Promising New Therapies in Non-Muscle Invasive Bladder Cancer

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

Dr. Joseph McCollom and Dr. Ramy Sedhom discuss precision palliative care, a new strategy that aims to align palliative care delivery with patient and caregiver needs instead of diagnosis alone. TRANSCRIPT ADN Podcast Episode 8-22 Transcript: What Is Precision Palliative Care? Rethinking a Care Delivery Problem Dr. Joseph McCollom: Hello and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Joseph McCollom. I'm a GI medical oncologist and palliative oncologist at the Parkview Packnett Family Cancer Institute here in Fort Wayne, Indiana. So, the early benefits of palliative care for patients with cancer have been well documented, but there are challenges in terms of bandwidth to how do we provide this care, given the workforce shortages in the oncology field. So today, we'll be exploring a new opportunity known as precision palliative care, a strategy that aims to align care delivery with patient and caregiver needs and not just diagnosis alone. Joining me for this discussion is Dr. Ramy Sedhom. He is the medical director of oncology and palliative care at Penn Medicine Princeton Health and a clinical assistant professor of medicine at the University of Pennsylvania Perelman School of Medicine. Our full disclosures are available in the transcript of this episode.  Dr. Sedhom, it's great to have you on the podcast today. Thank you so much for being here. Dr. Ramy Sedhom: Thank you, Joe. It's a pleasure to be here and lucky me to be in conversation with a colleague and friend. Yes, many of us have heard about the benefits of early palliative care. Trials have shown better quality of life, reduced symptoms, and potentially even improved survival. But as we know, the reality is translating that evidence into practice, which is really, really challenging. So Joe, both you and I know that not every patient can see palliative care, or I'd even argue should see palliative care, but that also means there are still many people with real needs who still fall through the cracks. That's why I'm really excited about today's topic, which we'll be discussing, which is precision palliative care. It's a growing shift in mindset from what's this patient's diagnosis or what's this patient's prognosis, to what matters most for this person in front of me right now and what are their individual care needs. I think, Joe, it's very exciting because the field is moving from a blanket approach to one tailored to meet people where they actually are. Dr. Joseph McCollom: Absolutely, Ramy. And I think from the early days when palliative care was kind of being introduced and trying to distinguish itself, I think one of the first models that came to clinicians' eyes was Jennifer Temel's paper in The New England Journal of Medicine in 2010. And her colleagues had really looked at early palliative care integration for patients with advanced non–small cell lung cancer. And in that era – this is a pre-immunotherapy era, very early targeted therapy era – the overall prognosis for those patients are similar to the population I serve as a GI medical oncologist, pancreatic cancer today. Typically, median overall survival of a year or less. And so, a lot of her colleagues really wanted her to track overall survival alongside quality of life and depression scores as a result of that. And it really was a landmark publication because not only did it show an improvement of quality of life, but it actually showed an improvement of overall survival. And that was really, I think, revolutionary at the time. You know, a lot of folks had talked about if this was a drug, the FDA would approve it. We all in GI oncology laugh about erlotinib, which got an FDA approval for a 2-week overall survival advantage. And so, it really kind of set the stage for a lot of us in early career who had a passion in the integration of palliative care and oncology. And I think a lot of the subsequent ASCO, NCCN, COC, Commission on Cancer, guidelines followed through with that. But I think what we realized is now we're kind of sitting center stage, there's still a lot of resource issues that if we sent a referral to palliative care for every single patient diagnosed with even an advanced cancer, we would have a significant workforce shortage issue. And so, Ramy, I was wondering if you could talk a little bit about how do we help center in on who are the right patients that are going to have the greatest benefit from a palliative care specialist intervention? Dr. Ramy Sedhom: Thanks, Joe. Great question. So you mentioned Dr. Temel's landmark 2010 trial published in the New England Journal of Medicine. And it is still a game changer in our field. The results of her work showed not only improved quality of life and mood, but I think very surprisingly at the time, a survival benefit for patients with lung cancer who had received early palliative care. That work, of course, has helped shape national guidelines, as you've shared, and it also helped define early, as within 8 weeks of diagnosis. But unfortunately, there remains a disconnect. So in clinical practice, using diagnosis or stage as the only referral trigger doesn't really match the needs that we see show up. And I think unfortunately, the other part is that approach creates a supply demand mismatch. We end up either referring more patients than palliative care teams can handle, or at the opposite extreme, we end up referring no one at all. So, I actually just wanted to quickly give, for example, two real world contrasts. So one center that I actually have friends who work in, tried as a very good quality improvement incentive, auto-refer all patients with stage IV pancreas cancer to palliative care teams. And while very well intentioned, they saw very quickly that in a two-month period, they had 30 new referrals. And on the palliative care side, there were only 15 available new patient slots. On the other hand, something that I often see in practice, is a situation where, for example, consider the case of a 90-year-old with a low-grade B-cell lymphoma. On paper, low-risk disease, but unfortunately, when you look under the microscope, this gentleman is isolated, has symptoms from his bulky adenopathy, and feels very overwhelmed by many competing illnesses. This is someone who, of course, may benefit from palliative care, but probably doesn't check the box. And I think this is where the model of precision palliative care steps in. It's not really about when was someone diagnosed or what is the prognosis or time-based criteria of their cancer, but it's really fundamentally asking the question of who needs help, what kind of help do they need, and how urgently do we need to provide this help? And I think precision palliative care really mirrors the logic and the philosophy of precision oncology. So just like we've made strides trying to match therapies to tumor biology, we also need to have the same attention and the same precision to match support to symptoms, to context of a patient situation and their caregiver, and also to their personal goals. So I think instead of a blanket referral, we really need to tailor care, the right support at the right moment for the right person to the right care teams. And I think to be more precise, there's really four core elements to allow us to do this well. So first, we really need to implement systematic screening. Let's use what we already have. Many of our centers have patient reported outcomes. The Commission on Cancer motivates us to use distress screening tools. And the EHR is there, but we do very little to flag and to surface unmet care needs. We have seen amazing work from people like Dr. Ethan Bash, who is the pioneer on patient-reported outcomes, and Dr. Ravi Parikh, who used to be my colleague at Penn, now at Emory, who show that you could use structured data and machine learning to identify some of these patient needs in real time. The second piece is after a systematic screening, we really need to build very clear referral pathways. One very good example is what the supportive care team at MD Anderson has done, of course, led by Dr. Eduardo Brera and Dr. David Huey, where they have, for example, designed condition-specific triggers. Urgent referrals, for example, to palliative care for severe symptoms, where they talk about it like a rapid response team. They will see them within 72 hours of the flag. But at the same time, if the unmet need is a caregiver distress, perhaps the social work referral is the first part of the palliative care intervention that needs to be placed. And I think this helps create both clarity and consistency but also it pays attention to that provider and availability demand mismatch. Third, I really think we need to triage smartly. As mentioned in the prior example, not every patient needs every team member of the palliative care team. Some benefit most from the behavioral health intervention. Others might benefit from chaplaincy or the clinician for symptom management. And I think aligning intensity with complexity helps us use our teams wisely. Unfortunately, the greatest barrier in all of our health care systems is time and time availability. And I think this is one strategic approach that I have not yet seen used very wisely. And fourth, I really think we need to embrace interdisciplinary care and change our healthcare systems to focus more on value. So this isn't about more consults or RVUs. I think it's really about leveraging our team strengths. Palliative care teams or supportive care teams usually are multidisciplinary in their core. They often have psychologists, social workers, sometimes they have nurse navigators. And I think all of these are really part of that engine of whole person care. But unfortunately, we still are not set up in care delivery systems that unfortunately to this day still model fee for service where the clinician or the physician visit is the only quote unquote real value add. Hopefully as our healthcare systems focus more on delivery and on value, this might help really embrace the structure to bring through the precision palliative care approach. Dr. Joseph McCollom: No, I love those points. You know, we talk frequently in the interdisciplinary team about how a social worker can spend 5 minutes doing something that I could not as a physician spend an hour doing. But does every patient need every member every time? And how do we work as a unified body to deliver that dose of palliative care, specialized palliative care to those right patients and match them? And I think that perfect analogy is in oncology as a medical oncologist, frequently I'm running complex next-generation sequencing paneling on patients' tumors, trying to find out is there a genetic weakness? Is there a susceptibility to a targeted therapy or an immunotherapy so that I can match and do that precision oncology, right patient to the right drug? Similarly, we need to continue to analyze and find these innovative ways like you've talked about, PROs, EHR flags, machine learning tools, to find those right patients and match them to the right palliative care interdisciplinary team members for them. I know we both get to work in oncology spaces and palliative and supportive spaces in our clinical practice. Share a little bit, if you could, Ramy, about what that looks like for your practice. How do you find those right patients? And how do you then intervene with that right palliative oncology dose? Dr. Ramy Sedhom: So Joe, when I first started in this space as a junior faculty, one thing became immediately clear. I think if we rely solely on physicians to identify the patients for palliative care, we're unfortunately going to be very limited by what we individually, personally observe. And I think that's what reflects the reality that many patients have real needs that go unseen. So over the past few years, I've really worked with a lot of my colleagues to really work the health system to change that. The greatest partnership I've personally had has been working with our informatics team to build a real time EHR integrated dashboard that I think helps us give us a broader view of patient needs. What we really think of as the population health perspective. Our dashboard at Penn, for example, pulls in structured data like geriatric assessment results, PHQ-4 screens, patient reported outcomes, whether or not they've been hospitalized, whether or not these hospitalizations are frequent and recurrent. And I think it's allowed us to really move from a reactive approach to one that's more proactive. So let me give you a practical example. So we have embedded in our cancer care team, psycho-oncologists. They share the same clinic space, they're right down the hall. And we actually use this shared dashboard to review weekly trends in distress scores and patient reported outcomes. And oftentimes, if they see a spike in anxiety or worsening symptoms like depression, they'll reach out to me and say, “Hey, I noticed Mrs. Smith reported feeling very anxious today. Do you think it'd be helpful if I joined you for her visit?” And I think that's how we could really use data and teamwork to offer and maximize the right support at the right time. Like many of our other healthcare systems, we also have real-time alerts for hospitalizations. And I think like Dr. Temel’s most recent trial, which we'll discuss at some point, I'm sure, it's another key trigger for vulnerability. I think whenever someone's admitted or discharged, we try to coordinate with our palliative care colleagues to assess do they need follow-up and in what timeline. And we know that these are common triggers, progression of disease, hospitalizations, drops in quality-of-life. And it's actually surprisingly simple to implement once you set up the right care structures. And I think these systems don't just help patients, which is what I quickly learned. They also help us as clinicians too. Before we expanded our team, I often felt this weight, especially as someone dual trained in oncology and palliative medicine, as trying to be everything to everyone. I remember one patient in particular, a young woman with metastatic breast cancer who was scheduled for a routine pre-chemo visit with me. Unfortunately, on that day, she had a very dramatic change in function. We whisked her down to x-ray and it revealed a pretty large pathologic fracture in her femur. And suddenly what was scheduled as a 30-minute visit became a very complex conversation around prognosis, urgent need for surgery and many, many life changes. And when I looked at my Epic list, I had a full waiting room. And thankfully, because we have embedded palliative care in our team, I was able to bring in Dr. Collins, the physician who I work with closely, immediately. She spent the full hour with the patient while I was able to continue seeing other patients that morning. And I think that's what team-based care makes possible. It's not just more hands on deck but really optimizing the support the patient needs on each individual day. And I think last, we're also learning a lot from behavioral science. So many institutions like Penn, Stanford, Massachusetts General, they've experimented with a lot of really interesting prompts in the EHR. One of them, for example, is the concept of nodes or the concept of prompt questions. Like, do you think this patient would benefit from a supportive care referral? And I think these low-level nudges, in a sense, can actually really dramatically increase the uptake of palliative care because it makes what's relevant immediately salient and visible to the practicing physician. So I think the key, if I had to maybe finish off with a simple message: It's not flashy tech, it's not massive change against staffing, but it's having a local champion and it's working smarter. It's asking the questions of how can we do this better and setting up the systems to make them more sustainable. Dr. Joseph McCollom: I appreciate you talking about this because I think a lot of folks want to put the wheels on in some way and they don't know where to get started. And so I think some of the models that you've been able to create, being able to track patients, screen your population, find the right individuals, and then work within that team to be able to extend, I think when you have an embedded palliative care specialist in your clinic, they expand your practice as a medical oncologist. And so you can make that warm handoff. And that patient and that caregiver, when they view the experience, they don't view you as a medical oncologist, someone else as a palliative care specialist, they view that team approach. And they said, "The team, my cancer team took care of me." And I think we can really harness a lot of the innovative technological advancements in our EHR to be able to prompt us in this work. I know that Dr. Temel had kind of set the stage for early palliative care intervention, and you did mention her stepped palliative care trial. Where do you see some of the future opportunities as we continue to push the needle forward as oncologists and palliative care specialists? What do you see as being the next step? Dr. Ramy Sedhom: So for those who are not familiar with the stepped palliative care trial, again, work by Dr. Temel, I think it's really important to explain not just the study itself, but I think more importantly, what it's representing for the future of our field. First, I really want to acknowledge Dr. Temel, who is a trailblazer in palliative oncology. Her work has not only shaped how we think about timing and delivery, but really about the value of supportive care. And more importantly, I think for all the young trainees listening, she had shown that rigorous randomized trials in palliative care are possible and meaningful. And I think for me, one quick learning point is that you could be an oncologist and lead this impactful research. And she's inspired many and many of us. Now let's quickly transition to her study. So in this trial, the stepped palliative care trial, patients with advanced lung cancer were randomized into two groups. One group followed the model from her landmark 2010 New England Journal of Medicine paper, which was structured monthly palliative care visits, again, within eight weeks of diagnosis. The second group, which is in this study, the intervention or the stepped palliative care group, received a single early palliative care visit. Think of this as a meet and greet. And then care was actually stepped up. If one of three clinical triggers happened. One, a decline in patient reported quality of life as measured by PROs. Two, disease progression, or three, hospitalization. And the findings which were presented at ASCO 2024 were striking. Clinical outcomes, very similar between the two groups. And this included quality-of-life, end-of-life communication, and resource use. But I think the take-home point is that the number of palliative care visits in the stepped group was significantly lower. So in other words, same impact and fewer visits. This was a very elegant example of how we can model precision palliative care, right sizing patient care based on patient need. So where do we go from here? I think if we want this model to take root nationally, we really need to pull on three key levers: healthcare systems, healthcare payment, and healthcare culture. So from a system alignment, unfortunately, as mentioned too often, the solution to gaps in palliative care is we need more clinicians. And while yes, that's partly true, it's actually not the full picture. I think what we first need to do and what's more likely to be achieved is to develop systems that focus on building the infrastructure that maximizes the reach of our existing care teams. So this means investing in nurse navigation, real-time dashboards with patient-reported outcomes and EHR flags, and again, matching triage protocols where intensity matches complexity. And the goal, as mentioned, isn't to maximize consults, but to really maximize deployment of expertise based on need. The second piece is, of course, we need payment reform. So the stepped palliative care model only works when it allows continuous patient engagement. But unfortunately, current pay models don't reward or incentivize that. In fact, electronic PROs require a very high upfront financial investment and ongoing clinician time with little to no reimbursement. Imagine if we offered bundled payments or value-based incentives for teams that integrated PROs. Or imagine if we reimbursed palliative care based on impact or infrastructure instead of just fee-for-service volume. There is a lot of clear evidence that tele-palliative care is effective. In fact, it was the Plenary at ASCO 2024. Yet we're still battling these conversations around inconsistent reimbursement, and we're always waiting on whether or not telehealth waivers are gonna continue. So I think most importantly is we really need to recognize the broader scope of what palliative care offers, which is caregiver support, improving navigation, coordinating very complex transitions. To me, and what I've always prioritized as a champion at Penn, is that palliative care is not a nice to have, and neither are all of these infrastructures, but they're really essential to whole person care, and they need to be financially supported. And last, we really need a culture shift. We need to change from how palliative care is perceived, and it can't be something other. It can't be something outside of oncology, but it really needs to be embraced as this is part of cancer care itself. I often see hesitancy from many oncologists about introducing palliative care early. But it doesn't need to be a dramatic shift. I think small changes in language, how we introduce the palliative care team, and co-management models can really go a very long way in normalizing this part of patient care. And I'm particularly encouraged, Joe, by one particular innovation in this space, which is really the growth of many startups. And one startup, for example, is Thyme Care, where I've seen them working with many, many private practices across the country, alongside partnerships with payers to really build tech-enabled navigation that tries to basically maximize triage support with electronic PROs. And to me, I really think these models can help scale access without overwhelming current care teams. So precision palliative care, Joe, in summary, I think should be flexible, scalable, and really needs to align based on what patients need. Dr. Joseph McCollom: No, I really appreciate, Ramy, you talking about that it really takes a village to get oncology care in both a competent and a compassionate way. And we need buy-in champions at all levels: the system level, the administrative level, the policy level, the tech level. And we need to change culture. I kind of want to just get your final impressions and also make sure that we make our listeners aware of our article. We should be able to have this in the show notes here as well to find additional tools and resources, all the studies that were discussed in today's episode. But, Ramy, what are some of your kind of final takeaways and conclusions? Dr. Ramy Sedhom: Before we wrap up, I just want to make sure we highlight a very exciting opportunity for residents considering a future in oncology and palliative medicine. Thanks to the leadership of Dr. Jamie Von Roen, who truly championed this cause, ASCO and the ABIM (American Board of Internal Medicine) have partnered to create the first truly integrated palliative care oncology fellowship. Trainees can now double board in just two years or triple board in three with palliative care, oncology, and hematology. And I think, Joe, as you and I both know, it's incredibly rewarding and meaningful to work at this intersection. To close our message, if there's one message I think listeners should carry with them, it's that palliative care is about helping people live as well as possible for as long as possible. And precision palliative care simply helps us do that better. We need to really develop systems that tailor support to individual need, value, and individual goals. Just like our colleagues in precision oncology mentioned, getting the right care to the right patient at the right time, and I would add in the right way. For those who want to learn more, I encourage you to read our full article in JCO, which is “Precision Palliative Care As a Pragmatic Solution for a Care Delivery Problem.” Joe, thank you so, so much for this thoughtful conversation and for your leadership in our field. And thank you to everyone for listening. Thank you all for being champions of this essential part of cancer care. If you haven't yet joined the ASCO Palliative Care Communities of Practice, membership is free, and we'd love to have you. Dr. Joseph McCollom: Thank you, Ramy, not only for sharing your insights today, but the pioneering work that you have done in our field. You are truly an inspiration to me in clinical practice, and it is an honor to call you both a colleague and friend.  And thank you for our listeners for joining us today. If you value the insights that you've heard on the ASCO Daily News Podcast, please subscribe, rate, and review wherever you get your podcasts. Thanks again. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today’s speakers:   Dr. Joseph McCollom @realbowtiedoc Dr. Ramy Sedhom @ramsedhom Follow ASCO on social media:   @ASCO on X (formerly Twitter) ASCO on Bluesky  ASCO on Facebook   ASCO on LinkedIn   Disclaimer: Dr. Joseph McCollom: No relationships to disclose Dr. Ramy Sedhom: No relationships to disclose

