Triplet Therapy in RCC: Insights from ASCO GU 2025

At the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium, a panel of experts discussed the latest research, emerging therapies, and best practices for treating renal cell carcinoma (RCC). Moderator Dr. Katy Beckermann of Tennessee Oncology was joined by Drs. David Braun, Matt Campbell, Brad McGregor, and Katie S. Murray in the discussion.

In the third segment of their discussion, the panelists evaluate the role of triplet therapy in RCC, including updates from CheckMate 9ER and COSMIC-313, considerations for frontline treatment selection, and whether triplet combinations provide meaningful survival benefits. The panel also assesses emerging biomarkers and strategies for refining treatment approaches.

View the next segment on Cytoreductive Nephrectomy and RCC Biomarkers: What’s Next in Kidney Cancer Treatment?

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Dr. Beckermann: Matt, you also kind of mentioned thinking about, well, what if that patient maybe already has metastatic disease? And so maybe let us move on and talk about how do we pick frontline treatments for our patients, first, just broadly. And then maybe we will try to weave in some of the data that we have seen here at GU ASCO, update from CheckMate 9ER, COSMIC-313 reading out. So would love to hear you all’s perspective on that. And then maybe, as we are talking, if there is anything there that has been informative, as you think about somebody maybe who has failed adjuvant treatment. So I know that is a lot, but..

Dr. Campbell: I would love to.

Dr. Beckermann: Yeah. Brad, maybe I will let you start. Any updates that you want to highlight?

Dr. McGregor: Yeah, I think it is really amazing how far we have come in the past eight years in the treatment of kidney cancer, where we went from this being a treatable disease to potentially, now maybe, a curable disease. I think with doubling the checkpoint blockade, with nivo-ipi, we see these really impressive tails of the curves. And now, with IO-TKI and we saw data from the follow-up from nivo-cabo, I mean there are impressive five-year survival rates with IO-TKI. So it is really amazing. I think the real question is how do you choose IO-IO versus IO-TKI in the clinic? I have talked to the patients, it is like it is a baseball game and I am at bat, I am going to hit the grand slam or strike out with nivo-ipi, whereas with the IO-TKI, I have a lot of doubles and triples. And so it is really, can you afford to be wrong? Right? There is that 20% best response with nivo-ipi.

Can you afford that PD and salvage with something else later on? And that is clinical judgment right now. I think there is some interesting data presented. We are looking at KIM-1, and not just absolute KIM-1 levels, but actually, changes in KIM-1. So KIM-1 is kidney injury molecule one. You know, Vincent Xu has done a lot of work on looking at this as a biomarker in the adjuvant setting, metastatic setting. And what he showed, looking at the CheckMate 214 data, is you just look at the baseline KIM-1 to week three. If you drop by 30% in that time period, your median progressive survival is over 70 months. If you did not, it was not there. So it is almost like you can tell after one dose of nivo-ipi if you are going to be that exceptional responder because you pivot. So I think those are the types of things you need to think about going forward. Novel biomarkers, cheap biomarkers, easily accessible biomarkers so we can start not having this just all about what we think makes the most sense and hopefully, have some true science to help guide us.

Dr. Beckermann: Maybe, actually, to kind of continue on that point. So the other way we have tried to attempt at this, without having a current biomarker, is to say, can we add TKI to IO-IO? And so we saw, we are seeing the final OS data presented at this meeting. And so given that there was no difference in overall survival in COSMIC 313, with that final data, is there a patient you would still consider giving triplet therapy to? And Matt, I will start with you.

Dr. Campbell: Yeah, not at present. I mean, outside of the context of a trial, I think, we were all hopeful when we saw the CheckMate 9ER data, that escalating further with the addition of ipi was going to, we were going to see responses that were at least at that 60% level. But we were all hoping we were going to be in the 70% level and we all thought that the PFS was going to be incredible and we were going to start seeing this extreme tail. And what we saw was that, potentially, with the toxicity of the combination and the need for holds and stops and other things, that giving this regimen was, I think, more challenging than what was necessarily anticipated. And I think being on the drug at least for a period of time is quite important. And if you are running into significant liver toxicity or other events and you are having to do prolonged holds of therapy and you are really trying to figure out, is this cabo induced? Is this IO induced?

You are working through all this, your density of treatment is going to go down. And I am guessing that that probably had some impact, but there is also a chance that there is potentially a negative impact of having this triplet where you are lessening the long-term impact of Ipi and that is harder to know.

So it was a trial that we were all, I think, had extremely high hopes for, and I think, unfortunately, it has not led to us having a paradigm shift in terms of doublet moving to triplet.

Dr. Beckermann: Yeah. And David, what about you? I know, I think the one, if you were to, and we have talked about this before, but definitely, the triplet does decrease the primary progressive rate. So to that point of you have got one chance, one ball to hit and you want to knock it out of the park, is there a patient, would you say, oh, this is a poor-risk patient and I do not have any other time? Would you give a triplet or?

Dr. Braun: It is tough. I wish I could say the answer was yes when I saw the beginning of the trial. I think, I similarly had a lot of hopes that this was either going to really increase the cure rate, really the durable response rate or effectively, sort of de-risk nivo-ipi, that you would still be able to get that shot at the grand slam but not have that 20% progressive disease rate. But I think Campbell is absolutely right. I think the toxicity really compromises, potentially, that ability to give a full dose of something that is going to lead to a durable response. And so with that, unfortunately, I do not think it is there, that same durability. There might be, again, a subset of patients who really benefit from it. And I think there is some analysis of that COSMIC-313 data set that shows that maybe, biologically, there might be patients where that makes sense, but until that is fully sussed out, it is not something that I would do.

Dr. Beckermann: Yeah.

Dr. McGregor: I would agree. And I think one of the things that the COSMIC-313 does give us some reassurance though, is that the way we get nivo-ipi in the clinic today is okay. Right? If you look at CheckMate 214, you had to get four doses of nivo-ipi to go on maintenance nivo. And the minute you had one thing, you were done. So if you could not finish the ipi, you could not go on continuing therapy. And so this trial did a more contemporary dosing, you could stop the ipi, continue nivo. They stopped at two years. And so I think that long-term follow-up does give us a little bit of reassurance that what we have all been doing in the clinic actually does play out. But I think the toxicity has just been too much.

We had the same… We had a companion trial, if you will, the Can I trial, looking at this in diverging histologies and we had the same problems. It is very tough to give the triplet, the hepatic toxicities. And so I think, not to say we should not be exploring triplets, I think, just not this triplet. And so ongoing trials are looking at other combinations I think are really important, like Nivolumab (NIVO), ipilimumab (IPI), and relatlimab (RELA), or lenvatinib-pembrolizumab with another CLA 4, or belzutifan, I think that will still inform patient care.

Dr. Braun: I absolutely agree. I think, I had a patient who always used to, he was very frank and he always used to say basically, is the juice worth the squeeze? And so I think for something like this, most patients would take, actually, a high degree of toxicity if there is a real chance of cure at the end of it. I just think, unfortunately, COSMIC-313, this was not the combination to do it.