Expanding Treatment Options for Breast Cancer: ADCs and Oral SERDs

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. Monty Pal and Dr. Jason Westin discuss the federal funding climate for cancer research and the persistent problem of drug shortages, two of the major concerns facing the oncology community in 2026. 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 and vice chair of academic affairs at the City of Hope Comprehensive Cancer Center in Los Angeles. There are always multiple challenges facing oncologists, and today, we discuss two of them that really stand out for 2026: threats to federal funding for cancer research and the persistent problem of drug shortages. I am thrilled to welcome Dr. Jason Westin, who believes that one way to meet these challenges is to get oncologists more involved in advocacy, and he will share some strategies to help us meet this moment in oncology. Dr. Westin is a professor in the Department of Lymphoma and Myeloma at the University of Texas MD Anderson Cancer Center, but he actually wears a lot of hats within ASCO. He is a member of the Board of Directors and has also previously served as chair of ASCO's Government Relations Committee. And he is also one of the inaugural members of ASCO's Political Action Committee, or PAC. He has testified before Congress about drug shortages and many other issues. Dr. Westin, I am really excited to have you on the podcast today and dive into some of these elements that will really impact our community in 2026. Thanks so much for joining us today. Dr. Jason Westin: Thank you for having me. Dr. Monty Pal: You've had such a range of experience. I already alluded to you testifying before Congress. You've actually run for office before. You wear so many different hats. I'm used to checking my PubMed every other day and seeing a new paper out from you and your group, and you publish in the New England Journal [of Medicine] on practice-setting standards and the diseases that you treat. But you've also done all this work in the domain of advocacy. I can't imagine that balancing that is easy. What has sort of motivated you on the advocacy front? Dr. Jason Westin: Advocacy to me is another way to apply our skills and help more people than just those that you're sitting across from at the time. Clinical research, of course, is a tool to try and take what we know and apply it more broadly to people that you'll never meet. And advocacy, I think, can do the same thing, where you can have a conversation with a lawmaker, you can advocate for a position, and that hopefully will help thousands or maybe even more people down the road who you'd never get to directly interact with. And so, I think it's a force multiplier in the same way that research can be. And so, I think advocacy is a wonderful part of how doctors care for our patients. And it's something that is often difficult to know where to start, but once people get into advocacy, they can see that the power, the rewarding nature of it is attractive, and most people, once they get going, continue with that through the rest of their career. Dr. Monty Pal: So, I'll ask you to expand on that a little bit. We have a lot of our younger ASCO members listening to this podcast, folks that are just starting out their careers in clinical practice or academia. Where does that journey begin? How do you get to the point that you're testifying in front of Congress and taking on these bigger sort of stances for the oncology community? Dr. Jason Westin: Yeah, with anything in medicine and in our careers, you have to start somewhere. And often you start with baby steps before you get in front of a panel of senators or other high-profile engagement opportunities. But often the first setting for junior colleagues to be engaged is doing things – we call them "Hill Days" – but basically being involved in kind of low-stakes meetings where you're with a group of peers, some of whom have done this multiple times before, and can get engaged talking to members of representatives' offices, and doing so in a way where it's a natural conversation that you're telling a story about a patient in your clinic, or that you're telling a personal experience from a policy that impacted your ability to deliver optimal care. It sounds stressful, but once you're doing it, it's not stressful. It's actually kind of fun. And it's a way that you can get comfort and skill with a group of peers who are there and able to help you. And ASCO has a number of ways to do that, both at the federal level, there's the Hill Day where we each April have several hundred ASCO members travel to Capitol Hill. There's also state engagement that can be done, so-called visiting at home, when representatives from the U.S. Congress or from state legislators are back in district. You can meet with your own representatives on behalf of yourself, on behalf of your organization, and advocate for policies in a way that can be beneficial to your patients. But those initial meetings that are in the office often they're low stakes because you could be meeting not with the representative but with their staff. And that staff sometimes is as young or even younger than our junior colleagues. These sometimes can be people in their 20s, but they're often extremely knowledgeable, extremely approachable, and are used to dealing with people who are new to advocacy. But they actually help make decisions within the office. So it's not a waste of time. It's actually a super useful way to engage. So, it's that first step of anything in life. The activation energy is always high to do something new. But I'd encourage people who are listening to this podcast already having some level of interest about it to explore ways that they could engage more. Dr. Monty Pal: You know, I have to tell you, I'm going to riff on what you just said for a second. ASCO couldn't make it any easier, I think, for folks to participate and get involved. So, if you're listening to this and scratching your head and thinking, "Well, where do I begin? How do I actually sign on for that meeting with a local representative?" Go to the ASCO ACT Network website. And I'll actually talk to our producer, Geraldine, to make sure we've got a link to that somewhere associated with this podcast after it's published, Jason, but I actually keep that on my browser and it's super easy. I check in there every now and then and see if there's any new policy or legislation that ASCO, you know, is sort of taking a stance on, and it gives me some fodder for conversation with my local representatives too. I mean, it's just an awesome, awesome vehicle. I'm going to segue right from there right to the issues. So, you and I are both at academic centers. You know, I think this is something that really pervades academia and enters into implications for general clinical practice. There's been this, you know, massive sort of proposal for decreased funding to the NCI and to the NIH and so forth. Tell us what ASCO is doing in that regard, and tell us perhaps how our community can help. Dr. Jason Westin: We live in interesting times, and I think that may be an understatement x 100. But obviously investments in research are things that when you're at an academic center, you see and feel that as part of your daily life. Members of Congress need to be reminded of that because there's a lot of other competing interests out there besides investing in the future through research. And being an elected representative is a hard job. That is something where you have to make difficult choices to support this, and that may mean not supporting that. And there's lots of good things where our tax dollars could be spent. And so, I'm sympathetic to the idea that there's not unlimited resources. However, ASCO has done an excellent job, and ASCO members have led the charge on this, of stating what research does, what is the benefit of research, and therefore why should this matter to elected representatives, to their staff, and to those people that they're elected to serve. And ASCO has led with a targeted campaign to basically have that message be conveyed at every opportunity to elected representatives. And each year on Hill Day, one of the asks that we have is to continue to support research: the NCI, NIH, ARPA-H, these are things that are always in the asks to make sure that there's appropriate funding. But effectively playing offense by saying, "It's not just a number on a sheet of paper, this is what it means to patients. This is what it means to potentially your loved ones in the future if you are in the opposite situation where you're not on the legislative side, but you're in the office receiving a diagnosis or receiving a difficult piece of news." We only have the tools we have now because of research, and each breakthrough has been years in the making and countless hours spent funded through the engine of innovation: clinical research and translational research. And so ASCO continues to beat that drum. You mentioned earlier the ACT Network. Just to bring that back again is a very useful, very easy tool to communicate to your elected representatives. When you sign up on the ASCO ACT website, you get emails periodically, not too much, but periodically get emails of, "This is a way you can engage with your lawmakers to speak up for this." And as you said, Monty, they make it as easy as possible. You click the button, you type in your address so that it figures out who your elected representatives are, and then it will send a letter on your behalf after like five clicks to say, "I want you to support research. I want you to vote for this particular thing which is of interest to ASCO and by definition to members of ASCO." And so the ACT Network is a way that people listening can engage without having to spend hours and significant time, but just a few clicks can send that letter to a representative in Congress. And the question could be: does that matter? Does contacting your senator or your elected representative do anything? If all they're hearing is somebody else making a different argument and they're hearing over and over again from people that want investments in AI or investments in something else besides cancer research, whatever it is, they may think that there's a ground shift that people want dollars to be spent over here as opposed to at the NIH or NCI or in federally funded research. It is important to continue to express the need for federal funding for our research. And so, it really is important for folks to engage. Dr. Monty Pal: 100%. One of the things that I think is not often obvious to a lot of our listeners is where the support for clinical trials comes from. You know, you've obviously run the whole gamut of studies as have I. You know, we have our pharmaceutical company-sponsored studies, which are in a particular bucket. But I would say that there's a very important and critical subset of studies that are actually government funded, right? NCI-funded clinical trials. If you don't mind, just explain to our audience the critical nature of the work that's being done in those types of studies and if you can, maybe compare and contrast the studies that are done in that bucket versus perhaps the pharmaceutical bucket. Dr. Jason Westin: Both are critical, and we're privileged that we have pharma studies that are sponsored and federally funded clinical research. And I think that part of a healthy ecosystem for us to develop new breakthroughs has a need for both. The pharma sponsored studies are done through the lens of trying to get an approval for an agent that's of interest so that the pharma company can then turn around and use that outside of a clinical trial after an FDA approval. And so those studies are often done through the lens of getting over the finish line by showing some superiority over an existing treatment or in a new patient population. But they're done through that lens of kind of the broadest population and sometimes relatively narrow endpoints, but to get the approval so that then the drug can be widely utilized. Clinical trials done through cooperative groups are sometimes done to try and optimize that or to try and look at comparative things that may not be as attractive to pharma studies, not necessarily going for that initial approval, but the fine tuning or the looking at health outcomes or looking at ensuring that we do studies in representative populations that may not be as well identified on the pharma sponsored trials, but basically filling out the gaps in the knowledge that we didn't gain from the initial phase 3 trial that led to the approval. And so both are critical. But if we only do pharma sponsored trials, if we don't fund federally supported research and that dries up, the fear I have, and many others have, is that we're going to be lacking a lot of knowledge about the best ways to use these great new therapies, these new immune therapies, or in my team, we do a lot of clinical trials on CAR T-cell therapies. If we don't have federally funded research to do the important clinical studies, we'll be in the dark about the best ways to use these drugs, and that's going to be a terrible shame. And so we really do need to continue to support federal research. Dr. Monty Pal: Yeah, there are no softball questions on this podcast, but I think everybody would be hard pressed to think that you and I would come on here and say, "Well, no, we don't need as much money for clinical trials and NCI funding" and so forth. But I think a really challenging issue to tackle, and this is something we thought to ask you ahead of the podcast, is what to do about the general climate of, you know, whether it's academic research or clinical practice here that seems to be getting some of our colleagues thinking about moving elsewhere. I've actually talked to a couple of folks who are picking up and moving to Europe for a variety of considerations, other continents, frankly. The U.S. has always been a leader when it comes to oncology research and, one might argue, research in general. Some have the mindset these days that we're losing that footing a little bit. What's your perspective? Are you concerned about some of the trends that you're seeing? What does your crystal ball tell you? Dr. Jason Westin: I am highly concerned about this. I think as you said, the U.S. has been a leader for a long time, but it wasn't always. This is not something that's preordained that the world-leading clinical research and translational research will always be done in the United States. That is something that has been developed as an ecosystem, as an engine for innovation and for job development, new technology development, since World War II. That's something that through intentional investments in research was developed that the best and brightest around the world, if they could choose to go anywhere, you wanted them to come to work at universities and academic places within the United States. And I think, as you said, that's at risk if you begin to dry up the investment in research or if you begin to have less focus on being engaged in research in a way that is forward thinking, not just kind of maintaining what we do now or only looking at having private, for profit sponsored research. But if you don't have the investment in the basic science research and the translational research and the forward-thinking part of it, the fear is that we lose the advantage and that other countries will say, "Thank you very much," and be happy to invest in ways to their advantage. And I think as you mentioned, there are people that are beginning to look elsewhere. I don't think that it's likely that a significant population of researchers in the U.S. who are established and have careers and families – I don't think that we're going to see a mass exodus of folks. I think the real risk to me is that the younger, up-and-coming people in undergraduate or in graduate school or in medical school and are the future superstars, that they could either choose to go into a different field, so they decide not to go into what could be the latest breakthroughs for cancer patients but could be doing something in AI or something in a different field that could be attractive to them because of less uncertainty about funding streams, or they could take that job offer if it's in a different country. And I think that's the concern is it may not be a 2026 