Cabozantinib Plus Nivolumab and Ipilimumab Maintains PFS Advantage in Clear Cell Renal Cell Carcinoma

Key Clinical Summary: 

• Design/Population: COSMIC-313 was a phase 3, double-blind trial evaluating cabozantinib plus nivolumab and ipilimumab versus nivolumab and ipilimumab alone in previously untreated advanced clear cell renal cell carcinoma. Final outcomes were assessed after a median follow-up of 45 months, including exploratory biomarker analyses.
• Key Outcomes: Cabozantinib significantly prolonged progression-free survival compared with the placebo, but no overall survival benefit was observed. Grade 3/4 treatment-related adverse events were more frequent with the triplet regimen.
• Clinical Relevance: These findings reinforce the progression-free survival advantage of adding cabozantinib to dual immune checkpoint blockade in advanced renal cell carcinoma. Exploratory biomarker data suggest that patients with higher M2-like macrophage levels may be more likely to benefit from the triplet approach.

Final results from the phase 3 COSMIC-313 trial demonstrate that cabozantinib plus nivolumab and ipilimumab continues to prolong progression-free survival (PFS) among previously untreated patients with advanced clear cell renal cell carcinoma.

“At primary analysis, [PFS] was significantly improved with cabozantinib plus nivolumab and ipilimumab versus placebo plus nivolumab and ipilimumab,” stated Robert Motzer, MD, Memorial Sloan Kettering Cancer Center, New York, New York, and coauthors. “Here, the final efficacy and safety results with 30 additional months of follow-up are reported.” 

In this double-blind, placebo-controlled study, 855 patients were randomized 1:1 to receive 40 mg of once daily cabozantinib (n = 428) or placebo (n = 427) plus 3 mg/kg of  nivolumab and 1 mg/kg of ipilimumab every 3 weeks for 4 cycles. Treatment was followed by maintenance cabozantinib or placebo plus 480 mg of nivolumab every 4 weeks for up to 2 years or until loss of clinical benefit or unacceptable toxicity. Patients were stratified by IMDC risk category and geographic region. The primary end point was PFS. Key secondary end points included overall survival (OS), objective response rate, duration of response, and safety.

At a median follow-up of 45 months, median PFS was 16.6 months in the cabozantinib arm and 11.2 months in the placebo arm. Median OS was 41.9 months in the cabozantinib arm and 42 months in the placebo arm (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.85 to 1.23; P = .84). The ORR was 46% with cabozantinib and 36% with placebo. Median duration of response was 31.1 months in the cabozantinib arm and not estimable in the placebo arm. 

The safety profile was consistent with prior analyses. Grade 3/4 treatment-related adverse events occurred in 75% of patients in the cabozantinib arm and 43% in the placebo arm. Subsequent systemic anticancer therapy was received by 50% of patients in the cabozantinib arm and 49% in the placebo arm, with a median time to next therapy of 14.5 months and 9.7 months, respectively. 

Exploratory biomarker analyses indicated that patients treated with cabozantinib who had higher levels of M2-like macrophages experienced significantly improved PFS and OS compared with patients receiving placebo. Responders in the cabozantinib arm exhibited elevated angiogenic signatures and reduced immune-related pathway activity, whereas responders in the placebo arm demonstrated robust immune activation.

“Long-term results from COSMIC-313 continue to demonstrate a PFS benefit with the addition of cabozantinib to nivolumab and ipilimumab…[however] there was no OS benefit,” concluded Dr Motzer et al. “Results from exploratory biomarker analyses suggest that M2-like macrophage levels are associated with baseline prognostic factors and may be predictive of clinical benefit.” 

Source:

Motzer RJ, Albiges L, Trevino Aguirre SA, et al. Cabozantinib plus nivolumab and ipilimumab in previously untreated, advanced renal cell carcinoma: Final results and biomarker analyses from the phase III COSMIC-313 study. Ann Oncol. Published online: February 18, 2026. doi:10.1016/j.annonc.2026.02.011