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Cheryl T. Lee, MD: Welcome to Medscape InDiscussion for season two of our bladder cancer series. I'm Cheryl Lee. Today we'll discuss combination systemic therapy for advanced urothelial carcinoma. In season one of this podcast, the topic of combination therapy came up in a few episodes but wasn't ever the focus. Today we'll take a deeper dive and focus on populations with advanced urothelial carcinoma. What are the limitations and benefits in terms of improving response rates, prolonging survival, and delaying disease progression? What can we learn from many of the recent clinical trials to sharpen our use of newer therapies and improve patient selection and management? And what are the challenges associated with accrual of patients and ensuring diversity in our clinical trials? To further explore combination therapy for advanced bladder cancer management, we've invited Dr Andrea Apolo to join us. Dr Apolo is an internationally known medical oncologist and tenured senior investigator in the Genitourinary (GU) Malignancies branch at the National Cancer Institute (NCI). Within the GU branch, she serves as chief of the bladder cancer section and director of the Bladder Cancer and Genitourinary Tumors Multidisciplinary Clinic. She's been instrumental in the clinical development of multiple immunotherapeutic agents and combinations from first-in-human studies through phase 3 clinical trials. And in fact, she led the bladder cancer study of avelumab that resulted in FDA approval in advanced bladder cancer. Welcome, Andrea.
Andrea B. Apolo, MD: Thank you, Cheryl. It's wonderful to be here with you discussing this important topic.
Lee: We're so grateful that you could join us today. You've led a broad array of translational and clinical cutting-edge studies on novel targeted and immune agents for GU cancers. What sparked your interest in GU malignancies and translational research? I'm also curious about how your position at the NCI has really shaped your access to novel agents, perhaps more than in a typical academic department.
Apolo: I think everything stems from mentorship and in who we end up working with. I had an early exposure to laboratory research and translational research when I was working as a college student and came to the NCI in Bethesda, Maryland, to do research under a scholarship and had the opportunity to work with physician-scientist and laboratory-scientists. I really learned about cancer research through that mechanism. And I was intrigued and captivated by the way that you can take something from the laboratory and then test it in patients, and then take patients' outcomes, go back to the laboratory, and then ask important questions to further the development of therapies. So that's where it all started. And then I did a residency in internal medicine and a fellowship in medical oncology. When I was at Memorial Sloan Kettering doing my fellowship, I had a fantastic mentor — and I picked the mentor, not the disease. My mentor happened to be working in bladder cancer. This is Dr Dean Bajorin, and he has really been instrumental in me choosing bladder cancer as one of the diseases that I have dedicated myself to understanding and learning and working in. It's really through mentorship, I think, and the person that you work with. Once I started working in bladder cancer, I realized all the need that there is in terms of new therapies and in terms of supporting patients with this disease, raising awareness and also understanding the biology of bladder cancer — so a lot of different perspectives from the research perspective. Within the NCI, we have access to drugs very similar to an academic center, through different mechanisms. We can use a Cancer Therapy Evaluation Program (CTEP) mechanism. We can go through investigator-initiated trials and develop Cooperative Research and Development Agreements (CRADAs). I think one of the really special things about the NCI is that we do get to ask questions that are high risk, and we're supported in doing these clinical trials that would otherwise not have been done by pharma or other academic centers because of the high risk. One of the things that I also get to work with is rare tumors, because there just are not a lot of trials being done in patients with bladder cancer and rare tumors. I've had the opportunity to do that because we see these patients at the NCI.
Lee: That is a tremendous story. And you've had a marvelous career thus far. I was listening to you comment about Dean Bajorin; I had a chance to interact with him when I was a fellow at Memorial Sloan Kettering. So, yes, I could easily see how he may have influenced your career choice. Just such an outstanding leader and giant in the field of GU medical oncology. As I was thinking about this episode, I was reflecting on the fact that there's been an explosion in therapeutic trials in advanced bladder cancer in the recent past. And I say "explosion" because for so long there was a dearth of trials. We may still not be at the number of trials like in other organ sites, but I would say in comparison to our past, we've made significant progress. I feel like these trials are really giving patients opportunities for second-, third-, even fourth-line therapies. So, I'm curious about what you see in the context of these trials as continued limitations that we face in developing and testing novel agents. How do we continue to improve our outcomes — our response rate, survival? Is the approach that we need combination therapy? Is that the way to see the future?
