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Sam Chang: Hello, my name is Sam Chang. I'm a urologist in Nashville, Tennessee, at Vanderbilt University Medical Center, and we are quite fortunate to have Professor Ignacio Duran, who is the coordinator of GU Oncology at the University Hospital in Marqués de Valdecilla in Santander, Spain. But I think more importantly, Professor Duran actually was asked by ESMO to give the highlights of the ESMO meeting in non-prostate GU oncology. And so he has actually agreed, and we're quite fortunate to have him today to go over those highlights and some very, very important findings and presentations that were given. So we look forward to your presentation and thanks so much for spending some time with us.

Ignacio Duran: Well, thank you so much for the kind introduction, Dr. Chang, and you did a wonderful job pronouncing Hospital Marqués de Valdecilla in Santander. Santander is a small city in the north of Spain that I think is just known by the bank, Banco Santander, but it's quite a nice place, so everybody's invited to visit us. So I'm going to try within the next five to ten minutes to give a very brief summary of the highlights of ESMO 2024 in Barcelona and the block of GU non-prostates. So in order to do so, these are my conflicts of interest and these are the key learning objectives. So I'm going to try to, as I said, give a very quick summary, a few brief and concise messages about what was the most relevant information presented in this section of the Congress.

So I'm going to start with kidney cancer, and I think in kidney cancer, this ESMO in Barcelona 2024, there were a couple of presentations that deserve attention because they actually were challenging the status quo in mRCC. The first presentation was trying to explore if adding a checkpoint inhibitor after having received a checkpoint inhibitor in advanced renal cell cancer actually made a difference and made any sense. So the question was, can we add any additional benefit to our patients if we introduce immunotherapy upon progression to previous immunotherapeutic agents in advanced renal cell cancer? Already a year ago in ASCO we heard some data about the CONTACT-03 study that tested already these hypotheses with a combination of drugs, at that time, cabozantinib and atezolizumab, and that study was negative and failed to demonstrate any benefit.

But today, or in this ASCO—or this ESMO, I should say—what we heard, it was trying to test the same hypothesis but with a different group of drugs. In this case, we heard data from the TiNivo-2 study that actually tested these hypotheses in patients with advanced kidney cancer who had received a checkpoint inhibitor-based treatment. Upon progression, they were randomized to either again receiving another combination with a checkpoint inhibitor, in this case nivolumab in combination with tivozanib, a TKI, or just tivozanib. Basically, if you look at the population of patients, you can see that most of them had received only one prior line of treatment, and most of them, the most recent therapy was a checkpoint inhibitor.

The news of this study are that it was completely negative. The study did not show any benefit in the primary endpoint that was the progression-free survival, but it did not demonstrate any benefit also in overall survival. So I think this study, the TiNivo-2, comes to demonstrate that sequencing checkpoint inhibitors in advanced kidney cancer is not the way to go. So this is the first challenge to what we should do in the clinic, the first message to take back home, and not sequencing checkpoint inhibitors in this context. The second study that was trying to re-challenge or challenge the status quo of managing metastatic kidney cancer was about the non-clear cell scenario. So in non-clear cell cancer... and I'm going to go back one slide... the truth is that we manage, according to these guidelines, with very little evidence, and the studies that have been conducted so far have been mostly phase II studies.

We've got data with not a very high level of evidence. So what we heard in the ESMO 2024 was the study SUNNIFORECAST. And SUNNIFORECAST was an academic study that was started in Germany and included a few European countries, Spain among others. And what they tried to test is whether ipilimumab in combination with nivolumab was superior to a standard of care in patients with non-clear cell advanced renal cell cancer, and the endpoint was the overall survival rate at 12 months. Essentially, if you look at the population of patients, it's not included in this slide, but basically it was a study comparing IPI-NIVO versus a TKI. As you can see here, the IPI-NIVO was superior in the overall survival rate at one year, 86% versus 76%, and that was statistically significant. Also, in terms of overall responses, it was superior. So when we look at these data, I think these challenge the current standard of care in non-clear cell and it generates a new option for IPI-NIVO.