Dr. Paul Hanona and Dr. Arturo Loaiza-Bonilla discuss how to safely and smartly integrate AI into the clinical workflow and tap its potential to improve patient-centered care, drug development, and access to clinical trials. TRANSCRIPT Dr. Paul Hanona: Hello, I'm Dr. Paul Hanona, your guest host of the ASCO Daily News Podcast today. I am a medical oncologist as well as a content creator @DoctorDiscover, and I’m delighted to be joined today by Dr. Arturo Loaiza-Bonilla, the chief of hematology and oncology at St. Luke’s University Health Network. Dr. Bonilla is also the co-founder and chief medical officer at Massive Bio, an AI-driven platform that matches patients with clinical trials and novel therapies. Dr. Loaiza-Bonilla will share his unique perspective on the potential of artificial intelligence to advance precision oncology, especially through clinical trials and research, and other key advancements in AI that are transforming the oncology field. Our full disclosures are available in the transcript of the episode. Dr. Bonilla, it's great to be speaking with you today. Thanks for being here. Dr. Arturo Loaiza-Bonilla: Oh, thank you so much, Dr. Hanona. Paul, it’s always great to have a conversation. Looking forward to a great one today. Dr. Paul Hanona: Absolutely. Let’s just jump right into it. Let’s talk about the way that we see AI being embedded in our clinical workflow as oncologists. What are some practical ways to use AI? Dr. Arturo Loaiza-Bonilla: To me, responsible AI integration in oncology is one of those that's focused on one principle to me, which is clinical purpose is first, instead of the algorithm or whatever technology we’re going to be using. If we look at the best models in the world, they’re really irrelevant unless we really solve a real day-to-day challenge, either when we’re talking to patients in the clinic or in the infusion chair or making decision support. Currently, what I’m doing the most is focusing on solutions that are saving us time to be more productive and spend more time with our patients. So, for example, we’re using ambient AI for appropriate documentation in real time with our patients. We’re leveraging certain tools to assess for potential admission or readmission of patients who have certain conditions as well. And it’s all about combining the listening of physicians like ourselves who are end users, those who create those algorithms, data scientists, and patient advocates, and even regulators, before they even write any single line of code. I felt that on my own, you know, entrepreneurial aspects, but I think it's an ethos that we should all follow. And I think that AI shouldn't be just bolted on later. We always have to look at workflows and try to look, for example, at clinical trial matching, which is something I'm very passionate about. We need to make sure that first, it's easier to access for patients, that oncologists like myself can go into the interface and be able to pull the data in real time when you really need it, and you don't get all this fatigue alerts. To me, that's the responsible way of doing so. Those are like the opportunities, right? So, the challenge is how we can make this happen in a meaningful way – we're just not reacting to like a black box suggestion or something that we have no idea why it came up to be. So, in terms of success – and I can tell you probably two stories of things that we know we're seeing successful – we all work closely with radiation oncologists, right? So, there are now these tools, for example, of automated contouring in radiation oncology, and some of these solutions were brought up in different meetings, including the last ASCO meeting. But overall, we know that transformer-based segmentation tools; transformer is just the specific architecture of the machine learning algorithm that has been able to dramatically reduce the time for colleagues to spend allotting targets for radiation oncology. So, comparing the target versus the normal tissue, which sometimes it takes many hours, now we can optimize things over 60%, sometimes even in minutes. So, this is not just responsible, but it's also an efficiency win, it's a precision win, and we're using it to adapt even mid-course in response to tumor shrinkage. Another success that I think is relevant is, for example, on the clinical trial matching side. We've been working on that and, you know, I don't want to preach to the choir here, but having the ability for us to structure data in real time using these tools, being able to extract information on biomarkers, and then show that multi-agentic AI is superior to what we call zero-shot or just throwing it into ChatGPT or any other algorithm, but using the same tools but just fine-tuned to the point that we can be very efficient and actually reliable to the level of almost like a research coordinator, is not just theory. Now, it can change lives because we can get patients enrolled in clinical trials and be activated in different places wherever the patient may be. I know it's like a long answer on that, but, you know, as we talk about responsible AI, that's important. And in terms of what keeps me up at night on this: data drift and biases, right? So, imaging protocols, all these things change, the lab switch between different vendors, or a patient has issues with new emerging data points. And health systems serve vastly different populations. So, if our models are trained in one context and deployed in another, then the output can be really inaccurate. So, the idea is to become a collaborative approach where we can use federated learning and patient-centricity so we can be much more efficient in developing those models that account for all the populations, and any retraining that is used based on data can be diverse enough that it represents all of us and we can be treated in a very good, appropriate way. So, if a clinician doesn't understand why a recommendation is made, as you probably know, you probably don't trust it, and we shouldn't expect them to. So, I think this is the next wave of the future. We need to make sure that we account for all those things. Dr. Paul Hanona: Absolutely. And even the part about the clinical trials, I want to dive a little bit more into in a few questions. I just kind of wanted to make a quick comment. Like you said, some of the prevalent things that I see are the ambient scribes. It seems like that's really taken off in the last year, and it seems like it's improving at a pretty dramatic speed as well. I wonder how quickly that'll get adopted by the majority of physicians or practitioners in general throughout the country. And you also mentioned things with AI tools regarding helping regulators move things quicker, even the radiation oncologist, helping them in their workflow with contouring and what else they might have to do. And again, the clinical trials thing will be quite interesting to get into. The first question I had subsequent to that is just more so when you have large datasets. And this pertains to two things: the paper that you published recently regarding different ways to use AI in the space of oncology referred to drug development, the way that we look at how we design drugs, specifically anticancer drugs, is pretty cumbersome. The steps that you have to take to design something, to make sure that one chemical will fit into the right chemical or the structure of the molecule, that takes a lot of time to tinker with. What are your thoughts on AI tools to help accelerate drug development? Dr. Arturo Loaiza-Bonilla: Yes, that's the Holy Grail and something that I feel we should dedicate as much time and effort as possible because it relies on multimodality. It cannot be solved by just looking at patient histories. It cannot be solved by just looking at the tissue alone. It's combining all these different datasets and being able to understand the microenvironment, the patient condition and prior treatments, and how dynamic changes that we do through interventions and also exposome – the things that happen outside of the patient's own control – can be leveraged to determine like what's the best next step in terms of drugs. So, the ones that we heard the news the most is, for example, the Nobel Prize-winning [for Chemistry awarded to Demis Hassabis and John Jumper for] AlphaFold, an AI system that predicts protein structures right? So, we solved this very interesting concept of protein folding where, in the past, it would take the history of the known universe, basically – what's called the Levinthal's paradox – to be able to just predict on amino acid structure alone or the sequence alone, the way that three-dimensionally the proteins will fold. So, with that problem being solved and the Nobel Prize being won, the next step is, “Okay, now we know how this protein is there and just by sequence, how can we really understand any new drug that can be used as a candidate and leverage all the data that has been done for many years of testing against a specific protein or a specific gene or knockouts and what not?” So, this is the future of oncology and where we're probably seeing a lot of investments on that. The key challenge here is mostly working on the side of not just looking at pathology, but leveraging this digital pathology with whole slide imaging and identifying the microenvironment of that specific tissue. There's a number of efforts currently being done. One isn't just H&E, like hematoxylin and eosin, slides alone, but with whole imaging, now we can use expression profiles, spatial transcriptomics, and gene whole exome sequencing in the same space and use this transformer technology in a multimodality approach that we know already the slide or the pathology, but can we use that to understand, like, if I knock out this gene, how is the microenvironment going to change to see if an immunotherapy may work better, right? If we can make a microenvironment more reactive towards a cytotoxic T cell profile, for example. So, that is the way where we're really seeing the field moving forward, using multimodality for drug discovery. So, the FDA now seems to be very eager to support those initiatives, so that's of course welcome. And now the key thing is the investment to do this in a meaningful way so we can see those candidates that we're seeing from different companies now being leveraged for rare disease, for things that are going to be almost impossible to collect enough data, and make it efficient by using these algorithms that sometimes, just with multiple masking – basically, what they do is they mask all the features and force the algorithm to find solutions based on the specific inputs or prompts we're doing. So, I'm very excited about that, and I think we're going to be seeing that in the future. Dr. Paul Hanona: So, essentially, in a nutshell, we're saying we have the cancer, which is maybe a dandelion in a field of grass, and we want to see the grass that's surrounding the dandelion, which is the pathology slides. The problem is, to the human eye, it's almost impossible to look at every single piece of grass that's surrounding the dandelion. And so, with tools like AI, we can greatly accelerate our study of the microenvironment or the grass that's surrounding the dandelion and better tailor therapy, come up with therapy. Otherwise, like you said, to truly generate a drug, this would take years and years. We just don't have the throughput to get to answers like that unless we have something like AI to help us. Dr. Arturo Loaiza-Bonilla: Correct. Dr. Paul Hanona: And then, clinical trials. Now, this is an interesting conversation because if you ever look up our national guidelines as oncologists, there's always a mention of, if treatment fails, consider clinical trials. Or in the really aggressive cancers, sometimes you might just start out with clinical trials. You don't even give the standard first-line therapy because of how ineffective it is. There are a few issues with clinical trials that people might not be aware of, but the fact that the majority of patients who should be on clinical trials are never given the chance to be on clinical trials, whether that's because of proximity, right, they might live somewhere that's far from the institution, or for whatever reason, they don't qualify for the clinical trial, they don't meet the strict inclusion criteria.  But a reason you mentioned early on is that it's simply impossible for someone to be aware of every single clinical trial that's out there. And then even if you are aware of those clinical trials, to actually find the sites and put in the time could take hours. And so, how is AI going to revolutionize that? Because in my mind, it's not that we're inventing a new tool. Clinical trials have always been available. We just can't access them. So, if we have a tool that helps with access, wouldn't that be huge? Dr. Arturo Loaiza-Bonilla: Correct. And that has been one of my passions. And for those who know me and follow me and we've spoke about it in different settings, that's something that I think we can solve. This other paradox, which is the clinical trial enrollment paradox, right? We have tens of thousands of clinical trials available with millions of patients eager to learn about trials, but we don't enroll enough and many trials close to accrual because of lack of enrollment. It is completely paradoxical and it's because of that misalignment because patients don't know where to go for trials and sites don't know what patients they can help because they haven't reached their doors yet. So, the solution has to be patient-centric, right? We have to put the patient at the center of the equation. And that was precisely what we had been discussing during the ASCO meeting. There was an ASCO Education Session where we talked about digital prescreening hubs, where we, in a patient-centric manner, the same way we look for Uber, Instacart, any solution that you may think of that you want something that can be leveraged in real time, we can use these real-world data streams from the patient directly, from hospitals, from pathology labs, from genomics companies, to continuously screen patients who can match to the inclusion/exclusion criteria of unique trials. So, when the patient walks into the clinic, the system already knows if there's a trial and alerts the site proactively. The patient can actually also do decentralization. So, there's a number of decentralized clinical trial solutions that are using what I call the “click and mortar” approach, which is basically the patient is checking digitally and then goes to the site to activate. We can also have the click and mortar in the bidirectional way where the patient is engaged in person and then you give the solution like the ones that are being offered on things that we're doing at Massive Bio and beyond, which is having the patient to access all that information and then they make decisions and enroll when the time is right.  As I mentioned earlier, there is this concept drift where clinical trials open and close, the patient line of therapy changes, new approvals come in and out, and sites may not be available at a given time but may be later. So, having that real-time alerts using tools that are able already to extract data from summarization that we already have in different settings and doing this natural language ingestion, we can not only solve this issue with manual chart review, which is extremely cumbersome and takes forever and takes to a lot of one-time assessments with very high screen failures, to a real-time dynamic approach where the patient, as they get closer to that eligibility criteria, they get engaged. And those tools can be built to activate trials, audit trials, and make them better and accessible to patients. And something that we know is, for example, 91%-plus of Americans live close to either a pharmacy or an imaging center. So, imagine that we can potentially activate certain of those trials in those locations. So, there's a number of pharmacies, special pharmacies, Walgreens, and sometimes CVS trying to do some of those efforts. So, I think the sky's the limit in terms of us working together. And we've been talking with corporate groups, they're all interested in those efforts as well, to getting patients digitally enabled and then activate the same way we activate the NCTN network of the corporate groups, that are almost just-in-time. You can activate a trial the patient is eligible for and we get all these breakthroughs from the NIH and NCI, just activate it in my site within a week or so, as long as we have the understanding of the protocol. So, using clinical trial matching in a digitally enabled way and then activate in that same fashion, but not only for NCTN studies, but all the studies that we have available will be the key of the future through those prescreening hubs. So, I think now we're at this very important time where collaboration is the important part and having this silo-breaking approach with interoperability where we can leverage data from any data source and from any electronic medical records and whatnot is going to be essential for us to move forward because now we have the tools to do so with our phones, with our interests, and with the multiple clinical trials that are coming into the pipelines. Dr. Paul Hanona: I just want to point out that the way you described the process involves several variables that practitioners often don't think about. We don't realize the 15 steps that are happening in the background. But just as a clarifier, how much time is it taking now to get one patient enrolled on a clinical trial? Is it on the order of maybe 5 to 10 hours for one patient by the time the manual chart review happens, by the time the matching happens, the calls go out, the sign-up, all this? And how much time do you think a tool that could match those trials quicker and get you enrolled quicker could save? Would it be maybe an hour instead of 15 hours? What's your thought process on that? Dr. Arturo Loaiza-Bonilla: Yeah, exactly. So one is the matching, the other one is the enrollment, which, as you mentioned, is very important. So, it can take, from, as you said, probably between 4 days to sometimes 30 days. Sometimes that's how long it takes for all the things to be parsed out in terms of logistics and things that could be done now agentically. So, we can use agents to solve those different steps that may take multiple individuals. We can just do it as a supply chain approach where all those different steps can be done by a single agent in a simultaneous fashion and then we can get things much faster. With an AI-based solution using these frontier models and multi-agentic AI – and we presented some of this data in ASCO as well – you can do 5,000 patients in an hour, right? So, just enrolling is going to be between an hour and maximum enrollment, it could be 7 days for those 5,000 patients if it was done at scale in a multi-level approach where we have all the trials available. Dr. Paul Hanona: No, definitely a very exciting aspect of our future as oncologists. It's one thing to have really neat, novel mechanisms of treatment, but what good is it if we can't actually get it to people who need it? I'm very much looking for the future of that.  