ASCO Daily News

Dr. Pauline Funchain and Dr. Allison Betof discuss practice-changing and paradigm-shifting abstracts in melanoma, Merkel cell carcinoma, and cellular therapies that were presented at the 2026 ASCO Annual Meeting. LINK TO FULL TRANSCRIPT

Dr. Marc Braunstein and Dr. Adam Kittai highlight top research on hematologic malignancies from the 2026 ASCO Annual Meeting, including studies on lymphoid malignancies, multiple myeloma, and plasma cell disorders. LINK TO FULL TRANSCRIPT

Dr. Monty Pal shares highlights from the final day of ASCO26, including new research on treating anemia in myelofibrosis, advances in RAS-mutated mCRC, novel therapies for AML, and a potentially practice-changing trial in TNBC. LINK TO FULL TRANSCRIPT

Dr. Monty Pal shares highlights from Day 3 of the 2026 ASCO Annual Meeting, including new research for the treatment of advanced CRC and mCRPC, TIL cell therapy in advanced non-uveal melanoma, and an ultra-low dose immunotherapy trial in head and neck squamous cell carcinoma. LINK TO FULL TRANSCRIPT

In the first episode of a special daily series during the 2026 ASCO Annual Meeting, Dr. Monty Pal discusses 3 abstracts, including a follow-up on the EV-302 study in urothelial carcinoma, a potential new treatment option for patients with PD-L1-positive advanced non–small cell lung cancer, and a novel psychosocial digital application that improves fatigue and distress in patients with multiple myeloma. LINK TO FULL TRANSCRIPT

Google DeepMind's Dr. Alan Karthikesalingam and Google research scientist Anil Palepu sit down with Dr. Monty Pal to discuss the potential of Articulate Medical Intelligence Explorer (AMIE), a large language model-based experimental medical AI system designed to augment clinical decision-making in oncology and beyond, as well as the future of AI-human collaboration and how it could reshape health care over the next decade. LINK TO FULL TRANSCRIPT

Dr. Monty Pal speaks with internationally acclaimed hematologists Dr. Vincent Rajkumar and Dr. Saad Usmani about the AQUILA trial in high-risk smoldering multiple myeloma, as well as advances in CAR-T and other evolving treatment strategies in the myeloma space. TRANSCRIPT Dr. Monty Pal: Hello everyone and welcome to the ASCO Daily News Podcast. I'm your host, Monty Pal. I'm a medical oncologist, underline medical oncologist, a professor, and vice chair of academic affairs at the City of Hope Comprehensive Cancer Center in Los Angeles. You're going to understand why I underlined "medical oncologist" there. I'm actually on the line today with two amazing hematologists. Today, we're going to actually explore treatments for high-risk smoldering multiple myeloma following the FDA's approval last year of daratumumab for the first-ever treatment of this indication. Now, this is based on the AQUILA trial, and this represents a huge shift in our traditional watch-and-wait approach to active disease interception. We're going to consider whether this landmark trial published in The New England Journal translates to day-to-day practice. I think it does, and we'll certainly make an argument for that. And I'm so fortunate today to have two internationally acclaimed experts here in the conversation: Dr. Vincent Rajkumar, senior author on the manuscript, and Dr. Saad Usmani, also an expert in his own right in myeloma. Dr. Rajkumar is the lead investigator of the AQUILA study. He's a professor of medicine and consultant in the divisions of hematology and hematopathology at the Mayo Clinic in Rochester, Minnesota. He actually chairs the Myeloma, Amyloidosis, Dysproteinemia Program. He is also editor-in-chief of the Blood Cancer Journal. Dr. Usmani, he and I actually go way, way back. We actually did the AACR Molecular Biology in Clinical Oncology course, I want to say in 2006, so this is our 20-year anniversary, Saad. He's the chief of the myeloma service at the MSK Cancer Center and a professor of medicine at the Weill Cornell Medical College in New York. Saad, Vincent, welcome. Dr. Saad Usmani: Thank you so much for having me, Monty. Dr. Vincent Rajkumar: Yeah, thanks, Monty. A pleasure to be here. Dr. Monty Pal: Thanks. And just a quick note for our listeners, all of our disclosures are available in the transcript of this episode. First off, Saad, did I get that right? Was it 2006 when we did that course together? Dr. Saad Usmani: Yeah, 20 years. We are coming up to our 20-year anniversary. It's remarkable to have seen our careers move the way they have, Monty. Dr. Monty Pal: Oh my gosh. And for all the fellows who are on the line, that AACR Molecular Biology and Clinical Oncology course, it's sometimes overlooked. Wonderful primer on translational science. Okay, now we're going to get to the heart of the matter here, the AQUILA trial. So this was a study, Vincent, that you led. I wonder if you'd walk us through the primary endpoints in the study. What are we looking at in the AQUILA trial specifically? Dr. Vincent Rajkumar: Thanks so much. Again, as you mentioned, smoldering multiple myeloma has just been a condition that we watch and wait. And the first thing that I want to clarify here is that the AQUILA trial is looking at only a subset of smoldering multiple myeloma. That is the high-risk smoldering multiple myeloma. It was defined the way high-risk smoldering myeloma was defined at the time the trial was designed. It randomized 390 patients. One arm got daratumumab single agent in an attempt to delay progression to active myeloma and possibly prolong survival. And the other arm was the traditional observation. The primary endpoint, therefore, was time to active multiple myeloma. Other endpoints included time to when patients needed to start therapy for active multiple myeloma, which can vary based on physician judgment, and overall survival. Of course, response rate, complete response rate, and others were also endpoints. Dr. Monty Pal: That's interesting. And you know, I wanted you to riff a little bit on this definition of high-risk smoldering myeloma. Can you tell our audience how that's sort of evolved over the years? Dr. Vincent Rajkumar: Yes. I mean, if you step back, monoclonal gammopathy of undetermined significance has only a 1% per year risk of progression. Smoldering multiple myeloma, all comers have a 10% per year risk of progression. And over the years, trials have been done in the whole population, and then more recently, we felt we should really focus on the people with high-risk smoldering, defined as a 50-50 risk of progression in 2 years. That's like a 25% per year risk of progression in the first 2 years, which is a very high risk for the patient and something that would justify prophylactic intervention. And that definition initially was based on just high levels of monoclonal protein like more than 3 grams, the IgA subtype of myeloma, the suppression of uninvolved immunoglobulins. Others have used bone marrow flow cytometry markers, cytogenetics. Those combinations of factors were available at the time the AQUILA trial was designed, and a select combination was used. Later on, we found that we could match almost all of that in a very simple risk stratification using just the percentage of bone marrow plasma cells, the level of the M-spike, and the free light chain ratio, all three of which are available to all patients with smoldering at the time of diagnosis. So you don't need any special testing. So more than 20% plasma cells, more than 20 for the light chain ratio, and more than 2 grams for the M-spike. If someone has any two of the three, that is high-risk smoldering multiple myeloma according to the IMWG, but that definition, of course, came in 2020 after the AQUILA trial completed accrual. Dr. Monty Pal: That's interesting because this sort of flips the traditional paradigm where biomarkers get more and more complex as time goes on. Am I right in saying this sort of simplifies things a little bit? It uses standard laboratory or clinical parameters to gauge this category? Dr. Vincent Rajkumar: Absolutely. People were using suppression of uninvolved immunoglobulins, and those levels are not standardized, often vary by race. Also, the other aspect was the abnormal plasma cells on flow cytometry. Again, labs define it differently. So this makes it much more simple. But the IMWG also did a separate exploratory cohort within that paper where we added cytogenetics and we added scoring systems to improve on this further. So it simplified it for regular clinical practice and for like trials. But if you have a patient in front of you, the IMWG paper also has more complex scoring systems where you can take more than 20; 21 is more than 20, so is 51. And so, you can use the actual numbers that a patient has, additional variables like cytogenetics, and get a more refined estimate of what is the true risk of progression. Dr. Monty Pal: That's really helpful. Now, you told us about the primary endpoints, you've helped us define high-risk smoldering myeloma. Can you give us a sense of the top-line results from AQUILA? Dr. Vincent Rajkumar: Yes, I think the most important one was the primary endpoint, time to multiple myeloma, was at 5 years, the progression-free survival was 63% in the daratumumab arm compared to 41% in the observation arm. So, you know, approximately 60% of patients in the observation arm had already progressed by 5 years. And that number was about 40% for the daratumumab arm. We also looked at time to starting myeloma therapy, which is clinically actually quite meaningful because, you know, myeloma therapy means patients get a quadruplet for induction, they get stem cell transplant, they get endless maintenance, they get ongoing therapy virtually for the entire duration. So, preventing the need for myeloma therapy is in and of itself, I think, a major endpoint. And that at 3 years, 40% of people in the observation arm required full myeloma therapy compared to only 20% in the daratumumab arm. So there's a significant reduction in the risk of developing active myeloma as well as the need for myeloma therapy by using a time-limited 3 years of daratumumab single agent. Dr. Monty Pal: Perfect summary of the results. And maybe, Saad, I'm going to bring you into the conversation now. How does this sort of influence your day-to-day practice for smoldering myeloma? Is this something that you've incorporated for that high-risk subset? Dr. Saad Usmani: Thank you, Monty, and I agree. I think that's a really nice summary from Vincent. This study is very important for several reasons. It's actually the third clinical trial that has demonstrated that patients who are in the high-risk smoldering myeloma category benefit from an early intervention that delays the progression to active myeloma or to end-organ damage. And so having a nuanced discussion with our patients in the clinic becomes very important. Having this discussion around as an option becomes very important. And like Vincent said, when we look at that high-risk smoldering myeloma patient population, someone who has 22, 23% plasma cells versus, you know, 45, 50, you know, it's going to be a different discussion each time. But I think it's a very important first step. And I think this sets up the stage for us to design clinical trials where we can ask other questions on what would be better than daratumumab alone in terms of delaying progression in these patients. The other thing that I do want to highlight, and Vincent touched upon this a little bit, that the treatment in this clinical trial was for a fixed duration of treatment. So it was not forever treatment. This is maybe something that Vincent, you can even comment on a little bit more because the question we get after having this discussion is, "Okay, what do we do with patients who are going to be progressing to active myeloma?" Whether we can utilize anti-CD38 therapies for those. So Vincent, I would love your take on this too. Dr. Vincent Rajkumar: Yeah, I think, you know, the main philosophical change for me was previously, the thing was 'don't treat', and now for high-risk smoldering multiple myeloma, the question is, is daratumumab the best treatment or can we do something better? And those trials are thankfully ongoing. One of them has already completed accrual, isatuximab-len-dex versus len-dex. And another one is ongoing in ECOG, almost close to finishing accrual. And in the future, we'll be trying to see if we can use early intervention to even cure and prevent progression altogether. So we are in this phase where we have one approved regimen, one approved drug, and we are not sure whether we can improve on that. The question is, "is a myeloma-like therapy better than monotherapy" would be the next question, and then what would we do further beyond that? In this context, whenever we have patients like this, one of the questions that comes up, as Saad mentioned, is how does this affect newly diagnosed myeloma therapy if somebody has been treated for smoldering and things like that? How will they be considered for clinical trials? Would they be considered as relapse myeloma or still newly diagnosed myeloma? And those are important discussions for clinical trialists to keep in mind, but I think for clinical practice, your duty is to the patient in front of you. If they have high-risk smoldering myeloma and there's data that there's treatments that can delay progression significantly, delay the need for myeloma therapy significantly, that's the highest priority. We'll cross that bridge. There are so few patients going on clinical trials right now that if such a patient were to later on progress and wants to enter in a newly diagnosed myeloma trial later, years later, we can figure that out later. I feel like the most important discussion is what to do for that patient today. I still prefer a clinical trial if one was available. If one was not available, I'd prefer early intervention, but have an informed discussion with the patient because some of them may wish to delay therapy still. Some of them may have very borderline numbers that you want to watch them closely. Some of them may be having other comorbidities that prevent need for therapy. Some of them maybe have had the smoldering for a long time and you already know it's stable. So a lot of factors go in, and I think it's not a one-size-fits-all. Dr. Monty Pal: This is a terrific discussion, and you know, it sort of segues into maybe a question around biology. And this is something I was going to get to a little bit later, but Saad, I'm glad you brought it up. I'll liken it to the only thing I know, which is kidney cancer. So, you know, in kidney cancer, we use checkpoint inhibitors as adjuvant therapy. And there's this question of whether or not it breeds some resistance in the localized setting to ultimately what the patient might potentially be exposed to in the metastatic setting. Tell me your thoughts on this, Vincent, then maybe Saad separately. If you treat a patient with daratumumab in this high-risk smoldering setting, could it theoretically sort of limit options in the refractory setting now that we have regimens like DRBD that are kind of being utilized, or daratumumab with teclistamab? Vincent, I'll throw that to you first. Dr. Vincent Rajkumar: This is a great question, and it's usually asked when we've done the lenalidomide trials actually. We try to put the question back. If that was your concern, how would you actually solve it? Is it really biology that's going to answer that? Or is it a randomized trial? So the experiment has been done three times now where early intervention has been given. And if there was some detriment because of that, that would be reflected in the overall survival. In all three trials, there's no such detriment seen. In the first lenalidomide-dex trial, there was an improvement in overall survival. In the AQUILA trial again, the confidence interval doesn't cross one, and patients had better long-term survival on AQUILA, but certainly not less. We've also examined PFS2 data, and that doesn't seem to be affected. So yes, there is a theoretical concern, and that concern cannot be allayed for new treatments which we have not even tried, like tec-dara, and whether that effect would be there or not. But so far, I don't see it. And I think the onus is on proof of that in order to prevent people from getting early therapy. Dr. Monty Pal: Yeah. Saad, your thoughts on that? And before you jump in, I'll mention, we're kind of taking