Laurence Albiges, MD, PhD, Gustave Roussy, Villejeuf, France, describes the final results from the COSMIC-313 trial, evaluating cabozantinib plus nivolumab and ipilimumab as compared to nivolumab plus ipilimumab for patients with previously untreated advanced renal cell carcinoma (RCC). Previously it was reported that the triplet therapy showed a PFS over the doublet. However, across all subgroups, the updated results demonstrate no overall survival benefit with the triplet.

Dr Albiges concluded, “We are eagerly waiting for further triplet studies to define what is the patient population that can derive benefit from such an intensified approach and should it be upfront or maybe based on response with an adaptative design.”

These results were first presented at the 2025 ASCO Genitourinary Cancers Symposium.

Transcript:

My name is Laurence Albiges. I'm a medical oncologist, head of the Medical Oncology Department at Gustave Roussy in France. That's the largest cancer center in Europe. At this ASCO GU 2025 meeting, I had the chance to present the final results of the randomized phase 3 COSMIC-313.

This study is the first plase 3 triplet study of patients with advanced metastatic RCC in first line setting. Here we already knew from prior reports that COSMIC-313, which randomized patients to receive either a triplet, namely cabozantinib plus nivolumab plus ipilimumab, followed by cabo[zantinib]-nivo[lumab] as a maintenance. I'm going to refer to this as the triplet, demonstrated a PFS [progression-free survival] benefit versus the doublet of nivolumab plus ipilimumab plus placebo, followed by nivolumab plus placebo maintenance. The study had previously been reported, and overall about 855 patients had been randomized to receive either the triplet cab-nivo-ipi versus doublet nivo-ipi and we already knew that the addition of cabozantinib was able to increase the progression-free survival from 11 months to 16 months with a hazard ratio in the range of 0.8.

At this ASCO GU meeting, with a follow-up of 45 months, we confirmed the PFS benefits, so this significant increase in progression-free survival, but unfortunately did not see an overall survival (OS) benefits. Indeed, the hazard ratio is 1.02 and the median OS is about 42 months in both arms. And this is true irrespective of the IMDC risk group, intermediate or poor IMDC risk group. It is true across all the different subgroup that have been investigated.

We should stress that the fact that the study was blinded and the fact that we saw toxicity including in the triplet arm that induced lower exposure to cabozantinib with a median average daily dose of 22.4 [mg], where usually we are supposed to treat the patient at 40 mg daily. And we also had a fewer exposure to ipilimumab; the number of patients able to receive the 4 cycles of ipilimumab induction was lower in the triplet than in the doublet arm. So very likely that the triplet is not easy in terms of safety and induced reduced exposure to the 3 drugs themselves.

What has been presented as well is biomarker analysis that has been conducted in this large randomized prospective phase 3 trial, that include analystic data, both for molecular clustering, but also what we call immune cell deconvolution. While we did not see a specific molecular cluster associated with the benefit of the triplet over doublet, the deconvolution model helped to identify that there are what we call M2-like macrophages that are a subset of immune cells that seems to be associated with the worst prognosis and that the addition of cabozantinib seems to reverse the dismal prognosis in this patient subpopulation.

Taken altogether, it is the first triplet versus doublet phase 3 trial, demonstrated PFS benefit, but not OS benefit. The safety signal with more follow-up is consistent with prior report and we are at the very beginning of further biomarker work in this dataset. We are not changing our standard of care, but we are eagerly waiting for further triplet studies to define what is the patient population that can derive benefit from such an intensified approach and should it be upfront or maybe based on response with an adaptative design. We'll see that in the future.

Source:

Albiges L, Motzer R, Trevino S, et al. Cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC): Final results of COSMIC-313. Presented at 2025 ASCO Genitourinary Cancers Symposium. February 13-15, 2025; San Francisco, CA. Abstract 438.