One of the last questions I want to ask you is another prevalent way that people use AI is just simply looking up questions, right? So, traditionally, the workflow for oncologists is maybe going on national guidelines and looking up the stage of the cancer and seeing what treatments are available and then referencing the papers and looking at who was included, who wasn't included, the side effects to be aware of, and sort of coming up with a decision as to how to treat a cancer patient. But now, just in the last few years, we've had several tools become available that make getting questions easier, make getting answers easier, whether that's something like OpenAI's tools or Perplexity or Doximity or OpenEvidence or even ASCO has a Guidelines Assistant as well that is drawing from their own guidelines as to how to treat different cancers. Do you see these replacing traditional sources? Do you see them saving us a lot more time so that we can be more productive in clinic? What do you think is the role that they're going to play with patient care? Dr. Arturo Loaiza-Bonilla: Such a relevant question, particularly at this time, because these AI-enabled query tools, they're coming left and right and becoming increasingly common in our daily workflows and things that we're doing. So, traditionally, when we go and we look for national guidelines, we try to understand the context ourselves and then we make treatment decisions accordingly. But that is a lot of a process that now AI is helping us to solve. So, at face value, it seems like an efficiency win, but in many cases, I personally evaluate platforms as the chief of hem/onc at St. Luke's and also having led the digital engagement things through Massive Bio and trying to put things together, I can tell you this: not all tools are created equal. In cancer care, each data point can mean the difference between cure and progression, so we cannot really take a lot of shortcuts in this case or have unverified output. So, the tools are helpful, but it has to be grounded in truth, in trusted data sources, and they need to be continuously updated with, like, ASCO and NCCN and others. So, the reason why the ASCO Guidelines Assistant, for instance, works is because it builds on all these recommendations, is assessed by end users like ourselves. So, that kind of verification is critical, right? We're entering a phase where even the source material may be AI-generated. So, the role of human expert validation is really actually more important, not less important. You know, generalist LLMs, even when fine-tuned, they may not be enough. You can pull a few API calls from PubMed, etc., but what we need now is specialized, context-aware, agentic tools that can interpret multimodal and real-time clinical inputs. So, something that we are continuing to check on and very relevant to have entities and bodies like ASCO looking into this so they can help us to be really efficient and really help our patients. Dr. Paul Hanona: Dr. Bonilla, what do you want to leave the listener with in terms of the future direction of AI, things that we should be cautious about, and things that we should be optimistic about? Dr. Arturo Loaiza-Bonilla: Looking 5 years ahead, I think there's enormous promise. As you know, I'm an AI enthusiast, but always, there's a few priorities that I think – 3 of them, I think – we need to tackle head-on. First is algorithmic equity. So, most AI tools today are trained on data from academic medical centers but not necessarily from community practices or underrepresented populations, particularly when you're looking at radiology, pathology, and what not. So, those blind spots, they need to be filled, and we can eliminate a lot of disparities in cancer care. So, those frameworks to incentivize while keeping the data sharing using federated models and things that we can optimize is key. The second one is the governance on the lifecycle. So, you know, AI is not really static. So, unlike a drug that is approved and it just, you know, works always, AI changes. So, we need to make sure that we have tools that are able to retrain and recall when things degrade or models drift. So, we need to use up-to-date AI for clinical practice, so we are going to be in constant revalidation and make it really easy to do. And lastly, the human-AI interface. You know, clinicians don't need more noise or we don't need more black boxes. We need decision support that is clear, that we can interpret, and that is actionable. “Why are you using this? Why did we choose this drug? Why this dose? Why now?” So, all these things are going to help us and that allows us to trace evidence with a single click. So, I always call it back to the Moravec's paradox where we say, you know, evolution gave us so much energy to discern in the sensory-neural and dexterity. That's what we're going to be taking care of patients. We can use AI to really be a force to help us to be better clinicians and not to really replace us. So, if we get this right and we decide for transparency with trust, inclusion, etc., it will never replace any of our work, which is so important, as much as we want, we can actually take care of patients and be personalized, timely, and equitable. So, all those things are what get me excited every single day about these conversations on AI. Dr. Paul Hanona: All great thoughts, Dr. Bonilla. I'm very excited to see how this field evolves. I'm excited to see how oncologists really come to this field. I think with technology, there's always a bit of a lag in adopting it, but I think if we jump on board and grow with it, we can do amazing things for the field of oncology in general. Thank you for the advancements that you've made in your own career in the field of AI and oncology and just ultimately with the hopeful outcomes of improving patient care, especially cancer patients. Dr. Arturo Loaiza-Bonilla: Thank you so much, Dr. Hanona. Dr. Paul Hanona: Thanks to our listeners for your time today. If you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. More on today’s speakers:    Dr. Arturo Loaiza-Bonilla @DrBonillaOnc Dr. Paul Hanona @DoctorDiscover on YouTube Follow ASCO on social media:      @ASCO on Twitter      ASCO on Facebook      ASCO on LinkedIn    ASCO on BlueSky Disclosures: Paul Hanona: No relationships to disclose. Dr. Arturo-Loaiza-Bonilla: Leadership: Massive Bio Stock & Other Ownership Interests: Massive Bio Consulting or Advisory Role: Massive Bio, Bayer, PSI, BrightInsight, CardinalHealth, Pfizer, AstraZeneca, Medscape Speakers’ Bureau: Guardant Health, Ipsen, AstraZeneca/Daiichi Sankyo, Natera

Dr. Diwakar Davar and Dr. Jason Luke discuss novel agents in melanoma and other promising new data in the field of immunotherapy that were presented at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Diwakar Davar: Hello. My name is Diwakar Davar, and I am welcoming you to the ASCO Daily News Podcast. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh’s Hillman Cancer Center. Today, I'm joined by my colleague and good friend, Dr. Jason Luke. Dr. Luke is a professor of medicine. He is also the associate director of clinical research and the director of the Phase 1 IDDC Program at the University of Pittsburgh's Hillman Cancer Center. He and I are going to be discussing some key advancements in melanoma and skin cancers that were presented at the 2025 ASCO Annual Meeting. Our full disclosures are available in the transcript of this episode.  Jason, it is great to have you back on the podcast. Dr. Jason Luke: Thanks again so much for the opportunity, and I'm really looking forward to it. Dr. Diwakar Davar: Perfect. So we will go ahead and start talking a little bit about a couple of key abstracts in both the drug development immunotherapy space and the melanoma space. The first couple of abstracts, the first two, will cover melanoma. So, the first is LBA9500, which was essentially the primary results of RELATIVITY-098. RELATIVITY-098 was a phase 3 trial that compared nivolumab plus relatlimab in a fixed-dose combination against nivolumab alone for the adjuvant treatment of resected high-risk disease. Jason, do you want to maybe give us a brief context of what this is? Dr. Jason Luke: Yeah, it's great, thanks. So as almost all listeners, of course, will be aware, the use of anti–PD-1 immunotherapies really revolutionized melanoma oncology over the last 10 to 15 years. And it has become a standard of care in the adjuvant setting as well. But to review, in patients with stage III melanoma, treatment can be targeted towards BRAF with BRAF and MEK combination therapy, where that's relevant, or anti–PD-1 with nivolumab or pembrolizumab are a standard of care. And more recently, we've had the development of neoadjuvant approaches for palpable stage III disease. And in that space, if patients present, based on two different studies, either pembrolizumab or nivolumab plus ipilimumab can be given prior to surgery for somewhere in the 6- to 9-week range. And so all of these therapies have improved time-to-event endpoints, such as relapse-free or event-free survival. It's worth noting, however, that despite those advances, we've had a couple different trials now that have actually failed in this adjuvant setting, most high profile being the CheckMate-915 study, which looked at nivolumab plus ipilimumab and unfortunately was a negative study. So, with RELATIVITY-047, which was the trial of nivolumab plus relatlimab that showed an improvement in progression-free survival for metastatic disease, there's a lot of interest, and we've been awaiting these data for a long time for RELATIVITY-098, which, of course, is this adjuvant trial of LAG-3 blockade with relatlimab plus nivolumab. Dr. Diwakar Davar: Great. So with that, let's briefly discuss the trial design and the results. So this was a randomized, phase 3, blinded study, so double-blinded, so neither the investigators knew what the patients were getting, nor did the patients know what they were getting. The treatment investigational arm was nivolumab plus relatlimab in the fixed-dose combination. So that's the nivolumab standard fixed dose with relatlimab that was FDA approved in RELATIVITY-047. And the control arm was nivolumab by itself. The duration of treatment was 1 year. The patient population consisted of resected high-risk stage III or IV patients. The primary endpoint was investigator-assessed RFS. Stage and geography were the standard stratifying factors, and they were included, and most of the criteria were balanced across both arms. What we know at this point is that the 2-year RFS rate was 64% and 62% in the nivolumab and nivolumab-combination arms, respectively. The 2-year DMFS rate was similarly equivalent: 76% with nivolumab monotherapy, 73% with the combination. And similar to what you had talked about with CheckMate 915, unfortunately, the addition of LAG-3 did not appear to improve the RFS or DMFS compared to control in this patient population. So, tell us a little bit about your take on this and what do you think might be the reasons why this trial was negative? Dr. Jason Luke: It's really unfortunate that we have this negative phase 3 trial. There had been a lot of hope that the combination of nivolumab with relatlimab would be a better tolerated combination that increased the efficacy. So in the metastatic setting, we do have 047, the study that demonstrated nivolumab plus relatlimab, but now we have this negative trial in the adjuvant setting. And so as to why exactly, I think is a complicated scenario. You know, when we look at the hazard ratios for relapse-free survival, the primary endpoint, as well as the secondary endpoints for distant metastasis-free survival, we see that the hazard ratio is approximately 1. So there's basically no difference. And that really suggests that relatlimab in this setting had no impact whatsoever on therapeutic outcomes in terms of efficacy. Now, it's worth noting that there was a biomarker subanalysis that was presented in conjunction with these data that looked at some immunophenotyping, both from circulating T cells, CD8 T cells, as well as from the tumor microenvironment from patients who were treated, both in the previous metastatic trial, the RELATIVITY-047 study, and now in this adjuvant study in the RELATIVITY-098 study. And to briefly summarize those, what was identified was that T cells in advanced melanoma seemed to have higher expression levels of LAG-3 relative to T cells that are circulating in patients that are in the adjuvant setting. In addition to that, there was a suggestion that the magnitude of increase is greater in the advanced setting versus adjuvant. And the overall summary of this is that the suggested rationale for why this was a negative trial may have been that the target of LAG-3 is not expressed as highly in the adjuvant setting as it is in the metastatic setting. And so while the data that were presented, I think, support this kind of an idea, I am a little bit cautious that this is actually the reason for why the trial was negative, however. I would say we're not really sure yet as to why the trial was negative, but the fact that the hazard ratios for the major endpoints were essentially 1 suggests that there was no impact whatsoever from relatlimab. And this really makes one wonder whether or not building on anti–PD-1 in the adjuvant setting is feasible because anti–PD-1 works so well. You would think that even if the levels of LAG-3 expression were slightly different, you would have seen a trend in one direction or another by adding a second drug, relatlimab, in this scenario. So overall, I think it's an unfortunate circumstance that the trial is negative. Clearly there's going to be no role for relatlimab in the adjuvant setting. I think this really makes one wonder about the utility of LAG-3 blockade and how powerful it really can be. I think it's probably worth pointing out there's another adjuvant trial ongoing now of a different PD-1 and LAG-3 combination, and that's cemiplimab plus fianlimab, a LAG-3 antibody that's being dosed from another trial sponsor at a much higher dose, and perhaps that may make some level of difference. But certainly, these are unfortunate results that will not advance the field beyond where we were at already. Dr. Diwakar Davar: And to your point about third-generation checkpoint factors that were negative, I guess it's probably worth noting that a trial that you were involved with, KeyVibe-010, that evaluated the PD-1 TIGIT co-formulation of vibostolimab, MK-4280A, was also, unfortunately, similarly negative. So, to your point, it's not clear that all these third-generation receptors are necessarily going to have the same impact in the adjuvant setting, even if they, you know, for example, like TIGIT, and they sometimes may not even have an effect at all in the advanced cancer setting. So, we'll see what the HARMONY phase 3 trial, that's the Regeneron cemiplimab/fianlimab versus pembrolizumab control with cemiplimab with fianlimab at two different doses, we'll see how that reads out. But certainly, as you've said, LAG-3 does not, unfortunately, appear to have an impact in the adjuvant setting. So let's move on to LBA9501. This is the primary analysis of EORTC-2139-MG or the Columbus-AD trial. This was a randomized trial of encorafenib and binimetinib, which we will abbreviate as enco-bini going forward, compared to placebo in high-risk stage II setting in melanoma in patients with BRAF V600E or K mutant disease. So Jason, you know, you happen to know one or two things about the resected stage II setting, so maybe contextualize the stage II setting for us based on the trials that you've led, KEYNOTE-716, as well as CheckMate-76K, set us up to talk about Columbus-AD. Dr. Jason Luke: Thanks for that introduction, and certainly stage II disease has been something I've worked a lot on. The rationale for that has been that building off of the activity of anti–PD-1 in metastatic melanoma and then seeing the activity in stage III, like we just talked about, it was a curious circumstance that dating back about 7 to 8 years ago, there was no availability to use anti–PD-1 for high-risk stage II patients, even though the risk of recurrence and death from melanoma in the context of stage IIB and IIC melanoma is in fact similar or actually higher than in stage IIIA or IIIB, where anti–PD-1 was approved. And in that context, a couple of different trials that you alluded to, the Keynote-716 study that I led, as well as the CheckMate 76K trial, evaluated pembrolizumab and nivolumab, respectively, showing an improvement in relapse-free and distant metastasis-free survival, and both of those agents have subsequently been approved for use in the adjuvant setting by the US FDA as well as the European Medicines Agency.  So bringing then to this abstract, throughout melanoma oncology, we've seen that the impact of anti–PD-1 immunotherapy versus BRAF and MEK-targeted therapy have had very similar outcomes on a sort of comparison basis, both in frontline metastatic and then in adjuvant setting. So it was a totally reasonable question to ask: Could we use adjuvant BRAF and MEK inhibitor therapy? And I think all of us expected the answer would be yes. As we get into the discussion of the trial, I think the unfortunate circumstance was that the timing of this clinical trial being delayed somewhat, unfortunately, made it very difficult to accrue the trial, and so we're going to have to try to read through the tea leaves sort of, based on only a partially complete data set. Dr. Diwakar Davar: So, in terms of the results, they wanted to enroll 815 patients, they only enrolled 110. The RFS and DMFS were marginally improved in the treatment arm but certainly not significantly, which is not surprising because the trial had only accrued 16% to 18% of its complete accrual. As such, we really can't abstract from the stage III COMBI-AD data to stage II patients. And certainly in this setting, one would argue that the primary treatment options certainly remain either anti–PD-1 monotherapy, either with pembrolizumab or nivolumab, based on 716 or 76K, or potentially active surveillance for the patients who are not inclined to get treated.  Can you tell us a little bit about how you foresee drug development going forward in this space because, you know, for example, with HARMONY, certainly IIC disease is a part of HARMONY. We will know at least a little bit about that in this space. So what do you think about the stage IIB/C patient population? Is this a patient population in which future combinations are going to be helpful, and how would you think about where we can go forward from here? Dr. Jason Luke: It is an unfortunate circumstance that this trial could not be accrued at the pace that was necessary. I think all of us believe that the results would have been positive if they'd been able to accrue the trial. In the preliminary data set that they did disclose of that 110 patients, you know, it's clear there is a difference at a, you know, a landmark at a year. They showed a 16% difference, and that would be in line with what has been seen in stage III. And so, you know, I think it's really kind of too bad. There's really going to be no regulatory approach for this consideration. So using BRAF and MEK inhibition in stage II is not going to be part of standard practice moving into the future. To your point, though, about where will the field go? I think what we're already realizing is that in the adjuvant setting, we're really overtreating the total population. And so beyond merely staging by AJCC criteria, we need to move to biomarker selection to help inform which patients truly need the treatment. And in that regard, I don't think we've crystallized together as a field as yet, but the kinds of things that people are thinking about are the integration of molecular biomarkers like ctDNA. When it's positive, it can be very helpful, but in melanoma, we found that, unfortunately, the rates are quite low, you know, in the 10% to 15% range in the adjuvant setting. So then another consideration would be factors in the primary tumor, such as gene expression profiling or other considerations.  