of care and how we can make it standard of care. Because if you're not accumulating that data, then it's going to become very difficult if accrual is lacking. Now, we treat patients either with standard-of-care treatments, but usually, we try to find something within clinical trials.  Dr. Mohamed Salem: I totally agree. And as we always say, the standard of care should be a clinical trial participation. So, I must say, both of you, Dr. Cercek and Dr. Chalabi, you made 2022 a very exciting year for us in GI cancers. You really changed the way we look at how to treat these patients and give them a huge chance of, I would say, actually cure and obviously organ preservation. So, I'm very curious to know what you are both are working on now and what we should expect in 2023 and 2024.  Dr. Andrea Cercek: So, for me, the study is ongoing, as I mentioned, and we've expanded to all mismatch repair-deficient solid tumors with the same approach of six months of dostarlimab and then the option of nonoperative management. And I think that it'll be important for us to learn in terms of responses on the luminal versus some of the other tumor types, like, for example, pancreas cancer, where we don't see these robust responses in the metastatic setting, that will be important to do. We're doing some correlative analysis, as Dr. Chalabi described as well in our patients.  And then, I'm interested in optimizing neoadjuvant approaches to minimize therapy in rectal cancer specifically. So, we have a study now for HER-2 amplified RAS wild-type patients with locally advanced rectal cancer with a similar approach of utilizing HER-2 targeted therapy first and then in combination with chemotherapy. In our case, it's a combination of trastuzumab and tucatinib and then chemotherapy with CAPOX and assessing for response and potential omission of radiation and surgery depending on responders. So, I'm very excited that study is open and actively accruing, and hopefully, we can get similar responses that we did in the MSI population with PD-1 blockade. Dr. Mohamed Salem: Is that only available at MSK? Dr. Andrea Cercek: It is at this time. However, we will likely be expanding, so if there's any interest, let me know. Dr. Mohamed Salem: Great. I'm sure many centers will be. Great. What about you, Dr. Chalabi? Any sneak peek in the future? Dr. Myriam Chalabi: So many sneak peeks, where to begin? I think it's very exciting to be working in this space at this time, and we're very lucky to be in it. So, for NICHE, we're actually accruing now in new cohorts for both MMR-deficient and MMR-proficient tumors. For the patients with MMR-deficient tumors, we're actually testing a new combination of nivolumab plus relatlimab, so anti-LAG-3 plus anti-PD1. And we're testing the same co-formulation in patients with pMMR tumors. In addition to another cohort for the pMMR tumors with nivolumab, all within this window of opportunity, as we did previously in NICHE, and to see if we're going to see more responses if these are going to be different tumors than the ones responding to nivolumab and ipilimumab. And for the MMR deficient tumors, we're treating longer with this combination now. So, we're operating after eight weeks instead of six weeks. We're giving two cycles, four weekly cycles, to see whether we can even improve the PCR rates, even though this is, of course, a different combination treatment. So, very exciting times for NICHE, and we'll have the readout for the DFS at the end of this year, so that's also very exciting. And then, well, it's similar to Dr. Cercek. So again, we're on the same page when it comes to these neoadjuvant treatments. We have actually an ongoing trial for neoadjuvant treatment of patients with MMR proficient rectal cancers, and that is using a combination of radiation therapy followed by a combination of atezolizumab or anti-PDL1 with Bevacizumab with the aim of organ sparing approach in these patients. And we actually presented stage 1 of this trial as a poster at ASCO GI, showing that we achieved 56% complete or near complete responses clinically at 12 weeks. And after at least a year of follow-up for all patients, we have 50% organ preservation. So those are very exciting data as well. Also, in the MMR proficient tumors, I'm very excited to hear about the HER-2-positive tumors and Dr. Cercek's study. So there's definitely a lot going on that we hope to share as soon as the data are available. Dr. Mohamed Salem: We'll be looking forward to your next presentation and seeing that. So again, most of your work showed us that we really have to choose the right patient with the right target for the right treatment to achieve the best possible outcome. So we're getting short on time here. But before we conclude, ASCO Daily News Podcast has a huge audience of oncologists, I wanted to give you the chance to share anything you'd like to share with our audience today before we finish. Dr. Cercek? Dr. Andrea Cercek: I believe this is an incredibly exciting time in colorectal cancer. I think it's finally our turn, which feels really nice, and obviously, we have a lot more work that needs to be done. But my personal belief is to keep trying to chip away at the pie and identify responders and keep working to have better-targeted drugs and better treatment options that will improve responses and improve outcomes for our patients. But I certainly believe that we are well on our way there, and it's very exciting. Dr. Mohamed Salem: I totally agree. Dr. Chalabi, any thoughts? Dr. Myriam Chalabi: I think after 2022 and the data that we've been showing, I think it's important to– and I think by now, maybe it's not even necessary anymore to say it– but I think it's important to really look at the tumors and look at these MMR proteins or MSI, and to make sure that you're treating the patient in the right way, and to consider that. Before, it wasn't as important in the neoadjuvant setting or these localized tumors, but now it's becoming essential.  And I think if you would have looked five years ago and you would say, yeah, these MSI tumors are important to find, it's a very small proportion of patients, in rectal cancer even lower than in colon cancer. But still, it has such a huge impact on what you're doing in these patients and your chances of cure. So I think that would be my most important giveaway to test for MMR deficiency before deciding on a treatment for your patients. And we're working on trials with neoadjuvant immunotherapy. Also in other tumor types, Dr. Cercek is also doing the same. I think those will be very important also outside of the GI field to see whether this approach works for a much larger patient population, despite the low incidence.  Dr. Andrea Cercek: Dr. Chalabi just made a critical point that that is most important is to remember that we do have biomarkers in colorectal cancer that, in the neoadjuvant setting and in the metastatic setting, especially MSI, that we need to test for. And then, just to add from a clinical perspective, in rectal cancer, the large majority of patients that have mismatch-repair deficient or MSI tumors actually have Lynch syndrome. So really, if you identify a patient that's mismatch-repair deficient or MSI-high anywhere, but especially in the rectum, they absolutely should get germline testing. Dr. Mohamed Salem: I echo that and second that. And Dr. Cercek, thank you, and I know you did a lot of work in colorectal cancer in the younger adult population, too, so I think you’ve had a huge impact on that area too. I would like to thank both of you again for being here today, but more for the great work you and your teams are doing to advance the field. It’s really a very exciting time in GI cancers now, and thank you so much for your work and for sharing your insights with us today on the ASCO Daily News Podcast. Dr. Myriam Chalabi: Thank you so much for having me. It's been great. Dr. Andrea Cercek: Thank you for having me. Dr. Mohamed Salem: Of course, and thanks to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today’s speakers:     Dr. Mohamed Salem @SalemGIOncDoc   Dr. Myriam Chalabi @MyriamChalabi   Dr. Andrea Cercek @AndreaCercek   Learn about other key advances in GI Oncology: SWOG 1815, PARADIGM, and Other Advances at GI23   Follow ASCO on social media:      @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Mohamed Salem: Consulting or Advisory Role: Taiho Pharmaceutical, Exelixis, Bristol-Myers Squibb, Exelixis, QED Therapeutics, Novartis, Pfizer, Daiichi Sankyo/Astra Zeneca Speakers' Bureau: Genentech/Roche, Taiho Pharmaceutical, Daiichi Sankyo/Astra Zeneca, BMS, Merck Dr. Myriam Chalabi: Consulting or Advisory Role: MSD, Bristol-Myers Squibb/Celegne, Numab Research Funding (Institution): Bristol-Myers Squibb, Roche/Genentech, MSD Travel, Accommodations, Expenses: Roche/Genentech, Bristol-Myers Squibb Dr. Andrea Cercek: Consulting or Advisory Role: Bayer, GSK, Incyte, Merck, Janssen, Seattle Genetics, G1 Therapeutics Research Funding (Institution): Seattle Genetics, GSK, Rgenix          

Guest host Dr. Neeraj Agarwal and Dr. Christian Kollmannsberger discuss practice-changing abstracts that were presented at the 2023 ASCO Genitourinary Cancers Symposium, including results from the TALAPRO-2, PROpel, TRITON3, ARASENS, KEYNOTE-057, CheckMate 274, and CheckMate 9ER studies. TRANSCRIPT Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Oncology Program, and professor of Medicine at the Huntsman Cancer Institute at the University of Utah, and editor-in-chief of the ASCO Daily News.  Today, we will be discussing practice-changing abstracts and other key advances in GU Oncology featured at the 2023 ASCO Genitourinary Cancers Symposium. Joining me for this discussion is Dr. Christian Kollmannsberger, the chair of this year's ASCO GU. Dr. Kollmannsberger is a GU medical oncologist at the BC Cancer Vancouver Cancer Center and a clinical professor at the University of British Columbia.  Our full disclosures are available in the transcript of this episode, and the disclosures of all guests on the podcast can be found on our transcripts at asco.org/DNpod.  Christian, thank you for joining us on the podcast today.  Dr. Christian Kollmannsberger: Thank you very much, Neeraj. It's a real pleasure to be here and have this discussion. Dr. Neeraj Agarwal: Thank you. So, Christian, the GU meeting featured remarkable progress in various GU malignancies. Could you please share some of the prominent topics that made the headlines this year and give us an overall feel of ASCO GU this year? Dr. Christian Kollmannsberger: Absolutely. I think it was a great meeting with over 5,800 attendees from more than 70 countries. And most of the attendees were in person, so it was a great event. ASCO GU is truly the premier global event to feature the very best of GU cancer research and treatment. The theme of this year's meeting was "Today's Science, Tomorrow's Treatment," and that was reflected in the novel scientific and clinical findings that were presented and will potentially lead to changes in our daily clinical practice. It also reminds us how quickly the development today is and how quickly novel scientific progress is immediately translated into clinical practice, particularly oncology.   I was very impressed by the meeting's emphasis on diversity, interactivity, networking, multidisciplinary collaboration, and evidence-based care. We introduced several new features such as a “Meet the Professor session, a women’s networking event, etc. And the first day really kicked off with a very rich focus on prostate cancer and much attention given to PARP inhibitors in our first session. As an example, LBA 17 was the first late-breaking abstract presented. And congratulations to you, Neeraj, on delivering this exciting data on the TALAPRO-2 trial, which were eagerly awaited. Let's start with that. Can you tell us about this trial? Dr. Neeraj Agarwal: Yes, of course. So the TALAPRO-2 trial was a phase 3 randomized trial where patients in newly diagnosed metastatic CRPC settings were randomized to standard of care enzalutamide plus placebo versus enzalutamide plus talazoparib PARP inhibitor. And as we know, Christian, the rationale has been that dual inhibition of PARP and AR may enhance the efficacy of each. And there's a laboratory preclinical rationale and based on which other studies have been done in the past. So, without getting into too much detail into the rationale for the trial, I'll come right to the results of the trial. So, this was the first-line mCRPC setting where rPFS was the primary endpoint as assessed by the independent radiology assessment. And in this trial, patients were recruited regardless of the homologous recombination repair gene alterations. So, patients were recruited and they were prospectively tested for whether they had these HRR gene alterations or not, but all comer population was included in this trial. And after a median follow-up of approximately 23 months, the trial read out, and we found that trial made the primary endpoint was improved radiographic progression-free survival with the rPFS being about 22 months in the enzalutamide arm and not reached in the combination arm with a 37% reduction in risk of progression or death.  If you look at the subgroup analysis of patients who were HRR+, there was a 54% reduction risk of progression or death. If you look at patients who were stratified in HRR- or unknown group, there was a 30% reduction risk of progression or death. If you specifically look at an exploratory analysis we did to look for patients who were HRR- by prospective tumor tissue testing; there was a 34% reduction in risk of death with a hazard ratio of 0.66 favoring the combination arm. So overall, the rPFS primary endpoint was met in all groups. We also see significant delay in PSA progression in the combination arm by more than nine months. We also see delays in the time to cytotoxic chemotherapy. We saw delay in progression or death on subsequent neoplastic therapy after the protocol treatment. We saw delays in deterioration of quality of life and global health status. All these were significant and happened on the talazoparib plus enzalutamide arm.  So overall, if you look at the totality of the data, these all favored the combination of talazoparib plus enzalutamide compared to enzalutamide alone. I want to highlight that overall survival is immature at 31% maturity with a hazard issue of 0.89, currently favoring enzalutamide plus talazoparib. But we'll have to look at more mature data as time passes.  Dr. Christian Kollmannsberger: Wow. Thank you, Neeraj. So, it sounds like that was a very positive trial, and it's potentially practice-changing. One of the concerns is always safety and toxicity. So can you tell us whether there were any new safety signals, and can you tell us more about the common adverse events that were noticed in TALAPRO-2? Dr. Neeraj Agarwal: No discussion is complete without talking about safety results, so I'm glad you asked me, Christian. The most common dose-affecting toxicity, if you will - so toxicities which led to dose modification and dose discontinuation of talazoparib were cytopenias, as we expect from this class of agents. So anemia, neutropenia, thrombocytopenia, these were the common toxicities. In fact, rate with anemia was 46.5%. Neutropenia and cytopenia were much less common.  I would like to highlight one fact which also came up during the discussion section after our oral presentation. The qualifying criteria for entry in this trial was a hemoglobin of 9-gram percent. And 49% of patients had grade 1 to 2 anemia at baseline, that is before starting treatment with talazoparib. So, we knew that if you mandate dose reduction, a lot of patients will not get adequate dosing of talazoparib. So, we waited for grade 3 anemia and then instituted dose reduction. And that I thought personally was a good strategy because the grade 3 anemia happened after a median duration of three months, 3.3 months to be more precise. And then, these patients underwent protocol-mandated dose reduction, following which the dose discontinuations were quite low actually. Only 8.3% patients discontinued talazoparib because of anemia, and the median dose intensity or median relative dose intensity of talazoparib in the talazoparib arm remained quite high at more than 80%, which translates to a talazoparib dose of 0.4 milligram daily when the starting dose was 0.5 milligram. So those were the hallmark of toxicities.   I do like to mention that those grade 3, 4 toxicities which are more known to affect the quality of life of our patients, such as grade 3, 4 anorexia, fatigue, nausea and vomiting, they were quite rare, happening in 1 to 4% patients who were on talazoparib. So overall, regarding the side effects, they were manageable, there were no new safety signals, and we could maintain adequate talazoparib dosing with dose reduction, which happened quite early during the protocol treatment.  Dr. Christian Kollmannsberger: Thank you, Neeraj. Very impressive results indeed. The patient population included in TALAPRO-2 was very similar to those included in the PROpel phase 3 trial, which tested the combination of abiraterone and olaparib in the first-line mCRPC setting. So, I'd like to just mention that we also saw LBA16 on the PROpel study, which was the final overall survival in PROpel, which was presented by Noel Clarke. So PROpel, as you know, was a randomized phase 3 trial evaluating efficacy and safety of olaparib plus abiraterone versus placebo plus abiraterone as first-line therapy for mCRPC in the first-line metastatic castration resistance setting. The enrollment in that study was independent of known defects in the homologous recombination repair gene pathway in contrast to other studies, such as MAGNITUDE, which tested the biomarker upfront. A total of 796 patients were randomly assigned to either olaparib plus abiraterone or placebo plus abiraterone. And we saw similar results, significant radiographic progression-free survival with olaparib plus abiraterone in PROpel, which was the primary endpoint similar to TALAPRO-2, and that was published last year in the New England Journal of Medicine Evidence.  Now, this abstract presented here at ASCO GU reported on overall survival with an overall survival majority of 47.9% and showed that with the addition of the PARP inhibitor olaparib to abiraterone, a statistically non-significant but clinically meaningful improvement in overall survival of about seven months were achieved compared to standard of care in abiraterone alone. The numbers were 42.1 versus 34.7 months in the all-comers population of patients in the first-line mCRPC setting. Importantly, I think the median overall survival of more than 42 months really represents the longest reported median overall survival thus far in a phase III trial for first-line metastatic castration-resistant prostate cancer. Although the median overall survival for the non-HRR group remains not statistically significant, with a hazard ratio of 0.89. Dr. Neeraj Agarwal: Such a great synopsis of the PROpel result data. Thank you, Christian, for highlighting these results. As we know, the combination is already approved by the EMA, the European Medical Agency, for patients in the first-line mCRPC setting who are not candidates for docetaxel chemotherapy. If this combination is approved by the FDA, we may have one more therapeutic option for our patients in first-line mCRPC.  So, just continuing on the PARP inhibitors, there was one more oral presentation with PARP inhibitor rucaparib by Dr. Alan Bryce from the Mayo Clinic, Arizona. This was Abstract 18 on the primary result of the TRITON3 trial. So to complete our PARP inhibitor section, I would like to summarize the result of the TRITON3 trial, which was a randomized phase III trial evaluating rucaparib versus physician choice, which notably included docetaxel in addition to abiraterone or enzalutamide in patients with chemotherapy-naive mCRPC with BRCA1, BRCA2 or ATM alterations. These patients had disease progression after having one novel hormonal therapy, or we call them second-generation androgen pathway inhibitors in any setting. So these patients had to have disease progression on a novel hormonal therapy.   In the BRCA subgroup and the subsequent intention to treat the population, the primary endpoint tested first was radiographic progression-free survival, and overall survival was the key secondary endpoint. The subgroup of patients with BRCA-altered disease had a median rPFS of 11.2 months with rucaparib compared to 6.4 months with physician choice of treatment - looks like almost doubling of the rPFS with the rucaparib. In the overall ITT population, median rPFS was 10.2 months with rucaparib and 6.4 months with the physician’s choice of treatment. Although the overall survival data are immature, we still see a trend for improved overall survival with rucaparib. Regardless, the study clearly demonstrates the value of rucaparib for treating BRCA1 and BRCA2-altered mCRPC after disease progression on an androgen receptor pathway inhibitor. So these were the impressive results from the TRITON3 trial.  But before we switch to non-prostate abstract, I would like to complete the prostate cancer discussion by talking about the Abstract 15, which was based on the results of the ARASENS trial presented by Dr. Maha Hussain. As we know, ARASENS is a randomized phase 3 trial evaluating the efficacy and safety of darolutamide plus androgen deprivation therapy plus docetaxel versus androgen deprivation therapy or ADT plus docetaxel. So the triplet of ADT plus darolutamide plus docetaxel being compared to ADT plus docetaxel chemotherapy in patients with newly diagnosed metastatic castration-sensitive prostate cancer. A total of 1,300 patients were randomly assigned to the doublet versus triplet. As presented in the last ASCO GU meeting exactly one year ago, the primary endpoint of the study was met with a significant improvement in overall survival and a 32% reduction in risk of death for patients on the triplet therapy with ADT plus docetaxel plus darolutamide versus ADT plus docetaxel chemotherapy. So triplet therapy was already approved based on these data.  The abstract presented by Dr. Hussain this year is a post-talk analysis where Dr. Hussain and colleagues investigated the impact of triplet therapy across patients with high volume versus low volume per chartered criteria and higher risk versus low risk using latitude trial criteria. And investigators knew that these results would be highly attractive to practicing oncologists who are now choosing treatment based on volume of disease or risk of disease, more commonly, volume of disease.  So, let's come to what was presented this ASCO GU. So, after 1,305 patients in ARASENS, the majority had high-volume disease and high-risk disease. Among patients with high-volume disease, the addition of darolutamide reduced the risk of death by 30% compared with ADT and docetaxel, with a hazard ratio of 0.69. In the risk groups, the addition of darolutamide seems to favor both high-risk and low-risk groups. Among patients with low-volume disease, there was a trend towards improvement in overall survival with the addition of darolutamide, but it did not reach statistical significance. The great news was that there was no new safety signal. So, to summarize these data, the triplet of darolutamide plus ADT plus docetaxel showed superior overall survival compared to doublet of ADT plus docetaxel, with an important caveat that triplet was not compared with any of the modern doublets of ADT plus a second generation androgen receptor pathways inhibitor such as abiraterone, apalutamide, or enzalutamide, or even darolutamide. So, I wish there was a third arm of ADT plus darolutamide.  Having said that, triplet can be considered a standard of care now based on these data for patients with metastatic hormone sensory prostate cancer, where we would be using ADT plus docetaxel chemotherapy. And from this meeting data, this efficacy of triplet can be applied to high-volume disease and all risk disease. And we just need more time to see how the data pans out in low-volume patients with metastatic hormone-sensitive prostate cancer.  Dr. Christian Kollmannsberger: Yes, I completely agree, Neeraj. I think all the data presented in these abstracts are really impressive and will impact our daily clinical practice and our patients more or less immediately. I think the use of PARP inhibitors, whether as a monotherapy or in combination with androgen receptor pathway inhibitors, as well as now the option of triplet therapy in the metastatic castration sensitive setting really offer patients with metastatic prostate cancer new treatment strategies and most importantly, improved survival outcomes. And it is impressive to see how we have pushed the prognosis and the outcomes for our patients with prostate cancer, I would say, in the last five to ten years. And similar to last year, I think the entire Prostate Cancer Day at ASCO GU 2023 was full with impressive data and featured dynamic content throughout the day. Dr. Neeraj Agarwal: Indeed. So, let's move on to bladder cancer. Christian, what are your key takeaways from the bladder cancer studies presented at the meeting? Dr. Christian Kollmannsberger: I think there were interesting abstracts in both the non-muscle-invasive and the muscle-invasive setting and the metastatic setting. So, for example, Abstract 442 was presented by Dr. Andrea Necchi on the cohort B of the phase 2 KEYNOTE-057 trial. As a background here, the standard treatment for high-risk non-muscle-invasive bladder cancer involves transurethral resection of the bladder tumor, a TURBT, followed by intravesical BCG therapy to eradicate any residual disease. And patients who fail to adequately respond to BCG are usually recommended to undergo radical cystectomy. So in the cohort B of the phase 2  KEYNOTE-057 trial that investigated the safety and efficacy of pembrolizumab as a single agent for patients with BCG-unresponsive, high-risk non-muscle-invasive bladder cancer who were ineligible or declined to undergo radical cystectomy, enrolled patients received standard-dose pembrolizumab of 200 milligrams every three weeks for up to 35 cycles. So very common as we do it with other disease sites. And at a median follow-up of 45.4 months, the primary endpoints of disease-free survival at twelve months was 43.5%. The median disease-free survival duration was 7.7 months. These are encouraging results, and we should keep in mind that a radical cystectomy has immense impact on our patients’ quality of life. So I think it is important that we do these trials.  Now in order to address potential biases in this phase II trial, such as the underlying heterogeneity of transurethral resection of bladder tumor quality, and to obtain a more comprehensive understanding of pembrolizumab's efficacy relative to a particular control group, we need further evaluation of pembrolizumab in a randomized trial before we can really go for regulatory approval. But overall, I think for the first time in a long time that we seem to be able to move the needle in non-muscle-invasive bladder cancer. Dr. Neeraj Agarwal: Thank you, Christian, for this great overview. Could you please also share the findings presented by Dr. Matt Galsky on Abstract 443? Dr. Christian Kollmannsberger: Of course, Neeraj. Abstract 443, presented by Matt Galsky, reported the extended follow-up results from the CheckMate 274 trial, which looked at another very important field where we haven't made that much progress, which is the adjuvant setting. And CheckMate 274 examined adjuvant nivolumab compared to placebo for patients with high-risk resected muscle-invasive urothelial carcinoma. In this trial, nivolumab was given at 240 milligrams every two weeks or placebo every two weeks for up to one year of treatment. After following up with patients for a median of 36.1 months, the study found that those who received nivolumab had a median DFS of 22 months compared to only 10.9 months for those who received placebo among the ITT patients. So basically, a doubling of the DFS with the addition of adjuvant nivolumab.  The results were particularly notable for patients with high PD-L1 expressions or PD-L1 expression of 1% or more, as those who are treated with nivolumab had a median DFS of 52.6 months, which was six times higher than the DFS in the control group where patients received placebo, which was only 8.4 months. And I think that is truly impressive. One year of adjuvant therapy with nivolumab continues to show a sustained disease-free survival benefit over a period of three years in both the ITT and the PD-L1-high patient population. In my view, these results reinforce the utility of nivolumab in the adjuvant urothelial carcinoma setting after surgery. And it will be interesting to see how the overall survival pans out in this study.  So, Neeraj, moving on to kidney cancer, what were your key takeaways from these studies on kidney cancer presented in this meeting?  Dr. Neeraj Agarwal: So, there were exciting results presented from multiple studies in this area as well. For example, Abstract 603 presented by Dr. Mauricio Burotto, senior author was, Dr. Toni Choueiri on the three-year follow-up from the phase 2 CheckMate-9ER trial. So, in this trial, patients were randomized one-to-one to nivolumab 240 milligrams every two weeks, plus cabozantinib 40 milligrams daily versus sunitinib 50 milligrams daily for four weeks, and it was a six-week cycle for sunitinib until disease progression or unacceptable toxicity. So this was the design of the phase 3 CheckMate-9ER trial. And after a median follow-up of three years, the benefit of nivolumab plus cabozantinib remained consistent with previous follow-ups. So, as we know, these data have been presented in the past, also published in the New England Journal of Medicine. But this meeting was a clear follow-up of these data.  Notably, the median overall survival of patients treated with cabozantinib plus nivolumab in the ITT population, which included all favorable intermediate and poor IMDC score patients, was significantly improved at 49.5 months compared to 35.5 months in the sunitinib arm. It is so heartening to see that median overall survival breaching the four-year mark in our patients with metastatic RCC in a consistent fashion. We saw similar data with the combination of ipilimumab plus nivolumab recently. And as these trials are maturing, we are probably going to see more combinations breaching this four-year mark. So importantly, no new safety signals emerged with the additional follow-up in either arm. And I think these results provide further support for the use of cabozantinib plus nivolumab as a first-line treatment option for patients with metastatic or advanced renal cell carcinoma. Dr. Christian Kollmannsberger: Indeed, I think it is extremely impressive what we've seen over the last 15 years in metastatic kidney cancer, going from a median overall survival of about a year to now more than four years. I think that is a great achievement, and we can see it on a daily basis in our clinical practice.  Now, before we wrap up, I would like to highlight another potentially practice-changing trial, LBA602, which titled, “Results from Phase 3 Study of 89Zr-DFO-Girentuximab for PET/CT Imaging of Clear Cell Renal Cell Carcinoma: The ZIRCON Trial” presented by Dr. Brian Shuch. The background of this is that the detection of renal masses poses a challenge due to the limitations of diagnostic options such as imaging and biopsy. And we often, in clinical practice, are confronted with "What exactly is this?" And what's even more importantly, “What's the histology of this?” And a non-invasive, accurate method is needed for pre-treatment risk stratification. Girentuximab, a monoclonal antibody that targets carbonic anhydrase IX expressed on clear cell renal cell carcinoma, can obviously now aid in the differentiation between clear cell renal cell carcinomas and other renal lesions when radiolabeled with this new agent.  The ZIRCON trial was open-label and designed to include patients with renal masses up to 7 cm in size or clear tumor stage cT1 who were scheduled for partial nephrectomy within 90 days of planned TLX250-CDx administration. The enrolled patients received a single intravenous dose of girentuximab on day 0 and underwent FDG PET/CT imaging on day 5 before their scheduled surgery. And the co-primary endpoints were to assess the sensitivity and specificity of girentuximab PET/CT imaging for detecting clear cell renal cell carcinoma in patients with indeterminate renal masses, with histology as the reference standard, which I think is a great way to test these agents because you get 100% validation.  In the primary analysis of 284 patients, the average sensitivity and specificity across all three central readers were 86% and 87%, respectively, exceeding the prespecified thresholds. The positive and negative predictive values were 93.4% and 78%, respectively. And with very few related adverse events reported, the study affirms that girentuximab PET/CT is safe and effective in identifying clear cell renal cell carcinoma in patients with indeterminate renal masses. And the findings hold potential for developing optimal management strategies for patients with indeterminate renal masses. I think this is important that we add a non-invasive method to this because we are confronted on a regular basis with patients who either cannot tolerate a biopsy or where the biopsy is indeterminate. And this could potentially be a great tool to help us with our pre-treatment planning of our treatment strategy. Dr. Neeraj Agarwal: Wow. So, it looks like a new PET scan using a unique tracer and antibody to detect the clear cell renal cell carcinoma with high specificity and sensitivity. It reminds me of drawing a crude analogy from the PSMA PET scan in prostate cancer. And hopefully, we will be able to use these newer scans that we call TLX250-CDx PET/CT scan. I hope they have a simpler name for this very soon. Or maybe follow up for patients who had kidney cancer, localized kidney cancer taken out by radical surgery, and then we are following them. And sometimes, we don't know if a small lung nodule is metastatic or not. And these kinds of imaging studies may help us down the line in monitoring those patients as well. So indeed, very exciting progress not only in the therapeutic area now but also in diagnostic fields at this GU ASCO.   So with that, we have seen multiple abstracts on prostate, bladder, and kidney cancer with real impact on how we practice medicine. Thank you, Christian, for sharing your insight with us today. It is an exciting time in GU Oncology, and we appreciate you taking the time to contribute to the discussion. Thank you so much.   Dr. Christian Kollmannsberger: Thank you, Neeraj, thank you for having me. And I completely agree it remains an exciting time in GU oncology.   Dr. Neeraj Agarwal: And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcripts of this episode.  Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today’s speakers:   Dr. Neeraj Agarwal  @neerajaiims Dr. Christian Kollmannsberger Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn    Disclosures:   Dr. Neeraj Agarwal:    Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences   Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, Arvinas   Dr. Christian Kollmannsberger: None disclosed  

Guest host Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss several crucial studies that will be presented at the 2023 ASCO Genitourinary Cancers Symposium, including ARASENS, TRITON3, and others in prostate cancer, as well as novel therapies in mRCC and urothelial carcinoma. TRANSCRIPT Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host of the ASCO Daily News Podcast today. I'm the director of the Genitourinary Oncology Program, a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I'm delighted to welcome Dr. Jeanny Aragon-Ching, a medical oncologist and the clinical program director of the Genitourinary Cancers Program at the Inova Schar Cancer Institute in Virginia.   Today we will be discussing key abstracts in genitourinary oncology that will be featured at the 2023 ASCO Genitourinary Cancers Symposium.   Our full disclosures are available in the show notes, and disclosures for all guests on the podcast can be found on our transcripts at asco.org/podcasts. Jeanny, it is great to have you on the podcast today.   Dr. Jeanny Aragon-Ching: Thank you so much, Dr. Agarwal, for having me.  Dr. Neeraj Agarwal: So Jeanny, let's begin with Abstract 15 on the update on the ARASENS trial, which Dr. Maha Hussain will present [at the meeting]. In March ‘22, as we know, almost a year ago, the results of the ARASENS trials were published in the New England Journal of Medicine. Darolutamide, which is an AR signaling inhibitor plus androgen deprivation therapy plus docetaxel chemotherapy, significantly reduced the risk of death by 32.5% versus placebo plus ADT plus docetaxel. The effect of triplet therapy, including darolutamide on overall survival, was consistent across prespecified subgroups. However, survival outcomes by disease volume were not reported at the time. Can you please tell us about Abstract 15?  Dr. Jeanny Aragon-Ching: Yeah, thank you so much, Neeraj, I would be happy to. So, this new data is actually very crucial for all clinicians. The title of this abstract is “Efficacy and Safety of Darolutamide in Combination with ADT and Docetaxel by Disease Volume and Disease Risk in the Phase 3 ARASENS Study.” So, as a quick reminder, in this trial, patients were randomized 1:1 to the standard dose of darolutamide 600 milligrams twice daily or placebo with ADT and docetaxel in the metastatic hormone-sensitive prostate cancer setting.    Now remember, too, high volume disease was defined per the charted criteria, which is visceral metastases and/or four or more bone lesions, of which at least one or more has to be beyond the vertebral column or pelvis. 8And high-risk disease was actually defined per the LATITUDE criteria, which is any two or more of the following three factors: Gleason scores eight or more, bone lesions that are three or more, and the presence of measurable visceral metastases. Of all the 1,305 patients, 77% of them were actually classified as having high-volume disease, and 70% of them had high-risk disease. So, in both of these high-volume and low-volume disease patients, the triplet therapy darolutamide, ADT, and docetaxel actually improved overall survival and hazard ratio was 0.69 and 0.68, respectively. Compared to the placebo and ADT, and docetaxel arm. So overall survival improvement was also significant in patients across all risk, high-risk, or low-risk disease.   Dr. Neeraj Agarwal: So, Jeanny, this is great news. So, the main message from this abstract for our audience is that triplet therapy of darolutamide plus docetaxel plus ADT is more efficacious than the doublet of ADT plus docetaxel chemotherapy, regardless of disease volume or risk status.   One important caveat I would like to note is that triplet therapy with the darolutamide was not compared with the doublet therapy of ADT plus darolutamide or any androgen receptor signaling inhibitor such as abiraterone or apalutamide or enzalutamide, all of which have shown benefit consistently, regardless of volume status, and in the case of abiraterone, also in the context of high-risk disease setting, as we saw in the LATITUDE trial.  Dr. Jeanny Aragon-Ching: Absolutely. I agree with that, Neeraj. Those are important points to consider.   Now, moving on to a different setting in prostate cancer across the disease continuum, let's discuss Abstract 18, titled “Rucaparib for Metastatic Castrate-Resistant Prostate Cancer.” This is TRITON3 entering overall survival and efficacy of rucaparib versus docetaxel or second-generation engine pathway inhibitor therapy, which will provide us with some additional data regarding overall survival. Neeraj, based on this new abstract, can you tell us more about TRITON3, which will be presented by Dr. Alan Bryce and colleagues from the Mayo Clinic Arizona?  Dr. Neeraj Agarwal: Of course. So TRITON3 is a randomized multicenter open-label phase 3 trial where rucaparib was compared with the physician choice of docetaxel chemotherapy or abiraterone or enzalutamide in those patients who had not received chemotherapy in the metastatic castration-resistant prostate cancer setting, and they had to be progressing on a prior androgen receptor signaling inhibitor in any setting prior. So, they just had to have disease progression either in the hormone-sensitive setting or CRPC setting on one of the AR inhibitors, and they had to have a BRCA1, BRCA2, or ATM alteration.   So, in this context, these patients were randomized to rucaparib versus physician's choice of agent, which could again be docetaxel chemotherapy, abiraterone, or enzalutamide. So, OS maturity is 54% in BRCA group and 59% in the intention to treat population. In BRCA1 and BRCA2 populations, radiographic PFS, which was the primary endpoint, was 11.2 months in rucaparib group and 6.4 months in the physician choice arm. In the intention to treat population where you include all patients BRCA plus ATM patients, ATM positive patients. Radiographic PFS was 10 months almost versus 6.4 months with standard of care. And both were statistically significant as well as clinically meaningful improvement in the radiographic progression-free survival with rucaparib over physician’s choice of either docetaxel or enzalutamide, or abiraterone. I would like to note that most frequent toxicity which we see with this group of agents is most frequent grade III or more toxicity was anemia, which was present in approximately 24% patients treated with rucaparib.  Dr. Jeanny Aragon-Ching: Yeah. This is a really exciting update, Neeraj. What do you think is the key takeaway from this abstract?  Dr. Neeraj Agarwal: The key takeaway is that TRITON3 trial met its primary endpoint, and rucaparib significantly improves radiographic progression-free survival in BRCA mutation-positive patients or BRCA ATM-positive patients. Overall survival is still immature, and these results further establish rucaparib as one of the standard of care options in those patients who have metastatic CRPC with prior treatment with the AR signaling inhibitor and who harbor one of the BRCA mutations or BRCA NAT mutations.   So, Jeanny, before moving on to the renal cell carcinoma section in this podcast, there is an Abstract in prostate cancer talking about correlation between the source of funding and disparities among patients with advanced prostate cancer. So, I'm referring to that Abstract 40, titled “Source of Funding and Enrollment Disparity in Prostate Cancer Clinical Trials.” I thought this was an interesting abstract. Could you please tell us more about this abstract?  Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. So, in Abstract 40, Dr. Riaz and Dr. Bryce, and colleagues actually looked at phase II and III clinical trials that involved prostate cancer patients that reported on patients with age by 65 years, and they got the data from the MEDLINE and Embase databases. Trials recruiting from the United States were considered eligible for analysis by race and ethnicity. So, in terms of race and ethnic enrollment, they found that black patients were significantly underrepresented in the industry's funded trials. Notably, no significant disparity was observed in the US government-funded trials, but Hispanics were also significantly underrepresented in industry-funded clinical trials. However, no significant disparity was seen in terms of older adults overall and by funding sources. Remarkably, Black patients' representation in industry-funded prostate cancer trials has actually decreased over the last three decades.  Dr. Neeraj Agarwal: That's concerning. So, what is your key takeaway from this trial, Jeanny?  Dr. Jeanny Aragon-Ching: The key message here is that Black and Hispanic men with prostate cancer are significantly less likely to be included in industry-sponsored clinical trials. A bigger concern is that black patients' representation actually continues to decline over time. So these results warrant a really more proactive role by regulatory bodies to ensure that a proportional representation of minorities in the industry trials, which in turn will make these results more applicable to a wider entire population of men with prostate cancer.  Dr. Neeraj Agarwal: Thanks, Jeanny. Let's move on to renal cell carcinoma. I saw some innovative research correlating the efficacy of immune checkpoint inhibitors with the time of the day these checkpoint inhibitors were administered. So, interestingly, there were two studies from two different groups of investigators showing very similar results. Please tell us about this innovative research correlating outcomes with immune checkpoint inhibitors with the time of the day these medicines or these drugs were infused into the patients.   Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. I think they're very exciting and interesting. So there's actually two abstracts, so Abstract 681 and 678, which we, of course, can discuss separately. So, let's probably start first with Abstract 678. Neeraj, do you want to explain to us further about this abstract?  Dr. Neeraj Agarwal: Yes. When our center participated in that abstract, which was led by Dr. Nazli Dizman from Yale University, Dr. Dizman and colleagues examined the relationship between the time of the administration of immune checkpoint inhibitors, or ICIs, as we call them, during the time of the day, and outcomes in patients with metastatic renal cell carcinoma. So, I'd like to point out that previously Dr. Qian and colleagues reported an association between the time of day of immunotherapy infusion and survival outcomes in patients with metastatic melanoma.   In this study, Dr. Dizman and colleagues, which included our center also, patients with metastatic RCC who received nivolumab with or without ipilimumab– so these patients all received either nivolumab alone or without ipilimumab. And patients who received less than 25% of infusion after 4:30 pm. were assigned to the early-time of infusion group. So, if they have received less than 25% infusion of these immunotherapies after 04:30 pm in the evening, they belong to the early infusion group, and the rest were assigned to the late infusion group.  In the univariate analysis, numerically higher objective responses and time to treatment failure were observed in the early infusion group compared to the late infusion group. So, differences were 33% versus 25% in objective responses in early versus late infusion group. If you look at time to treatment failure, 8.3 months versus 4.4 months in early versus late infusion group. In the multivariate models, which took into account the clinical characteristics such as age, gender, line of treatment, IMDC risk category, histological subtypes, there was a trend towards improved outcomes in those who received these infusions with ICIs early in the day. So, Dr. Dizman concluded that larger randomized and controlled investigations are warranted to examine the impact of this chronal modulation, if you will, on the efficacy of immune checkpoint inhibitors in metastatic RCC sets.  Dr. Jeanny Aragon-Ching: Yeah, this is very interesting data, Neeraj. And that actually resonates closely with this other abstract by Fernandez Manias and colleagues in Abstract 681. So, in this abstract, the primary outcome was overall survival, but they did look at other secondary endpoints like time on treatment, time to the next treatment, and overall response rates. Now, because of the small number of events, the authors actually focused on just patients who received second-line immune checkpoint inhibitors. And what they did was they looked at patients who received overall more than 20% of their infusions after 04:30 pm, and they found that those who did receive actually fewer infusions had a significantly shorter time on treatment and had a worse overall survival. And similar results were seen when they looked at those who got more than 50% of their dose of checkpoint inhibitors that were administered after 04:30 pm, so interestingly enough, there was a 16% increase in the risk of death for each 10% increment of checkpoint infusion after 04:30 pm. So the key message here is that administration of checkpoint inhibitors after 04:30 pm is associated, unfortunately, with inferior outcomes. Now, these results should, of course, be further considered in the organization overall of the outpatient clinic as it can impact patient survival and outcomes.  Dr. Neeraj Agarwal: Very interesting. So similar results from two independent groups of investigators from two different continents obviously made this research area very appealing and pertinent. Ideally, I think these results should be validated prospectively, but that will take time. But investigators who have already lagged multiple phase III trials should explore validating these results in the last phase 3 trials which have already been reported and where the data on the timing of infusion is available. Once validated, I think these results may profoundly influence how we organize, as you said, Jeanny, the outpatient scheduling of these checkpoint therapy infusions compared to those who are not checkpoint inhibitors. I think this is going to have very interesting data overall, no doubt.   Before moving onto bladder cancer, I would like to discuss an important abstract related to testicular cancer patients titled “Longitudinal Evaluation of Plasma MicroRNA-371 to Detect Minimal Residual Disease and Early Relapse of Germ Cell Tumors.” Could you please tell us more about this abstract?  Dr. Jeanny Aragon-Ching: Yeah, absolutely, Neeraj. So this is a very interesting up-and-coming Abstract, it's number 407, which will be presented by Dr. Lucia Nappi and colleagues. In this study, clinical patients with stage I germ cell tumor with available plasma samples after they underwent radical orchiectomy were all included. So, they looked at sensitivity, specificity, negative, positive predictive values, an area under the curve in predicting tumor recurrence, and they evaluated the microRNA-371, I'll just call it and truncate it as miR-371, and compared the same operating characteristics of current gold standard diagnostic tests. Relapse-free survival was correlated to post-orchiectomy miR-371 status, which could be either positive or negative.   So, at a median follow-up of 41 months, 101 patients with clinical stage one germ cell tumor were included. About 35% of them experienced a disease relapse during that time of follow-up. Now, what they found was miR-371 was positive in about 63% of the relapsed patients, and the miR-371 positivity preceded clinically evident disease by a median of about three months. The specificity and positive predictive values were 100%, sensitivity was like 63%, and negative predictive value was 83.5%, so very high. No false positive results were seen. And, the authors reported that the recurrence-free survival of the patients who had positive post-orchiectomy miR-371 was significantly shorter compared to those patients who had a negative biomarker for the miR-371. So, they concluded that the miR-371 sensitivity correlated with the tumor burden, time between tumor relapse, the microRNA testing, and histology. It was notably a little bit more sensitive in non-seminomas compared to those who had seminoma.  Dr. Neeraj Agarwal: Interesting findings, indeed. So, Jeanny, what is the take-home message from this abstract?   Dr. Jeanny Aragon-Ching: Yeah, so I think the key takeaway is that microRNA-371 seems to be a good test, like a biomarker for predicting disease relapse in patients with early-stage germ cell tumor. So, additionally, its high specificity and positive predictive value in predicting relapse could really be used and utilized to guide adjuvant therapy, selections, and decisions after orchiectomy. Further validation in other studies, such as swab 1823, are currently ongoing or planned to validate its clinical utility.   So Neeraj, moving on to bladder cancer, the last abstract I'd like to mention before we wrap up the podcast is Abstract 563, titled “Utility of ctDNA in Predicting Outcome and Pathological Complete Response in Patients with Bladder Cancer as a Guide for Selective Bladder Preservation Strategies.” Neeraj, can you tell us more about this abstract?  Dr. Neeraj Agarwal: Sure. So, this study was led by Dr. Lars Dyrskjøt. He and colleagues evaluated the prognostic value of circulating tumor DNA, or ctDNA, in predicting recurrence in a cohort of 68 patients with muscle-invasive bladder cancer who received new adjuvant chemotherapy prior to cystectomy. So ctDNA was analyzed two times at baseline before new adjuvant chemotherapy and then before surgery or before cystectomy. So, patients had ctDNA assessed before neoadjuvant chemotherapy and then before cystectomy after completion of new adjuvant chemotherapy. At baseline, of the 64 patients, around 60% were ctDNA negative, and 40% were positive for ctDNA. So of those patients who were ctDNA negative, 84% achieved pathologic complete response, while in those who tested ctDNA positive, only 35% achieved their pathologic complete response after surgery.   Prior to surgery, 84% of patients were ctDNA negative, and 81% achieved pathologic complete response. While none of the ctDNA-positive patients who were positive before surgery and after neoadjuvant chemotherapy, none of them achieved pathologic complete response, which translates into a positive predictive value of 100% and a negative predictive value of 81% for this test. So based on both ctDNA time points, the probability of ctDNA negative patients to achieve a pathologic complete response was significantly higher than ctDNA positive patients.   At a median follow-up of 59 months, ctDNA-positive patients without pathologic complete response demonstrated significantly lower recurrence-free survival and overall survival compared to those who were ctDNA negative. So, I want to repeat that, at a longer follow-up, which Dr. Dyrskjøt will be presenting, ctDNA positive patients without pathologic complete response had significantly lower recurrence-free survival and overall survival compared to ctDNA negative patients. Furthermore, ctDNA status at baseline, which is before neoadjuvant chemotherapy and before cystectomy, was a better predictor of recurrence-free survival compared to pathologic complete response, which is a remarkable finding here, although it's a smaller data set.  Dr. Jeanny Aragon-Ching: Agree completely, Neeraj. So, I think the importance here, too, is upon prospective validation in larger data sets, we will find that a negative ctDNA test would help in identifying patients who can benefit more from bladder-sparing strategies.   Neeraj, any final thoughts before we wrap up the podcast today?  Dr. Neeraj Agarwal: Before I share my final thoughts, Jeanny, I would like to thank you for joining us and sharing your insights. I always find them very valuable. So, thank you so much for taking the time.   I would like to wrap up the podcast by saying we are seeing an explosion in the development of novel therapeutic approaches for our patients with genitourinary cancers. At the 2023 ASCO GU meeting, we will have multiple studies with practice-impacting data presented by investigators from around the world. I urge our listeners to come and join us in the meeting not only to celebrate these successes but also to help disseminate these cutting-edge data to practitioners and maximize the benefit for our patients across the globe.   I would like to thank our listeners for joining us today. You will find links to the abstracts which we discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thank you so much.    Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.    Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.     Find out more about today’s speakers:   Dr. Neeraj Agarwal  @neerajaimms  Dr. Jeanny Aragon-Ching  Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Neeraj Agarwal:    Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences   Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, Arvinas   Dr. Jeanny Aragon-Ching:    Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc   Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, AstraZeneca/MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis   Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb , Astellas/Seattle Genetics   Travel, Accommodations, Expenses: Dendreon, Algeta/Bayer, Bristol Myers Squibb, EMD Serono, Astellas Pharma    

Dr. Rachna Shroff, chair-elect of the 2023 ASCO GI Cancers Symposium, and guest host Dr. Shaalan Beg discuss new research presented at GI23, including new data from SWOG 1815 in biliary tract cancers, advances in biomarker studies in mCRC such as the PARADIGM trial, and promising updates in ctDNA technology. She also highlights the exciting potential of AI in oncology. TRANSCRIPT Dr. Shaalan Beg:  Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I'm an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center and vice president of Oncology at Science 37. Today we'll be discussing key abstracts and other highlights from the 2023 ASCO Gastrointestinal Cancer Symposium, which celebrated 20 years of transformative care in GI cancers. I'm delighted to welcome Dr. Rachna Shroff, the chair-elect of this milestone meeting. Dr. Shroff is the interim division chief of Hematology Oncology at the University of Arizona Cancer Center. She also serves as the associate dean for Clinical and Translational Research and is the chief of GI Medical Oncology. Our full disclosures are available in the transcript of this episode, and disclosures related to all episodes of the podcast are available on our transcripts at ASCO.org/podcasts. Dr. Shroff, it's great to have you back on the ASCO Daily News podcast. Dr. Rachna Shroff: Thank you so much for having me. I'm so excited to be here. Dr. Shaalan Beg: The ASCO GI Cancers Symposium has been heralded as one of the biggest conferences in the GI cancer space and has occupied this space for the past two decades. Some would say that this year's conference was probably the best GI Cancers Symposium to date. Can you comment on the 20th anniversary milestone and the impact of the symposium on GI cancers? Dr. Rachna Shroff: Absolutely, and that's so great to hear that that's the feedback that you've heard. I have to say GI ASCO is absolutely my favorite meeting of the year, so that is my full disclosure. But I think that this was a tremendous meeting, and I think it was so beautiful that it was also coinciding with the 20th anniversary. It meant so much to us to have Dr. Margaret Tempero open the meeting because she really was the impetus for creating a GI cancer-focused meeting that really brought together multidisciplinary expertise. And so to us, that is what this 20th anniversary represented—20 years of multiple different specialties coming together to discuss how to improve cancer care for patients with gastrointestinal malignancies. And it has been a transformative meeting to see the impact of research presented at this meeting and how it has been implemented over the course of 20 years. And I completely agree that this year in and of itself had some incredible pivotal data that there is no doubt will be practice-changing, and that is absolutely the purpose. I also think that the beauty of this meeting is the networking opportunities for all of us to come out of our individual silos, come together, and discuss cross-cutting care across the spectrum of GI malignancies. And I think that this meeting really did that quite well. Dr. Shaalan Beg: There were many practice-changing studies that made headlines this year, and for me, one of the most anticipated studies was a trial that you led for cholangiocarcinoma and much-anticipated results. The study finished enrollment at a record pace. Can you share your key findings of cholangiocarcinoma? And I'd really like to hear your perspective on cholangiocarcinoma studies. Dr. Rachna Shroff: Yes, it was actually a really big year in the hepatobiliary space, and I was proud to present SWOG 1815, LBA 490, which was the pivotal randomized phase 3 trial looking at gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin. This was a study that was opened across the entire NCTN and based on a single-arm phase 2 trial that had shown some promising early efficacy of the triplet chemotherapy regimen. As you mentioned, this study accrued 441 patients in two years. And it's really a testament to the fact that the cooperative group mechanism can and should be asking important questions in large, randomized studies and that it is even possible to do in what are historically thought of as, quote-unquote, “rare tumors.” The study was a randomization of two to one to the triplet chemotherapy versus the standard of care for newly diagnosed biliary tract cancer patients. And the primary endpoint was median overall survival. And while the median OS of the triplet regimen was numerically improved at 14 months compared to 12.7 months, this did not meet statistical significance. Other efficacy endpoints, including median progression-free survival and overall response rate, were also numerically improved but not statistically significant, with an overall response rate of 31% with the triplet regimen versus 22%. There were some prespecified stratification factors, including disease site and disease stage, and there may be some interesting signals that bear out of that in terms of perhaps gallbladder cancer and locally advanced patients may be benefiting from the triplet regimen a little bit more, but these are small numbers, and we would really need to explore that in a more rigorous prospective manner. The toxicities were, not surprisingly, there, especially hematologic toxicities. I will say for those of us that use this regimen in practice, we use it a little bit differently than what was done in SWOG 1815, but you can't deny that there were significantly higher grade 3-5 toxicities with anemia neutropenia and thrombocytopenia, though the treatment discontinuation rate did not differ. I think the next steps are really going to be the ongoing biomarker analyses. The study had archival tissue and prospective blood collection and we know that in the space of cholangiocarcinomas and biliary cancers, molecular complexities absolutely play a role in how patients do and how they respond to therapies. So that's going to be an important next step, I think, for this study. Dr. Shaalan Beg: Speaking of biomarkers and an impact on GI cancers, the other malignancy where biomarkers are having a much greater impact than other GI cancers is colon cancer. Another year where we continue to see advances in our understanding of molecularly targeted treatments for colon cancer. What caught your eye? Dr. Rachna Shroff: Well, there were a lot of really interesting studies happening in this space and as a biliary person, one of the first things I got excited about was seeing Abstract 139 that looked at pemigatinib, which is the drug we are very familiar with in cholangiocarcinoma. This was a single-arm phase two study looking at the use of the FGFR inhibitor pemigatinib in metastatic colorectal cancer patients who had FGFR alterations. And so this was a study that was opened through the ACCRU mechanism. It was multicenter with assignment two-stage design and it was specifically for patients with FGF and FGFR-altered metastatic colorectal cancer who had progressed on standard therapies. There was a prespecified interim analysis for futility after 12 evaluable patients and so 14 patients were enrolled in the first stage of the study and evaluated for the primary endpoint of objective response. What was seen and the study was subsequently stopped is that there was really not much efficacy, there was no evidence of safety signals, but this did not seem to be a very active drug in patients with FGFR alterations with no objective response noted. So, the study was stopped with the recognition that perhaps the FGFR translocation or fusion patient population may be something to explore since they did not look at that in this study. The other kind of study that I think is really important was important work of Dr. Raghav and colleagues through SWOG. This was SWOG 1613 Abstract 140. This was the first real study that was investigating targeting HER-2 overexpressed and amplified metastatic colorectal cancer who had RAS wild-type tumors. And it was based on, obviously, some early signals of the effectiveness of HER-2 targeting in metastatic colorectal cancer. And this was a large study looking at pertuzumab and trastuzumab in these patients. They were compared to cetuximab and irinotecan, and the initial plan was for a much larger study. Unfortunately, accrual was really slow so the study was really kind of reformatted and a total of 54 patients were randomized, 26 to the trastuzumab arm and 28 to the CetIri or cetuximab and irinotecan arm. What was seen was that you can absolutely use HER-2 targeting therapies with trastuzumab and pertuzumab in these patients. It was safe and there were some obvious signs of efficacy in terms of overall response rate with an overall response rate of 31% compared to the CetIri arm. Crossover was allowed from the CetIri arm to trastuzumab and pertuzumab. So just that's important to keep in mind when they start to follow out the survival data. But unfortunately, because this study did not accrue, it was stopped early and it's really hard to understand in terms of power calculations the impact of trastuzumab pertuzumab. Of course, we can't talk about this without recognizing that the FDA approval based on the MOUNTAINEER study for tucatinib and trastuzumab came through during GI ASCO. So clearly HER-2 targeting is here to stay in colorectal cancer. Dr. Shaalan Beg: So technology is advancing every year and it's important that we are aware of these advances and how they impact our patients. Probably one of the most exciting technologies in oncology in general is the evolution of ctDNA. And it's been amazing to watch that field unfold as we understand how to use circulating biomarkers for early detection of cancer, for minimal residual disease detection, even as a biomarker of response. What caught your eye when it comes to the use of ctDNA in GI cancers, and how do you see this space develop in the next couple of years? Dr. Rachna Shroff: I completely agree. I think the technology of ctDNA is so incredibly exciting and as somebody who does not actively see and treat colorectal cancer, I'm a little bit envious of my colleagues in that space because the strides that have been made in terms of understanding the utility of ctDNA, especially in colorectal cancer, has just been tremendous and even for the last two to three years. One perfect example of integrating that sort of technology into treatment paradigms is the PARADIGM trial, Abstract 11, which was looking at the concept of hyperselection of patients with RAS wild-type metastatic colorectal cancer who were on the PARADIGM trial which basically looked at frontline FOLFOX with panitumumab versus bevacizumab in patients with RAS wild type left-sided metastatic colorectal cancer. So, you know, the initial data from PARADIGM had demonstrated a longer median overall survival 37.9 months versus 34.3 months, but very smartly, the investigators had also collected baseline plasma ctDNA in the biomarker component of this study and used a custom panel that looked at gene alterations for hyperselection and that included KRAS, NRAS, PTEN, and extracellular domain EGFR mutations HER-2 and MET amplifications, as well as some fusions like ALK, RET, and NTRK. And so out of the 802 patients in the full set, 91% - 733 patients - actually had pretreatment samples for ctDNA, which is really in and of itself, I think, tremendous. And when you break it down, about 28% had at least one gene alteration, and that was across each of those different genes that they were looking at. In the 72% of patients who were defined as hyperselected without any gene alterations, the OS was actually longer with panitumumab versus bev, and that actually was independent of sidedness with hazard ratios that kind of ranged from 0.76 to 0.82. And OS was similar or inferior with panitumumab versus bevacizumab again, regardless of sidedness in patients with any of these gene alterations. And so I think it's a really interesting concept that you can use ctDNA to define negative hyperselection rather than looking at left sided and right sided to really help select patients with frontline therapy in terms of using panitumumab versus bevacizumab. And with the speed with which ctDNA can be obtained, this actually seems like something that could be implemented into clinical practice, which is, I think, really the important component of that. There were a number of other really interesting abstracts. Abstract 5, presented by Dr. Cohen and colleagues, really looked at the kinetics of circulating cell-free DNA and how that kind of relates to minimal residual disease detection rates. And this was in patients with resected stages one through three colorectal cancer. And so, this was a retrospective study, so we have to keep that in mind. And it was multi-institutional in really over 16,000 patients with stages 1 through 3 colorectal cancer. But the complete dataset had about 417 patients and basically the patients' circulating cell-free DNA levels, the total cfDNA, were compared to the ctDNA MRD positivity rates and they looked at very specific time points after surgery. What the authors generally found was that the postoperative cfDNA correlated well with ctDNA positivity and that there was really the ability to see plasma cfDNA levels kind of track and follow with the very specific MRD windows that were being looked at, which really, again, just kind of talks about leveraging this technology in terms of real-world and real-time application and better understanding and informing us of minimal residual disease post what is thought to be curative resection. The last one that I thought was really interesting in relation to ctDNA was actually looking at anal cancer and following ctDNA in patients who were treated with definitive chemoradiation. This was a study that was looking at 31 patients with anal squamous cell carcinoma who were treated with definitive chemo radiation and underwent ctDNA response. The majority of these patients had stage 3 disease and the majority of them received the standard 5-FU Mitomycin with radiation. The patients had ctDNA testing performed in 25 of these patients at baseline and then a smaller number over the course of time, some during chemoradiation. And then they looked again at 30 days post chemoradiation. And at baseline, 88% of patients had detectable ctDNA with those with stage three disease having numerically higher baseline ctDNA levels. And basically what they found was that over the course of treatment, ctDNA levels decreased among the patients with detectable ctDNA. And then ctDNA that tested during chemo radiation showed a drop in decline and were going into molecular remission at a time point in which it was subsequently confirmed that they had a clinical complete response. So, the suggestion here is that the time to molecular ctDNA remission was significantly shorter than being able to see that clinical complete response, which suggests that using surveillance ctDNA monitoring could be an earlier response assessment for patients with anal squamous cell carcinoma who are undergoing definitive therapy. Now, obviously this needs to be confirmed in a larger manner, but again, really suggests that we could be understanding how we're doing with treatment in more of a real-time fashion, which I just think is incredible for those of us who are making sure that we are doing and taking the right approaches for these patients. Dr. Shaalan Beg: One of the major transformative announcements that took place only a couple of months before the GI Cancer Symposium was the announcement of ChatGPT. And we heard a lot of discussion on how it can be used for improving cancer care, improving drug development, and in general, artificial intelligence and machine learning. We've been hearing these buzzwords for such a long time, to the point that a lot of people are probably just filtering it out and then this tool comes up and it makes it real. And we're seeing different people apply these technologies in different ways. But there is tremendous potential in how this technology can improve clinical trials, drug development, and early diagnosis. And luckily, we had already secured a keynote speaker, Dr. Matthew Lundgren from Nuance Communications, and he was invited to talk about artificial intelligence, machine learning, and how it applies to cancer care. I'm really curious to hear what your highlights were from his address and how you see this impacting your day-to-day, or just the ecosystem of which we're all part of. Dr. Rachna Shroff: Yeah, I will say that his keynote was really one of the highlights of the entire meeting for me. And that is coming from somebody who doesn't really know– I know who I'm speaking to, but somebody who does not truly understand the way AI is moving. And so, I was joking with him that it was like AI 101. And I really, really appreciated the way he was able to kind of speak to a crowd that he doesn't normally speak to and help us really understand the way in which artificial intelligence can be integrated into healthcare, and specifically oncology. To me, I think what were the most salient takeaways from his address was really about how this is just a rapidly evolving field and we need to be a little bit ahead of the eight ball when it comes to thinking how we can smartly leverage artificial intelligence like you mentioned, to improve our clinical research efforts, to improve access, and to improve fully integrating AI into our EMR, so that we can really leverage that technology and ensure that we are capturing every potential patient for a clinical trial and be smarter about how we're even approaching things. I mean, I loved him talking about the prior authorizations and that sort of thing, and the ways in which we can decrease the burden on health care providers and really let us focus on the areas that we need to focus on. The one thing that I thought was a really important point, though, and I think a number of people asked him, was about how using this technology has the potential to create more gaps and disparities and how can we be smart to ensure that we don't broaden those gaps. And I think that is a really important point that we all need to think about because we know that especially when we think through clinical trials, there's already underrepresentation of certain populations and certain geographic regions. And so, I think that was a really important takeaway for me is how can we make sure that we work and partner with those who are creating these technologies to ensure that we aren't taking two steps forward and four steps back. Dr. Shaalan Beg: It really calls into question how we define productivity and what our value in the entire delivery system really is. And I think from people who are in middle school or high school to people who are in college and even folks who are in the field as you and I are, it's forcing us to rethink what we bring to the table in a way that we've never been challenged to ask that question ever before. Dr. Rachna Shroff: Absolutely. Dr. Shaalan Beg: So, thank you very much, Dr. Shroff. This was wonderful. Thank you for sharing your insights with us today. And we thank you and Dr. George Chang, the chair of the ASCO GI Cancers Symposium, and everyone who worked so hard to develop a robust program this year.  Dr. Rachna Shroff: Thank you. It was so wonderful to be able to speak about it. And thank you to all of the attendees for making it such a memorable meeting. Dr. Shaalan Beg: And thank you to all our listeners for your time today. You'll find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today’s speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Rachna Shroff @rachnatshroff Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn  Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. Rachna Shroff: Consulting or Advisory Role: Exelixis, Merck, QED Therapeutics, Incyte, Astra Zeneca, Taiho Pharmaceutical, Boehringer Ingelheim, SERVIER, Genentech, Basilea Research Funding: Pieris Pharmaceuticals, Taiho Pharmaceutical, Merck, Exelixis, QED Therapeutics, Rafael Pharmaceuticals, Bristol-Myers Squibb, Bayer, Immunovaccine, Seagen, Novocure, Nucana, Loxo/Lilly, Faeth Therapeutics        

A national survey of more than 1,000 female oncologists explores their difficult career choices amidst attempts to build families, their concerns about fertility, and their issues with discrimination during pregnancy and/or maternity leave. Dr. Fumiko Chino, Dr. Anna Lee, and Dr. Erin Gillespie discuss the survey’s findings and share their own insights and experiences as female oncologists. TRANSCRIPT Dr. Fumiko Chino: Hello, I am Dr. Fumiko Chino, a radiation oncologist and health equity researcher at Memorial Sloan Kettering Cancer Center and the guest host of the ASCO Daily News podcast today. In today's episode, we'll explore gender equity within the oncology workforce. Our discussion is centered on a newly published article in JAMA Network Open. This national survey of over 1,000 female oncologists found that 95% considered their career when planning a family, and about one-third faced fertility concerns when trying to become pregnant. Additional findings include that one-third faced discrimination during pregnancy and/or maternity leaves. Joining me for this discussion are study team members Dr. Anna Lee, an assistant professor in radiation oncology at the University of Texas, MD Anderson Cancer Center, and Dr. Erin Gillespie, an associate professor in radiation oncology at the University of Washington and a member of the Hutchinson's Institute for Cancer Outcomes Research. Our full disclosures are available in the transcript for this episode, and disclosures relating to all episodes of the ASCO Daily News podcast are available on our transcripts at asco.org\podcasts. We have all agreed to go by our first names today. Anna and Erin, it's great to have you on the podcast today. Dr. Anna Lee: Thank you, excited to be here. Dr. Erin Gillespie: Yeah, thanks so much, Fumiko. Dr. Fumiko Chino: Well, I'm hoping to just dive right in to talk about this study, which I was proud to be on the authorship team with both of you. I just want to give a little bit of setup about how this study started, which was essentially within our own group of junior female faculty. We have semi-regular meetings, and this idea for the study actually came up at a picnic for some young female faculty members. That then led to a small survey that I did on a Facebook group of young female oncologists and then, ultimately, to the national survey. So, Anna, do you mind telling me just a little bit about your research background and why this topic is important to you? Dr. Anna Lee: Yeah. So, when I was a resident along with my co-resident Virginia Osborn, we helped co-found a group called the Society for Women in Radiation Oncology, or SWRO. We were able to bring a group of women in our field who were interested in looking at the experiences of female radiation oncologists, both starting at the residency, the training level, but also into practice. And we had generated an initial survey looking at women's experience, and they found that even though the majority, almost 95% of women, felt like radiation oncology was a family-friendly field, only about half of the group actually felt that it was after their lived experiences. So, this kind of led me to being interested in participating in the development of this study. And personally, I have been going through the fertility journey myself. My partner and I got married last year and, you know, you think that for so long you put an effort into something and get a result and just how I did in academics or in terms of my career aspirations, you think that it'd be very straightforward, but it's been more of a challenge than I expected, and we are going through the whole workup process and considering our options. So this is a study that is of personal interest to me. Dr. Fumiko Chino: Thank you so much for sharing that. And Erin, do you mind just sharing a little bit about your background and why this topic is important for you? Dr. Erin Gillespie: My research really focuses on access to high-quality, patient-centered care. I'm from Anchorage, Alaska, so this idea of variation in quality and differences in care people receive has been central. And one thing that I've noticed over time is that the physician workforce has such an important—and physicians, in general, in oncology—have really big impacts on the care that patients receive. And in radiation oncology, we've seen for many decades now that we have only about 30% of our workforce is women. And to Anna's point, why is that? And I think this study sort of gets at some of the challenges that women may be foreseeing in entering an oncology career. For me personally, I started my first faculty position in my mid-30s. And it being a small field, I've moved around every few years from the best academic medical school to residency to a faculty position. And you know, in my mid-30s, I wasn't in a stable, long-term relationship, so I, as you were describing, went through the fertility preservation process and got to be fortunate to have a group of junior women faculty, like you, Fumiko, who would actually share and discuss. And it was in New York where all these discussions came to light, and in the actual fertility clinic, where you realize there's a lot of other career-oriented women with the same experiences. And so, how does this general phenomenon potentially impact us in oncology and downstream are patients who—there have done some studies that gender and sex sort of concordance between patients and providers can impact the types of treatments that people are receiving, so I think it's very important. Thanks for inviting me. Dr. Fumiko Chino: Yeah, I think that you bring up a really important point, which is that essentially when we think about equity issues, we're not just talking about access to high-quality care for patients, we're also talking about equity within our fields and within the workforce. And this concept of fertility research and gender equity within oncology, I think is, thankfully, rising in importance. And so, I was so happy to be able to be part of this study that looks at it. But, I guess, my next question is, what are the real barriers to doing this type of research, and what are the barriers to actually improving gender discrimination like what this study shows? Anna, do you want to take that first? Dr. Anna Lee: Yeah, sure. Well, there's certainly a strong amount of shame and stigma that comes along with infertility. Even being able to open up about it and share with your colleagues and go through a process that's very personal while you're working, but it kind of bleeds into or affects your day-to-day work life. So, that culture and that inability to be open about it I think is really making it difficult for people to share and discuss it publicly, and also, I think that there's some level of perception that this should not be discussed in an academic environment. But the reality is that even our survey study showed that women certainly thought about their career when it came to family planning. And so the more we discuss it, the more that we normalize this kind of conversation, it will bring to light how women are being affected by their careers. And also, I think that with our survey being completely anonymous, it was able to be an avenue for women to be able to share their experiences too. Dr. Fumiko Chino: Yeah, I know certainly I feel very privileged to have been at a large institution that really did have a very active and engaged group of young female faculty where I felt like almost protected by just numbers, for lack of a better term, and for us to be able to share our experience. Now, Erin, have you noticed anything in terms of, for example, the motherhood penalty on career or productivity in terms of the capacity for even getting the optimal position for yourself? You mentioned a little bit about your own experiences coming from a small area in Alaska and how that really made you have to hustle hard for optimal career outcomes. Dr. Erin Gillespie: I guess like when I think about—to Anna's point earlier, just having open discussion with people in the field, and like you said, being in New York, a fairly progressive environment and women are more open about these things early on, was definitely helpful. What I've heard of a lot of people beyond the career-driven nature, and you know, there was this article from The New York Times several years ago that I remember talked about women that had kids between 25 and 35, never were able to catch up to their peers because those are kind of the really critical career development phase and like really establishing yourself and your independence, which always kind of sat with me and I always justified it. It's just like, "Well, I guess the fact that I'm getting to these things later may have career benefits because I'm not actually ready to go through all these things in residency." And then, the other thing I've heard people talk a lot about in radiation oncology was the extensive oral boards, which just further—we do five years of radiation oncology and then there's another couple years, can be a couple of years of very intense studying and passing exams that used to be even more strictly timed. And so, people were literally delaying family planning in order to make sure that their jobs as a clinical radiation oncologist was safe and protected, and they could flourish in what they've spent their life working on. So, I do think, back to Anna's point, that just starting these conversations and engaging the board of radiology on how to actually accommodate women, a lot of it comes down to accommodations to encourage gender equity. Dr. Fumiko Chino: You know, one thing that was quite striking in our survey was just about essentially what people had to sacrifice in order to actually have kids, and this sort of patchwork formal paid family leave, and the fact that we really don't have a good national policy, and it's just very state- and institution-driven. And I know that Anna and Erin, you both actually each moved institutions within the last couple of years, moving from New York, which, as previously stated, is a pretty liberal state to your current institutions. So, I was just wondering if either of you could speak about how even the fact that we don't have a national policy in this patchwork leaves women sort of at the whims, in terms of planning their career and their family planning, at the whims of wherever they end up. Anna, I know you did a little bit more background research on this, do you want to take that first? Dr. Anna Lee: Yeah. Actually, when I moved out of New York to Texas, unlike New York where they have, I believe, it's a statewide policy for maternity leave paid, and we don't have anything like that here. But also, our insurance policy initially didn't cover OSI preservation or IVF. Recently, they do now cover that. So, I've been able to breathe a sigh of relief in knowing that I can start my journey in exploring these options and knowing that my institution supports me in that way by having that coverage. So, definitely having institutional buy-in allows us to have more freedom and flexibility and feel the relief in knowing that, "Okay, I can prioritize both my career and my personal life, and be able to support both, and have my career also support that part of my life." Dr. Fumiko Chino: Erin, anything to add for that? Again, I know that you just moved institutions. Dr. Erin Gillespie: Yeah. You know, it's interesting. When I was looking, my husband and I were actually not living in the same city. So, as we became pregnant, the desire to be in the same place became more real. But thinking about changing institutions was complicated, and ultimately, the state laws—you know, so, we learned about multiple states, and having state laws is helpful, although FMLA requires you to be in a place for usually about a year in order to qualify for any of the state benefits. And so, what I ended up finding was that the institutions ultimately still played a huge role in determining if you wanted to change your career, that it was up to the institution to really support a maternity leave situation. So, while I think that the state can set like some general guidance that probably helps the culture, ultimately, institutions play a huge role. I was actually just talking to one of my co-residents from UC San Diego, who is in a private practice in Anchorage, and he was asking me, "Are there any general guidelines in family leave for radiation oncology? Have you seen anything to help institutions, large or small, really establish best practices?" And I referred him to SWRO because I said if anybody knows of anything that's been drafted, it would be your organization. But I honestly don't think that there is anything, and I think that is a room for improvement. Dr. Fumiko Chino: That really segues into our next topic, which is how do we really advocate for ourselves and our colleagues to improve the status quo? Because as it stands, it's phenomenal that we have landed in places that have both the insurance and the policy coverage for maternity leave and for fertility concerns, but I think a lot of our colleagues aren't so lucky. Anna, do you want to take that first? Dr. Anna Lee: Yeah. I think when it's available, both men and women should take family leave or paternal leave. Taking leave when either sex has a child, it kind of normalizes the fact that child care should be an equal distribution of work, and also that we need to value both men and women being at home to take care of the first few months of a child's life. So, once we have that, I think that when you improve the culture of an organization, it can automatically help support the institutional buy-in as well. Dr. Fumiko Chino: Yeah, that whole “he for she,” and it's hilarious to think that just men taking paternity leave when allowed really does—number one, they have more bonding with their new baby, but also, it makes it normal that everyone is taking leave because that seems appropriate, what's best for the family and also what's best for the individual person to actually have that time with their child. Erin, additional thoughts in terms of how do we advocate for ourselves? Dr. Erin Gillespie: Yeah. To that point, I will say I really applaud Memorial Sloan Kettering for having people like Sean McBride in our leadership that were young enough to really advocate for having paternal leave in addition to maternal leave and making that something that the junior faculty were like, you know, it's not just something that's possible, but should be expected. And so, I see an opportunity for institutions to really give leadership opportunities to kind of these junior, mid-level faculty that really can have a cultural influence on how people—not that every man in our department has taken that leave, certainly, but I feel like there is this need to change the culture because until men are actually taking significant leave, there is still this disparity. Dr. Fumiko Chino: You know, I have to reflect kind of on my own role models. My mother had 5 kids in 6 years, as being a physician, a radiation oncologist. And in my mind now, as someone who is a radiation oncologist who has zero kids, I have no idea how she did it. I feel like it was so challenging for me to just build the career that I have. So, I was just wondering, are there people that you can look to as role models? I think, honestly, Erin, you said Sean McBride, as you know, an active and engaged father, who is very open and speaks frequently of his, you know, daddy duties. Again, it's hilarious that I'm pointing to Sean as a role model, but he really is. I mean, that's part of his persona. Anna, do you have role models in terms of thinking about how to have that delicate balance in this idea of like you could have it all? Dr. Anna Lee: Fortunately, I have so many peer mentors, and friends, and people in the field going back to residency, seeing my co-resident, Virginia Osborn, going through training, having 2—she had 2 kids during training, and then, you know, seeing even faculty here having children early in their mid-career, just being able to balance everything, and making sure that they really understand the policies of the institution so that they're taking what they can in terms of their leave and their benefits. So, I think that they're showing me that we don't need to be apologetic about taking leave. We don't need to necessarily ask our colleagues or be apologetic to our colleagues or to our institution for taking leave because it's a part of our life, it's a part of our fabric, in terms of being able to have children and raise them. And if that's something that one wants in their personal life, I feel like it's something that is, obviously, going to affect both their careers, but the career will affect their personal life, and being able to achieve both of those is something that we can all strive to help each other. Dr. Fumiko Chino: Yeah, absolutely. And I think, honestly, it's great to have role models and people who are, you know, working to make the environment better in terms of gender equity. I think one of the most surprising findings from this study was that, actually, there was a minority of women who actually felt discrimination during pregnancy and maternity leave that actually came exclusively from other women. Erin, do you have any comment on that? Is that reflective of anything that you've seen? Dr. Erin Gillespie: Yeah. This issue of there is still ongoing challenges of the idea that women discriminate as much or more against women. When I look back on my own mentorship, I've actually had mostly strong male mentors, and they were as family-oriented and work-life balance. I mean, Jim Murphy, as a resident, and then Justin Bekelman, as a faculty member. They've always been very imperative that your personal life is a high priority and that you don't necessarily sacrifice that. And to do that, you have to be smart about the commitments that you make and how you balance these things. But despite that, one of my mentors recently said, you know—and men can give great advice, and they can certainly advocate, and I think it's critical that they provide that. But one of my mentors recently said, "Ultimately, as you enter this new phase of being a mother, you need to find really close, strong, women mentors that have actually been through this because their experience is just not the same. As much as we can talk the talk, there is still a fundamental difference, and mentorship on both sides is critical." Dr. Fumiko Chino: Absolutely. Wrapping up this podcast, do you have any other final thoughts, either Erin or Anna, about our findings on how we can continue to make sure we're making improvements for ourselves but also for the field? Dr. Anna Lee: I am encouraged, though, that I think we're seeing incremental improvements in our field. You know, I can't speak on all of oncology, but in radiation oncology, even the timing is more flexible. We're able to be boarded through Zoom, and we don't have to travel to a single site. So, I think that we are seeing incremental improvements and there's a lot of, now with both the Society for Women in Radiation Oncology, but we have Radiation Oncology Women Physicians’ Group, we have different groups that are advocating and making sure that our voices are heard and that, you know, our voices also are translating into policy level changes. And so, we still don't have national level, or I don't think we have blanket society-level recommendations for maternity leave that we can refer to, and I don't think all institutions are adopting them universally, but I think that there's a growing course and a growing movement of people kind of advocating for that, and we're inching towards that slowly, but surely. Dr. Erin Gillespie: Yeah. And I think that to that point, just the thing that I've tried to change in my own practice has been to normalize the conversation because going back to what I said, moving to New York, it was a normal conversation that you talked about these things, which hadn't been the case before. And so, you know, with my medical students, residents, I'm very open about what are some challenges, but what are the solutions and how do you balance these things, so that they feel like this doesn't have to be something that you suffer, or think, or worry about without there being people to talk to. Dr. Fumiko Chino: No, I think that was a really true concept and the idea of like—I know when I was on my interview surge, I was told, “Don't ask about the maternity leave because future employers are going think that you're trying to get everything out of them.” But the idea that we shouldn't even ask about it, it seems insane, so I'm glad we're moving forward. I want to thank you both, Dr. Anna Lee and Dr. Erin Gillespie, for sharing your valuable insights with us today and for your dedication to addressing gender equity issues and oncology. Dr. Anna Lee: Thank you so much. Dr. Erin Gillespie: Thanks so much. Dr. Fumiko Chino: Thanks to our listeners for your time today. You'll find a link to the article discussed today in the transcript of this episode. If you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe, wherever you get your podcasts. Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.  Find out more about today’s speakers: Dr. Fumiko Chino Dr. Anna Lee Dr. Erin Gillespie Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn  Disclosures: Dr. Fumiko Chino: None disclosed. Dr. Anna Lee: None disclosed. Dr. Erin Gillespie: Other Relationship: eContour.org

Dr. Derek Raghavan, president of the Levine Cancer Institute at Atrium Health, and host Dr. John Sweetenham, of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, predict the challenges oncologists will grapple with in 2023, including the cost-benefit of new treatments, how to retain the best talent, prioritizing health equity, and the future of home infusion for patients with cancer.   TRANSCRIPT Dr. John Sweetenham: Hello, I'm John Sweetenham, the associate director for Clinical Affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News podcast. Today, I'm excited to welcome back Dr. Derek Raghavan, President of the Levine Cancer Institute at Atrium Health. And we'll be discussing some of the challenges that we anticipate are going to lie ahead for the oncology community in 2023. Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the ASCO Daily News podcast are available on our transcripts at: asco.org/podcasts. Derek, great to have you back on the podcast again today. Dr. Derek Raghavan: Thanks, John. Great to be back with you. Dr. John Sweetenham:  One of the issues that we believe is going to be a challenge for us in the oncology world during the coming year that you and I have discussed on a previous podcast is this issue of cost benefits of new therapies in oncology, and the need to compare new treatments against old established standard of care treatments, rather than against the most recent new treatment preceding the one that we have now if you see what I'm saying. This is clearly going to be an ongoing concern. Why do you think we should be thinking about cost benefits of new treatments? And clearly, I think we'd all agree that this matters, but I think maybe you could expand a little on why you think it is truly important that we kind of go back and make sure we're comparing these drugs with the more established standards of care. Dr. Derek Raghavan: You know, I think this is sort of a metaphor of modern oncology, John, because it brings in so many elements. As you've implied, the cost of cancer care and not just cancer care, I mean it's all medical care just going through the roof, and unfortunately, it's happening most particularly in the United States. And whether that's just because here the pharmaceutical industry and government seem to have a very tight relationship, or whether there's some other explanation that is not clear, but I would make the comment that a lot of the newer treatments that are horrendously expensive in the United States, may be purchased for half the cost or less in other OECD countries. And that suggests that at some regulatory level, one of the parameters is a little off in the United States. And the reason that this is such a big deal is that it ultimately is hitting patients very hard. I think everyone has agreed, and we've discussed it in some detail in the past, everyone is identifying financial toxicity as becoming one of the governing toxicities of cancer care, and we've talked about strategies of dealing with that. As you implied, you know, we have this sort of tendency to think that anything new is wonderful, and anything old is terrible. And often, that's true. But I think the problem is that often, we will test the brand new agent of today with last year's brand new agent, which hasn't necessarily been fully tested at the time. So, if you think about prostate cancer, you know, the Michael Hofman group tested against cabazitaxel, and I'm not quite sure why cabazitaxel suddenly became the only drug to use second-line in prostate cancer. You know, doxorubicin has been there for a long time. Mitoxantrone has activity, even the old chestnut oral cytoxan has some activity there. And each of the drugs I've just mentioned is way cheaper than cabazitaxel. I'm not implying cabazitaxel is a bad drug, I'm simply saying it's more expensive. And I think as patients are really being harmed by the cost of care, I think one of the things that's kind of a shame, and it goes to the way we were trained, is oncologists have been trained not to think about the costs of what they're doing because the thought is that if we're thinking costs, we will withhold the best treatment because of cost considerations. I think the other side of that coin is we need to be thinking about what is the damage to patients that the cost is doing, and if there is substantial damage, is the patient getting that much bang for the buck? In other words, say an old cheap drug gives you three months extra survival, and a brand-new, very expensive drug gives you four months extra survival, do we really want to be thinking that that somehow is a wash and we should use the newer drug? At the very least, physicians should now be trained to have that discussion with patients and raise the issues so that patients aren't embarrassed by their inability to pay. We do know the two areas that are really hard to get patients to confess about, as it were, financial toxicity, and sexual dysfunction. And if we as physicians don't address that, we are going to be complicit in making these sorts of problems worse. So, one of the things is the costs of care. I think one of the other issues that is a little troubling is how we're thinking about new standards of care. There is a growth industry of consensus guidelines, and the reality is that some of the consensus guidelines, I think particularly, ASCO's, are very meticulously done. I've had the privilege of being part of a couple of the panels, and they were very rigorously driven, and they were trying to identify level-1 data and trying to be honest about outcomes. But some of the consensus guidelines are basically a bunch of good old boys getting together, and just chatting about what they do, and if they all do the same thing, then that becomes a guideline. And that can be a flawed approach, so that we've got consensus guidelines that are terrific, and some consensus guidelines that might be terrific, but may not be predicated on the best evidence. And then finally, one of my bugaboos is this sudden emphasis on real-world data. And I tend to worry about the concept of 'garbage in, garbage out'. A lot of the real-world analyses are either looking at databases that weren't designed for the way they're being implemented, or there are very practical reports of stuff that has happened, but without the necessary scientific rigor, such as considering what are the case selection biases that have led to those sets of real-world data being produced? So, that sort of compounds the problem of the fact that we need to be focusing a little more on, "What are we doing? Why are we doing it, and how robust are the data that support our patterns of practice?" One of the real leaders in this space is Mark Ratain, who's gone right back to torts and has started to ask questions about the pharmacology of drugs. There are dosing schedules that come out of phase I and phase II trials. There are often schedules that will be of benefit to the pharmaceutical industry but may not be fully evidence-based. So, you know, with a drug like Radium-223, which is for prostate cancer, it is said that you should give 6 doses. I'm unaware of any robust data that say that 6 is better than 5 is better than 4. Dr. John Sweetenham: Yeah. Thanks, Derek. Great responses. And I particularly like your insight into real-world evidence. I know that there have been attempts by ASCO, and by FDA, to put some parameters around real-world evidence, and get some, I guess you'd call it quality assurance into this, but I do agree with you that it's a little bit uncontrolled at the moment, and I think if we are going to continue to use these very, very large real-world datasets as a comparator, particularly, for drug approval, as well for studies, then there's probably still significant amount of work to be done to make sure that those data are collected in a consistent and rigorous fashion. Dr. John Sweetenham: I'm going to change gear now and talk, for just a little while, it's a huge subject and the time constraints will prevent us from saying too much about this, but of course, you know, health equity continues to be a major concern across healthcare in general, and in oncology specifically. We've now seen, for example, the replacement for the Oncology Care Model, The Enhancing Oncology Model, which has been proposed by CMMI. And not surprisingly, I think they recognize the need for addressing health equity and are introducing some health equity components into that in the next phase of Oncology Care Models from that group. But I guess my question at this point is, do you think that this kind of approach whereby health equity is at least to some extent addressed in the context of, for example, an alternative payment model, is the way ahead in terms of actually bringing about effective change, rather than just recording that there are indeed disparities? Dr. Derek Raghavan: So, that's a complex question, and I think there are several strands to the answer. I think the first thing I would say is, it really is time for us to recognize that we are at an inflection point. And we need to move from analysis paralysis to a new paradigm, which I would call, equity of survival. I have to say, I'm really over the multiple meetings that most of the professional societies have where people seem to feel good about saying, "Yep, we've come together and we've decided there really are disparities." We've known that there were disparities of care for probably 20 years, and some of us have done something about it and others haven't. But I think it's time to define equity of survival, and you can certainly do it. And what I mean by that is as follows: so, if I could use an example of a study from our place at the Levine Cancer Institute, Dr. Bei Hu, who is a very talented young lymphoma specialist, analyzed our outcomes for poorly insured, or uninsured, predominantly black American populations versus wealthy whites. And she published in Cancer and also presented prior to that at ASH, the fact that we had identical outcomes for diffuse large B-cell lymphoma; our hypothesis is that we were able to improve the results by using nurse navigation to help the underprivileged patients be able to adhere to the rigorous constraints of cuff management of diffuse large B-cell lymphoma. But you know, the fact is we are able to show that survival is the same in those two population groups. So, it isn't a question of, "Did you do more? Did you spend more time?" At the end of the day, the parameter is, they lived the same, and the quality of their lives, as we've measured, it was the same. So, I think that's one piece. I'm a bit negative about the government's new EOM. I've kept my institute out of the first OCM model because I thought that they were going to waste our time, and they played with it, and they learned very little, and then they generated a new model. I am very happy that there are health equity components in it, but of course, what we already know is government doesn't enforce those very well. If you look at the National Cancer Institute, and from my time on the parent committee and doing reviews, I was constantly saying, "But we aren't seeing the appropriate representation of minorities." Journal editors are still allowing the NCI-designated comprehensive cancer centers to publish papers with less than 5% Black Americans. And the argument is, "Oh, that's not in our demographic." But that's nonsense because the demographic of Black Americans and Hispanics in most parts of the United States are pretty well known, and the centers that I'm thinking about have perfectly large numbers of Black American, and Hispanic, and Native American patients. You know, I think there are two dimensions; one is government actually has to mean that they want to see things happen and enforce it appropriately, but at the same time, the idea that we're checking a box by doing yet another study of underserved populations where we're looking at demography, and their eating habits, and so on, when we're not concentrating on treatment-based survival. And the journal editors are turning down papers as being too descriptive when they report smaller studies of African American or Native American patients. All of those things have to be fixed, in my opinion. Dr. John Sweetenham: Great, thanks. And I'm going to change gear again to another issue, which, certainly, at our center is becoming more prominent for us, and that's an issue of sites of care. So, we are increasingly becoming aware that reimbursement issues are driving where our patients receive certain components of their care, particularly their chemotherapy. At the same time, we're also seeing increasing interest, I think partly fueled by the COVID-19 pandemic towards home treatment, and specifically, home infusion. So, I'd be interested to know where you think the future lies in terms of; number one, how you think this dynamic is going to play out around payers to some extent driving sites of care. And then secondly, what you see as the future of home infusion for cancer patients and potentially the use of home chemotherapy. Dr. Derek Raghavan: Well, you know, I tend, as you know well, to be one of your more cynical friends. I have real trouble with the insurance companies declaring publicly that they're struggling to keep up with the cost of treatment, and therefore they need to influence treatment when despite this incredibly difficult situation in which they find themselves, they're able to give seven and eight-figure bonuses to their Chief Executives every year. So, they're not doing poorly, they're just crying poor. And so, when they claim that they're doing things for the benefit of patients, I just don't believe that. So, the first thing is, the imperative to move care from point A to point B is driven by people with self-interest rather than necessarily trying to do it for patients. Now, having said that, I actually think COVID has taught us a lot. We can do many things very effectively through telemedicine, and for example, at the Levine Cancer Institute, we surveyed our patients who are dealing with the Supportive Oncology teams, Psycho-Behavioral Medicine, and Complementary Integrative Medicine. And so, they've actually shown us that they would prefer to have video consultation, which saves them having to get dressed, jump in the car, drive into the city, or to their local branch of LCI and so on. And so, there are demands where it's quite clear that patients like telemedicine and home care, and we know that because the cancellation rate of these appointments has gone way down with the introduction of telemedicine. So, for certain things, it's really good. You mentioned the concept of home infusion, and I think that's a terrific idea, provided that you have the necessary checks and balances. You and I both know that patients will suddenly crash with an allergic reaction in response to a drug like taxol and taxotere, or even sometimes, cisplatin, so, you don't want to have the situation where the nurse is infusing at home by herself, and trying to manage someone who's just shut down with an allergic reaction without any help. So, you need to have standard operating procedures that maximize life safety. Having said that, the idea of making it easier for patients to have their treatment and having it close to home is really, I think something that I really support. Where I'm less enthusiastic is something that the insurance companies have started to play with, and I believe ASCO is opposing this, at an organizational level, and that's the concept of white-bagging and brown-bagging. The idea that the insurance companies will somehow supervise the preparation and distribution of drugs to their satisfaction, and then expect oncologists or hospitals to take those drugs and administer them on their behalf. There is no clear evidence of quality control; it's absolutely clear that this is being done in a fashion that will allow them to control costs, and maybe not in an appropriate fashion. And I think that should be really strenuously opposed. Now, they're not the only culprits. What we have found is many of the largest centers declining to use biosimilars, for no particularly good reason, other than the fact that they're not that familiar with them. Well, there are good data to suggest that many of the biosimilars have equal efficacy and equal toxicity to the parent compounds, and they're way less costly. And so, we need to be thinking through a whole paradigm of, where are biosimilars available, what is the track record for their safety and utility, and so on. So, I think there are a number of steps that we can actually be involved in that will improve the cost of care. But doing it just because the insurance companies are trying to save themselves money may not be the primary driver that would influence my thinking. Dr. John Sweetenham: Yeah. Thanks, Derek. I'm interested in your comments on biosimilars because, you know, at our center, at UT Southwestern, we have certainly embraced biosimilar usage. And one of the points of care challenges in that regard is knowing which biosimilar is covered by an individual patient's insurance. And I know at a number of centers, that's been a challenge, and it's something that our pharmacy team has worked on in order to find a more facile way for our clinicians to be able to understand coverage. And there are significant cost savings associated with that. So, I agree 100% And talking of costs, the final issue which we wanted to talk with you about briefly today is the issue of prior authorization. Many ASCO members in the United States spend a very large amount of time dealing with this, and in the community oncology practice, it’s estimated as much as 25% of an oncologist's time is now spent dealing with these issues, and obviously is very negative in terms of job satisfaction, physician burnouts, and so on, as well as just making things very, very difficult for our patients. Do you see a resolution to this? Do you think it will continue to be a big challenge, or do you think there are solutions available to us which will make this much easier for physicians, and save them some time as well as money? Dr. Derek Raghavan: No, I think it's here to stay. I mean, I think it's honestly multifactorial. I think it begins with government in the sense that we've just, once again, declared war on cancer. It's the third or fourth war that's been declared during my career, and that's all well and good. But you know, the reality is that that sets expectations in the community that can often be unrealistic. And so, that puts the unfortunate community, or academic oncologist in the situation of really struggling to say to a patient, "We've done what we can, and it's time to bring in supportive oncology or hospice." So, there are unrealistic expectations in the community. I think the second piece that relates to this is, the purveyors of computerized record systems are actually contributing more to burnout than probably anything else in the land. We've got unregulated industry where the service delivery for most of these companies is poor. And I think it all connects really with a broader issue, which is, for whatever reason, post-COVID, there is this phenomenon internationally of the so-called Great Resignation. It's partly burnout, it's partly anger about the world, I guess, at large. But what we are finding is, one of the pivotal areas for the Great Resignation is medical and nursing staff. I've never seen as many physicians retiring early, as many nurses getting out of oncology, and either going into the pharmaceutical industry or into data management or just going into simpler types of nursing. And that reflects the resistance of the healthcare industry to recognize that there are different stresses in different types and parts of the healthcare industry, and not compensating appropriately, and putting in safety valves to help these people get off the line. And you know, your question was, "Do I think it's here to stay?" I really do. I think the younger generation has, in many ways, a much more sensible approach to work-life balance than we did. They also have less experience. So, every time a crusty old veteran doctor, or nurse goes, they're replaced by someone with two decades less experience, and somewhat a different work ethic. I'm not saying it's a bad work ethic, but it's changing the way healthcare is delivered. So, I think this is going to be a real issue. And then finally, you know, in terms of the actual business of prior authorization, which I view largely as a tool that the health insurance companies use to avoid payment, I think we mentioned in a previous discussion on our financial toxicity tumor board, we have a pretty standard algorithm where we call the insurance companies before starting chemotherapy or radiotherapy; check in with them that their reading of their rules allows approval, and then we document who we spoke to, and what time. That seems to be quite a good way of stopping the insurance companies denying payment at a later time based on the technicality on page 253, line 27. While we're talking, John, what's happening at the Simmons Center and UT Southwestern? Are you seeing a change in the pattern of resignation of nurses and physicians, or have you managed to figure out strategies to avoid that? Dr. John Sweetenham: At UT Southwestern and Simmons Cancer Center, in particular, what we've seen is very similar, I think, to the national trends. And so, I think what we've seen is three main groups affected; our nursing staff, and as you say, I think there are various reasons why that's happened, our clinical trials staff, in particular, we've had an increasing problem in hiring and have lost many to industry actually. And then, on the physician front as well, we have seen a number of our physicians move to industry, both in terms of drug companies, and also some data companies where, you know, I think there is clearly an interest in having physician leadership. And, you know, I do agree with you, and I think part of the challenge, and there's been quite a lot of literature about this, as you’ll know, is, what are we going to do, particularly in the academic oncology community, what are we going to do for our younger faculty in terms of growth opportunities for them that keep them within academic medicine? And I think we probably really have to rethink the way academic oncology is running at the moment if we're going to retain the best people within our field. So, a short answer to your question is, yeah, we're seeing very similar trends to those that are reported nationally. We're planning interventions, but obviously, all of these things take quite a long time. It's been great talking to you as always, Derek. I think it's good to hear your insights on the podcast, particularly, with respect to what might happen in 2023. I think as always, it's important to remember that despite the challenges, I think if you look back year-on-year, there is for sure, going to be a lot to be excited about this year. And our patients, I think, can anticipate to see continued improvements in what we do, and hopefully improvements in their lives and the lives of the caregivers who take care of them. So, despite the challenges, I think we need to just remember that it's not all bad, and there are a lot of good things going on out there. Dr. Derek Raghavan: Yeah, I agree with that, John. One of the things we always forget, despite the fact that you and I were tasked with talking about the problems emerging, is, the most rapidly growing patient population in oncology is the long-term survivors, and we can both be justifiably proud of all the good things that have happened to create that scenario. Dr. John Sweetenham: Absolutely. So, thanks, once again. Always a pleasure to talk with you. And to you, our listeners, thank you for your time today. If you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe, wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement. Find out more about today’s speakers: Dr. John Sweetenham Dr. Derek Raghavan Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Derek Raghavan: Consulting or Advisory Role: Gerson Lehrman Group, Caris

Dr. Charles Ryan, president and CEO of the Prostate Cancer Foundation (PCF), joins ASCO Daily News Editor-in-Chief Dr. Neeraj Agarwal, of the University of Utah Huntsman Cancer Institute, to assess impactful prostate cancer research from the PCF’s recent conference and discuss Dr. Ryan’s vision for the future, including increasing access to cutting-edge care. TRANSCRIPT Dr. Neeraj Agarwal: Welcome, to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the editor-in-chief of the ASCO Daily News, and director of the Genitourinary Cancers Program at the University of Utah Huntsman Cancer Institute. Today, we'll be discussing compelling research that was featured at the recent Prostate Cancer Foundation Scientific Retreat, and I'm very pleased to welcome Dr. Charles Ryan, the president, and CEO of the Prostate Cancer Foundation. Our full disclosures are available on the transcript of this episode, and disclosures relating to all episodes of the ASCO Daily News Podcast are available on our transcripts at: asco.org/podcasts. Dr. Ryan, thank you for taking the time to be with us today. Dr. Charles Ryan: Dr. Agarwal, thank you. It's my pleasure to be with you. Dr. Neeraj Agarwal: So, Dr. Ryan, before I discuss the PCF meeting, I would like to ask you, what made you move to the PCF as the president and CEO when you had a flourishing career as a division chief of a large academic program, and as one of the top and internationally recognized investigators in prostate cancer? Dr. Charles Ryan: Well, thanks. That's a fair question, I guess. And it took me about three minutes to make the decision when I was offered the position, simply because the Prostate Cancer Foundation has been one of my intellectual homes for my entire career. I've been at the University of Wisconsin, Memorial Sloan Kettering Cancer Center, UCSF, and the University of Minnesota, and all those institutions were affected by the Prostate Cancer Foundation, or previously, CaP CURE. So, I was involved in their research during my time at all those institutions. In addition to my own personal legacy with the PCF, but more importantly, is the fact that it is an organization that funds the deepest scientific inquiry into prostate cancer and the ways that it can cause suffering and death for men with the disease and has made tremendous progress in identifying factors that lead to that lethality. It's also a community of scholars, a community of researchers, that is a platform really for collaboration. And it's also an organization with a world reach - we fund research in 28 countries around the world, and we fund research going from the scope of very basic research to correlative research, to quality of life, and health services research. Dr. Neeraj Agarwal: That is truly impressive and inspiring. So, what is the mission of the Prostate Cancer Foundation formally? Dr. Charles Ryan: Formally, it's pretty simple. The mission of the Prostate Cancer Foundation is to reduce the death and suffering from prostate cancer. Dr. Neeraj Agarwal: So, the 29th PCF Scientific Retreat was recently held on October 27 to October 29th in Carlsbad, California. What were the goals and objectives of this meeting? Dr. Charles Ryan: The meeting, we call it the retreat, it's an annual event and it always has several goals. One is, it's where we announce and hand out, if you will, our awardees of our various awards that we give. It's also a reporting-in process where those who have been using PCF funding are called to come and discuss their work. We also want it to be an open forum for individuals to come and interact - it's really a collaboration and an interaction vehicle as much as anything. So, when you come to our scientific retreat, we all stay at the same hotel, we all share meals together, nobody goes out for dinner. You don't leave the campus, essentially, of the hotel where we are. We have many, many round tables set out, it's designed to be interactive. We have a big room where people are giving their talks, but if you step outside of the room, there are likely to be many, many conversations happening, and those conversations range from collaborations being formed to people looking for jobs, to people getting advice and mentoring, and even people sharing, as I've done over the years, compelling and challenging patient stories around prostate cancer, and really engaging in what communities do - which is, share ideals, share a mission, and share a passion for what they do. Dr. Neeraj Agarwal: Very interesting. Very inspiring. Please tell us some of the highlights of the meeting. Dr. Charles Ryan: Sure. Well, there are many highlights. There are many things happening in prostate cancer research. Most notably, there are a number of papers and investigators that are looking at how prostate cancer evolves, and probably the most significant set of observations that have been made in the field in the last decade, have been understanding the diverse and numerous mechanisms that underlie the evolution of prostate cancer from a disease that responds to hormonal manipulation, to one that becomes resistant to hormonal manipulation. And so, a lot of the work that's happening now is identifying, for example, the evolution of neuroendocrine prostate cancer, or mixed types of prostate cancer, or this sort of evolution of it under constant therapy. And that is allowing the exposure of new targets that we can exploit for new therapy development, and that feeds into some of the grant-making process that's going on in the background. And so, you have a lot of individuals who are looking at this or that mechanism pathway related to disease resistance that they can exploit, and whether they can create small molecules to do that, or antibodies to do that, et cetera. At the same time, we have a strong component of discussion of how prostate cancer affects different populations. So, we had some really nice talks looking at healthcare disparities and different populations across the world, and how they're affected by prostate cancer, and how care delivery may be impacted in those groups of patients. And then you have topics ranging around survivorship and other factors that are looking at what is life like for a man with advanced prostate cancer, which is in many cases, you know, men who get prostate cancer, who have recurrent disease, who end up going on systemic therapy are frequently on the treatment for 5, 10, 15 years. And so, survivorship, and how they live their life, and what the complications are of that treatment, is tremendously important because it's such a daily experience for these men undergoing treatment. Dr. Neeraj Agarwal: So, how does the Prostate Cancer Foundation support and build the next generation of prostate cancer researchers? Dr. Charles Ryan: Right. So, the PCF supports the next generation in a very specific way, in addition to the informal way of bringing people together and inducing collaborations. We have a program called the Young Investigator Program. It started formally in 2008, but before that, there were one-off, if you will, Young Investigator Awards being given. So, our Young Investigator Awardees receive $75,000 per year to support their work, and we awarded 34 of those this year. The range is somewhere from 25 to 34 per year. We get over 100 applications for them every year. It's a straightforward application - they need to have a project that's going to be about three years in length, they need to be mentored, and they are best served by describing a mentorship plan for themselves and how that mentorship relationship will help them grow in their careers. Now, once you become a Young Investigator, it's not that we just write you a check and wish you well, we do that, but we also have annual check-ins. So, we try to visit the sites of our Young Investigators, see them in their home institution, and meet with their colleagues and their mentors. And that's one of the things I do, or Howard Soule does-- Howard Soule, is our chief scientific officer, one of those things we try to do. We also bring them to the scientific retreat that we just had last week, and we have them present their data. So, a vast number of the individuals who are presenting at the scientific retreat are in fact, Young Investigators, or they were Young Investigators when they started the projects that they are presenting. And then, the other thing we do is we have another retreat specifically for the Young Investigators, and that's called the Coffey-Holden Retreat, and that's named after Don Coffey, the late researcher from Johns Hopkins, who is really considered to be one of the grandfathers of prostate cancer research, and Stuart or Skip Holden, who is one of the founders of the Prostate Cancer Foundation, and a urologist at UCLA. So, that event that we do is designed for people to come to give highlights of the work that they're doing; it's designed to be incredibly interactive. In fact, we have 15 or so minutes of presentation, followed by sometimes 25 minutes of questions for each presenter. There's always a line of people who are waiting to ask questions, and it's designed to engage and have that dialogue with the Young Investigators, to make their science better, and to get it known. And so, the Young Investigator Program, it's about 30 individuals per year on average, and the average age is about 30. Many of these are postdoctoral PhDs, and many of them are fellows, or early-stage faculty, MDs. And I like to think that if somebody's going to work until the age of 70, we're stimulating, or launching a 40-year career with these Young Investigator awards. So, I like to think that if we give 25 out, times 40 years, that's 1,000 years of research that we're sort of stimulating with this Young Investigator program. And I bring that up for the reason that we're very proud of the fact that many of our Young Investigators may start out in prostate cancer, and their ideas, their science, takes them elsewhere. And that's what science does. And we, of course, are very, very focused on solving the problem of prostate cancer, and we want people to do that. But we also understand that by launching a scientist, by launching a scientific career, you may end up with people going off in different directions. And so, we have many examples of that. And in my talk this year, I actually highlighted a person who, let's say she won an investigator award when she was young, it was before the formal Young Investigator Award was named, and this was a person who is creating conjugates for the delivery of chemotherapy to prostate cancer cells. And this was Carolyn Bertozzi up at UC Berkeley, and she just won the Nobel Prize. She didn't win the Nobel Prize for research she did on prostate cancer, but at some point, at one point in her career, this was a direction she was going, and she got two grants from us in 1999 and 2000, that helped her work continue on and go the direction that it did. Dr. Neeraj Agarwal: Yeah. And congratulations. Dr. Charles Ryan: Sure. I'll take credit for that one. Dr. Neeraj Agarwal: Being the President and the CEO, you deserve the credit. Dr. Charles Ryan: Sure. That's my job. Dr. Neeraj Agarwal: So, we are coming to the end of the interview, but let me ask you this; the prostate cancer field is so constantly evolving. What is your vision for PCF going forward? Dr. Charles Ryan: Well, my vision for the organization is that we are going to continue on our mission to reduce the death and suffering from prostate cancer. But that's a fairly general statement, and one of the ways you can do that is you can research cancer at a molecular level, and you could try to develop new therapies - we're going to continue to do that. But there's also a real problem, especially, in the United States, and actually globally, with individuals with prostate cancer who are not receiving the cutting-edge care, not receiving the cutting-edge therapy. We have some data that in the United States, maybe upwards of 50% of men with metastatic hormone-sensitive prostate cancer are not getting the therapies that are supported by the latest findings from randomized phase III trials. And this may be for economic reasons, it may be communications or an education deficit with their treating clinicians, and there may be other factors as well. So, as we think about the vision of this, we need to be mindful of that, because if we only focus on studying the cancer molecularly, and we don't address what's happening on the other end, then we're not completing the story, and we're not completing the mission. And so, I've started calling Prostate Cancer Foundation the Global Public Square of Prostate Cancer, because I think of four sides of that square - funding research, as of what we just got done talking about, education and communication, is another one, and we do that in the same way that you are doing this today - through podcasts, and web content, and in-person meetings, as well as applied discovery, which is helping our researchers take their discoveries or their findings out into the clinic. Now, you might think, "Well, that's a small molecule, becoming a company going into a phase I clinical trial." Certainly, that's part of it, but it's also the epidemiologist who is making observations about diet and exercise, who is then empowered to do a clinical trial of exercise and diet intervention. It's also the health services researcher who is able to use their data to go talk to payers or talk to organizations about how care may be delivered differently. So, that's applied discovery. And then finally, supporting the patient is part of what we do. So, we also hold patient webinars every month, we've held patient summits at various points around the country where we bring patients together and talk to them about the latest research or about the factors we've discussed, such as survivorship, or quality of life after treatment, or treatment complications, and things like that. Dr. Neeraj Agarwal: That's wonderful. Thank you so much for sharing your insights. Any final remarks, Dr. Ryan? Dr. Charles Ryan: Dr. Agarwal, thank you so much. It's always a pleasure to speak to another Genitourinary Oncologist, of course, about the field, and the opportunity to talk about the Prostate Cancer Foundation and what we're doing, and the directions we are trying to grow. We've had a great collaboration with ASCO over the years, and I hope that that continues as well. I hope anybody who is interested would come and visit us at: pcf.org, and they can also check us out on: urotoday.com, where we have a lot of content that might be of interest to them. Dr. Neeraj Agarwal: Thank you, Dr. Ryan, for taking the time to be with us on the ASCO Daily News Podcast today. And thank you to our listeners for joining us today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe, wherever you get your podcast. Thank you very much. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement. Follow today’s Speakers: Dr. Neeraj Agarwal @neerajaimms Dr. Charles Ryan @charlesryanmd Want more related content? Listen to our podcast on therapeutic advances in prostate cancer and other GU cancers.   Advances in Genitourinary Cancers at #ASCO22 Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures: Dr. Neeraj Agarwal:  Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, Gilead Sciences  Research Funding (Inst.): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck , Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, Arvinas   Dr. Charles Ryan: Honoraria: Janssen Oncology, Bayer Consulting or Advisory Role: Bayer, Dendreon, AAA, Myovant Sciences, Roivant, Clovis Oncology  

Dr. Vamsi Velcheti and Dr. Benjamin Neel, of the NYU Langone Perlmutter Cancer Center, and Dr. John Heymach, of MD Anderson Cancer Center, discuss new therapeutic approaches for KRAS-mutant lung cancers and therapy options for RAS-altered tumors.   TRANSCRIPT Dr. Vamsidhar Velcheti: Hello, I'm Dr. Vamsidhar Velcheti, your guest host for the ASCO Daily News podcast today. I'm the medical director of the Thoracic Oncology Program at Perlmutter Cancer Center at NYU Langone Health. I'm delighted to welcome two internationally renowned physician-scientists, Dr. John Heymach, the chair of Thoracic-Head & Neck Medical Oncology at the MD Anderson Cancer Center, and my colleague, Dr. Benjamin Neel, the director of the Perlmutter Cancer Center at NYU Langone Health, and professor of Medicine at NYU Grossman School of Medicine. So, we'll be discussing new therapeutic approaches today for KRAS-mutant lung cancers, and we will talk about emerging new targeted therapy options for RAS-altered tumors. Our full disclosures are available in the show notes, and the disclosures of all the guests of the podcast can be found on our transcript at: asco.org/podcast. Dr. Heymach and Dr. Neel, it's such a great pleasure to have you here for the podcast today. Dr. John Heymach: My pleasure to be here. Dr. Benjamin Neel: Same here. Dr. Vamsidhar Velcheti: Dr. Neel, let's start off with you. As you know, RAS oncogenes were first discovered nearly four decades ago. Why is RAS such a challenging therapeutic target? Why has it taken so long to develop therapeutic options for these patients? Dr. Benjamin Neel: Well, I think a good analogy is the difference between kinase inhibitors and RAS inhibitors. So, kinase inhibitors basically took advantage of an ATP-binding pocket that's present in all kinases, but is different from kinase to kinase, and can be accessed by small molecule inhibitors. So, the standard approach that one would've thought of taking, would be to go after the GTP-binding pocket. The only problem is that the affinity for binding GTP by KRAS is three to four orders of magnitude higher. So, actually getting inhibitors that are GTP-binding inhibitors is pretty much very difficult. And then, until recently, it was felt that RAS was a very flat molecule and there weren't any surfaces that you could stick a small molecule inhibitor in. So, from a variety of biochemical and medicinal-pharmacological reasons, RAS was thought to be impervious to small molecule development. But as is often the case, a singular and seminal insight from a scientist, Kevan Shokat, really broke the field open, and now there's a whole host of new approaches to trying to drug RAS. Dr. Vamsidhar Velcheti: So, Dr. Neel, can you describe those recent advances in drug design that have enabled these novel new treatments for KRAS-targeted therapies? Dr. Benjamin Neel: So, it starts actually with the recognition that for many years, people were going after the wrong RAS. And by the wrong RAS, the overwhelming majority of the earlier studies on the structure, and for that matter, the function of RAS centered on HRAS or Harvey RAS. We just mutated in some cancers, most prominently, bladder cancer, and head & neck cancer, but not on KRAS, which is the really major player in terms of oncogenes in human cancer. So, first of all, we were studying the wrong RAS. The second thing is that we were sort of thinking that all RAS mutants were the same. And even from the earliest days, back in the late eighties, it was pretty clear that there were different biochemical properties in all different RAS mutants. But this sort of got lost in the cause and in the intervening time, and as a result, people thought all RASes were the same and they were just studying mainly G12V and G12D, which are more difficult to drug. And then, the third and most fundamental insight was the idea of trying to take advantage of a particular mutation in KRAS, which is present in a large fraction of lung cancer patients, which is, KRAS G12C. So, that's a mutation of glycine 12 to cysteine and Kevan’s really seminal study was to use a library of covalently adducting drugs, and try to find ways to tether a small molecule in close enough so that it could hit the cysteine. And what was really surprising was when they actually found the earliest hits with this strategy, which was actually based on some early work by Jim Wells at Sunesis in the early part of this century, they found that it was actually occupying the G12C state or the inactive state of RAS. And this actually hearkens back to what I said earlier about all RASes being the same. And in fact, what's been recently re-appreciated is that some RAS mutants, most notably, G12C, although they're impervious to the gap which converts the active form into the inactive form, they still have a certain amount of intrinsic ability to convert from the inactive form. And so, they always cycle into the inactive form at some slow rate, and that allows them to be accessed by these small molecules in the so-called Switch-II Pocket, and that enables them to position a warhead close enough to the cysteine residue to make a covalent adduct and inactivate the protein irreversibly. Scientists at a large number of pharmaceutical companies and also academic labs began to understand how to access various other pockets in RAS, and also even new strategies, taking advantage of presenting molecules to RAS on a chaperone protein. So, there's now a whole host of strategies; you have a sort of an embarrassment of riches from an impoverished environment that we started with prior to 2012. Dr. Vamsidhar Velcheti: Thank you, Dr. Neel. So, Dr. Heymach, lung cancer has been a poster child for personalized therapy, and we've had like a lot of FDA-approved agents for several molecularly-defined subsets of lung cancer. How clinically impactful is a recent approval of Sotoracib for patients with metastatic lung cancer? Dr. John Heymach: Yeah. Well, I don't think it's an exaggeration to say this is the biggest advance for targeted therapies for lung cancer since the initial discovery of EGFR inhibitors. And let me talk about that in a little more detail. You know, the way that lung cancer therapy, like a lot of other cancer therapies, has advanced is by targeting specific driver oncogenes. And as Dr. Neel mentioned before, tyrosine kinases are a large percentage of those oncogenes and we've gotten very good at targeting tyrosine kinases developing inhibitors. They all sort of fit into the same ATP pocket, or at least the vast majority of them now. There are some variations on that idea now like allosteric inhibitors. And so, the field has just got better and better. And so, for lung cancer, the field evolved from EGFR to ALK, to ROS1 RET fusions, MEK, and so forth. What they all have in common is, they're all tyrosine kinases. But the biggest oncogene, and it's about twice as big as EGFR mutation, are KRAS mutations. And as you mentioned, this isn't a tyrosine kinase. We never had an inhibitor. And the first one to show that it's targetable, to have the first drug that does this, is really such an important breakthrough. Because once the big breakthrough and the concept is there, the pharmaceutical companies in the field can be really good at improving and modulating that. And that's exactly what we see. So, from that original insight that led to the design of the first G12C inhibitors, now there's dozens, literally dozens of G12C inhibitors and all these other inhibitors based on similar concepts. So, the first one now to go into the clinic and be FDA-approved is Sotoracib. So, this again, as you've heard, is inhibitor G12C, and it's what we call an irreversible inhibitor. So, it fits into this pocket, and it covalently links with G12C. So, when it's linked, it's linked, it's not coming off. Now, the study that led to its FDA approval was called the CodeBreak 100 study. And this was led in part, by my colleague Ferdinandos Skoulidis, and was published in The New England Journal in the past year. And, you know, there they studied 126 patients, and I'll keep just a brief summary, these were all refractory lung cancer patients. They either had first-line therapy, most had both chemo and immunotherapy. The primary endpoint was objective response rate. And for the study, the objective response rate was 37%, the progression-free survival was 6.8 months, the overall survival was 12.5 months. Now you might say, well, 37%, that's not as good as an EGFR inhibitor or the others. Well, this is a much harder thing to inhibit. And you have to remember in this setting, the standard of care was docetaxel chemotherapy. And docetaxel usually has a response rate of about 10 to 13%, progression-free survival of about 3 months. So, to more than double that with a targeted drug and have a longer PFS really is a major advance. But it's clear, we've got to improve on this and I think combinations are going to be incredibly important now. There's a huge number of combination regimens now in testing. Dr. Vamsidhar Velcheti: Thank you, Dr. Heymach. So, Dr. Neel, just following up on that, unlike other targeted therapies in lung cancer, like EGFR, ALK, ROS, and RET, the G12C inhibitors appear to have somewhat modest, I mean, though, certainly better than docetaxel that Dr. Heymach was just talking about; why is it so hard to have more effective inhibitor of KRAS here? Is it due to the complex nature of RAS-mutant tumors? Or is it our approach for targeting RAS? Is it a drug-related problem, or is it the disease? Dr. Benjamin Neel: Well, the short answer is I think that's a theoretical discussion at this point and there isn't really good data to tell you, but I suspect it's a combination of those things. We'll see with the new RAS(ON) inhibitors, which seem to have deeper responses, even in animal models, if those actually work better in the clinic, then we'll know at least part of it was that we weren't hitting RAS hard enough, at least with the single agents. But I also think that it's highly likely that since KRAS-mutant tumors are enriched in smokers, and smokers have lots of mutations, that they are much more complex tumours, and therefore there's many more ways for them to escape. Dr. Vamsidhar Velcheti: Dr. Heymach, you want to weigh in on that? Dr. John Heymach: Yeah, I think that's right. I guess a couple of different ways to view it is the problem that the current inhibitors are not inhibiting the target well enough, you know, in which case we say we get better and better inhibitors will inhibit it more effectively, or maybe we're inhibiting it, but we're not shutting down all the downstream pathways or the feedback pathways that get turned on in response, in which case the path forward is going to be better combinations. Right now, I think the jury is still out, but I think the data supports that we can do better with better inhibitors, there's room to grow. But it is also going to be really important hitting these compensatory pathways that get turned on. I think it's going to be both, and it seems like KRAS may turn on more compensatory pathways earlier than things like EGFR or ALK2, you know, and I think it's going to be a great scientific question to figure out why that is. Dr. Vamsidhar Velcheti: Right. And just following up on that, Dr. Heymach, so, what do we know so far about primary and acquired resistance to KRAS G12C inhibitors? Dr. John Heymach: Yeah. Well, it's a great question, and we're still very early in understanding this. And here, if we decide to call it primary resistance - meaning you never respond in the first place, and acquired - meaning you respond and then become resistant, we're not sure why some tumors do respond and don't respond initially. Now, it's been known for a long time, tumors differ in what we call their KRAS-dependence. And in cell lines and in mouse models, when you study this in the lab, there are some models where if you block KRAS, those cells will die immediately. They are fully dependent. And there's other ones that become sort of independent and they don't really seem to care if you turn down KRAS, they've sort of moved on to other things they're dependent on. One way this can happen is with undergoing EMT where the cell sort of changes its dependencies. And EMT is probably a reason some of these tumors are resistant, to start with. It may also matter what else is mutated along with KRAS, what we call the co-mutations, the additional mutations that occur along with it. For example, it seems like if this gene KEAP1 is mutated, tumors don't respond as well, to begin with. Now, acquired resistance is something we are gaining some experience with. I can say in the beginning, we all knew there'd be resistance, we were all waiting to see it, and what we were really hoping for was the case like with first-generation inhibitors with EGFR, where there was one dominant mechanism. In the first-generation EGFR, we had one mutation; T790M, that was more than half the resistance. And then we could develop drugs for that. But unfortunately, that's not the case. It looks like the resistance mechanisms are very diverse, and lots of different pathways can get turned on. So, for acquired resistance, you can have additional KRAS mutations, like you can have a KRAS G12D or V, or some other allele, or G13, I didn't even realize were commonly mutated, like H95 or Y96 can get mutated as well. So, we might be able to inhibit with better inhibitors. But the more pressing problem is what we call bypass; when these other pathways get turned on. And for bypass, we know that the tumor can turn on MET with MET amplification, NRAS, BRAF, MAP kinase, and we just see a wide variety. So, it's clear to us there isn't going to be a single easy to target solution like there was for EGFR. This is going to be a long-term problem, and we're going to have to work on a lot of different solutions and get smarter about what we're doing. Dr. Vamsidhar Velcheti: Yeah. Thank you very much, Dr. Heymach. And Dr. Neel, just following up on that, so, what do you think our strategies should be or should look like while targeting KRAS-mutant tumors? Like, do we focus on better ways to inhibit RAS, or do we focus on personalized combination approaches based on various alterations or other biomarkers? Dr. Benjamin Neel: Yeah. Well, I'd like to step back a second and be provocative, and say that we've been doing targeted therapies, so to speak, for a long time, and it's absolutely clear that targeted therapies never cure. And so, I think we should ask the bigger question, "Why is it that targeted therapies never cure?" And I would start to conceive of an answer to that question by asking which therapies do cure. And the therapies that we know do cure are immune therapies, or it's therapies that generate durable immune response against the tumor. And the other therapies that we know that are therapies in some cases against some tumors, and radiation therapy in some cases against some tumors. Probably the only way that those actually converge on the first mechanism I said that cures tumors, which is generating a durable immune response. And so, the only way, in my view, it is to durably cure an evolving disease, like a cancer, is to have an army that can fight an evolving disease. And the only army I know of is the immune system. So, I think ultimately, what we need to do is understand in detail, how all of these different mutations that lead to cancer affect immune response and create targetable lesions in the immune response, and then how the drugs we'd give affect that. So, in the big picture, the 50,000-foot picture, that what we really need to spend more attention on, is understanding how the drugs we give and the mutations that are there in the first place affect immune response against the tumor, and ultimately try to develop strategies that somehow pick up an immune response against the tumor. Now in the short run, I think there's also lots of combination strategies that we can think of, John, you know, alluded to some of them earlier. I mean one way for the G12C inhibitors, getting better occupancy of the drug, and also blocking this so-called phenomenon of adaptive resistance, where you derepress the expression of receptor tyrosine kinases, and their ligands, and therefore bypass through normal RAS or upregulate G12C into the GTP state more, that can be attacked by combining, for example, with the SHIP2 inhibitor or a SOS inhibitor. Again, the issue there will be therapeutic index. Can we achieve that with a reasonable therapeutic index? Also in some cases, like not so much in lung cancer, but in colon cancer, it appears as if a single dominant receptor tyrosine kinase pathway, the EGF receptor pathway, is often the mechanism of adaptive resistance to RAS inhibitors, and so, combining a RAS inhibitor with an EGF receptor inhibitor is a reasonable strategy. And then of course, some of the strategies they're already getting at, what I just mentioned before, which is to try to combine RAS inhibitors with checkpoint inhibitors. I think that's an expected and understandable approach, but I think we need to get a lot more sophisticated about the tumor microenvironment, and how that's affecting the immune response. And it's not just going to be, you know, in most cases combining with a checkpoint inhibitor. I think we ought to stop using the term immunotherapy to refer to checkpoint inhibitors. Checkpoint inhibitors are one type of immunotherapy. We don't refer to antibiotics when we mean penicillin. Dr. Vamsidhar Velcheti: Dr. Heymach, as you know, like, there's a lot of discussion about the role of KRAS G12C inhibitors in the frontline setting. Do you envision these drugs are going to be positioning themselves in the frontline setting as a combination, or like as a single agent? Are there like a subset of patients perhaps where you would consider like a single agent up front? Dr. John Heymach: So, I think there's no question G12C inhibitors are moving to the first-line question. And the question is just how you get there. Now, the simplest and most straightforward approach is to say, “Well, we'll take our standard and one standard might be immunotherapy alone, a PD-1 inhibitor alone, or chemo with the PD-1 inhibitor, and just take the G12C inhibitor and put it right on top.” And that's a classic strategy that's followed. That may not be that simple. It's not obvious that these drugs will always work well together or will be tolerated together. So, I think that's still being worked out. Now, an alternative strategy is you could say, “Well, let's get a foot in a door in the first-line setting by finding where chemotherapy and immunotherapy don't work well, and pick that little subgroup.” There are some studies there using STK11-mutant tumors, and they don't respond well to immunotherapy and chemotherapy and say, “Well, let's pick that first.” And that's another strategy, but that's not to get it for everybody in the first-line setting. That's just to pick a little subgroup. Or we may develop KRAS G12C inhibitor combinations by themselves that are so effective they can beat the standard. So, what I think is going to happen is a couple things; I think they'll first be some little niches where it gets in there first. I think eventually, we'll figure out how to combine them with chemotherapy and immunotherapy so it goes on top. And then I think over time, we'll eventually develop just more effective, targeted combos where we can phase out the chemo, where the chemo goes to the back of the line, and this goes to the front of the line. Dr. Vamsidhar Velcheti: And Dr. Heymach, any thoughts on the perioperative setting and the adjuvant/neoadjuvant setting, do you think there's any role for these inhibitors in the future? Dr. John Heymach: Yeah, this is a really exciting space right now. And so that makes this a really challenging question because of how quickly things are moving. I'll just briefly recap for everybody. Until recently, adjuvant therapy was just chemotherapy after you resected a lung cancer. That was it. And it provided about a 5% benefit in terms of five-year disease-free survival. Well, then we had adjuvant immunotherapy, like atezolizumab, approved, then we had neoadjuvant chemo plus immunotherapy approved; that's a CheckMate 816. And just recently, the AEGEAN study, which I'm involved with, was announced to be a positive study. That's neoadjuvant plus adjuvant chemo plus immunotherapy. So now, if you say, well, how are you going to bring a G12C inhibitor in there? Well, you can envision a few different ways; if you can combine with chemo and immunotherapy, you could bring it up front and bring it afterwards, or you could just tack it in on the back, either with immunotherapy or by itself, if you gave neoadjuvant chemo plus immunotherapy first, what we call the CheckMate 816 regimen. So, it could fit in a variety of ways. I'll just say neoadjuvant is more appealing because you can measure the response and see how well it's working, and we in fact have a neoadjuvant study going. But the long-term benefit may really come from keeping the drug going afterwards to suppress microscopic metastatic disease. And that's what I believe is going to happen. I think you're going to need to stay on these drugs for a long while to keep that microscopic disease down. Dr. Vamsidhar Velcheti: Dr. Neel, any thoughts on novel agents in development beyond KRAS G12C inhibitors? Are there any agents or combinations that you'd be excited about? Dr. Benjamin Neel: Well, I think that the YAP/TAZ pathway inhibitors, the TEAD inhibitors in particular, are potentially promising. I mean, it seems as if the MAP kinase pathway and the GAPT pathway act in parallel. There's been multiple phases which suggest that YAP/TAZ reactivation can be a mechanism of sort of state-switching resistance. And so, I think those inhibitors are different than the standard PI3 kinase pathway inhibitor, PI3 kinase mTOR inhibitor, rapamycin. I also think as we've alluded to a couple of times, the jury’s still out in the clinic, of course, but it'll be very exciting to see how this new set of RAS inhibitors works. The sort of Pan-RAS inhibitors, especially the ones that hit the GTP ON state. So, the G12C inhibitors and the initial preclinical G12D inhibitors that have been recorded, they all work by targeting the inactive state of RAS, the RAS-GDP state. And so, they can only work on mutants that cycle, at least somewhat, and they also don't seem to be as potent as targeting the GTP or active state of RAS. And so, at least the Rev meds compounds, which basically use cyclophilin, they basically adapt the mechanism that cyclosporine uses to inhibit calcineurin. They basically use the same kind of a strategy and build new drugs then that bind cyclophilin and present the drug in a way that can inhibit multiple forms of RAS. So, it'll be interesting to see if they are much more efficacious in a clinic as they appear to be in the lab, whether they can be tolerated. So, I think those are things to look out for. Dr. Vamsidhar Velcheti: Dr. Heymach? Dr. John Heymach: Yeah, I agree with that. I'm excited to see that set of compounds coming along. One of the interesting observations is that when you inhibit one KRAS allele like G12C, you get these other KRAS alleles commonly popping up. And it's a little -- I just want to pause for a second to comment on this, because this is a little different than EGFR. If you inhibit a classic mutation, you don't get multiple other separate EGFR alleles popping up. You may get a secondary mutation in cyst on the same protein, but you don't get other alleles. So, this is a little different biology, but I think the frequency that we're seeing all these other KRAS alleles pop up tells us, I think we're going to need some pan-KRAS type strategy as a partner for targeting the primary driver. So for example, a G12C inhibitor plus a pan-KRAS strategy to head off these other alleles that can be popping up. So, I think that's going to be probably a minimum building block that you start putting other things around. And by partnering an allele-specific inhibitor where you might be able to inhibit it a little more potently and irreversibly with a pan-KRAS, you may solve some of these problems at the therapeutic window. You can imagine KRAS is so important for so many different cells in your body that if you potently inhibit all KRAS in your body, bad things are likely to happen somewhere. But if you can potently inhibit the mutant allele and then dampen the other KRAS signaling that's popping up, it's more hopeful. Dr. Benjamin Neel: There is a mouse model study from Mariano Barbacid’s lab, which suggests that postnatal, KRAS at least, complete inhibition is doable. So, you could take out KRAS postnatally and the mice are okay. Whether that translates to human of course, is not at all clear. And you still have the other RAS alleles, the HRAS, the NRAS that you’d still have to contend with. Dr. John Heymach: Yeah, it's an interesting lesson. We've shied away from a lot of targets we thought weren't feasible. I did a lot of my training with Judah Folkman who pioneered targeting angiogenesis. And I remember hearing this idea of blocking new blood vessels. I said, "Well, everyone is just going to have a heart attack and die." And it turns out you can do it. You have to do it carefully, and in the right way but you can separate malignant or oncogenic signaling from normal signaling in an adult, pretty reasonably in a lot of cases where you don't think you could. Dr. Vamsidhar Velcheti: All right. So, Dr. Neel, and Dr. Heymach, any final closing comments on the field of RAS-targeted therapies, you know, what can we hope for? What can patients hope for, let's say five years from now, what are we looking at? Dr. John Heymach: Well, I'll give my thoughts I guess first, from a clinical perspective, I think we're already seeing the outlines of an absolute explosion in targeting KRAS over the next five years. And I think there's a really good likelihood that this is going to be the major place where we see progress, at least in lung cancer, over these next five years. It's an example of a problem that just seemed insolvable for so long, and here I really want to acknowledge the sustained support for clinical research and laboratory research focused around RAS. You know, the NCI had specific RAS initiatives and we've had big team grants for KRAS, and it shows you it's worth these large-scale efforts because you never know when that breakthrough is going to happen. But sometimes it just takes, you know, opening that door a little bit and everybody can start rushing through. Well, I think for KRAS, the door has been opened and everybody is rushing through at a frantic rate right now. So, it's really exciting, and stay tuned. I think the landscape of RAS-targeting is going to look completely different five years from now. Dr. Benjamin Neel: So, I agree that the landscape will definitely look different five years from now, because it's reflective of stuff that's been in process for the last five years. And it takes about that long to come through. I want to make two comments; one of which is to slightly disagree with my friend, John, about these big initiatives. And I would point out that this RAS breakthrough did not come from a big initiative, it came from one scientist thinking about a problem uniquely in a different way. We need a basic science breakthrough, it almost always comes from a single lab person, thinking about a problem, often in isolation, in his own group. What big initiatives can help with is engineering problems. Once you've opened the door, and you want to know what the best way is to get around the house, then maybe big initiatives help. But I do think that there's been too much focus on the big team initiative and not enough on the individual scientists who often promote the breakthrough. And then in terms of where I see the field going, what I'd really like to see, and I think in some pharmaceutical companies and biotechs, you're seeing this now, and also in academia, but maybe not enough, is that sort of breaking down of the silos between immunotherapy and targeting therapy. Because I agree with what John said, is that targeted therapy, is just sophisticated debulking. If we want to really make progress-- and on the other hand, immunotherapy people don't seem to, you know, often recognize that these oncogenic mutations in the tumor actually affect the immune system. So, I think what we need is a unification of these two semi-disparate areas of therapeutics in a more fulsome haul and that will advance things much quicker. Dr. Vamsidhar Velcheti: Thank you both, Dr. Neel and Dr. Heymach, for sharing all your valuable insights with us today on the ASCO Daily News podcast. We really appreciate it. Thank you so much. Dr. John Heymach: Thanks for asking us. Dr. Benjamin Neel: It's been great. Dr. Vamsidhar Velcheti: And thank you all to our listeners, and thanks for joining us today. If you value our insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review and subscribe. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement. Follow today’s speakers: Dr. Vamsi Velcheti @VamsiVelcheti Dr. Benjamin Neel @DrBenNeel Dr. John Heymach Want more related content? Listen to our podcast on novel therapies in lung cancer.    Advances in Lung Cancer at ASCO 2022 Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Vamsi Velcheti: Honoraria: Honoraria Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline Dr. Benjamin Neel: None disclosed Dr. John Heymach: Stock and Other Ownership Interests: Cardinal Spine, Bio-Tree Consulting or Advisory Role: AstraZeneca, Bristol-Myers Squibb, Spectrum Pharmaceuticals, Guardant Health, Hengrui Pharmaceutical, GlaxoSmithKline, EMD Serono, Takeda, Sanofi/Aventis, Genentech/Roche, Boehringer-Ingelheim, Mirati Therapeutics, Janssen Global Services, Nexus Health Systems, Pneuma Respiratory, Eli Lilly Speakers' Bureau: IDEOlogy Health, MJH Life Sciences Research Funding (inst.): AstraZeneca Research funding: Spectrum Pharmaceuticals, GlaxoSmithKline Patents, Royalties, Other Intellectual Property: Licensing agreement between Spectrum and MD Anderson (including myself) regarding intellectual property for treatment of EGFR and HER2 exon 20 mutations    

