POPULARITY
Dr. Pedro Barata and Dr. Rana McKay discuss the integration of innovative advances in molecular imaging and therapeutics to personalize treatment for patients with renal cell and urothelial carcinomas. TRANSCRIPT Dr. Pedro Barata: Hello, I'm Dr. Pedro Barata, your guest host of By the Book, a podcast series featuring insightful conversations between authors and editors of the ASCO Educational Book. I'm a medical oncologist at University Hospitals Seidman Cancer Center and an associate professor of medicine at Case Western Reserve University in Cleveland, Ohio. I'm also an associate editor of the ASCO Educational Book. Now, we all know the field of genitourinary cancers (GU) is evolving quite rapidly, and we have new innovations in molecular imaging as well as targeted therapeutics. Today's episode will be exploring novel approaches that are transforming the management of renal cell and urothelial carcinomas and also their potential to offer a more personalized treatment to patients. For that, joining for today's discussion is Dr. Rana McKay, a GU medical oncologist and professor at University of California San Diego. Dr. McKay will discuss her recently published article titled, “Emerging Paradigms in Genitourinary Cancers: Integrating Molecular Imaging, Hypoxia-Inducible Factor-Targeted Therapies, and Antibody-Drug Conjugates in Renal Cell and Urothelial Carcinomas.” Our full disclosures are available in the transcript of this episode. And with that, Rana McKay, great to have you on the podcast today. Dr. Rana McKay: Oh, thank you so much, Dr. Barata. It's really wonderful to be here with you. So, thanks for hosting. Dr. Pedro Barata: No, thanks for taking the time, and I'm looking forward to this conversation. And by the way, let me start by saying congrats on a great article in the Educational Book. Really super helpful paper. I'm recommending it to a lot of the residents and fellows at my own institution. I would like to first ask you to kind of give our listeners some context of how novel approaches in the molecular imaging as well as targeted therapeutics are actually changing the way we're managing patients with GU, but specifically with renal cell carcinoma and urothelial carcinoma. So, what are the areas you would call out as like being big areas for innovation in this context, and why are they important? Dr. Rana McKay: Very good question. And I think this is really what this article highlights. It highlights where are we going from an imaging diagnostics standpoint? Where are we going from a therapeutic standpoint? And I think if we have to step back, from the standpoint of diagnostics, we've seen PET imaging really transform diagnostics in prostate cancer with the advent of PSMA PET imaging, and now PSMA PET imaging is used as a biomarker for selection for theranostics therapy. And so, we're starting to see that enter into the RCC landscape, enter into the urothelial cancer landscape to a lesser extent. And I think it's going to potentially be transformative as these tools get more refined. I think when we think about therapeutics, what's been transformative most recently in the renal cell carcinoma landscape has been the advent of HIF2α inhibition to improve outcomes for patients. And we have seen the approval of belzutifan most recently that has reshaped the landscape. And now there's other HIF2α inhibitors that are being developed that are going to be further important as they get refined. And lastly, I think when we think about urothelial carcinoma, the greatest transformation to treatment in that context has been the displacement of cisplatin and platinum-based chemotherapy as a frontline standard with the combination of enfortumab vedotin plus pembrolizumab. And we've seen antibody-drug conjugates really reshape treatment and tremendously improve outcomes for patients. So, I think those are the three key areas of interest. Dr. Pedro Barata: So with that, let's focus first on the imaging and then we'll get to the therapeutic area. So, we know there's been a paradigm shift, really, when prostate-specific targets emerged as tracers for PET scanning. And so, we now commonly use prostate-specific membrane antigen, or PSMA-based PET scanning, and really transform how we manage prostate cancer. Now, it appears that we're kind of seeing a similar wave in renal cell carcinoma with the new radiotracer against the target carbonic anhydrase IX. What can you tell us about this? And is this going to be available to us anytime soon? And how do you think that might potentially change the way we're managing patients with RCC today? Dr. Rana McKay: First, I'll step back and say that in the context of PSMA PET imaging, we have actually been able to better understand RCC as well. So, we know that PSMA is expressed in the neovasculature of tumors, and it can actually be used to detect renal cell carcinoma tumors. It has a detection rate of about 84% when used for detection. And so, you know, I don't think it's just restricted to carbonic anhydrase IX, but we will talk about that. So, PSMA expressed in the neovasculature has a detection rate of around 84%, particularly if we're looking at clear cell RCC. CAlX is overexpressed in clear cell RCC, and it's actually used in diagnosing renal cell carcinoma when we think of CAlX IHC for diagnosing clear cell RCC. And now there are CAlX PET tracers. The first foray was with the ZIRCON study that was actually an interestingly designed study because it was designed to detect the likelihood of PET imaging to identify clear cell RCC. So, it was actually used in the early diagnostics setting when somebody presents with a renal mass to discriminate that renal mass from a clear cell versus a non-clear cell, and it was a positive study. But when I think about the potential application for these agents, you know, I think about the entire landscape of renal cell carcinoma. This is a disease that we do treat with metastasis-directed therapy. We have certainly seen patients who've undergone metastasectomy have long, durable remissions from such an approach. And I think if we can detect very early onset oligometastatic disease where a metastasis-directed therapy or SABR could be introduced - obviously tested in a trial to demonstrate its efficacy - I think it could potentially be transformative. Dr. Pedro Barata: Wonderful. It's a great summary, and I should highlight you are involved in some of those ongoing studies testing the performance of this specific PET scanning for RCC against conventional imaging, right? And to remind the listeners, thus far, for the most part, we don't really do FDG-PET for RCC. There are some specific cases we do, but in general, they're not a standard scanning. But maybe that will change in the future. Maybe RCC will have their own PSMA-PET. And to your point, there's also emerging data about the role of PSMA-PET scanning in RCC as well, as you very elegantly summarized. Wonderful. So, let me shift gears a little bit because you did, in your introduction, you did highlight a novel MOA that we have in renal cell carcinoma, approved for use, initially for VHL disease, and after that for sporadic clear cell renal cell carcinoma. We're talking about hypoxia-inducible factor 2-alpha inhibitors, or HIF2α inhibitors, such as belzutifan. But there's also others coming up. So, as a way to kind of summarize that, what can you tell us about this breakthrough in terms of therapeutic class, this MOA that got to our toolbox of options for patients with advanced RCC? Tell us a little bit what is being utilized currently in the management of advanced RCC. And where do you see the future going, as far as, is it moving early on? Is it getting monotherapy versus combinations? Maybe other therapies? What are your thoughts about that? What can you tell us about it? Dr. Rana McKay: Belzutifan is a first-in-class HIF2α inhibitor that really established clinical validation for HIF2α as a therapeutic target. When we think about the activity of this agent, the pivotal LITESPARK-005 trial really led to the approval of belzutifan in patients who were really heavily pretreated. It was patients who had received prior IO therapy, patients who had received prior VEGF-targeted therapy. And in the context of this study, we saw a median PFS of 5.6 months, and there did seem to be a tail on the curve when you looked at the 12-month PFS rate with belzutifan. It was 33.7% compared to 17.6% with everolimus. And then when we look at the response rate, it was higher with belzutifan on the order of 22-23%, and very low with everolimus, as we've previously seen. I think one of the Achilles heels of this regimen is the primary PD rate, which was 34% when used in later line. There are multiple studies that are testing belzutifan in combination across the treatment landscape. So, we have LITESPARK-011, which is looking at the combination of belzutifan plus lenvatinib in the second-line setting. We've got the MK-012 [LITESPARK-012] study, which is looking at belzutifan in various combinations in the frontline setting. So there is a combination with IO plus belzutifan. And so this is also being looked at in that context. And then we also have the LITESPARK-022 study, which is looking at pembrolizumab with belzutifan in the adjuvant setting. So there's a series of studies that will be exploring belzutifan really across the treatment landscape. Many of these studies in combination. Additionally, there are other HIF2α inhibitors that are being developed. We have casdatifan, which is another very potent HIF2α inhibitor. You know, I think pharmacologically, these are different agents. There's a different half-life, different dosing. What is going to be the recommended phase 3 dose for both agents, the EPO suppression levels, the degree of EPO suppression, and sustainability of EPO suppression is very different. So, I think we've seen data from casdatifan from the ARC-20 trial from monotherapy with a respectable response rate, over 30%, primary PD rate hovering just around 10%. And then we've also seen data of the combination of casdatifan with cabozantinib as well that were recently presented this year. And that agent is also being tested across the spectrum of RCC. It's being looked at in combination with cabozantinib in the PEAK-1 study, and actually just at the KCRS (Kidney Cancer Research Summit), we saw the unveiling of the eVOLVE-RCC trial, which is going to be looking at a volrustomig, which is a PD-1/CTLA-4 inhibitor plus casdatifan compared to nivo-ipi in the frontline setting. So, we're going to see some competition in this space of the HIF2α inhibitors. I think when we think of mechanism of action in that these are very potent, not a lot of off-target activity, and they target a driver mutation in the disease. And that driver mutation happens very early in the pathogenesis. These are going to be positioned much earlier in the treatment landscape. Dr. Pedro Barata: All these studies, as you're saying, look really promising. And when we talk about them, you mentioned a lot of combinations. And to me, when I think of these agents, it makes a lot of sense to combine because there's not a lot of overlapping toxicities, if you will. But perhaps for some of our listeners, who have not used HIF2α inhibitors in practice yet, and they might be thinking about that, what can you tell us about the safety profile? How do you present it to your patients, and how do you handle things like hypoxia or anemia? How do you walk through the safety profile and tolerability profile of those agents like belzutifan? Dr. Rana McKay: I think these drugs are very different than your traditional TKIs, and they don't cause the classic symptoms that are associated with traditional TKIs that many of us are very familiar with like the rash, hand-foot syndrome, hypertension, diarrhea. And honestly, these are very nuanced symptoms that patients really struggle with the chronicity of being on a chronic daily TKI. The three key side effects that I warn patients about with HIF2α inhibitors are: (1) fatigue; (2) anemia; and (3) hypoxia and dysregulation in the ability to sense oxygen levels. And so, many of these side effects - actually, all of them - are very dose-dependent. They can be very well-managed. So, we can start off with the anemia. I think it's critically important before you even start somebody on belzutifan that you are optimizing their hemoglobin and bone marrow function. Make sure they don't have an underlying iron deficiency anemia. Make sure they don't have B12 or folate deficiency. Check for these parameters. Many patients who have kidney cancer may have some hematuria, other things where there could be some low-level blood loss. So, make sure that those are resolved or you're at least addressing them and supplementing people appropriately. I monitor anemia very closely every 3 to 4 weeks, at least, when people start on these medications. And I do initiate EPO, erythropoietin, should the anemia start to worsen. And I typically use a threshold of around 10g/dL for implementing utilization of an EPO agent, and that's been done very safely in the context of the early studies and phase 3 studies as well. Now, with regards to the hypoxia, I think it's also important to make sure that you're selecting the appropriate individual for this treatment. People who have underlying COPD, or even those individuals who have just a very high burden of disease in their lung, lymphangitic spread, pleural effusions, maybe they're already on oxygen - that's not an ideal candidate for belzutifan. Something that very easily can be done in the clinic before you think about initiating somebody on this treatment, and has certainly been integrated into some of the trials, is just a 6-minute walk test. You know, have the patient walk around the clinic with one of the MAs, one of the nurses, put the O2 sat on [measuring oxygen saturation], make sure they're doing okay. But these side effects, like I said, are very dose-dependent. Typically, if a patient requires, if the symptoms are severe, the therapy can be discontinued and dose reduced. The standing dose is 120 mg daily, and there's two dose reductions to 80 mg and 40 mg should somebody warrant that dose modification. Dr. Pedro Barata: This is relatively new, right? Like, it was not that we're used to checking oxygen levels, right? In general, we're treating these patients, so I certainly think there's a learning curve there, and some of the points that you highlight are truly critical. And I do share many of those as well in our practice. Since I have you, I want to make sure we touch base on antibody-drug conjugates as well. It's also been a hot area, a lot of developments there. When I think of urothelial carcinoma and renal cell carcinoma, I see it a little bit different. I think perhaps in urothelial carcinoma, antibody-drug conjugates, or ADCs, are somewhat established already. You already mentioned enfortumab vedotin. I might ask you to expand a little bit on that. And then in renal cell carcinoma, we have some ADCs as well that you include in your chapter, and that I would like you to tell us what's coming from that perspective. So, tell us a little bit about how do you see ADCs in general for GU tumors, particularly UC and RCC? Tell us a little bit about the complexity or perhaps the challenges you still see. At the same time, tell us about the successes. Dr. Rana McKay: Stepping back, let's just talk about like the principles and design of ADCs. So, most ADCs have three components. There's a monoclonal antibody that typically targets a cell surface antigen, which is conjugated by a linker, which is the second component, to a payload drug. And typically, that payload drug has been chemotherapy, whether it be topoisomerase or whether it be MMAE or other chemotherapeutic. We can start in the RCC space. There's been multiple antibody-drug conjugates that have been tested. There's antibody-drug conjugates to CD70, which is expressed on clear cell RCC. There's been antibody-drug conjugates to ENPP3, which is also expressed on RCC. There's antibody-drug conjugates to CDH6. And they have different payloads, like I said, whether it be topoisomerase I or other microtubule inhibitors. Now, when we think about kidney cancer, we don't treat this disease with chemotherapy. This disease is treated with immunotherapy. It is treated with treatments that target the VEGF pathway and historically has not been sensitive to chemo. So, I think even though the targets have been very exciting, we've seen very underwhelming data regarding activity, and in some context, seen increased toxicity with the ADCs. So, I think we need to tread lightly in the context of the integration and the testing of ADCs in RCC. We just came back from the KCRS meeting, and there was some very intriguing data about a c-Kit ADC that's being developed for chromophobe RCC, which is, you know, a huge unmet need, these variant tumors that really lack appropriate therapeutics. But I just caution us to tread lightly around how can we optimize the payload to make sure that the tumor that we're treating is actually sensitive to the agent that's targeting the cell kill. So, that's a little bit on the ADCs in RCC. I still think we have a long way to go and still in early testing. Now, ADCs for UC are now the standard of care. I think the prototypical agent, enfortumab vedotin, is a nectin-4-directed ADC that's conjugated to an MMAE payload and was the first ADC approved for advanced urothelial, received accelerated approval following the EV-201 trial, which was basically a multicenter, single-arm study that was investigating EV in cisplatin-ineligible patients with advanced urothelial carcinoma, and then ultimately confirmed in the EV-301 study as well. And so, that study ended up demonstrating the support superiority of EV from an overall survival standpoint, even PFS standpoint. Building on that backbone is the EV-302 study, which tested EV in combination with pembrolizumab versus platinum-based chemotherapy in the frontline setting. And that was a pivotal, landmark study that, like I said, has displaced platinum therapy as a frontline treatment for people with advanced urothelial carcinoma. And when we think about that study and the median overall survival and just how far we've come in urothelial cancer, the median OS with EV-pembro from that trial was 31 and a half months. I mean, that's just incredible. The control arm survival was 16 and a half months. The hazard ratio for OS, 0.47. I mean this is why when this data was presented, it was literally a standing ovation that lasted for several minutes because we just haven't seen data that have looked that good. And there are other antibody-drug conjugates that are being tested. We've all been involved in the saga with sacituzumab govitecan, which is a trophoblast cell surface antigen 2 (Trop-2) targeted ADC with a topoisomerase I payload. It was the second ADC to receive approval, but then that approval was subsequently withdrawn when the confirmatory phase 3 was negative, the TROPiCS-04 trial. So, approval was granted based off of the TROPHY-U-01, single-arm, phase 2 study, demonstrating a response rate of around 28% and a PFS of, you know, about 5 and a half months. But then failure to show any benefit from an OS standpoint. And I think there's a lot of controversy in the field around whether this agent still has a role in advanced urothelial carcinoma. And I think particularly for individuals who do not have molecular targets, like they're not HER2-amplified or have HER2-positivity or FGFR or other things like that. Dr. Pedro Barata: Fantastic summary, Rana. You were talking about the EV, and it came to mind that it might not be over, right, for the number of ADCs we use in clinical practice in the near future. I mean, we've seen very promising data for ADC against the HER2, right, and over-expression. It also can create some challenges, right, in the clinics because we're asking to test for HER2 expression. It's almost like, it's not exactly the same to do it in breast cancer, but it looks one more time that we're a little bit behind the breast cancer field in a lot of angles. And also has vedotin as a payload. Of course, I'm referring to disitamab vedotin, and there's very elegant data described by you in your review chapter as well. And it's going to be very interesting to see how we sequence the different ADCs, to your point as well. So, before we wrap it up, I just want to give you the opportunity to tell us if there's any area that we have not touched, any take-home points you'd like to bring up for our listeners before we call it a day. Dr. Rana McKay: Thank you so much. I have to say, you know, I was so excited at ASCO this year looking at the GU program. It was fantastic to see the progress being made, novel therapeutics that really there's a tremendous excitement about, not just in RCC and in UC, but also in prostate cancer, thinking about the integration of therapies, not just for people with refractory disease that, even though our goal is to improve survival, our likelihood of cure is low, but also thinking about how do we integrate these therapies early in the treatment landscape to enhance cure rates for patients, which is just really spectacular. We're seeing many of these agents move into the perioperative setting or in combination with radiation for localized disease. And then the special symposium on biomarkers, I mean, we've really come a long, long way. And I think that we're going to continue to evolve over the next several years. I'm super excited about where the field is going in the treatment of genitourinary malignancies. Dr. Pedro Barata: Oh, absolutely true. And I would say within the Annual Meeting, we have outstanding Educational Sessions. And just a reminder to the listeners that actually that's where the different teams or topics for the Educational Book chapters come from, from actually the educational sessions from ASCO. And your fantastic chapter is an example of that, right, focusing on advanced GU tumors. So, thank you so much, Rana, for taking the time, sharing your insights with us today on the podcast. It was a fantastic conversation as always. Dr. Rana McKay: My pleasure. Thanks so much for having me, Dr. Barata. Dr. Pedro Barata: Of course. And thank you to our listeners for your time today. You will find the link to the article discussed today in the transcript of this episode. I also encourage you to check out the 2025 ASCO Educational Book. You'll find an incredible wealth of information there. It's free, available online, and you'll find, hopefully, super, super important information on the key science and issues that are shaping modern oncology, as we've heard from Dr. McKay and many other outstanding authors. So, thank you, everyone, and I hope to see you soon. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today's speakers: Dr. Pedro Barata @PBarataMD Dr. Rana McKay @DrRanaMcKay Follow ASCO on social media: @ASCO on X (formerly Twitter) ASCO on Bluesky ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Pedro Barata: Stock and Other Ownership Interests: Luminate Medical Honoraria: UroToday Consulting or Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, AVEO, Merck, Ipson, Astellas Medivation, Novartis, Dendreon Speakers' Bureau: AstraZeneca, Merck, Caris Life Sciences, Bayer, Pfizer/Astellas Research Funding (Inst.): Exelixis, Blue Earth, AVEO, Pfizer, Merck Dr. Rana McKay: Consulting or Advisory Role: Janssen, Novartis, Tempus, Pfizer, Astellas Medivation, Dendreon, Bayer, Sanofi, Vividion, Calithera, Caris Life Sciences, Sorrento Therapeutics, AVEO, Seattle Genetics, Telix, Eli Lilly, Blue Earth Diagnostics, Ambrx, Sumitomo Pharma Oncology, Esiai, NeoMorph, Arcus Biosciences, Daiichi Sankyo, Exelixis, Bristol Myers Squibb, Merck, Astrazeneca, Myovant Research Funding (Inst.): Bayer, Tempus, AstraZeneca, Exelixis, Bristol Myers Squibb, Oncternal Therapeutics, Artera
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
A new clinical trial at the James is pioneering the use of telemedicine to create better treatment options for patients with a rare form of pancreatic cancer. “This is the first nationwide telemedicine therapeutic clinical trial for cancer,” said Sameek Roychowdhury, MD, PhD, a physician scientist and leader in creating innovative ways to look at, understand and treat cancer. “It's a new way of thinking and providing access to clinical trials.” Roychowdhury and his team at the James identified the fibroblast growth factor receptor (FGFR) gene and how “using a smart drug we could turn it off and slow the cancer growth” it caused. A traditional clinical trial using the smart drug showed promising results in patients with pancreatic cancer and the FGFR gene. Because this was a rare type of cancer, a national clinical trial would be costly. “How do we give patients access to this?” Roychowdhury said. The answer came during the COVID pandemic and the increased use of telemedicine. “That allowed us to connect the dots and utilize telemedicine,” he said. After a lengthy regulatory and approval process that created a well-thought out and workable plan, the clinical trial began in May. Patients identified with pancreatic cancer and the FGFR gene will be able to remain at home and coordinate their treatment with their local oncologists and Roychowdhury and his team, who will work in tandem. “Instead of a clinical trial in 50 locations and a $20 million price tag, we've reduced the cost to $2 million,” he said. Roychowdhury believes this clinical trial will lead to others for rare cancers and make it more cost effective for pharmaceutical companies to create smart drugs for rare forms of cancer. He is working to create a national alliance of oncologists to share ideas, best practices and create more telemedicine clinical trials for rare types of cancers that would otherwise never be opened. “We have identified seven more targets and clinical trials [here at the James],” Roychowdhury said.
CME credits: 0.25 Valid until: 23-05-2026 Claim your CME credit at https://reachmd.com/programs/cme/expert-perspectives-from-aua-2025-contextualizing-the-evolving-landscape-of-bladder-cancer/33076/ This online CME program features expert discussions on new research presented at AUA 2025. Drs. Neal Shore and Sarah Psutka explore emerging data on treatment strategies for high-risk BCG-naïve and BCG-unresponsive non–muscle invasive bladder cancer (NMIBC). They also highlight advances in biomarker-directed therapies, including investigational agents targeting HER2 and FGFR alterations. The program emphasizes the clinical relevance and practical application of these findings, offering clinicians actionable insights on evolving bladder cancer care.=
This series of video briefs features Dr. Neal Shore reporting from AUA 2025 in Las Vegas. Tune in for timely updates on innovatively delivered intravesical therapies for non–muscle invasive bladder cancer (NMIBC). Dr. Shore presents key findings from the SunRISe-1 trial, highlighting 1-year durability and patient-reported outcomes data in BCG-unresponsive high-risk NMIBC. He also covers the first results from cohort 4 of SunRISe-1, with a focus on papillary disease-only patients, along with the study design of the phase 3 MoonRISe-3 trial in patients with BCG-treated high-risk NMIBC and FGFR alterations. Each brief distills the clinical relevance of these studies and their potential impact on future NMIBC treatment strategies.
This series of video briefs features Dr. Neal Shore reporting from AUA 2025 in Las Vegas. Tune in for timely updates on innovatively delivered intravesical therapies for non–muscle invasive bladder cancer (NMIBC). Dr. Shore presents key findings from the SunRISe-1 trial, highlighting 1-year durability and patient-reported outcomes data in BCG-unresponsive high-risk NMIBC. He also covers the first results from cohort 4 of SunRISe-1, with a focus on papillary disease-only patients, along with the study design of the phase 3 MoonRISe-3 trial in patients with BCG-treated high-risk NMIBC and FGFR alterations. Each brief distills the clinical relevance of these studies and their potential impact on future NMIBC treatment strategies.
This series of video briefs features Dr. Neal Shore reporting from AUA 2025 in Las Vegas. Tune in for timely updates on innovatively delivered intravesical therapies for non–muscle invasive bladder cancer (NMIBC). Dr. Shore presents key findings from the SunRISe-1 trial, highlighting 1-year durability and patient-reported outcomes data in BCG-unresponsive high-risk NMIBC. He also covers the first results from cohort 4 of SunRISe-1, with a focus on papillary disease-only patients, along with the study design of the phase 3 MoonRISe-3 trial in patients with BCG-treated high-risk NMIBC and FGFR alterations. Each brief distills the clinical relevance of these studies and their potential impact on future NMIBC treatment strategies.
This series of video briefs features Dr. Neal Shore reporting from AUA 2025 in Las Vegas. Tune in for timely updates on innovatively delivered intravesical therapies for non–muscle invasive bladder cancer (NMIBC). Dr. Shore presents key findings from the SunRISe-1 trial, highlighting 1-year durability and patient-reported outcomes data in BCG-unresponsive high-risk NMIBC. He also covers the first results from cohort 4 of SunRISe-1, with a focus on papillary disease-only patients, along with the study design of the phase 3 MoonRISe-3 trial in patients with BCG-treated high-risk NMIBC and FGFR alterations. Each brief distills the clinical relevance of these studies and their potential impact on future NMIBC treatment strategies.
Welcome to the Oncology Brothers podcast! In this episode, Drs. Rohit and Rahul Gosain are joined by Dr. Ghassan Abou-Alfa, a medical oncologist specializing in the hepatobiliary space at Memorial Sloan Kettering. Together, they explored the current treatment landscape of biliary tract cancer, focusing on the advancements in HER2-driven therapies. Key topics discussed included: • The evolution of treatment options for biliary tract cancer, including chemotherapy and immunotherapy. • The significance of genetic testing, including IDH1 mutations, FGFR alterations, and HER2 status. • The role of multidisciplinary collaboration in managing hepatobiliary cancers. • Insights into the latest clinical trials and emerging therapies for HER2-positive biliary tract cancer. Join us as we delve into the complexities of biliary tract cancer and the promising developments in HER2-targeted treatments. Don't forget to check out our next episode, where we will take a deeper dive into the data surrounding HER2 therapies and discuss management strategies for common side effects. YouTube: https://youtu.be/pGiU7JJGNOc Follow us on social media: • X/Twitter: https://twitter.com/oncbrothers • Instagram: https://www.instagram.com/oncbrothers • Website: https://oncbrothers.com/ Subscribe to stay updated on the latest in oncology! #OncologyBrothers #BiliaryTractCancer #HER2 #CancerTreatment #MedicalOncology #CME #Podcast
The fibroblast growth factor receptor-3 (FGFR-3) inhibitor TYRA-300 has been found safe with dose-dependent responses and disease control in the Phase I SURF301 trial. The study included 41 patients who had been heavily pre-treated for their advanced solid tumors with activating FGFR3 mutations/fusions, bringing the hope of avoiding toxicities from the use of non-specific pan-FGFR inhibition. The findings were reported by Ben Tran, MBBS, FRACP, at the 2024 EORTC-NCI-AACR 2024 Molecular Targets and Cancer Therapeutics Symposium held in Barcelona, Spain. Tran is a Medical Oncologist and Associate Professor at the Peter MacCallum Cancer Centre Melbourne, Australia. He also is Chair of the Germ Cell Tumour Subcommittee for the Australian and New Zealand Urological and Prostate Cancer Trials.