And so I think the future of adjuvant clinical trials will be an integration of both the standard AJCC staging system as well as some kind of overlaid molecular biomarker that helps to enrich for a higher-risk population of patients because on a high level, when you abstract out, it's just clearly the case that we're rather substantially overtreating the totality of the population, especially given that in all of our adjuvant studies to date for anti–PD-1, we have not yet shown that there's an overall survival advantage. And so some are even arguing perhaps we should even reserve treatment until patients progress. I think that's a complicated subject, and standard of care at this point is to offer adjuvant therapy, but certainly a lot more to do because many patients, you know, unfortunately, still do progress and move on to metastatic disease. Dr. Diwakar Davar: Let's transition to Abstract 2508. So we're moving on from the melanoma to the novel immunotherapy abstracts. And this is a very, very, very fascinating drug. It's IMA203. So Abstract 2508 is a phase 1 clinical update of IMA203. IMA203 is an autologous TCR-T construct targeting PRAME in patients with heavily pretreated PD-1-refractory metastatic melanoma. So Jason, in the PD-1 and CTLA-4-refractory settings, treatment options are either autologous TIL, response rate, you know, ballpark 29% to 31%, oncolytic viral therapy, RP1 with nivolumab, ORR about 30-ish percent. So new options are needed. Can you tell us a little bit about IMA203? Perhaps tell us for the audience, what is the difference between a TCR-T and traditional autologous TIL? And a little bit about this drug, IMA203, and how it distinguishes itself from the competing TIL products in the landscape. Dr. Jason Luke: I'm extremely enthusiastic about IMA203. I think that it really has transformative potential based on these results and hopefully from the phase 3 trial that's open to accrual now. So, what is IMA203? We said it's a TCR-T cell product. So what that means is that T cells are removed from a patient, and then they can be transduced through various technologies, but inserted into those T cells, we can then add a T-cell receptor that's very specific to a single antigen, and in this case, it's PRAME. So that then is contrasted quite a bit from the TIL process, which includes a surgical resection of a tumor where T cells are removed, but they're not specific necessarily to the cancer, and they're grown up in the lab and then given to the patient. They're both adoptive cell transfer products, but they're very different. One is genetically modified, and the other one is not. And so the process for generating a TCR-T cell is that patients are required to have a new biomarker that some may not be familiar with, which is HLA profiling. So the T-cell receptor requires matching to the concomitant HLA for which the peptide is bound in. And so the classic one that is used in most oncology practices is A*02:01 because approximately 48% of Caucasians have A*02:01, and the frequency of HLA in other ethnicities starts to become highly variable. But in patients who are identified to have A*02:01 genotype, we can then remove blood via leukapheresis or an apheresis product, and then insert via lentiviral transduction this T-cell receptor targeting PRAME. Patients are then brought back to the hospital where they can receive lymphodepleting chemotherapy and then receive the reinfusion of the TCR-T cells. Again, in contrast with the TIL process, however, these T cells are extremely potent, and we do not need to give high-dose interleukin-2, which is administered in the context of TIL. Given that process, we have this clinical trial in front of us now, and at ASCO, the update was from the phase 1 study, which was looking at IMA203 in an efficacy population of melanoma patients who were refractory at checkpoint blockade and actually multiple lines of therapy. So here, there were 33 patients and a response rate of approximately 50% was observed in this population of patients, notably with a duration of response approximately a year in that treatment group. And I realize that these were heavily pretreated patients who had a range of very high-risk features. And approximately half the population had uveal melanoma, which people may be aware is a generally speaking more difficult-to-treat subtype of melanoma that metastasizes to the liver, which again has been a site of resistance to cancer immunotherapy. So these results are extremely promising. To summarize them from what I said, it's easier to make TCR-T cells because we can remove blood from the patient to transduce the T cells, and we don't have to put them through surgery. We can then infuse them, and based on these results, it looks like the response rate to IMA203 is a little bit more than double what we expect from lifileucel. And then, whereas with lifileucel or TILs, we have to give high-dose IL-2, here we do not have to give high-dose IL-2. And so that's pretty promising. And a clinical trial is ongoing now called the SUPREME phase 3 clinical trial, which is hoping to validate these results in a randomized global study. Dr. Diwakar Davar: Now, one thing that I wanted to go over with you, because you know this trial particularly well, is what you think of the likelihood of success, and then we'll talk a little bit about the trial design. But in your mind, do you think that this is a trial that has got a reasonable likelihood of success, maybe even a high likelihood of success? And maybe let's contextualize that to say an alternative trial, such as, for example, the TebeAM trial, which is essentially a T-cell bispecific targeting GP100. It's being compared against SOC, investigator's choice control, also in a similarly heavily pretreated patient population. Dr. Jason Luke: So both trials, I think, have a strong chance of success. They are very different kinds of agents. And so the CD3 bispecific that you referred to, tebentafusp, likely has an effect of delaying progression, which in patients with advanced disease could have a value that might manifest as overall survival. With TCR-T cells, by contrast, we see a very high response rate with some of the patients going into very durable long-term benefit. And so I do think that the SUPREME clinical trial has a very high chance of success. It will be the first clinical trial in solid tumor oncology randomizing patients to receive a cell therapy as compared with a standard of care. And within that standard of care control arm, TILs are allowed as a treatment. And so it will also be the first study that will compare TCR-T cells against TILs in a randomized phase 3. But going back to the data that we've seen in the phase 1 trial, what we observe is that the duration of response is really connected to the quality of the response, meaning if you have more than a 50% tumor shrinkage, those patients do very, very well. But even in patients who have less than 50% tumor shrinkage, the median progression-free survival right now is about 4.5 months. And again, as we think about trial design, standard of care options for patients who are in this situation are unfortunately very bad. And the progression-free survival in that population is probably more like 2 months. So this is a trial that has a very high likelihood of being positive because the possibility of long-term response is there, but even for patients who don't get a durable response, they're likely going to benefit more than they would have based on standard chemotherapy or retreatment with an anti–PD-1 agent. Dr. Diwakar Davar: Really, a very important trial to enroll, a trial that is first in many ways. First of a new generation of TCR-T agents, first trial to look at cell therapy in the control arm, a new standard of efficacy, but potentially also if this trial is successful, it will also be a new standard of trial conduct, a new kind of trial, of a set of trials that will be done in the second-line immunotherapy-refractory space. So let's pivot to the last trial that we were going to discuss, which was Abstract 2501. Abstract 2501 is a first-in-human phase 1/2 trial evaluating BNT142, which is the first-in-class mRNA-encoded bispecific targeting Claudin-6 and CD3 in patients with Claudin-positive tumors. We'll talk a little bit about this, but maybe let's start by talking a little bit about Claudin-6. So Claudin-6 is a very interesting new target. It's a target that's highly expressed in GI and ovarian tumors. There are a whole plethora of Claudin-6-targeting agents, including T-cell bispecifics and Claudin-6-directed CAR-Ts that are being developed. But BNT142 is novel. It's a novel lipid nanoparticle LNP-encapsulated mRNA. The mRNA encodes an anti–Claudin-6 CD3 bispecific termed RiboMAB-021. And it then is administered to the patient. The BNT142-encoding mRNA LNPs are taken up by the liver and translated into the active drug. So Jason, tell us a little bit about this agent. Why you think it's novel, if you think it's novel, and let's talk a little bit then about the results. Dr. Jason Luke: So I certainly think this is a novel agent, and I think this is just the first of what will probably become a new paradigm in oncology drug development. And so you alluded to this, but just to rehash it quickly, the drug is encoded as genetic information that's placed in the lipid nanoparticle and then is infused into the patient. And after the lipid nanoparticles are taken up by the liver, which is the most common place that LNPs are usually taken up, that genetic material in the mRNA starts to be translated into the actual protein, and that protein is the drug. So this is in vivo generation, so the patient is making their own drug inside their body. I think it's a really, really interesting approach. So for any drug that could be encoded as a genetic sequence, and in this case, it's a bispecific, as you mentioned, CD3-Claudin-6 engager, this could have a tremendous impact on how we think about pharmacology and novel drug development moving into the future in oncology. So I think it's an extremely interesting drug, the like of which we'll probably see only more moving forward. Dr. Diwakar Davar: Let's maybe briefly talk about the results. You know, the patient population was heavily pretreated, 65 or so patients, mostly ovarian cancer. Two-thirds of the patients were ovarian cancer, the rest were germ cell and lung cancer patients. But let's talk a little bit about the efficacy. The disease control rate was about 58% in the phase 1 population as a whole, but 75% in the ovarian patient population. Now tell us a little bit about the interesting things about the drug in terms of the pharmacokinetics, and also then maybe we can pivot to the clinical activity by dose level. Dr. Jason Luke: Well, so they did present in their presentation at ASCO a proportionality showing that as higher doses were administered, that greater amounts of the drug were being made inside the patient. And so that's an interesting observation, and it's an important one, right? Suggesting that the pharmacology that we classically think of by administering drugs by IV, for example, would still be in play. And that did translate into some level of efficacy, particularly at the higher dose levels. Now, the caveat that I'll make a note of is that disease control rate is an endpoint that I think we have to be careful about because what that really means is sometimes a little bit unclear. Sometimes patients have slowly growing tumors and so on and so forth. And the clinical relevance of disease control, if it doesn't last at least 6 months, I think is probably pretty questionable. So I think these are extremely interesting data, and there's some preliminary sense that getting the dose up is going to matter because the treatment responses were mostly observed at the highest dose levels. There's also a caveat, however, that across the field of CD3 bispecific molecules like this, there's been quite a bit of heterogeneity in terms of the response rate, with some of them only really generating stable disease responses and other ones having more robust responses. And so I think this is a really interesting initial foray into this space. My best understanding is this molecule is not moving forward further after this, but I think that this really does set it up to be able to chase after multiple different drug targets on a CD3 bispecific backbone, both in ovarian cancer, but then basically across all of oncology. Dr. Diwakar Davar: Perfect. This is a very new sort of exciting arena where we're going to be looking at, in many ways, these programmable constructs, whether we're looking at in vivo-generated, in this case, a T-cell bispecific, but we've also got newer drugs where we are essentially giving drugs where people are generating in vivo CAR T, and also potentially even in vivo TCR-T. But certainly lots of new excitement around this entire class of drugs. And so, what we'd like to do at this point in time is switch to essentially the fact that we've got a very, very exciting set of data at ASCO 2025. You've heard from Dr. Luke regarding the advances in both early drug development but also in advanced cutaneous melanoma. And Jason, as always, thank you so much for sharing your very valuable and great, fantastic insights with us on the ASCO Daily News Podcast. Dr. Jason Luke: Well, thanks again for the opportunity. Dr. Diwakar Davar: And thank you to our listeners for taking your time to listen today. You will find the links to the abstracts that we discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today’s speakers:    Dr. Diwakar Davar    @diwakardavar    Dr. Jason Luke @jasonlukemd Follow ASCO on social media:     @ASCO on Twitter       ASCO on Bluesky   ASCO on Facebook       ASCO on LinkedIn   Disclosures:     Dr. Diwakar Davar:      Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences     Consulting or Advisory Role: Instil Bio, Vedanta Biosciences     Consulting or Advisory Role (Immediate family member): Shionogi     Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences     Research Funding (Inst.): Zucero Therapeutics     Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy     Dr. Jason Luke:     Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX     Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine     Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure     Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)     Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio

Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss important advances in the treatment of prostate, bladder, and kidney cancers that were presented at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Neeraj Agarwal, your guest host of the ASCO Daily News Podcast today. I am the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute and editor-in-chief of the ASCO Daily News.  I am delighted to be joined by Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical program director of the GU Center at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing some key abstracts in GU oncology that were presented at the 2025 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode.  Jeanny, it is great to have you on the podcast. Dr. Jeanny Aragon-Ching: Oh, thank you so much, Neeraj. Dr. Neeraj Agarwal: Jeanny, let's begin with some prostate cancer abstracts. Let's begin with Abstract 5017 titled, “Phase 1 study results of JNJ-78278343 (pasritamig) in metastatic castration-resistant prostate cancer.” Can you walk us through the design and the key findings of this first-in-human trial? Dr. Jeanny Aragon-Ching: Yeah, absolutely, Neeraj. So this study, presented by Dr. Capucine Baldini, introduces pasritamig, a first-in-class T-cell redirecting bispecific antibody that simultaneously binds KLK2 on prostate cancer cells and CD3 receptor complexes on T cells. KLK2 is also known as human kallikrein 2, which is selectively expressed in prostate tissue. And for reference, KLK3 is what we now know as the PSA, prostate-specific antigen, therefore making it an attractive and specific target for therapeutic engagement. Now, while this was an early, first-in-human, phase 1 study, it enrolled 174 heavily pretreated metastatic CRPC patients. So many were previously treated with ARPIs, taxanes, and radioligand therapy. So given the phase 1 nature of this study, the primary objective was to determine the safety and the RP2D, which is the recommended phase 2 dose. Secondary objectives included preliminary assessment of antitumor activity. So, pasritamig was generally well tolerated. There were no treatment-related deaths. Serious adverse events were rare. And in the RP2D safety cohort, where patients received the step-up dosing up to 300 mg of IV every 6 weeks, the most common treatment-related adverse events were low-grade infusion reactions. There was fatigue and grade 1 cytokine release syndrome, what we call CRS. And no cases of neurotoxicity, or what we call ICANS, the immune effector cell-associated neurotoxicity syndrome, reported. Importantly, the CRS occurred in just about 8.9% of patients. All were grade 1. No patients required tocilizumab or discontinued treatment due to adverse events. So, this suggests a favorable safety profile, allowing hopefully for outpatient administration without hospitalization, which will be very important when we're thinking about bispecifics moving forward. In terms of efficacy, pasritamig showed promising activity. About 42.4% of evaluable patients achieved a PSA50 response. Radiographic PFS was about 6.8 months. And among patients with measurable disease, the objective response rate was about 16.1% in those with lymph node or bone metastases, and about 3.7% in those with visceral disease, with a median duration of response of about 11.3 months. So, altogether, this data suggests that pasritamig may offer a well-tolerated and active new potential option for patients with metastatic CRPC.   Again, as a reminder, with the caveat that this is still an early phase 1 study. Dr. Neeraj Agarwal: Thank you, Jeanny. These are promising results for a bispecific T-cell engager, pasritamig, in prostate cancer. I agree, the safety and durability observed here stand out, and this opens the door for further development, possibly even in earlier disease settings.  So, shifting now from immunotherapy to the evolving role of genomics in prostate cancer. So let's discuss Abstract 5094, a real-world, retrospective analysis exploring the prognostic impact of homologous recombination repair gene mutations, especially BRCA1 and BRCA2 mutations, in metastatic hormone-sensitive prostate cancer. Can you tell us more about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Sure, Neeraj. So this study was presented by Dr. David Olmos, represents one of the largest real-world analyses we have evaluating the impact of homologous recombination repair, or what we would call HRR, alterations in metastatic hormone-sensitive prostate cancer. So, this cohort included 556 men who underwent paired germline and somatic testing. Now, about 30% of patients had HRR alterations, with about 12% harboring BRCA1 or BRCA2 mutations and 16% having alterations in other HRR genes. Importantly, patients were stratified via CHAARTED disease volume, and outcomes were examined across treatment approaches, including ADT alone, doublet therapy, and triplet therapy. The prevalence of BRCA and HRR alterations were about similar between the metastatic hormone-sensitive prostate cancer and the metastatic castrate-resistant prostate cancer, with no differences observed, actually, between the patients with high volume versus low volume disease.  So, the key finding was that BRCA and HRR alterations were associated with poor clinical outcomes in metastatic hormone-sensitive prostate cancer. And notably, the impact of these alterations may actually be even greater in metastatic hormone-sensitive prostate cancer than previously reported in metastatic CRPC. So, the data showed that when BRCA mutations are present, the impact of the volume of disease is actually limited. So, poor outcomes were observed across the board for both high-volume and low-volume groups. So, the analysis showed that patients with HRR alterations had significantly worse outcomes compared to patients without HRR alterations. Median radiographic progression-free survival was about 20.5 months for the HRR-altered patients versus 30.6 months for the non-HRR patients, with a hazard ratio of 1.6. Median overall survival was 39 months for HRR-altered patients compared to 55.7 months for the non-HRR patients, with a hazard ratio of 1.5. Similar significant differences were observed when BRCA-mutant patients were compared with patients harboring non-BRCA HRR mutations. Overall, poor outcomes were independent of treatment of ARPI or taxanes. Dr. Neeraj Agarwal: Thank you, Jeanny. So, these data reinforce homologous recombination repair mutations as both a predictive and prognostic biomarker, not only in the mCRPC, but also in the metastatic hormone-sensitive setting as well. It also makes a strong case for incorporating genomic testing early in the disease course and not waiting until our patients have castration-resistant disease. Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. And I think this really brings home the point and the lead up to the AMPLITUDE trial, which is LBA5006, a phase 3 trial that builds on this very concept of testing with a PARP inhibitor, niraparib, in the hormone-sensitive space. Can you tell us a little bit more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. So, the AMPLITUDE trial, a phase 3 trial presented by Dr. Gerhardt Attard, enrolled 696 patients with metastatic hormone-sensitive prostate cancer and HRR gene alterations. 56% of these patients had BRCA1 and BRCA2 mutations. Patients were randomized to receive abiraterone with or without niraparib, a PARP inhibitor. The majority of patients, 78% of these patients, had high-volume metastatic hormone-sensitive prostate cancer, and 87% of these patients had de novo metastatic HSPC. And 16% of these patients received prior docetaxel, which was allowed in the clinical trial. So, with a median follow-up of nearly 31 months, radiographic progression-free survival was significantly prolonged with the niraparib plus abiraterone combination, and median was not reached in this arm, compared to abiraterone alone, which was 29.5 months, with a hazard ratio of 0.63, translating to a 37% reduction in risk of progression or death. This benefit was even more pronounced in the BRCA1 and BRCA2 subgroup, with a 48% reduction in risk of progression, with a hazard ratio of 0.52. Time to symptomatic progression also improved significantly across all patients, including patients with BRCA1, BRCA2, and HRR mutations. Although overall survival data remain immature, early trends favored the niraparib plus abiraterone combination. The safety profile was consistent with prior PARP inhibitor studies, with grade 3 or higher anemia and hypertension were more common but manageable. Treatment discontinuation due to adverse events remained low at 11%, suggesting that timely dose modifications when our patients experience grade 3 side effects may allow our patients to continue treatment without discontinuation. These findings support niraparib plus abiraterone as a potential new standard of care in our patients with metastatic hormone-sensitive prostate cancer with HRR alterations, and especially in those who had BRCA1 and BRCA2 mutations. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. This trial is especially exciting because it brings PARP inhibitors earlier into the treatment paradigm. Dr. Neeraj Agarwal: Exactly. And it is exciting to see the effect of PARP inhibitors in the earlier setting.  So Jeanny, now let's switch gears a bit to bladder cancer, which also saw several impactful studies. Could you tell us about Abstract 4502, an exploratory analysis from the EV-302 trial, which led to approval of enfortumab vedotin plus pembrolizumab for our patients with newly diagnosed metastatic bladder cancer? So here, the authors looked at the outcomes in patients who achieved a confirmed complete response with EV plus pembrolizumab. Dr. Jeanny Aragon-Ching: Sure, Neeraj. So, EV-302 demonstrated significant improvements in progression-free and overall survival for patients previously treated locally advanced or metastatic urothelial cancer, I'll just call it metastatic UC, as a frontline strategy, establishing EV, which is enfortumab vedotin, plus pembro, with pembrolizumab as standard of care in this setting.  So, this year at ASCO, Dr Shilpa Gupta presented this exploratory responder analysis from the phase 3 EV-302 trial. Among 886 randomized patients, about 30.4% of patients, this is about 133, in the EV+P arm, and 14.5% of the patients in the chemotherapy arm, achieved a confirmed complete response. They call it the CCR rates. So for patients who achieved this, median PFS was not reached with EV+P compared to 26.9 months with chemotherapy, with a hazard ratio of 0.36, translating to a 64% reduction in the risk of progression. Overall survival was also improved. So the median OS was not reached in either arm, but the hazard ratio favored the EV+P at 0.37, translating to a 63% reduction in the risk of death. The median duration of complete response was not reached with EV+P compared to 15.2 months with chemotherapy. And among those patients who had confirmed CRs at 24 months, 78% of patients with the EV+P arm remained progression-free, and around 95% of the patients were alive, compared to 54% of patients who were progression-free and 86% alive of the patients in the chemotherapy arm. Safety among responders were also consistent with prior reports. Grade 3 or higher treatment-related adverse events occurred in 62% of EV+P responders and 72% of chemotherapy responders. Most adverse events were managed with dose modifications, and importantly, no treatment-related deaths were reported among those who were able to achieve complete response.  