COSMIC-313 Trial Results and Implications for Triplet RCC Therapy

A roundtable discussion, moderated by Brian Rini, MD, of the Vanderbilt University Medical Center, focused on the spectrum of therapy for frontline renal cell carcinoma (RCC), including a comparison of monotherapy and doublet and triplet treatment options. Dr. Rini was joined by a panel that included Monty Pal, MD; Moshe Ornstein, MD; and Shuchi Gulati, MD, MSc.

In the next segment of the roundtable series, the panel discusses the disappointing results of the COSMIC-313 trial and whether there is a place for triplet therapy in RCC.

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Dr. Rini: Let’s talk about COSMIC-313, the triplet study. Then we’ll tie into other data you’re looking forward to in the next year, what’s coming up.

COSMIC-313, as you know, and Monty I’ll ask you to comment first since you did it at ESMO, was ipilimumab/nivolumab versus cabozantinib/ipilimumab/nivolumab makes all the sense in the world. We’ve been debating all these doublets. Let’s just put all the mechanisms together and we can sort of end the debate. It showed a progression-free survival (PFS) advantage, which was unsurprising. It really didn’t show much of a response rate advantage, a low complete response (CR) in both arms, although relatively immature data, and no survival advantage. We didn’t see the data, but we found that out in a press release. And at a cost of significant toxicity, I think the high-dose steroid use was 60%. High toxicity, marginal benefits, but no overall survival (OS) benefits. Give us your thoughts on the study. Where does the field stand? What did it teach us, and where do we go from here?

Dr. Pal: I don’t think anybody looked at that data and really thought that they’d be rushing into the clinic with the triplet afterwards, frankly. The toxicity signal was quite strong with it. We certainly didn’t see that pronounced benefit and response rate that we’d hoped for with it. The progression-free survival advantage was there, but sort of paradoxically was in this intermediate-risk population as compared to the poor-risk patients where I expected to see it. Lots of caveats to the data, but nothing that I think at this point moves the needle. It’s an important study. I certainly applaud it for using a contemporary control arm. I think it just teaches us that we might not be able to employ the same algorithm as, for instance, myeloma, where they’re up to quadruplets. I don’t think we’re necessarily going to be able to easily smash together all the treatments that we have right now in our arsenal frontline.

Dr. Rini: What do you think? What was your takeaway?

Dr. Gulati: I agree. The ipilimumab/nivolumab control arm is great, but I wonder what cabozantinib actually added to the combination because the response rates are very competitive.

Dr. Rini: Toxicity.

Dr. Gulati: Exactly. It’s definitely not practice-changing, and I’m hoping to look at some more data at this meeting. I think Tom [Powles, MD] is going to present on subgroups.

Dr. Rini: There’s some updated data.

Dr. Ornstein: The whole reason to give an immuno-oncology (IO)/tyrosine kinase inhibitor (TKI) over IO/IO in general is for the TKI benefit of the higher response rate, longer PFS. With the response rates that we saw, we weren’t getting the response rate we had hoped for upfront, and you saw the toxicity. We’ll see what the survival shows, but we have the press release and it’s negative.

Dr. Rini: We haven’t seen the curves. We did some Twitter polls around [The Uromigos] meeting that Monty put together, and it was consensus that you really needed a survival benefit to use it. I think we put out, “What if the CR rate is 20%?” We threw out some wild non-OS result data and that really didn’t sway people. It was really that it has to be OS, and I think that’s probably a lesson for triplets moving forward.

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Continue on to watch the next roundtable segment.