JCO PO author Dr. Alok A. Khorana, MD, FASCO, Professor of Medicine, Cleveland Clinic and Case Comprehensive Cancer Center, shares insights into the JCO PO article, “Molecular Differences With Therapeutic Implications in Early-Onset Compared With Average-Onset Biliary Tract Cancers.” Host Dr. Rafeh Naqash and Dr. Khorana discuss how multiomic analysis shows higher FGFR2 fusions and immunotherapy marker variations in early-onset biliary cancer. TRANSCRIPT Dr. Rafeh Naqash: Hello, and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO POarticles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today, we are joined by Dr. Alok A. Khorana, Professor of Medicine at the Cleveland Clinic and Case Comprehensive Cancer Center, and also the Senior Author of the JCO Precision Oncology article titled, “Molecular Differences With Therapeutic Implications in Early-Onset Compared With Average-Onset Biliary Tract Cancers.” At the time of this recording, our guest disclosures will be linked in the transcript. Dr. Khorana, it's an absolute pleasure to have you here today, and welcome to the podcast. Dr. Alok A. Khorana: Thank you. It's an absolute pleasure to be here and thank you for highlighting this article. Dr. Rafeh Naqash: Absolutely. We're going to talk about science, obviously, and a few other things. So to start off, for the sake of our audience, which comprises academicians and community oncologists as well as trainees, can you tell us a little bit about biliary tract cancers, what we have learned over the last decade or so, where the standard of treatment currently lies. And then we can dive into the article that you published. Dr. Alok A. Khorana: As many of you who treat GI cancers know, biliary tract cancers for a long period of time were sort of the orphan cancer in the GI cancer world. They're not nearly as common as, say, pancreatic cancer, and certainly not as common as colorectal cancer. They're sort of also, in this weird ‘no man's land' between well known sort of adjuvant therapy trials in pancreatic cancer or colorectal cancer, but because they're not as high in volume, there weren't really large trials done in this population. What's really changed in the past decade, especially, has been the slow but sure realization that biliary tract cancers are in fact a target rich cancer, almost similar to what you would see with lung cancer, and that's only a slight exaggeration. And in some studies, as many as up to 40% of patients with biliary tract cancers can have something that's targetable. And that's really revolutionized the way we think of biliary tract cancers. It also separated this field from pancreatic cancer where formerly the two used to be lumped together, and even within biliary tract cancers, we are now slowly realizing that there are differences between intrahepatic, extrahepatic and gallbladder cancers. Big change is really afoot in this field, particularly with the identification of mutation directed targets. Dr. Rafeh Naqash: Thank you for that explanation. Now, another question I have is, although I don't see any GI cancers, but I have good colleagues of mine at our cancer center who see a lot of GI pancreatic/biliary cancers, and one of the things that comes up in our molecular tumor board often is how certain cancers of unknown primary end up being identified or categorized as biliary tract cancers based on NGS. And again, the uptake for these NGS is perhaps isn't optimal in the field yet, but in your practice, how do you approach situations like that? Do you use NGS in certain cases where the tissue of origin or the patterns of the mutations indicate that this might be biliary tract cancer and then treat the patient accordingly? Dr. Alok A. Khorana: Yeah, that's true. And that's certainly how I approach things, and I would say even in my own personal practice, that has been a change. I was a little bit skeptical about the benefit of sort of tissue of origin type of testing in carcinoma of unknown, primarily, especially if you can sort of narrow it down to one or other area of the GI tract. But with the identification of sort of targeted subpopulations, especially of biliary tract cancer, I think it's become imperative. And I know we're going to get into the paper, but if you want to learn nothing else from this 20, 25 minute podcast, one lesson I just want to make sure everybody gets is that any patient with biliary tract cancer should have NGS done as soon as possible. Dr. Rafeh Naqash: Thank you for highlighting that important aspect. Now, going to the topic at hand, what was the driving factor? I've heard a lot about colorectal cancers, early onset versus later onset. What was the reason that you looked at biliary tract cancers? Is that something that you've seen on a rise as far as early onset biliary tract cancers is concerned? Dr. Alok A. Khorana: Yeah. So we got into this subject also from starting out at colorectal cancer. And as you know, and I'm sure most of your audience knows, there's been a lot of literature out there over the past five, six, seven years suggesting and then documenting and then sort of proving and reproving that colorectal cancer is on the rise, and especially in people younger than age 50. And even in that population, it's on the rise in two different subpopulations, people in their 20s and 30s and then people in their 40s that are close to the screening colonoscopy rates. That's been investigated heavily. We still don't fully understand why that's happening, but it's not restricted to the United States. It's a worldwide phenomenon. You can see it in the United States, in North America. You can see it in western Europe, but you can also see it in many Asian countries with specific sort of subpopulations. For instance, in some countries, men are more likely to have early onset cancers. And then a newer finding that sort of emerged over the past couple of years is that this early onset increase in cancers is not just restricted to colorectal cancer, although that's the one that sticks out the most, but in fact, is widespread across a bunch of different types of cancers. In my own research program, we had gotten into a sort of better understanding of early onset colorectal cancer a couple of years ago, driven primarily by the sort of patients that I saw in my practice. And it's just, as you know, when you have a couple of those heartbreaking cases and they're just impossible to forget, and it sort of just drives your attention, and then you want to do something to help them. And if you can't help them personally, then you want to do something that can change the field so that more of these patients are not coming in your clinic next year or the year after. So a couple years ago, at the Cleveland Clinic where I practice, we created a center for young onset cancers, and at the time it was primarily focused on colorectal cancer. But as we are getting into colorectal cancer, we realize that beyond colorectal cancer, we are also starting to see more younger people with other cancers, including pancreas cancer, including gastric cancer, and including bile duct cancers. And we realized that because so much attention was being focused on colorectal, that maybe we should also be paying a little bit of attention to what was happening in this space. I want to, for your listeners, point out that the problem in bile duct cancers is not to the same degree as you see in colorectal cancer. Just a couple numbers to sort of, to set this in perspective: about 5%, 7% of bile duct cancers are young onset - it's not a huge proportion - 90%+ percent of patients are not young onset. But the impact on society, the impacts on those providing care, is obviously substantial for younger patients. And it is true that even though the proportion of patients is not that high, the incidence is rising. And there's a very nice study done a couple of years ago and published that looked at what the cancers are that are rising at the highest rates. And bile duct cancer and gallbladder cancers were listed amongst the two with the highest rate, so about an 8% rate per year of increase. And so that's really what drove our interest was, as we're seeing early onset bile duct cancers, it's rising year by year, and what is this disease? Is it the same as you see in sort of the average patient with bile duct cancer? Is it different? How do we characterize it? How do we understand it? What are some of the causes precipitating it? And so that's what led us to sort of one of the investigations that we've documented in this paper. Dr. Rafeh Naqash: Excellent. So, talking about this paper, again, can you describe the kind of data that you use to understand the molecular differences and also look at potential immune signatures, etc., differences between the groups? Dr. Alok A. Khorana: Yeah. So the objective in this paper was to look at genomic differences between early onset and usual onset, or average onset biliary tract cancers. And this sort of followed the paradigm that's already been established for early onset colorectal cancer, where you take a bunch of people with early onset disease, a bunch of patients with average onset or usual onset disease, and then look at the profiling of the tumors. And we've done this for genomics, we've done this for microbiomics, we've done it for metabolomics. And the lessons we've learned in colorectal cancer is that, in many ways, the profiles are actually quite substantially different. And you can almost think of them as diseases of the same organ, but caused by different processes, and therefore leading to different genotypes and phenotypes and microbiomes. We had absorbed that lesson from colorectal cancer, and we wanted to replicate it in this type of cancer. But as we discussed earlier, this is a relatively rare cancer, not that many cases per year. For colorectal, we could do a single institution or two institution studies. But for this, we realized we needed to reach out to a source of data that would have access to large national data sets. We were happy to collaborate with Caris Life Sciences. Caris, many of you might know, is a provider of genomics data, like many other companies, and they house this data, and they had the age categorization of patients less than 50, more than 50. And so we collaborated with investigators at Caris to look at all the specimens that had come in of bile duct cancers, identified some that were young onset and some that were older onset. It was roughly about 450 patients with the early onset or young onset, and about 5000 patients with usual onset cases. And then we looked at the genomics profiling of these patients. We looked at NGS, whole exome sequencing, whole transcriptome sequencing, and some immunohistochemistry for usual, like PDL-1 and MSI High and things like that. And the purpose was to say, are there differences in molecular profiling of the younger patient versus the older patient? And the short answer is yes, we did find substantial differences, and very crucial for providers treating these patients is that we found a much higher prevalence of FGFR2 fusion. And that's important because, as I'm sure you've heard, there's a ton of new drugs coming out that are targeting specifically FGFR fusion in this and other populations. And hence my statement at the outset saying you've got to get NGS on everybody, because especially younger patients seem to have higher rates of some of these mutations. Dr. Rafeh Naqash: Excellent. You also looked at the transcriptome, and from what I recollect, you identified that later onset tumors had perhaps more immune favorable tumor microenvironment than the early onset. But on the contrary, you did find that FGFR2 early onset had better survival. So how do you connect the two? Is there an FGFR link, or is there an immune signature link within the FGFR cohort for early onset that could explain the differences? Dr. Alok A. Khorana: Yeah, that's a great question. So, to kind of summarize a couple of these things you talked about. So, one is we looked at these genomic alterations, and, yes, FGFR2 fusion was much more prevalent. It's close to 16% of young onset patients, as opposed to roughly 6% of average onset patients. So almost a threefold increase in FGFR fusion. And because there's so many drugs that are targeting FGFR fusion, and because the population included a period of time when these drugs had already been approved, we think some of the benefit or the improvement in median survival associated with being younger is likely driven by having more FGFR fusion and therefore having more drugs available to treat FGFR fusion related tract cancer with corresponding increase and increase in survival. And that was part of it. There was one other alteration, NIPBL fusion, that's been sort of known to be associated with a certain subtype of cholangiocarcinoma, but it doesn't really have a drug that targets it, so it's not sort of very useful from a clinical perspective. The other two things you talked about, so transcriptome and immuno oncology markers, we found a couple different results on this. So one is that we found in younger people, angiogenesis was enriched, and why this is so we don't quite have a good answer for that. The other was inflammatory responses. So there's a couple of gamma interferon pathways and a couple other types of pathways that you can sort of do pathway analysis, and we found that those were enriched in the older patients or the average onset patients. But the benefit for immunotherapy was similar across the two groups. So even though we saw these differences in signaling in terms of which pathways are upregulated or downregulated, it didn't seem to translate into the current generation of immune checkpoint inhibitors that we're using in terms of benefit for patients. But we did see those differences. Dr. Rafeh Naqash: I completely agree, Doctor Khorana. As you mentioned, that one size fits all approach does not necessarily work towards a better, optimal, personalized treatment stratification. So, as we do more and more sequencing and testing for individuals, whether it's early onset cancers or later onset cancers, figuring out what is enriched and which subtype, I think, makes the most sense. Now, going to the FGFR2 story, as you and most listeners probably already know, FGFR is an approved target, and there are a band of FGFR inhibitors, and there's some interest towards developing specific FGFR2, 3 fusion inhibitors. What has your experience with FGFR inhibitors in the clinic been so far? And what are you personally excited about from an FGFR standpoint, in the drug development space for GI cancers? Dr. Alok A. Khorana: Yeah, I think the whole FGFR fusion story sort of actually deserves more excitement than it's gotten, and it may be because, as I mentioned earlier, biliary tract cancers are a relatively low volume type of cancer. But the results that we are seeing in the clinic are very impressive. And the results that we are anticipating, based on some ongoing phase two and phase three trials, appear to be even more impressive for the very specific inhibitors that are about to hopefully come out soon. Also, the possibility of using successive lines of FGFR inhibitors - if one fails, you try a second one; if the second one fails, you try a third one because the mechanisms are subtly different - I think it will take a little while to figure out the exact sequencing and also the sort of the rates of response in people who might previously have been exposed to an FGFR inhibitor. So that data may not be readily available, because right now most patients are going in for longer trials. But having that type of possibility, I think, kind of reminds me of the excitement around CML back when imatinib suddenly became not the only drug and a bunch of other drugs came out, and it's kind of like that. I think again, it's not a very common cancer, but it's really wonderful to see so many options and more options along the way for our patients. Dr. Rafeh Naqash: Thank you. Now, going to your personal story, which is the second part of this conversation, which I think personally, for me, is always very exciting when I try to ask people about their personal journeys. For the sake of the listeners, I can say that when I was a trainee, I used to hear about Dr. Khorana's course, I always thought that Dr. Alok Khorana was a hematologist. My friends corrected me a few years back and said that you're a GI oncologist. Can you tell us about your love for GI oncology and the intersection with hematology thrombosis, which you have had a successful career in also? Can you explain how that came about a little bit? Dr. Alok A. Khorana: Yeah, sure. So it is a common, I guess I shouldn't say misperception, but it's certainly a common perception that I'm a hematologist. But I'll sort of state for the record that I never boarded in hematology. I did do a combined hem-onc fellowship, but only boarded in oncology. So I'm actually not even boarded in hematology. My interest in thrombosis came about- it's one of those things that sort of happen when you're starting out in your career, and things align together in ways that you don't sort of fully understand at the time. And then suddenly, 10 years later, you have sort of a career in this. But it actually came about because of the intersection of, at the time, angiogenesis and coagulation. And this is the late ‘90s, early two ‘00s, there was a lot of buzz around the fact that many of the factors that are important for coagulation are also pro angiogenic and many factors that are coagulation inhibitors. These are naturally occurring molecules in your body, and can be anticoagulant and anti angiogenic. A great example of this is tissue factor, which is, as you'll remember from the coagulation pathways, the number one molecule that starts off the whole process. But less widely appreciated is the fact that nearly every malignancy expresses tissue factor on its cell surface. This includes breast cancer, it includes leukemia cells, it includes pancreatic cancer. In some cancers, like pancreatic cancer, we've even shown that you can detect it in the blood circulation. And so for me, as a GI oncologist who was seeing a lot of patients get blood clots, it was particularly fascinating to sort of see this intersection and try and understand what is this interaction between the coagulation and angiogenic cascades that's so vital for cancers. Why is coagulation always upregulated in cancer patients? Not all of them get blood clots, but subclinical activation of coagulation always exists. So I would say I was fascinated by it as an intellectual question and really approached it from an oncology perspective and not a hematology perspective. But then as I got deeper into it, I realized not everybody's getting blood clots, and how can I better predict which patients will get blood clots. And so I had both a hematology mentor, Charlie Francis, and an oncology mentor, Gary Lyman. And using sort of both their expertise, I drafted a K23 career development award specifically to identify predictors of blood clots in cancer patients. And that's the multivariate model that later became known as the Khorana Score. So again, I approach it from an oncology perspective, not a hematology perspective, but really a fascinating and still, I would say an understudied subject is why are cancer patients having so many clotting problems? And what does it say about the way cancer develops biologically that requires activation of the coagulation system across all of these different cancers? And I think we still don't fully understand the breadth of that. Dr. Rafeh Naqash: Very intriguing how you connected two and two and made it a unique success story. And I completely agree with you on the tissue factor. Now there's ADCs antibody drug conjugates that target tissue factor, both a prude as well as upcoming. Now, the second part of my question is on your personal journey, and I know you've talked about it on social media previously, at least I've seen it on social media, about your interactions with your uncle, Dr. Har Gobind Khorana, who was a Nobel Prize winner in medicine and physiology for his work on DNA. Could you tell us about how that perhaps shaped some of your personal journey and then how you continued, and then also some personal advice for junior faculty trainees as they proceed towards a successful career of their own? Dr. Alok A. Khorana: Yeah, thank you for bringing that up. So very briefly, this is about my uncle. He's actually my great uncle. So he's my grandfather's youngest brother. And I grew up in India in the ‘70s and ‘80s, and at the time, I ran away from this association as fast as I could, because growing up in India in the 70s and ‘80s, it was a socialist economy. There wasn't a lot going on. There was certainly none of the IT industry and all of everything that you see right now. And so there were very few icons, and my great uncle was definitely one of those few icons. As soon as you mentioned your last name, that would sort of be the first question people would ask. But he did serve as a role model, I think, both to my father, who was also a physician scientist and a professor of medicine, and then to myself in sort of making me realize, one, that you can't really separate medicine from science. I think those are really integrated, and we want to ask questions and answer questions in a scientific manner. He chose to do it in a basic science world. My father did it in a clinical science world, and I have done it in a clinical and a translational science world. Again, sort of using science as the underpinning for sort of understanding diseases, I think, is key. And so that was certainly a massive inspiration to me. And then after I immigrated to the US in the late ‘90s, I met him on a regular basis. He was certainly very inspirational in his successes, and I realized the breadth of what he had done, which I did not realize in my youth growing up. But this is a person who came to the US. This was before Asian immigration was even legal. So he got here and they had to pass a special bill in Congress to let him be a citizen that was based on the sort of work that he had done in Canada and in the UK before he came here. And then he sets up shop in the University of Wisconsin in Madison and hires tons of these postdocs and essentially converted his lab into this massive factory, trying to figure out the genetic code. Really just the type of dedication that that needs and the amount of work that that needs and the ability to do that in a setting far removed from where he grew up, I think it's just really quite mind boggling. And then he didn't stop there. He got the Nobel for that, but I have these letters that he wrote after he got the Nobel Prize, and he was just completely obsessed with the possibility that getting the Nobel would make him sort of lose his mojo and he wouldn't be as focused on the next aspects of science. And he was just really dedicated to synthesizing DNA in the lab, so creating artificial DNA, which he ended up doing. And the offshoot of that work, so not just the genetic code, but PCR essentially was developed by his lab before it became sort of what we now know as PCR. And then ditches all of that in the ‘80s and ‘90s and moves to understanding the retina and just focuses on retinal disorders. And then signal transduction, essentially trying to figure out when a single photon of light hits your eye, what happens biologically. It's a completely different field. And just took that on and spent the next 20,30 years of his life doing that. So the ability to sort of change fields, I thought that was very inspirational as well, that you don't have to just stick to one question. You can get into one question, answer it as much as possible, and then find something else that's really interesting to you and that really grabs your attention, and then stick with that for the next couple of decades. So lots to learn there. Dr. Rafeh Naqash: Thank you. Thank you. And then, based on some of your personal lessons, what's your advice for junior faculty and trainees as you've progressed in your career? Dr. Alok A. Khorana: I think, number one, and I can't emphasize this enough, and sometimes it actually causes a little bit of anxiety, but it is finding the right mentor. And for me, certainly that was key, because my mentor, who was Charlie Francis, was not an oncologist who was a hematologist, but was like me, sort of supported this idea of trying to understand, hey, why does coagulation interact with cancer? And so he approached it from a hematology perspective, I approached it from a cancer perspective, but he sort of gave me the freedom to ask those questions in his lab and then later on in the clinical setting and clinical translational setting, and then got me access to other people who are experts in the field and introducing you and then getting you on committees and making sure you sort of get into clinical trials and so on. And so having a mentor who sort of supports you but doesn't stifle you, and that's really key because you don't want to just ask the question that the mentor is interested in. And as a mentor now, I don't want to have my mentee ask the question that I'm interested in, but also a question that the mentee is interested in. And so there's a little bit of a chemistry there that's not always replicable, and it can go wrong in sort of five different ways, but when it goes right, it's really vital. And I mentioned it causes anxiety because, of course, not every day is great with your mentor or with your mentee, but over a period of time, has this person done sort of their best to get your career off to a start? And have you served that mentor well by doing the things that are– there's responsibilities on both sides, on both on the mentor and on the mentee. And if you can find that relationship where there's a little bit of chemistry there and both of you are effectively discharging both your responsibilities and satisfying your intellectual curiosity, I think that can't be beat, honestly. To me, sort of number one is that and everything else follows from that. So, the networking, making sure your time is sort of allocated appropriately, fighting with sort of the higher ups to make sure that you're not having to do too much, things that are sort of away from your research interests, all of that sort of flows from having the right person. Dr. Rafeh Naqash: Couldn't agree with you more, Dr. Khorana, thank you so much. It was an absolute pleasure. Thank you for sharing with us the science, the personal as well as the professional journey that you had. And hopefully, when you have the next Khorana Score, Khorana score 2.0, JCO Precision Oncology will become the home for that paper and we'll try to have you again maybe in the near future. Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast. Thank you so much. 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. Disclosures: Dr. Khorana - Honoraria Company: Pfizer, Bayer, Anthos, Sanofi, BMS, WebMD/MedscapeConsulting or Advisory Role Company: Janssen, Bayer, Anthos, Pfizer, Sanofi, BMS Research Funding Company: Anthos, Bristol-Myers, Squibb Travel, Accommodations, Expenses Company: Janssen, Bayer, Bristol-Myers Squibb
From wound healing to cell growth to bone formation, fibroblast growth factors (FGF) and fibroblast growth factor receptors (FGFR) are responsible for a diverse range of biological processes. This episode begins with the basics: the functions of FGFs and FGFRs. We will then move on to an indepth dive into the structure of FGFRs and how they work with FGFs to initiate the desired cellular response. Finally, we will end the episode by exploring the three main pathways used by FGFs and their corresponding receptors. FGFR Model: https://images.app.goo.gl/FaZjvuh5H1QnTgfa8
JCO PO author Dr. Jun Gong shares insights into his JCO PO articles, “Phase II Study of Erdafitinib in Patients with Tumors with FGFR Amplifications: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol K1" and “Phase II Study of Erdafitinib in Patients with Tumors with FGFR Mutations or Fusions: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol K2”. Host Dr. Rafeh Naqash and Dr. Gong discuss the limited activity of FGFR inhibition in solid tumors with FGFR amplifications and mutations or fusions in this NCI-MATCH phase II trial. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the Stevenson Cancer Center at the University of Oklahoma. Today, we are excited to be joined by Dr. Jun Gong, Associate Professor in the Division of Medical Oncology at Cedars-Sinai Medical Center and lead author of the JCO Precision Oncology article entitled "Phase II Study of Erdafitinib in Patients with Tumors Harboring FGFR Amplifications: Results from the NCI-MATCH ECOG-ACRIN Trial EAY131 Subprotocol K1" and "Phase II Study of Erdafitinib in Patients with Tumors with FGFR Mutations or Fusions: Results from the NCI-MATCH ECOG-ACRIN Trial EAY131 Subprotocol K2." Our guest's disclosures will be linked in the transcript. Dr. Gong, welcome to our podcast and thank you for joining us. Dr. Jun Gong: Thank you, Dr. Naqash and JCO Precision Oncology for having me. Dr. Rafeh Naqash: We are excited to be discussing some interesting aspects that you have led and published on from the NCI-MATCH trial. We were trying to understand from a background perspective, since this master protocol has been going on for quite some time, could you give us a little bit of background for the sake of our listeners on what the NCI-MATCH is and what were the specific objectives for these two subprotocols? Dr. Jun Gong: Yes, of course, Dr. Naqash. So, as you may all know, the importance of targeted therapies in the current era of precision oncology. And on that backdrop, the NCI-MATCH was a national multicenter study designed essentially to look for signals of efficacy across various solid tumor and hematologic malignancy types, with a focus on specific mutations. The master protocol is unique in that there are several arms to the trial, each targeting a specific potential targetable alteration using available agents in cancer today. Dr. Rafeh Naqash: Excellent. Thank you for that background. I know this master protocol has been going on for quite some time with different subprotocols. I believe some of them are immunotherapy-based. Also, you've led two important subprotocols, which are the FGFR amplification and the FGFR mutation or fusion. There are some differences, from what I gather, in responses for the fusions versus the amplifications or mutations versus the amplifications. Could you first delve into the first paper of the fusions, and describe what were the tumor types? As you mentioned in the paper, some tumors were excluded. What was the reason for the exclusion of some of those tumor types? Why did you want to study the fusions and mutations versus the amplifications separately? What was the background for that? Could you highlight some of those points for us? Dr. Jun Gong: Firstly, as a kind of a more background, FGFR has been a recognizable target for a couple of tumor types. And if you look at the broad landscape of FGFR alterations, they occur in about 5%-10% of cancers, with the majority being FGFR amplifications actually, and mutations and rearrangements following second and third respectively in most commonly identified alterations. With that being said, FGFR mutations and rearrangements have already been established in a couple of tumor types. Actually, the first FDA approval for an oral FGFR inhibitor was erdafitinib, which was the agent used in both of these back-to-back trials. However, erdafitinib was first approved in urothelial carcinoma, and since then, there has been an explosion in oral FGFR inhibitors targeting fusions and mutations in other cancer types, such as cholangiocarcinoma. More recently, there was even an FDA approval in a myeloid malignancy as well. So, we used erdafitinib, being that it was the first FDA-approved, orally available agent to target this alteration. We conducted the two back-to-back studies in recognition that although rearrangements and mutations have already been established in certain tumor types, we were more interested in looking at the more common FGFR alteration, that being amplifications. However, the efficacy in that was a little unknown, and so these two separate subprotocols were developed: K2, which was to look at FGFR mutations and fusions in tumor types, excluding urothelial carcinoma, to look if there was a signal of efficacy beyond currently FDA-approved indications, and amplification as a separate cohort. Dr. Rafeh Naqash: That's a very good explanation of why you concentrated on the tumor types in these protocols. Now, going back to subprotocol K1, could you tell us what were some of the tumor types that you did include, and what was the sample size, and what was the hypothesis for the sample size as a meaningful level of activity that you wanted to see and would have potentially led to a bigger, broader trial? Dr. Jun Gong: So, subprotocol K1 was the arm investigating erdafitinib in those with FGFR amplifications, and these were predefined on the NCI-MATCH protocol, looking at FGFR 1, 2, 3, and 4 amplifications essentially. These were allowed to have local testing through a local CLIA-certified assay, but then they needed to be confirmed on a central assay, which is the NCI-MATCH Oncomine assay. These statistics are uniform for the NCI-MATCH trials, and the goal was at least 31 patients, with the hypothesis that if the response rate was 16% or more, this was considered a signal of activity. However, there was an additional protocol specific requirement in that if the sample size was fewer than 31 patients, then the primary efficacy population would be assessed against a null hypothesis overall response rate of 5%. Meaning that if there were less than 31 subjects, an overall response rate of greater than 5% would be defined as positive. Again, the NCI-MATCH was uniform. Secondary objectives included progression-free survival, overall survival, and safety and toxicity. With that being said, K1 originally began accrual. The NCI-MATCH actually launched in 2015, but in the subprotocol K1, 35 patients were initially enrolled in the study. If you go down the eligibility criteria, however, a lot of these patients dropped out due to a lack of central tumor confirmation and various reasons. Ultimately, 18 patients were included in the pre-specified primary efficacy cohort. Dr. Rafeh Naqash: Thank you. I did see for subprotocol K1, you mostly had stable disease in a couple of patients, no responses, and I think one individual with breast cancer had a prolonged stable disease. Now, from an FGFR amplification standpoint, did you or were you able to correlate - again, this is not objective responses, it's not a partial response or a complete response - was there any correlation from the level of amplification to the duration of stable disease? Dr. Jun Gong: That's actually the core of our discussion about why K1, despite a variety basket of solid tumor types, somewhere, preclinical data had suggested FGFR amplifications could be targeted, that K1 was ultimately a negative trial with a 0% response rate. We dive in that although we included as an eligibility criteria a copy number variation of seven as the threshold for amplification, we realized that if you look at some of the literature out there, that even in the FGFR 1 and 2 amplification cohorts, where these are the more common cohorts of amplified tumor types that have been targeted, you really needed a high level of amplification, more than 99% of tumor cells being amplified in the previous studies, to actually generate a response. The thought was that we assumed that FGFR amplification would lead to protein expression and dependence on FGFR signaling, providing sensitivity to FGFR inhibition. However, we realized that there is a certain degree where a high level of amplification needs to happen, and it may not be for all FGFR amplifications. We looked into the literature that FGFR 1 and 2 were the more commonly studied FGFR amplifications. FGFR 1, if you actually look at the amplicon structure, it tends to amplify a lot of other genes because it's such a huge amplicon structure. But FGFR 2 is shorter and centered on just FGFR 2 with a few other genes co-amplified. So, actually in the literature, they've already been seeing that maybe FGFR 2 amplification tumors are more readily targetable based on the robustness of evidence, rather than FGFR 1. But across all of these, the higher the level of amplification, seems the more targetable. Dr. Rafeh Naqash: Those are interesting discussions around protein expression on the tumor that could imply therapeutic vulnerability. So I've always thought about it, whether trials like NCI-MATCH trials or ASCO TAPUR, for example, would be perhaps more informative if, on a secondary analysis standpoint, proteomics is something that could be done on the tumor tissue, because similar to NCI-MATCH, ASCO TAPUR has other sub protocols where some of these mutations or amplifications don't necessarily result in antitumor responses. But I think from a biology standpoint, as you mentioned, a certain amplification might correspond to RNA expression and that might correspond to protein expression, which is downstream. So looking at that would be something interesting. Have you planned for something like that on these tumor specimens? If you have biobanked any of those specimens. Dr. Jun Gong: I think that's a great future direction. And I know you, Dr. Naqash, being involved in so many cooperative trials, I think it is possible, but it really depends on good trial planning from the onset. When designing such massive trials like this, I think the more important thing is if your trials are negative, but they are informative for the field to go back and have these postdoc available biobanks that you said. And I think having it integrated firstly, is way more efficient than to have kind of an amendment kind of going through halfway or when the trial is started. That could be a little bit more logistically difficult. Dr. Rafeh Naqash: I completely agree. And you mentioned corporate groups, I think we've been discussing, and I'm pretty sure you have also, there's a lot to be learned from clinical trials that are negative. We often, in the academic or non-academic setting, end up not publishing some of those negative results, pharma or corporate group based studies. And I think the