So these findings further reinforce EV and pembro as the preferred first-line therapy for metastatic urothelial carcinoma, offering a higher likelihood of deep, durable responses with a fairly manageable safety profile. Dr. Neeraj Agarwal: Thank you for the great summary, Jeanny. These findings underscore the depth and durability of responses achievable with this combination and also suggest that achieving a response may be a surrogate for long-term benefit in patients with metastatic urothelial carcinoma.  So now, let's move to Abstract 4503, an exploratory ctDNA analysis from the NIAGARA trial, which evaluated perioperative durvalumab, an immune checkpoint inhibitor, in muscle-invasive bladder cancer. So what can you tell us about this abstract? Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. So, in NIAGARA, presented by Dr. Tom Powles, the addition of perioperative durvalumab to neoadjuvant chemotherapy, gem/cis, significantly improved event-free survival, overall survival, and pathologic complete response in patients with cisplatin-eligible muscle-invasive bladder cancer. Recall that this led to the U.S. FDA approval of this treatment regimen on March 28, 2025.  So, a planned exploratory analysis evaluated the ctDNA dynamics and their association with clinical outcomes, which was the one presented recently at ASCO. So, the study found that the incidence of finding ctDNA positivity in these patients was about 57%. Following neoadjuvant treatment, this dropped to about 22%, with ctDNA clearance being more common in the durvalumab arm, about 41%, compared to the chemotherapy control arm of 31%. Notably, 97% of patients who remained ctDNA positive prior to surgery failed to achieve a pathologic CR. So, this indicates a strong association between ctDNA persistence and lack of tumor eradication. So, postoperatively, only about 9% of patients were ctDNA positive. So, importantly, durvalumab conferred an event-free survival benefit regardless of ctDNA status at both baseline and post-surgery. Among patients who were ctDNA positive at baseline, durvalumab led to a hazard ratio of 0.73 for EFS. So, this translates to a 27% reduction in the risk of disease recurrence, progression, or death compared to the control arm. In the post-surgical ctDNA-positive group, the disease-free survival was also improved with a hazard ratio of 0.49, translating to a 51% reduction in the risk of recurrence.  So, these findings underscore the prognostic value of ctDNA and suggest that durvalumab provides clinical benefit irrespective of molecular residual disease status. So, the data also supports that ctDNA is a promising biomarker for future personalized strategies in the perioperative treatment of muscle-invasive bladder cancer. Dr. Neeraj Agarwal: Thank you, Jeanny. It is great to see that durvalumab is improving outcomes in these patients regardless of ctDNA status. However, based on these data, presence of ctDNA in our patients warrants a closer follow-up with imaging studies, because these patients with positive ctDNA seem to have a higher risk of recurrence. Dr. Jeanny Aragon-Ching: I agree, Neeraj.  Let's round out the bladder cancer discussion with Abstract 4518, which reported the interim results of SURE-02, which is a phase 2 study evaluating neoadjuvant sacituzumab govitecan plus pembrolizumab in cisplatin-ineligible muscle-invasive bladder cancer. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure, Jeanny. So, Dr Andrea Necchi presented interim results from the SURE-02 trial. This is a phase 2 study evaluating neoadjuvant sacituzumab govitecan plus pembrolizumab, followed by a response-adapted bladder-sparing treatment and adjuvant pembrolizumab in patients with muscle-invasive bladder cancer.  So, in this interim analysis, 40 patients were treated and 31 patients were evaluable for efficacy. So, the clinical complete response rate was 38.7%. All patients achieving clinical complete response underwent bladder-sparing approach with a repeat TURBT instead of radical cystectomy. Additionally, 51.6% of patients achieved excellent pathologic response with a T stage of 1 or less after neoadjuvant therapy. The treatment was well tolerated, with only 12.9% of patients experiencing grade 3 or higher adverse events without needing dose reduction of sacituzumab. Molecular profiling, interestingly, showed that clinical complete response correlated with luminal and genomically unstable subtypes, while high stromal gene expression was associated with lack of response.  These results suggest that sacituzumab plus pembrolizumab combination has promising activity in this setting, and tolerability, and along with other factors may potentially allow a bladder preservation approach in a substantial number of patients down the line. Dr. Jeanny Aragon-Ching: Yeah, agree with you, Neeraj. And the findings are very provocative and support completing the full trial enrollment and further exploration of this strategy in muscle-invasive bladder cancer in order to improve and provide further bladder-sparing strategies. Dr. Neeraj Agarwal: Agree. So, let's now turn to the kidney cancer, starting with Abstract 4505, the final overall analysis from CheckMate-214 trial, which evaluated nivolumab plus ipilimumab, so dual checkpoint inhibition strategy, versus sunitinib in our patients with metastatic clear cell renal cell carcinoma. Dr. Jeanny Aragon-Ching: Yeah, absolutely, Neeraj. So, the final 9-year analysis of the phase 3 CheckMate-214 trial confirms the long-term superiority of nivolumab and ipilimumab over sunitinib for first-line treatment of advanced metastatic renal cell carcinoma. So, this has a median follow-up of 9 years. Overall survival remains significantly improved with the combination. So, in the ITT patient population, the intention-to-treat, the hazard ratio for overall survival was 0.71. So, this translates to a 29% reduction in the risk of death. 31% of patients were alive at this 108-month follow-up compared to 20% only in those who got sunitinib. So, similar benefits were observed in the intermediate- and poor-risk groups with a hazard ratio of 0.69, and 30% versus 19% survival at 108 months.  Importantly, a delayed benefit was also seen in those favorable-risk patients. So, the hazard ratio for overall survival improved from 1.45 in the initial report and now at 0.8 at 9 years follow-up, with 35% of patients alive at 108 months compared to 22% in those who got sunitinib. Progression-free survival also favored the nivo-ipi arm across all risk groups. At 96 months, the probability of remaining progression-free was about 23% compared to 9% in the sunitinib arm in the ITT patient population, 25% versus 9% in the intermediate- and poor-risk patients, and 13% compared to 11% in the favorable-risk patients. Importantly, at 96 months, 48% of patients in the nivo-ipi responders remained in response compared to just 19% in those who got sunitinib. And in the favorable-risk group, 36% of patients who responded remained in response, although data were not available for sunitinib in this subgroup.  So, this data reinforces the use of nivolumab and ipilimumab as a durable and effective first-line effective strategy for standard of care across all risk groups for advanced renal cell carcinoma. Dr. Neeraj Agarwal: Thank you, Jeanny. And of course, since ipi-nivo data were presented, several other novel ICI-TKI combinations have emerged. And I'm really hoping to see very similar data with TKI-ICI combinations down the line. It is really important to note that we are not seeing any new safety signals with the ICI combinations or ICI-based therapies, which is very reassuring given the extended exposure. Dr. Jeanny Aragon-Ching: Absolutely agree with you there, Neeraj.  Now, going on and moving on to Abstract 4514, which is the KEYNOTE-564 trial, and they reported on the 5-year outcomes of adjuvant pembrolizumab in clear cell RCC in patients who are at high risk for recurrence. Can you tell us a little bit more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. So, the KEYNOTE-564 trial established pembrolizumab monotherapy as the first adjuvant regimen to significantly improve both disease-free survival and overall survival compared to placebo after surgery for patients with clear cell renal cell carcinoma. So, Dr Naomi Haas presented the 5-year update from this landmark trial.  A total of 994 patients were randomized to receive either pembrolizumab or placebo. The median follow-up at the time of this analysis was approximately 70 months. Disease-free survival remained significantly improved with pembrolizumab. The median DFS was not reached with pembrolizumab compared to 68.3 months with placebo, with a hazard ratio of 0.71, translating to a 29% reduction in risk of recurrence. At 5 years, 60.9% of patients receiving pembrolizumab remained disease-free compared to 52.2% with placebo. Overall survival also favored pembrolizumab. The hazard ratio for OS was 0.66, translating to a 34% reduction in risk of death, with an estimated 5-year overall survival rate of 87.7% with pembrolizumab compared to 82.3% for placebo. Importantly, these benefits were consistent across all key subgroups, including patients with sarcomatoid features. In addition, no new serious treatment-related adverse events have been reported in the 3 years since treatment completion.  So, these long-term data confirm pembrolizumab as a durable and effective standard adjuvant therapy for patients with resected, high-risk clear cell renal cell carcinoma. Dr. Jeanny Aragon-Ching: Thank you for that wonderful summary, Neeraj. Dr. Neeraj Agarwal: That wraps up our kidney cancer highlights. Any closing thoughts, Jeanny, before we conclude? Dr. Jeanny Aragon-Ching: It's been so wonderful reviewing these abstracts with you, Neeraj. So, the 2025 ASCO Annual Meeting showcased a lot of transformative data across GU cancers, from first-in-class bispecifics to long-term survival in RCC. And these findings are already shaping our clinical practices. Dr. Neeraj Agarwal: I agree. And we have covered a broad spectrum of innovations in GU cancers with strong clinical relevance.  So, thank you, Jeanny, for joining me today and sharing your insights.  And thank you to our listeners for joining us. You will find links to the abstracts discussed today in the transcript of this episode. If you find these conversations valuable, please take a moment to rate, review, and subscribe to the ASCO Daily News Podcast wherever you listen. 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. Neeraj Agarwal     @neerajaiims     Dr. Jeanny Aragon-Ching   Follow ASCO on social media:       @ASCO on Twitter       ASCO on Bluesky   ASCO on Facebook       ASCO on LinkedIn       Disclosures:   Dr. Neeraj Agarwal:   Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences  Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas  Dr. Jeanny Aragon-Ching:   Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono   Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,    Speakers’ Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics

Dr. Vamsi Velcheti and Dr. Nate Pennell discuss novel treatment approaches in small cell and non-small cell lung cancer that were featured at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host of the ASCO Daily News Podcast. I'm a professor of medicine and chief of hematology and oncology at the Mayo Clinic in Jacksonville, Florida. The 2025 ASCO Annual Meeting featured some exciting advancements in small cell lung cancer, targeted therapies for non-small cell lung cancer, and other novel [treatment] approaches. Today, I'm delighted to be joined by Dr. Nate Pennell to discuss some of the key abstracts that are advancing the lung cancer field. Dr. Pennell is the co-director of the Cleveland Clinic Lung Cancer Program and also the vice chair of clinical research at the Taussig Cancer Institute. Our full disclosures are available in the transcript of this episode. Nate, it's great to have you back on the podcast. Thanks so much for being here. Dr. Nate Pennell: Thanks, Vamsi. Always a pleasure. Dr. Vamsi Velcheti: Let's get started, and I think the first abstract that really caught my attention was Abstract 8516, “The Randomized Trial of Relevance of Time of Day of Immunotherapy for Progression-Free and Overall Survival in Patients With Non-Small Cell Lung Cancer.” What are your thoughts about this, Nate? Dr. Nate Pennell: I agree. I thought this was one of the most discussed abstracts, certainly in the lung cancer session, but I think even outside of lung cancer, it got some discussion. So, just to put this in perspective, there have been a number of publications that have all been remarkably consistent, and not just in lung cancer but across multiple cancer types, that immunotherapy, immune checkpoint inhibitors, are commonly used. And all of them have suggested, when looking at retrospective cohorts, that patients who receive immune checkpoint inhibitors earlier in the day – so in the morning or before the early afternoon – for whatever reason, appear to have better outcomes than those who get it later in the day, and this has been repeated. And I think many people just sort of assumed that this was some sort of strange association and that there was something fundamentally different from a prognostic standpoint in people who came in in the morning to get their treatment versus those who came later in the afternoon, and that was probably the explanation. The authors of this randomized trial actually decided to test this concept. And so, about 210 patients with previously untreated advanced non-small cell lung cancer were randomly assigned to get chemo and immune checkpoint inhibitor – either pembrolizumab or sintilimab – and half of them were randomly assigned to get the treatment before 3 PM in the afternoon, and half of them were assigned to get it after 3 PM in the afternoon. And it almost completely recapitulated what was seen in the retrospective cohorts. So, the median progression-free survival in those who got earlier treatment was 13.2 months versus only 6.5 months in those who got it later in the day. So, really enormous difference with a hazard ratio of 0.43, which was statistically significant. And perhaps even more striking, the median overall survival was not reached in the early group versus 17.8 months in the late group with a hazard ratio of 0.43, also highly statistically significant. Even the response rate was 20% higher in the early patients; 75% response rate compared to 56% in the late-time-of-day patients. So very consistent across all measures of efficacy with pretty good matched characteristics across the different groups. And so, I have to tell you, I don't know what to make of this. I certainly was a skeptic about the retrospective series, but now we have a prospective randomized trial that shows essentially the same thing. So, maybe there is a difference between getting treated in the morning, although I have yet to hear someone give a very good mechanistic explanation as to why this would be. What were your thoughts on this? Dr. Vamsi Velcheti: It's indeed fascinating, Nate, and I actually think this was a very interesting abstract. Really, I was caught off guard looking at the data. I mean, if it were a drug, we would be so excited, right? I mean, with those kind of survival benefits. I don't know. I think circadian rhythm probably has something to do with it, like different cytokine profiles at the time of administration. I mean, who knows? But I think it's a randomized trial, and I think I would expect to see a mad rush for treatment appointments early in the morning given this, and at least I want my patients to come in first thing in the morning. It'll be interesting to see. Dr. Nate Pennell: It’s important to point out that in this study, everyone got chemo and immunotherapy. And, at least in our cancer center, most patients who are getting platinum-doublet chemotherapy and immunotherapy actually do get treated earlier in the day already, just because of the length of the infusion appointment that's needed. So it really is oftentimes people getting single-agent immunotherapy who are often getting the later, shorter visits. But if you have a choice, I think it would be very reasonable to have people treated earlier in the day. And I do think most of the impressions that I got from people about this is that they would like to see it reproduced but certainly well worth further investigation. And I personally would like to see more investigation into what the rationale would be for this because I still can't quite figure out, yes, if you got it at, say, you know, 5 PM, that's later in the day and I can understand that maybe your immune system is somewhat less receptive at that point than it would be in the morning. But because these checkpoint inhibitors have such long half-lives, it's still in your system the next morning when your immune system is supposedly more receptive. So I don't quite understand why that would be the case. Well, let's move on to the next study. I would like to hear your thoughts on Abstract 8515, “Plasma-Guided, Adaptive First-Line Chemoimmunotherapy for Non-Small Cell Lung Cancer.” Dr. Vamsi Velcheti: Yeah, this was another abstract that seems to be really interesting in my opinion. I think there's kind of a lot of emphasis lately on ctDNA and MRD-based assays to monitor disease. In the lung cancer space, we haven't had a lot of clinical trials looking at this prospectively, and this was one of those pilot studies where they looked at circulating free DNA (cfDNA)-based response-adaptive strategy for frontline patients who are PD-L1 positive. So, patients started with pembrolizumab monotherapy, and based on plasma molecular response after 2 cycles, those patients without response received early treatment intensification with a platinum doublet. So the approach essentially was to reduce the chemotherapy exposure in patients who respond to immunotherapy. And only about 17.5% of the patients on the trial received chemotherapy based on lack of molecular response. So, in this trial, what they found was patients with the cfDNA response had a markedly improved PFS of 16.4 months versus 4.8 months. So essentially, like, this is a really nice study to set a foundation on which we have to do larger studies to incorporate molecular markers trying to look at cfDNA response to inform treatment strategy, either escalation or de-escalation strategies. So, I thought it was a very interesting study. Dr. Nate Pennell: Yeah. I mean, we always have this question for patients, “Should they get immunotherapy alone or combined with chemo?” and I think this certainly is intriguing, suggesting that there may be ways you can monitor people and perhaps rescue those that aren't going to respond to single agent. I'd like to see a randomized trial against, you know, this strategy, perhaps against everyone getting, say, chemoimmunotherapy or make sure that you're not potentially harming people by doing this strategy. But I agree, it's time to move beyond just observing that cell-free DNA is prognostic and important and start using it to actually guide treatment. Dr. Vamsi Velcheti: Yeah, and I would just caution though, like, you know, I think we need more data, but, however, it's certainly a very interesting piece of data to kind of help inform future trials. So, there was another abstract that caught my attention, and I think this would be a very interesting abstract in the EGFR space. Abstract 8506, "Patritumab Deruxtecan (HER3-DXd) in Resistant EGFR-Mutant Advanced Non-Small Cell Lung Cancer Patients After Third-Generation EGFR TKI," it’s the HERTHENA-Lung02 study. What do you think about the results of this study? Dr. Nate Pennell: Yeah, this was, I would say, very widely anticipated and ultimately a little disappointing, despite being a positive trial. So, these are patients with EGFR-mutant non-small cell lung cancer who have progressed after a third-generation EGFR TKI like osimertinib. This is really an area of major unmet need. We do have drugs like amivantamab in this space, but still definitely an area where essentially patients move from having a highly effective oral therapy to being in the realm of chemotherapy as their best option. So, this HER3 antibody-drug conjugate, patritumab deruxtecan, had some good single-arm data for this. And we're sort of hoping this would become an available option for patients. This trial was designed against platinum-doublet chemotherapy in this setting and with a primary endpoint of progression-free survival. And it actually was positive for improved progression-free survival compared to chemo with a hazard ratio of 0.77. But when you look at the medians, you can see that the median PFS was only 5.8 versus 5.4 months. It was really a modest difference between the two arms. And on the interim analysis, it appeared that there will not be a difference in overall survival between the two arms. In fact, the hazard ratio at the interim analysis was 0.98 for the two arms. So based on this, unfortunately, the company that developed the HER3-DXd has withdrawn their application to the FDA for approval of the drug, anticipating that they probably wouldn't get past approval without that overall survival endpoint. So, unfortunately, probably not, at least for the near future, going to be a new option for these patients. Dr. Vamsi Velcheti: Yeah, I think this is a space that's clearly an unmet need, and this was a big disappointment, I should say. I think all of us were going into the meeting anticipating some change in the standard of care here. Dr. Nate Pennell: Yeah, I agree. It was something that I was telling patients, honestly, that I was expecting this to be coming, and so now, definitely a bit of a disappointment. But it happens and, hopefully, it will still find perhaps a role or other drugs with a similar target. Certainly an active area. Well, let's leave the EGFR-mutant space and move into small cell. There were a couple of very impactful studies. And one of them was Abstract 8006, “Lurbinectedin Plus Atezolizumab as First-Line Maintenance Treatment in Patients With Extensive-Stage Small Cell Lung Cancer, Primary Results from the Phase III IMforte Trial.” So, what was your impression of this? Dr. Vamsi Velcheti: Yeah, I think this is definitely an interesting study, and small cell, I remember those days when we had barely any studies of small cell at ASCO, and now we have a lot of exciting developments in the small cell space. It's really good to see. The IMforte trial is essentially like a maintenance lurbinectedin trial with atezolizumab maintenance. And the study was a positive trial. The primary endpoint was a PFS, and the study showed improvement in both PFS and OS with the addition of lurbinectedin to atezolizumab maintenance. And definitely, it's a positive trial, met its primary endpoint, but I always am a little skeptical of adding maintenance cytotoxic therapies here in this setting. In my practice, and I'd like to hear your opinion, Nate, most patients with small cell after 4 cycles of a platinum doublet, they're kind of really beaten up. Adding more cytotoxic therapy in the maintenance space is going to be tough, I think, for a lot of patients. But also, most importantly, I think this rapidly evolving landscape for patients with small cell lung cancer with multiple new, exciting agents, actually like some FDA-approved like tarlatamab, also like a lot of these emerging therapeutics like I-DXd and other ADCs in this space. You kind of wonder, is it really optimal strategy to bring on like another cytotoxic agent right after induction chemotherapy, or do you kind of delay that? Or maybe have like a different strategy in terms of maintenance. I know that the tarlatamab maintenance trial is probably going to read out at some point too. I think it's a little challenging. The hazard ratio is also 0.73. As I said, it's a positive trial, but it's just incremental benefit of adding lurbi. And also on the trial, we need to also pay attention to the post-progression second-line treatments, number of patients who received tarlatamab or any other investigational agents.  