Laurence Albiges, MD, on COSMIC-313 trial of triplet vs doublet combination in aRCC

In this video, Laurence Albiges, MD, PhD, shares final results from the phase 3 COSMIC-313 trial (NCT03937219), which compared cabozantinib plus nivolumab plus ipilimumab vs nivolumab plus ipilimumab for the first-line treatment of poor- or intermediate-risk advanced renal cell carcinoma (RCC).These data were presented at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California.

Albiges is a medical oncologist and professor of medical oncology at Institut Gustave Roussy in Villejuif, France.

Video Transcript:

COSMIC-313 trial is the first triplet trial in a phase 3 that has been tested against an active doublet. What was tested in this study was a combination of cabozantinib, a potent VEGF-TKI, plus nivolumab plus ipilimumab. As nivolumab/ipilimumab is a standard of care, as well as IO/TKI; here, it's a triplet strategy that has been tested and compared to ipilimumab plus nivolumab plus placebo, a doublet. The study initially reported the primary end point of progression-free survival after 15 months. At this ASCO GU 25 was presented the final analysis of the study.

The final analysis occurred at 45 months of follow-up, when we had enough overall survival events. What we have been able to report is that with this follow-up, we have a sustained benefit in progression-free survival in the triplet arm, from 11 months for the doublet to 16.6 for the triplet, so benefits [are] statistically significant. However, no difference in overall survival for the triplet vs the doublet.

I think this is important. It is something that could be related to the fact that patients in the comparator arm, the doublet, may have received a potent subsequent therapy, but also to the fact that, including in the investigational arm, we had an under exposition to the different component of the triplet. Indeed, the median daily dose of cabozantinib in the triplet arm was 22 mg per day, while it was 35 mg in the placebo plus doublet. We had only 58% of patients that had the fourth cycle of ipilimumab vs 75% in the doublet. Ultimately, 50% of the patients in the triplet arm had to discontinue 1 of the 3 drugs, vs only 25% in the doublet. This is something we knew; there was a clear underexposure related both to the toxicity that was noted in the triplet, but also on how to manage toxicity. It was a blinded trial, so when you have to manage toxicity, you have to take into consideration your patient could receive cabozantinib or the placebo, and therefore dose reduce this drug or potentially also the ipilimumab. I think this is very important on how we design trials in the future, especially for triplet, given this limitation with regard to managing toxicity. The other thing we have highlighted is that the safety profile with this long follow-up was the same as in the initial report. So, the toxicity was high, mostly driven by liver toxicity, elevated AST and ALT in the triplet arm.

To finish, it is also the opportunity to have biomarker exploratory analysis. Here it was conducted based on RNA-Seq data, 2 different analyses. One was about molecular clustering as it was done in the past for the IMmotion program. We did not find an association between the molecular clusters and the outcome. A second one was what we called deconvolution model. It's to assess the abundance of the immune cells that present using RNA-Seq data. Here, interestingly, we found that the M2-like macrophages population seems to be associated with worse clinical features, dismal PFS and overall survival, but the fact that you add cabozantinib seems to reverse this negative prognostic value. So, maybe here a lead for a biomarker that could help to go for the TKI plus IO strategy. Taken altogether, the study remains positive for PFS, but not for overall survival. It is not going to change our practice.

This transcript was AI generated and edited by human editors for clarity.