resources, the specimens, and the negative results could correlate to some other novel findings if some of those exploratory analyses are done in the appropriate manner. Now, going to the drug itself or the erdafitinib here, it's a pan-FGFR inhibitor. Is that something that you think is a limitation in the drug development space? I do early phase trials, and I'm pretty sure you do a lot of these basket early phase trials. Is that something that you feel is a limitation when you have a drug that targets different mutations or different protein changes of the same gene or different amplifications? Could that be a reason why something like this doesn't necessarily work because it doesn't have as much specificity against the isoform as one might need to inhibit the downstream kinase activation? Dr. Jun Gong: That is also a great point. The NCI-MATCH sub protocol K1 and K2 used erdafitinib, which was the first FDA-approved FGFR inhibitor. But as many of the listeners and yourself may know, there have been newer iterations in next-generation development of the FGFR inhibitors. And it's very fascinating, the tyrosine kinase inhibitors, with each iteration, you seem to have a little more potency and the ability to bypass some of the resistance mutations, almost paralleling the lung cancer space, where we kind of follow that, and they've been kind of the pioneers in that space. And to your point, yes, we consider– the NCI-MATCH was developed nearly a decade ago, and the available agents at that time, would it have changed the findings if we used a kind of a newer generation or more potent FGFR inhibitor? It's possible, I think, especially in the K1 cohort with the amplifications. We even suggested in the discussion of the paper future directions, is that one way to kind of bypass the amplification issue is to use more potent and specific FGFR inhibitors. And so I think it's very possible that you highlight this point. Dr. Rafeh Naqash: And for the sake of our listeners, Jun, especially trainees, could you highlight what are currently some of the FDA-approved FGFR inhibitors, and what tumor types are they currently approved in? Dr. Jun Gong: The first one, as we have hinted, was in treatment of refractory, essentially urothelial carcinoma with FGFR mutations and rearrangements, mainly 2 and 3. And this is where oral erdafitinib was approved. And it's interesting, I kind of teach my fellows and our health staff that erdafitinib is interesting in that its FDA label insert requires a starting dose of about 8 milligrams daily, and it's a 28-day cycle. But during the first 14 days, we're really looking at the serum phosphate levels. If they are within a certain level, if they are within 5.5 to 7, for example, you continue the current dose. But if they are less than 5.5, the FDA label actually mandates that you increase it to 9 milligrams oral daily, continuously. This is biologically logical to me. FGFR is located to the renal tubules, and so this is a major phosphate kind of metabolism pathway here. And so you're using that as a surrogate, essentially, if the right dosing is achieved. And so that's unique. And then the subsequent kind of FGFR inhibitors that came about, you had a couple in cholangiocarcinoma, where, unlike urothelial carcinoma, where it's about 30% of the time, you'll find the FGFR alterations of target. It's about half of that 15% in cholangiocarcinoma, and it's mainly intrahepatic cholangiocarcinoma in that sense. And here you have pemigatinib, which is one of the FGFR inhibitors approved for cholangiocarcinoma. And then you also had infragatinib, which is approved. But however, infigratinib eventually had their FDA label culled. It was withdrawn by the company, I think it was in 2022. And then more recently, you had even a more potent FGFR inhibitor in cholangio approved and futibatinib. It's interesting that with these more later generations of FGFR inhibitors, they do show a correlation with phosphate levels, but they don't have that specific kind of dosing early on in the first cycle, like erdafitinib. And so it's interesting to see that with the later generations, you're seeing more potency as well. Dr. Rafeh Naqash: Thank you for that overview, which I'm sure most of the trainees appreciate since this is an up and coming field in the space of precision medicine, especially FGFR. From a side-effect profile standpoint, you mentioned phosphate issues. Do you think that is a drug class effect here, or is that an FGFR receptor subtype effect, depending on which FGFR receptor, 1 or 2 or 3, that is being targeted? Dr. Jun Gong: I do think this is a class effect that you'll see across a lot of the trials where phosphorus elevations or decreases are going to be probably your most common treatment-related adverse event. And I actually emphasize this is probably one of the most trickier side effects of this class, where we're almost having to have to monitor the phosphorus levels pretty routinely, pretty closely. And you also have other class effects on the nails. There's some rare retinal ocular toxicities that's unique to the FGFR class as well. And so it's a very exciting class of compounds, but it does require some close monitoring of some unique class effects as you've hinted. Dr. Rafeh Naqash: Based on the results from your K1 sub protocol, are FGFR inhibitors still the approach within, let's say, within cholangio or urothelial with FGFR amplifications? Is that still something that has been established and seen from a clinical response standpoint? Dr. Jun Gong: The FDA approvals are really for mutations and fusions. So this K1 sub protocol, essentially, I think provides one answer that we've been all wondering about for the longest time, “Hey, could amplifications be targeted as well?” Unfortunately, we didn't include urothelial carcinomas in this study because of the FDA approval. But from a kind of a basket solid tumor perspective, I think this really dampens the enthusiasm. As of right now, it really is fusions and mutations that are targetable. Amplifications need further investigation before becoming established in solid tumors. Dr. Rafeh Naqash: Going to the discussion with the second K2 protocol, which is mutations and fusions, can you highlight again which tumor types there where you saw some clinical outcomes that you saw and any unique insights on certain mutations or protein changes that were a little more relevant than some others? Dr. Jun Gong: Sure. So this is the parallel study to K1, in that now we are looking at fusions and mutations of FGFR1, 2, 3, and 4. And essentially, we, again, excluded those with urothelial carcinoma, given the FDA approval for erdafitinib in this trial. The trial actually opened then the FDA approvals for the FGFR inhibitors for cholangiocarcinoma happened. So this trial didn't really exclude those with FGFR mutated or rearranged cholangiocarcinoma as well. If you look at the breakdown of the cohort in K2, you saw a good mix of breast cancers or a couple of gynecologic malignancies. There were a couple of head and neck cancers. There were several brain tumors as well. There was one lung cancer. There were four noted intrahepatic cholangiocarcinomas. Again, we could not exclude those due to the fact that the trial had opened and was accruing when the FGFR inhibitors approved for cholangiocarcinoma happened. Similar design, with a phase II, single-arm, open-label of erdafitinib, and again, the same statistical design was implemented in that if it's higher than 31 patients, 16% overall response rate was a primary endpoint goal. If it was less than that, it was against the 5% overall response rate. And here in K2, 35 patients were enrolled and 25 patients were ultimately included in the primary efficacy analysis. So because it was fewer than 31 in the primary efficacy cohort, it followed the NCI-MATCH to be specified with a primary endpoint goal of 5% or higher. And here, in a heavily pre-treated cohort of more than 50% of subjects who have received prior than 3 or higher lines of therapy, overall response rate essentially confirmed was 16% with the p value of 0.034, which met the positivity cutoff of 5%. However, an additional seven patients experienced stable disease as best confirmed response. And it's important to note that four of these were grade IV glioblastomas with prolonged progression-free survival. So ultimately, this trial was positive in reading the endpoint that outside of urothelial carcinoma, could FGFR inhibition be pursued in other tumor types that had FGFR rearrangements or fusions? Dr. Rafeh Naqash: You mentioned glioblastoma, which is an area of huge unmet need. Do you think a trial like this as an upfront approach in glioblastoma, perhaps maybe after Temodar, could be a more meaningful way using the strongest, more precise therapy earlier on when there are certain mechanisms that inhibition of which would result in anti-tumor responses? Do you think doing this earlier on rather than second, third, fourth line would be more intriguing in some ways? Dr. Jun Gong: I think you've hit upon several key points there. Firstly, just a high unmet need in glioblastomas, in general. And then to us, although it was a stable disease it was quite noticeable that four of these occurred in IDH1 and 2 wild-type brain tumors. We kind of discussed that in the discussion as well. And of these, we actually realized that in the pre-clinical and other published literatures space that for some reason, IDH1 and wild-type tended to have more FGFR alterations, while 0% were found in IDH1 and 2 mutant high grade gliomas. So I think there is something hypothesis generating coming out of this study as well even though there were stable disease. And that you may be selecting for– We may be able to have future studies to select for a specific niche of glioblastomas. And as to your point, Dr. Naqash, I think if we can have a design trial looking for these specific molecular subsets, I think it's wide open for trials of this nature in the first line, second line, or refractory space. Even piggybacking into cholangiocarcinoma, you see, they're now looking at these in the neoadjuvant and adjuvant space as well. So I think we can identify the subset - it's wide open out there. Dr. Rafeh Naqash: I completely agree. I remember my program director a few years back when immunotherapy was in the metastatic setting, it was very exciting. He gave a talk in which he said "Early, earlier, earliest," and the more early, the better it seems. So I'm guessing that it's probably something similar for precision medicine-based approaches like targeting FGFR perhaps earlier. So what is next for some of these two studies, or these ideas that have come out of these two studies? Are you trying to develop something subsequently, or is NCI-MATCH looking at it from a certain perspective? Or what would you want to do as a next step, ideally if you had the funding and the pharma support? Dr. Jun Gong: That's the million dollar question. So just from the broad strokes, I think what these two back to back papers and studies comment is that amplifications may not be the more targetable of FGFR subset, but there is avenue for improvement there and further investigation. FGFR fusions and mutations however seem to go along with what we know in some of the FDA approved types now. Now the next step is in the area of precision oncology is could we expand the label indications now to other subtypes with FGFR fusions and mutations. And this is I think following precedent. You and the audience may know that there are a lot of different tumor agnostic approvals now for both immunotherapy and other targeted therapy types. So I think the goal of this study was to provide momentum for, perhaps, advancements into a tumor agnostic indication for FGFR inhibitors. And we do cite in the K2 manuscript the results of a phase II study that was also published around the time we were writing the study up. It was the phase II RAGNAR study. And that enrolled patients, again, with FGFR fusions and mutations. And that trial was positive, too. That one was a larger study of 217 subjects. We highlight some differences in study populations as to why maybe the difference in responders were detected. Both were positive studies. It was reassuring that the overall survival impulse studies were about the same. And again, I think they don't compete. I rather think they complement each other in providing this body of evidence that may meet- at one point, the FDA should be approached with this evidence for a tumor agnostic mutation so that more patients with this subset could be benefitting. Dr. Rafeh Naqash: Excellent. Thank you so much, Jun. Now, could you tell us briefly what your background is, where you've trained, and your interests, and how you balance clinical research with some of your personal interests? Dr. Jun Gong: Sure. Thank you for that interest. I did my training in medical school in New York. I went to New York Medical College. And then I did my residency at Cedars-Sinai for medicine. And I went to City of Hope for fellowship where I was trained in GU by Dr. Monty Powell who maybe you folks are familiar with. And my GI training was with Dr. Fakih at City of Hope. And since then I returned back to Cedars-Sinai where I serve as a dual GI/GU focused medical oncologist. I do clinical trials in both and translational science, really focused on targeting tumor metabolism in both as well. My advice to the listeners and trainees and I tell my own fellows this, I think it's very rare now unless you're in phase I to do a dual focus. So I actually emphasized to my trainees that the more focused you can be, the better. Unless you are going into phase I, for example. With that, you can hone in, develop your craft. But then again, I have known several mentors who do multiple tumor types. But I think the more traditional mechanism is to focus as much as you can is my advice for the listeners. Dr. Rafeh Naqash: Thank you again, Jun, for all those interesting scientific and personal insights. We appreciate you and working with JCO Precision Oncology for both of your manuscripts. This is the first time we have ever invited a lead author for two manuscripts at the same time. It's always good to be the first in something, and I learned a lot and hopefully, our audience would have learned a lot. Dr. Jun Gong: Thank you, Dr. Naqash, for having me. It was a pleasure speaking with you and the crew. Dr. Rafeh Naqash: Thank you. Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Drs. Shaalan Beg and Aparna Parikh discuss the role of ctDNA as a powerful prognostic biomarker for GI cancers, along with its impact on risk stratification and the detection of recurrence. They highlight key studies in ctDNA that were featured at the 2024 ASCO GI Cancers Symposium, including COBRA, GALAXY, and BESPOKE in CRC, as well as the promise of ctDNA testing in the preoperative detection of iCCA. TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Shaalan Beg, your guest host for the ASCO Daily News Podcast today. I am an adjunct associate professor at UT Southwestern's Harold Simmons Comprehensive Cancer Center in Dallas. On today's episode, we will be discussing the emergence of circulating tumor DNA (ctDNA) technology in GI cancers. I am delighted to be joined by Dr. Aparna Parikh, an assistant professor of medicine at Harvard University and the director for colorectal medical oncology at the Massachusetts General Hospital Cancer Center, where she also serves as the medical director of the Young Adult Colorectal Cancer Center. Dr. Parikh will share her insights on key research on this hot topic in GI oncology that was featured at the recent ASCO Gastrointestinal Cancers Symposium. Our full disclosures are available in the transcripts of this episode, and disclosures related to all episodes of the podcast are available at asco.org/DNpod. Dr. Parikh, it's great to have you on the podcast today. Dr. Aparna Parikh: Thanks so much, Dr. Beg. Dr. Shaalan Beg: In recent years, it has become evident that liquid biopsy and other emerging ctDNA technologies are changing how we treat GI cancers, and colorectal cancer (CRC) is in the forefront of this space. Before we dive into key studies, can you briefly highlight for our listeners how ctDNA is advancing the field and how it can influence the care that we deliver to our patients in the future? Dr. Aparna Parikh: Absolutely, ctDNA is certainly a hot topic. What we have learned over the years is that ctDNA has emerged across many solid tumor types as one of the most powerful, if not the most powerful, prognostic biomarker we have to date. ctDNA has improved risk stratification. We have learned a lot about the role in what is called minimal or molecular residual disease in patients with early-stage disease, and ctDNA being a biomarker of recurrence for those patients, with ctDNA, we have a better understanding of tumoral heterogeneity, both spatially and temporally, getting a better glimpse of what is happening in a given patient with multiple metastases, as well as genomic evolution of tumors over time. So certainly many, many roles and areas where ctDNA is emerging. Dr. Shaalan Beg: This was a hot topic at the 2024 ASCO GI Cancers Symposium, and we're going to take a deep dive into some of the abstracts that were presented. Let's start with the COBRA study, which is the NRG-GI005. That was Abstract 5 at the ASCO GI Cancers Symposium, and the GALAXY study, which was Abstract 6 at the symposium. So, the COBRA study reported results of ctDNA as a predictive biomarker in adjuvant chemotherapy for people with colon cancer. At a high level, it was a negative study, but there are some important lessons for us to learn. Similarly, in the GALAXY study, investigators from Japan presented an updated analysis on the correlation of ctDNA dynamics with outcomes in colorectal cancer with minimal residual disease. How do you synthesize all this information and help the listeners understand our current state for ctDNA applications in colorectal cancer? Dr. Aparna Parikh: Yeah. Let's take the COBRA study first. Let's talk a little bit about the design of COBRA. COBRA was intended to look at patients that were resected, stage 2 colorectal cancer patients, or colon cancer patients who were 2A. These are patients where the treating physician would, at the outset, decide that there was no adjuvant chemotherapy indicated. These are patients where active surveillance would be entirely appropriate as the standard of care. Patients were randomized to arm 1, which was active surveillance, or randomized to arm 2, which was assay-directed therapy. If there were ctDNA positive in arm 2, then they were given chemotherapy, FOLFOX or CAPOX. And if they were “ctDNA not detected,” then they would also go on to active surveillance. And so, the plan was that nearly 1,500 patients are to be recruited, and at the time of this data cut, they had around 630-some patients. The primary objective was to look at the clearance rates of ctDNA between the ctDNA-positive cohorts, remember, the chemotherapy and the active surveillance cohorts at 6 months. They had around a 5% detection rate of ctDNA patients. Ultimately, that was around 16 patients. The reason that the study shut down was that what they found was that in the surveillance arm, the arm that was not getting any treatment, they had a ctDNA clearance of 43% versus 11% in the chemotherapy arm. They had an interim analysis to look at the clearance rate between the 2 arms, and what was surprising to the investigators and the community was what was happening in terms of clearance. Why do we have a 43% clearance rate in patients that were not getting anything? And so, because of that, the study was shut down as it did not meet its prespecified interim look at clearance in those 2 arms. Many things came up in terms of learnings from COBRA. Number one was the characteristics of the assay. And so, you take an assay in a low-risk patient population that has a fixed specificity, and when your baseline prevalence of recurrence is so low, for example, in low-risk stage 2 patients, your composite predictive value is very susceptible to small changes in that specificity. And so, your PPV is going to be a lot lower in a low-risk patient population than a higher-risk patient population. The COBRA study used an older version of a tumor-uninformed assay, so it definitely called into question some characteristics of the assay. Is one-time-point clearance sufficient, and is that the right endpoint? We have seen now, including the GALAXY study that we'll talk about here, previously reported just spontaneous clearance happening in 5%, 10% of patients. The question with that spontaneous clearance is: Was it actually clearance, or was chemotherapy just perhaps in a low ctDNA shedding state? Are you just suppressing the ctDNA below the level of limited detection? And then in this study, the clearance draw was actually done in the chemotherapy arm right before the last cycle of chemotherapy, again to that point of, are you just suppressing the ctDNA with chemotherapy? There is also stochastic sampling error that can happen in patients with very low residual tumor volume. So, I think this is a disappointing study in the sense that it is still a really important question. There are still 2A patients that recur, but maybe [this was] not the right test, or maybe single-time-point testing wasn't enough. And so, lots of lessons to be learned from this study in terms of test and design, but hopefully more to come. I think certainly stage 2 patients remain an area where I think, hopefully, ctDNA still plays a factor for those patients. Dr. Shaalan Beg: And how was the patient population for the GALAXY study? That was Abstract 6, compared to the COBRA study. Could you summarize those findings for us? Dr. Aparna Parikh: Yeah, so GALAXY was part of a large study in Japan that includes an observational cohort plus therapeutic cohorts as well. And so, GALAXY was just further reporting of the observational cohort. So unlike COBRA, which is a low-risk, stage 2 study that was actually asking that interventional question: Can you use it to guide therapy? The GALAXY and the updated GALAXY just continues to show more clinical validity data rather than clinical utility data. And it was nearly 3,000 patients, pan stages. Again, the lion's share were stage 2 and 3 patients, but there were also stage 1 and stage 4 patients as well. And what they showed was that ctDNA is undoubtedly prognostic. They showed very consistent Kaplan-Meier curves, which we've seen time and time again, where if you're ctDNA-positive, you don't do as well. What they showed was, not surprisingly, with longer-term follow-up – this is 24-month follow up, so longer-term follow up than was published in their paper last year – was that when you test at one time point, so landmark testing, the sensitivity of detecting recurrence was around 48%, and that fell from the publication last year which was around 58%, 59%, which is not surprising as you follow more people. I think single time point testing soon after surgery may miss those late recurrences, but it's still prognostic and showed a specificity of around 94%. They also continued to show that if you continued to test with serial testing, your sensitivity improves, but what was really interesting and new, what they presented this time, was a clearance analysis. And showing, again, comparable to COBRA, in many ways, in the sense that clearance can be a little bit finicky, especially at one time point, is what they showed is that patients who had sustained clearance, and these are patients that had at least two time points with their ctDNA remained to be negative, they did very well. But if you had transient clearance, and again, the definition was a little bit broad, at least having one negative and then one positive, those patients ultimately, at 24 months, the curves came together with the no clearance curve. So initially, they did better than the people that didn't have any clearance. But if you transiently cleared at two years, the curves came back together. And what was interesting is that in those patients that sort of transiently clear by 9 to 12 months, 80% of those are actually having a rapid return of ctDNA. And so this begs the question of was chemotherapy just suppressing that ctDNA or maybe if you have a better test you could have actually improved it. These were some of the updated, interesting learnings from GALAXY, which remains incredibly prognostic. And then the concept of clearance, which I think we have to look into a little bit more as a field, and understanding that maybe just one time point clearance isn't sufficient. Dr. Shaalan Beg: Yeah, and one of the most important applications for ctDNA can be its ability to inform adjuvant chemotherapy. Its ability to not only identify more people who may benefit from chemotherapy, but maybe even identify people who don't need chemotherapy. And along those lines, Abstract 9, the BESPOKE study, looked to understand the role of ctDNA-based detection of molecular residual disease to inform adjuvant therapy for stage 2 and 3 colorectal cancer. And they presented interim data at the GI ASCO this year. What were your takeaways from this study? Dr. Aparna Parikh: Exactly. Beyond the prognostic implications, I think what was really interesting was that there was the initial data looking at the benefit of adjuvant chemotherapy. So, what they did was they said, “Okay. We're going to take the MRD-positive patients and look at the benefit of adjuvant chemotherapy and then the benefit of adjuvant chemotherapy in the MRD-negative patients.” And again, remember, this is a prospective observational study, so it's not looking at negative and positive to guide therapy, but it's just looking prospectively and observationally at how those patients are doing. But what they showed again is that indeed, in the adjuvant chemotherapy group, the benefit of adjuvant chemotherapy again with the follow-up to date on the study was different in the MRD-positive patients. First of all, I guess taking a step back, the DFS in the ctDNA-negative patients at 2 years was very good. So negative patients had over 98% 2-year DFS in both the adjuvant chemotherapy and observational group. And there was no real difference between adjuvant or not. But in the positive patients, not surprisingly, the DFS was worse. But what was reassuring to see is that you can make an impact with adjuvant chemotherapy in the positive patients. And the difference in DFS between the positive and negative patients, with adjuvant or not, was 42% versus 12.5%, in the observational patients. So, it is benefitting the patients who are positive so it does give us more data that, again, at least in the positive patients, you may be able to reverse the recurrences there with adjuvant chemotherapy. And maybe if you're negative, eventually, we'll get to a point of de-escalation of care. Again, keeping in mind the kinds of sensitivity limitations as well. Dr. Shaalan Beg: Wonderful. And one of the other malignancies in the GI space where precision therapies and molecular biomarkers are making a huge difference are intrahepatic cholangiocarcinoma. Genomic profiling using ctDNA is increasingly being used in this population to inform precision oncology approaches and determine mechanisms of resistance to targeted therapies as well. In Abstract 528, investigators looked at the role of preoperative ctDNA testing for resectable intrahepatic cholangiocarcinoma. What are your thoughts on that study? Dr. Aparna Parikh: Yeah, it's such an important area, as you mentioned, in the metastatic space – FGFR, IDH1, all these alterations that are emerging in intrahepatic cholangios. This was a very small study, it was preoperative, and so the tumor was intact, and around 14 patients. They used a tumor-informed approach just for detection and quantification of ctDNA. So this was not a study that was looking at a next-generation sequencing approach where you're going to actually be able to detect the alterations, but it's actually looking for the detection and quantification of ctDNA rather than genomic characterizations. And patients had about a month or so where they had their baseline blood detected. And I think what was reassuring to say was that ctDNA was actually detected in all the patients with the primary tumor intact, except for one patient who was a very low-risk stage 1A patient. There was some correlation, against a small number of patients, between the concentration of ctDNA in patients that had the lower stage and then the higher stage groups. Small numbers were actually hard to characterize and correlate with recurrence or mortality, but at least, some correlation with pathologic tumor size, they were able to because it was a bespoke panel and you're sampling the tissue and then looking in the blood, IDH1 and 2 were mutations that were tracked based on the genomic profiling and a couple of the patients were able to have their IDH mutations tracked. So it gives us a sense, a little bit, that ctDNA, we know has a lot of variable shedding across disease states and tumor locations, but gives us some promise that it is reliably detected with the tumor-informed approach, at least preoperatively in cholangios. So may again open some more opportunities for MRD testing in cholangiocarcinoma as well. Dr. Shaalan Beg: Thank you. That's a wonderful review of ctDNA applications in gastrointestinal cancers from the 2024 ASCO GI Cancers Symposium. Thank you, Dr. Parikh, for sharing your valuable insights with us on the podcast today. Dr. Aparna Parikh: Thank you so much for having me. Dr. Shaalan Beg: Thank you to our listeners for your time today. You'll find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Aparna Parikh @aparna1024 Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. Aparna Parikh: Consulting or Advisory Role (An Immediate Family Member): PMV Consulting or Advisory Role: Checkmate Pharmaceuticals, Guardant Health, Foundation Medicine, Abbvie, Value Analytics Labs, Bayer, Taiho Oncology, Delcath, Seagen, CVS, SAGA Diagnostics, Scarce, Illumina, UpToDate, Takeda, AstraZeneca, Takeda, Pfizer, Kahr, Xilio Therapeutics, Sirtex Research Funding: PMV Pharma, Erasca, Inc, Syndax Research Funding (Institution): Bristol-Myers Squibb, Genentech, Guardant Health, Array, Eli Lilly, Novartis Pharmaceuticals UK Ltd., PureTech, Mirati Therapeutics, Daiichi Sankyo, Karkinos Other Relationship: C2i Genomics, Xgenomes, Parithera, Cadex
Dr. Pedro Barata, Director of the Clinical Genitourinary Medical Oncology Research Program at UH Seidman Cancer Center, provides an exclusive round-up of the most groundbreaking and practice-changing research unveiled at the ASCO GU 2024 meeting. With expertise and insight, he delves into pivotal studies such as CheckMate 914 Part B and KEYNOTE-564, exploring their implications for kidney cancer. The episode further unravels the transformative findings from the AMBASSADOR study, shedding light on adjuvant immunotherapy in bladder cancer; genetic testing and FGFR advancements in bladder cancer; life-prolonging therapies and radioligand therapies in castration-resistant prostate cancer; and the latest in minimal residual disease research. Check out Chadi's website for all Healthcare Unfiltered episodes and other content. www.chadinabhan.com/ Watch all Healthcare Unfiltered episodes on YouTube. www.youtube.com/channel/UCjiJPTpIJdIiukcq0UaMFsA
Drs. Shaalan Beg and Rachna Shroff discuss key abstracts on GI cancers that were featured at the 2024 ASCO Gastrointestinal Cancers Symposium, including SKYSCRAPER-08, EMERALD-1, and NEST-1 in esophageal squamous cell carcinoma, hepatocellular carcinoma, and colorectal cancer, respectively. TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I'm an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center and vice president of oncology at Science 37. Today, we'll be discussing key abstracts and other exciting highlights from the 2024 ASCO Gastrointestinal Cancers Symposium. Joining me to discuss some key takeaways from the meeting is the chair of this year's Symposium, Dr. Rachna Shroff. Dr. Shroff is the division chief of Hematology Oncology and chief of GI Medical Oncology at the University of Arizona Cancer Center. She also serves as the associate dean for clinical and translational research at the University of Arizona College of Medicine – Tucson. Our full disclosures are available in the transcript of this episode, and disclosures related to all episodes of the podcast are available at asco.org/DNpod. Dr. Shroff, welcome back to the ASCO Daily News Podcast, and congratulations on a great Symposium. The scientific advances and innovative, multidisciplinary approaches that were featured throughout the meeting were really inspiring and reflect the incredible strides we're making in GI cancer research. Dr. Rachna Shroff: Thank you so much for having me back. I am delighted to be here. Dr. Shaalan Beg: Dr. Shroff, the theme of this year's symposium was "Taking Personalized Care to the Next Level." I'd love to hear your reflections on the sessions that you found most exciting and really resonated with the attendees. Dr. Rachna Shroff: Yes, thank you. We were really excited about this theme because we really felt that “Taking Personalized Care to the Next Level” translated to thinking through personalized approaches to patient care, not just in the traditional ways that we think of with precision oncology and genomics driving our care, but also how we can think through multidisciplinary approaches and an individualized care plan. Thinking through how artificial intelligence and novel clinical trial designs can and should be implemented to meet the needs of our individual patients. And so we really highlighted that in what was a somewhat new reboot of a session called “Intersections,” which were every day and were really more cross-tumor; they were tumor agnostic but were thematic focused. As I mentioned, those themes were really based on feedback that we had from prior attendees, as well as from the program committee's feeling on what are really the questions that we are dealing with and that are burning in the clinic today and that includes the emerging role of artificial intelligence and machine learning and how we integrate that into our clinical care, approaches to oligometastatic disease, and it's not really just something that we think of in colorectal cancer but haven't fully used that paradigm to really apply it to other GI malignancies. And then the art and science of clinical trial design where, again, traditional randomized phase 3 trials might not be the best and most innovative and most expedient way of bringing novel therapeutics to our patients. And so, I thought that all of those sessions were really highlighting different important topics that we deal with day to day. Additionally, we had a really fantastic keynote lecture from Dr. Kimmie Ng of the Dana-Farber Cancer Institute. She is a world-renowned expert in the early-onset colorectal cancer space, and the timing of her keynote was perfect with the new cancer statistics that came out literally days before GI ASCO that demonstrated this just dramatic rise in early onset GI malignancies as a whole, not just colorectal. And she spoke really in a comprehensive manner not just on clinical approaches, screening approaches, and how to find these patients at an earlier stage, but also kind of gave us a call to action, if you will, in terms of public health initiatives, as well as like I said, clinical care and really thinking outside of the box for how to reach these patients. And then, of course, we always have what I think is one of my favorite aspects of the meeting, which are the networking opportunities that include the Trainee and Early Career Networking Luncheon, the Women's Networking Reception, and the Meet the Experts Luncheon where, especially as junior career investigators, you have an opportunity to meet what we think of as the “big names” in GI cancer. Dr. Shaalan Beg: Absolutely, I remember my first couple of GI ASCO meetings and those were probably the most memorable sessions that I attended as junior faculty as well. So let's take a deeper dive into some key abstracts from the meeting. I'd like to begin with Abstract 245. This is the SKYSCRAPER-08 study. It's first-line tiragolumab and atezolizumab with chemotherapy in an Asian patient population with esophageal squamous cell carcinoma. What are your key takeaways from this study? Dr. Rachna Shroff: Yeah. This was an exciting study in my opinion in the sense that thinking through how we can build on immunotherapy backbones is obviously a pressing question across the GI cancer space. So this was a phase 3 randomized, double-blinded, placebo-controlled trial that looked specifically at patients with esophageal squamous cell carcinomas. And the study was enrolled fully with an Asian population. It looked at taking the traditional chemotherapy backbone and adding to it an anti-PD-L1 with atezolizumab and an anti-TIGIT with tiragolumab. Again, that proof of principle of using anti-TIGIT and PD-L1 has been looked at across a lot of different GI cancer spaces and we know that the esophageal squamous cell cancers tend to be very immunotherapy responsive. So this was a really important question. This involved a number of patients, a little over 460 patients, who were randomized one-to-one to receive the tiragolumab with atezolizumab with the standard paclitaxel and cisplatin, that's used for esophageal squamous versus chemotherapy alone with placebo. And the primary endpoint was independent review of progression-free survival, and overall survival. And so, out of the 461 patients randomized, there was at the primary analysis, a median improvement in progression free survival, from 5.4 months in the control arm to 6.2 months with a tira-paclitaxel plus chemo arm with a hazard ratio of 0.56, highly statistically significant. Similarly the median overall survival was also improved from 11.1 months to 15.7 months again with a hazard ratio of 0.7 and some of the other key efficacy endpoints were also improved with the addition of the anti-TIGIT PD-L1 approach. And importantly, there was not really safety signals that jumped out at us. And so, to me, what this means is that, in our patients with esophageal squamous cell carcinoma, we really should be thinking about chemotherapy with immunotherapy as a backbone and how we can build on it. And, you know, I would imagine that it's hard to argue with both the PFS and OS endpoint that adding anti-TIGIT won't necessarily be kind of the new approach to these patients. And importantly, I'll point out that it seems to be a benefit across the subgroups, including PD-1 status, which is always our big question here. I think the only thing to keep in mind is this was an all-Asian population and whether or not that kind of immune profile of the immune responsiveness is different in those patients, but regardless, a positive phase 3 trial. Dr. Shaalan Beg: It's really exciting to see immune checkpoint inhibitors or immunotherapy beyond PD-1 targeted, CTLA-4 targeted treatments making their way into GI Cancers. Dr. Rachna Shroff: Absolutely. Dr. Shaalan Beg: Sticking with the immunotherapy theme, let's focus on hepatocellular carcinoma. So LBA432, the EMERALD-1 study of transarterial chemoembolization combined with durva with or without bevacizumab looked at people with unresectable hepatocellular carcinoma eligible for embolization. So really a highly anticipated study, I'm wondering what your thoughts are and whether it'll be practice-changing for this field. Dr. Rachna Shroff: I was excited to see the press release when it showed that the study was positive, and I think it's because now that we're using immunotherapy in the advanced HCC space, our obvious question is, can we integrate it into multimodality approaches? There are a lot of smaller studies looking at neoadjuvant IO approaches, and in this intermediate stage, unresectable hepatocellular carcinoma patients. We wanted to know if there was a utility to liver directed therapy with immunotherapy. So, this was a large study. It was a global study looking at unresectable HCC with preserved Child-Pugh function. But it was Child-Pugh A and up to B7, importantly. And there were 616 patients randomized in a 1:1:1 fashion, with the control arm being just TACE alone. But then, there was also an opportunity for durvalumab with TACE, as well as durvalumab plus bevacizumab with TACE. The patients would receive durvalumab during their TACE treatments and could receive up to four TACE treatments and then subsequently were either continued on durvalumab alone, durvalumab plus bevacizumab, or the placebo. The primary endpoint was progression-free survival, powered specifically to look at TACE versus durvalumab plus TACE. In this study, the primary endpoint was met with a significant improvement in PFS. Median PFS was 15 months versus 8.2 months, with a hazard ratio of 0.77. Most prespecified subgroups demonstrated this benefit. Importantly, there was a secondary endpoint looking at durvalumab plus TACE versus TACE alone, and that actually did not show a statistically significant improvement in median PFS from 8.2 months in the control arm to 10.0 months. The overall response rates were slightly higher with the durvalumab plus bevacizumab approach at 43.6%. And importantly in these patients, who oftentimes have a higher burden of disease in the liver, median time to progression is a really important and clinically meaningful endpoint. That was 22 months with the durvalumab plus bevacizumab and TACE versus 10 months for TACE alone. I would just point out that the overall concern we always have with bevacizumab is the increased risk of bleeding and the treatment-related adverse event profile. Overall, there were no safety signals that emerged from this, with nothing that really, especially in that bleeding risk category, jumped out at us. Of course, we haven't seen the overall survival data yet because we have not seen enough follow-up to really see that number. I do think that this is potentially practice-changing, and I think it just demonstrates that there's probably some synergy between anti-VEGF with anti-PD-1, and then the liver-directed treatments. The obvious question for us in the United States is that the vast majority of people are moving away from TACE and towards more radioembolization and what can we extrapolate from this? Does this really tell us much if people are using more of a Y90-based approach? I think those are a lot of the burning questions that most of us have. Dr. Shaalan Beg: Yeah, and it's a very interesting direction that the HCC space is taking because we heard in previous meetings, the role of PD-1 inhibition as adjuvant therapy after resection. Now, we have data for local-regionally advanced disease over local-regional treatments. And of course, you already mentioned the data for more advanced disease. So it sounds like immunotherapy may be impacting the management of anyone diagnosed with hepatocellular carcinoma. Let's talk about the MONET trial, Abstract 249, which compared thoracoscopic esophagectomy and open esophagectomy for thoracic esophageal cancer. Do you think this is a study which may influence the treatment of patients with thoracic esophageal cancer? Dr. Rachna Shroff: So, this was, again, I think, a really important question. It was a randomized, controlled phase 3 trial comparing a more minimally invasive approach with TE — thoracoscopic esophagectomy — versus an open approach. This had patients with clinical stage 1-3, excluding T4 thoracic esophageal squamous cell carcinomas. They were randomized 1:1 to the open versus the TE approach, with a primary endpoint of overall survival and an important secondary endpoint of relapse-free survival. 