the same approach in kidney cancer, we're trying to really do studies to see whether or not, you know, immunotherapy rechallenge in these contexts, you know, really lends any substantial benefit. So far, the results have been interesting. I don't think we have enough numbers as yet to capture the impact of adjuvant therapy as it translates to metastatic, but I see so many similarities between the scenarios that you're facing in myeloma and what we're facing in RCC. Saad, your thoughts? Dr. Saad Usmani: Thanks, Monty. I'll go back to something that Vincent alluded to a few minutes ago about the way that we risk-stratify patients within smoldering myeloma. Right now, we are relying more on a disease burden-based stratification looking at the percentage of plasma cells in the bone marrow, the monoclonal protein, as well as the involved light chain versus the uninvolved light chain ratio. However, there are efforts underway to actually incorporate genomics into that schema and try to refine that definition of high-risk smoldering. And there have been two papers that came out in the latter half of last year. In fact. Dr. Rajkumar and I are co-senior authors on one effort where we can identify genomic myeloma in patients in precursor conditions. One of the key things that came out of that effort was that within the high-risk smoldering myeloma category, about 90% of the patients are genomically myeloma. So this whole debate of whether we need to intervene for those patients, I think, you know, we have sufficient biologic evidence that yes, we need to intervene for those patients. I think that the next real step, like Vincent stated, is how do we intervene in those patients? And those clinical trials kind of are ongoing. We will probably need to have more validation of those genomic models being incorporated, but that's what I see in the future. I wouldn't be concerned for the patients being seen today with that query about the disease biology evolving because if I'm seeing a patient today in March of the first quarter of 2026 and offering them monotherapy daratumumab in their high-risk smoldering situation for the next 3 years and then they progress to myeloma after another couple of years, we are talking about what would be the treatment options for them in 2031, 2032. So I think the field is moving so fast, we have a lot of novel therapies coming into that frontline setting rapidly, so our options at that time would be very different. So, you know, I just wanted to kind of set up the stage for saying, you know, our tools are getting better in delineating which patients will need that intervention. And then eventually, I think, you know, we'll have much better options for newly diagnosed myeloma patients at the time when they need it in the future. Dr. Monty Pal: Just absolutely brilliant, absolutely brilliant. I love that summary. I think that you're absolutely right in saying that, you know, you've got to think about what you're going to do for that patient sort of in the moment, what's going to optimize their outcome and agree that the landscape is evolving very rapidly. I'd be remiss, Saad, if I didn't ask you about something that I've been following in terms of your career trajectory. You've developed quite a reputation for your leadership in trials looking at CAR T-cell therapies for myeloma. Can you give us a sense of where that stands in broad terms? Dr. Saad Usmani: Certainly, Monty. I think the CAR Ts have slowly made their way from late relapse to early relapse. And now we have clinical trials that have completed accrual in the frontline setting comparing them to standard-of-care treatment for both older myeloma patients or transplant-ineligible patients, as well as younger transplant-eligible patients where we're actually trying to replace transplants with BCMA-directed CAR T-cell therapies. The nuance there would be we want to equal or better the survival outcomes that we've accomplished without compromising on the safety side of things for patients. Those therapies are moving into earlier lines. And more excitingly, you know, that's just the first wave of CARs. The next wave of CAR technology is coming, and it's going to be in vivo CARs where we may not need lymphodepleting chemotherapy, we may not even need as stringent regulatory nuances that we do for cellular therapies today. So, you know, I think the field is moving rapidly, and it's going to be a very interesting landscape to see over the next 5 to 6 years. Dr. Monty Pal: Yeah, you know, it's so interesting. I know in the solid tumor space, we're trying to replicate the success that you've had with CAR T and bispecifics, and I do see some light at the end of the tunnel. I'm seeing some really promising agents being developed, but clearly, we have so much to learn from our colleagues in hematology. Well, I have to tell you, this has just been a phenomenal conversation. Vincent, congratulations on your leadership of the AQUILA trial. Clearly, a big paradigm shift in the field. Saad, thank you for offering your expert insights and really giving us also a glimpse at the future of myeloma. Really appreciate having you both on the podcast today. Dr. Vincent Rajkumar: Thank you, Monty. Dr. Saad Usmani: Thank you so much. Dr. Monty Pal: And thank you so much to our listeners for your time today. Finally, if you value the insights that you hear from 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. Monty Pal @montypal Dr. Vincent Rajkumar @VincentRK Dr. Saad Z. Usmani @szusmani Follow ASCO on social media: ASCO on X ASCO on Bluesky ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Monty Pal: Speakers' Bureau: MJH Life Sciences, IntrisiQ, Peerview Research Funding (Inst.): Exelixis, Merck, Osel, Genentech, Crispr Therapeutics, Adicet Bio, ArsenalBio, Xencor, Miyarsian Pharmaceutical Travel, Accommodations, Expenses: Crispr Therapeutics, Ipsen, Exelixis Dr. Vincent Rajkumar: Honoraria: Research to Practice, Medscape Patents, Royalties, Other Intellectual Property: Authorship Royalties from Up To Date Dr. Saad Usmani: Consulting or Advisory Role: Janssen Oncology, GlaxoSmithKline, Abbvie, Bristol-Myers Squibb/Celgene, Regeneron, AstraZeneca, Sanofi Research Funding: Janssen Oncology, Bristol-Myers Squibb, K36 Therapeutics, Abbvie, Regeneron

Dr. Monty Pal and Dr. Andrea Apolo discuss practice-changing studies and other novel approaches in bladder, kidney, and prostate cancers that were presented at the 2026 ASCO Genitourinary Cancers Symposium. TRANSCRIPT Dr. Monty Pal: Hello and welcome to the ASCO Daily News Podcast. I'm your host, Dr. Monty Pal. I'm a medical oncologist, professor and vice chair of academic affairs at the City of Hope Comprehensive Cancer Center in Los Angeles. And today is super exciting, we're highlighting key abstracts that were presented at the 2026 ASCO GU Cancers Symposium, and I'm just delighted to be joined by the chair of this year's meeting, who is also a dear friend, Dr. Andrea Apolo. Dr. Apolo serves within the Center for Cancer Research at the NCI as head of the Bladder Cancer Section, and she is also acting deputy chief of the Genitourinary Malignancies Branch. Welcome, Andrea, it is so great to have you on the podcast. Dr. Andrea Apolo: Oh, thank you so much for having me. What a great ASCO that we had, it is really exciting, lots of really great data. So I look forward to chatting about it. Dr. Monty Pal: Excellent. And you know, our full disclosures are available in the transcript of this episode in case our listeners want to have a peek. The theme of this year's GU meeting was "Patient-Centered Care: From Discovery to Delivery." I love that theme. And really, this is one of the most competitive meetings out there, more than 850 abstracts being presented on high-impact science. Andrea, I just wanted to get right into it and dive into what I think we both felt were some of the most exciting abstracts of the meeting. And the first of those is one that I know is near and dear to your heart, being a bladder cancer expert yourself, and that is the KEYNOTE-B15 study presented by Matt Galsky. Can you give us a flavor for what that study entailed and some of the key results? Dr. Andrea Apolo: Yeah, I think this was kind of the missing study that we have been waiting for since we saw the EV-302 data in metastatic disease in the frontline setting. We wanted to know how well this combination would work in muscle-invasive bladder cancer patients. And we saw half of that puzzle, you can say half of the piece of the puzzle, when we saw the data at ESMO, the EV-303 data in patients that were cisplatin-ineligible. And then now we are getting the full story with patients that are platinum-eligible, cisplatin-eligible, with the EV-304 data. So that study randomized patients to receive chemotherapy, so different than the EV-303 where the patients were randomized just to receive the radical cystectomy. These patients were randomized to receive neoadjuvant EV plus pembro and then adjuvant EV plus pembro versus neoadjuvant gemcitabine and cisplatin with no adjuvant component to the control arm. So I think this is a really, really important study. Dr. Monty Pal: And share with us some of the results because this in my mind is definitely practice-changing. This is one of those studies that I think you walked into the office on Monday and you are like, "Okay, this is what I am doing now," right? Dr. Andrea Apolo: Yeah. So the study was positive. The primary endpoint was event-free survival, and it met the primary endpoint. The secondary endpoint of overall survival was also met. So really, really great results. Consistent with what we saw with EV-303, the median event-free survival was not reached for the EV plus pembro arm, and it was 48 months for the patients receiving gem-cis. And then looking at the 24-month estimated event-free survival, it was 79% for the EV plus pembro and 66% for the chemo, the gem-cis arm. And that was a hazard ratio of 0.5. So that is really exciting. That is the event-free survival. And then the overall survival, the medians were not reached for either arm, but when you look at the 24-month estimated overall survival, it was 87% for the EV plus pembro versus 81% for the gem-cis, and that was a hazard ratio of 0.65. So very positive study. And then another question that we had was the pathologic CR rate. Very consistent with what we saw with the EV-303, the pathologic response rate was about 56% for the patients that received EV plus pembro and about 32%, 33% for the patients that received gem-cis. So very consistent with the findings that we have been kind of seeing in phase 2 studies, and this is a pT0N0, so that is important. Dr. Monty Pal: So Andrea, you know, I think that the big question in folks' minds is at this point, we see the data from NIAGARA, cis-gem-durva, we have now seen this data. Put it into context for us. Is there a patient in this day and age who maybe shouldn't get IO altogether, who should maybe get the NIAGARA regimen as opposed to EV-pembro in this context? What are your thoughts there? Dr. Andrea Apolo: Now, that is a great question. I would say with this data, it is very enticing to give EV pembro to our patients in the perioperative setting, and for that to be the new standard of care for all patients, regardless of cisplatin eligibility. So similar to what we saw with EV-302 really changing the standard of care in the frontline setting, I think these two studies, the EV-303 and the EV-304, change the standard of care for patients with muscle-invasive bladder cancer in the perioperative setting, and this should be the new standard of care if the patients don't have a restriction to receiving an immunotherapy. Dr. Monty Pal: I totally agree with that assessment. It is great to hear it from the expert's mouth as well. Thanks a lot for that, Andrea. The next abstract I wanted to tackle is one that is, I would say, near and dear to my heart because I know these folks really well. It is led by the SWOG group, and this is SWOG S1602. The number there for the audience gives you a sense of how long the study has been running for. The 16 prefix means it is something that we kicked off back in 2016. So this study is really 10 years in the making, right? So Rob Svatek presented this data. It is interesting, right, because it addresses this issue of the BCG (Bacille Calmette-Guérin) shortage, right, where we have needed to sort of rely potentially on other alternative sources or regimens and so forth. Tell us about this trial, Andrea. Dr. Andrea Apolo: This is one of my favorite studies. We talked about putting it in the main oral abstracts, but we put it in one of the educational sessions that talked about non-muscle-invasive bladder cancer because we thought that would be the best audience for it. But it doesn't take away from how important this abstract is, and the tremendous effort that went into the study. Almost a thousand patients enrolled. I think 984 were eligible to enroll in this study. So it is a very high enrolling, randomized, cooperative group study in high-grade non-muscle-invasive bladder cancer. And really the study was designed to address two questions. One is the BCG shortage and can we use a different strain, Tokyo versus TICE? And whether there is a priming effect if you gave intradermal BCG to patients with non-muscle-invasive bladder cancer, can that enhance the effect if you gave it a little bit earlier? I think the study is really important, and it met its primary endpoint, which was it is not inferior to TICE. The findings were really terrific in terms of the outcomes. Numerically. When you look at the endpoint, it looked like the Tokyo strain was as good, if not maybe a little bit better, but not statistically significant than the TICE. And then they broke it down by carcinoma in situ, they broke it down by papillary tumors, and the Tokyo strain was non-inferior in both of those instances. But interestingly, the intradermal BCG did not change outcomes. There was really no priming effect, which was really backed up by pre-clinical data that there would be, but there wasn't a priming effect when the intradermal BCG was given in the Tokyo strain. So that was a really, really interesting finding. But a great study, really important outcomes in the field for non-muscle-invasive bladder cancer. Dr. Monty Pal: Totally. And it just seems like we can't get away from BCG, right? You know, as hard as we try, I mean, I appreciate the studies that sort of build on it that are emerging right now, but it seems like BCG at least for the foreseeable future is kind of here to stay, right? Dr. Andrea Apolo: It works. It is one of the most effective treatments we have for non-muscle-invasive bladder cancer. So, you know, I think it is here to stay and, you know, we need to find alternatives in terms of strains so we don't deal with this shortage that we have been dealing with for so many years now. Dr. Monty Pal: Yeah, indeed. Moving on to some of the other highlighted studies from the meeting, you had mentioned the EV-303 data, so we probably don't need to rehash that study design in much detail. But there was also a rapid oral abstract presented by Dr. Ullén that I think is of interest here, right, that really hones in on pathologic outcomes and DFS from that trial. Do you mind just outlining that for our listenership? Dr. Andrea Apolo: This is the KEYNOTE-905, also known as the EV-303 study. This is a follow-up to the EV-303 data looking at the pathologic response rates, looking at the downstaging effect, looking at the surgical margins after treatment with the neoadjuvant EV plus pembro in the 303. Now, remember in the 303, patients got three cycles of neoadjuvant EV plus pembro and then six cycles in the adjuvant setting. A little bit different than the 304, where they got four cycles, which is really kind of the standard in the neoadjuvant setting, and then five cycles in the adjuvant setting. So still a total of nine cycles. But in the 303, the treatment arm had no systemic therapy, so it was just radical cystectomy. And they looked at the negative margins that you get with the EV plus pembro treatment, which was 92.6% versus 79% with patients receiving just the surgery alone. And then the pathologic CR rate, there was more follow-up on that, it was 57% for the patients receiving EV plus pembro, and as we would expect, about 9% for the patients that just went on to surgery alone because you can achieve a pathologic