Alicia Morgans: Hi. I'm so excited to be here at SOGUG 2022, where I have the opportunity to talk with Professor Toni Choueiri of the Dana-Farber Cancer Institute. Thank you so much for being here.

Toni Choueiri: Dr. Morgans, thank you.

Alicia Morgans: Well, always fun to talk to you. Always fun to see you in the office too. But here at SOGUG, you really enlightened us on some innovations and advances that we have seen and can expect to see in the coming years in kidney cancer. And it was a very, very exciting talk. I wonder, can you start us off by really setting the stage with where we stand in metastatic kidney cancer?

Toni Choueiri: Yeah. I mean, very privileged to be part of this field where we've seen patients living longer and longer. I think with metastatic disease, we had tried to be as smart as possible to avoid toxicity and optimize responses by not just not much combining, but we combined the drug concomitantly, and we gave them sequentially. So drug A followed by strategy A plus B. This has not worked. I wouldn't say I was surprised, but actually what we found is an extremely high attrition rate going from step one to step two.

So for example, starting with nivo. And if there isn't a response that we're looking for, then adding ipilimumab while keeping nivolumab. This strategy has not worked, mostly due to the attrition rate, and when it worked the complete responses, and even the partial responses, were lower than starting two drugs at the same time. So on the other hand, starting two drugs or, what we've seen in COSMIC-313, three drugs at the same time did work and led to positive results. Although, of course, when you use two versus one, three versus two, there is increased toxicity, so experience is very important.

Alicia Morgans: Absolutely. So what about for patients who have progressed after an immune sort of approach initially? What can we do for these patients?

Toni Choueiri: Yeah. Well, in patients whose tumor progress after a PD-1 and PD-L1 inhibitor, I think the main question... Of course, you can use a TKI you haven't used or a totally new strategy, but I think what's very important is to ask ourselves, now that we have a lot of first-line combinations that are PD-1 based, PD-L1 based, could we or should we use another PD-1 inhibitor as part of a strategy with a TKI? And at this point, we have no evidence, really, clinically that it does make a lot of sense despite some trials showing significant activity. That could be attributed to the single agent TKI or CTLA-4, which is in the FRACTION study.

So we have two studies. One finished accrual that is called CONTACT-03 that uses atezolizumab on top of cabozantinib versus cabozantinib alone. And another one that uses a novel TKI, tivozanib plus or minus nivolumab also. I think this will be a very important question.

Alicia Morgans: Absolutely. I think it's really exciting to talk with you because you've been involved in so many of these trials from their inception, and one of the recent advances that I know you were very involved in is the development of adjuvant therapy for patients with RCC. Can you tell me a little bit about that?

Toni Choueiri: Well, unfortunately, or fortunately, I don't know, but at least we had results at ESMO 2022. But these trials were very much practice-informing three trials, but they were negative, including very promising PROSPER study with a neoadjuvant approach. So all that we have left is pembrolizumab. Luckily, that study was designed well and was large, so near a thousand patients, and continued to show that 24 and 30 months disease-free survival to a degree that the next generation studies are using pembrolizumab as control. So we have LITESPARK-022 with pembrolizumab versus pembrolizumab plus HIF-2 inhibitor that showed activity in metastatic disease with a very favorable safety profile.

Alicia Morgans: Wonderful. Well, what about non-clear cell? This is the group of patients that is sometimes forgotten and frequently left out of these trials, but it certainly is an interest of yours. And in all clinicians, we need to take care of these patients and really try to elevate their care as well. What can we expect for non-clear cell disease?

Toni Choueiri: They're not one disease. They're multiple diseases. It's a Pandora's box. And actually, what's happening is with the VEGF-IO combination, what is really happening is that we are seeing high response rate and in all of the non-clear cell. Perhaps the exception in the IO-based is chromophobe renal cell cancer, which is a cold tumor for which we may mostly use lenvatinib-everolimus.

But one interesting thing emerging is strategies targeting MET in a specific subtype, which is papillary RCC which by itself is common in non-clear cell, the second most common kidney cancer. And in this subtype, around 30-40% do have MET alteration, mutation in the receptor or in amplification or the ligand is amplified, HGF, or sometimes chromosome 7. Actually, that's the most common duplication where MET resides. And in those patient, they will be subjected to a MET-based strategy plus a checkpoint inhibitor, the combination of durvalumab and savolitinib. And initial data in MET positive patients, small study, showed that that could provide very interesting and intriguing results. So we took this to a phase III trial that is just opening up in multiple centers.

Alicia Morgans: Well, wonderful. And definitely, I'm glad that it's multiple centers because these can be harder patients to find. So I'm glad that you have the support there, and we look forward to those results.

But other results that I know we're all eagerly anticipating are the biomarker results that are going to actually help us drive our decision-making from a rational and perhaps more precise perspective. What can we expect there?

Toni Choueiri: I mean, we hope so. At least people are thinking about that and designing studies to look at this. One of the issues, though, is that the drugs to use a certain design or a certain signature are different despite they may fall under IO, under VEGF, so it remains to be seen if they're going to validate prospectively. But this strategy actually remains very, very important, at least to be able to do the study, so that we can do the next study and learn. Because sometimes, it's all about the execution. Even if the hypothesis is not a hundred percent, sometimes it need to be good enough to take it to the next stage.

Alicia Morgans: So final thoughts, I guess. Where is the next stage? Where do we go from here?

Toni Choueiri: I think the next stage in kidney cancer is not just biomarker. I think liquid biopsy is going to be very, very important in real time to see how this tumor is, profiling a tumor that is metastatic, looking at minimal residual disease to see who can get pembrolizumab. One warning is that renal cell cancer is not a much shedding tumor.

But also, I'm excited about the field, especially as it tackles survivorship. It tackles diversity in trials. We're trying to open the studies and include a diverse population. If you see diversity in kidney cancer trials, there hasn't been much diversity that parallels at least the US population, per se. But now, at least we are aware. We're talking about it, and I think good things are going to happen in the next couple of years.

Alicia Morgans: Wonderful. Well, we know that you'll be able to share those advances with us each step of the way, and I sincerely appreciate your time and your expertise today.

Toni Choueiri: Dr. Morgans, UroToday, you are the best.