300 patients were randomized, and at the second planned interim analysis, the median follow-up was a little over two and a half years. The 3-year overall survival was 82% in the TE group versus 70.9% in the open group. The DSMC of this trial actually recommended early termination based on the non-inferiority, which is what they were specifically looking at. There was a very statistically significant one-sided p-value for non-inferiority. Importantly, the 3-year recurrence-free survival was also markedly better in the TE group versus the open group, with no real notable differences in R0 resection, or a large percentage of patients who needed to be converted from a TE to an open approach, and really not any significant difference in overall postoperative morbidity. I think this just supports the concept that minimally invasive approaches for our patients with GI malignancies can and should be considered. Again, esophageal squamous because they tend to be seen a lot more in Asia, this study was conducted in Japan, but I think that being said, a lot of our surgeons in Europe and in the U.S. are also very amenable to minimally invasive approaches. And I think this just supports the fact that an open approach is not necessary. So, I would think again, that this is something that is implementable and I think will affect the field. Dr. Shaalan Beg: Moving on to metastatic cholangiocarcinoma, there have been many FGFR inhibitors that have shown activity and promise and are approved for the management of cholangiocarcinoma with FGFR alteration. But at this ASCO GI, we heard the results of the safety and efficacy of an FGFR1, 2, and 3 inhibitor, tinengotinib, as monotherapy for advanced metastatic cholangiocarcinoma (Abstract 434). How do you see this fitting into the broad picture? Dr. Rachna Shroff: Yeah, so this was highly anticipated data, primarily because at this point, the FGFR space in cholangiocarcinoma is quite crowded. And so a lot of us were getting sick of the "me-too" drugs. What is really unique about tinengotinib is that, not only is it a selective multikinase inhibitor, but it also, in preclinical models as well as in early phase one trials, demonstrated potent inhibition of patients with FGFR2 fusions and rearrangements who had acquired resistance mutations. So, as we better understand the first generation of FGFR inhibitors and note the resistance mechanisms, these drugs are now being developed to try to circumvent or overcome those. This study looked at 4 different cohorts: 1 cohort with FGFR2 fusion patients who had primary progression who never responded to FGFR inhibitors, a second cohort with FGFR2 fusion patients who had progression after primary response, so those with acquired resistance, and then there was non-fusion FGFR alterations because we do know that a number of cholangiocarcinoma patients have other FGFR alterations that are not fusions, and then those with FGFR wild-type. The primary endpoint was objective response rate, with a total of 48 patients enrolled across the four cohorts. And so the 40 patients who were evaluable in the group that had primary resistance, which was the first cohort, there was a response rate was 9.1% and that was partial response, and 31% had tumor reduction with tinengotinib. And similarly in those with acquired resistance, 37.5%, 3 out of 8 patients had a partial response and tumor reductions were noted with an overall disease control rate between those patients with FGFR2 fusions of 94.7%, between those with primary and secondary resistance. In the patients who had FGFR alterations, there was 3 out of 9 patients with a partial response and again, tumor reductions were notable across the board and the disease control rate was 88.9%. The FGFR wild-type group, not surprisingly, did not see any partial responses, but interestingly, 75% of these patients had at least disease control, and the median progression-free survival was 5.26 months, again, kind of most notably impressive in the 2 cohorts that included FGFR2 fusions. The toxicity profiles are what we come to expect for FGFR inhibitors and we've gotten better at managing those and mitigating some of those so there was really nothing to jump out there. So there is now an ongoing randomized phase III trial specifically looking at tinengotinib versus physician's choice in patients with FGFR2-altered cholangiocarcinoma after having received prior FGFR inhibitors. So that's where I think it's in is for those of us who know that there are multiple drugs in the space, our big question is can we sequence through that? Can we offer multiple FGFR inhibitors in these patients? And I think we are all eagerly anticipating this data as well as the subsequent data to really justify the use of these novel second generation FGFR inhibitors. Dr. Shaalan Beg: It's been fantastic to see the evolution of these compounds in precision medicine, or precision oncology at its finest, in terms of understanding mechanisms of resistance and treating refractory disease. Let's focus on colorectal cancer. I'll tell you, there has been a lot of discussion, Dr. Shroff, on social media, on insurance companies sometimes rejecting one biologic or the other based on tumor sidedness. We have talked about tumor sidedness predicting response on this podcast based on data from previous studies. But this year in GI ASCO, Abstract 207 explored the role of tumor genomics and tumor sidedness and they said that it's tumor genomics, that tumor genomics better explains the differences on outcomes, and it explains it better than sidedness. What does this mean to the field? Because a lot of professional organizations have guidelines that are asking people to now incorporate sidedness. So how does that change based on these results? Dr. Rachna Shroff: I really commend these authors on leveraging real-world data, and I think we're getting better and better at recognizing that real world data actually informs our clinical decision making, possibly better than sometimes some of these studies that lead to the guidelines and algorithms that we develop. So this is a perfect example of a little bit cart before horse in trying to understand the way that sidedness and genomics may interplay. So this was a study that basically leveraged both the Foundation Medicine and Flatiron Health clinical genomic database and looked at patients with microsatellite stable metastatic colorectal cancer. There were a total of 3,845 patients included in a kind of two-thirds one-third split between left sided and right-sided colorectal cancer. And they found the typical genomic alterations that historically have been thought of more with left-sided colorectal cancer like APC and then more of the RAS BRAF alterations in the right-sided patients. But I think what they really thought and what I think was remarkable is they really looked at the patients and how they received chemotherapy with anti-EGFR or bevacizumab therapies, and they did a multivariate analysis to really see what is driving outcomes. And like you mentioned, what they found was patients in the RAS pathway, those classified as having alterations in the RAS pathway, had less favorable outcomes, while those with APC altered group had more favorable outcomes. And that was regardless of treatment received and sidedness. And so when they did an analysis of what was called a “likelihood ratio test,” they found that when genomics was added to the sidedness evaluation, there was an improvement in outcome prediction, but not when sidedness was added to genomics. Like you said, it kind of demonstrates, at least in this mining of real-world data from Flatiron that tumor genomics is probably a better driver and a more important driver in determining outcomes than sidedness. I totally agree with you. I would push for us to really kind of bring a little bit of noise to this and to make insurance companies and other companies that are looking at this to think through this a little bit more and make sure that we're putting all of the data together in a comprehensive passion before making the treatment plans and determinations. Dr. Shaalan Beg: The last abstract I'd like to ask you about is Abstract 117, the NEST-1 trial. This study looked at neoadjuvant botensilimab and balstilimab for resectable mismatch repair proficient and deficient colorectal cancer, both MSS and MSI. What are your key takeaways from this study? Dr. Rachna Shroff: This is another study that is demonstrating that there may potentially be a role for immunotherapy in microsatellite stable patients. I will make the caveat that this was a single-arm study that really was looking at feasibility safety, with efficacy as a secondary endpoint. The combination of bot-bal in the neoadjuvant space for colorectal cancer patients, they received one dose of boten and two fixed doses of bal two weeks apart and then were taken to surgery. They limited the number of patients and out of the 12 patients that were enrolled, they limited the number of mismatch repair deficient patients. So to your point, they allowed both, but they wanted to make sure it was not just MSI-high patients. What they basically found is that it was safe and did not delay surgery or increase risks of adverse events. But importantly, there was significant regression of tumor noted. And some interesting spatial biology analyses demonstrated potentially novel mechanisms of action, especially in the MSS population, and that ctDNA reductions correlated with pathologic response. There were a lot of different things that they were looking at, basically suggesting that bot-bal is safe and can be used in both mismatch repair–deficient and proficient patients with colorectal cancer. And now importantly, they've added some additional cohorts and expanding the study. As I mentioned, this is right now just 12 patients, but does definitely have a provocative result. Dr. Shaalan Beg: Thanks so much, Dr. Shroff. Finally, the role of cell-free DNA (cfDNA) in GI cancers has been an exciting and important development in our field. There's tremendous data that emerged at the GI meeting, and we have decided to do a separate ASCO Daily News Podcast dedicated to ctDNA. So listeners, please look out for our coverage of key studies on ctDNA in GI cancers very soon here on the ASCO Daily News Podcast. Many thanks, Dr. Shroff, for sharing your insights with us today and for your great work in building a robust GI meeting this year. Thank you very much. Dr. Rachna Shroff: Thank you so much. Dr. Shaalan Beg: And thank you to all our listeners for your time today. You'll find links to the abstracts discussed on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and inform. It is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Our guests on this podcast express their own opinions, experiences, and conclusions. These statements do not necessarily reflect the views of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an endorsement by ASCO. Find out more about today's speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Rachna Shroff @rachnatshroff Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. Rachna Shroff: Consulting or Advisory Role: Exelixis, Merck, QED Therapeutics, Incyte, Astra Zeneca, Taiho Pharmaceutical, Boehringer Ingelheim, SERVIER, Genentech, Basilea Research Funding: Pieris Pharmaceuticals, Taiho Pharmaceutical, Merck, Exelixis, QED Therapeutics, Rafael Pharmaceuticals, Bristol-Myers Squibb, Bayer, Immunovaccine, Seagen, Novocure, Nucana, Loxo/Lilly, Faeth Therapeutics
Goyal, Bishop, Kelley, and Kuhlman discuss ways to prepare patients with cholangiocarcinoma for FGFR inhibitor–related adverse effects.
You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this 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. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In this podcast, members of the Cancer.Net Editorial Board discuss the latest research, innovations, and discussions taking place across the field of genitourinary cancers, including prostate cancer, bladder cancer, kidney cancer, and testicular cancer. This podcast is led by Cancer.Net Associate Editor for Genitourinary Cancers, Dr. Petros Grivas. Dr. Grivas is the clinical director of the Genitourinary Cancers Program at University of Washington Medicine and a professor in the clinical research division at the Fred Hutchinson Cancer Research Center. He is joined by Dr. Neeraj Agarwal, Dr. Shilpa Gupta, Dr. Tian Zhang, and Dr. Timothy Gilligan. Dr. Agarwal is a Professor of Medicine, and a Presidential Endowed Chair of Cancer Research at the Huntsman Cancer Institute at the University of Utah. He directs the Genitourinary Oncology Program and Center of Investigational Therapeutics at the Huntsman Cancer Institute. He is also the Cancer.Net Specialty Editor for Prostate Cancer. Dr. Gupta is the Director of the Genitourinary Medical Oncology Program at Taussig Cancer Institute and Co-Leader of the Genitourinary Oncology Program at Cleveland Clinic. She is also the Cancer.Net Specialty Editor for Bladder Cancer. Dr. Zhang is an Associate Professor of Internal Medicine at UT Southwestern Medical Center and a medical oncologist at the Harold C. Simmons Comprehensive Cancer Center. She is also the Cancer.Net Specialty Editor for Kidney Cancer. Dr. Gilligan is a Medical Oncologist, Associate Professor of Medicine, and Vice-Chair for Education at the Cleveland Clinic Taussig Cancer Institute. He is also the Cancer.Net Specialty Editor for Testicular Cancer. View full disclosures for Dr. Grivas, Dr. Agarwal, Dr. Gupta, Dr. Zhang, and Dr. Gilligan at Cancer.Net. Dr. Grivas: Hello. I'm Dr. Petros Grivas. I'm a medical oncologist in Seattle, a professor at the University of Washington and Fred Hutchinson Cancer Center. I'm really excited and thrilled today to host wonderful superstars in the field of GU Medical Oncology who will share insights about the highlights of kidney cancer, prostate cancer, and bladder, urothelial, urinary tract cancers that happened in 2023. And this highlight aims to inform our great audience about what are the clinically relevant insights, what patients should be aware, what patients should ask for when they go to the clinic, or overall, how they can be most well-informed and have the necessary tools to improve their care and feel well-supported in regards to education. So without further ado, we're going to cover in first prostate cancer, a very important update in this year. So all the people out there that are interested in hearing about prostate cancer will find this very, very useful and insightful. I'm very excited to host Professor, Dr. Neeraj Agarwal from University of Utah. Neeraj, do you want to introduce yourself? Dr. Agarwal: Of course. It's such an honor to be here. My name is Dr. Neeraj Agarwal. I'm a professor of medicine and director of genitourinary oncology program at the University of Utah Huntsman Cancer Institute. Dr. Grivas: Neeraj, thank you so much for accepting the invitation and being with us. I would like to ask you, what's your take on the current state of genetic testing in patients with prostate cancer? And when we say genetic testing, maybe you can clarify the distinction between germline and somatic and comment on both if you could. Thank you. Dr. Agarwal: Of course, a very important topic. I must tell you that it is very clear from all the guidelines that in patients with advanced prostate cancer or metastatic prostate cancer, meaning when prostate cancer has spread to different parts of the body, both germline testing to look for hereditary mutations in the DNA repair genes and testing for the same genes inside the tumor tissue are considered standard of care. So, a patient with advanced prostate cancer should have germline testing and somatic tumor tissue testing to look for mutations that can predispose them to have prostate cancer, and if they have genes in the tumor which can be targeted by the current approved drugs, like drugs which are already approved right now or which are in clinical trials. Unfortunately, less than 50% of patients in many areas of the country and in the world, less than 20% of patients are being tested. And even more, unfortunately, patients are less likely to be tested are those who are not well-resourced, who are not living in rich countries, if you will. They are poor- or low-resourced countries. Even with high-income countries, within those countries, patients who are living in relatively not-so-affluent neighborhoods, they are less likely to be tested. From racial perspective, patients who are Black or who are Hispanics are less likely to be tested. Based on how many drugs are out there in the clinic and emerging through clinical trials. And the fact that we can use many of these mutations for prognostication, to inform survival, to inform aggressiveness of the disease. It is not only to treat those patients, but also how to monitor the disease. The genetic testing is very important. Dr. Grivas: Thank you so much, Neeraj. It's very insightful. And I think you did a great job outlining the clinical relevance for both the patient in terms of treatment decision-making and therapy options, especially for advanced prostate cancer, as well as the broader family and implications for cancer prevention and cancer screening for the broader family members. So definitely a very important topic. Neeraj, the other question I have, if you could tell us more about this class of medications called PARP inhibitors. If you can comment on the currently approved PARP inhibitors, either as a single agent, what we call monotherapy or combination therapies for patients with prostate cancer in the United States, and who is eligible to receive those therapies? Dr. Agarwal: And this is such a nice segue to talk about PARP inhibitors as we were just talking about genetic testing of prostate cancer. So, PARP inhibitors are a class of drug which are instrumental, critical in treatment of patients who harbor mutations in those DNA repair genes. And two monotherapies, meaning using these PARP inhibitors as single agents have been already approved in the United States and several other countries. These are olaparib or rucaparib. Olaparib is approved after patients have had disease progression on novel androgen-blocking therapies or androgen blockers such as enzalutamide or abiraterone or apalutamide. And these PARP inhibitors such as olaparib or rucaparib can be used for those patients as single agent if they have these DNA repair mutations. Now, last year, we saw several combinations of PARP inhibitors with these androgen or novel hormonal therapy, as we call them. And these include abiraterone plus olaparib, abiraterone plus niraparib, and talazoparib plus enzalutamide from various phase 3 trials. Now, I'd like to bring to your attention that these PARP inhibitor combinations are approved with different indications in the United States and in the European Union. And they continue to get approved in various other countries. So the combination of abiraterone and a PARP inhibitor, whether it is olaparib or niraparib, they are approved for patients who have new metastatic castrate-resistant prostate cancer, and they have BRCA1 or BRCA2 mutations in the cancer cells or they have germline BRCA1 and BRCA2 mutations. Enzalutamide and talazoparib combination is approved in the United States for patients with metastatic castration-resistant prostate cancer with BRCA1 and BRCA2 mutations, but also several other DNA repair gene mutations. And that's a big difference as far as approval is concerned in the U.S. In the European Union, for our patients who are listening from European Union, the combination of abiraterone and olaparib and enzalutamide and talazoparib are approved for patients with metastatic castrate-resistant prostate cancer where chemotherapy is not clinically indicated, regardless of whether they have mutations in the DNA repair genes or not. And the combination of abiraterone and niraparib is only approved for patients with metastatic castrate-resistant prostate cancer with BRCA1 and BRCA2 mutation. So I just wanted to outline the different indications in the United States and in the Europe. Dr. Grivas: Thank you so much, Neeraj. So eloquent and very relevant to multiple patients globally, as you pointed out, with some differences in terms of the regulatory approval and availability of those agents in different countries. So great insights. Maybe we'll ask you 1 more question again since we are doing the highlights of the year. Another very important area of therapeutic development has to do with these novel agents that target the prostate cancer cells, and we call them theragnostics as a broader term. And I will let you explain what that means maybe in lay terms for our audience. And specifically, if you can comment on the recently presented PSMAforetrial at the ESMO meeting in Madrid with lutetium-177 PSMA. What are the implications of these results for our patients, and what is the role of lutetium therapy in this particular therapy setting? Dr. Agarwal: Of course, very important and pertinent topic indeed. As our patients may know that lutetium-177 therapy, or simply speaking, lutetium therapy, has already been approved for patients with metastatic castrate-resistant prostate cancer who have had disease progression on this novel hormonal therapy and a chemotherapy with docetaxel or cabazitaxel. And this indication is already there in the U.S. and in various other countries. And patients are eligible to receive lutetium therapy as long as their disease has progressed on docetaxel or one of the taxane chemotherapy and a novel hormonal therapy. Now, in the European Society of Medical Oncology meeting, Dr. Oliver Sartor presented the data on PSMAfore trial where lutetium therapy was used before chemotherapy. In this trial lutetium therapy was compared with another novel hormonal therapy after disease progression on 1 novel hormonal therapy. And there was approximately 6-month improvement in progression-free survival, meaning there was a delay in disease progression by 5 to 6 months in patients who were receiving lutetium therapy. And at the time of the report, there was no improvement in overall survival, with the caveat that 84% patients who were receiving novel hormonal therapy, actually, they switched over to lutetium therapy after disease progression. So, overall, survival data may not be met. Having said that, we already know that lutetium therapy is an effective therapy, and it has a definitive role in treatment of our patients with metastatic castrate-resistant prostate cancer. Dr. Grivas: Thank you, Neeraj. That's very, very important data. And I'm so glad we have many more therapy options for our patients with prostate cancer. So involvement and accrual in clinical trials, I'm sure you will agree, is a very important and high priority. And I always encourage people with prostate cancer to ask about clinical trials that are relevant to their situation. Dr. Agarwal: Yeah. I'd just like to add a point regarding lutetium therapy that there was a phase 2 trial in from Australia which compared lutetium therapy with cabazitaxel therapy after disease progression and docetaxel chemotherapy. And efficacy of both agents were not very different. So just wanted to make that point. Dr. Grivas: Thank you, Neeraj. It's a very important point. And obviously, always want to think about pace and preference, convenience, distance from the cancer centers, all the relevant points, how we can individualize suggestions or recommendations for our patients. Thank you so much, Neeraj, for your wonderful input, insights, and all the work you do in the field. Dr. Agarwal: Thank you very much for having me. Dr. Grivas: Of course, of course. And now we're going to transition to a different cancer type. We're going to talk about bladder cancer and urothelial cancer in general, urinary tract cancer. And we're delighted and excited to have Dr. Shilpa Gupta from Cleveland Clinic, who's a professor there of oncology. Shilpa, I want to introduce yourself? Dr. Gupta: I'm Shilpa Gupta. I'm a genitourinary medical oncologist and the director of the GU Program at Cleveland Clinic. I'm really excited to be doing this podcast with you all. Dr. Grivas: Thank you, Shilpa. You have done amazing work in the field, pushing the field forward. You are part of those transformative studies. I will ask you in the beginning where I'm going to focus my first question for people who have advanced or metastatic bladder cancer or urinary tract cancer or upper or lower tract. And we saw really exciting, impressive data at the recent ESMO Congress in Madrid a couple of months ago. And I know you were there and were enjoying to see the improvement in patient outcomes that comes with better quality of life for patients in the last several years. And the question I have for you, if you want to summarize the key data in the first-line treatment, patients who have no prior treatment for metastatic urothelial cancer, what are the key data we showed at the ESMO meeting? Dr. Gupta: Thank you, Petros. As you said, this is a really exciting time for both patients as well as the physicians treating bladder cancer because of all the new developments which we've seen after decades. So at ESMO 2023, we saw the key data from the EV-302 trial, which was a phase 3 trial, which randomized patients to the standard of care, platinum-based chemotherapy, gemcitabine-cisplatin or gemcitabine-carboplatin, versus a novel drug, which is an antibody-drug conjugate called enfortumab vedotin and the immunotherapy pembrolizumab. And the primary endpoint was to see if patients lived longer and this delayed progression. And we saw that in this the progression-free survival, we saw that it was 12.5 months with enfortumab vedotin and pembrolizumab compared to 6.3 months, which means that the risk of progression or death was decreased by 55% with this new combination. And the benefit was seen across all the various factors, especially patients with liver metastases, visceral metastases, whether or not they had contraindications to receiving cisplatin or not or PD-L1 expression. So this is the first time we saw such a remarkable benefit with any treatment that beat platinums. And the overall survival was also doubled: 16 months in chemotherapy versus 31.5 months with this combination. So the risk of death was reduced by 53%. And we also saw that the overall response rates were 68% with this compared to 44% with chemo. And 29% of patients had complete responses. And this was really remarkable because we have not seen such data before. And in the same session, we also saw another phase 3 trial that was presented, which was the Checkmate 901 trial, in which the investigators tested whether the addition of immunotherapy called nivolumab to the standard of care, gemcitabine and cisplatin was better than gemcitabine and cisplatin alone. So this was a study only looking for patients who can receive cisplatin. So patients were randomized to 6 cycles of gemcitabine cisplatin versus nivolumab, gemcitabine cisplatin for up to 6 cycles. And after that, they continued nivolumab maintenance every month for up to 2 years. And in this, the primary endpoint of overall survival was also met, although the difference was not as huge as the other study. It was 18.9 months with chemotherapy versus 21.7 months with the combination. And progression-free survival was also improved by just 0.3 months with the combination. And the objective response rates were higher with the combination, 57% versus 43%, and there were 21% complete responses. So the bottom line is that both these trials showed us that the frontline treatment is not going to be just platinums anymore moving forward. We will have the option of the enfortumab vedotin and pembrolizumab for all comers, patients who can get platinums, and nivolumab and gemcitabine cisplatin for patients who are cisplatin eligible. Dr. Grivas: Thank you, Shilpa. Wonderful summary. Really, really exciting time to see the field moving forward and translate those results to longer life for our patients. In that context, I will also ask you—I asked Neeraj before about genetic testing in prostate cancer. I will ask you a similar question about genetic testing in bladder cancer. Again, reminding the audience about the distinction between germline testing, which is the DNA we are born with, and somatic testing, which is the cancer-specific genomic changes. Could you comment on the importance of genetic testing in bladder cancer? Dr. Gupta: Yes. Absolutely, Petros. Genetic testing in urothelial cancer is very important because for the first time a few years ago, we saw a drug targeting the fibroblastic growth factor receptor or FGFR alterations. This drug is called erdafitinib. It is the first targeted therapy to be approved in urothelial cancer. It is only seen in up to 20% of patients who harbor these alterations for whom this option may be viable. And we saw initially that erdafitinib was approved in patients who harbor these alterations in the phase 2 BLC2001 trial where it showed response rates of 40% and encouraging progression-free survival, and overall survival. And then we also saw in a phase 3 trial called the THOR trial where patients who harbored these alterations by genetic testing, erdafitinib was much better than chemotherapy, prolonged survival by almost 4.2 months compared to chemotherapy. So unless we are testing, we won't find this. So it is really important to test all our advanced disease patients so we are not depriving them of this additional targeted therapy. Dr. Grivas: Thank you, Shilpa. Very important message for our patients to definitely discuss the value of genetic testing. And if we think about therapy implications, specifically genomic changes, DNA changes in these FGFR-2 and FGFR-3 genes are very relevant and important for potential therapy with this agent called erdafitinib. Shilpa, a quick comment. We saw data from THOR cohort 2 comparing erdafitinib with this inhibitor of this FGFR that we just talked about compared to pembrolizumab, which is an immunotherapy drug inhibiting a checkpoint of the immune system. Could you quickly comment on that? And I think both options are available for our patients and sometimes just comes down to the sequence based on a particular patient case. Dr. Gupta: So Petros, as we had thought that patients who harbor these alterations in their tumors, they may benefit from using targeted therapy before immunotherapy. That was the premise of the cohort 2 of the THOR trial, that patients will do better if they received erdafitinib first after progressing on 1 prior line of therapy, which is not an immunotherapy. So patients were randomized to erdafitinib versus pembrolizumab. Of course, all of them had to have the FGFR alterations. The primary endpoint was overall survival. Initially, like I said, the study assumed that there'll be 46% improvement in overall survival with erdafitinib over pembrolizumab. However, the study was a negative study. There was no difference in the overall survival. And what that means for our patients is that erdafitinib right now is positioned for patients who've had prior platinums and immunotherapies. So erdafitinib should not be used before immunotherapy. So I think this is the first study that really settles the question of sequencing for our patients. And I think the message is that in a patient's journey, they should be getting all these therapies. We just now know that it's better to use pembrolizumab before erdafitinib and not vice versa. Dr. Grivas: Thanks, Shilpa. And then really, really interesting to see these trials being reported. And as you said, individual discussion with the patients and the response rate may be another factor to consider. If someone wants to have a more rapid control of the cancer of the disease, we may potentially think about an agent with high response rate and vice versa. So I think to your point, individual decisions. And I think patients asking those questions is very important in the clinic to help select the right patient for the right treatment for the right patient. Dr. Gupta: Yeah. Absolutely, Petros. They did see that the response rates were 40% with the erdafitinib versus 21% with the immunotherapy. So using that information can sometimes guide us if a patient has high disease burden. Dr. Grivas: Thank you, Shilpa. That was very insightful. And thank you for all you are doing for the patients and the field in general. You really, really have helped the field move forward. So congratulations and thank you. And we're going to transition to another superstar in the field of GU cancers. Very excited to host Dr. Tian Zhang. Dr. Zhang is in UT Southwestern in Dallas. Tian, you want to introduce yourself? Dr. Zhang: Hi, Petros. Thank you so much. Tian Zhang, I'm a GU medical oncologist and associate professor at UT Southwestern Medical Center in Dallas. Dr. Grivas: Wonderful. Thanks, Tian. Again, the same comments. All the work you're doing in the field is tremendous. Thanks for joining us today. Tian, we saw some very interesting data at the ESMO meeting. And since we're