The Future of RCC Treatment Sequencing and Individualized Patient Care

Part four of this roundtable features a deep dive into the challenges and possibilities of designing trials to understand treatment sequencing in renal cell carcinoma (RCC). Drs. Katy Beckermann, Monty Pal, Toni Choueiri, Hans Hammers, and Pedro Barata analyze the limitations of past studies like RECORD-3 and SWITCH, discuss the potential of ongoing trials such as PDIGREE and SPARK-11, and explore how these efforts could refine our approach to treatment strategies in RCC. This segment highlights the evolving landscape of RCC management and provides expert analysis on the future of treatment sequencing.

Watch the final part of this roundtable series: What’s Next for RCC Treatment? Promising New Targets and Clinical Trials

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Dr. Beckermann:
I have two big-picture questions, since I have such wonderful minds here in our virtual room. I guess one big-picture question is does anybody ever think that we’ll have a trial design that would allow us to understand sequencing in RCC? Because I think these two trials, again, we’ve all acknowledged, they’re very informative. They’ve been negative. They’ve told us while we were all trying to continue checkpoint inhibition, that at least in a PD-I, PD-L1 continuation, it’s not providing benefit. But is there a trial design that would allow us to understand how you sequence treatments after that frontline combination?

Dr. Choueiri:
We’ve been designing trial based on progression on first-line, et cetera, so that could inform. But to have an integration in the same trial has been difficult, because from the time of RECORD-3 or 4, I forgot, that Bob Motzer led, we see that a significant number of patients, up to 50%, don’t make it on the second part. For many reason: rapid progression, changed mind, standard of care change. But we do actually have one of the studies that still matter in renal cell cancer is PDIGREE. PDIGREE is over 1100-patient study, where based on the response to NIVO-IPI, in intermediate and poor risk, you’ll get cabozantinib or not. And I think this may inform our practice. Are we are going to see data in the next year happening? And I’m happy that this study, which is over six years old, and the design seven years, started, have survived the time of change of the landscape so far.

Dr. Beckermann:
I think that’s great. I think many of us are excited to see those results come out. I know you and Dr. Tian Zhang have certainly formed that trial through the Cooperative Group Network, and look forward to seeing what that shows.

Dr. Pal, you look like you have something.

Dr. Pal:
Yeah, no, I agree. It’s funny you brought up RECORD-3. And it’s taking me down memory lane to all these studies of sequencing that we’ve seen in years past. I was thinking of the SWITCH trial, which is sunitinib and sorafenib in sequence with one another. And I think that there’s certainly laudable goals in trials like this. But having said that, I think what we’ve learned over the years is if we try to restrict investigators to a sequence of A followed by B, versus B followed by A, typically, there’s just issues that you might face in terms of attrition as you go from first to second-line. That was one of the main lessons learned, I think, out of RECORD-3 and out of SWITCH.

But beyond that, there’s also that onus on the investigator to do whatever they feel is best for the patient. So very oftentimes, there’s poor protocol adherence, as you pivot at the second and third-line therapy. So I’m not optimistic about trials that involve switching. And frankly speaking, I think that the better resource allocation is into studies like Toni’s defined. Pointing this way, because that’s where he is on my screen. And also, the trials involving new investigational therapies and regimens. I think that’s definitely the way to go.

Dr. Barata:
So if I may add to that really quick, just to say, also came to me, I agree, great comments. Just maybe highlight one or two efforts in addition to that. One, we will see some of these questions, not really the sequence, I think, but probably start comparing them as much as possible. I mean, there’s a smaller study out at Houston, right? LENV-EV versus CABO, for example. So that study is ongoing. It’ll provide some, I think, potentially useful information that are smaller, randomized Phase 2.

But then at larger studies, not having the pure design of a SWITCH design, but things like SPARK-11 that Toni and others are leading. When you think about LENV in combination with belzutifan compared to CABO, right? Because you’re really thinking CABO is the standard second-line option, if you will. I think that can be informative as well.

So while I’m not particularly expecting to see it switch, I agree PDIGREE can get us there in a different way. I think other large efforts put together can also help us to keep doing what we’re doing, how we are prioritizing the different TKIs, by generating data in the settings where we feel that “You know what? This is the most robust data to support our choice as the default plan.”

Although also, I think all of us have the sense that, again, not everybody should get the same strategy of A followed by B, followed by C. That’s probably not going to be where we’re going to be in five years from now. And we all already picking different agents, depending on the patient in front of us. But I think the trial data that’s going to read out might get us to be able be smarter, hopefully, in how to decide. Anyway, I just want to give a highlight to those additional studies.

Dr. Beckermann:
No, that’s great. And thank you for bringing those up, and we’ll keep our eyes open for all of these exciting studies, which I do think will be again, also practice-informing.