It's true that this study has still some questions and we'd like to see the full publication to answer a few questions, but I think it opens a new possibility. There were other relevant RCC studies that were presented. We heard data about the LITESPARK-005 study testing belzutifan in advanced kidney cancer after progression to one to three prior systemic regimens. And the news is no benefit in overall survival. So this study demonstrated benefit in progression-free survival, and that was presented in previous conferences. And in this one, Brian Rini presented data, there is no OS benefit. So belzutifan may have a role in kidney cancer but it still has to be defined what is the ideal setting. We heard also some interesting data about the role of fecal microbiota transplantation in patients treated with axi/pembro, preliminary but interesting.

In summary, the take-home message for kidney cancer after this ESMO 2024 would be: one, we have enough evidence to recommend against sequencing checkpoint inhibitors in advanced renal cell carcinoma. TKI as a single agent should remain the standard of care upon progression to a checkpoint inhibitor in previous lines in this context. The second message is based on the results of the SUNNIFORECAST trial, IPI-NIVO could be considered as another valid option along with IO-TKIs in advanced non-clear cell mRCC. And two other messages: belzutifan is superior in PFS versus everolimus but failed to improve OS in advanced mRCC in the LITESPARK-005. And fecal microbiota transplantation could represent an interesting strategy in this context.

Let's switch gears and move to bladder cancer. So let me just summarize what was presented in ESMO 2024 regarding bladder cancer. And I'm going to use this schema that represents the sequence that we normally utilize in the muscle-invasive bladder cancer. First, we start with the pathologic diagnosis, CT imaging. When we get a patient with muscle-invasive bladder cancer confirmed, then we're going to treat these patients with neoadjuvant chemotherapy followed by a cystectomy. And in those cases considered as high risk, we'll take them to adjuvant immunotherapy. So what we heard in ESMO 2024 were three studies that actually are challenging this principle and that could actually have an impact on our practice tomorrow.

Three studies approaching this problem from different perspectives. The first one is the study SunRISe-4. SunRISe-4 is a study where we're exploring an alternative to cisplatin in that population of patients that cannot receive cisplatin-based neoadjuvant chemotherapy. The SUNRISE program works around an intravesical device called TAR-200 that releases gemcitabine in a continuous fashion, and SunRISe-4 was testing the Path-CR, the pathological complete response, in patients with muscle-invasive bladder cancer who were not fit to receive cisplatin in this context. This is the summary of the trial and you can see that the study was designed with two arms. In one, we were exploring the combination of TAR-200, the intravesical device, plus a systemic checkpoint inhibitor, cetrelimab.

In the other cohort, it was cetrelimab as a single agent. As I said, Path-CR was the primary endpoint. And you can see here the results: a Path-CR of 42% for the combination. And if you look at the different substages' activity in cT2 patients, it goes up to 48% of pathological complete response. So I think with this data, although it's still small numbers and preliminary, I think we can say that we've got another potential approach for patients with muscle-invasive bladder cancer who were not good enough to receive cisplatin-based chemotherapy. But there were other data presented around the muscle-invasive bladder cancer arena, and that was an interesting academic study called TOMBOLA from a Danish group. And this study, in very quick words, was exploring the role of ctDNA in patients after cystectomy to select for those who actually needed adjuvant immunotherapy.

Very preliminary data, but I think it opens a new avenue here for serial measurements of ctDNA following adjuvant chemotherapy and radical cystectomy. In this study in particular, it was highly specific. Those patients who were ctDNA negative after radical cystectomy, only a very, very small percentage of patients had a relapse. So probably ctDNA is going to help us in the future to identify those patients that would obtain more benefit from an adjuvant component after surgery. And let me move to the last study, but not the least important. It was actually a presidential session presented by Dr. Tom Powles from London, and that was the results of the NIAGARA study. So NIAGARA, to put things into perspective, again going back to the muscle-invasive bladder cancer scenario, is the first global phase III study that evaluates a perioperative immune checkpoint inhibitor, durvalumab, combined with neoadjuvant chemotherapy in patients that are cisplatin eligible.