Dr. Cardinale Smith, of the Mt. Sinai Health System, and Dr. Stephanie Wheeler, of the UNC Lineberger Comprehensive Cancer Center, discuss key research featured at the 2022 ASCO Quality Care Symposium, including practical solutions to advance equity, new trends in cancer care delivery, and novel approaches in palliative and supportive care.   TRANSCRIPT Dr. Cardinale Smith: Welcome to the ASCO Daily News podcast. I'm Dr. Cardinale Smith, a professor in the division of Hematology and Medical Oncology and Department of Geriatrics and Palliative Medicine at the Icahn School of Medicine at Mount Sinai in New York, and the chair-elect of the 2022 ASCO Quality Care Symposium. I'm your guest host today and delighted to welcome the chair of the Symposium, Dr. Stephanie Wheeler. Dr. Wheeler is a professor in the Department of Health Policy and Management and associate director of Community Outreach and Engagement at the University of North Carolina Leinberger Comprehensive Cancer Center. We'll be discussing practical solutions and key research to advance equity and quality in cancer care, new trends in cancer care in the home and local community, novel approaches in palliative and supportive care, and other key takeaways from the meeting. Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the ASCO Daily News podcast are available on our transcripts at: asco.org/podcasts. Dr. Wheeler, it's great to be speaking with you today. Dr. Stephanie Wheeler: Thank you, Dr. Smith. I'm excited to be here. Dr. Cardinale Smith: Well, I'm super excited that I just got to see you, and it was fantastic that we had a hybrid event that really allowed our participants to meet in person and allowed folks who couldn't be in person to participate virtually. Cancer health equity was a major theme this year with sessions that explored how to incorporate equity into our work. Can you highlight a few takeaways for us? Dr. Stephanie Wheeler: Absolutely. And yes, it was such a delight to see you in person. And I'll just note that at this 10th anniversary of the Quality Care Symposium, we had record attendance - over 700 participants. So, I was really excited to have that level of engagement in this meeting. So, you know that as a planning committee, we really prioritized centering equity in our content this year, and I think it was reflected in every session at the meeting. Our very first educational session featured Drs. Chanita Hughes Halbert, Meera Vimala Ragavan, Victoria Blinder, and Sam Cykert, as well as community advocate, Terrence Muhammad, from the Greensboro Health Disparities Collaborative. Together, they provided important foundational and conceptual context to really set the stage for the rest of the meeting. Most importantly, they discussed specific evidence-based interventions designed to improve racial, socioeconomic, and rural health equity. These included the Accure Realtime Health Alerts Intervention with Navigation and Bias Training and Financial Hardship screening. Later in the meeting, we heard from Dr. Joannie Ivory presenting Abstract 68, who shared that we really need to take our trials where minoritized and historically disadvantaged populations live. In that study, geographic areas with greater numbers of black residents did a better job recruiting black participants to clinical trials, and the trial itself built in structural factors designed to ensure that at least 30% black participants were accrued. I also want to shine a light on the wonderful abstracts that were presented by Drs. Qasim Hussaini and Qinjin Fan, Abstract 69 and 3, which focused on association between historical housing discrimination and modern-day mortgage discrimination in colon and lung cancer treatments and outcomes respectively. I think this work just further underscores that racism is structural and societal and that we need to be paying attention to not only how we deliver oncology care, but policy in the banking world, the housing world, education, transportation infrastructure, and so much more, if we're serious about undoing disparities in cancer. Dr. Cardinale Smith: Yeah, and I'm probably biased since I had a role in planning this meeting. I definitely appreciate the focus on not just calling out these issues, but really thinking about how we start implementing interventions to really overcome them. Thank you for that really wonderful summary. The symposium also featured many trends in quality care, such as patient-reported outcomes measurement to monitor quality and patients' experiences. What are the sessions and abstracts that you think will give our listeners new ideas about how to integrate patient-reported outcomes into real-world settings? Dr. Stephanie Wheeler: Well, as you know, this continues to be an ongoing theme of the ASCO Quality Symposium. And I was really particularly encouraged this year that the focus was on implementation of PRO monitoring in real-world settings. So, just to highlight a few of the sessions that stood out to me were, dual abstracts 243 and 242 that were presented by Drs. Sandra Wong and Jessica Bian, showing symptom-reporting implementation in the medical oncology space, as well as the surgical oncology space, participating in the eSyM study at multiple cancer centers. In addition, we had an educational session that followed in which Drs. William Dale, Manali Patel and Sarah Hawley, presented work describing their efforts to implement geriatric assessment, multimodal symptom-control monitoring interventions in racially diverse populations, and a prostate cancer symptom-focused self-management intervention respectively. Then towards the end of the meeting, we also heard from Mike Hassett, presenting Abstract 241, who talked about differences in web versus mobile devices for ePRO reporting, and how those can really elicit different types of symptoms that are reported by different types of patients. We know that the digital divide is real in America, and so as we think about how to get patients to report their symptoms in meaningful, actionable ways in real-time, we have to be mindful of the modalities in which we're eliciting those symptoms. So, it's clear to me that the discussion has really moved beyond why we need to monitor patient-reported outcomes. I think Ethan Basch’s work and others has really demonstrated that clearly to how best we can optimize it for patients' benefits while working within the constraints of existing EHRs and workflows, and of course, the constraints of our Wi-Fi connectivity in rural communities. Let me ask you a question. How about that? So, the palliative care abstract track was a new feature this year, and I was really excited about it. And I'd really love to know from your perspective as a specialist in Geriatrics and Palliative Medicine, how do new approaches that are going to be important in oncology best meet the needs of our patients? And how did this year's session content advance that field directly? Dr. Cardinale Smith: In addition to the implementation of patient-reported outcomes, which you spoke about, which I think is really incredibly critical, especially because we know that the data suggests that that's also associated with not only improvement of quality of life, but also survival. I was really excited to help moderate a session along with Dr. Shanthi Sivendran on the panel focused around advanced care planning, and really thinking about, "Is it time for a change?" And so, on that panel with us, were experts leading advanced care planning, Drs. Alcorn, Hickman, Montgomery, Paladino, and Rhodes. And really the topic of the conversation centered on changing the frame of thinking away from focusing just on documentation, but more about the conversation itself, and the focus on goal-concordant care, and how do we align goals and values with the cares received, and how do we talk about that? We also talked about how we align that with measurement. So, as we move towards value-based care in Oncology, how do we have better outcome measurements to capture impact? Like recently approved measures in the palliative care space of being seen and heard that was discussed. And shifting gears a little bit, we heard in an oral abstract presentation number 300 by Dr. Riaz, talking about outcomes of hospitalized patients with solid cancers receiving immunotherapy. We know that that is a group who are often receiving treatment closer to the end of their life in the hospital setting, and we don't have lots of data about how successful those treatments are. And what that data demonstrated among 159 patients over four academic medical centers, is that about approximately 30% of them who received inpatient immunotherapy actually died in the hospital. And so, I think that has really important implications as we think about the quality of life for these patients, as we also think about those quality metrics that we have to be adherent to. Continuing to think about how that impacts financial stressors for patients. You know, financial toxicity is a recurring theme at many of our ASCO meetings, and at this Quality meeting, we had a session that featured a multi-layered approach to financial toxicity solutions. Can you tell us about some of the key features of this approach? Dr. Stephanie Wheeler: Of course. Yeah. This was a wonderful session. I just have to note that the session on advanced care planning, one of the things that I really loved about that, before I talk about financial toxicity, was that the roundtable focus of that session, that particular modality, I think, just lent itself so well to the type of discussion that we were having, and it just felt very interactive. We had lots of great input from the audience, and I've continued to hear, since the meeting, that people really appreciated that. And I have to attribute your leadership there to thinking carefully about how to do that session. So, we should think about that more in the future as well. Turning to financial toxicity, this, like equity, I think, was a recurring theme of this meeting. And in particular, I think the poster sessions also covered a lot of content in the financial hardship space. So, you mentioned the educational session focused on multi-layered approaches to solutions here. And this session featured new work from folks like Dr. Maria Pisu, Samilia Obeng-Gyasi, and Emeline Aviki, and they were all talking about interventions in their cancer centers that were focused on timely identification of financial hardship, and different ways in which it can be screened for and that it can be actionably responded to. And then, Dr. Aviki described approaches that their center has used to really develop a multidisciplinary financial working group to address concerns. And I thought that was really creative and showed that all of the right stakeholders were at the table at Memorial Sloan Kettering. And then that session finished with remarks by Joanna Morales about the legal parameters of financial hardship, which I think are increasingly being understood as a really important determinant of poor outcomes. And we all know the legal system is incredibly difficult to navigate for people who don't have a legal background, and I love that she described some of the actionable ways in which people can do things like: better understand their employment protections, better advocate for themselves to be sure that their workplace accommodations are being responded to, and also thinking about their ability to advocate more for themselves when it comes to things like social security, disability insurance applications, and the legal parameters there. She also talked about policy options, and so I think this is a must-listen-to session for anybody who's interested in thinking about screening for and developing institution-wide efforts to address financial hardship through identification, and through legal approaches and levers that can mitigate and hopefully prevent it. By next year, I think it's important that we know that there are at least five NCI-funded clinical trials underway that are testing additional navigation and insurance literacy interventions in multi-sites across the country. And so, I think it'll be really important to see what happens with those studies as they move forward. And there is an NCI-supported financial hardship session and workshop that is happening later this week that Dr. Janet De Moor invited all ASCO Quality attendees to come to. So, more on this, I think in the future, but I don't see this as a topic that will be left off the agenda for the ASCO Quality Symposium for many years to come. Dr. Cardinale Smith: Yeah, and hopefully we'll be able to have some of that data presented at the next meeting next year. And just following up on that theme of financial burdens for our patients, I really would like to encourage anyone who didn't get a chance to hear this year's keynote lecture from Dr. Ezekiel Emanuel of The University of Pennsylvania, to really take some time and go take a listen to it. Dr. Emanuel focused on payment structure and models and had several key takeaways that I thought were really important. His main conclusions were that we need to think through new policies related to drug pricing and accelerated approval, as these have really important implications for the cost of cancer care. He also talked about how oncologists and those of us in the cancer care space and cancer care delivery space, have an increasing role to sort of nudge the NIH to think about their role in the research and development process for drugs, and to boost clinical trial enrollment. Specifically thinking about the enrollment of minoritized populations. And then lastly, and probably most provocative, which is one of the reasons why we really wanted him to come and to speak at this meeting, is that we know financial toxicity is significant and needs to be addressed. And he proposed that once a person is diagnosed with cancer, insurance companies, Medicare, should eliminate any deductibles, co-payments, or co-insurance, and other types of cost-sharing for our cancer patients, which I think is an interesting viewpoint. Dr. Stephanie Wheeler: Yeah, I couldn't agree more. And as a health policy scholar, I was sort of jumping in my seat with excitement over some of the bold and innovative solutions that he put forward. I think another compelling speaker, and I know you'll agree with me, is Dr. Otis Brawley. He's the Bloomberg Distinguished Professor of Oncology and Epidemiology at Johns Hopkins University, and he was honored with the Joseph Simone Quality Care Award, which of course, is focused on, really, lifetime achievements in the areas of quality care delivery in cancer. He's been such a champion of cancer care equity, and really has devoted his whole career to advancing cancer prevention, screening, and treatment strategies, to end the racial, socioeconomic, and rural disparities that we see in prevention, detection, and treatment of cancer. One of the things that he really emphasized that I appreciated is that we have to be more thoughtful about the ways in which we think about cancer health disparities, recognizing that more treatment is not always good treatment, and the more money that we spend on futile treatments and unnecessary treatments, and unnecessary care, that actually wastes resources that we could have otherwise distributed more fairly to our marginalized and minoritized populations. And so, he made a very direct argument between overspending, overdiagnosis, and overtreatment in cancer, and how that actually contributes to disparities in care, and disparities in outcomes. And I think that that really motivates us to not only look at the national movements in health policy reforms as important to do from an efficiency perspective and from a cost-control perspective because we know that healthcare costs in America are wildly out of sync with the rest of the world and unsustainable, but also because they're a key contributor to differences and outcomes that we see, and that we have a moral imperative to address. So, I was just really inspired by his talk. He covered so much territory in a small amount of time, and I think his talk in particular, combined with Dr. Emanuel's talk, really set the stage for us to think about the integration of policy, and equity, and care delivery together as we move forward in this field. Dr. Cardinale Smith: Yeah, I am definitely a fan, and I think to highlight both of them, there are tangible things that we can all walk away in our everyday lives and start putting into practice, which I think is key for us to move the needle on any of these things. Dr. Stephanie Wheeler: Yes. And I might say just in response to that, that towards the end of the session, we had that great oral abstract session that Melissa Simon and Blase Polite were the discussants for, and they really continued this theme of not just really unpacking these deeply-rooted social and historical root determinants of differences in outcomes, differences in quality, and problematic equity issues in cancer care delivery. But I think that they also gave us a number of things, as you said, that each of us can do in a more meaningful way on a daily basis. You know, being more aware, promoting others, sponsoring others from different backgrounds, really standing aside and allowing others to shine, and that has been a theme of this meeting. It's something that we wrote about last year, that this meeting is a place where junior scholars and trainees can come and connect and can really find not only a place here but can find a stage here. And so, I think some of the comments that they encouraged us to think about were specifically related to professional development and lifting up others, and paying it forward, and it resonated with me, in addition to the many other things they suggested around just how our healthcare systems are designed, and how we need to break down barriers. Dr. Cardinale Smith: Well said. I could not have said it any better. Thank you, Dr. Wheeler, for coming on the podcast to give us these highlights from the 2022 ASCO Quality Care Symposium. Our listeners can find the links to the abstracts we've discussed on the transcript of this episode. Dr. Stephanie Wheeler: Thank you, Dr. Smith. It's my pleasure to be here with you today and to have co-hosted this planning committee and this meeting with you, and I am so thrilled for your leadership next year as you take the gavel, take the stage, and lead us forward. Dr. Cardinale Smith: I can't wait to get started. And to you, our listeners, thank you for your time today. If you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement. Follow today’s speakers: Dr. Cardinale Smith @cardismith  Dr. Stephanie Wheeler @StephWheelerUNC Want more related content? Listen to our podcasts on interventions to address financial toxicity. A Novel Approach to Address Financial Toxicity Dr. Derek Raghavan Has a Remedy to Mitigate Financial Toxicity in Cancer Treatment Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Stephanie Wheeler: Research Funding (institution): Pfizer Foundation Travel, Accommodations, Expenses: Pfizer Dr. Cardinale Smith: None to disclose

Host Dr. John Sweetenham, of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, and Dr. Eduardo Sotomayor, director of the cancer institute at Tampa General Hospital, discuss the impact of Hurricane Ian on cancer care in Florida, and the importance of disaster preparedness to protect patients and clinicians in regions prone to natural disasters.   TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the associate director for Clinical Affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News podcast. Hurricane Ian, a large and destructive Category 4 hurricane, has caused fatalities and widespread damage in Florida after causing huge destruction in Cuba. Communities in the hardest-hit areas have been destroyed, and hospitals across the state have been forced to evacuate patients. Today, I will be speaking with Dr. Eduardo Sotomayor, the director of the Cancer Institute at Tampa General Hospital, about the impact of the hurricane on cancer care. Our full disclosures are available on the transcript of this episode, and disclosures relating to all episodes of the ASCO Daily News podcast are available on our transcripts at asco.org/podcasts. Dr. Sotomayor, thanks for being on the podcast today. Dr. Eduardo Sotomayor: Thank you, John, and the ASCO Daily News Podcast, for having me. Dr. John Sweetenham: To begin with, Dr. Sotomayor, could you tell us a little about how Hurricane Ian impacted cancer care at your institution, and how soon do you think you'll have all of your cancer services restored? Dr. Eduardo Sotomayor: Thank you for the opportunity to talk to you about the effect of Hurricane Ian on the state of Florida. But before we start, I would like to say that our thoughts and our prayers are for those Florida citizens who were severely affected by this hurricane, in particular, our cancer patients and their caregivers. So, Tampa General Hospital is located on Davis Islands. So, we were at high risk for having inundation, major destruction, and disruptions in cancer care if the hurricane hit us directly. We were blessed that at the last minute, the hurricane changed its path. But it's important to emphasize all of the preparation that took place, starting seven days before the potential landfall of the hurricane in the state of Florida. This started at the highest levels of the hospital, with the senior leaders getting together as well as the leaders of the cancer institute. We have different scenarios that we call scenario A, B, and C. So, scenario A was the worst-case scenario that we would have a direct hit, then one or two floors of the cancer institute and the hospital would be under water. So, for that scenario, we knew that we needed to be ready to move cancer care to other facilities that Tampa General has inland in areas called Riverview and Brandon. So, scenario C is the scenario that fortunately for us, was the scenario that we dealt with during the storm. We didn't have a direct hit; we had only minimal damage, and we were able to reopen our doors 48 hours after the storm hit Florida. Important to mention also is that during those 48 hours, there was significant disruption in cancer care. In the inpatient service, we had to decrease the number of inpatients to keep those patients that really needed to be in the hospital. We closed all our outpatient facilities and therefore needed to call every patient to let them know about the cancellation of appointments, but also re-scheduling those appointments for the days after the storm has passed. As I said, again, we were among the lucky cancer centers in the state of Florida, but south of us, there were hospitals and community oncology practices that were severely affected by Hurricane Ian. Dr. John Sweetenham: So, it sounds to some extent, Dr. Sotomayor, as if your institution kind of dodged a bullet, although clearly people south of you were very badly affected. But I'm assuming that there had been some disruptions to care for your patients. Can you comment a little on that, and what you're doing to address the disruptions to care, assuming that you experienced some, even though you didn't take a direct hit. Dr. Eduardo Sotomayor: What we have learned from this experience is that preparation is extremely important. Within 24 hours, we created a command center, an operations team, our logistics team, safety team, and we started canceling those appointments that were not critical. When we knew that the hurricane was coming in our direction, then we had to cancel all of our operations. But then we had meetings twice a day with different members of our team to start making phone calls also regarding cancellation of appointments. And then, as the days passed, we started to adapt our plans and starting calling back patients. What is important, I think a silver lining of the COVID-19 pandemic, has been the availability of telehealth, of easy communication with patients. I think that patients are now savvier with managing telehealth. So, the days after the hurricane hit us, we had some patients that had to come back to receive chemotherapy infusions or radiation, but the large priority of patients were able to manage via telehealth. Dr. John Sweetenham: Yes. Thank you. I know one of the questions that I was going to ask you a little later on was whether the telehealth infrastructure that was developed during the COVID-19 pandemic was helpful in response to the hurricane, and clearly from your comments, it has made it easier in terms of patients' familiarity with the platform and so on. So, that's good to know. Dr. Eduardo Sotomayor: Right. And also, just to add to that is that technology before the COVID-19 pandemic, when we were facing a similar situation. Basically, all our call centers would be closed. So, these days we have technology in which employees or members of our team that were receiving or making phone calls, now can do through through special apps in case the internet goes down or electricity goes down. Still, now there are systems that can allow temporary communication with patients in a timelier way. Dr. John Sweetenham: Yeah, that's very reassuring. The Florida Hospital Association has said that many hospitals are feeling capacity pressure. Can you comment on what the Tampa General Hospital is able to help by perhaps offloading other institutions that were badly damaged in the storm, particularly those in the Southwest of Florida? Dr. Eduardo Sotomayor: Yeah, that's a very important question. I think that when we knew that we would be okay and there would not be a significant impact of the hurricane on our facilities, we changed our course and started calling our partners in the oncology community, private practice groups, Florida Cancer Specialists that have offices and provide cancer care in those areas that were severely affected by the hurricane. We are working together. One of the things that I have learned is that a significant percentage of cancer care is performed in the community. Communities were affected by this hurricane and therefore I think it is important to keep that open communication between academic centers and oncology practice in the community. With reference to your question, Tampa General has six helicopters; it has a command center and as soon as it was safe for our helicopters to travel, they went to these affected areas. There were hospitals near our region that didn't have electricity or water. I am proud of the service provided by Tampa General Hospital to other hospitals and cancer care communities that were severely affected by the hurricane. I think so far, we were able to transfer between 50 to 70 patients who were in critical condition and needed to be removed from those areas that were significantly affected by the hurricane. And I have to say, Tampa General Hospital is just one of the hospitals that responded; all of the hospitals in the state of Florida joined a forces to help our patients in general during these difficult times. Dr. John Sweetenham: Yeah, it's certainly great to hear of the oncology community and healthcare community in general coming together to overcome the challenges for so many of these patients. You know, one of the challenges that occurs to me, which might be an issue for you because of your increased patient volumes, as well as for those centers that are more directly affected by the hurricane, and that's the issue of supply chain and availability of medicines, and particularly chemotherapy and other antineoplastic drugs. Can you comment on whether you are experiencing any supply chain issues with medicines, or whether you're aware of other organizations in the southern part of Florida who are having those challenges at the moment? Dr. Eduardo Sotomayor: So, there are two answers to your question; if we are lucky to be in urban communities, I think that the supply chain was not significantly affected, but the problem has been in the rural communities in Florida. And unfortunately, in addition to the areas near the ocean, including Fort Myers, Naples, and Port Charlotte, the track of the hurricane through Florida affected the rural communities. And in those rural communities the problem was flooding, several trees went down, access in those areas was problematic, and they are still dealing with significant issues in the supply chain. What we are doing as are all the other big centers, is  trying to do our best to either provide those supplies to these affected areas or to transfer some of the patients from those areas to, I would say, urban hospitals that have more capacity. Dr. John Sweetenham: So, this raises, I think, a really important issue. We know that very typically underserved communities are disproportionately impacted when there are natural disasters. And to your point, it's clear that you've seen the potential for significant disruption to rural versus urban communities as a result of the hurricane. Do you have any other thoughts or maybe any other examples of how disproportionate care may have arisen because of the effects on underserved communities? Dr. Eduardo Sotomayor: Even before any natural disasters, rural communities-- and I want to focus on rural communities in the state of Florida because there is a significant number of Floridians that live in rural communities. And if you look at the incidence of cancer and mortality associated with cancer in those rural communities, it is greater than the mortality that occurs in urban areas or big cities. So, number one. And there are several issues; there is transportation, access to care, very few oncology providers in those areas. So, even before the natural disaster that just happened, those communities were significantly disadvantaged. And unfortunately, not only the hurricane affected those rural areas, but now I would say the few organizational capabilities that they have have been further impacted. So therefore, when we think about the impact of the hurricane in the state of Florida, we should also be thinking about our rural communities. They are the ones that are going to take longer, perhaps months, or even a year, to recover from the significant damage that Hurricane Ian has imposed upon those communities. Dr. John Sweetenham: Thanks. Switching gears a little, are you concerned about the disruption of research and clinical trials in parts of Florida in the months ahead? I'm just thinking with issues such as-- you know, initially it will be scheduling of treatments, perhaps the transportation disruption, and so on. Do you see these as being potential threats to clinical trial activity in the state for the coming months, and possibly years? Dr. Eduardo Sotomayor: So again, I think that clinical trials in big centers, in urban areas are going to be able to recover relatively quickly. I mean, for instance, our clinical trials operation is back to normal, and was not affected. So, there is a big community oncology practice in the state of Florida, Florida Cancer Specialists, especially if they have active clinical trials, but they have locations in several of the areas that were significantly affected by the hurricane. So, I think in those areas, it is going to take time to recover. But in my early conversations with our colleagues, Florida Cancer Specialists especially, they're going to be moving some clinical trials operations from those affected areas to areas that are fully functional. But definitely, there is going to be a disruption, yes. And unfortunately, that disruption is going to affect those patients enrolled in clinical trials that live in underserved areas, and in particular, those who live in rural areas because access to transportation is going to be a significant problem for them. Dr. John Sweetenham: Yeah, absolutely. I think is one of the consequences of what the emerging climate changes that we've been seeing over many years now, and certainly, there has been a significant interest in the literature, and indeed, on previous ASCO Daily News podcasts regarding the impact of climate change on cancer care. And perhaps, the most immediate example of that is in terms of disaster preparedness of cancer centers. Certainly, that has been tested for you and for other centers in Florida in the last couple of weeks. How would you assess the readiness of your cancer centers to respond to disasters of this scale? Do you think there are areas of care that you've now learned need more attention, just as a direct consequence of this most recent hurricane? Dr. Eduardo Sotomayor: So, I think it's going to be location-dependent. You know, Florida is a big state. For us and other centers that are in the islands, the surge was probably the major threat for us. I mean, there is a technology now called AquaFence. So basically, there are panels that will help you, to be able to give you time to evacuate or to protect the lower floors of the cancer center of the TGH hospital as a whole. It's called AquaFence. So, we install those panels around the whole hospital, and I think that's one of the technologies. And we are going to see more and more of those technologies to try to protect or minimize the potential damage that a hurricane can cause. I mean, my prediction is that it’s going to be able to support a hurricane category two, three, or even four, but you know, five - time will tell. So, we need to start thinking more about technology, that's in our case. So, there are other cancer centers that are inland in which the problem for them is going to be flooding. So, one lesson that we have learned is, there has been constant communication between all the cancer centers in this region. In the academic institutions, the University of Miami, Florida, us, Moffitt Cancer Center, but also in the community - Florida Cancer Specialists, especially, community oncology practices. And I think that if you ask me, "What would be the next step?" It will be to foster stronger communication, a stronger collaboration that involves also our community oncology practices because as you know, John, most of the cancer care now is happening close to home. Dr. John Sweetenham: Well, thanks for that. I think that's such an important message, and I should add for our listeners that you can find information about disaster resources for care providers and patients on the ASCO website, at: asco.org. Dr. Sotomayor, I just want to thank you again for giving us your time today at what must be a really busy time for you all and would like to wish you and our many colleagues in the region, especially those in the hardest hit areas of southwest Florida, all the best during difficult and uncertain times as they try to recover from the hurricane. Dr. Eduardo Sotomayor: There are so many heroes here - talking about cancer care, you know, oncologists, nurses, APPs, MAs - they left their families at home and they went and they stayed with patients. So, I am proud to say that most of them, they offered to go there. We didn't need to say you, and you, and you. And I want to thank all of those, you know, our colleagues, providers, all the team members in all the hospitals, big, medium size, also small, in the state of Florida, that they left their loved ones to be support and take care of our patients. Dr. John Sweetenham: Certainly heartwarming to hear about that kind of response. And thanks again to you, Dr. Sotomayor. And thank you to our listeners for your time today. If you value the insights that you hear on ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement. Follow today’s speakers: Dr. John Sweetenham @JSweetenhamMD Dr. Eduardo Sotomayor Tampa General Cancer Institute   Want more related content? Listen to our podcast on climate change and cancer: Climate Change and Cancer   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Eduardo Sotomayor: Consulting or Advisory Role: Seattle Genetics, Genentech/Roche, Celgene, Kite Pharma, Bayer, AstraZeneca, Pharmacyclics Speakers' Bureau: Seattle Genetics, Pharmacyclics

Gastrointestinal cancer experts Dr. Aparna Parikh and Dr. Kristin Ciombor discuss the treatment implications of the phase 3 PARADIGM trial and other advances in colorectal cancer with guest host and ASCO Daily News Associate Editor, Dr. Shaalan Beg.   TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the ASCO Daily News Podcast today. I'm an adjunct associate professor at UT Southwestern's Simmons Comprehensive Center and vice president of Oncology at Science 37. I'm delighted to welcome Dr. Aparna Parikh, and Dr. Kristen Ciombor to the podcast today. Dr. Parikh is an assistant professor of Medicine at Harvard University and a GI medical oncologist at the Mass General Hospital Cancer Center. Dr. Ciombor is an associate professor of Medicine and GI medical oncologist at the Vanderbilt University Medical Center. Today, we'll be discussing exciting new approaches using EGFR inhibitors as frontline therapy in colorectal cancer, and promising advances with immune therapy in the treatment of rectal cancer. Our full disclosures are available in the show notes, and disclosures of all guests on the podcast can be found in our transcripts at: asco.org/podcasts. Dr. Parikh, and Dr. Ciombor, it's great to have you on the podcast today. Dr. Aparna Parikh: Thanks so much. Dr. Kristen Ciombor: Thanks so much for having us. Dr. Shaalan Beg: We've seen some exciting advances in GI oncology this year. Let's start with colorectal cancer. Dr. Parikh, there have been many trials looking to compare EGFR and VEGF inhibitors in colorectal cancer. We've heard about the IDEA studies, the FIRE trials, and CALGB 80405. At the 2022 ASCO Annual Meeting, we heard the results of the PARADIGM trial. Have we finally answered the question of when to use EGFR inhibitors as frontline therapy for colorectal cancer? Dr. Aparna Parikh: Thanks so much, Dr. Beg, for this great question. It has been a really exciting year for colorectal cancer across the board. So, the anti-EGFR story is really interesting and has evolved. And maybe just for a little bit of background, we know that colorectal cancer originating from both the right and left side of the colon differ. So, they differ embryologically, and epidemiologically; there are different genetic and molecular aspects to right and left sides of colon cancers. And we have learned over time that in the era of targeted therapy, the primary tumor location has been found to play a very important role, not only in the prognosis of patients but to predict treatment response. We know that patients that have left-sided colon cancers-- and when we think about left-sided colon cancers, we think about cancers that originate from the splenic flexure and descending colon, sigmoid colon, rectosigmoid junction, and sometimes include the rectum in this as well. The rectals have slightly different molecular features than distal colons. And we know that these left-sided patients, overall, have better survival benefits than patients that have right-sided CRC. And that includes again, cecum, ascending colon, hepatic flexure, and transverse colon. So, we know that that had prognostic implications, but what about the predictive implications? And with ASCO, we saw some really exciting data with the PARADIGM study, as Dr. Beg highlighted. We have seen many examples in the past showing the predictive power of anti-EGFR therapy, and anti-EGFR therapy showing a detriment for patients on the right side of the colon. But all these results historically have been obtained by retrospective analysis. So, retrospective analysis of the pivotal CALGB 80405 study, which is the first-line biologic trial. FIRE-3, which is a similar study, but done out of Europe, and KRYSTAL. So all these studies show the same finding but were all obtained basically by retrospective analysis. And what we saw with PARADIGM this year, which is exciting to see, is that this was the first prospective trial to test the superiority of an anti-EGFR inhibitor panitumumab versus bevacizumab in combination with standard doublet first-line chemotherapy for patients that were RAS-wild type. I guess I forgot to mention that again, anti-EGFR therapies are only eligible for patients that are RAS-wild type. We know that RAS-mutant patients and RAS, KRAS HRAS patients don't respond to anti-EGFR therapy. So, the study was looking at RAS-wild type patients, and again, asking the question “was panitumumab better than bevacizumab in combination with chemotherapy for these RAS-wild type patients and for left-sided tumors?” It was a multicenter trial done in Japan-- and I always commend the Japanese on their work and their designs and ability to do these studies that ask really important questions. And, overall survival was the primary endpoint of the study in patients with left-sided tumors, but they also did a full set analysis including patients that didn't have left-sided tumors. They had 823 randomized patients. Many patients, a handful did not receive per-protocol treatment, and some were excluded for other reasons relating to inclusion criteria. And they had 400 patients that ultimately received panitumumab and 402 patients that received bevacizumab in the full set analysis. And of those patients, there were 312 and 292 respectively had left-sided tumors. And although the PFS was comparable between the treatment group, we saw that panitumumab in the left-sided patients actually did improve the OS in both patient populations. But when you looked at the left-sided tumors, the difference was 37.9 versus 34.3 months meeting statistical significance. So, this was an exciting study because it confirmed prospectively what we have seen time and time again, and really behooves us to do early biomarker testing and know RAS status early for these patients with right-sided tumors, as they do derive benefit from anti-EGFR. Maybe I'll just pause there and open it up for more questions or comments from Dr. Ciombor as well. Dr. Kristen Ciombor: Yeah, Dr. Parikh, I thought these data were encouraging. And as you mentioned, the first prospective data that we have in this setting now that we know this primary tumor sidedness matters. Just on a practical note, what do you do in practice? Do you give a lot of anti-EGFR in the first-line? I find that the toxicity can be challenging sometimes and patients may not want to do that. So, it leaves us in a quandary sometimes. Dr. Aparna Parikh: Yeah. So, what's interesting and I don't think we have this data clearly answered yet is, I had, especially for kind of a fit patient-- with the previous data that we've seen with TRIBE and others showing a survival benefit with triplet chemotherapy for first-line therapy, my inclination had actually been to prefer triplet-- and we know that triplet and anti-EGFR toxicity-wise is really, really tough to manage, and really no benefit there that we've seen with OS or PFS, even though you maybe do get a little bit of a better response rate with that. And so where I have sort of struggled is triplet versus just doing first-line doublet plus anti-EGFR. You know, we are not having a discussion about triplet today, but we also saw some data at ASCO showing that perhaps the benefit of the triplet, with the triplet study, is not as much as we had hoped it would've been too. So, it's a good question. I do tend to prefer triplet, I guess, overall, for the healthy, good performance status patient. And then, if not, then doublet. And we, unfortunately, don't have kind of rapid EGFR testing, we're pushing for that. In practice, I think having RAS/RAF status up front would be entirely helpful. It's lumped into our pan-tumor profiling, comprehensive genomic panels. We get microsatellite instability (MSI) status, which I know we'll talk about here next right away. But I think another reason that oftentimes we don't add it right away, is because we don't have the RAS status right away. So, you just start with a doublet and you may end up sneaking it on later. And then, I'd love to, maybe in another podcast, where we can discuss second-line anti-EGFR therapies and what people do in practice for those right-sided patients should they never get anti-EGFR and later-lines of therapy too. And I would argue, perhaps not, because we do see some patients that do benefit, but it can be challenging sometimes with a fresh new patient to make these decisions. But at least, feel encouraged that we're doing the right thing by adding anti-EGFR therapy if they can tolerate it for the left-sided RAS-wild type patient. How about you? What do you do? Dr. Kristen Ciombor: Yeah. Largely, it's a great question. And I don't love giving anti-EGFR therapy. We have an additional issue where I am geographically in that we don't ever give cetuximab because of the high rates of an infusion reaction. So, we pretty much stick to panitumumab and are glad to have that option. But I have started to talk to patients about toxicity and I'm really upfront with the survival data. And it's interesting how people choose differently in terms of what's important to them. And whereas a few extra months in the overall survival may be overshadowed by the toxicity that they have to go through to accomplish that. So, it's good to have many options though, and that's the important thing, and I think the takeaway, as well. Dr. Shaalan Beg: So, kind of brings it back to the fundamentals of practicing medicine, right? Bringing our patients and giving them the options that are most available to them. But I'm going to ask both of you one by one: So, if we have our patient with left-sided colorectal cancer, known as KRAS RAS-wild type, do you recommend EGFR therapy and VEGF therapy and allow the patients to decide, or do you feel that we decide if their profile is such that we should continue with VEGF therapy instead? Dr. Ciombor, do you want to go first? Dr. Kristen Ciombor: Yeah, I think both are good options. I don't only do bevacizumab in the first-line by any means because we do have that survival data. It mostly comes down to a discussion with the patient in terms of toxicities and survival and how well those balance out. Dr. Aparna Parikh: Yeah, very similar. I think we have also gotten a little bit more adept at managing toxicity. I'm pretty aggressive about prophylaxis with even doxy and topicals for managing the rash. And so, for some of my younger patients who are wanting to be "aggressive" and want the exposure to anti-EGFR early but are still very mindful of how it's impacting their day-to-day semblance of self, especially for the younger patients, try to be very proactive about side effect management. And then, of course, we have the patients that have the electrolyte wasting and things too that sometimes if it's bad, we are stuck with infusions frequently and you may end up dropping for those patients. But I think the rash at least I feel like for most patients we can manage if you're aggressive about it too. And I think we have gotten better at that than we were many years ago. Dr. Kristen Ciombor: Never thought we'd be dermatologists, did we? In training, that was definitely not a path I was good at. Dr. Shaalan Beg: Dermato-Oncology, rapidly growing field. So, Dr. Ciombor, the rectal cancer space has evolved very rapidly in recent years, especially when we hear about total neoadjuvant therapy, short-course radiation, watch-and-wait, for those with complete clinical responses. So at ASCO this year, we heard results on immune therapy and rectal cancer. Can you summarize where we are with immune therapy and rectal cancer? Dr. Kristen Ciombor: So, yes. We heard a lot this year at ASCO; both at ASCO GI and ASCO, from the Memorial group and Dr. Cercek’s group. And this has been a really exciting advance that we're starting to see and potentially paradigm-shifting data. So, we know-- as you mentioned, that our treatment of rectal cancer, specifically, locally advanced rectal cancer has changed a lot in the last few years with a shift to more Total Neoadjuvant Therapy. And what the Memorial data showed was that for the patients who have microsatellite instability or mismatch repair deficiency, which admittedly, is a small group, but certainly ones that we see in clinic, those patients, on their trial were treated with six months of dostarlimab as neoadjuvant therapy prior to any other treatment; before radiation, surgery, et cetera, and no chemotherapy. And what they found was that actually, six months of dostarlimab in the first 14 evaluable patients actually induced a 100% clinical complete response rate. So, it's really unheard of in most of our trials to see 100%. And I think that caught everyone's attention for sure. I think we have to keep in mind who these patients were and are because they are currently being followed. So, for instance, these were patients that had pretty bulky node-positive disease, almost all these patients did. These were not really early-stage tumors. We did see that 100% were BRAF-wild type, so it does tell us maybe this is not completely the population that we're all seeing when we do see microsatellite instability since we see a lot of sporadic tumors with BRAF mutations. But on the whole, I mean, these were all MSI-high patients and treated with dostarlimab; the six months, that was the total amount of treatment that they received, though a few patients achieved that clinical complete response earlier at about three months, at the three-month reassessment. And what the clinical complete response rate was, was looking both radiographically, as well as endoscopically, and not seeing any sign of residual tumor. I think the important thing here is that median follow-up is still pretty short. There are a few patients who are approaching now two years past that dostarlimab therapy and have not had tumor recurrence, but overall, the median follow-up is still quite short. So, I think we do need to continue to follow these patients. We don't have overall survival data yet either. I think we still have a lot to learn, but this is a very encouraging start and certainly, something that could be really treatment-changing for these patients, which again, as Dr. Parikh was saying, we need this molecular profiling early to make treatment decisions right off the bat, not even only for metastatic now, but even for these locally-advanced rectal cancer patients. Because if you think about it, we've all taken care of patients who have to go through chemoradiation, and chemo, and surgery, and have a lot of morbidity from those treatments so that even if you cure them, they're left with a lot of toxicity. So, if we could avoid some of that, even potentially, surgery, that would be wonderful. But I do caution that this is not the standard of care yet. This is only based on 14 patients with short follow-ups at the current time. But the trial is ongoing, and there are other trials open in this space for patients who don't live in New York or can't get to New York. And for instance, ECOG-ACRIN study 2201 is treating these same patients with nivo and ipi, as opposed to dostarlimab. And that trial is open in about 80 sites now across the US. So hopefully, geographically near all of these patients. Dr. Shaalan Beg: I think a lot of us and a lot of our listeners, that Monday after the results were announced on ASCO had our phone lines and our patient secure messaging lines blowing up. Dr. Kristen Ciombor: We should have warned our nurses and our treatment teams that they would be fielding these questions, yes. On one hand, it's wonderful that our data and the science is getting out to patients. But I think we also have to be really careful as to what is reaching them because many of them didn't realize it was for this subset of patient populations. But great that they're asking those questions and wondering-- being advocates for themselves too. Dr. Shaalan Beg: You use the term clinical complete response. Can you talk about how we determine someone has a complete clinical response and what their follow-up looks like? Dr. Kristen Ciombor: Yeah. In the context of this study, it was actually, as I mentioned, it was both radiographic complete response, as well as endoscopic. So that's one thing that is a little bit tricky when you think about surveillance of these patients. So, it requires a lot, both in frequent surveillance, MRIs, FLEX SIGs often, digital rectal exams, sometimes doing PET scans or CTs, and patients who-- not only on this kind of study but also in non-operative management; watch-and-wait - really have to commit to very close, very frequent follow-up because if the cancer recurs, we don't want to miss that and lose our chance to cure them. So I think that's a little bit different everywhere, how that watch-and-wait approach really manifests, but I think we're learning how to do that, and working in a multidisciplinary group to make sure that patients get the surveillance that they need. Dr. Aparna Parikh: Yeah. I totally agree. If we offer, for the MSI-high patients, if we ultimately end up offering neoadjuvant immunotherapy-- and actually, I'm looking forward to your study, Dr. Ciombor, too, I think the monotherapy versus doublet, too, is going to come up for these patients. But I had a patient just a week or two ago that was starting on this approach with neoadjuvant immunotherapy, but for now, as a group, if we're proceeding down that and they do get a clinical complete response, we're deciding to forego even the radiation and surgery. We're following what they did in the OPRA study, which was pretty aggressive surveillance on the backend, both with direct visualization and MRIs, and you're seeing these patients every three months or so. Dr. Shaalan Beg: Well, thank you Dr. Ciombor and Dr. Parikh for sharing some valuable insights with us on the podcast today. Dr. Aparna Parikh: Thanks so much for having us. It was a lot of fun. Dr. Kristen Ciombor: Thanks for having us on. Dr. Shaalan Beg: And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review and subscribe, wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today’s speakers: Dr. Kristen Ciombor @KristenCiombor Dr. Aparna Parikh @aparna1024   Dr. Shaalan Beg @ShaalanBeg Listen to additional episodes on advances in GI oncology: Novel Therapies in GI Oncology at ASCO22 ASCO22: Key Posters on Advances in GI Oncology Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. Kristen Ciombor: Consulting or Advisory Role: Merck, Pfizer, Lilly, Seagen, Replimune, Personalis Research Funding (Inst.): Pfizer, Boston Biomedical, MedImmune, Onyx, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Novartis, Incyte, Amgen, Sanofi Recipient, Bristol-Myers Squibb, Array BioPharma, Incyte, Daiichi Sankyo, Nucana, Abbvie, Merck, Pfizer/Calithera, Genentech, Seagen Travel, Accommodations, Expenses Company: Array Dr. Aparna Parikh: Stock and Ownership Interests: C2i genomics Consulting or Advisory Role: Eli Lilly, Natera, Checkmate Pharmaceuticals, Pfizer, Roche/Genentech, Inivata, Biofidelity, Guardant Health Research Funding(Inst.): PMV Pharma, Plexxikon, Bristol-Myers Squibb, Genentech, Guardant Health, Array, Eli Lilly, Novartis Pharmaceuticals UK Ltd., PureTech, Mirati Therapeutics, Daiichi Sankyo

Professor Piotr Rutkowski, of the Maria-Sklodowska-Curie National Research Institute, discusses how Poland is managing the influx of 5 million Ukrainian refugees since the war began and tells host Dr. John Sweetenham, of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, about the future health needs of Ukrainian refugees with cancer. TRANSCRIPT  Dr. John Sweetenham: Hello. I’m Dr. John Sweetenham, the associate director for Clinical Affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News podcast. My guest today is Professor Piotr Rutkowski, who leads the department of Soft Tissue and Bone Sarcoma and Melanoma at the Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland. Prof. Rutkowski is also the deputy director for the National Oncological Strategy and Clinical Trials, and serves as president of the Polish Oncological Society. Prof. Rutkowski spoke with us earlier this year as millions of people were fleeing the war in Ukraine, and he described the really remarkable response from both the Polish government and his institution to this crisis. He's back on the podcast today to tell us about cancer care for Ukrainian refugees 5 months into the conflict, and how health systems are coping with the influx of millions of refugees. He will also share his insights on the kind of support that will be needed long-term to care for these patients in the future. Our full disclosures are available in the show notes and disclosures relating to all guests on the podcast can be found on our transcripts at asco.org/podcasts. Professor Rutkowski, thank you for being on the podcast today. It's been about 4 months since we last spoke. How are you doing? Dr. Piotr Rutkowski: I'm very privileged that we can speak again. I'm talking probably on behalf of many Polish physicians and citizens involved with this dramatic situation of war in Ukraine and helping our patients and citizens from Ukraine. And I feel okay, but of course, the situation is still dramatic, and we don't know what will happen during the next months. What we can tell, first, is what has been changed for these last 4 months, it is the number. So as of now, almost 5 million people from Ukraine crossed the border between Ukraine and Poland. And we can estimate that about 3 million refugees stay temporary or maybe even permanently in our country. This is a completely new situation because it means that it's about 10% of our citizens now. And what didn't change but still the cancer care for Ukrainian patients is the extension of regular cancer care within our national oncology network and our national health fund with this Polish insurance system. And this is the same for patients in Poland. And so all refugees from Ukraine are entitled to receive the same care as citizens of Poland. Still, this extraordinary legislation, which was adopted by the Polish parliament, covers all the refugees of war, social security, and health insurance. And we have a better situation because all comprehensive cancer centers or major cancer centers organize the help with a hotline, not only on the level of the whole country but also on the center level in the Ukrainian language. And the majority of these centers have staff speaking the Ukrainian language. Moreover, what I can say as a president of Polish Oncological Society, recently, with the help of an educational grant, we bought electronic translators for major oncological cancer centers. So they can help in the situation, like in the emergency situation, when we have access to live talk. So they can be used in that situation. And in my opinion, it is very, very helpful. So this is the current situation. And of course, I will present further the structure of oncological patients from Ukraine in Poland now and what's been done. Dr. John Sweetenham: Thank you. It's really quite extraordinary to grasp that your patient population almost overnight increased by 10%. That's just quite extraordinary. What aspects of the cancer care would you say are working well at the moment and what are your greatest remaining challenges with this population as of now? Dr. Piotr Rutkowski: First, with this challenge for the pediatric cancer population, and about 1,000 children with cancer were evacuated from Ukraine. They were transported to the Ukrainian hub near Lviv in western Ukraine and thereafter to Polish hub. And with help of many nongovernmental organizations (NGOs) and many organizations, many hospitals from Europe but also U.S. and Canada, many institutions helped within this operation to transfer after triage the pediatric, so children with cancer, to Polish, German, and U.S. physicians. So more than 1,000 children were transferred to these different hospitals around the world—so Europe, the USA, and Canada. But of course, when we look at specific other issues with Ukraine refugees with cancer, first we have a very extraordinary situation and demography because the majority are women with children and only a very small percentage of males, mostly in older age. So when we looked at the cost of hospital admission of patients from Ukraine until May, the signs and symptoms were not in abnormal laboratory tests, or not otherwise classified. So generally, [these were] different conditions, mostly internal conditions. The second one was obstetric gynecology, so pregnancy, childbirth, etc. And the third in the rank were neoplastic diseases. I looked also carefully how it looks on the level of our institution because Maria Sklodowska-Curie National Research Institution is the largest oncological center in Poland. And we have the central part in Warsaw, but also we have 2 branches in Poland. So when we looked at the populations, all together, we had about 1,000 visits with new patients in our institutions. And number 1 was breast cancer. And second were gastrointestinal, and thereafter gynecology. And the fourth in the rank was melanoma and also soft tissue tumors or cancers probably related to the younger population. But melanoma was also relatively frequent. But number 1 was breast and reconstructive in all our branches. And of course, the distribution of patients is also different. In the whole of Poland, the largest numbers are in our region because probably because Warsaw is the largest city in Poland. So they have a lot of relatives or colleagues. So about 20% of patients from Ukraine are concentrated in our region, but more than 10% are also near Katowice or Gliwice. So it's Silesia and also near Krakow. So this central and southeastern part of Poland have the majority of Ukrainian patients now. However, of course, some of the patients were also transferred to other parts of Poland. But as I said, in some of the departments, more than 10% of patients are now from Ukraine, especially in breast cancer units and also gynecological units. When I look in the department which I'm chairing, department of soft tissue, bone sarcoma, and melanoma, we have mostly patients from Ukraine involved in the treatment of advanced melanoma, some with earlier stages, and some patients with sarcoma, especially if they were contacted by physicians from Ukraine specifically for this type of disease. But generally, the state of disease is a little bit more advanced. So, many of these patients are receiving neoadjuvant therapy in breast cancer or they are going directly to treatment of stage IV disease with modern drugs like immunotherapy or targeted therapy for melanoma. This is also the real situation. One of my points I want to mention is, if the access to the cancer care, regular cancer care probably is good for patients, but the problem with communication exists, and still I think that patients or citizens from Ukraine do not participate too much in prevention programs because the participation in mammography, cytology for cervical cancer and other screening programs are at very low levels. So, of course, it's a new situation for these people. But still, probably it will be one of the points for which we have to undertake some strategies. Because we do not know how to get information on if they will be staying longer in our country what we can anticipate for next months and even years. So this can be problematic because it means that we'll have more and more advanced stages of disease. Dr. John Sweetenham: It's very interesting, and of course not surprising, that you have this very skewed demographic of predominantly female patients. I wonder whether you have any insights into whether the—maybe resistance to screening is the wrong word—but the reluctance to be screened? Is that do you think, a reflection of screening services in Ukraine? Or do you think it relates more to the current stresses and priorities that these patients face? Dr. Piotr Rutkowski: I think whether it's first for our colleagues from Ukraine, it's a new situation, and they still are not in a normal life. So I agree that first, of course, the participation in the screening programs in Ukraine is on the lower level, but still, maybe the people do not consider staying here, staying at home, of course, and staying in their own country. So they are a little bit in between of normal life and living as refugees only. So they did not start all normal activities. And of course, the information about the screening programs, about the normally functioning health care, it's also probably a little bit more difficult for them because they may not understand all the details of our health care. So I think that it is one of the points which we have to think about for new strategical enterprises in the coming months. So as I mentioned, for normal access to health care, I do not foresee now that it's problematic. Of course, it can be problematic if we'll have a shortage of our people. But still, we can manage this on a regular level. But as I mentioned, when I talked to our colleagues from the department of prevention, the percentage of the people who are coming for screening programs is very low as compared to the total number of refugees. Dr. John Sweetenham: You mentioned that the future for many of the Ukrainian refugees is uncertain at the moment. Now that the heaviest fighting appears to be concentrated on the east of the country, are you seeing any signs that Ukrainian patients will be able to go home for their treatments at any point in the near future? Dr. Piotr Rutkowski: Yes, I think so. Some of the refugees even started to come back home to Western Ukraine, especially when they felt that it was a little bit safer. But as we know, still the situation on the front and the plans of the Russian invaders are not predictable. So we cannot say how even we can behave in this situation. So, for example, in my hospital, we have psychologists from Ukraine who first escaped from Donbas to Kharkiv. And when Kharkiv started to be shelled by bombs, they escaped to Poland. So it's sometimes really dramatic fates for these people. So, of course, the movements between the border are relatively high because some of the people are trying to come back because they feel more comfortable in their homeland, in the country where they can all speak one language, but others they feel they've started to adapt to in living in Poland and we have more and more patients who are accompanied by people speaking Polish. So they started to try to live more normally in our country. I also noticed that we have some patients from Ukraine in the clinical trials. Of course, we also adapted the informed consent and some information sheets into the Ukrainian language. So Ukrainian patients interested in taking part in clinical trials are also included based on normal inclusion criteria. This is also important that we can propose this to patients from Ukraine because if they want to stay longer so they can get extra treatment within the frame of clinical trials. What is also interesting with our National Science Center is that it started to support researchers who are fleeing from war. And they prepared the special funding scheme for researchers from Ukraine to encourage the grant winners to employ researchers from Ukraine on ongoing projects. So there are many specific actions to adapt the citizens of Ukraine in Poland, and of course allow them to undertake normal work. We also allowed for specific temporary work in health care for physicians and nurses. And as it was announced recently by the Polish Minister of Health, more than 2,000 physicians from Ukraine decided to work in the Polish health system. So this is what we can do now. And probably we can do follow-up in half a year again. We'll see what will happen. Dr. John Sweetenham: I thank your responsiveness and that view of government. So this situation has been really remarkable and also remarkably quick. And as you've already pointed out, these patients are going to have needs for many months and many years to come. And you've touched on some of those, specifically the needs around cancer screening. Do you have any other insights into what you think the most pressing future needs for these refugees will be? And then what support your health system, which is presumably already overstretched, what additional support will it need to cope with the ongoing demands and needs of this population? Dr. Piotr Rutkowski: We really appreciate the help from the international community with material for our Ukrainian patients. Probably the next step will be a specific maybe European Union (EU) fund for a health care system which is affected now by numbers of patients from Ukraine, because, of course, we are doing this with our internal Polish funds. But I don't know how it would affect the next year with regular health service in Poland. So this is one of the points. The second point, of course, which we are always afraid of is the situation with the staff shortage for regular health care because Poland, generally in our part of Europe, we can see the shortage of nurses and educated oncological physicians. This is what we included in our national oncological strategy. However, we didn't anticipate it would have such an extraordinary situation which we have to face now. So these points can be one of the problems which can be raised next month. Dr. John Sweetenham: And so you you've indicated the potential support from the EU and other international agencies. I wonder if we could take that question a little bit further to the international oncology community, including organizations like ASCO, the European Cancer Organization (ECO), the American Cancer Society, and others, who've been collaborating to support Ukrainian patients and the oncology community in Poland and in the region. How do you think the international oncology community can continue to respond and help in the coming months and years? Dr. Piotr Rutkowski: It seems that it's a very continuous effort. So we have regular meetings between the national representatives, ECO, as you mentioned, ASCO, and also some NGOs to discuss the hottest problems with the situation in Europe and also how we can find solutions. Colleagues from Ukraine are also asking us about these specific issues like access to radiation therapy and the possibility to transfer the patients because the equipment is not working perfectly in the whole of Ukraine. This effort is very, very important. I feel that it will be a very excellent platform for next month, maybe for next year. I think that it's extraordinary because it was organized very fast, and it was not temporary, but it seems that it will be continuous for a long time. As I mentioned in this platform, we can exchange some materials, and some information very quickly and in an efficient way. I would like to thank you, ASCO, and ECO for the organization of this platform. Dr. John Sweetenham: Well, Professor Rutkowski, I want to thank you again for taking the time to join us for a follow-up discussion regarding the situation in your country with respect to Ukraine, and express, once again, our respect and admiration for the way that you and your colleagues and your country have responded to the crisis. It's been a real pleasure having you on the podcast today. So thank you for joining. Dr. Piotr Rutkowski: Thank you very much. Goodbye. Dr. John Sweetenham: And thank you to our listeners for your time today. If you're enjoying the content on the ASCO Daily News podcast, please take a moment to rate and review us wherever you get your podcasts.   Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Piotr Rutkowski: Honoraria: Bristol-Myers Squibb, MSD, Novartis, Roche, Pfizer, Pierre Fabre, Sanofi, and Merck Consulting or Advisory Role: Novartis, Blueprint Medicines, Bristol-Myers Squibb, Pierre Fabre, MSD, Amgen Speakers' Bureau: Pfizer, Novartis, Pierre Fabre Research Funding (institution): Novartis, Roche, Bristol-Myers Squibb Travel, Accommodations, Expenses: Orphan Europe, Pierre Fabre Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Host Dr. John Sweetenham, of the UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, and Dr. Bridgette Thom, of the Memorial Sloan Kettering Cancer Center, discuss a novel intervention to address financial toxicity and social need using the Electronic Medical Record.   TRANSCRIPT Dr. John Sweetenham: Hello. I’m Dr. John Sweetenham, the associate director for clinical affairs at UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News podcast. My guest today is Dr. Bridgette Thom, a researcher at Memorial Sloan Kettering (MSK) Cancer Center. We’ll be discussing a novel approach to address financial toxicity that uses the electronic medical record to streamline referrals to financial assistance and counseling for high-risk patients. Our full disclosures are available in the show notes, and disclosures of all guests on the podcast can be found on our transcripts at asco.org/podcasts. Dr. Thom, it’s great to have you on the podcast today. Dr. Bridgette Thom: Thanks so much for having me. Dr. John Sweetenham: Dr. Thom, the high costs of cancer care have caused major financial distress for many patients and their families. And this, of course, has been the subject of a great deal of literature in recent years. As you noted in your poster presentation at the recent ASCO Annual Meeting, there are limited interventions, despite a need for patient level and system-based solutions (Abstract 6596). Listeners to our podcast will remember a previous discussion that we had with Dr. Derek Raghavan from the Levine Cancer Institute, where they had instituted financial toxicity grand rounds to partially address this problem. Can you tell us about the novel approach that you and your colleagues explored using the electronic medical record to streamline referrals for financial assistance and counseling? Dr. Bridgette Thom: I first have to credit our team for this work. Dr. Emeline Aviki, who is a gynecological surgical oncologist with keen interest in affordability and payment models, founded the MSK affordability working group several years ago. The first priority of the group was to determine the scope of financial hardship at our institution. At the time, we were absent a systematic screening process. So she, our data analysts, and representatives from our Patient Financial Services Program, developed proxy measures to figure out which patients might be having financial issues. Looking through the medical record, we found those patients who had used one of our Patient Financial Services assistance programs, those who had billing issues, and those who had been referred specifically to social work for a financial issue. And in doing so, we found out that about 25% of our patients over a 2-year period were facing some sort of financial issue. Looking closer at that data, patients experiencing financial hardship weren’t necessarily being connected to the resources that we had available, which include copay assistance programs, financial assistance programs, and support for non-medical essential needs. So, for example, we had about 1 in 6 patients who had some sort of payment issue, but only about 20% of them had applied for financial assistance. And we wanted to figure out why this was happening and review the process. In doing so, we discovered that too much burden was being placed on already burdened social workers who had to triage all those issues. So Dr. Aviki in her wisdom realized that care providers, physicians, advanced practice providers (APP), nurses needed to make direct referrals to the resources that we had. So we had a place for patients to go, we just needed an easier mechanism for them to get there. And that was the birth of the financial toxicity order set. And she and her team really powered through the developmental and testing phases working with IT, our strategy administration groups, clinical end users, our PFS team, that’s Patient Financial Services. We built this order set that allows clinicians directly to refer to our resources. So clinicians, either through their discussions with patients or if patients bring up an issue, through the order set they can select a reason for a referral, the urgency of referral, the clinical location, etc. And then those orders go directly to our Patient Financial Services staff who then contact patients. We piloted this program in late 2020, early 2021 on 1 service, and then used that feedback to roll out the program first to our outpatient clinics and then to inpatient. That process involved a lot of educational efforts, getting the word out, and working with IT and our strategy team to stay on top of the data and monitor referrals over time. Dr. John Sweetenham: Thanks. Could you say just a little bit more about the educational process that you use? I noticed in looking at your poster that the bulk of referrals came either from the clinic nurse or from the APP. Did you tailor your education in any way to the specific provider that was involved? How did you do that piece? Dr. Bridgette Thom: Our affordability working group is an interdisciplinary team and we have nurses, social workers, physicians. So we did a lot of grand rounds work tailored to the audience be it by disease type or clinical role. Dr. John Sweetenham: Great, thank you. This is clearly great work. There’s a lot of useful and helpful information in your abstract and in your poster. What would you say are the key takeaways from the intervention? What would you say about the scalability of this approach into community practice as opposed to a very large institution such as yours? Dr. Bridgette Thom: One key takeaway from a process perspective was the need, like I said, for an interdisciplinary approach to handling the issues. That might seem obvious, but it was really crucial to the success of the project to engage key departmental stakeholders and decision makers very early in the process and keep them informed throughout the development of the order set. That definitely helped us to smooth a potentially bumpy road when we’re dealing with big systems change. From an outcomes perspective, a key takeaway is the importance of having actionable items to empower the care providers. So while our institution has this amazing program, our Patient Financial Services program which provides counseling, and connects patients to tangible resources, this type of intervention I think could be scalable or applicable to a community practice or smaller hospital, provided there’s somebody, a social worker, patient navigator, [or] nurse, that can be a connection for patients and those potential resources that do exist out there. For us going forward, we’re going to continue to evaluate the order set, both from the clinical end user and then also the Patient Financial Services staff to learn more about their perspectives and what can be adapted in the order. We also, of course, want to learn from our patients about their experience with the process, and so we have projects, both research and program evaluation, in the works to consider their perspective. Dr. John Sweetenham: Great, thank you. And I guess 1 of the other aspects of this where there is obviously substantial opportunity is that, of course, currently, you’re still reliant upon the provider to place the order. And I wonder whether you feel that some form of screening for social need and financial hardship could be embedded within the electronic health record as a key next step, so that you proactively identify those high-risk patients. Dr. Bridgette Thom: Definitely. And that is, in fact, our next step. We are currently piloting our financial hardship screening tool on 4 large services at our institution. The objective here is to, like you said, proactively identify patients who might be at risk and connect them to resources, be it tangible resources, or just counseling or insurance guidance, [and] do that before the hardship can occur. And the goals of our pilot phase are to (1) develop and refine a tool that’s both predictive, but also feasible to administer within a busy clinic setting. And then also (2) to work with our interdisciplinary team to adapt the workflow. We can have a great tool, but if we don’t have a way to administer it in a clinic, it’s not going to do us any good. So for us, that means listening to feedback from, first and foremost, our patients and then the key stakeholders in the process. Our nurses have been integral to this process. We also, of course, our Patient Financial Services, staff, the clinical operations staff, obviously, IT, social work. And once we have these processes figured out and we have our tool solid, we will hopefully expand the screening to all services, and then use data to figure out the optimal screening interviews by disease and treatment type because we feel that this could vary by a patient’s treatment trajectory. Dr. John Sweetenham: You note in your poster that additional multilevel interventions are needed to address the problem of financial toxicity at a systems level, and of course, what you have done here is a really great and important step in helping to identify those patients. But identifying those patients who are at particular risk is only beginning of addressing the issue. Could you elaborate a little bit more on other areas that you’re exploring in terms of the interventions that you’re using? Dr. Bridgette Thom: Sure. And this idea of multi-level interventions comes from my social work training, where there’s an emphasis on viewing the individual as being part of a series of dynamic and interconnected relationships and systems: the social ecological theory. So if we think of concentric circles with the patient at the center, there are cascading relationships that are going to impact the course of their care. We radiate out to families and caregivers, a patient's workplace if they’re employed, the hospital and the providers there, and then look to bigger systems where a patient lives, their town. If it’s in an urban setting or a rural setting, the type of insurance that they have, if it comes from their employer, or if it’s a different insurance system, their community and then of course, broader, social, societal, more macro issues. My point and that of many others who work in this space is that we have to consider the context. We can’t just build and test interventions that focus on a patient because the patient isn’t existing in a bubble. They’re existing in relationships with their caregivers, their health care providers, their health care system. And all of that exists in, for lack of a better word, a broken system of structural inequality, systemic racism, and conflicting values about health care as a right. Patient-level interventions are indeed important, but we can’t place the burden solely on the patient. And we, as researchers and clinicians in this space, really need solutions that are going to reach across systems. I think, like you said, this project demonstrates that and this is something that I hear from patients in other work that I’m doing. For example, I’m working on a digital intervention to help young adult cancer survivors to build their financial capability and build their understanding of the health care system and insurance systems and financing and all of that. As I co-develop this intervention with patients and survivors, I’m hearing, 'This is great. I’m glad I’m learning these things, but at the same time, my co-pays are unmanageable,' Or, 'I might have to skip my survivorship appointment because I can’t afford to take off work that day.' I think we have to really think about, like I said, the context and the bigger picture of the scope of the problem and build and develop interventions that acknowledge that. Dr. John Sweetenham: Well, as you say, very complex, multi-level problem and many interventions needed. But congratulations and kudos to you and your colleagues for addressing one component of this. And we’re really looking forward to seeing how this develops and progresses in the coming years. And I’d like to thank you, again, for sharing your insights with us today on the ASCO Daily News podcast and telling us a little bit more about this great work. Dr. Bridgette Thom: Thank you so much for having me. I want to just acknowledge all of the work of our team. It has really been a team effort. We’re looking forward to our next steps. Dr. John Sweetenham: And thank you to our listeners for joining us today. You’ll find links to the poster discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. You can hear more about the MSK Affordability Working Group’s efforts on the podcast, Cancer Straight Talk from MSK.   Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Bridgette Thom: Stock and Other Ownership Interests (Immediate Family Member): Caladrius Biosciences, Mediwound, Sierra Oncology, Lipocine, MEI Pharma, Oncternal Therapeutics, Avadel Pharmaceuticals, Chimerix, Avidity Biosciences, Sutro Biopharma, Adma Pharma, Concert Pharmaceuticals, Processa Pharmaceuticals, Curis           An, IMV, Arcus Biosciences, Iovance Biotherapeutics, Qiagen, Revance Therapeutics, DermTech, Zimmer BioMet, Axonics Modulation, Halozyme, Autolus, Pavmed Inc       , Mereo BioPharma, and AADi Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Pamela Kunz, of the Yale Cancer Center, and the JCO consultant editor for Meeting Abstracts, discusses “hidden gems” from ASCO22, highlighting abstracts that address EDI, global health, health care economics, and more. Abstracts/Tweetorials @PamelaKunzMD and @ryangentzler TRANSCRIPT ASCO Daily News: Hello, and welcome to the ASCO Daily News podcast. I’m Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Pamela Kunz, an associate professor of medicine and director of the Center for Gastrointestinal Cancers at the Yale School of Medicine. Dr. Kunz is also the Journal of Clinical Oncology’s (JCO) contributing editor for meeting abstracts. You may have seen her recent tweetorials highlighting compelling abstracts from the 2022 ASCO Annual Meeting. She’ll be telling us more about this initiative to highlight impactful studies that address equity, diversity, and inclusion, global oncology, and more. Dr. Kunz’s full disclosures are available in the show notes and disclosures relating to all episodes of the podcast can be found on our transcripts at asco.org/podcasts. Dr. Kunz, thanks for being on the podcast today. Dr. Pamela Kunz: Thank you. It’s my pleasure to be here. ASCO Daily News: Social media has created a global community in oncology, and you and Dr. Ryan Gentzler of the University of Virginia Cancer Center recently launched a great series of tweetorials to highlight compelling studies from the ASCO Annual Meeting. Some of our listeners will have seen these threads already, and others will be keen to find them and know more about these efforts. Can you give us the details? Dr. Pamela Kunz: Sure, I’d be happy to. This is a new initiative to really modernize the meeting abstracts. These used to be called meeting proceedings and were printed, and we felt that there was a real opportunity to use social media to disseminate more information around abstracts. And we decided this year to focus on four themes. They are diversity, equity, and inclusion; global health; health care economics; and the Merit Award recipients. And within each of these tweetorials, we have 4 to 5 abstracts that are highlighted that include takeaways and a visual from the poster or presentation. We intentionally decided to highlight abstracts that were not otherwise highlighted in the ASCO Annual Meeting in either oral sessions or poster discussions. So we are calling these hidden gems. There are so many great scientific abstracts that don’t get otherwise highlighted, and this was a really nice opportunity to do so. ASCO Daily News: Excellent. And I understand you’ll be highlighting a couple of abstracts for us today. I believe the first one concerns telehealth used by older patients. Can you tell us about this abstract? Dr. Pamela Kunz: Sure. So this is in the health equity tweetorial, and this is Abstract 1591 by Dr. Higashi and colleagues. And the takeaway from this, I found this interesting, and the disclosure is that I selected these abstracts, given my own personal interests, but I thought that they would be of broad interest to the ASCO membership. So telehealth really became used quite often during COVID, and I think that that has been a real silver lining that there is increased access to expert cancer care through the use of telehealth. This abstract demonstrated that the use of telehealth during cancer treatment was really received positively by older patients, providers, and staff. Most older patients, 66%, and providers and staff, 77%, intended to continue using telehealth after the pandemic. There are certainly some equity issues related to telehealth in terms of access to the internet and the ability to use the technology, but I thought this was interesting because it’s specifically focused on older patients. ASCO Daily News: Excellent. Telehealth certainly has been a gamechanger in oncology. I believe the second abstract that you’ll be highlighting addresses the use of supportive care in pancreas cancer, correct? Dr. Pamela Kunz: That’s exactly right. So this is in the Merit Award tweetorial, and there are so many fantastic Merit Award recipients. It was actually very difficult to select just a few to highlight. In the tweetorial, we will be providing the link to all of the Merit Award recipients. So I encourage listeners to really go look at that. So this specific abstract that I wanted to mention on today’s podcast is Abstract 4154 by Dr. Chris Cann and colleagues. They examined, through the National Cancer database, over 150,000 patients with locally advanced pancreatic cancer and found that only 2.9% received supportive care treatment despite over 65% of these patients receiving care at an academic program. And so I think that it just really highlighted the need for these patients to really utilize supportive care programs. Perhaps sometimes we have a bias that we refer patients with metastatic pancreatic cancer to supportive care programs. But there's an opportunity to take advantage of these services earlier. ASCO Daily News: Excellent. Well, Dr. Kunz, looking ahead, do you think there’s scope to leverage social media more in oncology? Tweetorials, for example, are a great vehicle for education and a way to address topics that don't get as much attention as we'd like? Dr. Pamela Kunz: Absolutely, Geraldine. You know, this was a pilot this year with Dr. Ryan Gentzler and myself. There is an active social media editor, Dr. Shannon Westin, who's a consultant member of the JCO editorial board as well. I think in partnering with the ASCO Annual Meeting Social Media Team, this has really been a team effort. And we are hoping to do more of this in future years, and in particular, take advantage of creating opportunities for perhaps fellows and junior faculty to assist in disseminating some of this information via social media. ASCO Daily News: Absolutely. This is an incredibly important initiative that will benefit oncologists, patient advocates, and patients alike who are on social media to learn about advances in care. So it's really important that we let our listeners know where they can find these tweetorials. You are on Twitter @PamelKunzMD and Dr. Ryan Gentzler is @ryangentzler. Dr. Kunz, is there anything else you'd like to add before we wrap up the podcast today? Dr. Pamela Kunz: Well, thank you for the opportunity to highlight this. I think we would also welcome suggestions from our listeners. If you are reading the tweetorials, you can send me a direct message, and we'd welcome suggestions for future years on how to highlight other science from our ASCO Annual Meeting. ASCO Daily News: Absolutely. And we'd certainly like to encourage our listeners to share these amazing tweetorials. Well, Dr. Kunz, thanks for coming on the podcast today and for your efforts to elevate abstracts and investigators who are working really hard to address some complex issues in cancer care. Dr. Pamela Kunz: Thank you for the opportunity. ASCO Daily News: And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode, and we'll post the Twitter handles of Dr. Kunz and Dr. Gentzler in the show notes. Finally, if you value the insights you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Show Guest Pamela Kunz, MD Ryan Gentzler, MD Tweetorials: By Pamela Kunz, MD Health Equity/DEI Merit Awards By Ryan Gentzler, MD Cost & Financial Hardship Global Health Disclosures: Dr. Pamela Kunz: Stock and Other Ownership Interests: Guardant Health Consulting or Advisory Role: Ipsen, Lexicon, SunPharma, Acrotech Biopharma, Novartis, Genentech/Roche, Amgen, Crinetics Pharmaceuticals, RayzeBio, Natera, HUTCHMED Research Funding (Inst.): Lexicon, Ipsen, Xencor, Brahms (Thermo Fisher Scientific), Novartis Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Rachna Shroff, of the University of Arizona Cancer Center, tells guest host, Dr. Shaalan Beg, of UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center and Science 37, about advances in precision medicine for pancreatic cancer featured at the 2022 ASCO Annual Meeting. She also highlights compelling new data from the FOLFOX, FOENIX-CCA2, and HERB trials in hepatocellular carcinoma, cholangiocarcinoma, and biliary tract cancer.   TRANSCRIPT Dr. Shaalan Beg: Hello and welcome to the ASCO Daily News podcast. I'm Dr. Shaalan Beg, your guest host of the ASCO Daily News podcast today. I'm an adjunct associate professor at UT Southwestern Simmons Comprehensive Cancer Center and vice president of oncology at Science 37. I'm delighted to welcome Dr. Rachna Shroff, the associate dean for clinical and translational research and the chief of gastrointestinal (GI) medical oncology at the University of Arizona Cancer Center where she's also the interim chief of Hematology-Oncology. Dr. Shroff is also the chair-elect for the Gastrointestinal Cancer Symposium. Today we'll be discussing key abstracts in GI cancer that were featured at the 2022 ASCO Annual Meeting. Our full disclosures are available in the show notes and disclosures of all our guests on the podcast can be found on our transcripts at asco.org/podcasts. Dr. Shroff, thank you for being on the podcast today. Dr. Rachna Shroff: Thank you so much for having me. Dr. Shaalan Beg: Let's begin by reviewing what is new in the realm of precision medicine in GI cancers. One of the diseases where precision medicine has not made adequate inroads is pancreatic cancer. One of the most common mutations in pancreas cancer is KRAS, but there haven't been a lot of treatments that can target the most common forms of KRAS. What did we hear at ASCO22 regarding precision medicine and pancreatic cancer? Dr. Rachna Shroff: I agree, I think that the area of precision oncology is, unfortunately, lagging behind a little bit in pancreatic cancer. But I think as we have gotten better and better with our comprehensive genomic profiling, we are identifying subsets of patients within pancreas cancer who are potentially amenable to targeted therapies. You already mentioned KRAS mutations, and we obviously have a number of inhibitors in development in that space, though, we are still missing that key G12D mutation that we see in pancreas cancer. But what I think was really interesting that came out of ASCO22, was a lot of interest and emphasis on better understanding the KRAS wild-type patients in pancreatic cancer. Now, this is obviously a smaller subset of patients, given that the majority of patients have KRAS mutations. But there was a really interesting abstract, LBA4011, that looked at patients with locally advanced or metastatic pancreatic cancer, who were KRAS wild-type. They actually received gemcitabine in combination with a monoclonal antibody targeting EGFR and nimotuzumab. This was a study that was done entirely in Asia. It involved 92 Chinese patients that were randomly assigned to receive the combination of nimotuzumab with gemcitabine. What was interesting in this study is that the patients were found in the full analysis set to have a significantly longer median overall survival of 10.9 months versus 8.5 months with a hazard ratio of 0.5. So, that of course was intriguing and provocative for sure. Similarly, the other endpoints were also somewhat intriguing in terms of improvements in the median progression-free survival (PFS), etc. And specifically, patients without biliary obstruction had a longer PFS, which was an interesting finding as well. The nimotuzumab overall was pretty well tolerated and not any sort of surprising treatment-related adverse events (TRAEs) were noted. And so, this is definitely a drug that, I think, piques our interest in terms of being able to target patients with KRAS wild-type pancreatic cancer. I think that questions, however, that remain, and I think require further study is really understanding what this drug could do in combination with the chemotherapy combinations that we use more frequently in metastatic pancreatic cancers such as gemcitabine and paclitaxel or 5FU-based regimens like FOLFIRINOX. I think given that it is a relatively well-tolerated drug, it would be a very reasonable thing to investigate this drug further in the KRAS wild-type population with the kind of modern-day chemotherapy regimens that we use. And I think, of course, we all know that it is useful to be able to look at these types of drugs in a more global population. And so, a larger patient set I think would be very useful as well, but at least it tells us that there is a way to think about our KRAS wild-type patients with pancreas cancer and that perhaps we really need to understand and identify those patients' potential for precision oncology. Dr. Shaalan Beg: One of the GI cancers that has been a hotbed for precision medicine is cholangiocarcinoma, a disease that's very close to your heart. What updates did we hear at ASCO22 regarding cholangiocarcinoma and precision medicine? Dr. Rachna Shroff: This space of targeted therapy and cholangiocarcinoma has been incredibly exciting for the last few years and I think drug development has been rapid-fire in that space. The oldest, if you will, target that we've been thinking about for some time is the FGFR2 fusion patient population. And in Abstract 4009 by Dr. Goyal and colleagues, we saw the results of the FOENIX-CCA 2 trial which was looking at an oral FGFR inhibitor (futibatinib) in patients with intrahepatic cholangiocarcinoma, who harbor FGFR2 fusions and gene rearrangements. We had initially seen some of this data presented a few years back, but this was the updated data set. It was a single-arm phase 2 study that involved patients with advanced intrahepatic cholangiocarcinoma who had identified FGFR2 gene fusions, and they received futibatinib daily until progression. This was a traditional single-arm phase 2 study with a primary endpoint of overall response rate. At the final data cut, with a median follow-up of 25 months, there's actually a confirmed overall response rate of 41.7%. And I think that what was really exciting about this is this is a refractory patient population. So, in patients who have refractory cholangiocarcinoma, the other drugs, the non-targeted therapy drugs that we think through, really have response rates more in the single-digit to 10% range and so to have a confirmed overall response (OR) over 40% is truly exciting. The duration of the response was also exciting. This is not just a drug that works briefly, it has a duration of response of 9.5 months. And the mature median overall survival was 20 months. And in a disease which we talk about with the ABC-02 data of GemCis, a median OS in advanced disease of 11.7 months. This is really, really exciting for patients who harbor this fusion or gene rearrangement. We know that that's seen in about 10 to 15% of patients. So, again, we're dealing with a smaller subset, but it clearly demonstrates the need to identify FGFR2 gene fusions, so that we can offer these types of targeted therapies. This was not the first FGFR inhibitor that we have seen data on and in fact, we have 2 drugs already U.S. Food and Drug Administration (FDA) approved. And so, when we look at the common treatment-related adverse events that were identified with the futibatinib, there are really class effects related to FGFR inhibition like hyperphosphatemia, alopecia, dry mouth, nothing that really stood out or that was concerning. And so, I think this final analysis for the FOENIX study really just reaffirms the utility of futibatinib in patients with FGFR2 gene fusions, and the mature OS data, the duration of response, all of this really aligns with the need to identify patients with this alteration so that we can, post-gemcitabine based therapies, offer this targeted therapy or an FGFR inhibitor in general to these patients. I think the other really exciting abstract in the glandular carcinoma or biliary tract cancer space was Abstract 4006. This was the updated data from the HERB trial, which was an investigator-initiated multicenter phase 2 trial looking at trastuzumab deruxtecan (T-DXd) in patients who have HER2 expressing unresectable or recurrent biliary tract cancer. Trastuzumab deruxtecan, I'm sure everybody has been hearing about because it has been incredibly effective in HER2 alterations across a myriad of different disease sites. And so, not wanting to be left out, biliary tract cancers were investigated in this study with patients who had HER2 expression, so, that was HER2-positive IHC3+ or IHC2+/ISH+, and they also looked at HER2-low expressing patients, and [whose disease] were refractory or intolerant to gemcitabine-based therapy with the primary endpoint of overall response rate. So, in the HERB trial, a total of 32 patients were enrolled. 24 of them were HER2-positive and 8 were HER2-low and they all received trastuzumab deruxtecan. When you look at the efficacy data, the confirmed overall response rate in the patients with HER2-positive was 36.4%, which again, as I said, in a refractory patient population is certainly very exciting data. And the overall disease control median, PFS, and median OS were all pretty encouraging in terms of efficacy. What was also kind of intriguing was that there was some efficacy seen even in the patients who are HER2-low. Now, this is, in my opinion, a slightly less exciting amount of efficacy, but still important to note that the overall response rate in HER2-low was 12.5% with a median PFS that was also somewhat exciting at 4.2 months. And so, there is a potential clearly for targeting patients with HER2-high or HER2-positive with trastuzumab deruxtecan, and I think in the patients who are HER2-low, we need to better understand the potential utility. The common treatment-related adverse events that we see were the typical things that we've heard about with trastuzumab deruxtecan, but I think the one thing that was really worth noting was 8 patients or 25% of patients had interstitial lung disease (ILD), which we know is an important identified safety concern for patients who receive trastuzumab deruxtecan, and I think that's a pretty sizable number of 25%, so, I think that's going to really require a little bit more fleshing out for us to understand the safety for these patients. One question that a lot of us have had is whether these are patients who have received gemcitabine, which we know can also cause pneumonitis. And so, I don't know if we're seeing a higher percentage of ILD because of, 'priming' with prior gemcitabine. But regardless, I think this is just proof of principle that again, we need to identify patients with biliary tract cancers that have HER2-positivity because we now have a number of drugs including potentially trastuzamab deruxtecan to target [their disease] with after gemcitabine-based treatments Dr. Shaalan Beg: Absolutely. Any new biomarkers to keep on the radar for our listeners? Dr. Rachna Shroff: I think there are a lot of really exciting targets. One that was talked about and that we saw data on at ASCO [Annual Meeting] was from Abstract 4048, which looked at claudin [18]. Claudin is basically a transmembrane protein that kind of helps maintain the tight junctions between cells. In gastric cancer, in particular, we look at claudin 18 isoform 2, and there are 18.1 and 18.2 gene expressions that have been identified in gastric cancer. So, there was a very comprehensive abstract that was presented of over 1,900 samples that underwent comprehensive profiling by next-generation sequencing. And the patients were identified with claudin 18.1, and 18.2, high versus low. Claudin 18.2 expression was actually detected in 97% of the samples. It’s slightly lower with claudin 18.1 at 63%. It's important to note that the primary tumors had higher expression levels than the metastatic tumors, so those were really the tumors in which they did a deeper dive. And in the process of doing this deeper dive, they did a really interesting kind of better understanding of the immune microenvironment and the immune profile in the samples that had claudin expression. And what was identified is that there was an inverse relationship basically between claudin 18.1 and 18.2 expression and correlation with PD-L1 positivity, tumor mutational burden (TMB)-high, M1 macrophages expression, NK cell presence, CD4 positive T-cells, myeloid dendritic cells. And so, there's clearly something between the presence of this claudin expression and the effect it has on the immune microenvironment. I think that's very relevant to keep in mind because as we all know, there's a whole space of drug development focused right now on anti-claudin 18.2 monoclonal antibodies, as well as a target for antibody-drug conjugates (ADC) and cellular therapies with CAR T-cell therapies being developed specifically against claudin 18. And so, understanding the immune microenvironment and the interaction between the claudin expression will be really important as we continue to charge forward in that space. Dr. Shaalan Beg: Absolutely. Very, very exciting. Sticking with the liver pancreas theme, what other studies piqued your interest with regards to hepatocellular carcinoma (HCC)? Dr. Rachna Shroff: It's a really exciting time in HCC. I mean, we actually have drugs that are working in the advanced space. And so, now there's a lot of interest in shifting to looking at preoperative neoadjuvant, and adjuvant approaches and what we can do to improve disease-free survival and overall survival in patients who are able to undergo prior resection. So, Abstract 4013 looked specifically at the efficacy and safety of adjuvant hepatic arterial infusion chemotherapy with FOLFOX. And this was a randomized open-label phase 3 trial. It actually included a total of 315 patients between 5 different centers and patients were randomly assigned to receive either 1 to 2 cycles of adjuvant HAIC FOLFOX (Hepatic Arterial Infusion Chemotherapy FOLFOX) versus just follow up, the control group had no adjuvant treatment, and the primary endpoint was disease-free survival here and in the intention to treat population, there was a significantly improved median disease-free survival at 27 months versus 11 months in the patients who were on the control arm. And there was a protocol analysis, there were a number of other efficacy endpoints including disease-free survival rates at 1, 2, and 3 years. And everything kind of leaned towards and or suggested an improvement with the utility of HAI FOLFOX in patients who undergo complete resection. It should be noted that this included patients specifically who had microvascular invasion on their resection. And so, these are patients who are at higher risk for recurrence as we know. This to me suggests that there could be a role for adjuvant treatment in patients who undergo complete resection with microvascular invasion (MVI). HAI is a very specific technique and it requires a highly skilled center in the placement of HAI pumps. And we're seeing more and more trials across the U.S. as well investigating the role of HAI in advanced disease and in perioperative approaches. And so, I think this is an area of much-needed continued research. There are, of course, a number of ongoing adjuvant studies looking at immunotherapy in the adjuvant setting. And so, it'll be really important to see how those read out and then to try to put all of these in context so that we can better understand local therapy like HAI FOLFOX versus more systemic adjuvant approaches like immunotherapy. Dr. Shaalan Beg: Thank you very much, Dr. Shroff for sharing your valuable insights with us. I really appreciate you taking the time to spend with us and our listeners. Dr. Rachna Shroff: Thanks so much. I enjoyed it. Dr. Shaalan Beg: And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode. Finally, we'd really like to hear your feedback. If you could please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much!   Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. Rachna Shroff: Consulting or Advisory Role: Exelixis, Merck, QED Therapeutics, Incyte, Astra Zeneca, Taiho Pharmaceutical, Boehringer Ingelheim, SERVIER, Genentech, Basilea Research Funding: Pieris Pharmaceuticals, Taiho Pharmaceutical, Merck, Exelixis, QED Therapeutics, Rafael Pharmaceuticals, Bristol-Myers Squibb, Bayer, Immunovaccine, Seagen, Novocure, Nucana, Loxo/Lilly, Faeth Therapeutics Disclaimer: The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  

Dr. Diwakar Davar and Dr. Jason Luke, both of the University of Pittsburgh’s Hillman Cancer Center, highlight key advances in early phase therapeutics and immunotherapy that were featured at the 2022 ASCO Annual Meeting and also address toxicities, including immune checkpoint inhibitor-associated myocarditis. TRANSCRIPT Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. My name is Dr. Diwakar Davar, and I’m an assistant professor of Medical Oncology, specializing in melanoma and phase 1 therapeutics at the University of Pittsburgh’s Hillman Cancer Center. I am the guest host of today’s podcast. My guest today is Dr. Jason Luke, a colleague and the director of the Cancer Immunotherapeutics Center at the UPMC Hillman Cancer Center here.  Today, we’ll be discussing advances in early-phase therapeutics and immunotherapy that were featured at the 2022 ASCO Annual Meeting.   You’ll find our full disclosures in the show notes, and the disclosures of all guests on the podcast are available on our transcripts at asco.org/podcasts.  Jason, thank you for coming on the podcast today.  Dr. Jason Luke: Thanks so much for the invitation. It was a great ASCO, and I hope everyone had a good time.  Dr. Diwakar Davar: So, onto our abstracts. So, the first one that we’ll be discussing, and Jason as you know we’ve done this before. We’ll be rapidly transitioning between phase 1 therapeutics, melanoma, and advanced phase 2 and 3 trials, but you know this is something you do very well. So Abstract 2504, it’s a phase 1 trial of TIM-3 inhibitor cobomilab immunotherapy and in combination with PD-1 inhibitors nivolumab and dostarlimab. The AMBER Trial that was presented recently, and in full disclosure, both you and I actually are on this abstract. So, what do you think of this abstract? What do you think of the data that is discussed, and how do we contextualize this in relation to what needs to be done in this space?  Dr. Jason Luke: So, I think this is an exciting abstract because it brings forward what may be the next high-priority immune checkpoint to try to target in clinical oncology. To level-set, I think everybody listening will know about PD-1 and CTLA-4 as immune checkpoints. In the last year, we’ve had LAG-3 come forward as now a standard of care element of armamentarium in melanoma, and we look forward to further studies of LAG-3 and other tumor types as we think it should be a good partner where PD-1 is otherwise approved.  So here now, we hear about TIM-3, which is another negative regulatory checkpoint on a number of different immune subsets. And in this abstract, the antibody targeting TIM-3 was cobolimab. So, TIM-3 is a very interesting molecule. It has, what you might call, pleiotropic effects in the immune system. So, while in the context of this abstract, it was being targeted as another immune checkpoint on T cells, it’s important to point out that TIM-3 has other regulatory roles in other immune subsets such as myeloid cells and very particularly dendritic cells, and that’s important because it might bring in another element of the innate immune system to try to drive anti-tumor responses. So, it’s an exciting target because it might be able to expand the groups of patients who could benefit from immune checkpoint blockade.  So, in this abstract, we see initially the phase 1 data of combining cobolimab, anti-TIM-3 with anti-PD-1 of a couple of different flavors. And what you could take from this abstract is that in the phase 1 setting, the drug was well-tolerated and combined well, and had pharmacokinetic properties that would be consistent with what we’d expect for this kind of a monoclonal antibody. I think we have to marry this abstract, which is really the phase 1 data about safety in pharmacokinetic (PK) to another abstract presented in the melanoma session, which showed an expansion cohort of patients who got cobolimab plus nivolumab or dostarlimab.  And there we did see a 50% response rate, albeit that there was heterogeneity of patients being treatment naïve versus treatment-experienced. So, what I would say to this on a high level is that I think these data are preliminarily exciting, suggesting that further investigation into TIM-3 may be valuable in terms of expanding the population of patients initially in melanoma, but there will data coming soon in lung cancer and in other tumor types with another novel checkpoint. And I think if we think ahead into the future, the question is probably going to end up being, which combinations of checkpoints for which patients. That’s pretty exciting to think about. We’ve seen a lot of data of PD-1 plus other molecules, and I think some future biomarker stratification really will be necessary to know which patient would benefit the most from which of these combos, but for the time being, this is exciting data to see where the field is going to go over the next couple of years.  Dr. Diwakar Davar: Great. And I guess, to your point, one important thing to highlight from the abstract is your point about the role of the different compartments. There was actually a very interesting dose-response relationship with the highest dose of the drug not necessarily being the most effective dose, suggesting that yes, as you escalate, you may have different effects in different compartments, and maybe therefore a broad selection of doses might be required to ensure that you have optimal engagement of the optimal target.  So, the next abstract is Abstract 3007. This is the tumor-agnostic efficacy and safety of erdafitinib. So, we now know that FGFR pathway aberrations are found from 77% of all malignancies, FGFR targets are now U.S. Food and Drug Administration (FDA) approved in cholangiocarcinoma with pemigatinib, infigratinib, and as well with erdafitinib metastatic urothelial cancer. We know that these agents are not necessarily effective tests in 1 tumor type because these alterations have risen in multiple tumor types. So, the RAGNAR trial, looking at this across multiple tumor types, what do you make of the interim analysis result presented by Dr. Loriot?  Dr. Jason Luke: So, I’d say that this is probably the future of targeted therapy. And so, I think that where we have activity in 1 disease, it’s very likely we would have activity in others. So, the author has described this as the largest basket trial of a molecularly defined subset that’s been pursued to date. There are upwards of more than 200 patients in the study. I think it’s really important, as we think about the data, to realize, though, that all FGFR alterations are not exactly the same thing. And so, in this study, they gave erdafitinib to patients with solid tumors of any FGFR altered status. And so that’s FGFR1, 2, 3, 4 mutations or gene fusions. And that’s a lot of heterogeneity in there actually.  And in this study, there were two-thirds fusions and one-third mutations, mostly in FGFR2 and 3. That will become relevant as we start to think about the results. On a high level, I have to say that it is impressive in pan-cancer fashion, just selecting by FGFR alteration, there’s about a 30% response rate observed. I think that no matter what, that’s going to be valuable considering these were patients with refractory tumors with 3 lines of prior therapy on median. I think what we need to know more is the breakdown of which specific molecular alteration and FGFR in which tumor types drove most of the benefit.  So, for example, in bladder cancer where erdafitinib is already approved, that’s almost entirely an FGFR3 fusion setting. So we know the drug is effective there. And so I think there will be a further breakdown of the data. As it matures more, you really start to tease out, is it really the case that any FGFR alteration can be treated or there are some that really ought to be the high priorities that we really ought to be going after. I think it would be remiss not to also note, however, that while there’s excitement about this sort of pan-cancer approach, the current generation of FGFR inhibitors are not exactly the easiest drugs to take.  And so, the in-class, hypophosphatemia and stomatitis really does lead to dose reductions in a lot of the patients. And I think that that’s probably really important to emphasize is that despite the pan-tumor activity, there’s still a lot of potential in this field to refine further because it’s almost certainly the case that if we had less off-target toxicity, so to say, we could improve the efficacy beyond that 30% that we saw here.  All the same, I think this is exciting for the concept of a pan-cancer tumor agnostic sort of approach, and we’ll really look forward to more data to come from this study over the next, hopefully, few months.  Dr. Diwakar Davar: And I guess 1 corollary to that is that we now need to start looking for FGFR alterations in multiple tumor types. So, tests, tests, tests. All right, Abstract 3004, phase 1a/1b dose escalation and expansion study of the MDM2-p53 antagonist BI 907828 in patients with multiple solid tumors including advanced, metastatic, liposarcoma. So, we’ve recently had data of the previously undruggable KRAS, and now we’ve got previously undruggable p53, for which we now have targets. So, Jason, what do you make of the p53 targeting approach, in this case, using MDM2 and this particular drug from Boehringer Ingelheim?  Dr. Jason Luke: So, I think that this is an exciting abstract exactly for the reason that you mentioned, which is that p53 has been, and unfortunately, to some degree, still remains, one of those holy grails but undruggable targets in oncology. So MDM2, for those who are listening but might not be aware, is a negative regulator of p53. So, the concept here then is if you drug it, you might release p53 to reactivate activity in that pathway, and then p53 being the guardian of the genome, so to say, potentially leading to apoptosis of cancer cells.  And so, this drug binds MDM2 and MDM2 can be amplified as a resistance mechanism in p53 and several tumor types. And so here, they showed data for the early part of a clinical trial investigating the small molecule, BI 907828, but then they focus specifically in liposarcoma, which is a disease known to be an MDM2 amplified. And so, the results were pretty interesting. The toxicity of this kind of an approach, just to note, is really in class. It leads to some gastrointestinal (GI) toxicities as well as hematologic problems, and this goes again for most regulators of the cell cycle will have these effects, whether they’re CDK inhibitors or MDM2 or p53 modulators.  But I think what was very interesting, this is a disease liposarcoma where chemotherapy, functionally speaking, has no role. We, unfortunately, give it to some patients sometimes, but it has almost no activity, and they observe that in poorly differentiated liposarcomas, the response rate was about 12%, but the stable disease was quite durable. And so, I think that really is potentially a big deal because this is an orphan disease. It really lacks any other treatment. But as you zoom out from that, if you start to think about targeting amplified MDM2 in other settings, I think the activity that we see here is intriguing, and potentially suggests that we may be coming to a future where we’ll have multiple, sort of, orthogonal approaches after reactivating p53. There were actually other abstracts at ASCO Annual Meeting of other molecules that were less mature also along this line.  So, I think, very exciting to take away from this, one, a potential treatment for liposarcoma for all of those patients that anybody listening actually sees, but secondarily this concept of targeting p53, which I think we’ll see a lot more of over the next couple of years.  Dr. Diwakar Davar: Excellent. Moving on to the Abstract 3002, this is a phase 1, two-part multicenter, first-in-human study of DS-6000a of an antibody-drug conjugate comprising the anti-CDH6 IgG1 monoclonal antibody that is attached to a topoisomerase I inhibitor payload via a cleavable linker. And so basically, a way in which you can give topoisomerase: (1) TOP1 inhibitor, (2) CDH6-expressing cells. This was studied in advanced renal cell carcinoma (RCC) and advanced ovarian cancer in this abstract presented by Dr. Hamilton. Jason, what do you think of the results and what do you think of this approach in general, this antibody-drug conjugate (ADC) approach using novel targets as well as novel payloads?  Dr. Jason Luke: I think this is one of those that you can’t help but be pretty excited about, and I think in the context of the data shown at the plenary session in breast cancer for antibody-drug conjugates (LBA3), I think this is really where the field is going to start to go. So, you mentioned that this is an antibody-drug conjugate that targets cadherin 6 or CDH6, which people will remember from biochemistry class and medical school, or something is a cell-cell adhesion molecule, really a basement membrane protein. So, the concept of targeting it really is just to go after a latch mechanism to get the molecule into the tumor where you want. And CDH expression is very high in renal cell carcinoma, upwards of 80% of samples, also high in ovarian cancer, which is why they chose those 2 tumors to go after.  So, the ADCC, and you described its structure just a little bit, but it’s essentially the same backbone as trastuzumab deruxtecan, which we saw this outstanding activity for HER2 and breast cancer on the plenary, with these 8 chemotherapies moieties attached to it, but here now, targeting it instead to HER2, with this molecule now to CDH6. And I think, again, you can’t help but be impressed. There were treatment responses on almost every dose level of the dose escalation in this study. There’s in fact only 1 patient whose tumor was not, at least, stable disease or a PR, and I think that that just goes to show the power of truly bringing the chemotherapy in a targeted manner into the tumor microenvironment. Responses were heterogeneous. They were not super deep responses per se, but the stable disease was quite durable in the study, and the patients were going out more than 7 months. And again, realizing this is at the lower dose levels as we’re increasing the dose and move this in their earlier lives of therapy is likely to be even more effective.  They did show a waterfall plot of the reduction in CA 125 for the patients with ovarian cancer that really looked quite impressive. And given that that’s our clinical biomarker that we commonly follow, it may actually even more indicative of the benefit we would see as opposed to resist.  Now, again, there is some toxicity. It is a chemotherapy moiety that’s conjugated to the ADCs. So, the most common toxicities were nausea, vomiting, and low platelet counts, but these are kind of toxicities that we’re quite accustomed to with chemotherapy. Just to summarize, I think there’s a lot of promise for this kind of antibody-drug conjugate targeting, and I think it can only be impressive that they had this amount of activity in the dose escalation of the study. [I] very much look forward to the expansion cohorts in renal and ovarian, which we’ll presumably expect to see later this year, early in the next year.  Dr. Diwakar Davar: And as you alluded to, this really was parallel that ASCO, by the standing ovation given to Dr. Modi when she presented the DESTINY04 data of trastuzumab deruxtecan in HER2-low breast cancer, basically now redefining breast cancer from 4 camps, now we have to think of not just HER2 amplified or HER2-high, but also HER2-low. So yes, really have to now rethink how we classify these diseases (LBA3).  So Abstract 2509, the efficacy of anti-PD-1/PD-L1 immunotherapy in non–small cell lung cancer dependent based on CD8 and PD-L1 status. So really Dr. Galon taking us into what he has now described as the immunoscore—really a way of characterizing tumors. A way of thinking about tumors that you’ve also championed, Jason, in terms of this T cell-inflamed and uninflamed hypothesis. So, tell us a little bit about how these jives with your work and how you would think about lung cancer patients responding and not responding to immune checkpoint inhibitors (ICI) therapy in this context?  Dr. Jason Luke: Yeah. I think the focus quickly here on the immunoscore, so the people are aware of that, I think is really important for diving into these specific results. You have to realize our fundamental underlying predicate for immune checkpoint blockade inhibitor response is that patients have mounted an adaptive immune response. So, CD8 T-cells have gone into the tumor where they elaborate chemokines and cytokines like interferon gamma, which upregulates the expression of PD-L1 in the tumor but also in the surrounding immune cells.  So, you realize that even though antibodies are targeting PD-1, it’s really that we’re targeting that tumor microenvironment. So, the more robustly we can measure that, and we understand it, the more likely we are to know whether or not the patient is going to benefit. So, this is where the immunoscore comes in. The immunoscore is actually a fairly simple test. It’s one slide, immunohistochemistry slide where they can stain jointly for CD8 and PD-L1 on the same slide. And that allows them to do a number of different things beyond just testing the total level of PD-L1. They can test the CD8 density, the PD-L1 expression, but then also the interaction between CD8 T-cells, their distance from each other, from PD-L1 expressing cells, and so on and so forth.  And so really [this] can give us a much more robust analysis of what all is going on in the tumor microenvironment again, off of a single slide. So here then, in this abstract, for patients with non–small cell lung cancer receiving anti-PD-1, they then compared the utility of only PD-L1 testing versus doing the immunoscore. And so, it was actually quite a large set. They had about 250 patients in their analytical set and then split about 150 or 180 or something into the training and validation sets, and they compared the immunoscore against 2 different standard PD-L1 antibodies, the 22C3 as well as the SP263. And what they saw was a high concordance for expression between PD-L1 and the immunoscore.  That’s good, because, again, they’re measuring PD-L1 in both of those. And so that was a good, sort of, level set. The immunoscore, however, allows them to look to 7 different parameters, again, beyond just PD-L1, as I mentioned. So, CD8 density, interaction, distance, and this kind of thing. Then in these test and training cohorts, they were able to actually split out patients who are PD-L1 positive into further groups, those that were immunoscore low and that were high. And in so doing, they were actually able to sort of dramatically predict the likely progression-free survival on PD-1 checkpoint blockade in those different non–small cell lung cancer groups.  So why is this important? Selection of patients by PD-1 has been very useful in the field of non–small cell lung cancer, but it’s hardly a panacea. You’re not at all assured your patient is going to do well just because they’re PD-L1. And here comes a second assay that can be done in a standard of care setting. So, the immunoscore is a test. You could just order it, and that really does give you much more predictive power about who’s likely to do well and who isn’t. And I think this test and more broadly multi-spectral imaging is really going to become a core component to how we risk stratify and predict outcomes to checkpoint blockade and lung cancer, but broadly in other tumor types over the next couple of years.  Dr. Diwakar Davar: Okay. Now, moving on from a biomarker for PD-L1 and PD-1 to a setting in which PD-1 was just recently U.S. Food and Drug Administration (FDA)-approved, so I’ll give a brief background to the trial that you’ve actually developed and led. And so, this is KEYNOTE-716, the abstract in question is LBA9500 (late-breaking abstract) 9500, but this is the distant metastasis-free survival (DMFS) data readout. The DMFS, distant metastasis-free survival with pembrolizumab versus placebo in the adjuvant setting for patients with stage IIB or IIC, that is high-risk node-negative melanoma and the data from the phase 3 KEYNOTE-716 study.  So, this data, at least the recurrence-free survival (RFS) data was actually earlier published, you had presented it earlier last year and also more recently this year, but it was published recently in Lancet. And we know that 716 is a study in which, for the first time ever, we have an immune checkpoint inhibitor PD-1 that was studied against placebo with the high-risk node-negative setting in stage IIB and C melanoma, demonstrated a significant RFS benefit in the setting against placebo. And now we have the DMFS readout.  Maybe you could tell us a little bit about both the RFS and the DMFS data, and why this is such an important advance for these patients.  Dr. Jason Luke: Thanks. And I agree this really is a sea change in how we thought about stratification of patients with melanoma, but I think this broadly has implications for other tumor types as well. So, in melanoma, we’ve historically thought of its involvement of the lymph nodes—stage III as being the high-risk disease, but we also, if you look at the outcomes from the AJCC, we see the patients with stage IIB and IIC, so deep primary lesions, actually have similar bad outcomes as those patients with stage IIIA and IIIB. And so anti-PD1 and adjuvant therapy and melanoma were originally proved for stage III, but having understood that about 5 years ago actually, started to think, well, why not also treat the patients with stage II if they’re at similar risk.  And we pursued KEYNOTE-716 as you mentioned, and it read out last year as a positive trial for recurrence-free survival. And the abstract here then was to look at the impact on distant metastasis-free survival. So, while the regulatory consideration for approval, and it is approved and it’s available for patients now, was based on relapse, what we really want to be preventing is the development of metastatic disease because presumably that would correlate with the eventual death of the patient from cancer.  So, in the abstract here, we see the first update for DMFS, which also was positive on its first analysis, the hazard ratio at 0.64. And so, again, very similar to the RFS benefit, showing about a 35-36% reduction in distant metastasis-free survival. And this is a theme that we’ve seen across adjuvant studies in melanoma, all the adjuvant studies in fact, is that the RFS improvement, the relapse-free survival hazard ratio mirrors very closely the distant metastasis-free survival ratio. We saw that again here. I think it just emphasizes that anti-PD-1 immunotherapy is highly effective in melanoma no matter what stage it’s in, but rather related to the risk of death for melanoma.  And so this really has a practice changing in the field of melanoma oncology. Patients need to be referred to medical oncology early for discussion around risk stratification and consideration of adjuvant therapy—I think even at the same time that they’re having resection of their primary lesion, and it even calls into  question of whether or not we should even fully be doing procedures like sentinel lymph node biopsies any longer, considering we can make the decision to give adjuvant therapy now based on the primary—albeit that’s a controversial area of discussion.  And I would just love for this to start to penetrate into other disease settings. We’ve seen more recently, approval for neoadjuvant therapy in lung cancer and we see in kidney cancer, bladder cancer. We see adjuvant therapy in—I think we’re going to see immunotherapy starting to become an important part of the armamentarium in these hard-to-treat cancers, even at the time that perioperatively before or after surgery.  So definitely a major change in the way we’re thinking about stratifying patients and emphasizes that you need to get those patients with melanoma in to have that discussion around adjuvant therapy probably at the time of the primary lesion resection.  Dr. Diwakar Davar: And finally, Abstract 2507, single-cell profiling of human heart and blood in patients with checkpoint inhibitor-associated myocarditis. So, this is data from the NGH Group, Dr. Villani and colleagues are presented by Dr. Blum. We know that myocarditis is an uncommon but very serious immune related adverse event (irAE), and here in this particular dataset, this group which has done a lot of underlying work to really uncover the role of certain key phenotypes, cellular phenotypes, in the development of myocarditis it's presenting the data in the context of ICI-related myocarditis. So, what do you think of this data, what do you think of the use of checkpoint inhibitors are now, as you’ve said, migrated linear in the lifecycle of the patient, what do we need to be thinking about and how does this improve our understanding of both the use of the drug and what we need to be worried about?  Dr. Jason Luke: I think the toxicities of immunotherapy, while, less frequent than, say, chemotherapy, can actually be more disastrous. In the rare patients, we have extreme immune-related adverse events, there is an incidence of actually life-threatening and fatal events. And so, myocarditis, associated with checkpoint blockade, is one of those things that could be seen, and here at ASCO Annual Meeting, we saw a couple of abstracts summarizing the experience from the National Cancer Institute following myocarditis events, and then this abstract in a translational level trying to better understand what is actually going on in terms of the immune response in those myocarditis cases.  And so, I thought this was actually a very interesting abstract. There was only a small number of patients. They had 13 samples from patients who had had endomyocardial biopsies in the context of immune-related myocarditis, and you might say, well, only 13 samples, but fortunately, this is quite a rare event, less than 1% of patients who get immune checkpoint inhibitors. And what they saw was relatively unsurprising, which is that in patients who were having myocarditis, they saw an increase in T cells and in K-cells, as well as activated CD8 and CD4 T-cells.  I think what was very interesting was when they started to dig into what were the phenotypes of the cells and what were the pathways that were turned on. Again, it was not especially surprising to see that they saw increased levels of interferon signaling and immune-receptor signaling as well as motility and adhesion, but this really, I think emphasizes that there are potentially interventions beyond just the general immune-suppression approaches that we give. They could be more nuanced but perhaps more efficacious because sadly, patients do pass away when they develop this. And in their cohort of 13 patients, 3 of those patients died. And specifically, in looking in those 3 patients, they actually saw that all 3 patients had a shared T cell cluster. And they can’t exactly say what it is exactly yet, but I think it’s very interesting to see that because it suggests that there’s probably something about the T cell response in those patients that disproportionately triggered a fatal event.  And if we can understand that better, we then may be able to really tailor our interventions in a way that is more useful. Because, frankly, the way these patients usually present is they show up in the emergency room (ER), and they’re seen by an ER doctor who thinks they’re having acute coronary. They ship them off to the catheterization (cath) lab. They open him up, and then they get in there, and there’s nothing going on. There’s no plaque. And so now, all of a sudden, everyone is quite confused. And so, if we had better ways to search for that ahead of time to be aware of it, we might have better interventions because usually what happens right at that moment is everybody gets very confused and starts calling the oncologist, and we start slapping on steroids and other immunomodulatory agents, but sometimes it’s late.  So, I think this is a great abstract. It’s really starting to preliminary give us an idea of what is the actual biology that underpins these terrible events, and we can hope that we can build off that over time hopefully to eventually come up with better predictors and then obviously better interventions to try to avoid these outcomes in a small but real number of patients.  Dr. Diwakar Davar: Excellent. One other point is you and I are both involved in drug development, and as we start thinking of side effects. Side effects are really on the flip side of responses in drug development. So really 1 point to make of this is that when people start developing side effects rather than, as you say, putting your hands up in the air and waving them around, 1 of the things that we should be doing in drug development is possibly biopsying these patients because we could get new PD insights into how these drugs work, why they work, and particularly which sub-populations themselves they work on, particularly in the early-drug development setting when you oftentimes don’t have that many responses.  With that, thank you, Jason, for sharing your insights with us today.  Dr. Jason Luke: Thank you.  Dr. Diwakar Davar: And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. So, thank you for your attention, and we will sign out.      Disclosures:  Dr. Diwakar Davar:   Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences  Consulting or Advisory Role: Instil Bio, Vedanta Biosciences  Consulting or Advisory Role (Immediate family member): Shionogi  Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences  Research Funding (Inst.): Zucero Therapeutics  Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy  Dr. Jason Luke:   Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical , Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX  Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine  Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure  Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)  Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.     

Dr. Stephen Ansell, of the Mayo Clinic in Minnesota, tells host Dr. John Sweetenham, of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, about ECHELON-1’s compelling overall survival analysis in newly diagnosed Hodgkin lymphoma and key advances in the SHINE, MOMENTUM, and ASCEMBL trials that were featured at the 2022 ASCO Annual Meeting.   TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the associate director for Clinical Affairs at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast.  My guest today is Dr. Stephen Ansell, a professor and chair of medicine at the Department of Hematology at the Mayo Clinic in Minnesota. Dr. Ansell shares his insights on key advances in hematologic malignancies that were featured at the 2022 ASCO Annual Meeting.  Our full disclosures are available in the show notes and disclosures of all guests on podcasts can be found on our transcripts at asco.org/podcasts.   Stephen, it's great to have you on the podcast today.  Dr. Stephen Ansell: Thanks so much for having me, John.  Dr. John Sweetenham: So, Stephen, I'd like to start with your thoughts on Abstract 7503, which of course is one that you authored, and this is a 6-year follow-up study of the ECHELON-1 trial. This includes a positive overall survival analysis for brentuximab vedotin in newly diagnosed advanced Hodgkin lymphoma. Can you tell us more about this?  Dr. Stephen Ansell: Yeah, sure, John. And you know, as you point out, the thing that’s really interesting and unique about this trial is we haven't had a lot of studies in Hodgkin lymphoma that show an overall survival advantage as you well know. Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy has actually been quite difficult to beat when it's been an overall survival endpoint that one has been looking at.  There have been some other strategies in the past that have been looked at—the escalation of therapies such as escalator BEACOPP, and maybe modification of therapy to minimize toxicity, such as the RATHL trial where bleomycin is dropped out.  In all of these studies, there have been advantages for progression-free survival, but not clearly against ABVD as the standard and overall survival advantage. So, our listeners would probably know that ECHELON-1 was a comparison between brentuximab vedotin ABVD chemotherapy, and ABVD chemotherapy as the standard, showing an initially modified progression-free survival advantage and subsequently a progression-free survival advantage. But now with 6 years of follow-up, an overall survival advantage. And I think that's really what makes this quite unique.  Dr. John Sweetenham: One of the reasons I think many people, myself included, thought that it was going to be a very high bar to show an overall survival difference in this study was simply the fact that treatments to relapsed and refractory Hodgkin lymphoma, in general, have improved really quite substantially, both before and during the conduct of this trial.  Do you have any thoughts on that? Were you surprised? And any thoughts on why we're seeing this in the face of the rapidly evolving treatment landscape in the relapse setting?  Dr. Stephen Ansell: Yeah, I think that's an excellent point. And, John, I think there have been 2 schools of thought, as you know, those that have felt that the first shot was always the best one. And you should go hard right off the bat and others have said, you don't need to give everybody intensive treatment, because as you say, subsequent therapies can be very effective.  This would actually challenge that second position because when we looked at how patients were managed in both groups when they relapsed, the vast majority of relapsing patients in the group that got ABVD subsequently got brentuximab vedotin, as part of their regimen. Most patients—and it was balanced in both arms—got the standard kind of salvage treatment, autologous stem cell transplant approach, and some patients in both arms, got novel agents, including PD1 blockade, that was a minority, partly because of the timing of when the study was done.  But I think all of the things that we would normally do were done, and yet there's still a survival advantage. The one interesting thing I think that's worth taking away from this is when one looked at some of the influences on what might have made that overall survival difference, there were more patients progressing and dying from Hodgkin's in the ABVD arm suggesting that adding brentuximab vedotin does make a difference to the disease itself. But also interestingly, there were fewer patients in the brentuximab arm, who got a second lymphoma.  And interestingly, there were quite a substantial number of people in the ABVD arm when they relapsed to or subsequently got a different lymphoma, suggesting that the brentuximab vedotin, may actually target a precursor cell in a heme malignancies space and actually may have a benefit that way.  Dr. John Sweetenham: So, what's your overall conclusion from this study now that brentuximab vedotin plus ABVD is the standard of care for patients with newly diagnosed advanced Hodgkin lymphoma?  Dr. Stephen Ansell: I would say that if you have advanced-stage disease with classical Hodgkin lymphoma histology, it's very difficult not to say that this would be the standard of care to manage the patients.  I think we've learned that this study applied to older patients who are often difficult to treat. And so, hence, that's also a very valid treatment to give. And it's very difficult to argue against giving treatment that has an overall survival advantage for patients. So, in my practice, this has become the standard of care.  Dr. John Sweetenham: Okay, great. Thanks, Stephen. Let's move on and talk about LBA7502. This reported on the primary results of a double-blind placebo-controlled study known as SHINE, which looks at the use of ibrutinib in combination with bendamustine and rituximab followed by rituximab maintenance as a first-line treatment for older patients with mantle cell lymphoma. What are your thoughts and key takeaways from this study?  Dr. Stephen Ansell: Again, I think this is a very important study in older patients with mantle cell lymphoma. So, as you well know and many of our listening audience would know that we kind of has 2 strategies in mantle cell lymphoma. In younger patients, we may treat them with a more intense approach, sometimes with autologous stem cell transplant, often with a kind of alternating high-intensity therapies.  For patients who are older, bendamustine rituximab is really a standard therapy for patients with that demographic. And this now really pushes the field forward by showing that if you take bendamustine rituximab and add ibrutinib an effective therapy in the relapse setting, in the upfront setting, there is a substantial advantage for how patients do.  If one looks at the overall outcomes, it shows that progression-free survival is improved; we don't have overall survival benefit yet. But as we track these patients, it'll be interesting to see if that does transpire in time.  I will say again that I always like placebo-controlled arms because it helps us really get a handle on toxicities. And in general, in this population of patients, it was well tolerated. So, I think this, again, is a regimen that is going to be very useful in older patients.  Dr. John Sweetenham: I think that the lack of an overall survival benefit so far could of course be because there was a crossover in a study for those patients who progressed on the placebo-controlled arm.  But my other question about this, just to get your impression, is that there is a subgroup of elderly patients or older patients with a very slowly progressive disease where the management approach has been more of a watch-and-wait and observation-only approach until they become symptomatic. Do you think results like this, which start to show a progression-free survival benefit from upfront therapy, change that philosophy? Should we be thinking harder about whether anyone should be observed now?  Dr. Stephen Ansell: I think that's a good question. And to be frank, I will say that in my practice, I still have a spirit of, I'm happy to watch patients who have a very low burden of disease to just get a sense of the pace of the disease. Because as you say, you may be surprised by a subset of patients whom you may not need to treat for a year or even longer. And my view is that a year of no treatment is always better than a prolonged progression-free survival interval on treatment. So, I take the view that if you don't need to treat, that is still the best management.  Dr. John Sweetenham: Great, thank you! So, we're going to change gear for a moment and move out of lymphoid malignancy and talk a little about Myeloproliferative Syndrome. I’m interested to hear your thoughts on the MOMENTUM study. So, this was Abstract 7002, another phase 3 randomized study, in this case, looking at the use of momelotinib versus danazol in symptomatic and anemic patients with Myelofibrosis, who previously had a JAK inhibitor. What are your thoughts on this study?  Dr. Stephen Ansell: I think again, this is really good and very interesting data because those that treat Myelofibrosis will know these are challenging to treat. And many times, the symptoms they experience, the transfusion challenges they have, and the difficulty they have with very large spleens are all things that impact the quality of life quite profoundly. And therapies, in general, that would benefit those symptoms are always highly valuable.  So, I did find, again, I'm not as much of an expert in Myelofibrosis, but certainly, my colleagues who are were very satisfied with these results, basically showing improvement when compared to danazol, which again, I would anticipate as modest control with not particularly good efficacy, again, some of those symptoms I just spoke about, but momelotinib really showed a substantial benefit for the symptoms that this disease causes, and obviously transfusion requirements and improved spleen sizes and spleen symptoms.  So, I think in general, for managing patients for whom the quality of life is profoundly impacted, this is going to be a useful agent moving forward.  Dr. John Sweetenham: Okay, great. Thanks. And staying on the theme of Myeloid diseases, Abstract 7004 reported on the efficacy and safety, from the so-called ASCEMBL study, another phase 3 study, in this case, looking at the use of asciminib versus bosutinib in patients with Chronic Myeloid Leukemia (CML) who are in chronic phase, and who had already received 2 or more tyrosine kinase inhibitors. And this was an update at week 56 of the study. Why do you think this study should be on our radar?  Dr. Stephen Ansell: Well, I think again, we're always looking for agents that make a difference, particularly with subsequent lines of therapy in this disease. I think bosutinib is really regarded as a standard of care in this population of patients and an agent that comes along, ascitinib in this case, that shows a significant benefit, that really brings yet another tool for us to utilize in these patients.  I must say, again, as I looked at the results, comparing also looking for the major molecular responses, and the benefit and durability thereof, this was pretty impressive data. And so, I think it's very useful in this disease to have a plethora of tools that we can reach to be able to really impact the outcome of patients. So, I think, again, this is highly relevant data that we would use in the clinic in the not-distant future.  Dr. John Sweetenham: Do you think it's likely it’ll move into frontline treatment over time?  Dr. Stephen Ansell: So, I think that is a good question. I don't know the answer to that, except to say that these results are pretty impressive. And so, I do believe that that's going to need to be tested, but as has been done in CML over the decades and which is really to be applauded, there have been randomized trials, comparing head-to-head agents showing which agent really has the greatest benefit and efficacy. So, I’ll watch that space with a lot of interest.  Dr. John Sweetenham: Thanks! And finally, I'd like to return to lymphoid malignancy. In the 2020s, it would be almost impossible to review a meeting such as ASCO without saying something about CAR T-cell therapy, and this podcast is going to be no exception.  So, I wonder if I could get your thoughts on Abstract 7571. And this was an abstract, which reported real-world outcomes for axicabtagene ciloleucel, otherwise known as the Axi-Cel, for the treatment of large B-cell lymphoma. And it looked at the outcomes according to race and ethnicity. What are your thoughts on this study?  Dr. Stephen Ansell: Well, John, I smiled when you were said there's not a possible to really have a conversation without bringing in CAR T-cell somewhere along the way, but what I liked about this abstract, is it really was bringing in the real-world data, because many times and again, I have to stress that real-world data, when it comes to CAR T-cells is probably not the real world in the most real-world nature of things. And that is just you have to have access to certain centers to be able to get this therapy. And I think that's what this abstract actually points to.  It does look at almost 1,400 patients treated with Axi-Cel. And now that in large cell lymphoma, this is a standard of care where we either use a post-transplant and now even as a first relapse therapy, this is becoming highly relevant. And the question is just always seeing discrepancies between various population groups when we look at how outcomes transpire from this therapy.  And as it turns out, if one looks at Asian populations, those are really not adversely impacted, or Hispanic populations. But the African American population continues to have a less favorable outcome, even with this sophisticated therapy.  And that does suggest that possibly, when those patients, in general, can get access to this care, might actually be a little later in the disease, greater disease burden, possibly a little later line of therapy, resulting in not as favorable results.  I think this is whereas health care providers, we need to turn our attention in the future. And that is to say, how can we make care be equally good for all patients everywhere within our country, rather than there being nuggets where certain people benefit a lot and other areas where people benefit very little.  Dr. John Sweetenham: Yeah, thank you. There was good discussion after this study was presented and I think much of it focused around exactly what you've just said. Most of this difference is almost certainly not biological but it's really related to access to care and so on and that was an important take-home message. So, thanks for emphasizing that.  Stephen, thanks so much for sharing your insights with us today regarding the 2022 ASCO Annual Meeting on our podcast. I really appreciate your being willing to talk to us.  Dr. Stephen Ansell: John, thank you very much for having me.  Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstract discussed today on the transcripts of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.    Disclosures:  Dr. John Sweetenham:  Consulting or Advisory Role: EMA Wellness  Dr. Stephen Ansell:  Honoraria: WebMD, Research to Practice  Research Funding (Inst.): Bristol-Myers Squibb, Seattle Genetics, Affimed Therapeutics, Regeneron, Trillium Therapeutics, AI Therapeutics, ADC Therapeutics  Disclaimer:  The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.       