response rate with TURBT alone. Then they looked at the pathologic downstaging, so anything less than a pT2, and that was 66% in the patients that received the EV plus pembro. So very interesting findings, and it is also really just nice to have now the EV-304 data, like I was saying, there were two pieces of it, the cisplatin-eligible and the cisplatin-ineligible, and just to have those contemporary controls are really important. How did the cisplatin-ineligible do versus the cisplatin-eligible patient in terms of the event-free survival and in terms of the overall survival? So I feel like now we have all of this data that we can kind of put together in the perioperative setting and we can really inform our patients a little bit more about their outcomes depending on whether they are cisplatin-eligible or not, which you know cisplatin-ineligible patients often just, they are sicker, they may have obstruction, their tumors may be larger, they just tend to be a more delicate population than the cisplatin-eligible patients. So not surprisingly, you know, we see that in the EV-303 the disease-free survival for the patients is pretty poor. So the disease-free survival that was reported for this follow-up of the specific abstract was 23.6 months for the patients that just got surgery, and it was not reached for the patients that had the EV plus pembro, and that was a hazard ratio of 0.37. Dr. Monty Pal: Excellent, excellent distillation. So Andrea, in the interest of time, I mean, we could probably talk about bladder cancer forever, but I am going to move us on to the subject of kidney cancer. We have two late-breaking abstracts, LITESPARK-011, which looked at lenvatinib and belzutifan versus cabozantinib in the advanced setting, and then we have an adjuvant study, LITESPARK-022, that looked at pembrolizumab with or without belzutifan in the adjuvant setting. Both studies positive. One for progression-free survival, the other for disease-free survival. Both I think making a big dent in how we treat kidney cancer. Can you tell us a little bit about that? Dr. Andrea Apolo: Yeah, we have been waiting for these trials for a long time. So one of the things that we have been talking about at GU ASCO is to have plenary sessions. And if we would have had a plenary session, these two abstracts would have been part of it because they are important data, really big studies where we are trying to improve the outcomes of our patients with kidney cancer. So the first one, the LITESPARK-011, like you said, this is for advanced renal cell carcinoma, clear cell renal cell carcinoma, where we really don't have a standard of care after IO therapy, right? So we give IO-IO, we give VEGF-IO, but we don't really have a good standard of care. We usually give monotherapy TKIs. So the combination of belzutifan and lenvatinib versus what a standard of care is, cabozantinib, is really an important question to ask. And you know, this is a pretty large study, about 750 patients were randomized. And belzutifan plus lenvatinib demonstrated an improvement in progression-free survival and overall survival versus cabozantinib, but not overall survival, at least not yet, is what the authors are saying. So for the progression-free survival, the hazard ratio was 0.7 and it was 14.8 months for the combination, belzutifan plus lenvatinib arm versus cabozantinib, which was 10.7 months. So I think that is significant. And for the overall survival, it did favor the combination again with a hazard ratio of 0.85. The median was 35 months versus 28 months for the monotherapy cabozantinib, but it did not reach statistical significance. And the authors said that this will be further tested at a final analysis, these were the interim results. And for the overall survival, the overall survival was 53% for the combination versus 40%. This is significant. And the CR rates were lowish for both of them, it was like 5% for the combo and 1% for cabo monotherapy. So I think that the findings are important because we don't have a standard of care. And although there is no survival benefit, there was a trend. So I think this could be considered in patients that are fit, a treatment option for these patients in the later line settings. Dr. Monty Pal: Great points. I mean lots of great discussion around toxicity as well as efficacy. I mean certainly this is a regimen that may not be suitable for every patient in my portfolio, but certainly one to consider. Now Andrea, let's shift focus to LITESPARK-022, the adjuvant trial that I mentioned previously. So this is again looking at pembrolizumab with or without belzutifan, met the primary endpoint of disease-free survival. What are your impressions there of the data? Dr. Andrea Apolo: Yeah, the data looks great. And this was a really large study, 1,800 patients were randomized, and the study met the primary endpoint of disease-free survival, benefiting the combination of pembro plus belzutifan. And that is really terrific. The medians were not reached for either arm. And in terms of the overall survival results, also the medians were not reached, but the hazard ratio was 0.78 and did not reach a statistical significance. So there was again a statistically significant improvement in disease-free survival for the combination of pembrolizumab plus belzutifan, but not an overall survival benefit. So I guess, Monty, you know, we can kind of talk about what that means. There was a lot of discussion about belzutifan and some of the side effects, specifically anemia and managing anemia in this setting and requirements for transfusions. Generally, the authors said it was well tolerated, but we know that combination studies do have more toxicity. So it may be a select group of patients again, similar to the advanced setting, where we opt for a combination, possibly until we see more follow-up data in terms of the overall survival. Dr. Monty Pal: I have to agree with you. You know, in my group, we have been talking about a lot of pembrolizumab-based studies that are running right now, some through the NCI, some, you know, our own sort of homegrown investigator-sponsored trials, and you know, I think for the foreseeable future we are comfortable just maintaining pembrolizumab. Things might change if, for instance, we ultimately see a survival advantage emerge, but I just have my own personal doubts around that, that will be interesting. Okay, so now we are going to move to the last disease category that we are going to cover, which is prostate cancer. So there, we have the long-awaited results from the PEACE-3 study. These are the final OS results from this trial looking at enzalutamide with or without radium-223 in metastatic castration-resistant prostate cancer. So Andrea, would love to get your perspectives on this. Dr. Andrea Apolo: Yeah, so this study had been presented before and we had seen positive results for the combination of enzalutamide and radium with some interim overall survival results also showing a benefit. But like you said, these are the final results with a median follow-up of 58 months. So it was really nice to see the final results. And with the combination of enzalutamide and six cycles of radium, it did show an improvement in overall survival with a hazard ratio of 0.76. The median overall survival increased from 32.6 months to 38.2 months with the combination. So that is really great. There was some crossing over of the overall survival curves around 18 months was still seen. And again, there was also an improvement in the rPFS with a hazard ratio of 0.71, and the median rPFS improved from 16.4 to 19 months with the combination. So, you know, we have been awaiting the final results, but we kind of knew a lot about the benefits of the combination. And it is something that is kind of slowly trickling into the community in terms of adapting it and using it. There is more buzz now about it and I think these overall survival results will hopefully shift the community into incorporating the combination in these patients. Dr. Monty Pal: Brilliant. So well said. I mean, Andrea, congratulations on a terrific meeting. You have really done it again. Incredible, incredible output from this year's ASCO GU. I just want to thank you for joining us on the program today. Dr. Andrea Apolo: Oh, thank you so much for having me, Monty. It was really a joy to work with the ASCO team and with all the investigators and the Education Committee and the Scientific Committee. Everyone was really outstanding. So to me it was an honor to be part of this meeting, and I am so happy that it was so successful and really presented some amazing data that I think will be practice-changing to our patients. Dr. Monty Pal: Oh, thanks a ton. And also a huge thanks to our listeners. If you enjoyed the content of today's podcast, please don't forget to like and subscribe to our channel wherever you listen to 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. Monty Pal @montypal Dr. Andrea Apolo @apolo_andrea Follow ASCO on social media: ASCO on X ASCO on Bluesky ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Monty Pal: Speakers' Bureau: MJH Life Sciences, IntrisiQ, Peerview Research Funding (Inst.): Exelixis, Merck, Osel, Genentech, Crispr Therapeutics, Adicet Bio, ArsenalBio, Xencor, Miyarsian Pharmaceutical Travel, Accommodations, Expenses: Crispr Therapeutics, Ipsen, Exelixis Dr. Andrea Apolo: No disclosures to report.

Dr. Monty Pal and Dr. Atul Batra discuss the PLANeT study from India, which evaluated low-dose pembrolizumab in addition to neoadjuvant chemotherapy for triple-negative breast cancer, and its place among a growing body of international research on improving efficacy while reducing costs and toxicity with lower doses of immunotherapy. TRANSCRIPT Dr. Monty Pal: Hello and welcome to the ASCO Daily News Podcast. I'm your host, Dr. Monty Pal. I'm a medical oncologist, professor, and vice chair of academic affairs at the City of Hope Comprehensive Cancer Center, Los Angeles. My guest today, I think, is going to be a really riveting one. It's Dr. Atul Batra, who is an additional professor of medical oncology at the All India Institute of Medical Sciences, or AIIMS, in New Delhi. And he's also the senior author of the PLANeT study. It's a very compelling study that evaluated low-dose pembrolizumab in addition to neoadjuvant chemotherapy for triple-negative breast cancer. And it's really a big part of a growing body of research that's showing balanced efficacy when we use lower doses of immunotherapy instead of standard doses to reduce cost, as well as potentially toxicity. I think this has huge implications for our global audience, and I'm so thrilled to have you on the podcast today, Dr. Atul Batra, welcome. Dr. Atul Batra: Thank you, Dr. Pal. Dr. Monty Pal: And we'll just take it with first names from here since we're both friends. I have to give the audience some context. Atul, I had the great honor of visiting AIIMS New Delhi. For those that don't know, this is really, you know, the Harvard Medical School of India. It's the most competitive institution for medical training. And on the back end of that, there's also incredible resources when it comes to clinical trials and infrastructure. I just wanted to have you give the audience sort of a scope of the types of trials that you've been able to do at AIIMS New Delhi. Dr. Atul Batra: Thank you, Monty. So, I work at the All India Institute of Medical Sciences, and we had the honor and pleasure of having Monty here this month. And people are still in awe of his lectures that he delivered there. Coming back to our institute, so it's kind of a medical college. It's one of the oldest ones, it was built in 1956. We are lucky enough that we get the best of the residents and fellows because they have to go through an exam, a competitive exam, and mostly it's them who come to us and we're able to do some good work out here. Regarding the trials that we have conducted, we do conduct some investigator-initiated studies, and we try to answer the questions where we can help our own patients. Like, for example, this PLANeT study. Every other patient in the clinic was almost not able to afford Keytruda at the full dose, pembrolizumab, and we had a lot of evidence creeping in that a lower dose might be helpful. And that's how we planned this study. Before that, there are certain cancers that are peculiar to India, like gallbladder cancer, head and neck cancers. These are much more common in India as compared to the U.S., and there are some good studies that have been conducted from our own institute by our senior colleagues which have been presented at ASCO and published in the JCO. We also did the capecitabine hand-foot syndrome study that was known as the D-ToRCH study: 1% diclofenac gel that became the standard of care to prevent hand-foot syndrome. So, that's kind of a brief overview of investigator-initiated studies. India is slowly and steadily becoming a partner of the global registration trials. And it's more recently, the last five years or so, we have seen that the number of phase 2 and phase 3 trials are increasing and we are able to offer now these trials as well to our patients. Dr. Monty Pal: That was a terrific overview. I just want to highlight for the audience, as we go through some of your discussions today around specific trials, the speed at which this can be done. Just for context, for me to accrue a clinical trial of 30 patients – I think many people have probably come across some of the work that I've done in the microbiome space – at a single institution, 30 patients, right, takes me about a year and a half, two years. We're going to go through some trials today where Dr. Batra and his team have actually, in fact, accrued close to 200 patients over a span of just a year, which is just remarkable by, I would say, any American standard. So, I see a real need for partnership and Atul, I'll kind of get back to that at the end. But without further ado, the focus of this podcast today, I think, is really this terrific presentation you gave in an oral session at ESMO and subsequently published in Annals of Oncology related to the PLANeT study. Would you give the listeners some context around what the study entailed and population and so forth? Dr. Atul Batra: So, we know the KEYNOTE-522 became the standard of care for triple-negative breast cancer, where Keytruda, when added at 200 mg, the standard dose every three weeks with neoadjuvant, increases the pCR from around 51% to 64% by a magnitude of around 13%. However, in India and other low-middle income countries, less than 5% of the patients actually have access to this dose of pembrolizumab. So, our standard of care was actually just chemotherapy till now. And this kind of led us to design this trial. There are data that come from previous trials conducted in India, from the Tata Memorial, done in head and neck space, some other studies done in Hodgkin's lymphoma, that a much lower dose, probably around one-tenth of the dose, works well in these cancers. So, that's where we designed the PLANeT study, where we gave the standard neoadjuvant chemotherapy in the control arm, and in the experimental arm we added 50 mg of pembrolizumab. This was given every six weeks for three doses. So, that's a total of 150 mg over the neoadjuvant period as compared to 1,600 mg that was given in the KEYNOTE-522 study. So, this was almost one-tenth of the study. Dr. Monty Pal: So, a tenth of the dose, which is just remarkable. I mean, that's just such an interesting concept. Dr. Atul Batra: And the results, when we – the primary outcome, this was a phase 2 study. We just wanted to see, is there a signal of activity? And to even our surprise, when we looked at the pathological complete response rates, in the control arm this was 40.5%, and in the experimental arm this was 53.8%. So, a difference came to around 13.3%; it was numerically, I mean, so much similar to what KEYNOTE-522 had with just these many doses. So, this was around 160 patients randomized over one year. We could randomize them in one year because of the load that we see. And the primary endpoint was met, and we could see that the path complete response did show a remarkable increase. We are still following these patients to see whether there is a difference in event-free survival at a longer follow-up. Until now, it's a small follow-up, so the number of events absolute, are different: four events in the experimental