Triplet Regimens in Advanced RCC in the Frontline Setting


Shared insight on the data from the COSMIC-313 trial and the potential for first-line triplet regimens in patients with advanced clear cell renal cell carcinoma.


Brian Rini, MD: We only have about 5 minutes left. I have about 2 minutes of a summary, so that gives you 1 minute each to talk about the COSMIC-313 press release. COSMIC-313 is ipilimumab/nivolumab/cabozantinib vs ipilimumab/nivolumab. It was recently reported only by press release, the PFS [progression-free survival] was positive, the hazard ratio, if I’m remembering correctly, was 0.74, or in that range. The overall survival [OS] was not significant. It was called immature. I’m pretty sure that’s the only data that was given in that press release. But it’s at least top-level data to say there’s a PFS benefit, which may not be surprising, but no OS.

Monty, maybe we’ll start with you. I know I’m asking you to comment on a press release, but it’s important. It’s the first triple to be reported and there has been other studies ongoing. We’ve alluded to triplets in this broadcast, so what do you think?

Sumanta Pal, MD, FASCO: Maybe it’s going to sound greedy, but I really want to have as many options available as possible. So even if we don’t see an OS signal, or a huge advantage, I still think that having cabozantinib/nivolumab/ipilimumab at my disposal is going to help in those situations where I really am struggling. I see that young patient, 45 years old, metastatic RCC [renal cell carcinoma], clear cell, and I think to myself, gosh. Then they’ve got really bulky, bad disease. Unfortunately, I think the 3 of us probably see these patients all the time. You just sort of think to yourself, gosh, I want to give them the response rate advantage that I get out of cabozantinib/nivolumab, but on the same note, I want to get them that tail on the curve that you potentially get with ipilimumab/nivolumab. I really want this triplet for those patients. And that’s kind of the picture that I’ve painted in my mind of who I’d offer this regimen to. I know it’s definitely not going to be for the faint of heart. My 85-year-old patient with metastatic disease is not going to be able to tolerate.

Brian Rini, MD: So maybe in a select subset of patients that you’ve described. Hans, what do you think?

Hans Hammers, MD: Yeah. I 100% agree. I don’t think this will be a regimen for everyone. Already now, in the last few years, I’ve been struggling with some of these patients, where I know, I would love to give nivolumab/ipilimumab, but I’m afraid of the tumor burden. I would love to have that option for triple therapy. So I think there’s a real population there, where this could be quite useful, I hope. Coming to the OS, I think we’ve been spoiled with OS. I think they’ve been spoiled with OS. I think it will be much harder moving forward to show OS. I don’t think, for example, even the Merck MK-6482-012, which is Lenvatinib/pembrolizumab vs 2 triple therapies can count an OS benefit. And I would not fault those regimens if they don’t. I think it’s just much harder to show an OS against a very active type of backbone vs VEGF-TKI [tyrosine kinase inhibitor] monotherapy. I think that’s going to be a struggle moving forward. I do feel that we are going to be back for a while into the PFS space, and then we have to see what the long-term outcome is in other markers of utility.

Brian Rini, MD: I think I’m a little less bullish than you both. I don’t disagree. It’s OK if there’s just a PFS benefit, but also depends on the magnitude. Can you get that same PFS with a doublet like lenvatinib/pembrolizumab? I kind of doubt the PFS of that triplet is going to be over 23.9 months. I want good therapies as well, but that doesn’t necessarily mean we should just throw the kitchen sink at people because we’re going to hurt some people with toxicity that is potentially life threatening. So, again, we need to see the data. None of us have seen the full data, so it’s a bit premature.

But I do think we’re all, in general, bullish on triplets that can cure more patients. I happen to think those will probably be triplet immune therapy. Hans, you might agree with me on that. I think triplets, of all immune regimens, to me, make a lot more sense. I think we, as a field, would, in some ways, love to get away from TKIs. We’ve been talking about toxicity, and this and that, a lot during this session. So if we could move to reduce our TKI use, whether it’s with HIF [hypoxia inducible factor] inhibitors or all immune regimens, I think, philosophically, that’s sort of where I would put my money.

Hans Hammers, MD: I totally agree with you. To me, the picture that’s emerging is that the TKIs really don’t synergize with immunotherapy. They’re not going to make somebody a better immunotherapy responder if they weren’t meant to be, anyway. That’s probably also the message, quite frankly, from COSMIC-313 is if you add a TKI, it’s not going to be magic. I think that’s the lesson learned from this one. Triplet therapies, improving immunotherapy, improving that backbone with agents that can truly improve the immune response, I think that’s going to be key here.

Brian Rini, MD: Monty, any last words for you?

Sumanta Pal, MD, FASCO: I can’t tell you how much I love these sorts of side-by-side tabular depictions you have across studies. I think it’s going to be really hard with the triplet therapy trials to do that. Only because I’m just putting myself in my investigator shoes, and thinking, gosh, it’s a very different patient that I put on CheckKMate9ER vs COSMIC-313. I’d probably be reserving COSMIC-313 for patients that are a little sicker, maybe younger, or a little bit robust. I don’t know what that means in terms of our PFS and response rate expectations. I, personally, think it's going to be very different, the composition of those trials.

Transcript edited for clarity.

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