Dr. Allison Zibelli, of the Sidney Kimmel Cancer Center – Jefferson Health, and Dr. Hope Rugo, of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, discuss the practice-changing DESTINY-Breast04 trial as well as novel therapies in metastatic HR+/HER2- breast cancer from the TROPiCS-02 and MAINTAIN studies, all of which were featured at the 2022 ASCO Annual Meeting.   TRANSCRIPT Dr. Allison Zibelli: Hello. I’m Dr. Allison Zibelli, your host for the ASCO Daily News Podcast today. I’m a vice-chair and breast medical oncologist at the Sidney Kimmel Cancer Center, Jefferson Health in Philadelphia. My guest today is Dr. Hope Rugo, a professor of medicine and the director of Breast Oncology and Clinical Trials Education at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. We’ll be discussing key advances in breast cancer that were featured at the 2022 ASCO Annual Meeting. Our full disclosures are available in the show notes, and disclosures of all guests on the podcasts can be found on our transcripts at asco.org/podcasts. Hope, it’s great to talk to you today. Dr. Hope Rugo: Nice to talk to you, too. Dr. Allison Zibelli: Let’s begin with perhaps the most exciting abstract at ASCO this year, which was the DESTINY-Breast04 study, that’s LBA3, a randomized phase 3 study of trastuzumab deruxtecan versus treatment of physician’s choice in patients with HER2-low, unresectable and/or metastatic breast cancer. What are your thoughts about this study? Dr. Hope Rugo: Well, of course, this is a hugely practice-changing study as was noted in the second-to-last slide by the discussant [Dr.] Pat LoRusso. So, antibody-drug conjugates are really the next step in delivering chemotherapy to cancer cells. The antibody-drug conjugates allow targeted delivery of a toxin to the cancer cell. I think we didn’t understand how important this was going to be. These second, sort of, verging on third-generation antibody-drug conjugates use an antibody approach and to then have a new generation of linkers, which allow the drug to be released locally, but to then have drugs which pack a big bang for the buck. So, the way antibody-drug conjugates are constructed, you need to have a drug that actually can’t be given as a naked drug because it’s too toxic because you’re giving just very small amounts of this drug that are delivered directly to the cancer cell. And the other really critical part of this is that the drug-to-antibody ratio of at least the successful and new antibody-drug conjugates (ADC) is quite high in the 7.5 to 8 toxins per antibody. Now, what that’s resulted in is really interesting, is that there’s a bystander effect. So, the toxin itself can leak out of the cancer cell that it’s targeted and kill neighboring cells, but also because of the construct of these antibody-drug conjugates, what’s likely happening is even if the cancer cell’s a very low expression of the target, really low, you’re able to actually get that ADC into the cancer cell to kill the cancer cell. So that may be a big part of the so-called bystander effect. So trastuzumab deruxtecan is biosimilar trastuzumab linked to a topoisomerase inhibitor deruxtecan, and what happened here was that of course, we saw remarkable data in HER2+ disease, unbelievable p-values in DESTINY-Breast03 compared to T-DM1, a first-generation ADC. But in DESTINY-Breast04, we targeted a population of patients largely with hormone receptor-positive disease who had a little expression of HER2, 1 plus or 2 plus by immunohistochemistry and no gene amplification. And this trial, which randomly assigned patients 2:1 and included just 58 patients with triple-negative disease. So in this trial, 480 had hormone receptor-positive breast cancer, a median of 1 line of prior chemotherapy. They were only allowed up to 2. They were refractory to endocrine therapy, a median of 3 lines of endocrine therapy. In the overall patients and in the hormone receptor-positive patients, there was actually a doubling in progression-free survival (PFS). It started very early, and it continued throughout, and at every landmark analysis, T-DXd was better than the treatment of physician choice that patients were randomly assigned to. It's also important when you’re thinking about trials like this to think about what the treatment of physician choice was, and it was all chemotherapy regimens we would use. Paclitaxel, nab-paclitaxel, capecitabine, eribulin, or gemcitabine. And, so, I think that that doesn’t bring up any questions. When they looked at the hormone receptor-positive group, they saw, if anything, even a bigger benefit overall. Now, the other endpoint of this trial was overall survival, and at this first analysis, they saw an improvement in overall survival that was quite dramatic. The absolute difference was 6.4 months, which is pretty amazing for an overall survival difference. And then they looked at this exploratory endpoint at the 58 patients who were valuable at triple-negative breast cancer, and then that group of patients, also saw an improvement in PFS of 5.6 months, an improvement in overall survival of 9.9 months, very small group, but amazing data. The forest plots are exactly what you want to see, all the dots line up to the left of 1, and overall responses improved. One of the concerns with this drug has been toxicity. The toxicity showed no new toxicity signals, which is really important. Nausea is the biggest issue that we deal with. It’s mostly grade 1 and 2, but still something that’s important to manage. A little bit of hair loss, not much in the way of bone marrow suppression, which is interesting. Interstitial lung disease (ILD) or pneumonitis continues to be an important issue to follow. 12% of patients had ILD of any grade. Most of it was grade 1 and 2, but 3 patients died, representing 0.8%. So, this really highlights the importance of monitoring and managing pneumonitis. Regardless of that, few patients had a reduced ejection fraction, but again, very, in general, low grade. This is really a new standard of care, and the standing ovation was really due to the fact that all we do is dedicate ourselves to trying to help patients live longer and better with their cancers, and in this trial, we have a huge win that has no qualifications. We can help patients not only control their disease longer but live longer with T-Dxd compared to standard chemotherapy. Dr. Allison Zibelli: So, Hope, I know as a practicing medical oncologist, I find that our metastatic triple-negative patients are often the biggest therapeutic challenges for us. Will they be doing larger studies with these patients that are HER2-low? Dr. Hope Rugo: It’s a really good point. About 65% of patients with hormone receptor-positive disease or so-called HER2-low, centrally confirmed in the study. So, a fair number of people, about a quarter, did not have HER2-low disease when they were tested centrally. In the triple-negative population, who really are ER, PR, HER2- by standard definitions, about a third of the patients might have HER2-low disease. So, there’s a lot of interest in further exploring that and looking at the patients who have ultra-HER2-low disease, so between and 1 plus a little bit of expression. That’s been studied in the hormone receptor-positive population in DESTINY-Breast06. But there’s a lot of interesting further defining that triple-negative population, so to speak, they’re going to be triple-negative plus now and understanding what the benefit is in that population. So definitely will be looked at more now moving forward. Dr. Allison Zibelli: Thank you. So, let’s move on to Abstract 1002. And the results from the phase 1, 2 study of patritumab deruxtecan, a HER3-directed antibody-drug conjugate, and patients with HER3 expressing metastatic breast cancer. What are your thoughts about this study? Dr. Hope Rugo: That’s a really interesting, another one of these second- to third-generation antibody-drug conjugates. It’s just the antibody, instead of being the usual, sort of, HER2 or TROP2 that we’re used to thinking about is directed to HER3, 1 of the HER family of proteins. This is interesting. There’s actually been a lot of work trying to target HER3 with naked antibodies with disappointing results, although I have to say most of the studies really didn’t push it too far. So, with this antibody drug construct, deruxtecan, which is the same as in T-DXd and another TROP2 ADC Dato-DXd is used. So, I will say they do need to change the toxin in the next generation of ADCs. But they looked at, at first did a dose-finding study which has previously been presented, and then a dose expansion in both hormone receptor-positive HER2-negative disease and triple-negative disease. All the triple-negative patients had HER3 high disease by immunohistochemistry, and the hormone-receptor-positive patients were enrolled in 2 cohorts, HER3 high and HER3 low. And the median number of prior treatment regimens that patients had received in the hormone-receptor-positive group was 6 and 2 for the triple-negative group, but there was a huge range, up to 13 lines of treatment. They only had 14 patients with HER2+ disease. So, it’s a little bit hard to know what to do with that patient group, but they were heavily pretreated 5.5 prior lines of therapy. The confirmed overall response rate in the 113 patients with combined HER3 high and low was 30%, very impressive, heavily pretreated patients. For triple-negative disease all HER3 high, it was 23%. Again, very nice. And there were 14 patients with HER2+ disease that also were HER3 high. It was about 43%. So those are nice responses, but we always want to know how durable is that. The duration of response ranged from 6 to over 8 months in those 3 different groups. So, these were quite durable. It wasn’t any 2- to 3-month duration of response. So very impressive. And then when they looked to see, did it matter whether you had HER3 expression that was high or low in the hormone-receptor positive group, they actually did see responses in the HER3-low group, some very good responses. Overall, there were less patients in that group, but it does suggest that maybe you would still see responses in the HER3-low group, very impressive. And then 1 really interesting correlative study they did was they looked to see what happened to the HER3 expression on the tumor cell over time, and it went down. So, you treated the HER3 expression in most of the patients just dropped off completely, which is really interesting. It didn’t have any association with clinical activity, but it’s sort of an interesting correlative endpoint. This is a drug that overall was pretty well tolerated. They saw a similar toxicity to T-DXd with a lot of nauseous, a little bit of alopecia, a little bit more bone marrow suppression than we’re used to seeing with T-DXd. So, neutropenia was seen in about 10% of patients at the lower dose and about a quarter of the patients at the higher dose. Overall, pretty well tolerated. Now, interstitial lung disease is a toxicity with this construct, and they saw ILD of 7% but most cases were grade 1 and 2. The other interesting toxicity that’s unique to this agent is thrombocytopenia. So, they saw a grade 3 or greater rate of thrombocytopenia of 27% in the lower dose group, and in the larger group that received the higher dose, 39% of grade 3 or greater thrombocytopenia, so platelets less than 100,000. Turns out that when you stop the drug, the platelets do come back, so that’s a good thing. Sometimes we saw long-term thrombocytopenia with T-DM1. They didn’t see bad toxicity like bleeding, but it is something that needs to be managed with this drug because we’re not great at managing thrombocytopenia. In any case, it has fast-track designation for another solid tumor, not breast cancer, and we’ll have to see where this fits into our dizzying array of very effective ADCs now. Dr. Allison Zibelli: The practicing medical oncologist is not used to testing for HER3 in our patients with breast cancer. How common is it? Dr. Hope Rugo: HER3 expression is quite common in hormone receptor-positive disease, a little less common in triple-negative breast cancer. So, I think that we would see expression if we were going to be treating patients with this particular approach. Dr. Allison Zibelli: All right. Let’s move on to Abstract 507, which reported long-term outcomes of adjuvant denosumab in breast cancer, specifically fracture reduction and survival results from 3,425 patients in a randomized double-blind, placebo-controlled ABCSG-18 trial. What are your thoughts about this study? Dr. Hope Rugo: Well, this trial, this is an update of a study that previously has been presented and published, most recent publication was in Lancet Oncology in 2019, and these patients were randomly assigned to receive denosumab at 60 milligrams, important to note the dose, subcutaneously every 6 months versus placebo every 6 months, and they did get placebo subcutaneous injections. And this treatment continued through their endocrine therapy. They showed a dramatic reduction in fracture rate, and that has been maintained over time. We were really surprised enough to suggest that maybe Austrian people didn’t go into the sun, so they got more Vitamin D deficiency, hard to know, but the hazard ratio is 0.5. It’s unbelievable the number of fractures, 92 for denosumab but 176 for placebo, a P value of less than .0001. So, this is a real endpoint, treating patients who are receiving endocrine therapy that, in this case, non-steroidal aromatase inhibitor therapy that can increase bone loss, have a reduced fracture rate when they received denosumab. So that is the big take-home message, and a medium follow-up of 8 years. But the secondary endpoints included disease-free survival. They had about 20% disease-free survival events and 8% deaths, and what they saw was really interesting. So, the caveat is that 16% of patients were unblinded at the first analysis and half of them got denosumab, so it messed up their results a little bit, but the disease-free survival was significantly better in patients who received denosumab, and the hazard ratio of 0.83 and the hazard ratio does not cross 1. So that’s very interesting, and even overall survival, they looked at 2 other endpoints, bone metastasis-free survival, and overall survival. They also trend towards an improvement with a hazard ratio of 0.8 for both of them. And they didn’t actually see toxicity. So, patients’ brittle bone fractures and osteonecrosis of the jaw (ONJ) are all concerning, but they really just did not see any risks in this patient population. I think there was 1 patient that had what they thought was a brittle bone fracture. Obviously, they watched the mouth very carefully as well. Really dramatic, and I think it’s kind of disappointing that we never had any registration approach in this, and also not well-understood why the D-CARE study did not show a benefit, but I think D-CARE was designed differently. This is a better design to focus on our patients and the specific issues, and I think it’s intriguing and should be considered as part of our treatment regimen for patients who are at risk for bone loss and have early-stage breast cancer on an aromatase inhibitor. Dr. Allison Zibelli: I’ve been using DEXA scans and offering denosumab to my patients on AIs that have osteopenia or osteoporosis. Should we be considering it in women with normal bone mass? Dr. Hope Rugo: I think not yet. Unfortunately, this trial was not immediately powered for cancer outcome, although the data are very encouraging. We don’t know what the relationship is to bone loss, and providing an environment that’s friendlier for cancer cells. So, do you have to have bone loss in order to have the risk that you’re reducing with these agents? Certainly, that’s what we’ve seen with zoledronate. So, I think that we don’t have sufficient data to use this simply to treat cancer, but I do think that we should be considering this as an agent to give patients who have bone loss, either when you’re starting an aromatase inhibitor or during the course of therapy. I think it’s well tolerated, and a subcutaneous injection is not difficult. One of the questions that’s come up for people is do you get bone loss that increases your risk of fracture after you stop therapy. But clearly from these updated data, these patients were off therapy. They did not have an increase of fractures and the patients treated with denosumab fared much better, I mean the hazard ratio of 0.5. Dr. Allison Zibelli: Let’s move on to TROPiCS-02. That’s LBA1001. This is a randomized phase 3 study of sacituzumab govitecan versus treatment of physician’s choice in patients with hormone receptor-positive, HER2-negative advanced breast cancer. How do you think this study will impact practice? Dr. Hope Rugo: That’s a great question. I presented this data, and I think I presented it on a Saturday, and on Sunday we saw the plenary talk of DESTINY-Breast04. These patients enrolled in TROPiCs-02 had a median number of lines of prior chemo 3 with a range of up to 8 actually, compared to a median number of lines as 1 in the DESTINY-Breast04 population. We included all hormone receptor-positive HER2 negative-advanced breast cancer, not centrally confirmed. They included just the HER2 low subset that was centrally confirmed. Everybody in our study had received prior CDK4/6 inhibitors compared to about 70% in DB04. And then 95% of patients in this trial had visceral mets. So, we did really treat a patient population who had very advanced high risk hormone receptor-positive breast cancer. As you know, we saw an improvement and progression-free survival with a hazard ratio of 0.66 meeting the endpoint. We needed a hazard ratio of 0.7, highly statistically significant P value .0003, but the median difference in PFS was only 1.5 months, and overall survival data is not yet mature. So that’s brought up the question about how this drug should be used because there was a big fall off in the first 2 months where patients had rapid disease progression with heavily pretreated chemotherapy-resistant disease. We did landmark analyses and there were big separations in PFS at 6, 9, and 12 months, and 12 months, it was 21% patients free of progression and death at 1 year versus 7% for the TPC arm. So, it was a tripling of patients who were free of progression at one year. I think that’s clinically relevant. This drug is associated with more neutropenia. That’s the primary issue to manage, and probably half of the patients need growth factors at some point. When we looked at other endpoints response to ratio response, etc., we’re better with Sacituzumab. So where does this all fit into our treatment paradigm. I think there’s the HER2-low patients who will now receive T-DXd up in the, I hope, second line and not in lieu of endocrine therapy, when they’re ready for chemo. But there are patients who don’t have HER2-low disease and then there are patients who are going to be in the later line setting. So, I do think it still has a place in the treatment department, receptor-positive metastatic breast cancer. The results show that it was better than chemotherapy, physician choice based on our national and international guidelines, and that’s better for our patients to have that option. Overall survival data obviously is looked for with great interest and that will help us put this into the right paradigm. And then I also hope that real world data will help us understand how sequential treatment with these different ADCs will benefit our patients. Dr. Allison Zibelli: This is really exciting. Do you think that we’re maybe coming toward the end of conventional chemotherapy, especially for women with HER2-positive disease? Dr. Hope Rugo: I wonder if we are. I think we were interested in T-DM1 for HER2-positive disease early on. We’ve seen some really nice pathologic complete response data as well as adjuvant data in the attempt trial in patients who had stage I disease. Now that we have these second-, third-generation ADCs, T-DXd, I think this could potentially completely replace our chemotherapy. We still have to deal with alopecia. And I will point out ADCs are still chemotherapy. They’re just a much more efficient and effective way of delivering treatment, and we need to be very careful to manage the toxicity. Dr. Allison Zibelli: Next, we’re going to talk about the main pain trial that’s LBA1004, which is a randomized phase 2 trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or hormone receptor-positive HER2-negative metastatic breast cancer, in other words CDK4/6 after CDK4/6. What are your takeaways here? Dr. Hope Rugo: First, just amazing that an investigator-initiated trial could do this well and be placebo-controlled. So, kudos to the principal investigator (PI) [Dr.] Kevin Kalinsky. This trial is a small phase 2 trial. A reasonable number, 119 patients were randomly assigned and evaluable patients could have received up to 1 line of prior chemotherapy for metastatic disease. If you had received prior exemestane, you received fulvestrant, if you received prior fulvestrant, you received exemestane, and actually if you looked at the number of patients who had received fulvestrant, it was 99 versus only 20 with exemestane. So important to keep in mind. If you looked at the overall population where the primary endpoint was progression-free survival, the hazard ratio is 0.57, just median PFS of 2.8 months in patients receiving endocrine therapy and placebo and 5.3 months for patients receiving endocrine therapy and ribociclib. So was this ribociclib after ribociclib or ribociclib after something else. 86% of patients had received palbociclib as their prior CDK4/6 inhibitor, and only about 10% to 14% had received prior ribociclib. So, there’s a predominance of palbociclib followed by ribociclib. The other thing that’s important to keep in mind is how sick this patient population was. Very few had received prior chemotherapy in the less than 10% range, visceral metastases in about 60%. So that’s helpful. Only 19% or so had received 2 or more endocrine therapies from metastases. So, most people did this as their second line treatment. The PFS, when you looked at fulvestrant or exemestane, looked like the benefit was relatively similar, but you know you got 20 patients in the exemestane arm. The hazard ratios, looking at the subgroup analyses, all looked pretty similar, and the overall response and clinical benefit rate were better with continuing the cyclin dependent kinases (CDK) inhibitor. There was interesting sub-analysis looking at mutations and how that affected things. And they looked at patients who had ESR1 mutations or had wild-type ESR1. 42% had ESR1 mutations at study entry, very similar to what we’ve seen. In that group of patients, remember it’s only 33 where they had this analysis, they saw a lot of other mutations. So p53, PIK3CA, FGFR, CCND1—those patients did not benefit. Only 33 patients. No benefit at all, very short PFS, about 3 months. The patients who had ESR1 wild type seemed to benefit a lot, 45 patients going from about 3 months to a little over 8 months. So, this is all hypothesis-generating data. I wouldn’t run out and use this as your standard of care now because it is small data. But when the patient doesn’t have other good options, I certainly would consider switching the CDK and going on, add that to the next line endocrine therapy. It’s important to switch the endocrine therapy. I think we really need to look at the ongoing phase 3 trials to give us better evidence basis and understand the impact of mutations and prior therapy on who might benefit from continued CDK inhibitors after progression on a CDK inhibitor. Dr. Allison Zibelli: I think this is a really exciting trial. We all have a lot of patients on palbociclib and letrozole who’ve been on for 4, 5 years, and would like to continue with this kind of treatment because the side effects are really manageable. So, I look forward to seeing what’s coming in the future with the phase 3 trials. So, let’s talk about Abstract 1015, which I thought is a great idea. It looks at the quality of life with ribociclib plus aromatase inhibitor versus abemaciclib plus AI as first-line treatment of hormone receptor-positive, HER2-negative advanced breast cancer, assessed via matching adjusted indirect comparison. Could you tell us what matching adjusted indirect comparison is and why you chose this for the study? Dr. Hope Rugo: It’s an interesting question. How do you compare across trials? So, matching this kind of make analysis, we’ll call it a make analysis for the purposes of this discussion, allows you to match patients and weight based on their characteristics that might affect patient reported outcomes. And that actually is a way of trying to do a fair cross-trial comparison. So basically, take the study population, you match the inclusion and exclusion criteria, and then you weigh the different criteria so that you can try and make a better association. It’s the best way we know of comparing across trials. You know, a lot of people ask why we didn’t have PALOMA-2 in here, and that’s because they used a different patient reported outcome tool. So, you have to use the same patient reported outcome tool in order to compare. So that’s why we did this analysis, and it sort of came on the heels of a survey that Fatima Cardoso presented at San Antonio in 2021, where patients identified diarrhea as a symptom they really didn’t like more than everything else. And you can imagine, I think we all have that experience in practice, the unexpected nature of diarrhea and the fact that it does limit your activities and, therefore, quality of life are important. In this analysis, interestingly but not surprisingly, ribociclib favored abemaciclib in diarrhea, and there can be associated appetite loss, so ribociclib also favored abemaciclib for appetite loss. And I thought the last one was interesting—fatigue—because I wouldn’t have assumed that fatigue would be different. And maybe it’s associated with diarrhea. They have these funny arm symptoms that were better. We don’t really know why that was, and it’s hard to assess again. We’re really not clear based on the differences between the drugs. So, there are limitations to the analysis, but I think that it helps us really in individual patients try and match patients’ underlying symptoms with the best treatment to offer them the best quality of life as they’re being treated in the metastatic setting. Dr. Allison Zibelli: I thought this study was great because it really centered the experience of the patient and the wishes of the patient. You don’t see that designed into many clinical trials, the way this was. So, I thought that was a great feature of this study. Dr. Hope Rugo: I will say that all of the 3 studies that looked at CDK inhibitors, all those 3 studies included patient-reported outcomes. That’s an important new approach that is really being focused on. Dr. Allison Zibelli: Do you consider the CDK4/6 inhibitors equivalent in efficacy, and could you substitute them to try to get the side effect profile that you want? Dr. Hope Rugo: Well, I think that we saw in the early stage setting that there are differences. Now, across the different trials, there are big differences in patient populations and inclusions as we saw in the PALOMA-2 results that were presented at ASCO [Annual Meeting], whether the patients had prior chemotherapy like in PALOMA-3, whether they had a short disease-free interval, the higher risk patients in PALOMA-2. The PALOMA trials were more broadly inclusive than the other 2 studies, the MONALEESA and MONARCH series of trials. So, we do have to be a little bit careful about comparing apples to oranges, but we have the early-stage results of MONARCH E showing a clinically important difference in outcome whereas the PALLAS and Penelope-B trials didn’t. So that sort of puts us into a little bit of a question period. Are these all patient populations or are there differences between the agents? The PFS and the metastatic setting, all the hazard ratios line up. So, in truth, although I know the activity against cyclin-independent kinases are different between agents, we don’t still really understand the clinical differences in efficacy, but I think we all are practicing using evidence-based medicine. I wouldn’t, for example, substitute a different CDK4/6 inhibitor for abemaciclib in the treatment of early-stage breast cancer. We have to just learn how to manage the diarrhea and use prophylaxis and dose reduce early to manage this and make it tolerable for our patients. And in the metastatic setting, I think we need to follow evidence-based guidelines and use the best data available to decide on the right treatment approach and sequencing for our patients. Dr. Allison Zibelli: Thank you, Hope, for coming on the podcast today. This was a really interesting review of one of the most exciting ASCO [Annual Meetings] I’ve been to. And thanks for sharing your valuable insights with us and helping us make sense of all this really new exciting data. We really appreciate it. Dr. Hope Rugo: Thank you. And thank you so much for inviting me. Dr. Allison Zibelli: And thank you to our listeners for joining us today. You will find the links to all the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. That really helps other listeners find us. Thank you.   Disclosures: Dr. Allison Zibelli: None disclosed. Dr. Hope Rugo: Honoraria: Puma Biotechnology, Mylan, Samsung Bioepis, Chugai Pharma, Blueprint Medicines Consulting or Advisory Role: Napo Pharmaceuticals Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Odonate Therapeutics, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Ayala Pharmaceuticals, Astellas Pharma, Seattle Genetics, Macrogenics, Boehringer Ingelheim, Polyphor Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Guest host Dr. Neeraj Agarwal, of the University of Utah Huntsman Cancer Institute and the ASCO Daily News editor-in-chief, discusses updated results from the ENZAMET trial and other advances in prostate cancer and highlights key studies in kidney and bladder cancer with Dr. Jeanny Aragon-Ching, of the Inova Schar Cancer Institute.   TRANSCRIPT  Dr. Neeraj Agarwal: Hello! My name is Dr. Neeraj Agarwal. I'm the director of the Genitourinary (GU) Cancer Program and a professor of Medicine at the University of Utah Huntsman Cancer Institute and editor-in-chief of ASCO Daily News.  I'm delighted to have Dr. Jeanny Aragon-Ching, who is one of the associate editors at the ASCO Daily News, to discuss key oral abstracts in the genitourinary cancers, which were presented in the recently concluded 2022 ASCO Annual Meeting.  Dr. Aragon-Ching is a medical oncologist and the clinical program director of the Genitourinary Oncology Program at the Inova Schar Cancer Institute in Virginia.   Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at the ASCO.org\podcasts.  Jeanny, it is great to be speaking with you again and to discuss these practice influencing oral abstract sessions.  Dr. Jeanny Aragon-Ching: Thanks, Neeraj. I'm so very happy to be here. So, let's begin with Abstract 5000 and the ANZUP 1603 trial. This is actually the therapy trial lutetium versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC), progressing after docetaxel overall survival after a median follow-up of 3 years. Neeraj, what can you tell us about the study?  Dr. Neeraj Agarwal: Of course, Therapy Study is a randomized trial comparing treatment with lutetium PSMA-617 cabazitaxel in mCRPC patients progressing after docetaxel.  Only patients with high PSMA expression and no sites of fluorodeoxyglucose (FDG) positive, and PSMA negative disease were eligible. Previously, the ANZUP investigators showed a significant improvement in the primary endpoint of the study, which was a prostate-specific antigen (PSA) 50% response rate with 66% for those in the lutetium PSMA arm versus 37% on the cabazitaxel arm. So, PSA 50% response was higher in the lutetium therapy arm over cabazitaxel.  Investigators also reported significant results for key secondary endpoints of progression-free survival with the hazard ratio of 0.63 favoring lutetium therapy, which translates into a 37% reduction in the risk of prostate-specific antigen (PSA), pain or radiographic progression and decreased adverse events of grade 3 or 4 side effects for patients in lutetium PSMA therapy compared to cabazitaxel.  So, this was presented in the past. In this update, Drs. Michael Hoffman and Ian Davis report results on this secondary endpoint of overall survival after a median follow-up of 3 years. In addition to reporting on overall survival, the reanalysis of PSA and radiographic progression-free survival continued to significantly favor the lutetium PSMA arm with a 38% reduction in the risk of progression. After a median follow-up of 36 months, the overall survival was similar in those assigned to lutetium PSMA versus cabazitaxel with a restricted mean survival time of 19.1 months for lutetium therapy versus 19.6 months for cabazitaxel therapy, respectively.  No additional safety signals were identified with the longer follow-up. An important point here is that the therapy trial was never powered for overall survival.  Dr. Jeanny Aragon-Ching: So, this is a very important study indeed, Neeraj. So, what do you think is the key takeaway from this trial?  Dr. Neeraj Agarwal: The key takeaway message here is that while the lutetium PSMA is a suitable option for men with PSMA-positive mCRPC progressing after docetaxel. The similar overall survival compared to cabazitaxel indicates cabazitaxel is also a suitable option for those patients with high PSMA expression.  However, while lutetium PSMA-based therapy and cabazitaxel had similar overall survival results, treatment with lutetium PSMA was associated with fewer adverse events and better patient-reported outcomes. So, given the option of both being available, after disease progression on docetaxel, I would lean towards using lutetium PSMA therapy first, followed by cabazitaxel chemotherapy.  Dr. Jeanny Aragon-Ching: That's wonderful, Neeraj. Now moving on to LBA5004, investigators reported updated overall survival outcomes in the ENZAMET Trial an international cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer. What are your thoughts about this abstract?  Dr. Neeraj Agarwal: So, ENZAMET was a large phase 3 trial in the metastatic hormone-sensitive prostate cancer setting, which randomly assigned 1,125 patients to androgen deprivation therapy or they called it testosterone suppression therapy, which I like more, plus older antiandrogen such as bicalutamide versus testosterone suppression therapy plus enzalutamide.  The trial originally matches the primary endpoint with a 33% improvement in overall survival with enzalutamide. One of the unique aspects of the trial was that patients were allowed to receive docetaxel during the protocol treatment and the receipt of docetaxel had to be predetermined before randomization.  So, a total of 503 patients received docetaxel, which represents 45% of all patients randomly assigned on the ENZAMET trial. In this timely update at the 2022 ASCO Annual Meeting, Drs. Ian Davis and Chris Sweeney report that a combination of enzalutamide plus testosterone suppression therapy continues to improve survival with a 30% reduction in the risk of death with enzalutamide after an additional 3 years of follow-up.  Interestingly, in the subgroup of patients who received concurrent docetaxel, there was no improvement in the overall survival with enzalutamide. Having said that, this is a subgroup analysis for which that trial was not independently powered, and the receipt of docetaxel chemotherapy was determined based on physician and patient judgment or their choice, and it was not randomized. So, I would say that in the overall ENZAMET trial population, the receipt of enzalutamide was associated with improved progression-free survival as well as overall survival.  Dr. Jeanny Aragon-Ching: That's a very great summary, Neeraj. So, what do you think is the key takeaway from this abstract?  Dr. Neeraj Agarwal: The updated results of the ENZAMET trial with a longer median follow-up of almost 6 years, showed that enzalutamide continues to show improved overall survival in men with metastatic hormone-sensitive or castration-sensitive prostate cancer.  Furthermore, the effect of enzalutamide on overall survival is independent of the receipt of docetaxel in the ENZAMET trial. Based on these results, upfront intensification of androgen deprivation therapy with a deeper androgen access inhibitor remains the standard of care and should be offered to all patients with metastatic castration-sensitive prostate cancer.  So, I think we have discussed this really exciting practice influencing prostate cancer abstract, Jeanny. I would like to move on to kidney cancer for a moment. I think we can discuss the CheckMate-9ER, which is Abstract 4501, which reported on the association between depth of response and clinical outcomes.  So, this was an exploratory analysis in patients with previously untreated advanced renal cell carcinoma who were treated with cabozantinib with nivolumab versus sunitinib in the CheckMate-9ER trial. So, any good news from this analysis, Jeanny?  Dr. Jeanny Aragon-Ching: Yeah, so as you may recall, at the 2022 Genitourinary Cancers Symposium, Dr. Powles reported updated results for the randomized phase 3 trial called CheckMate-9ER and this showed that treatment-naive patients with advanced renal cell carcinoma had a significantly improved progression-free survival. The hazard ratio was like 0.56 and overall survival of 0.7 and this is with nivolumab and cabozantinib compared to sunitinib alone.  So, in this exploratory analysis, Drs. Cristina Suárez and Andrea Apolo decided to evaluate the relationship between the depth of response and clinical outcomes. So, depth of response was defined as a breast percent reduction from baseline in the sum of diameters of targeted lesions. And this has been previously reported to be associated with efficacy outcomes in patients with advanced renal cell carcinoma treated with checkpoint inhibitors or targeted agents.  Now for this particular analysis, patients with a partial response were further divided into 3 subgroups. So, it was based on partial response with different tumor reduction thresholds.  So, for instance, patients in the first subgroup of partial responders, they call them PR 1, had a tumor reduction of at least 80%. And then PR 2 responders were categorized as those with a tumor reduction of less than 80%, but at least 60%. The last subgroup which is called PR 3 included patients with less than 60% tumor reduction.  So, all of these other subgroups, which included complete responders, stable disease, and progressive disease remain the same. So, overall, deeper responses were associated with improvements in progression-free survival (PFS) and overall survival (OS) benefits for patients with advanced renal cell carcinoma.  However, the association between the depth of response and improved PFS benefit for patients treated with nivolumab and cabozantinib was noticeably linear compared to those treated with sunitinib.  It's also interesting to note that the median duration of response improved numerically with each incremental depth of response with nivolumab plus cabozantinib arm but not really seen in this sunitinib arm.  Dr. Neeraj Agarwal: Very interesting data. So, what is your key takeaway from this trial, Jeanny?  Dr. Jeanny Aragon-Ching: Yeah, so I think the results from this exploratory analysis are very exciting and provide a useful tool that clinicians can further use to help counsel our patients when reviewing their scans, for instance, in the clinic.  Furthermore, based on such a robust correlation of the depth of response with PFS and OS, it may be time for us to consider objective response as a surrogate for PFS and OS by the regulatory bodies to expedite the hopeful drug approval.  So, moving on, Neeraj, to Abstract 5006. This is assessing the intermediate clinical endpoints as potential surrogates for overall survival in men with metastatic hormone-sensitive prostate cancer. Why do you think this study should be on our radars?  Dr. Neeraj Agarwal: During the last several years we have seen many of the agents, typically given for castrate-resistant prostate cancer, moving up front to the castration-sensitive setting. And this is especially true for androgen receptor access targeting agents like enzalutamide or abiraterone, which have moved from castration-resistant prostate cancer (CRPC) to castration-sensitive prostate cancer (CSPC) setting and chemotherapy with docetaxel.  An exciting outcome from these advances is a significant improvement in the overall survival of our patients, which is now extending beyond 6 to 7 years as reported by many of the recent trials.  However, as a consequence of these improvements, phase 3 clinical trials in the hormone-sensitive metastatic prostate cancer setting are taking significantly longer to report overall survival outcomes, thus requiring identifying valid surrogates in order to expedite results.  So, in Abstract 5006, Drs. Susan Halabi and Chris Swinney investigate the use of radiographic progression-free survival and clinical progression-free survival as intermediate clinical endpoints as potential surrogates for overall survival in men with metastatic hormone-sensitive prostate cancer.  This study was performed through the STOPCAP M1 Collaboration, which is an international collaboration of multiple investigators from institutions across the planet. Individual patient-level data from more than 8,500 patients from the randomized phase 2 and 3 clinical trials in patients with metastatic hormone-sensitive prostate cancer conducted between 1994 and 2013 were analyzed.  The median overall survival was 49.4 months in the cohort, and the radiographic progression-free survival and clinical progression-free survival were 26.8 and 25.2 months respectively.  The surrogate threshold effect was 0.82 for radiographic progression-free survival, and 0.84 for clinical progression-free survival, which tells us that both radiographic PFS and clinical PFS strongly correlate with overall survival. So, I think we have discussed exciting prostate cancer data and bladder cancer data.  Jeanny, I would like to move on to the bladder cancer and would like your take on this abstract, which created lots of buzz about cell-free DNA methylation as a predictive biomarker of response to neoadjuvant chemotherapy for patients with muscle-invasive bladder cancer in the SWOG S1314 trial, which is Abstract 4506. So, Jeanny, why should this study be on our radar?  Dr. Jeanny Aragon-Ching: Yes, absolutely. So, neoadjuvant chemotherapy has been the standard of care in muscle-invasive bladder cancer. However, treatment is often intense, the overall benefit is small, and there are no established biomarkers to identify patients who will benefit the most.  So, in this study, Drs. Yi-Tsung Lu and Amir Goldkorn characterize cell-free DNA methylation patterns from patients receiving neoadjuvant chemotherapy in the SWOG S1314 trial, and they correlated the methylation signatures with pathologic response.  So, the SWOG trial is a randomized phase 2 trial that primarily investigated a predictive biomarker for neoadjuvant chemotherapy in patients with localized muscle-invasive bladder cancer.  Now, in this exploratory analysis, the investigators developed a methylation-based response score, predictive of pathologic response to neoadjuvant chemotherapy for patients with localized muscle-invasive bladder cancer, by testing pre-treatment and on-treatment cycle 2, day 1 plasma cell-free DNA.  So, the results indicated that the combination of the methylation base response score and circulating bladder DNA fraction successfully predicted pathologic response outcomes in about 79% of patients based on plasma collected before and after cycle 1 of chemotherapy.  Dr. Neeraj Agarwal: This is so encouraging. It is such great news for our patients. So, what is the key takeaway from this trial?  Dr. Jeanny Aragon-Ching: Yeah, so I think the key takeaway from this abstract is that once validated, these cell-free DNA methylation patterns may be hopefully used to predict treatment response in patients with bladder cancer receiving neoadjuvant chemotherapy.  Now following validation of these results, we will hopefully be able to personalize neoadjuvant therapy for patients with localized muscle-invasive bladder cancer, and hopefully, improve the acceptability of this therapeutic modality in our clinics.  So, finally, moving forward with the last abstract that we would like to discuss today is Abstract 5018. It's called the BRCAAway trial. A randomized phase 2 trial of abiraterone, olaparib, or abiraterone with olaparib in patients with metastatic CRPC with DNA repair defects. What are your thoughts, Neeraj, on this one?  Dr. Neeraj Agarwal: As we have all seen over the last few years several PARP inhibitors have been approved or are in advanced phases of development for the treatment of patients with metastatic prostate cancer, both in the castrate-resistant phase as well as in hormone-sensitive setting, specifically those patients which are harboring germline or somatic mutations in homologous recombination repair genes.  We also know based on multiple reports that PARP 1 protein interacts with the androgen signaling pathway and concurrent or co-targeting of androgen receptors and one PARP pathway may have synergy.  The current study led by Dr. Maha Hussain addressed a pivotal question, are PARP inhibitors most effective as monotherapy or in combination with a novel androgen access inhibitor like abiraterone?  BRCAAaway is a randomized phase 2 trial of abiraterone or olaparib or abiraterone plus olaparib in patients with metastatic castrate-resistant prostate cancer, harboring inactivating alterations in BRCA1, BRCA2, and/or ATM genes.  This aspect of the trial is unique as none of the current trials have randomly assigned patients from monotherapy with a PARP inhibitor to monotherapy with a novel androgen axis inhibitor in the first line mCRPC setting.  The primary endpoint is progression-free survival, analyzed per Kaplan-Meier and Cox regression with multiple secondary endpoints. Both monotherapy arms were allowed to crossover at the time of progression. The 12-month progression-free survival was significantly improved with the 95% of patients treated on the combination of abiraterone prednisone plus olaparib arm, remaining on the protocol treatment compared to only 42% of patients on Abiraterone Prednisone arm or only 44% patients on the olaparib arm.  So, we saw a 12-month progression-free survival rate of almost double with a combination of abiraterone plus olaparib versus either of the monotherapies. And hence we can say that the PFS was significantly improved in combination therapy versus the monotherapy arm. And in addition, PSA response rates were also improved in the combination therapy arm.  Dr. Jeanny Aragon-Ching: So, this was really an important trial. So, what do you think is the key takeaway from this trial?  Dr. Neeraj Agarwal: The key takeaway from this abstract is that the combination of abiraterone, prednisone, plus olaparib was not only well tolerated, but was also associated with significantly improved progression-free survival and better PSA response rates compared to either agent alone. And this provides the rationale for using combination-based therapies rather than sequencing.  And obviously, this is a small trial, the data have to be validated in larger trials. But based on the fact that half of the prostate cancer patients who have advanced prostate cancer do not see subsequent lines of therapy is based on real-world results. The fact that combination therapy is so well tolerated and shows such significantly improved progression-free survival, I think these data are very encouraging for other trials, which are ongoing and may provide a solid rationale for combining these therapies rather than sequencing these therapies upfront.  So, Jeanny, any final thoughts? I think we have covered many of the important practices and influencing oral abstracts on the genitourinary sessions from the 2022 ASCO Annual Meeting. Obviously, we cannot cover all of them. There are many more we have left out. Having said that, any final thoughts before we wrap up our podcast today?  Dr. Jeanny Aragon-Ching: No, I think these are very interesting and very important abstracts that we discussed today. It's really a great way to wrap up the ASCO Annual Meeting for the GU section.  Dr. Neeraj Agarwal: Well, Jeanny, thank you for sharing all your insights with us today. It has been great discussing these abstracts with you.  Dr. Jeanny Aragon-Ching: Yeah, my pleasure, Neeraj.  Dr. Neeraj Agarwal: And thank you to our listeners for joining us today. You will find a link to the abstracts discussed today on the transcripts of this episode. Finally, if you value insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you very much!    Disclosures:  Dr. Neeraj Agarwal:  Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, Gilead Sciences  Research Funding (Inst.): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck , Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, Arvinas  Dr. Jeanny Aragon-Ching:  Honoraria: Bristol-Myers Squibb , EMD Serono, Astellas Scientific and Medical Affairs Inc  Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, AstraZeneca/MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis  Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics  Travel, Accommodations, Expenses: Dendreon,  Algeta/Bayer, Bristol Myers Squibb, EMD Serono , Astellas Pharma  Disclaimer: The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. 

Guest host Dr. Vamsi Velcheti, of the NYU Langone Perlmutter Cancer Center, and Dr. Brian Henick, of the Columbia University Herbert Irving Comprehensive Cancer Center, discuss advances in KRAS-mutated lung cancer in the KRYSTAL-1 trial, and the association of ctDNA with overall survival in the NADIM trial, as well as other key advances in lung cancer presented at the 2022 ASCO Annual Meeting.   TRANSCRIPT   Dr. Vamsi Velcheti: Hello, everyone! This is Dr. Vamsi Velcheti, I'm your guest host for the ASCO Daily News podcast, today. I'm an associate professor and medical director for the Thoracic Oncology Program at Perlmutter Cancer Center at NYU Langone Health. My guest today is Dr. Brian Henick, an associate director of the Experimental Therapeutics Program, and assistant professor of Medicine at Columbia University's Herbert Irving Comprehensive Cancer Center. We'll be discussing key abstracts in lung cancer that were featured at the 2022 ASCO Annual Meeting. Our full disclosures are available in the notes and disclosures of all guests on the podcast can be found on the transcripts at asco.org/podcasts. Brian, it's great to speak with you today. Dr. Brian Henick: Thank you so much, Vamsi, and ASCO Daily News for letting me join you to discuss these abstracts. Dr. Vamsi Velcheti: So, let's dive in. So, it's an exciting ASCO Annual Meeting. And I hope you had a great time at the Meeting. So, let's start off with the LBA9009 and KRYSTAL-1 clinical trial. The study showed the activity of adagrasib in patients with KRAS-G12C mutant non-small cell lung cancer and active untreated brain mets. So, what is the key takeaway from this trial? Dr. Brian Henick: Well, Dr. Sabari presented some encouraging data on this important population. As we know, patients with active central nervous system (CNS) metastases represent a population of unmet medical need who are often excluded from clinical trials. So, it's a credit to the investigators for including this cohort. As Dr. Sabari noted, and as Dr. Goldberg emphasized in her discussion of the abstract, the measured CNS penetration of adagrasib compares favorably with other CNS active compounds from other settings. The overall response rate was 35%, with a disease control rate of 80%. But impressively, the median duration of intracranial response and progression-free survival (PFS) wasn’t reached. This certainly seems to be a CNS active compound, and we'll need to see how sotorasib stacks up in their comparable cohort. Ideally, we'd have randomized data to prove superiority over the standard of care, but we may be a few steps away from that. Dr. Vamsi Velcheti: So, Brian, in terms of CNS mets, how big of a problem is it in patients with KRAS G12C mutant lung cancers? Dr. Brian Henick: We know that CNS metastases are a big problem for G12C mutant lung cancer. The rates have been quoted as high as up to 42% of patients. And in particular, as you know, Vamsi, a lot of times trials often don't include, specifically, cohorts with active untreated brain metastases. And so, this is a very unique cohort in that sense. Dr. Vamsi Velcheti: I just want to highlight that we really don't know the differential efficacy of sotorasib and adagrasib in the CNS met population because the trials were CodeBreak 100 and other trials and data readouts from sotorasib did not include patients with untreated brain mets. We did, however, [see] CNS progression-free survival data that go in line with sotorasib. So, it's really important to see that data from sotorasib. Dr. Brian Henick: I definitely look forward to seeing that. Dr. Vamsi Velcheti: So, let's talk about Abstract 8501. The primary endpoint that was presented at ASCO [Annual Meeting] was the pathologic complete response to chemotherapy and nivo vs. chemotherapy as a new adjuvant treatment for resectable stage 3, a non-small cell lung cancer. This was the phase 2 NADIM trial. So, what do you think about this study? And what's your key takeaway from the study? Dr. Brian Henick: Dr. Provencio from Spain presented data from this randomized study as you said, of nivo plus carbo taxol compared to carbo taxol as neoadjuvant therapy for potentially resectable stage 3-A and B non-small cell lung cancer. So, I did want to compare this to the randomized data that we have from Checkmate 816, which interestingly allowed for earlier-stage disease as low as 1-B. And they also allowed for more flexibility in the choice of platinum doublet regimens. This study, NADIM 2, employs 2:1 versus 1:1 randomization, which we saw in Checkmate 816. Another important difference was that NADIM 2 required adjuvant nivolumab for 6 months in the study arm, whereas Checkmate 816 didn't include any immunotherapy in the adjuvant setting, but they allowed for a standard of care chemotherapy. In NADIM 2, the control arm didn't include any adjuvant therapy. In keeping with the impressive improvements over historical pathologic complete response rates of about 5%, this chemotherapy-IO regimen yielded a path complete response (CR) rate of 36.8%. It also showed a major pathological response, which again is defined as less than 10% viable tumor of 52.6%, and an overall response rate of 75.4%. So, it looks like there's a benefit that's happening upfront with the immunotherapy and chemotherapy as opposed to this just being an adjuvant phenomenon. This is also in keeping with data that we saw with Checkmate 816, as well as neoadjuvant atezo plus chemotherapy in the phase 2 study that was led by Catherine Shu and colleagues here at Columbia a few years ago. Overall, this is more encouraging data for the neoadjuvant use of immunotherapy. The earlier immunotherapy marches into the treatment course of patients with lung cancer, the greater the cost of toxicity. So, I think an important thing for us to focus on going forward is trying to develop strategies to better identify the patients that are most likely to benefit. Dr. Vamsi Velcheti: So, Brian, I think from a practical standpoint, now that we have approval for neoadjuvant immunotherapy and adjuvant immunotherapy, we have some practical challenges in terms of how we manage our patients. Of course, the new adjuvant is very appealing because it's only 3 cycles of chemoimmunotherapy, but the challenge though, is a majority of the patients don't have a CR, or a significant proportion of the patients have an ongoing response or significant residual disease at the time of surgery. So, the question then would be what do you do after surgery if they're having an ongoing response? Do you think 3 cycles of immunotherapy are inadequate systemic therapy for these patients? Dr. Brian Henick: It's a really important question, Vamsi. I think until the data is mature, we're just kind of limited by the extent of what the data tells us so far, and then we have to kind of do our best as the treating doctor to navigate the patient's situation. So, tools that we'd still have available to us in the adjuvant setting that are approved are things like chemotherapy and radiation, leveraging things like circulating tumor DNA, I think maybe a promising path forward, as well to help guide strategies there, but I think until the data is mature, it has to be highly patient-focused to figure out what seems to be most appropriate there. How are you navigating those situations, Vamsi? Dr. Vamsi Velcheti: Yeah, as you said, it is very challenging. I think we need more data. And of course, the challenge now is like, if you use immunotherapy in the new adjuvant setting, it's very likely you're not going to get insurance authorization for 1 year of adjuvant atezolizumab. So, we really need studies to optimize treatment paradigms here. As you suggested, maybe circulating tumor DNA (ctDNA)-based approaches to look at residual disease, I think, that would be one great way to do it. Let's move on to the next abstract, Brian. I found Abstract 9001 really interesting. It's a U.S. Food and Drug Administration (FDA) pooled analysis that looked at outcomes of first-line immune checkpoint inhibitors, with or without chemotherapy based on the KRAS mutation status and PD-L1 expression. So, what is your take on this abstract and how do you think this is going to impact our practice? Dr. Brian Henick: So, Dr. Nakajima and colleagues explored the observation from individual trials that patients with KRAS-mutant lung cancer seem to have better responses than wild type with immunotherapy (IO) alone. But the favorability of these responses seems to be abrogated with chemotherapy-IO. We know that KRAS accounts for 25% of oncogene-driven non-small cell lung cancer predominantly at amino acid 12. And with the emergence of direct inhibitors of G12C, understanding the clinical features of these tumors may be critical to inform optimal integration of this new class of drugs and also to make sure that we've optimized treatment algorithms for KRAS patients in general. So, this study's authors at the FDA pulled data from 12 registrational clinical trials that were investigating first-line checkpoint inhibitor-containing regimens and they found no significant difference between KRAS wild type and mutant for overall survival regardless of the regimen used. The best outcomes were seen with chemoimmunotherapy regardless of KRAS status. This retrospective analysis does suggest that the notion of there being lesser benefit from chemoimmunotherapy from Dr. Gadgeel's study might not hold up in the overall population, but I think it raises important questions, like, are all KRAS mutations alike? The absence of KRAS mutation status for a majority of patients included in these studies limits the interpretation of the data. And also, the absence of commutation status makes it a little harder to interpret. And other important questions remain such as how G12C inhibitors will factor in? What were your thoughts, Vamsi? Dr. Vamsi Velcheti: No, I completely agree with you, Brian. I think we need more data and we know that commutation status is a very important aspect in terms of KRAS-directed therapies. And of course, with a lot of promising data from these KRAS inhibitors, there's an interest in moving these drugs into the front-line therapy for patients with KRAS mutations. But I think it's going to be quite challenging to incorporate them into the front-line therapies and we clearly will need better characterization of these patients with KRAS mutant [lung cancer] to further personalize treatment in the frontline setting for these patients. So, let's move on to the next abstract. This is the lung map study, Abstract 9004. This is a study sponsored by the National Cancer Institute (NCI), the lung map study, looking at overall survival from a phase 2 randomized study of ramucirumab and pembrolizumab, what's the standard of care in patients with advanced non—small cell lung cancer previously treated with immunotherapy. So, what were your key takeaway points here from this study? Dr. Brian Henick: So first of all, it's very exciting to see data from this very ambitious long map sub-study yield a positive result. Whereas many of the arms of this study were biomarker-guided, Dr. Reckamp presented the results from pembro plus ramucirumab as compared to the standard of care in unmarked patients with non-small cell lung cancer who had progressed after prior treatment with chemotherapy and immunotherapy. The data seems to suggest that pembro plus ramucirumab may be better tolerated than the standard of care chemo-containing regimens, as the experimental regimen had fewer serious adverse events. Pembro plus ramucirumab had a median overall survival of 14.6 months as compared to 11.6 months in the control arm and this was statistically significant. The PFS difference wasn't significant, but there was a late divergence in the curves. Dr. Bestvina nicely summarized some of the study's limitations such as the mixture of control regimens used, and there were really interesting signals that were found on subgroup analysis, such as benefit in those with mixed histology tumors, STK11 mutant tumors, and those who received chemotherapy prior to immunotherapy. The subgroups deserve further attention in the future. For now, this regimen may be an appealing option as an alternative to chemotherapy for the right patients. What do you think? Dr. Vamsi Velcheti: Yeah, I agree, Brian. I think it's a really promising combination. We've always seen some synergy with VEGF inhibitors and immunotherapy in multiple studies and multiple tumor types. So, we really need to develop better ways to select patients for VEGF combination-based approaches in lung cancer. So, let's move on to another interesting study. This is Abstract 9000. This explores the outcomes of anti-PD-L1 therapy with or without chemotherapy for first-line, metastatic non-small cell lung cancer with a PD-L1 score of greater than 50%. So, this is an FDA pooled analysis. So, what were your key takeaways from this abstract? Dr. Brian Henick: I thought this question was really well suited for a large pooled retrospective analysis and our colleagues at the FDA didn't let us down here. The question really was what's the optimal approach for patients with non-small cell lung cancer with greater than 50% PD-L1 in view of the absence of direct comparisons between these arms in prospective studies? I thought one of the most striking findings from Dr. Akinboro's presentation was the dismally low rate of underrepresented minority patients that were included in these registration trials. As far as the findings for the patients who were studied, although the Kaplan-Meier curves for overall survival showed early separation, the difference wasn't statistically significant. Subgroup analysis revealed a trend towards better outcomes for immunotherapy alone among patients who are [age] 75 and above, suggesting that this may need to be parsed out as a unique population in subsequent studies. But in all, our equipoise as a field on whether to include chemoimmunotherapy-based first-line regimens should persist and should be guided, in my opinion, largely by clinical considerations. Can the patient tolerate chemotherapy? Do you need a rapid response? Are there other things that you thought in hearing all this, Vamsi? Dr. Vamsi Velcheti: Yeah, absolutely. I think I am still struggling with the decision of whether to add chemotherapy for patients with greater than 50%. To a large extent, it's actually a clinical decision. In some patients who have a large disease burden, I tend to kind of opt for adding chemotherapy to immunotherapy in the front-line setting. But of course, we need more data here. And this is actually a very helpful piece of information from the FDA. And as you pointed out briefly, Brian, I think the fact that there are very few underrepresented patients in the pooled analysis, I think kind of speaks to the need for addressing increased diversity in clinical trial accruals. I think this is a great segue to also talk about Abstract 9012, talking about disparities in access to immunotherapy globally. This is a study from India looking at 15,000 patients who were checkpoint inhibitor eligible and who have very low rates of uptake of immunotherapy. This is something that reflects the global team of the ASCO Annual Meeting talking about disparities and improving access to treatments in underserved minority populations here in the United States, and also globally, in the developing world, the disparities in terms of access to care are humongous. So, what are your thoughts, Brian? And also, if you could highlight some of the work that you're doing at Columbia about disparities, I think that would be great. Dr. Brian Henick: Absolutely! I think access to medications is a really humbling topic for those of us who are involved in developmental therapeutics, particularly with the transformational impact we've seen with the advent of immunotherapy over the last decade-plus. Dr. Ravikrishna’s presentation is therefore extremely important. He described very low rates of uptake of immunotherapy by indication. And perhaps most strikingly, the discrepancy in uptake by patients' ability to pay for therapy with the vast majority of immunotherapy received by those who are private is very concerning. Even if the definition of restricted access was permissive, for example, I didn't see mention of the cancer stage as an eligibility factor, the fact that this represents a single referral center's data doesn't bode well for uptake elsewhere. So, I think we need to continue to work as a field on prioritizing strategies to help overcome these gaps, but good quality data such as this study is an important first step. And to that point, Vamsi, I'm very excited to be working with you in collaboration on an observational study for patients with lung cancer from underserved minority populations with lung cancer in New York City so that we can better characterize access to care, efficacy, and toxicity in this population. Dr. Vamsi Velcheti: Thank you, Brian. I'd really like to thank you for sharing your valuable insights with us today on the ASCO Daily News Podcast. We really appreciate it. Brian, thank you so much for joining us. Dr. Brian Henick: My pleasure. Thanks for having me. Dr. Vamsi Velcheti: And thank you to all our listeners for joining in today. You will find links to all the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thank you so much.   Disclaimer: The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Disclosures: Dr. Vamsi Velcheti: Honoraria: Honoraria Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline Dr. Brian Henick:  Consultant/Advisory: Ideaya, AstraZeneca Research Support: Neximmune

Dr. Sonali Smith, of University of Chicago Medicine, highlights dynamic sessions and hot topics that will be featured in the 2022 ASCO Annual Meeting Scientific Program, including practice-changing advances in breast cancer, colorectal cancer, sarcoma, and myeloma.     Transcript  ASCO Daily News: Hello and welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. I'm delighted to welcome Dr. Sonali Smith, professor and chief of the hematology-oncology section at University of Chicago Medicine.  Dr. Smith is also the Chair of the 2022 ASCO Annual Meeting Scientific Program and joins me to discuss the hot topics and must-see sessions that will be featured at the meeting.  Her full disclosures are available in the show notes and disclosures relating to all guests on the podcast can be found on our transcripts at asco.org/podcasts.  Dr. Smith, it's great to have you on the podcast today.  Dr. Sonali Smith: Thank you, Geraldine. It's a pleasure to be here.  ASCO Daily News: Well, thousands of abstracts were submitted for consideration this year and more than 2,900 were selected for presentation. We'll talk about some of the must-see sessions. First, can you tell us about the areas that have shown tremendous advances this year—the practice-changing abstracts that will make the headlines?  Dr. Sonali Smith: Yes, that's right. There were over 6,000 abstracts submitted for consideration this year and more than 2,900 abstracts were selected for presentation with over 250 oral presentations. We had 2,200 that were online publication only. And given the hybrid nature of ASCO [Annual Meeting] this year, we will have 86 sessions that will be livestreamed, including all of our abstracts that are oral.  I'm really excited about the Plenary. In particular, there are going to be some practice-changing abstracts involving breast cancer, colon cancer, sarcoma, and myeloma. We are really thrilled with the quality and the excitement around the data and I do think this is going to be very important for people who are in practice.  When we think about the different abstracts that have been submitted for the Plenary, they will focus on front-line colon cancer, the approach to Ewing sarcoma in pediatric patients, and the use of antibody-drug conjugates for breast cancer in a very specific subset. And then also some discussion about, or presentation about, the use of maintenance therapy in patients with myeloma.  ASCO Daily News: Excellent. Well, the Clinical Science Symposia are quite popular among participants. Can you tell us about some of the topics that will be featured this year?  Dr. Sonali Smith: Yes. So, the Clinical Science Symposia (CSS) were really a lot of fun to pull together. As this audience knows well, this is an opportunity for us to take a look at all of the abstracts submitted and look for cross-cutting themes between all of the different cancers that we take care of. They can focus on new technology. They can focus on new approaches to therapy. And after looking at all of the submitted data, we have 3 really outstanding special Clinical Science Symposia for which I'm really excited.  One is going to focus on circulating tumor DNA, “ctDNA: Dawn of a New Era,” and I really do believe in that title and encourage everybody to come and hear how this could be applied in practice.  The second special CSS will be on Bispecifics. Really asking the investigators as well as the discussants. “Bispecifics: Are Two Better Than One?” And then the third special Clinical Science Symposium will be called, “Is There a Ghost in the Machine? Putting Artificial Intelligence to Work.” And as many of us know, machine learning is finally finding its way into oncology. And I'm just thrilled at the abstracts that have been submitted.  I also just wanted to say that we've had a really outstanding speaker lineup and it's incredibly diverse with international perspectives brought to the table.  ASCO Daily News: Absolutely. And so, what are some of the other sessions that will be on your own list this year?  Dr. Sonali Smith: Well, I'm really excited about the opening session, which will be at 9:30 in the morning on Saturday, June 4th. We will have our president, Dr. Everett Vokes, speaking on his theme, Advancing Equitable Cancer Care Through Innovation.  We also have our FASCO presentations, and we have 2 special speakers. One will be Ned Sharpless, who is the head of the National Cancer Institute. And then we will also have Dr. Andre Ilbawi, who is the lead of cancer programs at the World Health Organization. He has had an incredible impact on improving access for children with cancer on a global level. And I think this series of speakers really fits with our theme this year.  Another session I'm really looking forward to is the [David A.] Karnofsky [Award and] lecture by this year's widely respected speaker, Dr. Jedd Wolchock. This is anticipated to be an incredibly thought-provoking and clinically relevant presentation, and I hope all of you will join us.  ASCO Daily News: In following up then on the theme of the meeting this year, it is, of course, Advancing Equitable Cancer Care Through Innovation, can you comment on how important it is that this theme is represented in as many of these programs, as many of these sessions as possible at meetings such as the [2022] ASCO Annual Meeting and other symposia?  Dr. Sonali Smith: A global approach and a global mentality when we are developing therapies, preventive approaches, are really incredibly important. In the United States, at least, the survival for patients with cancer has doubled, and I think it is really important to remember that we are a global organization and there are many people around the world who can benefit. And if we can put innovation into this, hopefully, it can be done better and faster.  ASCO Daily News: Absolutely! Well, thank you so much, Dr. Smith, for taking the time to be on the podcast today and for sharing some of these highlights. And a big thank you for your efforts to create a really robust scientific program for the 2022 ASCO Annual Meeting.  Dr. Sonali Smith: Thank you so much. It's been a real pleasure.  ASCO Daily News: And thank you to our listeners for your time today. If you're enjoying the content on the ASCO Daily News podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.      Disclosures:   Dr. Sonali Smith has been paid for any consulting or advisory role by ADC Therapeutics , Adaptive Biotechnologies , Gilead Sciences, Bristol Myers Squibb, MorphoSys, Janssen, Bantam Pharmaceutical, and Karyopharm Therapeutics, currently or during the past 2 years. Dr. Smith has received research funding from Portola Pharmaceuticals, Genentech, Acerta Pharma, Pharmacyclics, Celgene, Curis, Bristol Myers Squibb, TGTX, Merck, Forty Seven, and Novartis, currently or within the past 2 years.   Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   

Dr. Diwakar Davar and Dr. Jason Luke, both of the University of Pittsburgh’s Hillman Cancer Center, share the latest news on immunotherapy trials KEYNOTE-A10, LIBRETTO-001, and other key IO studies across tumor types featured at the 2022 ASCO Annual Meeting.  Transcript Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Diwakar Davar, and I'm an assistant professor of Medical Oncology in phase 1 therapeutics, at the University of Pittsburgh's Hillman Cancer Center, and the guest host of today's podcast. I'm delighted to welcome Dr. Jason Luke to this podcast. He's the director of the Cancer Immunotherapeutic Center at the Hillman Cancer Center, University of Pittsburgh, and a great colleague and friend.  Today we'll be discussing some key posters that highlight some advances in immunotherapy that will be featured and the 2022 ASCO Annual Meeting. You will find our collective disclosures in the show notes and the disclosures of all guests on the podcast are available on our transcripts at asco.org/podcasts.  So, Jason, thank you for coming on the podcast today.  Dr. Jason Luke: Well, thanks very much for the invitation. I always love doing these podcasts for ASCO, and never love anything more than hanging out with my friend Diwakar Davar.  Dr. Diwakar Davar: Well, thank you! Below are the abstracts we've selected. We will start with Abstract 2504. This is a phase 1 trial of the TIM-3 inhibitor cobolimab monotherapy, singly and in combination with the PD-1 inhibitors nivolumab or dostarlimab. Phase 1 data from the AMBER trial with the presenting author being Dr. Gerald Falchook. And this is a trial that initially started several years ago. And I know Jason, that you were involved with the inception of this agent, that TIM-3 inhibitor. So, walk us through, TIM-3. It's a third-generation checkpoint, we now have TIGIT LAG coming into the landscape. Definitely a first indication for LAG-3 melanoma with a positive trial, RELATIVITY 047. So, where are we with TIM-3? Why should we be excited about TIM in general, and this data in particular?  Dr. Jason Luke: It is quite exciting, especially building off the recent data that we saw for relatlimab or LAG-3 because it's becoming clearer that a number of these other immune checkpoints that we have been talking about for many years, actually really can be effective when used in the right setting.  So, this drug, this anti-TIM-3 antibody cobolimab monotherapy, as you mentioned, started out in a phase 1 clinical trial dating all the way back to I think about 2015. And that was at the time in immuno-oncology when everybody was so excited, [and] they thought everything was going to work immediately.  Subsequent to that, obviously, we've had some hurdles that we've had to come over. But we're coming back to some of these agents now, which are looking very exciting. So, just in the same way we think about blocking PD-1 or now blocking LAG-3 to reinvigorate T cells in the tumor microenvironment, there's a good chance and a high probability based on preclinical data that blocking TIM-3 could be just as effective as blocking LAG-3, so to say.  Now, one thing that I note in this abstract is really the safety finding and early PK analysis. And so, this is the important work we do early on to understand the drug. It's important to be aware that in a study like this, it's very hard to seek efficacy signals.  So, when you see this poster, really, you probably shouldn't be thinking, ‘Oh, this is a frontline phase 3 trial,’ but rather that the efficacy is going to be a secondary consideration. Rather, what's quite important is looking at the properties of the drug and looking at the safety signals around that. And what we can see here is that TIM-3 appears to be quite safe when blocking it in conjunction with anti-PD-1 across several different tumor types. And that really sets the stage then to think about moving this into earlier lines of therapy across many different cancers.  And so, here we see advanced solid tumors but focused on lung cancer and melanoma and kind of the usual tumors we think about, and people can keep their eyes open because there are other posters of this molecule with PD-1 in some of the other sections outside of developmental therapeutics.  Now, one thing I would like to get your opinion on because your group has focused a lot on TIM-3, as I described it as this T cell centric mechanism to reinvigorate exhausted T cells. But it's possible that TIM-3 does other things as well. And I don't know if you want to comment on that or give any other feedback that you've had when thinking about this AMBER Trial.  Dr. Diwakar Davar: That was an excellent summary, Jason, of really what is a truncated 8-year track record of developing this agent all the way from 2015. But you bring up a very interesting point, which is: exactly what does this drug does in the non-T-cell compartment?  Some very interesting data from Brian Ruffell in a paper that was published about 3 years ago now suggested that TIM-3 was actually potentially a myeloid checkpoint, meaning that, in a tumor model in which Dr. Ruffell was studying this in the context of breast cancer, the drug primarily appeared to work on the effect of antigen-presenting cells and augment the presentation of antigen to T cells suggesting that it may be, in addition to being a chronicle T cell exhaustion marker, it may also be reinvigorating antigen-presenting cells. And the question of whether or not the role of TIM-3 on APCs as well as the role of TIM-3 on T cells, and which of these compartments are more important, and how these compartments segregate in any given cancer across many different lines of therapy will hopefully be something that we disengage, and understand a little bit better as we look at biomarkers of this drug across different settings.  And especially to that point, Jason, the biomarker question, you'll notice that very interestingly, that was a signal in which that drug had a certain response rate. Again, as you correctly point out, we cannot read too much into response rates in very small patient numbers. But very interestingly, there was a slightly higher response rate at the 300 milligrams, which is not the top dose level of the drug, and a slightly lower response rate at the ceiling dose of the drug that was tested, 900 milligrams, leading the investigators to conclude that the RP2D, was actually 300 milligrams every 3 weeks and not 900 milligrams.  What are your thoughts on dose in the context of immunotherapy (IO) drug development? And why might it be that 300 is the optimal dose as opposed to 900?  Dr. Jason Luke: That's a complicated question. I mean, when we think about checkpoint blockade, we classically think about it as only blocking on T cells. But to your point, if there are multiple mechanisms in play, sort of modulating other cell compartments actually may start to do different things at different doses that maybe weren't our primary intent as we went into the trial.  That's a little bit of hand waving, immunologic hand waving, but I think the data are the data and once we hit an effective dose level, there's really no need to really push the dose that much further. But that really emphasizes the importance of these kinds of early phase clinical trials.  So, I'm really looking forward to seeing this data. For disclosure, obviously, we have both been investigators on this trial. But we're very excited about the idea that there may be hope for a fourth checkpoint to come forward in the field beyond just PD-1 CTLA-4, and LAG-3, maybe now here with TIM-3.  Dr. Diwakar Davar: So, with that we’ll go to the next abstract and that is Abstract 2516, “Phase I trial of adjuvant autogene cevumeran, an individualized mRNA neoantigen vaccine, for pancreatic ductal adenocarcinoma.”  So, this is an mRNA vaccine from our good friend, BioNTech. And that's been essentially evaluated in the context of highly lethal cancer, pancreatic ductal cancer, and specifically in the context of adjuvant vaccines, specifically in the setting of patients who had followed definitive pancreatic cancer surgery.  So, Jason, you know a lot of neoantigen vaccines, you've led some of these trials, really, the neoantigen vaccine is really the primary reason we are actually having an in-person meeting this year, because if not for this company and others like this, really this pandemic would not be behind us.  What are your thoughts on the role of neoantigen vaccines in cancer therapeutics, and also, particularly this particular trial in the data, the immunological data, and the clinical data regarding the development of neoantigen-specific T cells in this setting, and what this means for you?  Dr. Jason Luke: Right. So, the idea of targeting neoantigens as cancer immunotherapy was really all the rage a few years back, and it was thought based on preclinical animal models that this was just going to be the secret sauce, and this would be the new targeted therapy for immunotherapy. And it isn't to say that that's not true, but the first generation of neoantigen, peptide-based vaccines for the most part, unfortunately, just kind of didn't end up moving the needle the way we had hoped.  The question then was raised: is that because targeting neoantigens isn't reasonable, or is that because the setting where we were trying to do it in the refractory disease area was not the optimal way to leverage this?  And so, a couple of different companies and trials now are coming forward looking at targeting neoantigen in a minimal residual disease setting where the idea could be that immunologic responses that you could generate wouldn't be hampered by all the immunosuppression associated with the tumor microenvironment.  And so, here we have this molecule, which you eloquently pronounced, ‘autogene cevumeran.’ It’s an RNA-lipoplex neoantigen vaccine. So, it's not a peptide. It's more like the COVID-19 vaccines actually. And it's being given after surgery, followed by anti-PD-L1 followed by chemotherapy.  So, it's a complicated regimen, but it's very intriguing these early data, which do show that the patients who got the vaccine seemed to have better and longer-term outcomes. But then as you emphasize, really, I think probably what's at the heart of this that really makes it exciting is their ability to immune monitor the patients, meaning to look for antigen-specific immune cells from the peripheral blood in these patients to be able to identify those immune responses as being specific to cancer. Because this kind of a clinical trial, it's still signal seeking and proof of concept kind of trial.  In order to actually establish that a vaccine approach in a post-surgical setting would have efficacy, we need to do a large randomized trial. And so, this is not that yet. But I think these data really point in the direction that that could be a reasonable thing to try. And when you think about pancreatic cancer, where we've made no success with immunotherapy, really in a meaningful way in terms of checkpoint blockade, at least, that's pretty exciting actually to think about.  I would actually marry this dataset with another that we actually saw at the American Association for Cancer Research (AACR) meeting that also looked at neoantigen targeting and antigen-specific responses in colorectal cancer, again, and in a similar setting with the minimal residual disease setting.  And so, I think this highlights that we may need to start thinking about using immunotherapy in different ways than we had before. Obviously, everybody knows about using PD-1 blockade in lots of different cancer types that are really for metastatic disease, or maybe even for adjuvant now in melanoma a little bit. But maybe there's this space, which is the minimal residual disease setting where you might be able to detect by ctDNA after surgery, the patients are still positive. And maybe you could treat that before there's visible cancer, and maybe certain immunotherapies could be more valuable in that setting than others. And that's where I think maybe some of these mRNA technologies really might find their sweet spot.  So, coming back to this abstract, I think really, the emphasis point here is the novelty of generating patient-specific neoantigen vaccines, and then being able to track linearly over time the immune response against those vaccines.  I think with that kind of technology and being able to leverage that, I think we're really headed towards a real shift in the way we think about managing cancer in a post-surgical setting, again, thinking about MRD, or minimal residual disease, maybe in a way that our leukemia colleagues have been thinking it about for a long time.  Dr. Diwakar Davar: That's an excellent summary of a very, very complicated, both setting, and in this case, a therapeutic landscape. So, well said, well summarized, and we'll now pivot to Abstract 2514. So, this is ‘Efficacy and safety of NT-I7, long-acting interleukin-7, plus pembrolizumab in patients with advanced solid tumors: Results from the phase 2a study’ [and] the presenting author is Dr. Aung Naing from [The University of Texas] MD Anderson [Cancer Center].  So, Jason, you know, with checkpoints, we've got so many thoughts about checkpoints, particularly given the rather unfortunate failure of BEMPEG in the context of melanoma.  So, we've got lots of interesting cytokines that we think of as important in the context of immuno-oncology 2, certainly 12, 15. You've been very involved with IO-15. We've got a lot of clinical trials studying IL-12. And now we've got one studying IL-7. So, tell us what do you think of this IL-7 targeting approach in the context of cytokine-based therapeutics?  Dr. Jason Luke: I think it's really important to emphasize on first principles, for those that are listening, who don't think about immunology all the time that not all cytokines are the same thing.  So, interleukin 2 that many people have heard of is very different actually than interferon. And that's very different from many of the other cytokines, the ILs, and everything, right?  So, IL-7 is a very potent cytokine that's associated with the expansion of immune responses, and that can drive interferon gamma-dependent effects. And you should hear whenever I say interferon-gamma is sort of a link through to PD-1 responsiveness. Because we think the mechanism that underpins anti-PD-1 effectiveness in patients really is interferon gamma biology.  So, IL-7 has been a molecule, it's been of a lot of interest but really was too toxic to try to deliver. But now we have novel drug delivery sorts of approaches that are being developed to try to bring the drug in, in a way that doesn't cause such systemic toxicity.  So, in this clinical trial, this NT-I7 molecule is given intramuscularly, every 6 weeks in conjunction with pembrolizumab, and very interestingly, in a small number of patients, but there were resist responses observed across a series of tumors that you really wouldn't expect should be responsive in any way to pembrolizumab alone. And so, we're talking about microsatellite stable colorectal cancer, pancreatic cancer, and some others as well.  And in conjunction with that, they were able to identify some of the biomarker effects we would think we would see with IL-7, such as expansion of peripheral immune compartments. And the toxicity profile was really consistent with what we've seen with fevers and chills, but manageable in a way that previous approaches really weren't.  So, I think this is really exciting because I think the idea here then is with this IL-7 approach, we might expand the kinds of cancers that we could go after, in conjunction with anti-PD-1 again, pancreas, colorectal cancer. I think that's really where the unmet need lies in oncology.  So, I really applaud these kinds of approaches and several of these cytokine approaches, and what we're going to talk about them, I think, have the potential to do that over the next couple of years.  Dr. Diwakar Davar: Excellent! Pivoting now to a different cytokine, but one that was alluded to before IL-12. So, Abstract 2518 is ‘Phase II evaluation of the combination of PDS0101, M9241, and bintrafusp alfa in patients with HPV 16+ malignancies,’ and the presenting author here is Dr. Julius Strauss of the NCI Cancer Center and the Clinical Center of the National Cancer Institute at the National Institutes of Health.  So, what do you think, Jason, about the role of the HPV targeting vaccine, in this case, that was added to IL-12 immune-cytokine and bintrafusp alpha contextualizing the recent data that we have of bintra along with what is a very interesting result here?  Dr. Jason Luke: Yes, I think building on the last abstract where we talked about IL-7 as some novel biology now we move to IL-12, which again introduces other biology. So, interleukin-12 is a complicated cytokine, but one that's strongly associated with initial immune responses or immune priming, as well as enhancement of anti-tumor effects in the tumor microenvironment.  So, here we have sort of a 3-legged approach. So, the vaccination approach against HPV really can generate a strong immune response initially, and that can be supported with the IL-12. And then you come in with anti-PD-L1 and to whatever extent the TGF data is relevant here. And so, you have this cocktail where you're generating tumor-specific responses with a vaccine, you're supporting them with IL-12, and then blocking PD-L1.  And as we go back even a couple of abstracts we talked about, now we sort of have a cocktail right of approaches. And so, I think this is very exciting. It's unique in that, in these tumors, obviously, HPV is the driving force of cancer. So, developing a vaccine against that is fairly straightforward. But I really like this concept of bringing forward sort of a multi-dimensional immunotherapy approach. And we'll note they have previously presented data on this trial, I think last year at ASCO, actually. But what they see are pretty strong response rates, almost 30% range in PD-1 refractory tumors.  Again, that's our area of really high unmet need. It's hard to read through how useful a PD-1 naive treated patient here, although the response rates were high. But to me, it's really those patients who had progressed on PD-1 where they're getting these responses that tells me that this really could be something that's useful and potentially could be expanded beyond just say head neck cancer to any HPV relevant malignancy.  Dr. Diwakar Davar: Excellent! Now on to our last abstract. Abstract 2520, ‘Effect of intratumoral INT230-6 on tumor necrosis and promotion of a systemic immune response: Results from a multicenter phase 1/2 study of solid tumors with and without pembrolizumab (PEM) [Intensity IT-01; Merck KEYNOTE-A10].’ The first author is Dr. Jacob Thomas.  Jason, we've seen a lot of interesting intratumoral therapies. You and I have both done a lot of studies in looking at intratumoral agents from toll-like receptor agonists, TLR-9, TLR 7-8, and more recently, oncolytic viruses.  So, contextualizing IT230-6 in the spectrum of intratumoral therapies, how do you feel about this drug, which is actually a very interesting novel drug. It's not just a TLR agonist, or for that matter, an OV, very interestingly, it's an intratumoral therapy that has actually got chemotherapy in it. So, how do you feel about this drug? How do you feel about the responses that we've seen? And particularly how do you feel about the setting in neoadjuvant breast cancer?  Dr. Jason Luke: Yeah. I would pick up where you said that this drug INT230-6 is just a really interesting concoction. So, it's cisplatin mixed with vinblastine, in a specific amphiphilic molecule that allows it to diffuse in through the cancer.  And so, if you had said that to me a few years ago, I would have looked at you and been like, ‘What are you talking about?’ But I think the data that's been emerging for this is just really interesting because something about this chemotherapy cocktail actually drives immune responses. And really what the focus of this abstract is on is showing that you get an influx of CD foreign CDTa cells into the tumor microenvironment that's associated with a therapeutic benefit.  I think that's just really, really interesting to think about. It sort of makes one wonder when we're doing these intratumoral injections, how much of it is just the injection, and how much of it is the therapeutic agent, but I think it's a really novel therapy, and one that appears to be very well tolerated as well. And that's also the exciting part. When you hear cisplatin and vinblastine, you think, ‘Oh, well, that's not going to work.’  But apparently, it stays right in the tumor and generates these immune effects. I think it's very exciting. I think their approach here—going after what we usually call cold tumors, ones that don't respond to immunotherapy, you mentioned breast cancer—I think it's really interesting. I'm really looking forward to seeing the actual data from this abstract because, on first pass, it wouldn't have been what I thought about in terms of driving immune responses, but maybe it just goes to show that there's a lot more to understand there about immunogenic cell death and some of these other concepts that we bandy about. But I think this will be one of the most interesting abstracts actually to see the data for once it's available.  Dr. Diwakar Davar: Great! Taking a slight pivot from that. You've been involved in the development of novel response endpoints. One of the issues that we have with intratumoral therapies is that you're measuring a lesion that you inject, so now you inject something and it gets a little bigger. Is it getting bigger because it's growing? Is it getting bigger because the drug is working? We don't know. We have now itRECIST, which you have been working on.  What's very interesting is that whether you look at itRECIST, or RECIST, irRECIST, or imRECIST, when you have the monopoly of different response endpoints we have to deal with these days, these patients have monotherapy responses in non-injected tumors. How do you feel about that as a drug developer and somebody who's giving patients drugs like that? What is your impression of having shrinkage in the non-injected tumor?  Dr. Jason Luke: I think it's really exciting about this concept of the abscopal effect that we've bandied about for years. Despite being an investigator in this space, I'm really excited to actually see the data and to understand what these out of field responses are. If it's really true that this is robust, I mean, it could potentially be like a game-changer kind of thing. But I'll reserve judgment until I see the actual scans of the tumors that actually shrank that weren't injected.  Dr. Diwakar Davar: Fantastic insights, Jason. So, thank you for taking the time to join us on this podcast and to highlight these extraordinarily important advances in immunotherapy.  Dr. Jason Luke: I appreciate the opportunity to participate today.  Dr. Diwakar Davar: So, thank you, and thank you to our listeners for your time today, you will find the links to the abstracts that we discussed today in the transcript of the episode.  Finally, if you're enjoying the content on the ASCO Daily News podcast, please take a moment to rate review and subscribe wherever you get your podcasts.  So, thank you, Jason. And thank you to the team for putting this together.      Disclosures:   Dr. Diwakar Davar:   Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences  Consulting or Advisory Role: Instil Bio, Shionogi (Immediate Family Member), Vedanta Biosciences  Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, Zucero Therapeutics (Inst), GSK, Merck, Arcus Biosciences  Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231, and Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy  Dr. Jason Luke:  Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX   Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, Stipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences , Hotspot Therapeutics, SERVIER , STINGthera, Synthekine  Research Funding (Inst): Merck, Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma, EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure  Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)  Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio  Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. 

Dr. John Sweetenham, of the UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, and Dr. Marc Braunstein, of NYU Langone Health, discuss key data from the CAPTIVATE and GRIFFIN trials and other compelling studies in hematologic malignancies featured at the 2022 ASCO Annual Meeting. Dr. John Sweetenham: Hello. I'm John Sweetenham, the associate director for Clinical Affairs at UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News podcast. For my guest today, I'm pleased to introduce Dr. Marc Braunstein, a hematologist, and oncologist at NYU Perlmutter Cancer Center. We'll be discussing key posters on advances in hematologic malignancies that will be featured at the 2022 ASCO Annual Meeting. Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/podcasts.  Marc, it's great to have you on the podcast today.  Dr. Marc Braunstein: Thank you, John. It’s a pleasure to be here.  Dr. John Sweetenham: So, Marc, there are going to be some very interesting abstracts with some provocative results presented at the ASCO Annual Meeting this year. I know we've selected a number of these to speak about today, beginning with Abstract 8027 on the subject of multiple myeloma. And this I think is a long-term follow-up study for long-term survivors of multiple myeloma more than 12 years out now. Can you comment on this and let us know what you believe the key takehomes from this study are?  Dr. Marc Braunstein: Sure. Absolutely, John. So, this was a prospective registry that has been in place since 2009, and it's composed of various practice settings, but primarily community practices where most patients get their myeloma care. And what they did was they looked at about 1,400 patients with newly diagnosed multiple myeloma across 250 sites in the U.S. between 2009 and 2011 who were included in the registry. The participants also filled out the quality-of-life surveys, and they compared a group of long-term survivors who had more than 8 years of follow-up to patients who were not long-term survivors below that 8-year threshold. So, about 20% were in the long-term survival group and 80% in the non-long term survival group. And they basically characterized those 2 groups. What they found was that the individuals who did have long-term survival were generally younger—median age of 62 versus 68, and had better performance status, were more likely to receive stem cell transplants, about 66 versus 60%. And therefore, the implication of this is that patients who fit those criteria may have a better prognosis in addition to the other cytogenetics and other factors we use as prognostic indicators. And what was also interesting was that the 8-year overall survival of the overall group was about 36%. So, we still have room to go in terms of bringing new therapies to extend survival in this condition. And only 20% of the total population were long-term survivors at that 8-year threshold. So, those were the general findings of the abstract.  Dr. John Sweetenham: Do you think it gives us new information on patient selection for more intensive therapies upfront?  Dr. Marc Braunstein: Well, I think it certainly tells us which patients are more likely to have longer-term survival. I think we know in multiple myeloma that it's essential to really use the patient's presenting features, their disease features, their comorbidities, and their degree of fitness or frailty to guide how intensive a therapy or regimen we can devise for that individual patient. But I think it certainly says that if you have a patient who is on the younger side of the spectrum, who is eligible for stem cell transplant, who has a better performance status, those are the patients that are more likely to have the long-term survival. It doesn't necessarily say that if you're not in that category, you won't have long-term survival, but on average, those were the patients who fared better in the long term.  Dr. John Sweetenham: Okay. So, staying for a little while on the subject of multiple myeloma, Abstract 8037 is really addressing a very different question. It's the application of circulating tumor DNA analysis and its association with relapse in patients with refractory myeloma. Would you comment a little on this and maybe let us know what you think the significance of this will be for the future?  Dr. Marc Braunstein: Sure. My colleagues in the solid tumor space are using circulating tumor DNA regularly and in the myeloma field, we're a little bit jealous of them.  So, it's helpful to have a study like this that's looking at circulating peripheral blood markers, in this case circulating tumor DNA, to help guide various prognostic or predictive indices that will help us guide therapeutic decisions.  So, this was a study where they looked at patients who were enrolled in a phase 2 study of a free-drug regimen of carfilzomib-thalidomide-dexamethasone the MM17 study, and they took 50 transplant eligible multiple myeloma patients who were refractory to their first line of therapy, and they collected bone marrow samples and peripheral blood at 3 time points at the third cycle of treatment and at the end of the study or at the point of refractoriness to that regimen. They collected about 187 samples in total. They used a sequencing technique to determine the variance of 22 gene signatures known to be mutated in multiple myeloma. And what they found was a particular gene signature that was associated with shorter progression-free and overall survival in that phase 2 study. And those genes included known oncogenic drivers, including BRAF genes, ATM, and P53. What was particularly interesting among the circulating tumor DNA mutations was that they were found in about 88% of patients at the start of the study. So, what that tells us is, number 1, circulating tumor DNA offers a wealth of information that can be highly valuable in multiple myeloma, which is a disease where we typically rely on the bone marrow to assess the status of the plasma cells and status of the mutation profile. And number 2, that many of these mutations may be present earlier on in a disease that we know evolves in a clonal way that leads to disease progression. So, I think there's still a lot of information we have to learn about the utility of circulating tumor DNA in myeloma, but this study certainly shows that there's a lot to be explored in terms of the mutational profile and peripheral blood in myeloma. Dr. John Sweetenham: A couple of questions that arise for me out of this study. First of all, do you think this is going to have any implications for future study design and patient selection? Dr. Marc Braunstein: Definitely. I think the whole field in multiple myeloma is progressing quickly in terms of how we assess response, how we use minimal residual disease, and moving more towards using novel markers in peripheral blood, including mass spectrometry, and now perhaps circulating tumor DNA to look at surrogate markers for survival. And so, what this abstract is showing is that we could potentially use circulating tumor DNA both as prognostic markers, potentially as disease response markers, and prognostic markers to guide which patients may be more likely to have shorter survival. So, I think this has a lot of implications for how we design future studies. Dr. John Sweetenham: Yeah. And the second question, do you think this is the beginning of the end of bone marrow analysis in multiple myeloma?  Dr. Marc Braunstein: So, I can tell you if it is, patients I think will be very happy and so will clinicians because we really want to know at the core what the degree of residual disease is in a patient. And right now, the only way to do that is through a bone marrow biopsy.  And so, I think that this is the beginning of the use of peripheral blood studies with higher resolution to allow us to gain more information on patients that hopefully will allow us to obviate the need for more invasive testing like bone marrow biopsies.  Dr. John Sweetenham: Yeah, absolutely. Thanks. Just changing gears now, moving on to Abstract 7050. This is an abstract that addresses what I think we'd all agree is becoming an increasingly important question in the management of chronic myeloid leukemia (CML), and that is number 1, is it safe to discontinue therapy in responding patients? And number 2, when is it safe to discontinue that therapy?  Dr. Marc Braunstein: So, this is an abstract that is looking primarily at CML. You know that we're making a lot of progress when we can begin to talk about discontinuation and de-escalation of therapy.  And so, in the field of CML, the use of tyrosine kinase inhibitors (TKIs) and the targeting of the BCR-ABL mutation has brought about tremendous progress in patients in the chronic phase.  So, there have been several retrospective studies that have looked at the role of discontinuing one of the TKIs. Most of the studies have focused on imatinib since that was the first one that was discovered, but they've looked at others in the class as well. What struck me the most is that there's a remarkable consistency between these studies. So, when you discontinue one of these TKIs, the percentage of patients who remain in remission is somewhere between 40 to 50%. And what this abstract looked at was a single institution retrospective assessment of 284 patients with CML, between 1999 and 2017, who were treated with a TKI for their CML and then subsequently discontinued the therapy.  Now, what's worth noting in the various studies that have looked at discontinuation therapy is that patients who were taken off of the TKI generally were in a good molecular remission, MR 4 or 4.5, for at least 2 or 3 years. And in this study, about 70% of patients had electively discontinued and 24% of patients stopped due to adverse events.  So, it wasn't necessarily guided by their response to treatment at the time of discontinuation. What they found actually was fairly consistent with the literature that at a median follow-up of 36 months after TKI discontinuation, about 19% lost their molecular remission and 88% had achieved a molecular remission after resuming therapy. And that is consistent with the literature that fortunately, even if a patient loses their molecular remission off of the TKI therapy, the majority of patients will go back into molecular remission when you re-challenge them.  Dr. John Sweetenham: Important data, indeed. And you know, on something of a similar theme, the next abstract that we're going to look at is the Abstract 7519. In this case, in chronic lymphocytic leukemia (CLL), and certainly, those of us who remember when ibrutinib was initially introduced into the second-line treatment of CLL, didn't really know whether discontinuation or fixed duration treatment with agents like this was going to be something that we could pursue or whether treatment with these drugs was going to be indefinite. This abstract certainly addresses that specific question, and again, I’m interested in your insights into this.  Dr. Marc Braunstein: Sure. So, this is an abstract looking at CLL, where we've really begun to move away from chemotherapy, and we have a variety of targeted oral therapies that target the underlying pathology of this leukemia.  And so, as you mentioned, ibrutinib is approved both in the relapsed and more recently in the frontline setting, wherein the RESONATE-2 study that was published in the New England Journal of Medicine in 2015, there was actually an overall survival benefit of ibrutinib even in higher-risk patients.  So, the CAPTIVATE study is an ongoing phase 2 study that is looking at whether we can improve the efficacy of single-agent ibrutinib in the first-line setting when combined with venetoclax.  Ibrutinib targets protein tyrosine kinase and venetoclax targets Bcl-2, and that combination is hypothesized to further weaken the resistance of CLL and lead to better outcomes.  So, this was a multicenter phase 2 study. And in this abstract, they looked at the 3-year follow-up of patients who were actually able to discontinue therapy on this regimen. So, just as a bit of background, ibrutinib is typically continued until progression, and venetoclax as it's been studied in the first-line setting with obinutuzumab is given for about 12 months.  So, in this study, at 3-year follow-up, they looked at the patients in the cohort who were off therapy and looked at the percentage of patients who maintained a complete remission at 3 years. And that complete remission rate was about 57%.  The majority of patients, greater than 95% of patients, were alive at 3 years even in the high-risk cohort. So, I think the implications of the study is that upfront or oral targeted therapies when you combine ibrutinib and venetoclax really produce tremendous responses that are durable, and it's found even in the high-risk patients who are expected not to do quite as well at 3 years.  Dr. John Sweetenham: Yeah, I agree. I think it's very reassuring actually to see these durable responses with this fixed duration regimen. And to conclude, Abstract 8011 was an abstract which addressed treatment in the first-line setting for multiple myeloma. And again, I wonder if you could comment on this study.  Dr. Marc Braunstein: Sure! So, this is a study looking at the GRIFFIN regimen, which was a phase 2 randomized study of daratumumab (DARA), plus lenalidomide, bortezomib, and dexamethasone.  So, DARA RVd versus RVd alone. In that study, the primary endpoint was stringent, complete remission, and it has been previously presented and published that the stringent complete remission (CR) rate was significantly improved, 42% versus 32%, when you include daratumumab upfront.  In this abstract, they looked at the sustained rate of minimal residual disease negativity, which is basically the deepest possible remission you can achieve in upfront therapy and in myeloma.  What they found was that, again, when you looked at the quadruplet regimen versus the triplet regimen, the rates of minimum residual disease (MRD) negativity were just improved with the quad regimen.  So, at a median follow-up of 38.6 months, there were about 54 versus 20% of patients who were MRD negative at 12 months amongst the patients who had achieved a CR, and 59 versus 17% MRD negative among the patients who achieved a stringent CR favoring the daratumumab arm.  So, I think this abstract shows the benefit of including a monoclonal antibody upfront in newly diagnosed patients with myeloma combined with stem cell transplant and maintenance, allowing for sustained MRD negativity.  Dr. John Sweetenham: Do you think this represents a new standard of care?  Dr. Marc Braunstein: I do. At our institution, we've adopted this regimen for most newly diagnosed transplant-eligible patients. I think the data clearly show an improved depth of response and MRD negativity rates, and I think that there are a number of ongoing studies looking at the role of monoclonal antibodies in the maintenance phase as well.  I'm especially excited this year, at ASCO Annual Meeting there's a plenary session involving myeloma looking at patients who received RVd upfront and then went for transplant. But I think we can improve on that regimen by including monoclonal antibodies and immunotherapies upfront, and I do think it represents a new era of immunotherapies in multiple myeloma.  Dr. John Sweetenham: Well, thanks, Marc. I mean, to your last point, it sounds as if there is a lot, including these abstracts, to look forward to at the upcoming ASCO meeting. So, we really appreciate you sharing your insights into these abstracts with us today.  Dr. Marc Braunstein: Sure. My pleasure. Thank you for having me, John.  Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstract discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.      Disclosures:  Dr. John Sweetenham:  Consulting or Advisory Role: EMA Wellness  Dr. Marc Braunstein:  Consulting or Advisory Role: Celgene, Janssen, AstraZeneca, Amgen, Takeda, Verastem, Celgene, Janssen, Karyopharm Therapeutics, Epizyme, Morphosys, Takeda, Pfizer  Research Funding (Inst): Janssen, Celgene/BMS  Travel, Accommodations, Expenses: Takeda  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. 

Dr. Allison Zibelli, of the Sidney Kimmel Cancer Center – Jefferson Health, highlights key advances from the EMBER study and promising data on QOL for HR+/HER2- patients taking checkpoint inhibitors featured at the 2022 ASCO Annual Meeting.   Transcript:  ASCO Daily News: Hello and welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Allison Zibelli, a breast medical oncologist and assistant professor of medicine at the Sidney Kimmel Cancer Center Jefferson Health.  Dr. Zibelli will highlight key posters on breast cancer that will be featured at the 2022 ASCO Annual Meeting. Dr. Zibelli’s full disclosures are available in our show notes, and disclosures of all guests on the podcast can be found on our transcripts at asco.org/podcasts.  Dr. Zibelli, it's great to have you on the podcast today.  Dr. Allison Zibelli: Thank you. It's nice to be here.  ASCO Daily News: Let's begin with Abstract 1021 and the “Phase 1 EMBER Study.” Can you tell us why this study should be on our radar?  Dr. Allison Zibelli: This study was very interesting because it's testing a novel therapy, which is imlunestrant, an orally bioavailable SERD, or a selective estrogen receptor degrader. This drug is for patients with ER-positive, HER2-negative advanced breast cancer. And they're presenting updated data from the dose-escalation phase and the dose-expansion phase of the EMBER trial.  This trial enrolled 138 patients at a median age of 62 years. The median number of prior therapies for these women was 2. The adverse events were low. They could have prior platinum therapy but no prior fulvestrant or aromatase inhibitor. The premenopausal women in the study received concomitant GnRH antagonist. They had substantial clinical benefit with this therapy with no dose-limiting toxicities.  It had a favorable side effect profile with no cardiac or ophthalmic safety signals, and it had excellent efficacy in patients with heavily pretreated ER-positive advanced breast cancer. This is the first study showing efficacy and safety with an oral SERD. And we're all looking for new oral, well-tolerated therapies for our patients with metastatic estrogen receptor-positive breast cancer.  These patients were heavily pretreated, and they had a median of 2 prior therapies. Most of the patients with advanced breast cancer had prior endocrine therapy, 92% had a prior CDK 4/6 inhibitor, 50% had fulvestrant, and 26% had chemotherapy.  Despite this, they had an overall response rate of 5% with a clinical benefit rate of 47%. So, it'll be very interesting for us to see what happens with this new class of SERDs in the future.  ASCO Daily News: Excellent! So, moving on to Abstract 514. This study addressed patients with high-risk early breast cancer who received pembrolizumab within the new adjuvant biomarker rich I-SPY 2 trial. Can you tell us more about this study?  Dr. Allison Zibelli: This is a very interesting study, which is a platform study comparing various investigational treatments to a standard therapy which was ACT, with or without herceptin, depending on the HER2 status of the patient versus an experimental agent.  One arm of the I-SPY study was neoadjuvant pembrolizumab. This paper is very interesting to me because it's hard to know in advance who will respond to immune checkpoint inhibitors. And that's what this study was designed to answer.  So, they took 69 patients who were on the I-SPY study, they all had high-risk MammaPrint scores, and all of them were HER2 negative, and with these patients, they had 31 complete responses to neoadjuvant pembrolizumab and 38 patients with a residual disease after neoadjuvant pembrolizumab. Notably, of the 31 complete responses, 12 were ER-positive, and 19 were triple-negative.  In the residual disease patients, 28 were ER-positive and 10 were triple-negative. If you compare this with historical data, the response rate for pembrolizumab is about 20% for patients who are triple-negative and about 12% for patients who are ER-positive.  So, the response rates that they had were higher in general. So, what the study did was they found a signature of 53 genes which they named imprint, which was identified with a greater than 90% sensitivity and greater than 80% specificity for predicting complete response to pembrolizumab in all patients.  This worked equally well for the patients who are estrogen receptor-negative and estrogen receptor-positive. In KEYNOTE-086 cohort B, which was presented at the American Association for Cancer Research Annual Meeting (AACR), PD-L1 of greater than 1% only predicted a 23% response rate to pembrolizumab.  So, if we could use the imprint study to predict patients who would respond to pembrolizumab, it would save a lot of needless toxicity and a lot of needless expense, in treating the patients who would have benefit.  So, this is going to be a very useful method to identify patients that we want to treat with pembrolizumab, and perhaps other immune checkpoint inhibitors as well. I think this might be the next “Oncotype” as it were, in that it will be able to predict who will benefit from a specific therapy.  ASCO Daily News: Thank you! Let's move on to Abstract 519. This is a randomized pre-surgical trial of alternative dosing of exemestane in postmenopausal women with early ER-positive breast cancer. What are your key takeaways here?  Dr. Allison Zibelli: I thought this was a great design of a study. It was a window of opportunity for the test. So, what they did was, they tested 3 different dosing schedules of exemestane in patients waiting for surgery for ER-receptor-positive breast cancer.  The patients were randomly assigned to either receive exemestane 20 milligrams a day, the standard schedule, 25 milligrams 3 times a week, or 25 milligrams once a week for 4 to 6 weeks prior to surgery.  Their endpoint was percent decrease in circulating estradiol and what they found was the 3 times a week schedule was comparable to the daily schedule. The once-a-week schedule didn't seem to be adequate to decrease estradiol, but 3 times a week was equivalent to daily.  This was really interesting because we know that our patients have difficulty tolerating aromatase inhibitors. We know from formal studies that about 25% of patients discontinue aromatase inhibitors prematurely because of side effects. Small studies in actual practice settings show it's probably even higher than that—between 30 and 50% of patients discontinue aromatase inhibitors.  So, for the patient that can't tolerate daily therapy, 3 times a week therapy is an attractive option, that may be just as good as daily. I think it is very important for patients who have to take these drugs for years that they have a way to take them that is tolerable.  ASCO Daily News: Absolutely. Well, the last study I'd like to ask you about is Abstract 1015. This looks at the quality of life for patients with HR-positive, HER2 negative advanced breast cancer. So, what does this study tell us about quality of life with different CDK 4/6 inhibitors?  Dr. Allison Zibelli: So, we have a lot of studies of CDK 4/6 inhibitors. And we know that they dramatically improve the overall survival of women with ER-positive metastatic breast cancer. What we also know is that they have a lot of side effects. And for women that have to take these drugs for years, that's important.  So, this study was a matching adjusted indirect comparison study. This is a method that uses individual patient data to create balanced trial populations across separate studies, and they use patients from the MONALEESA-2 trial, which was ribociclib plus AI, compared to MONARCH 3, which used abemaciclib plus AI, the endpoint was something they called “time to sustain deterioration,” which was a decrease in 10 points in the quality of life score, they use the QLQ-C30 questionnaire. The upshot of their data was that ribociclib was more tolerable, mostly with less appetite loss, less diarrhea, and less fatigue than abemaciclib.  So, this is 1 of the first studies we've seen that directly compares, well sort of directly compares the quality of life between these 2 drugs, and this may be a data point that favors ribociclib.  ASCO Daily News: Well, thank you, Dr. Zibelli, for highlighting some really important advances in breast cancer that will be featured at the 2022 ASCO Annual Meeting. We really appreciate it.  Dr. Allison Zibelli: Thank you very much for having me.  ASCO Daily News: And thank you to our listeners for joining us today. If you're enjoying the content on the ASCO Daily News podcast. Please take a moment to rate review and subscribe wherever you get your podcasts.  Disclosures:   Dr. Allison Zibelli: None disclosed.  Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.     

Dr. Shaalan Beg, of UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center and Science 37, discusses hot topics in GI oncology, including KRAS wild-type pancreatic cancer, the SURF-Cohort trial in hepatobiliary cancer, and key studies in gastric cancer featured at the 2022 ASCO Annual Meeting.  Transcript ASCO Daily News: Hello and welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Shaalan Beg, who is an adjunct associate professor and gastrointestinal (GI) medical oncologist at UT Southwestern Harold C. Simmons Comprehensive Cancer Center.  Dr. Beg also serves as vice president of oncology at Science 37. Dr. Beg will be telling us about key posters in GI oncology that will be featured at the 2022 ASCO Annual Meeting. His full disclosures are on our show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/podcasts.  Dr. Beg thanks for coming on the podcast today.  Dr. Shaalan Beg: Thank you so much for having me.  ASCO Daily News: Let's begin with “A multicenter, non-randomized, controlled trial to evaluate the efficacy of surgery versus radiofrequency ablation for small hepatocellular carcinoma (SURF-Cohort Trial): Analysis of overall survival.” That's Abstract 4095. This study evaluated the efficacy of surgery versus radiofrequency ablation for small hepatocellular carcinoma. So, what are your key takeaways from this study?  Dr. Shaalan Beg: This is a very interesting and timely clinical trial from our investigator colleagues in Japan, Dr. Yamashita, and colleagues, where they evaluated the effectiveness of radiofrequency ablation versus surgery for patients with small hepatocellular carcinomas who have a good liver function.  History is that the best most effective treatment option has always been surgery and we know that ablative techniques like radiofrequency ablation (RFA) or stereotactic radiation can do a good job in controlling the individual cancers, but we don't know what the long-term effects can be in terms of recurrence, free survival, and overall survival.  So, this trial looks to compare RFA or radiofrequency ablation versus surgery for groups of patients who have a good liver function, so a Child-Pugh score of 7 or less, and those who had no lesion greater than 3 centimeters and less than 3 hepatocellular carcinoma (HCC) nodules.  All the people were evaluated by surgeons and hepatologists, to confirm that they would be eligible for both procedures. And then the patients received either 1 of those treatments and they followed them in the long term and found that there was no significant difference between how people who are treated with surgery fared versus RFA.  This is really interesting and practical and timely because the results of these clinical trials can inform our clinical practice today. The median follow-up period was 6.8 years in the surgery group and 6.7 years in the RFA group and the overall survival was not different. Their 5-year overall survival for surgery was 79.7%. And very similar to what they were seeing in both groups.  ASCO Daily News: Excellent! Great to hear some promising developments for this patient population. Well, in Abstract 4026, investigators are suggesting that the choice of PD-L1 immunochemistry assay influences clinical eligibility for gastric cancer immunotherapy. What are your thoughts on this study?  Dr. Shaalan Beg: Yeah! Clinicians, clinical investigators, and even patients have been really confused by the definitions of PD-L1 expression. PD-L1 expression is 1 of our biomarkers for response to immunotherapy and immune checkpoint inhibitors. But the challenge in this field is that there are multiple assays that define various criteria for PD-L1 expression. And if you look at different clinical trials, they look at different definitions of positivity. So, a trial may have 1 plus. Some may have 5 plus percent. Some have 50 plus percent.  So, this group out of Singapore took 362 gastric cancer samples, and they evaluated its PD-L1 expression using the combined positive score or the combined positive score (CPS), the tumor proportion score (TPS), and immune cell expression, and they compared them to see how well all of these performed because what's important to remember is we don't know how interchangeable the different immunohistochemistry (IHC) assays are. We have the Dako 22C3, we have the Dako 28-8, and then the Ventana assays and different clinical trials have used different versions of these at different expression levels. And regulatory bodies haven't really defined how to do the testing.  So, different sites and different physicians, and different practice groups are using different assays and may be interpreting differently. What this trial is telling us is that if you use the Dako 28-8 assay, you identify a much higher proportion of people who are positive for PD-L1, whether you use the 1% cut off or the 5% cut off, or the 10% cut off. Listen to these numbers. 28-8 at CPS of greater than 1, 70% with 28-8, and 49% with 22C3.  If you use the 10% cut-off, it's 13% if you use a 28-8 assay, but 7% for the 22C3 assay. So, that kind of throws into question how these assays are being used in daily practice. Well, some people may be, but a lot of people are not thinking about the cut-offs that were used in those clinical trials, especially when that comes to finding treatment options for our patients. And if we use the 28-8 assay, we’re bound to find more patients who are PD-L1 positive, but that may not be the assay that the trials used in their validation cohort.  So, we may end up treating the wrong patients. But at the same time, if we use the other assay, we may be missing out on people who are PD-L1 positive. So, I think this is a call. This is a call for the field to harmonize how PD-L1 expression is defined. We need more data on inter-assay concordance so we can find the right drug and the right biomarker for the right patients.  This is a call for better prospective data and a call for harmonization between different assays and between different trials because this is an issue that is plaguing clinical practice today.  ASCO Daily News: Thank you! So, let's talk about advances in pancreatic cancer and Abstract 4155. The authors of this study note that pancreatic adenocarcinoma is the fourth leading cause of cancer deaths, with an increased incidence among patients younger than 50 years old. This study is a comparative analysis of the targetable landscape in KRAS mutant and wild-type pancreatic adenocarcinoma. So, can you tell us about it?  Dr. Shaalan Beg: The pancreatic cancer field has really suffered from a lack of effective treatment options, especially targeted treatment options and lack of effectiveness of immunotherapy for this disease.  Most patients still receive chemotherapy and we only have a couple of different combination treatments to help treat this disease, which is increasing in terms of the number of new cases and cancer-related deaths, and by some estimates may be the third leading cause of cancer-related deaths in the U.S.  A big reason that the survival for this cancer has not improved is because we don't have a lot of actionable or targetable mutations for this disease. One of the biomarkers that does have a corresponding treatment option is people who have a BRCA mutation. PARP inhibitors like olaparib have been approved for that group of patients, but the effectiveness of that medicine is modest for this disease, and we still have to see how much it's incorporated into daily practice.  But outside of the BRCA mutations and other DNA damage repair alterations, KRAS is really the most common mutation and there are new drugs that are out there to target KRAS. 90 plus percent of pancreas cancers have KRAS and if you think about it the other way, a small proportion of patients with pancreas cancer don't have KRAS.  So, what this abstract is looking to study is what are the characteristics of patients with pancreas cancer who don't have a mutation in KRAS, and can be the absence of KRAS actually be a biomarker for other mutations and other treatment strategies for pancreas cancer.  And this was a fairly large study of about 5,000 patients with pancreas cancer that use a commercial NGS assay. The same commercial NGS assay, who performed gene analysis, as well as full transcriptome RNA-seq, were retrospectively reviewed. And they found that people who had a KRAS wild-type tumor meaning no mutation in KRAS were much more likely to have mutations in HRD and in BRAF compared to those that had mutations in KRAS.  And then when you look at fusions, there was a much higher rate of NRG fusions. At the 2021 ASCO Annual Meeting, we heard some data on some new agents that are primarily targeting tumors that have fusions in NRG. And what this abstract is telling us is that the absence of a KRAS mutation may indirectly prompt us to look for other mutations, particularly fusions that may have additional treatment options available. So, this indirectly may be a biomarker of other actionable mutations.  The overall proportion of KRAS wild-type in this cohort was 21%. So higher than what I would have expected, but it's 21% out of 5000 cases that they evaluated and they really set out to see if young-onset pancreas cancer folks have a different proportion of KRAS wild-type and the proportion of KRAS wild-type in both young and typical onset pancreas cancer was really the same.  So, I believe this prompts us to think about pancreas cancer in 2 buckets, the KRAS wild-type, and KRAS mutated pancreas cancer. If we ever come across someone who has no detectable KRAS mutation, we should make sure that they have full transcriptomic analysis so we can look and get better coverage on those fusion changes that may have more treatment options associated with them.  ASCO Daily News: I'd like to follow up with a question about Abstract 4130. Investigators analyzed the molecular profile and clinical outcome of a cohort of patients with KRAS wild-type pancreatic ductal adenocarcinoma, what does this study tell us about the treatment implications for these patients?  Dr. Shaalan Beg: Yeah, so this was an abstract by Dr. Aakash Desai from the Mayo Clinic, and they went back and retrospectively reviewed patients who were seen at their center. And they looked for similar questions as the other abstract had done, but this was from a single center, and it seems like people had had multiple different assays performed.  In this cohort, they found 240 patients. That's 8%, had KRAS wild-type disease. So, they found 19 patients who did not have a KRAS mutation. And they went to see if there were any hints of differences or specific mutations between the patients with wild-type and mutated. And they found that the landscape of KRAS wild-type in pancreas cancer was very heterogeneous, and it was difficult for them to generalize or make any statements on what that could suggest.  A couple of things to think about for this study. Well, first of all, I think it's important for us to acknowledge that this particular space, the KRAS wild-type space, is gaining a lot of attention and is being recognized as an independent entity. So, you have multiple abstracts that have looked to study this group of patients.  I think the second study is different from the prior one in that it's a single-center study. And from what I understand, they may have used multiple assays. So, there was less standardization on the actual mutation testing that was being performed. And that has relevance for this specific question because we know that we need deeper transcriptomic analysis in order to be able to perform RNA-seq and really understand the fusions that may be driving cancer, and it's hard to know what the coverage for the mutations that were evaluated in the second abstract, which mutations were really being covered.  But if we take a couple of steps back and look at this, with the lens of where the pancreas cancer field is headed, again, I want to emphasize that how I view these coming together is that KRAS wild-type, pancreas cancer is becoming recognized as its own identity.  ASCO Daily News: Excellent! Well, thank you Dr. Beg for sharing your valuable insights with us today on the ASCO Daily News podcast. It's certainly an exciting time in GI oncology.  Dr. Shaalan Beg: Absolutely! Thank you so much for having me.  ASCO Daily News: And thank you to our listeners for your time today. You'll find links to the abstracts discussed today in the transcript of this episode. Finally, if you're enjoying the content on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.  Disclosures:   Dr. Muhammad Shaalan Beg:  Employment: Science 37  Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine  Research Funding (Inst): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals  Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.     

Guest host Dr. Nathan Pennell, of the Cleveland Clinic Taussig Cancer Institute, and Dr. Vamsi Velcheti, of the NYU Langone Perlmutter Cancer Center, discuss the ATLANTIS trial and other novel therapies in advanced SCLC, NSCLC, and malignant pleural mesothelioma featured at the 2022 ASCO Annual Meeting Poster Sessions.  Transcript   Dr. Nathan Pennell: Hello, I'm Dr. Nathan Pennell, your guest host for the ASCO Daily News Podcast, today. I'm the co-director of the Cleveland Clinic Lung Cancer Program and vice-chair of Clinical Research for the Taussig Cancer Institute.  My guest today is my friend Dr. Vamsidhar Velcheti, an associate professor and medical director of thoracic oncology at the Perlmutter Cancer Center at NYU Langone Health.  We'll be discussing key posters on lung cancer that will be featured at the 2022 ASCO Annual Meeting. Although the oral sessions tend to get the most press, we want to make sure you don't miss out on some high-impact abstracts that are presented in the poster session.  Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org\podcasts.  Vamsi, it's great to speak with you today.  Dr. Vamsidhar Velcheti: Thank you, Nate. It's a pleasure to discuss these 5 outstanding abstracts.  Dr. Nathan Pennell: Why don't we start with Abstract 9021, “Genomic correlates of acquired resistance to PD-(L)1 blockade in patients with advanced non—small cell lung cancer (NSCLC).” Vamsi, what were your key takeaways from this study?  Dr. Vamsidhar Velcheti: This is an important study in my opinion. This was a very large study of 1,700 patients from Dana Farber and the investigators looked at 45 specimens and matched pre- and post- immunotherapy treated patients. And they looked at the data mechanisms of resistance that were identified in 25 out of the 45 patients, that is 55% of the patients.  5 patients had acquired STK11 mutations. One patient had a KEAP1 alteration. There were several patients who had like KEAP1 SMARCA4 mutations. And interestingly, there were also some patients who developed KRAS-G12C mutation as well on the post-treatment specimens.  So, this is an interesting abstract. We typically don't do biopsies on patients progressing on immunotherapy. At this point, we don't have a standard clinical indication to do so. However, identifying these new novel mechanisms of genomic mechanisms of resistance is actually very important, because a lot of new therapy medications are being developed to target, for example, KEAP1, and could be approached to target microglobulin mutations. So, it's very important to kind of understand the mechanisms of resistance.  Dr. Nathan Pennell: Yeah, I completely agree. I mean, most of the benefits in second line in the refractory setting with targeted treatments came about through studies like this where there was broad sequencing of resistance and trying to understand and I think we're still kind of in the infancy of understanding resistance to immunotherapy, but it's a good start.  Abstract 9019 was another interesting study in non—small cell lung cancer. That was “A phase II study of AK112 (PD-1/VEGF bispecific) in combination with chemotherapy in patients with advanced non—small cell lung cancer.” Can you tell us a little bit about that study?  Dr. Vamsidhar Velcheti: Yeah, this is a multicenter phase-2 trial. This is an interesting agent. It's a PD-1/VEGF bispecific antibody developed by Akeso Bio. This is a single-arm study, and they did the study in 3 different cohorts.  One of the cohorts was patients with advanced non—small cell lung cancer who had wild-type EGFR/ALK, and they were treatment-naive. There was another cohort of patients where they enrolled patients with EGFR mutation who developed resistance to EGFR tyrosine kinase inhibitors (TKIs) and essentially progressed on osimertinib. And there was another cohort where patients were enrolled who were PD-1 refractory, they had prior PD-1or PD-1 chemo combination, and they had progressions. So, they enrolled a total of 133 patients, it was a decent-sized study, but a very early efficacy finding study.  In the cohort-1 which is the cohort that is enrolled with untreated patients with advanced non—small cell lung cancer. They had like 20 partial responses out of 26 patients that were evaluable and enrolled in the cohort, and there were 6 patients who had stable disease.  So, overall, the response rate was 76.9% and 100% disease control rate. So, this is a very small cohort and small data set. So, we have to interpret this with caution. But suddenly, a very interesting signal here for this VEGF/PD-1 bispecific antibody.  Dr. Nathan Pennell: The 40% response rate in the immunotherapy (IO) and chemo refractory patients, I thought was fairly interesting, although, as you said, very small numbers in these cohorts will have to be reproduced in larger trials.  Dr. Vamsidhar Velcheti: Right. I think there was a lot of excitement early on the IMpower150, right? With the combination of bevacizumab with chemo-theralizumab.  There seems to be some signal in terms of the addition of a VEGF inhibitor to immunotherapy. And we've seen that consistently in renal cells and other tumor types. So, I think this is a really intriguing signal. I think this definitely warrants further exploration.  So, the other interesting thing was cohort-2 where they enrolled patients who had progressed on EGFR TKIs. So, in that cohort, they had like 19 evaluable patients and 13 patients had a partial response and 5 had stable disease. So, a very respectable response rate of 68.4% and 94.7 disease control rate. So, again, very small numbers, but a nice signal here for the efficacy of the drug.  There was another cohort, which is the cohort-3 where they enrolled patients who progressed on PD-1 therapy, and they enrolled a total of 20 patients with 8 patients having a partial response, following progression on PD-1 therapy.  Dr. Nathan Pennell: Yeah, I look forward to seeing further follow-up on this. It definitely sounds interesting. Moving on to Abstract 8541. This was “Durvalumab (durva) after chemoradiotherapy (CRT) in unresectable, stage III, EGFR mutation-positive (EGFRm) NSCLC: A post hoc subgroup analysis from PACIFIC,' which of course was the study that led to the broad use of durvalumab, the anti-PD-L1 antibody after chemoradiotherapy for unresectable stage III non-small cell, but this was the post hoc subgroup analysis of the EGFR mutation-positive group. And this is a subgroup we've really been curious about whether there was a role for consolidation, immunotherapy, or not. And so, what are your thoughts on the study?  Dr. Vamsidhar Velcheti: I agree with you, Nate, that this is actually some data that I was really, really looking forward to. Before we actually talk about the abstract. What do you do for those patients? If you have an EGFR mutation patient who has stage IIIB, what do you do right now?  Dr. Nathan Pennell: It's a great question. I have a discussion with them about the potential pluses and minuses of doing consolidation durvalumab. But I actually don't always use durvalumab in this setting, because of concerns about if you're using durvalumab and they recur, perhaps there is a problem with toxicity with using osimertinib. Honestly, I go back and forth about what the right thing is to do in this subgroup.  Dr. Vamsidhar Velcheti: No, I think that's the right context. I think that's a good setup to kind of discuss the data from the trial. I'm really excited about this. And I'm glad that we have this data to look at.  So, as you pointed out, the Pacific trial, its U.S. Food and Drug Administration (FDA) approval for durvalumab in the consolidation setting for patients with stage III after chemoradiation. This has now been the standard of care for like a few years now. The problem with the study is that patients with EGFR/ALK were allowed to enroll in the study.  Typically, for most IO trials, we generally tend to see patients with EGFR/ALK being excluded. So, this trial was an exception. In this study, they actually presented a post-hoc exploratory analysis of efficacy and safety of patients who did consolidation with durvalumab, but there was a total of 35 patients of the 713 patients that were randomized in the trial. And out of the 35 patients with EGFR mutation, 24 received durvalumab and 11 received a placebo.  So, of course, you're going to interpret this data with a little bit of caution. This is a full stock analysis, not pre-planned in small numbers. In this dataset, essentially, the median progression-free survival (PFS) was not different among patients treated with durvalumab or placebo, and the median survival was also not statistically significant. Overall, there was not much benefit from adding durvalumab in this setting in patients who have EGFR mutation-positive stage III lung cancer.  Dr. Nathan Pennell: I think that tends to track with what physicians, who have been treating patients with EGFR mutations for years, know about the disappointing response rates, certainly in the advanced stage with immunotherapy. I think we were concerned that in this consolidation phase that it would also potentially be a relatively marginal benefit. I agree with you that 35 patients are too small to make any definitive conclusions, but it certainly isn't supportive of a large benefit.  Dr. Vamsidhar Velcheti: But I think I'm excited about the LAUREL study that's ongoing, hopefully, that'll give us a little bit more definitive answers as to what we should be doing for patients with EGFR mutation-positive disease. Suddenly this is a piece of information that's helpful for treating physicians to make some decisions on clinical management for these patients.  Dr. Nathan Pennell: I agree. Now moving beyond the non—small cell. Let's talk about “Final survival outcomes and immune biomarker analysis of a randomized, open-label, phase I/II study combining oncolytic adenovirus ONCOS-102 with pemetrexed/cisplatin (P/C) in patients with unresectable malignant pleural mesothelioma (MPM).” That's Abstract 8561. What were your takeaways here?  Dr. Vamsidhar Velcheti: Yeah, it's always good to see some new therapeutic options for patients with mesothelioma. This is somewhat of an orphan disease and we haven't seen a lot of advances. Granted, we have some new therapeutic options with immunotherapy now, like, there is now a standard of care in the frontline setting.  So, this particular approach with ONCOS-102 is an oncolytic adenovirus expressing GM-CSF. And this is intended to stimulate the local and systemic immune response and remodulate the tumor microenvironment.  This was a small phase 1 study where they had a CFT run-in of 6 patients and a total of 25 patients were randomly assigned to receive ONCOS-102 intratumorally with ultrasound guidance or CT guidance and they injected this oncolytic virus into the tumor directly.  They were also getting treatment with platinum pemetrexed which is the standard of care in the frontline setting. The control here was 6 cycles of platinum pemetrexed. So, they enrolled both the treatment-naive patients in the frontline setting and they also enrolled patients who will progress on a platinum doublet.  I should note that none of these patients were treated with immunotherapy. I think that's something that we'll kind of get back to and we'll discuss. Overall, from a safety standpoint, there were some expected toxicities like pyrexia and nausea which is seen in the experimental group. It’s just kind of to be expected with an oncolytic virus. Overall, the 30-month survival rates were 34.3% and 18.2% in the control arm, and the median overall survival (OS) was 19.3 months and 18.3 in the controller.  So, for patients who were treated with the frontline chemotherapy, the survival rate was better with 30 months survival, it was 33.3 [months]. And in the experimental group, it was 0%.  So, overall, they also looked at tumor-infiltrating lymphocytes, they had CD4 around CD8 and granzyme B expressing CDA T-cells, and they had favorable PK from increased immune cell infiltration. So, this is very promising data but of course in a small study, and also in a population that hasn't had immunotherapy patients who are getting platinum doublet. In terms of safety, I think it looks promising. We need to see larger studies, especially with immunotherapy combinations.  Dr. Nathan Pennell: Yeah, I was impressed with the increased tumor infiltration of CD4 and CDA-positive T-cells, and the survival in the first line looked fairly impressive, although again, a very small subgroup of patients. But as you said, a standard of care these days is definitely going to involve immunotherapy. And so, I look forward to seeing combination trials in the future with this drug.  Shifting from mesothelioma over to small cell lung cancer, Abstract 8570 is “Stereotactic radiosurgery (SRS) versus whole brain radiation therapy (WBRT) in patients with small cell lung cancer (SCLC) and intracranial metastatic disease (IMD): A systematic review and meta-analysis.” Do you think that this would influence how we approach patients with brain metastases in the small cell?  Dr. Vamsidhar Velcheti: There are some in the community who kind of advocate for SRS in small cells if they have limited CNS disease. Certainly, I'm not one of them, but I think this is an interesting study in that light like we have never had any proper randomized trial. And we probably won't have randomized trials in that setting. So, at the end of the day, I think we all kind of customize our treatment approaches based on our patients and how much disease burden they have.  But having said that, the authors here have done a pretty large systemic analysis, and they looked at 3,700+ trials, they looked at random effects meta-analysis pooled hazard ratios for overall survival in patients who received SRS in the whole brain with or without SRS boost.  What they found was that overall survival following SRS was not inferior to whole brain RT. What do we really make out of this data? I think, given the heterogeneity, we have to see how the analysis was done and the kind of studies that went into the analysis. But however, I think the bigger question is, is there a population that we need to maybe—perhaps like, if somebody has an isolated brain met, you could potentially consider SRS with a whole brain RT for better local control.  So, the authors actually look at pooled data to look at local control versus intracranial distant control. So, this is a really interesting approach that asks the question, if patients had SRS and whole brain radiation, would it actually offer adequate intracranial distant control meaning like, do they develop new lesions?  So, it does look fairly decent. But again, it all depends on what kind of studies went into the analysis. And I don't think we should read too much into it. But at the same time, it kind of raises the question: is there a population of patients with small cell where it may be potentially appropriate to give SRS?  So, that's what I do in my day-to-day clinical practice. Sometimes there are situations where you kind of do the thing that we don't usually always do like in the small cell, we always think about whole brain radiation as something that we always have to offer, but I want to hear your perspectives too.  Dr. Nathan Pennell: No, I was always taught that you never did anything with whole brain radiation in the small cell even with a solitary metastasis. For a study like this, it's certainly interesting. You wonder how much selection bias there was towards people with fewer brain metastases and perhaps being in better health or better response to systemic disease that were referred for SRS, compared to whole brain radiation.  Part of the issue is the morbidity associated with whole brain radiation is significantly more than with SRS. And now that we are starting to, for the first time, see some patients with small cell [lung cancer] that are living substantially longer with immunotherapy, it might be worth exploring which patients might benefit from having that lower morbidity from whole brain radiation. But I agree with you that I'm not sure that we know who those patients are.  Dr. Vamsidhar Velcheti: Yeah, I think this is a difficult question to answer through a meta-analysis in my opinion. But having said that, your thought in terms of proving systemic therapies, then we kind of revisit the paradigm of offering SRS to some patients may be, especially with new BiTE T-cell engager studies that are ongoing, and hopefully, if you see some positive results, that might change what we do, but it's an important clinical question.  Dr. Nathan Pennell: And finally, in Abstract 8524, we have an interesting analysis of patients with relapsed small cell lung cancer, who received single-agent Lurbinectedin in the phase-3 Atlantis trial. What do you think about this poster, and why should this be on our radar?  Dr. Vamsidhar Velcheti: Yeah, I think this has been an interesting approval, of course, lurbinectedin FDA approved, as you know, like in June of 2020, based on data from a trial that uses 3.2 milligrams per meter square dosing every 21 days in second line setting post-chemotherapy.  What happened after that was there was a trial with the combination with doxorubicin in the second line setting comparative arm in that phase 3 trial topotecan or CAV.  In that trial, it was a negative trial, the primary endpoint was not met. The primary endpoint was overall survival, and it was a negative trial. And there were subgroup analyses done in the trial. The study that is presented now is actually a post-hoc analysis looking at patients who received treatment with this combination with doxorubicin that is like a lurbinectedin with doxorubicin, who had like a total of 10 cycles of the combination, and they switched to lurbinectedin monotherapy.  So, there were a total of 50 patients in that trial. They looked at the responses and the durability of responses in that population. It's a highly select population that made it to 10 cycles and they had stable disease or better and they switched to lurbinectedin monotherapy.  So, the highlight of the abstract is the median overall survival was 20.7 months. Of course, for small cell, that's really impressive. But I think we've got to be really careful in interpreting this data. This is like a small subgroup of highly selected patients who actually benefited from the trial. My question for you, Nate, is do you use lurbinectedin in the second line setting frequently or are you still treating them with topotecan?  Dr. Nathan Pannell: We still often use topotecan. I think lurbinectedin certainly seems to be an active drug, and it has some favorable schedule of administration pretty well tolerated from a tolerability standpoint, but from an efficacy standpoint, I still haven't really seen much that makes it stand out as significantly better than older options like topotecan or irinotecan.  That being said, it is intriguing that there is a subgroup of people who seem to have prolonged disease control with this. The problem, of course, is if you already select the people who make it 10 cycles without progression, then you're already picking the group of people who are doing extremely well. So, it's not surprising that they would continue to do extremely well.  Nonetheless, it's a sizable subgroup of people that seem to benefit and it would really be nice if there was, for example, a biomarker that might tell us which patients would truly benefit from this drug compared to our other options.  Dr. Vamsidhar Velcheti: Yeah, exactly. True. Right, I mean, like all of us have patients who have done exceedingly well on topotecan and I had a patient on paclitaxel for years. So, it's really important to kind of keep that in mind when we look at these sub-proof post hoc analyses.  Dr. Nathan Pennell: Well, thanks Vamsi for sharing these important advances in lung cancer that will be featured at the 2022 ASCO Annual Meeting.  Dr. Vamsidhar Velcheti: Thank you, Nate.  Dr. Nathan Pennell: And thank you to our listeners for joining us today. If you're enjoying the content on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.    Disclosures:  Dr. Nathan Pennell:   Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron  Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi  Dr. Vamsidhar Velcheti:  Honoraria: ITeos Therapeutics  Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine , AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen  Research Funding (Institution): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   

Guest host Dr. Neeraj Agarwal, of the University of Utah Huntsman Cancer Institute and the ASCO Daily News editor-in-chief, discusses key therapeutic advances in mRCC and mUC, as well as new research that proposes periodic scans to monitor patients with mCSPC for disease progression, with Dr. Jeanny-Aragon-Ching of the Inova Schar Cancer Institute.  Transcript:  Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Oncology Program, a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News.  My guest today is Dr. Jeanny Aragon-Ching, who is a medical oncologist and the Clinical Program Director of Genitourinary Cancers at the Inova Schar Cancer Institute in Virginia.  Today, we will be discussing key posters in genitourinary (GU) oncology that will be featured at the 2022 ASCO Annual Meeting. Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/podcast.  Jeanny, it is great to have you on the podcast today.  Dr. Jeanny Aragon-Ching: Thanks, Neeraj. It's a pleasure for me to be here as well.  Dr. Neeraj Agarwal: Jeanny, let's begin with Abstract 4510. This is a trial that represents a growing interest among researchers worldwide in the microbiome and how it is impacted by antibiotics and how it modulates immune checkpoint inhibitor response. Can you tell us about this study?  Dr. Jeanny Aragon-Ching: Thanks, Neeraj, I would be happy to. So, the title of the abstract is, “Characterization of the Microbial Resistome in a Prospective Trial of CBM 588 in Metastatic Renal Cell Carcinoma Offers Mechanism for Interplay Between Antibiotic Use and Immune Checkpoint Inhibitor Activity.”  So, this is an interesting abstract that originated likely from the observation that getting antibiotics while on checkpoint inhibitors typically results in worse outcomes, perhaps because antibiotics can clear the normal gut flora and thereby increase these pathogenic antibiotic-resistant bacteria.  Now, on the other hand, there were some retrospective studies using a live microbial product called CBM 588, which seems to improve outcomes in patients on checkpoint inhibitors and getting antibiotics.  So, the idea, therefore, is that shifting the genes encoding antimicrobial resistance could result in a better checkpoint inhibitor response. So, this Abstract 4510 is a small study conducted by Dr. Nazli Dizman and Dr. Sumanta (Monty) Kumar Pal, and colleagues, and enrolled 29 metastatic clear cell RCC patients with intermediate or poorest disease. And they were stratified into receiving either nivolumab or ipilimumab compared to nivo/IPI with CBM 588.  Now stool samples were collected at baseline in week 12. And they did this whole metagenome sequencing to analyze a stool microbiome composition, and they also looked at the antibiotic resistance genes for the most common classes of antibiotics.  The results showed an astounding improvement in objective responses. So, 58%, for instance, in nivo/IPI and the CBM 588 arm compared to only 20% in the nivo/IPI arm. And it seems like also the antibiotics resistance genes were also decreased in those getting the CBM 588 alongside nivo/IPI. Therefore, responses were improved by shifting the gut microbiome alone. So, these findings were published actually recently by these authors in Nature Medicine. So, in case anyone wants to take a deep dive, it would be a good interesting read for this dataset.  Dr. Neeraj Agarwal: Very interesting, indeed. Jeanny, what is the main message here for our colleagues?  Dr. Jeanny Aragon-Ching: I think, Neeraj, the key takeaway message is that this is a very provocative proof of concept trial that suggests shifting the gut microbiome has the potential to improve responses to checkpoint inhibitors and outcomes. So, this is a very up-and-coming trial and is seen also across the board in other cancers.  Dr. Neeraj Agarwal: Thanks, Jeanny. Moving on to urothelial cancer, there is a poster that I think is a must-see for our colleagues. This is Abstract 4577 titled, “Defining Platinum Ineligible Patients with Metastatic Urothelial Carcinoma.”  Dr. Jeanny Aragon-Ching: So, Neeraj, what can you tell us about this abstract?  Dr. Neeraj Agarwal: So, over the past few years, there has been a tremendous evolution in the treatment landscape for patients with metastatic urothelial carcinoma. For over 40 years the standard of care for these patients has been cisplatin-based chemotherapy.  However, approximately 50% of patients are cisplatin-ineligible, due to underlying comorbidities, and are offered carboplatin as an alternative. So, although the checkpoint inhibitors pembrolizumab and atezolizumab were approved as first-line therapy for these patients in 2017, the U.S. Food and Drug Administration (FDA) has now restricted the use of first-line pembrolizumab to platinum ineligible patients with metastatic urothelial carcinoma.  The challenge we face as oncologists since the FDA restriction is the absence of a formal definition of platinum ineligibility and the inclusion of this definition in the guidelines. So, in Abstract 4577, Drs. Shilpa Gupta and Jonathan Rosenberg, along with the team present an updated consensus definition for platinum ineligibility based on an online survey of 60 genitourinary oncologists in the United States.  Based on the results from this survey, any patient with metastatic urothelial carcinoma, meeting 1 of the following 5 clinical and or laboratory parameters should be considered platinum ineligible, and these are 1 of the following: an ECOG performance status of 3 or more, creatinine clearance of fewer than 30 mils per minute, or peripheral neuropathy of grade 2 or more, or heart failure class of 3 or more—so, this is NYHA heart failure class of 3 or more—and lastly, the combination of performance status of 2 or more, plus a creatinine clearance of less than 30 mils per minute.  Dr. Jeanny Aragon-Ching: Well, this is a timely update, Neeraj. So, what do you think is a key takeaway from this abstract?  Dr. Neeraj Agarwal: These criteria based on simple and easily available clinical and or laboratory parameters will now allow us to readily define platinum ineligibility in our patients with metastatic urothelial carcinoma, which is a need in busy clinics, both in academic and community settings.  So, I think once published and obviously once endorsed by guidelines, we really would like to be able to use this criterion to quickly define platinum ineligibility in our clinics.  Dr. Jeanny Aragon-Ching: Agree. Yeah.  Dr. Neeraj Agarwal: So, Jeanny, let me switch the gears. PSMA testing is a hot topic this year. And there is an abstract that could potentially have an impact on future guidelines, and how we will practice further down the road.  So, I'm referring to the Abstract 5088 titled, “Predictive Value of Extra Prostatic Disease Detection by Preoperative PSMAPET for Biochemical Recurrence-free Survival in Patients with Otherwise Localized Prostate Cancer and Who are Treated with Radical Prostatectomy.”  So, this is a follow-up analysis of a multicenter prospective phase 3 imaging trial. So, could you please tell us more about this abstract where they are using PSMA PET scan in the preoperative localized prostate cancer setting?  Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. So, you may recall that the multicenter prospective phase 3 imaging trial that garnered gallium PSMA approval by the FDA was actually based on this study that looked at the intermediate and high-risk patients with prostate cancer undergoing radical prostatectomy and lymph node dissection, and they underwent prior gallium PSMA PET scanning for pelvic nodal metastases prior to surgery.  So, this was actually previously reported by Dr. Calais and group. Now they are reporting on Abstract 5088 as a post hoc analysis of the same population and group of patients looking for extraprostatic disease. And the final pathology was also correlated to look at nodal disease in these patients in order to predict biochemical recurrence, so they follow these patients for biochemical recurrence occurrence.  So, of the 36% of patients who did undergo radical prostatectomy after they underwent PSMA PET scan, about 41% of them recurred with biochemical recurrence, and 40% of them underwent some kind of salvage therapy or some treatment.  What was very interesting was when they looked at the biochemical recurrence-free survival. It was better in those who were PSMA negative, and that recurrence-free survival was easily about 33 months, compared to only about 7.3 months in those who were PSMA-positive scans.  Furthermore, the ones who had the longest and the highest biochemical recurrence-free survival, intuitively, were those who were node-negative and PSMA PET-negative, so probably not surprisingly. And that rate was about 46 months—close to 4 years. Whereas those who are node-positive on final pathology and their PSMA PET was also positive, they only had about 3 months of biochemical recurrence-free survival.  Dr. Neeraj Agarwal: Very interesting. So, it looks like the PSMA PET scan is predicting biochemical recurrence-free survival in localized prostate cancer settings. So, Jeanny, what is the key takeaway from this trial?  Dr. Jeanny Aragon-Ching: I think, Neeraj, the bottom line is that patients with extraprostatic disease that is detected by their preoperative PSMA PET scan does predict strongly a high risk of biochemical relapse, and this can really be an additional tool that clinicians can use to help inform and guide future therapy.  Dr. Neeraj Agarwal: Thanks, Jeanny. The research on preoperative PSMA testing and its implications on future treatment strategies in the setting is going to be really interesting to watch in the very near future.  Dr. Jeanny Aragon-Ching: Yes, absolutely. I really think we should also discuss Abstract 5072, along those lines, the importance really of radiographic monitoring for disease progression in patients with metastatic hormone-sensitive prostate cancer.  Dr. Neeraj Agarwal: Yes, thanks for reminding and this is Abstract 5072. This is a post hoc analysis of the ARCHES trial, titled, “Radiographic Progression in the Absence of PSA Progression in Patients with Metastatic Hormone-sensitive Prostate Cancer.”  During the last several years, we have seen many of these agents typically given for gastric resistant prostate cancer moving upfront to the castration-sensitive prostate cancer setting. This is especially true for androgen receptor access targeting agents such as abiraterone, enzalutamide, and apalutamide, all being now approved for patients with metastatic castration-sensitive prostate cancer.  What is noteworthy from all these trials, and is reported in Abstract 5072, is the use of imaging studies to evaluate disease progression. So, in Abstract 5072, Dr. Andrew Armstrong and Dr. Arun Azad performed a post hoc analysis of the ARCHES trial to investigate the concordance between radiographic progression and the PSA Progression as defined by PCWG2 criteria, or between radiographic progression and any rise in the PSA above nadir, in patients who were being treated with this novel hormonal therapies, in this case, enzalutamide for metastatic castration sensitive prostate cancer.  And as a quick reminder, ARCHES was a phase 3 trial that showed a significant reduction and radiographic progression-free survival and improved overall survival for patients with metastatic castration sensitive prostate cancer treated with enzalutamide plus androgen deprivation therapy (ADT) versus those treated with placebo plus androgen deprivation therapy.  So, very interestingly, the findings from this study indicate that 67% of patients on the enzalutamide plus ADT arm did not have [Prostate Cancer Clinical Trials Working Group 2 criteria] PCWG2-defined prostate-specific antigen (PSA) progression at the time of radiographic progression. And discordance was present in the ADT-only arm as well, where they found 42% of patients on the ADT-only arm had radiographic progression but did not have PCWG2-defined PSA progression.  Interestingly, this discordance of radiographic disease progression was also seen with any rise in the PSA above nadir. And I personally found this information to be very clinically relevant when we are seeing the majority of patients actually experiencing radiographic disease progression, not experiencing PSA progression at the same time.  Dr. Jeanny Aragon-Ching: Yeah, absolutely. I agree with that, Neeraj. So, very interesting data. So, what do you think is the key takeaway message for the clinicians listening to us?  Dr. Neeraj Agarwal: I'll make the message very simple. I think the message is that patients with metastatic castration-sensitive prostate cancer need to be monitored for disease progression with periodic scans, and PSA monitoring alone is not sufficient in the majority of these patients.  Again, we cannot undervalue the role of periodic imaging studies in these patients so that we can timely diagnose them to have disease progression.  Dr. Jeanny Aragon-Ching: I agree with that.  Dr. Neeraj Agarwal: Jeanny, the last abstract I would like to mention before we wrap up the podcast is Abstract 4509, the results from the phase1 live SPARC 001 study. So, can you please tell us more about this study titled, “Phase-1 Live SPARC 001: The Study of Belzutifan in Advanced Solid Tumors,” which is an update of the renal cell carcinoma cohort with more than 3 years of total follow up?  Dr. Jeanny Aragon-Ching: Thanks, Neeraj. So, while the current therapeutic landscape for patients with metastatic clear cell renal cell carcinoma (RCC) has changed dramatically over the past several years, with significant improvement in patient outcomes. Most patients unfortunately still experience disease progression on current treatments.  So, in-depth molecular profiling of clear cell RCC has revealed recurrent loss of function mutations in VHL in actually greater than 90% of patients. So, the VHL protein, as you will recall, is part of the oxygen-sensing pathway, regulating levels of HIF which is hypoxia-inducible factor protein, it's a transcriptional activator that mediates the response to hypoxic conditions. So, HIF-2α is a key oncogenic driver in RCC.  So, previous data you may recall from the phase-1 Live SPARC 001 trial was designed to evaluate belzutifan so, this was a novel HIF-2α inhibitor which showed durable anti-tumor activity and acceptable safety profile in patients with metastatic clear cell RCC.  So, in Abstract 4509, Drs. Jonasch and Toni Choueiri presented updated results from this trial after more than 3 years of follow-up. Of the 55 patients enrolled 16% of patients remained in treatment. And 62% of patients had discontinued treatment because of, unfortunately, disease progression.  The median progression-free survival (PFS) for the total cohort was 14.5 months. And the overall disease control rate was 80%. Forty percent of patients experienced grade 3 treatment-related adverse events with the most frequent ones being anemia and hypoxia.  There were no great 4 or 5 treatment-related adverse events. And these results, therefore, show that belzutifan monotherapy continues to show a high rate of disease control and a safety profile in a heavily treated population of patients with metastatic RCC. So, it is great to see that there were no new safety signals.  Dr. Neeraj Agarwal: Very nice data indeed. So, Jeanny, what is the key takeaway message here for our listeners?  Dr. Jeanny Aragon-Ching: Yeah, I think the message here is that the use of belzutifan monotherapy continues to show efficacy and safety in patients with metastatic clear cell RCC, which have progressed on multiple prior contemporary therapies, and there are phase 3 trials currently underway.  Dr. Neeraj Agarwal: Jeanny, any final thoughts before we wrap up the podcast today?  Dr. Jeanny Aragon-Ching: Thanks, Neeraj. I think it's a really exciting time to be in genitourinary (GU) oncology, and I'm truly looking forward to seeing some great sessions at the 2022 ASCO Annual Meeting.  Dr. Neeraj Agarwal: Thank you, Jeanny, for sharing your insight with us today. It was a great conversation. And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.    Disclosures:   Dr. Neeraj Agarwal:   Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences  Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, Arvinas  Dr. Jeanny Aragon-Ching:   Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc  Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, AstraZeneca/MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis  Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb , Astellas/Seattle Genetics  Travel, Accommodations, Expenses: Dendreon, Algeta/Bayer, Bristol Myers Squibb, EMD Serono, Astellas Pharma  Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast expressed their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.       

Dr. Neeraj Agarwal, of the University of Utah Huntsman Cancer Institute, tells host Dr. John Sweetenham, of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, about the first study to examine the quality of diagnosis and treatment of breast cancer in sex and gender minority patients and other key studies on disparities associated with access to clinical trials and rising drug costs.  Transcript Dr. John Sweetenham: Hello, I'm John Sweetenham, the associate director for Clinical Affairs at UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News podcast.  I'm delighted to welcome my friend and colleague Dr. Neeraj Agarwal, the director of the Genitourinary Cancers Program and a professor of medicine at the University of Utah's Huntsman Cancer Institute. Dr. Agarwal also serves as editor-in-chief of the ASCO Daily News.  Today, he'll be sharing his insights on compelling studies that will be featured at the 2022 ASCO Annual Meeting, addressing access to clinical trials, disparities associated with high deductible health plans, rising drug costs, and more.  Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/podcasts.  Neeraj, it's great to have you back on the podcast.  Dr. Neeraj Agarwal: Thanks, John.  Dr. John Sweetenham: Neeraj, let's begin with Abstract 6503. This study looks at the impacts of high deductible health plans on delays in metastatic cancer diagnosis. What do you think about this study and why should it be on our radar?  Dr. Neeraj Agarwal: Well, John, in high deductible health plans, patients are liable for the cost of all cancer-related care, with the exception of screening tests, until their annual deductible is met. Due to increased out-of-pocket costs, patients may postpone seeing a physician for concerning symptoms or diagnostic testing, leading to delayed diagnosis.  So, in this study, Mr. Nicholas Trad and J. Frank Wharam assessed the impact of high deductible health plans on the timing of metastatic cancer detection.  The authors leveraged a nationally representative cohort of more than 340,000 privately insured members whose employers mandated a switch from a low deductible of less than $500 plan to a high deductible plan of more than $1,000.  So, the group consisted of more than 1 million individuals in a contemporary time frame, whose employers offered only low deductible plans. Participants were matched based on multiple baseline characteristics, time to metastatic cancer diagnosis, and the before and after switching to high deductible health plans was investigated using a weighted Cox proportional-hazards model.  After matching, there were no systematic differences between the 2 groups with regards to baseline characteristics, and there were no differences in time to metastatic cancer diagnosis prior to the switch to high deductible health plans.  However, after the employer-mandated switch to the high deductible health plans, these participants had lower odds of metastatic cancer diagnosis, which was significant, statistically speaking, and indicates delayed detection of metastatic cancer diagnosis relative to the control group.  Dr. John Sweetenham: This is certainly concerning data, Neeraj. What's your key takeaway from this study?  Dr. Neeraj Agarwal: So, the key takeaway from the study is that compared with conventional health plans, high deductible health plans are associated with delayed detection of metastatic cancer, implying that patients postpone seeking care for concerning symptoms or even defer diagnostic testing when they're exposed to high-cost sharing.  Dr. John Sweetenham: Thanks, Neeraj. So, let's continue with this theme of the financial burden of cancer care for our patients. Of course, we're all aware of the rising costs of targeted oral therapies, and this was addressed in Abstract 6504, where the study looks at the rising costs of targeted oral treatments among Medicare beneficiaries. And the study reported a substantial increase in the total cost and out-of-pocket costs of these medicines. Can you tell us more about this abstract?  Dr. Neeraj Agarwal: Yes! So, due to the rapidly rising cost of targeted oral anticancer medicines, Drs. Meng Li and Ya-Chen T. Shih examined recent trends and the financial burden of these oral medicines among patients with cancer with Medicare Part D insurance. So, eligible patients in the SEER-Medicare database had to be 65 years and older and had to have one primary cancer diagnosis.  The investigators estimated the trends in the share of patients who used targeted oral anticancer medicines, the percentage of users reaching catastrophic coverage, and the total and patient out-of-pocket spending on these medicines in the catastrophic phase in a year.  So, from 2011 to 2016, the uptake of these oral anti-cancer medicines increased from approximately 4% to 9%. The percentage of those who reached catastrophic coverage increased from 55% to 60%.  Among those who reached the catastrophic phase, the mean total annual gross spending on oral anti-cancer medicine increased 4-fold from approximately $16,000 to $64,000. And the mean out-of-pocket spending for the patients rose from approximately $600 to $2600.  Dr. John Sweetenham: Yes, this is more evidence that the financial toxicity generated from an increase in spending and out-of-pocket costs is going to have serious impacts on our patients. Would you agree with that, Neeraj?  Dr. Neeraj Agarwal: Yes, John. The key takeaway from this study is that the financial burden of these oral anti-cancer medicines continues to increase. In the relatively short period of time, we see here, 5 years from 2011 to 2016, there was a 4-fold increase in the total cost and out-of-pocket cost of these medicines. And in my view, these findings warrant immediate actions to rein in drug prices and cap out-of-pocket spending for our patients.  Dr. John Sweetenham: Absolutely. It's very difficult to know where this will end unless we see some kind of slowdown in these rising costs. I'm going to change gears just a little bit now to address the access to clinical trials, which is the subject of Abstract 6505.  This study looks at the implementation of the Affordable Care Act Medicaid expansion, which was associated with an almost threefold increase in the proportion of patients using Medicaid in cancer clinical trials by early 2020. What are your thoughts on this study?  Dr. Neeraj Agarwal: As you said, the Affordable Care Act Medicaid expansion resulted in increased use of this platform across the nation. However, its impact on access to clinical trials has not been examined.  So, in this study, Dr. Joseph Unger and Dr. Dawn Hershman examined the number and proportion of patients insured by Medicaid at enrollment over time using data from the SWOG Cancer Research Network.  In addition, they also examined all patients, 18 to 64 years old, enrolled in treatment trials between 1992 to 2020 using Medicaid versus private insurance.  So, the implementation of the Affordable Care Act Medicaid expansion was associated with a nearly threefold increase from 7% to 21% in the proportion of patients using Medicaid in cancer clinical trials by early 2020.  The increase per year of Medicaid uses for patients in these treatment trials from states that implemented the Affordable Care Act Medicaid expansion was 27% compared to 7% for patients from other states who did not implement this platform of Affordable Care Act Medicaid expansion.  So, the key takeaway from the study is that better access to clinical trials for more vulnerable patients is critical to improving confidence in how generalizable these trial findings are. In addition, these results suggest that the recently enacted Cancer Treatment Act may continue to improve access to clinical trials for those with Medicaid insurance or those who are vulnerable patients.  Dr. John Sweetenham: Yes, I think this is a really important study which adds to the growing literature on the benefits of the Affordable Care Act and Medicaid expansion on cancer care in general, in this case, specifically related to clinical trials. So, so important, I think.  On that theme of equity, I think the next 2 abstracts we're going to discuss address specific aspects of equity, which I think are both interesting and really important. So, Abstract 6510 has interesting research which conveys an urgent need to ensure equitable patient-reported access and implementation and to address the greater reported symptom burden among minority patients. Why do you think this study is important?  Dr. Neeraj Agarwal: The routine collection of patient-reported outcomes for patients with cancer is an evidence-based practice and a critical component of high-quality cancer care, but the real-world adherence and reporting patterns are poorly understood.  In this study, Dr. Samuel Takvorian and Dr. Ravi Parikh examined differences in adherence to the collection of patient-reported outcomes and reported symptoms by race and ethnicity.  This was a retrospective cross-sectional study using de-identified electronic health record data from an National Cancer Institute (NCI)-designated Comprehensive Cancer Center. The participants included adults seen in follow-up at 1 of the 2 medical oncology practices—one was in academics and one was in the community—from June 2019 to February 2020. Using ordinary least-squares regression, the authors modeled patient adherence as a function of race or ethnicity, and this was adjusted for age, sex, insurance, median area income, ECOG, performance status, and many other patient-related characteristics.  The results show that adjusted mean PRO adherence and reported symptoms varied by race and ethnicity, with Black and Hispanic patients being less likely to complete PRO questionnaires, but reporting significantly higher symptom burden compared to the White patients.  Dr. John Sweetenham: Right. So, it seems that more work is needed to ensure equitable access and adherence to PRO questionnaires so we can better address the symptom burden of our minority patients.  Dr. Neeraj Agarwal: Correct, John. In this large cohort reflecting real-world PRO collection patterns, Black and Hispanic patients were less likely than White patients to complete these PRO questionnaires, but more likely to report more severe symptoms. And I think there is an urgent need to ensure equitable PRO access and implementation and to address the greater reported symptom burden among minority patients.  Dr. John Sweetenham: Let's continue the theme of health equity and cancer care equity into the use of telemedicine. Of course, we saw a massive expansion of telemedicine for patients with cancer during the COVID-19 pandemic.  But studies are emerging now to show that there have been substantial disparities among the Black, uninsured, non-urban, and less affluent patients who are less likely to use telemedicine services.  Abstract 6511 reminds us that telemedicine may expand access to specialty care, but the proliferation of these services may widen cancer care disparities if vulnerable populations don't have equitable access. Can you tell us more about this abstract?  Dr. Neeraj Agarwal: These are indeed very interesting findings, John. The COVID-19 pandemic was associated with declines in in-person clinical visits, with a concurrent increase in the use of telemedicine.  In this study, Dr. Gregory S. Calip assessed demographic and socioeconomic factors associated with telemedicine use among patients initiating treatment for 21 common cancers at community oncology clinics.  This was a retrospective study and made use of the nationwide Flatiron electronic health record derived de-identified database of patients with cancer. The authors focused on differences in telemedicine use across race and ethnicity, insurance coverage, rural versus urban areas, and socioeconomic status.  They used logistic regression models for this analysis, which was adjusted for clinical characteristics to examine differences in telemedicine use among these different cohorts.  Results indicate Black patients were significantly less likely to use telemedicine services compared to White patients. Telemedicine use was also significantly lower among patients without documented insurance than well-insured patients. It was also lower in patients from rural and suburban areas versus patients who were living in urban areas. Lastly, telemedicine use was significantly lower in patients in the least affluent areas than those in the most affluent areas.  So, during the COVID-19 pandemic, nearly one-fifth of patients initiating cancer treatment using telemedicine services—among these patients, we see substantial disparities. So, Black, uninsured, non-urban, and less affluent patients were less likely to use telemedicine services.  So, the take home message from this study is that while telemedicine may expand access to care, the proliferation of these services may actually widen cancer care disparities if vulnerable populations do not have equitable access to these services.  Dr. John Sweetenham: Thanks, Neeraj. So, the final study that we'll discuss today also looks at another aspect of disparities, and that's Abstract 6517. It's a case-controlled study of health care disparities in sex and gender minority patients with breast cancer. What are the key takeaways from this study?  Dr. Neeraj Agarwal: Disparities and the quality of diagnosis and treatment of breast cancer in sex and gender minority populations are largely undefined. Only 24% of studies funded by the National Cancer Institute capture data on sexual orientation and only 10% capture data on gender identity.  In this case-control study, Drs. Eric Eckhert and Allison W. Kurian matched sex and gender minority patients with breast cancer to cisgender heterosexual controls in the Stanford University health care database. Ninety-two sex and gender minority patients were identified who were then matched by year of diagnosis, age, stage of cancer, presence of estrogen receptor (ER), and HER-2/neu receptor status to cisgender heterosexual controls within this database.  Additional data on demographics, diagnosis, treatment, and relapse were then manually abstracted from the electronic health care records. The sex and gender minority cohort were comprised of 80% lesbians, 13% bisexuals, and 6% transgender men.  One of the most pertinent findings was a significant, almost twice as much delay in time to diagnosis from the onset of symptoms in these minority patients versus control. Although there was no difference in the receipt of surgery or surgical radiation or new adjuvant therapy, sex, and gender minority patients were significantly less likely to undergo chest reconstruction surgery, and if they were estrogen receptor-positive, they were significantly less likely to complete at least 5 years of ER directed therapy.  Please also note that sex and gender minority patients used more alternative medicine, had a higher rate of documented refusal of recommended oncology treatments, and they experienced a higher recurrence rate.  So, the key takeaway from this study is that—this is the first study, I really want to congratulate the investigators who examined the quality of diagnosis and treatment of breast cancer in sex and gender minority patients. Several novel potential health care disparities are identified in these patients, which should be further evaluated in population-based studies to inform further interventions.  Dr. John Sweetenham: Neeraj, it’s always a pleasure to talk with you and have an opportunity to spend some time with you. Thanks very much for sharing your insights on these compelling studies today. Our listeners will find the links to these abstracts in the transcripts of this episode.  Dr. Neeraj Agarwal: Thanks, John.  Dr. John Sweetenham: And thanks to our listeners for your time today. If you're enjoying the content on the ASCO Daily News podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.    Disclosures:  Dr. John Sweetenham  Consulting or Advisory Role: EMA Wellness  Dr. Neeraj Agarwal:  Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Merck, Novartis, lily, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences    Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, CRISPR therapeutics, and Arvinas     Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. 