arm and 11 events in the control arm. So, we are seeing some signal even in this much short follow-up period as well. But we need to see more of what happens in the longer term. Dr. Monty Pal: That's so impressive. I wonder, with this lower dose, do you attenuate toxicity at all as far as you can gather? Dr. Atul Batra: So, although we shouldn't be doing kind of cross-trial comparisons, but if you look at thyroid dysfunction, we saw that around 10% of our patients had this thyroid dysfunction. This was compared to 15% in the KEYNOTE-522, that was a larger sample size though. But we're seeing that all the toxicities are somewhat less as compared to those in the standard dose. So, the exposure is less, but I mean, I can't really commit definitely on this. For this we would need much more data to say this with more confidence. Dr. Monty Pal: Yeah. I'm going to ask you a really tough question to follow up, and this is probably something that's on everyone's mind after reading a study like this. Is this something that is disease-specific that needs to be replicated across other histologies? The reason I ask this is, you know, you think about paradigms like, for instance, in the States we're toying between intravenous versus subcutaneous delivery of checkpoint inhibitors, and we have studies focused in specific histologies that might justify use across all histologies. With this particular phenomenon, do you think we need to do dedicated studies in renal cell or in colon cancer and other places where, you know, in selected settings we might use checkpoint inhibitors and then decide whether or not there's this dose equivalence, if you will? Dr. Atul Batra: That's a real tough one, though. But I'm happy to share that there are several ongoing studies within India currently. At our institute, my colleagues are leading studies in lung cancer space, cervical cancer. There was already a publication from Tata Memorial Hospital in head and neck cancers and we see that the signal has been consistent throughout. Regarding renal cancer, there was one study that was presented for sure at ASCO from CMC Vellore, that's again a center in South India. That was in RCC at a much lower dose. And for patients who cannot take the full dose, we actually are offering lower dose nivolumab in such patients and we are seeing responses. I mean, we haven't done those randomized trials again because the numbers are much lower in kidney cancers, we know. We could do this trial in triple-negative ones because we had support and we had numbers to conduct this trial. But I'm sure this should be a class effect. I mean, when we can get tumor-agnostic approvals, then some real-world data has come up in almost all tumors, we have seen that consistent effect across tumors. And as we speak of today, I'm also delighted to share that in India, yesterday, we had the first biosimilar of nivolumab and that's now available at a much, much lower price than the original patent product. There was a long ongoing lawsuit that was there, that's over now, and from yesterday onwards, I'm so happy to share here that we would have the first biosimilar of nivolumab that's available. That's going to bring the cost to almost like one-tenth already. Dr. Monty Pal: Wow. That's huge. I'm going to be very selfish here for a second and focus on a study that is in the renal cell space that your group has done. You know, when it came out, I was really sort of intrigued by this study as well and it reflects sort of a different capability, I think, of AIIMS New Delhi, and that's in the, what I'm going to call, biomarker space. This, for the audience, was a prospective effort to characterize germline variants in patients with advanced kidney cancer. And it's something that we talk about a lot in the kidney cancer literature, whether or not we're missing a lot of these so-called hereditary patterns of RCC. Can you tell us a little bit about that study too? Dr. Atul Batra: Yeah, so that was led by one of our fellows, Chitrakshi Nagpal, and she's just completed her fellowship. And two years back we published that. So, that was done in almost 160 consecutive patients that we recruited over the span of just one year and we saw, apart from the common known mutations in RCC, that was around 5% or so, but a lot of other mutations were also seen that we don't generally see in kidney cancers and we see in other cancers like BRCA1, BRCA2 and others. We are still, I mean, doing those analyses to see whether we get more things out of there in the somatic: is there a loss of heterozygosity or was it just present and in there? Dr. Monty Pal: I thought it was a terrific study and again, I was just so blown away at the pace. I mean, as I look at 140 patients accrued over a span of one year, this is something that would take us perhaps three times as long at City of Hope, and that's with a very sort of, what I consider to be large and dedicated kidney cancer program. So, it really underscores, I think, the need for collaboration. And ever since I came back from my visit to you at AIIMS Delhi, I think I've just been sort of transformed in the sense of trying to think of better ways for us to collaborate. One tangible thing that I'm going to get cracking on is seeing whether or not perhaps we can form some partnerships through SWOG or what we call the NCTN, the National Clinical Trials Network here within the U.S. Talk to me about collaboration. I mean, you've been really terrific at this. How do you sort of envision collaboration enhancing the global landscape of oncology? Dr. Atul Batra: That's really amazing, Monty. That's what we need. We have the infrastructure, we have the manpower, we have patients. I mean, these are all high-volume centers. Unfortunately, we are a little less in numbers, so we are more clinically occupied as well. So, sometimes it's kind of tougher, but again, when it comes to helping out the patients, global collaboration, we need to kind of take you guys along with us and have our patients finish trials earlier. This is a win-win situation for patients, one, because they also get exposure or an option to participate in the clinical trials, and second, we can answer all these scientific questions that we have at a much faster pace. All those things can be done within a much shorter span of time for sure. We are so happy to hear that, and with open hands we are ready to collaborate for all these efforts. Dr. Monty Pal: That's awesome. You know, I came back thinking, gosh, this would be so ideal for some of these rare subtypes of kidney cancer. Prospective clinical trials that I'm running in that space where really we're threatened with closure all the time. And if we just sort of extended a hand to, you know, our partners in India and other countries, you know, I'm sure we could get this research done in a meaningful way and that's got to be a win for patients. Atul, I had such a terrific time chatting with you today. I'm looking forward to seeing lots more productivity from your group there. By the way, for our viewership here, take a look and see what AIIMS New Delhi is doing under the leadership of Dr. Batra and others. It is just a real powerhouse and I think that after doing so, you'll be enticed to collaborate as well. I'm hoping this is the first of many times that we have you on the podcast. Thank you so much for joining. Dr. Atul Batra: Thank you so much for having me here, Monty. It was a pleasure as always speaking to you. And thank you again. Dr. Monty Pal: You got it. Well, and thanks to our listeners. I encourage you to check out Dr. Batra's paper. We'll actually have a link to the study in the transcript of this episode. Finally, if you value the insights that you heard today on the ASCO Daily News 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. More on today's speakers: Dr. Monty Pal @montypal Dr. Atul Batra @batraatulonc Follow ASCO on social media: ASCO on X ASCO on Bluesky ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Monty Pal: Speakers' Bureau: MJH Life Sciences, IntrisiQ, Peerview Research Funding (Inst.): Exelixis, Merck, Osel, Genentech, Crispr Therapeutics, Adicet Bio, ArsenalBio, Xencor, Miyarsian Pharmaceutical Travel, Accommodations, Expenses: Crispr Therapeutics, Ipsen, Exelixis Dr. Atul Batra: Stock and Other Ownership Interests: Zydus Pharmaceuticals, Glenmark, Caplin Point Laboratories, Laurus Research Funding: AstraZeneca, Astellas Pharma, Alkem Laboratories

Dr. Monty Pal and Dr. Hope Rugo discuss advances in antibody-drug conjugates for various breast cancer types as well as treatment strategies in the new era of oral SERDs for HR-positive breast cancer. TRANSCRIPT Dr. Monty Pal: Hello, and welcome to the ASCO Daily News Podcast. I'm your host, Dr. Monty Pal. I'm a medical oncologist and vice chair of academic affairs here at the City of Hope Comprehensive Cancer Center, Los Angeles. Today, I'm thrilled to be joined by Dr. Hope Rugo, an internationally renowned breast medical oncologist and my colleague here at City of Hope, where she leads the Women's Cancers Program and serves as division chief of breast medical oncology. Dr. Rugo is going to share with us exciting advances in antibody-drug conjugates (ADCs) that are expanding treatment options in various breast cancer types. She'll also address some of the complex questions arising in the new era of oral SERDs (selective estrogen receptor degraders) that are revolutionizing treatment in the hormone receptor-positive breast cancer space. Our full disclosures are available in the transcript of this episode. Dr. Rugo, welcome, and thanks so much for being on the podcast today. Dr. Hope Rugo: Thank you. Pleasure to be here. Dr. Monty Pal: So, I'm going to switch to first names if you don't mind. The first topic is actually a really exciting one, Hope, and this is antibody-drug conjugates. I don't know if I've ever shared this with you, but I actually started my training at UCLA, I was a med student and resident there, and it was in Dennis Slamon's lab. I worked very closely with Mark Pegram and a handful of others. This is right around the time I think a lot of HER2-directed therapies were really evolving initially in the clinics. Now we've got antibody-drug conjugates. Our audience is well-familiar with the mechanism there but tell us about how ADCs have really started to reshape therapy for HER2-positive breast cancer. Dr. Hope Rugo: Yeah, I mean, this is a really great place to start. I mean, we have had such major advances in breast cancer just this year, I think really changing the paradigm of treating patients. But HER2-positive disease, we've been used to having sequenced success of new agents. And I think the two biggest areas where we've made advances in HER2-positive disease, which were remarkably advanced this year in 2025, have been in antibody-drug conjugates with trastuzumab deruxtecan and with new oral tyrosine kinase inhibitors (TKIs) that have less of a target on EGFR and more on HER2, so they have an overall more tolerable toxicity profile and therefore a potentially better efficacy in the clinic. At least that's what we're seeing with these new strategies that we couldn't really pursue in the past because of toxicities of the oral TKIs. So, although our topic is ADCs, I'm going to include the TKI because it's so important in our thinking about treating HER2-positive disease. In the metastatic setting, we've seen these remarkable improvements in progression-free and overall survival in the second-line setting with T-DXd, or trastuzumab deruxtecan, compared to T-DM1. And then sequencing ADCs with giving T-DXd after T-DM1 was better than an oral tyrosine kinase or a trastuzumab combination with standard chemotherapy. That was DESTINY-Breast03 and DESTINY-Breast02. So, then we've had other trials since then, and T-DXd has moved into the early-stage setting, which I'll talk about in just a moment. But the next big trial for T-DXd in HER2-positive disease was moving it to the first-line setting to supplant what has become an established treatment for now quite a long time: the so-called CLEOPATRA regimen, which used the combined antibodies trastuzumab, pertuzumab with a taxane as first-line therapy. And then we've proceeded on with maintenance with ongoing HP for patients with responding or stable disease. And we'd seen long-term data showing, you know, at 8 years there was a group of patients whose cancers had never progressed and continued improved overall survival. So, T-DXd was studied in DESTINY-Breast09, either alone or in combination with pertuzumab compared to THP. The patient population had received a little bit more prior treatment, but interestingly, not a lot compared to CLEOPATRA. And they designed the trial to be T-DXd continued until progression with or without pertuzumab versus THP, which would go for six cycles and then stop around six cycles, and then stop and continue HP. Patients who had hormone receptor-positive disease could use hormone therapy, and this is one of the issues with this dataset because, surprisingly in this dataset and one other I'll mention, very few patients took hormone therapy. And even in the maintenance trial, the HER2CLIMB-05, less than 50% took hormone therapy as maintenance. This is kind of shocking to me and highlights an area of really important education, that outcome is improved when you add endocrine therapy for hormone receptor-positive HER2-positive metastatic disease in the maintenance phase, and it's a really important part of treatment. But suffice it to say, you know, you're kind of studying continued chemo versus stopping chemo in maintenance. And T-DXd, as we all expected, in combination with pertuzumab was superior to THP in terms of progression-free survival, really remarkably improved. And you could stop the chemo with toxicity, but most people continued it with T-DXd. Again, not a lot of people got hormone therapy, which is an issue, and you stop the chemo in the control arm. So, this has brought up a lot of interest in trying to use T-DXd as an induction and then go to maintenance, much as we do with the CLEOPATRA regimen with hormone therapy. But it brings up another issue. So first, T-DXd is superior; it's a great treatment. Not everybody needs to have it because we don't know whether it's better to give T-DXd first or second with progression - that we need a little bit longer follow-up. But just earlier this week, interestingly, the third week of December, the U.S. FDA approved T-DXd in the DESTINY-Breast09 approach with pertuzumab. So as I mentioned earlier, there was a T-DXd-alone arm; that arm has not yet reported. So very interesting, we don't know if you need pertuzumab or not. So what about the maintenance? That's the other area where we've made a huge advance here. So, we all want to stop chemo and we want to stop T-DXd. You don't want somebody being nauseated for two years while they're on treatment, and also there's a small number of patients with mostly de novo metastatic HER2-positive disease who are cured of their disease. We'd like to expand that, and I think these new drugs give us the opportunity to improve the number of patients who might be cured from metastatic disease. So the first maintenance study we saw was adding palbociclib, the CDK4/6 inhibitor, to endocrine therapy and HP, essentially. There, we had a remarkable improvement in progression-free survival difference of 15.2 months: 29 to 44 months, really huge. At San Antonio this year, we saw data with this oral tyrosine kinase inhibitor tucatinib, already showed it was great in a triplet, but as maintenance in combination with HP, it showed also a remarkable improvement in progression-free survival. But the numbers were all shifted down. So in PATINA, the control arm was in the 24-month range; here it was the tucatinib-HP arm that was in the 25 months and 16 months for control. So there was a differential benefit in ER-negative and ER-positive disease. So I think we're all thinking that our ideal approach moving forward would be to give T-DXd to most patients, we see how they do, and treat to best response. And then, stop the T-DXd, start HP, trastuzumab, pertuzumab for ER-negative, with tucatinib for ER-positive with palbociclib. We also have early data that suggests that both approaches may reduce the development of brain metastases, an issue in HER2-positive disease, and delay time to progression of brain metastases as seen in HER2CLIMB-05 in very early data - small numbers, but still quite intriguing that you might delay progression of brain metastases with tucatinib that clearly has efficacy in the brain. So, I think that this is a hugely exciting advance for our patients, and these approaches are quickly moving into the early stage setting. T-DXd compared to standard chemo, essentially followed by THP, so a sequenced approach resulted in more pathologic complete responses than a standard THP-AC-type neoadjuvant therapy. T-DXd alone for eight cycles wasn't better, and that's interesting. We still need the sequenced non-cross-resistant chemo. But I think even more importantly, the data from DESTINY-Breast05 looking at T-DXd versus T-DM1 in patients with residual disease after neoadjuvant HER2-targeted therapy showed a remarkable improvement in invasive disease-free survival with T-DXd versus T-DM1, and quite early. It was a high-risk population, higher risk than the T-DM1 trial with KATHERINE, but earlier readout with a remarkable improvement in outcome. We expect to be FDA approved sometime in the first half of 2026. So then we'll get patients who've already had T-DXd who get metastatic disease. But my hope is that with T-DXd, maybe with tucatinib in the right group of patients or even sequenced in very high-risk disease, that we could cure many more patients with early-stage HER2-positive breast cancer and cure a subset, a greater subset of patients with de novo metastatic disease. Dr. Monty Pal: That's brilliant. And you tackled so many questions that I was going to follow up with there: brain metastases, etc. That was sort of looming in my mind. I mean, general thoughts on an ADC versus a TKI in the context of brain mets? Dr. Hope Rugo: Yeah, it's an interesting question because T-DXd has shown quite good efficacy in this setting. And tucatinib, of course, had a trial where they took patients with new brain mets, so a larger population than we've seen yet for the T-DXd trials, and saw that not only did they delay progression of brain metastases and result in shrinkage of existing untreated brain mets, but that patients who develop a new brain met, they could stay on the same assigned treatment. They got stereotactic radiation, and then the patients who were on tucatinib with trastuzumab and capecitabine had a further delay in progression of brain mets compared to those on the placebo arm, even after treatment of a new one that developed on treatment. So, I think it's hard. I think most of us for a lot of brain mets might start with the tucatinib approach, but T-DXd is also a very important treatment. You know, you're kind of trading off a diarrhea, some liver enzyme elevations with tucatinib versus nausea, which you really have to work on managing because it can be long-delayed nausea, and this risk of ILD, interstitial lung disease, that's about 12%, with most but not all trials showing a mortality rate from interstitial lung disease of just under 1 percent. In the early-stage setting, it was really interesting to see that with T-DXd getting four cycles in the neoadjuvant setting, a lot less ILD noted than the patients who got up to 14 cycles, as I think they got a median of 10 cycles in the post-surgical setting, there was a little bit more ILD. But I think we're going to be better and better at finding this earlier and preventing mortality by just stopping drug and treating earlier with steroids. Dr. Monty Pal: And this ILD issue, it always seems to resurface. There are drugs that I use in my kidney cancer clinic, everolimus, common to perhaps the breast cancer clinic as well, pembrolizumab, where I think the pattern of pneumonitis is quite different, right? What is your strategy for recognizing pneumonitis early in this context? Dr. Hope Rugo: Well, it is, and you know, having done the very early studies in everolimus where we gave it in the neoadjuvant setting and we're like, "Hmm, the patient came in with a cough. What's going on?" You know, we didn't know. And you have mouth sores, you know, we were learning about the drug as we were giving it. What we don't do with everolimus and CDK4/6 inhibitors, for example, is grade 1 changes like radiation pneumonitis, we don't stop, we don't treat it. We only treat for symptoms. But because of the mortality associated with T-DXd, albeit small, we stop drug for grade 1 imaging-only asymptomatic pneumonitis, and some of us treat with a half dose of steroids just to try and hasten recovery. We've actually now published or presented a couple of datasets from trials, a pooled analysis and a real-world analysis, that have looked at patients who were retreated after grade 1 pneumonitis or ILD and tolerated drug very well and none of them died of interstitial lung disease, which was really great to see because you can retreat safely and some of these patients stayed on for almost a year benefiting from treatment. So, there's a differential toxicity profile with these drugs and there are risk factors which clearly have identified those at higher risk: prior ILD, for example. A French group said smoking; other people haven't found that, maybe because they smoked more in France, I don't know. And being of Japanese descent is quite interesting. The studies just captured that you were treated in Japan, but I think it's probably being of Japanese descent with many drugs that increases your risk of ILD. And, you know, older patients, people who have hypoxia, those are the patients. So, how do we do this? With everolimus, we don't have specific monitoring. But for T-DXd we do; we do every nine weeks to start with and then every 12 weeks CT scans because most of the events occur relatively early. Somebody who's older and at higher risk now get the first CT at six weeks. Dr. Monty Pal: This is super helpful. And I have to tell you, a lot of these drugs are permeating the bladder cancer space which, you know, is ultimately going to be a component of my practice, so thank you for all this. We could probably stay on this topic of HER2-positive disease forever. I'm super interested in that space still. But let me shift gears a little bit and talk about triple-negative breast cancer and this evolving space of HR-positive, HER2-low breast cancer. I mean, tell us about ADCs in that very sort of other broad area. Dr. Hope Rugo: So triple-negative disease is the absolute hardest subset of disease that we have to treat because if you don't have a great response in the early stage setting, the median survival is very short, you know, under two years for the majority of TNBCs, with the exception of the small percentage of low proliferative disease subsets. The co-question is what do we do for these patients and how do we improve outcome? And sacituzumab govitecan has been one strategy in the later line setting that was shown to improve progression-free and overall survival, the Trop-2 ADC. We had recently three trials presented with the two ADCs, sacituzumab govitecan and the other Trop-2 ADC that's approved for HR-positive disease, datopotamab deruxtecan. And they were studied in the first-line setting. Two trials with SG, sacituzumab govitecan, those trials, one was PD-L1 positive, ASCENT-04. That showed that SG with a checkpoint inhibitor was superior, so pembrolizumab was superior to the standard KEYNOTE-355 type of treatment with either a taxane or gemcitabine and carboplatin with pembrolizumab for patients who have a combined positive score for PD-L1, 10 or greater. So, these are patients who are eligible for a checkpoint inhibitor, and SG resulted in an improved progression-free survival. The interesting thing about that dataset is that few patients had received adjuvant or neoadjuvant checkpoint inhibitor, which is fascinating because we give it to everybody now. But access is an issue and timing of the study enrollment was an issue. The other thing which I think we've all really applauded Gilead for is that there was automatic crossover. So, you could get from the company, to try and overcome some of the enormous disparities worldwide in access to these life-saving drugs, you could get SG through the company for free once you had blinded independent central review confirmation of disease progression. Now, a lot of the people who got the SG got it through their insurance, they didn't bill the company, but 80 percent of patients in the control arm received SG in the second-line setting. So that impacts your ability to look at overall survival, but it's an incredibly important component of these trials. So then at ESMO, we saw the data from SG and Dato-DXd in the first-line metastatic setting for patients who either had PD-L1-negative disease or weren't eligible for an immunotherapy. For the Dato study, TROPION-Breast02, that was 10 percent of the patients who had PD-L1-positive disease but didn't get a checkpoint inhibitor, and for the ASCENT-03 trial population it was only 1 percent. Importantly, the trials allowed patients who relapsed within a year of receiving their treatment with curative intent, and the Dato study, TB-02, allowed patients who relapsed while on treatment or within the first six months, and that was 15 percent of the 20 percent of early relapsers. The ASCENT trial, ASCENT-03, had 20 percent who relapsed between 6 and 12 months. The drugs were better than standard of care chemotherapy, the ADCs in both trials, which is very nice. Different toxicity profiles, different dosing intervals, but better than standard of care chemotherapy in the disease that's hardest for us to treat. And importantly, when you looked at the subset of early relapsers, those patients also did better with the ADC versus chemotherapy, which is incredibly important. And we were really interested in that 15 percent of patients who had early relapse. I actually think that six months thing was totally contrived, invented, you know, categorization and doesn't make any sense, and we should drop it. But the early relapsers were 15 percent of TB-02 and Dato was superior to standard of care chemo. We like survival, but the ASCENT trial again allowed the crossover to an approved ADC that improved survival and 80 percent of patients crossed over. In the Dato trial, they did not allow crossover, they didn't provide Dato, which isn't approved for TNBC but is for HR-positive disease, and they didn't allow, of course, pay for SG. So very few patients actually crossed over in their post-treatment data and in that study, they were able to show a survival benefit. So actually, I think in the U.S. where we can use approved drugs already before there's a fixed FDA approval, that people are already switching to use SG or Dato in the first-line setting for metastatic TNBC that's both PD-L1 positive for SG and PD-L1 negative for both drugs. And I think understanding the toxicity profiles of the two drugs is really important as well as the dosing interval to try and figure out which drug to use. Dr. Monty Pal: Brilliant. Brilliant. Well, I'm going to shift gears a little bit. ADCs are a topic, again, just like HER2-positive disease we could stay on forever. Dr. Hope Rugo: Huge. Yes. Dr. Monty Pal: But we're going to shift gears to another massive topic, which is oral SERDs. In broad strokes, right, this utilization of CDK4/6 inhibitors in the context of HR-positive breast cancer is obviously, you know, a paradigm that's been well established at this point. Where do we sequence in oral SERDs? Where do they fit into this paradigm? Dr. Hope Rugo: Ha! This is a rapidly changing area; we keep changing what we're saying every other minute. And I think that there are three areas of great interest. So one is patients who develop ESR1 mutations that allow constitutive signaling through the estrogen receptor, even when there's not estrogen around, and that is a really important mutation that is subclonal; it develops under the pressure of treatment in about 40 percent of patients. And it doesn't happen when you first walk in the door. And what we've seen is that oral SERDs as single agents are better than standard single-agent endocrine therapy in that setting. The problem that we've had with that approach is that we're now really interested in giving targeted agents with our endocrine therapies, not just in the first-line setting where CDK4/6 inhibitors are our standard of care with survival benefit for ribociclib and, you know, survival benefit in subsets with other CDK4/6 inhibitors, and abemaciclib with a numeric improvement. So we give it first line. The question is, what do you do in the second-line setting? Because of the recent data, we now believe that oral SERDs should be really given with a targeted agent. And some datasets which were recently presented, which I think have helped us with that, have been EMBER-3 and then the most recently evERA BC, or evERA Breast Cancer, that looked at the oral SERD giredestrant with everolimus compared to standard of care endocrine therapy with everolimus, where 100 percent of patients received prior CDK4/6 inhibitor and showed a marked improvement in progression-free survival, including in the subsets of patients with a short response, 6-12 months of prior response to CDK4/6 inhibitor and in those who had a PIK3CA pathway mutation. The thing is that the benefit looks like it's much bigger in the ESR1 mutant population, although response was better, PFS wasn't better in the wild type. So, we're still trying to figure that out. We also saw EMBER-3 with imlunestrant and abemaciclib as a second line. Not everybody had had a prior CDK4/6 inhibitor; they compared it to imlunestrant alone, but still the data was quite striking and seemed to cross the need for ESR1 mutations. And then lastly, we saw data from the single arms of the ELEVATE trial looking at elacestrant with everolimus and abemaciclib and showed these really marked progression-free survival data, even though single-arm, that crossed the mutation status. At least for the everolimus combination, abemaciclib analysis is still to come in the mutated subgroups. But really remarkable PFS, much longer. Single-agent fulvestrant after CDK4/6 inhibitor AI has a PFS in like the three-month range and in some studies, maybe close to five months. These are all at 10-plus months and really looking very good. And so those questions are, is it ESR1 mutation alone? Is it all comers? We'd like all comers, right? We believe in the combination approach and we're learning more about combinations with drugs like capivasertib and other drugs as we move forward. Everybody now wants to combine their targeted agent with an oral SERD because they're clearly here to stay with quite remarkable data. The other issue, so the second issue in the metastatic setting is, does it make a difference if we change to an oral SERD before radiographic imaging evidence of progression? And that was the question asked in the SERENA-6 trial where patients had serial monitoring for the presence of ESR1 mutations in ctDNA. And those who had them without progression on imaging could be randomized to switch to camizestrant with the same CDK4/6 inhibitor or stay on their same AI CDK4/6 inhibitor. And they showed a difference in progression-free survival that markedly favored camizestrant. But interestingly, the people who were on the standard control arm had an ESR1 mutation, we think AIs don't work, they stayed on for nine more months. The patients who were on the camizestrant stayed on for more than 16 months. And they presented some additional subset data which showed the same thing: follow-up PFS data, PFS2, all beneficial in SERENA-6 at the San Antonio [Breast Cancer Symposium]. So, we're still a little bit unclear about that. They did quality of life, and pain was markedly improved. They had a marked delayed time to progression of pain in the camizestrant arm. So this is all a work in progress, trying to understand who should we switch without progression to an oral SERD based on this development of this mutation that correlates with resistance. And, you know, it's interesting because the median time to having a mutation was 18 months and the median time to switch was almost 24 months. And then there were like more than 3,000 patients who hadn't gotten a mutation, hadn't switched, and were still okay. So screening everybody is the big question, and when you would start and who you would change on and how this affects outcome. Patients didn't have access to camizestrant in the control arm, something we can't fix but we have experimental drugs. We're