problem, but it could be a 2036 or a 2046 problem that we reap what we sow if we don't invest in the future. Dr. Monty Pal: Indeed, indeed. You know, I've had the pleasure of reviewing abstracts for some of our big international meetings, as I'm sure you've done in the past too. I see this trend where, as before, we would see the preponderance of large phase 3 clinical trials and practice setting studies being done here in the U.S., I'm seeing this emergence of China, of other countries outside of the U.S. really taking lead on these things. And it certainly concerns me. If I had to sort of gauge this particular issue, it's at the top of my list in terms of what I'm concerned about. But I also wanted to ask you, Jason, in terms of the issues that are looming over oncology from an advocacy perspective, what else really sort of keeps you up at night? Dr. Jason Westin: I'm quite concerned about the drug shortages. I think that's something that is a surprisingly evergreen problem. This is something that is on its face illogical that we're talking about the greatest engine for research in the world being the United States and the investment that we've made in drug development and the breakthroughs that have happened for patients all around the world, many of them happen in the United States, and yet we don't necessarily have access to drugs from the 1970s or 1980s that are cheap, generic, sterile, injectable drugs. This is the cisplatins and the vincristines and the fludarabine type medications which are not the sexy ones that you see the ads in the magazine or on TV at night. These are the backbone drugs for many of our curative intent regimens for pediatrics and for heme malignancies and many solid tumors. And the fact that that's continuing to be an issue is, in my opinion, a failure to address the root causes, and those are going to require legislative solutions. The root causes here are basically a race to the bottom where the economics to invest in quality manufacturing really haven't been prioritized. And so it's a race to the cheapest price, which often means you undercut your competitor, and when you don't have the money to invest in good manufacturing processes, the factory breaks down, there's no alternative, you go into shortage. And this has been going on for a couple of decades, and I don't think there's an end in sight until we get a serious solution proposed by our elected officials. That is something that bothers me in the ways where we know what we should be doing for our patients, but if we don't have the drugs, we're left to be creative in ways we shouldn't have to do to figure out a plan B when we've got curative intent therapies. And I think that's a real shame.  There's obviously a lot of other things that are concerning related to oncology, but something that I have personally had experience with when I wanted to give a patient a CAR T-cell, and we don't have a supply of fludarabine, which is a trivial drug from decades ago in terms of the technology investments in genetically modified T-cells, to not then have access to a drug that should be pennies on the dollar and available at any time you want it is almost like the Air Force investing in building the latest stealth bomber, but then forgetting to get the jet fuel in a way that they can't use it because they don't have the tools that they need. And so I think that's something that we do need to have comprehensive solutions from our elected officials. Dr. Monty Pal: Brilliantly stated. I like that analogy a lot. Let's get into the weeds for a second. What would that proposal to Congress look like? What are we trying to put in front of them to help alleviate the drug shortages? Dr. Jason Westin: We could spend a couple hours, and I know podcasts usually are not set up to do that. And so I won't go through every part. I will direct you that there have been a couple of recent publications from ASCO specifically detailing solutions, and there was a recent white paper from the Senate Finance Committee that went through some legislative solutions being explored. So Dr. Gralow, ASCO CMO, and I recently had a publication in JCO OP detailing some solutions, more in that white paper from the Senate Finance. And then there's a working group actually going through ASCO's Health Policy Committee putting together a more detailed proposal that will be published probably around the end of 2026. Very briefly, what needs to happen is for government contracts for purchasing these drugs, there needs to be an outlay for quality, meaning that if you have a manufacturing facility that is able to deliver product on time, reliably, you get a bonus in terms of your contract. And that changes the model to prioritize the quality component of manufacturing. Without that, there's no reason to invest in maintaining your machine or upgrading the technology you have in your manufacturing plant. And so you have bottlenecks emerge because these drugs are cheap, and there's not a profit margin. So you get one factory that makes this key drug, and if that factory hasn't had an upgrade in their machines in 20 years, and that machine conks out and it takes 6 months to repair or replacement, that is an opportunity for that drug to go into shortage and causes a mad dash for big hospitals to purchase the drug that's available, leaving disparities to get amplified. It's a nightmare when those things happen, and they happen all the time. There are usually dozens, if not hundreds, of drugs in shortage at any given time. And this has been going on for decades. This is something that we do need large, system-wide fixes and that investment in quality, I think, will be a key part. Dr. Monty Pal: Yeah, brilliantly said. And I'll make sure that we actually include those articles on the tagline for this podcast as well. I'll talk to our producer about that as well.  I'm really glad you mentioned the time in your last comment there because I felt like we just started, but in fact, I think we're right at our close here, Jason, unfortunately. So, I could have gone on for a couple more hours with you. I really want to thank you for these absolutely terrific insights and thank you for all your advocacy on behalf of ASCO and oncologists at large. Dr. Jason Westin: Thank you so much for having me. I have enjoyed it. Dr. Monty Pal: Thanks a lot. And many thanks to our listeners too. You can find more information about ASCO's advocacy agenda and activities at asco.org. 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. Thanks so much. ASCO Advocacy Resources: Get involved in ASCO's Advocacy efforts: ASCO Advocacy Toolkit Crisis of Cancer Drug Shortages: Understanding the Causes and Proposing Sustainable Solutions, JCO Oncology Practice Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:     Dr. Monty Pal   @montypal   Dr. Jason Westin @DrJasonWestin   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. Jason Westin: Consulting or Advisory Role: Novartis, Kite/Gilead, Janssen Scientific Affairs, ADC Therapeutics, Bristol-Myers Squibb/Celgene/Juno, AstraZeneca, Genentech/Roche, Abbvie, MorphoSys/Incyte, Seattle Genetics, Abbvie, Chugai Pharma, Regeneron, Nurix, Genmab, Allogene Therapeutics, Lyell Immunopharma Research Funding: Janssen, Novartis, Bristol-Myers Squibb, AstraZeneca, MorphoSys/Incyte, Genentech/Roche, Allogene Therapeutics

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. Pauline Funchain discuss the latest efforts to diagnose, prevent, and treat the series of immune-related adverse events that have emerged in the era of immunotherapy. TRANSCRIPT Dr. Monty Pal: Hello, and welcome to the ASCO Daily News Podcast. I am Monty Pal, a medical oncologist, professor and vice chair of medical oncology at the City of Hope Comprehensive Cancer Center in Los Angeles, California. Now, it is probably no surprise to this audience that immunotherapy has transformed the treatment landscape for multiple cancer types. It remains a pillar of modern oncology. Having said that, I think we have all been baffled by certain toxicities that we run into in the clinic. Today, I am delighted to be joined by Dr Pauline Funchain to discuss some of the checkpoint inhibitor toxicities that people struggle with most. And we will also touch on some side effects of immunotherapy beyond checkpoint inhibitors: CAR-T cells, bispecifics, so on and so forth. Dr Funchain is a dear friend, and she is an associate professor and associate director of cancer research training and education at the Stanford Cancer Institute. She is co-director of the Immunotherapy Toxicity Program and the Skin Cancer Genomics Program at Stanford, where she also serves as associate program director of hematology and oncology fellowship. Dr. Funchain is also the co-founder of ASPIRE, and we are going to talk about that a little bit today, the Alliance for the Support and Prevention of Immune-Related Events. FYI for listeners, if you are interested in our disclosures, they are available at the transcript of this episode. Pauline, thanks so much for joining us today. Dr. Pauline Funchain: Monty, thank you for this invitation. It is always great to talk. Dr. Monty Pal: So, for the audience, Pauline and I know each other from my days as a fellow at City of Hope. She was a resident at Harbor UCLA and a stellar resident at that. It has just been amazing to sort of see your career grow and blossom and to witness all the cool things that you are doing. ASPIRE, in particular, sort of caught my eye. So again, for listeners, this is the Alliance for the Support and Prevention of Immune-Related Events. Can you tell us a little bit briefly about the genesis of that, how that came about? Dr. Pauline Funchain: So, there was a bunch of us who were really struggling, I mean, all of us have struggled with these immune-related adverse events, these irAEs. You know, they are new disease states, and even though they look like autoimmune diseases, they tend to need a whole lot more steroid than autoimmune diseases do and they do not totally present in the same way. And in fact, you know, Triple-M, or Triple-M overlap syndrome, is a completely new irAE, a new immune state that we have never had before the advent of checkpoint inhibitor. And so a Triple-M, for those of you who are not as familiar, that is the constellation of myocarditis, myositis, and myasthenia gravis, something that never occurs as a natural autoimmune disease. So we were starting to realize that there were some major differences with these irAEs and autoimmune diseases. We could not treat them the right way. We really needed to learn more about them. And a bunch of us who had interest in this said, "Look, we really need to be all in one space to talk about what we are doing," because all of our treatments were our own little homegrown brews, and we needed to really get together and understand how to treat these things, how to diagnose them, and then learn more about them. So, Dr. Alexa Meara from Ohio State, Dr. Kerry Reynolds from Mass Gen, we put together this research consortium, brought together all of our irAE friends, got our best subspecialists together in a research consortium, which is now only about a year and a half old. And we made this research consortium, the Alliance for Support of Prevention of Immune-Related Events, and we reached out to ASCO, and ASCO was so kind to grant us a [Alliance for Support and Prevention of Immune-Related adverse Events (ASPIRE)] Community of Practice. So we met for the first time as a Community of Practice at the ASCO Annual Meeting just this past June and really got an ASCO community together to really think about how to again, diagnose, prevent, treat irAEs. Dr Monty Pal: This is interesting to me. The ASCO Community of Practice phenomenon is something that I was not super familiar with. Can you explain to our listenership what is the ASCO Community of Practice model? If you have particular interests, how do you sort of get one started? Dr Pauline Funchain: Yeah, so ASCO has an entire page on their Community of Practice. There are multiple Community of Practice groups or COPs. There are ones for Supportive Oncology and Survivorship. There is Women in Oncology. There is a group for International Medical Graduates. And there is about, I think 10 or 12 now that have a physical presence at ASCO but also a virtual presence on the ASCO Community of Practice site. So, if you were interested in any one of these, and you can see them on the ASCO Communities of Practice sites, you would ask to become a member. Once granted membership, then there is a whole webpage of postings and conversations that people can have. You can get email digests of conversations that happen on the website, and then you can anchor it with in-person participation at the Annual Meeting. Dr Monty Pal: That is awesome, and I can think of so many different foci within oncology that really sort of deserve a Community of Practice. This definitely being one of them. You know, it strikes me as being so interesting. I mean, the checkpoint inhibitors have been around for a while now. I think when you and I were in training, gosh, back then, these were just a little bit of a pipe dream, right? But having said that, I would probably say that more than half of my kidney cancer practice is either on checkpoint inhibitors, and the vast majority have been on one at some point in their past, right? With that in mind, you know, we have all treated a lot of patients with these drugs. Why is it that we still struggle to manage the toxicities? And just to take that one step further, what are some of the toxicities that, perhaps through ASPIRE or through your experience, people struggle with the most? Dr Pauline Funchain: So, I think we are still struggling with these because again, they are new disease states, right? This is what we all experienced with COVID, a brand-new virus and a brand-new syndrome. We now have 20-plus of these as irAEs. And what we have realized about them is the immune activation that happens with these is so much more than what we have seen with autoimmune diseases. So for instance, if you have a Crohn's or ulcerative colitis, you will top out at 40 to 60 milligrams of prednisone if a Crohn's flare or ulcerative colitis flare happens. But for our severe IR colitises, you know, it is at least 1 mg per kg, often goes up to 2 mg per kg. We, in some cases, have done 1 gram pulses if we are worried that somebody is going to perforate. So that was sort of like the first 5 years of treating irAE, and then now in the sort of second 5 years of treating irAE, we have realized that that is a lot of immunosuppression, and we might be able to get away with less with the newer biologics that are on board. So, we are struggling to try to get the data for some of these irAEs that we knew, we have known for a while, but to try to get newer treatments that may immunosuppress less so that you may still be able to retain that tumor response. And in fact, some of the preclinical studies suggest that some of these biologics may actually synergize with the immunotherapy and actually make the immunotherapy more effective from a tumor perspective and calm down the irAE as sort of the bystander effect. So we are still trying to optimize those. Getting up trials in the space has been very difficult. That is one of the reasons for the genesis of ASPIRE because we realized we needed to band together to have a bigger voice in that realm. Then there are other things that are brand new. So we talked about Triple-M. So Triple-M, again, with Triple-M or any myocarditis or myasthenia, I mean, there is about a 50% chance of death from irAE based on the literature. I think we are getting better at recognizing this, and so at Stanford we have some data to say that if you serially follow troponin, that maybe your outcomes are better. You can potentially lower the percentage of cases that are fatal because you can catch them early. I mean, this is all preliminary data, but again, these are all things that are evolving, and we do not all have the right answer. I mean, even the serial troponin thing, I think, is pretty controversial. And in fact, at one of our quarterly Zoom meetings that we are doing in ASPIRE in December is going to sort of flush out that controversy about serial troponin measuring and what is the best thing to use? Would you use something like abatacept or would you use ruxolitinib? Which