Dr. Jhanelle Gray, of the Moffitt Cancer Center and chair of the 2022 ASCO Annual Meeting Education Program, highlights must-see sessions that explore strategies to advance equity, innovation, and impact across the global cancer community.  Transcript: ASCO Daily News: Hello and welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for ASCO Daily News. Today I'm delighted to welcome Dr. Jhanelle Gray. She is the department chair of thoracic oncology and co-leader of the Molecular Medicine Program at the Moffitt Cancer Center. She's also a professor at the University of South Florida Morsani College of Medicine and chair of the 2022 ASCO Annual Meeting Education Program. Dr. Gray will tell us about the hot topics and must-see educational sessions at this year's [ASCO] Annual Meeting. Dr. Gray's full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/podcasts. Dr. Gray, it's great to have you on the podcast today. Dr. Jhanelle Gray: Thank you for having me. I am excited to be here with you today and for the opportunity to chat with you about the upcoming 2022 ASCO Annual Meeting and the educational sessions. ASCO Daily News: Well, the theme of the Annual Meeting is advancing equitable cancer care through innovation. Can you tell us how equity and innovation are reflected in the Education Program? And what would you say are the must-see sessions in this year's program? Dr. Jhanelle Gray: I am excited about sharing and hearing the latest advances in our field so we can move toward impact innovation and equity across our global cancer care community. [In] many of the sessions that we have, the attendees will join us either online or in person, and really will help us come together with a common goal of reducing the cancer burden. The presidential theme from Dr. Everett Vokes has really helped us to formulate what these sessions are. A few of them that I think really align with where we want to go for this 2022 ASCO [Annual] Meeting are things such as looking at strategies to advance cancer equity in our cancer clinical trials. We also have sessions such as “Artificial Intelligence in Oncology: The Current Field and Where It Is Headed,” and this touches on our innovation piece. We also have some really great keynote speakers such as a session—our ASCO Town Hall, moderated by Dr. Monica Bertagnolli, a past ASCO president and she'll be talking to us about the future of the conduct of clinical trials after COVID-19. I hope this gives you a sense of the exciting topics we have as we work to identify and address the challenges in this global cancer care field. ASCO Daily News: Thanks. Well, a couple of other sessions that are really trying to address these challenges are 2 joint sessions. So, I'd like to ask you about those. The first one involves ASCO and the American Association for Cancer Research, or AACR. And the second one features ASCO and the European Cancer Organization (ECO). Can you tell us about the topics of these sessions and why you think it's important for participants to see these particular sessions? Dr. Jhanelle Gray: Thank you. That's a great question. And thank you to AACR and ECO for their engagement and collaboration in planning and designing these sessions. We work to ensure that both organization's priorities and expertise are truly represented. The ASCO-AACR joint session is titled, “ASCO/American Association for Cancer Research (AACR) Joint Session: The Promise of DNA Damage Response and Repair in Cancer,” and the ASCO-ECO joint session is on HPV vaccination prevention and treatment. These sessions include hot topics in oncology and were planned intentionally with a common approach that is across DNA damage repair and HPV vaccines. I really want the audience to hear: What is the existent data from which we can learn? How do we work to expand upon these gains across various tumor types? What are those key opportunities to expand platforms, and they should include diagnostics and therapeutics across global populations? Overall, I think both of these sessions will help the audience to understand not only what present-day data is, but also learn where these fields are heading in the future. ASCO Daily News: Thank you. Well, the ASCO Voices session is a favorite of the ASCO Annual Meeting. The speakers this year from Nigeria, Ireland, Germany, and the United States will share personal stories focused on equity, global health, and innovation. I've had a chance to interview the speakers and their stories really capture the human spirit and convey a true desire to find innovative ways to improve the lives of patients and survivors. Is this session 1 of your favorites at the [ASCO] Annual Meeting? Dr. Jhanelle Gray: Absolutely. The ASCO Voices is truly a compelling session. It helps to highlight where we should focus in what can seem like a very busy meeting. It helps all of us, including health care professionals, industry partners, caregivers, to take that breath and recenter. Our focus is ultimately the patient, and these personal stories help to crosscut that oncology continuum. We have, of course, chosen those that helped to showcase and support the importance of the presidential theme. And you'll see that many of those have topics focused on issues that are most relevant to global health, innovation, and/or cancer equity. So, congratulations, and looking forward to all of the speakers in this session [and] hearing their talks. ASCO Daily News: Thank you, Dr. Gray. Is there anything else you'd like to add? Before we wrap up the podcast? Do you want to mention maybe some of the sessions that are on top of your list to attend? Dr. Jhanelle Gray: Absolutely. We have also, in addition to the educational session, you'll hear from others throughout these podcasts on the scientific sessions, also obviously looking very much forward to the plenary, looking forward to the award ceremony also. It's just been an absolute pleasure to be working with Dr. Sonali on scientific sessions, as well as obviously Dr. Everett Vokes, our current president. ASCO Daily News: Well, thank you very much, Dr. Gray, for being on the podcast today. And thank you for your work as chair of the 2022 ASCO Annual Meeting Education Program. Dr. Jhanelle Gray: It's been an absolute pleasure to spend time with you today. If I can also take a moment to thank the ASCO staff, just what a phenomenal team and so those that are listening, I look forward to seeing you hopefully some of you at least in person at the meeting. ASCO Daily News: Wonderful! Thanks to our listeners for your time today. If you're enjoying the content on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclosure: Dr. Jhanelle Gray: Honoraria: Merck Sharp & Dohme, Axiom HC Strategies, Inivata Consulting or Advisory Role: Novartis, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, EMD Serono, Lilly, AstraZeneca, Sanofi, Merck Sharp & Dohme, Janssen Scientific Affairs, AstraZeneca/MedImmune, Loxo, Jazz Pharmaceuticals, Janssen Research Funding (Institution): Array BioPharma, Merck, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Genentech/Roche, G1 Therapeutics, Novartis, Pfizer, Ludwig Institute for Cancer Research Travel, Accommodations, Expenses: Merck Sharp & Dohme, Inivata, Merck, EMD Serono, Novartis Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Brooke Worster and Dr. Nathan Handley of Sidney Kimmel Cancer Center – Jefferson Health shine a spotlight on cannabis use in palliative oncology.  They discuss guidance on dosing, legal concerns, and resources for oncologists with host Dr. John Sweetenham of the UT Southwestern Simmons Cancer Center. Transcript Dr. John Sweetenham: Hello, I'm John Sweetenham, Associate Director of Clinical Affairs at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News podcast. Recent reports in oncology journals suggest that 20% to 40% of all patients with cancer use cannabis in some form during or after treatment to manage symptoms. However, a national survey of medical oncologists in 2018 found that 70% of oncologists did not feel equipped to make clinical recommendations regarding cannabis and only 46% recommended it clinically. Joining me to discuss cannabis use in palliative oncology are Dr. Brooke Worster, an associate professor and the director of supportive medicine at the Sidney Kimmel Cancer Center at Jefferson Health. And Dr. Nathan Handley, a medical oncologist and an assistant professor who is also at the Sidney Kimmel Cancer Center. Our full disclosures are available on our show notes and disclosures of all guests on the podcasts can be found on our transcripts and at asco.org/podcasts. Dr. Worster and Dr. Handley, thanks for coming onto the podcast today. Dr. Brooke Worster: Thanks for having us. Dr. Nathan Handley: Thank you. Dr. John Sweetenham: Dr. Worster, can you tell us how cannabis and cannabinoid-based medicines are used in palliative oncology and how prevalent this is? In addition, could you say a little about the use of cannabis in patients with cancer in the United States and how it compares with other countries? Dr. Brooke Worster: Yeah, absolutely. I think we are realizing more and more that cannabis or cannabinoid-based medications are used much more often than we as clinicians were aware. We just weren't asking our patients enough. And so, you mentioned other surveys about the kind of nationally sample representative of patients with cancer, we actually just also completed one that was a National Institutes of Health (NIH)-funded study, looking at cancer centers across the country and found similar rates that patients with cancer under the age of 65, at some point during treatment or survivorship, about 50% of them had tried cannabis. Interestingly, the largest growing segment of patients with cancer starting to use and inquire about cannabis are our [age] 65 and older patients. So, a quarter of them now report using it. And we actually found that 45% of patients over the age of 65 were interested but didn't feel comfortable having the conversation. Our country is kind of middle of the road in terms of what's accessible and what we use. Certainly, countries like Canada and some places in Europe, as well as Australia have a much more advanced marketplace as well as legislation and access to cannabis. And so, it’s used more prevalently across kinds of the oncology spectrum, but there are still a lot of countries across the world where cannabis remains completely illegal. So, the United States is sort of in the middle. Dr. John Sweetenham: Thanks. You and Dr. Handley recently co-authored an article in the ASCO Daily News along with other colleagues. And in that, you write the patients most often want guidance about the formulation and dosing, which as I read your article seems to be somewhat elusive still, given the diversity and composition of the plant-based strains. You point out that understanding the onset of action and duration of effects are important first steps. Could you say a little bit more about this? Dr. Brooke Worster: Yeah, absolutely. I think when someone is trying this for the first time, or for the first time in years, understanding how and when they're going to feel the impact or the effects of primarily tetrahydrocannabinol (THC) but also cannabidiol (CBD) and other minor cannabinoids is important for them to be patient. We see that people that ingest either sublingual absorption or oral ingestion of products, don't recognize that it can take up to 60 to 75 minutes, even if you have other food in your stomach to really feel the effect. And then will kind of overdose in some ways or sort of re-dose and get more of an effect of the THC than they were looking for. Versus if someone is inhaling something, you're really going to feel that quite rapidly, right? Five minutes in terms of onset of action. The duration of effect for that is much less. You're talking 2 to 3 hours maximum for an inhalation form, versus 5 to 7 hours for something that's sublingual, or orally ingested. Dr. John Sweetenham: Thanks! Dr. Handley, we've read in your article and in others, that cannabis as a palliative treatment for patients is well-tolerated, safe, and an effective option to help them cope with malignancy-related symptoms. Can you comment a little on whether or not there is a downside to cannabis and cannabinoid use and whether there are negative interactions with other cancer treatments? And are there certain patients who should avoid the use of cannabis? Dr. Nathan Handley: I would say that in general cannabis can be very safe if taken carefully and appropriately, and ideally with some guidance from a qualified practitioner. But it is important to consider some of the risks and side effects that cannabis carries. So, I think the first point is that if smoked, or otherwise, inhaled, the smoke can have many of the same carcinogens that are found in tobacco smoke. It's also interesting because smoking of marijuana or cannabis and tobacco are highly correlated. And so, it can be difficult for us to kind of assess if there are increased pulmonary risks associated specifically with cannabis use compared to tobacco use. And there have been a number of large cross-sectional and longitudinal studies that haven't found this link between cannabis use and impaired pulmonary function tests or chronic obstructive pulmonary disease (COPD) or lung cancer. But there are still potential risks associated with inhalational forms. There's also some evidence that there may be higher cardiovascular risks among cannabis users, specifically in patients who have heavy cannabis exposure. So, there have been some studies that have looked at the role cannabis can play in thrombosis, inflammation, and atherosclerosis. There have been some case reports that have linked its use to myocardial infarctions and arrhythmias, cardiomyopathy, stroke, and arthritis. But those haven't necessarily been played out in large clinical trials yet. And so, essentially, if someone is at increased cardiovascular risk at baseline, if they're elderly, or if they have pre-existing cardiovascular conditions, these are things worth discussing with the patient. So, I wouldn't say that they're necessarily absolute contraindications. I think some of the more immediate side effects of cannabis are also worth discussing with patients. And these are often related to the amount or the concentration of THC that is present in the preparation. A THC ingestion can result in a number of adverse side effects. There can be impaired concentration, impaired spatial relationships, memory can sometimes be affected. And in some rare cases, you can have increased anxiety, paranoia, or even psychosis. And so, there are not again, strong studies demonstrating a distinct correlation between cannabis use and psychiatric disorders. This is an area that merits further investigation still, and those risks likely vary based on the type of the product, the potency, the composition, if it's synthetic, if it's illicit, but we do have some hesitation about using cannabis in patients who have severe pre-existing mental health conditions like psychosis or schizophrenia, or something like that. On the issue of interactions with certain cancer treatments, I think one thing that patients often wonder is if cannabis can be used to treat cancer? And there is some interesting in vitro data and some in vivo data to suggest that cannabinoids can modulate tumor growth. But the data here is very limited. And so, really what we say is that more research needs to be done in this area. I think the other area of interest is there's some preliminary data, suggesting that patients who are on immunotherapy may have a reduced response to that treatment if they're taking cannabinoids, but these data are also very early. And so, we don't make any clinical decisions based on it at this point. Dr. John Sweetenham: Okay. Thank you. Another area, which I think is concerning certainly to some oncologists and other physicians is the legal issues surrounding the use of medical cannabis. And the core issue there, of course, is the contradiction in many cases between federal and state laws. Dr. Worster, can you tell us a little bit more about this and how oncologists can inform themselves of these issues and perhaps feel a little bit more comfortable about prescribing or recommending medical cannabis? Dr. Brooke Worster: Absolutely. I think at the crux of this issue, you're spot on. I mean, it's muddy. And if you look at the map of our country, the state-by-state variation changes year to year. So, I think one of the biggest things for all clinicians to recognize is that there have been challenges to the legality of recommending, we're not prescribing because that is still federally illegal, but certainly recommending cannabis to patients. There have been legal and court challenges that have worked their way up to federal courts, and have always supported that this is a right to free speech and well within your protected rights as a clinician to have a conversation with your patient along the lines of all kinds of other lifestyle choices we talk about with patients. So, there's no risk in terms of having the conversation, per se, or guiding patients into the space. Where I would tell people to familiarize themselves is really the intricacies of your own state's laws, as well as where a patient may be living if you're seeing them across state lines. One really great resource for this is the National Consortium of State Legislatures. They do a very good job and keep very up to date on a state-by-state basis in terms of what's legal, what conditions, how to access it, if there's reciprocity between states or not, if you can bring product across state lines, who can access it, all of the things that our patients are concerned about, and thus, bringing very valid questions to us that we want to be able to kind of help support them in this conversation. Dr. John Sweetenham: Yeah. Thank you! You know, another issue that you do bring up in your recent article is that of pain management, which of course is a very important component of cancer care in general. But studies in the Journal of Clinical Oncology and elsewhere have recently found there's been a sharp decline in access to opioids among patients with terminal cancer, and some patients have had to turn to hospital emergency departments for pain control. The decline in access has been in part a response to the opioid crisis in the U.S. But do you think this raises an important question about whether we're doing enough to proactively address pain management with some of our patients, Dr. Worster? Dr. Brooke Worster: That’s always a really important conversation that we aren't talking about enough. I think, truly, certainly, the pendulum has swung very far to the other side. And in some ways, this is beneficial, because as more and more of our patients with cancer are living into survivorship, we have certainly seen where iatrogenically, we have created dependency and substance misuse issues in the past, and it continues to happen. But I think that we need better ways to have honest conversations with our patients about both. What nuances to their pain exist? Pain is not pain is not pain, right? So, the etiology of their pain is important. And the way that we treat it shouldn't all be the same—neuropathic versus visceral versus a post-operative or inflammatory type of pain certainly should be looked at differently. I think access to opioids is critical for patients with cancer, although it really shouldn't be the only tool in our toolbox. Some of the work that we've done recently, it's interesting. There remains a wide racial gap in terms of access to opioids, as well, as we know this but less well-controlled pain in certain groups of patients with cancer, primarily minority Black and Hispanic patients versus White counterparts. And some of that has to do with the underlying responsiveness to opioids for various people, but also, how much are we talking about it? How much are we having the conversation? Is cannabis a helpful adjuvant, there? Are opioids something that are helpful? It should be talked about and continually readdressed. Dr. John Sweetenham: Thank you. Dr. Handley, Dr. Wooster just mentioned there in her previous comments, the issue of having honest conversations with our patients in the realm of pain control. But on a broader kind of perspective, do you have any recommendations on how to broach conversations with patients about cannabis use as a potential option for symptom management? Dr. Nathan Handley: Yeah, I think that's a really important question. These can be very difficult conversations. Cannabis use is something that is socially, culturally, and regulatory charged. It's very complex. And so, it can be a challenge to have these conversations. I think some general principles about how to effectively engage others, whether they're patients or friends or colleagues can be really helpful. So, I often reflect on this dictum from Stephen Covey, who is the author of this book called, The Seven Habits of Highly Effective People. In this book, he describes the fifth habit as being, “Seek first to understand then to be understood.” So, basically, what he's saying is if your goal is to motivate others, you have to understand where they're coming from before you can meaningfully affect their behavior. So, this sentiment is really a core principle behind the technique called motivational interviewing, which can be very useful to help motivate behavior change in patients and understand where patients are coming from, at the start of a conversation even. So, this technique is really built on 4 foundational principles. And those are acceptance, which is essentially empathizing with the patient, recognizing that they are an important participant in their own care. They're really the driver of their own care. Compassion, which is really emphasizing the well-being of the patient first and foremost. Collaboration, which is partnering with the patient, and not necessarily having a paternalistic relationship with them. And then curiosity, which is about understanding a patient's behaviors and motivations in a non-judgmental way. And so, I think this is really important because it can lead to openness when having a conversation with a patient. So, this has been summed up more simply as “Don't tell. Ask.” So, the idea with motivational interviewing, is you need to be open to understanding where a patient is, and this approach can be taken with 4 steps. So, first, you, you just listen, there's interesting data about how clinicians and physicians spend a lot of time talking in interactions with patients, and not as much time listening. And then we may have a tendency to jump in very quickly and be uncomfortable with silence. And so, this is just a real opportunity to just be open to patients and hear them to understand what pre-existing perceptions they may have. And so, it's hard to have a conversation with a patient about cannabis, if you think that they are going to be very open to it. And it turns out that 5 minutes into the conversation, they have some really deeply held reservations about the use of cannabis. So, first, you engage and listen to them to understand where they're coming from. And then you can focus. You can focus specifically on what the patient's goals are with respect to treatment, with something—in this case with cannabis. What are they hoping to get out of it? Is it improved pain management? Is it some other symptom that they're seeking? And then you can kind of evoke, this next step is evoking what their motivations are? Why do they want to improve this particular component of their treatment? Why did they want to feel better in this way? What are they hoping to achieve? And then, once you've kind of gotten through that groundwork, you can then plan together about how best to approach, in this case, cannabis use, in a way that is mutually agreeable, you can come to a plan together. And this approach epitomizes the concept of shared decision making where this is a conversation that happens together and between 2 people with the interest of the patient kept, first and foremost. Dr. John Sweetenham: Great advice. Thank you! Dr. Worster, just before we close up, you did mention earlier 1 potential resource for oncologists who need guidance on how to safely use cannabis for palliative pain management. Do you have any other recommendations in terms of resources that can be helpful to them? Dr. Brooke Worster: Yeah, absolutely. I wish there were a lot more here. And truth be told, we're still working hard to certainly develop the body of research and then disseminate it in terms of education. But if people are interested, there are increasing amounts of continuing medical education (CME) options that are out there. Each state that has medically legal or medically approved cannabis use on their state websites will have recommended or required depending on which state, I practice in Pennsylvania, and there are required CME courses that you need to take. But all of the states have different ones that are either recommended or required, and that's certainly an easy place to start in terms of some quality education. Thanks to the work that you and others are doing. I think it's certainly coming out through various oncology publications and multimedia access and things like that. And we also have, and some other academic centers around the country now have, online certificate and Master's programs that if people are really interested, they can kind of dive in and take courses or even get a certificate in cannabis medicine or cannabis science, things like that, to help them feel a lot more educated and informed. Dr. John Sweetenham: Well, I'd like to thank you both for sharing your insights with us on the podcast today. And also, for the valuable research that you've been doing on this topic. This is something that I'm sure is going to gain increasing importance to us all in elevating the awareness of this among the oncology community is really important. Thank you for the work that you're doing. Dr. Brooke Worster: Absolutely. Thank you for having us. Dr. Nathan Handley: Yes, thank you. A pleasure! Dr. John Sweetenham: And thank you to our listeners for your time today. If you're enjoying the call sent on the ASCO Daily News podcast. Please take a moment to rate, review and subscribe wherever you get your podcasts.     Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Brooke Worster: Consulting or Advisory Role: Ethos Cannabis (Inst), PAX Therapeutics Research Funding: Ethos Cannabis (Inst) Dr. Nathan Handley: Research Funding: Nektar Therapeutics (Inst) Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.        

Guest host Dr. Fumiko Chino, a radiation oncologist at Memorial Sloan Kettering Cancer Center, leads a discussion on how the continual improper aggregation of Asian American (AA) and Native Hawaiian and other Pacific Islander (NHPI) populations downplays cancer disparities with Dr. Scarlett Lin Gomez, a professor in the Department of Epidemiology and Biostats at UCSF Helen Diller Family Comprehensive Cancer Center, and Dr. Kekoa Taparra, a radiation oncology resident at Stanford University.   Transcript Dr. Fumiko Chino: Hello, I'm Dr. Fumiko Chino, a radiation oncologist and Health Equity researcher at Memorial Sloan Kettering Cancer Center, and the guest host of the ASCO Daily News Podcast today.  In today's episode, we'll explore the unequal burden of cancer across diverse communities, specifically looking at how the continual improper aggregation of Asian American, Native Hawaiian, and other Pacific Islander populations mask cancer disparities.  Joining me for this discussion are Dr. Scarlett Lin Gomez, a professor in the Department of Epidemiology and Biostats at the UCSF, Helen Diller Family Comprehensive Cancer Center, and Dr. Kekoa Taparra, a radiation oncology resident at Stanford University.  My guest and I have no conflicts related to our topic today. Our full disclosures are available in the show notes and disclosures for all guests on the podcast can be found on our transcripts at ASCO.org\podcasts. We've all agreed to go by our first names. Scarlett and Kekoa, it's great to have you on the podcast today.  Dr. Scarlett Lin Gomez: Thank you so much. Great to be here.  Dr. Kekoa Taparra: Thank you.  Dr. Fumiko Chino: I'm so excited to start. My first question is just really general, which is can you describe your background, how you got into this research and why it's really meaningful for you and your community.  I can start just a little bit with myself. I'm Japanese American, my grandfather came to the United States before World War II and was actually excluded from coming into the United States under the Asian Exclusion Act.  He managed to come into the country walking up from Chile, ultimately started a farm in the United States, but was interned during World War II under Executive Order Act 9066. And he and my father and the family suffered some hardships from that but managed to rebuild.  I think kind of overall, I've been interested in how Asian communities and groups within Asian America and other race and ethnicity groups have had differing experiences within the American history and within American health, and specifically within cancer. Scarlett, can you go ahead and tell me just a little bit about yourself?  Dr. Scarlett Lin Gomez: Absolutely. I think that we find amongst ourselves who identify as Asian-American, Native Hawaiian Pacific Islander, that many of our unique experiences, life experiences, do have an impact on the cancer research that we do today.  I am a first-generation Taiwanese American. My family came over after the repeal of the Asian Exclusion Act in the early-mid-70s. Like many Asian American families, we settled where we already had some family here in the United States, and so that happened for us to be in central Washington state.  I grew up in central Washington, a very largely rural homogeneously non-Hispanic White population, and went to school largely in Spokane, Washington. So, eastern Washington.  During my time growing up there, I certainly, and my family had experiences with structural racism. I definitely saw firsthand among my family and our social networks cancer as a very strong cultural stigma.  For example, my grandmother's colorectal cancer diagnosis was actually never disclosed to her. In fact, this is very common among many Asian cultural populations. I also observed firsthand the relevance of our neighborhoods, our neighborhood environments, our social environments, and the structural context within which we live, work, and play, and how that really has a strong impact, not only on our access to health care but health behaviors and degree of social connections.  I then moved to the San Francisco Bay Area. You can certainly imagine the vastly different cultural and structural and neighborhood environments of that in the Bay Area compared to growing up in central and eastern Washington.  This is in fact—little to my knowledge—actually largely shaped the area of research that I chose to go into. In my doctoral dissertation, I had the opportunity to be introduced to and become involved with working with cancer registry data.  I was actually surprised to learn that in fact, within Cancer Registry data, there were some several dozen codes for distinct Asian American, Native Hawaiian, [and] Pacific Islander ethnic groups, yet for me, it was surprising: why don't we see any statistics by these specific ethnic codes?  In fact, we continue to see statistics for the Asian American population, Asian American Pacific Islander population aggregated as a whole. So, I set out for my dissertation to understand a very non-sexy doctoral dissertation topic to understand the quality of that data and how can we get the data to a point where we could start to report on statistics for disaggregated populations. That has really become a whole research program for my group today.  Dr. Fumiko Chino: It's so nice to hear the history of how you got into that and even just if you had happened to end up in New York City, maybe your research could have gone a different direction. Kekoa, can you tell me a little bit about your history and what brought you to do the research that you do today?  Dr. Kekoa Taparra: Yeah, absolutely. I am part Native Hawaiian from both my mom's and my dad's side. And just as a note, when we say Native Hawaiian, it's not the same as saying, native Californian or native Texan. That's not what I'm talking about. I'm indigenous Native Hawaiian, from both my mom's and my dad's side.  I actually had the good fortune to attend the Kamehameha schools. That's a school for indigenous Native Hawaiian youth in Hawaii.  And so, I grew up learning a lot about our history or culture throughout the Pacific, from Melanesia to Micronesia, and Polynesia. And so, with that kind of sense of identity, I really got a grasp of our community and our community's needs. And within my own family, I've had 10 family members, all of whom were Native Hawaiian, all die from cancer.  That was something that I grew up with just thinking that cancer was just something that people couldn't overcome. It wasn't really until college that I got really interested in research, and that led to my eventual attending of Johns Hopkins. I was in the lab of Dr. Phuoc Tran, who was an MD, PhD, radiation oncologist, and he was really the first to bring me into the clinic and I'll never forget, the first time he ever told the patient, “Let's cure your cancer.”  That was just something that I'd never heard before, given all my family members really struggled with different types of cancer diagnoses, none of them had the same thing. And so, really, from that point on, that's what inspired me to go to medical school. And towards the end of my medical school years, when I was actually applying for radiation oncology, I was a true bench scientist, and I'm a lab rat—that's where I've always belonged and felt like I belonged. But towards the end of medical school, when I was interviewing for radiation oncology, I met one of my mentors, Dr. Curtiland Deville Jr., at [Johns] Hopkins.  He was really the first to, at least through my application, recognize the kind of cultural and historical context of what I've been through, what my family and my community in Hawaii, we call lāhui, what our lāhui has gone through. And so, he really encouraged me to write about it.  That's kind of how I've ended up in this niche of speaking on Pacific Islander health. Again, just full disclosure, as a part Native Hawaiian, I can’t even speak for the whole lāhui. I’ll speak for myself and what I know.  Again, the Native Hawaiian lāhui is very different from the rest of the Pacific Islands. But overall, I do research Pacific Islander health.    Dr. Fumiko Chino: I love having both of you on this podcast because I feel your voices are so unique, but again, you also represent sort of different ends of the spectrum in terms of your research career, someone who's a little bit more senior and someone who's more junior.  I think that really gives us a well-rounded perspective. Scarlett, can you tell me just a little bit about the history of Asian American, Native Hawaiian, and Pacific Islander aggregation and why it might be a problem?  Dr. Scarlett Lin Gomez: I honestly don't know why the data are aggregated for. We're talking about people who come from 30 different countries and speak more than 100 different languages.  My guess is that historically, we have tended to aggregate because of convenience, but potentially also just lack of knowledge about the vast heterogeneity among these populations.  And so, I think for us who do research in this field, our hope is that by continually putting out the data that we can start to educate folks about why it is harmful, in fact, to aggregate.  Why is this a problem? I think that we hide disparities. In fact, if you look, I think part of the reason why the practice of aggregation has continued is because when you look at the aggregated statistics, with regards to cancer, it actually paints a very rosy picture for the most part, for most cancer statistics that we look at.  That's because the data are largely based on the largest groups, statistically the largest groups of those who potentially have been here the longest, but in fact, when we disaggregate, we know dramatic heterogeneity, as we would expect, because we know socio-demographically and based on immigration patterns and language patterns, these populations are really different.  So, we would expect, in fact, we do see that translate into differences in cancer outcomes. I will give a direct answer to your question about why this is a problem. I like to note the very poignant story of Susan Shinagawa, who is a Japanese American woman who was diagnosed with breast cancer. She's also my friend and colleague, and she was one of the first advocates who really inspired me in doing this research.  And so, her story is that she had to go to 3 different surgical oncologists to finally have her very prominent breast lump biopsied and looked at. She will recall that the reasons why she had to go to all these different surgeons was because they continuously told her, “You can't have breast cancer. You're Asian, and you're too young. Asian women don't get breast cancer." Her story isn't unusual.  I think the other harm in aggregation is that the community then thinks that our risks of cancer are low and that this doesn't affect us, and in some of the first publications we put out, there was a paper where we documented both high survival rates among Asian immigrant women, as well as high rates among young Asian American women for breast cancer. This was published in the American Journal of Public Health in 2011.  I actually received personally several emails from Asian women out in the community saying, because we had received quite a bit of press, this was reported out in the media, and they noted to me that they themselves were shocked when they were diagnosed with the disease because they thought that this was a “white old woman disease.” But in fact, it's not.  I have a strong family history of breast cancer, as many of us do, and other cancer sites. And so, I think that perpetuates not only the model minority myth but the cultural stigma of cancer as a disease.  Dr. Fumiko Chino: I can't wait until those oncologists that passed her by find out about the history of lung cancer in young Asian American women.  Scarlett, can you talk a little bit and I know you had mentioned this before, in terms of when you first started digging into some of the data, how challenging this research can be in terms of, for example, do every databases have granular data in terms of the Asian races and countries of origin, ethnicities?  Dr. Scarlett Lin Gomez: I think it's incredibly challenging and as an epidemiologist, we need the data. That's if we don't have the data, we don't even have a place to start. I think we've been fortunate to some extent within the cancer space in that the major databases that we really rely on to report the burden of cancer among our various groups do, in fact, have a fairly good capture of detailed Asian American, Native Hawaiian, and Pacific Islander codes, yet there is much that can be improved. The information on place of birth, for example, is really incomplete.  Also, our group has really started working with data from electronic health records. And that is highly variable in terms of data capture availability, the granularity of codes, and the availability of the relevant variables like birthplace and language across the different groups.  So, I do firmly believe, and I would call to action that I think we need to make a concerted effort to improve the granularity of data that are being collected.  I think the other challenge that has really come about is the small data problem. I think that our epidemiologic and clinical toolbox is very limited in terms of what we can do, analytically with small populations. But I would put forth that just because a population is small in numbers doesn't mean that they're any less important.  And so, I think that we need to do better in terms of developing better methodological and statistical approaches to being able to not only quantify but understand the burden of cancer in all of our populations.    We also need better approaches to begin to study the intersectionality of multiple marginalized social determinants, statuses, language, and ensure language inclusion in terms of really being able to adequately study and incorporate and include these populations.  Dr. Fumiko Chino: Can you talk specifically about some of the disparities that you've actually uncovered with your research? What are we talking about when we say that aggregation masks disparities? If I just say, Asian Americans are doing great from a cancer standpoint, what am I missing?  Dr. Scarlett Lin Gomez: One particular disparity I can certainly highlight is the high burden that we recently documented in a publication last year in the Journal of National Cancer Institute that documented the high rates of lung cancer among certain groups of Asian-American, Native Hawaiian, and Pacific Islander females who have no history of smoking.  Ours was the first study to actually show what the rates of lung cancer are in these particular groups. And it's particularly high—1.5 to 2 times higher among some of the Asian American, Native Hawaiian, and Pacific Islander groups compared to non-Hispanic White female never smokers.  When we look across the Asian American, Native Hawaiian, and Pacific Islander ethnic groups, we note that there are differences in that risk. One example is that among Chinese American females 80% who have been diagnosed with lung cancer have no history of smoking, the vast majority, 80% have never smoked, in contrast to smaller percentages among, for example, Native Hawaiian and some Pacific Islander groups.  Another pattern in terms of heterogeneity is that we actually did not notice the higher rates of lung cancer among Japanese American female never smokers. And this is an interesting observation, we actually note similar patterns for Japanese American women for breast cancer as an example, and this is something that definitely needs further follow-up.  In fact, we're conducting a study right now called “FANS: Female Patient Never Smokers,” which is the first study to try to identify genetic and epidemiological risk factors for lung cancer among Asian-American females who have never smoked.  Dr. Fumiko Chino: Kekoa, can you speak about what your research has shown?  Dr. Kekoa Taparra: Yeah, definitely. From the perspective of a recent paper that we published in the JAMA Network Open, we looked specifically at the Hawaii Tumor Registry looking at patients in Hawaii, who were treated for premalignancy, the DCIS (ductal carcinoma in situ).  What we found were the patients who ended up developing a second breast cancer after being treated for that first DCIS [that] the rates of the second malignancies both from ipsilateral and contralateral breast cancer were primarily seen in Native Hawaiians. Also, to some extent, Filipinos as well compared to other Asian ethnic groups.  I think that there are definitely some trends that we continue to see in terms of who might potentially be at higher risk, but in other work that we have presented at [2021] ASCO Quality Care Symposium (Abstract 80) with yourself, we found that in terms of it in things like overall survival, there are potential differences in terms of Native Hawaiian and other Pacific Islanders as well as even Southeast and East Asian groups.  And so, I think there's a lot of work to be done in terms of what are the kind of implications for disaggregation? What are appropriate techniques for data disaggregation? What is too much to disaggregate because we can disaggregate for a Native Hawaiian female who is from a specific zip code and who never smoked, and like, is that kind of the data disaggregation that we end up wanting, or is there something a little bit broader, that still tells us the same story of who should we be paying attention to?  And so, I think there are a lot of unanswered questions. I think that Scarlett is doing amazing, amazing work that I continually follow. So, I think there's a lot to be done still.  Dr. Fumiko Chino: So, I guess that leads to my next question, which is the concluding question, which is, what is the next step? So, how do we either: get better data or how do we actually intervene?  So, Scarlett, I know you had talked a little bit about the FANS study. Can you talk a little bit about your breast cancer cohort study in terms of really thinking about getting together diverse data sets and making sure that it's powerful enough to actually draw some conclusions?  Dr. Scarlett Lin Gomez: Absolutely. Breast cancer is actually a really interesting disease that I think we are in the midst of seeing a very interesting and dynamic pattern of breast cancer.  We actually noted recently, in a small study in the Bay Area, that we may be seeing a reversal of higher rates among Asian American immigrant women compared to those who were born here. I think actually, this makes sense.  If we think about, especially in the San Francisco Bay Area, who were the immigrants over the past 10, 20, and 30 years. And in fact, we are seeing very high, rapidly increasing rates of breast cancer within many of the East Asian countries.  And so, I think we are really undertaking work to try to understand what some of these patterns are, but I think we are really well-positioned to invest in cancer research among Asian Americans, Native Hawaiian, and Pacific Islanders, because of these dynamic patterns, and the vast heterogeneity that we know exist within these groups.  I think that investing in research among these groups can really tell us a lot in terms of the discovery of novel risk factors. My last final thought would be to the funders out there to really think about what we can learn by focusing on these populations, but also being able to study the disparities that really have gone ignored for a long time.  Dr. Fumiko Chino: Kekoa, can you talk about some research that you have coming up that may or may not have recently been funded?  Dr. Kekoa Taparra: Absolutely. One of the things I definitely have to appreciate from ASCO is having the opportunity to kind of publish our work in JCO Oncology Practice on a paper with the historical context of Native Hawaiian and other Pacific Islanders with cancer.  Actually, a recent project that I have had, and I've been working on for the past year, really came about from a physician out actually in Micronesia, who read the paper and then contacted me, and this is a project specifically on betel nut induced oral cavity cancer.  Betel nut is something that is consumed throughout the Pacific Islands as well as Southeast Asia, but something specific to islands in Micronesia is that according to the WHO (World Health Organization), they have the highest rates of elementary and middle school students who consume betel nuts.  So, they had a very, very concerning epidemic right now of betel nut-induced oral cavity cancer. And so, one of the projects that I've been working on is a clinical trial, which we're calling NEO-CORAL. But the trial is specifically looking at a neoadjuvant immunotherapy approach to local or regionally advanced betel nut-induced oral cavity cancer.  We’re really excited to be working with teams from Guam, which is in Micronesia, as well as Queen's Medical Center in Hawaii, where I'm from, and at Stanford as well. And this tri-site approach we're hoping to kind of conduct a culturally careful and culturally aware clinical trial so that we can really try and make a difference in these patients' lives because the biology and just the aggressiveness are nothing like we've ever seen with tobacco-induced oral cavity cancer alone.  I'm really grateful for certain funders that we've had recently who have funded this grant. I think it really just goes to show the kind of excitement around really helping a very marginalized community.  Dr. Fumiko Chino: I think that that study and I think putting in the context of what Scarlett just said in terms of, we need this data, we need granular data, we need funding so that we can actually design interventions that are really tailored to unique, vulnerable communities to really provide the resources, education, and culturally competent care that actually gets people the best outcome so that there are not haves and have-nots in terms of health care, and that's really again everyone's goal.  I'm wrapping up now. I really like to thank Dr. Scarlett Gomez and Dr. Kekoa Taparra for sharing your really valuable insights with us today and for your dedication to addressing the unequal burden of cancer across diverse communities.  Dr. Kekoa Taparra: Thank you.  Dr. Scarlett Lin Gomez: Thank you.  Dr. Fumiko Chino: Thanks to our listeners for your time today; you will find links to all of the studies and presentations discussed today in the transcript of this episode. And, if you're enjoying the content of the ASCO Daily News podcast, please take a moment to rate, review, and subscribe.    Disclosures:  Dr. Fumiko Chino: None disclosed.  Dr. Scarlett Lin Gomez:  Employment: Bioinspire (Immediate Family Member), Valentia Bioanalytics (Immediate Family Member)  Stock and Other Ownership Interests: Amgen (Immediate Family Member), Bioinspire (Immediate Family Member)  Consulting or Advisory Role: GRAIL  Page Break  Dr. Kekoa Taparra: None disclosed.  Disclaimers: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product service organization, activity or therapy should not be construed as an ASCO endorsement.   

Dr. Arjun Gupta, a GI medical oncologist at the University of Minnesota Masonic Cancer Center in Minneapolis, speaks with host Dr. John Sweetenham, associate director for Clinical Affairs at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, about the concept of time toxicity in cancer treatment. Dr. Gupta proposes a measure of time toxicity and a framework for how it could be implemented in research and clinical practice.   Transcript Dr. John Sweetenham: Hello, I'm John Sweetenham, the Associate Director for Clinical Affairs at UT Southwestern Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News podcast. I'm delighted to welcome Dr. Arjun Gupta to the podcast today. He's an assistant professor and gastrointestinal medical oncologist at the University of Minnesota Masonic Cancer Center in Minneapolis. We'll be discussing the concept of time toxicity and its relevance for patients with cancer, especially those with advanced cancer who face treatment decisions in the context of limited time. Dr. Gupta will share his insights on how to measure time toxicity and discuss a framework for how it could be implemented in research and in clinical practice. My guest and I have no conflicts relating to our topic today. Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/podcasts. Dr. Gupta, it's great to have you on the podcast today. Dr. Arjun Gupta: I'm an avid listener of the podcast. It's a joy to be here. Dr. John Sweetenham: Thank you. It's a joy to have you on the podcast as well. We're particularly pleased to have you discuss this important topic that you and your co-authors addressed recently, in your commentary in the Journal of Clinical Oncology. Can you first explain the concept of time toxicity, particularly as it relates to cancer treatment? Dr. Arjun Gupta: Yes, we conceptualize time toxicity as the time spent in pursuing a treatment for cancer. Now, this includes time spent in coordinating treatments, in travel to treatments, in waiting rooms, in actually getting that treatment, in getting anticipated and unanticipated adverse events, follow up tests and rehabilitations, frequent visits to a health care facility, all of this time that a patient and their care partner are spending is what we think of as time toxicity. This concept of time toxicity is perhaps applicable to all patients but is perhaps most applicable to people with advanced solid tumors, who are facing treatment decisions in the context of limited time. And in some cases, the overall survival benefit, or the time benefit offered by treatment may actually be overtaken by the time spent in pursuing that treatment. So, that's how we came up with this concept of time toxicity. Dr. John Sweetenham: Thanks. In your article, you propose a measure of time toxicity provides a framework for how it could be implemented in research and in routine clinical practice. Can you tell us a little more about this? Dr. Arjun Gupta: The measure we describe and propose is days with physical health care system contact. This is the measure of time toxicity that we propose. So any day in which a patient has any contact with the health care system, whether that be for a 30-minute blood draw, whether that be for a 3-hour procedure, whether that be for a 6-hour chemotherapy infusion, a 12-hour visit to the urgent care center, or an overnight stay is treated the same. It's a day with physical health care system contact. And we recognize that not all of these are the same but for the patient and their care partner, these often represent that an entire day is lost. As a corollary, days not spent with health care contact are home days. So, in essence, your overall survival or the time from diagnosis to death is nothing but the sum total of time toxicity or days with health care system contact and home days. Now me and my mentors, Dr. Chris Booth, and Dr. Elizabeth Eisenhower spent a lot of time thinking about whether we should propose a metric at all, or wait for the science to be advanced even more. But there are a couple of reasons we decided to go forward and propose this metric. Even though there are some deficiencies that I'll come to. First of all, this metric recognizes that oncology care is delivered in multiple settings. It's delivered infrequent trips to the outpatient clinics and infusion centers, and patients often require inpatient admissions for rest and rehabilitation. My mentors, Dr. Chris Booth and Dr. Elizabeth Eisenhower, and I discussed long and hard whether we wanted to propose a metric or wait for the science of time toxicity to progress. Ultimately, we decided to propose this metric because it's practical and can easily be measured. It is patient-centered, which is perhaps the most important thing. And third, it recognizes that cancer care is delivered in multiple settings, both inpatient and outpatient. There are a couple of things that we need to keep in mind while thinking about this metric. The first is that people with cancer are often sick because of underlying cancer and cancer care and physical health care system contact by itself is not a bad thing. So, we need to separate the additional time imposed by a specific cancer treatment over and above the time toxicity of cancer itself, and we also need to keep in mind that this metric has some limitations in that decreased health care contact or decreased time toxicity could represent poor access to care and could widen disparities in health care access. Furthermore, care is increasingly being delivered in the home of patients. And while that may decrease time toxicity, and may be more comfortable for certain families, for unprepared families, this may be very burdensome. So, we recognize that this metric is not perfect but we hope that this can at least start conversations about time toxicity, to fulfill our ultimate goal for clinical trials to actually report time toxicity alongside more traditional endpoints. Dr. John Sweetenham: Yes, I think one of the things that really struck me from reading your commentary was the fact that of course, for a patient, a 1-hour or 30-minute trip to the laboratory for a blood draw can disrupt the whole day. And in many respects, that can be as disruptive as spending 12 hours in the emergency room from a family and caregiver perspective that really kind of sank home with me, I must say, having read the commentary. On that note, you know, could you give us some specific examples to show how time toxicity negatively impacts patients? Dr. Arjun Gupta: Yes, so for a couple of trials that we described in the paper, we demonstrated that the time toxicity associated with pursuing the treatment was actually more than the average survival benefit offered by the treatment. Now we have to keep in mind that traditionally, oncology clinical trials don't report time toxicity. So, this was my co-authors and myself getting together and getting a best-case scenario from clinical trial publications. But as an example, for people with advanced biliary tract cancers, or cholangiocarcinoma, in the second line, there was a recent trial that demonstrated that FOLFOX chemotherapy, on average, improved survival by 27 days. And we demonstrated through the trial level publication, that for the average patient who was getting the average number of chemotherapy doses, coming in for blood work, coming in for scans, coming in for oncology assessments, that for the average patient, the time toxicity was more than this 27-day benefit, it was 30 days. And so, this is a very clear example of a patient who potentially loses more time than what they gain. It's very important to recognize that patients may value these decisions differently, and we're not saying that this treatment is bad or should not be pursued. People have different values, and we should explore that, but the biggest issue right now is that oncologists don't have the data from clinical trials to even have these conversations with patients. Dr. John Sweetenham: Thanks. And so, I'll pick up on that point. Obviously, the literature is very full of studies that have looked at oncologists and their skills for wanting a better word at having the end-of-life discussions and goals of care discussions with their patients. Do you sense that there is or will be a reluctance on the part of oncologists to have these kinds of conversations about time toxicity for patients who may be nearing the end of their lives? Dr. Arjun Gupta: I don't think so at all. I will share that I've become much more humble since I've become an oncologist myself, and I've become less critical of oncologists. I think our jobs are incredibly difficult. And most, if not all, oncologists want to do the right thing and have these conversations. The 2 things that are missing right now are data. So, we just don't have the data, which is why we wrote this commentary as a call for clinical trials to report this. And the second is our own time toxicity or delay limitation of time in the clinic. A wise person recently said that the biggest technological advance in medicine will be more time with patients. So, I think we need more data on time toxicity and we need more time for ourselves with patients to have these conversations to help them reach the best decision for their own goals and values. Dr. John Sweetenham: Are there any other key takeaways that you would like to share with our listeners today? Dr. Arjun Gupta: I feel—yes. As the next steps, our team is looking at doing secondary analyses of completed clinical trials to show that using this metric of days with physical health care contact is feasible, even in the secondary analysis of clinical trials. While we advocate for this to be included prospectively in clinical trials. It's very important to note that in retrospective work, looking at time toxicity, we remember that the time toxicity of a treatment retrospectively represents not just the treatment itself, but the entire health care delivery system, and social determinants of health. So, we shouldn't get too far ahead of ourselves in interpreting treatments against each other. But that perhaps offers us an opportunity to look internally at ourselves and add our processes to see how we can improve. Lastly, there are several quality improvement initiatives going on to reduce time toxicity for patients, such as triage, and decreasing waiting room times, and we should perhaps advocate for and promote such work more broadly. Dr. John Sweetenham: Thanks so much, Dr. Gupta, for coming on to the podcast today and for sharing your thoughts on a subject, which I'm sure is going to be something that will provoke a lot of discussions and will make many of us think harder in the future. And we look forward to seeing your ongoing research in this area. Dr. Arjun Gupta: Thank you for this platform. Dr. John Sweetenham: Thank you to our listeners for your time today. If you're enjoying the content on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Arjun Gupta: None disclosed.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO the mention of any product or service organization activity or therapy should not be construed as an ASCO endorsement.

Host Dr. John Sweetenham, associate director for Clinical Affairs at UT Southwestern Harold C. Simmons Comprehensive Center, and Dr. Robert Carlson, CEO of the National Comprehensive Cancer Network (NCCN), discuss novel therapies and compelling health equity research featured at the 2022 NCCN Annual Conference.   Transcript:   Dr. John Sweetenham: Hello, I'm John Sweetenham, the associate director for Clinical Affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News podcast.   Today, I'll be speaking with Dr. Robert Carlson, the chief executive officer of the National Comprehensive Cancer Network or NCCN. Dr. Carlson will be telling us about key advances in cancer care that were featured at the 2022 NCCN Annual Conference.   Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/podcasts.   Bob, I'm really pleased to have you on the podcast today, and personally very excited to serve in my new role as chair of the NCCN Board of Directors.   Dr. Robert Carlson: John, it's a pleasure to be with you this morning and all of us at NCCN look forward to working with you as chair of the NCCN Board of Directors.   Dr. John Sweetenham: Thank you! Bob, there was such a wide breadth of topics that were covered at the NCCN Annual Conference this year. Could you tell us about some of the key abstracts that you think will advance care for patients?   Dr. Robert Carlson: I’d be happy to! We had over 1,000 participants from 40 countries at this year's Annual Meeting. And there were a number of high-quality abstracts reporting on a spectrum of studies, including NCCN young investigators and a number of other investigators.   Three abstracts that I would like to single out include an abstract entitled, “Real-World Data and Independent Predictors of Clinical Outcomes with CDK Inhibitors in Metastatic Estrogen receptor-positive Breast Cancer Patients” which was presented by Priyanka Reddy and colleagues from Case Western Reserve. They assessed how the real-world experience with the CDK 4/6 inhibitors in hormone receptor-positive metastatic breast cancer compared with a clinical trial experience. They retrospectively identified 269 patients with hormone receptor-positive metastatic breast cancer in the first-line setting and assessed progression-free survival and overall survival in the cohort overall, and also in the subset with bone-only metastatic disease in those who had liver involvement.   In the overall cohort, the results demonstrated progression-free survival of 21 and a half months and overall survival of 57.6 months. In those with the bone-only disease, at 5 years, 84% of patients were alive compared with 42% in those with bone plus other visceral sites of disease.   They performed multivariate cox regression, and bone-only disease was an independent predictor of a favorable outcome with a hazard rate of 0.48 for progression-free survival, and 0.38 for overall survival, both highly statistically significant.   In those patients with liver disease, multivariable regression predicted an unfavorable outcome with a hazard ratio of 2.53 for progression-free survival and 2.24 for overall survival. So, the study found that the real-world experience with the CDK 4/6 inhibitors is very similar to that in clinical trials. And that bone-only disease continues to be a positive predictor of outcome and liver disease an unfavorable predictor of outcome.   Another important abstract was entitled, “Reuterin in the Healthy Gut Microbiome Suppresses Colorectal Cancer Growth through Altered Redox Balance,” and was presented by Joshua Goyert and colleagues from the University of Michigan.   This abstract reported on a series of findings related to alterations in the intestinal microbiome, especially related to reuterin, the metabolite from the lactobacillus reuteri.   The investigators found that the fecal metabolites from healthy subjects and wild-type mice suppress colorectal cancer, while metabolites from patients or mice with colorectal cancer do not.   Reuterin was found to be the most potent metabolite in suppressing colorectal cancer. And further study found that Reuterin was effective in inhibiting proliferation and inducing cell death of colorectal cancer, but also in cell lines of lymphoma, ovarian cancer, melanoma, and pancreatic cancer. Normal cells were not found to be at all affected. While early, this all suggests a novel strategy for treatment for translational investigation.   The final abstract to be highlighted was actually funded by the NCCN Oncology Research Program and is entitled “Phase 2 Trial Trifluridine/Tipiracil in Combination with Irinotecan in Advanced Biliary Cancers” and was presented by Sri Tella and colleagues from the Mayo Clinic Comprehensive Cancer Center.   Historically, biliary cancers have had very few and limited treatment options. This current study was an open-label phase two clinical trial in patients with biliary cancer and at least one prior systemic therapy to assess the activity of combination trifluridine/tipiracil plus Irinotecan. The subjects were treated with a regimen of trifluridine/tipiracil 25 milligrams per meter squared, orally, on days 1 through 5 on 14-day cycles, and Irinotecan, 180 milligrams per meter squared intravenously on day one of the 14-day cycles. The primary endpoint for success was 16-week progression-free survival. They enrolled 28 patients 27 of whom were available. And they found a 16-week progression-free survival of 37%, which exceeded their target rate of response of 30% or greater.   Overall survival was just over 1 year. While tolerated reasonably well, those reductions were common, and the investigators concluded that further evaluation in a randomized trial was needed.   Dr. John Sweetenham: Thanks, Bob. All very interesting abstracts. I think that makes important contributions. And in the spirit of interesting discussions at the NCCN, I must say that I personally felt that there were some very interesting and excellent sessions around health equity at the conference, including the plenary sessions.   I wonder if you could give us some key takeaways from those sessions looking at health equity, and also the one that specifically looked at access to cancer care, and equity in the context of access.   Dr. Robert Carlson: So, there were a number of sessions at the NCCN Annual Conference that related directly or indirectly to issues of access and equity of cancer care. I'd like to focus specifically on a plenary session that was devoted to equity in cancer care.   We all know that equities in cancer care are pervasive, and we can't just wish or decree away these disparities. We need to be willing to evaluate how each of us can change our own practice and how we can be an active part of larger systems change. And that is what this plenary session was all about—actively eliminating existing disparities in cancer care.   The session was moderated by Dr. Carmen E. Guerra of the University of Pennsylvania. It started with Thomas Farrington of the Prostate Health Education Network discussing the importance of cancer early detection and screening strategies that are designed to account for the differences in incidence and age distribution of cancers in different racial and ethnic groups.   Mr. Farrington used prostate cancer as an example of where Blacks have an especially high incidence, younger age distribution, and more aggressive prostate cancer than do other racial groups.   Liz Margolies of the National LGBT Cancer Network followed and stated that cancer doesn't discriminate, but the health care system certainly does. She talked about making welcoming spaces for sexual and gender minorities in cancer care settings, of truly learning and understanding the perspectives and needs of the LGBT communities, and gaining their trust. She concluded by saying that being well-intentioned is not enough—hard work is necessary.   Shonta Chambers of the Patient Advocate foundation described the importance of social determinants of health that included socioeconomic factors, physical environment, health behaviors, and health care access and quality. She emphasized the central importance of patient navigation in assuring appropriate access. She described using data and the social vulnerability index to target resources where they are needed the most.   Dr. Maria Garcia-Jimenez from UCLA outlined efforts to improve appropriate racial and ethnic representation across clinical trials, specifically by breaking down barriers to patient participation. Dr. Garcia-Jimenez described how these barriers exist at the health system level, with the provider, at the community level, which typically is through lack of trust, and at the patient level, through lack of trust, language, cultural differences, and lack of awareness.   Alyssa Schatz from the NCCN discussed the Elevating Cancer Equity initiative, which is a collaboration of NCCN, the American Cancer Society Cancer Action Network, and the National Minority Quality Forum, involving a number of additional representatives with expertise in disparities in cancer care. This initiative has developed a health equity report card, which includes 17 measures across 4 different domains, and that has been piloted currently at 5 NCCN member institutions to identify areas of racial access and equity needing improvement. The initiative also developed a series of policy priorities, primarily at the federal level that aimed at minimizing disparities.   The summary of this session is that talking about disparities is inadequate. It is crucial that we take positive and focused action to address existing disparities so that we can improve and facilitate equitable care for all patients. And that equity is everyone's responsibility.   Dr. John Sweetenham: That's great. Thanks, Bob. Yeah, there were 2 statements from that session, which really sort of struck home with me. I think, to your final point there, I know that one of the comments that were made was, 'It is great that there has been so much research in recent years, and so much emphasis in the literature on cancer care disparities. But doing research that demonstrates disparities doesn't actually help the patient. It's what we do about that, which is important. And it's sort of a statement of the obvious, but it's very impactful to me to think about that it's become an area of really quite extensive research, but we actually need some actionable conclusions from those research and to work really hard on that.   The other thing that was said that really struck home with me was the comment that “Cancer is a disease of the family.”' And certainly, the person who said that wasn't talking in the inherited sense, but really more of the impacts that cancer has on the family and the caregivers as a whole.   I thought they were both really impactful statements from what was a really excellent session. Bob, I really appreciate you sharing your insights with us today. Are there any other important messages you'd like to get across before we wrap up?   Dr. Robert Carlson: Well, the Annual Conference of the NCCN serves as a forum to discuss important and rapidly evolving NCCN clinical practice guidelines, to discuss best practices in administering cancer care, and to share the results of a wide range of research activities that relate to improving cancer care. We at NCCN invite the oncology community to next year's NCCN Annual Conference and review the endured materials that will be available sometime this June, from the conference that will be posted on the NCCN website.   Dr. John Sweetenham: Great, thank you! Thanks once again for spending time with us on the podcast today, and for the many contributions that NCCN has made, both nationally and globally, and indeed continues to make to advance quality, effective, equitable, and accessible care for all patients with cancer.   Dr. Robert Carlson: And thank you, John, we look forward to working with you as the chair of the NCCN Board of Directors to further extend all these efforts.   Dr. John Sweetenham: Thanks! Thanks also to our listeners for your time today. If you are enjoying the content on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness   Dr. Robert Carlson: Employment (immediate family member): Flatiron Health Patents, Royalties, Other Intellectual Property: Patents relating to inventions as an employee of NCCN Other Relationship: National Comprehensive Cancer Network   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product or service organization activity or therapy should not be construed as an ASCO endorsement.    

Host, Dr. John Sweetenham, associate director of Clinical Affairs at UT Southwestern Harold C. Simmons Comprehensive Cancer Center, and Dr. Keith Argenbright, medical director of the Moncrief Cancer Institute, a non-profit, community-based cancer prevention and support center, discuss models of survivorship care, and likely challenges in addressing the needs of a growing population of survivors.  Dr. Argenbright is also the chief of Community Health Sciences at UT Southwestern Medical Center.   Transcript:     Dr. John Sweetenham: Hello, I'm John Sweetenham the associate director for Clinical Affairs at UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast. The number of cancer survivors in the United States is increasing each year, and this is a reflection of advances in cancer prevention and screening, as well as in cancer treatment. And the National Cancer Institute now estimates that there will be more than 22 million cancer survivors in the U.S. by the year 2030.     Joining us to discuss the future challenges of providing care for this growing population is Dr. Keith Argenbright. He is the director of the Moncrief Cancer Institute in Fort Worth, and a professor at the UT Southwestern Simmons Comprehensive Cancer Center, and a colleague and friend of mine.     My guest and I have no conflicts relating to our topic today. Our full disclosures are available in the show notes, and disclosures of all guests on the podcast can be found in our transcripts at asco.org/podcasts.     Keith, thanks for being on the podcast today.    Dr. Keith Argenbright: Thank you for having me, John.    Dr. John Sweetenham: So, the growing population of cancer survivors presents major challenges for providers, health care systems, and other stakeholders. Could you talk to us a little about models of survivorship care that you think could potentially meet the challenges of caring for millions of survivors in the future?    Dr. Keith Argenbright: Of course. I guess I'll start that response by recalling a meeting that I was at back in the 2008, 2009 timeframe, more than 10 years ago. And it was held in Washington D.C. and sponsored by Livestrong. And I think that that was the question that we were asking ourselves 10 plus years ago. What are these models going to look like to meet the challenge of the millions of cancer survivors in the future? And in some way, I think we've come a long way, and in other ways, I'm not so sure we have. Right now, I think we think of cancer survivorship maybe being delivered at an academic medical center and a structured model, maybe being delivered by a community physician in an informal way.    I think that 1 thing that is for certain is that the models of care are going to reflect the reality on the ground. And that there won't be 1 single model of survivorship, but there will be multiple models of survivorship that are created at the local level that understand the resources as well as resource limitations for any given community, for any given oncology practice, for any given group of survivors. And I think that that was probably a conclusion that we reached 10 years ago. And I think that that still holds true now as well as in the future.    Dr. John Sweetenham: Thanks, Keith. So obviously to your point, there are many models of survivorship and there clearly is not going to be a kind of 1 size fits all approach to how we address cancer survivorship. And maybe just to backtrack a little, 1 of the things that I should have said at the beginning of the podcast is that, although it's perhaps a little bit cliche to say this, I do think that now there is a widespread acceptance that cancer survivorship care begins from the day of diagnosis, and isn't something which kind of kicks in once cancer treatment is over. And to that point, I know that 1 of the models that you have adopted in Fort Worth has been to embrace primary care practice into the cancer center to assist with the survivorship and supportive care of patients. Could you just say a little bit about that model and talk to us a little about what you've experienced so far?    Dr. Keith Argenbright: Yeah, for sure. And to your earlier point, we've made great strides in actually recognizing the value of survivorship. And I don't want to dismiss that. I recall again thinking back 10, 15 years ago, I think that a lot of us thought, "Well if you're cured, that's great. And so that's the end of our responsibility." And I think that the medical community and the oncology community have realized that a lot of these cures come at a price and we're recognizing that price in the form of survivorship and survivorship care. So I don't want to neglect the fact that I think that we've come a long way in a very short period of time in embracing the idea of survivorship. What we are doing at Moncrief Cancer Institute is we're bringing in additional specialties into the survivorship milieu.   We talked about the numbers I think a little bit earlier in the podcast. Something like 17 million cancer survivors now with 13,000 practicing oncologists—there's just no way that our oncologists can or that they have the bandwidth, nor are they expected to be the only ones providing survivorship care.    What we did here at Moncrief and at UT Southwestern is we are bringing in different clinical specialties to assist in this team-based approach to survivorship care. And that's been led by our family and community medicine department which has established a primary care clinic in our cancer center for cancer survivors. Patients with cancer are introduced to these practitioners very early in their treatment cycles. Sometimes in their first or second visit with their oncologist here. We will also introduce them to the primary care physician who might be taking care of them at the end of their treatment, even though that might not be for another 6 to 12 months. It's been very well received. Cancer survivors a lot of times don't even have a primary care physician, to begin with. And so sometimes this is their first experience with a true primary care physician.    Oftentimes the primary care physician is able to look more comprehensively at some of the other issues that may or may not be cancer-related. It's been very well received. We bring in other specialties as well, physical medicine, rehabilitation, cardiology, psychiatry, and psychology. So it's something that we've been doing now for about a year. And we're very excited about the promise for a model like this in the future. Again, not all cancer centers or community practices have the ability to do this type of program but we're fortunate that we are. And hopefully, others will be able to take pieces of what we're doing and find them relevant and replicable in their situation.    Dr. John Sweetenham: Yeah. Thanks, Keith. And I do agree. I think it's a great innovation. And your comments pick up on another very important point and that's the workforce issue, which I think we're challenged with. Because of course, with an anticipated 22 million cancer survivors by the end of the decade, we are going to need a significantly expanded workforce of health care professionals of various types to work with these patients. And in addition to that, of course, we're going to need to be able to deliver care in community settings. It can't all be done in big health systems and academic oncology centers. So accepting that that will be the case and that we are going to need to develop community-based cancer survivorship services, what do you think are going to be the most challenging aspects of building those services and sustaining them out in the community rather than in big centers?    Dr. Keith Argenbright: Funding and reimbursement is always a challenge, right?    Dr. John Sweetenham: Right.    Dr. Keith Argenbright: A lot of these survivorship services, a medical visit with a practitioner, for instance, a visit with a psychologist or a psychiatrist regarding mental and behavioral health issues are reimbursable. But a lot of the things that we hear from our patients that they find most valuable in a survivorship program are not reimbursable. And I'm talking about things like nutritional programs, not just nutritional education, but an actual nutritional demonstration in cooking classes. Exercise programs are not currently reimbursable. The ability to speak with a financial counselor regarding the financial strain that has been placed on the patient with cancer and their family regarding the toxicity that they're left with after their cancer treatment. So these continue to be challenges for us, and I'm sure for the listeners of the podcast as well. These are challenges that are not easily overcome.    We are fortunate that we have some philanthropic partners who support a lot of our programs, not everyone is as fortunate as that. So that's one of the barriers. One of the things though, John, that I'm really encouraged about is the new and innovative ways that we've been able to use telemedicine and video conferencing throughout the pandemic. I personally have been amazed at how quickly our providers and our patients have adapted to telehealth, telemedicine, and video visits. In our survivorship care, we've taken that to the next level and have delivered a lot of our survivorship care services through Zoom and other video and electronic means. And this has just been a game-changer for us, as well as the patients. A lot of our patients travel a great distance to us to get cancer care chemotherapy, for example, and there's no way to deliver that remotely.    But we've become pretty adept at learning how to deliver a lot of this survivorship care by Zoom and a teleconference, and the patients just love it. They don't have to make the commute, they don't have to deal with our parking situation. So we're continuing to explore not only other ways and other cancer survivorship services to deliver through video and through remote means. But also, how to actually bring the team together so that it's not just the patient who is having a visit with a physician, but maybe the patient has a visit with the physician along with a nurse navigator, along with an exercise specialist altogether in real-time. And it's something that we're really excited about and exploring actively right now.    Dr. John Sweetenham: Yeah. Thanks, Keith. And in fact, that sort of dovetails into the next question I had for you. And I think you've partially answered that. But I'd just like to extend that theme, that sort of telehealth and new innovations theme a little bit further if we can. Obviously, as our patients are living longer, we need better supportive care strategies for them because of the many experiences that they're going to confront. And you've already mentioned a number of those; infections, neuropathy, depression, [and] the financial stresses that they're going to encounter. And I think, as you point out, the telehealth opportunities have really been a tremendous innovation in helping us to deliver that care. In addition to that though, there clearly are many other aspects of cancer survival, which can impact a patient's wellbeing and compromise their adherence to long-term cancer treatments and subsequent follow-up. And we need other ways of influencing wellness and healthy behaviors both during and after treatment.    So, in addition to the innovations that you've already mentioned of telehealth in our direct health care provider to patient interactions, do you see anything on the horizon in terms of technology or anything else, which is going to help us in the professional-to-professional communication space? And I guess what I'm thinking of particularly, is in making sure that our health care professional colleagues, let's say out in the community, are fully clued in, in terms of likely cancer recurrence, [and] what they should be looking for. They will all know which wellness and healthy behaviors they should be encouraging, but really in terms of providing some additional support and education for health care professionals in the community with respect to the needs of our cancer survivors.    Dr. Keith Argenbright: Yeah. Great question. And I want to circle back to what we spoke about earlier about this primary care physician clinic or this primary care clinic being embedded within our current cancer center. In working with our family medicine and internal medicine colleagues, when we developed this, we realized that not only is this a great opportunity for our survivorship patients, not only is a great opportunity for our current oncologist to offload some of the survivorship care to a primary care clinic, this is a great professional education opportunity. This is still a young program and it's got a long way to go before it matures. But pretty quickly, we're going to start bringing some of our medical students, some of our family medicine residents into this clinic, because they need to know more about the long-term effects of the medications. John, we're all learning about these new medications, right?    The CAR T therapies, the tyrosine kinase inhibitors, the antibody, we're all learning about this. And it's a focus of current oncology education so that the oncologist will understand these side effects and these late-term effects. We need to expand that education to our medical students, our residents, as well as in our community primary care physicians as well. As you know, I'm a primary care physician by training. And some of these drugs are very frightening to primary care providers because the oncologists are around these medications all the time, but not so much the primary care physicians.    And so, we need to educate our primary care physicians, both at the beginning of their training, as well as throughout their training to understand the medications better, understand the side effects better, understand what they are able to take care of themselves in their own primary care clinics, what they need to be able to refer back either to an oncologist or potentially a cardiologist. So I know that ASCO is very interested in working with some of the other professional family medicine and internal medicine and pediatric societies in order to expand this education into the providers. And I think we need to continue to look at that and continue to have that our focus.    Dr. John Sweetenham: Thanks, Keith. I think because as you were speaking, the other thing that does occur to me is, of course, that the communication piece, it's going to be so important that it's very much a two-way street. Because as you pointed out with a lot of these newer treatments, checkpoint inhibitors, and so on, we're going to see new toxicities, long-term toxicities emerge, one would anticipate, over the coming months and years. And making sure that there is two-way communication as community-based health care providers start to see some of these toxicities emerge, and making sure that we collect these data and ensure that we are keeping a very close eye on how this develops is going to be really important. So, I think two-way communication is going to be key.    So, Keith, we, I think are just about at the end of our time. Thank you very much for coming onto the podcast today and sharing your insights on models of care of cancer survivorship. I think although we have many challenges ahead, as we try to support our patients and design care models for them in the future, I think maybe the take-home message has to be that we are in, I think in many ways, the fortunate position of being able to have this discussion because we have so many more cancer survivors than we had some years back. So greatly appreciate your thoughts today. And thanks again for joining.    Dr. Keith Argenbright: My pleasure. Thank you, John.    Dr. John Sweetenham: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate and review us wherever you get your podcasts.    Disclosures:  Dr. John Sweetenham:   Consulting or Advisory Role: EMA Wellness  Dr. Keith Argenbright: None disclosed.  Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.   

Host Dr. John Sweetenham, associate director of Clinical Affairs at the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, and Dr. Zeina Nahleh, breast cancer medical oncologist and regional chair of the Cleveland Clinic Florida Cancer Institute, discuss the new ASCO Expert Panel report on the use of biosimilars in oncology, and their potential as an affordable, effective alternative for cancer care.   Transcript Dr. John Sweetenham: Hello, I'm John Sweetenham the associate director for clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News podcast. Today, we'll be discussing the use of biosimilars in oncology. These are licensed biological products that are largely analogous to the U.S. Food and Drug Administration (FDA)-approved originator or reference products, and a recent report from an ASCO Expert Panel found that biosimilars may be an affordable and effective alternative to their reference of biological product for cancer care.   Dr. Zeina Nahleh, was the co-chair of the Expert Panel that clarified the potential value and utility of biosimilars in oncology. I'm delighted to welcome her to the podcast today. Dr. Nahleh is a breast cancer medical oncologist who serves as the regional chair of the Cleveland Clinic Florida Cancer Institute.   My guest and I have no conflicts relating to our topic today. Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found in our transcripts at asco.org/podcasts. Dr. Nahleh, many thanks for being on the podcast today.   Dr. Zeina Nahleh: It's a great pleasure to be here.   Dr. John Sweetenham: Dr. Nahleh, oncology-related biosimilars were first approved by the FDA back in 2015. Could you open up by maybe giving us an explanation of exactly what biosimilars are and how these agents are currently being used specifically in oncology?   Dr. Zeina Nahleh: Biosimilars for oncology were developed for 2 purposes, basically: to hopefully decrease the overall costs of care, [and] to improve access to cancer therapies. The FDA has a clear definition of a biosimilar. It is a similar, but not identical to an already licensed biologic product. That's really the definition – it's similar in terms of quality, safety, and efficacy.   Now, biosimilars are produced in living cells. They are purified. They go through multi-step processes, so they're not really identical to the original product, but they're very similar. The use of biosimilars, as you mentioned, it started in 2015 as an unauthorized oncology product, and the FDA has since approved several biosimilar products. And the process to authorize this product goes through a lot of rigorous processes really of checks and balances, but they are really supposed to be equivalent in terms of safety and efficacy and not meaningfully different from the original reference product.   Dr. John Sweetenham: Thank you. One thing I should have mentioned right up front and apologize for not doing so is that I would certainly recommend that all our listeners take a look at the report that you co-authored with the other members of the panel because I think number 1, it's extremely informative in many domains, but I think it really gives an excellent description of the development process [of] biosimilars and [the] approval process, which is currently I think, relatively poorly understood.   On that theme, I think as a member of the panel, your panel report noted that there was a lack of clinician understanding about biosimilars and their utility. I think that's been reflected in the fact that the uptake of biosimilars in the oncology committee has been relatively slow. I think you probably agree with that. What do you think are the major barriers to biosimilar use that you found as you reviewed the literature? When do you think they are an acceptable alternative to the available reference biologics?   Dr. Zeina Nahleh: There are some barriers for clinicians to utilize biosimilars. For example, it could be a lack of fully understanding the way biosimilars are produced, whether they're safe because their development is not exactly the same. Sometimes they're confused with generic drugs, and they are not generic at all, they are completely different. Some other barriers would be mostly the efficacy because they haven't been, or the thought is that they are not compared head-to-head to a reference product, which is a normal way of identifying new cancer or oncology medications—to go through the phase 3 clinical trials and the usual process for research.   That's a little bit different from the way they approve biosimilars. It could be perceived that there is some inadequate evidence supporting these biosimilars. There are a lot of misbeliefs that I believe underscore the need for more education. It's great, John, that you're doing this podcast to clarify some of these questions.   Dr. John Sweetenham: Yes. In fact, although I don't think it's been absolutely definitely determined for most of the biosimilars, but I do think it's right to say that there are some signals that 1 or 2 of the biosimilars may even be superior in efficacy, at least in terms of response rates and so on to their originator products. There's been this term around of biobetters. I don't know what the panel's feeling was about that, and whether there is enough of a signal there for us to be thinking very seriously about them being possibly a better alternative to the originator product.   Dr. Zeina Nahleh: Like you mentioned, the manuscript really goes into some details and illustrates how the process has evolved to approve these biosimilars, so it may not be well known, but really the FDA approval process is very rigorous. It requires a lot of clinical and safety data. And many times actually, a request for a biosimilar drug is returned or rejected pending more investigation and more details.   Yes, there are some differences compared to the traditional clinical trial design, but really a lot of information and details go into these approvals, and whether it’s clinical data or safety data or pharmacokinetic, it's really based on robust data. Many times, several clinical trials are required. You're absolutely correct, and we believe strongly as a panel that the biosimilars available in the U.S. are quite safe and effective and therefore ASCO has endorsed the biosimilar use in many of the clinical guidelines.   Dr. John Sweetenham: Right. One of the things I think perhaps we haven't touched on so far is, of course, that for the most part, the biosimilars represent a significant cost saving both for health systems and also hopefully to patients compared with the reference product. That in itself brings me on to what I've perceived as 1 of the issues that perhaps makes clinicians a little bit nervous about the day-to-day use of biosimilars, and that's this concept of interchangeability. Your report certainly advocated for interchangeability. Could you just describe for our listeners what this actually means, this concept of interchangeability and why in the report you certainly address this in a pretty favorable way?   Dr. Zeina Nahleh: Interchangeability has different meanings, but just to make it simple, unless the biosimilar product is designated to be interchangeable, we still recommend that people do not just substitute a biosimilar for a reference product without notifying the prescriber. That's different than the generic. Generic is different where the pharmacist can easily switch between the 2. So far, we are still recommending that the prescribing provider is notified when a pharmacist is recommending changing the prescription to a biosimilar product. Just to clarify also, what's the difference between biosimilar and generic? Because I think sometimes there's some uncertainty here.   Dr. John Sweetenham: Yeah.   Dr. Zeina Nahleh: The generic version of the drug is expected to be identical to the brand name product. They have to be the same. Now, they are manufactured the same way, they're marketed the same way, so they are really the same version of the brand drug. This is different than the biosimilar. The biosimilar is a biologic agent produced by a living system. It's not manufactured the same way. It's actually not likely to be identical to the brand-name product.   This is 1 of the main principal differences between generic drugs and biosimilars is that the manufacturing process uses different production and purification processes. There are some inherent differences between biosimilars and generic drugs. There are some unresolved challenges, and in the U.S. actually, there is no biosimilar that is approved as an interchangeable product. There are some specific guidelines by the FDA for potentially granting the designation of being an interchangeable product.   Several states have put in place some guidelines on this, so it is recommended to review each state-by-state recommendation. But as a whole, we believe that biosimilars can be a safe and effective product, but still, the recommendation of the panel is to communicate with the providing physician if and when a biosimilar is to be replacing the main product, and that's really the recommendation.   So far, we don't recommend using interchangeability without including the prescribing team. Okay, so there are some safety concerns raised, but that's not the issue. The issue is that we believe it is not the same as a generic replacing a brand name—Pharmacy and Therapeutic Committees have to include the prescribing physician into this conversation.   Dr. John Sweetenham: Thanks that does help clarify that. It takes me onto my next question because I think we are getting to this issue of point of care decisions about whether to use a biosimilar and if so, which 1 to use. Of course, there are a couple of drivers of that. One of them is the health system itself and its “P and T” (Pharmacy and Therapeutics) Committee and so on and whether they will approve specific biosimilars.   Then the other issue that comes into play, and we certainly experienced this in our own institution is the 1 of insurance coverage. As I'm sure you know well, different insurance companies have variable policies and preferences about which biosimilars, if any, can be used in their covered patient. And if you are a physician at the point of care, trying to make a biosimilar decision, this makes it complicated because it can frequently lead to denials that can result in delays in treatment while this is figured out.   Could you comment at all on what decision support tools are already out there, or in development for physicians at the point of care to make this an easier process for them and for the patients and to avoid delays in treatment?   Dr. Zeina Nahleh: I have to say that it varies, there is really no standard. Speaking to several colleagues and several institutions, you would hear different responses, but in general, we know that insurance can vary substantially in terms of approving or authorizing certain biosimilars versus others. There was really no standard, and it is clearly important for all of us as clinicians to check with the pharmacy and with the insurance to make sure that we are delivering the treatment that is most appropriate for the patients based on their insurance.   In many cases, the insurance company would dictate sometimes what biosimilar and or what agent they would approve versus another. In this case, sometimes we are obligated to follow what the insurance is recommending in terms of reimbursement. It's a complex challenge, I believe, in health care. I believe it is important, though, to recognize that biosimilars are a safe and effective alternative to the original product, so people should feel comfort in using these agents we have outlined in the paper around 17 oncology FDA-approved biosimilars that have been supported by evidence, and these are very safe to use.   They go from supportive drugs like filgrastim to other products. I think it is important to recognize that the biosimilars are . . . well, first are here to stay and they could contribute, they can improve our care delivery if used appropriately. Now, the question of insurance and the payer, we always have to refer to those to make sure the patient receives the— does not incur extra cost.   Dr. John Sweetenham: Thanks for that great response. You mentioned safety and perhaps it will be worth just returning to that for a moment. Do you think that there are residual safety concerns around the use of biosimilars that we should be worried about? Do you think that we need data that we already have to track and monitor the individual biosimilars in a postmarking environment?   Maybe I'll just add onto that a partially related question, and that is, in your own institution, how have you handled the issue of consent to patients, patient consent to biosimilars, and addressing the issues of safety and efficacy with the patients?   Dr. Zeina Nahleh: I'll start with the consent. We have developed a process where we can write the biological name of the drug, say trastuzumab, and that should cover also the biosimilar version or any other commercial version, so that should be an acceptable way, at least in our institution to do this.   Of course, we educate the patients. Many times, patients expect 1 product and they see another name and we try to educate the patients that these are safe and equivalent products, and you should have no problem. It's a lot of education, a lot of communication with the patients, but we are able to provide the consent forms in that manner to minimize frequent consenting and different—doing it many times.   Now, going back to the issue of safety, like I mentioned initially, so biosimilars have been developed as a safe alternative, and they are approved after a very rigorous review by the FDA, and they have to exhibit no clinically meaningful differences. Many times they're compared to the original product. They look at their safety, their purity, potency, they look at a lot of criteria, both clinical data and pharmacokinetics. It goes through a rigorous process and sometimes it takes years to approve these products.   Again, we recommend that the biosimilars used in the U.S., the FDA-approved biosimilars be adopted because these have been looked at and validated, and they look at their competitive studies, analytical data, pharmacokinetic, so they compare to the original product, but they also make sure that there is really no deviation in terms of quality and safety.   [The] FDA also recognizes some of the uncertainties and therefore they have also requested post-approval monitoring, and that's important to mention because post-market surveillance is included in many of these products. They continue to recommend follow-up on these biosimilars after being approved and in the market. I hope that covers the question.   Dr. John Sweetenham: I think it does. Absolutely. Thank you for that. And I really appreciate your insights. Dr. Nahleh, many thanks for joining us on the podcast today. I'd like to congratulate you and the expert panel for the work that you've done on biosimilars, and for what I think is a great report that really clarifies the use of these agents and hopefully is going to help over time with the adoption of these agents into oncology practice.   I think there are clear benefits in terms of the cost-saving from these agents, both to our systems, but more importantly to our patients. Thank you so much for all of the work you've done, and thanks again for sharing your insights on the use of biosimilars in oncology with us today.   Dr. Zeina Nahleh: Thanks so much, John, for having me. It's great pleasure. Thank you for all you're doing and hope we covered some of these questions. We look forward to more updates from ASCO on biosimilars in the next few months and years to come.   Dr. John Sweetenham: Absolutely. And thank you too, to our listeners for your time today. If you enjoyed this episode, please take a moment to rate and review us wherever you get your podcasts.     Disclosures:  Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Zeina Nahleh: None disclosed. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Host Dr. John Sweetenham, of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, interviews Professor Piotr Rutkowski, of the Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland, about plans to provide cancer care for Ukrainians fleeing the war in Ukraine.   Transcript Dr. John Sweetenham: Hello, I’m John Sweetenham, the associate director for Clinical Affairs at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast. As many of you all know, 2 million people have now fled the war in Ukraine, according to the United Nations Refugee Agency—the UNHCR. Today, we’ll be discussing efforts underway in neighboring Poland to provide health care and other support to Ukrainian refugees, particularly for patients with cancer. It’s an honor to welcome Professor Piotr Rutkowski, who leads the department of Soft Tissue and Bone Cancer at the Maria Skłodowska-Curie National Research Institute of Oncology in Warsaw, Poland. He also serves there as the deputy director of the Institution for National Oncological Strategy and Clinical Trials. Additionally, Professor Rutkowski serves as the President-elect of the Polish Oncological Society. My guest and I have no conflicts relating to our topic today. Our full disclosures are available in the show notes, and disclosures relating to all guests on the podcast can be found on our transcripts at asco.org/podcast. Dr. John Sweetenham: Professor Rutkowski, thank you for coming on the podcast today. We are really pleased to have this opportunity to speak with you during what must be an incredibly difficult time. Dr. Piotr Rutkowski: Thank you for the invitation. That’s true, with this horrible time. And to be honest, we haven’t expected how it can be going on. But now we have a new reality, and we have to fight on. Dr. John Sweetenham: Just beginning with that new reality, my first question to you was going to be to ask you a little bit about details of the decisions made by Poland’s parliament. So, your parliament has adopted new legislation that provides health care for Ukrainian refugees and enables the creation of a call center at Poland’s National Health Fund. Could you give us some more details about these new developments, and how you anticipate this will help the Ukrainian refugees who are suffering, particularly those who are suffering with cancer? Dr. Piotr Rutkowski: Yes, that’s true. Until now, we have nearly 1 and a half million people from Ukraine who arrived in Poland during the last 2 weeks. And because of the increasing numbers of patients with cancer coming to our institution but also all the oncology call centers in Poland, the Polish parliament—together with the Polish National Health Fund decided that all refugees of war from Ukraine are authorized to receive health care the same as citizens of Poland. This is very important because it resolves a lot of bureaucratic issues. We do not need to get specific permission to treat the patients. And we can provide them the same care as every citizen of Poland, in terms of outpatient treatment, admission to the hospitals, surgical procedures, access to the drug, prescriptions of the drug . . . it is absolutely important. It also means that within the framework of this new law, we can treat the patients according to all the same regulations, or the same standards, as Polish oncological patients. Of course, I have to stress it, but Ukrainian oncological patients—except, of course—have no priorities. They are going to the same queue and [are under] the same care as Polish patients. Moreover, this is very important because for newly diagnosed oncological patients in Poland—we have so-called oncological cards, which allow for faster diagnosis including pathological evaluation, molecular evaluation, and imaging. So, they are undergoing the same diagnostic procedures as Polish patients. Of course, last week, we have admitted around 100 children in need of oncological treatment to centers in Poland. But probably it was the first wave of patients. Now we have an increasing number of normal adult patients with lung cancer, breast cancer, [and] GI cancers, coming to us. Some of them also need the continuation of the treatment, or they have to start specific treatment with innovative drugs—if they are reimbursed in Poland—it’s also allowed to treat with all these medicines in Poland. So, the second point which you mentioned that the Polish National Health Fund established this special, general, official hotline for oncological patients from Ukraine—and also a webpage. This hotline is in Ukrainian, Russian, English, and Polish languages, and with the use of this hotline, we are trying to direct the patients to the proper oncological centers because this hotline from the National Health Fund cooperates with 20 top Polish comprehensive cancer centers. So, using this official hotline, it’s much easier to be directed to the correct hospital treating the given type of cancer. This is very important because [patients can] contact directly to the hotline of the National Health Fund or the hotline of the oncology call centers in the region where the patients are temporarily staying in Poland. So, it’s the best we can recommend and this is what has been done until now in our country. Dr. John Sweetenham: It’s incredible how quickly the Polish government has moved to help the many Ukrainian patients with cancer and other patients who are coming into the country. The cancer centers in countries such as yours, who are accepting and treating these Ukrainian patients, presumably are going to struggle to have sufficient resources in terms of space, equipment, drugs, and staff to handle the large number of patients from Ukraine who will be showing up at your doors. What resources does Poland have? And what do you need from the international community to be able to help with this very large additional patient load that you’ll be seeing? Dr. Piotr Rutkowski: Yes, thank you. This is an excellent point because now, of course, the enthusiasm dominates, and normal human help—we involved everybody. So Polish oncological societies are working together, and we are providing different materials: translation for the patients; we also ask the pharmaceutical companies to provide the Ukrainian language material, which we had in the countries, and also patient advocacy groups are really helpful. And we are sending the required medical resources to Ukraine in some official actions. However, of course, you are right that the Polish oncological system had, even before, this increasing number of patients which we can calculate means that we’ll have 10 percent more patients with cancer in this year. So, it’s a really huge number. Until now, we also had some limitations in resources. The basic drug reimbursement was at a good level when we compare it to other central-eastern European countries, so we had a relatively good system. We also started, 2 years ago, our new national oncological strategy. However, we also transformed to this 3-level system of comprehensive cancer centers of reference.  So, we are also at the level of some transformational oncological systems. So, it's not the easiest time, especially, but generally, the numbers of nurses and health care providers, including different oncological specialties, are limited in Poland. And when we calculate per number of patients, it’s one of the lowest in Europe. Generally, we can expect a shortage of human resources. Of course, we can count that we easily and temporarily facilitate the qualification of Ukrainian medical staff for Poland. And this is also included in this package of new laws. But on the other hand, still, we are facing the problems of communication, even with medical staff. So, it’s not so easy. Moreover, when we calculated nowadays this number of patients, it costs about 50 to 70 million Euros per month additionally. So, it changes the priorities in health care in Poland. So, I cannot tell you now, but maybe we can make some calculations in 2 or 3 months. But nowadays, we can still resolve these issues, but what will be in 3 or 4 months, I really don’t know, And how delayed will the oncology health care be due to [the] increasing number of patients? So, it is what we can anticipate, and we try to reorganize at the level of different hospitals now. We had some meetings with the Ministry of Health and our National Health Fund. And the normal functioning levels—we cannot see. Things are changing. We have first patients now, but the numbers are increasing every day. So, I cannot definitely say what resources, except human resources, and of course, increasing funding, we need in the near future. We try to collaborate with different organizations. I really appreciate the meeting with ASCO and ECO that took place recently about how to transfer some patients to other oncological centers. However, it’s not so easy when we can’t transfer the patients somewhere else if the patient started the treatment in 1 given center. So, this is the situation now, and what we expect, but it can be more difficult in a few weeks or months. Dr. John Sweetenham: Yeah, thank you. I’d like to perhaps, pick up on that last point you made about medical information on patients that you’re accepting. So as a clinician yourself, how are you handling the issue of prior treatment history, and medical information of patients who are coming into your system? For example, are you able to get access to their pathology reports, their imaging, or their prior treatment reports? And if you don’t have access to those, how are you facing the challenges of treating those patients with an incomplete medical history? Dr. Piotr Rutkowski: Of course, we have to translate it. So, we have help in our institution, but it’s not common practice everywhere. Some of the patients have translated documents. We do not insist on the certified translations, just the original documents or copies of the documents with translation into Polish, because not all words are even well understood. The problem is that the level of health care in Ukraine is sometimes lower, and pathology reports are not perfect. So even if the pathological report, which we are receiving . . . if it’s even available from the patients . . . sometimes we need to redo the biopsy and establish some molecular factors. One patient who was admitted to my department yesterday with sarcoma, we redid the biopsy last week because the report was not complete. And we completely changed the diagnosis in 3 days. Other patients will probably also need [to be] re-biopsied. Sometimes we are lacking imaging . . . but some of the patients arrive with at least CDs of CTs or MRIs, so it’s much easier. Some of the refugees have only the copy in their mobile phone . . . so the documents are at a very different stage. If we have information about how the patient was treated in Ukraine, it’s perfect because they can continue the treatment. But not all kinds of treatment in Ukraine were provided according to the standards which we have in Poland. So, it’s also difficult because we have to discuss with patients how to change their treatment. There are really individual situations. This is what I can say. We have a lot of volunteers now helping with translation. We also employed some additional staff and it’s easier. But the problems with the documentation probably will also be increasing, that’s true. However, we try to simplify as much as possible, and in some situations, redo the biopsy and re-establish the diagnosis, if we have enough information. It’s really resolved case by case. Dr. John Sweetenham: Yes, gotcha. It sounds as if it certainly can add to everybody’s workload and degree of stress, unfortunately. Because of the additional tests that some of these patients are now having to face, on top of everything else that they’ve already confronted over the last couple of weeks. One of the other things which I think will be of interest to our listeners in that regard is whether you’re experiencing patients who are coming in, who have been part of a clinical trial? And if so, whether there are any mechanisms in place for that situation, or perhaps, a patient on a relatively early-phase clinical trial, who may have received part of their initial treatment in Ukraine? Dr. Piotr Rutkowski: Probably it is the easiest part because, for the last year, I have treated several Ukrainian patients in a clinical trial where they had access to new drugs. And we had the possibility, at least before the pandemic because the pandemic also complicated the transport or movement of patients.  But before, we had several patients in clinical trials, and many of them have relatives and are accompanied by translators who provided for compliance with the requirements for informed consent and of course, understanding all procedures. But because some companies ask us for [the] possibility to transfer patients from Ukraine to Poland within the clinical trials, so they are providing us the certified translation of the documents and also the informed consent in Ukrainian—at least 2 or 3 companies, because I’m responsible for clinical trials in our institute. So, they contacted us and of course, we agreed. This is much easier because it’s professional machinery and they have at least documents in the forms of CRF (case reporting form) so we can get the full history, and how the patient was treated, [and] in the majority of cases also imaging. So, it’s much easier because everything is provided, and we also inform the bioethical committee about the situation. But it’s probably, also, a little more work in the next few weeks. Dr. John Sweetenham: Yes, well it is good to hear that those patients are able to continue their treatment on trial, thanks to all of the backup support that you’ve been able to provide. I want to conclude by saying thank you, Professor Rutkowski, for coming on to the podcast today. And for everything that you and your colleagues, your institution, and the Polish people—are doing to support patients with cancer during what are obviously extremely difficult times. Dr. Piotr Rutkowski: Thank you very much. You know, cancer is a matter for all of us, and cancer has no borders, so we have to help each other in these difficult times, that’s true. Thank you very much. Dr. John Sweetenham: Thank you to our listeners, for your time today. If you’re enjoying the content on the ASCO Daily News Podcast, please take a moment to rate and review us wherever you get your podcasts.    Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness   Dr. Piotr Rutkowski: Honoraria: Bristol-Myers Squibb, MSD, Novartis, Roche, Pfizer, Pierre Fabre, Sanofi, and Merck Consulting or Advisory Role: Novartis, Blueprint Medicines, Bristol-Myers Squibb, Pierre Fabre, MSD, Amgen Speakers' Bureau: Pfizer, Novartis, Pierre Fabre Research Funding (institution): Novartis, Roche, Bristol-Myers Squibb Travel, Accommodations, Expenses: Orphan Europe, Pierre Fabre   Disclaimer:   The purpose of this podcast is to educate and to inform, this is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Host Dr. John Sweetenham, of the UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, interviews Dr. Mariia Kukushkina, of the National Cancer Institute of Ukraine in Kyiv, on the heroic efforts of oncologists to treat patients with cancer during Russia’s invasion of Ukraine. From her home in Kyiv, Dr. Kukushkina recounts how “some cancer centers have been destroyed.”   Transcript Dr. John Sweetenham: Hello, I'm John Sweetenham, the associate director for Clinical Affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast. On February 24th, Russia launched an unprovoked attack on Ukraine, which has led to international condemnation and sanctions against the Russian government. ASCO has joined its Ukrainian members, the worldwide oncology community, and healthcare providers in condemning Russia's invasion of Ukraine and has called for an immediate cessation of the hostilities and full protection and safety for all Ukrainian patients, healthcare workers, and medical facilities.  Today we'll be discussing the impact of the war on patients with cancer and how oncologists the coping under these extremely difficult circumstances. Joining me for this discussion is Dr. Mariia Kukushkina, a senior research associate in the Department of Skin and Soft Tissue Tumors at the National Cancer Institute of Ukraine in Kyiv. My guest and I have no conflicts relating to our topic today. Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found in our transcripts at ASCO.org/podcasts.   Dr. Kukushkina, we are so glad to speak with you today. I understand that you're speaking with us from your home in Kyiv, is that right?    Dr. Mariia Kukushkina: Yes, absolutely right. Thank you very much for this invitation and for this opportunity to share the information about the situation in Ukraine now.    Dr. John Sweetenham: Well, we really appreciate your taking the time to speak with us. Could you begin by describing the current situation, which is facing oncologists and patients under your circumstances at the moment?    Dr. Mariia Kukushkina: Okay. First of all, I would like to thank for incredible support Ukraine and Ukrainians all over the road. It's helped us to be strong, and I am very appreciative of ASCO Daily News for this opportunity to discuss the situation with cancer care in Ukraine. So, what do we have nowadays? Unfortunately, only some cancer centers in our country are working. Some cancer centers have been destroyed. Others are in areas where there are active hostilities.  In the majority of cases, active cancer centers can provide only outpatient-intended treatments and urgent surgery, and some staff are unable to get to work due to lack of public transport, as you will understand.   On the other hand, cancer centers in the west of Ukraine are overloaded by patients coming from other regions. And a lot of our patients are on the road because some countries, like Poland, Romania, Hungary, Slovenia, Baltics declared that Ukrainian refugees are entitled to the same medical services as Polish or Romanian, etc, and insured people without payment or social health insurance.  And on behalf of Ukrainian people, I would like to thank all countries that are accepting our patients, and helping them as much as they can. But some patients cannot leave their cities as you understand, and families, and so they are still staying in Ukraine. And almost all stopped except those who are mobilized into the army, or those who have decided to stay to take care of our patients because people in these countries are hit by both war and cancer, and almost all Ukrainian oncologists are providing free online consultations and try to help. Our oncologists, nurses, ambulances, volunteers, radiologists, surgeons, and everyone else in healthcare, do everything in their power to ensure that patients can continue treatment. And I really admire these people.    Dr. John Sweetenham: Yes, this is really absolutely remarkable under these really extraordinary circumstances. We've seen some news reports about pediatric patients with cancer who've been receiving their treatments in the basements of hospitals because obviously that was regarded as being the safest location for them. Can you comment a little on what is happening within inpatient cancer care in Ukraine at the moment, and perhaps also comment on whether you feel that the healthcare workers who are providing this essential care are placing themselves in the way of danger in those hospitals?    Dr. Mariia Kukushkina: No doubt that health workers and patients are in extra danger in the hospital nowadays because they are forced to be treated and to treat in conditions of hostilities. First of all, it's difficult to get to cancer centers. For example, I live on the one bank called the Dnieper River, but the National Cancer Institute where I work on the other bank [of the river]. And we now have the problems with public transport. So it's very difficult to get to work. And I prefer to do something like my online consultations, organization work, et cetera.  And of course all patients and our staff must go down to the shelter or basement during each air raid. And sometimes it could be up to 10 times per day. some cancer centers, the systemic treatment can be provided only in these basements. So these videos that you mentioned, it's true. Absolutely. And of course, all our patients and doctors don't know if the building will be intact when they come back from the shelters.    Dr. John Sweetenham: Of course. Yes. You mentioned online consultations and telehealth. And has that been adopted widely in Ukraine during the war so far? And also, could you comment on whether the COVID pandemic had helped you to enhance your telehealth capabilities in the country?    Dr. Mariia Kukushkina: I want to emphasize that nowadays we consult patients absolutely free. It's something like volunteer work for us. So a lot of our doctors and me too, post on Facebook, our own phone numbers. It's our private phone numbers because we understand that patients need help. Sometimes they need only something, right. And we need to call them. And it's very important too, but sometimes we can do something very practical for them even from a distance.    Dr. John Sweetenham: You mentioned earlier that many of your patients are now taking opportunities to be treated in other countries, such as Poland and Romania. Can you describe how you are able to find care for these patients in these other countries and whether the patients are needing help to leave the country?    Dr. Mariia Kukushkina: In my opinion, nowadays we have two different problems. One of them involves the cancer patients that stay in Ukraine and the other one is a system for Ukraine and the refugees. And as I know from the media that nearly one million people nowadays left Ukraine, one million people. And a lot of them are cancer patients and they need treatment. And now we need assistance for these refugees; safe passage for cancer patients and people in a similar situation. They need safe passage out of the country and support for the [health] structures in countries receiving Ukrainians. Again, I want to thank my colleagues in different countries [who are helping].  First of all, I want to thank my colleagues from Poland and Romania because on the first days of the war, they helped us. They made something like a list of cancer centers with contacts in which our patients can go. So it wasn't only let's go to Poland or let's go to Romania and you will receive the treatment. It was absolutely thanks to specific cancer centers. And I want to say, thank you again for my colleagues from all countries that have supported us. I'm sorry, I'm sure that I have maybe forgot someone now, but it wasn't intentional. We are currently under a lot pressure so you must understand.    Dr. John Sweetenham: You mentioned that you need assistance and I wonder what kind of assistance and what kind of supplies do you think is most useful to the oncology community and to other healthcare facilities right now? What are you most in need of in terms of assistance and supplies?    Dr. Mariia Kukushkina: I think that we need something like a list of cancer centers for every specific type of cancer [and their contact information]. It will be very useful for our patients. And of course, we need help with safe passage for our patients. Nowadays, it's very difficult to get to the west Ukraine and to cross a border. And of course, it's difficult for healthy people and [so] it's much more difficult for patients with cancer. And it's very important to note that sometimes our patients don't have medical documentation with them. Some of them don't have access to this medical documentation because their house was destroyed. And it's difficult to get this documentation for cancer centers in Ukraine, for example, because it's impossible to get to the office [or cancer center] or the building is maybe destroyed too.    Dr. John Sweetenham: Yeah. So if I understand you correctly, the urgent needs are number one, making sure that the patients are able to get to ongoing care, if not in Ukraine, then in one of the neighboring countries. Then number two ensuring their safe passage so that they can get to that country and receive their care.    Dr. Mariia Kukushkina: Yes. And I want to say that one of the biggest problems, in my opinion, is their palliative care in our country nowadays because a lot of patients don't have this opportunity - they don't have opportunity to go home. And we have a lot of difficulty with palliative care now and honestly said, I don't know how to solve this problem. When for example, Kyiv is bombed every couple of hours.    Dr. John Sweetenham: Right. What can organization like ASCO do at the moment to help Ukraine's oncology community?    Dr. Mariia Kukushkina: Now, the support of ASCO is very important for Ukraine's oncology community. Because our main task, even during the war is the treatment of cancer patients. Nowadays, we have a lot of tasks in our country. I want to say that a lot of pharmaceutical companies and a lot of hospitals are ready to help us and ready to donate drugs for our patients. And today we are working on the least number of drugs we need because we don't know how many patients go abroad. [We don’t know] how many patients stay in Ukraine.  And we are working on legislative documents that will allow the importation of drugs and provide patients with free medicines. And, of course, the big problem is how to transport these drugs to the different regions of Ukraine. So we have a lot of tasks in our own country and, in my opinion, the oncological community can help our patients with drugs and with supportive care and with assistance for our patients who [left Ukraine and] are now abroad.    Dr. John Sweetenham: One other important question to ask is how are you personally coping under what must be extraordinarily difficult circumstances at the moment?    Dr. Mariia Kukushkina: We have a lot of tasks and we don't have time for ourselves. We try to do as much as we can and all of us have families and we try to support our families too. Because in the majority cases, our relatives live in different regions of our country. So our mornings start with phone calls to all of our relatives, all our friends, but then we start to work. We begin to work from 6:00 AM and sometimes we finish it after 11:00 PM, but we are fine. I think that our situation, oncologists' situation, is much better than cancer patients’ situation.    Dr. John Sweetenham: Well, thank you. I know that I would speak on behalf of all of our listeners by just commenting on how much I personally and I'm sure they would agree with me, number one, the fact that the international oncology community has come to the assistance of cancer patients and cancer healthcare providers in Ukraine, it's good to hear that. And I would also comment, if I may, very humbly on your remarkable dedication to cancer care and to your patients. And we certainly thank you for coming onto the podcast today. We hope that you and your family will stay safe and please know that you and our other colleagues in Ukraine and the patients and their families are very much on our minds during these difficult days. We hope everyone will be safe. And thanks again for sparing some time to join us today.    Dr. Mariia Kukushkina: Thank you very much.    Dr. John Sweetenham: Thank you. And thank you to our listeners for your time today. If you're enjoying the content of the ASCO Daily News podcast, please take a moment to rate and review us wherever you get your podcasts.      Disclosures:  Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Mariia Kukushkina: None disclosed. Disclaimer:  The purpose of this podcast is to educate and to inform, this is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   

Dr. Neeraj Agarwal, ASCO Daily News editor-in-chief, and director of the Genitourinary Cancers Program at the University of Utah’s Huntsman Cancer Institute, highlights key studies on disparities in GU cancers featured at the 2022 ASCO Genitourinary Cancers Symposium. Transcript:   ASCO Daily News: Hello and welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. In today's episode, Dr. Neeraj Agarwal, the ASCO Daily News editor in chief, will highlight compelling studies on disparities in GU cancers featured at the 2022 ASCO Genitourinary (GU) Cancers Symposium. Dr. Agarwal has no conflicts relating to the topic of this episode and his full disclosures are available in the show notes. Disclosures of all guests on the podcast can be found in our transcripts at asco.org/podcasts.  Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Cancers Program and professor of medicine at the University of Utah Huntsman Cancer Institute. So, I'd like to start with Abstract 20 presented by Dr. Alicia Morgans from the Dana-Farber Cancer Institute. Multiple population-based studies have reported a higher incidence of prostate cancer in Black men. [This disease] usually presents with aggressive features, at an earlier age, and is associated with higher mortality rates compared to White men. In contrast, multiple reports suggest that Black men with advanced prostate cancer also have better survival outcomes to novel hormonal therapies compared to White men. Using electronic medical records retrieved from a urology specialty database, Dr. Alicia Morgans investigated whether improved survival outcomes in Black men treated with enzalutamide are due to better responses compared to White men. So eligible patients, who are chemotherapy and abiraterone naive and included 214 Black men and 1,332 White men with advanced prostate cancer.    Reserves from a multivariate analysis were adjusted for baseline characteristics and indicated a statistically significant delay in clinical progression-free survival for Black men treated with enzalutamide compared to White men. This supports the argument that given equal access to care, Black men may respond similarly or better than White men to treatment for advanced prostate cancer. The next abstract addressing disparities in GU cancers was Abstract 444 presented by Dr. Samuel Washington from UCSF School of Medicine. Radical cystectomy remains the gold standard for muscle-invasive bladder cancer, yet confers significant health care costs. Prior work on the impact of cost commonly relied on comparisons by insurance status and income. Few studies have examined the relationship between the net worth of the household and the encounter type, such as outpatient versus inpatient encounters. As we also know, outpatient encounters are usually cheaper or less expensive than more expensive inpatient encounters.    So, in this intriguing and novel study, Dr. Samuel Washington presented a real-world analysis of demographics, household net worth, health plan cost, out-of-pocket cost, and total health care cost accrued from the day of admission to 90 days after radical cystectomy for muscle-invasive bladder cancer. This was the largest study of its kind and included more than 140,000 commercially insured patients to examine variations in health care utilization by net worth in 90 days after radical cystectomy. Results are very interesting and indicate that patients with lower household net worth were at a greater risk for an acute inpatient encounter and thus higher medical cost, while patients with greater household net worth had greater odds of office visits or outpatient encounters, which are associated with lower cost. So, these findings indicate that a lower household network continues to be a significant factor in health care utilization and higher health care costs, even within a commercially insured patient population. So very interesting findings indeed and these findings definitely should pay for further future studies involving or looking at this aspect of disparities. Thank you very much for your kind attention.    ASCO Daily News: That was Dr. Neeraj Agarwal of the University of Utah's Huntsman Cancer Institute. If you've enjoyed this series, please take a moment to rate and review us wherever you get your podcasts.     Disclosures:   Dr. Neeraj Agarwal:   Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Merck, Novartis, lily, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences      Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, CRISPR therapeutics, and Arvinas      Disclaimer: The purpose of this podcast is to educate and to inform this is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Neeraj Agarwal, ASCO Daily News editor-in-chief, and director of the Genitourinary Cancers Program at the University of Utah’s Huntsman Cancer Institute, shares key takeaways from the practice-changing ARASENS trial in mHSPC, featured at the 2022 ASCO Genitourinary Cancers Symposium.   Transcript: ASCO Daily News: Hello, and welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. Today in our continuing coverage of the 2022 ASCO Genitourinary (GU) Cancer Symposium. Dr. Neeraj Agarwal, the editor in chief of the ASCO Daily News will share key takeaways from the practice-changing ARASENS trial, which showed promising results in metastatic hormone-sensitive prostate cancer. Dr. Agarwal has no conflicts relating to the topic of this episode and his full disclosures are available in this show notes. Disclosures of all guests on the podcast can be found in our transcripts at asco.org/podcasts. Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News podcast. I'm Dr. Neeraj Agrawal, the director of the Genitourinary Cancers Program and professor of medicine at the University of Utah Huntsman Cancer Institute. Let's discuss the results of the practice-changing ARASENS trial in patients with metastatic castration-sensitive prostate cancer as presented at the 2022 ASCO GU Symposium. This abstract, Abstract 13, was presented by Dr. Matthew Smith from the Massachusetts General Hospital and Hartford Medical School. ARASENS is a randomized phase 3 trial evaluating the efficacy and safety of darolutamide, a novel hormonal therapy, plus ADT (antiandrogen therapy) plus docetaxel versus placebo plus ADT plus docetaxel in patients with metastatic castration-sensitive prostate cancer. Randomization was stratified by the extent of disease and alkaline phosphatase levels, below versus upper limit of normal or above. It is important to know that this study only included patients that were eligible for ADT and docetaxel chemotherapy, to begin with. The primary endpoint was overall survival with multiple secondary endpoints, including time to CRPC (castration-resistant prostate cancer), time to pain progression, time to first symptomatic skeletal event, and time to start off the next anti-neoplastic therapy, and safety. A total of 1,306 patients were randomly assigned to triplet therapy with darolutamide plus ADT plus docetaxel versus placebo plus ADT plus docetaxel. Baseline characteristics were well balanced between the treatment arms. Analysis of the primary endpoint was pre-specified. After, 533 events had occurred results show the primary endpoint of this study was met with a significant improvement in overall survival and a 32.5% reduction in risk of death for patients on the triplet therapy on for darolutamide plus ADT plus docetaxel versus placebo plus ADT plus docetaxel. It is important to know that the triplet therapy improved overall survival, despite 76% of patients in the control arm having received the next life-prolonging therapy. Subgroup analysis indicates consistent benefit across the 3 specified groups. Secondary endpoints also were favored by the triplet therapy combination over the control arm. While this study offers an additional excellent option for our patients with metastatic cancer-sensitive prostate cancer in older populations, the use of docetaxel may be a significant limitation to this triplet combination. In addition, and importantly, this study did not answer the question of whether adding docetaxel chemotherapy to the ADT plus novel hormonal therapy backbone will also improve survival. With the advent of multiple doublets and triplet combinations in recent years, as we saw in the form of ADT plus enzalutamide ADT plus apalutamide in the recent years, it is very important to find biomarkers that may predict response to these treatment options, which will allow personalization of therapy with that. I would like to conclude this podcast on the ARASENS trial. Thank you very much for your kind attention. ASCO Daily News: You've been listening to Dr. Neeraj Agarwal of the University of Utah's Huntsman Cancer Institute. Thanks for joining us today. If you're enjoying the content on the podcast, please take a moment to rate and review us wherever you get your podcasts. Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Merck, Novartis, lily, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, CRISPR therapeutics, and Arvinas Disclaimer: The purpose of this podcast is to educate and to inform this is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Neeraj Agarwal, ASCO Daily News editor-in-chief, and director of the Genitourinary Cancers Program at the University of Utah’s Huntsman Cancer Institute, shares key takeaways from the PROpel and MAGNITUDE trials in mCRPC, featured at the 2022 ASCO Genitourinary Cancers Symposium.   Transcript: ASCO Daily News: Hello and welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. Today, in our continuing coverage of the 2022 ASCO Genitourinary (GU) Cancers Symposium, Dr. Neeraj Agarwal, the editor-in-chief of the ASCO Daily News will highlight promising advances in metastatic castration-resistant prostate cancer. Dr. Agarwal has no conflicts relating to the topic of this episode, and his full disclosures are available in the show notes. Disclosures of all guests on the podcast can be found in our transcripts at asco.org/podcasts.   Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Cancer Program, and professor of medicine at the University of Utah Huntsman Cancer Institute, and editor in chief of the ASCO Daily News. I'd like to start with the PROpel trial followed by a discussion on the MAGNITUDE trial. So, Abstract 11 was on the results of the PROpel trial and presented by Dr. Fred Saad from the University of Montreal. PROpel is a randomized phase 3 trial, which evaluated the efficacy and safety of olaparib, a PARP inhibitor plus abiraterone versus this placebo plus abiraterone in the first-line metastatic castration-resistant prostate cancer setting. Patients were allowed to have docetaxel chemotherapy is given in a metastatic castration-sensitive prostate cancer setting. Enrollment in the study was independent of the effects in the homologous recombination repair pathway. The primary endpoint was investigator-assessed radiographic progression-free survival (PFS) with multiple secondary endpoints, including overall survival and safety.   Approximately 800 patients were randomly assigned to the novel combination of olaparib plus abiraterone or placebo plus abiraterone. Baseline characteristics were well-balanced between the treatment arms, including homologous recombination repair or HRR mutation status. At the pre-planned interim analysis results show the trial meets its primary endpoint with significant improvement in radiographic PFS for all patients receiving the combination therapy versus control, regardless of the presence of homologous recombination repair gene mutations. Median PFS was 24.8 months versus 16.6 months for patients receiving olaparib plus abiraterone versus placebo plus abiraterone respectively with the hazard ratio of 0.66, and a P   Regarding the adverse effects, they were what you would expect from the combination of a PARP inhibitor, such as olaparib and abiraterone. We saw a higher sequence of all great events of anemia, fatigue, and nausea in the combination arm. While anemia was the only grade 3-4 adverse event observed at a significantly high frequency in the combination arm. It is also important [that] we get a better understanding of the molecular mechanism by which patients who are homologous recombination repair mutation-negative are benefiting from the combination treatment as well.   The next trial in this context, or this team, was the MAGNITUDE trial. Abstract 12 was presented by Dr. Kim Chi from British Columbia Cancer Center in Vancouver, Canada. MAGNITUDE is a randomized phase 3 trial evaluating the efficacy and safety of niraparib plus abiraterone plus placebo plus abiraterone in the first-line metastatic castration-resistant prostate cancer setting. The study population was slightly different from what we saw in PROpel trial. Taxane chemotherapy, as well as novel hormonal therapy, was allowed in metastatic castration-sensitive prostate cancer, as well as a prior novel hormonal therapy was allowed in the non-metastatic castration-resistant prostate cancer.   Also, patients were allowed up to 4 months of treatment with abiraterone in the first-line metastatic castrate-resistant prostate cancer. Prospective selection of patients with, and without homologous recombination repair (HRR) gene mutations were required. The primary endpoint was radiographic PFS by central review with multiple secondary endpoints, including overall survival and safety. A pre-specified fertility analysis was planned after enrolling 233 patients who were randomly assigned to niraparib plus abiraterone or placebo plus abiraterone. Evaluation of fertility was based on the composite PFS of PSA or radiographic progression, whichever occurred first. The pre-planned fertility analysis showed no benefit in the biomarker negative cohort. And thus the trial did not pursue further enrollment of those patients who were not positive for homologous recombination repair gene mutations.   Coming to the HRR positive cohort, 423 patients were randomly assigned to either niraparib plus abiraterone or placebo plus abiraterone. At the pre-planned interim analysis primary endpoint was met with a significant improvement in radiographic PFS for BRCA1 and BRCA2 and all patients who are homologous recombination repair mutation-positive, receiving the novel combination of niraparib plus abiraterone. Overall survival results are still immature. It is important to note that in the patients who are HRR positive, approximately 50% were BRCA1 and 2 positive. And these patients clearly derived the most benefit with a combination with an approximate 47% reduced risk of death. And if you look at other patients who are biomarker positive, there was a clear benefit and a significant improvement in median PFS (radiographic progression-free survival) with a hazard ratio of 0.73, which translates to a 27% reduction in the risk of death or progression. With the caveat of subgroup analysis, being underpowered following groups of patients seem to derive less benefit with the combination than the overall cohort with the combination of niraparib plus abiraterone. And these patients included patients who were age 65 or younger, or less than age 65, patients with visceral metastatic disease, patients with prior abiraterone or taxane chemotherapy, [and] patients who had a PSL level below the median, and patients with non-BRCA homologous recombination repair mutations.   In conclusion, the combination of niraparib plus abiraterone shows a significant improvement in the radiographic PFS for patients who are HRR positive in the first-line metastatic CRPC. Based on the available data in the public domain, without any doubt that both PROpel and MAGNITUDE trials established a combination of a PARP inhibitor with abiraterone in the first-line metastatic CRPC setting for patients who are positive for HRR mutation improve radiographic progression-free survival. Even though overall survival data are immature for both trials, I expect both combinations will be approved by the U.S. Food and Drug Administration in the near future and will be available to our patients. Regarding the HRR negative cohort in the PROpel trial, which also seems to derive significant benefit with the combination of abiraterone plus olaparib, I'm looking forward to the data on confirmation of HRR negative status by tissue-based genomic profiling results in the full-length publication which we expect to be published soon. If indeed confirmed by the tissue-based genomic profiling, I see the combination of abiraterone plus olaparib to be a reasonable option in the patients who are HRR negative in the first-line metastatic CRPC setting.   With this, I would like to conclude my discussion on the 2 practice-changing trials presented in the 2022 ASCO GU meeting, which were the PROpel and MAGNITUDE trials. Thank you very much for your kind attention. ASCO Daily News: That was Dr. Neeraj Agarwal of the University of Utah's Huntsman Cancer Institute. Thanks for joining us today. If you're enjoying the content on the podcast, please take a moment to rate and review us wherever you get your podcast.   Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Merck, Novartis, lily, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, CRISPR therapeutics, and Arvinas Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Guest host, Dr. Neeraj Agarwal, editor-in-chief of ASCO Daily News and director of the Genitourinary Cancers Program at the University of Utah’s Huntsman Cancer Institute, and Dr. Jason Efstathiou, chair of the 2022 ASCO Genitourinary Cancers Symposium, discuss key abstracts and innovations in GU oncology featured at #GU22. Dr. Efstathiou is a professor at Harvard Medical School and director of the Genitourinary Division in Radiation Oncology at Massachusetts General Hospital.   Transcript Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Neeraj Agarwal, the director of the Genitourinary Program and professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. Today we'll be discussing key advances in GU oncology featured at the 2022 ASCO Genitourinary (GU) Cancers Symposium. I'm delighted to welcome Dr. Jason Efstathiou, who was the chair of this year's GU ASCO meeting. Dr. Efstathiou is the professor at Harvard Medical School and the director of Genitourinary Division in Radiation Oncology and clinical co-director of The Claire and John Bertucci Center for GU Cancers at the Massachusetts General Hospital. Our full disclosures are available in the show notes and the disclosure of all guests on the podcast can be found on our transcript at asco.org/podcast. Jason, thank you for coming on the podcast today.   Dr. Jason Efstathiou: Thank you very much, Neeraj. It's a real pleasure to be with you.   Dr. Neeraj Agarwal: So, Jason, the GU meeting showcased some fantastic advances across the spectrum of GU malignancies, can you please tell us about some of the hot topics that made the headlines this year?   Dr. Jason Efstathiou: Absolutely. This certainly was a dynamic and interactive hybrid ASCO GU meeting for all those attending in person, live streaming, or accessing the content on-demand. With over 5,200 registrants this year, that's an actual record for this meeting and over 70 countries represented. This meeting truly serves as the premier global event for all those who diagnose, treat and study GU cancers. The meeting highlighted novel scientific and clinical findings that were high impact. [And] in many cases will lead to practice-changing care. The meeting had a real focus on diversity, global perspectives, enhanced interactivity, networking, multidisciplinary, collaborative, and evidence-based care. As you know, this year's theme was “World Class Science, Patient-Centered Care,” and this theme was highlighted throughout the program. The meeting kicked off with a rich day focusing on prostate cancer, lots on PSMA imaging, such as Abstract 9 and a very, very excellent session on PSMA targeting and beyond which explored opportunities and challenges with PSMA novel therapeutics, including biomarkers of response and mechanisms of resistance.   Then Abstract 10 looked at PSMA PET and FDG PET as predictors of response and prognosis in a randomized phase 2 trial of Lutetium PSMA (177Lu-PSMA-617) vs cabazitaxel and metastatic castration-resistant prostate cancer (CRPC) progressing after docetaxel. And it suggested that Lutetium PSMA be prioritized in men with high PSMA expression. And this could actually be predictive. We had some awesome abstracts. Abstracts 222 and 223 suggested that a nozzle digital pathology-based biomarker developed using artificial intelligence is more effective than clinical prognostic markers for predicting long-term outcomes in patients with prostate cancer. And that this AI tool can actually successfully guide the use of androgen deprivation therapy in men with intermediate-risk localized prostate cancer. And then, of course, there were some very exciting results in discussion with the primary results of 3 potentially practice-changing phase 3 trials in the setting of metastatic prostate cancer that were presented in the oral prostate session. These were: PROpel (Abstract 11), MAGNITUDE (Abstract 12), and the ARASENS trials (Abstract 13). Neeraj, as a practicing medical oncologist, what did you think of these 3 abstracts?   Dr. Neeraj Agarwal: I agree with you, Jason. These are indeed practice-impacting, practice-changing abstracts, which was a record for a prostate oral session, all 3 abstracts. In fact, the results of the phase 3 trials are [likely] going to influence or impact our practice in coming months. I would like to start with Abstract 11 on the results of the PROpel trial. So, PROpel is a randomized phase 3 trial evaluating the efficacy and safety of olaparib plus abiraterone vs placebo plus abiraterone. In the first-line metastatic cast of resistant cluster cancer, docetaxel therapy was allowed for these patients if given in the metastatic castration sensitive prostate cancer setting. Enrollment in the study was independent of the defects in the homologous recombination repair gene pathway. The primary endpoint was investigator assessed radiographic progression-free survival with multiple secondary endpoints, including overall survival and safety. A total of 796 patients were randomly assigned to olaparib plus abiraterone or placebo plus abiraterone at the pre-plant interim analysis.   Results show that with a significant improvement in the radiographic progression-free survival for all patients receiving the combination therapy, regardless of the presence of homologous recombination repair gene mutations. Overall survival analysis is still immature with only 29% event having occurred thus far. It is interesting that even patients deemed a negative for homologous recombination repair gene mutations showed significant improvement in video graphic progression-free survival when treated with the combination of olaparib plus abiraterone versus placebo plus abiraterone. I would like to mention the MAGNITUDE trial, which is Abstract 12, in the same context, as these have very similar populations and combination regimens.   So, MAGNITUDE is a randomized phase 3 trial evaluating the efficacy and safety of niraparib plus abiraterone vs placebo plus abiraterone in the first-line metastatic castration-resistant prostate cancer setting. The eligible patient population was slightly different from that in the PROpel trial—prior attacks in therapy or novel hormonal therapy in the metastatic castration sensitive prostate cancer or non-metastatic castration-resistant prostate cancer were allowed. Also, patients were eligible if they had received up to 4 months of abiraterone in the first-line metastatic CRPC setting. Prospective selection of the patients with, and without homologous recombination repair gene mutations was required.   So, the primary endpoint was radiographic progression-free survival by central with multiple secondary endpoints, including overall survival and safety. A pre-specified early fragility analysis was planned after enrolling 200 patients who are [homologous recombination repair] (HRR) negative and who were randomly assigned to receive either niraparib plus abiraterone or placebo plus abiraterone. The pre-planned fertility analysis showed no benefit in the biomarker negative cohort. Four hundred and twenty-three patients who were HRR positive were randomly assigned to receive either the combination of niraparib plus abiraterone or placebo plus niraparib at the pre-planned interim analysis. The results show that trial method—primary endpoint with a significant improvement in the radiographic progression-free survival for BRCA1 and 2 patients—and all patients who are homologous recombination repair mutation-positive [were] receiving the combination of niraparib plus abiraterone versus placebo plus niraparib. Overall survival reserve is still immature.   My combined take on the PROpel and the MAGNITUDE trial, based on the data presented so far or available in the public domain so far, is that both trials establish that combination of a PARP inhibitor plus abiraterone on in the first-line settings for me, for [patients with] HRR mutation-positive metastatic castration-resistant prostate cancer [will] improve radiographic progression-free survival. Even though overall survival data is immature for both trials, I expect both combinations will be approved by the U.S. Food and Drug Administration in the near future and will be available to our patients. The HRR negative in the PROpel trial also seemed to benefit with the combination of abiraterone plus olaparib.   I'm looking forward to data on confirmation of HRR negative status by tissue-based genomic profiling results in the full-length publication, which we expect to be published soon. If indeed confirmed, I see the combination of abiraterone plus olaparib to be a reasonable option for patients who are HRR negative in the first metastatic castration prostate cancer set. The last practice-changing abstract in the oral prostate session was Abstract 13 on the results of the ARASENS trial. ARASENS is a randomized phase 3 trial evaluating the efficacy and safety of darolutamide plus ADT or androgen deprivation therapy plus docetaxel versus placebo plus ADT plus docetaxel in patients with metastatic castration sensitive prostate cancer or mCSPC.   It is important to note that this study only included patients that were eligible for ADT plus docetaxel chemotherapy. The primary endpoint was overall survival with multiple secondary endpoints, including time to casted resistance, time to pain progression, time to first symptomatic skeletal event, and time to start of next antineoplastic therapy and of course, safety. A total of 1,300 patients were randomly assigned to the darolutamide plus ADT plus docetaxel vs placebo plus ADT plus docetaxel.   Results show the primary endpoint of the study was met with a significant improvement in overall survival and a 32% reduction in risk of death for patients on the triplet therapy with thalidomide plus ADT plus docetaxel. While this study offers an additional excellent option for our patients with metastatic castration-sensitive prostate cancer, in an older patient population [the] use of docetaxel may be a significant limitation to this combination. In addition, this study did not answer the question [of] if adding docetaxel to ADT plus a novel hormonal therapy backbone will also improve survival with the advent of multiple doublets and triplet combinations. In recent years, it is very important to find biomarkers that may predict response to these treatments and personalized therapy.   Dr. Jason Efstathiou: Well, Neeraj, it certainly is a mic drop moment. Isn't it? When you can announce that the New England Journal of Medicine has just released the publication of your ARASENS trial, as you're presenting it at ASCO GU don't you think (DOI: 10.1056/NEJMoa2119115)?   Dr. Neeraj Agarwal: Indeed, I think this is one of the most exciting ASCO GU meetings I've seen ever from GU ASCO. This is not an exaggeration.   Dr. Jason Efstathiou: I totally agree. It was a phenomenal meeting and a very dynamic rich prostate day.   Dr. Neeraj Agarwal: So, let's move on to bladder cancer. Jason, what are your key takeaways from the studies of bladder cancer presented in this meet?   Dr. Jason Efstathiou: Thanks, Neeraj. Yeah, the sessions on urothelial cancer were phenomenal and there were great sessions on novel therapies, such as antibody-drug conjugates in advanced urothelial cancer and management of toxicities. There were abstracts such as [Abstract] 440 suggesting that neoadjuvant gemcitabine and cisplatin produced a favorable pathologic response rate and was well tolerated in patients with high-grade upper tract urothelial carcinoma, and thus should be potentially deemed a new standard. Abstract 442 was a phase 2 trial that suggested that maintenance treatment with niraparib plus best supportive care did not improve outcomes compared to best supportive care alone, in patients with advanced urothelial carcinoma that did not progress after first-line chemotherapy.   There was Abstract 435, which was an earlier face study suggesting that neoadjuvant treatment with enfortumab demonstrated promising activity among patients who are cisplatin-ineligible with muscle-invasive bladder cancer. And then there was a lot of focus in the meeting on trimodality therapy and optimizing bladder preservation. Dr. Alexandre R. Zlotta presented Abstract 433, which was a large multi-institutional match comparison of radical cystectomy to trimodality therapy for patients with muscle-invasive bladder cancer. And it suggested equivalent oncologic outcomes for select patients, and that trimodality therapy should be offered as an effective alternative for these patients. So Neeraj, moving on to kidney cancer, what were your key takeaways from these studies on kidney cancer presented in this meeting?   Dr. Neeraj Agarwal: Yes, Jason, thank you. There were exciting results presented from multiple studies in kidney cancer as well. For example, Abstract 290 presented by Dr. Toni K. Choueiri from the Dana-Farber Cancer Institute on the 30-month follow-up of the KEYNOTE-564, which showed continued and strong disease-free survival benefit with adjuvant pembrolizumab in the context of localized or completely dissected renal cell carcinoma. I would like to highlight that highest benefit was seen in those patients who had oligometastatic disease, who on different surgery to remove those metastatic foresight and then were randomly assigned to receive pembrolizumab vs placebo in this trial. Abstract 291, presented by Dr. Matthew Zibelman from Fox Chase Cancer Center, showed the combination of axitinib with nivolumab was associated with close to 70% objective responses. Abstract 300 on kidney cancer on more than 1,000 patients—and on the International Metastatic Renal Cell Carcinoma Consortium, or IMDC Consortium—show that in the context of first-line immunotherapy regimens, presence of lung metastasis, CT nephrectomy and better MDC risk scores correlated with improved objective responses on this novel immunotherapy regimens.   Abstract 350 on the update of the cabozantinib nivolumab was a sunitinib trial in metastatic renal cell carcinoma in the first-line setting. And it showed that the combination of cabozantinib nivolumab continues to be associated with improved survival with the 30% reduced risk of death, even after this longer follow up—approximately 3 years. So, indeed, multiple abstracts on kidney cancer with real impact on how we practice medicine. So, Jason, let me switch gears here and talk about the education session. For example, there was a compelling keynote address by Dr. Karen Knudsen, the CEO of the American Cancer Society, about disparities in GU cancers in the United States. Are there any key messages that you would like to highlight briefly before we wrap up the podcast today?   Dr. Jason Efstathiou: Thanks, Neeraj. Absolutely. The educational sessions were phenomenal. There was a must-see session, by the way, on management of rare variants in GU cancers. They made management of nuanced, rare variants and rare situations, very practical. And then there was an exciting prostate focus session called “Regulating the Wild West: PET-Based Imaging in Trials and the Clinic.” This session was planned with representatives from the U.S. Food and Drug Administration as we have done for the past 3 years. But this year it looked at how often PET-based imaging affects clinical decision making and prostate cancer and how the integration of novel molecular-based imaging like PET informs clinical trial design and endpoints, including regulatory considerations. And yes, of course, as you noted this year's program also focused on identifying and addressing disparities in cancer care and research with sessions each day, focused on this topic (Abstract 225, 446, 472, and 26). There were great oral presentations and there was a phenomenal Virtual Poster Walk with Dr. Ahmedin Jemal from the American Cancer Society. He, by the way, is an author that we have all quoted. So, please check that out. But we were thrilled, absolutely thrilled to have Dr. Karen Knudsen, the CEO of the American Cancer Society (ACS) as our keynote speaker to address this important topic in her phenomenal and frankly, inspiring talk called “A Path Forward: Addressing Disparities in Genitourinary Cancers.” This talk was especially poignant because as you know, there is a new and robust collaboration between ASCO and the ACS that was announced earlier this month on February 1, regarding equity, diversity, and inclusion in cancer care. ASCO's work aims to address all of the important differences that can impact access to cancer care and outcomes, including age, gender, race, sexual orientation, and geography, both in the U.S. and internationally. ASCO has clearly aligned its equity, diversity, and inclusion (EDI) goals within the mission pillars of research, education, and quality.   Dr. Neeraj Agarwal: Thank you, Jason, for sharing your insights with us today. It is really an exciting time in GU oncology. Thank you.   Dr. Jason Efstathiou: Thank You, Neeraj. I totally agree.   Dr. Neeraj Agarwal: And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you like what you're hearing on the ASCO Daily News podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you so much.   Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Merck, Novartis, lily, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas   Dr. Jason Efstathiou: Consulting or Advisory Role: Blue Earth Diagnostics, AstraZeneca, Boston Scientific, Roivant Pharma, Merck, and Myovant Sciences   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Host, Dr. John Sweetenham, associate director of Clinical Affairs at UT Southwestern Harold C. Simmons Comprehensive Cancer Center, and Dr. Sandra Kurtin, director of Advanced Practice and Clinical Integration at the University of Arizona Cancer Center, discuss the future importance of advanced practice providers to the oncology workforce and how to enhance their role in cancer research. Transcript:  Dr. John Sweetenham: Hello. I'm John Sweetenham, the associate director of Clinical Affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News podcast. Today we'll be discussing the role of advanced practice providers in oncology and their future importance to the oncology workforce.     I'm delighted to welcome our guest, who's a former colleague of mine, Dr. Sandra (Sandy) Kurtin, the director of Advanced Practice and Clinical Integration and an assistant professor of Clinical Medicine at the University of Arizona Cancer Center. Dr. Kurtin is also the president and founding board member of the Advanced Practitioner Society for Hematology and Oncology and an associate editor for the American Society of Hematology News. Sandy, it's great to renew our acquaintance and to have you on the podcast today.     Dr. Sandy Kurtin: Thank you, and I'm delighted to be here.     Dr. John Sweetenham: Before we start, I should mention that my guest and I have no conflicts of interest relating to our topic today. Full disclosures of all guests on the podcast are available on our transcripts, asco.org/podcasts. So Sandy, workforce shortages have been a concern in oncology for some time now and there has been a concern expressed in the literature and especially by ASCO probably for more than 5 years now--suggesting that the oncology workforce, or at least the physician workforce, is diminishing and we really need to be looking at new opportunities in terms of who comprises the workforce in the future.     In addition to a growing and aging population in the United States and an increasing incidence of cancer, we also see new and emerging therapies and technologies which increase the number of cancer survivors. So, it seems more important than ever that we utilize all of our oncology workforce, and particularly advanced practice providers (APPs) to therefore scope in oncology. Based on the assumption that we would expect much of that APP practice in the future to be independent practice, what do you think, Sandy, of the cancer services where APP led services can offer the best opportunity?     Dr. Sandy Kurtin: I think that one of the really remarkable things that I've come to realize—I've been doing this for 37 years—is that we do have not only a growing cancer population, but we have a population of patients that are living much longer, thankfully, with their cancer, and as a result, become more and more complicated patients that require much more specific and complex care, and it really does take a full team. And so, I think using everyone to the full scope of their licensure is really critical to maximize any team. This takes a team.     So, using the word ‘independent,’ I think of that we are always collaborative as members of the interdisciplinary multidisciplinary team, but we can exceed and take the lead in a number of areas that I think are really critical given that population of patients. One of those things are symptom management clinics. I know we, in our practice, are part of the Oncology Care Model (OCM) initiative and we know that keeping people out of the ER and the urgent care settings, out of the hospital, is really critical for any practice and for patients.     And so, running symptom management clinics, same day outpatient clinics, having that same agility in an inpatient APP-supported practice is really important. There's been a lot of work overtime in survivorship clinics and continuity clinics overseeing infusion services. I know in our practice we more or less run a day hospital.     We have people there 12 hours a day and they're very sick and we're providing that level of service in an outpatient setting, granted that's an academic setting. And then there are some growing areas that are niches in genetics and benign hematology. So, I think there are a lot of opportunities that we are beginning to realize and hope to see grow going forward.     Dr. John Sweetenham: Yeah. Very interesting to hear what you say there, and a lot of those overlap with the initiatives that we're introducing UT Southwestern as well. And I'm grateful for you to pick up on the independent practice because I think obviously, we're all at our best when we are part of a team and I think your point is very well taken, of course, there are many aspects of what we do now that can be APP-led. Do you have any thoughts about procedure clinics or specific procedures where you think APPs could be taking the lead?     Dr. Sandy Kurtin: Oh, sure. So, we do, in my practice—well, I've done close to 30,000 bone marrow biopsies in my career.     Right? So, a lot. And I think that—so clearly there are areas where APPs do run procedure clinics and what I have found in doing as many as I've done is the more you do, the better you get and that's better for everybody, the patient, the sample, all of it. And it may be more efficient to have a group of people that do it regularly. Obviously, we still need to train our fellows and other colleagues, but I think that is something that is growing both in surgical oncology and medical oncology for sure.     Dr. John Sweetenham: So, those of us who advocate for expanding APP practice and expanding our APP workforce still encounter some barriers to doing that, as I'm sure that you have as well. Could you comment a little bit on that, on what you think are barriers that prevent us from having APPs reach their full potential in terms of the oncology workforce and any thoughts you have about how we can overcome those barriers?     Dr. Sandy Kurtin: Sure. So, I think probably the biggest barrier in my mind is the lack of understanding and that we are part of a team and it's the ever-looming relative value units (RVU), productivity measures, people trying to meet those metrics. And I think as we move toward value-based based care models where [it] is less driven by visit volume and more driven by outcomes for practices, it will become inevitable to have this interdisciplinary team.     And until we get to the point where if you're a physician [and] I'm working with you as your APP colleague and you're held to a certain RVU, then there's the sense of, well, if I give that to you then that takes away from me. So, rather than having internal competition, which I think is still unfortunately prevalent because we haven't moved away from that on a national level, but I think we will have too inevitably.     I think practices will begin to understand the value of bringing everyone up to their full potential, both in terms of direct patient care and all of those indirect care functions that have to happen to make a practice successful. So, we'll get there, but it's going to take some time, and that lack of understanding presents a barrier. Along with that comes some of the legislation—Medicare rules. Some of those were expanded during COVID-19 because we needed to maximize access to care. We've really tried to negotiate and advocate for keeping those expanded access to care initiatives in place post-COVID-19, even though we're not post-COVID-19, unfortunately. So, I think things are shifting, but we have a ways to go and that lack of understanding and that internal competition still presents a problem.     Dr. John Sweetenham: Yeah. Just changing gears a little, I think clinical trials, as we would recognize, are really a core part of our mission not just as academic medical centers, but as community oncology centers as well and, of course, they're crucial to our advancing patient care. And there are a number of studies, and without going into too many numbers here, there are a number of studies that have looked at the role that advanced practice providers play in clinical research, and particularly in recruiting eligible patients to clinical research.     There was one relatively recent study published in the JADPRO which just last year, which looked at APPs and I think it surveyed a number of APPs at academic centers. And 70% of these APPs said that they approach eligible patients about clinical trials, but not on a regular basis, and it seemed as though most APPs felt that they have more to offer in the space of clinical trials. What do you see as opportunities there? Again, do you think there are barriers that are preventing APPs from making a really solid contributions to clinical trial treatments and accrual and what could we do to elevate the APP role?     Dr. Sandy Kurtin: Sure. So, that study (DOI: 10.6004/jadpro.2021.12.5.2), a colleague Crista Braun-Inglis and was a collaborative effort between ASCO and ACCC and APPSHO, the Advanced Practitioner Society of Hematology Oncology—I happen to be the current president and founding board member of that—really brings to light the sense of I think comfort, really, with clinical trials. There's been, luckily, this robust, scientific discovery, new drugs approved on a regular basis. And as a result of clinical trials, every therapy we have comes as a result of clinical trials, and this is crucial for patient participation.     But I think if the majority of the people in that study that participated were—65% of them were in a community practice setting where they really tend to practice more as generalists as opposed to specialists. So, keeping abreast of all of that knowledge across tumor types, solid tumors, liquid tumors, for standard of care and understanding all the evolving science is really a challenge. So, I think we need to do better at just basic understanding of how a clinical trial is run. I actually published a recent paper on this.     How do you actually run a clinical trial? What is your role as an APP in terms of understanding the phase of the trial? How to do your attestation of adverse events. And we haven't done, I think, a good enough job in preparing our workforce to feel comfortable in taking more of a lead in that role. So, we're working on that in within APPSHO and collaboratively along with ASCO and ACCC and other organizations to really bring that level of knowledge up across the team in general, and I think that's what it's going to take.     Dr. John Sweetenham: Do you think we should all be doing more to promote APP-initiated and APP-led clinical trials? In other words, there are many questions and some of our APPs are now beginning to ask these questions very specifically about the practice or about specific areas of clinical intervention where they're really beginning to take the lead now. And again, what do you think that we can do to help promote that component rather than being a part of the overall clinical trials effort in helping to accrue patients? What do you think we need to do in terms of fostering original research questions from our APP colleagues?     Dr. Sandy Kurtin: That's a fantastic question and something—I think we lose an opportunity—I've been in academics my entire career and so I have been involved in numerous clinical trials. I've been involved in trials that have brought new drugs to market, which is one of the most rewarding things, to me, that we can do is to bring that option forward.     But I think along that way, the group of these clinicians, these APPs that are involved in the conduct of clinical trials—I know for me—sometimes understand the actual clinical management of these patients better than anybody because we tend to see them for those symptom management visits and more frequently than perhaps attendings might be able to accommodate and we can offer this enhanced knowledge. So yes, there's a trial.     This is the drug. Here's the mechanism of action. Here's how this was structured. But how do you actually do it? Right? How do you actually take this new drug and integrate it into your practice in a way that emulates the clinical trial so that you can achieve the outcomes seen in that trial.     And I think that's where APPs have an opportunity to step up and take the lead and say, is there a second question or third or fourth or fifth question in this trial where we can really look at symptom management in a broader scope, or particularly for drugs that have unique symptoms. We've seen many of those in hematology, which is my area of expertise.     Keratopathy as an example, like, what is that and what does that mean and how do we do that. Or some of the other more recent immunotherapies, and really excel in creating standards for management of these adverse events. So, I think that's an area where we could really bring things forward. Our pharmacy colleagues, obviously, also offer a lot along the lines of drug-drug interactions and all of the things that come with their expertise.     Dr. John Sweetenham: Yeah. I think you make a really great point there because certainly in one of my previous institutions for sure which had a very large kidney cancer practice, when a lot of the new agents for kidney cancer emerged, the folks at our institution who had the most expertise in recognizing and treating those toxicities were our APPs that were working with the research team.     So, I completely agree that there's a ton of opportunity there and a lot of untapped resource for the oncology community as a whole. And just closing on that theme in a way, when you look ahead over the next 5 to 10 years, how do you see the future role of APPs in the oncology workforce and what are year overall thoughts about the future? Do you feel optimistic or cautious about APP practice moving forward?     Dr. Sandy Kurtin: I'm an optimist anyway because I've been doing this for a long time and you have to be an optimist, right? So, I think that if we emerge from this COVID-19 pandemic, which we will, and we can get back to focusing on what we do best, I think the future is very bright. I think that I have witnessed a transformation in the collaborative environment and the willingness to—and this is an example of that is just having the opportunity to have this conversation—bring everybody up, because when we're all at our best [when] we do our best work for patients.     And I think as we see more APPs seeking advanced degrees and actually taking the steps that are required, it doesn't just come with a degree. You know that. You have to earn that respect by working hard, demonstrating clinical excellence and expertise, and being invited in, if you will, as a colleague. And so, it isn't something that you just are given, you have to earn it. That's true for physicians as well.   But I think then we all become better, and I actually think the future looks very bright. The science, I say, is crazy good. This is fantastic. The opportunities to prolong patients' lives just continue to get better and better, but we need to get better and better in how [we] preserve all those future treatment options by not letting any adverse event get too bad, so it limits those options going forward. So, it takes finesse and that takes the team, and I think we'll get there. I'm actually very optimistic.     Dr. John Sweetenham: Well, thanks, Sandy. It's great to end on a positive note. And thanks once again for agreeing to come on to the podcast today and for sharing some really thoughtful insights into APP practice now and in the future. And thanks also for all the work that you do both at your local level and nationally to advance the role of APPs in oncology. It's certainly recognized and greatly appreciated.     Dr. Sandy Kurtin: Thank you so much for having me.     Dr. John Sweetenham: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate and review us wherever you get your podcasts.     Disclosures:   Dr. John Sweetenham:  Consulting or Advisory Role: EMA Wellness    Dr. Sandra Kurtin:  Consulting or Advisory Role: Incyte, Takeda, Abbvie/Genentech, BMS, Astra Zeneca, GSK    Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   

Guest host, Dr. John Sweetenham, associate director for Clinical Affairs at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, and Dr. Leticia Nogueira, a senior principal scientist in the Surveillance & Health Equity Science Department at the American Cancer Society, discuss the threat of climate change on cancer prevention and control efforts, and how oncologists can mitigate against the risks of climate change. Transcript:   Dr. John Sweetenham: Hello. I'm John Sweetenham, the associate director for Clinical Affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and guest host of the ASCO Daily News Podcast. Today, we'll be discussing the impact of climate change on cancer prevention and control efforts in the United States and beyond. Climate change has increased cancer risk through increased exposure to carcinogens after extreme weather events, such as hurricanes and wildfires.   In addition, these major events disrupt cancer treatment, which has, until recently, poorly defined effects on cancer outcome. Dr. Leticia Nogueira, a senior principal scientist in the Surveillance & Health Equity Science Department at the American Cancer Society joins us today to discuss the threat from climate change and the importance of disaster preparedness and mitigation efforts by cancer centers. Our full disclosures are available in the show notes, and disclosures relating to all episodes of the podcast can be found at asco.org/podcasts. Dr. Nogueira, it's great to have you on the podcast today.   Dr. Leticia Nogueira: Thank you. It's my pleasure to be here.   Dr. John Sweetenham: Dr. Nogueira, when Hurricane Maria struck Puerto Rico in 2018, it closed several factories that provided life-saving IV fluids to US hospitals, causing shortages in cancer centers nationwide. That's really just one example of how an extreme weather event can compromise health care delivery. How is climate change impacting cancer outcomes today?   Dr. Leticia Nogueira: Yes. Climate change is impacting not only the frequency, but also the behavior of extreme weather events, which makes it harder for communities and institutions to prepare and respond to these events. And disruptions in the supply chain, as we saw with Hurricane Maria, are just one example how extreme weather events can impact access to cancer care.   As we saw recently with the tornadoes in Kentucky and the winter storms in Texas, extreme weather events can also damage medical infrastructure. And because cancer diagnosis and treatment can lead to several physical, psychological, and socioeconomic consequences, individuals who have been diagnosed with cancer have increased sensitivity to the health threats of climate change.   Dr. John Sweetenham: Thanks. And you led a study, which was published in JAMA couple of years ago, that investigated whether hurricane disasters that occurred during the time that patients were receiving radiation therapy for non–small cell lung cancer were associated with the poorer outcome in that patient group. Could you comment on that study and, furthermore, maybe comment on whether you think that other modalities of treatment are also likely to be compromised by natural disasters?   Dr. Leticia Nogueira: Yes, of course. In that study, we chose to focus on radiation therapy because it needs to be given daily, and it's highly dependent on electricity, which is frequently disrupted during hurricanes. But really, any cancer treatment modality is vulnerable to disasters that lead to power outages, supply chain disruptions, or damaged medical infrastructure, and that includes surgery, chemotherapy, immunotherapy, any cancer treatment modality.   Dr. John Sweetenham: That's for sure. And I guess, also, I'm not sure whether you have any data specifically related to this, but I'd be interested to know if you have any information about the effects of these disasters on screening programs, for example, and the downstream consequences of that. That may be something that still requires study, but we'll be interested in your thoughts on that.   Dr. Leticia Nogueira: Yes. That is definitely something that still requires studies. We currently don't have any publications evaluating the impact of extreme weather events on access to screening, which is a crucial stage towards the cancer care continuum. So, it starts with cancer prevention. Then, there is cancer screening, diagnosis, treatment, and survivorship. And at all of those stages, individuals have to interact with the health care system. And all of those stages are vulnerable to extreme weather events.   Dr. John Sweetenham: Yeah. Yeah, I'm sure it's only a matter of time before folks really get into that because, in a way, there are parallels with the COVID-19 situation in terms of delayed screening and the potential effects of that. Some cancer centers have begun now to adapt to climate threats, and a good example of that might be by implementing plans for resilience to future flooding events.   And I think many of us will vividly remember Hurricane Harvey, which had pretty devastating effects on a number of health care systems and facilities in the Houston area, including, of course, [The University of Texas] MD Anderson Cancer Center. Do you have any thoughts on whether these efforts have been successful and whether you think they're sustainable? And what do you think, for cancer centers in particular, are the most important elements of an effective disaster preparedness plan?   Dr. Leticia Nogueira: Yes. [The Centers for Medicare & Medicaid Services] (CMS) requires that Medicaid- and Medicare-participating providers and suppliers develop emergency preparedness plans. However, it does not require these plans to be publicly available. So, we can't tell how many cancer treatment centers are compliant.   Because these emergency preparedness plans are not shared, we also can't evaluate if these efforts have been successful, if they are sustainable, or have a pool of lessons learned from previous efforts to be able to identify the most important elements of an effective disaster preparedness plan. So, unless CMS makes these emergency preparedness plans publicly available, we just won't know.   Dr. John Sweetenham: So, that's very interesting. So, if I understood you correctly, the disaster preparedness plans that health care institutions have are not publicly available. Is that correct? So, this isn't information which is readily available to researchers or anyone else who might have an interest?   Dr. Leticia Nogueira: Exactly, yes. And that does not allow us to evaluate how well these are working and let other institutions learn from emergency preparedness plans that have been successful.   Dr. John Sweetenham: Just carrying on that theme for one moment, are there any national benchmarks or standards that apply in that regard in terms of how those plans should look?   Dr. Leticia Nogueira: CMS has guidelines about what should be included in those plans. However, there are no available data or guidelines about how each one of those guideline items need to be addressed for the emergency preparedness plan to be considered compliant.   Dr. John Sweetenham: OK, interesting to know that. Just changing gear a little, one of the things that I have to confess I had not really thought about very much before I read your articles was the fact that the health care industry itself is a significant contributor to greenhouse gas emissions. And what do you think are the interventions that we, as cancer centers, could adopt to address some of the sources of greenhouse gas?   Dr. Leticia Nogueira: Absolutely. So, all we have to do is look at our mission statements to realize we should be focusing heavily on climate change mitigation efforts. As a recent New England Journal of Medicine publication on decarbonizing the health care system stated, "Nowhere are the effects of climate change manifesting more clearly than in human health." And if we look at the health co-benefits of climate change mitigating efforts, this really is a no-brainer. The same air pollutants that cause the greenhouse effect also cause lung cancer and other health conditions.   The health care system is the second most energy-intensive industry in the United States. Interventions aimed at improving energy efficiency and increasing use of environmentally responsible energy sources, ideally generated on site, cannot only reduce the environmental impact of cancer centers but also make them more resilient to power outages, which are becoming more frequent. Cancer centers can also switch to purchasing more environmentally responsible pharmaceuticals, medical devices, supplies, and even food. And, of course, they can reevaluate how much waste is generated and how the waste is processed.   Dr. John Sweetenham: Thanks. Again, just switching gears slightly, it is clear, I think, to anyone who watches these events unfold in the media that, almost inevitably, there are health equity implications associated with climate change. And I know, on that theme, that you have been looking at the disproportionate impact of climate change on communities targeted for marginalization. Can you tell us a little more about this work?   Dr. Leticia Nogueira: Yes, of course. Structural racism has concentrated in three conditions that determine vulnerability to climate change in communities that have been targeted for marginalization. These conditions are exposure, sensitivity to the health hazards of climate change, and decreased adaptive capacity. And our current project is looking at one extreme weather event at the intersection of all three, heat waves. As you probably know, government-sponsored racially discriminatory policies, such as redline, created a platform for systemic disinvestment in communities with large Black populations, leading to increased risk of exposure to climate hazards.   Today, we see that historically redlined neighborhoods are disproportionately exposed to intra-urban heat, what is called urban heat islands. So that's the first one, increased exposure. But these racially discriminatory policies also led to uneven resource distribution in these communities, including limited access to full-service grocery stores, green spaces, and a clustering of alcohol outlets and tobacco marketing, leading to increased risk of developing chronic health conditions, which make you more sensitive to the health threats associated with heat waves, similar to how the health consequences of cancer diagnosis and treatment makes patients with cancer more sensitive to the health threats of climate change. So that's the second one, increased sensitivity.   The last one is adaptive capacity. Material circumstances can restrict access to resources that are necessary to prepare, respond, and cope with climate hazards. Lack of properly insulated housing or access to air conditioning, for example, can limit the ability of individuals from communities targeted for marginalization to cope with heat waves. And individuals diagnosed with cancer are more likely to experience financial hardship. So, there's a parallel or an overlap here too.   So, in this project, we are looking at the impact of heat waves and survival of individuals who have been diagnosed with cancer in large metropolitan areas of the United States and especially how individuals from communities targeted for marginalization might be more vulnerable.   Dr. John Sweetenham: Yeah. On that note, as we wind up our discussion today, I mean, clearly, the solutions to the issues that you raise, these huge issues that you raise, are global, although we may begin with our own actions in the US, but also a long term—clearly, climate change—the fixes to climate change are very long term. But do you have thoughts on perhaps what we, in cancer centers in the US, could be doing right now as an initial step? You've mentioned disaster preparedness plans, and I take the point that that would be an important step forward, since it would incorporate reducing gas emissions and so on. But do you have any thoughts about what we should be doing immediately to begin to address this problem within our own centers and our own communities?   Dr. Leticia Nogueira: Yes, of course. So definitely emergency preparedness plans if you are in a health institution is a good first step. You can also look at the energy sources that are consumed by your institution and your house. Are those environmentally responsible? And the amount of waste that is generated both at your institutions and at your community and how that waste is processed because, frequently, the waste ends up being stored and processed near communities that have been targeted for marginalization, which increases their exposure to health hazards.   Another thing is to look at your purchasing processes at home and at your institution and how environmentally friendly the supply chain that leads to your consumer purchases might be impacting climate change.   Dr. John Sweetenham: Well, thank you, Dr. Nogueira, for sharing your insights on this very important local and global problem and highlighting many important interventions for us to consider. It's certainly given us a lot of food for thought. So, thank you for joining us today.   Dr. Leticia Nogueira: Thank you.   Dr. John Sweetenham: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate and review us wherever you get your podcasts.     Disclosures:   Dr. John Sweetenham  Consulting or Advisory Role: EMA Wellness    Dr. Leticia Nogueira: None disclosed.     Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.       

