Advanced Renal Cell Carcinoma: Nuancing Triplet Therapy Trial Results

Shared insight on the results from triplet therapy–centered clinical trials in advanced renal cell carcinoma and how these might inform treatment strategies as the paradigm continues to evolve.


Brian I. Rini, MD: I know we don't have much time but the COSMIC-313 trial just reported, ipilimumab-nivolumab-cabozantinib vs ipilimumab-nivolumab, the first triplet data in kidney cancer. Do you want to summarize the data quickly and give your thoughts about what were the take-homes for you?

Matthew T. Campbell, MD, MS: The take homes for me were that the response rate was lower than I was anticipating on the study. To me, the toxicity in terms of seeing a lot more liver function elevation in grade 3 and higher, was higher than I anticipated based on the work that Andrea B. Apolo, MD, medical oncologist at the Center for Cancer Research within the National Cancer Institute in Bethesda, Maryland had done on the initial experience with cabozantinib-nivolumab or cabozantinib-nivolumab-ipilimumab. I think the data really is still early and we don't have long-term progression-free survival or overall survival, which will be very important to know if that's going to be a triplet that has a chance to be important or if potentially it's just going to be an RI [renal arterial resistive index] so a largely negative study where toxicity seems to add a lot without clear, additional benefit of using a triplet early on.

Brian I. Rini, MD: I agree. I think drug delivery was limited by toxicity. That's 1 lesson and I don't think it will change practice. I think it taught us a lot of important lessons. There's another big triplet study that Merck & Co.’s doing, lenvatinib-pembrolizumab control with or without belzutifan or with or without a CTLA4 [cytotoxic T-lymphocyte antigen 4] inhibitor. That's probably a year or 2 away from results. I think we're moving towards triplets, but I think the COSMIC-313 trial was a bit of a cautionary tale that jumping in and giving everybody all the drugs may not be the right way to do it.

Matthew T. Campbell, MD, MS: That study there with the triplet, I love the control arms now having very active therapy. If 1 of those arms beats lenvatinib-pembrolizumab what would you want to see in terms of what parameters would make you think that it's a very successful trial? Should we still consider doing more of a sequence as compared to doing everything all upfront?

Brian I. Rini, MD: In my opinion and most people that I talk to want to see overall survival because we're clearly going to increase toxicity, so I think without an overall survival signal, it's going to be hard to get widespread adoption, let alone regulatory approval. I think if there are eye-popping nonsurvival endpoints, so if the PFS [progression-free survival] is 36 months or the response rate is 90% or the CRA [competitive risk assessment] is 25%, something that's clearly better than our doublets, then I think we can have that conversation about maybe, even short of survival, there's some clinical benefit here obviously balanced against toxicity. I think it's overall survival with maybe a little room for a nonsurvival endpoint as mentioned.

Matthew T. Campbell, MD, MS: When we're building those studies and we have these new exciting agents like belzutifan that haven't quite made it, do you feel that patients in the control arm should, no matter where they are in the world, potentially have access to a drug like belzutifan, or do you think that because it's not yet proven that it's fair or not to potentially have access to those types of agents?

Brian I. Rini, MD: It's a good question and certainly we would never say it's wrong to allow crossover on trials or access to the agent the patient didn't get up front. That Merck & Co. triplet is a little unusual as you say because belzutifan is not a standard in the refractory setting so to give it in that setting, some would say it was not the standard that they should get a TKI [tyrosine kinase inhibitor]. I hadn't thought about it, but I think, in general, stepping away from that one trial we do want to allow access to drugs.

Number 1, I think it's beneficial for patients, more drugs and more drugs in sequence leads to better outcomes. Also, I think it diminishes what people usually say and we don't know whether those drugs would have worked in sequence just as well as in combination. We hear that for all these combo trials. I don't particularly believe that, because, unfortunately, some patients progress and die before they can get their second or third therapy. I think at least conceptually doing that might diminish those concerns that we can do just as good with the sequence. I'm a believer in as many active drugs as possible in the frontline setting but precisely studying that is very difficult, as you say.

Transcript edited for clarity.

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