one is better? I think there is a lot of controversy still about these things. Dr Monty Pal: You have really piqued my curiosity here because you think about the cons of treating irAEs, right? And I worry exactly about what you had mentioned, right, which is, "Gosh, what is going on with this tumor in terms of immunosuppression?" But you think about some of the newer agents, you mentioned ruxolitinib, I have heard of dasatinib, for instance, in this setting. Frankly speaking, a lot of these, as you point out, are really thought of as being also anticancer drugs. So you have really got me thinking about the potential synergy between perhaps suppressing an irAE and augmenting antitumor activity, which I think is very interesting. Am I on the right track with that? Dr Pauline Funchain: I think so, but you will find that a lot of people will not even go there because they are worried about how much immunosuppression you are going to cause. I am at heart a geneticist, but I think an immunologist will happily tell you that the immune system is very complex. There are multiple pathways, and these drugs do not all target the same immune pathways. So if we understand a little bit more about the pathways we are targeting and pick apart the pathways that are really, really tumor relevant and the other pathways that are not tumor relevant, you may be able to piece together a better marriage of tumor response and irAE control. Dr Monty Pal: Kind of on this topic, and again, leaning on your background in genetics, where are we in terms of predicting these irAEs? I mean, you would think the holy grail would be picking out a snip or something of this for it, right, that could potentially identify that patient who is going to get Triple-M or, you know, at the very least a significant high-grade irAE event. Are we anywhere closer to that in 2025? Dr Pauline Funchain: There have been data published. There have been some big GWAS studies. All of the effect sizes are pretty small. So there are some prediction algorithms, but none of them are clinically useful. And I think when you look at the odds ratios, they will increase risk by maybe 20%. I think one of the things that we found in a very small series and supported anecdotally is something as easy as family history of autoimmune disease is probably more predictive at this point than any of those types of markers. I think we will get there, but we are not anywhere near where we would like to be. Things like TMB also, actually, there is some good data about higher TMB, higher risk of irAE too. Dr Monty Pal: Interesting. I see all this data coming through, IL-8 polymorphisms, etc. And I just wondered if any of that was ready for prime time. But I mean, this is a good message for the practicing clinician. Sounds like we are not quite there yet. And I could probably keep you on for another entire podcast to talk about this topic, but let us see if we can at least skim the surface. I never thought I would see the day when BiTEs and CAR-Ts were entering into my kidney cancer practice, but in fact, it is really become central to a lot of our clinical trials in RCC these days. I would be lying if I did not say that I was not struggling with the toxicities and so forth associated with these drugs. Can you give us a quick primer, maybe just good resources that people can go to for managing toxicity with BiTEs and with CAR and with some of these novel therapeutic modalities that we are using in the oncology clinics? Dr Pauline Funchain: I know there is a recently published toxicity manual for BiTEs in hematologic malignancies, I think it was in Blood. CAR-T is covered in many irAE guidelines. So ASCO guidelines actually has a CAR-T [cell therapy guideline], and I would be remiss not to point out that actually ASCO has a, I am a little biased, but a wonderful guideline on irAE that is actually being updated as we speak. We are hoping for publication next year. I find the format of that, there are many guidelines out there, actually. There is ASCO, SITC, ESMO has a guideline for irAE, but I find the formatting of the ASCO guideline to be much easier to flip through during clinic, just because of the visual format of the tables. But that is going to be updated next year. And with CAR-T, there is now multiple publications also in terms of guidelines. But what I will say about bispecifics and CAR-T, so they have very similar toxicities in terms of the cytokine release and also with the ICANS, so the neurotoxicity. But what we have been finding that is really interesting with BiTEs and CAR-T, and actually even with TIL, cytokine release is very similar to some of the IL-2 toxicities but not identical that we see with TIL treatment. But now we are starting to see overlap. So patients who have been treated with immunotherapy and then go on to get a bispecific or then go on to get TIL, so I have seen some colitises that have occurred after the fact. Some of the newer CAR-Ts without checkpoint have been causing some really interesting, probably not in a good way, but interesting biologically, colitises that are really refractory. So we are starting to see some overlap, and again, I think this field is just evolving constantly. Dr Monty Pal: Yeah, no, I almost think I need to go back to that fellowship that you and I did together 20 years ago and, you know, and see if I could repeat some coursework on CAR-T management.  You know, Pauline, I could probably keep you on the horn for hours, but this has just been terrific. Thank you so much for sharing all of your insights with us today on the ASCO Daily News Podcast. Dr Pauline Funchain: Thank you for the invitation. It was wonderful to talk about this, and it was wonderful to catch up a little bit, Monty. Dr Monty Pal: Same here, same here. And thanks to our listeners too. If you value the insights 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. Find out more about today's speakers:      Dr. Monty Pal    @montypal   Dr. Pauline Funchain @FunchainMD Follow ASCO on social media:       @ASCO on Twitter      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. Pauline Funchain: Consulting or Advisory Role: Merck, Replimune, Sanofi/Regeneron, Immunocore, Tempus Research Funding (Inst.): Pfizer, Bristol-Myers Squibb, IDEAYA Biosciences, Linnaeus Therapeutics Travel, Accommodations, Expenses: Merck

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

Dr. Monty Pal and Dr. Matteo Lambertini discuss a compelling global study on the clinical behavior of breast cancer in young BRCA1 and BRCA2 carriers, the association of pre-diagnostic awareness of BRCA status with prognosis, and the importance of identifying healthy people who are at risk of carrying the BRCA1/2 pathogenic variants. TRANSCRIPT Dr. Monty Pal: Well, hello everyone, 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 medical oncology at the City of Hope Comprehensive Cancer Center in Los Angeles. Now, when we think about genetic testing, whether for patients diagnosed with breast cancer or for other family members of them, it seems to be widely underutilized. Today, we're going to be discussing a recently published study in the Journal of Clinical Oncology that reported on the clinical behavior of breast cancer and specifically young BRCA1 and BRCA2 carriers, and the association of pre-diagnostic awareness of BRCA status with prognosis. I thought this was just a fascinating piece, and I honestly couldn't wait to have this conversation. It's a really compelling paper that highlights the importance of identifying healthy people who are at risk of carrying the BRCA1/2 pathogenic variants, and really the need for genetic counseling and testing to inform people about early detection that could lead to a better prognosis. I'm really delighted to welcome the study's lead author, Dr. Matteo Lambertini. He really needs no introduction. He's very well known in the breast cancer world for his amazing contributions to fertility in the context of breast cancer, to pregnancy in the context of breast cancer, and genetic testing. He's an associate professor at the University of Genova, and a breast cancer medical oncologist at the San Martino Polyclinic Hospital in Genova, Italy.  Dr. Lambertini, thank you so much for joining us today. Dr. Matteo Lambertini: Thank you very much, Dr. Pal. It's a great pleasure. Dr. Monty Pal: Oh, thanks. And just FYI, if you're listening in and you want to hear our disclosures, they're all listed at the transcript of this podcast.  So, I poured through this paper [Clinical Behavior of Breast Cancer in Young BRCA Carriers and Prediagnostic Awareness of Germline BRCA Status] yesterday, Dr. Lambertini, and first of all, congratulations on this study. This was a huge international multicenter effort, 4,752 patients. How did you pool all these patients with young breast cancer? Dr. Matteo Lambertini: Thanks a lot for the question. Yes, this was an effort made by several centers all over the world. The main idea behind the creation of this network that we have named as BRCA BCY Collaboration, was to get as many data as possible in a sort of niche patient population in the breast cancer field, meaning women diagnosed with breast cancer at the age of 40 years or younger, and all of them being BRCA carriers. We know that around, in the Western world, around 5% of breast cancer cases are being diagnosed under the age of 40 years, and among them around 10-15% are BRCA carriers. So, I would say it's a relatively rare patient population where we did not have a lot of evidence to support our choices in terms of counseling on treatment, prevention, and oncofertility as well. That was the idea behind the creation of this network that includes many centers. Dr. Monty Pal: Yeah. You know, what's so interesting about this is that you sort of draw this line between patients who have BRCA testing at the time of diagnosis and then BRCA testing earlier in their course and then leading to a diagnosis perhaps. And I think that's where really sort of the dichotomy in outcome sits. Can you maybe elaborate on this and tell us about timing of genetic testing in this study and what that meant ultimately in terms of prognosis? Dr. Matteo Lambertini: In this specific analysis from this large network, including almost 5,000 women with breast cancer diagnosed at the age of 40 years or younger and being a BRCA carrier, we looked specifically into the timing of genetic testing because this is a retrospective study and the criteria for inclusion are those that I have just mentioned, so diagnosis at a young age plus carrying germline BRCA pathogenic or likely pathogenic variant. In this analysis, we have looked into the time the patient has got the genetic testing and particular we focused on two populations: those that were diagnosed, knowing already to be a BRCA carrier, and those that got tested after being diagnosed with breast cancer. And the main findings from this analysis have been that knowing to be a BRCA carrier was associated with a lower stage at the time of diagnosis, meaning more T1 tumors, so a tumor less than 2 cm, more node-negative disease, and this translated into less aggressive treatment, so less often axillary dissection, less often use of chemotherapy and anthracycline-based chemotherapy. And even more importantly, we have seen a better overall survival for those patients that were diagnosed already knowing to be BRCA carriers as compared to those tested after breast cancer diagnosis. These results after adjusting for all the confounding, stage, treatment and so on, there was not significant anymore, meaning that it's not the timing of test per se that is probably leading to a better survival, but it is the fact that knowing to be a BRCA carrier would likely translate into having access to all the preventive measures that we have in this setting and this will translate into an overall survival benefit, so in terms of saving more lives in young BRCA carriers. Dr. Monty Pal: I think it's such an important point, and it's one that I think might sound implicit, right, but it needs to be proven, I think, through a study like this. You know, the fact that finding this early, identifying the mutation, doing enhanced screening, and so forth, is really going to lead to superior clinical outcomes. One of the things that I think many people puzzle over, including myself, is what to do? I personally occasionally will see BRCA altered patients in the context of prostate cancer. But that's a very different population of individuals, right? Typically older men. In young females with BRCA mutation, I guess there's a specific set of considerations around reproductive health. You'd already highlighted preventive strategies, but what sorts of things should we be talking about in the clinics once a patient's diagnosed and once perhaps their breast cancer diagnosis is established? Dr. Matteo Lambertini: Yes, exactly. Knowing to be a BRCA carrier has a lot of implications from prevention to treatment to survivorship issues including reproductive counseling. And this is important not only for the patient that has been diagnosed with breast cancer but also for all the family members that will get tested and maybe identify with this sort of genetic alteration before diagnosis of cancer. Why this is important is because we have access to very effective preventive measures, a few examples: MRI screening, which starts at a very young age and normally young women don't have an effective screening strategy outside the BRCA field. Also, primary preventive measures, for example, risk-reducing surgery. These women are known to have a high risk of breast cancer and high risk of ovarian cancer. So the guidelines are suggesting to undergo risk-reducing salpingo-oophorectomy at a young age, so 35 to 40 years in BRCA1 carrier, 40 to 45 years in BRCA2 carrier. And also risk-reducing mastectomy should be discussed because it is a very effective way to prevent the occurrence of breast cancer. And in some situations, including the setting that we are talking about, so young women with breast cancer, BRCA carrier, also risk-reducing mastectomy has shown to improve overall survival.  On the other side, once diagnosed with breast cancer, nowadays knowing to be or not a BRCA carrier can make a difference in terms of treatment. We have PARP inhibitors in the early setting, in the adjuvant setting as well as in the metastatic setting. And in terms of survivorship implication, one of the critical aspects for young women is the oncofertility care which is even more complicated when we talk about BRCA carriers that are women candidates for gynecological surgery at a very young age. So this sort of counseling is even more complicated. Dr. Monty Pal: One of the other things, and this is subtle in your paper and I hope you don't mind me bringing it up, is the difference between BRCA1 and BRCA2. It really got me thinking about that because there are differences in phenotype and manifestation. Do you mind just expanding on that a little bit for the audience because I think that's a really important reminder that you brought up in the discussion? Dr. Matteo Lambertini: The difference between BRCA1 and BRCA2 carriers has been known that there are different phenotypes of breast cancer that are more often diagnosed in these two different populations. Normally BRCA1 carriers have a higher likelihood to develop a triple negative breast cancer as compared to BRCA2 carriers, more likely to develop a hormone receptor-positive HER2-negative disease. In this study, again, a specific population of young women with breast cancer, we have seen the same findings, mostly triple negative disease in BRCA1 carrier, mostly luminal-like disease in BRCA2 carrier. But what's novel or interesting from this study is to look also at the age at the time of diagnosis of this disease. And particularly in BRCA1 carriers, we should be sort of more careful about diagnosis of breast cancer and also other primary tumors including ovarian cancer because the risk of developing these malignancies is higher even at a younger age as compared to BRCA2 carriers. And this has implications also in the primary and secondary prevention that we were talking about earlier. Dr. Monty Pal: Oh, interesting. I guess the fundamental question then from your paper becomes, how do we get at the right patients for screening for BRCA1 and BRCA2? And I realize our audience here is largely oncologists who are going to be listening to this podcast, oncology providers, MDs, nurses, etc. But maybe speak for a moment to the general practitioner. Are there things that, for instance, a general practitioner should be looking for to say, "Wait a minute, this patient's high risk, we should consider BRCA1, BRCA2 testing or germline screening"? Dr. Matteo Lambertini: Yes, it's a very important question for the breast cancer community. After the updated ASCO guideline, the counseling is way easier because right now the age cutoff goes up to 65 years, meaning that all the patients diagnosed with breast cancer below the age of 65 years should be tested these days. And then above the age of 65, there are different criteria like triple-negative disease or family history. From a general practitioner standpoint, it's of course a bit more difficult, but knowing particularly the family history of the person that they have in front will be crucial to know if there are cases of breast cancer diagnosed at a young age, maybe triple-negative cases, knowing cases of ovarian cancer in first-degree relatives or pancreatic cancer in first-degree relatives, and of course cases of prostate cancer as well. So, I would say probably mostly the family side will be important from a general practitioner perspective.  