So I think it's a lot of questions still. I'm not quite sure I'd be able to embrace this completely. I think a vast majority of my patients might not be eligible anyway for cytotoxic chemotherapy maintenance right away, but yeah, it's tough. Dr. Nate Pennell: Yeah. I would call this a single and not a home run. It definitely is real. It was a real overall survival benefit. Certainly not surprising that a maintenance therapy would improve progression-free survival. We've known that for a long time in small cell, but first to really show an overall survival benefit. But I completely agree with you. I mean, many people are not going to want to continue further cytotoxics after 4 cycles of platinum-doublet chemo. So I would say, for those that are young and healthy and fly through chemo without a lot of toxicity, I think certainly something worth mentioning. The problem with small cell, of course, is that so many people get sick so quickly while on that observation period after first-line chemo that they don't make it to second-line treatment. And so, giving everyone maintenance therapy essentially ensures everyone gets that second-line treatment. But they also lose that potentially precious few months where they feel good and normal and are able to be off of treatment. So, I would say this is something where we're really going to have to kind of sit and have that shared decision-making visit with patients and decide what's meaningful to them. Dr. Vamsi Velcheti: Yeah, I agree. The next abstract that was a Late-Breaking Abstract, 8000, “Overall Survival of Neoadjuvant Nivolumab Plus Chemotherapy in Patients With Resectable Non-Small Cell Lung Cancer in CheckMate-816.” This was a highly anticipated read-out of the OS data from 816. What did you make of this abstract? Dr. Nate Pennell: Yeah, I thought this was great. Of course, CheckMate-816 changed practice a number of years ago when it first reported out. So, this was the first of the neoadjuvant or perioperative chemoimmunotherapy studies in resectable non-small cell lung cancer. So, just to review, this was a phase 3 study for patients with what we would now consider stage II or stage IIIA resectable non-small cell lung cancer. And they received three cycles of either chemotherapy or chemotherapy plus nivolumab, and that was it. That was the whole treatment. No adjuvant treatment was given afterwards. They went to resection. And patients who received the chemoimmunotherapy had a much higher pathologic complete response rate and a much better event-free survival. And based on this, this regimen was approved and, I think, at least in the United States, widely adopted.  Now, since the first presentation of CheckMate 816, there have been a number of perioperative studies that have included an adjuvant component of immunotherapy – KEYNOTE-671, the AEGEAN study – and these also have shown improved outcomes. The KEYNOTE study with pembrolizumab also with an overall survival benefit. And I think people forgot a little bit about CheckMate-816. So, this was the 5-year overall survival final analysis. And it did show a statistically and, I think, clinically meaningful difference in overall survival with the 3 cycles of neoadjuvant chemo-nivo compared to chemo with a hazard ratio of 0.72. The 5-year overall survival of 65% in the chemo-IO group versus 55% with the chemo alone. So a meaningful improvement. And interestingly, that hazard ratio of 0.72 is very similar to what was seen in the peri-operative pembro study that included the adjuvant component. So, very much still relevant for people who think that perhaps the value of those neoadjuvant treatments might be really where most of the impact comes from this type of approach. They also gave us an update on those with pathologic complete response, showing really astronomically good outcomes. If you have a pathologic complete response, which was more than a quarter of patients, the long-term survival was just phenomenal. I mean, 95% alive at 5 years if they were in that group and suggesting that in those patients at least, the adjuvant treatment may not be all that important.  So, I think this was an exciting update and still leaves very much the open question about the importance of continuing immunotherapy after surgery after the neoadjuvant component. Dr. Vamsi Velcheti: Yeah, I completely agree, Nate. I think the million-dollar question is: “Is there like a population of patients who don't have complete response but like maybe close to complete response?” So, would you like still consider stopping adjuvant IO? I probably would not be comfortable, but I think sometimes, you know, we all have patients who are like very apprehensive of continuing treatments. So, I think that we really need more studies, especially for those patients who don't achieve a complete CR. I think trying to find strategies for like de-escalation based on MRD or other risk factors. But we need more trials in that space to inform not just de-escalation, but there are some patients who don't respond at all to a neoadjuvant IO. So, there may be an opportunity for escalating adjuvant therapies. So, it is an interesting space to watch out for. Dr. Nate Pennell: No, absolutely. Moving to KRAS-mutant space, so our very common situation in patients with non-small cell lung cancer, we had the results of Abstract 8500, “First-Line Adagrasib With Pembrolizumab in Patients With Advanced or Metastatic KRASG12C-Mutated Non-Small Cell Lung Cancer” from the phase 2 portion of the KRYSTAL-7 study. Why was this an interesting and important study? Dr. Vamsi Velcheti: First of all, there were attempts to kind of combine KRASG12C inhibitors in the past with immune checkpoint inhibitors, notably sotorasib with pembrolizumab. Unfortunately, those trials have led to like a lot of toxicity, with increased especially liver toxicity, which was a major issue. This is a phase 2 study of adagrasib in combination with pembrolizumab, and this is a study in the frontline setting in patients with the G12C-mutant metastatic non-small cell lung cancer. And across all the PD-L1 groups, the ORR was 44%, and the median PFS was 11 months, comparable to the previous data that we have seen with adagrasib in this setting. So it's not like a major improvement in clinical efficacy. However, I think the toxicity profile that we were seeing was slightly better than the previous trials in combination with sotorasib, but you still have a fair amount of transaminitis even in the study. At this point, this is not ready for clinical primetime. I don't think we should be using sotorasib or adagrasib in the frontline or even in the second line in combination with checkpoint inhibitors. Combining these drugs with checkpoint inhibitors in the clinical practice might lead to adverse outcomes. So, we need to wait for more data like newer-generation G12C inhibitors which are also being studied in combination, so we'll have to kind of wait for more data to emerge in this space. Dr. Nate Pennell: I agree, this is not immediately practice changing. This is really an attempt to try to combine targeted treatment with immune checkpoint inhibitor. And I agree with you that, you know, it does appear to be perhaps a little bit better tolerated than some of the prior combinations that have tried in this space. The outcomes overall were not that impressive, although in the PD-L1 greater than 50%, it did have a better response rate perhaps than you would expect with either drug alone. And I do think that the company is focusing on that population for a future randomized trial, which certainly would inform this question better. But in the meantime, I agree with you, there's a lot of newer drugs that are coming along that potentially may be more active and better tolerated. And so, I'd say for now, interesting but we'll wait and see. Dr. Vamsi Velcheti: Yeah, so now moving back again to small cell. So, there was a Late-Breaking Abstract, 8008. This is a study of tarlatamab versus chemotherapy as second-line treatment for small cell lung cancer. They presented the primary analysis of the phase III DeLLphi-304 study. What do you think about this? Dr. Nate Pennell: Yeah, I thought this was really exciting. This was, I would say, perhaps the most important lung study that was presented. Tarlatamab is, of course, the anti-DLL3 bispecific T-cell engager compound, which is already FDA approved based on a prior single-arm phase II study, which showed a very nice response rate as a single agent in previously treated small cell lung cancer and relatively manageable side effects, although somewhat unique to solid tumor docs in the use of these bispecific drugs in things like cytokine release syndrome and ICANS, the neurologic toxicities. So, this trial was important because tarlatamab was approved, but there were also other chemotherapy drugs approved in the previously treated space. And so, this was a head-to-head second-line competition comparison between tarlatamab and either topotecan, lurbinectedin, or amrubicin in previously treated small cell patients with a primary endpoint of overall survival. So, a very well-designed trial. And it did show, I think, a very impressive improvement in overall survival with a median overall survival in the tarlatamab group of 13.6 months compared to 8.3 months with chemotherapy, hazard ratio of 0.6. And progression-free survival was also longer at 4.2 months versus 3.2 months, hazard ratio of 0.72. In addition to showing improvements in cancer-related symptoms that were improved in tarlatamab compared to chemotherapy, there was actually also significantly lower rates of serious treatment-related adverse events with tarlatamab compared to chemotherapy. So, you do still see the cytokine release syndrome, which is seen in most people but is manageable because these patients are admitted to the hospital for the first two cycles, as well as a significant number of patients with neurologic side effects, the so-called ICANS, which also can be treated with steroids. And so, I think based upon the very significant improvement in outcomes, I would expect that this should become our kind of standard second-line treatment since it seems to be much better than chemo. However, tarlatamab is definitely a new drug that a lot of places are not used to using, and I think a lot of cancer centers, especially ones that aren't tied to a hospital, may have questions about how to deal with the CRS. So, I'm curious your thoughts on that. Dr. Vamsi Velcheti: Yeah, thank you, Nate. And I completely agree. I think the data looked really promising, and I've already been using tarlatamab in the second-line space. The durability of response and overall, having used tarlatamab quite a bit - like, I participated in some of the early trials and also used it as standard of care - tarlatamab has unique challenges in terms of like need for hospitalization for monitoring for the first few treatments and make sure, you know, we monitor those patients for CRS and ICANS. But once you get past that initial administration and monitoring of CRS, these patients have a much better quality of life, they're off chemotherapy, and I think it's really about the logistics of actually administering tarlatamab and coordination with the hospital and administration in the outpatient setting. It's definitely challenging, but I think it definitely can be done and should be done given what we are seeing in terms of clinical efficacy here. Dr. Nate Pennell: I agree. I think hospital systems now are just going to have to find a way to be able to get this on formulary and use it because it clearly seems to be more effective and generally better tolerated by patients. So, should move forward, I think. Finally, there's an abstract I wanted to ask you about, Abstract 8001, which is the “Neoadjuvant osimertinib with or without chemotherapy versus chemotherapy alone in resectable epidermal growth factor receptor-mutated non-small cell lung cancer: The NeoADAURA Study”. And this is one that I think was also fairly highly anticipated. So, what are your thoughts? Dr. Vamsi Velcheti: You know, I wasn't probably surprised with the results, and I believe we were all expecting a positive trial, and we certainly were handed a positive trial here. It's a phase III trial of osimertinib and chemotherapy or osimertinib in the neoadjuvant space followed by surgery, followed by osimertinib. It's a global phase 3 trial and very well conducted, and patients with stage II to stage IIIB were enrolled in the study. And in the trial, patients who had a neoadjuvant osimertinib with or without chemotherapy showed a significant improvement in major pathologic response rates over chemotherapy alone. And the EFS was also positive for osimertinib and chemotherapy, osimertinib monotherapy as well compared to chemotherapy alone. So overall, the study met its primary endpoint, and I think it sheds light on how we manage our patients with early-stage lung cancer. I think osimertinib, we know that osimertinib is already FDA approved in the adjuvant space, but what we didn't really know is how was osimertinib going to work in the neoadjuvant space. And there are always situations, especially for stage III patients, where we are on the fence about, are these patients already close to being metastatic? They have, like, almost all these patients have micrometastatic disease, even if they have stage III. As we saw in the LAURA data, when you look at the control arm, it was like a very short PFS. Chemoradiation does nothing for those patients, and I think these patients have systemic mets, either gross or micrometastatic disease at onset. So, it's really important to incorporate osimertinib early in the treatment course. And I think, especially for the locally advanced patients, I think it's even more important to kind of incorporate osimertinib in the neoadjuvant space and get effective local control with surgery and treat them with adjuvant. I'm curious to hear your thoughts, Nate. Dr. Nate Pennell: I am a believer and have long been a believer in targeted adjuvant treatments, and, you know, it has always bothered me somewhat that we're using our far and away most effective systemic therapy; we wait until after they go through all their pre-op treatments, they go through surgery, then they go through chemotherapy, and then finally months later, they get their osimertinib, and it still clearly improves survival in the adjuvant setting. Why not just start the osimertinib as soon as you know that the patient has EGFR-mutant non-small cell lung cancer, and then you can move on to surgery and adjuvant treatment afterwards? And I think what was remarkable about this study is that all of these patients almost - 90% in each arm - went to surgery. So, you weren't harming them with the neoadjuvant treatment. And clearly better major pathologic response, nodal downstaging, event-free survival was better. But I don't know that this trial is ever going to show an overall survival difference between neoadjuvant versus just surgery and adjuvant treatment, given how effective the drug is in the adjuvant setting. Nonetheless, I think the data is compelling enough to consider this, certainly for our N2-positive, stage IIIA patients or a IIIB who might be otherwise surgical candidates. I think based on this, I would certainly consider that. Dr. Vamsi Velcheti: Yeah, and especially for EGFR, like even for stage IIIB patients, in the light of the LAURA study, those patients who do not do too well with chemoradiation. So you're kind of delaying effective systemic therapy, as you said, waiting for the chemoradiation to finish. So I think probably time to revisit how we kind of manage these locally advanced EGFR patients. Dr. Nate Pennell: Yep, I agree. Dr. Vamsi Velcheti: Nate, thank you so much for sharing your fantastic insights today on the ASCO Daily News Podcast. It's been an exciting ASCO again. You know, we've seen a lot of positive trials impacting our care of non-small cell lung cancer and small cell lung cancer patients. Dr. Nate Pennell: Thanks for inviting me, Vamsi. Always a pleasure to discuss these with you. Dr. Vamsi Velcheti: And thanks to our listeners for your time today. You will find links to all of the abstracts discussed today in the transcript of the episode. Finally, if you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate, review, subscribe wherever you get your podcast. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. More on today’s speakers:    Dr. Vamsi Velcheti   @VamsiVelcheti    Dr. Nathan Pennell   @n8pennell   Follow ASCO on social media:     @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn   ASCO on BlueSky   Disclosures:   Dr. Vamsi Velcheti:   Honoraria: ITeos Therapeutics   Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus   Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline   Dr. Nathan Pennell:     Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron    Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi 

Dr. Shaalan Beg and Dr. Kristen Ciombor discuss practice-changing studies in GI cancers and other novel treatment approaches that were presented at the 2025 ASCO Annual Meeting. Transcript Dr. Shaalan Beg: Hello, I'm Dr. Shaalan Beg, welcoming you to the ASCO Daily News Podcast. I'm a medical oncologist and an adjunct associate professor at UT Southwestern Medical Center in Dallas, Texas. There were some remarkable advances in gastrointestinal cancers that were presented at the 2025 ASCO Annual Meeting, and I'm delighted to be joined by Dr. Kristen Ciombor to discuss some exciting GI data. Dr. Ciombor is the Ingram Associate Professor of Cancer Research and a co-leader of Translational Research and the Interventional Oncology Research Program at the Vanderbilt Ingram Cancer Center. Our full disclosures are available in the transcript of this episode. Dr. Ciombor, it's great to have you on the podcast today. Dr. Kristen Ciombor: Thanks, Dr Beg. It's great to be here. Dr. Shaalan Beg: Alright, let's kick it off. Big year for GI cancers. We'll start off with LBA1. This was the ATOMIC study sponsored by NCI and the National Clinical Trials Network (NCTN) and the Alliance group. This is a randomized study of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for stage III mismatch repair deficient colorectal cancer. Dr. Kristen Ciombor: I think this study was really definitely practice-changing, as you can tell because it was a Plenary. But I do have some concerns in terms of how we're actually going to implement this and whether this is the final answer in this disease subtype. So, as you said, the patients were enrolled with stage III resected mismatch repair deficient colon cancer, and then they were randomized to either modified FOLFOX6 with or without atezolizumab. And that's where it starts to become interesting because not many of us give FOLFOX for 6 months like was done in this study. Obviously, the study was done over many years, so that was part of that answer, but also the patients received atezolizumab for a total of 12 months. So the question, I think, that comes from this abstract is, is this practical and is this the final answer? I do think that this is practice-changing, and I will be talking to my patients with resected mismatch repair deficient colon cancer about FOLFOX plus atezolizumab. I think the big question is, do these patients need chemotherapy? And can we do a neoadjuvant approach instead? And that's where we don't have all the answers yet. Dr. Shaalan Beg: Yeah, but it has been great to see immunotherapy make its way into the adjuvant space after having made such a big impact in the metastatic space, but still some unanswered questions in terms of the need for chemotherapy and then the duration of therapy, which I guess we'll have to stay tuned in for the next couple of years to to get a lot of those questions answered. Dr. Kristen Ciombor: Yeah, but a big congratulations to the study team, to the NCTN, the NCI. I mean, this is really a great example of federally funded research that needs to continue. So, great job by the study team. The DFS 10% difference is really very large and certainly a practice-changing study. Dr. Shaalan Beg: Yeah, and and sticking with colon cancer, and and this another federally funded study, but this time funded by a Canadian cancer clinical trials group was LBA3510. This is the CHALLENGE study. It's a randomized phase 3 trial of the impact of a structured exercise program on disease-free survival for stage III or high-risk stage II colon cancer. This study got a lot of buzz, a lot of mainstream press coverage, and a lot of discussions on what that means for us for the patients who we're going to be seeing next week in our clinic. What was your takeaway? Dr. Kristen Ciombor: Yeah, this is a really interesting study, and I was so glad to see it presented because this partially answers one of the questions that patients always have for us in clinic, right? You know, once they've completed their standard chemotherapy and surgery, what else can they do to help prevent recurrence? And so we've always known and sort of extrapolated that healthy lifestyle habits are good, but now we have data, particularly in these patients. Most of them were stage III colon cancer patients, those had high-risk stage II cancer. And basically, the goal was to increase their physical activity by at least 10 MET hours per week. So, my big question, of course, as I came into this presentation was, “Okay, what does that mean exactly? How does that translate to real life?” And really what the author presented and explained was that basically most patients could hit their target by adding a 45- to 60-minute brisk walk 3 to 4 times a week. So I think this is very approachable.  