Guest host, Dr. Muhammad Shaalan Beg, director for Gastrointestinal Medical Oncology at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and Dr. Manisha Palta, radiation oncologist at the Duke University Health System in North Carolina and chair of the 2022 ASCO Gastrointestinal Cancers Symposium, discuss key advances in GI oncology featured at #GI22.   Transcript Dr. Shaalan Beg: I'm Shaalan Beg. I'm the director for GI Medical Oncology at UT Southwestern's Simmons Comprehensive Cancer Center. And I'm the guest host for the ASCO Daily News podcast. Today we'll be discussing key advances in GI oncology featured at the 2022 ASCO Gastrointestinal (GI) Cancers Symposium. And I'm delighted to welcome Dr. Manisha Palta, the chair of this year's GI meeting. Dr. Palta is an associate professor and radiation oncologist at Duke University Health in North Carolina. Dr. Palta, thank you for joining the podcast today. Dr. Manisha Palta: Thank you for having me. Dr. Shaalan Beg: Before we begin, I should mention that my guest and I have no conflicts of interest related to our topics today. Our disclosures are available in the show notes and the disclosures for all episodes of the podcast can be found in the show transcripts at www.asco.org/podcast. Manisha, congratulations on bringing together many diverse voices from across the country and internationally to showcase some incredible advances in GI cancer. It's been a big year. I felt that the GI space was falling behind in 2021, and it looks like we've made a lot of progress. Can you tell us about some of the practice changing studies that were featured this year? Dr. Manisha Palta: Yeah, absolutely. So, I definitely think the pandemic slowed things down from a research perspective, but this year we heard some really exciting data. And the sessions that I'd highlight in particular is the hepatobiliary pancreas oral abstracts. So, we heard a number of practice changing studies, one of which is Abstract 379, the HIMALAYA study. This was a phase 3 multi-center study looking at tremelimumab and durvalumab as first-line therapy in unresectable HCC, and was comparing that regimen to the standard of care, sorafenib. In addition to the data for HCC, also presented at this year's meeting in the oral session was Abstract 378, which was the TOPAZ-1 study looking at the systemic therapy regimen of gemcitabine and cisplatin with and without durvalumab as first-line therapy in patients with advanced biliary tract cancers. So, what we're starting to see here is the theme of immunotherapy being incorporated into first-line therapy through these abstracts that were presented. The other particularly interesting abstract in that oral session is a little bit different. Not so much systemic therapy related, but a little bit more focused on the integration of systemic therapy with local regional therapy. And that's Abstract 380, which is lenvatinib combined with TACE as first-line therapy for advanced HCC. And this was a phase 3 multi-center randomized control trial, looking at the incorporation of a local regional therapy with an approved standard systemic therapy as well. So those were the abstracts that I thought were particularly interesting and practice changing in the hepatobiliary pancreas sessions, or the pancreas and hepatobiliary day. However, I also think I would be remiss to not mention another abstract in the first day, the upper GI or esophageal gastric day. Also in the oral session, Abstract 238, which was a randomized control phase 3 trial evaluating 2 chemotherapy regimens and chemotherapy radiation in the neoadjuvant treatment of locally advanced esophagus cancer. And this is the JCOG 1109 NExT study. I think it's a really interesting area, a very exciting area of exactly how we should be managing these patients with localized esophageal gastric cancer. Whether that should be a systemic therapy approach, a chemotherapy radiation approach, or perhaps an integration of both. So those are definitely the key abstracts and practice changing data that were presented at this year's meeting. Dr. Shaalan Beg: Definitely an exciting last couple of years for liver tumors. We saw the approval of atezolizumab and bevacizumab for frontline HCC. There were some concerns about potential toxicities around bleeding and the need for screening endoscopy prior to starting systemic treatments. And one would like to think that the result of the HIMALAYA study, which are looking at combining 2 immune therapy agents together, would have a lower risk of bleeding and maybe a less burdensome way to start systemic treatment for our patients. And gone are the days when we only had one oral kinase inhibitor for our patients. So, very exciting. So, when you think about local regional treatments for GI cancers, a lot of the oral presentations and the key takeaways were around systemic treatment options. When you thinks about supportive treatment options, biomarkers, radiation, surgery, are there any abstracts that come to mind that you feel would be ready for prime time when we return to the clinic next week? Dr. Manisha Palta: So, I think we're starting to see a lot of interesting data emerging with immunotherapy being incorporated earlier into the treatment paradigm. So, what's happened over the last 5 years or so is we're starting to see the use of immunotherapy in the metastatic stage IV setting. And now we're seeing the incorporation and integration of immunotherapy earlier. And so, there's another abstract that was presented in the poster rock session for the esophageal gastric day, looking at the integration of immunotherapy into a chemotherapy radiation backbone for patients who have locally advanced esophagus cancer. And I think we're going to start to see more and more studies incorporating and integrating immunotherapy earlier in the treatment paradigm. So, that would be the thing to look forward to. Is it ready to take to clinic yet? Probably not. But we're on the brink of it I think being incorporated into standard practice. Dr. Shaalan Beg: Yeah, very well said. And talking about early incorporation of immune therapy for GI cancers, there was a study looking at neoadjuvant IPI+NIVO for MSI high gastric cancer, and they found a pathologic complete response rate of 59%. And at first pass we're like, well, MSI high immune therapy, we already knew that. But if you peel that away a little bit, we're talking about path CRs in people who have a biomarker responding to immune therapy. And I wonder if the next question's going to be whether they can be spared surgery for their gastric cancer. Dr. Manisha Palta: Absolutely. Especially when we're talking about surgeries that carry and portend really high rates of morbidity and impair quality of life. Dr. Shaalan Beg: I was interested by a cell-free DNA study from Columbia University, where they reported a very large cohort of GI cancers, think about 30,000 patients cell-free DNA, and found that they're able to identify MSI high microsatellite in stable cancers at a similar proportion as people can identify them with tumor testing. So, remember, these folks with MSI-high disease have very high response rates to immune therapy, like we're seeing in the gastric study. And there was always this concern with cell-free DNA on whether it's as good as tissue testing. And now, this wasn't a paired analysis of tissue and blood in each patient, but overall, they were able to find a similar proportion of MSI-high disease and the different GI cancers. The survival was comparable to what we would expect in that situation. So, I think it's an important next step for cell-free DNA and liquid biomarkers in GI cancer. Dr. Manisha Palta: Absolutely. And I think that just speaks to the theme of the meeting, which is accelerating access to precision care through innovation. So, if we're able to identify these really important biomarkers from blood, rather than having tissue, I think it just allows us to bring these cutting-edge technologies and therapies to patients. And in many cases, therapies that result in significantly less toxicity compared to standard systemic therapies in particular. Dr. Shaalan Beg: Absolutely. One of the highlights of the meeting in my opinion, are the wonderful education sessions and our keynote speakers that addressed health equity, advocacy, and even more in line with ASCO's team for this year. What are the key messages that you'd like to highlight before we wrap up the podcast today? Dr. Manisha Palta: Well, so we had two fantastic keynote speakers this year that were both intended to highlight aspects of the meeting's tagline, accelerating access to precision care through innovation. So, our first speaker, Dr. [K. Robin] Yabroff, spoke about the impact of the COVID-19 pandemic on equity in access to care. I think we often talk about disparities in care, disparities in outcome, but we don't often focus on access. And I think the pandemic has allowed us some opportunities to change how we practice medicine through things like telehealth. And I think these are long lasting effects that will have an impact on cancer care, even after the pandemic becomes less burdensome on our lives. The second keynote speaker was Dr. Theodore Goldstein. He talked about health care technology and how we can use precision care through innovation. What I liked about his talk is that he thinks about cancer and cancer treatment more like a software problem, given his background, and talks about the ways that we can use healthcare innovation to optimize cancer care for patients. So, one thing I'd like to highlight this year was the fact that we had a new educational feature of "episodes" of cancer care. And what we wanted to do this year is we wanted to highlight topics that permeated all of the GI cancers, regardless of site, from upper GI to lower GI. And the first session on Thursday was a series of talks that were focused on the emerging roles of ctDNA on GI cancers. But the second 2 days, Friday and Saturday, were case-based discussions. The first one focusing on broadening access to cancer drugs and the right trials for the right patients. And through case presentations, they talked about how drugs go through the FDA approval process, how sometimes there may be FDA approval and then a change in FDA approval based on additional data, what types of data we may need to actually implement certain new therapies into our standard of care regimens. And then the last session, which was really interesting to me, was the tailoring of systemic and local regional therapies in oligometastatic patients. So, I think this is a really interesting topic. I loved the fact that it was a case-based discussion with multiple panelists from different specialties, talking about the role of local regional therapies in particular, in the treatment of oligometastatic disease. Dr. Shaalan Beg: Definitely a really exciting time in GI oncology. Thank you Dr. Palta for sharing your insight with us today and thank you for your leadership. Dr. Manisha Palta: Thank you very much. Dr. Shaalan Beg: And thank you to our listeners for your time today. You'll find links to the abstracts discussed on this episode in the transcript. And finally, if you'd like to see what we're up to on the ASCO Daily News podcast, please take a moment to rate, review and subscribe whenever you get to your podcast. Thank you very much.   Disclosures: Dr. Shaalan Beg: Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (institution): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. Manisha Palta: Employment: Duke University Honoraria: Oakstone Consulting or Advisory Role: Syntactx and VoxelMetrix Research Funding (institution): Merck, Varian Medical Systems, Galera Therapeutics Patents, Royalties, Other Intellectual Property: Up to Date- Annual royalties for being a section author   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Guest host, Dr. John Sweetenham, associate director for Clinical Affairs at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center and Dr. Syed Abutalib, medical director of the Hematologic Malignancies and Stem Cell Transplant Program at the Cancer Treatment Centers of America in Zion, Illinois, discuss advances in CAR T-cell therapy in the management of lymphoma, the toxicities associated with CAR T, and emerging bispecific antibodies for the treatment of lymphomas.   Transcript Dr. John Sweetenham: Hello, and welcome to the ASCO Daily News podcast. I'm John Sweetenham, the associate director for Clinical Affairs at UT Southwestern Harold C. Simmons Comprehensive Cancer Center and guest host of the podcast. I'm delighted to welcome my friend, Dr. Syed Abutalib, the medical director of the Hematologic Malignancies and Stem Cell Transplant Program at the Cancer Treatment Centers of America in Zion, Illinois. He's also associate professor at the Rosalind Franklin University of Medicine and Science, and founder and co-editor of Advances in Cell and Gene Therapy. Today, we're going to be discussing some of the recent advances in the use of CAR T-cell therapy in the management of lymphoma. Our full disclosures are available in the show notes, and disclosures relating to all episodes of the podcast can be found in our transcripts at asco.org/podcasts. Syed, it's great to have you on the podcast today. Thanks for coming. Dr. Syed Abutalib: Thank you, John. It's my honor. Dr. Sweetenham: Syed, the emergence of CAR T-cell therapy is having a transformed impact on the treatment landscape for hematologic malignancies in general, and for lymphoma in particular, and I'd like to give our listeners a sense of where we're at with CAR T-cell lymphoma. Can you tell us a little about the FDA approved agents which are now being used for the management of patients with malignant lymphoma? Dr. Syed Abutalib:  Sure, so there are, at this time, about five agents that are approved based on mainly a phase 2 single arm study controlling them with the historical data from Scholar One in diffuse large B-cell lymphoma. They are axicabtagene ciloleucel. We'll be calling this axi-cel, which was approved after the data ZUMA-1 for the treatment of adult patients with relapsed/refractory diffuse large B-cell lymphoma after two or more lines of systemic therapy. In this group, there were diffuse large B-cell lymphoma NOS, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and transformed diffuse large B-cell lymphoma from follicular lymphoma. The next agent that was approved was--let's see if I can pronounce it. It's the most difficult name--tisagenlecleucel which is tisa-cel was based on the JULIET trial. This drug was approved again for the adult patients with a relapsed/refractory large B-cell lymphoma after two lines of systemic therapy for the same indications as patients in ZUMA-1 trial except tisa-cel is not approved for the primary mediastinal large B-cell lymphoma. The next agent is lisocabtagene maraleucel. We will call this liso-cel. This agent was approved after the pivotal trial TRANSCEND NHL 001. And the unique thing about this trial was also there were two patients with CNS lymphoma in this trial. And again, the indications were similar to the axi-cel indication. And the fourth indication is for axicaptagene lisoleucel based on the ZUMA-5 trial, which was FDA approved for adult patients with relapsed/refractory follicular lymphoma after two or more lines of systemic therapy. And the last agent that has been approved is based on the trial of ZUMA-2, which is brexucabtagene autoleucel, brexu-cel. And this is approved for adult patients with relapsed or refractory mantle cell lymphoma. Dr. John Sweetenham: Syed, thanks for providing that background. As you've shown, there are multiple agents which have been through early phase clinical trials. They've been applied to various subtypes of malignant lymphoma. And furthermore, they've been used at various stages in the treatment algorithm for these lymphomas, albeit mostly in the relapsed and refractory setting. We've all been waiting for some time to start to see data emerging from prospective randomized trials of CAR T-cell therapy versus standard of care. And of course, we were exposed to some of the early data from these randomized trials at the American Society of Hematology Annual Meeting in December. And overall, there was the suggestion of a possible benefit to CAR T-cell therapy. Could you tell us a little bit about the data that caught your attention and your insights into how to interpret those data? Dr. Syed Abutalib: Yeah, definitely. So as I alluded earlier, right now, the FDA approval is mainly for patients after two lines of therapy in diffuse large B-cell lymphoma. Now what is happening is that this CAR T-cell is trying to move forward into failure after first line of therapy. And in order to do that it is important that they have a comparative arm, which they tried to do in three trials by comparing it with so-called standard of care therapy. However, it must be noted that the standard of care therapy in diffuse large B-cell is not that straightforward for all patients who relapse. So just to give you the background, about 30% to 40% of the patients with diffuse large B-cell lymphoma experience relapse, and 10% are refractory to first line therapy. Now out of these patients, the standard of care therapy applies in real world practice as to the patients who are transplant eligible. For the remaining patients who are transplant ineligible, there is no standard of care therapy. And the list is very long if you look at the NCCN guidelines for those patients. And the patients who are transplant eligible; if 100 patients go to transplant, 50% are cured. And there is a very good track record for this. And the ones who are cured are mainly the ones who are sensitive to chemotherapy, mainly platinum-based chemotherapy. So what these trials that were presented at ASH, one has to understand that what they call standard of care in their comparative arm because what happens is that if you have a comparative arm that is weak, that is not transplant-eligible patients, or the patients don't go to transplant, then your trial would look much better than what it really is. So there were three trials that caught my attention. One is, of course, ZUMA-7, the axi-cel and the second one is the TRANSFORM trial with liso-cel. And the third one is the BELINDA trial, tisa-cel.  ZUMA-7 and BELINDA trial have been published in the New England Journal of Medicine already. So what is important to acknowledge here is that the patients in ZUMA-7 were refractory to frontline therapy. About 74% of those patients were refractory, meaning that they did not respond to [INAUDIBLE]. Now we don't know how bad the refractory disease was, and ideally, these patients, if they are transplant eligible, which most of the patients were, would have gone to auto transplant, and 50% of them historically would be cured and the other patients who are relapsed within 12 months to frontline therapy. Now in ZUMA-7, they assumed that these patients who are early relapse will not respond to standard of care transplant. They divided those patients to CAR-T versus transplant or non-transplant. The reason I say non-transplant, because only 36% of the patients who were on ZUMA-7 received what you call, ‘standard of care therapy,’ high dose chemotherapy with transplant. So I don't think it was a fair comparison to standard of care therapy. Now the other thing is the follow up is not too long as it is for the auto transplant. So it remains to be seen how things will evolve. In the TRANSFORM trial, which was with the liso-cel, the large cell lymphoma group were either primary refractory or relapsed within 12 months. Again, they assume that the patients who relapsed early will not respond to platinum-based therapy. Ideally, these patients should go for auto-transplant. In BELINDA trial, what is significant is that only 23% of the patients received auto transplant. And out of the three transplants, BELINDA trial was the only one which did not show improvement in median event-free survival compared to the standard of care. The hazard ratio was 1.01. So it's difficult to say that these trials are truly positive for CAR-T over auto transplant because they did not compare auto transplant in the CAR-T. They compared all patients with relapsed or refractory disease who could have gotten transplant also to CAR-T, favoring the experimental arm. Dr. John Sweetenham: Yeah, thanks Syed. So I think the take-home message that I'm hearing from you is that there are some interesting signals in these randomized studies about the potential efficacy of CAR-T. It's probably a little bit early to claim victory just yet, and we need to let these studies mature out a bit more and I guess ultimately wait for some overall survival endpoints. You're absolutely right that there is still some uncertainty surrounding the interpretation of these results and the long-term effectiveness of CAR T-cell therapy. One thing there's no doubt about is that CAR T-cell therapy is associated with significant toxicities, the most common being Cytokine Release Syndrome and Immune Effector Cell Associated Neurotoxicity Syndrome, or ICANS. But of course, the list of adverse events is much longer. We recognize late toxicities, including prolonged cytopenias. So right now, CAR T-cell therapy is mainly performed at larger tertiary care centers, but obviously, things are changing as regional facilities begin to do CAR T-cell therapies themselves. And even if they don't actually provide CAR T-cell therapy, a lot of physicians are going to be seeing their patients locally after they have developed toxicities from this treatment. How far have we come, do you think, in managing the toxicities of CAR-T, and how can we better manage those adverse events in our patients as we move forward and it becomes a more widespread intervention? Dr. Syed Abutalib: I believe we are getting better in managing these therapies, but of course, the CAR T-cell therapy is at its infancy, and we are learning. In any case, it is important to understand what are the main toxicities-- as you had mentioned, the CRS and the neurotoxicity and the chronic B-cell achalasia or hypogammaglobulinemia, which basically reflects the persistence of CAR T-cell therapy. So, in an effort to improve on recognition and treatment of these side effects, ASTCT, which is the American Society of Transplant and Cellular Therapy, had the workshop in 2018 in Washington DC, and they published a paper subsequently in trying to educate everybody about these toxicities. What is important in CRS is early recognition, and CRS is divided into different grades according to the ASTCT criteria from grade 1 to grade 4. Grade 1 is when you have fever. Many patients that we will admit or who we will treat who are very sick patients will get fever. One should not assume that it is CRS. We should always exclude the infection and start the appropriate antibiotics. And as a transplanter, we are very well-aware of how to tackle this or as treating hematologic malignancies with a lot of neutropenic fevers. So, if you have fever, appropriate workup should be done. Grade 2 ASTCT criteria is fever with hypotension that does not require pressors or hypoxia that requires low-flow nasal-cannula oxygen. Grade 3 is worsening of the hypotension, requiring pressors without vasopressin or hypoxia getting worse. And grade 4 is an extreme with multiple pressures requirement for hypertension and hypoxia requiring CPAP or BiPAP. So all this requires close monitoring and one should also recognize the risk factors prior to the admission of the patient or prior to giving the CAR-T. What are the risk factors for this CRS. The risk factors, which include our high pre-infusion tumor burden, so it is important sometimes to debulk the patient.  Early onset of fever, presence of underlying inflammatory process or presence of infection--these things will help manage the CRS. The other thing is the neurotoxicity. And similarly, there has been criteria developed for that too.  There’s an algorithm at our institution, we have developed a card that has this criteria and algorithm imprinted on it. So, there is an ICE criteria which basically checks for patient orientation. And you have certain questions about ability to name three objects, following commands, writing, and attention. You give them certain points. And then you have them go into the neurotoxicity domain and check the level of consciousness and/or their seizures or motor findings or elevated cerebral intracranial pressures. So based on that, you find out what is their neurotoxicity grade. Having said that, it is also important to have toci, which is IL-6 inhibitor, on hand. And according to the regulatory authorities, these drugs are approved under the REMS program. So you have to have at least two doses of tocilizumab in-house before you give any patient these drugs. So, to answer your question in a nutshell now is that close hemodynamic monitoring is very important, and it is important to have trained staff on board who can check on patients at regular, frequent intervals to recognize these toxicities early and intervene early to prevent morbidity and mortality. Dr. John Sweetenham: Yes, thanks. And I think it emphasizes the fact that the initial patient selection for CAR T-cell therapy is extremely important bearing in mind not just the patient's disease state but also age, performance status, co-morbidities, and so on in the same way, really, as with transplant. I want to change gears just for a moment. There is no doubt that cellular immunotherapies like CAR-T remain of limited availability in part because of cost and effectiveness barriers. And without getting into a long discussion about that, I wonder if you could comment a little bit on other emerging therapies that in time could potentially, if it's the right expression, challenge CAR T-cell. I'm thinking in particular about some of the bispecific T-cell engaging antibodies which are now coming online. Dr. Syed Abutalib: Sure. So the bispecific antibodies are basically protein constructs with a specificity to two different antigens. And they commonly bind immune effector cell antigens and tumor-specific antigens, creating what we call an immune synapse, which results in activation of the effector cells, which are T-cells, and cause direct cytotoxic activity. For example, we have an FDA-approved agent in ELL, and it's also listed in NCCN as an-- in transplant-ineligible patients, which is blinatumomab, which is a CD3 and CD19 construct. Now in the clinical trials, there are many bispecific antibodies that are in development. The benefit of this is manifold, in my opinion. They are off-the-shelf immunotherapy. They have strategies to mitigate CRS and neurotoxicities such as that they are given those adjustments with lower rates of doses early on and then the dose is escalated. And we see less CRS and neurotoxicity in patients. The third advantage is they might be preferable, especially in older adults.  I'm not sure if they are going to replace the auto transplant at this time. The other advantage is that there is data emerging that they are effective even after CAR T-cell therapy failures although the data is not mature yet. And still, we need them to be approved and see how they will be in the real world setting. So some of them I will talk about. The one that really caught my attention was mosunetuzumab, which is called mosun. The unique thing about this is that it's IV, and there is a step up dosing to mitigate the CRS and neurotoxicity as I mentioned.  And it is a time limited therapy. It's not that you have to keep going, and that is important because of the cost effectiveness of the therapy. And this is a CD3 and CD20 construct. It is being tested in the third line follicular lymphoma as monotherapy in combination of Revlimid. The important thing is that the CR grade 3 and grade 4, very few patients, 2 patients out of 90 in follicular lymphoma, and no grade 4, grade 5 events occurred whether with monotherapy in follicular lymphoma with a CR rate of about 58%. They are also being combined with polatuzumab, which is an anti-CD79 antibody and also in relapsed/refractory diffuse large B-cell lymphoma as a subcutaneous dose because of, again, further trying to mitigate the CRS with a slow release form. The other important biphasic antibody is glofitamab, which is being tested in relapsed/refractory follicular lymphoma, relapsed/refractory mantle cell lymphoma after BTKI, failures. And also, the data in more than 200 patients was presented in patients with diffuse large B-cell lymphoma, mantle cell lymphoma, transformed follicular lymphoma, Richter syndrome. So these two are very important to watch for. There are others, such as epcoritamab, which is also C3 and CD20 bispecific antibody, which is also in a phase III trial, what is the standard of care in relapsed/refractory diffuse large B-cell lymphoma, and is also being tested upfront with R-CHOP. So I think these three are important to watch out for, and in my opinion, which might be incorrect, these are, as I alluded earlier, are more convenient, less laborious, can be less CRS, and might have about similar-- might have similar activity as CAR-T, might win the game over CAR-T. But it's too early to say. It's just an opinion. Dr. John Sweetenham:  Thanks, Syed. And I think however this plays out, however, ultimately, these bispecific antibodies line up versus CAR T-cell therapy, I think two things are true for sure. The first of those is that patients with aggressive lymphomas and indolent lymphomas now have available to them a number of treatment options they didn't have before, which, of course, is great news. The second thing which is undoubtedly true is at least for a while, CAR-T therapy is with us to stay. Syed, it's been a pleasure having you on the podcast today and hearing your insights into how CAR T-cell therapy is evolving and its potential to improve patient outcomes in the future. Dr. Syed Abutalib: Thank you, John. Dr. John Sweetenham: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness   Dr. Syed Abutalib: None Disclosed   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Karim Fizazi, medical oncologist at Gustave Roussy and professor in Oncology at the University of Paris-Saclay in France, tells guest host, Neeraj Agarwal, editor-in-chief of ASCO Daily News and director of the Genitourinary Cancers Programs at the University of Utah’s Huntsman Cancer Institute, about the practice-changing PEACE-1 trial, an ongoing phase 3 trial among men diagnosed with de novo metastatic castration-sensitive prostate cancer.   Transcript: Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the director of Genitourinary Oncology Program and professor of medicine at the University of Utah Huntsman Cancer Institute and editor-in-chief of the ASCO Daily News. Our topic today is the practice-changing PEACE-1 trial, an ongoing phase 3 trial among men with de novo metastatic castration-sensitive prostate cancer.   Joining me today to discuss the results of this trial is Dr. Karim Fizazi, who is a world-renowned medical oncologist practicing at Gustave Roussy and a full professor in Oncology at the University of Paris-Saclay in Villejuif, France. Dr. Fizazi has led multiple practice-changing trials in advanced prostate cancer and is also the founder of the Prostate Cancer Consortium in Europe known as PEACE Consortium. Our full disclosures are available in the show notes, and disclosures related to all episodes of the podcast can be found on our transcripts at the asco.org podcasts. Welcome, Karim. It is so great to have you on the podcast today, and thank you so much for taking time to be with us.   Dr. Karim Fizazi: Thank you very much, Neeraj. It's a pleasure and an honor.   Dr. Neeraj Agarwal: You recently presented the primary results of the phase 3 PEACE-1 trial in men with de novo metastatic castration-sensitive prostate cancer in the ESMO 2021 meeting. Could you please tell us more about the design of this study and why you did this study?   Dr. Karim Fizazi: Sure, yes, happy to do so. So, PEACE-1 is a large academic European phase 3 trial, which is enrolling patients with de novo metastatic prostate cancer. And it is basically asking 2 questions. Number 1, should we add abiraterone acetate on top of standard of care for these men? And in most of them, standard of care consisted in androgen prevention therapy plus chemotherapy with docetaxel. So, this is the number 1 question—in other words, 3 drugs instead of just 2.   And the second question is whether we should use radiation therapy directed to the primary cancer in these men who are treated with intensive systemic treatments? And we're doing that because we already know the answer regarding the radiation question, and it's a yes answer for men who received androgen deprivation therapy (ADT) alone, but we don't really know whether this applies when intensified treatment is being used.   So, it's a 2x2 design, and we were able to enroll almost 1,200 men in the trial. We completed the inclusion in the trial back in 2018, so the patients or at least those who are alive are on follow-up. And this year, 2021, we have analyzed the co-primary endpoints of radiographic progression-free survival and overall survival for the abiraterone equation. In probably 1 or 2 years from now, we will be able to do the same thing regarding the radiation therapy equations when we have sufficient number of events for these patients.   Dr. Neeraj Agarwal: Very interesting trial design and massive effort at the multinational level in Europe. So please tell us about the results of the study and how it will affect the current treatment paradigm of our patients with de novo metastatic castration-sensitive prostate cancer.   Dr. Karim Fizazi: Sure. So, as I said, right now, we have data regarding the abiraterone question. And again, the question is whether we should use ADT plus docetaxel with or without abiraterone acetate and prednisone. At ASCO [Annual Meeting] this year, we reported the radiographic progression-free survival data, which is a co-primary endpoint of the trial, and this is clearly positive (Abstract 5000). If patients received 3 agents—ADT, docetaxel, and abiraterone—they will enjoy 4.5 years without radiographic progression or death in the experimental arm versus only 2 years in the control arm. So, in other words, this mean 2 and a half year of additional life without problems, if you will, without a significant progression or death for this patient, which is big.   I think many people were already convinced with this data and thought this could be practice changing. I remember our discussion, you and me, Neeraj, at this time. But some others were not necessarily convinced and request the overall survival data before making their decision. Or if it's possible to collect the events, and of course, in the COVID-19 times, this has been challenging. But I think we made it, and we were able to show the data for overall survival at ESMO this year in September. And of course, this was planned—pre-planned and dependent on a pre-planned number of events, which was reached. The news here is good again. And actually, patients receiving ADT plus docetaxel plus abiraterone clearly have an improvement significantly by overall survival as compared to those who received just 2 treatments. The reduction in the risk of death was approximately 25% for these patients receiving the triplet treatment, and it's even greater for men with what we call high-volume disease, so those with multiple bone metastases, at least 4, or visceral metastases, of course, men with a poor outcome. For these men, the reduction in the risk of death achieved by the triplet treatment was 28% in reduction of risk of death and was translated in a marked difference in medians, 3.5 years in the control arm with ADT plus docetaxel, and this was actually what we were expecting for this population of men, as compared to 5.1 years for patients receiving the triplet treatment. So, in other words, it's more than 1 and a half additional year of life for these men receiving 3 treatments up front.   I think what is very unique also in this trial is that men in the control arm were treated very aggressively when they progressed. And actually, more than 80% of them received at least one next-generation hormonal agents, and basically, 85% of them received at least 1 drug associated with proven life prolongation. Again, this is in marked contrast to what we saw in previous pharma industry-sponsored trial conducted in the past, where patients in the control arm were not necessarily very aggressively treated. This is clearly showing us that—   Dr. Neeraj Agarwal: Yeah. This is very interesting. I was really impressed by the fact that patients in control arm and as well as experimental arm—so basically patient on ADT plus docetaxel versus ADT plus docetaxel plus abiraterone—more than 80% patients were receiving subsequent life prolonging therapies, which is in marked contrast to other trials we have seen in the recent past. And despite that, you were able to show a remarkable, clinically meaningful improvement in overall survival with the triplet therapy. I think that is the most important message I got from the updated presentation in ESMO 2021. Would you agree?   Dr. Karim Fizazi: Absolutely. I think it's truly a demonstration that early intensification is better than use—a subsequent use of these agents when the cancer is already more heterogeneous, more aggressive, and harder to treat. We should intensify treatment up front. I think this is very important, especially those with predicted poor outcome.   Dr. Neeraj Agarwal: So, Karim, these data are obviously very impressive, in my view, practice changing. Many of my community oncology colleagues have asked me about the potential side effects of this combination versus chemotherapy with docetaxel or abiraterone therapy alone in addition to ADT. Any tips for our colleagues and friends out there in the community on how to manage side effects or what should we be looking for as a community? What should we be telling the patients and any tips on managing the side effects?   Dr. Karim Fizazi: Absolutely. I think this is a key question, and also, this was great news from the trial. We couldn't find basically synergistic toxicity between docetaxel and abiraterone in the trial. So, in other words, what we saw was the expected toxicity from docetaxel, and we expected toxicity from abiraterone, but nothing additional or nothing worse, if you will. For example, the neutropenic fever incidence was exactly the same in the two arms. The GI toxicity from docetaxel was not increased, and actually, it was even a bit less, numerically speaking at least.   And regarding the abiraterone toxicity, what we saw mainly was an excess in hypertension, usually of lower grade, and an excess in transaminase increase, which was actually rare, approximately 6% if I recall well, which is really in line with what you would expect with the general use of this agent. And of course, this is something you can monitor, and you should monitor. We know how to handle toxicity with abiraterone, and the same also applies to the hypertension management with this agent.   Dr. Neeraj Agarwal: Got it. So, say a patient is hesitant, and of course, this was not addressed by the clinical trial. But given compelling survival benefit, if I'm talking to a patient in the clinic tomorrow morning and the patient is hesitant to start all 3 drugs at the same time, do you think it would be reasonable to start chemotherapy with docetaxel, finish 4 to 6 cycles, and then start abiraterone? With the caveat that this was not addressed by the trial, but I'm just asking a very practical question.   Dr. Karim Fizazi: Again, this is a difficult question you're asking. And I'm saying that because, as you rightly said, in PEACE-1 we combined abiraterone with docetaxel. So, in other words, abiraterone was given concomitantly with docetaxel and then was continued when docetaxel was stopped. So, we don't really know whether giving abiraterone as a maintenance strategy, if you will, in your example, post docetaxel would be associated with the same benefit. It's probably reasonable to think it does, but it's not a given. So, my preference would be actually to combine up front, if possible, of course.   Dr. Neeraj Agarwal: Absolutely. And as I said, this was not tested or addressed by the trial. So final message is, as far as combination therapy is concerned, there is no synergy—there is synergy with the efficacy, but we are not seeing synergy, if you will, from the side effect perspective. And if we are deciding to start triplet therapy, we should be starting all drugs at the same time. At least docetaxel and abiraterone should be started together and not sequenced. Any final message for our friends and colleagues in the community by you, Karim?   Dr. Karim Fizazi: Well, maybe just 1 or 2 final messages. The 1 is a hurrah message because I'm happy, of course, with the data. And just to put this into perspective, back in 2015, before we had all of the recent trials in M1 castration-sensitive disease, men with high-volume disease had approximately 3 years of life expectancy. And now just 5 or 6 years afterwards, thanks to all clinical research we conducted during this time frame, in PEACE-1, these patients can live more than 5 years, which I think is remarkable.   I think the second and last message is that we should soon have more data for these men regarding the triplet combination with ADT, docetaxel, and a next-generation hormonal agent. Specifically, the ARASENS trial (NCT02799602), which is testing darolutamide randomly in this setting, is to release its data probably very soon. And the same applies to the enzalutamide trial with ENZAMET, which should be updated specifically for these men receiving the triplet treatment. So, we should see even more data than what I was fortunate enough to report this year with PEACE-1.   Dr. Neeraj Agarwal: Thank you. So, thank you, Karim, again, for sharing these exciting data from the PEACE-1 trial. Congratulations for conducting this massive trial and coming out with such great news for our patients. I wish you all the best.   Dr. Karim Fizazi: Thank you very much, Neeraj. It was a pleasure. Thank you so much.   Dr. Neeraj Agarwal: And thank you to our listeners for your time today. If you enjoyed this podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much.   Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Foundation Medicine, Gilead Sciences Research Funding (inst.): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas   Dr. Karim Fizazi: Honoraria (inst.): Janssen, Sanofi, Astellas Pharma, Bayer Consulting or Advisory Role (inst.): Janssen Oncology, Astellas Pharma, Sanofi, AstraZeneca, ESSA, Amgen, Bristol-Myers Squibb, Clovis Oncology Consulting or Advisory Role: Curevac, Orion Pharma GmbH, Bayer Travel, Accommodations, Expenses: Janssen, MSD   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests’ statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Guest host, Dr. John Sweetenham, associate director for Clinical Affairs at the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, and Dr. Derek Raghavan, President of the Levine Cancer Center at Atrium Health in North Carolina, discuss some of the major issues ahead for the oncology community in 2022, including tension caused by the COVID-19 pandemic, achieving true equity of care, how to use molecular testing in an optimized fashion, and the future of the oncology workforce. Transcript  Dr. John Sweetenham: Hello, and welcome to ASCO Daily News podcast. I'm John Sweetenham, the associate director for Clinical Affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and guest host of the podcast. Today, we'll be discussing the challenges ahead for the oncology community in 2022 with Dr. Derek Raghavan, President of the Levine Cancer Institute at Atrium Health in North Carolina. Our full disclosures are available in the show notes, and disclosures relating to all episodes of the podcast can be found on our transcripts at asco.org/podcasts. Derek, always a pleasure to have you here, and great to have you back on the podcast again.   Dr. Derek Raghavan: Hey, John. Always enjoy chatting together.   Dr. John Sweetenham: Derek, we're interested today to get your insights into what you think are going to be the major challenges facing the oncology community in 2022. I think each of us could come up with a pretty substantial list, but very interested to hear what you think are going to be those issues which are going to be uppermost in our mind as we move into the new year.   Dr. Derek Raghavan: Well, I think there are a number of important issues, John. I think everybody in clinical practice, medical or nursing, or whatever, have been brutalized somewhat by the COVID-19 pandemic, and I think everyone's tired and a bit cranky, and they're upset with a schism between the fringe and the science-based clinicians. So, I think that underscores everything. And there's an anxiety and a tension that I think is just new.   From the practical standpoint, which is where I think your question is directed, yeah, I think there will be issues that relate to achieving true equity of care. And I think hopefully, the focus will move from analysis paralysis to actually doing things and measuring outcomes. I think there will be the tension between value, price, and cost. People are spending an awful lot of money on health care. That's going to be an issue.   We have very good information on molecular prognostication, but a lot of the data that are coming out are from technologies that are not fully validated and not even standardized. There's a lot of disinformation and misinformation coming out, and I think we're going to have to address that. I think those are 3 themes that could keep us talking for quite a while.   I think the other thing, which is more up your alley than mine, is we've been watching CAR T[-cell therapy] emerge. I think we've got a beginnings of a pretty good handle on how CAR T[-cell] relates to hematological malignancy. It's much less clear in the solid tumors, and there is a bit of a tendency to do what used to happen in the 1970s and '80s, which is here's a new treatment. Let's give it a whack and see what happens.   But this is very expensive. We don't want to fall into the trap of how bone marrow transplant was introduced as a standard of breast care management for nearly a decade, based on somewhat flimsy evidence. So, we need to be a little more thoughtful about how we introduce CAR T[-cells] into the solid tumors.   Dr. John Sweetenham: Thanks. Yeah, plenty to discuss there, as you say. And what I'd like to do just because it is such a topical issue and continues to be at the moment is just pick up a little on the COVID-19 theme. I think that we've all seen a great deal of discussion in recent months about many of the consequences of COVID-19, including delayed screenings, late diagnosis, clinician burnout, and so on. But I'm interested in your insights on a couple of things.   Number 1, since we're now seeing the emergence of further new variants, what do you think that this is going to mean for the oncology community in terms of handling these new variants within the context of our patients with cancer? And then secondly, because I'm intrigued by one of the things you mentioned in our discussions about this podcast, you mentioned the changed relationship between health professionals and parts of the community as a consequence of COVID-19. And interested to hear you expand just a little bit on that. So, kind of 2 questions wrapped up in 1 there.   Dr. Derek Raghavan: Yeah. Well, I think the 2 are connected. The old style of physicians has always liked to be sure of their ground and to have a firm database when they talk about things. Particularly with the new variants, while it's completely appropriate to be transparent about the fact that they knew that they seemed different and so on, I think there is the problem that there are a lot of physicians who are now becoming TV personalities as much as physicians and who are talking all the time.   I'm not critical of that, but the problem is that they're being honest in saying we don't really know this, but this is what I think, and then they have to change direction. So, what's happening is, for the first time in a long time, physicians are regularly being quoted and being seen as saying things that are not necessarily correct, and that reduces confidence by the community and the physicians. At the same time, COVID-19, in my view, highly, inappropriately became a political football.   You have people who have absolutely no training, so radio hosts, football quarterbacks, basketball stars making extraordinary statements about COVID-19 and their approach to vaccination, masking, and other things where they have absolutely no business doing it. But they are people who are believed. They're high profile. And so, there's now a schism emerging between patients who listen to people who have no medical training at all and no basis for what they say and those particularly in the political domain who have politicized this and created a situation where, once upon a time, a physician was at least seen as coming from the right place and with good intent.   But we've both seen so many of these public demonstrations where physicians and public health physicians are being castigated for simply espousing good practice. Now, with respect to managing the variants, I think the fact is we have some basic principles that I have believed now for 2 years. Masks reduce the chance of getting any type of COVID-19. They just do. If you wear a mask most of the time when you're out and about, you're going to cut your chances down. Vaccination reduces the chance of ending up in the ICU unless you have some sort of immunological deficit.   Dr. John Sweetenham: Yeah. I'm going to switch gears now and return to the first thing that you mentioned right up front, which is the issue of equity and how we are going to address equity issues in the coming year. I think that in many ways, 2020, going into 2021, has been 2 years where issues of equity in health care have really come to the fore. And of course, there's been a great deal of discussion around this.   And I think you'd agree with me that we've seen, at the same time, that some of the strategies that we have been using during the COVID-19 pandemic, including telehealth, which one would have hoped would be a great equalizer, actually has the potential to exacerbate some of the disparities that we've been seeing in health care. But you mentioned analysis paralysis, and just to pick up on that theme, despite the huge amount of coverage that equity has received in medical journals and the media, where do you think we actually are in finally truly addressing some of the cancer care disparities that we see?   Dr. Derek Raghavan: Well, I think, John, you know that I was one of the early chairs of the ASCO Task Force. Otis Brawley and I chaired that task force together. Very early in the piece, I'm going to say probably 15 years ago, we wrote really quite a strong position paper on this whole issue. And so, we got started early in doing stuff on what we thought would be important, and we did, with support from the Komen Foundation, was to start training people of color in the oncology space and keeping them working in underserved communities by paying off their college loans for the period of time that they did that.   So, people have been doing stuff for a while. I think what's happened in the last decade, and it has been a slow change, is that there's been more a move to saying, let's get started. So, if you look at Chris Lathan up at Harvard, at one of their underserved hospitals, if you look around the country, consider the Bristol Myers Squibb Foundation, which puts money into active projects that are about doing stuff rather than having meetings to consider doing stuff. I think there's been that swing.   Dr. John Sweetenham: When we think about equity and disparities of care, we're often drawn towards the cost of cancer care and how much that plays into disparities and inequity in the delivery of cancer care. And picking up on that theme that you mentioned around value, cost and price, and maybe we could think about linking that with the use of CAR T-cell therapy and the application of CAR T-cells in the solid tumor world, if that is going to happen, what do you think we can do during 2022 to confront some of the cost and price issues that we're seeing within our cancer care environment right now?   Dr. Derek Raghavan: Well, I sometimes think in a utopian fashion, which doesn't get me very far, I have to say. What I'd love to see in the United States, because we spend far more money on everything health-wise than any other country in the civilized or uncivilized world, but what I'd like to see is a bipartisan initiative run by people who actually understand health care and health care economics that would go to the issue of, how do you get better bang for your buck? And it would include doing some tough things.   We waste money outrageously. We'll treat third-line metastatic pancreas cancer off trial. Nothing works in third-line metastatic pancreas cancer off trial. It's worth maybe a clinical trial to help the next person in line. That's how we make progress. But just to keep giving the same old litany of drugs in the hope that it might work is a waste of money. As I talked about before, BMT for breast cancer turned out to be a huge waste of money over a long period of time. So, if you can actually create a scenario where government set some rules and took the courageous, and this why it would have to be bipartisan, it would actually start to rationalize health care.   You know, John, the Oregon experiment many years ago, where one party started to rationalize care, and the other party accused them of rationing care. I mean, you can't have that happen. We've also seen both sides allocate the task of developing health care algorithms to people who are great politicians but know nothing about health care or economics. So, I mean, there are easy ways to do it. What we can do ourselves is be honest. Tell people what bang they'll get for their buck.   The person who is likely to have, say, an 80% chance of being dead within 4 months may not wish to mortgage his house if he's told that. On the other hand, he might well want to mortgage his house if he thinks that a very expensive treatment will give him the chance of being alive in 5 years. So, we, as physicians, shouldn't make that decision. It's the patient's right to be able to choose life versus the life of their offspring and spouse and future generations. So, I think it's not that complex, and I think if we brought more transparency about good expectations versus poor expectations, gave a better reason for patients getting more involved in trials, we're still at less than 15% of patients with cancer in the USA getting involved in trials, and that's a tragedy.   Dr. John Sweetenham: Yeah, I think also, the other thing that's occurred to me in this context, is the fact that while we tend to hone in on costs of treatment when we get into these discussions, I've been seeing some emerging literature around the cost of follow-up and unnecessary follow-up and imaging and so on in those patients who are in survivorship part of their cancer journey. And there's a huge opportunity there, I think, for us to reduce costs of care with no impact whatsoever on survival, no difficult treatment decisions to be made because we're simply doing an enormous amount of unnecessary testing in these patients who have completed treatment that we know doesn't impact survival. So, I do think that we could take a really serious look at that and make very significant savings. So, I think there's lots of potential there too.   Dr. Derek Raghavan: Yes. I agree, John. And I'd actually give kudos to ASCO in this space because they were early adopters of the Choosing Wisely campaign. They wrote two sets of guidelines about stupid things that we do that make no difference. And to be honest, I think that--I was on that committee, and the committee got tired.   I was one of the few people that actually felt we should keep going and very actively keep issuing guidelines of things that just aren't worth doing and having symposia at the ASCO ASM say that the symposia that are entitled “How to Waste Money” or alternatively entitled “How to Stop Doing Dumb Stuff” would be really quite important. And it would give the basis for sensible medicine to people who do medical legal protection work. So, most people who do multiple PET scans on lymphoma where the patient is completely well and blah, blah, blah are doing it for medical-legal reasons. They're not doing it because they think it will make a huge difference.   And I, of course, am not talking about the people where they're following PET scans as markers of response. So, I think we can do this work. I'd love to see a presidential campaign which is about not doing dumb stuff and where ASCO takes the bully pulpit and says, “we're spending a year policing ourselves, talking about all the things we do that don't actually make things better for patients.”   Dr. John Sweetenham: So, let's extend this theme of expensive therapies. And you mentioned CAR T-cell therapy. And in the hematologic malignancy world, we're now just beginning to see 1 or 2 results, which will be presented at the American Society of Hematology meeting in a couple of weeks from now, positive results from a couple of randomized clinical trials in hematologic malignancy with CAR T-cell therapy. So, what are your thoughts on the application of this treatment in the solid tumor world, and where do you think we are, what do you think we might see during 2022?   Dr. Derek Raghavan: Well, let's talk strategy first. I think a good place to begin is with a good scientific hypothesis. So, we both know how CAR T[-cells] work. We don't have to have a long discussion here about them. It would be patronizing to the audience. But you might think about, what solid tumor is actually going to benefit from immunological manipulation? Where have the checkpoint inhibitors been helpful, and where have they not been helpful? And so, you might focus the initial part of CAR T[-cells] and solid tumor work on those where there's a hypothesis that makes sense.   Then the second thing you could do would be to actually come to the companies that make all their money from CAR T[-cells] and say, perhaps you could invest in this research with us, and we'll do a couple of Hail Mary passes. So, let's look at the tumors where there isn't a good hypothesis, but nothing works, and see if we can get an experience. So, that'd be a nice, simple, easy way to do it. And then measure tight outcomes, have very robust entry criteria so you don't get confused about various toxicities because you're actually starting with patients in reasonable shape and then expanding to all populations.   So, the first part would be phase 1 and 2. Then you, early in the piece, make sure that you have inclusiveness so that you know all the population groups that might benefit from the treatment. I think that'd be a reasonable way to go.   Dr. John Sweetenham: Talking about identifying targets appropriately and target populations for treatment, you had mentioned as one of your other challenges for 2022 the concept around identifying molecular subgroups and molecular prognostication as a way of patient selection. So, could you say a little bit more about that and what you think we're going to need to do in the coming year in terms of refinement of targets?   Dr. Derek Raghavan: Well, John, this is an area of your expertise as well, coming from the hematological malignancy world. Now, I hope we would both agree that having robust reproducible technology is important. The fact that there are so many molecular diagnostic companies that hype their product doesn't necessarily mean that the product is good. So, there needs to be standardization of approaches to using technology, to measuring outcomes.   We need to have comparative sets of data, looking at different technologies to see how they work, and those sorts of studies need to be funded by government because there's no particular reason for the companies to agree to perhaps show that their diagnostic technology is not as good as somebody else's. But this would be a good initiative for the government to actually start to rank order of the products that are out there. I, frankly, think when you think of the impact of all of these molecular diagnostic tests, I've never understood why so many of them are out there without tight U.S. Food and Drug Administration (FDA) regulation. So, I think that's a place to begin.   If you think back to the old breast cancer days when there was immunohistochemistry and a bunch of molecular technologies, the outcomes were so varied when compared on common tumor samples. So, we just seem to be quite comfortable to make the same set of mistakes again. I do think there are responsible investigators doing excellent work in the space, so I'm not critical of the space. I'm answering the question, which is we need now to bring some regulation in to ensure that the quality of the work, reproducibility of the work. You'll even see, and I know you and I have talked about this in the past, there'll be Mr. X who has prostate cancer and gets his PSA measured, which is Prostate-Specific Antigen, looking at how active the cancer is regularly in different labs. That makes absolutely no sense. There's no common standard. PSA in my lab is going to be different from PSA in your's. And so there just should be some nice, simple rules of how to use molecular testing in an optimized fashion.   Dr. John Sweetenham: Yeah, and I wonder also whether we need to be looking a little bit more closely at point of care clinical decision support for some oncologists who may not be as molecularly literate as others because I do think that's another real challenge at the moment is giving guidance to everyone who might see these patients in terms of treatment selection.   Dr. Derek Raghavan: Well, I agree with you completely. I mean, kudos to the major companies because most of them provide pretty good decision support. One with which we worked tended to be a little too positive about its product, and we worked to change that. And now they're actually very useful. We have a big series from our molecular tumor board here that runs over I think a 5-year period that Carol Farhangfar, PhD, has just submitted for publication, which shows that you can heavily influence people who are out in the community by providing centralized support for their use of molecular diagnostic tests. But again, we only deal with the major companies so that we think there's good quality control there. And we don't flip back and forth in an individual patient between one company and another.   Dr. John Sweetenham: Right. Well, I think we're almost out of time, Derek, but I did want to ask you one more question, and it's a real change of gear. But over the last year or so, I think that probably largely because of the COVID-19 pandemic, we have seen some exacerbation of workforce issues in the oncology workforce that we knew already existed. I think there is undoubtedly more burnout being reported than there was before. Certainly, within our own organization, we have seen some increased staff turnover and a number of people who I think, frankly, have realized that they want to move closer to their families.   And so, there's been a certain amount of churn, which I think many of us in cancer centers are experiencing. Interested to know whether you've seen anything similar and what strategies you're using in terms of staff retention and oncology clinician burnout at your center.   Dr. Derek Raghavan: I think this is a difficult problem. The morale at the Levine Cancer Institute, much like the Simmons Cancer Center, is high, and that's driven by the leadership cadre being out there with their troops, visible and actively engaged so that the troops on the line feel that the bosses are part of the deal. And we do silly little things that matter, which is parties and celebrations and thank yous and all that sort of stuff. We get the staff to thank each other. We encourage the patients to thank the staff just with an attaboy or something that just says we appreciate the care.   So, I think this is a challenge. I do think work-life balance in old geezers like you and me has been a slightly different thing from some of the younger physicians who are spending, I think sensibly, more time with their families and don't want to spend these long hours. I think the other thing is there is still a town-gown issue where there are people who can make a lot more money much more quickly in some parts of non-academic practice, and it's getting harder to publish in academic practice, so the rewards for that are slipping a little.   I actually don't really have a solution. I think that the august colleges drawing to the attention of the world that this is a big deal and engaging bipartisan support from the political machinery will be important. I think ASCO can, through its government relations people (ASCO Advocacy), continue to prosecute these issues, which they do. I think there is the mistake that we make in the cancer space is we do still tend to compete between societies.   I've always thought it would be much healthier to have ASCO, ASTRO, ACS, SUO, SSO and all those people having a common council that speaks on this sort of issue with one voice and draws to attention of the people out there that this is a big issue. The best of the doctors (docs) are getting older. The younger docs come through the Taylor laws are less experienced and less well-trained and have a different ethos. So, we're going to lose an aspect of practice that's been part of the tradition of medical practice since the time of Osler, and it's definitely going away.   I have a superb physician fellow working with me at the moment who I would rate as one of the best 3 in 10 years. The reason she's one of the best 3 in 10 years is she practices the style of medicine that my fellows did 25, 30 years ago, most of whom are now professors of medicine somewhere. And good with patients, knows her staff, does research, and somehow manages to have reasonable time for a family. That tradition is starting to go away, and I don't think there is a simple change. And then the final point, the people who run health care today see it as a business. I was in a meeting recently outside my own domain where someone said, you know, I have to figure out whether medicine is really importantly a health care business or whether it's an IT business focused on health care. And that's going to start to lose the human side of medicine. We spent some time on that today. The outcomes will go down if this is just a business.   Dr. John Sweetenham: Well, thanks, Derek. Really appreciate all of your insights today. I think there's no doubt that 2022 is going to be a year of many challenges for those of us in the oncology community and for our patients, but I think it's also inevitably going to be a very exciting year in terms of new developments.   And hopefully, if we're recording another podcast like this in a year from now, the COVID-19 pandemic will be a little bit more in the rearview mirror, and we will be able to focus on many of the other important issues that face us. So again, really appreciate your sharing your insights with us, and wish you all the best for 2022.   Dr. Derek Raghavan: John, always a pleasure chatting, and the same to you and Caroline and the family.   Dr. John Sweetenham: Thank you. And thanks to our listeners for your time today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness   Dr. Derek Raghavan: Consulting or Advisory Role: Gerson Lehrman Group, Caris Life Sciences   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on the podcast do not express the opinions of ASCO.  The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Guest host, Dr. Neeraj Agarwal, ASCO Daily News editor-in-chief and director of the Genitourinary Cancers Program at the University of Utah’s Huntsman Cancer Institute, discusses the practice-changing KEYNOTE-564 and SWOG 1500 trials with Drs. Toni Choueiri and Sumanta "Monty" Pal. Dr. Choueiri is director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute and Dr. Pal is co-director of City of Hope’s Kidney Cancer Program and associate editor of Cancer.Net. (This episode was recorded on 11/18/2021) Transcript Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News podcast. I am Dr. Neeraj Agarwal, the director of the Genitourinary Oncology Program, and the professor of Medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I'm delighted to welcome two internationally recognized leaders in the field, Dr. Toni Choueiri and Dr. Sumanta (Monty) Pal, for a discussion about two practice-changing studies in kidney cancer published this year-- KEYNOTE-564 and SWOG 1500. As a quick introduction, Dr. Choueiri is the director of Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute. He's also the Jerome and Nancy Kohlberg Chair, and professor of medicine at the Harvard Medical School. Dr. Sumanta "Monty" Pal is a professor in oncology, and co-director of City of Hope's Kidney Cancer Program, and he is an associate editor of cancer.net of ASCO. Our full disclosures are available in the show notes. And disclosures relating to all episodes of podcasts can be found on our transcripts at ASCO.org/podcast. Toni and Monty, what a day it has been for our patients with kidney cancer. I woke up with the news of the U.S. Food and Drug Administration (FDA) approval of the first ever adjuvant immunotherapy for patients with renal cell carcinoma. It is so great to have you both on the podcast today.   Dr. Monty Pal: Glad to be here. Thanks, Neeraj.   Dr. Toni Choueiri: Thank you, Neeraj. So glad to be here.   Dr. Neeraj Agarwal: So, let me start by asking questions to you first, Toni. So, you recently published the primary results of the phase 3 KEYNOTE-564 study, showing the efficacy of adjuvant therapy with pembrolizumab and immune checkpoint inhibitor in patients with renal cell carcinoma. And this study led to the approval of pembrolizumab this morning. So, please tell us more about the study design and why did you do this study.   Dr. Toni Choueiri: Thank you, Neeraj. And thank you, really, ASCO for this wonderful podcast series. And a big hit, I always listen to them when I'm driving or jogging. And really, thanks for this opportunity because kidney cancer adjuvant therapy has been something like a holy grail we're trying to find for a long, long time. The first adjuvant trial, a randomized trial, in renal cell cancer was in 1973 with radiation therapy. And since that time, all the trials except for one have been a complete failure in a way. And the first adjuvant immunotherapy trial was with old immunotherapy cytokine that we don't use much anymore and was in 1992. I was not done with medical school. I was not actually done with high school at that time, let alone medical school. And now that we have, as we all know, a revolution in the oncology field through these immune checkpoint inhibitors that reinvented immunotherapy in cancer, and now that pembrolizumab has shown activity in patients with more advanced disease, we thought about taking this into the adjuvant setting, a setting of patients where they were subjected to surgery. But on the pathology report, we knew that their risk of this cancer coming back, of recurrence, is somewhat intermediate high or high. These are patients that have stage 2 but grade 4, stage 3, D3, D4. These are patients that had node-positive resected. And we took even patients where the kidney is out, but, also, they had a removal of a metastatic site--let's say a lung metastasis--within a year of removing the kidney. And we know these patients we refer to as M1NED are at quite high risk of recurrence. And we randomly assigned 994 patients to receive pembrolizumab for a year versus placebo. And after a median follow-up of only 2 years--so I want to insist here that this is short for any trial in general--we saw a decrease in the risk of recurrence or death. The hazard ratio for disease-free survival was 0.68. So, a 32% decrease in the risk of recurrence or death. We looked at safety, and we already are familiar in the field of GU oncology with pembrolizumab. And we didn't see when we looked at the safety profile any surprises, any enhanced toxicity. Of course, immune-related adverse events are the number one concern with pembrolizumab. There were no deaths on trial related to pembrolizumab. We saw around 7% of patients needing high dose steroid to medicate these immune-related adverse event, and some patients had to come off therapy for that. We also took a look, Neeraj, an early look, at overall survival. We only had 25% of events, 51 deaths. And we did not meet the very rigorous statistical significance that is needed to say that study is positive for overall survival. But the hazard ratio was 0.54, a 46% decrease in the risk of death, which is kind of encouraging. And after a year, the curve starts to separate. Before a year, they're not separating. And that is consistent with prior studies in general.   Dr. Neeraj Agarwal: This is a very interesting point you just raised, that DFS, disease-free survival, is strongly positive. And even overall survival is trending in the right direction, right?   Dr. Toni Choueiri: Correct.   Dr. Neeraj Agarwal: That's great. So obviously, I would like to raise another point here. When we talk about adjuvant study, we usually think about a localized kidney cancer, which is removed by the surgeon, and then [the] patient is coming to see us for treatment in adjuvant setting. But this study, I would like to highlight, as you said, also included patients who had oligometastatic disease, had successful surgical removal of the oligometastatic disease, and they were also eligible for this trial.   Dr. Toni Choueiri: Yes, absolutely. And I think this is somewhat on the recent side in clinical trials in kidney cancer. The reason for that is that, in practice, we see those patients. And we even had two small trials in the TKI era with sorafenib and pazopanib, small studies, were also completely negative. So, we thought here that we should not exclude these patients. They end up being 6%, 7% of all participants, but this remains an area of unmet medical need.   Dr. Neeraj Agarwal: So, how is the hazard ratio in those patients who had metastatic disease removed and then treated with pembrolizumab?   Dr. Toni Choueiri: Yeah, it was very low. It was 0.2, so 0.29. And this was great to see. I don't want to go into really over-interpreting these results. All the hazard ratio--when you look at subgroup analysis or in the forest plot, all the hazard ratio are less than 1. We didn't see something--let's say 1.5--in favor of pembrolizumab. Now you go into a smaller subgroup, then your confidence intervals are very large and hard to interpret, except that to say, look, on average there could be a significant benefit here, but we can't tell.   Dr. Neeraj Agarwal: Sure, absolutely. I agree with you. So, how this is going to affect the current treatment paradigm, which is for patients with newly diagnosed metastatic RCC, where combination of VEGF-TKI plus immunotherapies (IOs) or IO/IO combinations have become standard of care or treatment paradigm?   Dr. Toni Choueiri: I do believe it will be a standard of care currently in the right population. There are a lot of unanswered questions, but that will be answered hopefully with more follow up. We have already, beside these results, reported--so these results were reported in the plenary session at the 2021 ASCO [Annual Meeting]. But later on, another analysis dealing with patient-reported outcome and quality of life was reported at ESMO and also showed no detriment in quality of life--that's the voice of the patient--no detriment with pembrolizumab (pembro). There is a lot still to do and a lot of unanswered questions, such as the non-clear cell histology, those patients who had surgery of their metastatic disease more than a year. But most important, I think, two questions. One, how can you know from the get-go who are the patients that need adjuvant pembrolizumab? We do not have any valid ctDNA. And I know Dr. Pal was involved with a lot of these type of research. We don't have any ctDNA test that is really that faithful and sensitive in the MRD space in renal cell. Many of us are working, so we don't know. We may end up over-treating patients that need surgery only. And actually, we may end up under-treating patients that need, perhaps, pembro, and another drug. And the second thing in those patients--and I hope it does not happen, but unfortunately, it will to some extent--whose tumor progress on adjuvant pembrolizumab, what do you do? What's the treatment paradigm? And actually, there is no data. This is a data-free zone. And I would think somebody whose tumor progressed, tumor continued to grow or grows, while they're actively on pembrolizumab, on IO, is way different than someone whose tumor comes back after 2 or 3 years from stopping the drug. Should we treat them with the same drug? Should we treat them with the TKI plus IO? Luckily, there are trials that are ongoing in patients whose tumor progressed after PD-1/PD-L1 inhibitor to give them a TKI as a control arm, or a TKI plus an immune checkpoint inhibitor. And I know Dr. Pal is very heavily involved with such trials. So, hopefully, we will answer this question, but not anytime soon.   Dr. Neeraj Agarwal: Very interesting, and definitely new results are posing new challenges in how we practice medicine here in the coming future. So, Monty, you are leading a trial with a very similar trial with atezolizumab. And I'm really hoping, we are all really hoping, that we see the other trial being positive, so we have more treatment options for our patients.   Dr. Monty Pal: I couldn't agree with you more. I mean, I definitely think that Toni's study really adds a lot of fuel to the fire suggesting that this strategy of adjuvant immunotherapy may be successful in localized renal cell.   Dr. Neeraj Agarwal: And I'm not going to really delve into the side effects of pembrolizumab and atezolizumab because these drugs are used quite often. They are in widespread use for different types of cancer. But just a quick question, any safety signal, Toni? Did you see any safety signal with pembrolizumab in this patient population?   Dr. Toni Choueiri: Yeah, this is an excellent question. So, nothing that would be different than using pembrolizumab overall knowing in other diseases as a single agent. So, this drug not first in human, as you know, and it's been approved in combination or as a single agent in many diseases. A tumor that the three of us treat is bladder cancer, and we know from another study how to use pembrolizumab. I think that the use of corticosteroid is somewhat of an objective way, at least to me, in looking at immune-related adverse event. And it has been between 5% to 10%, so we're not way off here. But there is no doubt that there are patients that we had no death on trial attributed to drug that may have, with pembrolizumab, some serious toxicities. We had patients that had autoimmune diabetes, hypophysitis, pneumonitis--quite uncommon, but not impossible.   Dr. Neeraj Agarwal: We'll still need to keep an eye for that, basically.   Dr. Toni Choueiri: No doubt.   Dr. Neeraj Agarwal: Yes. So, changing gears, let's talk to you, Monty. You recently presented the primary results of the SWOG 1500 trial in patients with metastatic non-clear cell renal cell carcinoma. Could you please tell us why you did this study and how this study's design was unique compared to similar studies in this setting?   Dr. Monty Pal: Yeah. No, absolutely. Toni did a great job of outlining areas that are sort of free of data in the adjuvant space, particularly with immunotherapy. I think that data-free area for us in kidney cancer for a long time has been non-clear cell histology. We just don't really know how to treat them. And I actually got advice from Toni when I was devising SWOG 1500. We planned it out as a very simple study comparing sunitinib and cabozantinib. And Toni will remember this history well. It sort of went through several iterations. The study blossomed into a six-arm trial. Ultimately, it turned into a four-arm study, looking at sunitinib versus cabozantinib versus two other MET inhibitors--savolitinib and crizotinib. And ultimately, the study was boiled down to essentially what we'd originally proposed. Two of the MET inhibitors--savolitinib and crizotinib--failed to surpass that initial analysis for PFS. So, ultimately, we demonstrated a superiority with cabozantinib over sunitinib for progression-free survival.   Dr. Neeraj Agarwal: So, what is the current treatment paradigm for patients who have newly diagnosed metastatic papillary RCC now?   Dr. Monty Pal: I think for patients who don't have genomic selection, I think that cabozantinib remains the standard. I really want to champion- and maybe Toni can talk a little bit more about this--a study that Toni is leading called the SAMETA trial, which I think has a really innovative design. And it's going to be genomically characterizing patients and randomizing to savolitinib with durvalumab or sunitinib. Tell me, Toni, if I have the design right there.   Dr. Toni Choueiri: Yes. Actually, this is a specific study in a specific population. It's not in papillary RCC as much as in those 30%, 40% of papillary RCC that have MET-driven tumors, so MET alteration, whether through chromosome 7 duplication, through chromosome 7 trisomy, through mutation or amplification. These patients will get either control arm or they will get savolitinib, which is a pure MET inhibitor that is devoid of VEGF-related toxicities, savolitinib plus durvalumab, or durvalumab alone. So, two experimental arms and one control. And the reason for this is we saw activity and quite a good toxicity profile with savolitinib, a pure MET inhibitor, over sunitinib in an earlier trial that was sunitinib against savolitinib in selected patient populations. The study had to close early. So, despite the numerical difference, this was not statistically significant. And then in another study led by Dr. Powles and colleagues, there was also some interesting activity how durvalumab could augment that activity. So, we're launching a phase 3 trial with three arms that you described very well.   Dr. Neeraj Agarwal: That's wonderful. So, what are the next steps, Monty? I mean, this is amazing to see you designing an investigator-initiated trial. This was your concept. You designed it. You built this to be a huge multicenter trial, which was open across the country, funded by the National Cancer Institute. And congratulations for making that happen. It's rare for us to see these trials going from a concept stage to a national trial, and then changing the standard of care. So, what are the next steps now for you and your team in SWOG for papillary RCC or metastatic papillary RCC? How do you build out further with the backbone of cabozantinib?   Dr. Monty Pal: I really appreciate the question, Neeraj. It's so critical to understand that we're just not quite done yet. Toni's study, as I've mentioned, is incredibly innovative. I'm also really thrilled to be working with someone who you've mentored so well, Ben Maughan, at the Huntsman Cancer Institute in Utah. And he's actually designed a brilliant study, which we're going to be leading together, which looks at cabozantinib with or without atezolizumab. Recently, in a study that you and I and Toni were a part of that we just published in JCO, we actually saw quite impressive response rates with the combination of cabozantinib and atezolizumab in patients with papillary RCC, around 47%. Those response rates were actually replicated in a separate study run by Joe Lee at Memorial Sloan Kettering. In the context of papillary disease response rates were again above a threshold of around 40%. So, I think there's something to it. But until we really subject this to randomization, I think we're not going to know whether or not cabo plus IO is standard. So, I encourage everyone to consider Toni's study. I encourage everyone to look out for our trial of cabo plus or minus atezo, which should be rolling out next year.   Dr. Neeraj Agarwal: What is the name of the trial, or the number, for our audience?   Dr. Monty Pal: Yeah, we lucked out with another great number. We got 1500 for the first trial. This is going to be SWOG 2200. So SWOG 2200, and I think it's due to open maybe in the first quarter of 2022.   Dr. Neeraj Agarwal: That's fantastic news. Any new signal? We know cabozantinib is already approved for our patients with metastatic RCC, courtesy METEOR trial led by Dr. Choueiri. Toni, it's amazing to see how many times you have changed standard of care for our patients with metastatic RCC. So, any new safety signal of cabozantinib in this patient population with metastatic papillary RCC?   Dr. Monty Pal: Nothing that appreciated. The toxicity profile was pretty much on par with what you'd anticipate for cabozantinib in the setting. Major side effects were hypertension, hand-foot syndrome, [and] diarrhea. Nothing that really sort of stood out relative to what we would expect in a clear cell population of patients.   Dr. Neeraj Agarwal: That's great. Any final messages for our patients, for our audience, for our listeners?   Dr. Toni Choueiri: Well, let me start, and maybe Monty can add. It's been, and it hopefully will continue to be, this humbling experience, where median survival from metastatic RCC in mid-2000--not long time ago during our training--has been 1 year. And now in metastatic disease, it's 4 to 5 years. And that is only going to get better. And then it's even more humbling to be in a time where you can talk about adjuvant treatment in this disease, renal cell cancer, that continues every year to kill, unfortunately, 14,000 Americans. That's just in the U.S. alone. So, we have to continue in getting more targets, more drugs, more reasonable combination, and the right patient, whether through specific biomarker that are tissue or blood-based or specific liquid biopsies that can tell you who has and who doesn't have cancer at the microscopic levels.   Dr. Neeraj Agarwal: Thank you. How about you, Monty? Any final message for our audience?   Dr. Monty Pal: I couldn't have summarized it better than Toni, just such a wonderful statement around optimism for what we've achieved so far and what's yet to come. And if I could emphasize to anyone in the audience today the need to keep progressing the field further with clinical trials, I think that would be my underlying message.   Dr. Neeraj Agarwal: Thank you again, Toni, Monty, for your valuable insights and thoughts. Thank you for all the inspiration. This is indeed so inspiring to see your work, which is changing the lives of our patients on a daily basis. Our listeners will find links to your studies in the transcript of this episode. I wish you all the best.   Dr. Toni Choueiri: Thank you.   Dr. Neeraj Agarwal: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you so much.   Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Pfizer, Merck    , Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Foundation Medicine, Gilead Sciences Research Funding (inst.): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas   Dr. Sumanta (Monty) Pal: Consulting or Advisory Role: F. Hoffmann LaRoche, F. Hoffman Research Funding (inst.): Eisai, Genentech, Roche, Exelixis, Pfizer Travel, Accommodations, Expenses: Genentech, Seattle Genetics   Dr. Toni Choueiri: Employment: Dana Farber Cancer Hospital Leadership: Dana Farber Cancer Hospital, NCCN, KidneyCan, ASCO, ESMO Stock and Other Ownership Interests: Pionyr, TEMPEST Honoraria: NCCN, UpToDate, Michael J. Hennessy Associates, ASCO, Harborside Press, Analysis Group,                AstraZeneca, Alexion Pharmaceuticals, Sanofi/Aventis, Bayer, Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck          , Novartis, Peloton Therapeutics , Pfizer, Corvus Pharmaceuticals, Ipsen,                 Foundation Medicine, Eisai, PlatformQ Health, Clinical Care Options, Navinata Healthcare, Kidney Cancer Journal, Exelixis, Prometheus, Lpath, NEJM, Lancet Oncology, Cerulean Pharma, alligent, EMD Serono, HERON, Lilly, Janssen Oncology, IQvia, Aveo, and NCI. Consulting or Advisory Role: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus Laboratories, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, Peloton Therapeutics, UpToDate, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Journal, Clinical Care Options, Paltform Q, Navinata Healthcare, Harborside Press, ASCO, NEJM, Lancet Oncology, EMD Serono, HERON, Lilly, ESMO, NiKang Therapeutics, Kanaph Therapeutics, Infinity Pharmaceuticals, and Aravive Research Funding (inst.): Pfizer, Novartis, Merck, Exelixis               , TRACON Pharma, GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca, Peloton Therapeutics, Roche/Genentech, Celldex, Agensys, Eisai, Takeda, Prometheus, Ipsen, Corvus Pharmaceuticals, Cerulean Pharma, Seattle Genetics/Astellas, Bayer, Foundation Medicine, Roche, Calithera Biosciences, Analysis Group, NCI, GATEWAY for Cancer Research, and Congressionally Directed Medical Research Programs (DOD) Patents, Royalties, Other Intellectual Property (inst.): International Patent Application No. PCT/US2018/058430, entitled “Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy, International Patent Application No. PCT/US2018/12209, entitled “PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response Patents, Royalties, Other Intellectual Property: ctDNA technologies Travel, Accommodations, Expenses: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, UpToDate, Peloton Therapeutics, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Journal, Clinical Care Options, PlatformQ Health, Harborside Press, Navinata Healthcare, NEJM, Lancet Oncology, EMD Serono, HERON, Lilly, and ESMO Other Relationship: Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, Parexel   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Guest host Dr. Neeraj Agarwal, editor-in-chief of ASCO Daily News and director of the Genitourinary Cancers Program at the University of Utah Huntsman Cancer Institute, interviews Dr. Oliver Sartor, medical director of the Tulane Cancer Center in New Orleans, on the practice-changing VISION trial and its impact on the current treatment paradigm for mCRPC. Transcript ASCO Daily News: Welcome to the ASCO Daily News Podcast. Our topic today is the practice-changing VISION trial, a phase III trial of radioligand therapy in patients with metastatic castration-resistant prostate cancer. Our guest host, Dr. Neeraj Agarwal, the editor-in-chief of the ASCO Daily News and director of the Genitourinary Cancers Program at the University of Utah's Huntsman Cancer Institute, will speak with one of the trial's investigators, Dr. Oliver Sartor, the medical director of the Tulane Cancer Center and Laborde Professor for Cancer Research. Their full disclosures are available on the transcript of this episode, and disclosures relating to all episodes of the Daily News Podcast are available on our transcripts at asco.org/podcasts.   Dr. Neeraj Agarwal: Hi, my name is Dr. Neeraj Agarwal. I am with Dr. Oliver Sartor. Today, we are going to discuss one of the practice-changing trials in the context of metastatic castration-resistant prostate cancer. Welcome to the ASCO Daily News Podcast, Dr. Sartor. Thanks for taking the time to be with us today.   Dr. Oliver Sartor: Thank you, Neeraj. A pleasure to be here.   Dr. Neeraj Agarwal: You recently published the primary results of the phase III VISION trial, which tested the efficacy of a novel radioligand therapy, Lutetium-177-PSMA-617, in men with metastatic castrate-resistant prostate cancer. Could you please tell us more about this compound and why you did this study?   Dr. Oliver Sartor:  So I'll start off with the compound itself. Radioligand therapy is a therapy that has a little warhead, and that warhead in this case is Lutetium-177. But it's guided by binding to PSMA. Now, PSMA is prostate-specific membrane antigen, and many of us are familiar with it, but some may not be. So PSMA is a protein expressed on the surface of most prostate cancer cells. Not all patients have it, but most do. And the ability of the PSMA Lutetium-177 to target the cancer was indicated in some preliminary studies, but they have not been to phase III. So the purpose of the phase III VISION trial was really to design a definitive study to look at overall survival, in particular, to determine whether or not this agent was truly active. And the good news is, it is truly active. And in the VISION trial, we were able to not only extend life with an overall survival benefit, haz ratio 0.62, but there was also a time-to-progression image-based radiographic progression-free survival. It was also much in favor of the PSMA Lutetium with a haz ratio of 0.4. So whether or not you look at time to cancer progression or whether or not you look at overall survival, this is an effective therapy. It, of course, does have some adverse side effects. We can talk more about that, but it's reasonably well tolerated. And I do anticipate that there'll be an FDA approval as a consequence of these pivotal findings.   Dr. Neeraj Agarwal: These are wonderful results and news for our patients. Please tell me how it will affect the current treatment paradigm of our patients with mCRPC. As we know, you selected patients who had disease progression on chemotherapy with taxanes and novel hormonal therapy. But real-world studies, many of which were published by you, have shown that docetaxel is received by a minority of patients with metastatic prostate cancer. So how do you envision treating your patients who do not want to be treated with chemotherapy as many of my patients do? How will you apply Lutetium-177 in their treatment?   Dr. Oliver Sartor:  Well, Neeraj, I think that we're going to be restricted in accordance with the label that the FDA provides. And I fully expect that the label will include a progression after treatment with docetaxel or at least one taxane-based therapy because that's the way the VISION trial was constructed. Now, you're raising a very critical point, and that is, what about the individuals that do not want to receive or are ineligible to receive a chemotherapy such as docetaxel? And for those individuals, we now have a new trial called PSMA4, and that trial is going to be testing the Lutetium-177-PSMA-617 in the context of chemotherapy-naive patients. So I think we're going to have to wait until we have more results, more clinical trials completed, prior to the application of PSMA-617 into the more general population of chemotherapy-naive patients. But those clinical trials are now underway.   Dr. Neeraj Agarwal: That's great. So, Oliver, in the VISION trial, you did mandate a diagnostic PSMA PET scan, and patients who were positive on the diagnostic PSMA PET scan were deemed to be eligible for enrollment on the VISION trial. Do you expect FDA to include diagnostic PSMA scan for eligibility for treatment with the Lutetium-177 in the real-world setting? If it doesn't or if it does, how it is going to affect the treatment of our patients, that availability of treatment for our patients?   Dr. Oliver Sartor:  That's really a great question. And I do expect that PSMA PET imaging will be a criteria given that it was used for patient selection. Now, as it turned out, about 87% of the patients actually did qualify after getting a PSMA PET scan. And given that that was part of the inclusion criteria, I anticipate that the FDA will also incorporate such imaging. Now, it does get to be a bit of an issue because it turns out that PSMA PET is just now coming into more widespread use. We did have, in May of this year, the approval by the FDA for the PSMA PET imaging agent and-- I shouldn't say "the"-- a PSMA PET imaging agent. Prior to that, in December of last year, there was both UCLA and UCSF approval by the FDA for yet another PSMA PET imaging agent. As we move forward, I anticipate that PET imaging is going to be more widely available. And of course, we don't have the approval as of yet today for the PSMA-617-Lutetium-177. And when we do get the anticipated approval, which likely will be in 2022, then I also anticipate that PSMA PET will be more widely available. Now, there are still issues with reimbursement for PSMA PET, and we've encountered those in our own practice. But that's a rapidly changing area, and we're working with the insurance companies in an effort to ensure that patients will get the imaging that they need.   Dr. Neeraj Agarwal:  Got it. And obviously, I asked this question because many of my community friends and colleagues have asked me this question.  Before we talk about the side effects of Lutetium-177, would you have any message for our friends and colleagues in the community who are bracing themselves for treating their patients with the Lutetium-177, whether they should be proactive in establishing contacts and relationships with the nuclear medicine facilities and so on?   Dr. Oliver Sartor:  That's a great question, Neeraj, because I think you're raising a very important point. This is going to be the type of therapy that involves multidisciplinary care. We can see that there'll be diagnostic PET imaging as being a component of the study. There'll be the necessity of licensed physicians, typically either nuclear medicine or radiation oncology, to actually administer the drug. And then, quite frankly, the medical oncologists or those urologists who are trained in advanced prostate cancer are going to need to manage the patient. This is a lot more than just getting an injection. Many of these patients are ill. They need to have symptom management. They need to manage their bone health. They need to manage their hormonal manipulations. They need management with regard to pain. So this is not just about giving an injection. And I encourage those people who are interested to involve multidisciplinary teams starting now. And I realize that the therapy is not available now, but you have to anticipate that it will be. And I think it will be a game changer of a therapy, and many patients are going to want it. So that means it's incumbent upon the physicians to be prepared, and that means multidisciplinary care.   Dr. Neearj Agarwal:  Excellent point. So basically, we should be ready. We should start establishing relationships with nuclear medicine facilities or radiation oncologists who are going to deliver Lutetium-177. Overall, when I was reading the New England Journal paper, the side effect profile seemed very reasonable. I did not see any red flags. To me, it sounded like a pretty well-tolerated drug. So what is your take on the side effects of Lutetium-177?   Dr. Oliver Sartor: I think the side effects are quite manageable. One of the unique side effects is that of dry mouth and that's because the PSMA can actually be expressed in the salivary glands and that there is some potential for salivary gland binding in the PSMA-617-Lutetium. And that means that you can have damage to the salivary glands, and that means dry mouth. It turns out that a little over 40% of the patients actually did complain of a dry mouth, and that needs to be managed typically with fluid intake or various ways of mouth moisturizers. Fatigue is a potential issue. It was raised, as well as some bone marrow suppression. And if you look at the grade 3/4 toxicities, anemia was present a little more than 10% of the time. And that, of course, needs to be monitored. There is some potential collateral damage to the bone marrow. So these patients need to have their counts monitored. They need to have their symptoms assessed. And they need to be managed as they go through the process. It's not just about giving an injection, but clearly, the licensed individuals, including nuclear medicine and radiation oncology, need to be engaged, because without them, there is no injection. So this is a complex multidisciplinary care paradigm. And emphasizing the point, symptom management, yes; adverse event management, yes. But you have to deliver the drug, and that means multidisciplinary care.   Dr. Neeraj Agarwal:  Those are fantastic points. Thank you very much, Dr. Sartor, for taking time to be with us. And I'm really hoping that this podcast will be very enriching to our listeners. Thank you very much.   Dr. Oliver Sartor: Thank you, Neeraj. Glad to be here.   ASCO Daily News:  You've been listening to Dr. Neeraj Agarwal of the Huntsman Cancer Institute and Dr. Oliver Sartor of the Tulane Cancer Center. Our listeners will find a link to the VISION study in the transcript of this episode. Thank you to our listeners for joining us today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Neeraj Agarwal Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai,    Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences   Research Funding (Inst.): Bayer Your Institution, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen,    AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas     Disclosures: Dr. Oliver Sartor Stocks & Other Ownership Interests: Lilly, GlaxoSmithKline, Abbvie, Cardinal Health, United Health Group, PSMA Therapeutics, Clarity Pharmaceuticals, Noria Therapeutics, Inc., Clovis Consulting or Advisory Role: Bayer, Sanofi, AstraZeneca, Dendreon, Constellation Pharmaceuticals, Advanced Accelerator Applications, Pfizer, Bristol-Myers Squibb, Bavarian Nordic, EMD Serono, Astellas Pharma, Progenics, Blue Earth Diagnostics, Myovant, Myriad Genetics, Novartis, Clarify Pharmaceuticals, Fusion, Istopen Technologien Meunchen, Janssen, Noxopharm, Clovis, Noria Therapeutics, Point Biopharma, TeneoBio, Telix, Theragnostics Research Funding (Inst): Sotio, Janssen, Progenics, Bayer, Sanofi, Endocyte, Merck, Invitae, Constellation Pharmaceuticals, Advanced Accelerator Applications, Dendreon, AstraZeneca Expert Testimony: Sanofi Travel, Accommodations, Expenses: Bayer, Johnson & Johnson, Sanofi, AstraZeneca, Progenics   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Dr. Oliver Sartor on the VISION Trial and Improving Care for Patients With mCRPC       ASCO Daily News: Welcome to the ASCO Daily News Podcast. Our topic today is the practice-changing VISION trial, a phase III trial of radioligand therapy in patients with metastatic castration-resistant prostate cancer. Our guest host, Dr. Neeraj Agarwal, the editor-in-chief of the ASCO Daily News and director of the Genitourinary Cancers Program at the University of Utah's Huntsman Cancer Institute, will speak with one of the trial's investigators, Dr. Oliver Sartor, the medical director of the Tulane Cancer Center and Laborde Professor for Cancer Research. Their full disclosures are available on the transcript of this episode, and disclosures relating to all episodes of the Daily News Podcast are available on our transcripts at asco.org/podcasts.   Dr. Neeraj Agarwal: Hi, my name is Dr. Neeraj Agarwal. I am with Dr. Oliver Sartor. Today, we are going to discuss one of the practice-changing trials in the context of metastatic castration-resistant prostate cancer. Welcome to the ASCO Daily News Podcast, Dr. Sartor. Thanks for taking the time to be with us today.   Dr. Oliver Sartor: Thank you, Neeraj. A pleasure to be here.   Dr. Neeraj Agarwal: You recently published the primary results of the phase III VISION trial, which tested the efficacy of a novel radioligand therapy, Lutetium-177-PSMA-617, in men with metastatic castrate-resistant prostate cancer. Could you please tell us more about this compound and why you did this study?   Dr. Oliver Sartor:  So I'll start off with the compound itself. Radioligand therapy is a therapy that has a little warhead, and that warhead in this case is Lutetium-177. But it's guided by binding to PSMA. Now, PSMA is prostate-specific membrane antigen, and many of us are familiar with it, but some may not be. So PSMA is a protein expressed on the surface of most prostate cancer cells. Not all patients have it, but most do. And the ability of the PSMA Lutetium-177 to target the cancer was indicated in some preliminary studies, but they have not been to phase III. So the purpose of the phase III VISION trial was really to design a definitive study to look at overall survival, in particular, to determine whether or not this agent was truly active. And the good news is, it is truly active. And in the VISION trial, we were able to not only extend life with an overall survival benefit, haz ratio 0.62, but there was also a time-to-progression image-based radiographic progression-free survival. It was also much in favor of the PSMA Lutetium with a haz ratio of 0.4. So whether or not you look at time to cancer progression or whether or not you look at overall survival, this is an effective therapy. It, of course, does have some adverse side effects. We can talk more about that, but it's reasonably well tolerated. And I do anticipate that there'll be an FDA approval as a consequence of these pivotal findings.   Dr. Neeraj Agarwal: These are wonderful results and news for our patients. Please tell me how it will affect the current treatment paradigm of our patients with mCRPC. As we know, you selected patients who had disease progression on chemotherapy with taxanes and novel hormonal therapy. But real-world studies, many of which were published by you, have shown that docetaxel is received by a minority of patients with metastatic prostate cancer. So how do you envision treating your patients who do not want to be treated with chemotherapy as many of my patients do? How will you apply Lutetium-177 in their treatment?   Dr. Oliver Sartor:  Well, Neeraj, I think that we're going to be restricted in accordance with the label that the FDA provides. And I fully expect that the label will include a progression after treatment with docetaxel or at least one taxane-based therapy because that's the way the VISION trial was constructed. Now, you're raising a very critical point, and that is, what about the individuals that do not want to receive or are ineligible to receive a chemotherapy such as docetaxel? And for those individuals, we now have a new trial called PSMA4, and that trial is going to be testing the Lutetium-177-PSMA-617 in the context of chemotherapy-naive patients. So I think we're going to have to wait until we have more results, more clinical trials completed, prior to the application of PSMA-617 into the more general population of chemotherapy-naive patients. But those clinical trials are now underway.   Dr. Neeraj Agarwal: That's great. So, Oliver, in the VISION trial, you did mandate a diagnostic PSMA PET scan, and patients who were positive on the diagnostic PSMA PET scan were deemed to be eligible for enrollment on the VISION trial. Do you expect FDA to include diagnostic PSMA scan for eligibility for treatment with the Lutetium-177 in the real-world setting? If it doesn't or if it does, how it is going to affect the treatment of our patients, that availability of treatment for our patients?   Dr. Oliver Sartor:  That's really a great question. And I do expect that PSMA PET imaging will be a criteria given that it was used for patient selection. Now, as it turned out, about 87% of the patients actually did qualify after getting a PSMA PET scan. And given that that was part of the inclusion criteria, I anticipate that the FDA will also incorporate such imaging. Now, it does get to be a bit of an issue because it turns out that PSMA PET is just now coming into more widespread use. We did have, in May of this year, the approval by the FDA for the PSMA PET imaging agent and-- I shouldn't say "the"-- a PSMA PET imaging agent. Prior to that, in December of last year, there was both UCLA and UCSF approval by the FDA for yet another PSMA PET imaging agent. As we move forward, I anticipate that PET imaging is going to be more widely available. And of course, we don't have the approval as of yet today for the PSMA-617-Lutetium-177. And when we do get the anticipated approval, which likely will be in 2022, then I also anticipate that PSMA PET will be more widely available. Now, there are still issues with reimbursement for PSMA PET, and we've encountered those in our own practice. But that's a rapidly changing area, and we're working with the insurance companies in an effort to ensure that patients will get the imaging that they need.   Dr. Neeraj Agarwal:  Got it. And obviously, I asked this question because many of my community friends and colleagues have asked me this question.  Before we talk about the side effects of Lutetium-177, would you have any message for our friends and colleagues in the community who are bracing themselves for treating their patients with the Lutetium-177, whether they should be proactive in establishing contacts and relationships with the nuclear medicine facilities and so on?   Dr. Oliver Sartor:  That's a great question, Neeraj, because I think you're raising a very important point. This is going to be the type of therapy that involves multidisciplinary care. We can see that there'll be diagnostic PET imaging as being a component of the study. There'll be the necessity of licensed physicians, typically either nuclear medicine or radiation oncology, to actually administer the drug. And then, quite frankly, the medical oncologists or those urologists who are trained in advanced prostate cancer are going to need to manage the patient. This is a lot more than just getting an injection. Many of these patients are ill. They need to have symptom management. They need to manage their bone health. They need to manage their hormonal manipulations. They need management with regard to pain. So this is not just about giving an injection. And I encourage those people who are interested to involve multidisciplinary teams starting now. And I realize that the therapy is not available now, but you have to anticipate that it will be. And I think it will be a game changer of a therapy, and many patients are going to want it. So that means it's incumbent upon the physicians to be prepared, and that means multidisciplinary care.   Dr. Neearj Agarwal:  Excellent point. So basically, we should be ready. We should start establishing relationships with nuclear medicine facilities or radiation oncologists who are going to deliver Lutetium-177. Overall, when I was reading the New England Journal paper, the side effect profile seemed very reasonable. I did not see any red flags. To me, it sounded like a pretty well-tolerated drug. So what is your take on the side effects of Lutetium-177?   Dr. Oliver Sartor: I think the side effects are quite manageable. One of the unique side effects is that of dry mouth and that's because the PSMA can actually be expressed in the salivary glands and that there is some potential for salivary gland binding in the PSMA-617-Lutetium. And that means that you can have damage to the salivary glands, and that means dry mouth. It turns out that a little over 40% of the patients actually did complain of a dry mouth, and that needs to be managed typically with fluid intake or various ways of mouth moisturizers. Fatigue is a potential issue. It was raised, as well as some bone marrow suppression. And if you look at the grade 3/4 toxicities, anemia was present a little more than 10% of the time. And that, of course, needs to be monitored. There is some potential collateral damage to the bone marrow. So these patients need to have their counts monitored. They need to have their symptoms assessed. And they need to be managed as they go through the process. It's not just about giving an injection, but clearly, the licensed individuals, including nuclear medicine and radiation oncology, need to be engaged, because without them, there is no injection. So this is a complex multidisciplinary care paradigm. And emphasizing the point, symptom management, yes; adverse event management, yes. But you have to deliver the drug, and that means multidisciplinary care.   Dr. Neeraj Agarwal:  Those are fantastic points. Thank you very much, Dr. Sartor, for taking time to be with us. And I'm really hoping that this podcast will be very enriching to our listeners. Thank you very much.   Dr. Oliver Sartor: Thank you, Neeraj. Glad to be here.   ASCO Daily News:  You've been listening to Dr. Neeraj Agarwal of the Huntsman Cancer Institute and Dr. Oliver Sartor of the Tulane Cancer Center. Our listeners will find a link to the VISION study in the transcript of this episode. Thank you to our listeners for joining us today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Neeraj Agarwal Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai,    Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences   Research Funding (Inst.): Bayer Your Institution, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen,    AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas     Disclosures: Dr. Oliver Sartor Stocks & Other Ownership Interests: Lilly, GlaxoSmithKline, Abbvie, Cardinal Health, United Health Group, PSMA Therapeutics, Clarity Pharmaceuticals, Noria Therapeutics, Inc., Clovis Consulting or Advisory Role: Bayer, Sanofi, AstraZeneca, Dendreon, Constellation Pharmaceuticals, Advanced Accelerator Applications, Pfizer, Bristol-Myers Squibb, Bavarian Nordic, EMD Serono, Astellas Pharma, Progenics, Blue Earth Diagnostics, Myovant, Myriad Genetics, Novartis, Clarify Pharmaceuticals, Fusion, Istopen Technologien Meunchen, Janssen, Noxopharm, Clovis, Noria Therapeutics, Point Biopharma, TeneoBio, Telix, Theragnostics Research Funding (Inst): Sotio, Janssen, Progenics, Bayer, Sanofi, Endocyte, Merck, Invitae, Constellation Pharmaceuticals, Advanced Accelerator Applications, Dendreon, AstraZeneca Expert Testimony: Sanofi Travel, Accommodations, Expenses: Bayer, Johnson & Johnson, Sanofi, AstraZeneca, Progenics   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Dr. Oliver Sartor on the VISION Trial and Improving Care for Patients With mCRPC       ASCO Daily News: Welcome to the ASCO Daily News Podcast. Our topic today is the practice-changing VISION trial, a phase III trial of radioligand therapy in patients with metastatic castration-resistant prostate cancer. Our guest host, Dr. Neeraj Agarwal, the editor-in-chief of the ASCO Daily News and director of the Genitourinary Cancers Program at the University of Utah's Huntsman Cancer Institute, will speak with one of the trial's investigators, Dr. Oliver Sartor, the medical director of the Tulane Cancer Center and Laborde Professor for Cancer Research. Their full disclosures are available on the transcript of this episode, and disclosures relating to all episodes of the Daily News Podcast are available on our transcripts at asco.org/podcasts.   Dr. Neeraj Agarwal: Hi, my name is Dr. Neeraj Agarwal. I am with Dr. Oliver Sartor. Today, we are going to discuss one of the practice-changing trials in the context of metastatic castration-resistant prostate cancer. Welcome to the ASCO Daily News Podcast, Dr. Sartor. Thanks for taking the time to be with us today.   Dr. Oliver Sartor: Thank you, Neeraj. A pleasure to be here.   Dr. Neeraj Agarwal: You recently published the primary results of the phase III VISION trial, which tested the efficacy of a novel radioligand therapy, Lutetium-177-PSMA-617, in men with metastatic castrate-resistant prostate cancer. Could you please tell us more about this compound and why you did this study?   Dr. Oliver Sartor:  So I'll start off with the compound itself. Radioligand therapy is a therapy that has a little warhead, and that warhead in this case is Lutetium-177. But it's guided by binding to PSMA. Now, PSMA is prostate-specific membrane antigen, and many of us are familiar with it, but some may not be. So PSMA is a protein expressed on the surface of most prostate cancer cells. Not all patients have it, but most do. And the ability of the PSMA Lutetium-177 to target the cancer was indicated in some preliminary studies, but they have not been to phase III. So the purpose of the phase III VISION trial was really to design a definitive study to look at overall survival, in particular, to determine whether or not this agent was truly active. And the good news is, it is truly active. And in the VISION trial, we were able to not only extend life with an overall survival benefit, haz ratio 0.62, but there was also a time-to-progression image-based radiographic progression-free survival. It was also much in favor of the PSMA Lutetium with a haz ratio of 0.4. So whether or not you look at time to cancer progression or whether or not you look at overall survival, this is an effective therapy. It, of course, does have some adverse side effects. We can talk more about that, but it's reasonably well tolerated. And I do anticipate that there'll be an FDA approval as a consequence of these pivotal findings.   Dr. Neeraj Agarwal: These are wonderful results and news for our patients. Please tell me how it will affect the current treatment paradigm of our patients with mCRPC. As we know, you selected patients who had disease progression on chemotherapy with taxanes and novel hormonal therapy. But real-world studies, many of which were published by you, have shown that docetaxel is received by a minority of patients with metastatic prostate cancer. So how do you envision treating your patients who do not want to be treated with chemotherapy as many of my patients do? How will you apply Lutetium-177 in their treatment?   Dr. Oliver Sartor:  Well, Neeraj, I think that we're going to be restricted in accordance with the label that the FDA provides. And I fully expect that the label will include a progression after treatment with docetaxel or at least one taxane-based therapy because that's the way the VISION trial was constructed. Now, you're raising a very critical point, and that is, what about the individuals that do not want to receive or are ineligible to receive a chemotherapy such as docetaxel? And for those individuals, we now have a new trial called PSMA4, and that trial is going to be testing the Lutetium-177-PSMA-617 in the context of chemotherapy-naive patients. So I think we're going to have to wait until we have more results, more clinical trials completed, prior to the application of PSMA-617 into the more general population of chemotherapy-naive patients. But those clinical trials are now underway.   Dr. Neeraj Agarwal: That's great. So, Oliver, in the VISION trial, you did mandate a diagnostic PSMA PET scan, and patients who were positive on the diagnostic PSMA PET scan were deemed to be eligible for enrollment on the VISION trial. Do you expect FDA to include diagnostic PSMA scan for eligibility for treatment with the Lutetium-177 in the real-world setting? If it doesn't or if it does, how it is going to affect the treatment of our patients, that availability of treatment for our patients?   Dr. Oliver Sartor:  That's really a great question. And I do expect that PSMA PET imaging will be a criteria given that it was used for patient selection. Now, as it turned out, about 87% of the patients actually did qualify after getting a PSMA PET scan. And given that that was part of the inclusion criteria, I anticipate that the FDA will also incorporate such imaging. Now, it does get to be a bit of an issue because it turns out that PSMA PET is just now coming into more widespread use. We did have, in May of this year, the approval by the FDA for the PSMA PET imaging agent and-- I shouldn't say "the"-- a PSMA PET imaging agent. Prior to that, in December of last year, there was both UCLA and UCSF approval by the FDA for yet another PSMA PET imaging agent. As we move forward, I anticipate that PET imaging is going to be more widely available. And of course, we don't have the approval as of yet today for the PSMA-617-Lutetium-177. And when we do get the anticipated approval, which likely will be in 2022, then I also anticipate that PSMA PET will be more widely available. Now, there are still issues with reimbursement for PSMA PET, and we've encountered those in our own practice. But that's a rapidly changing area, and we're working with the insurance companies in an effort to ensure that patients will get the imaging that they need.   Dr. Neeraj Agarwal:  Got it. And obviously, I asked this question because many of my community friends and colleagues have asked me this question.  Before we talk about the side effects of Lutetium-177, would you have any message for our friends and colleagues in the community who are bracing themselves for treating their patients with the Lutetium-177, whether they should be proactive in establishing contacts and relationships with the nuclear medicine facilities and so on?   Dr. Oliver Sartor:  That's a great question, Neeraj, because I think you're raising a very important point. This is going to be the type of therapy that involves multidisciplinary care. We can see that there'll be diagnostic PET imaging as being a component of the study. There'll be the necessity of licensed physicians, typically either nuclear medicine or radiation oncology, to actually administer the drug. And then, quite frankly, the medical oncologists or those urologists who are trained in advanced prostate cancer are going to need to manage the patient. This is a lot more than just getting an injection. Many of these patients are ill. They need to have symptom management. They need to manage their bone health. They need to manage their hormonal manipulations. They need management with regard to pain. So this is not just about giving an injection. And I encourage those people who are interested to involve multidisciplinary teams starting now. And I realize that the therapy is not available now, but you have to anticipate that it will be. And I think it will be a game changer of a therapy, and many patients are going to want it. So that means it's incumbent upon the physicians to be prepared, and that means multidisciplinary care.   Dr. Neearj Agarwal:  Excellent point. So basically, we should be ready. We should start establishing relationships with nuclear medicine facilities or radiation oncologists who are going to deliver Lutetium-177. Overall, when I was reading the New England Journal paper, the side effect profile seemed very reasonable. I did not see any red flags. To me, it sounded like a pretty well-tolerated drug. So what is your take on the side effects of Lutetium-177?   Dr. Oliver Sartor: I think the side effects are quite manageable. One of the unique side effects is that of dry mouth and that's because the PSMA can actually be expressed in the salivary glands and that there is some potential for salivary gland binding in the PSMA-617-Lutetium. And that means that you can have damage to the salivary glands, and that means dry mouth. It turns out that a little over 40% of the patients actually did complain of a dry mouth, and that needs to be managed typically with fluid intake or various ways of mouth moisturizers. Fatigue is a potential issue. It was raised, as well as some bone marrow suppression. And if you look at the grade 3/4 toxicities, anemia was present a little more than 10% of the time. And that, of course, needs to be monitored. There is some potential collateral damage to the bone marrow. So these patients need to have their counts monitored. They need to have their symptoms assessed. And they need to be managed as they go through the process. It's not just about giving an injection, but clearly, the licensed individuals, including nuclear medicine and radiation oncology, need to be engaged, because without them, there is no injection. So this is a complex multidisciplinary care paradigm. And emphasizing the point, symptom management, yes; adverse event management, yes. But you have to deliver the drug, and that means multidisciplinary care.   Dr. Neeraj Agarwal:  Those are fantastic points. Thank you very much, Dr. Sartor, for taking time to be with us. And I'm really hoping that this podcast will be very enriching to our listeners. Thank you very much.   Dr. Oliver Sartor: Thank you, Neeraj. Glad to be here.   ASCO Daily News:  You've been listening to Dr. Neeraj Agarwal of the Huntsman Cancer Institute and Dr. Oliver Sartor of the Tulane Cancer Center. Our listeners will find a link to the VISION study in the transcript of this episode. Thank you to our listeners for joining us today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Neeraj Agarwal Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai,    Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences   Research Funding (Inst.): Bayer Your Institution, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen,    AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas     Disclosures: Dr. Oliver Sartor Stocks & Other Ownership Interests: Lilly, GlaxoSmithKline, Abbvie, Cardinal Health, United Health Group, PSMA Therapeutics, Clarity Pharmaceuticals, Noria Therapeutics, Inc., Clovis Consulting or Advisory Role: Bayer, Sanofi, AstraZeneca, Dendreon, Constellation Pharmaceuticals, Advanced Accelerator Applications, Pfizer, Bristol-Myers Squibb, Bavarian Nordic, EMD Serono, Astellas Pharma, Progenics, Blue Earth Diagnostics, Myovant, Myriad Genetics, Novartis, Clarify Pharmaceuticals, Fusion, Istopen Technologien Meunchen, Janssen, Noxopharm, Clovis, Noria Therapeutics, Point Biopharma, TeneoBio, Telix, Theragnostics Research Funding (Inst): Sotio, Janssen, Progenics, Bayer, Sanofi, Endocyte, Merck, Invitae, Constellation Pharmaceuticals, Advanced Accelerator Applications, Dendreon, AstraZeneca Expert Testimony: Sanofi Travel, Accommodations, Expenses: Bayer, Johnson & Johnson, Sanofi, AstraZeneca, Progenics   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Mohamed Salem, gastrointestinal medical oncologist at the Levine Cancer Institute at Atrium Health in North Carolina, tells guest host Dr. John Sweetenham, associate director of clinical affairs at the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, about the disturbing rise of early-onset colorectal cancer, the impact of socioeconomic disparities on patient outcomes and potential interventions to improve detection.   Transcript Dr. John Sweetenham: Hello, I'm John Sweetenham, the associate director of Clinical Affairs at UT Southwestern Harold C. Simmons Comprehensive Cancer Center and guest host of the ASCO Daily News podcast today. I'm delighted to welcome Dr. Mohamed Salem, a gastrointestinal medical oncologist at the Levine Cancer Institute at Atrium Health in North Carolina. Dr. Salem is going to be discussing with us the disturbing rise in early onset colorectal cancer and the impact of socioeconomic disparities on patient outcomes and potential interventions to increase screening, particularly in younger populations. Mohamed, many thanks for joining us on the podcast today. Dr. Mohamed Salem: Thank you, Dr. Sweetenham for the kind invitation. And I have to tell you, I'm very grateful for this invitation to cover this topic. And also, thanks to the ASCO Daily News team for shedding the light on this. Dr. John Sweetenham: Great. Before we start, I should mention that my guest and I have no conflicts of interest relating to the topic today. Full disclosures of all guests on the ASCO Daily News podcast are available on our transcripts at ASCO.org/podcast. Mohamed, low socioeconomic status has been associated with worse survival in patients with colorectal cancer, otherwise known as CRC. But there hasn't been as much focus on the impact of socioeconomic status for those patients who have early onset colorectal cancer and, specifically, I guess, we mean by that, those patients who develop this condition in early adulthood. Of course, it's quite well known, generally, that adolescents and young adult patients who develop various types of cancer appear to have worse outcomes than both their childhood and their adult counterparts. Your study, published in The Oncologist, looked at the impact of sociodemographic disparities and insurance status on survival of patients with early onset colorectal cancer and, maybe not surprisingly, in some respects, based on experience in other diseases, demonstrated worse outcomes. Could you talk to us a little about the data in your study and how that might inform programs to improve early detection and treatment of patients with colorectal cancer? Dr. Mohamed Salem: Sure. As you mentioned, Dr. Sweetenham, there are two problems. A socioeconomic problem, which is, by itself, a huge challenge we are facing as a community. On the other hand, two, this colorectal cancer problem in younger adults is another issue that we have been facing now for maybe a decade or two. Rebecca Siegel just published a paper a couple of years ago showed that the increased incidence of [colorectal] cancer in adults, it's on the rise. And it brings many challenges to this population in terms of the diagnosis, their care, and their outcome. But when you couple this with the challenge that socioeconomic status impact on the outcome of our patient, this becomes a very, very complicated problem. So, our group wanted to look not only on the impact of socioeconomic status, but the impact on that problem on patients with early onset colorectal cancer and see how complicated this will be to their outcome. We examined more than 30,000 patients, and we chose the cutoff [at age] 40. Early onset definition could vary a little bit, so you have 40, you have 45, some people think even 50, but we choose 40 just because we wanted to focus on the very young group. We utilized National Cancer Database and we obviously thank them for giving us access to this data. And we tried to look at the impact of socioeconomic status, and it was stunning. We found that survival decreased with the decrease of socioeconomic status. So, the patient who carried the best survival was those with highest socioeconomic status and then the lower SES goes, the worse is their survival outcomes. And also, not just survival. We found that if you have low socioeconomic status, you are more likely to have stage III or IV tumors, which is, as you know, more advanced cancer, you're more likely to have node-positive disease, and also, you're more likely to present with stage IV colon cancer. So, just to highlight how impactful the socioeconomic status or factor in the presentation in disease and the outcome, and not only this one. We will also looked at insurance status. It was very clear that patients with no insurance or Medicaid, they do much worse. They had the higher risk of mortality compared to patients with commercial private insurance. And you have to wonder having this issue with being young adult and having a cancer and then having no insurance, have no means to access care. That's something, as you mentioned, perhaps we could, as a community, look into it and try to remove those barriers, to hopefully improve the patient outcome. Dr. John Sweetenham: Yeah, one of the things that struck me from looking at your paper was the fact that stage to stage, age for age. If patients had insurance, it did mediate some of the adverse prognostic effects of socioeconomic status, if I read the paper correctly, which does suggest to me that part of the problem at least is access to care. Would you agree with that? Dr. Mohamed Salem: I totally agree, 100%. And it's also interesting that we even looked at multiple angles. We looked at uninsured, by itself. We looked at Medicaid insurance. We looked at private versus not private. And it doesn't matter how we look at it, and adjusting for all other co-founders and stage, insurance status played a significant role on the impact of survival for those patients. Dr. John Sweetenham: Very interesting that I think that there are several other studies in other diseases which are beginning to show very similar emerging patterns. Just moving on from that a little, I think remarkable numbers that stood out from the studies which you cite in your article in The Oncologist is that 2015 study by Bailey et al. which was predicting that, by 2030, the incidence rates will have increased really quite substantially. And for the younger age group, those aged 20 to 34, the estimate was at a 90% increase in incidence. And for those in the 35 to 49 year age group, the suggestion was that incidence rates would increase by almost 28%, so I think there are a couple of questions that I have regarding that. The numbers are pretty sobering. Can you talk to us a little bit about what we know about the factors that are driving this increase in incidence? Dr. Mohamed Salem: Sure. I do agree with you, Dr. Sweetenham. I think this are very alarming numbers and very alarming phenomena. I'm sure you remember when we're in medical school and fellowship, we used to think colorectal cancer is a disease of older people. Unfortunately, now, we're seeing younger patients getting this. Not the age of 50 or 40 or 30 as you mentioned, even 20 years old. My youngest patient is 17-years-old. And it's not uncommon for me to see patients who are like 20-21 years old coming with this disease. There are many risk factors for colorectal cancer, as you know, obesity, diabetes, tobacco, alcohol, exercise, and other genetics and hereditary reasons. But the truth is that many of those patients come to our clinic are fit. They eat well, they don't smoke, they don't drink, so it appears there is something else going on. And there are many theories going into this, but the truth is that we're actually not sure 100% what are the exact reason for that rise in incidence among young adults. Some people think microbiome might have a role here. Some people think obesity, as I mentioned, has more impact on younger people than older people, but I think also is this is an area of research now. And we hope they'll continue to look into this and try to identify the exact reason why this is happening. But I also wanted to touch base a little bit about an important issue, because the paper you cited, both the American Cancer Society and the task force took the screening or issued recommendations regarding the screening to be from [age] 50 to go now to 45. We used to have a screening recommendation at age of 50 for average risk. Now, as of 2018, the American Cancer Society said you should be screened at 45, and most recently, the task force said the same thing. However, if you think about it, our study looked at patients who are [age] 40. So, the change in the screening really is not going to impact them, because it's still not even at the age of screening and, therefore, education, outreach and educating our patients, our population about the risk and the symptoms and signs of this disease is extremely important  because it makes a huge difference if the cancer gets detected at stage I, which most of the prime surgery is enough and 99% of patients or more than 90% of patients would be cured and don't even need anything besides surgery, versus, as I mentioned, when they start to come into the office with stage IV disease. Now, it's a totally different story and totally different outcome. Dr. John Sweetenham: Yeah, and I guess one of the other questions, the whole screening strategy issue is obviously a very big issue right now and I guess somewhat controversial as well. But I think it's true to say, and if I'm wrong, I stand corrected, that in general, compliance with screening as a whole tends to diminish with age. So, I'm sure, for all kinds of reasons, many of which may be kind of socioeconomic, financially-related, younger individuals are less likely to get screened, either because of insurance or what other issues they may have. And so, I wonder as age goes down, and I'd make the assumption that it may be true, that compliance with screening protocols also goes down. It'll be interesting to speculate on what are going to be useful interventions, particularly in that very young age group, might lead to earlier detection of colorectal cancer in, let's say, a 22-year-old. It can be a difficult issue to unravel, I think. Dr. Mohamed Salem: I totally agree. I think it gets very complicated very quickly because, one, as you mentioned, access to care and coverage and being able to afford this is one issue. But also, if you think about it from logistics, younger people need to work. Maybe they have kids, they need to take care of them. They already have a busy schedule and busy life going on to begin with. So, for them, to take the time off and start to do this office visit takes away time from them, so it affects the compliance. So, hopefully, more awareness and more recognition and encouraging each other to take a day off and just go to get screened might actually result in life saving. Also, I would like to say something important. Most of us, as physicians, when we see an older patient with rectal bleeding, for example, we always think about, OK, maybe he has colon cancer, maybe she has colon cancer. But we don't think the same way when we see a 25 year-old old bleed. So, I think, as a family doctor or somebody who is a medical doctor that will actually seeing that patient, the threshold should be lowered for symptoms and also for early referral. And the other thing I would like to encourage your viewer is that none of us would be excited and happy to talk to their loved one or their friend about his or her old habits as having their rear bleeding, abdominal colics, or so on, and so forth. But sometimes, those symptoms are the symptoms because of colon cancer. I always say, you know your bodies are best, so if you thinks there's something wrong, don't be embarrassed to talk about that. You have to share those symptoms with your family doctor, or at least your loved one to get an advice and get evaluated. And this gets complicated among minorities, because somehow there is a shame in this. And I think looking for safe environment, community network, as you mentioned at the beginning, easy access to medical care is crucial. You're not going to be able to get screened if you don't have the bus ticket to get to the center to be screened there. The last thing I would just like to stress also, if I may, most people think a screening is connected to colonoscopy, which is partially true, but colonoscopy is not the only way patients can get screened. There are many, many other ways that people can get screened including stool tests that you can do at home and send it to your doctor. So, colonoscopy is not the only way you can get screened. You can also discuss with your family doctor or even loved one about other means that you can get screened. Dr. John Sweetenham: Yeah, I think that's a really important point, and it raises another question actually, which may be difficult to answer in this specific age group. But I just wonder, in general terms, whether you can make any comments about how much ground do you think we may have lost during the pandemic in terms of delayed screening and delayed diagnosis. Are you are you seeing evidence of that in the literature or in your own practice and your own institution now? Dr. Mohamed Salem: I think that's a pretty important question. I would say yes to both. Last year, there was data showing that colorectal cancer cases declined. All of us know nothing had change. I mean, the cases are the same out there. It's just not been diagnosed yet because most hospitals obviously, including ours, and many, many other hospitals throughout the country were trying to survive the COVID-19 pandemic, and that got a lot of patients to be delayed for screening. Many patients didn't feel comfortable going to the hospital to get either their colonoscopy or even to the family doctor visit, and so on, and so forth. So, I think this delay in the detection of the cancer. The cancer did not didn't appear. It just was not detected yet. And the risk of that, as I mentioned earlier, the more time passed without intervention, if someone has a cancer, that means more advanced stage. It goes from stage I to II and III and IV with time, and with that, the survival and outcomes get worse. So, that also brings another point that we think, it's that younger patient has more aggressive disease. I think there is some data about that. But also, I wonder if is this really more aggressive disease or just delayed in diagnosis. When you go to your family doctor or even get it checked then they say they're having rectal bleeding. This could be, yes, because of hemorrhoid, but also, it could be because of colon cancer. And I'm not saying everyone with rectal bleeding has colon cancer, but I'm saying that could be one of the reasons. And I would say you really have to seek medical advice if you have symptoms because, again, early detection is the best part about this, and it really saves lives and it changes a lot of things. So, yes, it's a pandemic. It had definitely, no doubt, impact on the colorectal cancer care. And I would predict is that we're going to start seeing more and more patients with more advanced disease in the coming months and years. Dr. John Sweetenham: Yeah, that's an alarming prediction. Of course, taken in conjunction with the other prediction that we mentioned earlier from the study by Bailey et al., it really should give us cause for concern. And I think, maybe my final question to you would be, given what you've just said, plus those data in somewhat dire predictions for 2030, what do we need to do now to prevent that prediction from Bailey et al. from coming true, do you think, if there's anything we can do at this stage? Dr. Mohamed Salem: I think that's a very complex question. But I think, the way I think about this, every one of us, as an individual and organization and even in government and political entity, we really have a role to play. As an individual, I would say, as I mentioned before, you know your body well, so I always say this phrase, 'If you feel something, say something.' This could be a life changing behavior. So, if you feel like there's something wrong with you, please don't be embarrassed to share this. Talk to your family doctor, talk to your friend, and seek medical advice. As a community, we have to encourage each other to share this information, to teach each other certain habits that might help early detection. And if you are at risk, please go ahead and get screened. As I mentioned, colonoscopy is one mean, but there are many others. As an institution, I think raising awareness is important. I think providing easy access to care, that's also very important. And from the government and political entity, I think looking at those people with diversity and disparity, and people with no insurance, people who need special support and need to get help, I think we should have a community program out there. Some help out there, whether this comes through insurance, means, or other programs that we need to look at. And I think this might have some impact on our ability to detect this cancer early on. I always say, which, I think maybe some people might think is an exaggerated statement, but no one really should die from colorectal cancer. Because again, if you detect the cancer early, minimal care should take care of that. The problem happens when we don't detect it early and the patient presents with stage III or IV disease. Dr. John Sweetenham: Yeah, so it's kind of a multifaceted approach, everything from the personal right through to the political aspect is involved in what we all need to do to contribute to this. So, I really appreciate your time today and sharing your insights, and congratulations on the study, which, I think, highlighted actually not just one, but several really important issues in this kind of growing incidence of colorectal cancer and what appeared to be growing disparities as well. Thanks so much for joining me on the podcast today. I hope that you continue to make an impact on these disturbing trends in the years to come. Dr. Mohamed Salem: Thank you, Dr. Sweetenham, for having me, and it's a pleasure to be with you tonight. Dr. John Sweetenham: And thank you also to our listeners for your time today. If you enjoyed this episode, please take a moment to rate and review us wherever you get your podcasts.   Disclosures:  Dr. John Sweetenham: None disclosed.  Dr. Mohamed Salem: Consulting or Advisory Role: Taiho Pharmaceutical, Exelixis, Bristol-Myers Squibb Speakers' Bureau: Genentech/Roche, Taiho Pharmaceutical   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Gabrielle Rocque, chair of the 2021 ASCO Quality Care Symposium, breast oncologist and health services researcher at the University of Alabama at Birmingham, and symposium chair-elect, Dr. Stephanie Wheeler, professor in the Department of Health Policy and Management at the University of North Carolina at Chapel Hill, discuss key interventions in quality care and compelling patient perspectives presented at #ASCOQLTY21. Transcript ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. On today's episode, we'll discuss promising interventions to improve the quality of care for patients and survivors and other key takeaways from the 2021 ASCO Quality Care Symposium. I'm delighted to welcome the chair and chair-elect of the [ASCO Quality Care] Symposium, Dr. Gabrielle Rocque and Dr. Stephanie Wheeler, for this discussion. Dr. Rocque is a breast oncologist and health services researcher. She is also associate professor of medicine in the Division of Hematology and Oncology and Gerontology, Geriatrics, and Palliative Care at the University of Alabama at Birmingham. Dr. Wheeler is a professor in the Department of Health Policy and Management at the University of North Carolina at Chapel Hill. She also serves as associate director of community outreach and engagement at the UNC Lineberger Comprehensive Cancer Center. My guests' full disclosures are available in our show notes, and disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/podcasts. Dr. Rocque and Dr. Wheeler, thanks for being on the podcast today. Dr. Gabrielle Rocque: Thank you for having us. ASCO Daily News: Dr. Wheeler, it was wonderful to have a hybrid event this year, with people participating in person in Boston and virtually. This is surely a sign of things to come. Can you tell us about some of the most important interventions in quality improvement that were presented at the [ASCO Quality Care] Symposium? Dr. Stephanie Wheeler: Absolutely, and thank you so much for hosting us. It was a really terrific [ASCO Quality Care] Symposium. And the fact that we had hybrid engagement from investigators all over the country and internationally was really exciting. There's a couple of intervention classes, if you want to call it that, that I think were particularly inspiring and interesting to me. The first were sets of interventions that focused on strategies to improve goals of care conversations and advanced care planning directives for patients with cancer or people with terminal illness in particular. And I just wanted to highlight a couple of those that I thought were particularly innovative. One was Abstract 8, which focused on using computer modeling and care coaches to increase advanced care planning conversations for people with advanced cancer. And this was presented by Dr. Divya Gupta. And it was just a wonderful example of how we can utilize technology and also care coaches. And in many cases, these don't necessarily have to be clinicians. They sometimes can be community health workers and others who can help direct those conversations and make it more comfortable for people living with advanced disease, and also their families, to consider next steps. In a similar vein, there were two other presentations--Abstract 1 delivered by Dr. Manali Patel and Abstract 2 delivered by Dr. Divya Parikh--that also utilized a similar model in a different care setting. And in those cases, the care settings ranged from VA to integrated health care settings. And we even had a conversation about how to do this work in community rural oncology practices. And I think that this kind of intervention has the potential for translation across a variety of settings. And the next steps are going to be figuring out exactly how to implement it in these settings. So, that's one class that I thought was particularly interesting. And I just want to highlight another group of interventions and studies that I found really innovative. And those were the presentations about hospital at-home models and how we can better deliver oncology care in the comfort of individuals' homes. And I thought Dr. Cardinale Smith did a great job from Mount Sinai describing the landscape of those interventions and the future for this kind of care delivery (“Overview of Programs and Ethics”). ASCO Daily News: Excellent. Great to hear about those promising new approaches. Dr. Rocque, the [ASCO Quality Care] Symposium captured many trends in quality care, including patient-reported outcomes measurement as an important way to monitor quality of care and patients' experiences. Can you highlight the studies that will help inform our listeners about how to integrate patient-reported outcomes into real-world settings? Dr. Gabrielle Rocque: Yeah. This was a major topic of the conference this year to think about how patient-reported outcomes are informative both in traditional research settings and in real-world settings. So, I was really intrigued by the Abstract 154 by Joy Jarnagin. And that abstract talked about how the changes in patient-reported outcomes actually had a very strong association with patients' treatment response, and in fact, was even more informative than those patients' tumor markers and I think show a novel way that patient-reported outcomes can be used. We also saw some more traditional abstracts on patient-reported outcomes. I'd like to highlight Abstract 152 by Valerie Lawhon, which really used patient-reported outcomes to identify patients' experience and their mental health outcomes during the COVID-19 pandemic, and I think provided us some really important insight into the experiences of our patients. And then as you mentioned, there is a lot of focus on real-world settings and how to transition from typical research patient-reported outcomes to a more broad scale implementation. And the session implementing PROs in oncology practice was really outstanding in terms of considering how this can be done. So, Dr. Terry Mulvey from Massachusetts General Hospital presented their experience on how to get these patient-reported outcomes into routine care, and what are some of the challenges associated with that, and how did they have to adapt to make sure that this was doable in real-world settings (“Challenges to Getting Started in a Practice Setting”). I was also impressed with the study by Dr. Raymond Osarogiagbon on the potential populations where there can be barriers of care and their study looking at an intervention in which they're implementing patient-reported outcomes over a wide variety of different practice types across the country (“Potential Populations Where This Can Be a Barrier to Care”). And I think these early insights also pointed us to future questions. Dr. Wynne Norton did a wonderful job of outlining some of the future questions that are likely to come up as we move into an era where patient-reported outcomes are a part of standard of care, and really think about how do we refine these for maximal benefit (“Overview of Current Strategies”). So, I think all of these sessions were highlighting the promise of patient-reported outcomes, as well as the future questions in this space. ASCO Daily News: Excellent. As a specialist in gerontology, geriatrics, and palliative care, please tell us about new approaches that oncologists should be aware of as they strive to provide high quality care for older patients and those receiving palliative care. Dr. Gabrielle Rocque: Absolutely. So, we've talked a bit about the patient-reported outcomes. And I think we'd be remiss in not highlighting the presentation on geriatric assessment--the presentations on the geriatric assessments into clinical practice by Dr. [Rawad] Elias (“Incorporating Geriatric Assessments Into Practice”). And I think this highlights another opportunity for us to move the field forward and take better care of our older adults. In terms of palliative care, there were multiple very informative abstracts. Dr. Wheeler has highlighted a few in the space of care guides or lay health coaches providing support in advanced care planning. In addition, we saw an interesting discussion of caregiver interventions for patients that are receiving--with cancer treatment by Dr. Nick Dionne-Odom (“Caregiver Interventions”). And I think it's important that we remember both the patients and the caregivers who are affected by cancer and by the amount of work that has to be done to support a patient with cancer going through their journey. ASCO Daily News: Absolutely, so important to remember caregivers and their needs and resources that could be available to them as well. Dr. Wheeler, financial toxicity is an enormous concern for many patients and their families, and the oncology care community has been trying for some time to figure out how best to address the concerns of patients and the health care system. Are there any new interventions that we should be aware of? Dr. Stephanie Wheeler: Yes, and I think that the [ASCO Quality Care] Symposium was an opportunity to hear about several of those. And some of them didn't make it onto the main stage but were featured in abstract sessions and poster sessions. So, as we're all well aware, financial toxicity is a multidimensional set of constructs that includes patients and their family’s material out-of-pocket burden, as well as the psychological distress and potentially harmful care altering behaviors that financial hardship induces. And so, we continue to hear at the [ASCO Quality Care] Symposium multiple talks about the strain that patients are undergoing, including the non-medical hardship that's introduced by a cancer diagnosis. And that was really interesting, and I think important to document. But I think that where the field is moving is more towards interventions, both behavioral interventions and systems interventions, multilevel approaches to dealing with the hardship itself as well as the importance of policy. So, there were several abstracts that talked about the introduction of biosimilars and generics and how that affected price of many of the oncologic drugs available on the market. And frankly, the message is a bit discouraging. Prices continue to rise. And in some cases, the price increases are not limited to pharmacologic products. In some cases, we saw abstracts presenting the increased cost of surgery, of outpatient care appointments, and things like that as well. So, we're not going to fix the problem by managing drug pricing alone. In terms of patient and family-directed interventions, I thought that there were some interesting abstracts. I want to highlight a number 53--or excuse me, Abstract 43 by Melissa Beauchemin that focused on the existence of hospital specialty pharmacies and partnering with freestanding care coordination organizations to improve access to oncology medications, as well as Abstract 96 presented by Ms. Rachel Marquez which was focused on resolving transportation disparities and access to cancer treatments. These kinds of interventions are obviously patient directed but have tremendous potential. And then I also want to just note a couple of additional studies that are ongoing that are important to recognize in this field. There are at least five National Cancer Institute (NCI)-funded R01 trials underway right now investigating the role of financial navigation and various iterations of it in different care settings. So, I think we will want to look to this meeting as an opportunity to hear about that work as it moves forward. And how that work is implemented is going to be vital, because the types of care settings where it's being done--ranging from AYA populations in Utah, to urban populations in Washington state, to integrated care organizations in Northern California, all the way to parts of rural North Carolina--we're going to see a diversity of outcomes and different ways in which those types of interventions can manifest in those different studies. I also want to note that the NCI has funded a series of supplements through its Cancer Center Core Grant Initiative that are all focused on identification, timely identification of financial toxicity in practice. And many of the investigators leading that work were attending the [ASCO Quality Care] Symposium, and so that will be important to keep an eye on as we move forward as well. ASCO Daily News: Excellent. Dr. Rocque, let's focus on health equity and access. I'd like to ask you about the session on eliminating barriers to clinical trial access. The presenters of this session shared strategies to directly address inclusion and diversity in cancer care. Can you tell us about approaches that caught your attention? Dr. Gabrielle Rocque: Absolutely. So, this was a really great session talking about clinical trial access and barriers, and particularly as it relates to health equity. And so, in Abstract 74, Dr. Joe Unger presented a really interesting conceptual model that highlighted that the barriers to clinical trial access are not necessarily always at the patient level, but they are at the system level, the provider level. And this framework for considering how do we target in the future our ability to engage patients in clinical trials was really important, and I think was complemented well by the patient perspective from Rick Bangs, who's worked closely with SWOG, in thinking about how do patients view clinical trials and how can we better engage them. And I think folding together these different experiences and models to develop future interventions. I also thought the Abstract 75 looking at survival in the real-world analysis was noteworthy. And in particular, the ability to consider patients who are typically excluded from clinical trials based on their laboratory criteria and potentially having something like chronic kidney disease, and how little data there is on those patients who actually, in this study, had different outcomes after chemotherapy for breast cancer. I think when you think about clinical trial access and inclusion, I also think you need to think about how we collect our data and how we consider race and other social determinants of health. So, there were a few other abstracts that, although not in this session, I think were incredibly important for us to consider. The first is Abstract 78 by Ms. Niveditta Ramkumar that talked about the association between rurality and race and surgical treatment and outcomes for non-metastatic colon cancer. And so, she talked a bit about the intersectionality between race and rurality, and I think brings up an important topic that we need to think about these constructs, not only as individual constructs but how they impact each other as we consider analysis in the future. And also Abstract 80 by Dr. Kekoa Taparra, which was a really interesting abstract that talked about the disaggregation of Pacific Islanders in major Asian subpopulations to reveal hidden cancer disparities. So, in this abstract, he discussed how we often lump together different populations, potentially because of small numbers, who really may have very different experiences and characteristics. And I think challenges us to move the field forward by identifying populations in groups that are, in fact, very similar to each other and not just pulling this together. And I think that will have an impact on how we view engaging patients in clinical trials, as well as reporting those clinical trial results that allows our providers to understand how the trial results fit for the patient that is sitting in their clinic for whom they're making their decisions. ASCO Daily News: Indeed. Dr. Wheeler, is there anything that you'd like to add on the issue of access to clinical trials? Dr. Stephanie Wheeler: So, there was an abstract that particularly sparked my attention, [Abstract] 79 presented by Dr. Jenny Xiang about the VA Connecticut Cancer Experience, where universal pre-screening and using computer algorithms to identify patients who might be eligible for clinical trials was used. And I think that this is an important approach that can help us rely less on the assumptions and the biases that exist in clinical care practice about whether a patient may or may not participate in a clinical trial, and instead use the vast amounts of information that we know about them in their electronic health record to try to preemptively identify them and approach them. We know that when patients are asked and invited to be part of trials, they are much more likely to say yes than people assume. And this could be a more unbiased way of assessing that eligibility, and then proactively identifying people, ideally, with a trial navigator. I think that would enable us to potentially overcome some of the barriers that exist and that are, frankly, institutionally biased in many cases. ASCO Daily News: Thank you, Dr. Wheeler. Dr. Rocque, the [ASCO Quality Care] Symposium featured an excellent keynote address by Dr. Ben Corn of Hebrew University of Jerusalem (“Integrating Hope – Real Hope! – Into Clinical Oncology”) and a wonderful lecture by Dr. John Cox, who was honored with the Joseph V. Simone award for advancing quality cancer care (“Reshaping Practice: Necessary Trouble”). Can you share some highlights from their talks? Dr. Gabrielle Rocque: Definitely. So, the keynote address by Dr. Ben Corn was perfectly timed for this meeting. I think everyone has had a difficult past 2 years with the pandemic. And his message of the importance of hope really struck a chord with me and many of the attendees, and how this is something that we can strategically work to improve, and that hope is something we can modify and train for. And so, I'm really excited to both hear this lecture and then also see what's to come in the future in this domain of hope-related research. Another session that I would like to highlight as well is Dr. Cox's talk after receiving the Joe Simone Achievement Award. And his lecture highlighted that change is coming. And he emphasized the importance of changing payment structures to be able to improve the quality of care that patients receive and to be able to leverage those changes for infrastructure that allows us to enable our health system to have a more patient-centered approach with many of the types of interventions that we've been talking about here today. So, I think both of those sessions are really must-watch sessions that I would like to highlight today. ASCO Daily News: Excellent. Well, the [ASCO Quality Care] Symposium also heard some compelling patient perspectives. Dr. Wheeler, can you share some of these messages with us? Dr. Stephanie Wheeler: One of the most powerful sessions in the entire meeting was the very first one, which was focused on the metavivor experience (“The Patient Voice: “Metavivors” and Long-Term Survivorship Care”). And I think because part of the intention of the planning committee was to proactively feature patients' voices at this meeting, this particular session was almost entirely comprised of patients and survivors. And living with advanced disease, as we know now, is very different than it was in the past. And we know that patients living with incurable disease may sometimes go on to live 15, 20, 25 years. And their needs are quite different than patients who have early-stage cancer. And so, this session was impactful because it represented a range of experiences. We heard from a caregiver. We heard from a young woman who's living with stage four melanoma, Dr. Tarlise Townsend (“An AYA Perspective”). And one of the things that I took away from this session in particular was that our approaches in the way that we talk to metavivors has to be fundamentally different, that they want providers to be truthful, they want providers to acknowledge the uncertainty and prognosis and the sometimes complex and rapidly changing regimens that may be available for them in terms of dealing with their disease. But they don't want to be condescended to, they don't want to feel like there's information that is being withheld. One of the things that Dr. Townsend shared that was very powerful was that she talked about how her providers, in many cases, outlined an optimistic future for her and would give her maybe unfair expectations about what the future might hold and think about it in terms of the outlier effect. But that's not the case for many people with her condition. And so, she talked about having to do her own death work--and that's her term--and how much time she spent really trying to understand for herself what the future looked like. And it just resonated so much with me. And everybody on this panel had similar stories to share about their experiences. And it reminded me that at the end of the day, we're all human. None of us deal with uncertainty well. None of us deal with death well, or the prospect of death. But the best that we can do in these situations is to be open and honest and straightforward and recognize the fear and the hope and all of that being intermingled, and really respect the person's autonomy and the person's experience and their ability to make plans for themselves going forward. ASCO Daily News: Thank you, Dr. Wheeler. We will have links to these important patient perspectives in the transcript of this episode, as well as the other abstracts discussed today. Dr. Rocque and Dr. Wheeler, thank you very much for sharing these important highlights from the 2021 ASCO Quality Care Symposium. Dr. Stephanie Wheeler: Thank you for having us. Dr. Gabrielle Rocque: Thank you so much. ASCO Daily News: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclosures: Dr. Gabrielle Rocque: Consulting or Advisory Role: Pfizer, Flatiron Research Funding: Carevive Systems, Genentech, Pfizer Travel, Accommodations, Expenses: Carevive (an immediate family member) Dr. Stephanie Wheeler: Research Funding (institution): Pfizer Foundation Travel, Accommodations, Expenses: Pfizer Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Scout and Dr. Charles Kamen discuss the findings of a key survey by the National LGBT Cancer Network of LGBTQI cancer survivors and strategies to improve cancer care for sexual and gender minority patients and survivors. Dr. Scout is the executive director of the National LGBT Cancer Network. Dr. Kamen is a clinical psychologist, assistant professor in the Department of Surgery at the University of Rochester Medical Center, and assistant director for community outreach and engagement at the Wilmot Cancer Institute.   