Cabozantinib Plus Nivolumab and Ipilimumab Maintains Progression-Free Survival Benefit in Clear Cell Renal Cell Carcinoma

Clinical Summary: 

• Design/Population: The phase 3 COSMIC-313 trial evaluated cabozantinib plus nivolumab and ipilimumab versus nivolumab and ipilimumab alone in previously untreated patients with advanced clear cell renal cell carcinoma. Final efficacy, safety, and exploratory biomarker analyses were conducted after a median follow-up of 45 months.

• Key Outcomes: Cabozantinib continued to improve progression-free survival compared with placebo but did not improve overall survival. Grade 3 or higher treatment-related adverse events remained more frequent with the triplet regimen. Exploratory analyses suggested greater benefit among patients with tumors enriched for M2-like macrophages.

• Clinical Relevance: These long-term findings confirm the progression-free survival benefit of adding cabozantinib to nivolumab plus ipilimumab while highlighting the need for biomarker-guided patient selection to identify those most likely to benefit from triplet therapy.

Final results from the phase 3 COSMIC-313 trial demonstrated that cabozantinib plus nivolumab and ipilimumab maintained a progression-free survival (PFS) benefit but did not improve overall survival (OS) compared with nivolumab and ipilimumab alone in 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 trial, 855 patients were randomized 1:1 to receive 40 mg of once daily cabozantinib (n = 428) or placebo (n = 427) in combination with 3 mg/kg of nivolumab and 1 mg/kg of ipilimumab every 3 weeks for 4 cycles, followed by 480 mg of maintenance cabozantinib or placebo plus nivolumab every 4 weeks for up to 2 years or until disease progression or unacceptable toxicity. Patients were stratified by International Metastatic RCC Database Consortium (IMDC) risk category and geographic region. The primary end point was PFS. Key secondary end points included OS, objective response rate (ORR), duration of response, and safety.

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

The safety profile remained consistent with previous analyses. Grade ≥3 treatment-related adverse events occurred in 75% of patients receiving cabozantinib compared with 43% of those receiving placebo. Approximately half of patients in each treatment arm received subsequent systemic therapy, although the median time to next treatment was longer with cabozantinib (14.5 vs 9.7 months).

Exploratory biomarker analyses suggested that patients with tumors enriched for M2-like macrophages derived greater PFS and OS benefit from the addition of cabozantinib. In addition, responders receiving cabozantinib demonstrated higher angiogenic signaling and lower immune pathway activity, whereas responders treated with nivolumab plus ipilimumab alone exhibited stronger immune activation signatures.

“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