Apolo: Great, great questions. And it's a very broad topic because there definitely has been an explosion of therapeutic trials and advances in bladder cancer, and our patients are doing better. Really understanding the biology of bladder cancer has been important. For example, for immunotherapy, we know that bladder tumors express PD-L1, and that is a strong rationale for testing checkpoint inhibitors in patients with bladder cancer. It has led to multiple agents being approved for patients with advanced bladder cancer, and now even muscle-invasive bladder cancer and non-muscle-invasive bladder cancer, with checkpoint inhibitors. Also understanding the mutations that are important in bladder cancer. We know that FGFR3 is an important driver mutation in patients with bladder cancer. And now we have a therapy, erdafitinib, that we use in the metastatic setting for patients who are FGFR3 positive, that their tumors have FGFR3 or FGFR2. So that's also an important advancement. We also use antibody drug conjugates (ADCs) that have been used in other tumors for years. Now we have ADCs that have specific targets for bladder cancer, such as enfortumab vedotin, which targets NECTIN4 which is expressed in bladder tumors; and sacituzumab govitecan, which targets TROP2, also expressed in bladder cancer. So now we have these agents to combine. The natural question, then, is, can we do better by using these in combination? The standard of care for bladder cancer has always been cisplatin-based chemotherapy or platinum-based chemotherapy in patients who can't get cisplatin. So, if checkpoint inhibitors are so active, what if we combine them? There have been many trials asking that question of the combination of chemotherapy and checkpoint inhibitor, including the IMvigor130 study, the KEYNOTE-361 study, and the CheckMate-901 study. Unfortunately, we have not seen that the outcomes are improved with the combination of chemotherapy and checkpoint inhibitor in the first-line setting in patients with urothelial carcinoma. So sometimes combining is not the answer. One of the theories is that the patients who are responding to the chemotherapy are probably the same patients who are responding to the checkpoint inhibitors. So there's an overlap there. Maybe we need to look at other mechanisms to improve outcomes.
Lee: What a great overview of many of our new agents. You mentioned several that are really directed at molecular targets, and it reminds me that precision medicine has allowed many patients in other organ sites to have highly directed therapy. It seems like we're beginning to see more of this in our space of advanced urothelial cancer. How do you see genomic testing impacting the treatment of urothelial carcinoma? I know you mentioned it just now in the context of combination therapy, but perhaps you see other things on the horizon. I'm wondering if we can learn anything from some of these recent trials that you mentioned, in terms of patient selection and therapeutic response. I know we're always looking for even a small number of patients who could have an extreme response. How do you see our future there in terms of molecular targets?
Apolo: I think we are heading in that direction by incorporating correlative studies, collecting tumors, and sequencing; and then going back and seeing who's responding; and designing clinical trials with biomarkers to best treat the patients. From a genomic standpoint, we are still looking at additional genes that are important for patients and their response to treatment. DNA repair genes have been implicated in in the response to patients with chemotherapy and with checkpoint inhibition, but which genes specifically? We still have a lot of questions, but the research is being done and hopefully we'll have better answers and be able to target more specifically a lot of these alterations that we're seeing in these patients. We have these active therapies, and I wanted to mention another combination study that is very important. I mentioned enfortumab vedotin (EV) and I mentioned checkpoint inhibitor. The combination of EV plus pembrolizumab has been showing some terrific responses in the first-line setting in patients who are cisplatin ineligible. It has recently received FDA accelerated approval for patients with metastatic bladder cancer. We're awaiting the phase 3 data from the EV-302 study, which randomized patients in the first-line setting — both platinum ineligible and platinum eligible — to receive chemotherapy vs EV plus pembrolizumab. We're awaiting the outcomes of that, but for now it's got accelerated approval. How do we sequence these therapies now, and how do we test new drugs if patients are already getting these therapies so early? I just mentioned that nivolumab now is also being given in the adjuvant setting for patients with muscle-invasive disease and pembrolizumab in non-muscle-invasive bladder cancer patients. So that in a way hinders subsequent studies, and where would these additional combinations fit? I think that has been an issue in trial design for patients with advanced bladder cancer, in that we're seeing some responses with some combinations. For example, I have the cabozantinib/nivolumab study that was done in all GU tumors, and we took it forward in kidney cancer. But I've also wanted to take it forward in bladder cancer because we saw an overall response rate of 42% with a complete response rate of 21% in the second-line setting. But now, if EV plus pembrolizumab goes to the first-line setting, where would that combination fit? And that's true for other agents that are being combined with checkpoint inhibitors, where you see a very promising overall response rate but it's hard to find a place for it now that we're seeing more effective therapy. So, we really need to develop therapies now post-platinum, post-checkpoint, post-EV, and now maybe even post–sacituzumab govitecan (SG). SG has accelerated approval, but we're waiting full approval once the phase 3 data are out.