From an oncology one, the other point that I think is important to stress also based on the data that we have shown in this publication is that having a case of breast cancer known to carry a BRCA pathogenic or likely pathogenic variant. It means that all the people around this case should get tested and if found to be BRCA carrier and healthy carrier, these people should also undergo the primary and secondary prevention strategies because this is very critical also to improve their outcomes and try to avoid the developing of breast or ovarian cancer, but also in the case of diagnosis of this disease, a diagnosis at an earlier stage, as we have seen in this paper. Dr. Monty Pal: Brilliant. I'm going to diverge from our list of questions here and close by asking a question that I have at the top of my mind. You're very young. I know our podcast listeners can't see you, but you're very, very young. Dr. Matteo Lambertini: Thank you. Thank you for that. Not so young but yeah. Dr. Monty Pal: You have nearly 300 papers. Your H-index is 67. You've already made these seminal contributions, as I outlined it from the outset, regarding fertility, regarding use of GnRH analogs, regarding pregnancy and breast cancer. What are you studying now? What are you really excited about right now that you're doing that you think might potentially be practice changing? Give us a little teaser. Dr. Matteo Lambertini: Yeah. Thanks a lot, Dr. Pal. Receiving this compliment from you is fantastic. So, thanks a lot for that. From my side, in terms of my research, I've been interested in the field of breast cancer in young women since the start of my training. I've had very good mentors from Italy, from Europe, from the U.S. I'm still interested in this field, so I think we still have a lot to learn to try to improve the care of young women with breast cancer. For example, the oncofertility care, which is something I worked a lot over the past years. Now with all the new treatment options, there's a sort of new chapter of oncofertility counseling. So, what's the impact of immunotherapy? What's the impact of the new targeted agents?  More on the genetic aspects, now we know that there's not only BRCA1 or BRCA2. There are a lot of other different genes that may increase the risk of breast cancer and other malignancies. And also for these genes, we really don't have a lot of evidence to counsel women on prognosis, treatment, prevention strategy. So we need to learn way more for this special patient population that are quite rare, and so we really need a multicenter academic effort to try to give some evidence in this field. Dr. Monty Pal: Yeah. It's tough because these are rare circumstances, but, you know, I think that you've done really well to sort of define some collective experiences that I think really define therapy. I mean, I just remember when I was in training 25 years ago, just reading through textbooks where all the experience around breast cancer and pregnancy was really just very sort of anecdotal almost, you know? And so it's great to see that the state of the science has moved forward.  Well, gosh, I really enjoyed our conversation today. I think your study really reminds us how powerful genetic information is in terms of improving outcomes. And, you know, hopefully this will lead some individuals to perhaps test more broadly in appropriate settings. So, thank you so much, Matteo, for joining us today with your fantastic insights on the ASCO Daily News Podcast. Dr. Matteo Lambertini: Thank you very much, Dr. Pal. It's a real pleasure. Dr. Monty Pal: And thanks to our listeners too. You'll find a link to Dr. Lambertini's 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. Thanks a ton. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:    Dr. Sumanta (Monty) Pal  @montypal  Dr. Matteo Lambertini @matteolambe   Follow ASCO on social media:     @ASCO on Twitter    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. Matteo Lambertini: Consulting or Advisory Role: Roche, Novartis, Lilly, AstraZeneca, Pfizer, MSD, Exact Sciences, Gilead Sciences, Seagen, Menarini, Nordic Pharma Speakers' Bureau: Takeda, Roche, Lilly, Novartis, Pfizer, Sandoz, Ipsen, Knight Therapeutics, Libbs, Daiichi Sankyo, Gilead Sciences, AstraZeneca, Menarini, AstraZeneca, Menarini Research Funding (Inst.): Gilead Sciences Travel, Accommodations, Expenses: Gilead Sciences, Daiichi Sankyo Europe GmbH, Roche

Dr. Monty Pal and Dr. Mina Sedrak discuss the science behind cancer treatment-induced accelerated aging and the development of drug therapies and technologies aimed at helping older patients and cancer survivors. TRANSCRIPT Transcript: Cancer and Aging: Researching the Path to Longer, More Vibrant Lives Dr. Monty Pal: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Monty Pal. I am a medical oncologist and professor and vice chair of medical oncology here at the City of Hope Comprehensive Cancer Center. I am also host of this podcast. Today, we are going to be talking to somebody that I consider to be my little brother, if you will, in oncology, Mina Sedrak. Mina is an expert in the area of cancer and aging, which really includes the development of drug therapies and technologies that help enable older adults and survivors to live longer, healthier, and more vibrant lives. I am really excited to chat with him. He is an expert not just in cancer and aging but also breast cancer. He was my former colleague here at City of Hope before he moved over to the UCLA Jonsson Comprehensive Cancer Center, where he is an associate professor and director there of the Cancer and Aging Program. Dr. Sedrak's research involves mechanisms behind cancer treatment-induced accelerated aging and really aims to take this science into more of a therapeutic direction, which I am super, super excited about.  Mina, thanks so much for joining us today, and just FYI for our listeners, we have all of our disclosures in the transcript of this episode. Dr. Mina Sedrak: Thank you, Monty. Thank you, Dr. Pal, for having me. I am really excited to be here. Dr. Monty Pal: I feel like we have to go on a first-name basis here with how well we know each other. So Mina, you and I together have witnessed this evolution in cancer and aging. I mean, both of us worked together here with just a legendary figure in the field of geriatric oncology, I will call it, Dr. Arti Hurria, mentor to me, mentor to you, mentor to so many. Can you give us a sense of where cancer and aging has gone since the time that you and I started here together at City of Hope? Dr. Mina Sedrak: Dr. Hurria and her collaborators, Dr. [Willliam] Dale and Dr. [Supriya] Mohile, they were like huge pioneers in the field. They were one of the very first people to highlight the importance of looking at older adults beyond just their chronological age and their comorbidities and moving us beyond just seeing patients and making decisions using what we call the eyeball test. "Oh, this person looks fit or not fit, frail or robust," to really using objective measures to assess our patient's health status and incorporate that assessment into our evaluation of the treatment, prognostication, and discussions with our patients throughout the cancer continuum. And so that is what geriatric oncology has and continues to be, and it is a huge, important part. And their work has laid the foundation to show that when we look at our patients beyond just their chronological age and we look at their functional age, and we do these objective assessments, we can gain much more deeper information to tailor the treatment for our patient that is sitting in front of us, rather than do a prescriptive treatment or over- or undertreatment in that population. So that is sort of where the field is growing, and a lot of the work now is, how do we implement that? How do we put that into clinical practice? Dr. Monty Pal: Well, let me kind of spearhead that discussion, right? I have these moments when I go to the ASCO Annual Meeting – I remember this happened to me a while ago when Dr. Jennifer Temel presented that terrific work around early palliative care interventions, right? Or it even happened to me this year, right, when Dr. Christopher Booth presented the CHALLENGE trial around exercise and colon cancer. You know, these amazing, I am going to say simple, they are not simple, but they are simple interventions relative to, you know, some of the complex drugs and mechanisms that we are using nowadays that really help outcomes for our cancer patients. The big question becomes, how do you implement, right? But my understanding is that there are easy ways for us to take tools in cancer and aging and sort of plug them into our daily practice. Am I right about that? Dr. Mina Sedrak: Yes, and that is something that they are – the Cancer and Aging Research Group, which was founded by Dr. Hurria and now is co-led by Dr. Dale, Dr. Mohile, and Dr. [Heidi] Klepin, they have been incredible at really trying to develop practical tools, like the Practical Geriatric Assessment, which is now endorsed by the ASCO and other NCCN guidelines. And so, there are tools that are becoming more and more practical to help incorporate that into clinic.  Now, what might be practical in a resource-intensive setting may not be practical in some of the limited resources, whether it is rural and/or other countries where the resources may be more limited. So that is why Cristiane Bergerot, Enrique Soto, and others have been really working hard. There was actually a really beautiful paper that was just published in the Journal of Global Oncology, where they have shown that there are guidelines [ASCO Geriatric Assessment Global Guideline] about how to implement these tests, these tools, these assessments in clinical practice, even in different resource settings. So I think we are going to get to the future where this is much more – it is definitely important, but it is much more easily 'incorporatable' into our practice. Dr. Monty Pal: Yeah, you know how close I am to Cris, and I was so proud when I saw that paper come out. That was really exciting. You know, I skimmed it. I have to tell you, I did not get into the weeds, but it was apparent to me that, you know, some of these geriatric oncology tools are things that, you know, I could probably plug and play into my practice where I am double- and triple-booked over, you know, most slots, right? I mean, I could still probably afford a little bit of time or maybe have, like, a nurse or an extender kind of help participate in the evaluation process. I thought that was, yeah, really, really interesting. Dr. Mina Sedrak: I will just say that at UCLA, we are working with Dr. Arash Naeim, who is a geriatric oncologist, and he has developed an AI platform where the assessments can be done by an AI computer. So it is like talking to your ChatGPT. They can talk to you, and for a few minutes, they will ask you the questions. So you do not even have to fill it out on a piece of paper. You could give the patient a little iPad, put them in a private room while they are waiting for their doctor, and get the results, and it is right there for you. And so, we have been trying to think about how can technology help with the completion of the assessment, at least doing that? And I think it is actually, it has been very cool. We did a pilot study. He is writing that up, and we are going to continue to do some of this exciting work. How do we think about AI in the context of this? And, you know, older adults, they are not like what they used to be. A lot of older adults are very familiar with and comfortable with phones and computers and iPads, much more so today than they were even at the time when Dr. Hurria was alive. Dr. Monty Pal: That is so interesting. You mentioned this, the AI approach is something I have been thinking about in this context because what if, for instance, you know, we have got video monitors all over our hospital, right? What if you are actually just taking a look at that patient as they make their way towards your clinic? Capture that video, use an AI algorithm to say, "Hey, you know, the timed get-up-and-go test in this patient is not particularly good based on what I am seeing here," right? There are so many ways that you could, you know, stir the pot and come up with creative ways to get these tests done. Dr. Mina Sedrak: That's right. And Arash is looking at also sensors. So he has some studies where he is putting sensors inside people's homes, where they would put them, like, on top of an Alexa app or the equivalent. A lot of people have these apps, and basically, they can sense how you are moving around and what you are doing, just movement-wise. And then they can collect that information to gain information about your life beyond just what we are seeing in the 20-minute visit in the clinic. Even when I do a walk test where I get gait speed or physical performance, short physical performance battery, the chair sit-up, those are oftentimes a single, cross-sectional, static measure. But what about the dynamic ability of capturing what has been happening for the last 7 days? What has been happening for the last 25 days between the visits, between the cycles of chemotherapy? And could that inform how I make decisions when I see patients and who do I need to target and identify? And so, we are very excited because really at UCLA, Arash is leading the technology efforts and thinking about implementation of these important measures and these important tools but leveraging new technology. And we do not want to be behind; we want to be ahead of the game. Dr. Monty Pal: I love that idea because there is a Hawthorne effect, isn't there, where you observe a process, and it naturally gets better. I mean, when you ask that patient to get up in the clinic and move, they are probably functioning to the best of their abilities, but we could probably learn a lot from just watching how fast that patient picks up a remote control at home. Some simple movement like that that is volitional would probably help out a ton. And I got to tell you, it is so funny when you mention Arash Naeim's name. I distinctly remember him serving as an attending on the wards when he was brand new at UCLA on faculty when I was a resident there. And his dad is a legendary hematopathologist, right? Dr. Mina Sedrak: I did not know that. Dr. Monty Pal: Yeah, yeah. Faramarz Naeim wrote the book on a lot of heme-path malignancies. Incredible guy. Very, very storied hematopathologist at UCLA.  