actually planning a trial, I hope in collaboration with the French group Unicancer, and looking at this exact question. You know, if you switch and you change the CDK4/6 inhibitor and then you also allow crossover, what will we see? Dr. Monty Pal: We're coming right to the tail end of our time here, and I could probably go on for another couple of hours with you here. But if you could just give us maybe one or two big highlights from San Antonio, any thoughts to leave our audience with here based on this recent meeting? Dr. Hope Rugo: Yeah, I mean, I talked about a lot of those new data already from San Antonio, and the one that I'd really like to mention which I think was, you know, there were a lot of great presentations including personalized screening presented from the WISDOM trial by my colleague Laura Esserman, fascinating and really a big advance. But lidERA was the big highlight, I think, outside of the HER2CLIMB-05 which I talked about earlier in HER2-positive disease. And this study looked at giredestrant, the oral SERD versus standard of care endocrine therapy as treatment for medium and high-risk early-stage breast cancer. And what they showed, which I think was really remarkable with just about a three-year median follow-up, was an improvement in invasive disease-free survival with a hazard ratio of 0.7. I mean, really quite remarkable and so early. It looked as though this was all driven by the high-risk group, which makes sense, not the medium risk, it's too early. And also that there was a bigger benefit in patients who were on tamoxifen compared to giredestrant versus AI, but for both groups, the confidence intervals didn't cross 1. There's even a trend towards overall survival, even though it's way too early. I think that, you know, really well-tolerated oral drug that could improve outcome in early-stage disease, this is the first advance we've seen in over two decades in the treatment of early-stage hormone receptor-positive disease with just endocrine therapy. I think we think that we don't want to give up CDK4/6 inhibitors because we saw a survival benefit with abemaciclib and a trend with giving ribociclib in the NATALEE trial. So we're thinking that maybe one approach would be to give CDK4/6 inhibitors and then switch to an oral SERD or to have enough data to be able to give oral SERDs with these CDK4/6 inhibitors for early-stage disease. And that's all in the works, you know, lots of studies going on. We're going to see a lot of data with both switching 8,000 patients with an imlunestrant switching trial, an elacestrant trial going on, and safety data with giredestrant with abemaciclib and soon to come ribociclib. So, this is going to change everything for the treatment of early-stage breast cancer, and I hope cure more patients of the most common subset of the most common cancer diagnosed in women worldwide. Dr. Monty Pal: Super exciting. It's just remarkable to hear how this has evolved since 25 years ago, which is really the last time I sort of dabbled in breast cancer. Thank you so much, Hope, for joining us today. These were fantastic insights. Appreciate you being on the ASCO Daily News Podcast and really want to thank you personally for your remarkable contribution to the field of breast cancer. Dr. Hope Rugo: Thank you very much, and thanks for talking with me today. Dr. Monty Pal: You got it. And thanks a lot to our listeners today as well. You'll find links to all the studies we discussed today in the transcript of this episode. Finally, if you value the insights that you hear today on the ASCO Daily News 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 opinion 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. Monty Pal @montypal Dr. Hope Rugo @hoperugo Follow ASCO on social media: ASCO on X ASCO on Bluesky ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Monty Pal: Speakers' Bureau: MJH Life Sciences, IntrisiQ, Peerview Research Funding (Inst.): Exelixis, Merck, Osel, Genentech, Crispr Therapeutics, Adicet Bio, ArsenalBio, Xencor, Miyarsian Pharmaceutical Travel, Accommodations, Expenses: Crispr Therapeutics, Ipsen, Exelixis Dr. Hope Rugo: Honoraria: Mylan/Viatris, Chugai Pharma Consulting/Advisory Role: Napo Pharmaceuticals, Sanofi, Bristol Myer Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Merck, Daiichi Sankyo, AstraZeneca, Gilead Sciences, Hoffman La-Roche AG/Genentech, In., Stemline Therapeutics, Ambryx

Dr. Linda Duska and Dr. Kathleen Moore discuss key studies in the evolving controversy over radical upfront surgery versus neoadjuvant chemotherapy in advanced ovarian cancer. TRANSCRIPT Dr. Linda Duska: Hello, and welcome to the ASCO Daily News Podcast. I am your guest host, Dr. Linda Duska. I am a professor of obstetrics and gynecology at the University of Virginia School of Medicine. On today's episode, we will explore the management of advanced ovarian cancer, specifically with respect to a question that has really stirred some controversy over time, going all the way back more than 20 years: Should we be doing radical upfront surgery in advanced ovarian cancer, or should we be doing neoadjuvant chemotherapy? So, there was a lot of hype about the TRUST study, also called ENGOT ov33/AGO-OVAR OP7, a Phase 3 randomized study that compares upfront surgery with neoadjuvant chemotherapy followed by interval surgery. So, I want to talk about that study today. And joining me for the discussion is Dr. Kathleen Moore, a professor also of obstetrics and gynecology at the University of Oklahoma and the deputy director of the Stephenson Cancer Center, also at the University of Oklahoma Health Sciences. Dr. Moore, it is so great to be speaking with you today. Thanks for doing this. Dr. Kathleen Moore: Yeah, it's fun to be here. This is going to be fun. Dr. Linda Duska: FYI for our listeners, both of our full disclosures are available in the transcript of this episode. So let's just jump right in. We already alluded to the fact that the TRUST study addresses a question we have been grappling with in our field. Here's the thing, we have four prior randomized trials on this exact same topic. So, share with me why we needed another one and what maybe was different about this one? Dr. Kathleen Moore: That is, I think, the key question. So we have to level-set kind of our history. Let's start with, why is this even a question? Like, why are we even talking about this today? When we are taking care of a patient with newly diagnosed ovarian cancer, the aim of surgery in advanced ovarian cancer ideally is to prolong a patient's likelihood of disease-free survival, or if you want to use the term "remission," you can use the term "remission." And I think we can all agree that our objective is to improve overall survival in a way that also does not compromise her quality of life through surgical complications, which can have a big effect. The standard for many decades, certainly my entire career, which is now over 20 years, has been to pursue what we call primary cytoreductive surgery, meaning you get a diagnosis and we go right to the operating room with a goal of achieving what we call "no gross residual." That is very different – in the olden days, you would say "optimal" and get down to some predefined small amount of tumor. Now, the goal is you remove everything you can see. The alternative strategy to that is neoadjuvant chemotherapy followed by interval cytoreductive surgery, and that has been the, quote-unquote, "safer" route because you chemically cytoreduce the cancer, and so, the resulting surgery, I will tell you, is not necessarily easy at all. It can still be very radical surgeries, but they tend to be less radical, less need for bowel resections, splenectomy, radical procedures, and in a short-term look, would be considered safer from a postoperative consideration. Dr. Linda Duska: Well, and also maybe more likely to be successful, right? Because there's less disease, maybe, theoretically. Dr. Kathleen Moore: More likely to be successful in getting to no gross residual. Dr. Linda Duska: Right. Yeah, exactly. Dr. Kathleen Moore: I agree with that. And so, so if the end game, regardless of timing, is you get to no gross residual and you help a patient and there's no difference in overall survival, then it's a no-brainer. We would not be having this conversation. But there remains a question around, while it may be more likely to get to no gross residual, it may be, and I think we can all agree, a less radical, safer surgery, do you lose survival in the long term by this approach? This has become an increasing concern because of the increase in rates of use of neoadjuvant, not only in this country, but abroad. And so, you mentioned the four prior studies. We will not be able to go through them completely. Dr. Linda Duska: Let's talk about the two modern ones, the two from 2020 because neither one of them showed a difference in overall survival, which I think we can agree is, at the end of the day, yes, PFS would be great, but OS is what we're looking for. Dr. Kathleen Moore: OS is definitely what we're looking for. I do think a marked improvement in PFS, like a real prolongation in disease-free survival, for me would be also enough. A modest improvement does not really cut it, but if you are really, really prolonging PFS, you should see that- Dr. Linda Duska: -manifest in OS. Dr. Kathleen Moore: Yeah, yeah. Okay. So let's talk about the two modern ones. The older ones are EORTC and CHORUS, which I think we've talked about. The two more modern ones are SCORPION and JCOG0602. So, SCORPION was interesting. SCORPION was a very small study, though. So one could say it's underpowered. 170 patients. And they looked at only patients that were incredibly high risk. So, they had to have a Fagotti score, I believe, of over 9, but they were not looking at just low volume disease. Like, those patients were not enrolled in SCORPION. It was patients where you really were questioning, "Should I go to the OR or should I do neoadjuvant? Like, what's the better thing?" It is easy when it's low volume. You're like, "We're going." These were the patients who were like, "Hm, you know, what should I do?" High volume. Patients were young, about 55. The criticism of the older studies, there are many criticisms, but one of them is that, the criticism that is lobbied is that they did not really try. Whatever surgery you got, they did not really try with median operative times of 180 minutes for primary cytoreduction, 120 for neoadjuvant. Like, you and I both know, if you're in a big primary debulking, you're there all day. It's 6 hours. Dr. Linda Duska: Right, and there was no quality control for those studies, either. Dr. Kathleen Moore: No quality control. So, SCORPION, they went 451-minute median for surgery. Like, they really went for it versus four hours and then 253 for the interval, 4 hours. They really went for it on both arms. Complete gross resection was achieved in 50% of the primary cytoreduced. So even though they went for it with these very long surgeries, they only got to the goal half the time. It was almost 80% in the interval group. So they were more successful there. And there was absolutely no difference in PFS or OS. They were right about 15 months PFS, right about 40 months OS. JCOG0602, of course, done in Japan, a big study, 300 patients, a little bit older population. Surprisingly more stage IV disease in this study than were in SCORPION. SCORPION did not have a lot of stage IV, despite being very bulky tumors. So a third of patients were stage IV. They also had relatively shorter operative times, I would say, 240 minutes for primary, 302 for interval. So still kind of short. Complete gross resection was not achieved very often. 30% of primary cytoreduction. That is not acceptable. Dr. Linda Duska: Well, so let's talk about TRUST. What was different about TRUST? Why was this an important study for us to see? Dr. Kathleen Moore: So the criticism of all of these, and I am not trying to throw shade at anyone, but the criticism of all of these is if you are putting surgery to the test, you are putting the surgeon to the test. And you are assuming that all surgeons are trained equally and are willing to do what it takes to get someone to no gross residual. Dr. Linda Duska: And are in a center that can support the post-op care for those patients. Dr. Kathleen Moore: Which can be ICU care, prolonged time. Absolutely. So when you just open these broadly, you're assuming everyone has the surgical skills and is comfortable doing that and has backup. Everybody has an ICU. Everyone has a blood bank, and you are willing to do that. And that assumption could be wrong. And so what TRUST said is, "Okay, we are only going to open this at centers that have shown they can achieve a certain level of primary cytoreduction to no gross residual disease." And so there was quality criteria. It was based on – it was mostly a European study – so ESGO criteria were used to only allow certified centers to participate. They had to have a surgical volume of over 36 cytoreductive surgeries per year. So you could not be a low volume surgeon. Your complete resection rates that were reported had to be greater than 50% in the upfront setting. I told you on the JCOG, it was 30%. Dr. Linda Duska: Right. So these were the best of the best. This was the best possible surgical situation you could put these patients in, right? Dr. Kathleen Moore: Absolutely. And you support all the things so you could mitigate postoperative complications as well. Dr. Linda Duska: So we are asking the question now again in the ideal situation, right? Dr. Kathleen Moore: Right. Dr. Linda Duska: Which, we can talk about, may or may not be generalizable to real life, but that's a separate issue because we certainly don't have those conditions everywhere where people get cared for with ovarian cancer. But how would you interpret the results of this study? Did it show us anything different? Dr. Kathleen Moore: I am going to say how we should interpret it and then what I am thinking about. It is a negative study. It was designed to show improvement in overall survival in these ideal settings in patients with FIGO stage IIIB and C, they excluded A, these low volume tumors that should absolutely be getting surgery. So FIGO stage IIIB and C and IVA and B that were fit enough to undergo radical surgery randomized to primary cytoreduction or neoadjuvant with interval, and were all given the correct chemo. Dr. Linda Duska: And they were allowed bevacizumab and PARP, also. They could have bevacizumab and PARP. Dr. Kathleen Moore: They were allowed bevacizumab and PARP. Not many of them got PARP, but it was distributed equally, so that would not be a confounder. And so that was important. Overall survival is the endpoint. It was a big study. You know, it was almost 600 patients. So appropriately powered. So let's look at what they reported. When they looked at the patients who were enrolled, this is a large study, almost 600 patients, 345 in the primary cytoreductive arm and 343 in the neoadjuvant arm. Complete resection in these patients was 70% in the primary cytoreductive arm and 85% in the neoadjuvant arm. So in both arms, it was very high. So your selection of site and surgeon worked. You got people to their optimal outcome. So that is very different than any other study that has been reported to date. But what we saw when we looked at overall survival was no statistical difference. The median was, and I know we do not like to talk about medians, but the median in the primary cytoreductive arm was 54 months versus 48 months in the neoadjuvant arm with a hazard ratio of 0.89 and, of course, the confidence interval crossed one. So this is not statistically significant. And that was the primary endpoint. Dr. Linda Duska: I know you are getting to this. They did look at PFS, and that was statistically significant, but to your point about what are we looking for for a reasonable PFS difference? It was about two months difference. When I think about this study, and I know you are coming to this, what I thought was most interesting about this trial, besides the fact that the OS, the primary endpoint was negative, was the subgroup analyses that they did. And, of course, these are hypothesis-generating only. But if you look at, for example, specifically only the stage III group, that group did seem to potentially, again, hypothesis generating, but they did seem to benefit