Lee: You mentioned an interesting point about perhaps the development of resistance and the fact that we're using some of these agents earlier and earlier. There's been a mixed response to pembrolizumab in patients with non-muscle-invasive disease, in part because of costs and adverse events and that risk-benefit ratio, especially with other agents coming along for BCG-unresponsive disease. It is an interesting point about where pembrolizumab should fit now that other agents are being FDA approved for non-muscle-invasive disease. So, we'll have to keep that in mind. Are there any novel combinations you see coming down the line or that you're about to study? Anything you can give us a peek at through the looking glass?
Apolo: There are a lot of combinations that that are currently being studied right now that would need to be validated in larger trials, like combining ADCs, other ADCs like sacituzumab, with checkpoint. I think some of the early data for that were presented. Combining erdafitinib in patients who are FGFR3 positive or any FGFR3 inhibitor with a checkpoint inhibitor — that's another interesting concept. And there were early data from the NORSE study that combined erdafitinib plus a checkpoint which showed in a very small cohort of patients doubling of the overall response rate. I think there's a lot of interesting combinations, taking two active agents and combining them, to see if there's improvement in outcomes. There was a very nice study that was presented about a year ago with ephrin B1, which is a transmembrane protein that's highly expressed in urothelial carcinoma. And they did a combination with pembrolizumab with an Ephrin-B4 inhibitor and saw very nice response rates of 52%. So that was great and they're doing a larger trial now to validate these responses. There are a lot of exciting things on the horizon. Incorporation of radiation therapy at multiple different levels to enhance the absorption effect is currently being studied in a lot of clinical trials in bladder cancer. So I think it's a very exciting time to be doing research in bladder cancer right now, with all of the new developments. Incorporating biomarkers is very important and also things like ctDNA and CTCs, and really selecting the patients who need these therapies, because we have a tendency to overdo it. We say, well, let's take two things or three things and combine them, but we must think about the toxicity. We must think about whether these patients really need this much therapy. Can we do a sequential approach? Once we have a response, can we dose de-escalate? Can we stop therapy? These markers will be great in making those decisions, and I think it's wonderful that a lot of trials are currently being designed this way.
Lee: Thank you for that overview. The last thing I want to ask you about relates to patient representation on clinical trials. A lot of the correlative studies that we see in large trials are really used to drive new hypotheses and sometimes even fuel regulatory approvals. I'm wondering about your thoughts on increasing the racial and ethnic diversity of clinical trial participants so that we can fully understand therapeutic response, but also so that we diversify our tissue and data repositories.
Apolo: I think this is such an important question and it's become a key issue now in trial development and within the cooperative groups, and within the NCI in terms of increasing diversity, because our trials have really had low diversity. It has to do a lot with the incidence being lower in some diverse populations, but I think we need to make greater efforts in order to include a more diverse population of patients. One of the first steps is to talk about it and to bring this up as an issue, which is being done right now. So, there are a lot of efforts ongoing right now to improve this. And hopefully we'll be seeing this in the trials that are currently accruing and in the trials that are about to open — a more diverse population of patients.
Lee: I know we'll all be looking forward to that. We've covered quite a bit of ground today. Any key takeaways for our listeners?
Apolo: Patients with metastatic bladder cancer are now living longer due to the incorporation of these active therapies that we have, and it's important for us to learn to sequence in addition to learn to combine the therapies to improve the efficacy that we're seeing right now. But as we do see efficacy in improving, we also have to find ways — and I think it will be through biomarkers — to stop therapies, de-escalate, because it's important that the patients not only live longer but also live better and have a good quality of life. If they're dealing with a lot of toxicities from combination therapies, it's important to be able to incorporate dose reduction or dose stopping within clinical trials. In terms of tumor biology, there's a lot of promising biomarker work that's being done right now prospectively, and it will be important to use these also in finding new targets, but also incorporating them into trials, like ctDNA, in order to de-escalate therapies and eventually stop therapies in patients who are responding.
Lee: Andrea, thank you so much for being here today and for sharing your expertise. And thanks for listening to our conversation with Dr Apolo. There's much more ahead in our final two episodes of the season, so be sure to check out the Medscape app and share, save, and subscribe if you enjoyed this episode. I'm Cheryl Lee for Medscape InDiscussion.
Study of Nivolumab in Combination With Ipilimumab or Standard of Care Chemotherapy Compared to the Standard of Care Chemotherapy Alone in Treatment of Participants With Untreated Inoperable or Metastatic Urothelial Cancer (CheckMate901)
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Cite this: Advancing Urothelial Cancer Care: Combined Therapies - Medscape - Jun 21, 2023.