I could probably go on this topic forever, but in the interest of time, I am going to shift to something that again, I could probably talk about forever, which is this area of senescence that you are involved in. You know, you had mentioned this to me, I am going to say during your outro from City of Hope and towards your transition to UCLA, it is such an exciting area. I mean, understanding the actual biologic process of aging and using those underpinnings to really sort of tailor therapy. So tell us where the state of the science is there with this body of work that you are doing. Dr. Mina Sedrak: As I said before, we have tools now to assess patients and to then do something about the deficits. So if a patient is falling, what we do is we refer them to physical therapy where they can do fall precautions and strength training to give them the information. But all of these supportive care interventions are very important. They are great. But they oftentimes are not targeting the root cause of why they are happening. And so that is really where I have been very interested in, how can we understand why is it that something like chemotherapy or immunotherapy is causing a decline in cognitive function or a decline in physical function? And so that has really led us to think about geriatric oncology rather than a discipline of older adults, but to think about aging as a physiologic process. We are all aging. As every day goes by, we are aging. And what that means is that our bodies are accumulating damage, the cells are being exposed to various stressors, and the repair mechanisms are declining. And as we get older, it is really more damage and less repair mechanism at the cellular molecular level. And it turns out that these processes of how our cells repair and respond to damage are fundamental processes of biological aging. And there has been a large amount of preclinical and now really exciting clinical work to show that there are hallmarks that could be used to assess the rate of which we age by looking at these processes. And that includes things like epigenetics, telomeres, inflammation, and something called 'cellular senescence.' And we have been interested in my lab in senescence because it is a unique process that has an important role in aging, but it also has a really important role in cancer. Senescence is a cell state. Cells, when they are stressed, they respond to entering this state of senescence. The stress could come from anything. It could come from an oncogene activation. It could come from a reactive oxygen species. It could come from a direct damage to the cell. But it is a cell state, just like apoptosis, necrosis. Senescence is a state in which the cell, in response to that stressor, undergoes an arrest from the G to the S phase. And that arrest is oftentimes associated with a resistance to apoptosis. So then the cell does not die, but it is alive, and it remains metabolically active. And in fact, downstream pathways of these cell cycle inhibition of this G-to-S phase lead to the increase of these transcription factors in the chromatin and lead to the development of these pro-inflammatory factors. So these cells, which can occur in various tissues in the body, can continue to live despite having developed these changes, and then they secrete these proinflammatory molecules like cytokines, chemokines, metalloproteinases, all of these, which are called the senescence-associated secretory phenotype, or SASP. And as we age, we accumulate more and more of these cells, and our bodies are no longer able – our immune system, like macrophages and T cells – are no longer able to remove them effectively. And as we accumulate them in various organs, these organs release a lot of inflammatory cytokines, and the chronic inflammation in that tissue leads to the tissue being damaged, and it does not work as well, and then it starts to decline in function. And that is believed to be how senescence plays a role in aging. It is the accumulation of senescent cells that occurs with increased damage and then the repair mechanism of clearing these cells effectively, which then leads to build up of inflammation and chronic inflammation leads up to damage in multiple tissues. Dr. Monty Pal: This concept to me is fascinating. And I guess the big question is – senescence is bad, right – is it not reasonable to think that this body of research, I mean, if you are able to sort of have a meaningful impact on senescence, it could have implications well beyond oncology. Is that fair? You really could extend lifespan all around. Is that reasonable to think, all-cause mortality? Dr. Mina Sedrak: One hundred percent. And that is what they have been shown in animal models. And the reason senescence is exciting is because it turns out that you can target these cells and you can induce apoptosis of these cells, but it requires active targeting of various pathways, but it can occur. And when it does, and it is done either genetically or pharmacologically in mice, we see that the mice can reverse damage. So if you take an old mouse and you genetically engineer it to remove senescent cells, that mouse will go from being frail to fit. And if you take a young mouse and you induce senescent cells at a high rate and you accumulate them in that mouse, that mouse, even though it is young, will become frail.  So that has really led to this exciting opportunity of, can we translate this finding that we are seeing in animals and in in vivo cells, cell cultures, into humans? And could that have a benefit beyond just one disease? Could it have a benefit in multiple diseases? And not just really longevity, which I think it would be great, but what people are really looking for is, how do we live healthy as we get older? How do we move the curve so that people are not developing chronic diseases in their 60s, but they are developing them in their 80s towards shortening the period of their life with disability rather than what we have currently, which is people are living to 70s, the average life expectancy is in the mid-70s, but they are spending 10 or 11 years in disability of that life. And so, how could we reduce that time frame? Dr. Monty Pal: This is brilliant, Mina. And for our audience, this compelling dialogue that we have had here thankfully is translating to funding for Mina's work. He just scored in the second percentile for his NIH R01 based on this topic. We are so, so proud of you. I mean, it is just remarkable work. It is not easy in the current climate to get funding, and a second percentile score is just absolutely wonderful. You know, Mina, I could probably go on with you for a couple more hours here talking about your work in cancer and aging. I think I am going to have to have you back on the podcast here. But a million thanks for sharing your thoughts here today on the ASCO Daily News Podcast.  And thanks to our listeners too. If you value the insights that you heard today on the ASCO Daily News Podcast, please do not forget to rate, review, and subscribe wherever you get your podcasts. Thanks, Mina. Dr. Mina Sedrak: Thank you so much. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:     Dr. Sumanta (Monty) Pal   @montypal  Dr. Mina Sedrak @minasedrakmd   Follow ASCO on social media:      @ASCO on Twitter     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. Mina Sedrak: Patents, Royalties, Other Intellectual Property: Up-to-Date

Dr. Sumanta (Monty) Pal and Dr. Petros Grivas discuss innovative new intravesical therapies and other recent advances in the treatment of non-muscle invasive bladder cancer. TRANSCRIPT Dr. Sumanta (Monty) Pal: Hello and welcome. I'm Dr. Monty Pal here at the ASCO Daily News Podcast. I'm a medical oncologist and professor and vice chair of academic affairs at the City of Hope Comprehensive Cancer Center in Los Angeles. And I'm really delighted to be your new host here. Today's episode is going to really sort of focus on an area near and dear to my heart, something I actually see in the clinics, and that's bladder cancer. We're specifically going to be discussing non-muscle invasive bladder cancer, which actually comprises about 75% of new cases. Now, in recent years, there's been a huge shift towards personalized bladder-preserving strategies, including innovative therapies and new agents that really are reducing reliance on more primitive techniques like radical cystectomy and radiation therapy. And I'm really excited about this new trend. And really at the forefront of this is one of my dear friends and colleagues, Dr. Petros Grivas. He's a professor in the Department of Medicine and Division of Hematology Oncology at the University of Washington. It's going to take a while to get through all these titles. He's taken on a bunch of new roles. He is medical director of the International Program, medical director of the Local and Regional Outreach Program, and also professor in the Clinical Research Division at the Fred Hutch Cancer Center. Petros, welcome to the program. Dr. Petros Grivas: Thank you so much, Monty. It's exciting for me to be here. Dr. Sumanta (Monty) Pal: Just FYI for our audience, our disclosures are available in the transcript of this episode.  We're going to get right into it, Petros. Non-muscle invasive bladder cancer, this is a really, really challenging space. We see a lot of recurrence and progression of the disease over time, about 50% to 70% of patients do have some recurrence after initial treatment, and about 30% are ultimately going to progress on to muscle-invasive or metastatic disease. Now, I will say that when you and I were in training, non-muscle invasive bladder cancer was something that was almost relegated to the domain of the urologist, right? They would use treatments such as BCG (Bacillus Calmette-Guérin) in a serial fashion. It was rare, I think, for you and I to really enter into this clinical space, but that's all changing, isn't it? I mean, can you maybe tell us about some of the new therapies, two or three that you're really excited about in this space? Dr. Petros Grivas: Monty, you're correct. Traditionally and conventionally, our dear friends and colleagues in urology have been managing patients with non-muscle invasive bladder cancer. The previous term was superficial bladder cancer. Now, it has changed, to your point, to non-muscle invasive bladder cancer. And this has to do with the staging of this entity. These tumors in superficial layers of bladder cancer, not invading the muscularis propria, the muscle layer, which makes the bladder contract for urine to be expelled. As you said, these patients have been treated traditionally with intravesical BCG, one of the oldest forms of immunotherapy that was developed back in the 1970s, and this is a big milestone of immunotherapy development. However, over the years, in the last 50 years, there were not many options for patients in whom the cancers had progression or recurrence, came back after this intravesical BCG. Many of those patients were undergoing, and many of them still may be undergoing, what we call radical cystectomy, meaning removal of the bladder and the lymph nodes around the bladder. The development of newer agents over the last several years has given the patients the option of having other intravesical therapies, intravesical meaning the delivery of drugs, medications inside the bladder, aiming to preserve the bladder, keep the bladder in place. And there are many examples of those agents. Just to give you some examples, intravesical chemotherapy, chemotherapy drugs that you and me may be giving intravenously, some of them can be given inside the bladder, intravesical installation. One example of that is a combination of gemcitabine and docetaxel. These drugs are given in sequence one after the other inside the bladder, and they have seen significant efficacy, good results, again, helping patients keeping the bladder when they can for patients with what we call BCG unresponsive non-muscle invasive bladder cancer. And again, there's criteria that the International Bladder Cancer Group and the FDA developed, how to define when BCG fails, when we have BCG unresponsive non-muscle invasive bladder cancer. Dr. Sumanta (Monty) Pal: And we're actually going to get into some of the FDA requirements and development pathways and so forth. What I'm really interested in hearing, and I'm sure our audience is too, are maybe some of the new intravesical treatments that are coming around. I do think it's exciting that the gemcitabine and docetaxel go into the bladder indeed, but what are some of the top new therapies? Pick two or three that you're excited about that people should be looking out for in this intravesical space. Dr. Petros Grivas: For sure, for sure. In terms of the new up-and-coming therapies, there are a couple that come to mind. One of them is called TAR-200, T-A-R 200. This agent is actually a very interesting system. It's an intravesical delivery of a chemotherapy called gemcitabine, the one that I just mentioned a few minutes ago, that is actually being delivered through what we call a pretzel, which is like a rounded [pretzel-shaped] structure working like an osmotic pump, and that is being delivered inside the bladder intravesically by urologists. And this drug is releasing, through the osmotic release mechanism, this chemotherapeutic drug, gemcitabine, inside the bladder. And this can be replaced once every 3 weeks in the beginning. And the data so far from early-phase trials are really, really promising, showing that this agent may be potentially regulatory approved down the road. So TAR-200 is something to keep in mind. And similarly, in the same context, there is a different drug that also uses the same mechanism, and this osmotic release, this pretzel, it's just encoded with a different agent. The different agent is an FGFR inhibitor, a target therapy called erdafitinib, a drug that you and me may give in patients with metastatic urothelial carcinoma if they have an FGFR3 mutation or fusion. And that drug is called TAR-210. Dr. Sumanta (Monty) Pal: And can I ask you, in that setting, do you have to have an FGFR3 mutation to receive it? Or what is the context there? Dr. Petros Grivas: So for TAR-210, TAR-2-1-0, usually there is a checking to see if there is an FGFR3 mutation or fusion. And the big question, Monty, is do we have adequate tissue, right? From a limited tissue on what we call the TURBT, right, that urologists do. And now there is a lot of development in technology, for example, urine circulating tumor DNA to try to detect these mutations in the urine to see whether the patient may be eligible for this TAR-210. Both of those agents are not FDA approved, but there are significant promising clinical trials. Dr. Sumanta (Monty) Pal: So now let's go to a rapid-fire round. Give us two more agents that you're excited about in this intravesical space. What do you think? Dr. Petros Grivas: There is another one called cretostimogene. It's a long name. Dr. Sumanta (Monty) Pal: They really make these names very easy for us, don't they? Dr. Petros Grivas: They are not Greek names, Monty, I can tell you, you know. Even my Greek language is having trouble pronouncing them. The cretostimogene, it's actually almost what we call a growth factor, a GM-CSF. The actual name of this agent is CG0070. This is a replicating mechanism where GM-CSF is replicating in cells. And this agent has shown significant results again, like the TAR-200, in BCG unresponsive non-muscle invasive bladder cancer. I would say very quickly, two agents that actually were recently approved and they're already available in clinical practice, is nadofaragene firadenovec, another long name. That's a non-replicating vector that has the gene of interferon alfa-2b that stimulates the immune system in the bladder. It's given once every 3 months. And the last one that was, as I mentioned, already FDA approved, it's an interleukin-15 superagonist. It's another long name, which is hard to pronounce, but I will give it a try. It's a drug that was recently actually approved also in the UK. The previous name was N-803. It's given together with BCG as a combination for BCG unresponsive non-muscle invasive bladder cancer. Dr. Sumanta (Monty) Pal: This is a huge dilemma, I think, right? Because if you're a practicing, I'm going to say urologist for the moment, I guess the challenge is how do you decide between an IL-15 superagonist? How do you decide between a pretzel-eluting agent? How do you decide between that and maybe something that's ostensibly, I'm going to guess, cheaper, like gemcitabine and docetaxel? What's sort of the current thinking amongst urologists? Dr. Petros Grivas: Multiple factors play into our account when the decision is being made. I discuss with urologists all the time. It's not an easy decision because we do not have head-to-head comparisons between those agents. As you mentioned, intravesical chemotherapy with gemcitabine and docetaxel has been