Transcript ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. The National LGBT Cancer Network has released the findings of a key survey of LGBTQI cancer survivors about their cancer treatment experience. To discuss the survey's findings and strategies to improve care for sexual and gender minority patients, I'm joined by Dr. Scout, executive director of the National LGBT Cancer Network, and Dr. Charles Kamen, a clinical psychologist and assistant professor in the Department of Surgery at the University of Rochester Medical Center and assistant director for Community Outreach and Engagement at the Wilmot Cancer Institute. Dr. Kamen also leads the University of Rochester's health equity research for the NCI Community Oncology Research Program. My guests report no conflicts of interest relating to our discussion today. Their full disclosures and those relating to all episodes of the podcast are available on our transcripts at asco.org/podcasts. Dr. Scout and Dr. Kamen, welcome to the ASCO Daily News podcast. Dr. Scout: Thanks. We're really happy to be here. Dr. Charles Kamen: Thanks so much for having us. ASCO Daily News: Dr. Scout, the survey captured the experience of over 2,700 individuals. And I think it's important to let our listeners know that approximately 100,000 LGBTQI people are diagnosed with cancer in the United States every year. So although the survey represents just a fraction of this total patient population, these data are important and shed light on the many challenges facing these patients and survivors from diverse communities across the country. What are the major themes that emerged from these data? And can you give us some specific examples from the survey. Dr. Scout: Yeah, absolutely. And first of all, I just want to say I'm happy that ASCO is paying attention to this. It's something that we're really proud of having done with the help of about 150 community partners. So, it was really kind of a community-wide effort. And we're really delighted to have this much information about a topic that is so important. The main takeaway is--we have really kind of four overarching themes we really think about a lot related to the survey. One of them--and this is nice, because we did a survey about 11 years ago, and this is actually pretty different--and that's that many people were able to report that they were able to get welcoming care. So, that we can't directly compare. But we do think that that is kind of a sign of changing times, a sign of the fact that a lot of providers really are trying to do a better job in this arena. But, unfortunately, there's a few big caveats to that. One is that people often had to go through a much longer journey to get to welcoming care, whether that be physical distance or trying several doctors, different things like that. No one needs that when they're under the duress of a cancer diagnosis. Second of all, if you were any underserved or underrepresented population within the queer communities, like trans or a person of color, your chance of getting that welcome care, of course, dropped. And then the second big theme is that our families, our chosen families, not only are they a real source of resilience for us, but our support teams are different, usually, than general population support teams. It might be an ex, a best friend, and one cousin kind of thing. But if they're really our chosen family, we need to do a better job of having hospitals acknowledge and recognize and treat them as the people who are our key support teams. Not as much work is being done on that as we'd really like to think is the case. The third big theme is that a lot of us, we're really looking for tailored resources about all sorts of things, including cancer prevention strategies, even right down to we wanted LGBTQ-tailored resources for physical-activity strategies. And we were almost uniformly unable to get those resources. So there is, especially these days, in a time when you can tailor things down to lots of different subpopulations, we still have a pretty big miss related to what's happening with the queer population on that. And then the fourth thing--and this we can only really kind of hypothesize--but people were talking about some kind of brutal statements that their doctors were making to them, people who were being told they have cancer in a very rough way, things like that. And we don't wonder if this could be the phenomena of the microaggressions emerging through standard care. And that's something that concerns us and, I think, something to watch. Dr. Charles Kamen: It's amazing to me, Scout, that the themes from this survey are so similar to the previous survey that you conducted back in, what was that, 2011? Dr. Scout: Yeah. Dr. Charles Kamen: So it's been 10 years, and still the same themes are coming up for this population. Dr. Scout: It is the case. Geraldine, you may not even know this, but Charlie is the other human who is the best expert in the world on what our last survey was, because he worked with us to do a bunch of publications off of it. And yeah, I would say it's distressing. We might have had, potentially, a reduction in some of the phenomena. But we had action steps, coming out of the last survey, that we've been training and we've been going around talking to everybody about for obviously over a decade now. And unfortunately the news is still the same. ASCO Daily News: Well, Dr. Scout, I'd like to follow up on a point you made about the importance of welcoming care. Certainly the environment in which people receive care can have a significant impact on their experience. Only 12% of respondents in the survey felt that they had received care in a welcoming environment where they saw, for example, a rainbow flag, they saw affirmative messages, and so forth. This is a very significant takeaway for oncologists in community practice and elsewhere. So, Dr. Scout, do you have any tips for providers about how to make LGBTQI individuals feel welcome, in a safe space, whether they are face to face with their oncologist, or getting blood work done, or even a biopsy? Dr. Scout: Yeah, we absolutely do. If you think about it, there is a history of bias and discrimination against this set of communities. And unfortunately, right now, if you're not doing something to distinguish yourself from that history, we can't tell. You know, we can't tell that you're not part of the problem. So, what we say and all the cultural competency trainers say to providers would be, show us. Do something. Don't just think to yourself, well, I support Pride or something like that. But, do something so we can tell as the patients. So, there's a whole bunch of strategies that are very simple. Put the Rainbow Pride flag up in your office. Partner with a local queer organization to do some outreach. Make sure that you have tailored materials on your website. If I go on your website and search the word, bisexual, and find nothing, not even a non-discrimination statement, then how in the world am I supposed to understand that I might potentially be welcomed there? And in addition, one of the ways you can do it in a regular, routine, everyday interaction, people often ask, well, what about if I'm [doing this]--work on the systems at your organization, work on the media, work on what's in your waiting room, but then what do you do in that face-to-face interaction? Simplest thing is--it's a beautiful new thing--introduce yourself with your pronouns. So just say, hi, my name is Scout. My pronouns are he/him. So, I'd like to get to know you. If you can tell me your name and your pronouns. And go from there. It doesn't say that you're queer, it simply says that you acknowledge one aspect of the difficulties experienced by the queer communities and that you're open and trying to be welcoming so that people, if they have unexpected pronouns or even if they have expected pronouns, they still get that little bit of a message that you're welcoming. ASCO Daily News: Dr. Kamen, do you have any thoughts on approaches that oncologists should be taking? And do you have a sense that these tips are being heard? Dr. Charles Kamen: I think that extra level to everything that  Scout said, which I 100% agree with, is don't put the rainbow sticker on the door unless your staff are competent to treat LGBTQ patients. So, before you have the visible sign of being affirming and welcoming, make sure that you're doing some training of the staff. Make it mandatory if you can. And think about how you are identifying and reaching out to your LGBTQI patients in your practice so that their identities are acknowledged and that they're referred to appropriate services after their cancer care ends or even during their cancer care. Dr. Scout: You know, I will also just say, related to that--and I completely agree--lots of providers, when you refer anybody out to another provider, if you're welcoming, you want to refer them to a welcoming provider. And unfortunately the strategy for figuring that out right now is still usually a provider calling another provider and figuring out how welcoming they are, and then doing follow-up with the patient. So, kind of even above and beyond that, remember, especially as an oncologist, your patient is going to now have to experience a bunch of other people. What have you done to make sure that you're able to refer them to welcoming providers instead of just having your own office be welcoming? Dr. Charles Kamen: And how are you working within the community to be sure that about resources that are outside the walls of your institution, but that may be very LGBTQ-affirming? You may not have an LGBTQI support group in your cancer center, but there may be a great one in town that you could refer patients to. So, I think it is both acknowledging visibly that you are an ally, but putting action to that by looking around for resources to send people to. Dr. Scout: And if not, we have new national ones you can refer people. Dr. Charles Kamen: Yes. ASCO Daily News: Thank you both for making those great points. Dr. Kamen, you've done [so] much research on the experience of LGBTQI individuals in cancer care and have stressed the need for research that is specific to the needs of this population. Can you tell us about the role that identity plays among LGBTQI individuals in determining levels of distress? Dr. Charles Kamen: If I can dip back into history for just one second, people probably know that, up until 1973, homosexuality was listed by the American Psychiatric Association as a mental illness. And there's still, to this day, discussion around diagnoses like, quote unquote, "transsexualism," or gender identity disorder, or gender dysphoria as sources of psychological distress. So, there's been a longstanding recognition that LGBTQI identities carry with them a burden of distress. But it wasn't really until the early 2000s that researchers like Vickie Mays or Susan Cochran and Ilan Meyer started to recognize that issue wasn't the LGBTQI identities themselves, the issue was living in a society where LGBTQI individuals were exposed to constant stigma and discrimination. And this led to the development of the Minority Stress Model which many researchers still use today as a way to understand why LGBTQI people experience higher levels of distress and have higher rates of diagnoses like anxiety and depression than heterosexual and cisgender people. I won't go into an incredible description of Minority Stress, but just the basic premise of it is that LGBTQI individuals walk around the world every day with a stigmatized identity. They could be directly exposed to discrimination as a result of this identity, or they could see people in their community being discriminated against, or anticipate discrimination going into a new environment or situation. So, all of this can cause chronic underlying stress. There was some very cool pioneering work by Mark Hatzenbuehler and his team that showed that really it's the process of ruminating about these experiences that causes physiologic changes like inflammation. And that has a cascade effect, downstream, on having high rates of distress among LGBTQI people. And I think, in cancer, we can see this whole process playing out very clearly. We were talking before about the survey that was done in 2011 that I worked on with Scout. And I always talk about this one participant in that study who said, "My oncologist knew about me."--she was a lesbian patient--"My oncologist knew I was a lesbian." But every time I had to encounter a new person, whether for an X-ray or a blood draw, I had all the anxiety of that cancer procedure plus the possibility of homophobia and having to watch out for myself. Cancer is stressful for everybody. But then, if you have to constantly negotiate whether and how to come out to your providers, you have to brace yourself for discrimination if you do come out. And then, if you don't come out, you have to worry, well, does my provider really know me as a human being if they don't know this important part of myself? All of that can exponentially magnify the stress that LGBTQ people with cancer experience. And so that's really, I think, at least the theoretical framework for understanding these rates of distress. Dr. Scout: Hey, Charlie, you may not know this, but did I ever tell you that I was diagnosed as a homosexual in 1984? Dr. Charles Kamen: I wasn't sure how much to go into it. Yeah, I mean, it was still floating around in the Diagnostic and Statistical Manual until 1987, I believe, you could be diagnosed. Dr. Scout: Also, just really bring home what Charlie is talking about on the other end of it, you know, here I am, the executive director of the National LGBT Cancer Network. And trust me, my partner had to push me to go to the dermatologist to get something checked out, which ultimately was cancer. You know, it's fully treatable. But there's this real difference between those of us who are kind of like, stiffly this is what we should do, you know? And then when you face the fact of standing naked in front of a provider who you think could be cruel to you, it's a very daunting possibility. So, there's a million ways you can find something else that's going to be your priority that day other than take care of your health needs. Dr. Charles Kamen: Absolutely. And it also causes people to not want to disclose. But then we had another person from the survey who said there's a part of the cancer experience that never gets shared with providers if they don't know who you really are as an LGBTQI person. So, it's really a catch-22. ASCO Daily News: So, what is the absolute best practice, in your opinion, to get an assessment of sexual orientation or gender identity that doesn't rely on the patient's disclosure? How should this ideally be done? You've discussed it before, earlier, in our conversation. But is there a best practice that our listeners can take away with them today? Dr. Charles Kamen: I mean, just based on the minority stress model, it's definitely incumbent on the practices to assess Sexual Orientation and Gender Identity, or SOGI, in a way that's comfortable and affirming for patients. And most of the time, as we're saying, right now, the onus is on the patient to disclose, which is super unfair. Usually it happens organically. A patient will come in, an LGBT patient will come up with the same-sex partner, and introduce their partner to the provider. And then it is just kind of known that they are a sexual minority person, or based on a med list, or pronouns, or name on an insurance card, a transgender status is known. But sometimes it doesn't happen that way. It doesn't happen organically. And there's a real breakdown in communication then. And beyond that, a patient's dealing with a million things at the beginning of a cancer journey anyway. So, having them be the ones to figure out how to talk about this is very unfair. I think the best research we have on this topic is from the EQUALITY study which was done a couple of years ago now by researchers from Harvard and Johns Hopkins. And it focused specifically on the emergency medicine context. But they surveyed a ton of people and providers and found that the overwhelming majority of patients were willing to disclose SOGI, but that they preferred to do it non-verbally, so through a form or a survey or a patient portal, and not verbally, face to face with a provider. That felt less stigmatizing and intense to the respondents in this survey. Dr. Scout: The other key piece about that is that an overwhelming number of providers thought that they shouldn't know that information because it was too invasive. So, we really need to close that gap. Dr. Charles Kamen: I forget the exact percentages, but it was something like-- Dr. Scout: It was 90% were willing to disclose, but 80% of providers thought that they shouldn't know. Dr. Charles Kamen: Yes, yes, thought that patients would not disclose. And there was some variation by the LGBTQI identity, with heterosexual patients being a little lower, like 84%, and lesbian respondents, like 98% of them were like, yes, ask us, we want to tell you. So, there is that mismatch. And I think the takeaway message, though, is patients are comfortable providing this data if it's asked of them in a respectful and affirming way. Dr. Scout: And I was going to say, just kind of bringing this down to just real-life experience, I had an experience at a health center recently that I think really is--it was certainly the best practice I'd ever had. And that's that I walked into a waiting room. And in the waiting room, I could see three different cues that they were LGBTQ welcoming. There was a big banner sign saying, "We welcome everybody." There was some stuff up about their Pride activities even though it wasn't Pride Month. And then there was a rainbow sticker on the window or something like that. By the time I saw those three signs, the fourth thing was they asked me my sexual orientation and gender identity on my intake form. And by then I was like, absolutely, no question, I'm absolutely going to give it. And I will say they even had a fifth thing. I then went through the patient--and it was like a dental procedure--I went through the procedure, and afterwards something happened that literally made my hair stand up on my neck because I realized how far away we are from this. Someone called me and said, "I'm from the health center. This is Thundermist"--our local federally-qualified health center. "I saw that you marked down that you were trans. I just wanted to welcome you. I'm the trans outreach coordinator. And I wanted to talk to you about some different trans support activities that we have going on across the health center, like swim night, game night, yoga night, things like that." So, I mean, really it made the hair stand up on my head. I'm like, wow, I'm not just tolerated here, I'm valued. And it was the first time I think that I had ever considered or thought that in a health interaction in my life. Dr. Charles Kamen: That's incredible. And I think that's the real next step we have to take as organizations, health care organizations, and as a society. If we're going to collect these data, why? What is it being used for? Dr. Scout: What are we giving back? Yeah. Dr. Charles Kamen: Yeah. How are we referring people to things like a trans yoga night? Make sure there's action behind collecting the data. Dr. Scout: But even before that, before we collect, are we showing them it's safe before we ask them to disclose? So, basically are we going out on a little bit of--not even a limb, first, but are we putting our cards on the table before we ask them to put their cards on the table? Dr. Charles Kamen: Yeah, don't go in cold. Let them know it's a safe place to have this disclosure. Dr. Scout: Yes. Dr. Charles Kamen: I will add in, too, we in the ASCO Sexual and Gender Minority Task Force recently conducted a survey with the support of ASCO's Center for Research and Assessment. And we found, by polling over 200 ASCO members, that the two main factors that predicted whether a practice would collect SOGI data was leadership support, which makes sense--if the top is saying, this is important to do, we need to collect SOGI data, it's going to happen across multiple levels of the institution--but also having resources. And I think that's resources both for collecting the data itself, like IT resources or even knowing what questions to ask, but also resources like Scout's saying, to have banners and stickers and training and activities and support. All of that together makes the practice able to do this in a holistic and affirming way. Dr. Scout: You know, I will say, with the IT support, though, everybody has it in their software package these days. It's just a question of flipping the switch. There's built-in, pre-baked questions. They're not the best in the universe, but they're perfectly functional. So, I hope people realize that that's already there. Dr. Charles Kamen: Yeah. As of 2018, every electronic medical record has to, by federal law, have a SOGI data collection element within it. And then I think the resource may as much be knowing how to do it as the time and effort to turn those modules on. ASCO Daily News: Absolutely. So, here's a scenario. We have an LGBTQI individual who is receiving cancer care. And that person comes to the appointment with their caregiver. How should the clinician acknowledge the relationship of a patient or survivor and their partner? This is a very important aspect of care. Dr. Scout, what are your thoughts on this? Dr. Scout: Well, I presume this isn't the only set of people you're going to see where it may not be husband or wife. The concept of husband and wife have been expanding these days. So, I hope that the oncologist is asking who the person is who's with them. Is this your primary support person? Is this your partner? I just want to make sure, because, of course, having the right support and the best support is going to be important to you doing the best job getting through this whole health event. So, I would hope that the oncologist is introducing themself with their own pronouns, again, and then asking who all the people at the table are and how they relate to the patient. Because I think we know by now that all those other people are really going to be providing them with a lot of health care support in all those hours when the oncologist is not in front of that patient. Dr. Charles Kamen: I agree with that. And I think there are lots of examples of this process not going well, the question not being asked, and then the caregiver not being acknowledged for the relationship they have to the patient. And the real problem there is you don't get to offer the caregiver resources then. And a lot of LGBTQ patients and their caregivers report that the caregivers experience as much stress or more stress than the patient does. So, by getting at this relationship, by asking a simple question like, "Who do we have with us today?" you can then refer that caregiver to a support group or resources as needed. ASCO Daily News: Of course. I'd like to focus on mental health for a moment. Mental health is a huge concern. And 70% of respondents of the National LGBT Cancer Network survey reported that they never received resources related to mental health developed for LGBTQI individuals. I'd like to read a quote from one respondent, who wrote, "With respect to mental health in particular, it seems that, locally, there are no criteria for what constitutes LGBTQI care. Mental health providers state that they are, quote unquote, 'friendly,' and have no means of describing what that means. Some are not at all aware of their own biases and subtle homophobia." Dr. Scout, what is your reaction to this statement? Dr. Scout: I think it's all too true. I've had a lot of challenges with the mental health system myself, as has probably most of the people that I know. So, it's yet again an area where I think the fix is not that complicated. I hope, by now, mental health providers understand [that] they do not see a homogeneous group of people. And I think, especially these days, since most people are going to the internet for their resources, this really begs the question of, you know, we don't have to wait for the National LGBT Cancer Network to create a bunch of resources. Because trust me, we're not that well funded. But if anybody makes a resource, send it to us. We'll put it on our resource library. And it can be available for anybody around the country. So, this really is going to take a village of providers to fix some of these issues. I'm not going to ask any one provider or provider group to fix all of them. But if everybody can do a little something, we'll pull all those together and make it available to everybody else. And that will really help build a basis of information. Also, just FYI, in cultural competency, there's a bunch of standards about to be released related to cultural competency. And we do provide trainings, as do other organizations. So, as with all of these things, take some steps. Inaction is hurting us. ASCO Daily News: Dr. Kamen, do you have any thoughts on this? Dr. Charles Kamen: Definitely. I agree with everything that Scout just said. And I think the one maybe silver lining to living through the COVID-19 pandemic has been that we are way more facile now at navigating telehealth services than we were pre-pandemic. I know, in our cancer center, our psycho-oncology service has had more business during the pandemic than before because they're offering virtual visits to patients. Even if an LGBTQI patient doesn't find a provider within their health care facility that they feel is competent or welcoming, you can go on the internet, as Scout is saying, and you can find really excellent queer-focused and affirming therapists that you can see virtually. So, that's, I guess, one benefit and one thing I hope that we continue to innovate on as we move through 2021. Dr. Scout: The one thing I would say about that is a lot of that's being threatened by these licensing issues. Because a lot of that is only being provided under licensing exceptions for COVID-19. Likewise our support groups are living under a licensing exception for COVID-19. So, there has been increasing pressure at a lot of places. I was literally just talking to the White House about it 2 days ago--no, that would be over the weekend--right before the weekend, about how telehealth really is a huge concern for our communities. And continuing these exemptions for all rare and underserved and discriminated-against populations and rural populations that just don't have a big provider base around them, is going to be really, really critical. So, I hope that there's going to be action on this telehealth front to make these licensing exceptions stick and not just be a little bright light that goes away once we've decided COVID-19's done. Dr. Charles Kamen: Absolutely agree. And I think that's at the federal level and the state level too. We need advocacy to make sure that these telehealth expansions remain in practice long term. ASCO Daily News: Dr. Kamen, you cited some interesting research earlier in the conversation. Is there any other research that is specific to the needs of the LGBTQI population that you'd like the oncology community to be aware of? Dr. Charles Kamen: Oh my gosh, I feel like there's so much good stuff going on now. And it's an amazing change from 2011, when I first started working with Scout on that survey, which was really the only survey of its type anywhere. Now there is more of a groundswell of interest and effort around LGBTQI cancer care. I'll just highlight three of the projects that are happening with members of the ASCO SGM Task Force. So, I've been working with the Fenway Institute in Boston, which has pioneered a lot of LGBTQI cultural competency training. And we're trying to bring that training and SOGI data collection elements to community oncology. And that's part of the NCI Community Oncology Research Program research base that I work with. So, that's one thing. Mandi Chapman, another member of the ASCO SGM Task Force, has a beautiful, very comprehensive training that's called the Together Equitable Accessible Meaningful, or TEAM, training. And she's tailored this to SGM-specific care and is testing it with multiple cohorts of health care providers. I think there'll be a publication coming out about that sooner rather than later so keep an eye out for that. And also I believe she is recruiting additional cohorts. So, keep an eye out for that as well. And then Ash Alpert, another member of the ASCO SGM Task Force, got a Young investigator Award from the Conquer Cancer, [the ASCO Foundation]. And they are developing patient-centered, non-stigmatizing gender identity data collection methods that can be implemented across oncology settings. And they're also looking at connections between violence and cancer risk for the transgender population. Really, I think this work is incredibly timely. Because people may know or may not know that right now the National Academies of Sciences, Engineering, and Medicine, they're working on a consensus document that's really trying to summarize how best to collect SOGI data across settings. So, Dr. Alpert's work to get a trans-community perspective on this topic is super critical. Of course, I would be remiss if I didn't mention the National LGBT Cancer Network and their training that they're doing as well, which I believe is still in existence and can be accessed, though Scout, you can correct me if I'm wrong on that. Dr. Scout: We're actually also doing a partnership right now, with Society for Gynecologic Oncology, to convert it to an online enduring training so it can scale wider. And we actually expect that to be debuting at the beginning of next year. Dr. Charles Kamen: Yeah, it's so great that there are so many of these efforts happening, because it means that multiple groups can access the training through different channels. And we can end up, hopefully, with a much better pipeline of LGBTQI-competent and trained providers. The last thing I'll mention is that the ASCO SGM Task Force had done that survey to look at the factors that predict SOGI data collection. And we're now doing a phase II follow-up where we're going to be doing qualitative, in-depth interviews and focus groups with member organizations to try to understand what the factors are on the ground that predict people collecting SOGI or not. So, we'll definitely be looking for organizations to participate in that study, probably in the next couple of months. Dr. Scout: And I would say you're hearing us talk a lot about data collection because that really is the biggest next horizon related to advancements in SOGI care. Because just to be clear, we can't tell you what our cancer rates are because we don't have any data in any of the registries because that's all abstracted from health records. So, until we get these questions asked as you go into a health care environment, we won't be able to tell you what our disproportionate COVID-19 impact is, we won't be able to tell you our cancer rates. And of course, without a lot of that hard data, we also can't even apply for more research or do interventions to try and fix it. So, that's why one of the things we really try and encourage providers to look at is when are you going be able to flip that switch and actually do that data collection. If you're really committed to being inclusive for our population, that's a key step. ASCO Daily News: Absolutely. Well, we will share a link to the National LGBT Cancer Network survey in the transcript of this episode, along with all of the other research and resources that you discussed today. Thank you so much, Dr. Kamen and Dr. Scout, for being on the podcast today and shining a spotlight on a very important topic in cancer care. Thanks so much. Dr. Scout: Absolutely. Thank you. ASCO Daily News: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Charles Kamen: None disclosed  Dr. Scout Research Funding (institution): Bristol Myers Squibb Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Steve Pergam, associate professor of the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center and the Infection Prevention Director at Seattle Cancer Care Alliance, discusses new guidance from the National Comprehensive Cancer Network’s COVID-19 Vaccination Advisory Committee, regarding a third dose of the Pfizer-BioNTech or the Moderna COVID-19 vaccines for patients with cancer.   Transcript Dr. John Sweetenham: Hello, I'm John Sweetenham, associate director of clinical affairs at the UT Southwestern Harold C. Simmons Comprehensive Cancer Center and guest host of the ASCO Daily News Podcast today. The U.S. Food and Drug Administration (FDA) has authorized an additional COVID-19 vaccine dose for people with certain medical conditions who received the Pfizer-BioNTech, or the Moderna COVID-19 vaccines. Following the FDA'S announcement, the National Comprehensive Cancer Network's COVID-19 Vaccine Advisory Committee released new guidelines regarding the third COVID-19 vaccine doses for people with cancer. Joining me to discuss the booster shots is the committee's co-leader, Dr. Steve Pergam. He is associate professor of the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center and the Infection Prevention Director at Seattle Cancer Care Alliance. Steve, thanks for coming on the podcast today. Dr. Steve Pergam: Well, thank you so much Dr. Sweetenham. It's an honor to talk to my colleagues from oncology who I work with every day and to speak to patients and others who might be listening, so thanks for having me on. Dr. John Sweetenham: Great, thank you. Before we start, I should mention that my guest and I have no conflicts of interest relating to the topic today, and full disclosures for all guests on the ASCO Daily News Podcast are available on our transcripts at ASCO.org/podcasts. Steve, can you tell us a little about the groups that should be considered eligible for a third dose of the mRNA COVID-19 vaccines right away based on the latest FDA decision? Dr. Steve Pergam: Sure, the guidelines from the Centers for Disease Control and Prevention (CDC) and from the ACIP after the approval by the FDA are quite broad, and they include patients who are immunosuppressed by medications, such as steroids, drugs like tacrolimus, and then patients with cancer as well, many of whom are often considered immune-suppressed. It gets into patients with immunodeficiencies, and it really addresses a large group of people who are considered immunosuppressed. And I think part of the reason the guidance was written that way is defining what is immunocompromised to a level where you're not going to respond well to the vaccine is a little bit complex because immunosuppression is such a broad term. So they've left the guidance pretty broadly worded, and so I think it's important that when we think about what this guidance looks like, it's really about trying to be inclusive and trying to be somewhat specific at the same time, which is a really, really hard balance to go across, if that makes sense. Dr. John Sweetenham: Sure. For those patients who are immunosuppressed in some way, can you say a little about what the data shows regarding the level of protection that these patients may get from a third dose? Dr. Steve Pergam: Sure, so first, it's actually a little bit difficult to speak to patients with cancer directly. There's not very much data if at all regarding third doses for patients with cancer. So much of the data that supports these recommendations is focused on data that we understand that second dose, receiving that first primary dose, followed by a booster, which is what is common and what's recommended for mRNA vaccines, suggests that patients who have cancer may not respond well to that two-dose regimen. And it's varied between different groups. Some groups have much less response. So, a patient receiving rituxan (rituximab), which is the anti-CD20 antibody, clearly do not have adequate responses. As an example, patients who are receiving anti-CD20 antibodies like rituxan (rituximab) clearly do not have good responses versus solid tumor patients, which may have a better response to these vaccines. But regardless, those with immune suppression appear to have decreased responses overall, and the antibody levels that they receive, that they can maximize too are less than the general public. And so there was data looking at different groups who were immune-suppressed and demonstrating some benefit to boosting. And primarily the data is in and amongst solid organ transplants. There's actually two papers. There is a paper dealing with solid organ transplant recipients, one from France and another from the University of Toronto. And both of these have shown that despite poor responses after the second dose that additional doses amongst those who have solid organ transplants were improved with a third dose approximately at least 28 days post that second booster. So, that third dose did provide improvements. And in some of that data, up to 60% of those individuals responded to the third dose, where the first dose was only about 4%, and the second dose only about 40%. So you get about, I would say, somewhere around half of the people that had no response in the solid organ transplant population had a defined response with that extra dose. So, looking at data from other populations of immune-suppressed individuals who have in trials been given these third doses does suggest that there's improved responses. In addition, in some data they have been able to look at T cell immunity and although T cell immunity can be documented in some that received second doses, there are some suggestions that potentially third doses may also potentially improve that. So I think the immune response appears to be better after a third dose, but there are caveats to that. Dr. John Sweetenham: That's really interesting, and it provokes me to ask a question, which I guess in some ways is a little off the wall, but it's certainly something that I've already heard from a number of patients with cancer. And that is, if as it appears to be the case that a third dose in these patients can get them somewhere closer to the kind of response you might anticipate in the normal population, do you see any role for a fourth dose looking forward? Appreciating that there are no data, but do you think there might be a role for a fourth dose in some of these patients? Dr. Steve Pergam: Yeah, well, first, I think it's important to understand that a third dose, it's not a panacea. It is not suggesting a third dose is going to protect all patients with cancer. In fact, many of our patients with cancer are highly immunosuppressed, and a third dose, while it may improve the responses in some, it won't completely improve responses. And of those who do respond, they may have a detectable antibody, but the level of protection that they receive with that extra dose may not be a level that is fully protective against infection. What's hard is the data that's available right now is we don't know whether that third dose is effective or protective against things like hospitalization and death, which are the outcomes that are the most important. So, I think there's still some gaps in our knowledge. But what we do know is that you need a significant amount of antibody to be protected, and some of the data from the Moderna trial has suggested that you need an antibody level of over 1,000 to really be fully protected. That's what they've determined as a correlate of protection. And I think most of the patients that we're talking about, while some can get over that level, others may have a harder time reaching that level of protection. So, it's important when you're thinking about antibodies and detecting antibodies that it's important to remind your patients that just because they have any antibody doesn't mean it's necessarily fully protective. Now I think the question of fourth dose is hard because we don't have any data in this space. And more is better is often a mantra in medicine that sometimes is discussed, but I really encourage before we go down that pathway to just giving a fourth dose because we can. And because now Pfizer is an FDA-approved medication that we have a little more flexibility that I think we really should be doing trials to better understand what that extra dose might do, and are we providing more benefit? I mean, we've seen this with some drugs is that there is a limit to how much cancer response there is with certain agents before we get into issues like toxicity. While I'm not concerned so much about toxicity with mRNA vaccines, what we don't know is what these multiple doses might do. And there's theoretical concerns where if there's been myocarditis seen in younger adults, someone who's receiving multiple doses of one of these agents who's also received cardiotoxic chemotherapy as an example, there might be a change in risk with additional doses. So, that's all theoretical. I'm not suggesting that's true. But I think what's really important is if we're going to be going down pathways where we're doing additional doses beyond what is FDA recommended, then I would not recommend that at this point that studies need to be done. We need really robust studies in our patients with cancer to really determine whether additional doses are beneficial. Dr. John Sweetenham: OK, that's really helpful. Thank you. Just switching gears a little bit, could you say a little bit about the timing recommendations for the third shot in immunocompromised patients? And I wonder whether, particularly based on some of the discussions that were held in the National Comprehensive Cancer Network (NCCN) panel, whether you could comment on the timing for those undergoing stem cell transplantation or CAR T-cell therapy. And perhaps say a little bit about those patients who may be undergoing surgery and the appropriate timing for them. Dr. Steve Pergam: Yeah, so we hope that most of the patients that we're discussing have already received their two doses of one of the mRNA vaccines. And that for those patients who would be potentially eligible to get a booster, we would encourage getting it as soon as possible. The caveats to that, of course, are the bone marrow transplant recipients and those who are CAR T-cell recipients. Where we really encourage people to delay any doses of the vaccine to a point where the immune response is more likely, and that tends to be around--from data from other vaccines--tends to be around 3 months post-stem cell transplant or 3 months post-cellular immunotherapy. So that's the time frame, and we definitely recommend that. And then for patients who are undergoing really aggressive chemotherapy, for those that are patients with acute myeloid leukemia (AML) who are getting myelo-specific treatments, maybe they like to organize for them to have their count recovery before they're given their doses. So, patients who were inpatient actively receiving leukemia therapy as an example, as their counts recover, starting their doses after they've completed their therapy, and their counts have recovered, maybe at the time of discharge would be great to give that booster. And then with those who are getting surgery, what we don't want to do is give somebody a booster the day before surgery, where they might develop some of the symptoms that can occur with people that got these vaccines, which can be general fatigue, but additionally things like fever, which can occasionally happen in patients who have a really robust immune response. And if you have a fever, it can delay your cancer surgery. So, to think about the idea of planning to get your doses after you've had your surgery and had a bit of time to recover might be best.  Planning your vaccine, at least a week before your surgery would be ideal before getting it immediately prior to a surgical procedure would probably be the best. Dr. John Sweetenham: Right, and I'm assuming that we'll maintain the same guidance for those patients if they're undergoing some kind of radiological procedure that they should avoid undergoing that imaging. Dr. Steve Pergam: Correct. Yeah, it's a really important comment that's discussed in the guidance is, if you know you're going to be getting something like a PET scan that will be looking for lymphadenopathy or evidence that you might have tumor in other locations for rescreening or restaging, have a discussion with your team about when it would be appropriate because we have seen with these vaccines, they can lead to enlargement of some lymph nodes on the side where your vaccine has been given. And there have been some images that many of us have seen where your lymph nodes can light up slightly because of an immune response. And what we don't want people to be worried that they have changes in their cancer treatment.  I think what's important is having that discussion prior to a screening that you're going to have with your team to determine the best time to get that extra dose. Dr. John Sweetenham: Great, thanks. Another question that we've heard in our own practices quite a lot, and it goes back to the beginning of the pandemic really, when the government was recommending that patients at that time got whatever vaccine they could get. So, for our patients with cancer who may have had the Johnson & Johnson (J&J) vaccine as their initial vaccine, what would be your advice now regarding how we should manage those patients as they look for what, for them, would be a second shot. Should they get an mRNA vaccine at this point or should they wait? Dr. Steve Pergam: Currently according to FDA approval documents, there is not really a pathway to get an extra dose for patients to receive the Johnson & Johnson. You can, of course, have patients get this through--because the Pfizer vaccine is fully approved, it's possible to offer it through that mechanism. But, generally that the FDA approval components at this point don't suggest doing that. And I think part of the reason is Johnson & Johnson was a later vaccine, so it was rolled out at a later time frame. So, the timing between when Johnson & Johnson was available to now is less time. And so the thought is that potentially waiting for a additional dose may be important. And I think what's critical about this is that there is data, there is a study that the Johnson & Johnson trial was approved through a trial called the ENSEMBLE trial. And ENSEMBLE 2, which is a trial, which looks at additional doses of Johnson & Johnson--it's a mechanism similar to how mRNA vaccines are given, where there is a prime boost strategy, is actually nearly finalized. And early reports in the news media--I haven't seen any of the actual data--does suggest that the second dose is quite effective and may improve responses. So my inclination is that Johnson & Johnson patients may eventually have the option of getting either another Johnson & Johnson preferably, but if not available, could receive an mRNA vaccine. I just don't know the timing of that. So at the moment, what I've been telling patients is to hold tight. And then as soon as we know more and what's available and whether they can get a second Johnson & Johnson dose or if there's further recommendations for additional dosing to just hang tight at the moment. Dr. John Sweetenham: OK, thanks. Again, just switching gears just a little bit here, one of the other discussions that was held in the NCCN Advisory Committee was around people living in the same house as the immunocompromised. I wanted to just take a moment just to say as a member of that panel how much the group appreciated your leadership and how much I personally learned from listening to you and the other leaders of that group. I think it's been a very engaging conversation. And the group acted, I think, with your leadership, very quickly to get these recommendations out. And I have to tell you that from our own cancer community and cancer center down in Texas, we were very grateful for the guidance we got from the Committee as a whole and from the leadership in particular. But just a question about those who are living in the same home as the immunocompromised. Could you say a little bit more about the advice the Advisory Committee had for those folks who are living with patients who are immunocompromised? Dr. Steve Pergam: Sure. So, first, thank you for that comment. I would just say at first that this committee is a committee that makes decisions together. And it's been a wonderful group who has gotten together and been able to develop guidelines quickly as a group. As much as you've learned from those who lead the group, I would say we've all learned from the members of the committee. It's been really wonderful to see the cancer community come together to make guidance that can really, I think, help providers and patients. So it's important. I think, in terms of household members and close contacts and family of patients cancer, this fits into what some would call a cocoon strategy, some would call a ring strategy. Where really what you want to do is you want to protect the people around that patient with cancer. Because with patients with cancer, the biggest risk they have for transmission is from a household member. You're often not masked at home. You are in much more prolonged contact. You're in a household where you can't necessarily socially distance. You're sharing the same air space. Ventilation in homes is also not the level as it is in clinics and such. The levels of protection that you get at home are significantly less. And so having someone who is a close contact who's positive is quite risky for our patients. And so what we really recommend is for those who are and live in households of patients with cancer that they get vaccinated because even decreasing a small amount of the potential that they get infected doesn't really protect those around them. I think it's really important that the efforts that are made shouldn't just focus on patients with cancer themselves. And so when our cancer centers are meeting with patients and they're interacting with caregivers and family members that come with them, those conversations should include efforts to ensure that those around them are vaccinated, because that is likely the most clear pathway for infection of an individual. And that really it really crosses a lot of issues, right? So, a caregiver of a patient with cancer is the person who's most likely to go out to the pharmacy or out to get groceries or do activities where a patient with cancer who is getting therapy may not feel up to that. The patient with cancer themselves is likely to wear personal protective equipment like masks and to socially distance and be staying home and really go to clinic and other things, but to try to avoid social exposure. So, if we can do everything we can to protect that individual, one of the most important things is to get those vaccinated around them. And I think it's a really important conversation for patients to have with their loved ones and to include the providers in those conversations to help change their opinions about this. And also, I think it's really important for those who live and work in our communities [and] that it needs to be something that businesses understand and that our friends and families understand beyond the even household itself that all of the people a patient with cancer comes into contact with ideally are vaccinated. And the way we do that is by vaccinating our community. By vaccinating people in our community, we protect the most vulnerable. And we've seen that with vaccines for things like measles, where it takes 95% of the community to be vaccinated to really protect the most vulnerable, where it's important. So, the more we can get out there and talk about the importance of [the] vaccine in our communities and why it's important for vulnerable patients and to really convince those in close households to get vaccinated, I think we're doing our patients a major service and really can help protect them from developing COVID. Dr. John Sweetenham: Yeah, thanks for those comments. And you did raise the issue of wearing masks. And do you have any comments to make on some of those other measures which we are still working very hard with our patients and our communities over, such as mask wearing and so on? Could you comment a little on that? Dr. Steve Pergam: Yeah, so what I tell patients is even if they've received both doses of the primary series of mRNA vaccines or a Johnson & Johnson vaccine, and even if they've received a booster that they should still assume that they're not fully protected. Now, it may be that if they are potentially exposed, their chances of developing COVID-19, and for needing hospitalization and for going on to need ICU admission, et cetera are substantially reduced with [the] vaccine. But since we don't understand for an individual what an individual's protection is going to be, because of the wide variety of cancer therapies that patients receive, what my general approach is to say, even if you've been vaccinated, to continue to be cautious. And I think that's particularly important with the Delta strain, which is much more infectious and much more able to spread amongst individuals that our patients with cancer, despite receiving full doses of vaccine, should continue to mask up in public, should try to avoid close contacts with large groups, to socially distance when possible, and to have discussions with everyone in their household to get vaccinated. I even recommend to try to avoid interacting with other households where there are others that are not vaccinated because of the advantages that you get from having those around you vaccinated. This is really challenging, as you can imagine, within the patients who live in households with young children who are going back to school. And so in those situations, having a discussion with the school if possible and having your children wear masks when they go to school can be helpful. We don't know the total benefit in terms of protecting an individual at home, but any way that you can protect yourself from getting COVID-19 is really critical. So what I suggest is [to] get everyone who can be vaccinated vaccinated, wear masks in public, socially distance, wash your hands really well, and avoid crowds as much as possible. And if it means doing a few more Zoom calls with your family that have unvaccinated individuals, then that's something that may need to be something you do. And let's say you're an older patient who's a patient with cancer who's received your third dose of the vaccine, and you want to go visit your grandchildren who are unvaccinated. Well, have a conversation with family about that. First, is it necessary to do in-person? If you can do it by virtual methods, you can. But if you do need to go see them, plan to do those interactions outside and consider wearing a more protective mask, something like a KN95 or a surgical mask with potentially even a cloth mask on top--so a double mask. But I think a can KN95 mask would be my best recommendation. And then you can interact with them outside and not indoors where the potential risk of transmission may be higher. And that may not be what everyone wants to do, but it's all about being there for your grandchildren and your family for the long term, and that's the goal in all of this is to protect our patients as long as we can. Dr. John Sweetenham: Great, thanks, Steve. That's great common sense advice, and I think a great way to round out our conversation today. I want to thank you very much for sharing the update on COVID-19 third shots today for our patients with cancer. And also once again, just to say thanks for the work that you've been doing with the NCCN and beyond in helping the oncology community navigate the pandemic. So, [I] really appreciate your time today. Dr. Steve Pergam: Well, thanks for having me, and best of luck to all my colleagues out there and to all of the patients who are listening in. Know that all of us are working really hard to do what we can to protect you. Dr. John Sweetenham: Thanks, Steve. And thanks to our listeners for joining us today. If you enjoyed this episode, please take a moment to rate and review us wherever you get your podcasts. Thanks and goodbye.   Disclosures:  Dr. John Sweetenham: None disclosed Dr. Steve Pergam: Research Funding: Global Life Technologies, Chimerix, Merck & Co., Sanofi Pasteur Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Transcript: Dr. John Sweetenham: Hello, I'm John Sweetenham, Associate Director of Clinical Affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and the guest host of ASCO Daily News Podcast today. I'm joined by my friend and colleague, Dr. Derek Raghavan, President of the Levine Cancer Institute to discuss a new study that he and his group published in JCO Oncology Practice outlining a novel approach adopted by his institution to address financial toxicity caused by the rising costs of cancer care. Dr. Raghavan is going to tell us about the creation of a Financial Toxicity Tumor Board, which shows promise as a potential solution to significantly ease the financial burden of cancer treatment on patients and their families (DOI: 10.1200/OP.21.00124). Dr. Raghavan's full disclosures are available on our show notes, and disclosures relating to all episodes of the podcast can be found in our transcripts at asco.org/podcasts. Derek, it's always a pleasure to be speaking with you again on the podcast. Dr. Derek Raghavan: Hi, John. It's a pleasure to have time with you again. Dr. John Sweetenham: You know, I've had an opportunity to read the publication in JCO Oncology Practice, and it really is fascinating and a very interesting new approach. We know from many studies that financial toxicity is among the most rapidly growing adverse effects of cancer treatments. And patients report financial distress is a major hurdle to the quality of life. And its association with worse outcomes is now very well documented. At the Levine Cancer Institute, as your paper describes, you created a Financial Toxicity Tumor Board, which you abbreviate to FTTB, to address this problem. And I wonder if you'd be able to describe a little bit about this tumor board, and perhaps in particular which components of this you feel are really a new approach to addressing the issue of financial toxicity. Dr. Derek Raghavan: Thanks, John. Yeah. I mean, I guess it's important just to define what we're talking about because there are still people, particularly clinicians, who don't really understand the concept. So, I think it was probably Jonas de Souza, among others, from Mark Ratain's group, who were early in both identifying this as an issue and studying it. And so, the concept of financial toxicity is really pretty simple. And that is that people are struggling to pay their bills and the bills are going up. With the way the pharmaceutical industry is able to set prices ad libitum, the fact that there's a lot of lobbying that goes on in Washington, and elsewhere, the prices that people have to pay can be really quite extreme. People that are insured are, perhaps in this domain, particularly at risk because if you have, for instance, a good insurance policy with a 10% copay, and think about the cost of maybe half a million or a million dollars a course of targeted therapies or for CAR T treatment, or whatever, 10% of $500,000 is an awful lot of money for someone to come up with unexpectedly. So, the whole idea of financial toxicity is something that has emerged with the rising costs, and more particularly, the rising prices of health care. I think the other thing that that's important is while we are seeing this reported more, and you know this from your experience, as to why, patients really protect their financial status almost more than anything else. They don't like to admit that they're struggling financially. And there will be people who are mortgaging the house, but who don't share with the medical team that they've run out of money, that the health insurance plan isn't working. And so, they're really making choices that are very tough. If you have no income and no insurance, I'm not implying that it isn't a problem. There are people who will still have bills to pay and have to make choices between buying food and buying their drugs. And in your practice and in mine, we both know that sometimes patients select in favor of food, which makes perfect sense, because they can't afford food and drugs. So, the whole concept of the Financial Toxicity Tumor Board came from understanding that. At the Levine Cancer Institute, we have a big commitment to outreach and underserved populations that the team that's led by my colleague, Melissa Wheeler, last year had 68,000 people that they saw at outreach. And that included a lot of uninsured or underinsured people. And they were bringing back to me stories of the difficulties these folks were having in terms of why they weren't seeking medical care. Given that we are the safety net in this part of North Carolina, that's particularly troubling. And then the final thing that I'd say is with respect to underreporting, we here use a system called Tridiuum, which is an electronic system that asks patients about their quality of life. And one of the cases--one of the questions that is asked is, are you having difficulty paying your bills? And when we compare what we've learned at the FTTB, the Financial Toxicity Tumor Board, with the answers on Tridiuum, it's quite clear that patients, while they'll talk about nausea, and vomiting, and pain, and things like that--depression--they will often say, no, I'm not having trouble financially. They'll answer to the question, no, I'm not having trouble. But we actually find out they are. And the final point I'd make--and I suspect that because you and I went through medical school a couple of decades ago, we were both taught that it's rather inappropriate to discuss something as unpleasant as money with patients because it will make them feel that we're judging them or that we're withholding treatment. As a consequence of that, physicians have been trained really not to discuss the costs of care. And that becomes a pretty big deal when you're actually going to have a patient that might give up little Johnny's college education for a new treatment. I mean, it might be worth it if it's going to cure them. It might be worth it if it's going to give them a 10-year survival. But if you're talking phase I study, or a drug in the third or fourth line, which might give 2 or 3 months of extra survival, giving up little Johnny's education might be a bad trade-off. And so, the whole concept of the FTTB was to get us to do things to help patients, but also to get a physicians and the advanced practice nurses and the whole team to be focusing a little more carefully on the whole issue of this problem for patients. So, coming back to your core question, we developed a tumor board, much like breast cancer tumor board, or GI, or whatever, that is multidisciplinary. It has all the service chiefs at our institute, several of the physicians from different domains, the nurse navigators--we have about 40, 45--our financial counselors, the people in the billing office--so administrators. I'm at present, at these finance people. We get together and identify the worst of the problems. We have a couple of our finance people and a couple of our financial counselors who triaged the cases. If it's something simple--so Mr. Smith is age 70 and hasn't managed to get Medicare for some reason. That's not an FTTB problem. That just gets handled by the financial counselor or the navigator. But if it's one of the big problems that we found, like people who don't have insurance, people who are getting impediments from the payers, issues that relate to coding and billing, problems of precertification, that's the time when the FTTB becomes involved. Dr. John Sweetenham: That's great. Thanks. And I think that the point you make about these are issues which affect the insured as well as the uninsured are really important. And interesting that you have--it sounds like you have a pretty systematic way in which you can identify and engage those patients who might be embarrassed or reluctant to disclose that they have some level of financial distress. Dr. Derek Raghavan: Yes. That's correct, John. We have some signs posted. All of our staff are trained to raise the issue in as nonjudgmental and as engaging and passionate as they can. Interestingly, it's often the front-line staff at the front desk or the nurse navigators that get the information. A proportion of our patients will actually just ask for help and see a financial counselor. But the whole group has been trained to be as empathetic as possible and to create a scenario where it's kind of put to the patient that we understand this is not on you. This is the way health care is today. There are gaps that relate to how we pay for it. So, let us try to help you. And I think for that reason, patients are much more comfortable to address the issues once they understand how this works. Dr. John Sweetenham: Right. Could you say just a little bit more and expand on how the patient assistance program kind of fits into this model? And then as a follow-on question to that, could you tell us a little bit about what the cost savings for your patients have been and how many patients have been impacted by the tumor board so far? Dr. Derek Raghavan: Sure. Well, the process, as I explained, is multidisciplinary with a whole bunch of different people. We've folded all the bits together. So, we have social workers and financial counselors who can access philanthropic support for the people where we simply can't figure out an answer. And so, in that context, that'll be copay assistance or other philanthropic things. We actually measured this in 2020 and 2019. And so, in 2019, we gave out about $1.4--a little bit more--million to about a little over 1,200 patients. In 2020, it was about $1.39 million, and it was about 1,000 patients we helped. In terms of saving out-of-pocket expenses, I was surprised when we actually measured it and looked at it. So, in 2019, we helped nearly 600 patients. And we saved them out of pocket expenses of $55 million. Dr. John Sweetenham: Wow. Dr. Derek Raghavan: In 2020, it was 749 patients. And there, to my surprise, it was $60.7 million. So, this is not chump change. This is really big sums of money. We did an analysis and we reported this in JCO OP and found that 29% of the patients just were dealing with lack of insurance or under insurance. Oftentimes, a policy that had fine print that said, while you're well, we'll cover you. And when you're sick, we won't. So, we had to deal with that. There were payer impediments. And you and I both--I know we've chatted about this over the years. There are wonderful payers and health insurance companies and there are some that are pretty tough. They all pay their insurance executives seven or eight-figure sums--and claim to be struggling. But the payer impediments will relate to changing their rules, having fine print that doesn't cover the rules. One month, you'll have to get--so for example, at one point, we discovered that they were turning down rituxan for diffuse large cell lymphomas. And there was one word in the diffuse large cell that was missing from what the doctors might have been writing. And so, they were denying payment for that and sending bills to patients. There will be coding or billing complexities. That's, again, at about 20% of the cases we've seen. The toughest one is only a small proportion at the moment because we've worked on it, but it's variable--and that's precertification. And the problem there is the companies change their rules for who needs it and who doesn't. For example, in North Carolina, Medicare recently required precertification for chemotherapy that didn't require it previously. And they set a start date and suddenly we had to cancel a bunch of patients for that date because the website to allow precertification didn't open until the day began. And so, we had to just defer by 24 hours chemotherapy so that we could get the patients precertified to avoid them getting bills. And then I have to say--I mean, 20% of our problems have been inadequate internal processes. And that means if we'd done things better internally, we could have avoided problems. And so that brings in the way we approach management of denials. We've become very proactive. So, I now have a team of pharmacy techs who, for example, chemotherapy will go through the rules for each health plan for the individual patient to make sure that we're actually doing the precertification correctly as of the day of treatment because the rules may have changed. So that's pretty much how it works. We've got pharm techs who work the cases in advance. We often spend an awful lot of time talking to insurance companies. As you know, they can make it very difficult to get to the right point with the recent changes with white bagging and brown bagging where they're deflecting and deferring referrals of treatment to their own pharmacy companies, that will often not be patently obvious till we have a patient here ready to go, and we suddenly discover that they want us to get the drug from a specialty pharmacy that's their special one. So, all of this requires an awful lot of advanced planning. Now I think if government took a little more interest in the way the insurance companies work, it would make life easier--but they don't. And so, we have used this strategy of Financial Toxicity Tumor Boards to move this forward. And I will say that one of the very useful things it's done, it's sort of like ripping a Band-Aid off. It's created a scenario where we are now able to educate our physicians about things that they simply didn't know existed in terms of problems of reimbursement insurance and so on. Dr. John Sweetenham: Right. And so, the process and the success that you've described with this tumor board is really pretty remarkable. I'm quite struck by the fact that this requires a lot of resource-- particularly, human resource--and a lot of organization to make it work. So, we often talk about whether a new initiative is something that's scalable. Do you think that this FTTB model is something that's scalable down, if you see what I mean, so that it could be successful in relatively small practices as it has been in a large system such as the one that you operate? Dr. Derek Raghavan: Yeah, John, I think that's a really good question. So, if you're thinking about scalability, if you're thinking about a place like the Simmons Cancer Center at UT Southwestern led by Carlos Arteaga and yourself, I'm sure that you could do something similar. It's a big center, it's a national referral center, it's NCI designated, and you've got reasonable support and philanthropy. So, you could do this, if you wanted to, easily.   If you then scale it down to a private practice or an office oncology practice, I think the answer is, you can do much of it. You might not be able to do everything that we do. But it's certainly reasonable that if you have, say, 30 patients coming up over 5 days for chemotherapy, your chemotherapy nurses can be rostered to actually do some of the work that we do in terms of checking insurance situations and so on. Many of the smaller practices worked predominantly with two or three health insurance companies, so therefore there are less sets of rules. I think the other thing is a lot of the stuff is repetitive. So, I gave you an example of rituxan and lymphoma. So, if you've got people focusing on those who can send a note around the practice to say, moving forward, if you want to prescribe rituxan, is the phrase that needs to be there to describe the type of diffuse large cell lymphoma you're addressing. So, I think it is scalable. It's more a question of changing attitudes and accepting that medicine has changed, people are struggling to pay their bills. And physicians--particularly in an oncology space--can actually spend a little time going through the cost of care with patients, thinking about the alternatives. We use biosimilars a lot. We're very careful to use biosimilars where the evidence really supports the fact that they are an equivalent product. Occasionally, we struggle with that because the insurance companies obviously are doing deals with some of the biosimilar companies, and we may be at short notice discovering that we need to prescribe biosimilar number two rather than number three when we thought number three was the best drug. That becomes an ethical issue. And then I think you just have to look at the quality of the data and decide whether it's reasonable or not. Some of the biosimilars, I think, are ones where we're not sure that they're equivalent and then we do not use them. Dr. John Sweetenham: So, we've talked a lot at a system level and the kind of global problem that we all face now with the financial toxicities. But ultimately, this is an issue for individual patients. And with the system that you've put in place, the ultimate beneficiary of this, of course, is the patient. And I just wondered if you may be able to share perhaps one example or a couple of examples of patients whose stories kind of exemplify how helpful this can be. Dr. Derek Raghavan: Yeah. Yeah. I think in the story that we told; we described a patient where there was confusion on the explanation of benefits that was provided to the patient. This was a person with--who'd had adjuvant chemotherapy following surgical treatment of pancreatic cancer and then suddenly got a whole bunch of bills because it was noted that one of the drugs--just one of the drugs in the chemotherapy regimen--required specific precertification, which actually was not clearly seen in most of the documentation that was available. So, in that situation, our financial counselor actually talked to the company and was able to make things better. In the situation of patients with malignant lymphoma heading to bone marrow transplantation, that's been one where various companies have used denials as a mechanism of creating leverage for contracting. There, what we've done is generally approach doctor-to-doctor to the physicians who work for the companies. As a general rule--and I don't think this is an overstatement--I think it's easier if you talk doctor-to-doctor to a company that will employ an oncologist or a retired oncologist. Unfortunately, sometimes it'll be a retired surgeon or an internist who's punching well above his or her weight. And that's a little bit more tricky. Frankly, I in my own practice in the past have used politicians. When we get finally to a dead end, I will provide a letter that describes what we've done, give it to the patient, and say I suggest you go and see your local congressman or senator. It's amazing how quickly payers respond to a phone call from a politician. And that's because there's an awful lot of lobbying that goes on in Washington. The companies certainly don't want to bring attention on themselves. But I think, generally, it can be quite a good partnership if the physicians are doing their part and thinking about the bang for their buck. In other words, are they providing treatment that's going to make a difference? They make sure they're following the rules, and that requires proactive management. Develop a good relationship--the companies certainly respond to a group that are trying to provide cost-effective care. Dr. John Sweetenham: Thanks. And just one last question before we wind up. And that is, I think this wasn't the primary motivator for setting up your tumor board, but what do you think the impact of this kind of approach--if we were all to adopt this more formalized approach, what do you think might be the impact that it would have on cancer care disparities? Dr. Derek Raghavan: I think it can help. I think the biggest problem--and John, you'll roll your eyes because you've heard me say it before--I have a problem with analysis paralysis. So many people working in the NCI-designated network and beyond it love to do studies of underserved populations. And my thought is, why don't you start trying to problem solve and tweak it as you go along? And so, I think what this sort of approach does is it makes physicians and advanced practice nurses, and oncology pharmacists think more about the issue of the cost versus outcome. It allows us to help patients to deal with the problem. And because we're trying to bring all the costs down, it really goes to the value proposition. As I think you know, we have electronically accessible pathways that are evidence-based, but certainly looking at the costs of care for equi-active and equitoxic drugs is a big piece of that. That's why we sometimes use biosimilars. So, it will generally bring the costs and prices down while also trying to help reduce the out-of-pocket costs for our patients and make us more value-orientated in terms of the whole product. And the other thing I think is really important is if we can do it in oncology, then the cardiovascular people, and the neuroscience people, and so on can equally be thinking along these lines. Dr. John Sweetenham: Yeah, absolutely. I agree with you. And I'd have to say, I really appreciate having an opportunity to talk with you about this. When I read the article, I immediately fired it off to our leadership team here to take a look at because I think there is much to learn and commend this particular article and the application of this type of tumor board to everyone who's listening. It's a really very, very interesting and novel approach to what is clearly going to become an increasing problem for our patients with cancer. So, in conclusion, I would just like to say, thanks again, Derek, for sharing some time with us and sharing your insights into the tumor board. Dr. Derek Raghavan: John, it's always a pleasure to chat with you, and especially to be interviewed by, and I've enjoyed this discussion. I hope it's been helpful to your audience. Dr. John Sweetenham: I'd also like to thank our listeners for joining us today.  You'll find a link to Dr. Raghavan's study in the transcript of this episode. And finally, if you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thanks, and goodbye.   Disclosures: Dr. John Sweetenham: None disclosed. Dr. Derek Raghavan: Consulting or Advisory Role: Gerson Lehrman Group, Caris Life Sciences Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Ana Maria Lopez, professor and vice chair Medical Oncology at the New Jersey division of the Sidney Kimmel Cancer Center – Jefferson Health, discusses the future of telemedicine in cancer care and how to make it sustainable and accessible to all patients and survivors. Transcript: ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Ana Maria Lopez, a medical oncologist, professor, and Vice Chair of Medical Oncology of the New Jersey division of the Sidney Kimmel Cancer Center, at Jefferson Health.  Dr. Lopez is a member of ASCO's Telemedicine Working Group, and joins me to discuss the future of telemedicine in cancer care and how to make it sustainable in the years to come while striving for quality care for all patients and survivors. Dr. Lopez's full disclosures are available on the transcript of this episode, and disclosures relating to all episodes of the podcast can be found on our transcripts at ASCO.org/podcasts. Dr. Lopez, it's great to have you on the podcast today. Dr. Ana Maria Lopez: Thank you so much. Happy to be here. ASCO Daily News: Dr. Lopez, do you think that the COVID-19 pandemic and the increased use of telemedicine will permanently change the way patients with cancer are cared for? Dr. Ana Maria Lopez: You know, I hope so. And the reason I say that is because we've learned a lot. And we've learned that there are ways that we can care for people better at a distance. And so, what we've learned and what we can take forward, I do hope that we'll be able to do. So, for example, we know that a lot of the screening for a cancer clinical trial may be able to be done at a distance. And that way, when the patient actually comes for the appointment, there can be a more rapid entry into the trial. We know that patients may be able to stay at home safely at certain time points--perhaps at time points during survivorship, perhaps if they're doing very well with their treatment. Or if they need an acute assessment, something that needs to be done right away, the camera could be opened, and the conversation can be had. We also have some recent data that being able to care for patients at home may be able to pre-empt some hospitalizations. And to be able to do this with the benefit of telemonitoring, of visual monitoring--that all of these may be very helpful for patients, and may be able to improve their quality of life as well as let us help them with whatever the acute problem is at the time. ASCO Daily News: Absolutely. Those are very positive developments. I know you do have some concerns about disparities in care that emerged during the pandemic. You know, the COVID-19 pandemic exposed a host of disparities in cancer care, including access to telemedicine. During the 2021 ASCO Annual Meeting, you chaired an education session that assessed disparities in digital access and implications for telemedicine. Our listeners will find a link to the session in the transcript of this episode. So, Dr. Lopez, can you tell us about the major barriers to telemedicine that are of concern to you today? Dr. Ana Maria Lopez: Yes. It's really been such a learning experience. You know, telemedicine was really developed to increase access to care. And then to realize during the pandemic that in some situations, telemedicine, telehealth was really a barrier to care. And the reason for that is we used to do telemedicine--for example, a rural patient. The rural patient would go to the local clinic, the local clinic would have this incredible telemedicine setup that maybe included a tele-stethoscope, a tele-otoscope, so that you were really able to do the full exam virtually, with the exception of palpation. And everything was very well set up. But when telemedicine, during the pandemic, really translated--and this began before the pandemic as well, but not to the massive scale. But telemedicine really went to the patient's device. So, the patient needed to have some sort of a smartphone or a tablet, or some device that was connected, preferably, to broadband internet. And not everyone has that. And even if they're in an area where they might have access, it might be spotty in a certain part of the house. Or everybody is trying to get on the network for home schooling, for work. They may not have enough access, enough bandwidth, for the telemedicine appointment. So, access to broadband internet is critical. And then if people had access, their device might not have the right access, or they may not know quite how to get onto their device to get to the telemedicine visit. So digital literacy really came up. You know, we've always talked about literacy. We've talked about numeracy. But now, digital literacy. And we, as clinicians, really needed to advocate for our patients so that they would have the digital literacy to do the telemedicine visit. And I think, actually, also for us, as clinicians, and for the health care team, did education training on the technology, but also on how to engage. You know, there's so many questions that people will have. Well, can I really engage the patient well enough? Can I really make that connection with the patient, which is really what we treasure in the patient/physician relationship? Will I really be able to make that through this machine? And so how can we help people so that they can engage? And again, it may not be the same. But can it provide the care that both parties can really feel, yes, that meets the need at the time? So, I think all of those factors can be important. And they are all, I think, areas that can be overcome. ASCO Daily News: Absolutely. You spoke about access to broadband; you spoke about digital literacy. These things, of course, impact patients in rural settings, [and] older patients. So, it is very important for oncology practices and advocates to be thoroughly aware of best practices, and be knowledgeable about telemedicine tools moving forward to increase access for patients and to help stakeholders learn how to use the tools more effectively. Can you highlight best practices and ways to ensure that clinicians are using telemedicine to best serve the needs of patients and survivors? Dr. Ana Maria Lopez: There's so much in that question. So best practices, I think, we're still learning, which is one of the, I think, great things. I often think of telemedicine as a translational science because we go to the engineers, you know, I've got this problem, and they work it out. And then we can take it back to the bedside, or as some people say, the website, and try it out, really develop these approaches so that they can really help our patients best. But I think what you're pointing to is the real importance of education and training for the clinical teams. Something as simple as, you know, when a patient comes in normally to an appointment, there are vital signs. And again, in the pandemic, in many settings, we didn't have a way to collect those vital signs. So how can we, now that we have our lessons learned, work together to develop processes so patients can do their vital signs at home? Do we send a blood pressure cuff? A pulse-ox often has the heart rate on it. So, do we send these as a little kit? Or do we give these test kits to patients, and educate them on how to take their vital signs at home, so that those data are not missing when we see our patients through telemedicine? I also think when we were talking about engaging earlier, we're taught, in medical school, how to engage with the patient who's sitting next to us. But how do we engage with the patient when our connection is the camera? How do I look at the camera so that the patient--it appears that I'm looking at them, as opposed to looking at their eyes on the screen? So that that's engaging of the patient? I may find myself speaking a little more slowly or pausing more often in order to facilitate that engagement through the telecommunications technology. So, I think there are best practices just from the how to use the technology piece that we need to think about. But also, we need to better understand. What are the areas where telemedicine is most apt? Where do I really feel confident that this is the application to use, and in what situations do I say, you know what? I really need a hands-on approach. And how do I educate so that--let's say I'm following a patient who has a skin lesion. How do I educate the patient to be able to transmit those images faithfully to me, so I can really get a good-quality image, so that my interpretation is clinically appropriate? I think the most important best practice is that we shouldn't think that we're settling. Telemedicine, the technology, has incredible capacity. And if we are ever in doubt as a clinician that, you know, I wish I could do x, or if I had such and such, I would be better able to make this interpretation, if that crosses my mind, then I should see the patient in person. The assessment that I am giving the patient at the time, as a clinician, I should be really comfortable in, whether it's telemedicine, in-person, medicine, telephone, it should really be--I should feel confident. And if I'm not confident, then I should do what I need to do to care for the patient. ASCO Daily News: Absolutely. Is it your sense that oncology practices, [and] smaller community practices, are hearing your call, so to speak, and putting proper trainings in place and follow-up, et cetera? Oncology practices are very busy places. What are your thoughts on this? Dr. Ana Maria Lopez: So, in the same way that--what I said to the med students, you know, is you'll always do the right thing if you put the patient first. Always. Because you'll read, if you're not sure. You'll go talk to a colleague. You'll do what you need to do if you keep your goal the best care of the patient. And similarly, here, if we are going to use telemedicine, then as a clinician, I want to be proficient. I want to do the best job that I can. And so, then I want to get the training that I need in order to get that done. One of the things that we're instituting is, really, new doctors come in. Whenever anybody comes in, you're accustomed to, there is a whole set of learnings that have to happen, right? Because every institution is a little different. And we have our telemedicine trainings that are a part of that. And I think that's really important, because that shows that the health system, that the University system, that the Cancer Center has, as its core, that we understand you may not be 100% proficient at all of this. We don't expect you to. But we expect you to take these learnings and boost your knowledge in this area. ASCO Daily News: Right. In that context, then, of quality care, putting the patient first, how do you think telemedicine will serve patients and survivors in the future? Do you see great improvements in technology? Building better platforms for patients? Do you see these technologies on the horizon? Dr. Ana Maria Lopez: Absolutely. I think we sometimes think, for example--so cancer care. Cancer is a disease, predominantly, of elders, in the sense that as we get older, we're at higher risk for the disease. And as we get older, for example, our eyes age, our hands may become arthritic. Any of these issues could happen to any one of us. And technologies are being developed so that these are easier--so it's easier to maneuver the keypad, so that the lighting is more appropriate. And I think that all patients have a keen interest--and certainly patients that have been diagnosed with cancer--have a keen interest in their health care, and have a keen interest in maximizing their health care. So, bringing to them, you know, here are ways where you can maximize your telemedicine visit is generally very welcome. That sort of education is generally very welcomed by patients. ASCO Daily News: Right. What do you see as the biggest challenges for telemedicine in oncology in the future? There's been the promise of federal funding for these things. What are your thoughts? What what's your checklist for the future? Dr. Ana Maria Lopez: So, one of the things that really helped telemedicine expand as widely as it did during the pandemic and currently is that telemedicine is reimbursed. Very simple. But it's something that we've been working towards for a long time. So, telemedicine reimbursement really needs to continue if telemedicine is to continue. So, advocacy. And ASCO, other professional associations, are certainly at the forefront in advocacy. Reimbursement, tele-education for patients, for clinicians. Broadband, we've talked about. But something that we need to do as a profession is really be able to say, in what way do we want telemedicine to be sustainable in the future? And what will that require? So, for example, things like when patients, let's say, join a practice. Do they receive a telemedicine kit for vital signs? We know, for example, some practices in pediatrics--otitis media are a very common pediatric problem. Parents receive a little otoscope that they can be taught to use, and can have available should they need it. So, for us to really think, what do we need for sustainability? The camera on the phone is now, generally, a pretty high-quality camera. So, in what way can those tools be leveraged to be able to transmit more diagnostic-type images? That's probably not the right term, but images that are of higher quality that one can really make a better interpretation if that is something that's being looked at during a clinical exam. So, we really need to think of sustainability. As you may know, the numbers shot up during the COVID epidemic, the peak of it. We're not past the epidemic. And they have now--telemedicine has not decreased in use in many, many places. So, the easiest thing for us to do as clinical people, as patients, is to just go back to what we're used to. And then we would really lose all the lessons learned. So, I think it's really important to think proactively. Where are the benefits? How can we maximize them? How can we sustain them? ASCO Daily News: You mentioned sustainability. With sustainability in mind, would you agree that further research is necessary to leverage the best of telemedicine in oncology while making changes to improve the patient experience in a sustainable way? And are there any studies, any research, that you're keeping an eye on at the moment? Dr. Ana Maria Lopez: Yes. I think research is critically important to inform telemedicine sustainability, and to think about, really, what are the right applications for future care? And that these are ways, again, to increase access. Fundamentally, this will increase access. So, I think there are many studies to even think of what are the right metrics? What is it that we really are looking at, and what is it that we need to measure? There are things, for example, in cancer care. Cancer care is multidisciplinary by nature. So, there's teleradiology. There's telepathology. In what ways can those services be helpful to the patient, whether the patient is seen in person or at a distance? We've talked a little bit about the access to clinical trials. And again, in what ways can "tele" be integrated in order to increase access to clinical trials? And I think that area, will really blossom. That's an area, again, where hopefully, our lessons learned will not just retreat as something of historical interest. And then is there a right interval, for example, for seeing patients, whether in survivorship, or even during treatment, where you can do an assessment and feel comfortable that if you're doing a visual assessment or if you're doing an assessment that is at a distance with different tools that can do more of the traditional type of physical exam, that we can feel comfortable that that was the right exam? So, these are things that are very concrete, and are very studiable. And I'll give you an example. So, we could have a patient who is being treated for a malignancy. They could have an in-person exam, an in-person assessment, and then they could go into another room and receive a tele-exam, tele-visit, with another clinician. And then the assessments could be compared. Did we get to the same outcome? And is it maybe every other visit that would be comfortable to do at a distance? So, I just think these are really important questions to think about sustainability. And although they may seem very concrete, they're very important to think about how we will carry telemedicine into the future, as well as some of the aspects that we talked about--helping the telemedicine tools be more useful, be more, really, user-friendly for the patient population. And also, to take into consideration that there may be times where the patient, where the clinician, may say, you know, yes, we could do it through telemedicine, but I think it's time for us to see each other face-to-face. And so, too, there's the flexibility to honor the patient's preferences as well. ASCO Daily News: Absolutely. You've raised so many very important [and] interesting points today. Are there any other thoughts you'd like to share before we wrap up the podcast today, Dr. Lopez? Dr. Ana Maria Lopez: One of my favorite images--and I know it's a podcast, so you can't show the image--but there was a cartoon in the front of a magazine that was called “The Radio Doctor.” And I think it was from the 1920s. And I was always so impressed by this because it basically showed a telemedicine setup. And of course, telemedicine didn't happen until much later. And here we are, probably close to 100 years from that image in the front of that magazine, and we're tackling what was visualized, what was envisioned then. So, change, growth, takes time. So, I think that that's really important to remember, that things take time. So sometimes, we may get impatient. At the same time, we want to do it right. And we want to do it with the patient, really, at the center of all of this. So, I very much feel that we've learned a lot of lessons. I look forward to thinking about telemedicine sustainability in cancer care and in clinical care overall. And a part of that work really needs to be working with patients and hearing their voice, and hearing how we can work together so that the clinical experience is as good as [it can be], and there are some data that in certain settings, patients prefer the experience. So, to help us understand what feels better to them, then, and how we can improve the experience overall. So, it's an exciting time. And I look forward to what the future will bring. ASCO Daily News: Indeed. Well, thank you very much, Dr. Lopez, for shining a spotlight on the role of telemedicine in cancer care. Some interesting times ahead. Thank you, Dr. Lopez. Dr. Ana Maria Lopez: Thank you very much. Thank you. ASCO Daily News: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosure: Dr. Ana Maria Lopez: None disclosed. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Transcript: ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. The American Cancer Society reports that at least 42% of newly diagnosed cancers in the United States, excluding non-melanoma skin cancer, are potentially avoidable because they are attributable to lifestyle factors. Today we will discuss strategies and resources to help the oncology community focus on health promotion as a key component of cancer risk reduction as well as in survivorship care. Joining me for this discussion are Dr. Amy Comander, the director of breast oncology and cancer survivorship at the MGH Cancer Center in Waltham and at Newton-Wellesley Hospital, and Dr. Poorvi Desai, a hematologist-oncologist at Comprehensive Hematology Oncology in Tampa Bay, Florida. Both Dr. Comander and Dr. Desai are board certified in lifestyle medicine. My guests report no conflicts of interest relating to our topic today. And their full disclosures and those relating to all episodes of the podcast are available on our transcripts at asco.org/podcasts. Dr. Comander and Dr. Desai, it's great to have you on the podcast today. Dr. Amy Comander: Thank you so much for the invitation. Dr. Poorvi Desai: Thank you, it's really great to be here. ASCO Daily News: Dr. Comander and Dr. Desai, you recently co-wrote an interesting editorial featured in the ASCO Daily News that raises concerns about newly diagnosed cancers in the United States that are potentially avoidable because they are attributable to lifestyle factors. You also note that as the population of cancer survivors in the U.S. continues to grow, risk factors for cancer development are becoming more prevalent. So the obesity epidemic in the United States is a huge concern. This is just one risk factor for cancer. Dr. Comander, can you tell us about this and other risk factors and why oncologists should be addressing these risk factors sooner rather than later? Dr. Amy Comander: As you clearly stated, there's increasing prevalence of obesity in this country. And this has troubling consequences in terms of cancer risk and outcomes for specific types of cancer. Interestingly, just this week, we learned data from the annual report to the nation on the status of cancer that, overall, cancer death rates in the United States are declining, especially for lung cancer and melanoma. And this is amazing. And that is due to the incredible advances in treatments that we've witnessed over these past few years. But interestingly, for prostate cancer, colorectal cancer, and female breast cancers, death rates continue to increase or these declines have slowed or even leveled off. And in terms of understanding why that may be the case, it seems that lifestyle factors, such as obesity, lack of physical activity, [and] increased alcohol use, may be risk factors for why we are seeing these results. And therefore, further research will certainly need to be done in this area, but attention to these factors is very important. ASCO Daily News: Well, Dr. Desai, I'd like to ask you about your interest in lifestyle medicine. I understand you became interested in lifestyle medicine during your fellowship training. Can you tell us about this? Dr. Poorvi Desai: Yes, I recently just graduated from my hem-onc fellowship at USF and Moffitt Cancer Center. And I was really impressed during my fellowship looking into all of the data very particularly when it comes to every single different type of cancer. But one thing I thought was lacking was just the overall picture of lifestyle factors, and especially modifiable risk factors, when it comes to pre-survivorship along with things that patients can do during active treatment and in the survivorship phase. And I think that there are structures that are starting to appear to help guide us with more evidence-based data. And so I became very interested, as I had an attending in my internal medicine residency who was a part of lifestyle medicine. And through the American College of Lifestyle Medicine, I met several people around the country who had been working with organizations such as AICR, as well as the World Health Organization, [and] American Cancer Society. And there was a very big push on these lifestyle factors to look at them in a way that is actually studied through evidence and actual guidelines that I was never really taught about throughout my fellowship. So I made it a point to kind of self-teach a lot of this. But I definitely think that there's a role moving forward in bringing this to not just fellowship education but just all of oncology care, whether it's medical oncology, surgical, radiation, but just any oncology care team. ASCO Daily News: Well, you make a really great point. Evidence-based guidelines do exist to help facilitate lifestyle modification in cancer care, but there are barriers to health promotion in cancer care. Dr. Comander, what are the major barriers? Dr. Amy Comander: That's an excellent question because we know this is an important issue. And actually, it was an issue studied recently by ASCO. Dr. Ligibel and colleagues published a paper in 2013 that was a survey of oncologists and their understanding of obesity and other lifestyle factors and how they address these issues in clinic (DOI: 10.14694/EdBook_AM.2013.33.52).  And I think we can all say that our colleagues are well aware that obesity and lifestyle factors play an important role in cancer outcome. But in terms of the practical steps of how to address these issues with our patients, how to get our patients to lose weight, how to get our patient to exercise, how to help our patient cut back on alcohol use--those are just some examples--there really are limitations. And in that paper, they really outlined some of the reasons for that. Some of it is lack of education, as Dr. Desai just noted. She sought out teachings and lifestyle medicine as part of her fellowship training. She had to go elsewhere to look for that because it really wasn't part of the standard curriculum. So a lack of education, lack of resources. I'm fortunate to work in a cancer center with excellent oncology colleagues with expertise in nutrition, exercise, et cetera. But we know, in the rest of the country, not every doctor has access to these resources. And the third reason is really lack of clinician time. Our visits are very focused. And often the priority, of course, is discussing the patient's treatment, how is--I'm a breast cancer doctor. How is my patient doing on her endocrine therapy? What kind of side effects is she experiencing? How can I ensure she's complying with her medication? So there really isn't a lot of time to address these issues in a visit. So these are all factors we need to work on. ASCO Daily News: Well, how about solutions? How tough is it to convince patients who are grappling with the physical and emotional toll of cancer treatment to prioritize their nutrition and exercise? Dr. Desai, what do you think are the next steps? What would you say to oncologists who really do need to pay more attention to this? Dr. Poorvi Desai: So I think that one of the biggest things to take out of our article is that oncologists don't need to carry the burden of doing this by themselves. I think that while it does take a lot of resources, which is a big constraint, especially financially, I do think that there is a lot of worth in building a care team that's dedicated towards this. Or if that's not possible, then seeking out community, local, or national resources and kind of bringing together any other structure that's already in place and having a good referral to those areas, so that patients do understand that it is important to continue physical activity and working on nutrition. And I definitely think that it's something that patients feel they can have some control over. I think a lot of oncologists don't feel qualified to talk about these things because they are not very well taught in our education. And so I think then a lot of patients in this realm of lifestyle feel on their own in trying to figure out what's good for them, what's not good for them. There's a lot of misinformation online and unsolicited advice that can be given to our patients. There's a lot of fear around foods and what the right type of activity is. And I think that the more evidence-based information that we have to provide to our patients, we can be more confident in making these suggestions. And again, we don't--as oncologists, we don't need to be the ones who are actually doing all the counseling, doing all of this, making sure that they have their exercise prescriptions or whatever it may be, but at least acknowledging that this should be a part of the care team and seeking out resources that the care team can then take over. So that in conjunction with active treatment or in conjunction with survivorship care, this then becomes something that patients feel they have some kind of control over. And I also think that it's important that we don't over-promise and under-deliver as well. I think that it's important to show patients that these are things that are as important as their active treatment to pay attention to, but also as oncologists start becoming more comfortable with the idea of risk reduction and having the information to back up our claims that lifestyle is of the utmost important in cancer. ASCO Daily News: Absolutely. Dr. Comander, do you have any thoughts on this? Is it more difficult to do what Dr. Desai has described in a community practice than where you are in a larger institution? Dr. Amy Comander: I think Dr. Desai answered that question beautifully. I will add that, as an oncologist, what we say makes such an impression on our patients. Often our patients are recording what we say, or they have a family member with them writing down everything we say. So if we just tell our patient, it's really important for you to exercise--and that might just mean a 10 minute walk each day or walking to the mailbox to get the mail, starting with something very basic in terms of exercise counseling--can make a big difference. And so I think just the fact that, as Dr. Desai just stated, a doctor acknowledging that exercise has a role, nutrition has a role, stress management has a role, I think just that simple act has a big impact on our patients. And it's very important. ASCO Daily News: Indeed. Well, patients and survivors often grapple with depression, anxiety, fear of recurrence, financial issues, and more. Sleep disorders and insomnia can interfere with adherence to a nutrition plan or an exercise regime. Are there helpful tools available, or what are the helpful tools available to oncology practices to help them address these issues with their patients? Dr. Amy Comander: I think that's a really important question. We know that distress screening is actually incorporated into each visit. And that's recommended through the NCCN guidelines really to assess these issues you just inquired about--coping skills, anxiety, depression, financial issues, et cetera. So certainly, it's very important to ask our patients about these issues and refer them to appropriate colleagues, whether that's a mental health provider or social worker, to help address these concerns. I will also acknowledge ASCO has a number of great resources to help guide patients to. The website Cancer.Net has many resources that help patients find perhaps something in the community that could help them address these specific concerns. Dr. Desai, I'm interested in your comments as well. Dr. Poorvi Desai: I absolutely agree with you. I think that the NCCN is doing a really great job in compiling a comprehensive set of resources in their survivorship guidelines. There is that distress assessment thermometer that we had addressed in our article. We definitely understand that these psychosocial evaluations are pretty much of utmost importance. There's a lot of anxiety and distress that comes with a cancer diagnosis. And we know that it lasts. It has an impact that's lifelong. And so definitely one of the big pillars of lifestyle medicine is stress and social connectivity. And so we definitely are an advocate for having mental health professionals as a part of the care team and looking at mental and physical well-being going hand-in-hand. And I think one of the biggest things to understand is that we have to meet our patients where they are. And so we don't want to advocate for anybody saying, OK, now you have to exercise five times a day strenuously, and you have to eat perfectly, and all of these things that can be extremely overwhelming. And so I think that there are great guidelines. And I think the NCCN Survivorship Panel has put together a good amount of resources for us to show patients how to work on mindfulness strategies and sort of systematically work them through a very difficult diagnosis in order to slowly, but surely, result in those healthy lifestyle changes. I like to tell my patients that it's a marathon, not a sprint. Any progress is good progress. You don't have to be perfect. And I think that's definitely something that we should be mindful of when we talk about changing lifestyle behaviors. ASCO Daily News: Right. Dr. Comander, do you think there is a role for increased collaboration between oncology providers and primary care providers in the context of cancer survivorship, for example? Survivors might see their oncologists every few months, every 6 months, every year, but who is monitoring the hypertension, the weight gain? Who should own that responsibility, or is it a collaboration? Dr. Amy Comander: That's a great question. And as you stated at the beginning, thankfully due to advances in treatment and screening, the number of cancer survivors in this country is increasing greatly each year. And therefore, it is very important that we have a strong collaboration with our primary care colleagues in terms of providing excellent care for our patients following completion of primary treatment. So in my practice, it definitely is a collaboration. I'm fortunate to work with so many wonderful primary care physicians [and] we work together in terms of monitoring our patients' blood pressure, risk for cardiovascular disease, risk for diabetes and other chronic diseases, and certainly when it comes to other lifestyle interventions, such as weight management, management of substance abuse, et cetera. So that collaboration is really key. And I see primary care providers already playing a huge role in survivorship care. And I think that will continue to grow in time to come. ASCO Daily News: Well, as you said, the number of cancer survivors continues to grow. It's projected to increase to 22 million in the United States by 2030. So do you think the focus on lifestyle medicine will increase in the future? Let's start with Dr. Desai. Dr. Poorvi Desai: Yeah, I think that this has to become one of the major things that we regard. I think that most oncologists are very aware that our treatments are--they have long term consequences. We had mentioned in our article that there are two major themes to look at when it comes to survivorship care. One is infection-related mortality. But the other big one, which is what we focused on, was lifestyle--cardiovascular disease, cerebrovascular disease, accelerated aging with telomere shortening and metabolic changes that happen after cancer diagnosis and the treatments that patients receive. So a lot of what we are subjecting our patients to is truly aging in nature. And we have evidence to suggest that we can work on these lifestyle modifications as the forefront way to really help them overcome the fact that we have given them radiation to their chest or cardiotoxic medications, or whatever it may be. And that when they are overweight or obese, this can then further accelerate that process of metabolic aging. I think one of the things that's really important to talk about is assessing metabolic health. And so not just looking at their BMI, but how does their BMI actually break down into metabolic patterns? How much of this is bone density or muscle weight? We put patients a lot on hormonal treatments, which can then affect their fracture risk moving forward. And I think that we are very well aware of that. And so these are the things that should really be assessed because, like we've mentioned, one of the biggest reasons for, I guess, moving forward with the number of cancer survivors that we're going to have, a lot of it--the focus needs to shift, basically, to long term chronic disease management, in which lifestyle really does play a huge role. ASCO Daily News: Absolutely. Dr. Comander, is there anything else that you'd like to share before we wrap up the podcast today? I certainly do think your article pointed out the importance of using evidence-based guidelines to strive for the best possible outcomes for survivors and patients to prevent newly diagnosed cancers. Dr. Amy Comander: Yes, I think, as summarized in our article, we did provide resources that can help our colleagues address these concerns with our patients, since, again, some of us have not been educated about these topics during our medical training. So in addition to the excellent resources provided by ASCO, I would really refer our listeners to the AICR website, American Institute for Cancer Research. In addition, the American Cancer Society is playing a role in helping provide further education about the role of nutrition and physical activity in cancer survivorship. So the American Cancer Society is a great resource, as is the American College of Sports Medicine when it comes to exercise recommendations. And on their website, they have some great graphics that really illustrate what the recommendations are for exercise and what the benefits are for cancer survivors as well. And finally, we referred to the NCCN during this podcast. And of course, their guidelines are excellent and address these lifestyle behaviors as well. So I would just highlight those resources for our listeners in case they want to get more information. ASCO Daily News: Absolutely, some great resources there. Well, thank you, Dr. Comander and Dr. Desai, very much for sharing your valuable insight with us today on the ASCO Daily News podcast. Our listeners will find a link to your article in our show notes. Thank you very much. Dr. Amy Comander: Thank you so much for the invitation. Dr. Poorvi Desai: Thank you so much. ASCO Daily News: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Amy Comander: Consulting or Advisory Role: Advance Medical, CRICO Harvard Risk Management Foundation, Harvard University Consulting or Advisory Role (immediate family member): Applied Genetic Technologies Corporation, Beam Therapeutics, Biogen, Inc., Blue Cross Blue Shield Association, Editas Medicine, GenSight Biologics, infiniteMD, RBC Investments, Sanofi SA, Vedere 1, WAVE Life Sciences Dr. Poorvi Desai: None disclosed.  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Transcript: Dr. Ben Corn, professor of Oncology at Hebrew University of Jerusalem Medical School, and deputy director of the Shaare Zedek Medical Center, discusses his current research with NRG Oncology and SWOG on the study of the science of hope, and it's role as a mediator in well-being and health care improvement. Dr. Corn is co-founder and CEO of the NGO, Life's Door, which teaches health professionals, patients and others strategies for hope, meaning and well-being throughout illness and at the end-of-life.   Transcript ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. Our guest today is Dr. Benjamin Corn, a professor of oncology at the Hebrew University of Jerusalem Medical School and deputy director of the Shaare Zedek Medical Center. Dr. Corn is the co-founder and chairman of the nonprofit organization Life's Door, which teaches health professionals, patients, and caregivers strategies for hope, meaning, and well-being throughout illness and at the end of life. Dr. Corn was honored with the 2021 ASCO Humanitarian Award and joins me to discuss his work, including his current research on the study of the science of hope and its role as a mediator in well-being and health care improvement. Dr. Corn's full disclosures are available in our show notes, and transcripts for all episodes are available at asco.org/podcasts. Dr. Corn, it's great to have you on the podcast. Dr. Benjamin Corn: It's a pleasure to be here, and thank you very much, Geraldine. ASCO Daily News: Dr. Corn, can you tell us about the experiences early on in your personal life and then your medical training that prompted your interest in helping patients find hope and meaning while navigating cancer treatment? Dr. Benjamin Corn: Sure. I think everyone has a story that sent them on their way for a career in medicine, which for many of us is not a job. It's not a career. It's a mission. My personal story had to do with losing a parent, my dad, at a very young age. He died of prostate cancer, left behind three young children and a lovely widow, who was my mom. And I was quite disappointed with the way the system tried to cope with the reality that was now forced upon us. There were no viable options for somebody with metastatic prostate cancer then. But yet, there was not a cognizance of some of the psychological trauma that we would all have in trying to navigate our daily lives. And I was very surprised also the way my dad's death was communicated to the family. And I've spoken about this in a variety of podcast settings and written a piece for the JCO narrative section about 10 years ago on that, some of what I found to be harshness, coldness of telling us that our dad was not going to make it and how the bad news was conveyed (PMID: 24733795). And so, with that, I was an 11-year-old child, and I very much was intent on curing this thing called prostate cancer to make sure other middle-aged men wouldn't suffer from it, and their families wouldn't have to pick up the pieces. And I went to medical school. I entered my residency in oncology at University of Pennsylvania, thinking that that was my destiny. And when I got to the wards, I was quite disillusioned because I saw a variety of scenarios that told me things hadn't changed drastically in 7 or 8 years since losing my dad and initiating my medical studies. I saw many cases of senior attending physicians, who were fantastic scientists, brilliant researchers, and yet didn't seem to pay enough attention to the subtleties of making sure that a family was whole, bringing in other resources. This was right before what I would call a palliative care revolution. We didn't have the Tamil paper, the Zimmermann paper, the Bakitas paper. And we didn't really know the value of early interventions with teams that included not only oncologists but also nurses and psychologists, chaplains, who could help navigate such a difficult period for patients and for the people in the concentric circles around those patients. So it was very important for me to begin to explore those issues. I never found it to be a conflict for pursuing an academic career that asks bread-and-butter questions about disease, areas of interest. I published a lot in gynecologic malignancy, in prostate cancer itself, and in central nervous system tumors. But by the same token, I thought it was very important to be looking at the psychosocial dynamics that are involved. And that's pretty much the genesis of how I got interested in this area. ASCO Daily News: Well, your work integrating hopefulness into cancer care has had an important impact even on communities beyond the medical setting. Can you tell us about this work, about the hope enhancement model, and how you've used this approach to train medical professionals, patients, and caregivers? Dr. Benjamin Corn: Well, first of all, I want to say that, in many ways, even though I've been blessed with having terrific education at outstanding institutions of higher learning, my greatest teachers have really been the patients, and I'll bet you most colleagues would say the same thing. And I noticed there was a subset of patients who were very intuitively aware of what was important to them, patients for whom the prognosis was very bleak and yet managed to maintain hopefulness. And I saw that the common thread for these patients was that, even though they couldn't be hopeful for cure, they could still find other goals, other objectives that they could pursue. And that sent me on a quest of sorts to see if anybody had formally tried teaching people how to become more hopeful. And with not too much effort, I found literature of Professor Rick Snyder from University of Kansas. It basically modeled this notion of hope theory. And without turning this into a lecture, very briefly, Snyder said that there are three conditions that will allow hopefulness to thrive. The first is defining a goal. And by that, he meant some kind of an objective that was not only plausible but also that could provide meaning in one's life. So it would be a good goal in hope theory if I said my goal is to win the lottery tomorrow because that's really not anything I can have an impact on, so it's not really statistically plausible. But likewise, if I took a goal that was just very mundane and didn't add that much purpose to my life, it would be out there, and I'd be interested in pursuing it. But I probably wouldn't have the same degree of motivation if I thought about something that, without too much effort, could really make my day or make the day of the people around me. So, the first thing was the goals that have these two criteria--plausibility and meaning. The second is a pathway to get to the goal. And when Snyder discusses pathways of thinking, he's supposedly speaking to a mature audience and saying none of us were born yesterday. We all realize that on almost every path that we travel on during our lifetimes, we see that there are obstacles. The question is, how do we manage and circumvent those obstacles, or how do we dance with those obstacles if, in fact, it's something very much within me, an obstacle such as anger, an obstacle such as jealousy? How do I deal with those particular factors? A hopeful person is a creative person, is a resourceful person, who finds a way to sally forth even when these obstacles are out there. So we have goals. We have pathways. And finally, the other secret sauce that I mentioned before is motivation. The word that Snyder used for motivation is called "agency." Agentic thinking, like almost an agent that might represent an NBA basketball player or a Hollywood movie star. That agent will do everything on behalf of his or her colleague so that they'll succeed. And so to the person who has an agentic way of seeing the world is going to be an activist, is going to want to set out on those trails, those pathways, to reach those goals. So those are the three components. And what we found is that--and this is based on some work that was done by one of Snyder's proteges, Dr. David Feldman, who's at Santa Clara University--one could actually construct workshops that are very palatable, that take less than 2 hours to conduct, in which a tool called hope mapping is used. Hope maps are basically dependent on those three components. So you can actually sit there in dyads, buddying up with people in this workshop, people who you know before the workshop, or people who you meet in the workshop, because there's a similarity, a selection for those who attend such workshops. People want to work together. And it's a wonderful energy, because let's say, as I said before, I have a goal, and I have a pathway. But there's a big, bad obstacle there, and I don't know how to get around it. What could be that my buddy in the workshop is going to say, "You know what, Ben? Here's a great way. You might not have thought about this. Why don't we contemplate creating a workaround?" And they're very, very instructive. And we've done some of these workshops now, both in Israel, where I practice, as you mentioned at the opening, and with colleagues at Johns Hopkins in Baltimore with really thought leaders in hopefulness--Tom Smith, who has for many years written the ASCO guidelines on palliative care, and Anna Ferguson, who is the coordinator of the hope enhancement program at Hopkins. And together, we've proven, especially in a population of women suffering from stage IV breast cancer, that we really can invest 2 hours or less and make them much more hopeful. Now, you mentioned in your question that some of this has an impact on communities beyond the medical setting, and that's exactly what's been happening. As the word has trickled out, especially during the COVID pandemic, we've been approached by a variety of communities on the international level--communities in London, communities in Athens, communities in South Africa, communities in the Pacific Rim--who are very interested in bringing together different strata within those communities, perhaps people who have recently become married or people who have recently become parents, who have a similar set of struggles, and to help us help them become more hopeful, especially when you add on to that a little something called COVID-19. So I'm an oncologist. I think there's tremendous upside for this in the setting of cancer care for patients and for the health care professionals who have the privilege of treating these patients. But the spillover phenomenon has really been marvelous to behold, especially during 2020. ASCO Daily News: Well, you're also collaborating with the National Cancer Institute groups of NRG Oncology and the Southwest Oncology Group to study the science of hope and its role as a mediator in well-being and health care improvement. Can you tell us about this research? Dr. Benjamin Corn: Sure. So in the context of NRG Oncology, there are two protocols. One is called CC003 (NCT02635009). That's a protocol for patients with small cell lung cancer. And another one is a protocol called BN005, which is a protocol for individuals with, I guess, what we want to call low-grade gliomas, to look at neuroanatomic loci that could constitute a source for hopefulness (NCT03180502). I'll just give you one example, which is from the small cell lung cancer study I mentioned before. So in years past, at least, it's been a standard of care to provide prophylactic cranial irradiation--that is, prevention with radiation--where there's a tumor, small cell lung cancer, that has a proclivity to spread to the brain. And so one of the hot areas that has emerged in radiation research over the last decade is hippocampal avoidance. It seems trivial, but it took us a while to understand how to protect concentric circles, such as, let's say, the spinal cord when treating the vertebral body or to protect the hippocampus when treating the whole brain. So in prophylactic cranial irradiation, we typically treat the whole brain. And a randomized trial was developed by NRG investigators, where the randomization was between prophylactic cranial irradiation itself to 25 Gray in 10 fractions versus that same regimen with hippocampal avoidance. Now, when I saw that study design, I actually put forward the idea that this could be a wonderful model to study the neuroanatomic correlative hopefulness because there are several candidate anatomic structures in the brain, which are thought to be associated with hopefulness. No one, by the way, is saying that the circuitry is so primitive that all of hopefulness resides in one structure. But if I had to say that there's a lead candidate that's been identified in the literature, it's exactly the hippocampus. So the proposal to the NRG committee and to the PI of the protocol, Dr. Vinai Gondi, and the head of the brain tumor committee, Dr. Minesh Mehta, was, could we very simply administer one of the validated scales for hopefulness that was built by Snyder. It has all of 12 questions. It takes about 5 minutes to complete. Give that to a patient at baseline, then have them randomly assigned to either prophylactic cranial irradiation of the whole brain or the same treatment wherein the hippocampus is protected. Re-challenge the patients 6 months after the irradiation is completed, and see if there is less of a decrement in hopefulness on these validated scales among the group that had the hippocampus protected. When you compare the hopefulness among the groups that didn't have the hippocampus protected, that would offer some interesting, at least circumstantial, evidence that the hippocampus is implicated in the hope pathways. And so this has been very interesting to NRG Oncology. We've enrolled now over 250 patients en route to 300 patients. We have very meticulous quality assurance, where the co-investigators sit down once a month and make sure that the hippocampus was properly contoured and protected. And in the other study, we're looking at particular dosimetric analyses in case someone thinks that 25 Gray might be, for instance, below the threshold of hippocampal tolerance. There, we'll look at a variety of doses to see where we might see the correlation with hippocampal toxicity and decrements in hopefulness. So those are two variations of ideas that are on burners in NRG Oncology. SWOG has taken a different tack. And here, I want to truly applaud SWOG leadership, the group chair of SWOG, Dr. Charles Blanke, as well as the leaders in the palliative care movement at SWOG, including Mark O'Rourke, Marie Bakitas, and Ishwaria Subbiah, who have said, "Look, we know that you've got some preliminary pilot data on the impact of a hope workshop for patients with cancer. Can we, first of all, look at this now among the SWOG investigators?" That had never been done before. In other words, we talk all the time about levels of burnout among health care providers who are treating a patient with cancer. It's very gratifying on the one hand, but it's very challenging on the other hand. It can even be demoralizing for some, and as you know, there are very high rates of burnout. So they've been very interested, first of all, in meticulously establishing levels of hopefulness at baseline and correlating that with levels of burnout among SWOG investigators. So by "investigators," I'm talking about physicians, nursing professionals, even patient advocates. And we have some data that were just recently published in JCO Oncology Practice (DOI: 10.1200/OP.20.00990). In addition, we've been very interested in offering now these hope enhancement workshops that I told you about before to the SWOG investigators. So in the month of May, we got together every Monday night--at least for me, it was Monday night at midnight, I have to say, which was about 5:00 PM Eastern time. And we did these 2-hour workshops every week for about a dozen SWOG investigators. And we actually have some data right now that we just submitted to the ASCO Quality Conference, showing the feedback we got from the SWOG investigators. And to me, the most encouraging part was that these investigators were so enamored of these techniques and found them to be so useful that they--almost all wanted to find ways to bring them into their own clinical environment to share them with their patients, wanted to learn how to become facilitators of such workshops to also help prophylax burnout and increase hopefulness among their colleagues. So SWOG has taken the tack of using this intervention to help providers. We're soon going to be trying to do it among the patients and roll it on to our protocols. And there, what we want to do is take meaty, challenging questions. Let's say the question of adherence, a situation where perhaps women who need endocrine therapy are somewhat--want to take the endocrine therapy but are somewhat reluctant to be adherent to the regimen because of all the hormonal side effects. So we want to see if we can use our workshop to align this value of a patient and this motivation with the patient to help them, in fact, become very adherent, because as I'm sure you know, upwards of 40% of these patients just don't want to take these therapies. So we're interested in using this for adherence. And we're also interested in using it as a tool for medical decision making. We give a lot of lip service to the idea of shared decision making between provider and patient, but most of us haven't really been trained in how to have a robust experience that helps me as a provider understanding what my patient wants. When I counsel patients with prostate cancer, it's almost impossible for me to do such a consultation in less than 90 minutes because there's such a range of options. And before I can really get to understanding which of those options might be most appropriate for a patient, I have to really know the patient. I have to know, in the case of prostate cancer, what makes him tick. And so I think there's going to be tremendous upside for these hope enhancement techniques, not just using it for hope's sake but also for these other epiphenomenon in medicine, like adherence and like decision making, that we speak about all the time, but I wonder to what extent we're really committed to doing a better job on those parameters. ASCO Daily News: Right. Do you see a role for technology to grow hope enhancement workshops, to make them accessible to more people in other parts of the world, in other medical settings? How do you think technology has changed the way people confront the experience of illness? And what role do you think you can play in this? Dr. Benjamin Corn: Yeah. Well, I guess all of us were brought in very rapidly, sometimes kicking and screaming, into this new era. And health care providers are smart, and they're resourceful, and they've figured out a way to ride this challenging wave that COVID has brought into our lives, this tsunami, if you will. So COVID has pushed us all into digital health. My organization, Life's Door, which developed an application, a smartphone app, called Hopetimize--kind of a  play on the words "hope" and "optimize"--in other words, the idea is to optimize your life with using these hope techniques I described before. So we had a game plan to get to digital work in the year 2022. That was a strategy that we basically developed about 5 years ago. When COVID came along, we realized that we had this wonderful product called hope enhancement workshops that we thought could really help oncologists who we thought could help their patients. But we couldn't get people together because of the new criteria for social distancing. So what was once a tailor-made concept for intimate settings with 15 people, I can tell you that even in our IRB-approved protocol--and people can see this on nih.gov, clinicaltrials.gov--our protocol specifies the kind of environment one has to have to conduct these workshops when you're doing it face to face. But that just couldn't happen for a full year, maybe a little bit more than that. So we very quickly developed the smartphone app, and we found a way to move our entire workshop to a Zoom platform. And we'll have some data that we'll be sharing that basically says that we can do it just as well with the Zoom platform as doing it face to face. And what's more, it gives more people access to the technology. It allows for more sustainability because we're not only using Zoom, we're using different social media outlets. Most of the literature on hope enhancement--it's sometimes called hope augmentation--can demonstrate a spike in hopefulness after such an intervention. But the challenge then becomes how to sustain that hopefulness, and that's not easy. Well, by creating these digital communities of hopefulness, with the aid of different social media, we think that maybe this is exactly how we can deal with the sustainability question. And finally, this kind of technology gives us scalability. I mentioned before that we've been approached by groups around the world, throughout Europe, now throughout Asia, parts of Africa, not to mention North America. Haven't heard much from South America and Antarctica now that I'm thinking about it, so we're waiting for you guys. But we could never--all of us--I'm a busy physician as well. So there's a limit to how many times my colleagues would have to cover me when I say, "Oh, I'm off on another trip, teaching these hope techniques to people." But once we have it on Zoom platform, and we can bring, let's say, 15 to 20 people into the experience by bringing them into a Zoom room, I don't have to go anywhere. I can do it right from my living room, just like they're in their living room. And it sounds very simple, but I don't think anybody would have really imagined that we could be on our way like this if you sat down to contemplate this upside of 2019. ASCO Daily News: Right. And do you feel the response from the oncology community, from your peers across the world, has been quite positive? Scientists are sometimes skeptical about things such as hope enhancement techniques. Or have you found that not to be the case? Dr. Benjamin Corn: Yeah. That--so there's another example. I think that a barrier is the working assumptions of, let's say, my colleagues--let's say, me myself before I got into it. I mean, we're trained in a truly biological, scientific model. We talk about a biopsychosocial model, sometimes a biopsychosocial narrative model, but at its core, we pride ourselves as being scientists, and this kind of an idea was very off-putting to a lot of people. When we started publishing on this and the word got out that there were actually reproducible results showing that we can enhance hopefulness, people said, "Wait a second. I'm having a problem myself with patients who are just not hopeful." "Wait a second. I'm having a problem myself with my own burnout and my own compassion fatigue." And these colleagues have been seeking this out now in droves. And what our challenge has been right now is to be training facilitators so that we can really fan out and make sure that we answer this need of people saying, "I want to learn these techniques." Again, not just hope for hope's sake--I mean, I'm for hope. But for all the other upsides that we mentioned before--anti-burnout, increased adherence, probably bettered medical decision making--I think these are the motivators for people as opposed to just saying, "Make me more hopeful." So whatever gets you to the workshop, I couldn't care less. Everybody comes with their own reasons. That's always quite fascinating to hear why somebody decided to enroll in one of our workshops. But once people are there, most of them find that they really benefited from it. Typically, if we do a workshop with 20 people, the next day, we'll get a third to 40% of the participants saying, "You know what? I love this so much. I took these techniques, and I called in my children after dinner, and we talked about their goals and what struggles they're having in trying to reach the goals." So to me, that's very touching. And to get through your earlier question about the impact of this thing in communities outside of medicine, I think we're really on the cusp of forming what I like to describe as communities of hopefulness. And I think, again, we saw that in the COVID era. There was, in particular, a community in London that was very interested and brought us in also for a series of four workshops. And one of the things that we're working on right now in a hospital setting is what we call the seal of hopefulness. And that's based on, when I was growing up, this notion of the Good Housekeeping Seal of Approval. Well, we want to be able to approach hospitals and to say, "Just like you like to go through the accreditation process, perhaps you want to go through this process of making your staff more hopeful." Patients pick up on these things. So imagine, Geraldine, a world in which the physicians were taking care of you and the people you love, the nurses, the orderlies who bring them down to CT scans and the MRI. There's a lot of time that a patient in a hospital spends outside his or her bed. Imagine if en route to having a study, which you're very anxious about, you have somebody who's been trained and knows how to speak to you about your goals and your value. I think that would be the kind of environment I'd want to be taken care of in. I mean, of course I want to know that the knowledge base is top shelf. But could you imagine if there was this hope seal on the door that said, "People here really give a damn. They care about you, not just your tumor, and that is their commitment." I think that can be very reassuring. And we've begun to pitch that idea to hospital administrators, both in Israel, where I'm based, and in large-scale hospitals both on the community level and the academic level in the U.S. and Canada. ASCO Daily News: Excellent. Thank you so much, Dr. Corn, for telling us about your innovative work today. You really seem to be having a great impact. And I thank you very much for taking the time today. Dr. Benjamin Corn: Thank you. It was a pleasure. ASCO Daily News: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Ben Corn: None disclosed.  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. David Freyer, professor of clinical pediatrics at the University of Southern California; Dr. Michael Roth, director of the AYA Program and Childhood Cancer Survivorship Program at The University of Texas MD Anderson Cancer Center; and onco-fertility expert Dr. Leslie Appiah, associate professor of Obstetrics and Gynaecology at the University of Colorado Anschutz, weigh in on the challenges and advances in care for adolescents and young adults with cancer and survivors. Transcript ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. On today's episode, we'll discuss the unique challenges facing adolescents and young adults with cancer. I'm delighted to welcome three experts for this discussion. Dr. David Freyer is a professor of clinical pediatrics, medicine, and preventive medicine at the University of Southern California's Keck School of Medicine. Dr. Michael Roth is director of the AYA Program and Childhood Cancer Survivorship Program at The MD Anderson Cancer Center. And Dr. Leslie Appiah is associate professor of obstetrics and gynecology and director of the Fertility Preservation and Reproductive Late Effects Program at the University of Colorado and Children's Hospital Colorado. My guests report no conflicts of interest relating to our discussion today, and full disclosures relating to all episodes of the podcast are available on our transcripts at ASCO.org/podcasts. Dr. Freyer, Dr. Appiah, and Dr. Roth, it's great to have you on the podcast today. Dr. David Freyer: Thanks, Geraldine. It's really great to be here. Dr. Leslie Appiah: Thank you for having us. It's our pleasure. Dr. Michael Roth: Yeah, really great to be here. ASCO Daily News: So today we're highlighting some of the issues and strategies you all presented during the ASCO Annual Meeting that addressed equity issues and strategies to improve outcomes for AYAs. Our listeners will find a link to the presentation in the transcript of this episode. Dr. Freyer, there are approximately 89,000 AYA patients diagnosed with cancer in this country each year. Tell us about the challenges they confront and why they're so vulnerable to health care disparities. Dr. David Freyer: Absolutely. I'd like to say, first of all, thanks, Geraldine, for the opportunity for us to participate in this podcast. I think, as your question points out, AYAs who developed cancer are in a sort of double jeopardy, because not only of the challenges of cancer, but also their life stage where there's so much change and vulnerability. Normal changes for AYA life stage differ across the spectrum. 15 to 39 years is a very broad range. And at the younger age, I would say in the 15 to 21-year-old group, these challenges commonly involve education. It's finishing high school, possibly education or trade school, pursuing a career or vocation, expanding and reorienting their social network from their nuclear family, experiencing serious relationships for the first time, and then starting to explore intimacy and sexuality. For that younger group, self-image and physical appearance is very, very important. And there's overall a move toward greater personal autonomy and independence. When you get into the middle years, roughly [ages] 22 to 29, I would say that the issues begin to take on a financial character. It's becoming financially independent, paying for housing, starting or maintaining their own health insurance, maybe having their first meaningful employment. And a great many in this group are saddled with substantial debt from previous education. And then in this age group, they're starting to identify significant partners for the first time. And then finally, in the later years, roughly [ages] 30 to 39, the concerns really begin to focus on career advancement, maintaining a home life, starting or building families, raising children, taking on new financial obligations of adulthood like owning a home. And interestingly and importantly, some in that latter phase, we're seeing more and more, are beginning to feel the pinch from above as they're beginning to take care of unwell or older dependent parents who also need the financial support of this normally productive age group. So there's this developmental continuum. And to add cancer on top of all of that is, to say the least, highly disruptive. So even the experience of being treated for AYA cancers that have a good prognosis, and many do nowadays, it still interrupts education, delays career starts and return to work, upends their social networks, [and] undercuts their independence. They revert to being dependent on their nuclear family, and they have enormous financial burden. And then on top of all of that, of course, many of these patients are dealing with long-term health problems, because they have late effects from their treatment. And so to get your point about why this is an equity issue, I think that this session is perfect for this 2021 ASCO meeting actually, because AYAs, it's a cancer population that's defined by age. It's characterized by life stage dependent challenges. And so for that reason, they're systematically disadvantaged in ways that other cancer populations are not. And that's the definition of health care disparity. So they need special support in all these areas. And as a final note, I would say that AYAs who represent other disadvantaged cancer populations, such as low income or racial and ethnic minorities, I mean, they're actually in triple jeopardy, because they're at the intersection of their age, cancer, and also their background social status. ASCO Daily News: Absolutely. AYAs confront a host of disparities. AYAs frequently identify fertility threat as a major concern, and many patients have suffered fertility loss due to the effects of treatment. Thankfully, there continues to be much progress in fertility preservation, but not everyone has access to this care. Dr. Appiah, you've done a lot of work in onco-fertility and have even engaged with legislators to help pass bills mandating insurance coverage of fertility preservation for patients with cancer. Can you tell us about best practices in fertility preservation and your concerns that not all patients and survivors have access to available technologies? Dr. Leslie Appiah: Thank you, Geraldine, for that question. As you stated, with 80,000 plus AYA patients being diagnosed a year, we know that there are approximately 100,000 survivors. And so survivors are living longer. Up to 75% of them will experience at least one adverse event or late effect of their cancer therapy. Infertility, as you stated, is the most prevalent, one of the most discussed reproductive late effects in the literature, affecting up to 12% and 66% of female and childhood cancer survivors respectively. And then in addition to the infertility or fertility-related effects, there are other reproductive late effects that cancer survivors experience. And so as in many aspects of adolescence and young adult care, disparities also exist in onco-fertility or fertility preservation. The governing bodies of our societies--so the American Society for Reproductive Medicine, the American Society of Clinical Oncology--have all put out consensus statements describing how we should be caring for this population and how we should be providing equal care to these patients (DOI: 10.1200/JCO.2018.78.1914). And all of the societies or the guidelines recommend that physicians inform every patient of reproductive age about the risk of therapies to fertility and the options for fertility preservation. And by reproductive age, we mean from birth through, typically, for women age 42 and our male counterparts can be fertile much later into 50s and 60s. And so all of these patients should be counseled about the risks and then referred or offered the opportunity to see a reproductive specialist for further counseling, and that this really should occur before any treatment is provided. We know that once patients receive any cancer therapies that our options are limited in terms of what we can provide them for fertility preservation. So this conversation should occur regardless of the patient's age, gender, culture, socioeconomic status, or health care team bias. And these discussions should continue into survivorship, because even at the end of therapy, there may be some options for these patients. Despite recommendations, however, less than 50% of patients ever recall having these discussions with their providers, and then less than 30% of patients go on to use fertility preservation therapies. This disparity is sometimes due to information overload. Many times the patients don't recall the discussion, even though the discussion was had. But really when we look at the data, many times they are not being offered this information. We know that in terms of disparities, men are more often referred for counseling and referred for fertility preservation therapies because of the idea that it's easier to bank. And for those men who are feeling well and are of age, sperm banking can be a simple process. But many of these patients are very ill, and so extracting sperm becomes an issue for them and it becomes very challenging. We know that patients with fewer financial resources are less likely to be offered fertility preservation counseling. So our patients in the lower socioeconomic statuses, these patients are less likely to be referred. And again, that's not providing equitable care. There are many resources available for patients that can provide some financial resources. And so these patients really should be given the opportunity to have a discussion and seek resources, or we can provide options for them. And then lastly, I'll say that in terms of disparities, cultural biases play a huge part in this. Our providers come with their own biases as to how many children they feel that a family should have, and that can be a bias. Sometimes prognosis can be a form of bias. If the patients have a poor prognosis, then perhaps the provider is uncomfortable referring them for fertility preservation therapy. But there are some options for patients if they should succumb to their cancer diagnosis, there are some posthumous reproductive options that our young adults can participate in or agree to. And it requires a lot of legal discussion and documentation and contracts, but there are options. And we really should be providing our patients the opportunity to decline these options. And in that way, we can really address the disparities in fertility preservation for our patients. And then lastly, I will say cost is a factor, but there are I think now 13 states with insurance mandates for fertility preservation. And these mandates are starting to occur more and more often. And so we need to continue to push our legislatures to move the needle forward in this way. ASCO Daily News: Can you highlight some of the new technologies in fertility preservation that oncologists should be aware of? Dr. Leslie Appiah: Absolutely. I think two of the very important aspects of this is that we are able to provide fertility preservation for adolescents in terms of egg freezing. So until recently, we limited this option for girls who were 18 and older or late adolescents, but we now can provide egg freezing for girls once they reach puberty, and especially once they are monarchal or have achieved menses. And so that is something that we really want our oncology colleagues to know. It's also important for our colleagues to understand that we can start for egg freezing at any point in the patient's menstrual cycle. Historically, the patient needed to be on their cycle in order to stimulate, but now we have random start protocols. So if we see a patient today, we can start stimulating tomorrow or the next day. And the average number of days to stimulate the ovaries to be able to grow eggs to freeze is about 10 to 12 days. And so we really can intervene for these patients if we are informed of their diagnosis very early. And in that way, there will be no delay in their cancer therapies. And then lastly, we are very excited to share that ovarian tissue freezing is no longer experimental. As of December 2019, the experimental ban was lifted by the American Society for Reproductive Medicine and ASCO. And so patients from birth through age 40 can have an ovary removed, or part of an over removed, and frozen for their future fertility. And this is considered clinical care. We're able to put this through the insurance, and therefore alleviate the financial burden on many of our families. ASCO Daily News: That's great, Dr. Appiah. Thanks for highlighting these positive developments in fertility preservation. Managing the care of AYA patients and survivors as they age and deal with toxicities from treatment and other physical and mental health issues requires collaboration between providers. Dr. Roth, can you share some strategies to address the unique challenges of AYAs and the providers who care for them through various phases of their lives? Dr. Michael Roth: Thank you, Geraldine, for that important question. As Dr. Appiah and Dr. Freyer clearly noted, AYAs face many unique challenges both during and after cancer treatment. And it really is essential that, as medical providers, we seek to meet and treat these challenges. Unfortunately, the system as it's currently set up is really not well suited to care for some of these unique needs. Specifically, many of our younger AYAs who deal with cancer such as leukemias and lymphomas, they're treated within the pediatric oncology department. And often, the approach to their care is focused on the care of younger children. On the flip side, many patients in their 30s with breast cancer, colorectal cancer, these AYAs are treated within the medical oncology community and are often seen in clinics with many older adults. So most of the care across the country is not specifically tailored to the unique needs of AYAs, and that's really where collaboration comes specifically into play. We know that there are many opportunities to address these psychosocial needs, the education and work needs, the onco-fertility needs, the genetic counseling needs of our AYAs, but it really takes a champion, or a number of champions, at each site to ensure that AYAs needs are prioritized. Recently, there has been a large growth in the number of AYA programs. And what a number of institutions have done is they've brought medical oncology together with pediatric oncology to centralize these specific AYA resources under one house. Some of these AYA programs are treatment-based programs. For example, some sites have an AYA heme-malignancy program, where they will provide both the cancer care, as well as the supportive care required for their AYA patients with leukemias and lymphomas. Other AYA programs are purely supportive care-based programs, where patients will be referred to them for their onco-fertility needs, for their psychosocial health needs, for their education and work needs as well. At the end of the day, we really just need to do what's right for our patients. And we've learned over many, many years that just treating our AYAs the same as we treat our younger children, or just treating our AYAs the same as we treat our older adults, doesn't cut it. And we really need tailored, focused approaches to make sure that we both optimize cure rates, as well as to optimize health-related quality of life for these patients both during and long after treatment. ASCO Daily News: Right. So Dr. Roth, what will it take to improve collaboration between providers? Dr. Michael Roth: Cancer care is traditionally very siloed. And these silos do decrease the rate of progress in which we can make within cancer care. But specifically within AYA oncology, historically, pediatric oncologists did not interact much with medical oncologist. By having AYA tumor boards, by having more multidisciplinary clinics, essentially you're taking down those barriers. You're breaking down those walls. And being face to face, or now in the virtual world, being able to connect and to collaborate, it really allows the optimization of care for our AYAs. It's not possible to know everything about every AYA oncology diagnosis. And when you're in a large academic center, you often have many subspecialists within each of the different cancer types. When you're in a smaller community setting, oftentimes you have more generalists who take care of all patients with a large number of diagnoses. And often in the community settings, there aren't many specialists who focus on AYAs with breast cancer or young adults with colorectal cancer. And oftentimes, it really takes teamwork and a real consensus and an approach within a team setting to make sure that both the cancer-directed care is appropriate and is the most appropriate treatment approach, but also there's a need to focus on that health-related quality of life, and specifically that often gets lost for many of our patients during their treatment. Dr. Leslie Appiah: We are also finding that when we incorporate our fertility preservation colleagues, our experts, into the multidisciplinary oncology meetings that were also able to break down those silos and help educate our colleagues about fertility options for patients as they are diagnosed. And that really does expedite the care that we provide to these patients. We also want to look at leveraging technology to improve how we incorporate fertility preservation into oncology care and using our best practice advisories within our Epic systems, as well as using the Epic referral process to really expedite the referrals of patients. And by that I mean, there are ways to do an opt-out referral system where the referral is automatic, unless the oncologist opts out of that referral. And in order to opt-out, the oncologists will have the discussion with the patient about their fertility risk and then recommend consultation. And the patient can then decline, and that's when the provider would opt-out of that consult. So utilizing technology that we have already can really expedite the care for these patients and break down some of those barriers. ASCO Daily News: Absolutely. Well, there's a huge need for more research on AYAs. Dr. Freyer, how does clinical trial accrual among AYAs compare to older patients? Are there any innovative strategies that could improve trial accrual among this patient population? Dr. David Freyer: This is a really important issue, and I'm glad you raised it, Geraldine. So clearly, to continue advancement of AYA oncology and really every realm, whether it's survival or supportive care, more epidemiology studies, studies on basic biology questions about cancer types in this age group, long-term outcomes, and so forth, we can't make any advancements in AYA or any other age without conducting the research. Clinical trials for many years have been sort of the heart and soul of clinical oncology science, because it's actually testing new questions, new therapies, and following in an organized way the outcomes of the patients who are enrolled in clinical trials. The problem is that the proportion of AYA patients who are enrolled in clinical trials is exceedingly low. The gold standard, I think, or benchmark for clinical trial enrollment actually tends to be children, pediatric oncology, which for decades has been very, very successful at enrolling patients on clinical trials. And they have improved survival and improved knowledge around cancer to show for that effort. So most studies--there's a little bit of variation--but most studies indicate that about 20% to 40%, at any given time, of children enroll on a clinical trial if they're newly diagnosed with cancer. For AYAs, that number is less than 10%, usually more around 5%. And that's actually similar to older adults. The drop off occurs sometime between 15 and 20 years of age in terms of enrollment on clinical trials. So the question is, how can AYA patients--how can the picture be shifted to look more like that of younger children? And it turns out, I think it's really a complicated scenario. There's multiple levels to this problem. Part of the challenge is having the right kinds of trials available for the diseases that occur in adolescents and young adults. And then another layer is getting those trials that are developed by the, say, the National--the NCTN Oncology groups getting those opened up at the sites where the AYA patients are being treated. There are a lot of barriers that institutions need to overcome in order to get those trials opened up. And if they can be opened up, then they're available to the AYA patients. But it doesn't stop there. Then the next step is that you've got to get those trials presented to the AYA patients. So the pediatric or medical oncologist that's taking care of the children--or excuse me, the AYA patients--need to be aware of these trials. They need to have access to research infrastructure that can make it feasible to offer these and enroll the patients. And then finally, of course, the AYA patient himself or herself needs to be convinced that this is the right thing for them to do and to go ahead an enroll on the clinical trial. So there's multiple steps to this. And clearly, addressing any single step won't ensure that more AYAs are being enrolled into clinical trials. So it requires a multi-level, multipronged approach. I think, in terms of innovative strategies, again, it's all of these things at one time. So on the national level, there's a good deal of work being done to try to increase the collaboration across the different NCTN groups--the National Cancer Institute (NCI) National Clinical Trials Network groups, the adult groups, and children's oncology group--to increase collaboration across those groups. So that there are more trials being opened that are appropriate for that entire spectrum of 15 to 39 years of age, which, as Dr. Roth pointed out earlier, cannot be addressed without collaboration between the pediatric and the medical oncology groups. So trying to pull those together. And then on the delivery end to the patient, trying to find better ways to support our oncologists and to make the information about clinical trials more digestible, more maybe less threatening, more understandable to AYA patients, so that they can make a good, well-informed decision for themselves. Perhaps the least exciting for most of us, but in some ways maybe the most crucial and the most overlooked, is that middle stage of getting these trials opened at the sites. That requires resources to get these passed through the IRBs at the institutions. It takes resources to have clinical research coordinators there to shepherd them through the regulatory processes and then to make those readily available to the practicing oncologists. I think at the local level, that's where some of the greatest challenges are. And I think one of the factors that sort of feeds and aggravates or exacerbates the health disparities issue for AYA patients is where these patients are being treated. There are a number of studies that show that AYAs tend to be treated at community sites rather than traditional academic centers. And that's wonderful in terms of making health care accessible to these patients in their home communities. There's a lot to be said for that actually. But one of the features of that treatment setting that may undercut the clinical trial question at least is that some sites, many of them, don't necessarily participate in a regular way or have fewer resources to participate in the clinical trial enterprise. So those patients, if they're treated in the convenience of their home community, they may not have access to the same sorts of clinical trials of those who are treated in academic centers. We need to figure out a way to overcome those kinds of challenges. It's not easy. ASCO Daily News: Right. Dr. Roth, what are your thoughts on clinical trials for AYAs? Dr. Michael Roth: So a couple of the layers that Dr. Freyer addressed in terms of barriers to enrolling more AYAs in clinical trials, I do think at the national level, we've made a lot of progress over the past decade with these collaborations within the NCTN network groups. Currently, we have a record number of truly AYA collaborative trials open and available for our sites to be able to have available for their local patient population. And like Dr. Freyer said, a lot of these trials, they're really getting stuck at the local level because, in many ways, there's not an incentive to open the AYA trials when you have limited resources, because it's easier to enroll many more patients on the prostate cancer trial or the older adult breast cancer trial just due to patient numbers. So we really do need to overcome that large barrier of when we have trials available at the national level, they need to be opened up at all sites really across the board to make sure that our AYAs have access. The other point on the local level is to address the challenges we have in lack of knowledge on disparities in AYA enrollment and care. And we've tried to overcome that by having local AYA site champions, having folks on the ground really spreading knowledge. These folks typically are investigators, sometimes they work in the research office. And their goal is to help prioritize the opening, activation, and enrollment on AYA specific trials. There's still a lot of work to be done. It's a complex situation, but I do believe we are chipping away at many of these issues. ASCO Daily News: Great. I'd just like to wrap up with a final question about models of survivorship care delivery. So AYA patients who complete treatment need to be supported. They need appropriate follow up to monitor treatment-related health problems and psychosocial support. Dr. Freyer, what are the models of survivorship care delivery that can successfully address these needs? Dr. David Freyer: I think, again, similar to the clinical trial situation that we just discussed, I think that survivorship care for this population--in other words, patients treated during the 15 to 39-year-old age group--is in a process of emerging and growing and taking many of its leads from the pediatric oncology experience. Survivorship care in pediatric oncology is well established. It's been now decades in the development. And there's been a huge amount of research, really high quality research, done to map out the spectrum of late effects of cancer treatment, both medical and psychosocial, for patients who are treated. Those children then grow up into adulthood and they become AYA patients, but they were treated as younger children. So that landscape is pretty well mapped out, and there are excellent models of care in place around the country. That has now become the standard of care in pediatric oncology for comprehensive holistic care of these patients long term. That situation is emerging in AYA oncology--in other words, for patients treated in the 15 to 39-year-old age group. Of course, part of what drove that in pediatrics is that survival rates improved so dramatically that these issues were staring oncologists in the face. And it was absolutely necessary to deal with it. It's taken a little bit longer for survival to come up to those levels in AYA and older adults, but we're there in many cases. And with the high survival now that we're seeing in the AYA age group, the same question is begging itself as was in pediatric oncology, which is now we've got these patients who have completed treatment with all of the problems that you just mentioned. I mean, many do very, very well. And it's important not to paint a more negative picture than is warranted, but I think the data are beginning to show that many long-term survivors of AYA cancer also deal with health problems that are getting superimposed on the normal problems of aging that all human beings develop over time. Now how to deliver that, again, the experience is just emerging. I think that different centers have developed programs that sort of play to their own strengths and overcome their own challenges, just like Dr. Roth said with AYA programs and I'm sure Dr. Appiah could say about fertility preservation programs. Every place has its own experience of one. And while there are some common themes, there are some things that need to be addressed that are individual. I think probably the basic requirements for a survivorship care model for AYA patients is having somebody, a champion, who has some expertise in this area, commitment on the part of the facility to put together at least the basic resources to begin to bring these patients together. There are different kinds of models. The models can be doing survivorship care in the context of each disease team. Breast cancer may have their own survivorship focus, colorectal cancer, leukemias and lymphoma, and so forth. And they may be delivered within the context of the diseases or another model is, I would say, more the classic pediatric model, which is to have a survivorship clinic that can meet the needs across these different diagnoses. And it's important for each program to determine these for themselves. I'll put one final closing pitch in for the clinical research, which is needed in this area as well. Just as clinical trials are needed to improve survival with treatment and also our understanding of these diseases and the cancer hosts that the AYA [patients] represents, there's also a need for research in the long-term as well. And the best way to do that is in the context of survivorship efforts that are organized and have resources like databases and participation in larger cohort studies, so that we can begin to amass the data in the same way that we've done for children. Dr. Michael Roth: So, I completely agree with Dr. Freyer. I think AYA survivorship is still in its infancy. And we're really only learning now about what happens to our patients diagnosed as AYAs with cancer in 15 years, 20 years. What are some of the cardiovascular events that are happening in these patients as they age into their 50s, early 60s? I think there's a real need for standardization of how we care for our AYAs post-treatment based on exposures, based on cancer diagnoses. And currently, with the models in place for survivorship within some of the large institutions, there's a lack of standardization across departments, and then across institutions as well. There really are no set guidelines as to how do we monitor for cardiotoxicity. What should we be doing in terms of monitoring for psychosocial health concerns? And I worry even more, as you go into the community setting, that many of these sites don't have the resources to offer expert survivorship care. As Dr. Freyer mentioned, this is really a plug, a call to action, to focus more attention on our patients' lives, not just during treatment but well beyond treatment. We know that 5-year overall survival for AYAs is approximately 85%. So the majority of our AYAs diagnosed with cancer will live long and well past beyond their cancer diagnosis. And it really is essential that we help them live long, healthy, and happy and productive lives. Dr. Leslie Appiah: And I will add one final word to that. So the U.S. news and World Report reporting system has now started to include fertility preservation as a marker of providing excellent care in the children's hospitals. And of course, that's going to go into the adolescent population as well. So I think that's one impetus for our colleagues and our institutions to really make this a priority. Additionally, as Dr. Roth stated, using national databases, where we can really bring together all of the information so that we can standardize how we care for this population, is really important. And the University of Colorado is developing a national database in fertility preservation as a data coordinating center for the Oncofertility Consortium and will be including various sites across the country, so that we can start to look at this data longitudinally. And then lastly, I would say, again, leveraging technology. I don't think that, in medicine, we utilize technology the way that we should. And I think using our electronic medical record to signal to us, as fertility specialists, when a patient has completed their treatment and they are in survivorship, this is a time for us to intervene again into this patient's care and to make sure we've really addressed all of their fertility and reproductive and gynecologic/urologic needs that they are going to experience. So those are the ways that I think we can incorporate better fertility preservation care into the survivorship care model. ASCO Daily News: Excellent. Thank you, Dr. Appiah. And thank you, Dr. Roth and Dr. Freyer as well, for highlighting the challenges facing AYAs and approaches in care for this patient population. Dr. David Freyer: Thank you, Geraldine. Dr. Leslie Appiah: Thank you for having us. It's been a pleasure. Dr. Michael Roth: Thank you so much. ASCO Daily News: And thank you to our listeners for joining us today. If you've enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.     Disclosures: Dr. Michael Roth Research Funding: Eisai, Pfizer Dr. David Freyer: None disclosed.  Dr. Leslie Appiah: None disclosed. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

