According to results from the phase 3 COSMIC-313 study, cabozantinib plus nivolumab and ipilimumab continued to demonstrate a benefit to progression-free survival (PFS) and objective response rate (ORR) in the first-line setting among patients with advanced renal cell carcinoma.

These data were first presented by Laurence Albiges, MD, PhD, Gustave Roussy, Paris, France, at the 2025 American Society for Clinical Oncology (ASCO) Genitourinary Cancers Symposium.

In this randomized, double-blind phase 3 trial, 855 previously untreated patients with intermediate or poor risk advanced renal cell carcinoma were enrolled. Patients were randomized to receive nivolumab plus ipilimumab every 3 weeks for 4 cycles, plus either 40 mg cabozantinib (cabozantinib arm; n = 428) or placebo (placebo arm; n = 427), once a day. Both arms followed with nivolumab every 4 weeks for up to 2 years. This trial met its primary end point, significantly improving PFS with cabozantinib plus nivolumab and ipilimumab when compared to placebo plus nivolumab and ipilimumab, in the first-line setting. The secondary end point was overall survival (OS) among all randomized patients.

With a median follow-up duration of 45.0 months, the improvement in PFS was maintained, with a median PFS of 16.6 in the cabozantinib arm and 11.2 in the placebo arm (HR, 0.82). The median OS was 41.9 months in the cabozantinib arm vs 42.0 months in the placebo arm, which did not represent a significant different between the 2 arms (hazard ratio [HR], 1.02; P = .84). This similarity was observed in the intention-to-treat population and by risk group. ORR was higher in the cabozantinib arm (46% vs 37%), with a lower incidence of progressive disease as the best response (8% vs 20%).

There were no significant differences in OS outcomes based on baseline c-et or PD-L1 levels. Exploratory analyses found that higher M2 macrophage abundance was associated with improved OS in the cabozantinib arm (HR, 0.51), poor risk, high baseline sum of target lesions, and the presence of visceral metastasis.

Grade 3/4 treatment-emergent adverse events occurred in 81% of patients in the cabozantinib arm vs 62% of patients in the placebo arm, with the most common being increased ALT and increased AST. There were grade 5 treatment-related adverse events in 1% of patients in each arm. Study authors also noted that “no new safety signals emerged.”

Dr Albiges et al concluded first-line treatment with cabozantinib plus nivolumab and ipilimumab “continued to demonstrate PFS and ORR benefit” over placebo plus nivolumab and ipilimumab, and that “OS was comparable between the two arms.” They added patients “whose tumors have high M2 macrophage abundance had improved OS” with cabozantinib plus nivolumab and ipilimumab.

Source:

Albiges L, Motzer RJ, 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