used over the years and this is the lowest cost, I would say, the cheapest option with good efficacy results. Obviously, the nadofaragene firadenovec every 3 months and the interleukin-15 superagonist, N-803, plus BCG have also been approved. The question is availability of those agents, are they available? Are they reimbursed? Cost of those agents can come into play. Frequency of administration, you know, once every 3 months versus more frequent. And of course, the individual efficacy and toxicity data, preference of the patients; sometimes the provider, the urologist, may have something that they may be more familiar with. But we lack this head-to-head comparison. Of course, I want to make sure I mention that radical cystectomy may still be the option for appropriate patients. So that complicates also the decision making and has to be individualized, customized, and personalized, taking into account all those factors. And there is not one size fitting all. Dr. Sumanta (Monty) Pal: So I think we discussed five intravesical therapies. As you point out, and you know, I'm going to get some calls about this: I think I referred to radical cystectomy as being a more primitive procedure. Not true at all. I think it's something that still is, you know, a mainstay of management in this disease space. But I guess it gets even more complicated, am I right, Petros? Because now we have systemic therapies that we can actually apply in this non-muscle invasive setting for at this point, refractory disease. Can you maybe just give us a quick two-minute primer on that? Dr. Petros Grivas: Absolutely, and systemic therapies now come into play, as you said. And a classical example of that, Monty, came from the KEYNOTE-057 trial that we published about 6 years ago. This is intravenous pembrolizumab, given intravascularly, intravenously, as opposed to the previously discussed intravesical administration of agents. Pembrolizumab was tested in that KEYNOTE-057 trial and showed efficacy about, I would say, one out of five patients, about 20%, had a complete response of the tumor in the bladder in a year after starting the treatment. Again, it's hard to compare across different agents, but obviously when we give something intravenously, there is a risk of toxicity, side effects systemically, what we call immune-related adverse events. And this can also play in the decision making, right? When you have intravesical agents versus intravascular agents, there is different toxicity profiles in terms of systemic toxicity. But intravenous pembrolizumab has been an option, FDA approved, since, if I remember, it was early 2020 when this became FDA approved. There are other agents being tested in this disease, but like atezolizumab through the SWOG study that Dr. Black and Dr. Singh led, but atezolizumab is not FDA approved for this indication. Again, this is for BCG unresponsive, high-risk, non-muscle invasive bladder cancer. Dr. Sumanta (Monty) Pal: So maybe teach us how it works, for instance, at an expert center like the Fred Hutch. When you see a patient with non-muscle invasive bladder cancer, there's obviously the option of surgery, there's the intravesical therapies, which I imagine the urology team is still really at the helm of. But then, I guess there has to be consideration of all options. So you've got to bring up systemic therapy with agents like pembrolizumab. In that context, are you involved that early on in the conversation? Dr. Petros Grivas: That's a great discussion, Monty. Paradigm is shifting as we mentioned together. The urologists have been treating these patients and still they are the mainstay of the treaters, the managers in this disease. But medical oncologists come to play more and more, especially with the FDA approval of intravenous pembrolizumab about 5 years ago [GC1]  [KM2] . We have the concept of multidisciplinary bladder cancer clinic here at Fred Hutch and University of Washington. This happens every Tuesday morning, and we're very excited because it's a one-stop shop for the patients. We have the urologist, a medical oncologist, radiation oncologist, and experts from radiology and pathology, and we all review cases specifically with muscle-invasive bladder cancer. But every now and then, we see patients with BCG unresponsive non-muscle invasive bladder cancer. And this is where we discuss and we talk to the patient about pros and cons of all those options. And that's a classic example where medical oncologists may start to see those patients and offer their input and expertise. In addition to that, sometimes we have clinical trials, we may see these patients because there are systemic agents that may be administered in this setting. We have the SunRISe trial program that includes also a systemically administered checkpoint inhibitor. So that's another example where we see patients either in the context of multi-clinic or in individual solo clinics to counsel the patients about the pros and cons of the systemically administered agents in the context of clinical trials. Usually checkpoint inhibitors are the class of agents that are being tested in this particular scenario. Dr. Sumanta (Monty) Pal: I can see a scenario where it's really going to require this sort of deep dive, much in the way that we do for prostate cancer, for instance, where the medical oncologist is involved very early on and planning out any sort of systemic therapy component of treatment or at the very least, at least spelling out those options. I think it's going to be really interesting to see what this space looks like 5 or 10 years down the road. In closing, I wanted to go through something that I think is so different in this space, at least for the time being, and that is the paradigm for FDA approval. When you and I have our fellows in the clinics, we always say, "Look, you know, the paradigm in this disease and that disease and the other disease needs to be phase 3 randomized trials, right? Big thousand patient experiences where you're testing clinical endpoints." That's tough in non-muscle invasive bladder cancer, right? Because thankfully, outcomes can actually be quite good, you know, in this setting, right? It's tough to actually estimate overall survival in some of these early-stage populations. Tell me what the current regulatory bar is, and this is a tough thing to do in 2 minutes or less but tell me where you see it headed. Dr. Petros Grivas: You alluded to that before, Monty, when I was giving the background and we talked about the regulatory approval. And I have to very quickly go back in time about 10 years ago because it's important for context that can help us in other disease types too. We had workshops with the FDA and the NCI with the help of the International Bladder Cancer Group and other colleagues. And we try to define a framework, what endpoints are meaningful for those patients in this disease. It was a multidisciplinary, multiple stakeholders meeting, where we tried to define what is important for patients. What are the available agents? What are the trial designs we can accept? And what are the meaningful endpoints that the regulatory agencies can accept for regulatory approval? And that was critical in that mission because it allowed us to design clinical trials, for example, single-arm trials in a disease where there was no standard of care. There was intravesical valrubicin and chemotherapy anthracycline that was approved for many years, but was not practically used in clinical practice, despite being approved, the valrubicin. And because of that, the FDA allowed these single-arm trials to happen. And obviously the endpoint was also discussed in that meeting. For example, for carcinoma in situ, complete response, clinical complete response, because the bladder remains intact in many patients, clinical complete response was a meaningful primary endpoint, also duration of response is also very important. So what is the durable clinical complete response in 1 year or 18 months is relevant. And when you have papillary tumors like Ta or T1 with CIS, for papillary tumors, event-free survival becomes one of the key endpoints and you look at it over time, for example, at 12 or 18 months, what is the event-free survival? So clinical complete response, duration of response, event-free survival, depending on the CIS presence or papillary tumors, I think these are endpoints that have allowed us to design those trials, get those agents approved.  Now, the question going forward, Monty, and we can close with that is, since now we have the embarrassment of riches, many more options available compared to where we were 6 and 7 years ago, is now the time to do randomized trials? And if we do randomized trials, which can be the control group? Which of those agents should be allowed to be part of the control group? These are ongoing discussions right now with the NCI, with other agencies, cooperative groups, trying to design those trials and move forward from here.[GC3]  Dr. Sumanta (Monty) Pal: Well, it's awesome to have you here on the program so we can get some early looks into some of these conversations. I mean, clearly, you're at the table at a lot of these discussions, Petros. So I want to thank you for sharing your insights with us today. This was just tremendous. Dr. Petros Grivas: Thank you, Monty. You know, patients in the center, I just came back from the Bladder Cancer Advocacy Network meeting in Washington, D.C., and we discussed all those questions, the topics you very eloquently mentioned and asked me today, and patients gave us great feedback and patients guide us in that effort. Thank you so, so much for having me and congratulations for the amazing podcast you're doing. Dr. Sumanta (Monty) Pal: Oh, cheers, Petros, thanks so much.  And thank you to the listeners who joined us today. If you really like the insights that you heard on this ASCO Daily News Podcast, please rate, review, and subscribe wherever you get your podcasts. Thanks, everyone. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's speakers:      Dr. Sumanta (Monty) Pal  @montypal  Dr. Petros Grivas @PGrivasMDPhD   Follow ASCO on social media:     @ASCO on Twitter    ASCO on Bluesky   ASCO on Facebook     ASCO on LinkedIn     Disclosures:    Dr. Sumanta (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. Petros Grivas: Consulting or Advisory Role: Merck, Bristol-Myers Squibb, AstraZeneca, EMD Serono, Pfizer, Janssen, Roche, Astellas Pharma, Gilead Sciences, Strata Oncology, Abbvie, Bicycle Therapeutics Replimune, Daiichi Sankyo, Foundation Medicine, Bicycle Therapeutics, Eli Lilly, Urogen Pharma, Tyra Biosciences Research Funding (Inst.): Bristol-Myers Squibb, Merck, EMD Serono, Gilead Sciences, Acrivon Therapeutics, ALX Oncology, ALX Oncology, Genentech Travel, Accommodations, Expenses: Gilead Sciences

Dr. Sumanta (Monty) Pal and Dr. Arielle Elkrief discuss the clinical relevance of the gut microbiome in cancer immunotherapy and the importance of antibiotic stewardship, as well as interventions currently being explored to treat gut dysbiosis and optimize immunotherapy response. TRANSCRIPT Dr. Sumanta (Monty) Pal: Hi everyone, I'm Dr. Monty Pal, welcoming you to the ASCO Daily News Podcast. I'm a medical oncologist. I'm a professor and vice chair of academic affairs at the City of Hope Comprehensive Cancer Center in Los Angeles.  Today we're here to discuss one of my favorite topics, which is the gut microbiome. It's almost hard to avoid the gut microbiome nowadays if you look at medical literature within oncology. It's an emerging phenomenon, but there are a couple of individuals that I would really define as pioneers in the field. And one of them is actually with me today, Dr. Arielle Elkrief, to discuss the clinical relevance of the gut microbiome, particularly amongst patients receiving immunotherapy, although I imagine our conversation today will take many twists and turns. Arielle is an assistant professor and clinician scientist in the Department of Oncology at the University of Montreal, and she is co-director of the CHUM Microbiome Center there.  FYI for the listeners, we have our full disclosures in the transcript of this episode.  Arielle, thank you so much for joining us today. Dr. Arielle Elkrief: Thanks so much, Monty. This is going to be amazing. Dr. Sumanta (Monty) Pal: Well, I have to tell you what sort of inspired me to bring you on as a guest. It was one of many things, but it was this really terrific ASCO Educational [Book] article that you wrote. Now, I have to tell you, I've read all the articles sort of cover to cover in the book, and they're always a wonderful primer, so if our audience is studying for board research or something of that sort, it's a terrific resource to go through. I have to tell you, this piece on the gut microbiome that you wrote is nothing short of a masterpiece. If you read this cover to cover, it's actually going to give you, I think, a sense of the current state and future state of the field. I wanted to start by just sort of beginning with sort of the origin story for a lot of this, which is this association between the gut microbiome and immunotherapy response. This takes us back several years to this pivotal series of papers in Science. Maybe you could walk our audience through that. Dr. Arielle Elkrief: Absolutely. Well, thank you so much for your kind words about the ASCO [Educational] Book. It was a team effort with a lot of key opinion leaders in the field, so I'm really glad to learn that you've liked it.  Moving backwards in terms of how we came to understand that the gut microbiome is essential to priming a response to cancer immunotherapy actually goes back to 2015 and seminal papers that looked at what happens when we take mice that are germ-free mice that have never been exposed to a microbiome. These are mice that are born by cesarean section and essentially live in a bubble. And when we give those mice tumors and treat them, in the first papers with anti-CTLA-4 treatment, we realized that these antibodies don't work at all. And that was the first observation that the presence of a gut microbiome was essential to mounting an anti-cancer immune response. When we supplemented those same mice with beneficial bacteria or feces from responder patients, we were able to restore the response to immunotherapy. And so those were really the first preclinical observations that made us understand the critical role of the microbiome in immunotherapy response. Moving a little bit in the future, we examined the fecal microbiome composition using shotgun metagenomic sequencing in different cohorts of patients with solid tumors, namely lung cancers, kidney cancers, and also skin tumors like melanoma, and found that patients who responded to immunotherapy had a distinct microbiome that was characterized by beneficial bacteria compared to patients who experienced resistance to immunotherapy that had a dysbiotic or diseased microbiome. Dr. Sumanta (Monty) Pal: So, you know, it's interesting, these techniques that we're using to sequence the gut, they're a little bit different. So I wonder if you can give the audience a quick primer on these techniques that you're so well versed in, shotgun metagenomic sequencing, 16S rRNA sequencing. If you had to describe this in 30 seconds, which is a tall task, how would you do that? Dr. Arielle Elkrief: That's a tall task. Much of what we know about the microbiome initially came from a technique called 16S rRNA sequencing. This is a technique that amplifies the 16S region and basically tells you at the genus level what's going on at the level of bacterial composition. This technique is fast, relatively cheap, and can be performed on a laptop computer, which is excellent. The problem is that it's prone to a lot of technical variations. Different primers might give you different results, and you're really limited at the genus resolution. You can't get a good resolution in terms of species, and we're learning that different species from the same genus might have different physiological properties, and the same thing goes at the strain level. So when we really zone in and look at inter-species changes, we're seeing that these actually have specific functions in the host. So that brings us to metagenomic sequencing, which is a whole genome sequencing, next-generation sequencing based method that looks at the whole composition and gives you information not only on bacteria, but you might also get fungal and viral properties. You can zoom in on the strain level. You can also get functional output, so we can examine what the metabolic properties of specific species or strains might look like. The negative aspects of shotgun metagenomic sequencing is that it takes a lot of computational power in order to analyze the results and it might take a little bit longer. And certainly, within the clinical setting, not something that's feasible yet.  