On today’s episode, Dr. Pamela Kunz, director of the Center for Gastrointestinal Cancers at the Yale School of Medicine, and vice chief of Diversity, Equity and Inclusion for Medical Oncology at Yale, discusses compelling sessions from the 2021 ASCO Annual Meeting that addressed gender disparities in the global oncology workforce and sexual harassment experienced by oncologists.   Transcript: ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Pamela Kunz, an associate professor of medicine in the division of oncology at the Yale School of Medicine where she also serves as the director of the Center for Gastrointestinal Cancers. Dr. Kunz also serves as the vice chief of Diversity, Equity, and Inclusion for medical oncology at Yale. Today, Dr. Kunz will highlight strategies to dismantle gender disparities in the global oncology workforce featured at the 2021 ASCO Annual Meeting. She will also tell us about the first study in oncology to systemically characterize the incidence of sexual harassment experienced by oncologists. Dr. Kunz reports no conflicts of interest relating to our discussion today and her full disclosures are available on the transcript of this episode. Dr. Kunz, welcome back; it's great to have you on the podcast again.  Dr. Pamela Kunz: Thank you so much. My pleasure to be here. ASCO Daily News: The theme of the 2021 ASCO Annual Meeting was Equity. Every Patient. Everyday. Everywhere.  Equity issues also apply to the oncology workforce and there were some very interesting discussions at the meeting on workplace disparities and harassment. You chaired an education session on dismantling gender disparities in the global oncology workforce. This session brought together a really interesting and diverse panel of experts  in medicine.  They discussed compelling data around gender disparities and steps to diversify leadership in medicine. They also looked at the role of male allies and how allies and advocates can support all women, and shared strategies on how to activate and empower female leaders.  Can you tell us more about this session? ("Dismantling Gender Disparities in the Global Oncology Workforce Together").  Dr. Pamela Kunz: Sure. This was--thank you for asking about that session. I think that really the theme of equity permeated so many different aspects of this Annual Meeting. And I think it was really inspiring and I think incredibly helpful to think about really reimagining how we provide cancer care. And I think I really like to think of workforce disparities as the other side of the same coin of patient disparities or inequities in patient care. I think that in order for us to provide equitable patient care, we really have to provide and create a diverse, inclusive, and equitable workforce. And so this is really one aspect of that is around gender disparities or, of course, other disparities in the workforce. And we actually do touch on that in one of the talks. So we put together a diverse panel that represents a number of different viewpoints. They were not all oncologists. In fact, I was the only medical oncologist on. Dr. Reshma Jagsi is a radiation oncologist. And Dr. Hannah Valentine is a cardiologist who was previously at the National Institutes of Health (NIH) and the inaugural director of their diversity program. Dr. Leon McDougle also spoke. He's a family medicine physician, the current president of the National Medical Association. And Mrs. Dee Anna Smith is the CEO of Sarah Cannon Research Institute. So we had this really incredibly diverse group of perspectives. And as you mentioned, we really touched on a whole variety of topics. I think it's also worth just mentioning kind of the scenes for this. This session originated well over 2 years ago. And I think that the timing of this now happening in 2021 following the pandemic I think was really incredibly important. I think we didn't really recognize it at the time. We were supposed to do this session last year in 2020. And it was really the 2020 planning committee that approved the session with Dr. Howard Skip Burris and Dr. Tatiana Prowell and Dr. Melissa Johnson. We had all these conversations of how do we get men in the room to talk about gender disparities? And we really crafted this panel to try to address a diverse audience and get everyone in the room. And then it was really so well timed with Dr. Pierce's ASCO theme of equity for every patient, every day, everywhere. It really just tied in nicely. ASCO Daily News: Excellent. What are the key takeaways here for oncologists?  Dr. Pamela Kunz: Sure. I can add some of that. I think that the first--and this was really addressed by Dr. Reshma Jagsi--is that we need to collect the data. We need to measure evidence of disparities at our institutions, in our organizations in order to really know where we're starting and in order to know how we're getting better. We have a lot of objective data already. But I think that I want to challenge all of our listeners to think about how can we be better about collecting that data in our own institutions. I think that the takeaways from Dr. Valentine's talk were some really wonderful concrete solutions to diversify the workforce. She took some lessons learned from programs she initiated at the NIH. And I'd like to specifically highlight a program at the NIH called the Scientific Workforce Diversity Toolkit. And in that, they instituted a program for cohort hiring in the Distinguished Scholars program. And this was bringing together a diverse group of underrepresented minorities and women into this scholars program. And they demonstrated really increased rates of female tenure track investigators. And I think that we can all do that in our institutions and organizations by instituting cohort hiring. From Dr. Leon McDougle's talk, he really highlighted this concept of intersectional feminism. And this term was coined by Kimberle Crenshaw. She's a professor of law at Columbia University. And it speaks to the fact that many marginalized characteristics or people who are in underrepresented groups may have characteristics that intersect. So that includes gender, age, sexuality, education, race, culture, ethnicity. And if any one person has a number of these characteristics, they may, in fact, increase the burden on that individual and may increase their risk for discrimination and for disparities. And I think it's recognizing the intersection. Intersectionality happens. And our women of color and our women who may have these other marginalized characteristics may be especially at risk. He also talked about a program at the Ohio State where he is on faculty entitled Advocates and Allies. And it's a National Science Foundation-funded program that trains men how to be advocates and allies. And then lastly, Miss. Dee Anna Smith spoke about creating a tapestry of allyship. She had this beautiful visual metaphor of really bringing together not just mentors. It's sort of modernizing the idea of mentorship and to really thinking more about allyship and how our trainees need to bring together, yes, perhaps mentors, but that allies really can represent an alternative to mentorship and a tapestry meaning that you need more than one person to serve as an ally for you. So I think those were--it it truly was--I moderated. I think these folks did all of the work in presenting. But it was really inspiring and I think very solution focused. ASCO Daily News:  Well, you were also the discussant of session that addressed a new study, Abstract 11001 on sexual harassment of oncologists. Now, few studies have used comprehensive validated measures to investigate the incidence and impact of workplace sexual harassment experienced by physicians and none, according to the authors of this study, by oncologists. So this is really important. What can you tell us about it? Dr. Pamela Kunz: Yes, absolutely. And I think the points that you made already really make this important and validate it. And I think the findings then in and of themselves are quite striking. So this group of authors led by Dr. Ishwaria Subbiah conducted a study. It was a cross-sectional survey of ASCO's research survey pool. And they then used the sexual experiences questionnaire, which is a validated questionnaire, as you mentioned. And this is really I think a real strength of the study. And they examined various aspects of sexual harassment. I think it's important for our listeners to understand the definition of sexual harassment. So this includes gender harassment, unwanted sexual attention, and sexual coercion. And gender harassment includes things that if we use the iceberg analogy, which they included in their presentation and was so nicely described in the NASEM, the National Academies of Science Engineering and Medicine report from 2018, the iceberg really underneath the surface contains many of these aspects of gender harassment that go unnoticed and unrecognized and include things like microaggressions. And in this study, they evaluated four downstream domains impacted by workplace sexual harassment including mental health, job satisfaction, sense of safety at work, and turnover intentions, meaning if an individual planned on leaving that specific job. And they looked at incidents of sexual harassment both by perpetrator, so institutional insiders or patients and families, and then by type of sexual harassment. So they received about a 30% response rate. They had 304 practicing oncologists access the survey link. And 273 provided responses. And I'll just hit some of the take-homes. So I think what I was struck by is the high rate of sexual harassment when the perpetrator is an institutional insider. So those are peers or supervisors. 70% of physicians reported one or more incidences of sexual harassment. This was higher in women. So, 80% of women reported sexual harassment compared to 56% of men. So, that was statistically different. But I was really struck by the fact that men were experiencing this as well. And then in terms of sexual harassment incidents when the perpetrator was a family or patient, 53% of physicians reported one or more incidences of sexual harassment. And this was 67% for women and 35% for men, also statistically significant. In terms of that difference. And then really a significant downstream impact from these experiences both for physicians who experienced this harassment from institutional insiders or from patients and families. And I think that we saw that really across the board for mental health, workplace safety, job satisfaction, and turnover intentions. And I think the take home for our listeners is that this can really lead to a significant loss of talent. And I think that if we are really hoping to--see, this is me editorializing. We are hoping to improve the diversity of our workforce because we know that that leads to better patient care and better patient outcomes. This is really important for our workforce to try to tackle and solve this problem of sexual harassment. ASCO Daily News: Absolutely. Well, thank you, Dr. Kunz, for highlighting some really important issues in oncology today. Dr. Pamela Kunz: Thank you so much. ASCO Daily News: Our listeners will find links to the two sessions discussed today on the transcript of this episode. And thank you to our listeners for joining us today. If you enjoyed this episode, please take a moment to rate and review us wherever you get your podcasts.   Disclosures: Dr. Pamela Kunz Stock and Other Ownership Interests: Guardant Health Consulting or Advisory Role: Ipsen, Lexicon, SunPharma, Acrotech Biopharma, Novartis (Advanced Accelerator Applications) Research Funding (institution): Lexicon, Ipsen, Xencor, Brahms (Thermo Fisher Scientific), Novartis (Advanced Accelerator Applications) Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Mitul Gandhi, medical oncologist-hematologist at Virginia Cancer Specialists of the US Oncology Network, highlights therapeutic advances in multiple myeloma featured at the 2021 ASCO Annual Meeting.   Transcript:  ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Mitul Gandhi, a medical oncologist specializing in hematologic malignancies at Virginia Cancer Specialists, which is part of the US Oncology Network. Dr. Gandhi will discuss therapeutic advances in multiple myeloma featured at the 2021 ASCO Annual Meeting. He reports no conflicts of interest relating to our discussion today, and full disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/podcasts. Dr. Gandhi, welcome to the ASCO Daily News podcast. Dr. Mitul Gandhi: Thank you for having me. ASCO Daily News: Let's first look at the OPTIMUM MUKnine trial. It's Abstract 8001. And it reported high overall response rates in patients with ultra high-risk multiple myeloma with Dara-CVRd induction therapy. What are your takeaways from this study, Dr. Gandhi? Dr. Mitul Gandhi: Sure. So, the OPTIMUM study was conducted by the UK group, and it's noteworthy for several reasons. The way they had constructed the trial, they designed and developed a platform primarily to enrich for a predefined subset of very high-risk individuals, whether it was through a set of genetic assessment or with central gene expression profiling. And the way the trial was conducted, while patients were waiting to ascertain the results of the gene expression profiling (GEP) they could receive two cycles of bridging therapy. Once those results were furnished or they met the cytogenetic risk criteria, patients who subsequently consented to the intervention protocol which was a dose intensified regimen, five drug regimen, incorporating daratumumab, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone. So, patients would receive induction for up to six cycles, and that would include the two cycles of potential bridging therapy as GEP was being evaluated on an every 21 day basis. And then this was followed by a modified conditioning regimen consisting of high-dose melphalan at 200 milligrams per meter squared along with weekly bortezomib which was continued even following autologous stem cell rescue, really until count recovery. Subsequently, patients received an additional six cycles of daratumumab, bortezomib, revlimid, or lenalidomide followed by 12 cycles of daratumumab and rituximab until progression. This was a complex study design with an intensified induction consolidation and maintenance phase, but it did yield a impressively high OR rate, or overall response rate, at 94% with very good partial response or greater seen in 77% after assessment following autologous transplantation, including 46% complete response (CR). And of those with CR, they had identified 63% achieving MRD negativity as well. And I think the authors should be commended for one, enriching a high-risk subset of patients both on conventional cytogenetics and/or GDP, and then two, utilizing the most active agents that we currently have to elicit high responses and then to consolidate on those following transplant. I think some of the take homes from the study are the ability to demonstrate feasibility of central genomic risk stratification related to more precisely identify and select high-risk patients as this is kind of an area of unmet need of where to augment therapy appropriately. I think it's still a question whether or not this is the exact dose intensified regimen that's going to elicit the best long-term outcomes in these highest risk patients and whether or not the conventional surrogates for a long-term progression-free survival (PFS) benefits such as MRD really apply to this as there is some controversy regarding that. Nonetheless, I think this offers a kind of a reproducible platform that can be emulated to identify the highest risk patients. You can do that prospectively, and then to selectively incorporate the most active agents and potentially the next generation of novel agents, including immunomodulators, cellular therapy, bi-specific antibodies earlier in the treatment course, and really try to elicit the deepest initial response and hopefully see that translate into longer term durable control. So, this was a complex study design that was impressively executed, and again with an ability to enrich for the highest risk subsets. ASCO Daily News: Excellent. Thanks for sharing your takeaways from the OPTIMUM trial. Well let's focus on the phase II CARTITUDE-2 study. That's Abstract 8013. This study reported that deep and early responses were yielded with a single infusion of cilta-cel in patients who had received one to three prior lines of therapy for multiple myeloma. What are your thoughts on this trial? Dr. Mitul Gandhi: So, Dr. Usmani presented the CARTITUDE-2 update on behalf of his co-collaborators. And the listeners probably are aware of some of the preliminary data that was presented at ASH as well in 2020, but this is a phase I/II protocol. Currently the phase II data are being presented with a proprietary CAR T platform which has two BCMA single domain antibodies on the CAR T construct along with a co-stimulator domain. And as kind of summarized in the title, the single dose was infused. So, amongst 113 patients who were initially recruited, 97 ultimately were treated with some fallout attributed to progressive disease. Like many of the other CAR T studies, this was a uniformly high-risk and heavily pretreated population. Median age was 61. High-risk cytogenetics were in 23% of patients. And there was about 20% of patients who had harbored plasma cytomas as well. Response rates were impressively high at almost 98%, and 67% obtaining a stringent complete response (CR). Much like the other CAR T experience, response continued to deepen over time. And encouragingly, duration of response was actually not reached time of presentation. Kind of amplifying the depth of response, of the patients assessable for MRD, 93% had achieved an MRD negative state at a sensitivity of 10 to the minus fifth cells, leading to a 12-month PFS of 77% and an OS of 89%. So, these are all welcome numbers and response data, again, in a heavily pretreated population who have been exposed to what we believe all the more active agents in the disease. In parallel with kind of response, with particularly with CAR T is the toxicity data. And encouragingly, while CRS, or cytokine release syndrome, which is typified in CAR T therapy was seen in about 95% of patients, only 4% had grade 3 to 4 CRS. So, on the whole, quite manageable. Median time to onset was 7 days with duration of 4 days and resolved with appropriate medical therapy, including tocilizumab. They did report one patient who had grade 5 CRS with hemophagocytic lymphohistiocytosis (HLH) with the remainder, I was summarizing kind of the low level of grade 3, 4 experience. There was additionally neurotoxicity and 21%, with 10% having grade 3 or higher. Again, resolved with supportive care measures. So, in totality this builds on the CAR T experience with high response rates, deep response, rates including achievement of stringent CR and high rates of MRD negativity with only a single dose of CAR T cells infused, again amplifying the efficacy of this platform on a heavily pretreated population and potentially allowing for extended treatment-free intervals as well or options for retreating in people who don't achieve MRD with a manageable toxicity profile at experienced centers. Certainly there's still work that's going to be done to better delineate the extent of CRS and how to appropriately treat that along with the neurotoxicity, but along with several other abstracts presented at this meeting and meetings prior, builds on the CAR T experience, knowledge rapidly coming to the forefront in myeloma therapy. ASCO Daily News: Great. So, some good developments for previously treated patients. Well, now I'd like to focus on newly diagnosed multiple myeloma. Let's look at the CARDAMON trial, Abstract 8000, and the FORTE trial, Abstract 8002. These studies explored novel therapies that are emerging for newly diagnosed multiple myeloma. So in their presentations, these trial investigators seem to question the value of standard of care autologous stem cell transplant (ASCT). So do you think these new data call into question the advantages of the up front ASCT approach in newly diagnosed multiple myeloma? Dr. Mitul Gandhi: That's a great question. And as providers in the myeloma community know, there's still an ongoing debate whether or not to ubiquitously apply a high dose melphalan conditioning and stem cell rescue across the spectrum of all patients with myeloma who are transplant eligible or reserving it for certain patients or not. Some of this is borne out of saving unnecessarily aggressive therapy, who would otherwise achieve an excellent response of induction. Along with some concern for secondary genotoxic effects imparted by the melphalan itself and perhaps propagating more biologically aggressive subclones. And to that end, these two abstracts explored whether or not transplant-free approaches would be feasible. So, the CARDAMON study enrolled 281 patients where all patients received kyprolis, cyclophosphamide, and dexamethasone for four cycles, and of those patients achieving at least a partial response (PR), they were subsequently randomly assigned to continuous KCd or autologous stem cell transplant. And what the authors concluded, KCd induction followed by KCd maintenance was not inferior to autologous stem cell transplant with PFS at 2 years measured at 70% versus 76%, and that difference meeting the criteria that was prespecified in terms of their confidence interval for noninferiority. So, on the surface you could argue based on the results that were presented that there was equivalence. But a few caveats that are important to bring up, the first was that follow-up was short. It was only two years, and so it's very plausible that with longer follow up, the noninferiority that was seen may not be borne out with extended follow up. The other point the author's note was that MRD negativity was higher in the autologous stem cell group at 53% compared to 35.8% of the non-transplant group. And various studies have reported this to be a reasonable surrogate for long-term PFS, not always. And so again highlights the fact that with longer follow up, we may see a separation of the curves. Their subset analyses did not demonstrate any obvious areas, rather a subset of patients that would have derived preferential benefit, although the numbers were quite small. So, while an initial conclusion may be that there was a relative equivalence for a transplant-free approach, I'd argue that it's probably still a bit premature to make that conclusion and noninferiority may not be identical with longer follow up. And additionally, this probably is an induction regimen that is not as commonly employed in the U.S. But it does again help to the body of literature regarding this question of transplant for all versus not, although there may be hopefully more discriminatory power to see where it would be beneficial. The FORTE study presented by Dr. Gay and her colleagues was a bit larger at 464 patients and slightly different. Patients were randomly assigned to one of three arms, carfilzomib plus cyclophosphamide plus dexamethasone for four cycles induction followed by autologous stem cell rescue, carfilzomib, lenalidomide, dexamethasone induction for four cell cycles followed by autologous stem cell rescue, or carfilzomib, lenalidomide, dexamethasone without autologous stem cell for 12 cycles. So, those were the three arms, and then there was a second randomization to lenalidomide versus lenalidomide plus carfilzomib maintenance. Patients were prespecified in terms of their cohorts of high-risk, standard risk, or the so-called double hit which was people, patients rather, harboring two high-risk cytogenetic features. And so what the authors concluded that across the board, the arm containing carfilzomib, lenalidomide, dexamethasone with autologous stem cell rescue demonstrated superior PFS compared to all of the other, rather, the other two arms. And similarly intensification of maintenance incorporating kyprolis plus revlimid resulted in superior 3 year PFS compared to revlimid alone in 90% versus 73%. So what do we take away from this? Well, it's not a conventional induction approach in the U.S., with RVd still predominantly being used, particularly after the endurance data was presented at last year's ASCO showing equivalence of a bortezomib induction strategy versus carfilzomib strategy. It does support and lend credence to the use of high dose melphalan autologous stem cell rescue as patients who are in this arm seem to enjoy a more longer and durable progression-free survival across all subsets, including standard risk, high-risk, and the double hit strategy. So there wasn't any particular subset that could be identified that would have performed equally well with KRd alone without autologous stem cell rescue. Putting these two abstracts together, I would still argue that there remains a very important role for our high dose melphalan and autologous stem cell rescue currently an induction, rather following induction, in appropriately selected patients. And while we may not have identified patients on preselected criteria based on their cytogenetic risk, it's conceivable that we might identify response based criteria, whether it's MRD or otherwise, to perhaps see who may be able to abstain from transplantation. And there are several protocols that are actively accruing, some that have been preliminarily presented, and some that will be presented in subsequent meetings that might lend evidence to this. But for now based on the data sets that were presented at this year's meeting at ASCO, there still seems to be support for use of high dose melphalan and autologous stem cell rescue. ASCO Daily News: Right. Well staying with the issue of transplantation, for over a decade investigators have been exploring the curative ability of alloHCT in select patients with high-risk multiple myeloma. Fast forward to 2021 and the phase II double blind, placebo controlled, blood and marrow transplant clinical trials network 1302 trial. That's Abstract 7003. This study found that when performed with a reduced intensity conditioning regimen of bortezomib, fludarabine, and melphalan, alloHCT was safe in patients with high-risk multiple myeloma. What are your thoughts on this, and do you anticipate further research on the role of alloHCT in patients with multiple myeloma and high-risk features? Dr. Mitul Gandhi: So, this is an interesting abstract presented by Dr. Nishihori and her colleagues specifically looking at the role of ixazomib maintenance following a reduced intensity conditioning regimen of fludarabine, melphalan, and bortezomib in patients with high-risk myeloma. So this study was a phase II study enrolling patients under the age of 70 with high-risk myeloma defined by cytogenetics, or presence of plasma cell leukemia, or relapse within 24 months of an autologous stem cell transplant, which has been identified as a prognostic factor independent of baseline risk of poor outcomes, with the goal of administering the reduced intensity conditioning followed by HLA matched donor unmanipulated graft with methotrexate and tacrolimus GVHD prophylaxis, and starting at day 60, randomization ixazomib versus placebo maintenance. It should be noted that the goal initially was to enroll 110 patients, but ultimately only 57 patients were accrued over the course of 4 years from 2015 to 2018, 52 ultimately receiving an allogeneic HCT and 43 proceeding to maintenance. And so this in and of itself highlights the challenges of running an alginate transplant trial in myeloma mainly because sick patients may be by the point where allogeneic transplant is being entertained or inability to achieve sufficient disease control in order to pursue the transplant. But with respect to the study itself, they reported a PFS and overall survival (OS) outcome at 24 months, of 52% and 85% respectively, with transplant-related mortality at a respectable 11%. So in context of the small studies that had previously been reported in this space of allo SCT and myeloma, this was improved treatment-related mortality related to the procedure itself. With respect to the question at hand regarding the role of ixazomib maintenance, interestingly they showed no difference in PFS, with ixazomib versus placebo at 55% and 59% and OS at 95% and 87%. In terms of the toxicity, it was not trivial. Grade 3 to 4 acute GVHD at day 100 was 9.5% in the ixazomib arm, 0% in the placebo arm. And chronic GVHD was 69% versus 64%. So, where do we take all of this data in context? I think there is a signal of lower transplant-related mortality compared to historical controls, and so it probably speaks to the improved ability to identify patients and also get them through transplant with this modified conditioning. The follow up, however, was abbreviated, and so there may be increased relapse over time as well. In terms of where does this fit in the armamentarium of therapy with refractory myeloma, I think that's still to be determined. And perhaps it's going to be occupying more of a niche role given the blossoming repertoire of highly efficacious immune-based agents, whether it's modified cellular therapy with CAR T a upcoming NK cell products that are being explored, and of course by specifically antibodies that have been robustly presented at this meeting demonstrating impressive responses. So, it's very conceivable that patients who were previously would be entertained for allogeneic SCT will now be in are treated with this kind of repertoire of novel immune agents. And so it may become a more of a niche role in patients who have exhausted all conventional or investigational approaches, but it does suggest that with this modified reduced intensity conditioning, treatment-related mortality can be lowered. With respect to the question at hand, it does not appear as though maintenance ixazomib helps these patients. And so observation alone following transplant versus an alternative maintenance strategy would be indicated. ASCO Daily News: OK. Well I'd like to ask you about the Apollo trial. That's Abstract 8046. This study looked at health-related quality of life of previously treated patients with multiple myeloma on a regimen of pomalidomide and dexamethasone plus subcutaneous daratumumab. Any surprises here, Dr. Gandhi? Dr. Mitul Gandhi: So, the Apollo study is a phase III trial primarily evaluating the efficacy of pomalidomide plus dexamethasone versus pomalidomide dexamethasone plus the incorporation of subcutaneous daratumumab in patients with myeloma who had received one prior line of therapy. And primary outcomes data had already been presented with improved rates of disease control with incorporation of daratumumab. With respect to this abstract, Dr. Terpos presented quality of life and patient-reported outcomes that was collected in parallel with the intervention arm of this study, and so they utilized the EORTC 30 item questionnaire to assess quality of life and subjective data from patients. And what they found was in the patients who had been on the DPD arm, or the daratumumab arm, there was a greater reduction in pain and no real augmentation or introduction of increased adverse events related to the additional agent. Moreover, there was no decline in physical or emotional functioning with DPD, but there was worsening decline in those elements compared to baseline for patients receiving pomalidomide and dexamethasone alone. There were higher rates of improvement with respect to control of disease symptoms, physical functioning, emotional functioning on the DPD arm. So, what does this tell us? Well in general, I think we've seen a plethora of agents that have improved outcomes with our patients with myeloma who are now living for years on therapy, increasingly and often even into a second decade. And so gaging the impact of therapy on quality of life, subjective sense of well-being is critical as these patients are going to be on therapy for quite a while. And so independent of serologic and laboratory response, we certainly want the interventions to improve functional capacity. And this data would suggest that you can achieve that in parallel with achieving better and deeper responses, which intuitively makes some sense, and they are often congruous. Involving the incorporation of an additional agent didn't worsen the sense of adverse events, but in fact improved the general sense of well-being. So this adds to the body of work of daratumumab on a MM dexamethasone backbone parting benefit without toxicity and also lending credence to the notion that by improving myeloma parameters, we're going to be in parallel improving quality of life. And so with the advent of all the other agents and novel compounds that are being developed after the acute toxicity period, we'd also expect to see improvement in quality of life as well. And so I think this was an important contributor to telling us this. ASCO Daily News: Excellent. Well thank you so much, Dr. Gandhi. I really appreciate your time today. Before we wrap up, any final thoughts from you on advances in multiple myeloma? There's certainly some really impactful work being done in the field. Dr. Mitul Gandhi: Yeah. I think I would encourage all the listeners to review the abstracts presented, particularly the oral abstracts as they get into some of the granularity on detail regarding the individual CAR T and bispecific antibody products, and very nicely demonstrate the durable responses that are being achieved in heavily pre-treated patients. Obviously kind of the next sort of hurdle in the field is to democratize these agents and make sure they're readily available for all patients. And there's a lot of work being done to ensure that management of the acute toxicity can be managed more broadly. So I think I'd pay particular attention to the oral abstract sessions which really demonstrate the novel agents that are being investigated. ASCO Daily News: Dr. Gandhi, thanks again for being on the podcast today to highlight some great new therapies in multiple myeloma. Dr. Mitul Gandhi: Thank you for having me. ASCO Daily News: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate and review us wherever you get your podcasts.   Disclosures: Dr. Mitul Gandhi: None disclosed.  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Jason Luke, director of the Cancer Immunotherapeutics Center at UPMC Hillman Cancer Center, discusses advances in immunotherapy across the spectrum of malignancies featured at the 2021 ASCO Annual Meeting.   Transcript:  ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Jason Luke, the director of the Cancer Immunotherapeutics Center at UPMC Hillman Cancer Center. Dr. Luke also serves as associate professor of medicine at the University of Pittsburgh School of Medicine. His clinical focus is on immunotherapy for advanced solid tumors, as well as cutaneous malignancies and melanoma. He joins me to discuss advances in immunotherapy featured at the 2021 ASCO Annual Meeting. Dr. Luke has relationships with most of the pharmaceutical companies that have funded the research discussed in this episode. His full disclosures are available on the transcript of this episode. Dr. Luke, always great to have you on the podcast. Dr. Jason Luke: Well, thanks so much for the invitation today. ASCO Daily News: Well, there was an abundance of novel therapies and practice-changing studies presented during this year's [ASCO] Annual Meeting. Did you detect any themes among all of the great studies presented during the meeting? Dr. Jason Luke: Well, I agree. And as I was sort of taking the fire-hose of abstracts in this year, I thought there were four themes that really seemed to stand out to me. And when I was thinking through them, I think the first one was the validation of a new checkpoint, or a third validated checkpoint for use in clinical practice. A second one was really the emergence of immunotherapy, now being used in the curative setting, meaning either in adjuvant studies or in neoadjuvant studies. And the third area was advancements in this management of metastatic disease with practice-changing trials. And then the fourth area, which is always near and dear to me, is novel therapeutics with the development of the next generation of immunotherapies, and those early data that might give us a hint towards what might be coming next. ASCO Daily News: OK, so let's first look at the third validated checkpoint for use in clinical practice. That's Abstract 9503. Dr. Jason Luke: Yeah, absolutely. So this year at ASCO, we saw the results of a clinical trial described as the RELATIVITY-047 study, which was a global randomized double blind phase II/III study comparing anti-PD-1 antibody with nivolumab (nivo) versus a combination of nivolumab with the anti-LAG-3 antibody relatlimab. And so LAG-3 is a molecule that many will be familiar with, but perhaps not everyone. And LAG-3 is another receptor on T cells that can become up-regulated as T cells become dysfunctional in the tumor microenvironment. And so all are aware of the concept that infiltrating lymphocytes can get into tumors, and then they get blocked by these immune checkpoints. And so LAG-3 is another immune checkpoint expressed on these tumor infiltrating lymphocytes. And I don't have time to go into all of this, but in the preclinical space, blocking LAG-3 with an antibody is actually, in many mouse models, more effective than blocking a PD-1 or PD-L1. And so there's been a lot of interest. LAG-3 was one of the first targets to really develop as a co-target to PD-1. And just to zoom forward then to the clinical trial, this was a study where patients with advanced, untreated, metastatic melanoma were randomized one to one to either get relatlimab plus nivolumab, in what they are describing as a fixed dose combination, meaning that there's an infusion of the dose once a month, relatlimab 160 milligrams plus nivolumab 480 milligrams. And that was the same dose. And so it's only one infusion, even though it's two drugs, one infusion. That was compared with nivolumab. And there were a number of stratification factors, et cetera, in the study. And they're useful to get into the minutia, but right now, I think not so important. This, like I said, was a gated study, meaning they did a phase II trial first, to try to prove that there was a benefit in a smaller sample of patients. And if they hit the endpoint, they then went on to a phase III trial. And that's exactly what happened. So in this trial, progression-free survival (PFS) was the primary endpoint. And, interestingly, it was evaluated by blinded independent central radiology. And that may sound like a mouthful, but we'll come back to why that's important a little bit later. And there was a hierarchical testing strategy, such that the PFS had to be established first, before the investigators can look at overall survival and overall response rate. But given that background, there really was a quite substantial and clinically impressive difference between these two arms. And so we call relatlimab "rela" for short. So rela plus nivo demonstrated a substantial improvement, markedly statistically significant improvement, compared with nivolumab monotherapy, so that at 1 year, at 12 months, the progression-free survival for the combination arm was 47.7%, compared to 36% for nivolumab. And the median PFS was 10.1 months for the combination versus 4.6 months from nivolumab. So you can see that's more than a doubling of progression-free survival, with a hazard ratio at 0.75 and a p value at 0.006 or 0.0055. So why does that matter? Well, we have thought for a long time in the field about combination immunotherapy, and people think of PD-1 and CTLA-4 combination. And these data, when compared sort of across trial comparison, which is always a little dangerous, but they look very similar to what we saw with nivolumab plus ipilimumab (ipi), in terms of the absolute improvement in the benefit in terms of median progression-free survival, between relatlimab plus nivo, as compared with ipi plus nivo in the CheckMate-067 study. And I mentioned this blinded independent central radiology, that complicates things a little bit, because the landmark comparisons between having the radiologist evaluate the scans and having the investigators evaluate the scans, actually gives a little bit of variation in terms of the outcomes. But if you just compare them on a high level, they actually look very similar. And along those lines, the really important thing is that relatlimab plus nivolumab is much better tolerated with much less side effects than nivolumab plus ipilimumab. So, in fact, in this clinical trial, we see that the rates of grade 3-4 adverse events are on the order of what we saw with nivolumab monotherapy in CheckMate-067. Now, interestingly, in this study, RELATIVITY-047, the rates of grade 3 adverse events for nivolumab monotherapy were actually about half of what they had been seen in the previous phase III trial. And I think that that just suggests that all of us, as a field, are getting better at managing these immune therapy toxicities. One other piece of information that was very interesting to look at was when the outcomes were broken down by subgroups, particularly the biomarkers of PD-L1 positivity, and LAG-3 positivity. These biomarkers actually did not inform the outcomes, in which case, I mean, that nivolumab plus relatlimab was actually effective across all the subgroups. And so one might have hypothesized, going into this, that patients with high LAG-3 would do better with a LAG-3 treatment. That was not what was seen. In fact, all patients benefited with the combination. And that's relevant to clinical practice, because, as we think about applying this treatment, I do not think we're going to be able to use biomarkers, at least initially, to be able to differentiate who should get what. And rather this just suggests that basically all patients who are going to get PD-1 monotherapy would be better served by giving the combination. So I was the discussant actually for this abstract, and one of the questions I tried to get at was, well, does that mean that you would just essentially replace PD-1 monotherapy across the board in melanoma with this combination? And I think the answer is, not quite yet, but maybe someday. And what I mean by that, is that there are still some very high-risk patients that we treat. And particularly those are patients with high lactate dehydrogenase, brain metastases, rapid progression, et cetera. And those are the patients where, at least I, predominantly use nivolumab plus ipilimumab, or nivo plus ipi. And that's because nivo plus ipi is the treatment for which we have the best long-term data, and we know the most about it in terms of treating high risk patients. So I would continue to use that until this trial, at least. Is more mature, so that we can get data about the response rate, the overall survival, and so on and so forth. But I think there's really no question, looking at this relatlimab plus nivolumab data, that it does change the standard of care in melanoma, and that, for most patients, who would have gotten PD-1 monotherapy, they're now going to be directed towards this combination, given it's well tolerated and appears to be highly active. And I think, thinking beyond melanoma now, if this is now a second, a third checkpoint, but a second one we can combine with nivolumab with little toxicity, I think it opens up a huge new world of clinical investigation, possibly adding doublet checkpoint to chemotherapy. Basically everyone everywhere we've seen PD-1 combined with chemotherapy, and obviously that's quite exciting just thinking about improving outcomes. And we're going to discuss all the different ways that PD-1's been impacting the standard of care across different settings. ASCO Daily News: Excellent. Well, let's shift our focus now to the curative use of immunotherapy. Let's start in the adjuvant setting with the KEYNOTE-564 study. That's LBA 5. Dr. Jason Luke: So plenary presentation for the KEYNOTE-564 study, which was adjuvant pembrolizumab versus placebo in high-risk renal clear cell renal cell carcinoma. And so this is an important trial, because there have been decades, actually, of immunotherapy clinical trials in the adjuvant setting, which have not demonstrated a benefit. That also includes actually VEGF-TKIs, which also did not show a benefit. But in this large study, so almost 1,000 patients, 994 patients, they were randomized one to one to receive pembrolizumab or placebo. And the eligibility population were pathological T2 with intermediate and high risk features all the way through metastatic disease that's been fully resected. And the outcomes here, again, I think were very impressive. And so the disease-free survival was statistically significant, with a hazard ratio of 0.68. And what does that mean in reality? Well, the 2 year disease-free survival was 77.3% for the patients getting pembrolizumab compared to 68.1% for those getting the placebo. So you can see basically a 10% 2 year improvement in disease-free survival. And though the data were quite immature, the early analysis of overall survival also suggested a statistically significant benefit. So p value was 0.02 and hazard ratio was 0.54. Now we'll be very interested to see how that matures over time. But I think again these are practice-changing data, to suggest that, basically, all high-risk patients with clear cell renal cell cancer are now going to be receiving anti-PD-1 immunotherapy in the adjuvant setting. I think it does raise the question, and we'll discuss it now across other diseases as well, in terms of, are we over-treating patients. But this has been a constant struggle in medical oncology for many, many years. But it's very hard to see a treatment like this, with such a benefit, and not think that you want to give this basically to almost all the patients. But, hopefully, biomarkers to inform which patients benefit most will be coming over the relatively near future for renal cell. But I think those are becoming a little bit more obvious in some other diseases. ASCO Daily News: Looking at non--small cell lung cancer, Abstract 8500, that's the IMPOWER-10 trial, that caught a lot of attention. That was trending on Twitter for a while. What are your thoughts on that trial? Dr. Jason Luke: Yeah, absolutely, so the IMPOWER-010 or 010 study, this study looked at PD-L1 inhibition in the adjuvant setting, versus a placebo. So this was another very large trial where patients with early to later high-risk disease, so stage 1b to 3a, they received standard chemotherapy as adjuvant treatment, but then were randomly assigned to get PD-L1 versus best supportive care. And this was an interesting clinical trial, [ and] had a complicated statistical design where the first analysis was to look at the impact in PD-L1 positive patients. Secondarily, then, they looked at randomized patients. And then thirdly, they looked at intention-to-treat. And this was a positive study. So in the disease-free, in the PD-L1 high patient population, the disease-free survival did not reach the median, with a 2 year benefit at 74.6% versus 61%, so again a 13% improvement in 2 year disease-free survival. And that was highly statistically significant, hazard at 0.66. And, again, that's the PD-L1 high population. So, thinking about biomarkers then, it looks clear that the PD-L1 positive group is the one that disproportionately benefits, because as we went through the rest of the hierarchical testing, the disease-free survival in randomly assigned patients, and then in intention-to-treat patients, those numbers got a little less strong. And it really probably suggests that the PD-L1 positive group is the one that's going to drive almost all of the benefit. So it'll be interesting to see how this data matures, and how it's interpreted in the community. I mean, you mentioned the discussions on Twitter, which I sometimes participate in. And I'm going to come back to a little later how it's very interesting to see how thought leaders for various malignancies sort of take these data into consideration. I think clearly in GU cancers, when we talked about the KEYNOTE-564 pembrolizumab data, the sense was, this is an immediate change in the standard of care. When we look at this data for non--small cell lung cancer, however, the sense I've gotten from some investigators is, this is early data. And they really do want to see that overall survival before that's really going to have high uptake. But we'll have to kind of see how that goes. Maybe selecting for PD-L1 in that population would make that difference, to really let you feel confident. But it'll be interesting again, like I said, as more time passes and as we see more data, and as other PD-1, PD-L1 agents come into this same space, if there's reproducible data that will help them feel more confident. ASCO Daily News: Right, well, another trial that attracted a lot of attention was CheckMate-577. That's Abstract 4003. Do you think this trial will move the needle in esophageal or esophagogastric junction (GEJ) cancers? Dr. Jason Luke: So I think this is a real important trial, because we've historically thought of certain tumor types as immunotherapy sensitive versus not sensitive, melanoma, lung cancer, et cetera. And gastrointestinal (GI) tumors predominantly have fallen into that latter group, where we think where there isn't as much of a benefit. Obviously there are approvals for esophageal and gastric cancers, but I think this study really shows how we can move the needle in terms of maybe curing more patients. So CheckMate-577 looked at adjuvant nivolumab. And these were stage II and stage III patients with esophageal or GEJ, and they got neoadjuvant chemoradiation treatment and then surgery, all of that being standard of care, but then went on to get a randomization 2 to 1 to either nivolumab or placebo. And again, as you mentioned, this is an important trial. The disease-free survival (DFS) was statistically and substantially improved for the patients getting nivolumab versus placebo, after that definitive therapy. So in the group receiving nivolumab, the median disease-free survival was 22.4 months, compared to only 11 months in the patients getting the placebo. That was a hazard of 0.69 and a p value at 0.003. And, again, thinking about biomarkers here, there was a broad population of patients treated. But when you look at the breakdown of who benefited the most, the patients benefiting in this trial were almost entirely those patients who had a PD-L1 composite signature at greater than 5,  combined positive score (CPS) greater than 5. And so it's really the case that the PD-L1 positive patients with esophageal cancer seemed to benefit the most. And so I don't know how you think this doesn't impact the standard of care. In the total population there was a doubling of DFS, and in the PD-L1 high it was actually almost a tripling. And so I think, immediately, at least for PD-L1 high patients, they should go on to get adjuvant PD-1 after definitive chemotherapy, radiotherapy (RT), then surgery. And I think this is really exciting, when we think about, this is disease, obviously, it's very, very difficult to treat. And outcomes in metastatic disease are not what we want. And this really suggests we may be able to really benefit a lot of patients moving forward. ASCO Daily News: Excellent. So what are your takeaways from Abstract 9500, the KEYNOTE-054 trial of adjuvant pembrolizumab for melanoma? Dr. Jason Luke: Yeah. Thanks, so in melanoma we've had immunotherapy with checkpoint blockade now for a decade. And adjuvant clinical trials have been ongoing for most of that decade. And it's been standard of care to give our patients checkpoint blockade again for several years. I think what was really interesting about the update for KEYNOTE-054, which was the study of pembrolizumab (pembro)  versus placebo in stage III melanoma, was the authors on this update looked at the impact of crossover after initial progression. So in the clinical trial, patients were randomized one to one to either receive pembro or placebo. And at the time of progression, they could then cross over and get the other treatment, right? So this trial was the first trial to be designed to be able to ask that question, immunotherapy now versus immunotherapy later. And what we observed in this study was that the response rate to getting pembrolizumab in the metastatic setting, if you had gotten the placebo on the adjuvant trial, was approximately similar. It was right around 40% And that's actually what we saw on the KEYNOTE-006 study that got pembrolizumab registered. So that was really, really interesting. And it suggested that if patients progress in the adjuvant setting and get treatment with PD-1 in the frontline metastatic, and they're still in good shape, they actually can have similar outcomes than what we would have expected if they had not had that adjuvant experience. And so I think this is really important. It doesn't actually answer the question about overall survival, which is really what we want to know. Does adjuvant immunotherapy improve overall survival? But it does suggest that patients can have this benefit, even if they wait for treatment. One thing that was really interesting to see was that, for those patients who had pembrolizumab, in the adjuvant setting, and then had a progression event, who went on to get pembrolizumab again, actually had much lower outcomes. And so I think that that's something to be cautious about. I think if patients progress on adjuvant PD-1, the data from this trial really suggest that going back to PD-1, even if there's been a period of time, is not a real great idea. And many of us in the field have kind of advocated of going to CTLA-4 combination in those patients anyway. But I would think these data really do suggest that that's important. So broadly speaking, then, I think these data are important to suggest that if you wait to give immunotherapy, you can still get a good benefit, at least in melanoma. And what I thought was really interesting across all of these abstracts, so for kidney cancer, lung cancer, esophageal, melanoma, was we saw, I think, based on the investigator feedback, or the thought leaders in the field, was that disease-free survival or relapse-free survival was really interpreted somewhat differently in different settings. And so I think, in melanoma, I think we have for a long time thought that adjuvant therapy was important, despite the fact, we don't have overall survival for PD-1 antibodies. In the renal cell data, again, where immunotherapy has been a backbone, albeit with IL-2 and various different immunotherapies, again, a lot of enthusiasm. When we looked at lung cancer and esophageal cancer, where I think investigators are more used to biomarker selection, they were a little more nitpicky about which populations we should treat. And so I'm very interested to see how this entire field sort of develops, and how the thought leaders for each disease take these data in. But, if you take a step back, on a really high level, when we think about giving PD-1 checkpoint blockade, it's generally speaking a low-toxicity treatment. And there's a tremendous impact on recurrence and potentially cure in the adjuvant setting. And that is just so exciting when we think about truly making a difference on cancer. We're talking about people never having recurrence and never dying of metastatic disease. And if we think about the outliers among the thousands of patients that have these diseases, and just go out to 5 years, 10 years from now, that's going to be a lot of people alive because they got immunotherapy after surgery. ASCO Daily News: Well, that would be fantastic. Thanks, Dr. Luke, for your great analysis of the adjuvant setting. Let's focus now on the neoadjuvant setting. Abstract 8503, the CheckMate-816 trial, seems to be on everyone's radar. What can you tell us about it? Dr. Jason Luke: Absolutely, so I think we just got done talking about adjuvant therapy. But an alternative would be to say, is there a way that we can deliver this immunotherapy, perhaps to enhance the immunotherapy and either improve the surgery or actually maybe even avoid the surgery, moving into the future. And so that is a really exciting paradigm as well. And so the first of these was in non--small cell lung cancer, the CheckMate-816 study. And the initial results of this study were actually presented at AACR earlier this year, but now updated here at ASCO. And what we saw was that there was a major improvement, 10 times improvement, in pathologic complete response for giving nivolumab plus chemotherapy. I mean literally 2% pathologic complete response with chemotherapy, up to more than 20% with this combination with immunotherapy. And what the investigators updated here was a number of details around the surgical plans, showing that the surgeries were easier, and the patients had better time recovering, due to lower disease burden for those that got the combination with immunotherapy. And I think that's really, really exciting, because, I mean, it suggests a paradigm in the future where we can reduce the amount of surgery. So one of the things was they looked at the number of open thoracotomies versus VATS procedures. And a number of patients who got immunotherapy had a much lower surgical burden. So, I think those data are really exciting. They're not quite ready for prime time yet, because I think we need larger studies to prove this, but I think the trend is, we'll talk through these different disease settings, really does suggest that immunotherapy is going to really change all of oncology, in terms of surgical paradigms, how we follow patients, et cetera. ASCO Daily News: Excellent. Dr. Luke, you spoke earlier about the phase III study of relatlimab and nivolumab. There's another study, Abstract 9502 in the neoadjuvant setting, right? Dr. Jason Luke: Yep, and so, in addition to the phase III data for relatlimab, there was also a neoadjuvant study from The University of Texas MD Anderson Cancer Center group, which I think was really, really useful in helping us feel more confident actually about the metastatic disease data, and about understanding where the field in melanoma is going. So, in melanoma, that's where, sort of taking a step back quickly to note that there have been a whole bunch of neoadjuvant clinical trials done over the last 3 to 4 years, and actually so many that we've already started to have meta-analyses to look and see and observe, I should say, that those patients actually who have major pathologic responses, and those with complete responses, generally speaking, don't recur. And this is really exciting. It's actually even led to clinical trial designs where we're actually deferring surgery in melanoma, where we give neoadjuvant therapy. We take out one node. And if it's a complete response (CR) we don't even do the surgery. So in the Abstract 9502, again relatlimab, the anti-LAG-3 antibody was combined with nivolumab. And I think what the important thing to highlight here was that the rates of pathologic complete response and major partial response actually looked very similar to what we saw with nivo plus ipi in previous clinical trials. So if you remember, the relatlimab data in the metastatic setting was only the PFS data, due to the statistical plan. But what we see here is that in the neoadjuvant setting, very similar outcomes for relatlimab plus nivo as what would have been expected for ipi plus nivo. And I think that gives us, again, more strength and more confidence that this is a very active combo, again, with lower toxicity relative to nivo plus ipi. ASCO Daily News: OK, well, Abstracts 4503 and Abstract 4504 looked at alternative management strategies in bladder cancer. Can you tell us about these data? Dr. Jason Luke: So these were two really interesting abstracts, I thought, from my perspective. And they really looked at management, alternative management strategies for muscle invasive bladder cancer. And so the first one, 4503, was the Hoosier Oncology GU study 16-257. And this was a study that looked at neoadjuvant nivolumab plus gemcitabine and cisplatin, with an evaluation for clinical outcome. So what I mean by that was, after the patients got this treatment, they were evaluated for whether or not they had had a clinical complete response, and then they were offered the opportunity to either not pursue cystectomy, which obviously is highly morbid, or to continue to be followed. And, very interesting, the study, for those patients who were deemed to have had a complete clinical response, 70% of them did not recur. And that's really exciting, because if you think about the population of patients with bladder cancer, many of them elderly, those cystectomies are highly morbid surgeries. And this suggests that we may be able to move into a future where we could give them upfront medical therapy and actually potentially avoid that surgery. The other abstract I thought was really interesting was sort of married to that, which was the 4504 abstract. And that was a clinical trial that looked at the neoadjuvant administration of pembrolizumab plus gemcitabine chemotherapy and radiation treatment. And, again, what they observed in that study was very high rates of pathologic complete response, and longer term outcomes that looked very exciting. And I think what both of these studies show, as phase II studies, is the possibility that medical therapy might actually be curative in some patients. And there are a number of phase III efforts now ongoing to try to amplify these trials and actually confirm them on a larger scale. ASCO Daily News: Shifting our focus now to practice-changing trials in metastatic disease, GI oncologists were very pleased to see the data from CheckMate-648. What was observed in this trial, LBA 4001? Dr. Jason Luke: So CheckMate-648 in esophageal cancer was a study in the frontline metastatic setting, looking at the impact of immunotherapy plus chemotherapy, or immunotherapy alone versus chemotherapy. And so what I mean by that was one arm in the study looked at nivolumab with standard chemotherapy, compared to chemotherapy, and the other arm looked at nivolumab plus ipilimumab versus chemotherapy. And, very briefly, what was observed was that both of the active arms, so the immunotherapy containing arms, the nivo plus chemotherapy or the nivo plus ipi, both of them improved outcomes compared with chemotherapy. And so, moving forward, there's really no question now that the standard of care in the frontline management of esophageal cancer should include immunotherapy, either as a combination with chemotherapy, or possibly with leaving out the chemotherapy and giving just nivolumab plus ipilimumab. Now the sub-stratification of patients and their outcomes by sub-stage was important in this study, and again emphasized that it's mostly the PD-L1 positive patients who benefited the most from immunotherapy. So but the idea of potentially having a regimen that's chemotherapy-free for frontline esophageal cancer, I think is really exciting. And I'd be really interested to follow where this field goes in terms of which patients are getting selected for the nivo chemotherapy versus ipi plus nivo arms, in standard practice kind of moving into the future. And obviously further biomarkers will be really important. But I think this is really a practice-changing trial, again, to emphasize that all patients with esophageal cancer should be getting immunotherapy in the frontline, moving forward. ASCO Daily News: Indeed, what can you tell us about Abstract 6000 using camrelizumab for nasopharyngeal carcinoma (NPC)? Dr. Jason Luke: Yeah, absolutely. So I think that this is a really interesting study and I think important. This is a study actually looking at the impact of adding immunotherapy to chemotherapy in nasopharyngeal carcinoma. So all the oncologists in the United States will be like NPC, oh, yeah, I heard about that during fellowship. But this is actually a major source of morbidity and mortality throughout the rest of the world, especially in the developing world. And so this clinical trial to me is very interesting. So the short story here is that adding camrelizumab improved outcomes relative to chemotherapy, which I think is probably not surprising, because across many other settings we've seen that adding PD-1 to chemotherapy would improve outcomes. I think the difference here was that this is an antibody that was developed in China. And is it part of a growing trend to see competitor PD-1 PD-L1 antibodies entering the space. So to close the loop on NPC, I think these data really strongly suggest that we should be giving immunotherapy in combination with chemotherapy in the frontline to these patients. But I think, more broadly, start to open this conversation about how are we going to evaluate new drugs that are getting developed, say, only in China, or in other parts of the world where there are no patients from the United States that are actually participating in the clinical trial. Are those drugs going to get approved by the U.S Food and Drug Administration (FDA)? And if they do get approved by the FDA, how are they going to get priced, because as we're moving into the era now of more than 10 anti-PD-1, PD-L1 antibodies that have shown a benefit in the metastatic setting in phase III trials, one could imagine the time has finally come for price control, and not control, but price competition. It'll be really interesting to see whether or not that actually comes true. I don't know the answer yet. But this trial, I think, is very important in that regard. ASCO Daily News: And back to melanoma, can you tell us about advances in the metastatic setting? Dr. Jason Luke: Absolutely. So I think there were two to hit on quickly. Obviously there were more, but two quickly to hit on. One was Abstract 9506, which was the long term update, 6 and a half years of CheckMate-067, which people remember was the nivolumab plus ipilimumab versus ipi trial. And just to summarize this quickly, it really was amazing to see that now at 6 and a half years, we finally hit the median for overall survival for patients with metastatic melanoma in the frontline setting. And the median was 49%. So it just barely went under the median. But I just can't emphasize, when I was a fellow, and actually I'm a melanoma oncologist, and coming into this, the outcomes for patients at that time, the median survival was 9 months. And now we're talking about 10 years later, and the median is basically, it's 6 and a half years, almost 50%. So it's just outstanding. And I can't emphasize it enough. Clearly not good enough. We still have 50% of patients who need better treatments. But it's pretty exciting. The other abstract I wanted to highlight, because I think it differentiates where things stand, was the Abstract 9505, which was the tumor infiltrating lymphocyte (TIL) lifileucil in melanoma. And, again, just to highlight this, 36.5% response rate to re-infusion of TIL with interleukin-2. And I think that that's going to be an important part of the armamentarium for melanoma management, moving into the future. One final metastatic disease abstract to highlight was the development of T cell receptor (TCR) T cells for synovial sarcoma. So this was a really important abstract as well, going along with the lifileucil abstract, because I think this showed that this is a really active regimen with adoptive cell transfer for synovial sarcoma. And I would very much expect to see that both the TCR T cells and the TIL product get approved by the FDA within the coming year. ASCO Daily News: Excellent, well, before we wrap up the podcast, can you share some highlights from your main research area, developmental therapeutics? Dr. Jason Luke: Yeah, finally, so in the realm of developmental therapeutics, which is my major research area, there's always a lot going on. And I think this year's ASCO Annual Meeting I would just highlight a few things. So one is the continued development of VEGFR2 tyrosine kinase inhibitors (TKIs) with immunotherapy, we saw long term updates with lenvatinib and pembrolizumab in melanoma (Abstract 9504). And we saw other updates with new combinations in colorectal cancer. Another area in terms of considerations were small molecule inhibitors. And so there was a really interesting abstract about an MDM2 inhibitor. And people will remember that's a regulator of P-53, being combined with pembrolizumab. And preclinically and translationally, in this abstract, it appears that modulating the P-53 pathway via MDM2 actually has immunomodulatory effects. So it'll be very interesting to see where alrizomadlin goes (Abstract 2506).  There are a number of other novel targets. And there's so many abstracts on these that I'm not going to really go through them in a lot of detail. But TLR-7/8 agonism with checkpoint blockade looks interesting (Abstract 2512). There were a number of abstracts around transforming growth factor, TGF beta. And this is a really important target in cancer. And it'll be interesting to see how that gets developed out further. There were a number of approaches looking at targeting of human papillomavirus or HPV, one of them, which was a triplet regimen of an HPV vaccine plus a cytokine plus a PD-L1 antibody, and another one which was some viral vectors expressing HPV proteins. So all of this, I think, very interesting and taking sort of orthogonal to checkpoint approaches in terms of immunotherapy, vaccines, cytokines, viral vectors, et cetera. And then the final area, just to highlight, there was one very interesting Abstract 2507, which was a novel CAR T-cell product, which included a 41BB activation domain, attached actually to a bispecific CAR that binds to both CD19 and CD20. And this was Abstract 2507, and what I thought was very interesting was the rates of response for this molecule are really high, almost 100%. And that even included patients who had previously progressed on other CAR T products. So not enough time to go and give justice to any of these, but there's so much going on in developmental therapy for immuno-oncology. And I think that just emphasizes how bright the future is, building on this tremendous benefit in the standard of care setting in the adjuvant and metastatic settings. So, very excited to see where all these molecules go, and hopefully to advance the outcomes for all of our patients. ASCO Daily News: Indeed. Dr. Luke, thank you, as always, for your fantastic insight on some tremendous advances in immunotherapy, across the spectrum of malignancies. Our listeners will find links to all of the studies that you discussed in the transcript of this episode. Thank you, Dr. Luke. Dr. Jason Luke: Well, thanks so much for the opportunity. ASCO Daily News: And thanks to our listeners for joining us today. If you enjoyed this episode of the podcast, please take a moment to rate and review us wherever you get your podcasts.   Disclosures: Dr. Jason Luke Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, and Arch Oncology Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, Immunocore, KSQ Therapeutics, Inzen, Pfizer, Silicon Therapeutics, TRex Bio Research Funding (Institution): Merck, Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Research Funding: Array BioPharma, Agios, Astellas Pharma, EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., Trishula Therapeutics, BioNTech AG, Scholar Rock Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof) Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Pamela Kunz, associate professor of medicine and director of the Center for Gastrointestinal Cancers at the Yale School of Medicine, discusses promising advances in metastatic esophageal squamous cell carcinoma, and HER2-positive metastatic gastric or gastroesophageal junction cancer featured at the 2021 ASCO Annual Meeting.   Transcript:  ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Pamela Kunz, associate professor of medicine in the Division of Oncology at the Yale School of Medicine, where she also serves as the director of the Center for Gastrointestinal Cancers. Dr. Kunz will highlight promising advances in metastatic esophageal squamous cell carcinoma and HER2-positive metastatic gastric or gastroesophageal (GE) junction cancer featured at the 2021 ASCO Annual Meeting. Dr. Kunz has served in a consulting or advisory role for Acrotech Biopharma, Advanced Accelerator Applications, and Ipsen, among other organizations. Her full disclosures and those relating to all episodes of the podcast are available on our transcripts at ASCO.org/podcasts. Dr. Kunz, it's great to have you on the podcast today. Dr. Pamela Kunz: Thank you so much, my pleasure to be here. ASCO Daily News: Let's start with the KEYNOTE-811 study. That's Abstract 4013. This ongoing global study is assessing whether adding pembrolizumab to standard of care improves efficacy for HER2-positive metastatic gastric or GE junction cancer. There's very promising data in this study. What are your takeaways from KEYNOTE-811? Dr. Pamela Kunz: Thank you. I think this was an exciting interim analysis of this study. And as you said, it's really one of our first assessments of adding pembrolizumab plus trastuzumab in the first line setting for treatment of HER2-positive metastatic gastric or GE junction cancer, and I think that's why it's really exciting. We don't have an immuno-oncology (IO) agent approved in the first line setting for HER2-positive disease, so I think we are eagerly awaiting the final results. And Dr. Janjigian presented some early efficacy results of this study. So, just to review for our audience the design of the study, so we know exactly what interim data were presented. This is a study, it's a two-arm study, randomized 1 to 1 of patients with advanced gastric or GE junction adenocarcinoma, no prior therapy, and are HER2-positive. And patients are randomly assigned to receive pembrolizumab plus trastuzumab and fluoropyrimidne or capecitabine/oxaliplatin versus placebo plus trastuzumab and the same chemotherapy backbone. And in this interim analysis, about 260 patients out of the planned a total of 692 were presented. And this was a planned analysis. It was really based on these 260 participants enrolling for about 8--and it was about 8 1/2 months of follow-up. And the authors presented objective response rate. We do not yet have overall survival or progression-free survival, but the objective response rate was quite promising. So in the pembrolizumab containing arm, there was a 74% objective response rate compared to 51% in the placebo arm. And this absolute difference was about 22%. This was statistically significant. And I think other key take-homes--but I know our audience does not have the visuals of the waterfall plot--but suffice it to say that in the pembrolizumab waterfall plot, we had deeper responses, so meaning higher level of objective responses. About 30% of this population had decreases of 80% or more by RECIST criteria. And the duration of response was longer in the pembrolizumab arm compared to the placebo arm, 10.6 months median duration of response compared to 9.5 months in placebo. I think that the adverse events were as one would expect with adding pembrolizumab to this arm--I'm sorry, to this regimen. So I think it's very promising. It did, in fact, lead to accelerated approval of this combination, but we are of course awaiting the primary endpoint. ASCO Daily News: Excellent. Well, let's turn our attention to the CheckMate-648 study. This is LBA 4001. This is the first global phase III study to evaluate both a chemoimmunotherapy combination and an immunotherapy combination in advanced esophageal squamous cell carcinoma. Can you tell us about potential new treatment options to emerge from this study? Dr. Pamela Kunz: Sure. I think this study, similarly, is really important because it's the first immunotherapy in the first line setting for squamous cell carcinoma. We had already nivolumab and pembrolizumab approved in the second line setting, but no IO agent in the first line setting. So, this study was a three-arm study to evaluate, as you'd mentioned before, first line squamous cell carcinoma that's advanced or metastatic. And the arms are as follows. So, it was nivolumab plus chemotherapy, versus nivolumab plus ipilimumab, versus chemotherapy. And the chemotherapy was a fluorouracil plus cisplatin backbone. Over 900 patients were enrolled to this phase III study. The randomization was 1 to 1 to 1. And statistically, the comparison, the way the study team designed the study, was to compare nivolumab plus chemotherapy versus chemotherapy and nivolumab plus ipilimumab versus chemotherapy. And so this was--the analysis was conducted in that manner. I think it's also important to note that PD-L1 status was collected and was balanced between the arms, as were other standard baseline characteristics. So, when we're looking at the data, I'll first just describe the nivolumab plus chemotherapy versus chemotherapy. And perhaps, maybe, we'll just take a big kind of 30,000-foot view of what these results say. So really, what were the take-home is that both ipilimumab and nivolumab and nivolumab plus chemotherapy were better than chemotherapy alone. So, I think that what we will see is that--I'm hopeful--these are not U.S. Food and Drug Administration approved yet. But I think that in a large phase III study, we're hopeful to see these become available for the first-line treatment for advanced squamous cell carcinoma. So we saw an improvement in overall survival of nivolumab plus chemotherapy versus chemotherapy alone. This was seen in both the PD-L1 greater than or equal to 1% and all patients, regardless of PD-L1 status. And in terms of the overall survival (OS) difference, the median OS for nivolumab plus chemotherapy was 15.4 months versus 9.1 for chemotherapy alone. This was a hazard ratio of 0.54, so a very clinically significant difference. And we also saw a statistically significant and clinically significant difference for all randomized patients, regardless of their PD-L1 status. So that's overall survival with the nivolumab plus chemotherapy. We also saw a benefit in terms of progression-free survival for that same arm, so the nivolumab plus chemotherapy arm. And then moving to the nivolumab plus ipilimumab arm.  And I want to just comment that I think it's really important for our patients to have a chemo-free option. Some of these patients are quite sick. The cytotoxic chemotherapy can have a different set of side effects compared to our immunotherapy agents. And I think it's important to be able to tailor these treatments to the patient that you see in front of you. So, some patients may better tolerate cytotoxic chemotherapy, and some may better tolerate IO. So, I think that that's important. So, this nivolumab plus ipilimumab also showed a statistically significant difference in median overall survival. So, the median OS for the nivolumab/ipilimumab arm was 13.7 months compared to chemotherapy alone of 9.1 months, with a hazard ratio of 0.64. And we also saw a difference for all randomly assigned patients, regardless of their PD-L1 status. So, the difference, really, for both of the IO containing arms was higher for the PD-L1 greater than or equal to 1%, but the benefit was maintained regardless of the PD-L1 status. Similarly, progression-free survival, we saw a benefit compared of nivolumab plus ipilimumab versus chemotherapy alone. So, I think we are hopeful to see an ability to use this for our patients in the first line setting. I think what's really remarkable is that in the last, really, three to four months, we have seen an explosion of U.S. Food and Drug Administration approvals and phase III results for esophageal, GE junction, and gastric cancers with IO. So, it's exciting. It's frankly hard to keep track of. ASCO Daily News: Absolutely. Dr. Kunz, thanks very much for joining us today to highlight these key abstracts in the gastrointestinal cancer field. Dr. Pamela Kunz: Thank you so much. ASCO Daily News: Well, before we go, I'd like to tell our listeners about an upcoming episode of the podcast that will feature another interesting discussion with Dr. Kunz. She'll tell us about an interesting session from the ASCO Annual Meeting that looked at ways to dismantle gender disparities in the global oncology workforce. Dr. Kunz will also tell us about a new study on sexual harassment of oncologists. And finally, thank you to our listeners for joining us today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Pamela Kunz Stock and Other Ownership Interests: Guardant Health Consulting or Advisory Role: Ipsen, Lexicon, SunPharma, Acrotech Biopharma, Novartis (Advanced Accelerator Applications) Research Funding (institution): Lexicon, Ipsen, Xencor, Brahms (Thermo Fisher Scientific), Novartis (Advanced Accelerator Applications) Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Stephen Liu, associate professor of medicine and director of Thoracic Oncology and Developmental Therapeutics at the Georgetown Lombardi Comprehensive Cancer Center, highlights key abstracts in lung cancer featured at the 2021 ASCO Annual Meeting.   Transcript:  ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Stephen Liu. He is an associate professor of medicine and the director of thoracic oncology and developmental therapeutics at the Georgetown Lombardi Comprehensive Cancer Center. Dr. Liu joins me to highlight advances in lung cancer featured at the 2021 ASCO Annual Meeting. Dr. Liu has served in a consulting or advisory role for Genentech, Pfizer, and AstraZeneca, among other organizations. His full disclosures and those relating to all episodes of the podcast are available on our transcripts at ASCO.org/podcasts. Dr. Liu, it's great to have you on the podcast today. Dr. Stephen Liu: Thanks for having me. ASCO Daily News: Dr. Liu, a lot of people were talking about the IMpower010 study during the annual meeting. That's abstract 8500, an interim analysis that showed really promising results for patients with resected non-small cell lung cancer. Can you tell us about this practice-changing study? Dr. Stephen Liu: Well, IMpower010 was a global randomized phase III trial, and I think this really was one of the highlights of the ASCO Annual Meeting from a lung cancer standpoint. As a reminder, our current standard of care is cisplatin-based chemotherapy for patients with resected stage II to III non-small cell lung cancer and for select patients with stage IB. We know from decades of experienced multiple phase III trials, large meta-analyses, that the risk of recurrence is quite high for resected stage II/III lung cancer. And the use of up to four cycles of cisplatin-based chemotherapy does lead to an improvement in survival, and that's our standard of care. That survival improvement, however, is modest, with an absolute improvement and 5-year survival of about 5%. And so we've been trying to improve outcomes in this setting for quite some time. We know from last year's ASCO that the subset of patients whose tumor harbors an EGFR mutation received some benefit from disease-free survival with the use of adjuvant osimertinib. IMpower010 presented at this year's ASCO by Dr. Heather Wakelee looks at the use of immunotherapy as a complementary adjuvant therapy. And we knew from press release that this study had met its primary endpoint. This was our first chance to look at the data first-hand and really see how it would impact practice. And I think the data were quite impressive. It's a fairly simple design. This study included patients with completely resected stage IB to IIIA non-small cell lung cancer, either histology. Note that this used AJCC version 7, and so the stage IB that were included had a size of at least four centimeters, and that's the subset that seems to derive the most benefit from chemotherapy. Now patients received cisplatin-based chemotherapy one to four cycles first. And those who received at least one cycle of chemotherapy were then randomly assigned 1 to 1 to receive 1 year of atezolizumab, PD-L1 inhibitor, or best supportive care. This was a large study, over 1,000 patients randomly assigned. It began enrollment in 2014. So it did include some EGFR and some ALK when maybe we didn't know quite as much about including those patients in these studies, but the EGFR was about 12%, the ALK was 3%. Some were unknown EGFR and ALK status, but these were likely the squamous histology, as those numbers line up. The PD-L1 testing, importantly, was done by the VENTANA SP263 assay, looking at tumor cell expression only, which is a fairly straightforward assay. And what we saw after a median follow up of almost 3 years was that in the primary high-risk population stage II to IIIA resected non-small cell lung cancer with the PD-L1 expression of at least 1%, the use of adjuvant atezolizumab significantly improved disease-free survival. And the hazard ratio there was 0.66. If we look at the 2-year disease-free survival (DFS) rate, it improved from 61% with best supportive care to 75%, and at 3-year DFS from 48% to 60%. So an improvement in the 3-year DFS rate and a hazard ratio of 0.66. The fourth plot showed that signal was greater in node-positive. As expected, no signal in that ALK subset, though it was small. But this is a pretty substantial improvement in disease-free survival. When we look at these Kaplan-Meier curves, they split immediately, really right at the first scan. And when we look at a study like this, this phase III trial, it reminds us how poor our current standard is; how many patients do suffer relapse and recurrence and death from this potentially curable cancer. Atezolizumab clearly improving outcomes in this subset. We then saw analyses of the resected stage II to III across PD-L1 strata, so positive and negative. And there the hazard ratio, as expected, less impressive, 0.79. If we look at the forest plot there, the hazard ratio for PD-L1 high, using that 50% cutoff we're used to, was substantial at 0.43. So overall, the DFS and PD-L1 positive 0.66 and the PD-L1 high 0.43. So no report on the PD-L1 low, which is what we're waiting for, that one at 49%, presumably not as impressive as 0.66. And we'll wait for those data to come out. But PD-L1 positive, a clear benefit. PD-L1 high, a substantial benefit. That's really where the formal analyses stopped. The stage IB to IIIA overall population was too immature for analysis, and overall survival was not yet formally tested. This will take a few years to breathe out. They did provide an early look at overall survival. And in that stage II to IIIA PD-L1 positive, there was the right trend, with a hazard ratio of 0.77, though not statistically significant. We did see these curves start to come apart at about 12 to 18 months, which is what you would expect if this study ultimately would lead out to be positive. We do want to wait for OS results. But one has to wonder, is a DFS benefit this substantial enough to change practice? And atezolizumab not yet approved in this setting, but the trial did meet its primary endpoint. And to me, for PD-L1 positive, and certainly for PD-L1 high, I do think these data aren't practice- changing. ASCO Daily News: Absolutely. Well, another trial that attracted a lot of attention was the CheckMate-816 trial. That's Abstract 8503. What can you tell us about the surgical outcome data reported in CheckMate-816? Dr. Stephen Liu: So CheckMate- 816 was a randomized phase III trial that looked at neoadjuvant therapy. So this also focused on resectable lung cancer. This is an area where we hope for cure, but for some of the more advanced stages, we don't necessarily expect it. Much room for improvement. We saw the IMpower010 data showing adjuvant immunotherapy improved DFS. Here we're looking at the neoadjuvant space. And at AACR in 2021, Dr. Patrick Forde presented some of the early PCR results. And that showed the pathologic complete response rates with neoadjuvant nivolumab plus chemotherapy for three cycles was superior to chemotherapy alone for three cycles. So the addition of nivolumab to chemotherapy improved the pathological CR rate from 2% to 24%. Really astounding. What Dr. Jonathan Spicer presented at ASCO 2021 were the surgical outcomes from that study. And we see that adding immunotherapy to chemotherapy significantly improves the pathologic CR rate. Does it come at a cost? Does it lead to more surgical complications? This is always a concern with neoadjuvant therapies. We've got someone in our clinic with a resectable lung cancer. If we mismanage that patient, we may lose the window for resection. So we always worry about delayed surgeries, canceled surgeries, more complicated surgeries. There have anecdotally been reports of increased perihilar fibrosis after neoadjuvant immunotherapy. Wouldn't that lead to longer, more complicated surgeries? And what we saw, frankly, was a bit surprising, for me. Surgery consistently easier, better in the experimental arm really across the board. The rates of going to surgery, completing surgery, 83% with nivolumab/chemotherapy, versus 75% with chemotherapy. So more patients going to surgery, fewer canceled surgeries. If we look at the type of surgery, minimally invasive surgery rates 30% with nivolumab/chemotherapy, [and] 22% with chemotherapy alone. Conversion to open thoracotomy was more common in the chemotherapy alone at 16%, the additional nivolumab 11%. And the complete R0 resection was achieved in 83% with nivolumab/chemotherapy, 78% with chemotherapy alone. Adverse events delayed surgery in six patients getting nivolumab and chemotherapy. It's important to watch that. But it was nine patients in getting chemotherapy alone. And if we look at the duration of surgery, and certainly there are many confounders in a statistic like this, but the surgery was shorter with nivolumab, certainly not lengthening the surgery. 184 minutes for nivolumab/chemotherapy, 217 [minutes] with chemotherapy alone. So these data are very reassuring to someone with a potentially resectable cancer. And I think that when I take a step back and look, maybe these results do make sense. Maybe this is what I should have expected. If we give a treatment that is more effective, that is a higher response rate, it works better. Those patients are less likely to have progressive disease, and the surgery should be more straightforward if there's less cancer to resect. So the CheckMate-816 surgical data, we've been waiting for this shoe to drop, and it was very reassuring. Perioperative immunotherapy is going to be an important part in the management of stage II/III non-small cell lung cancer in the years to come. Now going forward, we'll need to compare these adjuvant and neoadjuvant approaches and the relative merits of either strategy, but these results, I thought, were very reassuring. ASCO Daily News: Excellent. Well, moving on to the PACIFIC trial, Abstract 8511, this study reported improvements in 5-year overall survival and progression-free survival for unresectable stage III non-small cell lung cancer. What are your takeaways from this study? Dr. Stephen Liu: Sure. The PACIFIC study is a randomized phase III trial that's really set our standard of care for unresectable stage III locally advanced non-small cell lung cancer. This is a group where our standard of care, historically, has been concurrent chemoradiation, with the goal of cure, though, unfortunately, not necessarily the expectation, with recurrence rates quite high. We saw years ago the addition of 1 year of durvalumab improved progression-free survival, then ultimately improved overall survival compared to placebo. This was a fairly straightforward study. It enrolled unresectable stage III non--small cell lung cancer after chemoradiation, who did not have evidence of progression after completing therapy, to receive 1 year of durvalumab or placebo, a 2 to 1 randomization. The results markedly positive, leading to U.S. Food and Drug Administration (FDA) approval and really our new standard of care. These are long-term survival data, and it was presented by Dr. David Spigel. These are really important. Immunotherapy, the whole appeal of the strategy is the durability, the induction of memory T cells, meaningful long-term survival. Will this increase the rate of cure really is what we're going for. And when we saw the survival benefit with durvalumab, we knew that we were curing more patients. Long-term follow up is important to make sure that we don't have late recurrences, that we really are curing and not just delaying a recurrence for some patients. And in this analysis, with a 5-year follow up, we see durvalumab improve the median survival from 29 months with chemoradiation alone to 48 months with the addition of durvalumab. That's a hazard ratio of 0.72, 28% reduction in the risk of death, pretty substantial. That 5-year survival rate was 43% versus 33%. And importantly, these were very similar to the 4-year data that were presented by Dr. Corinne Faivre-Finn at World Conference in Lung Cancer, really very little drop off between year 4 and 5. And we refer to that as flattening of the tail, where the events are early, and at some point, they kind of stop happening. It's really what we want to see. While survival is what we hone in on, in an abstract like this, we also need to pay attention to progression-free survival (PFS). And the PFS rate at 5 years was 33% with durvalumab, versus 19% with chemoradiation alone. So 33% with no evidence of progression at 5 years. And if you are cured from lung cancer, then you can't have progression. So one in the three patients with no progression at 5 years, I think, is very reassuring, that PFS hazard ratio of 0.55. So prior to ASCO21, durvalumab was our standard of care. Now we just have longer term follow up to really solidify that choice. These are important data for patients and families to set expectations right, but our clear standard. Still, though, room for improvement in that 5-year PFS rate of 33%. We would like to see that higher, and ongoing strategies hopefully will help push that up. ASCO Daily News: Excellent. Some great survival data in the PACIFIC trial. Well, Abstract 9007 sparked a lot of interest as well. This is an expansion study of patritumab/deruxtecan in patients with EGFR-mutant non-small cell lung cancer. That's a difficult drug to pronounce, so I'm sure you'll do a better job. What can you tell us about this? Dr. Stephen Liu: Well, yeah, all these antibody drug conjugates do have tricky names, and so they are kind of fun to say. So patritumab/deruxtecan is a HER3 antibody drug conjugate. I suspect it will be better known as HER3-DXd, a little easier off the tongue. This was a study that looked at this agent in patients with EGFR-mutant non--small cell lung cancer after TKI therapy. And when we turn our attention to targeted agents, we have really transformative drugs with very wide therapeutic windows, little toxicity, very high efficacy, [and are] really game changers in patients with driver positive non--small cell lung cancer. But as we know, these treatments aren't cures. And we do expect resistance to osimertinib. The third generation TKI has been pretty heterogeneous. And once patients progress in osimertinib, the next standard therapy really is chemotherapy. And there's a bit of a drop off, with more toxicity, [and] less efficacy overall. So this remains an unmet need. Many studies are looking at different strategies there. We've seen the addition of MET inhibitors if MET is amplified for certain subtypes, RET, BRAF, for example, the addition of the targeted agents. This study, Abstract 9007 presented by Dr. Pasi Janne, looked at the HER3-DXd antibody drug conjugate. So patritumab/deruxtecan has a monoclonal antibody targeting HER3, a proprietary linker, and then a topoisomerase 1 warhead. And this was a phase I study that looked at 57 patients with EGFR-mutant lung cancer after TKI therapy mostly, but 90% were coming off of osimertinib. And what we saw, I thought, was very encouraging. This is a small, early study. These are very selective patients. But the response rate here almost 40%, disease control rate 72%, and the median progression-free survival with monotherapy of patritumab/deruxtecan was 8.2 months. These numbers may change as the studies get larger, but there's a clear signal of efficacy for patients who'd received chemotherapy before and then moved on to patritumab/deruxtecan. The response rate didn't really drop off, 37%. So even those that were more heavily pretreated, we're seeing a clear signal with response rates that really are higher than chemotherapy. What was, I think, most important, we saw efficacy of patritumab/deruxtecan across multiple different mechanisms of resistance. And so it wasn't one biomarker select. It really was active, very versatile agent. And really, I think that's what we need. While biomarker-driven resistance will be something we always hone in on and try to focus, we do need something that's much more versatile for rapid implementation. And this is having a lot of potential. [It was] very well tolerated. If we look at treatment-emergent adverse events, only one person stopped from a TEAE. Only 4% stopped due to TEAEs, so very well tolerated treatment. Response was also durable. One response listed was after 4 years of therapy, and so the potential for long-term disease control, long-term responses. So clearly an active drug. This is an area where we need a lot of drug development. Well tolerated, only 4% stopping due to adverse events and a nice signal of activity. Our next steps will be to make this a larger study to look in more patients to really hone in on the mechanisms and where this really is working. Can we widen that therapeutic index? And can we look at combinations? Is there a role to continue TKI with this, maybe for better CNS coverage or activity? That's what we'll see in the years to come. ASCO Daily News: Excellent. Well I'd like to ask you about a trial that you were involved in, the ARROW trial, Abstract 9089. Can you tell us about this impactful study? Dr. Stephen Liu: Yeah, sure. The ARROW trial is a study that I've been a co-investigator on for many years. This was presented by Dr. Giuseppe Curigliano. And this looks at a RET inhibitor called pralsetinib, originally when we first got involved called BLU-667. RET fusions are present in about 1% of non- small cell lung cancer. These are important events, because we know from other studies, such as the immunotarget registry led by Julien Mazieres,  that RET-positive lung cancers don't seem to respond as well to immunotherapy. However, in the past, the kinase inhibitors, the targeted agents we had the targeted RET, weren't very good. They had response rates around 30%, 40%, a lot of toxicity. These are drugs like vandetanib, cabozantinib. With the introduction of selective RET inhibitors, we've seen striking efficacy and much better tolerability. And we now have two approved RET inhibitors in this space--selpercatinib and pralsetinib--both receiving FDA accelerated approval based on their respective single arm studies. What we saw at ASCO 2021 from Dr. Curigliano was an update on the RET fusion positive lung cohort of ARROW. Again, this was a phase I/II trial looking at pralsetinib given at a dose of 400 milligrams by mouth once daily. We look at the patients with RET fusion-positive lung cancer. Now we just have longer follow up and more patients. And overall, the cohort exceeded 200 patients, so 216 patients for a pretty rare driver. And the response rate, 69%, very durable. The duration of response, 22 months. So really solidifying the efficacy and confirming the role in patients with RET fusion-positive lung cancer. If we break those data down a little bit, patients who had prior chemotherapy, which was 125 patients, response rate was 62%. The disease control rate, 91%. These responses are quick. The median time to responses is 1.8 months, so really that first scan. And that's what we see with targeted therapy. And we look at these waterfall plots, and I encourage you to take a peek at that. It's exactly what we want to see, the vast majority of patients, almost all patients, with some reduction and some with a quite substantial reduction. Again, the disease control rate after chemo was 91%. So really, the waterfall plot has that look that we seek for effective targeted therapy. The outcomes were even better in the first-line setting. Response rate originally 79% as first-line therapy. But the way the trial was originally written, it only included frontline patients who weren't eligible for chemotherapy for whatever reason. So that's going to be a more selective cohort. That was changed with an amendment. And once that was removed for people that were eligible for whatever frontline therapy you wanted to give, really our real world first line cohort, the response rate was 88%, disease control rate of 96%. So to think of a response rate in almost 90% of patients really gives us that confidence we want when we have a driver that we detect when we start a new agent. We're very confident that we're going to see efficacy in these drugs, very well tolerated, very few patients stopping due to a adverse event. A disease control rate of 96% in that first-line setting gives me the confidence to really use this in the first-line setting. ASCO Daily News: Absolutely. Well, as you know, the Annual Meeting this year focused on equity in cancer care. And there were a number of studies presented in the lung cancer space. I just wanted to get your thoughts on how this issue was addressed at the Annual Meeting in the lung cancer setting. I'm thinking of Abstract 9005 that looked at racial disparities. What are your thoughts on this issue? Dr. Stephen Liu: Yeah, this was an important abstract, I think. And the theme that Dr. Lori Pierce set of equity really was met by several different abstracts and was a recurrent focus for many important and really overdue discussions. Abstract 9005 was presented by Dr. Debora Bruno, and this really looked at disparities in biomarker testing. And we just talked about advances for EGFR-mutant lung cancer for RET fusion-positive non--mall cell lung cancer. We have many, many more, but we can only offer these agents if we know the target is present. And if we don't do proper biomarker testing, our care will not be optimal. If we don't know the molecular genotype of the cancer, we can't treat it properly. We are just guessing, and we're much more likely to deliver an ineffective therapy. We are potentially making subsequent therapies more dangerous. Knowing the right biomarker is critical to the proper management of non-small cell lung cancer. And if we don't have that, the outcomes will not be as good. The testing really is critical for the management of lung cancer. And what we saw from this abstract was there are disparities in how patients with non-small cell lung cancer are being tested, which simply isn't acceptable. This was a retrospective analysis that looked at Flatiron data, recent data, 2017 to 2020, a large data set, almost 15,000 patients with non-small cell lung cancer. Demographics were 66% white, 9% Black. If we look at biomarker testing specifically, patients who were Black were less likely to be tested, less likely to have proper biomarker testing, 73% versus 76%, less likely to have full next generation sequencing with a 10% difference, and less likely to get tested early. We know that testing really influences treatment from the jump right away. And if we don't have that information, our outcomes won't be as good. Our Black patients weren't being tested properly, weren't being tested in a timely manner. And more data showed that clinical trial participation was also decreased among Black patients, 4% involvement for white patients, 2% with Black patients. And these were actually very similar to what we saw in Abstract 9001 that was presented by Dr. Akinboro from the FDA. And that looked at patients who'd received chemoimmunotherapy. This was a pooled analysis looking at different PD-L1 cohorts. And what was noted on the demographics is that in the phase III registrational landmark studies, Black patients only represented about 2% of patients there as well. So strikingly similar numbers and a gross under-representation. It really is inexcusable and something we need to address. And we need to correct, because this is showing that our care is simply not up to par.  Trial participation is how we move the field, but many cases, especially in lung cancer, a field that moves so quickly, a clinical trial often represents the best possible option. And Black patients simply aren't enrolling in studies. And I think some of the disparities in clinical trial participation likely reflect some of the disparities in clinical trialists. And I think that if we continue to improve diversity in our workforce, in our oncology subspecialty, that'll be an important step into rectifying this. But this is something we need to look at critically. We need to assess all of our processes and think how we can do better today, and not tomorrow. ASCO Daily News: Absolutely. Thank you so much, Dr. Liu, for highlighting these really critical points and sharing your valuable insight on all of these impactful studies in lung cancer. Thank you so much. Dr. Stephen Liu: My pleasure. Thanks for having me. ASCO Daily News: And thank you to our listeners for joining us today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Stephen Liu Consulting or Advisory Role: Genentech, Pfizer, Lilly, Bristol-Myers Squibb, AstraZeneca, Takeda, Regeneron, G1 Therapeutics, Guardant Health, Janssen Oncology, MSD Oncology, Jazz Pharmaceuticals, Blueprint Medicines, Inivata, PharmaMar, Daiichi Sankyo/UCB Japan, BeiGene, Amgen, Turning Point Therapeutics, Elevation Oncology, and Novartis Research Funding (institution): Genentech/Roche, Pfizer, Bayer, Merck, AstraZeneca, Blueprint Medicines, Lilly, Rain Therapeutics, Alkermes, Bristol-Myers Squibb, Turning Point Therapeutics, RAPT, Merus, Elevation Oncology, and Erasca, Inc Travel, Accommodations, Expenses: AstraZeneca, Roche/Genentech, and MSD Oncology   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Hope Rugo, professor of medicine and director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco Helen Diller Comprehensive Cancer Center, highlights key studies in breast cancer featured at the 2021 ASCO Annual Meeting.   Transcript: ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Hope Rugo. She is a professor of medicine and the director of Breast Oncology and Clinical Trials Education at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. Dr. Rugo joins me to discuss key advances in the breast cancer field featured at the 2021 ASCO Annual Meeting. Dr. Rugo has received research support for clinical trials through the University of California from Pfizer, Merck, Novartis, Lilly, Roche, and other organizations. Her full disclosures are available on the transcript of this episode at asco.org/podcasts. Dr. Rugo, it's great to have you on the podcast today. Dr. Hope Rugo: Oh, it's great to be here. ASCO Daily News: There were many interesting studies in breast cancer featured at the Annual Meeting. Thank you for being here to highlight some of them. Let's start with the OlympiA trial. This is LBA1. This remarkable study found that adjuvant olaparib extends disease-free survival in BRCA-mutated early stage HER2-negative breast cancer. What can you tell us about this trial? Dr. Hope Rugo: Well, this is really such an amazing study, in terms of the results and its practice-changing impact. The study actually kind of interestingly was published in the New England Journal [of Medicine] 2 days before it was presented. And even though we had all seen the data, it was really such a, I think, moving presentation in terms of really changing the face of treatment for women and men with BRCA1 and BRCA2 associated breast cancer. Of course, olaparib and talazoparib are both PARP inhibitors that are approved to treat metastatic breast cancer associated with BRCA1 and BRCA2 mutations. And in those randomized trials, they showed improvement in response and progression-free survival, but not clear differences in overall survival. So, of course, when we have an impact in the metastatic setting, the next step is to move into early-stage breast cancer. But that's quite a challenge given the fact that you have to test and find the mutation, which is challenging in some parts of the world. And then you have to decide which group of patients need more than standard therapy. So the OlympiA trial randomly assigned patients who had pathogenic BRCA1 or BRCA2 mutations and HER2-negative, either hormone receptor-positive or triple negative breast cancer, to receive a year of olaparib or a placebo. And the patient eligibility was further defined. If you had triple negative breast cancer, you could have had any residual disease after neoadjuvant therapy, or you had to have a tumor greater than two centimeters or a positive node. If you have hormone receptor-positive disease keeping in mind the benefit of adjuvant endocrine therapy. If you didn't have a pathologic complete response to neoadjuvant therapy, you had to have a few other high-risk features using the CPS plus EG score. And if you received adjuvant therapy, you had to have four or more positive nodes, so stage III disease. All patients had to have received at least six cycles of chemotherapy, radiation as indicated, and of course, hormone therapy was given for hormone receptor-positive disease. There were over 1,800 patients randomly assigned, which was pretty, I think, impressive given the fact that everybody had to be tested. And the whole idea behind the trial is that you would enroll a group of patients who still had a high residual risk of recurrence, even though you got standard and reasonable adjuvant or neoadjuvant therapy. It's important to keep in mind when you think about the results of this trial is that having a BRCA mutation, and in particular BRCA1, increases sensitivity to chemotherapy. So the pathologic complete response rates, for example, in the neoadjuvant setting for triple negative breast cancer with the BRCA1 gene mutation, are higher than in patients who don't have a germline mutation. And so you're really looking at a group of patients who have high-risk disease because they didn't have a pathologic complete response if it was the neoadjuvant setting. Now, of the patient population, a little over 70% had BRCA1 mutations. The rest had BRCA2 mutations. And for the triple negative group, that represented a large portion of the population, about 80%. Again, the rest, a little under 20%, had hormone receptor-positive disease. As you would expect, more than 50%, about 60%, were premenopausal. And about 50% received neoadjuvant therapy. There's always a question about whether or not treatment with prior platinum-based therapy, which is also effective when you have DNA repair deficiency, such as in the germline BRCA mutations, whether or not that would affect sensitivity. A little more than a quarter of the patients had received a platinum chemotherapy agents. And the invasive disease-free survival, the primary endpoint of this trial, was really remarkable. There was an 8.8% improvement in a 3-year invasive disease-free survival rate in patients taking olaparib versus placebo, a very big p-value, and a hazard ratio 0.58. This is really dramatic. The curves separated early, and they remained separated. So that it was the IDFS was 77% for patients on placebo and about 86% in patients who were receiving olaparib, just really very impressive. And one of the things you want to find out about is are you changing the rate of distant recurrence. And indeed, not only were there less distant recurrences, but if you look at distant excluding the brain, that's where you really saw the biggest difference. There was a small difference--hard to know if it really is significant--1.5% less brain recurrence is a big issue for patients, particularly with triple negative disease. It was a little less contralateral invasive disease, but it wasn't anything significant. So really, what you were preventing was the kind of recurrence we don't want to see, which is distant recurrence. And then if you looked at the distant disease-free survival, the absolute improvement for metastatic disease was 7.1%. Again, the curve separated early and stayed separated over time. Now, overall survival, of course, is the golden endpoint that you want to look at. There were numerically less deaths in the olaparib arm, 59 versus 86 in the placebo arm. Most of these deaths were due to breast cancer. And the hazard ratio is 0.68. Although the p-value was 0.024, that didn't meet the statistical plan, which was a p less than 0.01 in terms of how the statistics can be balanced in this trial. But the overall difference was 3.7%. And of course, there were subgroup analyses done, which showed that everybody benefited. It was impossible to see a difference. And again, only a small number of patients relatively receive platinum, so it's hard to know whether or not that changed the response. In terms of the side effects--you always want to think about side effects--it was exactly what you would have expected from what we [expect] in the metastatic setting. Not a lot of grade III or greater toxicities. Mainly anemia was the most common at 9%, and 5% neutropenia, a little bit increase of grade III fatigue, but only 2%. The rest of the toxicities were all grade I and II. And of note, olaparib does cause nausea, 57% of patients versus 23% reported nausea with olaparib versus placebo. But normally, you can manage this nausea and the anemia by actually dose reducing and first holding and then dose reducing. One of the big questions, of course, with PARP inhibitors is if you're inhibiting repair of DNA, are you causing leukemia--new primary cancers? And it was very encouraging. Again, it's 3 years, so we need to be followed a little bit longer, maybe 5, but it was 0.2% or 0.3%. There was no increase in myelodysplasia or myeloleukemias with the use of the PARP inhibitor, which is really important. And the global quality of life scores were identical. So even with these side effects, they could be managed and didn't impact global quality of life. And then in terms of the paper, the additional information the paper gave is that most of the people who required a transfusion received only one transfusion of red blood cells. So I think with the caveat that there are some additional side effects, they are generally able to be managed well. Quality of life is maintained. And there's a huge early difference in the most important endpoints that we look for in these trials--invasive disease-free survival and most importantly, distant disease-free survival. So definitely history in the making. ASCO Daily News: Excellent. Thank you for sharing these fantastic results from the OlympiA trial. The ECOG-ACRIN Research Group presented EA1131, a study of platinum-based chemotherapy or capecitabine in patients with residual triple negative basal-like breast cancer following neoadjuvant chemotherapy (Abstract 605). This interim analysis really highlighted the need for better therapies for this patient population. What are your thoughts on this trial? Dr. Hope Rugo: Well, this, I think, is an important trial. Ingrid Mayer from Vanderbilt designed the trial with ECOG and actually presented the data. There will be a lot more data coming from this study because they collected tumor tissue and are doing a lot of different analyses, which might help us understand the benefits of different treatments in different subgroups of patients with triple negative breast cancer. Now, this trial really focused on patients who have the highest risk disease after neoadjuvant therapy, clinical stage II or III triple negative breast cancer diagnosis. They received the standard neoadjuvant chemotherapy. And they had to have tumors that were greater than one centimeter in the breast at the time of surgery or any positive lymph nodes. So this is actually a group of patients who we already know have a high-risk of distant recurrence. They did do an analysis of the tissue using a PAM50 assay to understand which tumors were basal or non-basal like. And patients were randomly assigned to receive capecitabine by the CREATE-X trial, which showed an improvement in overall survival when capecitabine was given to patients with residual triple negative breast cancer after neoadjuvant chemotherapy in Japan and Korea, versus carboplatin or cisplatin by treating physician discretion (DOI: 10.1056/NEJMoa1612645). The patients received four cycles every 3 weeks of carbo or cisplatin. Now, one thing that's important to keep in mind is in Japan where the CREATE-X trial was designed in Korea where it also participated, the capecitabine dose was the original U.S. Food and Drug Administration (FDA)-approved dose, where it was a little bit higher, 1,200 milligrams per meter squared twice a day, 2 weeks on, 1 week off. In the U.S., patients don't tolerate this very well. And there is a different metabolism in Asian patients, where they can tolerate a higher dose of 5FU and capecitabine with not as much toxicity due to pharmacogenomics. The patients in the ECOG-ACRIN trial received capecitabine at 1,000 milligrams per meter squared twice daily with the same schedule, which is really all that's tolerated. So the objective of this trial was to see whether or not you could do better or the same if you received a platinum versus capecitabine with the idea that DNA damaging agents work very well in basal-like triple negative breast cancer. So the patients were enrolled in this trial. 415 patients were randomly assigned. And then the data safety monitoring group who were following the results at the interim analysis ended up closing the trial because they found that based on the statistics so far that it was unlikely that the platinum arm would either be better or worse than the capecitabine arm. And they saw more toxicity in the platinum arm. So the trial was closed. And that's the data that was presented. So there was a total of 160 patients who received capecitabine, [and] 148 [patients] who received platinum. Most of the patients had basal-like disease. The age, it was about 52. It's all what you would have expected to see in this patient population. So I don't think we have any concerns about the patient population. The 3-year invasive disease-free survival in patients with basal-like triple negative breast cancer, the primary endpoint of the trial, was identical between the two arms. But actually, discouragingly, it wasn't great. So IDFS for capecitabine was 49% and platinum 42%. So this was actually very disappointing data. And I think it just highlights how we really need to provide better treatment for our patients who don't achieve pathologic complete responses to the best neoadjuvant therapy. It is true that the ECOG-ACRIN trial didn't require that patients receive anthracyclines, but 85% did. So I think that we feel really comfortable that they got good chemotherapy. They looked in the non-basal-like sub-type. And in the non-basal-like sub-type, which are cancers that are more likely to be responsive to capecitabine in the metastatic setting, actually, the outcome, although small numbers, looked better with capecitabine than with getting the platinum-type therapy. And if you looked at non-basal versus basal, regardless of therapy, the patients who had non-basal-like disease did much better than the patients who had basal-like disease, something that we would have guessed, but hasn't been shown before. So I think it was really important, [and] really helps us to identify the patients who need the most intervention. But even the basal group, the IDFS, the non-basal group, it was 55.5%. So better than basal at 46%, but still you got 45% of patients with invasive disease-free survival event over a 3-year medium follow-up. Overall survival at 3 years, also, was disappointing at about 66% for capecitabine and 58% for platinum. So I think that, really, this trial just identified, I think, in a very confirming way how we need to make progress in the treatment of these patients who have residual disease after neoadjuvant chemotherapy. In terms of toxicity, the platinum-based therapy clearly was more toxic. Most of the toxicity that was seen was grade I and II, as you would expect, but there was more grade III toxicity even with the platinum-type therapy. Again, as you would expect. You get hand-foot syndrome with capecitabine and not with platinum. But there was more of the standard toxicities that you would expect with the platinum or bone marrow suppression, primarily some thrombocytopenia, et cetera. So when they looked overall at the trial population, I mentioned that most had basal sub-type by PAM50. It was 80%. So it is a group of patients where I think even going into neoadjuvant therapy about 80% have basal-like disease. So I think it makes us very interested in the results that we expect to see in the very near future from the KEYNOTE 522 trial, where we've seen an improvement in pathologic complete response, particularly in patients with node positive disease with the addition of pembrolizumab, to standard taxane platinum and anthracycline-based neoadjuvant chemotherapy (DOI: 10.1056/NEJMoa1910549).  But a very recent press release noted that they have reached their event-free survival endpoint. And that pembrolizumab improves event-free survival. And the importance of this data, which, of course, has not yet been shared, so we have to see what it looks like and what the differences are, is that they had shown earlier at the FDA's ODAC meeting in February of this year that possibly patients who don't achieve a PCR, who received pembrolizumab before and after surgery, had a better outcome than patients who did not receive pembrolizumab and received placebo. So how we incorporate capecitabine into the post-neoadjuvant treatment or other novel agents will very much be a subject of the next few years as we sort this out. But if the pembrolizumab data is indeed exciting--and we'll talk more about the durvalumab data in just a moment--then I think the question would be, what chemotherapy do you give? And based on this trial, there is absolutely no indication for platinum postoperatively in patients with residual disease after neoadjuvant therapy. Capecitabine should be given. But clearly, we need better options for therapy. And this is also being studied with some of the new antibody drug conjugates, like sacituzumab govitecan to see whether or not we can improve outcome in these patients. ASCO Daily News: Right. Well, let's look at Abstract 506. This is the phase II GeparNuevo study. The data presented by the German Breast Group showed that neoadjuvant durvalumab improves long-term outcomes for patients with triple negative breast cancer. What is your takeaway from this study? Dr. Hope Rugo: You know, this was really interesting, and I think unexpected results based on their original presentation. This was a phase II neoadjuvant trial in patients with triple negative breast cancer. And the data by the GBG and Sibylle Loibl, who runs the GBG, had already presented the data from the primary endpoint of this smaller neoadjuvant trial, which was pathologic complete response. And what they did in this trial was they treated patients with a nab-paclitaxel followed by epirubicin and cyclophosphamide. And the patients were randomly assigned to receive the checkpoint inhibitor durvalumab versus placebo. There were 174 patients stratified by a low, medium, or high TILs. And their main endpoint, as I mentioned, was PCR. So this is a secondary endpoint of invasive disease-free survival. A group of patients received 2 weeks of durvalumab as sort of a lead-in first. And they've looked at that group separately. But it's hard to know because it's such a small trial what that means. And nobody is using a lead-in right at the moment. So their primary endpoint, as I mentioned, has been published already in Annals of Oncology in 2019 (DOI: 10.1093/annonc/mdz158). Although numerically there was a higher PCR rate in the durvalumab treated arm, this was not statistically significant. The p-value is in no way significant. And they looked at, in a forest plot, they showed that the patients who had the window seemed to have a higher PCR, but it was hard to justify exactly why that was the case in this group of patients. Now, it's important to keep in mind that the data that we have from KEYNOTE 522, the neoadjuvant trial with pembrolizumab, and IMpassion 31, the trial with the atezolizumab, showed the benefit, particularly in patients with node-positive disease. In this trial, about a third of the patients had stage zero or I breast cancer. So 61 out of the total of 174 patients did not have positive nodes. So we thought the PCR difference really wasn't seen because they had a low-risk population. But now, they're presenting their secondary endpoint of invasive disease-free survival in this group of patients. And what they saw, actually, at a median follow-up of about 44 months, they saw a 12 IDFS events in the durvalumab arm and 22 in the placebo arm. And actually, there were twice as many distant recurrences in the patients treated with placebo versus durvalumab. So 13 versus six events for distant recurrence. So I think that's actually a really important endpoint. And if you looked at the invasive disease-free survival at 3 years, it was 77% for placebo and almost 86%. So almost a 9% difference in favoring the patients who received durvalumab. Pretty dramatic, you know? A hazard ratio of 0.48. And they did have a p-value of 0.0398. So that was quite interesting. And they looked at distant disease-free survival. Numbers are small here, but I think it's a really important endpoint, and overall survival. Overall survival is early to see, but they could see--this is a long follow-up, but it's a small study rather than early--and they showed that overall survival difference was 83.5% in the placebo arm and 95.2% in the durvalumab arm. Again, secondary endpoints with a hazard ratio is 0.24 and, again, a p-value of 0.1. Distant disease-free survival, such an important endpoint, was a huge difference 78.4% versus 91.7%. Again, hazard ratio of 0.31. So pretty dramatic. And when you looked at subgroups of patients, and they looked at PD-L1 positive versus negative. Almost all of the patients had PD-L1 positive disease, so 138 versus 20 that were PD-L1 negative. So it's kind of hard to interpret any of that. And that trial was stratified by stromal TILs anyway. They did show that patients who had a PCR had a better outcome than patients who did not have a PCR. But among the patients who had a PCR, the patients who had durvalumab did better, again, with almost a 10% difference, favoring durvalumab versus placebo. Now, this is a phase II randomized trial, so it's small. And so this is really hypothesis generating. But given the fact that KEYNOTE 522 and IMpassion 31 (NCT03197935) gave the checkpoint inhibitor for a year, and in this situation patients received durvalumab only in the neoadjuvant setting, it suggests that they saw this impact in patients who had a PCR that was greater in patients receiving durvalumab placebo. So it suggests that even though the PCR improvement was not significant, that just the treatment with a checkpoint inhibitor changes long-term outcome. And we know that there's more toxicity by giving longer course checkpoint inhibitor therapy, so we expect that we might see approval of pembrolizumab based on the KEYNOTE 522 trial. And it will bring up the question of whether or not you need a whole year of treatment to improve outcome. And whether or not simply treatment preoperatively might be sufficient, particularly in the patient group who achieves a PCR. It will be, I think, very, very important to be able to evaluate this in order to reduce the toxicity, both the physical toxicity, as well as financial toxicity from use of checkpoint inhibitors in patients with triple negative breast cancer. Also, we know that a third of these patients had stage I disease. And I think we really need to look at the larger trials quite carefully to understand whether or not all patients need checkpoint inhibitors who have triple negative disease. Or whether or not we could more correctly focus on the patients who have higher risk disease, node-positive disease who've been shown to have less tumor infiltrating lymphocytes than patients who have less burdensome disease at diagnosis. ASCO Daily News: Right. So what about the subset analysis in Abstract 1011 that looked at outcomes in patients who are age 65 and older in the phase III ASCENT study of sacituzumab in metastatic triple negative breast cancer? Can you tell us about ASCENT and the toxicities associated with this antibody drug conjugate in this older patient population? Dr. Hope Rugo: Well, ASCENT, of course, is a practice-changing trial as well. It led to the final formal approval of sacituzumab govitecan for patients with metastatic triple negative breast cancer in the second line or greater earlier this year after accelerated approval was granted earlier in 2020. This antibody drug conjugate is given 2 weeks on, 1 week off. And the primary toxicity is neutropenia, and then to a lesser degree diarrhea. But overall, the drug is quite well-tolerated. In the overall parent ASCENT trial, as the listeners know, showed an improvement in progression-free and overall survival at the first analysis. Very impressive data with sacituzumab in these heavily pretreated triple negative breast cancer population, compared to treatment of physician choice with standard chemotherapy options, where about 50% of the patients received eribulin, which had already been shown to be better in terms of overall survival compared to other chemotherapy in the subset of patients treated in the past with eribulin who had triple negative disease. So at ASCO this year, Kevin Kalinsky presented on behalf of our authorship group a subset analysis looking at patients who were age 65 and older to better understand whether there was more toxicity and as much benefit in this group of patients. So important when we're looking at novel therapies. So overall, there were 44 patients treated with sacituzumab and 46 with treatment of physician choice who were age 65 or older. Most of the patients had received two to three lines of therapy. And about 40% had received greater than three lines of therapy. The median prior anticancer regimen was pretty similar to the overall group. Most of the patients had initially been diagnosed with triple negative disease, but really, interestingly, about a third of the patients had ER-positive or something else disease initially and were triple negative on biopsy in the metastatic setting. So an interesting subgroup of patients that were also looked at separately and appeared to benefit to the same degree as the triple negative patients. So we looked at progression-free survival in this group of patients looking at patients under age 65 and age 65 and older. A hazard ratio was even greater in the age 65 or older for--it's hard. These are subset comparisons, but the hazard ratio is 0.22 going from 2.4 months with standard therapy to 7.1 months with sacituzumab. The hazard ratio in the younger group was 0.46. But still a big difference in progression-free survival. And then in terms of overall survival in the age 65 and older group, it went from 8.2 to 15.3 months with a hazard ratio of 0.37. And so also really quite dramatic. And overall response was also significantly increased with, in fact, the only responses seen in the age 65 or older group seen in the sacituzumab group. There were no complete or partial responses in the treatment of physician choice group. Of course, really important to look at safety in our older patients because we know that generally there is more toxicity in that group of patients. But actually looking at grade III or greater toxicity, keeping in mind it was 49 [patients] in the older group versus 209 patients in the younger group, there was no difference in grade III or greater toxicities. There were more dose reductions. So 35% reduced their dose versus 19% older versus younger. But there was no difference in adverse events that led to discontinuation between the younger and older group. So that was really encouraging. We see this in almost all trials that older patients have more dose reductions and that was seen here as well. And we also looked at this very small subset of patients who are age 75 or older versus age 65 or older. And the rates of adverse events were similar, albeit smaller number of patients. There was, if you looked at specific treatment-related adverse events that led to dose reduction, it was a neutropenia, fatigue, diarrhea, febrile neutropenia in a small number, 6% versus zero in the treatment of physician choice and nausea. So it's helpful to know what those toxicities are when you're thinking about treating these patients in clinical practice. And in a patient who might be a little less strong, a little older, more comorbidities, so slightly more frail, I would consider starting potentially at a 3/4 of the dose and then going up if they tolerate it well, versus starting at the full dose and getting a lot of toxicity. But this was really encouraging data that showed that you can give the drug to patients who are older and even elderly at age 75 or greater. So that was good to see. And then Lisa Carey presented additional data looking at patients who were treated in the second line or greater because the formal approval by the FDA is in second or greater line. But most of the data looked at patients who were treated in the third or greater line. So you were supposed to have at least two chemotherapies for advanced disease, but you could have had one in the early stage setting if your progression occurred within 12 months. So there were 33 and 32 patients in the sacituzumab and treatment of physician arm, respectively, who had a recurrence within 12 months of neo or adjuvant chemotherapy. They got one line of chemotherapy in the metastatic setting. And then they were randomly assigned on the ASCENT trial. And as you would expect, tiny numbers, right? 33 and 32 patients. But you get a lot of events in this patient population. The PFS was much greater in patients getting sacituzumab than treatment of physician choice. Hazard ratio of 0.41. And also, if you looked at overall survival, it was double. The hazard ratio is 0.51, even in the second line setting. I think it's really interesting to look to see what the toxicity is relative to the lines of therapy. But because the numbers are so small, it's really hard to look at this now. We'll see more data on toxicity when we see data in the first line, as well as the post-neoadjuvant setting in ongoing trials. And I think that will help us a lot to understand what I think we see in the current clinical trials and in practice, which is that patients who are treated in this second line setting have less hematologic toxicity as well as GI toxicity and need less growth factor intervention, et cetera. And I expect that we'll see that in the post-neoadjuvant setting as well. These numbers are too small to really look at any differences in toxicity. But all of this data I think was incredibly encouraging for us in terms of the use of sacituzumab in patients with metastatic triple negative disease, as well as the expansion to the first line and to post-neoadjuvant setting. ASCO Daily News: Excellent. Investigators of the phase III MINDACT trial, that's Abstract 500, evaluated the survival of patients with an ultra low risk 70 gene signature. How will MINDACT inform clinical practice? And do you think this study might guide more appropriate choices of chemotherapy in women with node-negative or one to three node-positive disease? Dr. Hope Rugo: Well, how MINDACT will inform clinical practice is a very big question. And it already has informed clinical practice identifying patients who are better candidates for chemotherapy and endocrine therapy versus endocrine therapy alone who have stage I and II hormone receptor-positive early stage breast cancer based on their primary outcome results. This particular analysis was something different. So we think about using this 70 gene score and the recurrence score from the TAILORx trial (DOI: 10.1056/NEJMoa1804710) and RxPONDER to try and identify which patients need more therapy versus less therapy. Now, we also know that these scores have some prognostic impact. Clinically, we mainly have used them to decide who should get chemotherapy in addition to endocrine therapy. This trial looked at a different way to use a gene expression scoring system. It's really to identify which patients need less. Given the fact that your middle of the line therapy is endocrine therapy, which patients do we know who will do very, very well with any endocrine therapy and don't need extended duration endocrine therapy? That's really the question here. So they looked at the patients who were in the MINDACT trial and used data published by my colleague, Laura Esserman who looked at a cohort of patients retrospectively and found that patients who had an ultra low score in MINDACT. And that's a score greater than 0.355 where plus 1 is the lowest end of low risk, and minus 1 is the highest end of high-risk, so greater than 0.355. She identified a group of patients who did well, regardless of whether they received tamoxifen or not apparently in this retrospective long-term outcome where there was 15-year follow-up. So they use that data to go into the MINDACT population and to try and understand which patients benefit. And the MINDACT is a much higher risk group of patients. So if you looked at that original trial that Laura Esserman published, these patients had screen detected cancers. And in fact, the 70 gene signature low and ultra low-risk tumors are, as you would expect, over-represented in screen detected cancers. So you've got this excellent survival regardless of treatment. So how did they apply to MINDACT? So in MINDACT, patients were randomly assigned, of course, who had clinical low, genomic high, or clinical high genomic low to receive chemotherapy or not. In this situation, you're really looking at the patients who have genomic ultra low disease. So most of those patients would not be getting chemotherapy because they would already have ultra low disease. So what they found actually when they looked at the overall population of MINDACT, 6,700 or so patients, they found 15% of patients or 1,000 patients fell into this ultra low category. And if then you looked at the patients who were high-risk, it was 36%. And patients who fell into the big low-risk group, it was about 49%, so about half of the population of patients. So they looked at the different metastasis-free interval rates in patients who had genomic low and ultra low-risk disease, regardless of the treatment the patients receive. They all receive endocrine therapy, remember? So they actually found that in patients who were ultra low versus low-risk, that the hazard ratio is 0.65, showing that patients who had ultra low-risk--remember, this was 1,000 patients at 8 years--there was only 36 events. So they had a 97% 8-year distant metastasis-free interval, compared to 94.5% for low-risk and 89.2 in high-risk disease. They looked at breast cancer-specific survival rates as well. And for ultra low-risk in 1,000 patients, there were exactly eight events. 99.6% 8-year breast cancer-specific survival. So really, quite remarkable. So clinical high-risk tumors tend to have larger size, higher grade, be node-positive. We already know that. For the 1,000 genomic ultra low-risk patients, about almost 70% were greater than 50 years. 80% were node negative. 81% had tumors that were T1, so up to two centimeters. And most of them, except for 4%, were grade I and II. 97% were hormone receptor-positive HER2-negative. Only 14% of patients who had ultra low-risk disease received chemotherapy in MINDACT. And most of the rest received endocrine therapy. Some actually didn't receive endocrine therapy. 16% had no adjuvant systemic treatment at all. So if you looked at the genomic ultra low-risk patients and divided them into clinical low-risk and clinical high-risk, there was really no difference in the events overall, a little bit less 8-year distant metastases-free survival, but not much of a difference. So really, a quite remarkable outcome. Now, what you want to know, of course, then is, does it make a difference if you get endocrine therapy at all? And they looked at the patients who had chemotherapy versus no chemotherapy. And as you would expect, it made no difference. Again, it was a tiny number of patients. But if you looked at endocrine therapy versus no endocrine therapy, it was hard to tell. Because, again, no adjuvant systemic therapy was only 157 patients. There were four events. And for the patients, 685 patients who got endocrine therapy, there were 23 events. So the 8-year metastasis-free interval was identical, but there just aren't enough patients in that no adjuvant systemic therapy group to really understand. So what we know is ultra low-risk defines a group of patients who have excellent outcomes. Does it tell us that they don't need adjuvant systemic therapy? No. Eight years really isn't enough time, unfortunately, in is group because 50% of recurrences occur after five years and out to 20 plus years. We have to keep in mind the Early Breast Cancer Trials Group data showing how many recurrences occurred after five years of endocrine therapy. But in this group of patients who have ultra low-risk disease, they clearly do not benefit from chemotherapy. And I think that's regardless of their clinical risk. And it's likely that 5 years of adjuvant endocrine therapy is absolutely all those patients would ever need. If you have a small cancer that's ultra low-risk, could you get by with less than 5 years of endocrine therapy in a patient with a lot of toxicity? Potentially. And I think that's a really important bit of information to take back into clinical practice when you're talking to patients about the duration of endocrine therapy. But a stage I tumor or stage II with ultra low-risk disease, in general, I would treat for 5 years. I think it's important to keep in mind that premenopausal women, even with ultra low-risk stage II disease, have an ongoing risk of recurrence. And I still think that those patients should be treated with a varying function suppression and aromatase inhibitor if tolerated and tamoxifen otherwise because our very young patients tend to have higher risk of recurrence over time. And it's very hard to separate them out in these studies. Interestingly, there are a few young women who have ultra low-risk disease. So I think this really helps us understand yet another impact of genomic tests, which is who needs less therapy, not just who needs more. ASCO Daily News: Great. That's good to hear. Well, finally, the theme of the Annual Meeting was equity. And in Abstract 1092, you and your colleagues at University of California, San Francisco (UCSF) looked at decreased enrollment of patients with advanced lobular breast cancer compared to ductal breast cancer in interventional clinical trials. Can you tell us about this study? Dr. Hope Rugo: Yes, this was a really interesting evaluation. My colleague surgeon Rita Mukhtar at UCSF actually led this evaluation with a very good student who's working with us on some of our research trials. And the idea was that we had observed anecdotally, as have others, that patients with invasive lobular cancer tend to be less likely to meet criteria for clinical trials. So they don't have measurable disease as much. We tend to see sclerotic bone lesions, diffuse infiltration without measurable disease. And it can be much, much more difficult to meet the criteria for clinical trials. So actually, what my colleagues did in this trial is look at whether or not patients with lobular breast cancer are underrepresented in clinical trials. And so they looked at the proportion of interventional stage IV clinical trials that used RECIST in clinicaltrials.gov. And then actually looked at the patients who have RECIST measurable disease who have lobular cancer. And it's really interesting. I mean, we just have a lot less RECIST measurable disease. And in the UCSF cancer registry, patients who were enrolled in clinical trials, if you looked at invasive lobular cancer were markedly decreased if you compare it to patients with other sub-types of breast cancer. So we think that that's probably due to the requirement for measurable disease. And that what we should do in patients who have metastatic lobular cancer is develop trials that are specifically for lobular cancer that focus on the unique biology. And there's a lot of work going on now looking at that biology. And allow patients to enroll based on their disease control rates rather than response. So that we don't require RECIST measurable disease since that's hard to come by in invasive lobular cancer. So I think it's a really important area. It's about 15% of invasive breast cancers. We see a lot of lobular cancer in the metastatic setting. And I think it's unfortunate not to be able to enroll these patients in clinical trials. There is a lot of interest in the cooperative groups in the United States in Europe and in Asia, of course, in trying to do trials that are focused on addressing the needs of patients with lobular cancer, both in the early and late-stage setting. ASCO Daily News: Excellent. Thank you, Dr. Rugo. It's been great to have you on the podcast today. Thanks so much for sharing your valuable insight with us on the ASCO Daily News podcast. Dr. Hope Rugo: It was really a pleasure to participate and thank you for putting together these podcasts. ASCO Daily News: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate and review us, wherever you get your podcasts.     Disclosures: Dr. Hope Rugo Honoraria: Puma Biotechnology, Mylan and Samsung Research Funding (Institution): Pfizer, Merck, Novartis, Lilly, Roche, Odonate, Daiichi, Seattle Genetics, Macrogenics, Sermonix, Boehringer Ingelheim, Polyphor, Astra Zeneca and Immunomedics. Travel, Accommodations, Expenses: Pfizer, Novartis, Mylan, AstraZeneca, Merck Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. John Sweetenham, associate director for clinical affairs at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern and editor-in-chief of ASCO Daily News, discusses compelling approaches in cancer care featured at the 2021 ASCO Annual Meeting, including key studies on financial toxicity, drug prices, disparities in clinical trial accrual, and the impact of the COVID-19 pandemic on cancer screening.   Transcript ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. John Sweetenham, associate director for clinical Affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center. Dr. Sweetenham also serves as editor-in-chief of ASCO Daily News. He joins me to discuss compelling approaches in cancer care featured at the ASCO Annual Meeting, including key studies on financial toxicity, trends in oncology drug revenue, disparities in clinical trial accrual, and the impact of the COVID-19 pandemic. Dr. Sweetenham reports no conflicts of interest relating to our discussion today. Full disclosures relating to all episodes of the podcast are available at asco.org/podcasts. Dr. Sweetenham, it's great to have you on the podcast again. Dr. John Sweetenham: Thanks, Geraldine. It's good to be here. ASCO Daily News: There's been a lot of interesting research on the impact of the COVID-19 pandemic on patients with cancer. Sadly, the pandemic caused the postponement or cancellation of countless screening procedures. Abstract 6501 looks at the impact of the pandemic on stage presentation of breast and colorectal cancers. What can you tell us about this study? Dr. John Sweetenham: I think this particular study is very important because it is a confirmatory study of observations that have been made in other environments. But in this case, it's a single institution study from UC San Diego. The implication, the basis of this study, obviously, is that screening programs have really been critical in reducing death rates from certain cancers. And breast and colorectal cancer would probably be the best examples of that. And as we know, during the pandemic, many people postponed or cancelled their screening procedures. And so there have naturally been concerns about what that will do to stage at presentation, and an anticipation that we will see more patients eventually showing up for our services with more advanced stage of disease. So in this study, the workers at UC San Diego looked at their patients who had been treated in the years 2019 and 2020. And the treating clinicians used stage at presentation, which was determined by standard AJCC staging modules pulled out of their electronic medical record. And they did a pretty straightforward comparison of the stage distribution for their patients between 2019 and 2020. And they focused especially on colorectal and breast cancer because those are diseases where screening is known to have a significant impact. The interesting data from this study are that the total number of new patient visits for cancer during 2019 and 2020 were actually remarkably similar. And if you look at the stage distribution across all cancer types and compare 2019 and 2020, there really isn't very much difference. But what's disturbing is that for patients with breast cancer, they observed a lower number of patients with stage I disease, which reduced from 64% in 2019 to 51% in 2020, and a higher number of patients presenting with stage IV disease, which went from 2% to 6%. And very similar trends were seen for the patients with colorectal cancer, where they saw a decline in stage I presentations and an increase in stage IV presentations. So these are, again, confirmatory data which highlight the problem with delayed screening. The investigators mentioned that they're going to continue to follow these numbers closely and are planning to present data from their experience in 2021 as well. I think that what this does is really--it emphasizes the need for us for ongoing efforts to encourage our patients to return to care, to return to their screenings, and frankly, to get vaccinated so that they will have more confidence in coming back and returning to care. ASCO Daily News: Thank you for sharing these data. There are a lot of financial toxicities associated with cancer care. And there's an interesting study, Abstract 6504, that uses data from patients' credit reports to measure the relative risk of adverse financial events in cancer patients after diagnosis compared to individuals without cancer. Can you tell us more about this? Dr. John Sweetenham: Yes. And my first disclaimer would be that I'm certainly not a health economist. But as someone who is a non-expert in this domain, I found this to be a very interesting study which looked at the relative risk of adverse financial events in patients with cancer compared with a control group. And it did this by using data that they pulled from the patient's credit reports, which, from my perspective, is a really interesting way of looking at the financial hardship. And the way they did this was they used the Western Washington SEER cancer registry for their cases who they investigated in this study. And they used the voter registry to identify their control patients or control cases, I should say. And then they used data from one of the credit reporting agencies to look for signals for what they describe as adverse financial events in the patients with cancer compared with the population. And they were able to identify levels of severity of adverse financial effects within this analysis. So to cut to the chase here, what's interesting is they identified more than 300,000 individuals, of whom just over 84,000 were patients with cancer. And the remaining 250,000 or so were control patients. And they looked at the available line of credit for these patients, and then also looked for signs of what they described as severe, or more severe, or most severe adverse financial effects. And the most severe would have been, for example, foreclosures on homes or repossessions of homes and properties. So obviously, pretty significant and very serious adverse financial effects. And if we just look overall at their results, so for example, severe adverse financial effects, there was a highly significant difference which demonstrated that these were significantly more common in the population of patients with cancer, the same being true for both the more severe and the most severe adverse effects. And so, in a way, you could argue not surprising. But I think it put some numbers around the fact that there are long lasting effects financially for our patients with cancer, for a significant proportion of them, as a direct consequence of their diagnosis and compared in quite a robust way against a non-cancer population. And these are real life and very long term consequences, so something that we just have to keep uppermost in our minds as we're planning the financial advice and the financial navigation that we provide to our patients during their cancer journey. ASCO Daily News: Absolutely. Well, let's focus on the price of cancer drugs. Abstract 6505 looks at trends in oncology drug revenue among the world's major pharmaceutical companies. The study's authors cite a 70% increase in the number of clinical trials for cancer drugs over the past decade, and a substantial increase in the price of cancer drugs. In fact, the study found a 96% increase in sales revenue from cancer drugs among the world's top pharmaceutical companies over the past decade. So what are your thoughts about this? And why, in your opinion, is this study important? Dr. John Sweetenham: Thanks, Geraldine. Yes, I think that this study is important on a number of levels. I think when one first looks at the results of this study, it would be easy to conclude that, well, this is just one more piece of data that shows that the cost of cancer drugs is rising and is too high. And that's reflected in the extraordinary financial toxicity that we see in our patients with cancer. And you know, I think that there are elements of that which are probably true. But I do think there are other interesting observations from this. For example, as you mentioned, they demonstrated that sales revenue from cancer drugs has increased by more than 96%. And interestingly, revenues from non-cancer drugs among the same companies have actually decreased during that time. I would also mention, because it may be relevant, that although the analysis primarily included true antineoplastic drugs, they did include a number of supportive care drugs in this analysis as well, which are primarily used in patients with cancer. And so, certainly, I think in addition to the antineoplastic drugs, probably, the supportive care drugs have been part of the driver of this increase in revenue. The other interesting part of this is that during the study period, oncology revenues have grown, whereas revenues for other non-oncology drugs across all of the companies involved have remained stagnant. So what can we draw from this? First of all, as I said, I think the message about the cost of drugs is familiar to all of us and is not a new one. I think it is very interesting that there's been a 70% increase in the number of clinical trials of cancer drugs. And I think what that's telling us is that clearly, there has been enormous activity and substantial opportunity for the development of new cancer drugs. So as we look at these numbers, I think one of the positive spins to put on this is the fact that there are a lot more anti-cancer drugs coming online, a lot more trial activity. And in the long run, I think that has to be good for our patients. And we should be, to some extent, reassured by the fact that there are so many more drugs. I think also, what's interesting, although I certainly wouldn't editorialize over this, is the fact that this apparent explosion in activity and revenue around anti-cancer drugs has apparently been at the relative disadvantage of patients with other diseases, not really a thing for us to comment on that from what I classify as an editorial perspective. But I think the message for us and for our patients from this study is mixed, that, yes, there does seem to be some imbalance in terms of the amount of revenue generated out of these drugs. On the other hand, there are many of these agents now in clinical trials and on the market that weren't there a number of years ago. And overall, I think that that indicates the positive side of this story. ASCO Daily News: Well, I'd like to address a very important and timely topic, access to care. Abstract 100 reports the outcomes of a 5-year initiative of community outreach and engagement to improve enrollment of adult Black patients in clinical trials. How would you assess this initiative? Dr. John Sweetenham: I think this initiative and the results that they've produced really underlines, more than anything else, number one, the complexity that is involved in addressing this issue and the sort of multifaceted approach one has to minority accrual. And secondly, it underlines to me that there's no quick readout. One has to wait a while to see the effects of this kind of intervention. And there have been successful attempts to improve minority accrual to clinical trials. There are many ongoing initiatives. What struck me as being interested about this study from the University of Pennsylvania was the kind of multi-pronged approach they took to this. So they report that in 2014, Black residents comprised 19% of their population, [and] 16% of the cancer cases seen in the Philadelphia area. But only 11% of patients at the Abramson Cancer Center at the University of Pennsylvania were Black. And the number of Black participants who were recruited onto their treatment and interventional studies were relatively low, ranging between 8% and 13%, depending upon the type of study. So they developed a center-wide program with a number of key elements, which included tailored marketing. They had plans within each individual protocol for how they were going to enroll African American patients. They developed partnerships with faith-based organizations and conducted educational events. They provided Lyft and Ride Health to address transportation barriers. They had patient education by nurse navigators and an improved informed consent process. So they really approached this addressing several of the factors that play into the disparity in clinical trials accrual. And what they found is after 4 to 5 years of taking this approach, the percentage of Black patients seen at their center had increased to 16.2 from 11.1. And when they looked at the percentages of African American patients who they accrued onto their trials, it was really quite substantially increased. So if you remember, prior to this intervention, the range was from 8% to 13%. At the conclusion of this study, the rate was from 22% to 33%. So they had seen a 1.7 to 4-fold increase in 5 years. So I think that this persistent multi-pronged approach addressing many of the factors that play into these disparities was really interesting. And it demonstrates that to really make a significant impact on some of these disparities requires a lot of work over a long period of time. And as I said, the readout may not come immediately. It takes a while for the effects to truly be seen. ASCO Daily News: Exactly. Some great approaches there for people to look at in Abstract 100. Well, my final question relates to concerns from health insurers, that clinical trial participation can increase the total cost of care for patients. So in this study, Abstract 6513, investigators looked at the impact of clinical trial participation on total costs paid by Medicare during the oncology care model program in a large community-based practice. Can you tell us more about this study? Dr. John Sweetenham: Yes. This is an interesting study which is based on patients enrolled into the oncology care model. For those who may not be aware of this model, it's an alternative payment model which has been developed by the Centers for Medicare and Medicaid Innovation to address improvements in quality of care, as well as address issues of cost of care for patients with cancer. This study is based out of the community-based practice of 90 oncologists who practice [at] over about 30 sites of care. And what they did in this study was to link trial data and electronic medical record data with data generated from the oncology care model for patients undergoing treatment for various cancers between 2016 and 2018. And important to point out that the OCM includes patients who are Medicare beneficiaries only, so represents patients over age 65. And what they were trying to address in this study was whether the entry of patients onto clinical trials actually results in increased costs, which is, I think, some of the sort of received wisdom that's out there, that clinical trials are expensive. The OCM provides a slightly more controlled environment in which to study that and find out whether costs of care associated with clinical trials actually do overall increase the cost of care, something which clearly will be of great interest to insurers. So in addition to exploring this from the perspective of antineoplastic treatment, the group also had the opportunity to look at some non-trial episodes, and in particular, study the impact of the receipt of active treatments in the last 14 days of life as well as hospice use and hospitalizations. So these are other kind of issues which are important to us now which the OCM provides a window on. So the study was conducted and included just over 8,000 OCM episodes which met criteria for the study. And of those, 459 of the episodes included patients who were on a clinical trial. And interestingly enough, on average, episodes when the patient were on a clinical trial cost almost $6,000 less than matched non-trial episodes. And it was independent of whether it was an early phase or a late phase study. And interestingly, but perhaps not surprisingly, the primary reason for these lower costs was because of the increased drug costs. Because typically, the cost of the drug would have been covered by the trial. Interestingly, there were no differences in the rates of treatment within the last 14 days for the patients who were on the study. And there was no difference in rates of hospitalization or hospice use for the patients who were on the studies either. So the take-home message from the study was that the inclusion of patients in a clinical trial actually, overall, led to a reduction in Medicare costs for Medicare beneficiaries. And so it didn't support the concern that many third party payers have, that entry of their covered patients onto clinical trials actually cost more. Just one possible note of caution is that this was a community oncology-based practice. And it's possible that the breakout of patients on early phase versus late phase clinical trials might have been very different from what we might encounter in a more academic oncology setting. But nevertheless, I found this to be an important study which, to some extent, explodes a misconception that putting patients on studies costs a lot more money. ASCO Daily News: Absolutely. Well, Dr. Sweetenham, thanks for highlighting some really interesting studies on a range of very important issues impacting the cancer care community. Dr. John Sweetenham: Thanks, Geraldine, a pleasure as always. ASCO Daily News: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate and review us wherever you get your podcasts.   Disclosures:  Dr. John Sweetenham: None disclosed.  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Neeraj Agarwal, director of the Genitourinary Oncology Program at the University of Utah Huntsman Cancer Institute and incoming editor-in-chief of ASCO Daily News, highlights key abstracts in GU oncology featured at the 2021 ASCO Annual Meeting.   Transcript: ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Neeraj Agarwal, a medical oncologist and director of the Genitourinary Oncology Program at the University of Utah Huntsman Cancer Institute. He joins me to discuss key abstracts in the GU field featured at the 2021 ASCO Annual Meeting.   Dr. Agarwal has served in a consulting or advisory role for AstraZeneca, Bristol Myers Squibb, Exelixis, and Merck, among other organizations. He is a co-author of a study, Abstract 5073, that will be discussed in this episode. Dr. Agarwal's full disclosures and those relating to all episodes of the podcast are available on our transcripts at asco.org/podcasts.   Dr. Agarwal, it's great to have you on the podcast again.   Dr. Neeraj Agarwal: It's my pleasure, and an honor. Thank you very much for having me.   ASCO Daily News: Dr. Agarwal, let's start with some exciting news in the field of kidney cancer. LBA5 addressed the Keynote 564 trial, which evaluated pembrolizumab versus placebo as adjuvant therapy for patients with renal cell carcinoma. This study reported stunning results. What can you tell us about this trial?   Dr. Neeraj Agarwal: These are very important results from the Abstract LBA5, which is being presented by Dr. Toni Choueiri, from Dana Farber Cancer Institute, and colleagues on interim results from the KEYNOTE-564 trial, which showed that adjuvant therapy with pembrolizumab after complete resection of intermediate high, high-risk, localized or oligometastatic renal cell carcinoma improves survival outcomes.   So, let me give you a background first. Partial and radical nephrectomy is considered standard of care for treatment of men or women with localized renal cell carcinoma. However, approximately half of these patients eventually recur. In addition, many patients with limited metastatic disease undergo surgical resection.   Currently, there is no standard of care systemic therapy available for these patients. So, the KEYNOTE-564 study is a phase III trial evaluating pembrolizumab versus placebo--which is a standard of care, by the way, for these patients as adjuvant therapy for patients with clear cell renal cell carcinoma with intermediate high risk, high-risk, or those with metastatic disease who have undergone complete resection of metastatic disease.   Primary endpoint was disease-free survival for investigator assessment, in intent-to-treat population. Overall survival was a key secondary endpoint. In this study, a total of 994 patients were randomized, one to one, to pembrolizumab or placebo. At the time of data cutoff, median follow up was 2 years. There were no patients remaining on the study treatment.   If you look at the baseline characteristics, they were evenly balanced between the two arms. At the first, prespecified interim analysis, the primary endpoint of disease-free survival was met, though the median values were not reached for both arms. Pembrolizumab was associated with a significantly longer disease-free survival than placebo, with a hazard ratio of 0.68 and a one-sided p-value of 0.001, which translates into 32% reduction in risk of recurrence of disease or death with adjuvant pembrolizumab.   The 2- year rate of disease-free survival was 77.3% with pembrolizumab, as compared to 68% of the placebo. Overall, disease-free survival benefit was consistent across subgroups. Median overall survival was not reached for either groups, and the estimated 24 months survival rate was high in both groups at 96% and 93.5% with pembrolizumab and placebo, respectively. And really, there were no new safety signals seen with pembrolizumab.   So, I'd like to summarize these important results by saying that KEYNOTE-564 is the first positive, phase III study with a checkpoint inhibitor for patients with renal cell carcinoma, which has been surgically resected completely. And for them, right now, there is no real standard of care after the surgical resection. So, in my view, these results support pembrolizumab as a potential new standard of care for these patients who present to us after a complete surgical resection of their renal cell carcinoma.   ASCO Daily News: Excellent. Thank you for sharing those practice-changing results. There's another late-breaking abstract that people are excited about. That's LBA4 and the VISION phase III study, which used a novel PSMA-targeting agent for patients with metastatic, castration-resistant prostate cancer. What can you tell us about the VISION trial?   Dr. Neeraj Agarwal: The VISION trial was reported by Dr. Mike Morris, from Memorial Sloan Kettering Hospital, and colleagues from across the planet. And this trial investigated the use of the Lutetium PSMA-617 in patients with metastatic, castration-resistant prostate cancer. As a background, Lutetium PSMA 617 is a targeted, radioligand therapy which delivers beta particle radiation to PSMA-expressing prostate cancer cells and surrounding microenvironment.   So, VISION was a randomized, open-label, phase III study, which evaluated Lutetium PSMA-617 in men with PSMA-positive, metastatic, castration-resistant prostate cancer, who had received prior treatment with the next generation androgen signaling inhibitors, such as enzalutamide and one or two taxane therapy regimens. Primary endpoint was radiographic progression-free survival, as well as there was another primary endpoint.   So, there were two primary endpoints--radiographic progression free survival, and overall survival. A total of 831 patients--so this is a large study--where 831 patients were randomly assigned in 2 to 1 fashion to receive Lutetium PSMA-617, plus standard of care, or standard of care therapy alone. I would like to point this out, that standard of care therapy was to be determined by the investigator, but excluded cytotoxic chemotherapy and radium 223.   The median study follow up was 20.9 months at the time of data cutoff. The baseline characteristics were well balanced between treatment arms. Lutetium PSMA-617 plus standard of care therapy significantly improved radiographic progression free survival and overall survival, versus standard of care therapy alone. The median radiographic progression free survival with lutetium PSMA-617 plus standard of care was 8.7 months, as compared to 3.4 months with standard of care alone, with a hazard ratio of 0.40, favoring the lutetium PSMA- 617.   The median overall survival with lutetium PSMA-617 plus standard of care was 15.3 months, as compared to 11.3 months with standard of care, with a hazard ratio of 0.62. These results basically translate into an absolute 4-month improvement in median overall survival, and a 38% reduction in risk of death, with PSMA-617 plus standard of care over the standard of care. I would like to point out that key secondary endpoints of objective response rates, disease control rate, and time to subsequent or first symptomatic skeletal event were statistically significant, and favored lutetium PSMA 617.   Overall, if you look at the treatment emergent adverse events, they were higher in the lutetium PSMA arm, at 52.7%, compared to those on the standard of care arm, which was 38%. And these were high grade treatment emergent adverse events. So, I'd like to conclude by saying that lutetium PSMA-617 plus standard of care treatment was a well-tolerated regimen that improved radiographic progression-free survival, and overall survival, as compared with standard of care therapy alone, in men with PSMA-positive, metastatic, castration-resistant prostate cancer, after prior treatment with novel hormonal receptor signaling inhibitors, such as enzalutamide or abiraterone and taxane chemotherapy.   Once approved by regulatory bodies, I am looking forward to using this agent in my clinic for our patients with metastatic, castration-resistant prostate cancer who have had disease progression on prior therapy with normal hormonal therapy and taxane chemotherapy. So, this is indeed a great news for our patients.   ASCO Daily News: Absolutely. Well, I'd like to ask you about adolescents and young adults with cancer. As you know, AYA patients navigate a lot of challenges in their cancer experience. Can you tell us about any studies that address this patient population?   Dr. Neeraj Agarwal: Indeed. There was an abstract--Abstract 5006, which is being presented by Dr. Hellesnes and colleagues from University Hospital of North Norway. The study team investigated non-testicular cancer mortality in relation to testicular cancer treatment in a large population-based cohort. Overall, 5,700 men, diagnosed with testicular cancer from 1980 to 2009, were included and identified from the cancer registry of Norway.   Clinical parameters and treatment data were abstracted from the medical records and linked with the Norwegian cause of death registry. During a median follow up of 18.7 years--it is a long follow up, by the way--in total, 665--or 12% of men--were registered with non-testicular cancer deaths. The overall excess non-testicular cancer mortality was 23% in men with a history of testicular cancer, as compared with the general population.   So, I'd like to repeat. There was an overall excessive non-testicular cancer mortality in men with a history of testicular cancer compared to the general population--by 23%. That's the first message I'm giving here. Second, there was an increased risk observed with platinum-based chemotherapy and radiation therapy, but not after surgery. So, I thought it was very interesting that there was an increased risk of non-testicular cancer mortality seen after platinum-based chemotherapy and/or radiation therapy, but not after surgery given the context of testicular cancer.   The standardized mortality ratios increased significantly, with increasing follow up time of 10 or more years. The most important cause of death wasn't second cancer. Treatment with platinum-based chemotherapy was associated with a significant 1.69 to 6.78-fold increased standardized mortality ratio for cancers of the oral cavity, pharynx, esophagus, lungs, bladder, and leukemia. After radiation therapy given for testicular cancer, there was an increased--significantly increased--and we are talking about 3.02 to 4.91-fold increase--the standardized mortality ratio for cancers of oral cavity, pharynx, stomach, liver, pancreas, and bladder. Even non-cancer mortality was also increased by 15% after both platinum-based chemotherapy and radiation therapy.   I would like to highlight that there was an excess in suicides after platinum-based chemotherapy with a standardized mortality ratio of 1.65. So long term, overall cardiovascular mortality--and I found it interesting, because it is going against the dogma here--that long term, overall cardiovascular mortality was not increased with either chemotherapy or radiation therapy. So, I'd like to conclude--regarding this abstract--by saying that testicular cancer treatment with platinum-based chemotherapy or radiation therapy was associated with significantly increased long term, non-testicular cancer mortality, with non-testicular second cancer being the most important cause of death in these patients.   So, in my view, these results have important implications on patient counseling, selection of treatment for testicular cancer, and, very importantly, long term follow up of our young patients with testicular cancer after they are apparently cured of testicular cancer with platinum-based chemotherapy and/or radiation therapy. And usually we stop following them, in most cases, after 5 years. And how these results are going to impact the decision making regarding their long-term follow up. So, I think this study brings up a very important issue from those perspectives.   ASCO Daily News: Absolutely. Dr. Agarwal, I'd like to get your thoughts on Abstract 5004. That addresses PSA screening for African American men. What can you tell us about this study?   Dr. Neeraj Agarwal: So, this abstract, which is Abstract 5004, presented by Dr. Edmund Qiao and colleagues, examined the association of intensity of PSA screening with the disease severity of prostate cancer at the time of diagnosis, as well as prostate cancer-specific mortality in African American men younger than 55 years of age. So, I'd like to highlight two things, which this study is presenting.   Number one, the screening intensity in African American men, and second, how it is affecting the time of diagnosis, the type of diagnosis--meaning is it a high grade or metastatic prostate cancer--and most importantly, is it affecting prostate cancer-specific mortality in African American men? So, this was a retrospective review of Veterans Health Administration records of African American men, aged 40 to 55 years, who were diagnosed with prostate cancer between the years of 2004 to 2017.   The screening intensity was defined as percentage of years screened within the pre-diagnostic observation period. The cohort included 4,654 African American men, with a mean age of 51.8 years--so quite a younger population. A median pre-diagnostic observation period of 5 years, and a median follow up of 7 years. And these are pretty decent, long median follow ups of 7 years.   So, in this large national cohort, African American men aged 40 to 55 years, increased intensity of PSA screening was significantly associated with decreased risk of metastatic prostate cancer, or high Gleason Score localized prostate cancer, and more importantly, prostate cancer-specific mortality. So, in my view, these results have important implications on how to screen African American men in the age group of 40- to 55-year-olds.   Obviously, we don't screen for prostate cancer. And please note that these are the men who are more likely than others to present and die of aggressive prostate cancer. And even more importantly, these men are underrepresented in PSA screening studies. So, I think a lot of good lessons coming from this study.   ASCO Daily News: Indeed. Well, racial disparities are also addressed in a Medicare database study captured in Abstract 5073. The study set out to evaluate the real-world utilization of advanced therapies over time, and to provide data on utilization patterns among racial minorities that are often underrepresented in clinical trials. Can you tell us more about this study?   Dr Neeraj Agarwal:  Yes. Indeed. These data, presented by Dr. Steve Freedland from Cedars-Sinai, and colleagues, which highlighted a critical issue of unacceptably high number of patients with metastatic castration-sensitive prostate cancer not receiving standard of care, life-prolonging therapy in the United States. In this study, which I also had the opportunity to co-author, the investigators evaluated real-world utilization of systemic therapies backed by level 1 evidence from large randomized phase III trials, which showed treatment intensification with docetaxel, or novel hormonal therapies, such as abiraterone, dramatically improved overall survival in men with metastatic castration-sensitive prostate cancer.   In addition, the study team also evaluated the receipt of these therapies by racial minorities who are usually underrepresented in these clinical trials. So, this was a retrospective study of a Medicare database, which covered the time period between January 2009 and December 2018. Adult men with new diagnosis of metastatic prostate cancer were included. The first line treatments were grouped by prostate cancer specific drugs prescribed within 30 days prior to, and 120 days after the index date, which was the date of diagnosis of metastatic disease.   Remarkably, a total of more than 35,000 patients with metastatic castration-sensitive prostate cancer were included in the study. These comprise 12% patients who are African American, 5.3% patients [who were] Hispanic men, and 78.5% men who were white. So, the study had a good representation of racial minorities.  The results were startling to me.   Starting in the year 2015 or ‘16, when docetaxel was already approved after showing dramatic improvement in overall survival, which was soon followed by similar results with abiraterone, within a couple of years showing similar overall survival benefit--less than one third patients with metastatic castration-sensitive prostate cancer received these therapies from 2015 until 2018. The treatment intensification, which is the terminology used for combination of androgen deprivation therapy with docetaxel or novel hormonal therapy such as abiraterone, enzalutamide, and apalutamide--so treatment intensification was even lower for Black patients than white patients.   So, to summarize, in this large and nationally representative patient population with diagnosis of metastatic castration-sensitive prostate cancer, less than one third patients received standard of care treatment intensification, even in the year 2018. More importantly, the data showed even less frequent use of treatment intensification in Black patients versus white patients. A similar study, by my colleague, Dr. Umang Swami from Huntsman Cancer Institute, in the Abstract 5072, also showed that despite level 1 evidence demonstrating improved survival with intensified regimens with ADT plus docetaxel or normal hormonal therapy, such as, as I said, abiraterone, enzalutamide, apalutamide--frequent intensification was underutilized in men with metastatic castration-sensitive prostate cancer, in more than 4,000 patients studied.   And importantly, these patients were included from the claims data from commercially insured--I want to repeat--commercial insured and Medicare Advantage populations. So, these patients you would expect to have good financial coverage for their treatment. And even then, less than one third patients were receiving this standard of care, intensified treatments backed by level one evidence from phase III trials. Less than one third patients were receiving this therapy.   Even in patients with visceral metastasis--which we know is the most aggressive form of prostate cancer--there was a similarly low level of treatment intensification. So, I think these data are very important for us to know. And there are important steps for us to take down the line. We do not know why this is happening.   Why are our patients are not being offered standard of care, life prolonging therapies for castration-sensitive disease? Is it an access problem? Is it a problem with education, awareness? We do not know. So, I think a lot of works needs to be done in this direction.   ASCO Daily News: Absolutely. These data are very, very concerning. Dr. Agarwal, thank you very much for sharing your incredible insight with us today, and highlighting these very impactful studies in the GU field.   Dr. Neeraj Agarwal: Thank you very much for having me.   ASCO Daily News: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate, review, and subscribe, wherever you get your podcasts.     Disclosures: Dr. Neeraj Agarwal  Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai,   Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences  Research Funding (Inst.): Bayer Your Institution , Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen,   AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas  Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Dr. Norah Henry, Breast Oncology Disease Lead at the University of Michigan’s Rogel Cancer Center, and chair of the 2021 ASCO Annual Meeting Scientific Program, highlights key abstracts and a host of dynamic sessions on equity and innovation in cancer research that will be featured during #ASCO21.   Transcript ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Nora Henry, who is the breast oncology disease lead at the University of Michigan's Rogel Cancer Center. She is chair of the 2021 ASCO Annual Meeting Scientific Program, and joins me to highlight key abstracts and a host of dynamic sessions that will be featured during the meeting. Dr. Henry reports no conflicts of interest relating to our discussion today and full disclosures relating to all episodes of the podcast are available at ASCO.org/podcasts. Dr. Henry, welcome to the ASCO Daily News podcast. Dr. Norah Henry: Hi, and thank you so much for inviting me. ASCO Daily News: Dr. Henry, I think everyone is curious to know what the hot topics will be at the Annual Meeting. So what are the disease sites that are showing tremendous progress this year? Dr. Norah Henry: Yeah, the last year has obviously been challenging because of the pandemic. That clearly hasn't stopped researchers around the world from continuing their exciting work and submitting their findings for presentation at the upcoming ASCO Annual Meeting. I strongly encourage everyone to attend the Plenary Session on Sunday, June 6, at which time we'll be highlighting practice-changing global research in breast cancer, nasopharyngeal cancer, cervical cancer, prostate cancer, and kidney cancer. In addition to what is being presented in the Plenary Session, please also be sure to check out the Oral Abstract Sessions, Clinical Science Symposia, Poster Discussion Sessions, and Poster Sessions for each of the tracks you're interested in, as well as the Highlights of the Day sessions. As you will see, there has been exciting progress across the spectrum of malignancies, especially with targeted therapies and immunotherapy. I have to say it's really difficult to narrow the abstracts down to just one or two key headlines. One study that comes to mind is an update of the EORTC 1325 KEYNOTE, 054 study by Dr. Eggermont and colleagues Abstract 9500. At the ASCO Annual Meeting they're reporting important findings about the use of pembrolizumab in patients with high risk stage III melanoma, who were initially treated with placebo, and who crossed over to pembrolizumab, or who were re-challenged with pembrolizumab after recurrence of disease. In hematologic malignancies, Dr. Byrd will present the results of the head-to-head comparison, a frontline acalabrutinib versus ibrutinib for CLL. That's Abstract 7500. And there's a third example, Dr. Wakeley will present Abstract 8500. The results of a phase III trial studying maintenance immunotherapy versus best supportive care in patients with stage II and III non-small cell lung cancer. These are just three examples of the tremendous progress that is being reported at this meeting from across the spectrum of oncology. In addition to these sessions I would also like to highlight the three special Clinical Science Symposia that are centered around the themes across multiple tracks. These are scheduled for live broadcast on Saturday, Sunday, and Monday with Q&A to follow. One session is about the use of artificial intelligence and machine learning in oncology, with a focus on its use in radiology and pathology (Artificial Intelligence: Optimizing Cancer Care Using Imagine and Pathology). This is a rapidly expanding area of interest and with potential implications for improving the care of patients around the world. The second session is about virally-induced cancers, including those screening and use of virus-related biomarkers for tailoring treatment (Virally Induced Cancers: Epidemiology and Biomarker-Guided Care). Finally, the third session is highlighting key studies that demonstrate how to implement research findings into clinical care with an emphasis on reducing disparities and opioid use in patients with cancer (Novel Initiatives to Address Disparities in Cancer).  Overall, the Scientific Program includes potentially practice-changing research findings from across oncology and hematology, including results of trials of novel therapies, studies examining tailoring of treatment based on biomarkers, and studies evaluating approaches to improve quality of life and reduce symptoms. We invite everyone to join us. ASCO Daily News: That sounds like a great variety of sessions and some incredible advances in cancer care. The theme of the Annual Meeting this year is equity. Can you tell us how this is incorporated into the Scientific Program? Dr. Norah Henry: Certainly. So this year's presidential theme is equity. Every patient, every day, everywhere. And this statement really underlies everything that we do and strive for. And therefore, we have tried to incorporate it throughout the Scientific Program. You'll see glimpses of it throughout the meeting, especially within the insightful presentations of the abstract discussions. And also, as I mentioned earlier, the special Clinical Science Symposia that will be broadcast on Saturday morning is focused on implementation science. And the abstracts selected for that session are related to disparities. Key work will be highlighted from a number of institutions that demonstrate how to successfully increase accrual of Black participants on clinical trials, how to reduce time to lung cancer surgery using an anti-racism intervention, and how to reduce unnecessary or inappropriate opioid use, both in the perioperative setting and also in patients with cancer more broadly. These investigators have done excellent work developing and implementing these interventions. And I encourage everyone to attend the session so they can get ideas for how to reduce disparities and improve equity at their own institutions. ASCO Daily News: Well, Dr. Henry this is our second virtual Annual Meeting. And there's no doubt that some aspects of the virtual format are here to stay as they enable more people across the globe to learn about new developments in cancer care. And it can spare others the time and cost of traveling to the meeting. When you think about the impact of the Covid-19 pandemic on how knowledge is shared within the oncology community, and the expanded use of telemedicine, for example, what are your thoughts on how the oncology community will emerge from the pandemic? Dr. Norah Henry: Thank you. And I find this to be a very difficult question, but obviously very timely. You know, I hope that this experience will have been an opportunity for us to grow as a community, and overall make changes for the better. Obviously, we were forced to make rapid changes last year as everything quickly became virtual. This year, however, we've had more time to plan and technology has advanced. And therefore, ASCO 2021 promises to be a very different experience compared to last year, with significantly more opportunities for interaction. Going forward, I think it'll be important to maintain some of these changes to the format. Having at least a portion of the meeting be virtual and interactive will allow more people from around the world, from oncologists to trainees to patients and patient advocates, to participate in the meeting in a meaningful way. Obviously, if you don't have to travel, there are upsides to that because it definitely allows more people to participate. But there are downsides as well in terms of decreased ability to have interactions as you meet (peers) in the hall, as we always do when we're in Chicago. But I think that with technological advances it'll be easier to do that going forward. Enabling more participation is truly a win for everyone. Also, from a patient care perspective, we now all have substantial experience with telehealth, whether we want it or not,  which is I think another positive that has come out of the pandemic. Using telemedicine, we are able to better follow up with our patients with less inconvenience, cost and hassle. This can certainly help improve access for patients. But we also need to ensure that better access is available across the board, and that patients who live in rural areas, for example, or who don't have a fast internet connection aren't left out from these improvements. So I think overall I'm very enthusiastic and hopeful that we can all learn from our experiences during the past year, and use this new knowledge to improve the care of our patients and the lives of both patients and providers alike. ASCO Daily News: Thank you Dr. Henry for that hopeful message, and for your efforts to put together a really robust and dynamic Scientific Program. Dr. Norah Henry: Thank you very much. And I really hope everyone thoroughly enjoys the meeting and is able to learn a lot about the new research advances that are ongoing, as well as take advantage of the excellent educational programming that will be going on simultaneously. ASCO Daily News: Absolutely. And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate and review us wherever you get your podcasts.   Disclosures: Dr. Norah Henry Research Funding (Institution): Pfizer, Abbvie   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In today’s episode, we celebrate Dr. John Sweetenham, outgoing Editor-in-Chief of ASCO Daily News after nearly a decade of service. He is also the associate director for Clinical Affairs at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. This episode brings together Dr. Sweetenham and his longtime friend, and today’s guest host, Dr. Derek Raghavan, President of the Levine Cancer Institute. They discuss the luminaries who shaped Dr. Sweetenham’s career path, practicing oncology on both sides of the Atlantic, and editorial roles in oncology publications.   Transcript ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. We have a very special episode for you today to celebrate Dr. John Sweetenham, the outgoing editor-in-chief of ASCO Daily News after nearly 10 years of service. Dr. Sweetenham is also the associate director for Clinical Affairs at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, and specializes in hematologic malignancies. We are honored to have his longtime friend and mentor, Dr. Derek Raghavan, in the host's chair today for this engaging conversation. Dr. Sweetenham and Dr. Raghavan report no conflicts of interest relating to today's discussion, and full disclosures relating to all episodes of the ASCO Daily News podcast are available at asco.org/podcasts. Dr. Derek Raghavan: I'm Derek Raghavan. I'm the president of the Levine Cancer Institute, and really delighted to be able to help to note and to mark the retirement from a specific role with the ASCO Daily News of John Sweetenham, who has guided that ASCO publication for the past decade, and has guided it so well. I guess there must have been people at ASCO who weren't thrilled with John because they made me his interviewer for this session. And I think it is fair to say that John and I have been really good pals for many, many years. I had the delight of working with him at the Cleveland Clinic. And it gives me an opportunity to kind of review the many things he's done thus far in his career. And obviously, he's got so many more contributions to make. One of the things that's been interesting, John, is the two of us are from other nations. We speak grammatically correct English, and that's allowed us to become quite good friends without correcting each other. But you started out in the United Kingdom. And perhaps you could just quickly review how you got started in oncology, and where you worked and the people that you thought influenced your career. Dr. John Sweetenham: Yeah. So first of all, thanks for doing this. It's really great to have an opportunity to talk with you, and for it to go on the record for once, as well, which will be fun. You know, I started out in the UK Medical School in London at St. Bartholomew's Hospital. And quite what motivated me to go into medicine in the first place I still reflect on quite often. And if I'm really, really honest with myself, I think it is that, when I was really quite young, there was a black-and-white American TV program that used to show in the UK--Dr. Kildare. Derek, you're probably not old enough to remember it. That was a sort of--I thought at the time, when I was, I don't know, 5 or 6 years old, that wow, that seems like that's a pretty cool job. And I didn't ever really think about doing anything else seriously. And so I sort of went through high school and so on, medical school in London. And while I was there, became interested in cancer really more at the level of just finding it sort of scientifically very intriguing, and the whole idea of this sort of loss of control. And then once I was lucky enough to get exposed to clinical experience with oncology at Barth's Hospital, which, at the time, was actually the very first academic medical oncology outside of the Royal Marsden, I believe. And so there was a very strong tradition of medical oncology at my medical school. And I think the influence of people, some of whom you know, Jim Malpas, Andrew Lister, my subsequent boss Michael Whitehouse are all people who I found quite inspirational. And so that's when I decided to go down that path. And it's probably why I ended up with an interest in lymphoma because hematologic malignancies were a very big part of what they did there. In terms of mentorship, there are a couple of people, maybe three, who I really value as being my UK mentors. Mike Whitehouse, who was my boss for a number of years. Ben Mead, who was a lymphoma and GU oncologist with a particular interest in testis cancer, who was--indeed, still is incredibly kind of intellectually honest person who taught me a lot about how to think and how to think critically, which is something that I think I hadn't really learned up to that point. Another individual, Brian Vaughan Hudson, who was a statistician, actually, who was very involved with one of the British lymphoma groups at the time. And he was very influential as well. So I would say those were my three sort of primary mentors during my medical school years and as I went through postgraduate training and developed my lymphoma interest. Dr. Derek Raghavan: So they were true luminaries. I knew Mike and Ben. I just never really understood why Ben, as a GU guy, wanted to dilute his time with lymphoma, but I'm sure you understand that much better than I do. John, one of the things that I remember from when we first met was--we were chatting because I did, as you know, my PhD in London--and we chatted about the fact that you were involved in something rather unusual and rather awful. And that was, as a young fellow, you actually were injured in a horrible railway incident at Clapham or Clapham Commons in London. And I've always thought that must have given you kind of a unique perspective of being a patient and dealing with pain and stuff. And I just wondered, how do you recall that, and do you think it had an influence on your subsequent evolution? Dr. John Sweetenham: Yeah, I think it did. So very briefly, I was involved in a rail crash that happened, as Derek said, just outside London. This was in 1988 just before Christmas of that year. And it was essentially a signaling failure, and that the train on which I was traveling, and was in the front car of that train, was traveling at about 70 miles an hour and collided with the stationary train that was on the track ahead of it. And I think the final number was 37 people were killed in that accident, including the person that I was sitting next to that I didn't know, and another person who I was kind of back to back with. In terms of how it affected me, I think there's this assumption that you emerge from that with kind of a new perspective on life and so on. If I'm really honest, I don't really think that that's what I got from it. I did learn a number of things about being a patient. And the thing that sticks in my mind most of all from that experience, I would say, would have been I remember very clearly the nursing staff who came across to me as extremely kind and competent, and those who came across to me as extremely kind, but maybe just not quite so confident and competent. And so what it really made me understand a little bit better is, particularly if you're in the hospital and you're an inpatient, you really put your trust in the nursing staff because they're the ones who are there the whole time. Physicians come and go. They make rounds and they come and go. But the nurses are there much more. And I really developed the very, very deep respect for the nursing profession from having been on the wrong end of an accident and spending some time in the hospital. So I would say that that was sort of my abiding impression. The other thing that often occurs to me-- and this is a little bit more philosophical, I suppose-- but I do remember getting on the train that morning. And I had the option of going to the front half of the car or the rear half of the car. And it was a totally random decision to go to the rear half of the car, and nobody in the front half survived. So it was just this sort of unusual reflection on sort of how sometimes what's seemingly the most trivial decision that you could possibly make can have very, very profound consequences, which is something I've kept with me as I've tried to make career decisions over the years, that what seems like not a very big decision can actually turn out to be an extremely big one in terms of the consequences. Dr. Derek Raghavan: Clearly the recognition of the extraordinary value of nursing and nurses stuck with you because I can attest, as one of your clinical partners at the Cleveland Clinic Taussig Cancer Institute, that you're one of the nursing favorites. And the reason, apart from being competent, was the fact that you treated them well and with respect, and that obviously has stuck with you. And when I visited you to the Huntsman Utah and met some of your nursing staff there, they said the same thing. So that clearly had an impact, John. Did you feel ever that you had some survivor's guilt from that episode? Did that ever impact you at all? Dr. John Sweetenham: You know, it really didn't. And in fact, if anything, I sometimes felt a little guilty that I hadn't had that, if you see what I mean, because it was interesting that we all were fortunate enough to be offered counseling after the event, and I had some. But the theme of it was, I think, trying to relieve us of any guilt that we may have felt, which I understand. But in fact, quite the opposite. I actually just felt extremely fortunate, especially in terms of the people around me and what had happened to them. I just felt very fortunate that I was alive and able to fully recover. And it's actually quite interesting because I gave evidence at the public inquiry. And coming out of the inquiry, there were a load of press around. And the reporter from The Independent, which was quite a reputable newspaper at the time in the UK, actually said to me, Dr. Sweetenham, do you do you still feel haunted by guilt and by memories of that day? And I said, actually, really, I don't, no. I just feel very fortunate. And in the newspaper the following morning it said, Dr. John Sweetenham, and then in parentheses, 32, because they always put your age, Dr. John Sweetenham said, I'm still haunted by memories of that day. So I think there's a little bit of an expectation of that sort of guilt thing. But I think I was very fortunate that my feelings were quite the opposite. I just felt, frankly, lucky to be alive and very grateful for it. Dr. Derek Raghavan: Moving away from that, you worked in the UK for a long time, and then you had the opportunity of coming to the USA. How did you find the contrast of practicing medicine in Britain and the move here? What were the most strident or amusing differences in style and the way things work? Dr. John Sweetenham: Yeah, so I'd say right up front--and I don't know whether the experience was the same for you coming from Australia--but overall, despite my expectations, I was more struck by the similarities than differences. I think people are the same the world over. I think the patients and the problems that they encounter and the challenges they have are pretty much the same the world over. I would say the big difference is probably three things. Number one, documentation and billing. I think in the UK, because it is a government-funded health system for the most part, your communication with a patient's primary physician could be a two-line letter that essentially said, I saw your patient today and he's doing fine. We'll see him in 3 months or something like that. And that was about all the documentation that was necessary. So I think it took me a long time--not a long time, but it took me a while to adapt to a high level of documentation, which I think is actually a good thing, and trying to unravel and navigate the billing process, which was foreign to me for quite some time. The other things that I would say that really struck me were number one, the fact that health care--clearly there are major disparities in health care in the U.S.--but when it's at its best, I think the health care and oncology care in the U.S. is well-resourced. And that opens up the possibility for patients, and to me as a physician, to do things that I simply couldn't do in the UK. And then the third thing, actually, is simply that the expectation of patients, what they're expecting of their physician in terms of engagement, communication, and so on is much higher in the USA than it is in the UK. Now I have not worked in the UK for 20 years now. That may have changed. I think it's a positive thing. But I think my experience would be that patients in the USA expect much more of us, and as they should. Dr. Derek Raghavan: One of the interesting things that you and I both shared is we've worked for nationalized medical system, and we've worked for the hybrid of for profit, not for profit with some nationalized elements and so on. And I always wonder, people tend to say that--because you mentioned the disparities of care--that nationalized medicine is sort of the panacea for disparities of care. Do you think that's true, or do you think that in a nationalized health system, disparities still exist, and so physicians there actually need to focus just as clearly on those issues? Dr. John Sweetenham: I think disparities exist. I mean, I think, to me, the contrast between the two systems, having experienced both, is that I think for somebody with a very serious life-threatening illness like a cancer in a nationalized health system such as the one that exists in the UK, somehow it has to be less scary because you know that if you, for example, need a bone marrow transplant, you're probably going to get your bone marrow transplant, and it isn't going to be expensive for you at the level of having to shell out money, although obviously it's expensive in many other ways, and the loss of income and so on are big factors. But I think it's also we have to be realistic that a lot of the factors that play into health care disparities are social determinants of health and factors which exist within a country that has a government-funded health system in just the same way as it does in one where it's an entirely private system. And then play into that the implicit and explicit biases that exist within our societies anyway. So I absolutely think that there are very significant disparities, or at least there were during my time in health care and oncology care within the system that I came from, for sure. Dr. Derek Raghavan: Yeah, and I agree. Dr. John Sweetenham: I'm sure you'd say the same. Dr. Derek Raghavan: Same deal in Australia. The one other thing I wondered about, you might know or not know that John and I were co-editors in chief of HemOnc Today for several years, 7, I think it was. And you might remember, John, I wrote on the topic of death is an un-American activity. And I wonder, do you think that also is a difference? From my experience moving from Australia to the USA, the Australian will certainly fight cancer very actively, but when there isn't a lot of hope left, is much more comfortable with reaching out supportive oncology and palliative medicine than is often the case in the USA. And that applies, also, to the physician's approach. Did you find a change in that side of things when you moved from the United Kingdom to the USA? Dr. John Sweetenham: You make a really good point. And I often quote you, actually, because I remember that when I was at Huntsman, you came and gave a talk in Salt Lake City. And one of the things that you mentioned in your talk--I won't get it absolutely right, but I know you said that the USA is a country where many people believe that death is optional. And that really stuck with me because I think that that is a marked difference, bearing in mind that I came from the UK, which was really where the hospice movement, in particular, really sort of started to develop. And so I do think that there is, to your point, a similarity with the Australian psyche in that regard, that there is probably more of an acceptance of the reality of death both among patients and among the profession. And so the likelihood of getting into many of these kind of end-of-life treatment issues which confronts us almost every day here, certainly I did not experience so much in the UK. Dr. Derek Raghavan: Between the two of us, we've been in an awful lot of different cancer centers. I think people would say that we share in common the inability to hold a job. But you've been in some fantastic places. You were at the University of Colorado. And you might even want to tell the story of how you found your way to the Cleveland Clinic. And so you were there for a while. Then you were at the Nevada Cancer Center, then at Huntsman, and now at UT Southwestern, all amazingly good places. What characterized the differences between the places? What did you feel you can compare and contrast in terms of the way things were done? Were they all pretty much the same, just in different places? How did how did you view the different places you worked? Dr. John Sweetenham: Yeah. It's a really interesting question. And I would say that for the most part, that the challenges and the opportunities at all of the places I've worked with have been similar. And I think that you can take conversations about whatever it might be. It might be how you organize your clinical trials. It might be how you set up advanced practice providers and have them partnering with physicians. I mean, there are so many of these issues that I know that you confront on a regular basis as well. I would say that in general, the challenges and opportunities of everywhere I've worked--with one possible exception, but it wouldn't be fair to single out anything out--would have been fundamentally the same. I think the difference has very much been in how that's approached. And this may seem a bit soft and a bit lame in some respects, but I would say that for me, what really has distinguished the cancer centers and made them different has been two things. One of them is something which I can only define as institutional culture, which I didn't used to believe in, really. But I think that having not been able to hold down a job, I've sort of experienced various different institutional cultures and realized that that can actually make a very significant difference to how things move along. And then even more so, I think the cancer center leadership, and in particular, the cancer center director, just by their engagement and their attitude, really does, in my opinion, set the tone. And so I think that as I look across all of the places that I've worked--and I've had the good fortune to work for really an extraordinary group of people--but I would say that that's where the real difference is. The issues are the same. How those issues are addressed is very much driven by the individual leadership of each of the cancer centers. And it can be quite a contrast from one to the other. Dr. Derek Raghavan: Do you think that scientists with a PhD approach cancer center leadership differently from clinical, medical, radiation, surgical oncologists with an MD plus or minus a PhD? So in other words, is their training creating differences, or is it more personality, past experience, and focus? How do you see that? Dr. John Sweetenham: I would say it's the latter. Now I've only worked for one cancer center director who was not an MD. But I would say that that individual had a very good understanding of clinical issues. So I can't really pull that out as a reason why there's a difference. I think, honestly, it's much more personality-based, and that's where I see the contrast. And I would say the person that was not an MD who led one of the cancer centers that I worked at was able to really engage in the clinical issues and was extremely well-informed and very effective, actually. Dr. Derek Raghavan: So I'm not going to go to the obvious fact that you were the happiest when you were at the Cleveland Clinic working with me until you got to your current employment status. Dr. John Sweetenham: It goes without saying. Dr. Derek Raghavan: But what I do want to touch on is, you've had two significant and pretty influential editorial roles. You're a prolific, great author yourself. You write very clearly and very well. But you've been the editor guiding the ASCO Daily News for a decade, and then you and I jointly worked on HemOnc Today together. What did you learn from that? What opportunities came to you? Did you change your perspective on any aspect of oncology or oncology reporting from either or both of those roles? Dr. John Sweetenham: First of all, I think both of them have been extraordinarily helpful and actually very useful to me over the last 10 years or so. ASCO Daily News, the story there is--and you'll remember this well--but when I first went to Colorado, Paul Bunn had just become president of ASCO. And he was very helpful to me in getting me involved in what at the time was called People Living with Cancer, which you'll remember well because we worked on that together for some years. It was the forerunner of what's now Cancer.Net. Once we got involved in people living with cancer, I had the good fortune then of having a number of other things that opened up for me at ASCO, one of which was I was asked to join ASCO Daily News as associate editor to actually provide some insight into hematologic malignancy. And then over time, I took on the editor-in-chief role there. But it was really interesting to start to go back and sort of re-engage in issues outside of hematologic malignancy that I hadn't really been involved with for a number of years. And I can remember starting to read emerging data around colon cancer and some of the new agents, and thinking to myself, wow, this is really cool. I should start to get back into this more. So I think starting with ASCO Daily News, and then within HemOnc Today, number one, I think it gave me an opportunity to sort of just broaden my perspective over what was going on in general. And the timing of that was great for me because it was just around the time that I was moving sort of out of a hardcore hematologic malignancies academic role and doing something which was a little bit more administrative in nature. And then likewise with HemOnc Today, it gave me the opportunity to start thinking about issues that really had not been uppermost in my mind when I was only a lymphoma guy, so perspectives on anything from cancer care disparities to financial toxicity to drug costs to statistical analysis of clinical trials to some more kind of historical things. So I think that both roles really have enabled me to broaden my perspective on things a little bit, probably to de-skill, I would say definitely to de-skill in some areas as this has gone on. But as I've taken on this somewhat more kind of administrative role, it's been really helpful, added to which, of course, there's been the added pleasure of being able to interact with you on an almost weekly basis with HemOnc Today for a number of years now. And I and I have to tell you that it's been a few months since we stopped HemOnc Today, and I'm bereft. I'm actually having major withdrawal, which is, I think, one of the reasons why talking to you today is such a big deal. Dr. Derek Raghavan: Well, the good news is we're both tied into ASCO publications, the ASCO Post. And so I'm sure there'll still be opportunities. Hopefully next year ASCO will actually meet in person, and we'll have that opportunity. Dr. John Sweetenham: Yeah, what I'd really like to do, actually, one of the things I still aspire to, is that I know when you do things in ASCO Post, they do one of those little drawn pictures of you instead of a photograph. I've seen yours appear on there several times, and I still aspire to that. It's one of my remaining ambitions. I want one of those pictures. Dr. Derek Raghavan: It's really unseemly to beg to ASCO on your own podcast, but I'm sure that Cara Glynn will hear this. My advice would be don't waste your time. But she's a kind little soul, and she'll probably get you the picture that you're looking for. I would actually say to Cara Glynn, if you do get that, get the artist who can make a picture that ages annually because that'll put him in his place. So John, just again, thinking in terms of working with ASCO Post and the other various journals that are out there, COVID has been a cataclysm in medicine. And you and I have jointly been able to be quite editorial and philosophical. I, at least, had a couple of political targets that I used to joust at, which I wasn't able to do through the ASCO Post because it's a not for profit organization. But what do you think was the impact of 2020 on medicine and nursing and the people who prosecute medicine and nursing? It was a cataclysm. How did you experience it? What do you think comes out of it at the other end? Dr. John Sweetenham: I guess part of the answer to that is, in terms of what it's actually done for us, I don't know yet. I mean, I think that there are some very kind of practical and obvious consequences of this which we're all becoming familiar with now. The telemedicine thing that we've all become familiar with, remote working, with remote patient care, up to a point. And I think that there are elements of that which are probably going to stay with us. I have to confess personally that I'm still a little on the fence about that. I think that there are clearly areas where telemedicine is going to help us overcome disparities in terms of rural populations and so on. And it's going to be incredibly important from that perspective. You know, I still wonder about the nature of telemedicine interactions. And it may be a generational thing, I don't know. But there are aspects of it that still trouble me. And from a cancer center perspective, there's a part of me that thinks that because what we do is so high touch, I'm not sure that I want to be necessarily in a situation where we are renowned for being the virtual cancer center, if you know what I mean. I just have worries about that. And the way I often think about it is the quality of the interactions over telemedicine is a little bit like a contrast between listening to music on vinyl and listening to digital music in that when you have digital music, something isn't quite the same, and there's something missing, but you can't quite put your finger on what it is in that communication and the way it comes over. And I do still think that to some extent, telemedicine kind of has that aspect. Those are important challenges, having said that, breaking down some of these barriers to practice across state lines and so on. I think the most profound thing, though, to me from this whole experience has been the politicization of medicine and of science, and the erosion of the credibility of science in the eyes of the public, and the erosion of common sense medicine. And I think when you look at what will be the lasting effects, the really lasting effects, I don't think so much it's going to be the practical aspects of how we deliver cancer care. I don't think it's going to be the trust of the public in what we do and what we say. Dr. Derek Raghavan: I agree with all that, I, like you, share some concerns about telemedicine, although it's clear that patients like telemedicine. I think the other thing that happened in 2020 is it refocused doctors and nurses on what their primary responsibility is. I will never forget the image of those five ICU nurses standing with their arms folded against a mob of screaming idiots. And that made, I think, all of us realize what an important profession we're in. So John, we're running out of time. And I was going to ask you about lymphoma because you've been a real contributor there, but you've published most of your thoughts on that. So in the last two moments, looking to the future, what do you see coming down the road for John Sweetenham? What's going to be happening at UT Southwestern Oncology? Closing thoughts? Dr. John Sweetenham: Yeah, thanks. So two things, I guess, at a professional and personal level. From the perspective of UT Southwestern, I'm loving my role here. Despite what my gray hair might suggest, I'm not even close to wanting to move away from this right now. We're in a phase of growth, and I think that it's really exciting. Really aspire to getting us to a situation very much like one that you've built at Levine, where we can really give access geographically as well as in every other sense to our patients wherever they are within our region, and help to eliminate disparities. And as I said, I kind of think that what you've done in Levine is a real model of how that can and should be done. So that's one big part for me. I think also continuing to focus on patient-centered care, and how we can really organize care around what works best for our patients rather than what works best for us. And then, I think increasingly I feel drawn towards issues like disparities, and whether working through other organizations like NCCN is a way to sort of help us to address some of those issues as well. And I enjoy my role there, and that's something which I really hope I can continue for some time to come. On a personal level, I think I'm going to be continuing to work and enjoy my family. You asked me right at the beginning about what had drawn me to medicine, and I said that it was really the only thing I ever considered. It's not entirely true because the other thing that I really did consider when I was much younger is that I was really very interested in a career in music in some form. The only thing that really helped me back in that regard was a complete absence of any talent. But I still figure that there's a chance. So I very tentatively started to try to learn to play the piano, which Caroline, my wife, encourages me to do, although I notice that she usually puts her ear buds in when I start to play it. But that's one other thing that I would really like to do. No intention of slowing down at the moment, having said that. So my piano practice is sporadic, as anyone who listens to me play will understand. So, I think for now, it's going to be more of the same. And I'm really enjoying it and hope to continue to do so for a long time. Dr. Derek Raghavan: Well, John, we've been friends for decades. It's been a pleasure to interview you. I guess my takeaway for it is the fact that you draw a distinction between the lack of talent that you could bring to music compared to what you brought to medicine. And I'm happy you see that distinction. I think people out in reader land have benefited from wisdom and good choices that you've shared with your editorial team, and you've really prosecuted a wonderfully useful broadsheet. And it's been a pleasure to partner with you on a number of activities and I look forward to reading how you evolve UT Southwestern Cancer Center with Carlos and the other leadership team there, and look forward to collaborating on other things. And thank the audience for listening to us both. Dr. John Sweetenham: Yeah. Thanks, it's been great. I really have enjoyed speaking with you as well. And looking forward to the next chapter. This chapter with ASCO Daily News finishes for me officially on June 8 of 2021. And it would be remiss of me not to acknowledge the extraordinary work that the editorial staff do, who really do all the heavy lifting. And my job there has been really very easy because of all they do. And in particular, I express my thanks to Faith Hayden for everything that she's done to help and support me during the time that I've been doing this. And thanks again to ASCO for giving me the opportunity to take on this role. I have thoroughly enjoyed it. That was Dr. John Sweetenham of UT Southwestern speaking with Dr. Derek Raghavan, President of the Levine Cancer Institute. Dr. Sweetenham, we thank you and we'll miss you at ASCO Daily News. We wish you all the best.     Disclosures: Dr. Derek Raghavan: Consulting or Advisory Role: Gerson Lehrman Group, Caris Life Sciences Dr. John Sweetenham: None disclosed Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. John Sweetenham, associate director for Clinical Affairs at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center and Editor-in-Chief of ASCO Daily News, discusses key abstracts on hematologic malignancies featured at the 2021 ASCO Annual Meeting.   Transcript ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll. My guest today is Dr. John Sweetenham, the associate director for clinical affairs at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center. Dr. Sweetenham is also the editor-in-chief of the ASCO Daily News, and joins me to discuss key abstracts on hematologic malignancies featured at the 2021 ASCO annual meeting. Dr. Sweetenham reports no conflicts of interest relating to our discussion today, and full disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/podcasts. Dr. Sweetenham, it's lovely to have you back on the podcast. Dr. John Sweetenham: Thanks, Geraldine. It's a pleasure to be able to speak with you again. ASCO Daily News: Dr. Sweetenham, there are some really promising developments in therapies for adult patients with acute lymphoblastic leukemia. Can you tell us about these studies? Dr. John Sweetenham: Yes. There are two abstracts in particular at this year's meeting, which I think are of particular interest for adult patients with acute lymphoblastic leukemia. This is typically a difficult disease to treat in adults. And two abstracts in particular caught my eye. The first of these is Abstract 7001. And this describes a phase II study of a combination of a tyrosine kinase inhibitor, ponatinib, and a bispecific T cell engaging antibody, blinatumomab, which is directed against CD19 for patients with a particularly refractory type of ALL, and that's patients with Philadelphia chromosome positive ALL. This is a single arm phase II study for patients with both newly-diagnosed and relapsed or refractory Philadelphia-positive ALL. And in the protocol as described, the patients received up to five cycles of blinatumomab as a continuous infusion of the standard approved dose. And combined with this was ponatinib initially at a dose of 30 milligrams daily during cycle 1, and then subsequently reduced to half that dose until a complete molecular remission was achieved. Thereafter, the patient was continued on ponatinib for at least 5 years. And the treatment was also supplemented by intrathecal prophylaxis. Only 28 patients are on this small study. But nevertheless, I think the results are very intriguing. 95% of the patients responded to this treatment. And in the previously untreated patients, the response rate was 100%, compared with 88% in the relapsed and refractory group. And among the responding patients, 86% achieved a complete molecular remission. Remarkably, none of the patients in the newly diagnosed cohort required stem cell transplantation. And overall, with a median follow-up now of 14 months--so still relatively early, admittedly--the estimated 1 year overall survival rate is 94%, with an event-free survival rate of 81% for the entire study population. In the previously untreated cohort, no patients have relapsed or died. The 1-year overall and event-free survival rate in this particular subgroup is 100%. So what, to me, is really intriguing and exciting about this is a chemotherapy-free regimen for the upfront treatment of a particularly difficult-to-treat subtype of adult ALL. So these are truly encouraging and really quite remarkable results. Of course, they need to be qualified because it's very early days, small numbers, relatively limited follow-up, but intriguing nevertheless. The second study, which I think is really confirmatory of some earlier results, is described in Abstract 7002. And this describes the phase II results of the so-called ZUMA-3 study evaluating a CAR T-cell products directed against CD19 in adult patients with relapsed and refractory B-cell acute lymphoblastic leukemia. The phase I efficacy results were previously reported a couple of years ago at ASH. And this study represents the follow-up phase II study. Eligible patients for this study all had relapsed and refractory B-cell ALL treated with CAR T-cells that the dose that was described from the original phase I study, with a primary endpoint of complete remission rates. And key secondary endpoints in the study included duration of remission, relapse-free survival, overall survival, and the presence or absence of measurable residual disease by flow cytometry. As of September 2020 when this study was originally reported, 55 of the 71 enrolled patients that received their CAR T cell products and the complete response rate combining CR and CRI rate was 71%. And 31% of the responders had ongoing responses. Looking at the median duration of response, relapse-free survival, and overall survival, these were respectively 12.8, 11.6, and 18.2 months. But for those patients who responded, the relapse-free and overall survival were respectively 14.3 months and not yet reached. So, again, relatively early results, but nevertheless very interesting, showing after a median follow-up of 16.4 months, there was clear and quite compelling clinical benefits in heavily pretreated adults with relapsed and refractory B-cell ALL, with a median overall survival not yet being reached. So, given, again, that this is a particularly difficult group of patients to treat, it's another example of a very promising result from CAR T cell therapy in a difficult clinical situation. ASCO Daily News: Absolutely, some very interesting advances there in ALL. Well, patients who have received a stem cell transplant have felt especially vulnerable during the COVID-19 pandemic. A couple of abstracts assess the outcomes of allogeneic stem cell transplant recipients amid the pandemic. What are your thoughts on these studies? Dr. John Sweetenham: Yes, thanks. So, two abstracts of particular interest, Abstract 7033 is a study which addresses the outcomes for all patients undergoing hematopoietic stem cell transplants and cellular therapy, both autologous and allogeneic, as well as a few patients with CAR T cell therapy during the COVID-19 pandemic, really just looking overall at outcomes compared with essentially, historical controls. It was a single center prospective study, which included in all, approximately 40 patients undergoing either hematopoietic stem cell therapy or other cellular therapies who were diagnosed with COVID-19 between April of 2020 and January of 2021. As I mentioned, 40 patients were included, 25 of whom underwent allogeneic transplants, 13 autologous transplants, and 2 underwent CAR T cell therapy. And these were done for a variety of hematologic malignancies. And in the allogeneic patients, a variety of STEM cell sources were chosen. And the patients had a number of treatments for their COVID-19, directed specifically at the COVID-19, which included remdesivir, convalescent plasma, dexamethasone, and some monoclonal antibodies. The bottom line from the study, and perhaps this is really not too surprising, is that the patients undergoing hematopoietic stem cell transplantation with COVID-19 had an increased risk of mortality. And that particularly related to undergoing allogeneic versus other types of cellular therapy and the presence of concurrent immune suppression. So this study demonstrated something which I think is intuitive, but for which there hasn't been a lot of literature yet, essentially saying that patients who undergo transplant in the presence of active COVID-19 have relatively poor outcomes compared with those who are non-COVID-19 positive. The other abstract which drew my attention was Abstract 7032, a very different abstract in many ways, in that it looked at the association of COVID-19 with distress and the quality of life for patients undergoing hematopoietic stem cell transplantation. And this was a cross-sectional analysis of data from 205 patients with hematologic malignancies undergoing stem cell transplantation and enrolled in a multi-site randomized supportive care trial that they compared baseline pre-transplant distress which included depression, anxiety, and post-traumatic stress disorder symptoms, and quality of life between participants enrolled pre-COVID-19 and during the COVID-19 pandemic. Prior to the COVID-19 pandemic, 124 participants enrolled, and then 81 enrolled during the COVID-19 pandemic. Interestingly enough, in multivariate regression models, enrollment during COVID-19 was not associated with pre-transplant depression, anxiety, PTSD symptoms, or quality of life. So the conclusion is interesting in that this study reports that contrary to the generally held notion that the COVID-19 pandemic has worsened distress in patients with cancer, there was no difference in distress or quality of life in these patients with hematologic malignancies prior to or during the COVID-19 pandemic. ASCO Daily News: Yes, that's an interesting conclusion as you say, and a little unexpected. Well, let's focus on chronic lymphocytic leukemia. Are there any new therapies on the horizon for patients with CLL? Dr. John Sweetenham: So, two abstracts this year's ASCO [Annual Meeting] describe what I think is significant advances with newer therapies, which I think are now really finding their place in the therapeutic algorithm for CLL. Abstract 7500 reports the results of a large randomized comparison on a head-to-head basis between ibrutinib, the first in class Bruton tyrosine kinase inhibitor, and a more selective tyrosine kinase inhibitor, acalabrutinib. This was a randomized, head-to-head non-inferiority study which compared acalabrutinib with ibrutinib in patients with previously treated CLL of all risk groups. And overall, 533 patients were randomly assigned between these two therapies. And at the median follow-up of around 41 months. Now, acalabrutinib was found to be non-inferior to ibrutinib, with a median progression-free survival of 38.4 months in both arms of the study. But importantly, acalabrutinib was found to be superior to ibrutinib in terms of toxicities, which included the incidence of atrial fibrillation. Among the other secondary endpoints of the study were incidences of grade 3 infection, which were comparable between the two arms, as was the rates of Richter's transformation. Not surprisingly, because the routine tyrosine kinase inhibitors are such effective drugs in CLL, the median overall survival was not reached in either arm of the study. Acalabrutinib demonstrated a lower incidence of hypertension, arthralgia, and diarrhea compared with ibrutinib, but a somewhat higher incidence of headache, 34% versus 20%, and cough at 28% versus 21%. And of note, adverse events led to treatment discontinuation in just over 14% of patients on acalabrutinib versus 21% of those treated with ibrutinib. So in summary, acalabrutinib demonstrated a non-inferior progression-free survival with less cardiotoxicity and fewer discontinuations due to adverse events when compared with ibrutinib. So I think that this does pave the way for some of the later generation tyrosine kinase inhibitors, which certainly appear to maintain the efficacy of ibrutinib, but appear to have somewhat lower toxicity. This study was conducted in the relapse refractory setting. And clearly, the next question is going to be whether in the frontline setting, we would expect to see similar findings with acalabrutinib. The other study of note, I think, from the CLL abstracts this time is Abstract 7501. And this is a summary of the so-called CAPTIVATE study. This is a multi-center phase II study of first line ibrutinib combined with venetoclax, a BCO2 inhibitor, for patients with CLL. The study is important because it uses a fixed duration regimen. And to give that some context, many of the newer treatments, oral treatments for CLL with ibrutinib being the initial drug of this type, have been given continuously into either disease progression or until the patient becomes intolerant of the treatment because of side effects. And so there has been an ongoing series of investigations looking at whether it's possible to give these treatments in a fixed duration way rather than indefinitely because of the risks of long-term toxicity and so on. So in this study, patients less than age 70 with previously untreated CLL received three cycles of ibrutinib, and then 12 cycles of the combination of ibrutinib plus venetoclax, and then study was completed at the end of those 12 cycles. The primary endpoint of this study was the complete response rates with secondary endpoints of overall response rate, duration of response, minimal residual disease rate, and then progression-free and overall survival. To date, 159 patients have been enrolled on this study, with a median time on study of around 27.9 months. With a fixed duration combination, the complete response rate was reported at 55%, and the overall population was consistent across all of the high-risk groups, including those with adverse cytogenetic findings. Of the 88 patients who achieved a complete response, 78, representing 89%, had a duration of greater than 1 year. And the overall response rate for the entire group was 96%. And as I mentioned, there was no difference in those patients who had a 19p deletion, so another example of a novel first line regimen given at fixed duration which is chemotherapy-free and is providing really quite remarkable and intriguing results in the upfront setting for patients with CLL. ASCO Daily News: Great. Thanks for highlighting those two interesting studies on CLL. So focusing on Hodgkin lymphoma, can you tell us about advances using PET-directed therapy? And how do you see this evolving in the future? Dr. John Sweetenham: Yeah, absolutely. So, Abstract 7507 describes what I think is a very important study further investigating the use of functional imaging in therapy of that adaptation in patients with Hodgkin lymphoma. So typically, in the early-stage setting for patients with non-bulky early-stage Hodgkin lymphoma, there is now a wealth of evidence that interim PET scanning after a couple of cycles of ABVD chemotherapy, or other induction therapy, is a strong predictor of eventual outcome and can enable you to tailor the use of radiotherapy and potentially omit radiation therapy in patients who are PET negative early in the course of their chemotherapy. In patients with bulk early-stage Hodgkin lymphoma, that's been a little more controversial as to whether PET scanning on an interim basis early in the course of treatment is really reliable. So this is really quite an important Alliance study, CALGB 50801, which has tested the PET adapted approach in patients with bulk Hodgkin lymphoma. So eligible patients had stage IA through IIB classical Hodgkin lymphoma with disease bulk, which was defined as greater than 10 centimeters or more than 1/3 of the maximum intrathoracic diameter on a conventional chest X-ray. And the patients received two cycles of ABVD chemotherapy followed by a centrally viewed PET scan. If the PET scan was negative, defined as Deauville 1 through 3, patients who were PET negative received four additional cycles of chemotherapy but no radiation therapy. If the PET after two cycles was positive, the patients received intensified chemotherapy with escalated BEACOPP plus 30 Gray of involved site radiation therapy, with a primary endpoint in this study of progression-free survival. 101 patients have been enrolled on the study, of whom 94% were evaluable. 78% of these patients were PET negative after two cycles of ABVD. And in this group, the progression-free survival is 93.1. Of the remaining patients who were PET positive after two cycles of ABVD and went on to receive more intensified chemotherapy plus radiation therapy, the progression-free survival was also impressive at 89.7%. The overall survival in the study is also excellent. But the take-home message here is that excellent progression-free survival outcomes can be observed in patients with early-stage bulk Hodgkin lymphoma if they are PET negative after two cycles of ABVD, go on to complete six full cycles, but did not receive radiation therapy. And this is really a further important advance and omits the long-term risks of radiation therapy for a very significant proportion of these patients with bulk disease. Similarly, for those who are PET positive after two cycles and their treatment has escalated to more intensive chemotherapy retaining radiation, their long-term progression-free and overall survival is excellent. So, I think this is one more piece of evidence for the usefulness of functional imaging as a biomarker for response in patients with Hodgkin lymphoma which can lead to de-escalation of therapy in those patients with a good prognosis, and escalation of therapy for those who are likely to need more intensive therapy to achieve an equivalent outcome. ASCO Daily News: Excellent. Well, that's great news. Well, my last question is about mantle cell lymphoma. There's an interesting study that has real-world data for outcomes in MCL in community-based practices across the United States. What can you tell us about this study, Abstract 7504? Dr. John Sweetenham: Yes, thanks. So, as you mentioned, this is a study which is retrospective in nature and included patients with adult mantle cell lymphoma [who were] treated over a 10-year period from 2011 through the end of 2020. Just over 3,400 patients were included in this analysis, of whom 85% had been treated in a community oncology setting, and 85% were patients undergoing front line therapy. From a demographic point of view, the disease characteristics were very consistent with published data. Chemoimmunotherapy was the most common first line treatment, usually with either bendamustine and rituximab or R-CHOP. And the cytarabine-based regimens comprised a minority with only 14% of patients receiving these. 667 patients received rituximab maintenance in this study, and 243 received a frontline stem cell transplant in first remission, most of these transplants being autologous. The median follow-up for survival on this study was 45.3 months. The 36-month overall survival for the entire group was 67%. This large real-world cohort of patients primarily treated in community-based practices demonstrates outcomes which are somewhat inferior to those which we've seen reported from prospective trials. This suggests the need to focus on developing treatments that can be delivered effectively in the community setting. And perhaps the best example of this is that the use of stem cell transplantation in a community setting was uncommon even in those patients who are less than age 65. And what this gives us a clue to is the fact that maybe real-world considerations, including access to trials, access to treatments as a whole, suggests that these considerations may influence the eligibility for stem cell transplantation and some of the other more intensive approaches to treatment. ASCO Daily News: Absolutely. Well, thank you so much, Dr. Sweetenham, for highlighting these interesting advances in therapy for hematologic malignancies. It's always a great pleasure to speak with you. Dr. John Sweetenham: Thanks, a pleasure to speak with you too, Geraldine. And thanks for giving me the opportunity to talk about some of these exciting data. ASCO Daily News: Of course. And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate and review us wherever you get your podcasts.   Disclosures: Dr. John Sweetenham: None disclosed Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In this episode, Dr. Taofeek Owonikoko, lung cancer specialist at the Winship Cancer Institute at Emory University and chair of the 2021 ASCO Annual Meeting Education Program, discusses the diverse ways that cancer care equity will be featured during #ASCO21.   Transcript ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Taofeek Owonikoko, a lung cancer specialist at the Winship Cancer Institute at Emory University. Dr. Owonikoko serves as the chair of the education program of the 2021 ASCO Annual Meeting. And he's here to tell us about the diverse sessions that will be featured this year. Dr. Owonikoko reports no conflicts of interest relating to our discussion today. His full disclosures and those relating to old episodes of the podcast are available at asco.org/podcast. Dr. Owonikoko, it's great to have you on the podcast today. Dr. Taofeek Owonikoko: Thank you. Glad to be here. ASCO Daily News: Health equity is the major theme of this year's Annual Meeting. And as you know, ASCO's President, Dr. Lori Pierce, has been focusing on patient care equity during her term. Can you tell us about how the concept of cancer care equity has been incorporated into the education program this year? Dr. Taofeek Owonikoko: Thank you very much. I actually want to use this opportunity for us to thank all the ASCO volunteers, who spent countless hours putting together a very educational program for the Annual Meeting. It's very difficult for me to come out and say [that] this is the best session to go to. I think all of the sessions are very important and educational. The challenges that we've faced with COVID-19 that is making this a virtual meeting, actually, I think is an opportunity for people to be able to participate in all these sessions. Having said that, there are some sessions that we intentionally placed within the Education Program based on how important we felt these topics were to our patients, to their caregivers, family members, and also to ASCO members. We want sessions that focus on various aspects of health equity from individual patient interaction with their providers, to patient experience within the larger context of how health care systems are built, and how we deliver care. Some of the sessions that I really encourage members to listen to and participate in will be--there is a session that is going to bring diverse viewpoints from across the world, not just in the U.S. We want to see how oncologists practice in a limited resource setting, how they go about taking care of patients, and how they are able to use the challenges that they face as a stepping stone to bring the best care forward for that patient. So we have this session where we're going to have a speaker from Uganda in Africa. We have another speaker from Pakistan representing the Asian viewpoint. We are going to have a speaker who will speak to delivering care to the inner city population here in the U.S. And that session will also have a speaker that will discuss how we take care of our patients within the Native American community here in the U.S. So you're going to see these diverse viewpoints that we feel will shed light on the important point that Dr. Pierce has been trying to make with the presidential theme, that we need to focus on every patient, everywhere in terms of equitable care delivery. ASCO Daily News: Intersectionality in cancer care is a topic that has been getting more attention over the past year. How will this issue be addressed during the Education Program? Dr. Taofeek Owonikoko: We've talked about determinants of health outcomes for patients. How we look at all of these issues in isolation, whether it's gender, sexual orientation, race or ethnic background, rural versus urban, big city versus small towns, and different regions of the world. There's actually now this emerging consensus that a lot of these factors actually do not stand alone. There is an intersection of where someone lives and what type of access they have to health care--where someone lives and what type of care providers, someone's gender, and their socioeconomic status influencing the outcomes of care that they get. So this session on intersectionality, I think will really bring this to the forefront of our discussion about how to address health inequities--that we don't want to focus on one issue at a time. All these issues are important and they are interrelated. I think this type of session will help all of us to understand that there's a lot going on that determines the outcome for patients, especially for patients with cancer. One additional session I want to highlight, which is also very important to the presidential theme is the session on viruses and cancer. While there is this pandemic with the COVID-19 virus that we are very aware of, what we also did not want to lose sight of is the fact that viruses are etiology for cancer. This has been a topic that we've been struggling with for decades. And now that everyone is paying attention to the COVID-19 virus and development of a vaccine to prevent the infection or make the severity less for those who eventually get infected, I think we also need to bring that focus back to what viruses have done as etiology for different types of cancer--from either neck cancer to cervical cancer to liver cancer. And bringing this session together which speaks to how viral infection could be a key driver of the geographical differences in incidence of cancer around the world, I think will be very important for ASCO members and the general audience attending the meeting. ASCO Daily News: Absolutely, well you spoke about the pandemic and of course today health care inequality is more relevant than ever. As you say, the pandemic has disproportionately affected people of color, so clearly changes must occur if the oncology field if it is to make strides in improving outcomes for patients of color, increasing representation in clinical trials, for example, improving access to precision medicine and more. So what do you hope that people will take away from this meeting, that will stay with them in the months and years ahead? Dr. Taofeek Owonikoko: Yeah, I'm very hopeful that at the end of the Annual Meeting, with all the offerings we have in terms of educational sessions and topical issues that we want to address and some of them very provocative, we will learn that we have to be honest and open. Some of these issues are not easy to discuss, but we have to confront them if we are going to get past that, and not just brush them aside but actually have genuine discussion and be open about what the challenges are. I think that, when we look at the impact of cancer care delivery and the disparate outcomes that we see across different minority communities, including people of color, this doesn't just start from where you're delivering care, it also has to do with how we actually develop treatments that are given to patients. And nothing brings that to the surface [more] than what we've observed in terms of participation of people of color in cancer clinical trials. I know that this is a vaccine issue it's not something that I just started today, but we have to then become more systematic as to how we address it. If we are going to develop drugs that are going to be applicable to all populations, we have to be intentional in making sure that we have equitable and fair representation of all people, and that the treatment would be applicable too, so that we can start learning right from the beginning of the earliest stages of drug development. Whether there are unique differences in the way these drugs work, whether there are cultural influences that would determine whether or not the way we want to administer the drug is going to have any impact. And I want to use this to highlight one session that we have put together that's going to talk about minority patient enrollment in clinical trials. This session is not about the problem. We all recognize what the problem is. This is actually a session that is meant to show potential solutions, where we invited experienced investigators in this area to talk about gaps in how we conduct clinical trials, and what can be done to improve that process. They will talk about communications and blind-spots that we as oncologists and investigators may not even be aware of when we talk about clinical trials and we want someone to participate--what are the things that we can do to make sure that we convey the information about this study in a culturally appropriate manner, so that our own attitude of presenting the trial does not alienate and discourage participation from people of color and other minority groups? And then, there will be a talk about a real world experience of a large trial where key factors led to success in recruiting people of color on a large randomized phase III trial of prostate cancer that will be shown and shared with the audience. And people can take this back home to their individual practices and countries to see whether or not some of these strategies will also be applicable to them to help get around this problem of poor enrollment of minority patients in cancer clinical trials. ASCO Daily News: Thank you, Dr. Owonikoko, for highlighting some of these important issues on minority enrollment in cancer clinical trials, intersectionality, and cancer care, the management of DNA virus associated cancers, and the always popular ASCO voices session, which this year will use the power of the narrative to advocate for equity in cancer care. Dr. Owonikoko, thank you again for taking the time to speak with me today. Dr. Taofeek Owonikoko: Thank you. ASCO Daily News: And thank you to our listeners for joining us as well. If you're enjoying the content on the podcast, please take a moment to rate, and review us wherever you get your podcasts.   Disclosures: Dr. Taofeek Owonikoko Stock and Other Ownership Interests: Cambium Oncology Consulting or Advisory Role: Novartis, Celgene, Abbvie, Eisai, G1 Therapeutics, Takeda, Bristol-Myers Squibb, MedImmune, BerGenBio, Lilly, Amgen, AstraZeneca, PharmaMar, Boehringer Ingelheim, EMD Serono, Xcovery, Bayer, Merck, Jazz Pharmaceuticals, Zentalis, Wells Fargo, Ipsen, Eisai, Roche/Genentech, Janssen Speakers' Bureau: Abbvie Research Funding (Institution): Novartis, Astellas Pharma, Bayer, Regeneron, AstraZeneca/MedImmune, Abbvie, G1 Therapeutics, Bristol-Myers Squibb, Corvus Pharmaceuticals, United Therapeutics, Amgen, Loxo/Lilly, Fujifilm, Pfizer, Aeglea Biotherapeutics, Incyte, Merck, Oncorus, Ipsen, GlaxoSmithKline, Calithera Biosciences, Eisai, WindMIL, Turning Point Therapeutics, Roche/Genentech, Mersana, Meryx, Boehringer Ingelheim Patents, Royalties, Other Intellectual Property (Institution): OVERCOMING ACQUIRED RESISTANCE TO CHEMOTHERAPY TREATMENTS THROUGH SUPPRESSION OF STAT3, SELECTIVE CHEMOTHERAPY TREATMENTS AND DIAGNOSTIC METHODS RELATED THERETO, DR4 Modulation and its Implications in EGFR-Target Cancer Therapy Ref:18089 PROV (CSP) United States Patent Application No. 62/670,210 June 26, 2018 (Co-Inventor), Soluble FAS ligand as a biomarker of recurrence in thyroid cancer; provisional patent 61/727,519 (Inventor) Other Relationship: Roche/Genentech, EMD Serono Uncompensated Relationships: Reflexion Medical Disclaimer: The purpose of this podcast, is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