What they did in this study was randomize about 1,000 patients to receive either the classical CIS-GEM followed by radical cystectomy—that would be standard of care—or CIS-GEM plus durvalumab followed by cystectomy and then an adjuvant component of durvalumab. The endpoints were event-free survival and Path-CR. They presented the Path-CR here that is superior in the experimental arm and this is statistically significant, but more importantly, what they presented was that the event-free survival and the overall survival were superior in the experimental arm and this was statistically significant and I think we could say clinically meaningful. It's true that the follow-up is still relatively short, but I think the benefit is there and it's unquestionable.

So the take-home message from bladder cancer is that new approaches such as intravesical devices are being developed in muscle-invasive bladder cancer, and the example of TAR-200 and the SunRISe-4 data I think are interesting. There are also strategies being tested to refine the perioperative treatment that might help us better select patients for these types of treatment, so treatment after cystectomy and ctDNA, and the TOMBOLA study is an example. And lastly, the use of neoadjuvant chemotherapy plus durvalumab by adjuvant durvalumab has demonstrated an improvement in event-free survival and overall survival when compared with chemotherapy alone and could represent a new standard of care in this setting. And with this, I'd like to finalize my presentation and thank you all for your attention.

Sam Chang: Dr. Duran, that was amazing. If I am part of the committee to put together the meeting for ESMO, I'd be worried about asking you to do this again—not because your job that you did was fantastic; people won't go to the meeting. They just need to listen to your five-minute introduction review of the key highlights. That review is as good as I've heard, and we've heard different types of reviews. So thank you so much. Obviously a lot to cover in a short period of time. I'd like to ask difficult questions but ask for short answers for each of kind of these key studies. So let's start off with the idea of a combination vis-à-vis sequencing for those patients with metastatic clear cell RCC. At this point, the sequencing doesn't seem to help. So what do we do with these patients then that progress? What's our next step? What do you recommend at this point?

Ignacio Duran: Well, thank you, Dr. Chang. I think this is a very good question. My recommendation here I think would be to go to a tyrosine kinase inhibitor. I think the difference that also the TiNivo-2 study adds to this scenario is that we can use other tyrosine kinase inhibitors beyond cabozantinib. That was probably the ideal option until this data has been presented. So probably in this scenario, my choice would be cabozantinib or tivozanib. Those two would be valid options in this context.

Sam Chang: For those patients then where we have used in the past everolimus and now have belzutifan, we see a benefit in progression-free survival but don't see it in overall survival. I can tell you in Nashville with Dr. Rini, with our group, we've tended to shift over almost totally to belzutifan. Now this data doesn't show an overall survival benefit. What would you do now for these patients?

Ignacio Duran: Well, I think we all had a little bit this feeling, and I have some experience with some patients that received belzutifan within trials and they actually experienced a significant advantage or improvement in their disease. So to me, I have to admit, the data was a little bit disappointing. I was expecting more from belzutifan, and I was expecting more when actually we were comparing belzutifan with everolimus. That has not been the best drug in advanced kidney cancer unfortunately. So I think we are probably missing something, and I don't know whether this is the setting where we're using this drug, whether we should use it earlier in the history of the disease and maybe we avoid other paths that may be overcompensating and then angiogenesis is not the only valid point.

Sam Chang: Is no longer the key driver, yes.

Ignacio Duran: Yeah, that could be one of the reasons.

Sam Chang: I think that's our thought process here, and we are definitely utilizing it sooner than we have in the past, and we're still hopeful for a benefit but we don't know. So for non-clear cell, has IPI-NIVO now become your choice of the day, at least, for non-clear cell disease?