And that brings us to more novel point-of-care biomarker tools that we've collaborated in developing along with Dr. Laurence Zitvogel and Dr. Lisa Derosa at Gustave Roussy, that learning from the shotgun metagenomics results designed a probe using quantitative PCR which looks for this specific bacteria we know to be important and developed a ratio of harmful bacteria to beneficial bacteria. This is called the TOPOSCORE, and it actually is able to predict quite nicely the response to immunotherapy using a stool sample and a really good turnaround time of almost 72 hours. Dr. Sumanta (Monty) Pal: That was a perfect overview and a lot of information in a short amount of time. It also makes you take out your high school biology textbooks, doesn't it, to understand that the bacterial ribosome, right, is a different size and shape, and that's what we're sequencing here. But these techniques I think are incredibly important, and I'm glad you actually discussed this, this RT-PCR based strategy of calculating the TOPOSCORE. It lends itself to this phenomenon of dysbiosis, and I think for our audience, that's going to be an important term to understand as time goes on. There's the normal healthy gut and then there's this phenomenon of dysbiosis, which is, I guess, simply put, an unhealthy gut. But tell us about, you know, how often you see dysbiosis in a cancer patient, maybe versus a normal healthy adult. Dr. Arielle Elkrief: So, I think we can split up your question into two parts. One is we know from cohort studies and population level-based studies that the microbiome of patients with cancer is distinct from healthy patients or healthy people. And we know that because of the global composition. We also think that there are diversity metrics that lend themselves to being described as dysbiotic. But we do know that the microbiome of people with cancer is distinct from healthy volunteers. That's the first point.  In terms of how frequently dysbiosis occurs in patients with cancer, it's not very well defined. We know that even among healthy people, there is a certain level of dysbiosis. Laurence in her talk mentioned that to be about 10% to 20%. And the other fascinating component is that when we're thinking about dysbiosis and the cancer associated microbiome, in terms of the species that are enriched, it's quite striking that a lot of these dysbiotic or negative bacteria are also found to be enriched in patients with metabolic disease, like cardiovascular disease, for example. And so it's unclear if dysbiosis is the cause or consequence, but there definitely seems to be a general pattern of disease when looking at the microbiome compared to healthy people. Dr. Sumanta (Monty) Pal: That's interesting. So, I'll tell you, my second favorite portion of your article, and I'll tell you my favorite portion as well in the context of this podcast, but my second favorite part was the section around antibiotic stewardship. You know, the utilization of antibiotics in a very pragmatic fashion amongst our patients. Can you describe why that's so critical in the context of the microbiome? Dr. Arielle Elkrief: Antibiotics can disrupt the gut microbiome composition. We know this from mouse studies, but also cohort studies of patients that are exposed to antibiotics. And most importantly, we know that patients who are exposed to antibiotics, either before or during the immunotherapy period, have significantly worse progression-free survival and overall survival to immunotherapy. And this is true for immunotherapy in the monotherapy setting, but also when combined with chemotherapy. What's striking is that when we look at patients who are just treated with chemotherapy, we don't see the negative outcome of antibiotics on outcome and progression-free survival and overall survival, suggesting that the negative impact of antibiotics on outcomes is really specific to immunotherapy backbones. The other important point is that this negative signal is maintained even after adjusting for standard prognostic variables in the specific malignancies that we're looking at. And then most importantly, at the mechanistic level, we were able to actually pinpoint the mechanism behind this antibiotic related dysbiosis. And we see this with a bloom of negative bacteria which induces a loss of MAd-CAM, which is an endothelial gut checkpoint immune marker, and that causes an efflux of immunosuppressive T cells, which are usually in the gut, to go straight into the tumor where they make the tumor unamenable to an immunotherapy response. And so now we finally have the mechanism as to why antibiotics are harmful and why we need to practice antibiotic stewardship. Dr. Sumanta (Monty) Pal: And just to be clear for the audience, I mean, if a patient needs antibiotics, they need antibiotics. But perhaps it just suggests that, and we have, I suppose, this predilection as oncologists, just for the minor cold or cough or what have you, we maybe should be a little bit more cognizant of whether or not antibiotics are truly necessary. Is that fair? Dr. Arielle Elkrief: Absolutely. So what we're advocating for is antibiotic stewardship, and this is the clear recommendation that we can make. So that means confirming a bacterial infection. If it's there and antibiotics are indicated, to choose the most narrow spectrum for the shortest course and constantly re-evaluate the indication of antibiotics. And of course, we need to work with our colleagues in infectious diseases who've done incredible work in antibiotic stewardship. And all along this process we also need to be mindful of other medications and polypharmacy, such as proton pump inhibitors or narcotics, for example, we think that these other medications which are frequently prescribed in our cancer population can also potentially have negative impacts on the microbiome and immunotherapy response. Dr. Sumanta (Monty) Pal: I think that's a terrific summary and big guidance for the audience.  I promised you I'd tell you my favorite part of your article, and this is this huge table. I think the table is two and a half pages long, if I remember correctly, but it's an awesome table, and I highly recommend our audience to check this out. It lists literally every therapeutic trial for the microbiome under the sun. And so it begins with the approach of fecal microbiota transplant, which I'm going to ask you to tell us about in a second, but it also hinges on a lot of really cool sort of novel therapies, live bacterial products, mixes of different microbial products. Maybe take us through this whole approach of FMT (fecal microbiota transplantation). I actually wasn't aware of the dozens of trials that you listed there in this space. It seems like it's a very active area of research. Dr. Arielle Elkrief: Definitely. So, as you alluded to, FMT or fecal microbiota transplantation is the most well studied and direct way to modify the patient's microbiome. This technique aims to replace the patient's dysbiotic microbiome with that of a healthy microbiome, either from a healthy donor volunteer that's been heavily screened, or from a patient who experienced response to immunotherapy. And, as three landmark studies so far that have been published demonstrated the potential of FMT to reduce primary resistance or secondary resistance to immunotherapy, and this has been in melanoma.  We also recently reported on the results of our FMT-LUMINate trial, which looked at patients with lung cancer and melanoma. Once again, FMT, when combined with immunotherapy was safe and led to a higher proportion of responses than we would normally expect.  We're now also looking at randomized trials that have come out. So the first being the TACITO trial in kidney cancer, which compared FMT plus pembrolizumab and axitinib to placebo in patients with RCC, and again, FMT was safe and feasible and also led to an increased progression-free survival at one year, meeting the study's primary endpoint.  And so, so far, there's a wealth of data really showing the promise of FMT when combined with immunotherapy, and we're now in the process of conducting larger randomized trials, including in melanoma with the CCTG (Canada Cancer Trials Group) in our ME17 or Canbiome2 trial, where we're going to be enrolling 128 patients with metastatic melanoma to receive FMT and standard of care immunotherapy compared to standard of care immunotherapy alone. Dr. Sumanta (Monty) Pal: You're very humble, so I've got to highlight for our audience. This was a mega grant that Arielle received to fund really the largest prospective exploration of FMT that will exist to date. So I'm really excited about that. I wish this was something we could participate in stateside.  Before we jump into the other approach, which is live bacterial products and mixes thereof, where do you see FMT going? I think that one of the perceived challenges with FMT is that it's hard to implement, right? You need to have a really robust framework when it comes to gastroenterology, the preparation's challenging. Is there a way to envision FMT use being more generalized? Dr. Arielle Elkrief: Those are great questions. So we're lucky in Canada to work with pioneers in FMT, Michael Silverman, Saman Maleki, and John Lenehan in London, Ontario, who had this really robust FMT healthy donor screening program, which literally screens for every pathogen under the sun, and we haven't had any problems with feasibility or implementing FMT in Canada. But I think that once we're going to hopefully start doing larger scale, randomized phase three studies, that we might run into problems with scalability. And I think also with regards to reproducibility, and that's the feedback that we're getting from some regulatory authorities, especially at the level of the FDA, where there are some concerns around inter- and intra-donor variability because, of course, we can't guarantee that every fecal sample is going to be the same. So that has really pushed the field to think about other strategies, such as live biotherapeutic products which take modified FMT or bacteria from stools from either healthy donors or from responder patients and basically turn them into drugs that are regulated as drugs and can then be studied in the context of investigational new drugs or products. Dr. Sumanta (Monty) Pal: I like this and, you know, I do think that there's a future for it. We just have to kind of put our heads together and figure out how to get over all of these logistical hurdles, but, you know, I agree, I think your group and others have demonstrated, especially with this trial that you're fanning out all throughout Canada, that it can potentially be done.  This is a topic that could probably go on for another couple of hours, right, especially based on the size of the table that you put together in this brilliant article, but tell us about live bacterial products or LBPs, as we call them these days. What's the current status, what's the future there? And maybe I'll give you less than two minutes here, although again, I realize it's a two-hour topic. Dr. Arielle Elkrief: You're probably better suited to speak about that because you've been one of the pioneers in terms of this. So we can think about LBPs in terms of single strain organisms, like CBM588 for an example, which your group did some amazing work in showing that, in a randomized setting, that this led to better responses than we would expect compared to just work with controls. We also know that LBPs can have multiple strains, up to 30. We're collaborating with a company called Cannabis Bioscience that is actually working on much larger communities of consortia. And so we're really excited about the direction that that's taking in terms of taking these LBPs and developing them from the drug perspective. In addition to LBPs, we know that there are other ways that we can change the microbiome, notably prebiotics, which are compounds which can have a beneficial impact on the microbiome. And one of these is camu camu, which I know your group is leading a clinical trial looking at camu camu and kidney cancer, and we're excited to see how that compares to FMT or LBPs, because that might be a potentially scalable alternative. Dr. Sumanta (Monty) Pal: That's awesome. What a terrific overview, and that was less than two minutes. I don't know how you did it. That's terrific.  Arielle, this has been such an insightful conversation. I just want to thank you for, again, a terrific article in the ASCO Educational Book. I highly recommend all of our listeners to go there and check it out, and also for sharing all these terrific insights on the podcast today. Dr. Arielle Elkrief: Thank you so much, Monty. Dr. Sumanta (Monty) Pal: And thanks to our listeners, too. 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. Thanks, everyone. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:    Dr. Sumanta (Monty) Pal  @montypal Dr. Arielle Elkrief Follow ASCO on social media:     @ASCO on Twitter    ASCO on Bluesky   ASCO on Facebook     ASCO on LinkedIn     Disclosures:    Dr. Sumanta (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. Arielle Elkrief: Honoraria: AstraZenica, Bristol-Myers Squibb, Merck, EMD Serono Consulting or Advisory Role: Bristol-Myers Squibb Research Funding (Inst.): Kanvas Bioscience, AstraZeneca, Merck Other Relationship: Royal College of Surgeons and Physicians of Canada, Cedar's Cancer Center (Henry R. Shibata Fellowship), Canadian Institutes of Health Research (CIHR)