Now, in the confines of the study, this was a structured exercise program, so it wasn't just patients doing this on their own. But I do think kind of extrapolating from that, that this is very achievable for most patients. And not only did this prevent recurrence of their prior cancer, but actually the rate of new primary cancer diagnoses, was less, which is really interesting, especially in the breast and prostate cancer. So this was a really interesting, and I think practice-changing study as well, especially given that this is something that most patients can do. Dr. Shaalan Beg: Yeah, and there was a lot of discussion in the hallways after the presentation in terms of how this really changes our existing practice because most folks already recommend exercise as a way for improving outcomes in cancer patients. So we've already been doing that. Now we have some data on how much it can impact the benefit. But there was some discussion about what the actual degree of impact was. There was a drop-off rate in terms of how long folks were able to stick with this exercise regimen. But you've seen this in clinic when someone have their surgery, they have their chemotherapy, they've been so intimately involved with the oncology world, with the oncology practice, and they somehow feel that they're being let loose into this mean, angry world without any guidance and they're looking for something to do. “What more can I do in terms of my lifestyle?” And then here we have very solid data, as solid as can be for an intervention like exercise, showing that there is an impact and you can give a prescription for exercise when someone wraps up their chemotherapy for colon cancer, thanks to the study. Dr. Kristen Ciombor: Yeah. It was a great study. Dr. Shaalan Beg: Moving to gastroesophageal cancer, another late-breaking abstract. This is LBA5. The MATTERHORN trial was a phase 3 trial of durvalumab plus FLOT for resectable GE junction and gastric cancer. And again, another area where immunotherapy has made an impact, and here we're seeing it move closer for earlier-stage disease. What was your take-home for the MATTERHORN trial? Dr. Kristen Ciombor: Yeah, so this study looked at neoadjuvant perioperative durvalumab plus our current standard chemotherapy of FLOT versus placebo plus FLOT. And this was a large study, almost 1,000 patients were randomized. And the primary endpoint was event-free survival, and it was definitely met in favor of the D + FLOT arm, as Dr. Klempner discussed after Dr Janjigian's presentation. I do think there are still some unanswered questions here. Overall survival is not yet mature, so we do have to wait and see how that shakes out. But it's very interesting and kind of is reflective of what, as you said, we're looking at earlier and earlier lines of therapy, particularly with immunotherapy, in these GI cancer spaces. So it makes a lot of sense to test this and and to look at this. So the toxicity was pretty similar to what we would expect. Primary endpoint was met, but again, we'll have to wait and see what the survival data looks like. Dr. Shaalan Beg: Yeah, and in oncology, we know, especially for treatment that does add additional cost, it does add additional potential toxicity that we want to see that overall survival nudged. I did see some polls on social media asking folks whether their practices changed from this, and I think the results were favoring adding durvalumab for this group of patients but understanding that there are caveats to the addition of treatments and the eventual FDA approval in that indication as well. Dr. Kristen Ciombor: Exactly. I completely agree with that. Dr. Shaalan Beg: All right. How about we stick with gastroesophageal cancer? LBA4002 was trastuzumab deruxtecan versus ramucirumab plus paclitaxel for second-line treatment in HER2-positive unresectable or metastatic gastric cancer or GE junction cancer. This was the DESTINY-Gastric04 study. And again, antibody-drug conjugates making a big impact across different diseases. And here we have more data in the HER2-positive gastric cancer space. Your thoughts on this study? Dr. Kristen Ciombor: Yeah, so this is a really important space in gastroesophageal cancer because the HER2 positivity rate is fairly high as compared to some of our other tumor types. So, I do think one of the important things was that patients did have biopsy confirmation of HER2 status, which was very important, and then they were randomized to either T-DXd versus the kind of second-line standard of ramucirumab-paclitaxel. So this was a great practical study and really answers a question that we had for a while in terms of does anti-HER2 therapy in the second-line really impact and improve survival. So we did see a statistically significant improvement favoring T-DXd. I do think it's always important to look at toxicity, though, too. And there was about almost 14% rate of interstitial lung disease, which of course is the most feared toxicity from some of these antibody-drug conjugates, especially T-DXd. So I do think it's important to keep that in mind, but this is definitely a great addition to the armamentarium for these HER2-positive patients. Dr. Shaalan Beg: And pancreas cancer was on the stage after a very long time with a positive clinical trial. This is Abstract 4006. These were preliminary results from a phase 2 study of elraglusib in combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel alone for previously untreated metastatic pancreas cancer. This is a frontline clinical trial of gemcitabine/nab-paclitaxel plus/minus the study drug. There were other cohorts in this study as well, but they reported the results of their part 3B arm. And great to see some activity in the pancreas space. And your thoughts? Dr. Kristen Ciombor: Yeah, we definitely need better treatments in pancreas cancer. This was a very welcome presentation to see. The elraglusib is an inhibitor of GSK-3beta, and it's thought that that mediates drug resistance and EMT. And so this is, I think, a perfect setting to test this drug. So patients basically were randomized. Patients with metastatic pancreas cancer were randomized 2: 1 to gemcitabine/nab-paclitaxel plus or minus this elraglusib. So, what we saw was that overall survival was better with the addition of this new drug. And overall, not only the 1-year overall survival, but also median overall survival.  The thing that was interesting, though, was that we saw that the overall survival rates were 9.3 months with the combination versus 7.2 months with just gemcitabine/nab-paclitaxel. And that's a little bit lower than we've seen in other studies. So, not sure what was going on there. Was it the patients that were a bit sicker? Was it a patient selection, you know, thing? I'm not really sure how to explain that so much. Also, the toxicity profile was much higher in terms of visual impairment, with over 60% of patients being treated with the combination versus 9% with gemcitabine/nab-paclitaxel. So these were mild, grade 1 and 2, but still something to be cautious about. Dr. Shaalan Beg: And especially with this being a phase 2 trial, making sure that in a larger study we're able to better evaluate the toxicity and see if the control arm in the larger confirmatory study performs differently will be really important before this compound makes it to the clinic in our space. But very exciting to see these kinds of results for pancreas adenocarcinoma. Dr. Kristen Ciombor: Yeah. Dr. Shaalan Beg: We've talked, it seems, a couple of times on this podcast about the BREAKWATER clinical trial. We did hear PFS and updated OS data, updated overall survival data on first-line encorafenib plus cetuximab plus modified FOLFOX6 for BRAF-mutated colorectal cancer. This was LBA3500. And eagerly anticipated results – we have all previously heard the progression-free survival results – but here we heard updated overall survival results, and very well-received study it seemed from the audience that time. So what are your takeaways on the updated results for BREAKWATER? Dr. Kristen Ciombor: In my opinion, this was one of the most practice-confirming studies. As you mentioned, we've already seen some of the preliminary data of BREAKWATER at prior meetings. But really what was particularly impactful for me was the median overall survival with the BREAKWATER regimen. So, again, patients received FOLFOX, encorafenib cetuximab in the first line if they had BRAF-mutated V600E-mutated colorectal cancer. And the median PFS was 12.8 months, which was actually really remarkable in this traditionally very aggressive, poor prognosis subtype of tumors. So, by seeing a median overall survival of 30.3 months was just incredible, in my opinion. Just a few years ago, that was considered the median overall survival for all comers for metastatic colorectal cancer. And we know the median overall survival was more in the less than 12 months range for BRAF. So this was incredibly impactful, and I think should be absolutely practice-changing for anyone who is eligible for this regimen.  I think again, where the practice meets the study is what's kind of important to think about too, how long did patients get FOLFOX, and certainly it adds toxicity to add a BRAF-targeted regimen on top of FOLFOX already. So, one of the other interesting things about the study, though, was that even though it didn't complete treatment, they actually did look at encorafenib/cetuximab alone and in the first line without chemotherapy. And those preliminary results actually looked okay, especially for patients who might not be able to tolerate chemotherapy, which we certainly see in practice. So, overall, definitely more data. And I agree that it's certainly practice-changing. Dr. Shaalan Beg: And it completely, as you mentioned, changes the outlook for a person who's diagnosed with BRAF-mutated metastatic colon cancer today versus even 7 or 8 years ago. Dr. Kristen Ciombor: And we're seeing this over and over in other subtypes too, but how you choose to treat the patient up front really matters. So really giving the right regimen up front is the key here. Dr. Shaalan Beg: And along the same lines, Abstract 3501 wanted to answer the question on whether people with MSI-high metastatic colorectal cancer need double checkpoint inhibitor therapy or is single therapy enough. So this [CheckMate-8HW] study compared nivo plus ipi with nivo alone, nivo monotherapy for MSI-high metastatic colorectal cancer. And we've known that both of these are fairly active regimens, but we also know the chance of immune-related adverse events is significantly higher with combination therapy. So this was a much-needed study for this group of patients. And what were your takeaways here? Dr. Kristen Ciombor: This, of course, has been really nivo-ipi in the first-line MSI-high metastatic colorectal cancer is now a standard of care. And not everybody is eligible for it, and there could be reasons, toxicity reasons, and other things too. But as we've been seeing for the last couple of years, immunotherapy clearly beats chemo in this space. And now looking at doublet versus single immunotherapy treatment in the first line, I think really nivo-ipi does beat out monotherapy. I will say, however, there is a caveat in that we still haven't seen the nivo-ipi versus nivo in the first line. So what has been presented thus far has been across all lines of therapy, and that does muddy the waters a little bit. So definitely looking forward and and we've asked this many times and based on the statistical plan and and what not, you know, we just haven't seen that data yet. But I do think it's becoming increasingly important to consider doublet immunotherapy for these patients as long as there are no contraindications. With the again, with the caveat that we have to have these toxicity discussions in the clinic with patients because many patients can tolerate it, you know, this regimen fairly well, but there can be very severe toxicities. So, I think an informed discussion should really be had with each patient before moving forward. Dr. Shaalan Beg: Yeah, informed decision, making them aware of the potential of real significant toxicities, immune-related toxicities with double therapy. But I am curious in your practice, how often do you see people choosing doublet therapy as frontline? Dr. Kristen Ciombor: So patients are really savvy, and a lot of times they've heard this data before or have come across it in patient advocacy groups and other things, and it's really nice to be able to have that conversation of the risk versus benefit. So I will say not all of my patients choose doublet, and many of them are still cured with immunotherapy monotherapy. So the big question there is, will we ever understand who actually needs the doublet versus who can still be cured or have very good long-term outcomes with just the single agent? And that has not been answered yet. Dr. Shaalan Beg: What a great point. So the last abstract I was hoping we could talk about is POD1UM-303 or the INTERAACT2 subgroup analysis and impact of delayed retifanlimab treatment for patients with squamous cell carcinoma of the anal canal. What were your thoughts here? Dr. Kristen Ciombor: This was a study, actually we saw at ESMO, we saw the primary data at ESMO last year, and this was an update with some exploratory analyses. But this was really an important study because once again, we're looking at immunotherapy in later lines of therapy. That's how we started looking at and investigating immunotherapy, and now we're moving it up and up in the treatment course. So this was a study of carboplatin/paclitaxel plus or minus retifanlimab. Actually it was retifanlimab versus placebo. And it was a positive study, as we heard last year. This actually led to FDA approval of this regimen last month, just before ASCO, and it has now been incorporated in the NCCN guidelines as the preferred first-line option.  So what I thought was important from the additional data presented at ASCO was looking at the different subgroups, it did not appear that patients with liver mets or not had different outcomes. So that was really good to see because sometimes in colon cancer we see that immunotherapy doesn't work as well when patients have liver mets. And interestingly, because we use immunotherapy in anal cancer without any biomarkers, unlike with colon cancer or some of the other tumor types, also the authors looked at PD-L1 status, and it did look like maybe patients did a little bit better if they had higher PD-L1 expression, but patients still could benefit even if they were PD-L1 negative. So that was important, I think, and we will continue to see further data come out from this study. I want to mention also that EA2176 just completed accrual, so that was carbo-taxol plus or minus nivolumab. And so we should be seeing that data sometime soon, which will hopefully also confirm the ongoing role for immunotherapy in the first-line setting for anal cancer. Dr. Shaalan Beg: That was a fantastic review. Thank you, Dr Ciombor. Thanks for sharing your valuable insights with us today on the ASCO Daily News Podcast. Dr. Kristen Ciombor: Thanks for having me here. Dr. Shaalan Beg: And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode. And if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe, wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, 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. Shaalan Beg  @ShaalanBeg  Dr. Kristen Ciombor @KristenCiombor Follow ASCO on social media:    @ASCO on Twitter   @ASCO on BlueSky  ASCO on Facebook    ASCO on LinkedIn    Disclosures:   Dr. Shaalan Beg:   Consulting or Advisory Role: Ipsen, Cancer Commons, Foundation Medicine, Science37, Nant Health, Lindus Health Speakers’ Bureau: Sirtex Research Funding (Inst.): Delfi Diagnostics, Universal Diagnostics, Freenome Dr. Kristen Ciombor: Consulting or Advisory Role: Pfizer, Incyte, Exelixis, Bayer, ALX Oncology, Tempus, Agenus, Taiho Oncology, Merck, BeiGene Research Funding (Inst.): Pfizer, Boston Biomedical, MedImmune, Onyx, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Novartis, Incyte, Amgen, Sanofi, Bristol-Myers Squibb, Array BioPharma, Incyte, Daiichi Sankyo, Nucana, Abbvie, Merck, Pfizer/Calthera, Genentech, Seagen, Syndax Travel, Accommodations, Expenses: Incyte, Tempus

Dr. Allison Zibelli and Dr. Rebecca Shatsky discuss advances in breast cancer research that were presented at the 2025 ASCO Annual Meeting, including a potential new standard of care for HER2+ breast cancer, the future of ER+ breast cancer management, and innovations in triple negative breast cancer therapy. Transcript Dr. Allison Zibelli: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Allison Zibelli, your guest host of the podcast today. I'm an associate professor of medicine and a breast medical oncologist at the Sidney Kimmel Comprehensive Cancer Center at Jefferson Health. There was a substantial amount of exciting breast cancer data presented at the 2025 ASCO Annual Meeting, and I'm delighted to be joined by Dr. Rebecca Shatsky today to discuss some of these key advancements. Dr. Shatsky is an associate professor of medicine at UC San Diego and the head of breast medical oncology at the UC San Diego Health Moores Cancer Center, where she also serves as the director of the Breast Cancer Clinical Trials Program and the Inflammatory and Triple-Negative Breast Cancer Program.  Our full disclosures are available in the transcript of this episode. Dr. Shatsky, it's great to have you on the podcast today. Dr. Rebecca Shatsky: Thanks, Dr. Zibelli. It's wonderful to be here. Dr. Allison Zibelli: So, we’re starting with DESTINY-Breast09, which was trastuzumab deruxtecan and pertuzumab versus our more standard regimen of taxane, trastuzumab pertuzumab for first-line treatment of metastatic HER2-positive breast cancer. Could you tell us a little bit about the study? Dr. Rebecca Shatsky: Yeah, absolutely. So, this was a long-awaited study. When T-DXd, or trastuzumab deruxtecan, really hit the market, a lot of these DESTINY-Breast trials were started around the same time. Now, this was a global, randomized, phase 3 study presented by Dr. Sara Tolaney from the Dana-Farber Cancer Institute of Harvard in Boston. It was assessing essentially T-DXd in the first-line setting for metastatic HER2-positive breast cancer in addition to pertuzumab. And that was randomized against our standard-of-care regimen, which was established over a decade ago by the CLEOPATRA trial, and we've all been using that internationally for at least the past 10 years. So, this was a large trial, and it was one-to-one-to-one of patients getting T-DXd plus pertuzumab, T-DXd alone, or THP, which mostly is used as docetaxel and trastuzumab and pertuzumab every three weeks for six cycles. And this was in over 1,000 patients; it was 1,159 patients with metastatic HER2-positive breast cancer. This was a very interesting trial. It was looking at the use of trastuzumab deruxtecan, but patients were started on this treatment for their first-line metastatic HER2-positive breast cancer with no end date to their T-DXd. So, it was, you know, you were started on T-DXd every 3 weeks until progression. Now, CLEOPATRA is a little bit different than that, though, as we know. So, CLEOPATRA has a taxane plus trastuzumab and pertuzumab. But generally, patients drop the taxane after about six to seven cycles because, as we know, you can't be really on a taxane indefinitely. You get pretty substantial neuropathy as well as cytopenias, other things that end up happening. And so, in general, that regimen has sort of a limited time course for its chemotherapy portion, and the patients maintained after the taxane is dropped on their trastuzumab and their pertuzumab, plus or minus endocrine therapy if the investigator so desires. And the primary endpoint of the trial was progression-free survival by blinded, independent central review (BICR) in the intent-to-treat population. And then it had its other endpoints as overall survival, investigator-assessed progression-free survival, objective response rates, and duration of response, and of course, safety. As far as the results of this trial, so, I think that most of us key opinion leaders in breast oncology were expecting that this was going to be a positive trial. And it surely was. I mean, this is a really, really active drug, especially in HER2-positive disease, of course. So, the DESTINY-Breast03 data really established that, that this is a very effective treatment in HER2-positive metastatic breast cancer. And this trial really, again, showed that. So, there were 383 patients that ended up on the trastuzumab plus deruxtecan plus pertuzumab arm, and 387 got THP, the CLEOPATRA regimen. What was really interesting also to note of this before I go on to the results was that 52% of patients on this trial had de novo metastatic disease. And that's pretty unusual for any kind of metastatic breast cancer trial. It kind of shows you, though, just how aggressive this disease is, that a lot of patients, they present with de novo metastatic disease. It's also reflecting the global nature of this trial where maybe the screening efforts are a little bit less than maybe in the United States, and more patients are presenting as later stage because to have a metastatic breast cancer trial in the United States with 52% de novo metastatic disease doesn't usually happen. But regardless, the disease characteristics were pretty well matched between the two groups. 