doing the highlights of the year, I think the predominance of the data we saw at the ESMO meeting was about this drug called belzutifan, where I will ask you to enlighten us what exactly this is. And particularly, we saw 3 different trials. I would probably ask you to focus more on the LITESPARK-005. What was the trial design and what was the primary goal of the study? When patients go on this drug, what they should be aware in terms of side effects? And what was all this discussion that the take-home message at the end of ESMO regarding belzutifan? Thank you. Dr. Zhang: Sure. We'll parse that one at a time. Belzutifan, I hope many of our audience knows is a small molecule inhibitor of the HIF complex, a hypoxia-inducible factor complex, which is implicated in the development of kidney cancers. And this biology actually contributed to the Nobel Prize in 2019. Understanding the structure of the HIF complex and how to target it. For a long time, HIF was thought to be un-targetable. And so the fact that there were small molecules identified actually here in Dallas at UT Southwestern that inhibits the dimerization of the HIF complex is really novel and shows us the bench-to-bedside translatability of these preclinical discoveries. And so there were a couple of molecules that were discovered here on campus and they paved the way for what became molecules that have now made it to clinic, in particular belzutifan. And so we've had belzutifan now approved for Von Hippel-Lindau Syndrome over the last 2 years or so. So many of us are familiar with using this drug in the clinic. It's an oral agent that's able to target the HIF complex and block it and really control the spread of clear cell kidney cancers, in particular in Von Hippel-Lindau disease. LITESPARK-005, the trial that you're alluding to, there was a registrational trial for belzutifan across other kidney cancer populations. And this trial was the 1 that made, I think, the biggest impact of the 3 trials that were presented at ESMO this year. LITESPARK-005 was a phase 3 trial of patients who had metastatic or locally advanced clear cell kidney cancer who had progressed after prior systemic therapies, not more than 3 prior lines. And they were randomized to either belzutifan at the 120 milligrams daily dose or everolimus at the 10 milligrams daily dose. And the primary endpoint was delay of progression. So progression-free survival as well as overall survival. So we saw the primary endpoint of these was met for progression-free survival. There was about a 26% risk reduction for progression for patients treated with belzutifan versus those that were treated with everolimus. The objective response rate I would highlight is also significant for the patients treated with belzutifan. There was actually a 3.5% complete response rate and objective responses. So including partial responders was about 23%. I would say that patients who are treated with belzutifan need to be aware of the side effects of anemia and also hypoxia [low levels of oxygen in the body]. And in fact, higher grades of anemia can occur in up to a third of patients and higher rates of hypoxia. So low oxygen saturations can occur in up to 10% or so of patients. And so that's really important when we're thinking about those toxicities and how we might hold or support the side effects with growth factors, for example, for the anemia. Otherwise, it's quite well tolerated as a single agent. As you alluded to, there was 1 controversial aspect of this particular trial because the control cohort was treated with everolimus. And everolimus as a single agent may not be what people use at this point in the refractory setting. But it is an acceptable approved treatment option for patients in the refractory kidney cancer setting, and therefore, it was chosen as the control cohort. And belzutifan did improve compared to a known standard of treatment. So I think that's really important to add to our armamentarium in refractory disease. Dr. Grivas: Wonderful, Tian. Thank you so much for a really, really comprehensive and detailed review. We'll have to see whether it will be available for patients with advanced clear-cell kidney cancer. To your point, it's already available for patients with this condition that you mentioned, the Von Hippel-Lindau genetic condition. So it's great to see more options available for our patients. Maybe I'll ask you another quick trial to comment on Tian, and I'll ask you individual questions to make it easier, to your point, for the audience to follow. And I'm referring to the RENOTORCH trial. This was conducted in China, and I think it was practice-changing there. Could you tell us the study design? Dr. Zhang: RENOTORCH was another phase 3 randomized trial. It was conducted all in China of patients with unresectable metastatic clear cell kidney cancer, no systemic prior therapy, and also intermediate- and poor-risk disease by IMDC criteria. So these were all first-line metastatic disease, and patients were randomized to either toripalimab, which is their PD-1 inhibitor, plus axitinib versus sunitinib. So this is a trial design that mirrors many of our prior trials in the first-line metastatic setting that have led to approvals of VEGF IO [immunotherapy] combinations. But this is the first one that was carried out purely in the Chinese population and important for the Chinese population to gain access to these types of combinations. Dr. Grivas: Thank you, Tian. Very important to see this global approach, as you mentioned, oncology and see trials from different countries. What were the main findings of this trial? Dr. Zhang: Sure. The primary endpoint was progression-free survival of the 2 cohorts. And they randomized about 420 patients. About 80% per cohort had intermediate-risk disease. And the combination of axitinib with toripalimab did improve progression-free survival. So it had a 35% risk reduction for progression over time. So it did meet its primary endpoint. Dr. Grivas: Thank you, Tian. It's great to see progress in the field. As I mentioned, new agents, positive trials. Could you comment a little bit on the side effect profile and the significance of this trial for our patients worldwide? Dr. Zhang: Sure. When we're talking about VEGF IO combinations very similarly as to the prior trials that we've seen in the toxicity profiles, we're thinking a lot about the immunotherapy toxicities of rashes and colitis [inflammation of the colon], endocrinopathies [hormone problems], as well as the rare inflammatory reactions of the liver, lungs, or kidney, but also added in the small molecule effects of hypertension, hand-foot syndrome, and mucositis [mouth sores] and taste changes. So very important to think through those side effect profiles as our patients are being treated with these combinations. Dr. Grivas: Thank you so much, Tian. Great to see, again, this progress made worldwide. And I think it speaks to the idea of how we can have equitable healthcare delivery across the globe, right, and have agents accessible in different parts of the world. Dr. Zhang: Absolutely. In fact, I would just add that the Chinese population haven't actually had access to drugs like cabozantinib. And this is their first phase 3 grade 1 evidence for a combination of VEGF with IO combination. So it's really important that these trials are carried out in the populations where we try to find the effect and see that the consistent benefit is there so that those patients have access to all of these treatment options. Dr. Grivas: Thank you, Tian. I appreciate your wonderful insights and all your amazing contributions in the field and your research. It's really, really inspiring to see. And I'm going to transition now. Last but not least, we're having the honor of hosting professor, Dr. Tim Gilligan, who is in Cleveland Clinic, and Tim is a world-known expert in urinary cancers, including testicular cancer. Tim, would you like to introduce yourself? Dr. Gilligan: Yes. Hi. So I think you just did. Tim Gilligan, an oncologist at Cleveland Clinic. I chaired the NCCN panel on testis cancer and edit the UpToDate sections on testis cancer with their help. Dr. Grivas: Fantastic. Thanks, Tim, for being with us today. And all the work you have done for our patients with GU cancers, testicular cancer, and a lot of work is being done with the NCCN and other guidelines. And you are co-chairing the NCCN guidelines, to your point. Tim, a lot of discussion is happening nowadays across cancer types regarding the role of what we call biomarkers, which are potential features that can help us select patients for the right treatment or help us estimate the prognosis, how long people live. Could you comment a little bit on this biomarker called microRNA in patients with testis cancer? How do you envision this being developed in the future? Is it ready for prime time or not yet? Dr. Gilligan: And that's an important question. It's not ready for prime time yet, but we are making progress. There are a couple of areas where it could be very useful. So for example, in stage I testicular cancer, we tell patients to go on surveillance because they're usually cured with orchiectomy [surgical removal of the tumor and testicle], but there is a risk of relapse, and that risk of relapse is highly variable. And our current risk stratification systems for predicting who's going to relapse, who has stage 1 disease, are helpful, but they're far from perfect. And so there was data presented this year that mRNA may be more accurate at predicting for men with stage I non-seminomas who's destined to relapse. And so the implication of that would be if you are positive for mRNA, this particular mRNA for non-seminoma and you have stage I disease, normal scans, normal markers, you could identify a high-risk group of patients who maybe should get a cycle of BEP chemotherapy rather than waiting. If you know they're going to relapse, you're going to have to get them 3 cycles of BEP, why not just treat them right away? Or maybe RPLND [retroperitoneal lymph node dissection] could be helpful in that setting. We don't know. But we would need to do studies validating that approach. There is data showing that it does predict relapse, but it's not at the point of saying, "Are the patients really going to do better with immediate treatment and which treatment is going to be best for them?" But I thought that was an important finding and really an example of how we think we're going to use it, which is to find relapse a lot earlier and so that we can give a less toxic treatment. And the benefit of that is that we know more and more that chemotherapy is toxic and resulted in second cancers. For men who get multiple cycles of cisplatin-based chemotherapy, or if they get radiation therapy, they're at higher risk of dying of other cancers than the general population. So if this could help us find early relapses, treat it more gently, less aggressively, have late, less toxicity, and the same cure rate. That would be great. So we're not there yet, but I think we're going to get there. Dr. Grivas: Thanks, Tim. Very, very helpful to know. So this microRNA 371 that we talk about is not ready for prime time, but you definitely see promise for the future, and more trials, more studies are being done. Again, illustrating the importance of clinical trials that can help us evaluate the added value of a particular biomarker, including this particular microRNA that we talked about. Dr. Gilligan: Before you change the subject on getting to crude biomarkers, there was also an interesting abstract showing that for stage I seminoma. If we actually use our current markers, we may be able to predict much more accurately. And it'll be interesting to see if that changes. They looked at the variables of lymphovascular invasion, invasion of the hilum of the testis, whether or not preoperative markers were elevated, LDH, and beta HCG. What was interesting to me about that paper was that this is about 900 patients. It was pretty large. That if you had all 4 risk factors, the relapse rate was about 64%. Whereas your average relapse risk for stage I seminoma is about 15%. We put everyone on surveillance. If we started if that model is persuasive to the community and starts getting used, then maybe patients with those 4 risk markers who most of whom are going to relapse, according to this data, maybe you want to treat those people and not put them on surveillance. So that'll be interesting to follow up on too. Dr. Grivas: Thanks, Tim. And you are referring to currently available blood tests, right, that can be used, and we use them in clinical practice. So we just put them together, try to get a sense of the chance of cancer coming back, what we call recurrence, and how long people may live. That can help us make a therapy decision. Thank you, Tim. This is very, very interesting. And I'm glad to see the progress in the field. I think you alluded to that before, but there is a trend discussing when we have a removal of the testicle for a patient with testis cancer, what to do next, depending on the stage, those markers that the blood tests you told us about. What about the role of surgery for removal of lymph nodes, for example? And do you see a trend going forward that in many selective cases, certain scenarios, we may potentially select surgery as opposed to chemotherapy or radiation to avoid these potential complications down the road? And if so, which are those patients who may benefit from surgery? Dr. Gilligan: Yeah, an important question. I think surgery, there's been a growing interest in using surgery rather than chemotherapy in order to avoid late effects. So retroperitoneal lymph node dissection (RPLND) is the most obvious example of that. There is data now showing that most patients with stage II seminoma can be cured with retroperitoneal lymph node dissection. We used to treat those patients with chemotherapy or radiation, but as I've noted, both of those are associated with an increased risk of second cancers down the line. So there are papers on both sides of the Atlantic showing that you can cure most people. However, it is important to note that the relapse rate after surgery is significantly higher than the relapse rate after chemotherapy or radiation. If you take a stage II patient and treat them with chemotherapy or radiation, you're going to cure well over 90% of them. Whereas the relapse risk with surgery, depending on what you find at surgery, is going to be higher. So on average, it's going to be in the realm of 20%, maybe as high as 30%, depending on which paper you look at. And if you take patients who have PN2 disease, so a lymph node is 2 centimeters or bigger, 25% or more of those patients are relapsing after surgery. So it's important for patients to understand that this treatment has the benefit of avoiding chemotherapy for most patients, but it also has a higher risk of relapse than the old treatments. We still think it's attractive because if you can avoid chemotherapy in 3 out of 4 patients or 4 out of 5 patients, that's a benefit to those patients. And also, if you go in and find a significant amount of cancer at surgery, you can give 2 cycles of chemotherapy right away and almost eliminate the risk of relapse, which is less chemo than they would be getting upfront, which would be 3 or 4 cycles. So one of the emphasis now is really trying to avoid late toxicities if we can. You sometimes see that even in the metastatic setting in terms of resecting residual masses and situations where we maybe in the past would have thought about second-line chemotherapy. I think people are more thinking about opportunities to use surgery instead to try to limit the quantity of chemo that we're giving. Those are much trickier decisions than the stage II decisions, but definitely a growing interest in surgery rather than chemo. Dr. Grivas: Thank you so much. It's really, really exciting to see that testis cancer was really transformed in the past with developments of therapies like chemotherapy, radiation therapy, and surgery. And it's great to see this evolving down the road. And I think all of the above that you mentioned evolves through the conduction of clinical trials. And as I mentioned before, I think it's so important to give the opportunity for patients and families to review clinical trial options. I think it's critical to try to help them, but also help other patients, the community, the society in general. So I always try to underline the importance of clinical trials across the board. And on that note, I think we had such a successful year, 2023 across GU cancers. It's so great to see the progress being made. All of us are looking forward for more exciting research being done in 2024 and beyond. And on that note, I want to thank so much Dr. Agarwal, Dr. Gupta, Dr. Zhang, and Dr. Gilligan for wonderful insights and all the great work they're doing in the field of GU cancers. As the editor for the GU Cancers for the wonderful Cancer.Net, I'm so proud of this team and really, really looking forward to further podcasts like this and how we can better serve the educational mission for ASCO, working with the wonderful staff at Cancer.Net. Thank you so much, all of you, for your time today and all you are doing. Dr. Gupta: Thank you, Petros. Dr. Zhang: Thank you, Petros. ASCO: Thank you, Dr. Grivas, Dr. Agarwal, Dr. Gupta, Dr. Zhang, and Dr. Gilligan. You can learn more about new research in genitourinary cancers at www.cancer.net. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.
Drs. Neeraj Agarwal and Jeanny Aragon-Ching discuss several key abstracts to be presented at the 2024 ASCO GU Cancers Symposium, including sequencing versus upfront combination therapies for mCRPC in the BRCAAway study, updates on the CheckMate-9ER and CheckMate-214 trials in ccRCC, and a compelling real-world retrospective study in mUC of patients with FGFR2 and FGFR3 mutations. TRANSCRIPT Dr. Neeraj Agarwal: Hello, everyone, and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host of the podcast today. I am the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah's Huntsman Cancer Institute, and editor-in-chief of ASCO Daily News. I am delighted to welcome Dr. Jeanny Aragon-Ching, a genitourinary oncologist and the clinical program director of Genitourinary Cancers at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing key posters and oral abstracts that will be featured at the 2024 ASCO Genitourinary Cancer Symposium, which is celebrating 20 years of evolution in GU oncology this year. You will find our full disclosures in the transcript of this podcast, and disclosures of all guests on the podcast at asco.org/DNpod. Jeanny, it's great to have you on the podcast today to highlight some key abstracts for our listeners ahead of the GU meeting. Dr. Jeanny Aragon-Ching: Thank you so much, Neeraj. It's an honor to be here. Dr. Neeraj Agarwal: Jeanny, as you know, this year we are celebrating the 20th anniversary of the ASCO GU Cancers Symposium, and judging from this year's abstracts, it's clear that this meeting continues to play a major role in advancing GU cancer research. Dr. Jeanny Aragon-Ching: Indeed, Neeraj. This year's abstracts reflect the important strides we have made in GU cancers. So, let's start with the prostate cancer abstracts. What is your takeaway from Abstract 19 on BRCAAway, which will be presented by Dr. Maha Hussein, and of which you are a co-author? As our listeners know, several PARP inhibitor combinations with second-generation androgen receptor pathway inhibitors, or ARPIs, have recently been approved as first-line treatment for patients with metastatic castrate-resistant prostate cancer, or metastatic CRPC, and the question of sequencing PARP inhibitors and ARPIs instead of combining them has emerged. From that perspective, the results of the BRCAAway trial are very important. Can you tell us a little bit more about this abstract, Neeraj? Dr. Neeraj Agarwal: I totally agree with you, Jeanny. The BRCAAway study attempts to answer the crucial questions regarding sequencing versus upfront combination of therapies in the mCRPC setting. It is a phase 2 trial of abiraterone versus olaparib versus abiraterone with olaparib in patients with mCRPC harboring homologous recombination repair mutations. Enrolled patients had mCRPC disease and no prior exposure to PARP inhibitors or ARPIs or chemotherapy in the mCRPC setting and had BRCA1 or BRCA2 or ATM mutations. As previously mentioned, these patients were randomized to 3 arms: abiraterone monotherapy at 1000 milligrams once daily, or olaparib monotherapy at 300 milligrams twice daily, or the combination of abiraterone and olaparib. The primary endpoint was progression-free survival per RECIST 1.1 or Prostate Cancer Working Group 3-based criteria or clinical assessment or death, so, whichever occurred first was deemed to be progression. Secondary endpoints included measurable disease response rates, PSA response rate, and toxicity. This was a relatively small trial with 21 patients in the combination arm, 19 patients in the abiraterone monotherapy arm, and 21 patients in the olaparib monotherapy arm. It should be noted that 26% of patients had received docetaxel chemotherapy in the hormone-sensitive setting, and only 3% of patients had any prior exposure to an ARPI, and these were darolutamide or enzalutamide or in the non-metastatic CRPC setting. The results are very interesting. The median progression-free survival was 39 months in the combination arm, while it was 8.4 months in the abiraterone arm and 14 months in the olaparib arm. An important finding that I would like to highlight is that crossover was also allowed in the monotherapy arms. Of the 19 patients receiving abiraterone, 8 crossed over to receive olaparib, and of the 21 patients receiving olaparib, 8 crossed over to the abiraterone arm. The median PFS from randomization was 16 months in both groups of patients who received abiraterone followed by olaparib or those who received olaparib followed by abiraterone. This is striking when compared to 39 months in patients who started therapy with the combination therapy of abiraterone with olaparib. Dr. Jeanny Aragon-Ching: Thank you so much for that wonderful summary, Neeraj. So the key message from this abstract is that combining olaparib and abiraterone upfront seems to be associated with improvement in PFS compared to just sequencing those agents. Dr. Neeraj Agarwal: Exactly, Jeanny. I would like to add that these results are even more important given that in real-world practice, only half of the patients with mCRPC receive a second-line treatment. Based on these results, upfront intensification with a combination of an ARPI plus a PARP inhibitor in the first-line mCRPC setting seems to have superior efficacy compared to sequencing of these agents. Dr. Jeanny Aragon-Ching: Thank you so much. Now, moving on to a different setting in prostate cancer, there were a couple of abstracts assessing transperineal biopsy compared to the conventional transrectal biopsy for the detection of prostate cancer. So let's start with Abstract 261. Neeraj, can you tell us a little bit more about this abstract? Dr. Neeraj Agarwal: Sure, Jeanny. So, in Abstract 261 titled "Randomized Trial of Transperineal versus Transrectal Prostate Biopsy to Prevent Infection Complications," Dr. Jim Hugh and colleagues led a multicenter randomized trial comparing these 2 approaches, so, transperineal biopsy without antibiotic prophylaxis with transrectal biopsy with targeted prophylaxis in patients with suspected prostate cancer. The primary outcome was post-biopsy infection. Among the 567 participants included in the intention-to-treat analysis, no infection was reported with the transperineal approach, while 4 were detected with the transrectal approach, with a p-value of 0.059. The rates of other complications, such as urinary retention and significant bleeding, were very low and similar in both groups. The investigators also found that detection of clinically significant cancer was similar between the 2 techniques and concluded that the transperineal approach is more likely to reduce the risk of infection without antibiotic prophylaxis. Dr. Jeanny Aragon-Ching: So the key takeaway from this abstract sounds like office-based transperineal biopsy is well-tolerated and does not compromise cancer detection, along with better antibiotic stewardship and health care cost benefits. Moving on to Abstract 273, also comparing these two approaches, what would be your key takeaway message, Neeraj? Dr. Neeraj Agarwal: In this Abstract 273, titled "Difference in High-Risk Prostate Cancer Detection between Transrectal and Transperineal Approaches," Dr. Semko and colleagues found that the transperineal biopsy based on MRI fusion techniques was also characterized by a higher possibility of detecting high-risk prostate cancer and other risk factors as well, such as perineural and lymphovascular invasion or the presence of cribriform pattern, compared to the conventional transrectal method. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So we can see that the transperineal approach is gaining more importance and could be associated with more benefits compared to the conventional methods. Let's now switch gears to kidney cancer, Neeraj. Dr. Neeraj Agarwal: Sure, Jeanny. Let's start by highlighting Abstract 361, which discusses patient-reported outcomes of the LITESPARK-005 study. So what can you tell us about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So as a reminder to our listeners, based on the LITESPARK-005 trial, it was a Phase 3 trial looking at belzutifan, which is an inhibitor of hypoxia inducible factor 2 alpha or I'll just call HIF-2 alpha for short, was very recently approved by the FDA as a second-line treatment option for patients with advanced or metastatic clear cell renal cell carcinoma after prior progression on immune checkpoint and antiangiogenic therapies. The title of Abstract 361 is "Belzutifan versus Everolimus in Patients with Previously Treated Advanced RCC: Patient-Reported Outcomes in the Phase 3 LITESPARK-005 Study," and this will be presented by Dr. Tom Pells at the meeting. At a median follow-up of 25.7 months, the median duration of treatment with belzutifan was 7.6 months, while it was only 3.9 months with everolimus. At the time of data cutoff date for the second interim analysis, 22.6% of patients remained on belzutifan while only 5% remained on everolimus. In the quality of life questionnaires, the time of deterioration to various quality of life scores, as assessed by standardized scales, was significantly longer in patients randomized to the belzutifan arm compared to those in the everolimus arm. Also, patients in the everolimus arm had worse physical functioning scores. Dr. Neeraj Agarwal: Yes, Jeanny. In addition to the improved outcomes associated with belzutifan, patient-reported outcomes indicate better disease-specific symptoms and better quality of life among patients treated with belzutifan compared to everolimus. This is great news for patients with advanced renal cell carcinoma. Now, Jeanny, can you please tell us about the two abstracts that reported longer follow-up of CheckMate 9ER and CheckMate 214 trials in untreated patients with advanced or metastatic renal cell carcinoma? Dr. Jeanny Aragon-Ching: Yes, Neeraj. So you are referring to Abstracts 362 and 363. Let's start with Abstract 362. This abstract reports the results after a median follow-up of 55 months in the CheckMate 9ER trial, comparing the combination of nivolumab and cabozantinib to sunitinib in patients with advanced RCC without any prior treatment, so first-line therapy. The primary endpoint was PFS per RECIST 1.1 as assessed by an independent central review. So there were key secondary outcomes including overall survival (OS), objective response rates, and safety. Consistent with prior analysis at a median follow-up time of 18.1 and 44 months, the combination of nivolumab and cabozantinib at a median follow up of 55.6 months continues to show a significant reduction in the risk of progression or death by 42% and in the risk of death by 23% compared to sunitinib. Dr. Neeraj Agarwal: And Jeanny, what can you tell us about the efficacy results of this combination by IMDC risk categories? Dr. Jeanny Aragon-Ching: Similar to prior results in patients with intermediate to poor risk IMDC risk category, the combination treatment maintained significant efficacy and reduced the risk of progression or death by 44% and the risk of death by 27%. To put it simply, the update now shows a 15-month improvement in overall survival with the cabozantinib-nivolumab combination compared to sunitinib, which is amazing. Also, in patients with favorable IMDC risk group, which represented truly a small number of patients in the trial, there was a strong trend for improvement of outcomes as well. I would like to point out that no new safety concerns were identified. Dr. Neeraj Agarwal: So, it looks like the key message from this abstract is that with longer follow-up, the combination of nivolumab and cabozantinib maintains a meaningful long-term efficacy benefit over sunitinib, supporting its use for newly diagnosed patients with advanced or metastatic renal cell carcinoma. Let's move on to Abstract 363, which compares nivolumab with ipilimumab to sunitinib in first-line advanced renal cell carcinoma. What would you like to tell us about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Yes, Neeraj. The title of this abstract is "Nivolumab plus Ipilimumab versus Sunitinib for the First-Line Treatment of Advanced RCC: Long-Term Follow-Up Data from the Phase 3 CheckMate 214 Trial." In this abstract, Dr. Tannir and colleagues report outcomes with the longest median follow-up in first-line advanced RCC setting for any clinical trial. So the median follow-up now is about 18 months. The primary endpoints were OS, PFS, and objective response rates, as assessed by an independent review according to RECIST 1.1 criteria in the intermediate to poor risk IMDC risk group, which is the intent-to-treat (ITT) analysis, while secondary outcomes included the same outcomes in the ITT population of patients. Although the progression-free survival was similar in both arms, the combination of nivolumab-ipilimumab reduced the risk of death by 28% compared to sunitinib in the ITT population of patients. When stratifying the results by IMDC risk groups, the combination arm of nivolumab-ipilimumab showed significant improvement in the intermediate to poor risk group, but there was no difference in the favorable risk group. But in the study, no new safety signals were identified. Dr. Neeraj Agarwal: Thank you, Jeanny, for such a comprehensive description of the results of these two studies. I'd like to add that the median overall survival of patients with metastatic renal cell carcinoma in the ITT population in the CheckMate 214 trial has now reached 53 months, which would have been unimaginable just a decade ago. This is wonderful news for our patients. So the key takeaway from these two abstracts would be that immune checkpoint inhibitor-based combinations remain the backbone of first-line advanced renal cell carcinoma treatment. Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. This is wonderful news for all of our patients, especially for those who are being treated for first-line therapy. Now, let's move on to the bladder cancer abstracts. We have two exciting abstracts from the UNITE database. What are your insights on Abstract 537, titled "Outcomes in Patients with Advanced Urethral Carcinoma Treated with Enfortumab Vedotin After Switch-Maintenance of Avelumab in the UNITE Study"? Dr. Neeraj Agarwal: As our listeners know, enfortumab vedotin is an antibody-drug conjugate that binds to a protein called Nectin 4 expressed on bladder cancer cells. In this abstract, Dr. Amanda Nizam and colleagues describe outcomes in 49 patients receiving third-line enfortumab vedotin after prior progression on platinum-based therapy and maintenance avelumab. At a median follow-up of 8.5 months, the median progression-free survival was 7 months and the median overall survival was 13.3 months with enfortumab vedotin in this treatment-refractory setting, the objective response rates were 54%. The message of this study is that enfortumab vedotin is an effective salvage therapy regimen for those patients who have already progressed on earlier lines of therapies, including platinum-based and immunotherapy regimens. Dr. Jeanny Aragon-Ching: Thank you, Neeraj, for that comprehensive review. I want to focus on another patient population in the UNITE database, which is the use of fibroblast growth factor receptor (FGFR) alterations. Can you tell us more about the sequencing now of erdafitinib and enfortumab vedotin in these patients with metastatic urothelial cancer, as discussed in Abstract 616? Dr. Neeraj Agarwal: Sure, Jeanny. As a reminder, erdafitinib is a fibroblast growth factor receptor kinase inhibitor approved for patients with locally advanced or metastatic urothelial carcinoma harboring FGFR2 or FGFR3 alterations after progression on platinum-based chemotherapy. However, the optimal sequencing of therapies in these patients is unclear, especially with enfortumab vedotin being approved in the salvage therapy setting and now in the frontline therapy setting. So in this retrospective study, all patients with metastatic urothelial carcinoma had FGFR2 or FGFR3 alterations. Dr. Cindy Jiang and colleagues report outcomes in 24 patients receiving enfortumab vedotin after erdafitinib, 15 patients receiving erdafitinib after enfortumab vedotin, and 55 patients receiving enfortumab vedotin only. This is a multicenter national study. Interestingly, patients receiving both agents had a longer overall survival in a multivariate analysis, regardless of the treatment sequencing, than patients receiving enfortumab vedotin alone or only with a hazard ratio of 0.52. The objective response rate of enfortumab vedotin in the enfortumab vedotin monotherapy arm was 49%. When these agents were sequenced, the objective response with enfortumab vedotin was 32% after erdafitinib and 67% when used before erdafitinib. Dr. Jeanny Aragon-Ching: Thank you so much, Neeraj. I think these are important real-world data results, but I would like to point out that larger and prospective studies are still needed to confirm these findings, especially regarding the outcome of erdafitinib after enfortumab vedotin, particularly when the latter is used in the first-line setting. Dr. Neeraj Agarwal: I totally agree, Jeanny. Now, let's discuss some abstracts related to disparities in the management of patients with genitourinary cancers. Dr. Jeanny Aragon-Ching: Sure, actually, I would like to discuss 2 abstracts related to disparities in patients with prostate cancer. So the first one, Abstract 265, titled "Patient-Provider Rurality and Outcomes in Older Men with Prostate Cancer." In this study, Dr. Stabellini, Dr. Guha and the team used a SEER Medicare-linked database that included more than 75,000 patients with prostate cancer. The primary outcome was all-cause mortality, with secondary outcomes included prostate cancer-specific mortality. The investigators showed that the all-cause mortality risk was 44% higher in patients with prostate cancer from rural areas who had a provider from a non-metropolitan area compared to those who were in a metropolitan area and had a provider also from a metropolitan area. Dr. Neeraj Agarwal: Those are very important data and highlight the healthcare disparities among the rural population with prostate cancer that still exist. So what is your key takeaway from Abstract 267, titled "Rural-Urban Disparities in Prostate Cancer Survival," which is a population-based study? Dr. Jeanny Aragon-Ching: Of course. This abstract discusses, actually, a very similar issue regarding access to healthcare among rural versus urban patients. In this study, Dr. Hu and Hashibe and colleagues and team at the Huntsman Cancer Institute assessed all-cause death and prostate cancer-related death risk in a retrospective study in which patients with prostate cancer based on rural versus urban residencies looked at 18,000 patients diagnosed with prostate cancer between 2004 and 2017. 15% lived in rural counties. Similar to the prior abstract we talked about, patients living in rural areas had about a 19% higher risk of all-cause mortality and a 21% higher risk of prostate cancer-specific mortality in comparison to patients living in urban areas. Dr. Neeraj Agarwal: So Jeanny, we can say that both of these abstracts, led by different groups of investigators, highlight that patients with prostate cancer living in rural areas have inferior survival outcomes compared to those living in urban areas, and it is time to focus on the disparities experienced by the rural population with prostate cancer. Dr. Jeanny Aragon-Ching: Yeah, absolutely Neeraj. I concur with your thoughts. So, any final thoughts before we wrap up the podcast today? Dr. Neeraj Agarwal: Yes, before concluding, Jeanny, I want to express my gratitude for your participation and the valuable insights you have shared today. Your contributions are always appreciated, and I sincerely thank you for taking the time to join us today. As we bring this podcast to a close, I would like to highlight the significant advances happening in the treatment of patients with genitourinary cancers during our upcoming 2024 ASCO GU meeting. Many studies featuring practice-impacting data will be presented by investigators from around the globe. I encourage our listeners to not only participate at this event to celebrate these achievements, but to also play a role in disseminating these cutting-edge findings to practitioners worldwide. By doing so, we can collectively maximize the benefit for patients around the world. And thank you to our listeners for joining us today. You will find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much. Disclaimer: The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guest speakers express their own opinions, experience, and conclusions. Guest statements on the podcast do not necessarily reflect the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers: Dr. Neeraj Agarwal @neerajaiims Dr. Jeanny Aragon-Ching Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas Dr. Jeanny Aragon-Ching: Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis, Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics.
