Brian Rini, MD, and Monty Pal, MD, Discuss RCC Clinical Trials

In the second segment of a debate series, Brian Rini, MD, and Monty Pal, MD, address kidney cancer clinical trials of interest.

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Dr. Rini: Our next topic is talking about clinical trials broadly in the advanced kidney cancer space. I’ll start with the adjuvant setting where the largest ongoing trial now is pembrolizumab plus belzutifan versus pembrolizumab, a Merck-sponsored trial, quite obviously building on the pembrolizumab monotherapy KEYNOTE data. There also is a large study in the UK called RAMPART that was in the first generation of immuno-oncology (IO) studies that does include CTLA-4 inhibition. Those are 2 big pieces of adjuvant data that will add to that story.

In the frontline setting, with COSMIC-313, we’ve moved into triplets. COSMIC-313 was a little disappointing from a toxicity standpoint and lack of survival signal, but I still believe triplets are viable and need to be tested in kidney cancer. Merck has a large triplet study of lenvatinib/pembrolizumab as a control, and then the 2 experimental arms either add belzutifan or CTLA-4 inhibition. That’s an exciting trial that’s nearing completion.

Then there are other plans in the frontline setting. I think there are some other triplet plans. We’re moving into this. I think we’re going to have to do so thoughtfully. I think COSMIC-313 taught us we can’t just stick drugs together and expect good tolerance and outcomes.

The other thing I should mention is biomarker-based trials. Monty, you’re involved with our study of OPTIC looking at RNA-seq to select patients. I’m biased because it’s our study, but I think that kind of study is really important. We do a lot of talking about biomarkers. We don’t do a lot of acting on it, and we just need to put our money where our mouth is and try it and see what happens and do the hard metastatic biopsies and the hard sequencing and informatics if we really truly want to individualize therapy.

Dr. Pal: I think you’ve highlighted 3 of the most important trials, in my opinion, moving forward in the field. The biomarker study, as you suggested, represents us actually doing something as opposed to just talking about it, which is terrific. I really applaud you for taking the plunge.

I actually think your first-line study looking at lenvatinib/pembrolizumab plus belzutifan versus lenvatinib/pembrolizumab plus a CTLA-4 inhibitor versus lenvatinib/pembrolizumab actually really stands a good chance to work despite COSMIC-313, or maybe in support of it to some extent. I think the reason for that is that COSMIC-313 took this major element out of the investigator’s hands, which is knowing what compound they’re dealing with a placebo-controlled design. I just feel like that toxicity management with a triplet might be so critical. I don’t know how you feel about that, Brian, but I think that’s a key advantage.

Dr. Rini: Yeah, having treated patients on that trial, and even with doublets, toxicity management and knowing what drug is causing what, even in practice with the doublets, is difficult when obviously you know what drugs you’re giving patients. In a trial, when it’s blinded, it adds an element of uncertainty, which I think is never good for patient care.

Dr. Pal: I’ll just mention too, there’s some really exciting stuff happening in the advanced disease space. We’ve talked about HIF-2 inhibitors in the past and belzutifan and so forth. I think that’s going to be another key element in our armamentarium for kidney cancer. Beyond that, there’s some really cool novel stuff looking at chimeric antigen receptor (CAR) T cells and bispecific T-cell engagers. It’s all really in its infancy, but there’s some really selected targets I think that we can exploit in kidney cancer. Much like in lymphoma, they’ve got CD19, and, for instance, myeloma, they’ve got BCMA. In kidney cancer, I think CD70 and this new target we’re working with right now called ENPP3 really have legs and might not necessarily be a great target to exploit with a tyrosine kinase inhibitor (TKI) but might actually be great fodder for a homing missile like a CAR T cell.

Dr. Rini: We saw data at ASCO GU about a G250-based imaging agent, that ZIRCON study that Brian Shuch, MD, presented, and I think we all are thinking of the next step of that as a therapeutic modality, and I think there are some early studies going on. I think you’d agree, we desperately need new targets in kidney cancer. We’ve beaten the heck out of VEGF and PD-1 as targets, I mean to patient benefit, but I think we’re all searching for new targets. As you say, there are a number of studies going on.

Maybe to close, I just wanted to ask you about that second-line setting where we have some IO/TKI versus TKI studies ongoing. What do you think is the next advance in that PD-1-refractory second-line setting?

Dr. Pal: I had a lot of physical and emotional energy invested in CONTACT-03, and we just saw in a press release the study is negative and didn’t meet its primary endpoint for progression-free survival. I do think that it challenges the notion that immunotherapy following immunotherapy, at least with PD-1 followed by PD-L1—my guess is this is going to apply to PD-1 followed by PD-1 as well—is probably a no-go. I think it really just makes us want to push the envelope with some of these novel targets that we just discussed. I think we’ve got to get away from our current axis and focus on different axis to hit kidney cancer.

Dr. Rini: I agree. I think we’ve seen this with CTLA-4 inhibition, that if you’re going to give it, you really need to give it up upfront. Maybe that’s the lesson, if we’re giving multiple immune therapies, we need to stack them upfront as opposed to in sequence. But lots of exciting things going on.

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Watch part 3 of this debate.