54% of the patients were triple positive, or you could say hormone-positive because whether they were PR positive or ER positive and PR negative doesn't really matter in this disease. And so, the interim data cutoff was February of this year, of 2025. So, the follow-up so far has been about 29 months, so the data is still really immature, only 38% mature for progression-free survival interim analysis. But what we saw is that T-DXd plus pertuzumab, it really improved progression-free survival. It had a hazard ratio that was pretty phenomenal at 0.56 with a confidence interval that was pretty narrow of 0.44 to 0.71. So, very highly statistically significant data here. The progression-free survival was consistent across all subgroups. Overall survival, very much immature at this time, but of course, the trend is towards an overall survival benefit for the T-DXd group. The median durable response with T-DXd plus pertuzumab exceeded 3 years. Now, importantly, though, I want to stress this, is grade 3 or above treatment-emergent adverse events occurred in both subgroups pretty equally. But there were 2 deaths in the T-DXd group due to interstitial lung disease. And there was a 12.1% adjudicated drug-induced interstitial lung disease/pneumonitis event rate in the T-DXd group and only 1%, and it was grade 1-2, in the THP group. So, that's really the caveat of this therapy, is we know that a percentage of patients are going to get interstitial lung disease, and that some may have very serious adverse events from it. So, that's always something I keep in the back of my mind when I treat patients with T-DXd. And so, overall, the conclusions of the trial were pretty much a slam dunk. T-DXd plus pertuzumab, it had a highly statistically significant and clinically meaningful improvement in progression-free survival versus the CLEOPATRA regimen. And that was across all subgroups for first-line metastatic HER2-positive breast cancer here. And so, yeah, the data was pretty impressive. Just to go into the overall response rate, because that's always super important as well, you had 85.1% of patients having a confirmed overall RECIST response rate in the T-DXd plus pertuzumab group and a 78.6 in the CLEOPATRA group. The complete CR rate, complete response was 15.1% in the T-DXd group and 8.5 in the CLEOPATRA regimen. And it was really an effective regimen in this group, of course. Dr. Allison Zibelli: So, the investigators say at the end of their abstract that this is the new standard of care. Would you agree with that statement? Dr. Rebecca Shatsky: Yeah, that was a bold statement to make because I would say in the United States, not necessarily at the moment because the quality of life here, you have to think really hard about. Because one thing that's really important about the DESTINY-Breast09 data is that this was very much an international trial, and in many of the countries where patients enrolled on this, they were not able to access T-DXd off trial. And so, for them, this means T-DXd now or potentially never. And so, that is a really big difference whereas internationally, that may mean standard of care. However, in the US, patients have no issues accessing T-DXd in the second- or third-line settings. And right now, it's the standard of care in the second line in the United States, with all patients basically getting this second-line therapy except for some unique patients where they may be doing a PATINA trial regimen, which we saw at San Antonio Breast Cancer in 2024 of the triple-positive patients getting hormonal therapy plus palbociclib, which had a really great durable response. That was super impressive as well. Or there is the patient that the investigator can pick KADCYLA because the patient really wants to preserve their hair or maybe it's more indolent disease. But the quality of life on T-DXd indefinitely in the first-line setting is a big deal because, again, that CLEOPATRA regimen allows patients to drop their chemotherapy component about five to six months in. And with this, you're on a drug that feels very chemo-heavy indefinitely. And so, I think there's a lot more to investigate as far as what we're going to do with this data in the United States because it's a lot to commit a patient in the first-line metastatic setting. These de novo metastatic patients, some of them may be cured, honestly, on the HER2-targeting regimen. That's something we see these days. Dr. Allison Zibelli: So, very interesting trial. I'm sure we'll be talking about this for a long time.  So, let's move on to SERENA-6, which was, I thought, a very interesting trial. This trial took patients with ER positive, advanced breast cancer after six months on an AI (aromatase inhibitor) and a CDK4/6 inhibitor. They did ctDNA every two to three months, and when they saw an ESR1 mutation emerge, they changed half of the patients to camizestrant plus CDK4/6 and kept the other half on the AI plus CDK4/6. Can you talk about that trial a little bit, please? Dr. Rebecca Shatsky: Yeah, so this was a big trial at ASCO25. This was presented as a Plenary Session. So, this was camizestrant plus a CDK4/6 inhibitor, and it could have been any of the three, so palbo, ribo, or abemaciclib in the first-line metastatic hormone-positive population, and patients were on an AI with that. They were, interestingly, tested by ctDNA at baseline to see if they had an ESR1 mutation. So, that was an interesting feature of this trial. But patients had to have already been on their CDK4/6 inhibitor plus AI for at least 6 months to enroll. And then, as you mentioned, they got ctDNA testing every 2 to 3 months. This was also a phase 3, double-blind, international trial. And I do want to highlight again, international here, because that's important when we're considering some of this data in the U.S. because it influences some of the results. So, this was presented by Dr. Nick Turner of the Royal Marsden in the UK. So, just a little bit of background for our listeners on ESR1 mutations and why they're important. This is the most common, basically, acquired resistance mutation to patients being treated with aromatase inhibitors. We know that treatment with aromatase inhibitors can induce this. It makes a conformational change in the estrogen receptor that makes the estrogen receptor constitutively active, which allows the cell to signal despite the influence of the aromatase inhibitor to decrease the estrogen production so that the ligand binding doesn't matter as much as far as the cell signaling and transcription is concerned. And camizestrant, you know, as an oral SERD, just to explain that a little bit too; these are estrogen receptor degraders. The first-in-class of a selective estrogen receptor degrader to make it to market was fulvestrant. And that's really been our standard-of-care estrogen degrader for the past 25 years, almost 25 years. And so, a lot of us are just looking for some of these oral SERDs to replace that. But regardless, they do tend to work in the ESR1-mutated population. And we know that patients on aromatase inhibitors, the estimates of patients developing an ESR1 mutation, depending on which study you look at, somewhere between 30% to 50% overall, patients will develop this mutation with hormone-positive metastatic breast cancer. There is a small percentage of patients that have these at baseline without even treatment of an aromatase inhibitor. The estimates of that are somewhere between 0.5 and up to 5%, depending on the trial you look at and the population. But regardless, there is a chance someone on their CDK4/6 inhibitor plus AI at 6 months’ time course could have had an ESR1 mutation at that time. But anyway, so they got this ctDNA every 2 to 3 months, and once they were found to develop an ESR1 mutation, the patients were then switched to the oral SERD. AstraZeneca's version of the oral SERD is camizestrant, 75 mg daily. And then their type of CDK4/6 inhibitor was maintained, so they didn't switch the brand of their CDK4/6 inhibitor, importantly. And that was looked at then for progression-free survival, but these were patients with measurable disease by RECIST version 1.1. And the data cut off here was November of 2024. This was a big trial, you know, and I think that that's influential here because this was 3,256 patients, and that's a lot of patients. So, they were all eligible. And then 315 patients ended up being randomized to switch to camizestrant upon presence of that ESR1 mutation. So, that was 157 patients. And then the other half, so they were randomized 1:1, they continued on their AI without switching to an oral SERD. That was 158 patients. They were matched pretty well. And so, their baseline characteristics, you know, the two subgroups was good. But this was highly statistically significant data. I'm not going to diminish that in any way. Your hazard ratio was 0.44. Highly statistically significant confidence intervals. And you had a median progression-free survival in those that switched to camizestrant of 16 months, and then the non-switchers was 9.2 months. So, the progression-free survival benefit there was also consistent across the subgroups. And so, you had at 12 months, the PFS rate was 60.7% for the non-treatment group and 33.4% in the treatment group. What's interesting, though, is we don't have overall survival data. This is really immature, only 12% mature as far as overall survival. And again, because this was an international trial and patients in other countries right now do not have the access to oral SERDs that the United States does, the crossover rate, they were not allowed to crossover, and so, a very few patients, when we look at progression-free survival 2 and ultimately overall survival, were able to access an oral SERD in the off-trial here and in the non-treatment group. And so, that's really important as far as we look at these results. Adverse events were pretty minimal. These are very safe drugs, camizestrant and all the other oral SERDs. They have some mild toxicities. Camizestrant is known for something weird, which is called photopsia, which is some flashing lights in the periphery of the eye, but it doesn't seem to have any serious clinical significance that we know of. It has a little bit of bradycardia, but it's otherwise really well tolerated. You know, I hate to say that because that's very subjective, right? I'm not the one taking the drug. But it doesn't have any serious adverse events that would cause discontinuation. And that's really what we saw in the trial. The discontinuation rates were really low. But overall, I mean, this was a positive trial. SERENA-6 showed that switching to camizestrant at the first sign of an ESR1 mutation on CDK4/6 inhibitor plus AI improved progression-free survival. That's all we can really say from it right now. Dr. Allison Zibelli: So, let's move on to ASCENT-04, which was a bit more straightforward. Sacituzumab govitecan plus pembrolizumab versus chemotherapy plus pembrolizumab in PD-L1-positive, triple-negative breast cancer. Could you talk about that study? Dr. Rebecca Shatsky: Yeah, so this was also presented by the lovely Sara Tolaney from Dana-Farber. And this study made me really excited. And maybe that's because I'm a triple-negative breast cancer person. I mean, not to say that I don't treat hundreds of patients with hormone- positive, but our unmet needs in triple negative are huge because this is a disease where you have got to throw your best available therapy at it as soon as you can to improve survival because survival is so poor in this disease. The average survival with metastatic triple-negative breast cancer in the United States is still 13-18 months, and that's terrible. And so, for full disclosure, I did have this trial open at my site. I was one of the site PIs. I'm not the global PI of the study, obviously. So, what this study was was for patients who had had at least a progression-free survival of 6 months after their curative intent therapy or de novo metastatic disease. They were PD-L1 positive as assessed by the Dako 22C3 assay of greater than or equal to a CPS score of 10. So, that's what the KEYNOTE-355 trial was based on as well. So, standard definition of PD-L1 positive in breast cancer here. And basically, these patients were randomized 1:1 to either their sacituzumab govitecan plus pembrolizumab, day 1 they got both therapies, and then day 8 just the saci, as is standard for sacituzumab. And then the other group got the KEYNOTE-355 regimen. So, that is pembrolizumab with – your options are carbogem there, paclitaxel or nab-paclitaxel. And it's up to investigator's decision which upon those they decided. They followed these patients for disease progression or unacceptable toxicity. It was really an impressive trial in my opinion because we know already that this didn't just improve progression-free survival, because survival is so poor in this disease, of course, we know that it improved overall survival. It's trending towards that very much, and I think that's going to be shown immediately. And then the objective response rates were better, which is key in this disease because in the first-line setting, you've got a lot of people who, especially your relapsed TNBC that don't respond to anything. And you lose a ton of patients even in the first-line setting in this disease. And so, this was 222 patients to chemotherapy and pembro and 221 to sacituzumab plus pembro. Median follow-up has only been 14 months, so it's still super early here. Hazard ratio so far of progression-free survival is 0.65, highly statistically significant, narrow confidence intervals. And so, the median duration of response here for the saci group was 16.5 months versus 9.2 months. So, you're getting a 7-month progression-free survival benefit here, which in triple negative is pretty fantastic. I mean, this reminds me of when we saw the ASCENT data originally come out for sacituzumab, and we were all just so happy that we had this tool now that doubled progression-free and overall survival and made such a difference in this really horrible disease where patients do poorly. So, OS is technically immature here, but it's really trending very heavily towards improvement in overall survival. Importantly, the treatment-related adverse events in this, I mean, we know sacituzumab causes neutropenia, people who are experienced with this drug know how to manage it at this point. There wasn't any really unexpected treatment-related adverse events. You get some people with sacituzumab who have diarrhea. It's usually pretty manageable with some Imodium. So, it was cytopenias predominantly in this disease in this population that were highlighted as far as adverse events. But I'm going to be honest, like I was surprised that this wasn't the plenary over the SERENA-6 data because this, in my mind, there we have a practice-changing trial. I will immediately be trying to use this in my PD-L1 population because, to be honest, as a triple-negative breast cancer clinical specialist, when I get a patient with metastatic triple-negative breast cancer who's PD-L1 positive, I think, "Oh, thank God," because we know that part of the disease just does better in general. But now I have something that really could give them a durable response for much longer than I ever thought possible when I started really heavily treating this disease. And so, this was immediately practice-changing for me. Dr. Allison Zibelli: I think that it's pretty clear that this is at least an option, if not the option, for this group of patients. Dr. Rebecca Shatsky: Yeah, the duration of responses here was – it’s just really important because, I mean, I do think this will make people live longer. Dr. Allison Zibelli: So, moving on to the final study that we're going to discuss today, neoCARHP (LBA500), which was neoadjuvant taxane plus trastuzumab, pertuzumab, plus or minus carbo(platin) in HER2-positive early breast cancer. I think this is a study a lot of us have been waiting for. What was the design and the results of this trial? Dr. Rebecca Shatsky: I was really excited about this as well because I'm one of those people that was waiting for this. This is a Chinese trial, so that is something to take note of. It wasn't an international trial, but it was a de-escalation trial which had become really popular in HER2-positive therapy because we know that we're overtreating HER2-positive breast cancer in a lot of patients. A lot of patients we're throwing the kitchen sink at it when maybe that is not necessary, and we can really de-escalate and try to personalize therapy a little bit better because these patients tend to do well. So, the standard of care, of course, in HER2-positive curative intent breast cancer with tumors that are greater than 2 cm is to give them the TCHP regimen, which is docetaxel, carboplatin, trastuzumab, and pertuzumab. And that was sort of established by several trials in the NeoSphere trial, and now it's been repeated in a lot of different studies as well. And so, that's really the standard of care that most people in the United States use for HER2-positive curative intent breast cancer. This was a trial to de-escalate the carboplatin, which I was super excited about because many of us who treat this disease a lot think carbo is the least important part of the therapy you're giving there. We don't really know that it's necessary. We've just been doing it for a long time, and we know that it adds a significant amount of toxicity. It causes thrombocytopenia, it causes severe nausea, really bad cytopenias that can be difficult in the last few cycles of this to manage. So, this trial was created. It randomized patients one to one with stage 2 and 3 HER2-positive breast cancer to either get THP, a taxane, pertuzumab, trastuzumab, similar to the what we do in first-line metastatic HER2-positive versus the whole TCHP with a carboplatin AUC of 6, which is what's pretty standard. And it was a non-inferiority trial, so important there. It wasn't to establish superiority of this regimen, which none of us, I think, were looking for it to. And it was a modified intent-to-treat population. And so, all patients got at least one cycle of this to be assessed as a standard for an intent-to-treat trial. And so, they assumed a pCR rate of about 62.8% for both groups. And, of course, it included both HER2-positive triple positives and ER negatives, which are, you know, a bit different diseases, to be honest, but we all kind of categorize them and treat them the same. And so, this trial was powered appropriately to detect a non-inferiority difference. And so, we had about 380 patients treated on both arms, and there was an absolute difference of only 1.8% of those treated with carbo versus those without. Which was fantastic because you really realized that de-escalation here may be something we can really do. And so, the patients who got, of course, the taxane regimen had fewer adverse events. They had way fewer grade 3 and 4 adverse events than the THP group. No treatment-associated deaths occur, which is pretty standard for- this is a pretty safe regimen, but it causes a lot of hospitalizations due to diarrhea, due to cytopenias, and neutropenic fever, of course. And so, I thought that this was something that I could potentially enact, you know, and be practice-changing. It's hard to say that when it's a trial that was only done in China, so it's not necessarily the United States population always. But I think for patients moving forward, especially those with, say, a 2.5 cm tumor, you know, node negative, those, I'd feel pretty comfortable not giving them the carboplatin here. Notes that I want to make about this population is that the majority were stage 2 and not stage 3. They weren't necessarily your inflammatory HER2-positive breast cancer patients. And that the taxane that was utilized in the trial is a little different than what we use in the United States. The patients were allowed to get nab-paclitaxel, which we don't have FDA approval for in the first-line curative intent setting for HER2-positive breast cancer in the United States. So, a lot of them got abraxane, and then they also got paclitaxel. We tend to use docetaxel every 3 weeks in the United States. So, just to point out that difference. We don't really know if that's important or not, but it's just a little bit different to the population we standardly treat. Dr. Allison Zibelli: So, are there patients that you would still give TCHP to? Dr. Rebecca Shatsky: Yeah, great question. I've been asked that a lot in the past like week since ASCO. I'd say in my inflammatory breast cancer patients, that's a group I do tend to sometimes throw the kitchen sink at. Now, I don't actually use AC in those because I know that that was the concern, but I think the TRAIN-2 trial really showed us you don't need to use Adriamycin in HER2-positive disease unless it's like refractory. So, I don't know that I would throw this on my stage 3C or inflammatory breast cancer patients yet because the majority of this were not stage 3. So, in your really highly lymph node positive patients, I'm a little bit hesitant to de-escalate them from the start. This is more of a like, if there's serious toxicity concerns, dropping carbo is absolutely fine here. Dr. Allison Zibelli: All right, great.  Thank you, Dr. Shatsky, for sharing your valuable insights with us on the ASCO Daily News Podcast today. Dr. Rebecca Shatsky: Thanks so much, Dr. Zibelli and ASCO Daily News. I really want to thank you for inviting me to talk about this today. It was really fun, and I hope you find my opinions on some of this valuable. And so, I just want to thank everybody and my listeners as well. Dr. Allison Zibelli: And thank you to our listeners for joining us today. You'll find the links to all the abstracts discussed today in the transcript of this episode. Finally, if you like this podcast and you learn things from it, please take a moment to rate, review, and describe because it helps other people find us wherever you get your podcasts. Thank you again. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. More on today’s speakers Dr. Allison Zibelli Dr. Rebecca Shatsky @Dr_RShatsky Follow ASCO on social media:  @ASCO on Twitter  @ASCO on Bluesky  ASCO on Facebook  ASCO on LinkedIn   Disclosures: Dr. Allison Zibelli: No relationships to disclose Dr. Rebecca Shatsky: Consulting or Advisory Role: Stemline, Astra Zeneca, Endeavor BioMedicines, Lilly, Novartis, TEMPUS, Guardant Health, Daiichi Sankyo/Astra Zeneca, Pfizer Research Funding (Inst.): OBI Pharma, Astra Zeneca, Greenwich LifeSciences, Briacell, Gilead, OnKure, QuantumLeap Health, Stemline Therapeutics, Regor Therapeutics, Greenwich LifeSciences, Alterome Therapeutics