from upfront surgery. And then one other thing that I want to touch on before we run out of time is, do we think it matters if the patient is BRCA germline positive? Do we think it matters if there is something in particular about that patient from a biomarker standpoint that is different? I am hopeful that more data will be coming out of this study that will help inform this. Of course, unpowered, hypothesis-generating only, but it's just really interesting. What do you think of their subset analysis? Dr. Kathleen Moore: Yeah, I think the subsets are what we are going to be talking about, but we have to emphasize that this was a negative trial as designed. Dr. Linda Duska: Absolutely. Yes. Dr. Kathleen Moore: So we cannot be apologists and be like, "But this or that." It was a negative trial as designed. Now, I am a human and a clinician, and I want what is best for my patients. So I am going to, like, go down the path of subset analyses. So if you look at the stage III tumors that got complete cytoreduction, which was 70% of the cases, your PFS was almost 28 months versus 21.8 months. Dr. Linda Duska: Yes, it becomes more significant. Dr. Kathleen Moore: Yeah, that hazard ratio is 0.69. Again, it is a subset. So even though the P value here is statistically significant, it actually should not have a P value because it is an exploratory analysis. So we have to be very careful. But the hazard ratio is 0.69. So the hypothesis is in this setting, if you're stage III and you go for it and you get someone to no gross residual versus an interval cytoreduction, you could potentially have a 31% reduction in the rate of progression for that patient who got primary cytoreduction. And you see a similar trend in the stage III patients, if you look at overall survival, although the post-progression survival is so long, it's a little bit narrow of a margin. But I do think there are some nuggets here that, one of our colleagues who is really one of the experts in surgical studies, Dr. Mario Leitao, posted this on X, and I think it really resonated after this because we were all saying, "But what about the subsets?" He is like, "It's a negative study." But at the end of the day, you are going to sit with your patient. The patient should be seen by a GYN oncologist or surgical oncologist with specialty in cytoreduction and a medical oncologist, you know, if that person does not give chemo, and the decision should be made about what to do for that individual patient in that setting. Dr. Linda Duska: Agreed. And along those lines, if you look carefully at their data, the patients who had an upfront cytoreduction had almost twice the risk of having a stoma than the patients who had an interval cytoreduction. And they also had a higher risk of needing to have a bowel resection. The numbers were small, but still, when you look at the surgical complications, as you've already said, they're higher in the upfront group than they are in the interval group. That needs to be taken into account as well when counseling a patient, right? When you have a patient in front of you who says to you, "Dr. Moore, you can take out whatever you want, but whatever you do, don't make me a bag." As long as the patient understands what that means and what they're asking us to do, I think that we need to think about that. Dr. Kathleen Moore: I think that is a great point. And I have definitely seen in our practice, patients who say, "I absolutely would not want an ostomy. It's a nonstarter for me." And we do make different decisions. And you have to just say, "That's the decision we've made," and you kind of move on, and you can't look back and say, "Well, I wish I would have, could have, should have done something else." That is what the patient wants. Ultimately, that patient, her family, autonomous beings, they need to be fully counseled, and you need to counsel that patient as to the site that you are in, her volume of disease, and what you think you can achieve. In my opinion, a patient with stage III cancer who you have the site and the capabilities to get to no gross residual should go to the OR first. That is what I believe. I do not anymore think that for stage IV. I think that this is pretty convincing to me that that is probably a harmful thing. However, I want you to react to this. I think I am going to be a little unpopular in saying this, but for me, one of the biggest take-homes from TRUST was that whether or not, and we can talk about the subsets and the stage III looked better, and I think it did, but both groups did really well. Like, really well. And these were patients with large volume disease. This was not cherry-picked small volume stage IIIs that you could have done an optimal just by doing a hysterectomy. You know, these were patients that needed radical surgery. And both did well. And so what it speaks to me is that anytime you are going to operate on someone with ovary, whether it be frontline, whether it be a primary or interval, you need a high-volume surgeon. That is what I think this means to me. Like, I would want high volume surgeon at a center that could do these surgeries, getting that patient, my family member, me, to no gross residual. That is important. And you and I are both in training centers. I think we ought to take a really strong look at, are we preparing people to do the surgeries that are necessary to get someone to no gross residual 70% and 85% of the time? Dr. Linda Duska: We are going to run out of time, but I want to address that and ask you a provocative question. So, I completely agree with what you said, that surgery is important. But I also think one of the reasons these patients in this study did so well is because all of the incredible new therapies that we have for patients. Because OS is not just about surgery. It is about surgery, but it is also about all of the amazing new therapies we have that you and others have helped us to get through clinical research. And so, how much of that do you think, like, for example, if you look at the PFS and OS rates from CHORUS and EORTC, I get it that they're, that they're not the same. It's different patients, different populations, can't do cross-trial comparisons. But the OS, as you said, in this study was 54 months and 48 months, which is, compared to 2010, we're doing much, much better. It is not just the surgery, it is also all the amazing treatment options we have for these patients, including PARP, including MIRV, including lots of other new therapies. How do you fit that into thinking about all of this? Dr. Kathleen Moore: I do think we are seeing, and we know this just from epidemiologic data that the prevalence of ovarian cancer in many of the countries where the study was done is increasing, despite a decrease in incidence. And why is that? Because people are living longer. Dr. Linda Duska: People are living longer, yeah. Dr. Kathleen Moore: Which is phenomenal. That is what we want. And we do have, I think, better supportive care now. PARP inhibitors in the frontline, which not many of these patients had. Now some of them, this is mainly in Europe, will have gotten them in the first maintenance setting, and I do think that impacts outcome. We do not have that data yet, you know, to kind of see what, I would be really interested to see. We do not do this well because in ovarian cancer, post-progression survival can be so long, we do not do well of tracking what people get when they come off a clinical trial to see how that could impact – you know, how many of them got another surgery? How many of them got a PARP? I think this group probably missed the ADC wave for the most part, because this, mirvetuximab is just very recently available in Europe. Dr. Linda Duska: Unless they were on trial. Dr. Kathleen Moore: Unless they were on trial. But I mean, I think we will have to see. 600 patients, I would bet a lot of them missed the ADC wave. So, I do not know that we can say we know what drove these phenomenal – these are some of the best curves we've seen outside of BRCA. And then coming back to your point about the BRCA population here, that is a really critical question that I do not know that we're ever going to answer. There have been hypotheses around a tumor that is driven by BRCA, if you surgically cytoreduced it, and then chemically cytoreduced it with chemo, and so you're starting PARP with nothing visible and likely still homogeneous clones. Is that the group we cured? And then if you give chemo first before surgery, it allows more rapid development of heterogeneity and more clonal evolution that those are patients who are less likely to be cured, even if they do get cytoreduced to nothing at interval with use of PARP inhibitor in the front line. That is a question that many have brought up as something we would like to understand better. Like, if you are BRCA, should you always just go for it or not? I do not know that we're ever going to really get to that. We are trying to look at some of the other studies and just see if you got neoadjuvant and you had BRCA, was anyone cured? I think that is a question on SOLO1 I would like to know the answer to, and I don't yet, that may help us get to that. But that's sort of something we do think about. You should have a fair number of them in TRUST. It wasn't a stratification factor, as I remember. Dr. Linda Duska: No, it wasn't. They stratified by center, age, and ECOG status Dr. Kathleen Moore: So you would hope with randomization that you would have an equal number in each arm. And they may be able to pull that out and do a very exploratory look. But I would be interested to see just completely hypothesis-generating what this looks like for the patients with BRCA, and I hope that they will present that. I know they're busy at work. They have translational work. They have a lot pending with TRUST. It's an incredibly rich resource that I think is going to teach us a lot, and I am excited to see what they do next. Dr. Linda Duska: So, outside of TRUST, we are out of time. I just want to give you a moment if there were any other messages that you want to share with our listeners before we wrap up. Dr. Kathleen Moore: It's an exciting time to be in GYN oncology. For so long, it was just chemo, and then the PARP inhibitors nudged us along quite a bit. We did move more patients, I believe, to the cure fraction. When we ultimately see OS, I think we'll be able to say that definitively, and that is exciting. But, you know, that is the minority of our patients. And while HRD positive benefits tremendously from PARP, I am not as sure we've moved as many to the cure fraction. Time will tell. But 50% of our patients have these tumors that are less HRD. They have a worse prognosis. I think we can say that and recur more quickly. And so the advent of these antibody-drug conjugates, and we could name 20 of them in development in GYN right now, targeting tumor-associated antigens because we're not really driven by mutations other than BRCA. We do not have a lot of things to come after. We're not lung cancer. We are not breast cancer. But we do have a lot of proteins on the surface of our cancers, and we are finally able to leverage that with some very active regimens. And we're in the early phases, I would say, of really understanding how best to use those, how best to position them, and which one to select for whom in a setting where there is going to be obvious overlap of the targets. So we're going to be really working this problem. It is a good problem. A lot of drugs that work pretty well. How do you individualize for a patient, the patient in front of you with three different markers? How do you optimize it? Where do you put them to really prolong survival? And then we finally have cell surface. We saw at ASCO, CDK2 come into play here for the first time, we've got a cell cycle inhibitor. We've been working on WEE1 and ATR for a long time. CDK2s may hit. Response rates were respectable in a resistant population that was cyclin E overexpressing. We've been working on that biomarker for a long time with a toxicity profile that was surprisingly clean, which I like to see for our patients. So that is a different platform. I think we have got bispecifics on the rise. So there is a pipeline of things behind the ADCs, which is important because we need more than one thing, that makes me feel like in the future, I am probably not going to be using doxil ever for platinum-resistant disease. So, I am going to be excited to retire some of those things. We will say, "Remember when we used to use doxil for platinum-resistant disease?" Dr. Linda Duska: I will be retired by then, but thanks for that thought. Dr. Kathleen Moore: I will remind you. Dr. Linda Duska: You are right. It is such an incredibly exciting time to be taking care of ovarian cancer patients with all the opportunities. And I want to thank you for sharing your valuable insights with us on this podcast today and for your great work to advance care for patients with GYN cancers. Dr. Kathleen Moore: Likewise. Thanks for having me. Dr. Linda Duska: And thank you to our listeners for your time today. You will find links to the TRUST study and other 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. 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. More on today's speakers: Dr. Linda Duska @Lduska Dr. Kathleen Moore Follow ASCO on social media: @ASCO on X (formerly Twitter) ASCO on Bluesky ASCO on Facebook ASCO on LinkedIn Disclosures of Potential Conflicts of Interest: Dr. Linda Duska: Consulting or Advisory Role: Regeneron, Inovio Pharmaceuticals, Merck, Ellipses Pharma Research Funding (Inst.): GlaxoSmithKline, Millenium, Bristol-Myers Squibb, Aeterna Zentaris, Novartis, Abbvie, Tesaro, Cerulean Pharma, Aduro Biotech, Advaxis, Ludwig Institute for Cancer Research, Leap Therapeutics Patents, Royalties, Other Intellectual Property: UptToDate, Editor, British Journal of Ob/Gyn Dr. Kathleen Moore: Leadership: GOG Partners, NRG Ovarian Committee Chair Honoraria: Astellas Medivation, Clearity Foundation, IDEOlogy Health, Medscape, Great Debates and Updates, OncLive/MJH Life Sciences, MD Outlook, Curio Science, Plexus, University of Florida, University of Arkansas for Medical Sciences, Congress Chanel, BIOPHARM, CEA/CCO, Physician Education Resource (PER), Research to Practice, Med Learning Group, Peerview, Peerview, PeerVoice, CME Outfitters, Virtual Incision Consulting/Advisory Role: Genentech/Roche, Immunogen, AstraZeneca, Merck, Eisai, Verastem/Pharmacyclics, AADi, Caris Life Sciences, Iovance Biotherapeutics, Janssen Oncology, Regeneron, zentalis, Daiichi Sankyo Europe GmbH, BioNTech SE, Immunocore, Seagen, Takeda Science Foundation, Zymeworks, Profound Bio, ADC Therapeutics, Third Arc, Loxo/Lilly, Bristol Myers Squibb Foundation, Tango Therapeutics, Abbvie, T Knife, F Hoffman La Roche, Tubulis GmbH, Clovis Oncology, Kivu, Genmab/Seagen, Kivu, Genmab/Seagen, Whitehawk, OnCusp Therapeutics, Natera, BeiGene, Karyopharm Therapeutics, Day One Biopharmaceuticals, Debiopharm Group, Foundation Medicine, Novocure Research Funding (Inst.): Mersana, GSK/Tesaro, Duality Biologics, Mersana, GSK/Tesaro, Duality Biologics, Merck, Regeneron, Verasatem, AstraZeneca, Immunogen, Daiichi Sankyo/Lilly, Immunocore, Torl Biotherapeutics, Allarity Therapeutics, IDEAYA Biosciences, Zymeworks, Schrodinger Other Relationship (Inst.): GOG Partners