The Cancer.Net podcast is featuring an episode with Dr. Lidia Schapira of the Stanford Comprehensive Cancer Institute and Dr. Daniel Mulrooney of St. Jude Children's Research Hospital about a new study published in the Journal of Clinical Oncology on mental health outcomes for adolescents and young adult cancer survivors.  They also discuss resources to help young survivors get the mental health support they need after cancer.  Go to cancer.net/podcasts or you can download the episode wherever you get your podcasts.

Dr. David Fajgenbaum, physician-scientist and director of the Center for Cytokine Storm Treatment and Laboratory at the University of Pennsylvania, returns to the podcast to discuss the CORONA Project, a database of drugs being used to treat patients with COVID-19, and how these data are helping in the fight against the disease. Dr. Fajgenbaum is also the national bestselling author of Chasing My Cure, a memoir about his experience with Castleman disease, a rare condition that nearly killed him five times before he discovered a treatment that saved his life.   Transcript ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. David Fajgenbaum, a physician and scientist who leads the Center for Cytokine Storm Treatment and Laboratory at the University of Pennsylvania. He joins me to discuss the CORONA Project, a database of off-label and new agents that are being used to treat patients with COVID-19, and how these data are helping in the fight against the disease. Dr. Fajgenbaum is also the national bestselling author of Chasing My Cure, a memoir about his experience with Castleman Disease, a rare condition that nearly claimed his life five times before he discovered a treatment that saved his life. Dr. Fajgenbaum reports no conflicts of interest relating to our topic today. His full disclosures and those relating to all episodes of the podcast are available on our transcripts at asco.org/podcasts. Dr. Fajgenbaum, it's great to have you back on the podcast. Dr. David Fajgenbaum: Thanks so much for having me back. ASCO Daily News: So tell us about the CORONA Project and how it has helped in the fight against COVID-19. Dr. David Fajgenbaum: Sure. So through the CORONA Project, our goal is to bring together all data available to identify the most promising treatments for COVID-19. Many of us have heard about the dozens, in fact, even hundreds of drugs that have been tried thus far to treat COVID. But, unfortunately, there was no central resource or repository for all that information, all that data to go, and so we've created that, and it's helping us to identify more and more promising treatments for this terrible pandemic. ASCO Daily News: Can you tell us about specific advances? What drugs have specifically been identified as effective? Dr. David Fajgenbaum: Sure. So we now know that over 400 different drugs have been tried to treat COVID patients worldwide, which is really just an astronomical number. And we also know that out of those over 400 drugs that have been tried, just a few of them have been definitively shown to be effective. So one of those is dexamethasone, an old and inexpensive immunosuppressant, that is most effective in the most severe cases of COVID. And we also know that a drug called baricitinib, which also is an immunosuppressant, works in a specific window of patients with the most severe forms of COVID. Also, a drug called tocilizumab also seems to be effective in this really severe late stage. Unfortunately, there are fewer drugs as you move earlier into the disease course that have shown to be beneficial. A drug called fluvoxamine, which is actually approved for obsessive compulsive disorder and is an antidepressant, showed a really promising result in an outpatient trial and now is being studied in larger numbers. So where we are now is that there are almost a handful that we know are effective if given at the right time of COVID. But we also know that there are at least a handful, maybe closer to 10, that look really promising, but they now need to be moved forward into a large scale randomized controlled trial. ASCO Daily News: So the project has been useful in ruling out drugs that aren't effective, which is important as well. Dr. David Fajgenbaum: That's right. And actually, there are a few that have made a lot of headlines. The drug hydroxychloroquine, in our data set we have found that it is the most prescribed drug according to our data set. We have over 270,000 patients worth of data in our data set, and over 80,000, almost one in three of those patients has received hydroxychloroquine. Despite its widespread use, there have now been 18 randomized controlled trials that have assessed whether hydroxychloroquine is effective at various stages of COVID. And actually, out of those 18 trials, only one of them has shown an effect or a benefit, highlighting why it's so important to do these trials, and why it's so important to centralize the data in one place, so that we're not just kind of looking at things in a piecemeal fashion. It's about getting it all together in one place, so we can systematically even compare one drug to another. ASCO Daily News: Absolutely. Well, is there any lesson or application from the CORONA Project in tracking and mobilizing against variants of the disease that threaten the effectiveness of some vaccines? Dr. David Fajgenbaum: It's a really important question. We don't have any data on which drugs are more or less promising against certain variants. We both don't have data that would suggest that drugs that work against one variant will or will not work. But we also just don't have the data on when drugs are used for a particular patient with COVID, we basically never have data on which variant that patient had. So this is a problem of missing data. The data doesn't exist. So our project is about bringing together all the data that do exist. That the challenge where the data just don't exist. Unfortunately, most of us, when we get tested for COVID, we don't know what variant we had and almost never is that variant ever connected to the treatments that we got and whether they worked or didn't. I do suspect that as time goes on, I suspect more and more randomized controlled trials, and we'll at least do some testing for specific variants, so we can get a sense for whether some drugs work better against one than the other. But I would say that though there is some fairly solid data to support this idea that certain variants are more or less responsive to certain vaccines, there is not equivalent data to suggest that these variants would maybe make some drugs more or less effective. But of course, we're in pretty much a data-free zone. ASCO Daily News: Right. Well, COVID-19 will never be eradicated unless it is stamped out everywhere. This means that working to get rid of it in the developing world is really important. What possible applications could the CORONA Project have here? Dr. David Fajgenbaum: I think at the end of the day, no matter where you are in the world, no matter really anything else, it's all got to be about the data. We've got to lead with data. We've got to make decisions based on data. And there's a hierarchy of data, in the sense that you can sometimes hear about anecdotal reports of a drug in some cases, drugs like hydroxychloroquine, that looked really positive if you give them to a small number of people, and you don't have a comparator group. But as you marched up the chain of rigor, towards these double-blind randomized controlled trials, where patients are either randomly given a drug or randomly not given that drug, then you can really get a sense for whether drugs actually work or don't work. And so I think regardless of whether you are in the United States or another country, I think we have to follow the data. And it goes in the other direction too. So here in the United States, we need to pay attention to the data from all over the world. There are a number of really powerful and important trials that have come out of Brazil. There are trials all over the world that are being done, and so I think it's about forgetting about these geographic boundaries that exist between what we call countries. When it comes to a pandemic, the virus doesn't care where you are or what country you may be from. And so I think it's about breaking down these walls and making sure that at all times, we follow the data that the drugs that look most promising are those that move forward to randomized controlled trials. And if they show benefit in a randomized controlled trial, that's when they get used in widespread use. And I think that it's about creating an infrastructure and a system so that happens efficiently, and that's what we're trying to do with the CORONA Project. ASCO Daily News: Dr. Fajgenbaum, are there lessons learned in your endeavors that could be applied to put the principles of the CORONA Project to work on other conditions? Dr. David Fajgenbaum: Absolutely. So as you know, one of the reasons that I was so motivated to want to go into studying repurposed drugs for COVID is that I'm alive today because of a repurposed drug for Castleman Disease. This idea of taking a drug approved for a completely different condition and trying it based on really strong data, in my case, in the lab. And so this idea of repurposing, I'm talking to you today, and I'm alive because of a repurposed drug, so I certainly believe strongly in this idea. But I also recognize that repurposing can't be done without data. And so I'm very much inspired by the fact that I'm alive today because of repurposing and data behind repurposing. I feel really committed and compelled that we need to continue to build these sort of data structures so that we can identify the right drug for the right patient, regardless of what the drug was initially developed for. These drugs, dexamethasone was not made for COVID. Tocilizumab was not made for COVID. Tocilizumab was actually made for Castleman Disease 30 years ago in Japan, and now here it is saving patients' lives from COVID, from rheumatoid arthritis, from heart CRS. And I think this concept of repurposing is such an untapped opportunity because unfortunately, there aren't really incentives to do it. So we've got to figure out ways to overcome the lack of incentives and find new uses for all drugs. ASCO Daily News: Dr. Fajgenbaum, many people have been inspired by your bestselling memoir, Chasing My Cure: A Doctor's Race To Turn Hope Into Action. It was recently released in paperback. Congratulations on the success of the book. Are there any other big projects in the works? Dr. David Fajgenbaum: Well, thank you so much. It's been so special to hear from readers about what it's meant to them. I learned so many lessons about life and hope and leadership from all of my ups and downs. And of course, I didn't, and I still don't, know how long this drug will work and how long I'll be fortunate to be here. But it just is so special for me to know that this book and these lessons are reaching people far beyond me. And of course, this drug, as well, that I'm on is also reaching further than me. The new project that I'm focused on is really about thinking, how do we scale what we've done for Castleman's, both the drug that's saving my life, but also another drug that we've identified that we're repurposing for Castleman's. And how can we go beyond what we've done for COVID to pull together data from all over the world, identify the most promising treatments, to think bigger than Castleman's and COVID and trying to get a sense for how can we solve this problem of drugs not being utilized for all of the different diseases that they could be effective for? Cancer is a really great example of a field where there is a lot of repurposing done. There's a lot of really thoughtful data driven repurposing. One drug may have been developed for lung cancer, but we are going to use it for melanoma, and vise versa. This is done really well in cancer. But unfortunately, it's not done nearly as well outside of cancer. And I think if we can learn from the Castleman experience from the cancer experience, from the COVID experience and prove to ourselves that this can work, and it can save lives. We've got to figure out how to apply it to other diseases, as well. ASCO Daily News: Well, I so appreciate you taking the time today to talk about the CORONA Project and the amazing work that you're doing. Is there anything else you'd like to add before we wrap up our discussion today? Dr. David Fajgenbaum: I'd love for all listeners to check out the CORONA Project. We've made the project completely open source and freely available. If you go to cdcn.org/corona, you can access the data. You can play with the data. You can see the 400 plus drugs that have been tried. You can see the rating scale that we've assigned to each of the drugs to get a sense for what the drug was the most promising and least promising. So I really encourage you to go to that website. In addition to following our work, you can also get involved in our work. We actually have a number of positions open where we're looking for immunologists. We're looking for data scientists, data coordinators, individuals who want to be a part of identifying treatments as quickly as possible for COVID-19 and looking beyond COVID. So you can go also to cdcn.org/corona to understand about and to learn about some of our job opportunities. And we'd just be thrilled for anyone to reach out that's interested. I also encourage you to go to chasingmycure.com. You can follow the work that we're doing. You can learn more about the lessons that I'm trying so hard to share from my journey, and also related to drug repurposing and certainly follow us in real time by finding out all the different social media handles. And I would love to engage anyone and everyone listening that is excited about drug repurposing, whether it's for COVID or cancer or any other condition. I would love for you to reach out, and you can find my information at chasingmycure.com. ASCO Daily News: Fantastic. Thank you so much, Dr. Fajgenbaum, for talking to us today on the ASCO Daily News podcast. Dr. David Fajgenbaum: Thanks so much for having me. ASCO Daily News: And thank you to our listeners for your time today. If you're enjoying the content on the podcast, please take a moment to rate and review us wherever you get your podcasts.   Disclosures: Dr. David Fajgenbaum Honoraria: Foundation Medicine Consulting or Advisory Role: SOBI Research Funding: EUSA Pharma, Janssen Patents, Royalties, Other Intellectual Property: Provisional patent pending Travel, Accommodations, Expenses: EUSA Pharma Other Relationship: Pfizer Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In today’s episode, Dr. Daniel Weisdorf, hematologist/oncologist and bone marrow transplant physician at the University of Minnesota, discusses advances in allogeneic transplantation amid the expansion of donor registries globally and approaches to limit the morbidity of graft-versus-host-disease after allo HCT.   Transcript ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Daniel Weisdorf, a hematologist and oncologist, and bone marrow transplant physician at the University of Minnesota. Dr. Weisdorf joins me to discuss the recent expansion in potential stem cell sources to treat hematologic malignancies. We'll also discuss approaches to optimize donor choice and limit the morbidity of graft-versus-host disease after allogeneic HCT. Dr. Weisdorf reports no conflicts of interest relating to our discussion today. Full disclosures relating to all episodes of the podcast are available at asco.org/podcasts. Dr. Weisdorf, welcome to the ASCO Daily News podcast. Dr. Daniel Weisdorf: Thank you very much. Happy to be here. ASCO Daily News: Dr. Weisdorf, your review article in the Journal of Clinical Oncology outlines the design and development of approaches to select the best donor and limit the morbidity of graft-versus-host disease after allogeneic HCT (DOI: 10.1200/JCO.20.01771). The field has grappled with the toxicity and morbidity of GVH for many years. Can you tell us about these challenges? Dr. Daniel Weisdorf: Well, graft-versus-host disease, it's been the dominant non-relapse mortality and morbidity problem that follows allogeneic hematopoietic stem cell transplantation for its entire 60, 70 years of existence. It's less of a problem than it used to be. But in terms of the morbidity and mortality associated directly with the complication of the therapy, this is the one that is dominant. And because it's a disease that sadly we create in our recipient patients, there's always been an enormous interest in learning how to prevent it or even better, perhaps, modulate it, because there are some associated antineoplastic benefits that come with the development of at least limited severity GVH. ASCO Daily News: Well, your article highlights the significance of expanding donor options to prevent toxic and morbid graft-versus-host disease. Can you tell us about this and other key takeaways from your review? Dr. Daniel Weisdorf: Well, all GVH isn't bad, but there is toxic and morbid GVH that we try very hard to prevent because GVH, as I alluded to a moment ago, carries with it the genetic anti-tumor effect, the nickname graft-versus-leukemia effect, but it doesn't have to be leukemia only. So the allogeneic response of the donor cells against the recipient residual tumor can limit the risk of relapse and increase the number of people who are cured. So the goal was to highlight the issues that are associated with limiting the toxic morbidity and mortality of GVH. And they come from choosing the best donor and preventing the clinical syndrome as best as possible. And it was also clear, and we tried to emphasize through this paper, that the approaches for different donor types may vary because the best approach for HLA match sibling donor may not be the best approach for those who receive a partially matched unrelated donor or a partially matched family donor for that matter. ASCO Daily News: Dr. Weisdorf, can you give us a sense of the progress that has been made in expanding donor registries globally? Dr. Daniel Weisdorf: Well, there's almost a donor for everyone nowadays. It's not quite true because there are people with no first degree relatives, siblings, parents, or children who are either available or have the right constitution themselves, meaning they have to be healthy enough to become a haploid identical donor, but about 90% people have a potentially partially matched and suitable donor in their family. People from Northern and Western Europe have about a 70% to 80% chance of finding a very well-matched, allele-matched, if you will, donor in the international registries in the U.S., the National Marrow Donor Program, the Be the Match Registry, but linked to international searching for donors all over the world. But that's for people from Northern and Western European heritage. People from mixed ethnic or mixed racial backgrounds, or from minorities that are not well-represented in the international registries around the world have a much smaller chance, in the ballpark of 20% for the average African-American who has mixed ethnic backgrounds because they have genetic elements from ancestors from Africa and many genetic elements from ancestors from Europe that create less common tissue types. And therefore, they're less well-represented in the international registries. And the third option - the third non-family option - is umbilical cord blood units, which have many millions to seek out. We know now that matching is not essential at the HLA level, it's beneficial. There are better outcomes with better match cord blood units. And the limitation there is cell dose. And so bigger people with smaller grafts that are in cord blood banks may have an unsatisfactory outcome. So sometimes double cords, two units at once are used. And there's a variety of promising cord blood expansion approaches, none of which are simple, but there are a number that are very promising and have been used in a variety of platforms to overcome that cell dose limitation. And then finally we come back to where it all started was with matched brothers and sisters. One in four siblings who have the same parents, will have the same HLA types. But as family size has gotten smaller over the last 100 years, in many parts of the world, the chances of having a well-matched and available family sibling donor are a little less, particularly as transplantation has moved into older ages, whereas now we in most big centers regularly offer transplantation to people in their 50s, and 60s, and with caution to people in their 70s, the ages where most hematologic malignancies exist. Many times, even if they have a matched sibling, the sibling is not medically suitable to proceed with being a donor, because the sibling has their own medical issues of one sort or another that preclude the sibling from being available.  But we do have all these options. And therefore, it's become more relevant to understand how to create a hierarchy of donor choice that is what is best for the patient, suitable for the experience and protocols that are given transplant center, and adapt the GVH HCT prophylaxis and supportive care measures to make that donor choice as suitable and safe as possible. ASCO Daily News: Well, I'd like to address donor options for patients from underrepresented minority groups, many of whom have not had acceptable donor options until recently. So surely the recent expansion in donor options is an excellent development for this patient population. Dr. Daniel Weisdorf: It's made a very big difference in availability of transplantation when it was limited by the availability of donor. So patients from underrepresented minorities or from mixed ethnic and racial backgrounds can look to cord blood units where mismatching is really the norm, or they can look to haploid identical or half-matched relatives within their own family - that can be parents, or siblings, or adult children. And that has produced availability of a donor for patients in minority groups with much greater frequency. It is important to emphasize that donor availability is not the only thing that has kept people from minority populations from having access to transplantation. They first have to have easy and affordable access to high quality hematology care if it's for hematologic malignancy. And they have to have the insurance support, family support, and proximity to a sophisticated and experienced transplant center, where they can take advantage of that better chance of finding a good donor. ASCO Daily News: Absolutely. Was there anything in the data, in your review, that surprised you or your colleagues? Dr. Daniel Weisdorf: I think the surprise is that even though--and this wasn't necessarily emphasized in this particular paper--even though donor options are much more broadly available, we still don't have clear internationally recognized standards of how to balance all the other factors that are important beyond simple HLA compatible or suitable donors because the other issues of the age of the donor, the health of the donor, ABL compatibility, issues of CMV serology, and previous exposure to that virus, family predisposition to certain malignancies in some disease settings, particularly important for non-malignant disorders where transplantation is the right treatment, like inherited hemoglobin disorders, thalassemia or sickle disease, the carrier states may or may not be suitable for transplantation as a donor. And there are also genetic predispositions to germline mutations and we don't know whether those impair the judgment about suitability for a donor, what is now called CHIP or genetic abnormalities of indeterminate potential, Clonal Hematopoiesis of Indeterminate Potential is what the word CHIP stands for. There's a couple of others; the other acronym is ARCH, but those are people or families who acquire mutations in some of the genetic elements that have been associated with the malignancies or leukemias. They've to-date been recognized as more likely to have cardiovascular disease rather than a predisposition to leukemia, but we don't really have very strong data about whether people with CHIP are suitable and if there's any difference in outcome when they're used for transplantation. We couldn't really explore that, because that's a field that has not been fully developed because the recognition of this as a cardiovascular disease risk is 3 to 5 years old only and hasn't been explored in the depth that we would like. ASCO Daily News: Indeed, there are a lot of other complex factors at play here, but do you think these advances and improvements in donor options can potentially help accelerate progress across the oncology field? Dr. Daniel Weisdorf: Absolutely. Now the oncology field still focuses on--when we're talking about allogeneic transplantation, we're still looking at non-malignant disorders that are based in the bone marrow. So metabolic diseases, hemoglobin disorders, anaplastic anemia, and a whole broad array of hematologic malignancies, which is where the vast majority of all the transplants are performed, there has been limited expansion of allografting into the solid tumor arena, because many solid tumors, first, don't express HLA target molecules that make them amenable to the immunologic graft-versus-tumor approach. And the understanding of how to regulate immune responses against solid tumors with checkpoint inhibitor therapy has been much more exciting, still has plenty of limitations, but has been much more exciting in recent years. What we are learning is that as many more people, particularly older people up until the 60s and at least the early 70s, are suitable candidates for transplantation, because an allograft is first more available and way safer than it used to be even 10 years ago. There's substantially less transplant associated morbidity and mortality than even the last decade. We can figure out when and how to approach those older patients, which is where the majority of people with hematologic malignancies are. We can approach them with allo transplant as a potentially curative therapy. And we really couldn't until or at least people were extremely reluctant to do so until 5 to 10 years ago. ASCO Daily News: So looking ahead, Dr. Weisdorf, how do you see the field evolving with respect to allogeneic transplantation? Dr. Daniel Weisdorf: Well, we used to think that allo transplant was primarily a T cell mediated attack on host tissue leading to GVH and host tumor leading to graft-versus-leukemia, but we know that the host environment is much more complex and interesting. So genetic predispositions to things that are related to tissue repair, the microbiome, and its metabolic crosstalk with epithelial targets that can be the targets of GVH or crosstalk with the immune system that is so important for the immunologic reason we do allo transplant in the first place. All of those elements are starting to become first much more important, but also of greater fascination in figuring out how we can make patients better. It's not just improving the suppression. It might be stimulation of tissue repair. It might be alteration of the microbiome to make it more facilitative of a good allo-response. There's lots more that we need to learn, but it makes the biology much broader then--I don't want to use the word simple immunologic attack of GVH versus GVL--but it's much more intriguing and therefore much more amenable to bringing the new tools of research into the field. ASCO Daily News: Excellent. Well, thank you, Dr. Weisdorf, for sharing your valuable insight with us today on the ASCO Daily News podcast. Dr. Daniel Weisdorf: Thank you very much. ASCO Daily News: And thank you to our listeners for your time today. Dr. Weisdorf's article is available in the transcript of this episode. And if you're enjoying the content on the podcast, please take a moment to rate and review us wherever you get your podcasts.   Disclosures: Dr. Daniel Weisdorf Consulting or Advisory Role: Incyte, Fate Therapeutics Research Funding: Incyte Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Lauren Byers, associate professor of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, highlights a new study published in Cancer Cell that features a transformative new framework to classify small-cell lung cancer into four subtypes based on gene expression, paving the way for personalized treatment options (DOI: 10.1016/j.ccell.2020.12.014).   Transcript ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for ASCO Daily News. My guest today is Dr. Lauren Byers, associate professor of Thoracic, Head, and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center. Dr. Byers is the lead author of a new study published in Cancer Cell that features a transformative new framework to classify lung cancer into four small-cell lung cancer subtypes based on gene expression, and, for the first time, a personalized treatment option for the second most common type of lung cancer. Dr. Byers serves on advisory committees and receives research funding from AstraZeneca, Genmab, and Sierra Oncology, among other organizations. Her full disclosures and those relating to all episodes of the podcast are available on our transcripts at asco.org/podcasts. Dr. Byers, welcome to the ASCO Daily News Podcast. Dr. Lauren Byers: Thank you, Geraldine. ASCO Daily News: Small-cell lung cancer is known for its aggressive growth and resistance to treatment with predictably poor outcomes. There has been some progress with immunotherapy and targeted therapy, but can you tell us why advances in small-cell lung cancer have been more modest in recent years?  Dr. Lauren Byers: We've seen incredible progress in personalizing treatment for patients with non-small cell lung cancer. And for those patients, we routinely use biomarkers, such as EGFR mutations, ALK fusions, or PD-L1 expression, to match our patients to the most effective targeted therapy or to immunotherapy. And this really allows us to have a more personalized approach to their treatment. And last year in the New England Journal of Medicine, there was a very encouraging report showing that deaths from lung cancer had gone down sharply (DOI: 10.1056/NEJMoa1916623). And this was in part because of those improvements in terms of targeted and personalized treatments. Unfortunately for patients with small-cell lung cancer, which makes up about 13% of newly diagnosed lung cancers, the advances have really been more modest. And to date, we have not had any validated biomarkers for small-cell lung cancer that we can routinely use in the clinical setting. And this means that currently patients are really treated with a one size fits all approach. And this could be chemotherapy in combination with radiation, or chemotherapy plus immunotherapy. But I think we really in the field had a growing appreciation that small-cell lung cancer was essentially more than one type of lung cancer, and that certain small-cell lung cancers can respond very differently to different treatments depending on what genes are turned on and what's driving the growth of these cancers. And we had had a few leads in terms of what some of the potential biomarkers might be. But we found that many small-cell lung cancers didn't fit into one of the groups or categories that we predicted might be some of the important subtypes. ASCO Daily News: Right. So can you tell us about the approach that you and your co-investigators used to identify the small-cell lung cancer subtypes based on gene expression data? Dr. Lauren Byers: So what our group did was we really used that data-driven approach where we took an unbiased computational approach to let the data tell us how many distinct molecular groups are there within small-cell lung cancer. And we did this by looking at gene expression data, so looking at what genes were turned on or off in different patient tumors. And based on this, we found that there were four major distinct molecular subtypes of small-cell lung cancer. Three of these were ones that we predicted were probably important players. And these are ones that are defined by expressing different transcription factors. These are master regulator genes, specifically the genes ASCL1, NeuroD1, and PALB2 F3. Those three made up three of the four groups that were identified in our study. But there was a novel fourth group that emerged from this analysis which had not been previously appreciated. And we called this group the small cell lung cancer inflamed subtype, because it really was distinct from the other small-cell cancers by having increased immune cell infiltration and increased expression of multiple immune markers, including higher levels of immune checkpoints. And so when we saw this, we predicted that this inflamed subtype might be the group that was responding better to immune checkpoint inhibitors, such as atezolizumab. And together with our collaborators on our publication, we had the opportunity then to test whether or not the small-cell inflamed subtype was in fact more responsive to immunotherapy. And we did this by looking at patient samples, gene expression data from over 250 patients who were treated on the randomized phase III IMpower133 clinical trial (NCT02763579). This was a trial that changed the standard of care for small-cell lung cancer and tested the question for patients with extensive stage disease, whether the addition of atezolizumab's immune checkpoint inhibition to standard front-line chemotherapy with platinum-etoposide could improve outcomes for patients. And so what we found in this retrospective analysis of the IMpower133 study was that, first, we again found these four major subgroups, including the inflamed group, which made up about 20% of patients. And then as we predicted, one of the really exciting findings from this analysis was that in fact the small-cell inflamed group did have improved survival with the addition of immunotherapy to chemotherapy. In patients that were in that small-cell inflamed group, their overall survival with the addition of the atezolizumab was approximately 18 months as compared to when the inflamed patients received the standard chemotherapy by itself. And importantly also, if we looked at across the four small-cell subtypes in terms of how patients did in the inflamed group as compared to the other three groups when there was the addition of the immunotherapy, the benefit really was enriched in that small-cell inflamed where, again, those patients had a much longer survival as compared to patients in the subtypes where their survival was around 10 months or similar to what was seen with the standard chemotherapy. So I think that was really an exciting finding and I think gives us a path forward to think about how we might start personalizing treatment. The other thing related to this was that the three subtypes that were not as responsive to immunotherapy, the ASCL1, NeuroD1, and PALB2 F23, in our paper we described certain targeted therapies that actually work quite well in preclinical models in those other groups. And so I think it gives us a path forward in terms of the potential to identify a personalized approach for each of the four groups. ASCO Daily News: Absolutely. Now, I understand in some cases you and your co-investigators observed more than one of the small-cell subtypes within a patient's tumor. Can you tell us about this? Dr. Lauren Byers: I think one of the really interesting things that we also found in the study was that in some cases we saw more than one of the small-cell subtypes present within an individual patient's tumor. So in a small-cell lung cancer tumor, there could be, for example, cells that were in ASCL1 group, and then others that were expressing markers of the NeuroD1 group. And when we did further investigation into this using some of our preclinical models, we found that one way that these cancers were becoming resistant to chemotherapy was by switching from one subtype to another. ASCO Daily News: Dr. Byers, did the subtype switching surprise you, and have other investigators seen this before? Dr. Lauren Byers: This subtype switching was not totally unexpected. There have been other groups that do work in the field of small-cell lung cancer that have also recently reported a similar type of subtype switching. And in the case of our publication, we also found that tumors could switch to the inflamed group. And I think, again, this provides us additional insights into how small-cell lung cancer adapt and what might be driving resistance. And I think, more importantly, also, as a medical oncologist, this gives us ideas about how we might potentially combine drugs that target more than one subtype to overcome resistance or also the importance of getting repeat biopsies after a patient has relapsed so that we can see what is their current subtype and, again, personalize the treatment to the subtype of their cancer at that time when we're making a treatment decision. The other thing that we've been very focused on is developing and also sharing ways that we will be able to test for the small-cell subgroups and biomarkers that can be used. So this can be done easily in clinic. And so I think that both from tumor as well as ultimately, hopefully, minimally invasive approaches, such as blood-based testing, will be ways that we'll be able to do this routinely, and then move us forward in terms of having more precision oncology approaches for our patients. ASCO Daily News: Yes, there are surely new tailored approaches on the horizon as the work continues to find ways to test for the small-cell subgroups in clinic. Dr. Byers, is there anything else you'd like to share before we wrap up our discussion today? Dr. Lauren Byers: I think I would just say that we're very excited, that we think that this work, together with a lot of the other very exciting work in this field, is opening the door to precision medicine for small-cell lung cancer. And I think this is a very exciting time for our patients and for hopefully seeing accelerated progress because of these findings. The other thing that I think will be really exciting is that ultimately I think we look forward to having trials where we do start matching patients to specific treatments based on their molecular classification. And I think that also will really help accelerate progress the same way that those types of studies in non-small cell lung cancer have. And then the last thing I wanted to say is I would just like to recognize Dr. Adi Gazdar, who was a world-renowned thoracic pathologist, and we dedicated our paper to--he really was the father of lung cancer pathology. And he always encouraged all of us in lung cancer research that small cell was not a single disease and that we needed to keep looking and refining what the small cell subtypes were. So I just want to acknowledge his contributions and give the role that he has played on the field for so many of us. ASCO Daily News: Well, thank you Dr. Byers for telling us about these exciting developments in small-cell lung cancer. I'll just remind listeners of the title of your study published in Cancer Cell is "Patterns of Transcription Factor Program and Immune Pathway Activation Defined for Major Subtypes of SCLC with Distinct Therapeutic Vulnerabilities." Thanks again, Dr. Byers. Dr. Lauren Byers: Thank you, Geraldine. I really appreciate you having me. ASCO Daily News: And thank you to our listeners for joining us today. If you're enjoying the content on the podcast, please take a moment to rate and review us, wherever you get your podcasts.   Disclosures: Dr. Lauren Byers Consulting or Advisory Role: Abbvie, AstraZeneca, PharmaMar, Genmab, Bristol-Myers Squibb, Sierra Oncology, Pfizer, Merck, Jazz Pharmaceuticals, Genentech Research Funding: Tolero Pharmaceuticals, Sierra Oncology, AstraZeneca (institution), Genmab (institution)  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Karen Winkfield, a radiation oncologist and Executive Director at the Meharry-Vanderbilt Alliance, and Jeanne Regnante, Chief Health Equity and Diversity Officer at the LUNGevity Foundation, discuss a new actionable framework published in JCO Oncology Practice that addresses disparities across the cancer care continuum in medically underserved communities in the United States.   Transcript ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guests today are Dr. Karen Winkfield, a radiation oncologist and Executive Director at the Meharry-Vanderbilt Alliance in Nashville, Tennessee, and Jeanne Regnante, the Chief Health Equity and Diversity Officer at the LUNGevity Foundation. We'll discuss a new actionable framework published in JCO Oncology Practice that addresses disparities across the cancer care continuum in medically underserved communities across the United States (DOI: 10.1200/OP.20.00630). My guests report no conflicts of interest relating to our topic today. Dr. Winkfield's full disclosures and those relating to all episodes of the podcast are available on our transcripts at ASCO.org/podcasts. Dr. Winkfield and Jeanne, it's great to have you on the podcast today. Dr. Karen Winkfield: Thank you so much, Geraldine. Ms. Jeanne Regnante: Thank you, Geraldine. ASCO Daily News: Well, the COVID-19 pandemic and its disproportionate impact on communities of color and other vulnerable populations underscore the importance of addressing inequities in health care, and perhaps the pandemic also increased our appetite for understanding real-world solutions that address real-world disparities. So Jeanne, how did the working group behind this framework harness the expertise required to take on this task? Ms. Jeanne Regnante: In 2018, I chaired the now still active National Minority Quality Forum Diverse Cancer Communities Working Group. And this working group is made up of patient advocacy groups, industry leaders, diversity inclusion experts in cancer centers across the United States. And this research assessment was conceived in mid-2018. And specifically, this work was envisioned by an active workstream that we had focused on patient and community engagement led by Ellen Sonet at Cancer Care and Dr. Michelle Vichnin at Merck and Company. And what the team did is they acknowledged two things from the start. The first was that they knew that unless patients can move along the cancer care continuum in a way that's patient-centric, personal, and respectful of their values, their care will be suboptimal and their outcomes will continue to suffer. The team also knew that there were initiatives by multiple dedicated stakeholders across the US that were active and underway to address inequities and improve outcomes for these populations. But oftentimes, these practices are not published because stakeholders are actually very busy doing this hard work. So the team recognized that we needed to gather the expertise of multiple stakeholders who are doing best practices across the cancer continuum of care in real world communities across [North] America, and that's how this work was envisioned. ASCO Daily News: Right. So building this actionable framework was a complex undertaking. Dr. Winkfield, can you tell us about the key barriers that the group identified which ultimately led to these expert recommendations? And please explain how you define medically underserved cancer populations in this context. Dr. Karen Winkfield: Yeah. Well, we actually had extensive discussions. And even before the convening of the roundtable, there were surveys that were being sent to all of our experts regarding the barriers. And the knowledge of the experts really became a foundation for us to build this actionable and expert-informed framework. And as you noted, the purpose is really to address the cancer care disparities in medically underserved populations in the United States. And most of the time when people talk about health disparities, they are thinking a lot about racial and ethnic groups, which I think is incredibly important, particularly since some of the greatest disparities from a cancer perspective are seen in the Black community, also seen in the Native American/American Indian population. That's important. But the recommendations as expressed by the final framework are actually applicable to many medically served communities overall, including low socioeconomic status populations, rural populations, which we've heard a lot about particularly related to the National Institutes of Health and some of their work. Racial and ethnic minority populations, of course, are in there, but subgroups--intersectionality between LGBTQ+ communities, immigrant population, and aging populations. So all of these are considered as part of the framework when we're thinking about medically underserved populations. And the participants in the roundtable identified the barriers within and between four domains. So the four domains are screening, diagnosis, treatment, and survivorship. And for each of the target populations, we actually had discussions around what some of the barriers would be. And in terms of highlights, some were common to all the domains, including a lack of coordination. We know that cancer care is so incredibly complex. And so that lack of coordination between multiple visits or different providers and testing particularly related to transitions in care. I think that's an important thing, those logistics around that. Financial barriers were also identified [such as] difficulty in addressing and documenting social determinants of health. And we need to make sure that those sorts of data points actually get included into the electronic medical record and communicated to different providers along the cancer continuum. So there were a lot of different things that were really provided in terms of barriers, but we also tried to identify different settings that really could make themselves conducive to touch points that could provide improvement in care, including navigation and other sorts of resources. So there were lots of different barriers that were expressed and were identified. And I think, again, it's important to know that all the experts really apply their expertise for this particular work on high prevalence cancers. So we know that there are some cancers that may not be as predominant in the communities, but the authors felt that it was really important that the recommendations be applicable to as many cancers as possible and to those that we see the highest prevalence in the United States. And particularly for those, again, when you're thinking about communities that are oftentimes disenfranchised, they oftentimes have comorbidities. So we took that into consideration as well. ASCO Daily News: Well, Jeanne, as Dr. Winkfield just pointed out, understanding the needs and challenges of all stakeholders who are impacted by disparities is crucial. So can you tell us a bit more about the groups that you're hoping will really use this framework? Ms. Jeanne Regnante: So there are so many stakeholders that greatly impact care and trusted engagement of medically underserved cancer communities. And just to mention teams and the types of roles that we feel who will use this framework, they really include health care system leaders, diversity inclusion leaders in cancer, patient advocacy leaders, [and] patient navigators. And when I say patient navigators, I mean lay navigators, clinical navigators, nurse navigators. Often, centers use patient scientists. They call them different things, but they're really people in the community who work to engage populations in a trusted manner. Of course, social workers, community health workers, community-based organization leaders--so barbershop networks, beauty parlor networks, the AME Church network--they can use this framework. And also, industry leaders and policy leaders, and also, importantly, community outreach leaders in cancer centers and also leaders that do outreach in federally qualified health centers in the United States. ASCO Daily News: Well, Dr. Winkfield, you have worked for many years to address disparities in cancer care in your own community and across the country. So why do you think this new framework, these expert recommendations, will make a difference now? And how do you hope they'll be applied by oncologists in practice and beyond? Dr. Karen Winkfield: What's incredible about this publication, again, this framework that has been pulled together from experts around the country, we're hoping it's going to serve as a toolkit to bolster health care, navigation, [and] community stakeholder efforts that are dedicated to this work. And you're right, I've been doing this for a long time. And while originally the impetus for the paper was cancer health equity, things have been so heightened by COVID-19. There are so many other stakeholders that are now invested because of COVID-19 that understand the issues that those of us who have had boots on the ground for a long time for decades have understood. Now other people's eyes are being opened. You think about the fact that the Spanish speaking population had some of the highest levels of COVID-19 infection, right? So what's the communication strategy when you have diverse languages that are spoken in communities? And you think about the geographic and social isolation. We've been hearing about how there are issues with getting the vaccine out to individuals who are in rural, isolated positions. These are things that we've been dealing with from the cancer care perspective for a very long time. And so I think now that people are understanding that we need to have a much better framework in thinking about how to deal with the lack of familiarity with resources that can address financial and other social support needs, including things like transportation. How do you get the vaccine, for instance, to individuals if they don't have transportation? These are things that those of us who have been dealing with cancer disparities have been dealing with for decades and trying to identify the things that work. And so I do think that now the time is right, that there is a better appetite for understanding real world solutions to these real world problems, instead of just continuing to describe the disparities that exist. ASCO Daily News: Absolutely. So Jeanne, let's focus on patient advocacy. You're at the LUNGevity Foundation, a patient advocacy organization. So how will you be implementing the recommendations in this report? Ms. Jeanne Regnante: Sure. I always say that one person can do anything, but many people can do everything. And at the LUNGevity Foundation, we have capability in a number of different functional areas--research, precision medicine policy, communications, patient engagement. And when I first started in March of this year (2020), I looked to amplify the work that we're doing as a organization to understand our capabilities. And then we looked at the framework and we chose two things that we're going to implement deliberately as a start. So to me, this framework gave us, the LUNGevity Foundation team, really clear choices for our health equity strategy. So we're doing two major things that I'll talk about. One is, that was recommended by the framework, we're actively developing a library of health literate, culturally sensitive, and linguistically appropriate educational materials with experts in the field, including patients who we feel are experts and health literacy experts. And we do have award-winning, graduate level educational material that's available across the lung cancer continuum of care. But to many patients, it's not understandable in a way that they could understand it. So this strategy is critically important. Also, based on the importance of a community engagement capability, we decided to partner with a robust network of cancer center community outreach leaders in high risk geographies where lung cancer lives, who have trusted relationships with community-based organizations. And this partnership strategy, we feel, is really critical for engaging populations in a trusted manner moving forward. So those are the two deliberate strategies we have enabled based on the recommendations that came out of this framework. ASCO Daily News: Absolutely. So in the framework, there is a recommendation regarding the importance of workforce diversity and related health care system changes. Dr. Winkfield, how important is this issue in cancer care, and what do you and your co-authors believe needs to be done to address this? Dr. Karen Winkfield: Yeah. So this area of workforce diversity is something that's near and dear to my heart. And there has been a body of knowledge that has, again, been in existence for decades that has highlighted the importance of workforce diversity in terms of stemming some of the health inequities that we see. There were studies that were commissioned part of the Sullivan Commission that came out a decade or so ago. And even the Affordable Care Act recognized the importance of workforce diversity. There are critical things that are related to one's ability to identify with the person who's providing your care, right? And look, part of the challenge is that there is an issue in the United States with respect to ensuring that everyone has access to advanced education, so that's one barrier. But when we look at the oncology workforce, only 3% are black, only 4% are Latinx, right? And so how are we, in this country where by the year 2040, 2050 there's an expectation that we'll be a majority/minority city, how--I mean state or country--majority/minority country, how are we keeping pace? Well, we're not. And I think that's a challenge. And so part of the thing that I really think is important around workforce diversity is not just diversifying the physician workforce. I think that's a component, that patients feel comfortable having a provider who looks like them or comes from a similar background. Again, we're talking about socioeconomic status or individuals who may be from a rural community, because there's this identity that comes with knowing that somebody has a similar background and there's an automatic comfort level. And there's research to show that patients actually feel better heard by individuals who come from similar backgrounds and they have better experience as part of their care. But it can't just be physicians. It has to mean that institutions, that practices, private practices, that programs that take care of cancer patients need to also think about the other members of the care team. So we're talking about nurses. We're talking about radiation therapists. We're talking about medical assistants. We're talking about people who sit at the front desk. Do the people who work for your institution look like the communities that you're taking care of? And that's a really, really important factor that needs to be considered. And so in thinking about this framework, again, we want to take a high level view of where are all of the areas, where are all the touch points that really need to be considered in terms of thinking about how to move the needle? We've already talked about the fact that people have known about these cancer disparities for a long time, but we need to have action around these items. And so the hope, again, is that the toolkit was comprehensive enough that institutions that are considering change, organizations that are advocating on behalf of patients will really think about how can we advocate on behalf of ensuring that there is a workforce that is reflective of the communities that we're serving, particularly those that are so underserved and that this toolkit is intended to improve care for. ASCO Daily News: Well, I so appreciate the time that you've both taken today to explain the new framework. Jeanne, first to you. Is there anything else on your mind before we wrap up our discussion today? Ms. Jeanne Regnante: I just want to say that I, personally, am so inspired by the many people that work in this area across the country to make a difference. And in order to have impact with sustainability, we need to make some choices and actually do the work. And thank you for inviting us to publish this paper. And we did appropriately make it open access because we wanted it to be accessible to all. ASCO Daily News: Absolutely. Dr. Winkfield, is there anything else on your mind before we finish our discussion today? Dr. Karen Winkfield: Well, again, I just want to thank you for your interest in this paper. We are very hopeful that while these are complex issues that people will identify real world solutions. And remember, these are things that have been proven. They may not have all been in a publication form, but these are solutions that have worked in different communities. And we hope that there will be folks who find something that resonates for them. And I've got to say, look, I've been working with ASCO for years now as part of their Health Equity Committee, formerly the Health Disparities Committee. But we really wanted to turn that around and say, hey, we need to think about equity. We need to make sure that we are thinking about how do we make sure that everyone, every community has what they need. And it is hard, it's complex, but we wanted to provide this framework to help support that work that ASCO has been doing, and also ASCO's work on health workforce diversity. So I'm just really excited that I was asked to participate. I'm very grateful for the minds, the brilliant minds that came together. And I'm really grateful for the patients who have allowed us to care for them. And my hope is that the oncology community will continue to put the patients first and to put their care first. And my hope is that this toolkit will help provide some real world examples of how best to do that. ASCO Daily News: Well, thank you both very much for sharing your insights today and for your efforts to truly move the needle on addressing health inequities and disparities in cancer care. Thank you very much. Dr. Karen Winkfield: Thank you. Ms. Jeanne Regnante: Thank you. ASCO Daily News: And thanks to our listeners for joining us today. If you've enjoyed this episode of the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Karen Winkfield Consulting or Advisory Role: Merck, Pfizer, Bristol-Myers Squibb, Grail Bio, AstraZeneca   Disclosures: Ms. Jeanne Regnante Employment: Merck Sharp & Dohme   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In today’s episode, Dr. Stephen Boorjian, professor of urology at the Mayo Clinic, in Minnesota, and chair of the GU Cancers Symposium, discusses key advances across GU malignancies.   Transcript ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Stephen Boorjian, professor of urology at the Mayo Clinic in Minnesota and chair of the 2021 Genitourinary Cancer Symposium. Dr. Boorjian joins me to discuss new developments in the GU field featured at the meeting. Dr. Boorjian serves as a consultant for Ferring, FerGene, and ArTara. Full disclosures relating to all episodes of the podcast are available on our transcripts at ASCO.org/podcasts. Dr. Boorjian, it's great to have you on the podcast today. Dr. Stephen Boorjian: Thank you very much. It's a privilege to be here and I'm happy to participate. ASCO Daily News: There was a lot of interest in the CheckMate 274 trial. What can you tell us about this study and its likely impact on the future management of patients with muscle invasive urothelial carcinoma after radical surgery? Dr. Stephen Boorjian: Absolutely. Thanks, Geraldine. So this trial was presented in Abstract 391. This was the first results released from this phase III randomized, double blind, multicenter clinical trial. The trial tested adjuvant therapy with the immune checkpoint agent nivolumab versus placebo in patients with muscle invasive urothelial carcinoma following radical surgery. This was a trial that enrolled over 700 patients. Patients were randomly assigned in a one to one fashion for 1 year of treatment. The primary endpoints of the trial were disease-free survival in all patients, as well as in patients with tumor expression of PD-L1 ≥ to 1%. Very importantly, the primary endpoint of disease-free survival was met in both of those study cohorts, specifically in the intention-to-treat population. The median disease-free survival in the patients treated with nivolumab was 21 months versus 10.9 months in the placebo arm. And that result was highly statistically significant. Likewise, in the cohort of patients with PD-L1 expression ≥ 1%, the median disease-free survival was actually not reached in the nivolumab arm versus 10.8 months in the placebo arm. And again, highly statistically significant. Grade 3-4 treatment-related adverse events in the study occurred in 17.9% and 7.2% in nivolumab and placebo arms, respectively. I selected this trial for highlighting because I believe this has the potential to significantly impact future management of these patients' [disease]. The role of adjuvant therapy after radical surgery in urothelial carcinoma has remained very poorly defined. These results, I should say, really represent an opportunity, I think, for our patients to now receive an adjuvant therapy with demonstrated subsequent efficacy in the median disease-free survival, as we saw. ASCO Daily News: It's great to hear about such promising data on the role of adjuvant therapy for this patient population. Moving on to the SEMS trial, Abstract 375. This study reported promising results for a young patient population with early metastatic seminoma. You were a co-investigator on this trial. What can you tell us about it? Dr. Stephen Boorjian: So Abstract 375 reports the results from a Phase II multi-institutional surgical trial in early metastatic seminoma. What was particularly exciting to me about this trial is it gave the opportunity to incrementally impact a long-held management paradigm and to change it. So the management for patients with early stage metastatic seminoma has historically been with radiotherapy or chemotherapy, and each of these carry with them the potential for long-term adverse side effects in what is otherwise a very young and healthy patient population. So this trial tested the use of retroperitoneal lymph node dissection, so surgical resection, in patients with early metastatic seminoma. It accrued at 12 sites in the United States and Canada. Patients had isolated retroperitoneal lymphadenopathy between one and three centimeters and testicular seminoma. The primary endpoint of the trial was 2-year recurrence-free survival. Fifty five patients were enrolled in the trial and with a median follow-up of 24 months, the overall recurrence rate was 18% for a 2-year recurrence-free survival of 87% and overall survival of 100% There were only two Clavien [Dindo] grade 3 complications in the perioperative period and no long-term complications associated with it. So I think this trial has the potential to establish retroperitoneal lymph node dissection as a therapeutic option in first-line therapy for early metastatic seminoma. It's effective. It's safe in both the short and the long term. And I was really privileged to be part of a surgical trial, which can be often quite difficult to conduct. And I want to congratulate Dr. Daneshmand, the trial's principal investigator. ASCO Daily News: Absolutely. Focusing on kidney cancer for a moment, can you tell us about the CLEAR study--that's Abstract 269--and the opportunity it represents to offer another potential first-line therapy to patients with advanced renal cell carcinoma? Dr. Stephen Boorjian: Sure. So Abstract 269 reported the phase III trial, which was a three-armed prospective randomized trial for patients with advanced renal cell carcinoma. These patients were randomly assigned in the study to receive either the combination of lenvatinib and pembrolizumab, or lenvatinib and everolimus, or sunitinib. The primary endpoint of the study was progression-free survival. And the study was targeted at patients with no prior systemic therapy. So this was a first-line therapy trial. The trial enrolled over 1,000 patients, and with a median follow-up of 27 months, the trial demonstrated that progression-free survival was significantly improved among patients who received the combination of lenvatinib and pembrolizumab at 24 months versus sunitinib at 9 months. Likewise, the complete response rate in the cohort of patients treated with the combination of lenvatinib and pembrolizumab was 16% compared to 4% with patients treated with sunitinib. And the median duration of response was quite durable at 26 months among the lenvatinib-pembrolizumab arm. So the trial was exciting to me as an opportunity to bring forth another potential first-line therapeutic management strategy for patients with advanced renal cell carcinoma. I think as we continue to evolve in this field, treatment selection will depend on biomarkers as they continue to be explored and developed, differences in side effects, [and] patient tolerability profiles. So I think having one more option in the armamentarium can only help to benefit our patients going forward. ASCO Daily News: Indeed. There were multiple studies about the impact of health disparities. Abstract 14 is really interesting because it provides a real-world snapshot of the genomic landscape of advanced prostate cancer in a hospital that serves racial and ethnic minority communities. The study highlights the importance of next generation sequencing in guiding therapies for these patients. So improving access to this care is crucially important. What are your thoughts on this study? Dr. Stephen Boorjian: Abstract 14, I thought, highlights a very important and very timely topic and that is to evaluate the genomic landscape of advanced prostate cancer in racial minority populations. It used a real-world safety net hospital experience and demonstrated higher frequencies of androgen receptor as well as other homologous recombination repair gene mutations in African-American cohort compared to patients with prostate cancer of other races and ethnicities. As the study utilized next generation sequencing, I thought the approach was quite elegant. And I think, ultimately, this demonstrates the potential importance of that type of next generation sequencing strategy to guide therapy as we move more and more towards targeted therapies in patients with advanced prostate cancer. And I think it emphasizes the need to decrease barriers to access to such types of investigative modalities such as next generation sequencing for racial minorities. So I liked the fact that that abstract sort of specifically brought forth a couple of different themes around a very important and timely topic. ASCO Daily News: Absolutely. Staying in the prostate cancer space, a University of California Health System registry study looked at androgen deprivation and the risk of COVID-19 infection in men with prostate cancer. This is a very timely topic. Can you tell us about it, Abstract 37? Dr. Stephen Boorjian: Yeah, Abstract 37, I thought again, addressed a very timely topic in 2020 and 2021, which was the association of men receiving androgen deprivation therapy with COVID-19 infection. So we are getting lots of questions about the potential interaction of cancer diagnosis and cancer therapies and COVID-19 diagnosis, and this study, which was conducted using a retrospective registry of adult men with prostate cancer in the University of California Health System, evaluated the correlation between COVID-19 diagnosis and androgen deprivation therapy use. Androgen deprivation therapy is a baseline therapy for men with advanced prostate cancer used quite frequently. And therefore, understanding the potential interaction that androgen deprivation therapy might have with COVID diagnosis is important for patient counseling and treatment going forward. And in fact, what the study found was no association between the use of androgen deprivation therapy and the risk of testing positive for COVID-19 in their patient cohort population. And I think that can be looked at in one of two ways. Androgen deprivation therapy is not protective, based on these data, against COVID-19 infection, as it might have been speculated to be because of intracellular expression modification. But at the same time, there wasn't a negative association, and there was no increased risk of COVID-19 diagnosis noted among men receiving androgen deprivation therapy. So I think this sort of can help us going forward, as we understand more and more about the potential interactions of our cancer therapies with COVID-19 diagnosis. ASCO Daily News: Dr. Boorjian, Thanks so much for taking the time to share these really interesting highlights from the GU Cancer Symposium with us. Dr. Stephen Boorjian: Thanks very much for having me. It is my pleasure. ASCO Daily News: And thanks to our listeners for joining us today. If you enjoyed this episode, please take a moment to rate and review us wherever you get your podcasts.   Disclosures: Dr. Stephen Boorjian Consulting or Advisory Role: Ferring, Sanofi, ArTara, FerGene Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In today’s episode, Dr. Neeraj Agarwal, medical oncologist and director of the Genitourinary Oncology Program at the University of Utah’s Huntsman Cancer Institute, highlights recent advances in prostate cancer research.   Transcript ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Neeraj Agarwal, who is a medical oncologist and director of the genitourinary oncology program at the University of Utah's Huntsman Cancer Institute. Dr. Agarwal joins me to discuss promising new therapies for patients with prostate cancer featured at the 2021 Genitourinary Cancer Symposium. Dr. Agarwal has served in a consulting or advisory role for AstraZeneca, Bristol-Myers Squibb, Exelixis, and Merck, among other organizations. His full disclosures, and those relating to all of our episodes, are available on our transcripts at ASCO.org/podcasts. Dr. Agarwal, the symposium featured some really promising advances in the prostate cancer space. Can you highlight some of the key studies for us? Dr. Neeraj Agarwal: Yes. I would like to mention the final analysis from the TITAN study, Abstract 11, which I had the privilege of steering with Dr. Kim Chi and Dr. Simon Chowdhury, along with other colleagues. As most listeners know, the TITAN study was a phase III trial, which randomly assigned patients with newly diagnosed metastatic castration-sensitive prostate cancer receiving androgen deprivation therapy to either apalutamide or placebo. So all patients were receiving androgen deprivation therapy, and then patients received either apalutamide or placebo. The dual primary endpoints of overall survival and radiographic progression-free survival were reported at the first interim analysis, with a median follow-up 22.7 months and significantly favored apalutamide. These data were published in New England Journal of Medicine and led to regulatory approval of apalutamide for men with newly diagnosed metastatic prostate cancer in the year 2019. At the first analysis, the study was unblinded. So when the study reported positive results, the study was unblinded, and patients that had not progressed on the control arm were allowed to cross over from the control arm to the apalutamide arm. Now, at a median follow-up of 44 months, OS continued to significantly favor apalutamide arm, including those patients who crossed over. So these are the data, presented by Dr. Kim Chi in the symposium. So what we saw was that all other endpoints also significantly favor the apalutamide arm. The final analysis from this trial confirmed that these patients treated with apalutamide derive significant improvement in overall survival with a 35% reduction in the risk of death. I would like to bring your attention this important point that when they adjust for the patients who crossed over from control to apalutamide arm, hazard ratio for overall survival benefit with apalutamide improved further to 0.42, which translates into a 48% reduction in risk of death with apalutamide compared to the control. Such magnitude of improvement in survival with apalutamide is great news for our patients with newly diagnosed metastatic prostate cancer. And these data have already positioned apalutamide as one of the top choices when we discuss treatment options with our patients with newly diagnosed metastatic prostate cancer. ASCO Daily News: Dr. Agarwal, are there any other clinical trials that really stood out for you this year? Dr. Neeraj Agarwal: Yes, I would like to mention Abstract 13, presented by Dr. Johann de Bono, where he discussed biomarker analysis from the phase III high-potential 150 trial of ipatasertib plus abiraterone in metastatic castrate-resistant prostate cancer. This trial randomly assigned patients to either ipatasertib plus abiraterone or placebo plus abiraterone. Importantly, patients in this study were stratified by PTEN loss, which was evaluated pre-randomization using the VENTANA immunohistochemistry assay. All primary endpoints of radiographic progression-free survival in the ITT and PTEN loss population were reported last year by Dr. de Bono. Treatment with ipatasertib plus abiraterone significantly reduced the risk of disease worsening or death in patients with PTEN loss by tumor immunohistochemistry, but not in the ITT population. An exploratory analysis further refined the cut-off for PTEN loss, which was originally predefined at more than 50% tumor cells lacking cytoplasmic PTEN staining by immunohistochemistry. So their results indicate a consistent benefit with the combination therapy, with a more stringent cutoff for PTEN loss by IHC. In contrast, no benefit was observed in patients harboring intact PTEN by IHC. Furthermore, patients harboring genomic alterations in PIK3CA, AKT1, or PTEN by NGS testing also derived significantly greater radiographic progression-free survival benefit with the combination therapy of ipatasertib with abiraterone compared to those harboring new alterations in these genes. So to summarize my findings in a simpler wording, patients who are harboring these mutations, such as PIK3CA, AKT1, or PTEN by NGS testing, are a more stringent cutoff for PTEN loss by immunohistochemistry at 50% or more, seem to derive radiographic progression-free survival advantage with the combination of ipatasertib with abiraterone. In my view, these data are not ready to allow approval of ipatasertib for our patients with metastatic castrate-resistant prostate cancer. However, these data provide a strong rationale for continued development of ipatasertib, and this class of drugs, actually, known as AKT inhibitors, for men with metastatic prostate cancer, especially in those whose tumors are deficient in PTEN. ASCO Daily News: Well, staying in the metastatic prostate cancer space, there have been some interesting studies addressing the role of circulating tumor DNA. Would you like to address some of these? Dr. Neeraj Agarwal: I would like to highlight the role of circulating tumor DNA in detecting DNA repair mutations--or, as we call, homologous recombination mutations--in men with metastatic prostate cancer. These data have been reported in three abstracts, Abstract 25, 256, and 27. However, before I discuss the significance of the findings from these abstracts, I would like to provide our listeners with some background. Obtaining and profiling the genomic landscape of tumor biopsies in patients with prostate cancer is challenging. For example, in the PROFOUND trial, which was the first positive randomized phase III trial of a PARP inhibitor in prostate cancer overall, more than 4,400 patients--I want to repeat, 4,400 patients--were prescreened at 206 sites across 20 countries. Of these 4,400 patients, more than 4,000 patients had tumor biopsies available for testing. However, only 2,792 patients--so basically, we lost 30% patients out there--were successfully sequenced. Why we lost those 30% patients? We lost them because of poor quality or quantity of the tumor tissue. So out of 4,400 patients, only 2,700-plus patients were allowed to be screened genomically for the PROFOUND trial. These data indicate that 30% of the patients may not be offered a life-prolonging therapy with PARP inhibitors due to a lack in adequate quantity or quality of the biopsied tumor tissue. In addition, by the time of onset of castrate-resistant prostate cancer patients, most primary prostate biopsies are often too old for genomic profiling. And biopsying metastatic sites in prostate cancer patients is challenging due to bone-predominant nature of prostate cancer metastasis. Lastly, we have to remind ourselves that obtaining tumor biopsies can be time consuming, invasive, expensive, and may be associated with morbidity, such as bleeding, infections, perforation, and more, especially in this elderly patient population. Given all this, circulating cell-free DNA genomic profiling offers a viable alternative for patients with prostate cancer. So the first two studies I would like to mention evaluated the concordance between detection of BRCA1/2 alterations and either tissue results in Abstract 25, or historic results reported in the literature in Abstract 256. Overall, the findings from these two abstracts indicate a high degree of concordance regarding the detection of BRCA1 and 2 alterations, supporting its utility in complementing genomic profiling in cases where tumor tissue is unavailable or of low quality. So to summarize these two abstracts, 25 and 256, what we see here is that sequencing and detection of BRCA1 and BRCA2 mutation is feasible in circulating tumor DNA and matches--the results matches to what we see when we sequence tumor tissue DNA. And this is great news because now we can delve into circulating tumor DNA profiling when we do not have good quantity or quality of tumor tissue available without having to worry about repeat biopsies in these elderly patients. So the last study in this context I would like to highlight is Abstract 27 by Dr. Matsubara, reporting on the findings regarding identification of patients with BRCA1 and 2 mutations by circulating tumor DNA or cell-free DNA in the context of the PROFOUND study. Patients treated with olaparib who were detected to have BRCA1, 2, and ATM mutation by circulating tumor DNA had significantly improved outcomes in radiographic progression-free survival compared to the control population. So these data further support the use of circulating tumor DNA testing for identification of patients harboring BRCA1, BRCA2, and ATM alteration who may benefit with PARP inhibitor therapy. And I think personally, Geraldine, these data will definitely bring in circulating tumor DNA testing to our clinic earlier than expected. ASCO Daily News: Well, thank you very much, Dr. Agarwal, for highlighting some really promising developments in the GU field. Dr. Neeraj Agarwal: Thank you for inviting me, Geraldine. It's always a pleasure. ASCO Daily News: And thank you to our listeners for joining us today. If you're enjoying the content on the podcast, please take a moment to rate and review us wherever you get your podcasts.   Disclosures: Dr. Neeraj Agarwal Consulting or Advisory Role:  Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Foundation One Inc, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai, Seattle Genetics,  EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech Research Funding (Institution): Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Takeda, Novartis, Pfizer, BN ImmunoTherapeutics, Exelixis, TRACON Pharma, Rexahn Pharmaceuticals, Amgen, AstraZeneca, Active Biotech, Bavarian Nordic, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Newlink Genetics, Prometheus, Sanofi Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

In today’s episode, Dr. Neeraj Agarwal, medical oncologist and director of the Genitourinary Oncology Program at the University of Utah’s Huntsman Cancer Institute, discusses the superior clinical efficacy and improved quality of life for newly diagnosed patients with metastatic renal cell carcinoma in the CheckMate-9ER trial.   Transcript ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll a reporter for the ASCO Daily News. My guest today is Dr. Neeraj Agarwal, who is a Medical Oncologist and director of the Genitourinary Oncology Program at the University of Utah's Huntsman Cancer Institute. Dr. Agarwal will discuss a promising new first-line treatment for patients with advanced kidney cancer, featured at the 2021 Genitourinary Cancer Symposium. Dr. Agarwal has served in a consulting or advisory role for AstraZeneca Bristol Myers Squibb, Exelixis, and Merck, among other organizations. His full disclosures and those relating to all of our episodes are available on our transcripts at asco.org/podcasts. Dr. Agarwal, there was a lot of buzz at the symposium over the CheckMate 9ER trial, which showed significantly improved patient-reported quality of life outcomes with first-line nivolumab plus cabozantinib versus sunitinib for patients with advanced kidney cancer. Do you think this study will confirm that the superior clinical efficacy of the first-line doublet versus sunitinib is matched with superior quality of life? Dr. Neeraj Agarwal: So Geraldine, this is a really interesting question in light of the January 22 U.S. Food and Drug Administration approval of the doublet cabozantinib with nivolumab as first-line treatment for patients with metastatic renal cell carcinoma. Before I delve into your question, let me refresh our listeners' memories on the CheckMate 9ER trial (NCT03141177). This was a phase III trial presented last year that randomly assigned patients with metastatic renal cell carcinoma, glial cell type to either cabozantinib plus nivolumab, the experimental arm, or sunitinib, the control arm. The experimental arm in this study met both primary progression-free survival and secondary endpoint of overall survival, objective responses, and safety with significant improvements in outcomes. So the patient-reported outcomes, results, presented by Dr. David Cella on the CheckMate 9ER trial, were an exploratory endpoint and made use of the Functional Assessment of Cancer Therapy Kidney Symptom INDEX 19--short form would be FKSI-19--and European quality five-dimensional three-level questionnaires. Quality of life questionnaires were completed at baseline, on treatment visits, and during common follow-up appointments, and changes from the baseline were assessed using mixed-model repeated measures after adjusting for baseline scores and stratification factors. So to summarize, patients received very extensive questionnaires at different time points during the study to assess how they experienced their own quality of life, as reported by patients themselves, without interference by doctors, by nurses, or by any medical provider in the team. So let's look at the results. Patients on the experimental arm experienced lower treatment burden and decreased risk of confirmed deterioration across most measurements. Hazard ratios for time to confirmed deterioration for all measurements also favor the combination of cabozantinib plus nivolumab. Therefore, Geraldine, to answer your question, I believe these results indicate that superior clinical efficacy of the combination cabozantinib plus nivolumab over sunitinib is also associated with a significantly improved quality of life for these patients. I think these data will definitely position the combination of cabozantinib plus nivolumab as one of the top choices for our patients with newly diagnosed metastatic renal cell carcinoma, which is a great news for our patients. ASCO Daily News: Yes, that's a great development for this patient population. Thanks again, Dr. Agarwal, for taking the time to tell us about it today. Dr. Neeraj Agarwal: Thank you for inviting me, Geraldine. It's always a pleasure. ASCO Daily News: And thank you to our listeners for joining us today. If you're enjoying the content on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Neeraj Agarwal Consulting or Advisory Role:  Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Foundation One Inc, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai, Seattle Genetics,  EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech Research Funding (Institution): Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Takeda, Novartis, Pfizer, BN ImmunoTherapeutics, Exelixis, TRACON Pharma, Rexahn Pharmaceuticals, Amgen, AstraZeneca, Active Biotech, Bavarian Nordic, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Newlink Genetics, Prometheus, Sanofi Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In today’s episode, Dr. Neeraj Agarwal, medical oncologist and director of the Genitourinary Oncology Program at the University of Utah’s Huntsman Cancer Institute, highlights the EV-301 study and its promising developments in treatment for patients with metastatic urothelial carcinoma.   Transcript ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Neeraj Agarwal, who is a medical oncologist and director of the genitourinary oncology program at the University of Utah's Huntsman Cancer Institute. Dr. Agarwal will discuss the EV-301 trial, featured at the 2021 Genitourinary Cancer Symposium, and its potential as the preferred treatment for some patients with metastatic urothelial carcinoma. Dr. Agarwal has served in a consulting or advisory role for AstraZeneca, Bristol Myers Squibb, Exelixis, and Merck, among other organizations. His full disclosures and those relating to all of our episodes are available on our transcripts at asco.org/podcasts. Dr. Agarwal, looking at abstract 393 and the primary results of the EV-301 trial. So this study demonstrated a significant survival advantage with enfortumab vedotin over standard chemotherapy in patients previously treated for locally advanced or metastatic urothelial carcinoma. Will EV be the new standard of care for this patient population? Dr. Neeraj Agarwal: Yes. So short answer is yes. So let me start with the background first. In December 2019, enfortumab vedotin received accelerated approval by the U.S. Food and Drug Administration based on the response waves from the phase II single arm EV-201 trial (NCT03219333). Moreover, in February 2020, the U.S. Food and Drug Administration designated this agent as a breakthrough therapy for this patient population. Therefore, we have been waiting with great anticipation the primary results of the phase III EV-301 trial, which Dr. Tom Powles presented at the GU 2021 Symposium. This trial randomly assigned patients to either enfortumab vedotin, the experimental arm, or investigator's choice of standard chemotherapy with the either docetaxel, paclitaxel, or vinflunine, which comprise control arm. The primary endpoint of this trial is overall survival with secondary endpoint of progression-free survival, objective responses, and safety and tolerability. Eligible patients must have received a platinum-containing chemotherapy and had progression during or after immune checkpoint inhibitor therapy. 608 patients enrolled in this trial, with 301 randomized to the enfortumab vedotin and 307 to the control arm, respectively. The results from the prespecified interim analysis presented at the symposium by Dr. Powles further support the findings from the earlier EV-201 study. With the 11.1 month median follow up, median overall survival was significantly prolonged in the enfortumab vedotin arm at 12.9 months versus 9 months in the control arm, with a p-value equaling 0.001. Secondary endpoints of progression-free survival, objective responses, and disease control rates significantly favored enfortumab vedotin arm, while safety and tolerability were comparable between both arms. Based on these outstanding primary results, I believe enfortumab vedotin will likely become the preferred treatment for patients with metastatic urothelial carcinoma with prior disease progression on a platinum-based chemotherapy and an immune checkpoint inhibitor. ASCO Daily News: Thank you, Dr. Agarwal, for sharing your insight with us today. I look forward to hearing more of your highlights from the symposium in our next episode of the podcast. Dr. Neeraj Agarwal: Thank you for inviting me, Geraldine. It's always a pleasure. ASCO Daily News: And thanks to our listeners for joining us, as well. Please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Neeraj Agarwal Consulting or Advisory Role:  Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Foundation One Inc, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai, Seattle Genetics,  EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech Research Funding (Institution): Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Takeda, Novartis, Pfizer, BN ImmunoTherapeutics, Exelixis, TRACON Pharma, Rexahn Pharmaceuticals, Amgen, AstraZeneca, Active Biotech, Bavarian Nordic, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Newlink Genetics, Prometheus, Sanofi Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In today’s episode, Dr. Neeraj Agarwal, medical oncologist and director of the Genitourinary Oncology Program at the University of Utah’s Huntsman Cancer Institute, discusses the SWOG 1500 trial and a potential new standard of care for patients with metastatic papillary renal cell carcinoma.   Transcript ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Neeraj Agarwal, who is a medical oncologist and director of the genitourinary oncology program at the University of Utah Huntsman Cancer Institute. Dr. Agarwal will discuss a potential new standard of care for patients with metastatic papillary renal cell carcinoma, featured at the 2021 Genitourinary Cancer Symposium. Dr. Agarwal has served in a consulting or advisory role for AstraZeneca, Bristol Myers Squibb, Exelixis, and Merck, among other organizations. His full disclosures and those relating to all of our episodes are available on our transcripts at asco.org/podcasts. Dr. Agarwal, papillary renal cell carcinoma is an area of great unmet need. The SWOG 1,500 trial explores new therapy for patients with metastatic papillary RCC. What can you tell us about this study, abstract 270? Dr. Neeraj Agarwal: This study presented by Dr. Monty Pal from the City of Hope sets the standard of care for a rare disease for which there previously was not. So this is a phase II trial originally designed as a four arm randomized study comparing sunitinib to three investigational agents, cabozantinib, crizotinib, and savolitinib. The three investigational agents hit a target called MET, which is often altered in papillary kidney cancer. The primary endpoint of the trial is progression-free survival, with secondary endpoints of overall survival, objective responses, and adverse events. The accrual in two arms, savolitinib arm and the crizotinib bar was halted early for futility due to poor progression-free survival seen with these agents. This was surprising, actually, given that both are potent and selective MET inhibitors. Since these arms were closed, I will focus on results from the experimental arm with cabozantinib versus sunitinib. A total of 46 patients were accrued in the control arm, sunitinib, and 44 patients in the experimental arm with cabozantinib. These are relatively large numbers given the rare nature of papillary renal cell carcinoma. The primary endpoint of improved progression-free survival in the cabozantinib arm was reached at 9.2 months versus 5.6 months in this sunitinib arm. The results are statistically significant, with progression-free survival HR of 0.61 and a p-value of 0.021, which translates into a 40% reduction in disease progression or death with cabozantinib. Adverse events were as expected for these two ages, with 69% versus 72% events occurring in the sunitinib and the cabozantinib arms, respectively. Moving forward, cabozantinib should represent the standard of care for patients with metastatic papillary kidney cancer. And I'd like to add that my colleague, Benjamin Maughan at the Huntsman Cancer Institute will hopefully be carrying these results forward in a clinical trial he and Dr. Monty Pal will be running in SWOG, which will be comparing cabozantinib with and without immunotherapy, so a lot more to come. ASCO Daily News: Thank you Dr. Agarwal for sharing your insight with us today. I look forward to hearing more of your highlights from the symposium in our next episode of the podcast. Dr. Neeraj Agarwal: Thank you for inviting me, Geraldine. It's always a pleasure. ASCO Daily News: And thanks to our listeners for joining us, as well. Please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Neeraj Agarwal Consulting or Advisory Role:  Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Foundation One Inc, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai, Seattle Genetics,  EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech Research Funding (Institution): Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Takeda, Novartis, Pfizer, BN ImmunoTherapeutics, Exelixis, TRACON Pharma, Rexahn Pharmaceuticals, Amgen, AstraZeneca, Active Biotech, Bavarian Nordic, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Newlink Genetics, Prometheus, Sanofi Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.