Triplet Therapy With Cabozantinib, Nivolumab, and Ipilimumab as First-line Treatment in Patients With Advanced Renal Cell Carcinoma, COSMIC 313 - Toni K. Choueiri

October 3, 2022

Alicia Morgans is joined by Toni Choueiri in a discussion on the COSMIC-313 examining the role of triplet therapy with cabozantinib, nivolumab and ipilimumab as first-line treatment in patients with advanced renal cell carcinoma (RCC). The COSMIC-313 trial made strides at the 2022 ESMO meeting being a presidential symposium reporting the first phase 3 clinical trial in advanced RCC to use a contemporary control arm (nivolumab/ipilimumab), the first phase 3 trial comparing triplet to doublet therapy in aRCC, and the first trial of its kind to meet its primary endpoint. Drs. Choueiri and Morgans highlight where the data is most applicable in terms of patient selection and the decision to use the triplet combination or to use these agents in sequence over time when considering the toxicity profile. At the time of the ESMO 2022 presentation, overall survival results were not yet reported.


Toni K. Choueiri, MD, Jerome and Nancy Kohlberg Professor of Medicine, Harvard Medical School, Attending Physician, Solid Tumor Oncology, Dana-Farber Cancer Institute, Director, Genitourinary (GU) Oncology Disease, Center, Dana-Farber Cancer Institute, Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm so excited to be speaking today at ESMO 2022 with Dr. Toni Choueiri. Thank you so much for talking with me today.

Toni Choueiri: Thank you Dr. Morgans.

Alicia Morgans: Wonderful. Well, you know, you gave a wonderful presentation at ESMO this year, COSMIC 313. Can you tell us a little bit about it, set the stage and then we'll dig into the details?

Toni Choueiri: Well, the team had the honor to have COSMIC 313 as part of the presidential session on Monday. COSMIC 313 is the first phase three trial, randomized phase three trial that uses a modern contemporary control, a doublet with Nivolumab and ask the question whether adding Cabozantinib at 40 milligrams once a day to Nivolumab Ipilimumab, nivo ipi, result as a primary endpoint in improved PFS. And the results were clear that the triplet is superior to the doublet in term of progression-free survival. That hazard ratio was point 73. This is a statistically and clinically relevant result.

Nevertheless, the toxicity, especially some toxicities with liver function tests, some diarrhea and the skin toxicity were higher with the triplets as well, the steroid use. And overall we're going to continue looking at COSMIC 313 with time to see if overall survival happens. The first interim analysis, and there was a press release about it, that the study didn't meet secondary endpoint of OS. But overall this is very exciting. We are way away from now a single agent syntonin and even with doublets now we're seeing phase three trial like COSMIC 313 using a doublet as a control. So this is a new era in kidney cancer.

Alicia Morgans: Absolutely, and I'd love to hear your thoughts really on where you find this data most applicable. Of course, we're waiting for overall survival, so we'll have to see how that story pans out and what the details are. But how do you choose your patients if you're thinking already that these are approved agents and you might get this into your clinic, how would you do that?

Toni Choueiri: So we presented some of the early data showing that there's a significant improvement in intermediate risk over poor risk. The responses overall and the progression-free survival in poor risk patient were similar across both arms. And this was a bit counterintuitive because we would think that the triplet would work better in poor risk patient, but at the same time it's possible that these patients were too sick to stay on therapy and didn't receive enough therapy. Nevertheless, the result were more pronounced in the IMDC intermediate risk, which were 75% of patient. So we need to know if, when the overall survival results are in the final ones, which going to take some time. If also that trend continues favoring intermediate risk.

I would think some patient that have more aggressive disease, they can tolerate therapy, they could start with triplet. One of the things also, the response rate where numerically higher. We're not really much higher than we expected at least. But nevertheless these are early results and many of the stable disease PR could become a CR. The COSMIC 313 also has the most patients with kidney implast. I mean I would say the least patient with nephrectomy, 65% only. So if these were captured during tumor measurements, it's hard then to start seeing these responses, especially the complete responses, which could be understandable.

Alicia Morgans: Absolutely. So I wonder if you're thinking about this and you're considering the toxicity profile and really trying to make a decision about whether you use the triplet or maybe whether you use these agents in sequence over time, what do you think?

Toni Choueiri: So there is a trial, actually they're trying to answer that with the alliance with Dr. Chenjiang and myself and this study, take the intermediate patient and the poor risk patient with clear cell and give them Nivolumab Ipilimumab if they have a CR. So they would get Nivolumab maintenance for a year. If they have PD, they get Cabozantinib. But if they have SD or PR, then they get randomized to Nivolumab control. That's what we do in practice versus adding Cabozantinib to Nivolumab. And the primary endpoint is in the second randomization. And I think that's a very important study and it's accruing, the study is accruing well, it's an inter group study and it's a bit different question than COSMIC 313.

Alicia Morgans: Absolutely. Well this is wonderful and I really appreciate your taking the time to talk with us about it today. Any overarching message or summary you'd like to give to the viewers.

Toni Choueiri: I think kidney cancer is very, very thriving. I think in 2005 the survival was probably a year and now it's approaching 5, 6, 5 years. So it's really important and I think part of it is the new therapies.

Alicia Morgans: Absolutely. Well thank you so much again for taking the time. We appreciate your expertise.

Toni Choueiri: Thank you, UroToday.