Next up on the ESMO 2023 rollercoaster is an episode that is likely to be the shortest in our series: upper gastrointestinal and hepatobiliary oncology. As always, this remains a very challenging subarea of medical oncology, both in the clinical and trial spheres. However, our esteemed colleagues at ESMO remain undaunted by this challenge, and thus several studies of interest bear discussing. Will any of these studies lead to massive upheavals for clinicians and patients alike? For that answer, you'll have to listen on.Links to studies discussed in this episodes (subscription may be required):Tinengotinib in patients with advanced, fibroblast growth factor receptor (FGFR) inhibitor refractory/relapsed cholangiocarcinoma https://esmocongress.esmo.org/esmo/esmo2023/en-GB/presentation/638034GEMSTONE-303: Prespecified progression-free survival (PFS) and overall survival (OS) final analyses of a phase III study of sugemalimab plus chemotherapy vs placebo plus chemotherapy in treatment-naïve advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma https://esmocongress.esmo.org/esmo/esmo2023/en-GB/presentation/639003Nab-paclitaxel plus gemcitabine versus modified FOLFIRINOX or S-IROX in metastatic or recurrent pancreatic cancer (JCOG1611, GENERATE): A multicentred, randomized, open-label, three-arm, phase II/III trial https://esmocongress.esmo.org/esmo/esmo2023/en-GB/presentation/637982For more episodes, resources and blog posts, visit www.inquisitiveonc.comPlease find us on Twitter @InquisitiveOnc!If you want us to look at a specific trial or subject, email us at inquisitiveonc@gmail.comArt courtesy of Taryn SilverMusic courtesy of Music Unlimited: https://pixabay.com/users/music_unlimited-27600023/Disclaimer: This podcast is for educational purposes only. If you are unwell, seek medical advice. Hosted on Acast. See acast.com/privacy for more information.
Discussing GU (Genitourinary) Cancer ASCO 2023 Highlights, focusing on practice changing studies with Dr. Toni Choueiri, Director, Lank Center for Genitourinary Oncology and Professor of Medicine at Harvard Medicine School - Dana-Farber Cancer Institute. Covering four important studies: - TALAPRO-2: Ph3 study of talazoparib + enzalutamide vs placebo + enzalutamide as first-line (1L) treatment for mCRPC with homologous recombination repair (HRR) gene alterations - CLEAR: 4-year follow-up of lenvatinib plus pembrolizumab vs sunitinib in pts with advanced renal cell carcinoma - CONTACT-03: efficacy and safety of atezolizumab plus cabozantinib vs cabozantinib alone after progression with prior checkpoint inhibitor in metastatic renal cell carcinoma - THOR: Erdafitinib vs chemo in pts with advanced or metastatic urothelial cancer with select FGFR alteration
Featuring perspectives from Dr Matthew D Galsky, Prof Andrea Necchi and Dr Scott T Tagawa, including the following topics: Current and Future Management of Nonmetastatic Urothelial Bladder Cancer (UBC) Introduction (0:00) Management of non-muscle-invasive bladder cancer (5:30) Neoadjuvant and adjuvant therapy for muscle-invasive bladder cancer (18:39) Management of nonmetastatic UBC in patients who are not candidates for cystectomy (27:55) Recent Advances in the Treatment of Metastatic UBC (mUBC) Selection and sequencing of therapy for platinum-eligible patients with FGFR wild-type mUBC (31:03) Selection and sequencing of therapy for platinum-ineligible patients with FGFR wild-type mUBC (41:26) Selection and sequencing of therapy for patients with FGFR-altered mUBC (45:07) Novel agents and strategies under investigation in UBC (53:53) CME information and select publications
Featuring perspectives from Dr Anthony El-Khoueiry, Dr Robin K (Katie) Kelley and Prof Arndt Vogel, includingthe following topics: Hepatocellular Carcinoma (HCC) Introduction (0:00) Adjuvant therapy for HCC (1:47) First-line systemic therapy for advanced/metastatic HCC (10:36) Management of HCC in the second-line setting and beyond (18:27) Biliary Tract Cancers (BTCs) First-line systemic therapy for metastatic BTCs (26:41) Management of metastatic cholangiocarcinoma with FGFR fusions/rearrangements (35:16) Management of metastatic cholangiocarcinoma with IDH1 mutations (43:54) Management of metastatic HER2-positive BTC (48:47) CME information and select publications
Drs. Rana McKay and Jonathan Rosenberg highlight key advances in genitourinary cancers featured at the 2023 ASCO Annual Meeting, including the THOR study in mUCC, VESPER in muscle-invasive bladder cancer, CONTACT-03 in mRCC, and TALAPRO-2 in mCRPC. TRANSCRIPT Dr. Rana McKay: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Rana McKay, your guest host for the podcast today. I'm a GU medical oncologist at the Morris Cancer Center at the University of California in San Diego and an associate professor at the University of California in San Diego School of Medicine. Joining me today is Dr. Jonathan Rosenberg, the chief of the Genitourinary Oncology Service at the Memorial Sloan Kettering Cancer Center in New York. We'll be discussing practice-changing studies and other key advances in genitourinary cancers that were featured at the 2023 ASCO Annual Meeting. You'll find our full disclosures in the transcript of this episode, and disclosures of all guests featured on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod. Jonathan, it's great to have you with us today. How are you? Dr. Jonathan Rosenberg: I'm doing very well. Thanks so much for hosting today. Dr. Rana McKay: Oh, of course. It's always fun to step back from ASCO and reflect on all the practice-changing and practice-informing studies that were presented. Dr. Jonathan Rosenberg: Absolutely. Dr. Rana McKay: Maybe we can dive right in with LBA4619. This is the much-talked-about THOR study of erdafitinib versus chemotherapy in patients with advanced or metastatic urothelial cancer with select FGFR alterations. What are your key takeaways from this study? Dr. Jonathan Rosenberg: It is indeed a study we've been waiting for, for quite some time, to see the results in the confirmatory study after the accelerated approval of erdafitinib. This is half of the THOR trial. There were 2 cohorts of patients. One cohort were patients who previously received a checkpoint inhibitor randomized to chemotherapy or erdafitinib, and those data were reported at ASCO this year. The other cohort was randomized against a checkpoint inhibitor in patients who have not received a checkpoint inhibitor, and we'll see those data in a future meeting. The bottom line for the THOR study is that FGFR3 inhibition improved overall survival compared with chemotherapy, and the chemotherapy in this study was a taxane. The overall survival was 12.1 months for erdafitinib compared to 7.8 months for chemotherapy with a hazard ratio of 0.64. This led to the DMC to stop the study and blind the data and cross people over. There was also a PFS advantage. There really weren't a lot of new toxicity signals seen; the usual suspects in terms of mucositis, hyperphosphatemia, diarrhea, dry mouth, and onycholysis. And so, what it tells us ultimately is that in a patient who's progressed on a checkpoint inhibitor, we can feel comfortable about using erdafitinib knowing it provides a survival advantage in patients who've been previously treated for advanced urothelial cancer and have an FGFR alteration, either an FGFR2 or 3. And hopefully, we'll see more data in the future from the study, maybe not too long in the future from the other part of the study, comparing it to checkpoint inhibition. Dr. Rana McKay: That's really exciting. I think it's exciting to see the data about the positivity of erdafitinib versus chemotherapy in this context. Looking at the phase 3 data is going to be really important. Looking at the data in the IO naive context is going to be really important. I feel like this sort of reaffirms what we've been doing in clinical practice. But how do you feel that the study is practice-changing? Dr. Jonathan Rosenberg: I think it gives us reassurance that for these patients, erdafitinib is an appropriate option. There's no randomized data between erdafitinib and other choices, such as sacituzumab, which is also based on an accelerated approval, or enfortumab, which is based on randomized phase 3 trial. But it gives us level-1 evidence. I do wonder whether the comparison against the checkpoint inhibitor may turn out differently, but we'll see. Those data aren't in evidence. And I do think it was interesting that the majority of patients who were enrolled on the trial were PDL-1 low. We'll see what the comparison to a checkpoint inhibitor is like and whether those patients have similar characteristics. Dr. Rana McKay: Yeah, you're almost kind of selecting for people that were not primed to respond. Dr. Jonathan Rosenberg: Exactly. Dr. Rana McKay: Well, that's really exciting, I think. Moving on to localized bladder cancer, Dr. Pfister presented the results of the VESPER trial. That's LBA4507. I think this study was really important. This was a trial that explored dose-dense MVAC with methotrexate, vinblastine, doxorubicin, and cisplatin or gemcitabine-cisplatin as a perioperative chemotherapy for muscle-invasive bladder cancer. I think there's always been some discussion around these regimens and how they pair up against one another. Can you tell us about these data? Dr. Jonathan Rosenberg: It's a very interesting study. It was designed back when it was felt that we could not give patients neoadjuvant therapy. And it was designed as either a neoadjuvant or adjuvant approach. Although, in reality, almost everybody who was enrolled in the study got neoadjuvant chemotherapy, which I think speaks to the shift in practice over the last 10 to 15 years towards neoadjuvant rather than adjuvant therapy. It's an interesting trial in that it used a duration of chemotherapy for the MVAC regimen, the dose-dense MVAC regimen that we don't usually use, which is 6 cycles. And functionally, about 40% of patients couldn't make it to 6 cycles and had to stop sooner, versus 4 cycles of q3-week gemcitabine and cisplatin. And what the data show is that the progression-free survival for the entire intent-to-treat population didn't reach significance. But if you looked at the neoadjuvant population only, there was an improvement in progression-free survival as well as overall survival. So, it's sort of a negative positive trial. Negative for the primary endpoint, but positive for key secondary endpoints. They did a very interesting analysis looking at the number of cycles that patients received regardless of arm, but looking at it by arm. And it's clear from that analysis that the more chemotherapy they got, the better they did. Although, the flaw in that analysis is that the healthier patients are, the more chemotherapy they're able to tolerate, and therefore that may translate to an improved overall survival irrespective of the amount of chemotherapy. And this was not necessarily a pre-specified analysis. I think some of the statisticians were clutching their chests during the report of this trial, having talked to several afterward. On the other hand, it does say to me that for a fit, younger patient, it is important to consider dose-dense MVAC instead of gemcitabine and cisplatin. I'll also note, reading the publication from the first part of the trial, that it appears that nobody over 70 was enrolled from everything I could tell. And so, I question the validity of the tolerability of the results for the average 75-year-old that I see in my practice. Although age is not a bright line cut-off for anybody in terms of cancer treatment. But my own experience has been that dose-dense MVAC has been harder to tolerate for a lot of patients in their 70s, whereas I think we should feel quite comfortable giving it to patients in their sixties. And if you ask me how many cycles I would give, I probably wouldn't say 6, for dose-dense MVAC, I would probably say 4. Dr. Rana McKay: Was there a predilection that there was a more aggressive disease like nodal disease or other things to prompt the 6 versus 4? Dr. Jonathan Rosenberg: I think that they stopped primarily for toxicity reasons, but it wasn't clear to me that it was a disease-based issue. And for the neoadjuvant therapy, everyone was supposed to be clinically node-negative on entry, so that probably wouldn't have explained it. Dr. Rana McKay: Very exciting. I know that the data were quite provocative, but I think it's always difficult to interpret these sorts of subgroup of subgroup analyses, and there's a lot of bias in why people may get more versus less. And I think trying to reduce these data to clinical practice is going to be really important, as you've stated. Dr. Jonathan Rosenberg: Rana, I'd also like to talk about some key advances in renal cell carcinoma that were reported at ASCO. Dr. Choueiri presented data on LBA4500, the CONTACT-03 study, which really was the first study of its kind in solid tumors because it addressed a major question in the kidney cancer field and in other fields: Is there a role for immunotherapy rechallenge after progression on immunotherapy? Specifically, the study looked at the efficacy and safety of atezolizumab plus cabozantinib versus cabozantinib alone after progression with prior immune checkpoint inhibitor therapy in metastatic RCC. I'd like you to tell me what you think of this study and the results and how they may affect our practice. Dr. Rana McKay: Absolutely. This was a critically important study looking at the role of IO post-progression on IO. It was a large phase 3 trial that enrolled patients with clear cell and non-clear cell patients. It actually allowed patients with papillary RCC, unclassified RCC, to enroll in the study, whereas most of these studies are excluding patients with non-clear cell disease. Patients had to have progressed on an immune checkpoint inhibitor given either as adjuvant first line or second line, given either as a single agent or in combination with one of the other combos, whether a VEGF or IO. And patients were randomized one-to-one to receive the combination of atezolizumab plus cabozantinib versus cabozantinib alone. And the dosing of the cabozantinib here is at 60 milligrams in the combination, which is the standard dosing of cabozantinib monotherapy. And the primary endpoints for the trial included PFS and OS. And in essence, this trial was a completely negative study. The primary endpoint, which was centrally reviewed, rPFS, was negative. The hazard ratio there was 1.03. Overall survival was also negative with a hazard ratio of 0.94. And when you look at the subgroup analyses, there really wasn't any specific subgroup that seemed to derive any benefit, potentially those that had a prior response to an immune checkpoint inhibitor, but in essence, a negative study. And I think these data are really informative because the discussion at ASCO was conducted by Dr. David Braun, and he actually had conducted a very highly scientific Twitter poll to help guide how to interpret the data and what people do. And from that, about 30% of individuals that completed the poll were actually layering on IO therapy, and continuing IO therapy after somebody progressed on therapy layering in a TKI while keeping the IO backbone going. And I think what this study proves is that we really don't have any really robust data to guide doing that at the present time. And what we may end up doing is compromising the efficacy of the oral TKI or dose-compromising the oral TKI to try to maintain an ineffective IO. And so, I think at the present time these data, while negative, were truly practice-informing. There are other studies that are looking at this strategy as well. I think one of the criticisms here is that atezolizumab really has not had a great track record in renal cell carcinoma in every single context where it was tested, either alone or in combination. It has not met its primary endpoint and it's not utilized as a treatment in RCC. So, there's some discussion that could this be the fact that this is a PDL-1 inhibitor and that it's atezolizumab. And additionally, I think the thing to point out for is that in the modern era if we look at the cabozantinib control arm, cabozantinib in the refractory setting had a PFS of 10.8 months, which is pretty impressive for a later line PFS, if you will. So, there is another study currently ongoing called the TiNivo-2 study that's looking at tivozanib plus nivolumab versus tivozanib alone in a similar patient population. That trial is enrolling only clear cell patients that had progressed on prior IO. So, I think we'll have additional data, but very, I think, informative. I think this question comes up in a lot in other tumor sites as well because of the broad use of checkpoint inhibitors across hematologic and solid tumor malignancies. Dr. Jonathan Rosenberg: I think this was the most informative negative study and the most negative trial I've seen in a while as well. But it did highlight the importance of asking these questions where people assume they know the answer already, and in fact, we often don't, and our assumptions are wrong. So, I thought that was fascinating and very well described. Staying in the kidneys arena. I'd like to talk to you also about the phase 2 KEYNOTE-B61, that's Abstract 4518. It looked at first-line lenvatinib and pembrolizumab across non-clear cell carcinomas. Tell me what you thought of the trial and what your takeaways were. Dr. Rana McKay: This is an important study. I think the treatment of non-clear cell RCC has lagged. I guess the advances have lagged behind clear cell RCC, and really robust phase 3 randomized studies in people with non-clear cell histologies are very limited. This was a single-arm phase 2, so I think we need to kind of take that for what it's worth, that enrolled patients who had non-clear cell RCC per investigator that had received no prior systemic therapy. So, this was a frontline study, and patients received pembrolizumab plus lenvatinib until disease progression or toxicity. The study enrolled a very robust 158 patients, which is pretty impressive for a modern-day non-clear cell cohort. We've seen data from nivo-cabo that had gotten presented previously by Dr. Lee. That study was a single institution, about 40 patients or so if you will. The primary endpoint of this study was objective response rate, and the bulk of the patients that were enrolled were papillary RCC. As you would imagine, around 60% of patients were papillary. It did include around 18% with chromophobe RCC. And when we break things down by IMDC risk category, about 44% of patients were favorable-risk disease. I think the percentage of patients who were favorable is higher than if we were to take an all-comer metastatic RCC patient population. But the objective response rate was pretty impressive at 49% with this combination. The CR rate was right around 5.7%. So, I think certainly a pretty solid signal of efficacy. But again, this is a single-arm phase 2 study. I think what's also really interesting, and I think we have to take subset analyses with a grain of salt if you will, but there were responses that were seen across all histologies. And the prior nivo-cabo study that I had shared with you had previously done a futility analysis for patients with chromophobe RCC, and that cohort actually closed down. And in this study, the response rate for the chromophobe patients, though it wasn't a lot of patients, 29 patients with chromophobia RCC, was around 27.6%, so I think these data are certainly informative. If you look at the waterfall plot, there were some deep responses that were certainly observed, and the bulk of patients had some degree of tumor shrinkage with very little patients that had primary PD. Dr. Jonathan Rosenberg: It's really provocative. So, are we getting to a point where we might start thinking about randomized trials in the non-clear cell population to try to establish the best standard of care? Dr. Rana McKay: Well, I think PAPMET2 is currently enrolling patients. That study is looking at the combination of cabozantinib with atezolizumab versus cabozantinib alone for frontline papillary. PAPMET1, which was led by Dr. Pal, I mean, these studies are really magnanimous because it takes all hands on deck to get these patients enrolled because they're few and far between. So, I definitely think we need to be moving in that direction. And I think we need to be moving away from lumping all non-clear cells into one bucket because I think what we're seeing is that, one, the biology of these tumors is very distinct and unique, and they don't all behave the same to any one given therapy. So, we really need to move away from just lumping all non-clear cells into one bucket and try to actually conduct studies for each specific subtype. Dr. Jonathan Rosenberg: Understood and agree. Let's switch gears for a second and talk about prostate cancer. Can you talk about the data from Abstract 5004, the TALAPRO-2 study of talazoparib and enzalutamide compared to placebo and enzalutamide as a first-line treatment with metastatic CRPC that have HR homologous recombination repair gene alterations? Dr. Rana McKay: Absolutely. So the TALAPRO-2 study is one of three studies that have looked at the combination of PARP inhibitors with an ARSI in the frontline mCRPC setting. And this trial randomized patients to talazoparib and enzalutamide versus placebo enzalutamide. And again, this was first-line mCRPC. Patients were allowed to have received prior docetaxel or prior abiraterone in the castration-sensitive setting, and the primary endpoint was overall survival. At GU ASCO this year, we saw the top-line data from TALAPRO-2 first get presented. And what was actually presented at this meeting was the subset of patients that were HRR-mutated only. They had two cohorts: an all-comer cohort that was previously presented, and then now they're presenting the subset of the patients that were HRR-mutated. And I think what we've seen across the board is that the efficacy of PARP inhibitors kind of differs by underlying HRR mutations. When we look at the entire population of HRR-deficient patients, the study was positive, talazoparib plus enzalutamide resulted in an improvement in rPFS compared to enzalutamide placebo. The hazard ratio there was 0.45. And then when we break things down by selected gene groups, they did this subset analysis in patients with only BRCA1, only BRCA2, only PALB2, only CDK12, ATM CHEK2 if you will. The data are most robust for those patients with a BRCA1/2 alteration with hazard ratios of 0.17, 0.19. Again, this is for rPFS. But then, when we look at some of these other mutations, like ATM CHEK2, hazard ratios are higher, 0.76, 0.90. So, the effect size really kind of drops off for those non-BRCA1/2 altered HRR genes. But if we look across the different subgroup analyses, the interim OS data for the HR deficient, the time to PSA, time to cytotoxic chemo, all of that favored the combination versus placebo enzalutamide for patients that were HR deficient if we just lumped everybody all together. Dr. Jonathan Rosenberg: How does this fit into the general landscape around this question with selection versus not selecting for HRR alterations? Dr. Rana McKay: The data that were presented were for the selected patients, and I think that that's not where the controversy is. I think that the selected patients are the ones that seem to derive the most benefit. It's interesting because in looking at the data from PROpel and the final FDA label based off of the PROpel data, the label is only for BRCA1 and 2 patients and not for all comer HRR. It's even a more restricted label than olaporib monotherapy. So, I think it's going to be interesting. I don't know what the right answer is. I think it's going to be interesting to see how this is going to unfold for TALAPRO-2 and even for MAGNITUDE, if you will, like, how select is the selected population going to be. But at the present time, I think the label is what it is for olaparib plus abiraterone in those BRCA1/2 frontline. My hope is that this population is shrinking because everybody should be getting escalated in the metastatic hormone-sensitive setting, and we shouldn't be having people who are naive to an ARSI in frontline mCRPC. Dr. Jonathan Rosenberg: Understood and agreed. Dr. Rana Mckay: Well, thank you so much, Jonathan, for joining me today. It's really been a pleasure kind of going through all of the compelling advances in GU cancers from ASCO. I think it was a really exciting meeting, and thanks for your time. Dr. Jonathan Rosenberg: My pleasure. It's been great to talk to you today. Dr. Rana Mckay: And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today's speakers: Dr. Rana McKay @DrRanaMcKay Jonathan Rosenberg @DrRosenbergMSK Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Rana McKay: Consulting or Advisory Role: Janssen, Novartis, Tempus, Exelxis, Pfizer, Bristol-Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion, Calithera, AstraZeneca, Myovant, Caris Life Sciences, Sorrento Therapeutics, AVEO, Seattle Genetics, Telix, Eli Lilly, Pfizer, Bayer, Tempus Dr. Jonathan Rosenberg: Honoraria: UpToDate, Medscape, Peerview, Research To Practice, Clinical Care Options, Physician Education Resource, MJH Life Sciences, EMD Serono, Pfizer Consulting or Advisory Role: Lilly, Merck, Roche/Genentech, AstraZeneca/MedImmune, Bristol-Myers Squibb, Bayer, BioClin Therapeutics, QED Therapeutics, Pharmacyclics, GlaxoSmithKline, Janssen Oncology, Astellas Pharma, Boehringer Ingelheim, Pfizer/EMD Serono, Merck Therapeutics, Immunomedics, Tyra Biosciences, Infinity Pharmaceuticals, Gilead Sciences, Hengrui Pharmamedical, Alligator BioScience, Imvax Research Funding (Institution): Genentech/Roche, Seattle Genetics, Bayer, AstraZeneca, QED Therapeutics, Astellas Pharma Patents, Royalties, Other Intellectual Property (Institution): Predictor of platinum sensitivity
Arndt Vogel, MD - Options and Opportunities in Cholangiocarcinoma: Novel Approaches for Targeting FGFR Alterations
Arndt Vogel, MD - Options and Opportunities in Cholangiocarcinoma: Novel Approaches for Targeting FGFR Alterations
Arndt Vogel, MD - Options and Opportunities in Cholangiocarcinoma: Novel Approaches for Targeting FGFR Alterations
ASCO 23 explored novel anti-cancer agents in the genitourinary space. The future of oncology is etching closer daily. In this episode, Michael and Josh dissect ertafitinib, an FGFR inhibitor used in bladder cancer, talazoparib in prostate cancer and immunotherapy and TKI combinations in renal cell cancer. All these studies reflect the desire to target cancers further with some astonishing results. StudiesTHOR: https://meetings.asco.org/abstracts-presentations/217894PEACE-1: https://meetings.asco.org/abstracts-presentations/218388TALAPRO-2: https://meetings.asco.org/abstracts-presentations/222733RENAL CELL CARCINOMA: https://meetings.asco.org/2023-asco-annual-meeting/15007?presentation=219853#219853Many thanks to Merck for supporting this episode. Merck provided virtual access to ASCO 2023 but did not review or approve any part of OftiM's coverage of ASCO.For more episodes, resources and blog posts, visit www.inquisitiveonc.comFind us on Twitter @InquisitiveOnc!If you want us to look at a specific trial or subject, email us at inquisitiveonc@gmail.comArt courtesy of Taryn SilverMusic courtesy of Music Unlimited: https://pixabay.com/users/music_unlimited-27600023/Disclaimer: This podcast is for educational purposes only. If you are unwell, seek medical advice. Hosted on Acast. See acast.com/privacy for more information.