Ignacio Duran: This is a very good question, and let me tell you that the discussion of this presentation was quite critical. And I have to say these guys deserve credit because this is an academic study. We all know how complicated it is to run an academic study in any setting. And in the non-clear cell, it's even more challenging because recruiting patients is difficult and these studies are quite tricky, so they need to be congratulated. And they included mostly papillary cancer cells and—sorry, papillary renal cell cancer—and they included also chromophobe renal cell cancer. And the data is there. I think it's a randomized study where you compare IPI-NIVO versus the standard of care; the standard of care was in almost 90% of the patients a TKI, so I think they demonstrated an improvement in that endpoint that they selected, the 12-month overall survival rate. And if you look at the curves, it's true that they don't show a significant separation.

But I think this gives me some kind of reinforcement about using IPI-NIVO in some of my patients. Is it the only option? Probably not. I think also combining a tyrosine kinase inhibitor plus a checkpoint inhibitor in this context would be ideal, but it probably shifts a little bit the trend that, at least in the European guidelines, was pretty much focused on only using cabozantinib in papillary renal cell cancer. So I think to me, this study has value. As I said, I'd like to see the full data presented, but I think it opens a new option for these patients that perhaps we thought would not benefit as much from a checkpoint inhibitor combo.

Sam Chang: Well, let's end this conversation with urothelial carcinoma. In clinic tomorrow I know I'll have at least a few patients come in with muscle-invasive bladder cancer, no evidence of metastatic disease. So, should I now talk to them, switch from a discussion about neoadjuvant chemotherapy by itself—let's say they're platinum-eligible—to this combination therapy, and should I be checking then ctDNA at multiple different levels, after the neoadjuvant treatment, after the cystectomy, etc.? Are we at that point yet?

Ignacio Duran: Well, that's a great point. I think right now we are at the point where we have for the first time data supporting the concept of combining chemo plus IO in muscle-invasive bladder cancer followed by adjuvant IO. And I think the NIAGARA study may have criticisms; we're lacking some data, we don't know about subsequent therapies yet that might have interfered in the overall survival signal. But I think what I'd have to do with my patients is discuss right now until we get approval from FDA or EMA, cisplatin-gemcitabine or dose-dense MVAC is the way to go. But maybe in the near future we're going to have data to combine chemotherapy with something else in your situation. And we believe that probably giving you something after doing a radical cystectomy is going to add your benefit in terms of event-free survival. The question here to me is whether all patients in NIAGARA actually benefited from receiving the adjuvant component of this study and what was the impact that that adjuvant component had in their lives in terms of chronic toxicities that was not presented.

Apparently it hasn't been that significant, but all of us use adjuvant checkpoint inhibitors in the clinic and we see toxicity all the time. Not severe, but sometimes we see patients that may have to live for the rest of their lives with a low-grade arthritis or with an endocrine-related toxicity, and maybe those patients were already cured. So going back to your point, I think we need to find something that in the future will help us to stratify those patients that will actually need that adjuvant component, and ctDNA right now is the one that has more points. The data is not compelling yet. We'll have to wait for IMvigor011, and when we see the results of IMvigor011 maybe that will wrap up the story of ctDNA and we hopefully will have something to help us decide in the clinic. But tomorrow, CIS-GEM or dose-dense MVAC, this is what it is as per today.

Sam Chang: No, I think excellent points and it really adds to the future in terms of the provocative questions of are we going to need cystectomy for these patients with pathologic CRs and then following them with ctDNA, will that be enough? Your point regarding adjuvant therapy, it's a combination of just as Tom Powles says—I mean, he's been provocative in terms of we're not going to be doing cystectomies in the future with combinations, etc. We can monitor, we can follow. I think really it's a combination of who needs escalation of therapy, who can get by with de-escalation of therapy, and then choosing what that actual therapy will be. I think it's a very exciting time because we now have options for patients. So we very much appreciate all the efforts that you and your team have made, and this kind of summary of the key highlights is really one of the things that is actually really helpful for any of these international meetings.

Thank you so much for spending some time with us and thank you for answering some provocative questions that I've put out there because there are no, obviously at this point, black-and-white answers to these questions. But the fact that we have more options I think really is a testament to really the increased research interest in these disease processes and the options that our patients have. So Dr. Duran, thank you for spending some time with us. I hope we can do it again.

Ignacio Duran: Thank you so much. Thanks a lot.