Dr. Monty Pal and Dr. Fumiko Chino discuss several of the top abstracts presented at the 2025 ASCO Quality Care Symposium, including research on federally funded clinical trials and financial reimbursement for trial participation. TRANSCRIPT Dr. Monty Pal: Hello, and welcome to the ASCO Daily News Podcast. I am your host, Dr. Monty Pal. I am a medical oncologist, professor, and vice chair of academic affairs at the City of Hope Comprehensive Cancer Center in Los Angeles. Today, we are highlighting key abstracts that were presented at the 2025 ASCO Quality Care Symposium. I am delighted to be joined today by the chair of this year's meeting, Dr. Fumiko Chino. Dr. Chino is an associate professor in radiation oncology at MD Anderson Cancer Center with a research focus on access, affordability, and equity. She is also a consultant editor of JCO Oncology Practice and the host of the Put into Practice podcast. I have got to listen to that. Dr. Chino, welcome, and thanks so much for being on the podcast today. Dr. Fumiko Chino: I am overjoyed to be here, and absolutely, you should take a listen. Dr. Monty Pal: Definitely. And FYI for listeners, our full disclosures are all available in the transcript of this episode, so do have a look if you are inclined. Now, we have really seen some fantastic advances in health services and quality and supportive care, digital health, and beyond. There are some great abstracts that were presented at this year's meeting. I have actually picked a couple that I am particularly interested in and that I believe you share my interest in as well. So, the first is an abstract actually from my friends at SWOG (Abstract 94). So, this was a terrific abstract from Joe Unger and Michael LeBlanc and Dawn Hershman. And this, I think, really hits on a very, very key issue right now, which is the benefit of federally funded trials. Do you mind just kind of spelling out some of the observations from what I think is a really brilliant piece of work? Dr. Fumiko Chino: Absolutely, and I think Dr. Unger's work is really important for our current funding environment. I think that this research is really essential to do to show the role of federal sponsorship in the design and conduct of clinical trials. Because what they did was really look at a landscape analysis over the last 20 years looking at funding and were able to show quite clearly that federal funding really matters for advancing the science in cancer care. So what they showed was that the federal funding was more commonly essential for early-stage clinical trials, so those phase 1, phase 2 trials that really help advance the science. And that federal funding was really essential for multimodality drug combinations, combinations with drug and surgery, combinations with drug and radiation. Those trials were much more likely to be federal funded. And then the last thing is that they showed that the patients that are, I think, the largest at risk for gaps in care who really need the advancements in science that keep U.S. health care amazing and wonderful and world-leading, so the kids, the pediatric patients, the patients with rare cancers, and the patients actually that could benefit from de-escalation or right-sizing of treatment, they were also all more likely to have federal funding. So I think this research that was presented really shows that if, unfortunately, current status of restricted federal funding continues, that we are going to lose out in terms of the next generation of cancer cures, cancer de-escalations, and the type of combination treatments that make advancements in science. Dr. Monty Pal: Indeed. You know, I always point to Joe Unger's paper, and I think it is in JAMA Oncology, right, that showed life-years gained from NCI trials. It is such an important piece of work. I think this is a really nice complement to that, isn't it, to show the specific areas that otherwise would be, am I right in saying, kind of largely untouched? Dr. Fumiko Chino: I think you are right in that what we know from what industry will sponsor versus what the federal government will sponsor, that the federal government really helps make up the gap to really make those advancements that save lives, that lead to more birthdays, that advance our knowledge and our capacity for providing more cures and more successful futures for our patients. I always like pointing to the de-escalation research, which is, and this is not to dig pharma, but no pharmaceutical company is going to run a trial that says you can give less of their drug, right? It just does not make sense for the business end of the science. And so, thinking about how to right-size treatments, how to do more with less, that really is the purview of the federal government. Dr. Monty Pal: Absolutely. Absolutely. I am going to shift gears here and bring up another abstract that I found to be quite intriguing, and this relates to reimbursement of expenses, et cetera, for clinical trials. This is an abstract from Courtney Williams and team. It brings to mind the importance, I think, of recognizing the hardships that patients take on by clinical trials, but I also would love for you to comment on that sort of fine line between reimbursement for expenses and then, you know, sort of undue enticement. It is a challenging balance there. But give me your reflections on this abstract. Dr. Fumiko Chino: Absolutely. You are speaking about Dr. Williams' Abstract 93 from the Alabama group, and Alabama actually has this incredible group of health services researchers which is, are doing really important work in this space. What this trial shows is that, you know, it is a small pilot study, it is 30-something patients that received some support primarily for their travel and additional expenses related to their clinical trial participation for breast cancer. It showed that the money helps, and I think what we all know is that it is expensive to participate in clinical trials. It requires additional visits. It often requires some significant travel burden for our patients, and I do not feel that money reimbursement for clinical trial expenses is an inducement. Nobody participates in a clinical trial to get the money for their gas, right? We know that our patients are making some pretty significant sacrifices in order to participate in clinical trials, and what this type of program does is just actually reimburse them for their outlaying of funds. And I loved this trial because the patients were actually given $1,000 a month for the first 4 months of their trial participation, and what the study showed is that the patients were using it for things like travel-related food, for things like transportation, caregiver expenses, or even some of their out-of-pocket medical expenses like cost sharing or prescriptions. And that they said that overall, the reimbursement really made a difference in terms of their capacity for staying on the clinical trial. Because we know our clinical trials really are not able to enroll the full diversity of patients that often have a disease, and that the patients that are at biggest risk for a health care disparity or a gap in care are also the least likely to enroll in a clinical trial. Programs like this are an essential part of showing how financial toxicity can be overcome with pretty straightforward assistance to patients to help reimburse them for the things that they are already taking out of their pocket, for parking costs, for that $10 soup that they buy at the cancer center, for those additional expenses that we are, unfortunately, putting on them. Dr. Monty Pal: Very well said. And you know, I have started to dabble in clinical trials looking at CAR T-cell therapies for kidney cancer, and I have to tell you, it is just insane the amount of cost that a patient would have to take on to comply with the stipulations for some of these novel therapies. We require that they stay within 30 minutes of the facility for 28 days, and unless we are compensating for some of that, I mean, how can one afford a hotel stay that is that long? I mean, it is just, it is unprecedented, and it would certainly provide a huge barrier to many patients who would otherwise enroll. Really well said. I also wanted to bring up another financially driven topic, and treating renal cell, again, I would say the vast majority, 90% plus of my patients in clinic are on oral drug therapies. And I cannot tell you how often a patient will show up in my practice and say, "Doc, I have got 15 days out of this 30-day prescription left. What do I do with it?" You know, or some come with pill bottles from a deceased loved one. And it is so frustrating to say, "Take it to the pharmacy and they will just get rid of it for you." But sounds like there is an abstract from Dr. Mackler, Abstract 102, that seems to address this topic quite well. Am I right? Dr. Fumiko Chino: Absolutely. This presentation, I was the most excited about seeing because this group, which helps run a cancer drug repository, theirs is called YesRx, presented their data from the last approximately two years of running this repository, and they were able to show incredible benefit for their patients in Michigan. And it is a really straightforward program. It is run by pharmacists. It has support from the legislation in Michigan. And what they were able to show is that they repurposed medications that would otherwise have been discarded. They delivered them directly to the oncologist, which then actually dispersed them to the patients. They helped 1,000 patients in less than two years. They saved them millions of dollars, over $15 million presented in the abstract. And it is just a win-win-win because I know that patients actually, and sometimes patient caregivers, they feel very sad to have spent a lot of money out of pocket for their medication, and then if they have a dose reduction or, obviously, you know, if the surviving spouse then has to get rid of their medication, just dispose of them, it is very disheartening. And this is a way of kind of reclaiming power for patients. So they were able to accept donations from all over the state of Michigan and then also help over 1,000 patients. And so, it is a phenomenal program. Dr. Monty Pal: Just wild when I came across the dollar amounts, right, that they were saving. It just, it seems like a place that, you know, we just have to look, as cancer centers, right, and really take this on. Just brilliant. On that same theme of cost savings and so forth, you know, I think there has been a lot of focus on what recent policies have done in the context of us having access to therapies and so forth. And one of the topics that has come up is the Inflation Reduction Act and how changes pertaining to the IRA have really played a role in one's ability to take on some of these expensive prescriptions. And I believe John Lin and colleagues tackled that issue in Abstract 97. Could you comment on that, Fumiko? Dr. Fumiko Chino: Absolutely. Dr. Lin is one of my colleagues here at MD Anderson, so I know him very well, and he has been doing really phenomenal work over the last several years with looking at drug affordability and access. And what his analysis shows is that for patients, after the Inflation Reduction Act's cap on out-of-pocket expenses, is that it really did show that out-of-pocket expenses decreased. So what the Inflation Reduction Act did is that it eliminated the 5% co-insurance and placed this $2,000 cap on out-of-pocket expenses. And what that led to for these patients that were not able to have the low-income subsidy is that there were lower costs, and that there was a lower rate of drug abandonment, meaning that the prescription was not refilled. There was also a lower rate of unfilled prescriptions as well. And I think that it shows that health policy really can improve access to care. I think the flip side of the fact that the IRA, this policy, really did seem to help people is that what his research showed is that actually, even with the benefits of this cap, is that actually it is still really high in terms of the rate of people who are not able to fill their prescriptions or that completely abandon them over time. And that unfortunately, even with this change, that over half of people without the low-income subsidy were potentially not getting the full benefit of their medications because they were not able to afford them. And so I think it really kind of highlights that we still need to do more work about making drugs affordable. Dr. Monty Pal: Indeed, indeed. And I mean, in a setting like this, I mean, I think it is important to recognize that $2,000 is a lot, it is a big chunk of change, right, for a lot of families in the U.S. What do you think of the prospect of, like, decreasing that cap? Is that something that from a policy standpoint you would be supportive of? Dr. Fumiko Chino: Well, so something that is a real option for patients on Medicare is there is something called the Medicare Prescription Payment Plan, and what it allows you to do is actually prorate the $2,000 over the whole year. And so instead of having to pay $2,000 as soon as you fill your prescription, because you are going to have, if you have an expensive medication, it is essentially you have to pay the $2,000 in January, right? It allows you to prorate it, so essentially $170 a month, and that comes to you as like a regular bill. And I think that as rolled out as part of the IRA is a really lovely way of thinking about how do we make these payments more stable over time, so it is not a huge hit sort of at the beginning of the year. And I think that alone actually can make a difference in terms of trying to help make sure that people can actually get their medications. Dr. Monty Pal: That is an excellent tip. Excellent tip. We are going to shift gears entirely. We have been talking a lot about the dollars and cents of things and talk about an abstract from Sophia Smith and colleagues. So this is Abstract 550 at your meeting. And this hinged on a program of sorts to deal with post-traumatic stress disorder. We do not often think about PTSD in the vernacular for oncology patients, but indeed, I mean, it is something that they must face, especially in the context of long-term survivorship. Can you talk a little bit about Dr. Smith's abstract? Dr. Fumiko Chino: Absolutely. I love this work from Dr. Smith, who is at Duke. She worked with Dr. Applebaum, who was my old colleague at Memorial Sloan Kettering. And this group of researchers really is trying to figure out how to best support people into survivorship so that they can actually thrive. And their patient population for this work was actually people who received stem cell transplant, and they focused on people who had PTSD symptoms. And what they were able to show through this SMART design, which is essentially this serial, multiple randomized trial, so everyone got randomized upfront to either usual care or this app, so this digital app that actually helped coach people through cancer distress. And then for the people who were non-responders, they were then additionally randomized to either the app plus coaching or a therapist versus the cognitive behavioral therapy or CBT. And what they were able to show is that, number one, anyone who had the app seemed like they did better than those who did not start the path with the app. But then the additional help of either the therapist or the coach or the CBT made additional benefit over time. And so, I think this shows a really nice stepped care, which is you can potentially have some right-sizing of treatments cost saving, if we sort of give everyone the app, which is, I think, overall pretty low cost. And that for the people who do not get the full benefit from the app, then you can think about these maybe more tailored approaches, the therapist, the coach, the CBT, but that some people actually just respond to the app. And I think it allows us to, again, right-size the care for our patients. And I think it is really innovative to think about how technology can help improve access to care in the setting of something like PTSD. Dr. Monty Pal: Brilliant summary. Brilliant summary. Gosh, it looks like such an exciting meeting this year. Congratulations on a terrific program for the ASCO Quality Care Symposium. I know you played a huge role in developing it, and thanks for sharing your insights on the ASCO Daily News Podcast. Dr. Fumiko Chino: No, I really appreciate you having me. ASCO Quality is my favorite meeting of the year. You know, it is really a phenomenal meeting, and I am so excited for next year in Boston in 2026. Dr. Monty Pal: Awesome. And thanks to our listeners too. You are going to find links to all the abstracts that we discussed today in the transcript of this episode. Finally, if you value the insights that you heard today on the ASCO Daily News 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. More on today's speakers: Dr. Sumanta (Monty) Pal @montypal Dr. Fumiko Chino @fumikochino Follow ASCO on social media: @ASCO on Twitter ASCO on Bluesky ASCO on Facebook ASCO on LinkedIn Disclosures of Potential Conflicts of Interest: Dr. Monty Pal: Speakers' Bureau: MJH Life Sciences, IntrisiQ, Peerview Research Funding (Inst.): Exelixis, Merck, Osel, Genentech, Crispr Therapeutics, Adicet Bio, ArsenalBio, Xencor, Miyarsian Pharmaceutical Travel, Accommodations, Expenses: Crispr Therapeutics, Ipsen, Exelixis Dr. Fumiko Chino: Consulting or Advisory Role: Institute for Value Based Medicine Research Funding: Merck