Dr. Sumanta (Monty) Pal and Dr. Kimmie Ng discuss the disturbing rise of early-onset gastrointestinal cancers, the unique challenges faced by younger patients, and key research that is shedding light on potential drivers of early diagnoses in colorectal cancer. TRANSCRIPT Dr. Sumanta (Monty) Pal: Hello, everyone. I'm Dr. Monty Pal, and I'm a medical oncologist and professor and vice chair of medical oncology at the City of Hope Comprehensive Cancer Center in Los Angeles. I'm really delighted to welcome you all to the ASCO Daily News Podcast as the show's new host. I'll be bringing you discussions with leaders in the oncology space on a variety of topics. I've been working hard with the ASCO team on picking the ideal topics to bring to you, and I'm really delighted to introduce my first guest, a dear friend, Dr. Kimmie Ng, to discuss this huge problem that we're seeing nowadays of early-onset GI cancers. Dr. Ng is the associate chief of the Division of Gastrointestinal Oncology at the Dana-Farber Cancer Institute, and she's an associate professor of medicine at Harvard Medical School in Boston. She serves as co-director of the Colon and Rectal Cancer Program. She's also the founding director of the Young-Onset Colorectal Cancer Center at Dana-Farber. I'm sure we'll talk a little bit about that today.  Just to note, our full disclosures are available in the transcript of this episode.  Dr Ng, it's so great to have you on the podcast. Thanks so much for joining us. Dr. Kimmie Ng: Thank you so much for having me. It's great to be here. Dr. Sumanta (Monty) Pal: I'm going to refer to you as Kimmie, if you don't mind, for the rest of the podcast here. Please, we'll go by first names, if you don't mind.  Your research has really done so much to help improve our understanding of early-onset GI cancers. You've done a lot of work to increase awareness in this space. I don't think there's a couple of months that passes by when I don't see you on television on Good Morning America or other shows really broadcasting this really critical message. I think there's a certain sensitivity that we all have to this issue, right? I mean, because receiving a cancer diagnosis at any age is very challenging, but I'm sure that young patients who face a colorectal cancer diagnosis have some very unique challenges. Could you give us a sense of some of those? Dr. Kimmie Ng: I think the other reason why so many people are interested in this and feel touched by this is that it's not just gastrointestinal cancers that are increasing in young people, but actually a multitude of different cancers have been rising in young individuals. And while it is difficult at any age to receive a cancer diagnosis, we do all know that young people getting a diagnosis like this do face unique challenges. Studies have shown that over 80% have children under the age of 18 when they are diagnosed with colorectal cancer, for example, under the age of 50. And many experience career and education disruptions. They are in what we call the 'sandwich generation,' where they're not only taking care of young families or starting to think about starting a young family, but they're also taking care of elderly parents. So it's just a very busy stage of life, and to then be facing a usually terminal cancer diagnosis, it is extremely challenging. The other factors that we've seen that seem to be unique or more prevalent in young patients is that there are higher levels of psychosocial distress, depression, and anxiety, and a majority of patients do need medical attention and treatment for those things, whether it's medication treatment or whether it's counseling or support from psychosocial oncologists. And so the other big issue is fertility. We know that so many of the treatments that these young patients receive do permanently and negatively impact fertility. And for a person who is young, who may still be trying to expand their family or again start a family, it is very important that these young patients do receive counseling about fertility preservation prior to starting treatment. Dr. Sumanta (Monty) Pal: You know, it's so interesting you bring this up, and I think about a patient who's in their 40s diagnosed with this disease. They're in the same demographic as I am, as you are. You know, I'm 44 years old, and you know, I'm thinking about my 11- and 12-year-old and my aging parents, right? I mean, the dilemmas that you highlighted are precisely what I'm facing in life, and it's so true, right? If I had to take my day-to-day and superimpose on that a colorectal cancer diagnosis, it would just be problematic in so many spheres, so many spheres. Dr. Kimmie Ng: Absolutely. And because we did think going into this, starting our Young-Onset Colorectal Cancer Center, that these patients will need unique supports, we did conduct a qualitative study and held some focus groups of young-onset colorectal cancer patients as well as their caregivers. And we really identified four primary themes that I think reflect a lot of the experience of patients with cancer, no matter what type of cancer when they're diagnosed young. And the first is the need, feeling overwhelmed by the healthcare system, and the need for patient navigation. As we know, a lot of these patients are previously healthy before they're facing this very serious diagnosis. The second is the need for peer-to-peer support, where they really value connecting with other young patients going through a similar experience. The third, we talked about already, the need for kind of formal psychosocial support in the form of psychosocial oncologists or psychiatrists or social workers. And the last is an interest in research. They are really very invested in getting germline genetic testing as well as somatic genomic profiling to help guide their therapy. Dr. Sumanta (Monty) Pal: That's really encouraging to hear that they themselves are interested in participating in research. I mean, obviously, that's a great way to move the field forward. I view your area of work here as being such a vexing problem because no matter what way you slice it, young-onset colorectal cancer still remains a relatively small proportion of all diagnoses. So how do you go about studying this phenomenon? I mean, it must be challenging to really sort of investigate underlying causes when ostensibly this is still a small piece of the pie. Dr. Kimmie Ng: That is such a great question and is one of the challenges me and my research team think about every single day. As you mentioned, one of the major barriers is that although these cancers are rising in young people, the absolute number of patients being diagnosed is still relatively small, and if it's going to take large scale epidemiologic studies to really understand, for example, what the dietary and lifestyle risk factors are, you need a considerable number of patients in order to have enough power to reach definitive conclusions.  And so this is where it is so important to collaborate. Any single institution is not going to see enough young-onset patients with colorectal cancer to be able to do this work on their own. And so I have really been intent on establishing an international prospective cohort study of patients with young-onset colorectal cancer so that we can increase the numbers of patients we partner with to try to answer these questions, but also so that we can study this on a global scale, because unfortunately this is not something that's just plaguing the United States. It is actually happening in multiple countries around the world. So that is one barrier.  The second, I would say, is that we think it's early life exposures to whatever environmental factor it is that's causing the rise that is likely contributing the most. And so if you imagine how difficult it would be to start studying individuals from when they're children through adolescence, through adulthood, and then all the way until a cancer diagnosis is obtained, a study like that would take too long, would cost too much, and really wouldn't be feasible. So we need to think of alternative ways to really try and answer this question of what is driving this rise in young-onset colorectal cancer. Dr. Sumanta (Monty) Pal: Honestly, Kimmie, this seems like almost an unfair question in the context of what you just mentioned, the challenges in terms of ascertaining causality, right? I'll tell you, I cheated a little bit ahead of this podcast. Kimmie and I had dinner together in Los Angeles a couple months ago. She came out to deliver a Presidential Lectureship at City of Hope. We were delighted to have her. And we did have a couple of thoughts exchanged over potential drivers of these early diagnoses, leaning on perhaps one of the things that you and I are both interested in, the microbiome. But amongst all these things, vitamin D, microbiome, etc., and I won't hold you to this, do you have at least a general sense of what might be contributing to this early-onset phenomenon? Dr. Kimmie Ng: Yeah, as we talked about during my visit there to City of Hope, we do hypothesize that it is a complex interaction between our exposome, which is everything we are exposed to in our environment, which does include diet and lifestyle factors, interacting with host immunity and antitumor immunity, and as well as the microbiome and shaping the composition and diversity of the gut microbiome that are likely interacting to increase susceptibility to colorectal cancer at a younger age. And I will say one of the biggest discoveries, if you will, about what might be driving young-onset colorectal cancer was published a few months ago in Nature. And that paper identified a specific mutational signature caused by the genotoxin colibactin, which is often produced by an organism called pks+ E. coli, as being much more prevalent in younger patients with colorectal cancer than older patients. And so while it doesn't explain necessarily all of young-onset colorectal cancer and why it's rising, it does give us a clue that the microbiome is likely very important in perhaps why this is rising in young people. Dr. Sumanta (Monty) Pal: After you mentioned it, I went back and dove deep into that paper. I was fascinated, fascinated by the content there. And this is just a massive exploration across thousands of patients worldwide. So, I mean, if there is a way to get at least some hint of what's driving this phenomenon, I suppose that's it. So thank you for pointing me in the direction of that manuscript. Now that we've addressed the issue of diagnosis, if we could just, you know, verge on the topic of treatment, right? And this is something that I struggle with. When I have my young patients with kidney cancer, I don't know necessarily that my treatment paradigm changes a whole heck of a lot. I guess what I will say is I might be a little bit more aggressive about concepts like definitive management with surgery. I suppose perhaps their treatment tolerance is a little bit higher. But tell us about the setting of young-onset colorectal cancer. Is the philosophy any different in terms of the actual sort of management of these patients? Dr. Kimmie Ng: That's a great question, and actually I was honored to participate in the first international consensus guidelines group to try to come up with uniform recommendations for how to treat young patients with colorectal cancer. And you know, the overall consensus is just as you said, the medical care of these young patients right now is really not that much different than that of an older patient with colorectal cancer. There are a couple of distinctions. One is that all young patients should get germline genetic testing, given that there is a higher prevalence of pathogenic germline variants when you are diagnosed at a young age. And the second is what we've already talked about, which is that all young patients should be referred for counseling about fertility preservation prior to starting treatment. But otherwise, the chemotherapy regimens recommended, you know, surgery, radiation, all of that seems very similar to older patients. I will say that because most of our young patients with colorectal cancer are diagnosed with left-sided cancers, including rectal cancers, where some of the treatment may be morbid and result in lifelong complications, we do consider de-escalation of therapy and try to consider the long-term implications when it's safe to do so and won't compromise outcomes. The other concerning thing is that younger patients don't necessarily have a better prognosis than older patients. And multiple studies have shown this, that even though we both often treat younger patients more aggressively – they more often receive multi-agent chemotherapy, and more often undergo surgery and radiation – their survival is not necessarily correspondingly better than an older patient with colorectal cancer. So that suggests to us that maybe these cancers are indeed biologically different and perhaps more aggressive or perhaps less responsive to treatment. And so that is some of the focus of our research too, to understand what is actually different about these cancers and how they respond to treatment. Dr. Sumanta (Monty) Pal: It's such a paradox, isn't it, right? Because you just brought this to my mind. I guess on the one hand, our younger patients may be able to tolerate perhaps a greater amount of chemotherapy, targeted therapy, etc. But you're absolutely right. I mean, they do sort of have these lingering issues with side effects that may persist for much longer than the 80- or 90-year-old that we're treating in the clinic. I mean, these tend to be sort of lifelong consequences and sequelae that they're dealing with. So that really does evolve to be a challenge. You've kind of changed my mindset there a little bit. Dr. Kimmie Ng: Yeah, I do think survivorship issues and long-term complications of therapy do need to be considered, especially for a young person who we hope will live a very, very long time. And so part of the work that our Young-Onset Colorectal Cancer Center is doing, we are participating in a pilot navigation study where we navigate patients to survivorship earlier than we typically would, perhaps, for an older patient. And that's so we can get a head start on addressing some of those potential complications of therapy and hopefully mitigate them so that they don't become an issue long term. Dr. Sumanta (Monty) Pal: Do you think there's a role for de-escalation studies formally in these young populations of patients? Dr. Kimmie Ng: I think de-escalation studies are important overall, and specifically for locally advanced rectal cancer, which again is one of the most common types of colorectal cancer diagnosed in our young patients, there are certain populations that may be able to forgo the radiation treatment to the pelvis, for example, and there's more and more patients who now may become candidates for non-operative management where they may not necessarily need to have their rectal cancer surgically removed. And elimination potentially of both of those modalities of treatment can really avoid some of the most serious and morbid complications that often occur with these treatments. Dr. Sumanta (Monty) Pal: Really interesting. Now, this is not and will never be a political podcast, but you know, obviously we're dealing with the consequences of changes on funding and so forth that have evolved over time. And I think it's worth sort of speculating how the landscape of research may change on account of that. Could you comment perhaps a little bit on how some of the funding cuts that we've seen recently at the NIH might affect the body of work that you're so integrally involved in? Dr. Kimmie Ng: I am honestly very worried about the current funding environment. Colorectal cancer is the third most commonly diagnosed cancer among men and women in the United States and globally, and when you combine men and women together, the second leading cause of cancer death. But proportionally, we receive much less funding for colorectal cancer compared to other cancer types. And my thoughts have always been that perhaps this is because there is this stigma around colorectal cancer and maybe some of the symptoms associated with colorectal cancer. And so on top of that, to have additional challenges in obtaining funding, I worry what it will do to the pace of progress for especially young patients with this disease. Also, because of some new stipulations that perhaps international collaborations are being discouraged, I also worry about that aspect of it because young-onset colorectal cancer and gastrointestinal cancers in general is a global phenomenon happening in multiple countries around the world. And if we are to understand what the environmental factors are affecting the different rates of rise in these different countries, we do so much need that international collaboration. So yes, I am worried, and I do hope that conversations like this will spark an awareness of the need for more funding and continued funding into this disease. Dr. Sumanta (Monty) Pal: I will say that, and the audience can't see this because this is an audio program, but I'm wearing my Southwest Oncology shirt here, a SWOG, and it's one of the National Cancer Institute-funded cooperative groups. And you know, I was recently dismayed to find that, you know, funding got cut for international collaborations and enrollment in South America and Latin America. And this was traditionally actually a mainstay of our enrollment for many trials, including trials in rare cancers that present themselves in younger patients in the GU space. So, I completely agree with you. We've got to do something to address this funding issue to make sure that this body of work, both yours and mine, continues, without a doubt. Kimmie, this has been a delightful conversation. I really want to thank you for, you know, leading the charge in the young-onset colorectal cancer space, and you've done so much tremendous work here. Dr. Kimmie Ng: Thank you for having me. Dr. Sumanta (Monty) Pal: If you value the insights that you hear on the ASCO Daily News Podcast, please rate, review, and subscribe wherever you get your podcasts. And again, thank you for joining us today. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:   Dr. Sumanta (Monty) Pal @montypal Dr. Kimmie Ng @KimmieNgMD Follow ASCO on social media:    @ASCO on Twitter   ASCO on Bluesky  ASCO on Facebook    ASCO on LinkedIn    Disclosures:   Dr. Sumanta (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. Kimmie Ng: Honoraria: Seagen, GlaxoSmithKline Consulting or Advisory Role: CytomX Therapeutics, Jazz Pharmaceuticals, Revolution Medicines, Abbvie, Bayer, Pfizer, Agenus, Johnson & Johnson/Janssen, Etiome, AstraZeneca Research Funding (Inst.): Pharmavite, Janssen Other Relationship: JAMA