JCO PO author Alexander E. Drilon, MD, shares insights into his article, “Efficacy and Safety of Larotrectinib in Patients With Tropomyosin Receptor Kinase Fusion–Positive Lung Cancers” and the article's findings of the activity of larotrectinib in patients with advanced lung cancer harboring NTRK gene fusions. Host Dr. Rafeh Naqash and Dr. Drilon discuss drug development, testing for fusions, resistance mechanisms, and cancer metastases. Click here to read the article! TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I am your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology, and Assistant Professor at the OU Stephenson Cancer Center. Today we are excited to be joined by Dr. Alexander Drilon, Chief of the Early Drug Development Service and Medical Oncologist on the Thoracic Oncology Service at the Memorial Sloan Kettering Cancer Center and lead author of the JCO Precision Oncology article “Efficacy and Safety of Larotrectinib in Patients With Tropomyosin Receptor Kinase Fusion–Positive Lung Cancers.” Our guests' disclosures will be linked in the transcript. Dr. Drilon, welcome to the podcast and thank you for joining us today. We're really excited to be discussing this topic with you. Dr. Alexander Drilon: It's my pleasure and thank you for the invitation. Dr. Rafeh Naqash: For the sake of this podcast, we will refer to each other using our first names. So, Alex, you've led the development for some of these agents targeting NTRK. So it's really timely that you're coming onto this podcast to not just discuss this very interesting paper that you published in JCO Precision Oncology, but also the general landscape of NTRK. So could you briefly tell us about the history of the drug development process behind NTRK fusions, when it started, how you got involved, and where it stands currently? Dr. Alexander Drilon: Sure. So, as you mentioned, my background is in lung cancer, where when I came on as a fellow, there was a lot of excitement around EGFR and ALK, but then subsequently other oncogene drivers were also discovered and many of them were fusion. So, as we know, ALK in the fuse state is a driver of many tumors, as is ROS1 and RET. And interestingly, NTRK fusions share many similarities with ALK, RET, and ROS1 in that you have an intact kinase domain that's in the three prime position, it's fused to a different gene in the five prime position and basically describes oncogenesis. And the beautiful thing about NTRK fusions is that they are widely found across many different cancers. And I like to think of these cancers in two major buckets. So there is a bucket for cancers that are rare where we see these NTRK fusions with a very high frequency. And examples here are your secretory carcinomas of the salivary gland and the breast, for example, more congenital fibrosarcoma, where the frequency exceeds 90% in some series, and then there are much more common tumors where the frequency is much lower. So lung cancer is an example where you find it in less than 1% of cases. There are some other tumors like GI cancers also where the frequency is low. And beyond these two major groups, we also see these NTRK fusion-positive cancers occur not just in the adult population, but the pediatric population. All of that thrown together means that it was a really great setup for exploring the activity and safety of targeted therapy in what we call a ‘basket trial' paradigm, where you design a trial and instead of selecting patients based on cancer type, you ignore cancer type and, of course, you accrue by an enrolling alteration, which in this case is the NTRK fusion. Dr. Rafeh Naqash: Excellent. Thank you for that summary. It's interesting that just yesterday in my phase I clinic, I had an individual who was supposed to go on a certain study, and liquid biopsy came back and showed an NTRK fusion for a very odd presentation of a prostate cancer, which, again, got me thinking about the paper that you published trying to read about NTRK and then this happened and I got thinking about a bunch of other questions. But, for starters, though, from a receptor standpoint and I know you published on this in different journals, could you briefly tell, for the sake of the audience, describe the pathway and the tyrosine kinase signaling and associated resistance pathways that are concurrently acting in a different direction, perhaps, and also discuss briefly from neural development? I know the pathway, the NTRK gene or TRK gene as such is involved in different neuronal signaling aspects. Could you briefly touch on that? Dr. Alexander Drilon: Sure. And thankfully there are a lot of parallels with other things that perhaps some of the listeners are more familiar with. We'll start with the fact that it is a receptor tyrosine kinase, NTRK. It's a gene that encodes a receptor tyrosine kinase just like other receptor tyrosine kinases that may be fused such as ALK, RET, and ROS1. But remember also that other RTKs are EGFR, FGFR, which are also well known. The important thing to remember for NTRK is that you have three different genes, NTRK 1, 2, and 3 that encode three different proteins which are called TRK A, B, and C. And as you intimated, in the non-oncogenic state, these are very important for the development and the maintenance of the nervous system. And in the fused state, of course, similar to other fusions that we spoke about, the chimeric oncoprotein will drive downstream signaling and tumor growth and metastases. And in general, these cancers can be very reliant on downstream signaling in the MAP Kinase pathway but may also on occasion activate other downstream pathways like the PI3 Kinase pathway. Dr. Rafeh Naqash: And I know some of that could potentially play into resistance mechanisms for some of these first or second-generation NTRK inhibitors. From a fusion partner standpoint, the data that I came across that you're very well aware of is different fusion partners, and maybe some have a slightly better prognosis than some other fusions. But, in your practice and in your experience, does it matter what the other fusion partner is if the kinase domain is intact, meaning the signaling for the NTRK gene is intact? Have you seen any differences there from the other fusion partner standpoint? Dr. Alexander Drilon: From a patient-matching perspective, as long as you think the fusion is real, and by that I mean that you look at the report and you're sure the kinase domain is there and you're sure it's in frame, meaning connected well to the five prime partner so that the DNA strand is read through, the five prime partner does not play a major role in my deciding to give a TRK inhibitor or not. I would give anyone with a functional NTRK 1, 2, or 3 fusion a TRK inhibitor. Now, the data on whether or not select fusions do better than others is, I would say, still a little immature and perhaps conditioned by a few things. There are some of the cancers in the first bucket that we talked about, like the secretory carcinomas that harbor a recurrent event such as ETV6 NTRK3. And those cancers, in my experience in clinic, patients with those tumors can be on a TRK inhibitor for a very long time. And it's unclear if that's because of the exact fusion event or if it's because of the cancer type that might be more, say, genomically naïve compared to a gastrointestinal tumor, like a colorectal cancer with an NTRK fusion. So I hesitate to say that there are very strong and convincing data that if you have a particular five prime partner, you'll absolutely do better or worse. So, in the interim, I think the most important piece is just making sure that the event is real and actionable, and if it is, then you can give a TRK inhibitor. Dr. Rafeh Naqash: Thank you so much. I totally agree. And I think, for the sake of our listeners, as we see more and more sequencing being done on patients with cancer in the advanced stage setting especially, it's important to keep in mind when you have something that you can act on that has an actionable target that is FDA approved, then it's important to give the patient that option, especially in rare fusion events such as NTRK or TRK. Now, you've touched upon this in your paper, but before we go into the details of the paper, specifically, I wanted you to briefly talk about the testing mechanisms which are important for some of these fusions and play into, for example, ROS1 ALK fusions also. Could you tell us what are the most appropriate ways to test for these fusions in patients harboring cancers, both from a tissue standpoint and from a blood-based assay standpoint? Dr. Alexander Drilon: This is a great question because if you don't have a test that's optimally poised to pick up an NTRK fusion, then you can't act on it. And a patient who would have benefited very durably from a TRK inhibitor won't get access to it. So there are different ways of testing for NTRK fusions, and I like to think of the central dogma here where you have DNA becomes RNA becomes protein because that really helps anchor the different types of assays that you might use. We commonly use next-generation sequencing of DNA, but even if you have a very good next-generation sequencing assay, that does have its limitations because there are some fusions that are structurally just difficult to pick up even with a great DNA-based NGS assay. And for that reason, we and others have found that in tumors that have an equivocal NTRK fusion, or perhaps where you didn't find something but you really suspect that you missed something, particularly in cases where, historically, like congenital fibrosarcoma where you know there's a very good likelihood of finding NTRK fusion, we then reach for an RNA-based assay because at the RNA level, you've removed things like the intra-DNA based capture challenging. And so I think that from a nucleic acid standpoint, leveraging a test that looks both at DNA and RNA, maximizes the likelihood of finding this fusion. And just remember that there are different NGS assays in terms of the approach to design and some might be more Amplicon-based and that's less optimal, but the hybrid-capture-based ones tend to be better. The DNA and RNA tests can be done on tumors, and in blood, you could do a liquid biopsy. It's very hard to fish out RNA in blood given the current technology so we're still limited to circulating tumor DNA which shares the liabilities of doing DNA testing on a tumor sample. But if you find it and it looks real, then it's certainly actionable even if you detect an NTRK fusion with a liquid biopsy. Now going back to the central dogma there, the third piece which we haven't touched on is protein. And there have been many papers published now on the utility of immunohistochemistry, and this helps you confirm that the TRK A, B, and C proteins are actually expressed. And what tends to happen is in many fusions, the chimeric oncoproteins strongly express as TRK A, B, and C that helps provide a complementary test or assay that confirms that you're dealing with something that is actionable. So that is a very contemporary approach and a very thorough approach to looking for these NTRK fusions where you do DNA and RNA if possible. And if you still have questions, ask your pathologist to see if they can do Pan-TRK IHC. But depending on the resource environment that you're in, there are older tests like FISH which we use for ALK that can also find these fusions. RT-PCR which only finds particular events, these can detect NTRK fusions but really don't have the breadth and comprehensiveness as the other assays that we discussed like NGS. Dr. Rafeh Naqash: Thank you so much, Alex, for that amazing summary of all the methods that potentially could help detect this rare but important event. From a therapeutic standpoint, now, taking a deeper dive into your very interesting JCO Precision Oncology paper that looked at larotrectinib data from a pooled analysis of two trials, a phase II and a phase I. Could you tell us a little background about these two trials, the patient population and what kind of data were you trying to evaluate? And then we can discuss some of the interesting results that you showcase in the paper. Dr. Alexander Drilon: It really helps as a background to realize that the initial approach to this was really on a basket trial where the programs for larotrectinib, which is a selective TRK A, B, and C inhibitor, and the other drug entrectinib, which inhibits ROS1 in addition to TRK, really accrued pediatric and adult cancers with NTRK fusions. And this paper pulls out the lung cancer subset and we'll discuss that in detail. But before getting into that, it's important to know that in the tumor agnostic data set of all patients with an NTRK fusion of any type, larotrectinib achieved a response rate of approximately 80%, entrectinib of approaching 60%, and disease control was durable with a median PFS for larotrectinib of approximately 28 months, and with entrectinib numerically, the number was lower at 11 months. So with that background, this paper in JCO PO, in the interest of featuring the activity for lung cancers with NTRK fusions, pulled out 20 patients with NTRK fusion-positive lung cancers. And the punchline is that the activity was pretty comparable to that seen with a bigger data set. So the objective response rate was 73% and many patients had a partial response, 67% of the cases, 7% had a complete response, and really only a minority had primary progressive disease, 1 patient out of the 15 evaluable patients. These responses and clinical benefit overall were durable and the median duration of response was almost 34 months, with a median progression-free survival of almost 35 and a half months and an overall survival median of 40.7 months. And just to talk about how that stacks up compared to other targeted therapies, this certainly is in the ballpark of some of the best ALK inhibitors that we have for ALK fusion-positive lung cancer. It's also comparable to osimertinib for EGFR mutant lung cancer. So we can confidently view TRK inhibition in lung cancers with NTRK fusions as a highly-active therapy. Dr. Rafeh Naqash: Absolutely. I think you touched upon this earlier where in your cohort at least 50% of patients had central nervous system involvement, and it looks like larotrectinib does have CNS activity and benefit. Could you speak to the differences between potential entrectinib and larotrectinib from a CNS efficacy standpoint? And the second part of that question was going to be when you identify this fusion in patients, for example, with lung cancer, now, since TRK does have a role in neuronal development, do you think there is a role for closer CNS monitoring in these patients if they have not had brain metastasis identified because of the fact that they have an NTRK fusion? Is there some predilection for CNS involvement from a metastasis standpoint? It's just something that I've been thinking of over the last couple of days after I saw my patient who does have CNS involvement but with prostate cancer, which I have not seen in the phase I setting in all the prostate patients that I've come across. So what are your thoughts on that? Dr. Alexander Drilon: These are great questions. In lung cancers with NTRK fusions, there is a proclivity for metastasis to the CNS. And thankfully, both of these TKIs, larotrectinib and entrectinib, do have coverage of the CNS. Now, from a design perspective, the initial thought was perhaps entrechtinib was more CNS-penetrant. But if you look at the overall response rates in patients with brain metastases and the intracranial response rates where you have patients with target lesions in the brain that you're able to measure; if you look across the aisle, entrectinib and larotrectinib have comparable results, with the objective response rate being in the order of 50% to 60% and the intracranial response rate being also in the order of about 50% to 60%. So at the end of the day, it appears as if, despite the previous hypothesis that maybe one drug would work better in the CNS than the other, we're seeing equally good effects with both drugs. For the second question you asked, it's also a very interesting question because, like you mentioned, the TRK receptors play a role in nervous system development. But we have not observed a much higher frequency of CNS metastases in NTRK fusion-positive lung cancers or cancers in general that I know of, compared to cancers that are wild type for an oncogene or have other oncogenes. So what's more important really to think about when you sort of chew on the fact that these TRK inhibitors are involved in nervous system development are the potential side effects that you may see in patients that you treat with these TRK inhibitors. Dr. Rafeh Naqash: Absolutely. Now, from the therapy standpoint that you discuss here, duration of responses, objective responses that you saw in your analysis were very impressive for these patients with lung cancer. In your clinical practice if you see a lung cancer patient with this fusion and you treat them with larotrectinib or entrectinib, and they have, let's say, de novo CNS metastases that are asymptomatic, do you generally try the targeted therapy first and hold off, perhaps, brain directed therapy in that setting? Similar to what one would do with osimertinib perhaps or alectinib? Dr. Alexander Drilon: Absolutely. It's the same paradigm because we know that we are seeing in a larger population of patients, just generally good activity, both extracranially and intracranially. The goal is to try to spare patients the extra side effects of doing radiation by only giving the TKI. And in practice, even outside of the trial, in patients that I've treated with CNS metastases, the activity has been very good. Dr. Rafeh Naqash: Thank you so much. Now, all TKI therapies have, unfortunately, resistance mechanisms that come up eventually, in my experience at least. What is your experience as far as understanding resistance mechanisms on TRK-based therapies and potential second options after that, whether it's second-generation TRK inhibitors or subsequent targeted therapies in this space? Dr. Alexander Drilon: Thankfully, this has been looked at extensively and I like to categorize resistance into two major groups. So there's a type of resistance which we call on-target resistance and another type which we call off-target resistance. In simple terms, cancers that acquire on-target resistance are still dependent on the NTRK or TRK pathway. And often what happens is, like with other oncogene-targeted therapy pairs, you see the acquisition of a resistance mutation in the kinase domain of NTRK 1, 2, 3 that either changes the dynamics of the kinase or sort of kicks the drug off of the binding site due to steric hindrance. And for those patients, companies have designed next-generation TRK inhibitors that abrogate resistance, meaning they were designed so that they would work despite the presence of these resistance mutations. And a few of them include repotrectinib, talatrectinib, and selitrectinib that are thought to have activity, but there are many other newer ones that are currently being explored. I will say that there's proof of concept that has been published as well showing that patients who progress on a first-generation TRK inhibitor like larotrectinib or entrectinib who develop acquired resistance that's on-target can respond very well to a next-generation NTRK inhibitor. And while these aren't approved just yet, these are of course available in clinical trials. Now, the second major group is more problematic. This is off-target resistance. And when I describe this to patients, what I usually say is that the cancer sort of ‘phones a friend' and activates a second gene perhaps that isn't NTRK. And examples of that include KRAS or MET or BRAF, very well-known oncogenes in other contexts, but it leads to a reliance outside of the NTRK or TRK pathway per se, which still effectively reactivates the MAP kinase pathway. What to do in that situation? Well, there are select cases and there have been case reports published of patients who get a combination. Say if it's acquired MET amplification, you give a MET inhibitor with a TRK inhibitor and that combination can work. But in many other cases where you don't have access to a combination on a clinical trial or on compassionate use, then you really default to the standard of care for that cancer type. So if it's lung cancer and they've never had chemotherapy before, then it would be platinum-based chemotherapy, say with pemetrexed and a third drug, perhaps if they have lung adenocarcinoma. Dr. Rafeh Naqash: Thank you so much. This is definitely an exciting field and exciting time to be in this space of drug development, and especially when we have so many interesting tumor-agnostic approvals that have come along in the last few years and more to come. And you've led a lot of this development with several other leaders in this field. So it was very nice discussing this with you, and hopefully, our listeners find it equally interesting and educationally relevant to what we see day in and day out as we perform more and more sequencing for patients with cancer and try to identify some of these rare or not so rare events that are targetable and can definitely change the course of a patient's therapy and outcomes. So thank you once again, Alex, for the discussion on this paper. But before we end, we'd like to spend a couple of minutes trying to know about the investigator. So could you tell us a little bit about your career trajectory, how you started your fellowship perhaps, how you ended up in drug development, and how you've successfully contributed so much in this field to date? Dr. Alexander Drilon: Sure. So I'm originally from the Philippines, was born there, finished med school, and really wanted to come to the United States to sort of broaden my education and my residency program in internal medicine, then called St. Luke's Roosevelt under Columbia, had a program that sent people to rotate through Memorial Sloan Kettering Cancer where I currently work. So that was my first exposure with oncology. I fell in love with it and eventually became a fellow, fortunately, at Memorial Sloan Kettering. And I mentioned earlier that during that time I had subspecialized in lung cancer and there was a lot of excitement around targeted therapy for oncogene-driven lung cancer. And that was my point of entry. I saw these drugs work very well and I said that if I were in a position to develop newer agents, perhaps for other oncogenes where there wasn't anything developed just yet, that would be really cool. And that was my entry into the phase I world where things later on expanded really the tumor agnostic interrogation using the same principles that were familiar to me in the lung cancer world. And I think I've been very fortunate with the environment and the ability, especially with good in-house sequencing, to match many patients to these trials. And it's been wonderful to see several of these drugs approved. Larotrectinib was the sort of seminal tumor-agnostic approval of a targeted therapy for the first time by any regulatory body. And like you said, the hope is that we see several more of these. Dr. Rafeh Naqash: Awesome. That sounds like a very interesting, phenomenal journey that you've had, and a lot of it is also probably related to the kind of people that you met, mentors, and other people who helped you along the way. And then, of course, you've done a lot for other fellows and trainees in this space of drug development. So thank you again, Alex, for joining us, and thank you for choosing JCO Precision Oncology as a destination for your work. I look forward to interacting with you further subsequently and hopefully seeing more development in this space of novel therapies for fusions and other interesting targets in the lung cancer space. So thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. 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. Bio: Alexander E. Drilon, MD, is a medical oncologist specializing in the treatment of lung cancer. He is chief of early drug development service at Memorial Sloan Kettering Cancer Center. He has clinical expertise in lung cancer and early-phase clinical trials. COIs Alexander Drilon Honoraria: Medscape, OncLive, PeerVoice, Physicians' Education Resource, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, PeerView Consulting or Advisory Role: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Verastem, Takeda/Millennium, BerGenBio, MORE Health, Lilly, AbbVie, 14ner Oncology/Elevation Oncology, Remedica, Archer, Monopteros Therapeutics, Novartis, EMD Serono/Merck, Melendi, Repare Therapeutics Research Funding: Foundation Medicine Patents, Royalties, Other Intellectual Property: Wolters Kluwer (Royalties for Pocket Oncology) Other Relationship: Merck, GlaxoSmithKline, Teva, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma Biotechnology
Sia Daneshmand describes two prospective studies with erdafitinib in NMIBC.
Go online to PeerView.com/FKB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. New science continues to support a diverse management model for advanced biliary tract cancers (BTCs), including immune-based and targeted platforms, culminating to the first meaningful advancements in frontline therapy for advanced/metastatic BTC in over a decade. Collectively these clinical trends have expanded the use of individualized management strategies, leading to enhanced clinical outcomes for patients with advanced BTC. In this activity, based on a recent live symposium, expert panelists provide data and practical guidance on the current status of care in BTC and new developments related to the use of novel and emerging immunotherapies and targeted options (eg, PD-1 and PD-L1 inhibitors, FGFR, IDH, TRK, and HER2-directed agents). Case presentations explore next-generation care for today's patients with BTC using personalized upfront and sequential treatment management models. Don't miss this chance to get personal with advanced BTC! Upon completion of this activity, participants should be better able to: Summarize the latest clinical evidence supporting the use of immunotherapy and targeted platforms for patients with advanced BTCs; Develop personalized management plans for patients with advanced BTCs based on up-to-date clinical evidence on novel immunotherapeutic and targeted approaches, expert recommendations, comorbidities, and other factors at baseline; and Manage unique safety considerations associated with the use of novel targeted and immunotherapy options for BTCs
Go online to PeerView.com/FKB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. New science continues to support a diverse management model for advanced biliary tract cancers (BTCs), including immune-based and targeted platforms, culminating to the first meaningful advancements in frontline therapy for advanced/metastatic BTC in over a decade. Collectively these clinical trends have expanded the use of individualized management strategies, leading to enhanced clinical outcomes for patients with advanced BTC. In this activity, based on a recent live symposium, expert panelists provide data and practical guidance on the current status of care in BTC and new developments related to the use of novel and emerging immunotherapies and targeted options (eg, PD-1 and PD-L1 inhibitors, FGFR, IDH, TRK, and HER2-directed agents). Case presentations explore next-generation care for today's patients with BTC using personalized upfront and sequential treatment management models. Don't miss this chance to get personal with advanced BTC! Upon completion of this activity, participants should be better able to: Summarize the latest clinical evidence supporting the use of immunotherapy and targeted platforms for patients with advanced BTCs; Develop personalized management plans for patients with advanced BTCs based on up-to-date clinical evidence on novel immunotherapeutic and targeted approaches, expert recommendations, comorbidities, and other factors at baseline; and Manage unique safety considerations associated with the use of novel targeted and immunotherapy options for BTCs
Go online to PeerView.com/FKB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. New science continues to support a diverse management model for advanced biliary tract cancers (BTCs), including immune-based and targeted platforms, culminating to the first meaningful advancements in frontline therapy for advanced/metastatic BTC in over a decade. Collectively these clinical trends have expanded the use of individualized management strategies, leading to enhanced clinical outcomes for patients with advanced BTC. In this activity, based on a recent live symposium, expert panelists provide data and practical guidance on the current status of care in BTC and new developments related to the use of novel and emerging immunotherapies and targeted options (eg, PD-1 and PD-L1 inhibitors, FGFR, IDH, TRK, and HER2-directed agents). Case presentations explore next-generation care for today's patients with BTC using personalized upfront and sequential treatment management models. Don't miss this chance to get personal with advanced BTC! Upon completion of this activity, participants should be better able to: Summarize the latest clinical evidence supporting the use of immunotherapy and targeted platforms for patients with advanced BTCs; Develop personalized management plans for patients with advanced BTCs based on up-to-date clinical evidence on novel immunotherapeutic and targeted approaches, expert recommendations, comorbidities, and other factors at baseline; and Manage unique safety considerations associated with the use of novel targeted and immunotherapy options for BTCs
A new research paper was published in Oncotarget's Volume 14 on February 11, 2023, entitled, “Oncogenic driver FGFR3-TACC3 requires five coiled-coil heptads for activation and disulfide bond formation for stability.” FGFR3-TACC3 represents an oncogenic fusion protein frequently identified in glioblastoma, lung cancer, bladder cancer, oral cancer, head and neck squamous cell carcinoma, gallbladder cancer, and cervical cancer. Various exon breakpoints of FGFR3-TACC3 have been identified in cancers. In this recent study, researchers Clark G. Wang, Malalage N. Peiris, April N. Meyer, Katelyn N. Nelson, and Daniel J. Donoghue from University of California San Diego analyzed these FGFR3-TACC3 exon breakpoints to determine the minimum contribution of TACC3 for activation of the FGFR3-TACC3 fusion protein. “In this work, we characterize the signaling, transforming abilities, and post-translational modifications of FGFR3-TACC3 fusion proteins arising from different exonic breakpoints to determine the requirements for dimerization and constitutive activation of the fusion protein.” While TACC3 exons 11 and 12 are dispensable for activity, the researchers' results show that FGFR3-TACC3 requires exons 13-16 for biological activity. A detailed analysis of exon 13, which consists of 8 heptads forming a coiled coil, further defined the minimal region for biological activity as consisting of 5 heptads from exon 13, in addition to exons 14-16. These conclusions were supported by transformation assays of biological activity, examination of MAPK pathway activation, analysis of disulfide-bonded FGFR3-TACC3, and by examination of the Endoglycosidase H-resistant portion of FGFR3-TACC3. These results demonstrate that clinically identified FGFR3-TACC3 fusion proteins differ in their biological activity, depending upon the specific breakpoint. This study further suggests the TACC3 dimerization domain of FGFR3-TACC3 as a novel target in treating FGFR translocation driven cancers. “Taken together, these results provide a better understanding of the mechanism for activation of FGFR3-TACC3 and narrow the scope of targeting TACC3 to create effective dimerization disruption-based therapies for treating patients with FGFR3-TACC3 driven tumors.” DOI: https://doi.org/10.18632/oncotarget.28359 Correspondence to: Daniel J. Donoghue - ddonoghue@ucsd.edu Keywords: oncogenic fusion protein, chromosomal translocation, glioblastoma, FGFR3-TACC3, coiled-coil About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957
Dr. Rachna Shroff, chair-elect of the 2023 ASCO GI Cancers Symposium, and guest host Dr. Shaalan Beg discuss new research presented at GI23, including new data from SWOG 1815 in biliary tract cancers, advances in biomarker studies in mCRC such as the PARADIGM trial, and promising updates in ctDNA technology. She also highlights the exciting potential of AI in oncology. TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I'm an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center and vice president of Oncology at Science 37. Today we'll be discussing key abstracts and other highlights from the 2023 ASCO Gastrointestinal Cancer Symposium, which celebrated 20 years of transformative care in GI cancers. I'm delighted to welcome Dr. Rachna Shroff, the chair-elect of this milestone meeting. Dr. Shroff is the interim division chief of Hematology Oncology at the University of Arizona Cancer Center. She also serves as the associate dean for Clinical and Translational Research and is the chief of GI Medical Oncology. Our full disclosures are available in the transcript of this episode, and disclosures related to all episodes of the podcast are available on our transcripts at ASCO.org/podcasts. Dr. Shroff, it's great to have you back on the ASCO Daily News podcast. Dr. Rachna Shroff: Thank you so much for having me. I'm so excited to be here. Dr. Shaalan Beg: The ASCO GI Cancers Symposium has been heralded as one of the biggest conferences in the GI cancer space and has occupied this space for the past two decades. Some would say that this year's conference was probably the best GI Cancers Symposium to date. Can you comment on the 20th anniversary milestone and the impact of the symposium on GI cancers? Dr. Rachna Shroff: Absolutely, and that's so great to hear that that's the feedback that you've heard. I have to say GI ASCO is absolutely my favorite meeting of the year, so that is my full disclosure. But I think that this was a tremendous meeting, and I think it was so beautiful that it was also coinciding with the 20th anniversary. It meant so much to us to have Dr. Margaret Tempero open the meeting because she really was the impetus for creating a GI cancer-focused meeting that really brought together multidisciplinary expertise. And so to us, that is what this 20th anniversary represented—20 years of multiple different specialties coming together to discuss how to improve cancer care for patients with gastrointestinal malignancies. And it has been a transformative meeting to see the impact of research presented at this meeting and how it has been implemented over the course of 20 years. And I completely agree that this year in and of itself had some incredible pivotal data that there is no doubt will be practice-changing, and that is absolutely the purpose. I also think that the beauty of this meeting is the networking opportunities for all of us to come out of our individual silos, come together, and discuss cross-cutting care across the spectrum of GI malignancies. And I think that this meeting really did that quite well. Dr. Shaalan Beg: There were many practice-changing studies that made headlines this year, and for me, one of the most anticipated studies was a trial that you led for cholangiocarcinoma and much-anticipated results. The study finished enrollment at a record pace. Can you share your key findings of cholangiocarcinoma? And I'd really like to hear your perspective on cholangiocarcinoma studies. Dr. Rachna Shroff: Yes, it was actually a really big year in the hepatobiliary space, and I was proud to present SWOG 1815, LBA 490, which was the pivotal randomized phase 3 trial looking at gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin. This was a study that was opened across the entire NCTN and based on a single-arm phase 2 trial that had shown some promising early efficacy of the triplet chemotherapy regimen. As you mentioned, this study accrued 441 patients in two years. And it's really a testament to the fact that the cooperative group mechanism can and should be asking important questions in large, randomized studies and that it is even possible to do in what are historically thought of as, quote-unquote, “rare tumors.” The study was a randomization of two to one to the triplet chemotherapy versus the standard of care for newly diagnosed biliary tract cancer patients. And the primary endpoint was median overall survival. And while the median OS of the triplet regimen was numerically improved at 14 months compared to 12.7 months, this did not meet statistical significance. Other efficacy endpoints, including median progression-free survival and overall response rate, were also numerically improved but not statistically significant, with an overall response rate of 31% with the triplet regimen versus 22%. There were some prespecified stratification factors, including disease site and disease stage, and there may be some interesting signals that bear out of that in terms of perhaps gallbladder cancer and locally advanced patients may be benefiting from the triplet regimen a little bit more, but these are small numbers, and we would really need to explore that in a more rigorous prospective manner. The toxicities were, not surprisingly, there, especially hematologic toxicities. I will say for those of us that use this regimen in practice, we use it a little bit differently than what was done in SWOG 1815, but you can't deny that there were significantly higher grade 3-5 toxicities with anemia neutropenia and thrombocytopenia, though the treatment discontinuation rate did not differ. I think the next steps are really going to be the ongoing biomarker analyses. The study had archival tissue and prospective blood collection and we know that in the space of cholangiocarcinomas and biliary cancers, molecular complexities absolutely play a role in how patients do and how they respond to therapies. So that's going to be an important next step, I think, for this study. Dr. Shaalan Beg: Speaking of biomarkers and an impact on GI cancers, the other malignancy where biomarkers are having a much greater impact than other GI cancers is colon cancer. Another year where we continue to see advances in our understanding of molecularly targeted treatments for colon cancer. What caught your eye? Dr. Rachna Shroff: Well, there were a lot of really interesting studies happening in this space and as a biliary person, one of the first things I got excited about was seeing Abstract 139 that looked at pemigatinib, which is the drug we are very familiar with in cholangiocarcinoma. This was a single-arm phase two study looking at the use of the FGFR inhibitor pemigatinib in metastatic colorectal cancer patients who had FGFR alterations. And so this was a study that was opened through the ACCRU mechanism. It was multicenter with assignment two-stage design and it was specifically for patients with FGF and FGFR-altered metastatic colorectal cancer who had progressed on standard therapies. There was a prespecified interim analysis for futility after 12 evaluable patients and so 14 patients were enrolled in the first stage of the study and evaluated for the primary endpoint of objective response. What was seen and the study was subsequently stopped is that there was really not much efficacy, there was no evidence of safety signals, but this did not seem to be a very active drug in patients with FGFR alterations with no objective response noted. So, the study was stopped with the recognition that perhaps the FGFR translocation or fusion patient population may be something to explore since they did not look at that in this study. The other kind of study that I think is really important was important work of Dr. Raghav and colleagues through SWOG. This was SWOG 1613 Abstract 140. This was the first real study that was investigating targeting HER-2 overexpressed and amplified metastatic colorectal cancer who had RAS wild-type tumors. And it was based on, obviously, some early signals of the effectiveness of HER-2 targeting in metastatic colorectal cancer. And this was a large study looking at pertuzumab and trastuzumab in these patients. They were compared to cetuximab and irinotecan, and the initial plan was for a much larger study. Unfortunately, accrual was really slow so the study was really kind of reformatted and a total of 54 patients were randomized, 26 to the trastuzumab arm and 28 to the CetIri or cetuximab and irinotecan arm. What was seen was that you can absolutely use HER-2 targeting therapies with trastuzumab and pertuzumab in these patients. It was safe and there were some obvious signs of efficacy in terms of overall response rate with an overall response rate of 31% compared to the CetIri arm. Crossover was allowed from the CetIri arm to trastuzumab and pertuzumab. So just that's important to keep in mind when they start to follow out the survival data. But unfortunately, because this study did not accrue, it was stopped early and it's really hard to understand in terms of power calculations the impact of trastuzumab pertuzumab. Of course, we can't talk about this without recognizing that the FDA approval based on the MOUNTAINEER study for tucatinib and trastuzumab came through during GI ASCO. So clearly HER-2 targeting is here to stay in colorectal cancer. Dr. Shaalan Beg: So technology is advancing every year and it's important that we are aware of these advances and how they impact our patients. Probably one of the most exciting technologies in oncology in general is the evolution of ctDNA. And it's been amazing to watch that field unfold as we understand how to use circulating biomarkers for early detection of cancer, for minimal residual disease detection, even as a biomarker of response. What caught your eye when it comes to the use of ctDNA in GI cancers, and how do you see this space develop in the next couple of years? Dr. Rachna Shroff: I completely agree. I think the technology of ctDNA is so incredibly exciting and as somebody who does not actively see and treat colorectal cancer, I'm a little bit envious of my colleagues in that space because the strides that have been made in terms of understanding the utility of ctDNA, especially in colorectal cancer, has just been tremendous and even for the last two to three years. One perfect example of integrating that sort of technology into treatment paradigms is the PARADIGM trial, Abstract 11, which was looking at the concept of hyperselection of patients with RAS wild-type metastatic colorectal cancer who were on the PARADIGM trial which basically looked at frontline FOLFOX with panitumumab versus bevacizumab in patients with RAS wild type left-sided metastatic colorectal cancer. So, you know, the initial data from PARADIGM had demonstrated a longer median overall survival 37.9 months versus 34.3 months, but very smartly, the investigators had also collected baseline plasma ctDNA in the biomarker component of this study and used a custom panel that looked at gene alterations for hyperselection and that included KRAS, NRAS, PTEN, and extracellular domain EGFR mutations HER-2 and MET amplifications, as well as some fusions like ALK, RET, and NTRK. And so out of the 802 patients in the full set, 91% - 733 patients - actually had pretreatment samples for ctDNA, which is really in and of itself, I think, tremendous. And when you break it down, about 28% had at least one gene alteration, and that was across each of those different genes that they were looking at. In the 72% of patients who were defined as hyperselected without any gene alterations, the OS was actually longer with panitumumab versus bev, and that actually was independent of sidedness with hazard ratios that kind of ranged from 0.76 to 0.82. And OS was similar or inferior with panitumumab versus bevacizumab again, regardless of sidedness in patients with any of these gene alterations. And so I think it's a really interesting concept that you can use ctDNA to define negative hyperselection rather than looking at left sided and right sided to really help select patients with frontline therapy in terms of using panitumumab versus bevacizumab. And with the speed with which ctDNA can be obtained, this actually seems like something that could be implemented into clinical practice, which is, I think, really the important component of that. There were a number of other really interesting abstracts. Abstract 5, presented by Dr. Cohen and colleagues, really looked at the kinetics of circulating cell-free DNA and how that kind of relates to minimal residual disease detection rates. And this was in patients with resected stages one through three colorectal cancer. And so, this was a retrospective study, so we have to keep that in mind. And it was multi-institutional in really over 16,000 patients with stages 1 through 3 colorectal cancer. But the complete dataset had about 417 patients and basically the patients' circulating cell-free DNA levels, the total cfDNA, were compared to the ctDNA MRD positivity rates and they looked at very specific time points after surgery. What the authors generally found was that the postoperative cfDNA correlated well with ctDNA positivity and that there was really the ability to see plasma cfDNA levels kind of track and follow with the very specific MRD windows that were being looked at, which really, again, just kind of talks about leveraging this technology in terms of real-world and real-time application and better understanding and informing us of minimal residual disease post what is thought to be curative resection. The last one that I thought was really interesting in relation to ctDNA was actually looking at anal cancer and following ctDNA in patients who were treated with definitive chemoradiation. This was a study that was looking at 31 patients with anal squamous cell carcinoma who were treated with definitive chemo radiation and underwent ctDNA response. The majority of these patients had stage 3 disease and the majority of them received the standard 5-FU Mitomycin with radiation. The patients had ctDNA testing performed in 25 of these patients at baseline and then a smaller number over the course of time, some during chemoradiation. And then they looked again at 30 days post chemoradiation. And at baseline, 88% of patients had detectable ctDNA with those with stage three disease having numerically higher baseline ctDNA levels. And basically what they found was that over the course of treatment, ctDNA levels decreased among the patients with detectable ctDNA. And then ctDNA that tested during chemo radiation showed a drop in decline and were going into molecular remission at a time point in which it was subsequently confirmed that they had a clinical complete response. So, the suggestion here is that the time to molecular ctDNA remission was significantly shorter than being able to see that clinical complete response, which suggests that using surveillance ctDNA monitoring could be an earlier response assessment for patients with anal squamous cell carcinoma who are undergoing definitive therapy. Now, obviously this needs to be confirmed in a larger manner, but again, really suggests that we could be understanding how we're doing with treatment in more of a real-time fashion, which I just think is incredible for those of us who are making sure that we are doing and taking the right approaches for these patients. Dr. Shaalan Beg: One of the major transformative announcements that took place only a couple of months before the GI Cancer Symposium was the announcement of ChatGPT. And we heard a lot of discussion on how it can be used for improving cancer care, improving drug development, and in general, artificial intelligence and machine learning. We've been hearing these buzzwords for such a long time, to the point that a lot of people are probably just filtering it out and then this tool comes up and it makes it real. And we're seeing different people apply these technologies in different ways. But there is tremendous potential in how this technology can improve clinical trials, drug development, and early diagnosis. And luckily, we had already secured a keynote speaker, Dr. Matthew Lundgren from Nuance Communications, and he was invited to talk about artificial intelligence, machine learning, and how it applies to cancer care. I'm really curious to hear what your highlights were from his address and how you see this impacting your day-to-day, or just the ecosystem of which we're all part of. Dr. Rachna Shroff: Yeah, I will say that his keynote was really one of the highlights of the entire meeting for me. And that is coming from somebody who doesn't really know– I know who I'm speaking to, but somebody who does not truly understand the way AI is moving. And so, I was joking with him that it was like AI 101. And I really, really appreciated the way he was able to kind of speak to a crowd that he doesn't normally speak to and help us really understand the way in which artificial intelligence can be integrated into healthcare, and specifically oncology. To me, I think what were the most salient takeaways from his address was really about how this is just a rapidly evolving field and we need to be a little bit ahead of the eight ball when it comes to thinking how we can smartly leverage artificial intelligence like you mentioned, to improve our clinical research efforts, to improve access, and to improve fully integrating AI into our EMR, so that we can really leverage that technology and ensure that we are capturing every potential patient for a clinical trial and be smarter about how we're even approaching things. I mean, I loved him talking about the prior authorizations and that sort of thing, and the ways in which we can decrease the burden on health care providers and really let us focus on the areas that we need to focus on. The one thing that I thought was a really important point, though, and I think a number of people asked him, was about how using this technology has the potential to create more gaps and disparities and how can we be smart to ensure that we don't broaden those gaps. And I think that is a really important point that we all need to think about because we know that especially when we think through clinical trials, there's already underrepresentation of certain populations and certain geographic regions. And so, I think that was a really important takeaway for me is how can we make sure that we work and partner with those who are creating these technologies to ensure that we aren't taking two steps forward and four steps back. Dr. Shaalan Beg: It really calls into question how we define productivity and what our value in the entire delivery system really is. And I think from people who are in middle school or high school to people who are in college and even folks who are in the field as you and I are, it's forcing us to rethink what we bring to the table in a way that we've never been challenged to ask that question ever before. Dr. Rachna Shroff: Absolutely. Dr. Shaalan Beg: So, thank you very much, Dr. Shroff. This was wonderful. Thank you for sharing your insights with us today. And we thank you and Dr. George Chang, the chair of the ASCO GI Cancers Symposium, and everyone who worked so hard to develop a robust program this year. Dr. Rachna Shroff: Thank you. It was so wonderful to be able to speak about it. And thank you to all of the attendees for making it such a memorable meeting. Dr. Shaalan Beg: And thank you to all our listeners for your time today. You'll find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Rachna Shroff @rachnatshroff Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. Rachna Shroff: Consulting or Advisory Role: Exelixis, Merck, QED Therapeutics, Incyte, Astra Zeneca, Taiho Pharmaceutical, Boehringer Ingelheim, SERVIER, Genentech, Basilea Research Funding: Pieris Pharmaceuticals, Taiho Pharmaceutical, Merck, Exelixis, QED Therapeutics, Rafael Pharmaceuticals, Bristol-Myers Squibb, Bayer, Immunovaccine, Seagen, Novocure, Nucana, Loxo/Lilly, Faeth Therapeutics
PeerView Family Medicine & General Practice CME/CNE/CPE Video Podcast
Go online to PeerView.com/YEM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The therapeutic landscape of bladder cancer has undergone a significant transformation with the addition of immune checkpoint inhibitors to the treatment armamentarium. In addition, the research on actionable targets has led to regulatory approval of the FGFR-targeted therapy, erdafitinib, for FGFR mutation–positive bladder tumors, as well as the antibody–drug conjugates enfortumab vedotin and sacituzumab govitecan. Further, novel bladder preservation opportunities and important combination approaches expand the therapeutic capacity across the disease spectrum available to patients with bladder cancer. In this PeerView activity, a panel of leading bladder cancer experts pairs important analyses of the latest evidence on a new generation of therapeutics with practical insights that can be used to guide therapeutic decision-making in the clinic. This CME/MOC-certified activity will highlight strategies for optimal care of patients with bladder cancer in light of current evidence on and indications for the use of immune, targeted, and antibody-based therapies and guidance on safely integrating these agents into treatment plans. Using patient cases drawn from clinical practice and interactivity that allows participants to see how their treatment choices compare with their colleagues, the faculty will address the mechanistic rationale for these new therapies, therapeutic decision-making, and AE mitigation strategies. Upon completion of this activity, participants should be better able to: Synthesize new evidence on multi-faceted strategies for bladder cancer management based on modern immunotherapeutic agents, small molecule targeted therapies, and antibody–drug conjugates, among others; Integrate novel and emerging therapeutic approaches into personalized treatment plans for patients with bladder cancer, considering the available evidence, current guidelines, and principles of multidisciplinary and patient-centered care; and Implement evidence- and team-based management protocols to address the unique suite of adverse events associated with novel therapeutics for bladder cancer
Go online to PeerView.com/YEM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The therapeutic landscape of bladder cancer has undergone a significant transformation with the addition of immune checkpoint inhibitors to the treatment armamentarium. In addition, the research on actionable targets has led to regulatory approval of the FGFR-targeted therapy, erdafitinib, for FGFR mutation–positive bladder tumors, as well as the antibody–drug conjugates enfortumab vedotin and sacituzumab govitecan. Further, novel bladder preservation opportunities and important combination approaches expand the therapeutic capacity across the disease spectrum available to patients with bladder cancer. In this PeerView activity, a panel of leading bladder cancer experts pairs important analyses of the latest evidence on a new generation of therapeutics with practical insights that can be used to guide therapeutic decision-making in the clinic. This CME/MOC-certified activity will highlight strategies for optimal care of patients with bladder cancer in light of current evidence on and indications for the use of immune, targeted, and antibody-based therapies and guidance on safely integrating these agents into treatment plans. Using patient cases drawn from clinical practice and interactivity that allows participants to see how their treatment choices compare with their colleagues, the faculty will address the mechanistic rationale for these new therapies, therapeutic decision-making, and AE mitigation strategies. Upon completion of this activity, participants should be better able to: Synthesize new evidence on multi-faceted strategies for bladder cancer management based on modern immunotherapeutic agents, small molecule targeted therapies, and antibody–drug conjugates, among others; Integrate novel and emerging therapeutic approaches into personalized treatment plans for patients with bladder cancer, considering the available evidence, current guidelines, and principles of multidisciplinary and patient-centered care; and Implement evidence- and team-based management protocols to address the unique suite of adverse events associated with novel therapeutics for bladder cancer
Go online to PeerView.com/YEM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The therapeutic landscape of bladder cancer has undergone a significant transformation with the addition of immune checkpoint inhibitors to the treatment armamentarium. In addition, the research on actionable targets has led to regulatory approval of the FGFR-targeted therapy, erdafitinib, for FGFR mutation–positive bladder tumors, as well as the antibody–drug conjugates enfortumab vedotin and sacituzumab govitecan. Further, novel bladder preservation opportunities and important combination approaches expand the therapeutic capacity across the disease spectrum available to patients with bladder cancer. In this PeerView activity, a panel of leading bladder cancer experts pairs important analyses of the latest evidence on a new generation of therapeutics with practical insights that can be used to guide therapeutic decision-making in the clinic. This CME/MOC-certified activity will highlight strategies for optimal care of patients with bladder cancer in light of current evidence on and indications for the use of immune, targeted, and antibody-based therapies and guidance on safely integrating these agents into treatment plans. Using patient cases drawn from clinical practice and interactivity that allows participants to see how their treatment choices compare with their colleagues, the faculty will address the mechanistic rationale for these new therapies, therapeutic decision-making, and AE mitigation strategies. Upon completion of this activity, participants should be better able to: Synthesize new evidence on multi-faceted strategies for bladder cancer management based on modern immunotherapeutic agents, small molecule targeted therapies, and antibody–drug conjugates, among others; Integrate novel and emerging therapeutic approaches into personalized treatment plans for patients with bladder cancer, considering the available evidence, current guidelines, and principles of multidisciplinary and patient-centered care; and Implement evidence- and team-based management protocols to address the unique suite of adverse events associated with novel therapeutics for bladder cancer
Go online to PeerView.com/YEM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The therapeutic landscape of bladder cancer has undergone a significant transformation with the addition of immune checkpoint inhibitors to the treatment armamentarium. In addition, the research on actionable targets has led to regulatory approval of the FGFR-targeted therapy, erdafitinib, for FGFR mutation–positive bladder tumors, as well as the antibody–drug conjugates enfortumab vedotin and sacituzumab govitecan. Further, novel bladder preservation opportunities and important combination approaches expand the therapeutic capacity across the disease spectrum available to patients with bladder cancer. In this PeerView activity, a panel of leading bladder cancer experts pairs important analyses of the latest evidence on a new generation of therapeutics with practical insights that can be used to guide therapeutic decision-making in the clinic. This CME/MOC-certified activity will highlight strategies for optimal care of patients with bladder cancer in light of current evidence on and indications for the use of immune, targeted, and antibody-based therapies and guidance on safely integrating these agents into treatment plans. Using patient cases drawn from clinical practice and interactivity that allows participants to see how their treatment choices compare with their colleagues, the faculty will address the mechanistic rationale for these new therapies, therapeutic decision-making, and AE mitigation strategies. Upon completion of this activity, participants should be better able to: Synthesize new evidence on multi-faceted strategies for bladder cancer management based on modern immunotherapeutic agents, small molecule targeted therapies, and antibody–drug conjugates, among others; Integrate novel and emerging therapeutic approaches into personalized treatment plans for patients with bladder cancer, considering the available evidence, current guidelines, and principles of multidisciplinary and patient-centered care; and Implement evidence- and team-based management protocols to address the unique suite of adverse events associated with novel therapeutics for bladder cancer
PeerView Kidney & Genitourinary Diseases CME/CNE/CPE Video Podcast
Go online to PeerView.com/YEM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The therapeutic landscape of bladder cancer has undergone a significant transformation with the addition of immune checkpoint inhibitors to the treatment armamentarium. In addition, the research on actionable targets has led to regulatory approval of the FGFR-targeted therapy, erdafitinib, for FGFR mutation–positive bladder tumors, as well as the antibody–drug conjugates enfortumab vedotin and sacituzumab govitecan. Further, novel bladder preservation opportunities and important combination approaches expand the therapeutic capacity across the disease spectrum available to patients with bladder cancer. In this PeerView activity, a panel of leading bladder cancer experts pairs important analyses of the latest evidence on a new generation of therapeutics with practical insights that can be used to guide therapeutic decision-making in the clinic. This CME/MOC-certified activity will highlight strategies for optimal care of patients with bladder cancer in light of current evidence on and indications for the use of immune, targeted, and antibody-based therapies and guidance on safely integrating these agents into treatment plans. Using patient cases drawn from clinical practice and interactivity that allows participants to see how their treatment choices compare with their colleagues, the faculty will address the mechanistic rationale for these new therapies, therapeutic decision-making, and AE mitigation strategies. Upon completion of this activity, participants should be better able to: Synthesize new evidence on multi-faceted strategies for bladder cancer management based on modern immunotherapeutic agents, small molecule targeted therapies, and antibody–drug conjugates, among others; Integrate novel and emerging therapeutic approaches into personalized treatment plans for patients with bladder cancer, considering the available evidence, current guidelines, and principles of multidisciplinary and patient-centered care; and Implement evidence- and team-based management protocols to address the unique suite of adverse events associated with novel therapeutics for bladder cancer
Featuring a slide presentation and related discussion from Dr Scott Tagawa, including the following topics: Managing patients with FGFR-altered urothelial bladder cancer (UBC) (0:00) Antibody-drug conjugates as treatment for metastatic UBC (10:22) Strategies for using systemic therapies to treat metastatic UBC (27:31) CME information and select publications
Featuring an interview with Dr Scott Tagawa, including the following topics: Sequencing therapies for patients with metastatic urothelial bladder cancer (UBC) (0:00) Case: A man in his mid 80s with UBC with multiple lung and lymph node metastases (4:55) Case: A woman in her mid 80s with metastatic UBC who is undergoing treatment with erdafitinib (46:21) Case: A man in his mid 60s with FGFR-altered metastatic UBC (49:45) CME information and select publications
The pancreatic cancer of Robert Baioni had returned. After his initial diagnosis in 2016, Baioni was treated near his Cincinnati home, treatment that included surgery to remove his pancreas, followed by chemotherapy. A few months later, “my oncologist told me the chemotherapy wasn't working,” Baioni said, adding his doctor also told him about a unique clinical trial at the James run by Sameek Roychowdhury, MD, PhD. “I went in there feeling kind of hopeless and by the time my wife and I left we both felt very optimistic,” Baioni said of his initial meeting with Roychowdhury. In this episode of the James Cancer-Free World podcast, Baioni and Roychowdhury describe the two clinical trials Baioni has taken part in at the James. Both trials were initiated by Roychowdhury and utilize drugs that target a specific genetic mutation that was in the cells of Baioni's cancer: Fibroblast growth factor receptors (FGFRs). This was one of the first clinical trials that focused on the specific genetic mutation causing the cancer and not the type of cancer, Roychowdhury said. “This trial was designed for any type of cancer with the FGFR mutation, the liver, the uterus, the stomach,” he said. “How could we get a therapy to patients based on the genetic mutation; how could we break the mold [of standard treatment.” Baioni and Roychowdhury describe the science behind the clinical trials, what was going on inside the patient's body, how the drugs that target FGFR work, and the side effects associated with this type of treatment. It's a fascinating look at the advances being made in cancer research and treatment, as well as an uplifting story of the bond between a patient and his James physician.
PeerView Family Medicine & General Practice CME/CNE/CPE Video Podcast
Go online to PeerView.com/VRE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Metastatic urothelial carcinoma (UC) is a devastating illness with limited treatment options, especially for patients who have been previously treated with platinum-based chemotherapy and anti–PD-1/L1 therapy. This educational activity features two experts in a lively discussion about this rapidly evolving treatment landscape. The activity also features a patient and his caregiver's perspective on their first-hand experience with the treatment strategies and his journey. These experts review the latest data and ongoing research on platinum-based chemotherapy, antibody–drug conjugates, and pan-FGFR inhibitors for the treatment of bladder cancer and discuss the management of adverse events associated with novel therapeutics. Upon completion of this activity, participants should be better able to: Integrate novel antibody-drug conjugates (ADCs) into individualized management plans for appropriate patients with metastatic UC, taking into consideration treatment history, latest clinical evidence, and current guideline recommendations; Implement team-based strategies to monitor for and manage treatment-related adverse events that may occur in patients with metastatic UC who are receiving novel ADCs as part of their care; Apply an interprofessional team-based approach to care for patients with metastatic UC that incorporates shared decision-making, appropriate patient education and counseling, and effective interprofessional collaboration and care coordination
Go online to PeerView.com/VRE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Metastatic urothelial carcinoma (UC) is a devastating illness with limited treatment options, especially for patients who have been previously treated with platinum-based chemotherapy and anti–PD-1/L1 therapy. This educational activity features two experts in a lively discussion about this rapidly evolving treatment landscape. The activity also features a patient and his caregiver's perspective on their first-hand experience with the treatment strategies and his journey. These experts review the latest data and ongoing research on platinum-based chemotherapy, antibody–drug conjugates, and pan-FGFR inhibitors for the treatment of bladder cancer and discuss the management of adverse events associated with novel therapeutics. Upon completion of this activity, participants should be better able to: Integrate novel antibody-drug conjugates (ADCs) into individualized management plans for appropriate patients with metastatic UC, taking into consideration treatment history, latest clinical evidence, and current guideline recommendations; Implement team-based strategies to monitor for and manage treatment-related adverse events that may occur in patients with metastatic UC who are receiving novel ADCs as part of their care; Apply an interprofessional team-based approach to care for patients with metastatic UC that incorporates shared decision-making, appropriate patient education and counseling, and effective interprofessional collaboration and care coordination
Randomised trial of rogaratinib in bladder cancer with Cora Sternberg.
A new FGFR inhibitor, futibatinib, is approved. Is ESR1 mutation monitoring the next thing in HR+ metastatic breast cancer? The PADA-1 trial offers insight. What the heck is GPRC5D (rhymes with CAR-T)? PADA-1: https://doi.org/10.1016/S1470-2045(22)00555-1 GPRC5D CAR-T in Myeloma: https://www.nejm.org/doi/full/10.1056/NEJMoa2209900
Featuring perspectives from Prof Ghassan Abou-Alfa, including the following topics: Introduction (0:00) Case: A woman in her early 50s with metastatic hepatoid carcinoma of the ovary with an FGFR fusion — Syed M Ahmed, MD, PhD (2:56) Key recent data sets (5:59) Case: A man in his mid 60s with a history of Child-Pugh B cirrhosis and Grade 1 esophageal varices who is receiving atezolizumab/bevacizumab for multifocal HCC — Raji Shameem, MD (22:28) Case: A man in his late 60s with previously treated HCC cirrhosis who is now diagnosed with potentially resectable HCC — Syed F Zafar, MD (29:30) Case: A woman in her late 70s receiving adjuvant anastrozole for Stage I breast cancer who is now receiving atezolizumab/bevacizumab for metastatic HCC — Sunil Gandhi, MD (33:41) Case: A man in his late 70s with metastatic HCC and portal vein thrombosis receiving atezolizumab/bevacizumab (NGS [next-generation sequencing] with PIK3CA mutation, PD-L1 50%) — Susmitha Apuri, MD (35:47) Management of Biliary Tract Cancers (40:18) Case: A man in his late 50s with resected Stage IIB gallbladder cancer s/p adjuvant capecitabine who now has metastatic disease (HER2-positive; MSS, PD-L10) — Nasfat Shehadeh, MD (44:01) Case: A woman in her early 40s with a history of ductal carcinoma in situ and family history of breast cancer, now with metastatic cholangiocarcinoma (NGS with IDH2 mutation) — Joanna Metzner-Sadurski, MD (53:41) CME information and select publications
Featuring an interview with Professor Juan Valle, including the following topics: Immunotherapy for patients with biliary tract cancers (BTCs) (0:00) Etiology and presentation of and recent advances in the management of cholangiocarcinoma (4:18) Targeting FGFR alterations in cholangiocarcinoma and other BTCs (12:47) Spectrum and management of toxicities associated with FGFR inhibitors (19:33) Targeting driver mutations beyond FGFR (28:16) Case: A man in his early 60s with intrahepatic cholangiocarcinoma, an FGFR2 fusion and an IDH1 R132C mutation (35:53) Case: A woman in her early 60s with intrahepatic cholangiocarcinoma and an IDH1 mutation that did not respond to third-line ivosidenib (41:49) Case: A woman in her early 60s with gallbladder cancer who received first-line chemotherapy with pembrolizumab (46:15) CME information and select publications
Featuring perspectives from Dr Shannon Westin, including the following topics: Introduction (0:00) Case: A woman in her late 50s with Stage IIIC high-grade serous carcinoma with a gBRCA2 mutation — Gigi Chen, MD (19:58) Case: A woman in her mid 60s with Stage IIA BRCA1/2 wild-type, high-grade serous ovarian adenocarcinoma — Syed M Ahmed, MD, PhD (23:16) Case: A woman in her early 60s with metastatic MSS ovarian carcinoma with a gBRCA1 mutation — Syed Farhan Zafar, MD (30:14) Case: A woman in her early 60s with multiregimen-recurrent advanced ovarian cancer with a gBRCA1 mutation — Rajalaxmi McKenna, MD (39:13) Case: A woman in her early 50s with metastatic hepatoid carcinoma of the ovary with an FGFR fusion — Dr Ahmed (56:54) CME information and select publications