Cabozantinib, Nivolumab, Ipilimumab Provides Lasting PFS and ORR Benefit for Intermediate- and Poor-Risk aRCC: Updated Results of COSMIC-313

The phase III COSMIC-313 study demonstrated that the addition of cabozantinib to nivolumab and ipilimumab significantly improved progression-free survival (PFS) compared with nivolumab and ipilimumab alone in the first-line treatment of patients with intermediate- or poor-risk advanced renal cell carcinoma (aRCC), successfully meeting the study’s primary endpoint.

At the American Society of Clinical Oncology 2025 Genitourinary Cancers Symposium, results of the trial’s secondary endpoint of overall survival (OS) in all patients were presented, along with updated efficacy and safety results and biomarker analysis.

In the study, a total of 855 patients with previously untreated, intermediate- or poor-risk (based on International Metastatic Renal Cell Carcinoma Database Consortium [IMDC] risk criteria) aRCC were randomized to receive 40 mg of cabozantinib once daily or placebo. Each group also received nivolumab, 3 mg/kg, intravenously every three weeks, with 1 mg/kg, intravenously every three weeks for four cycles, followed by 480 mg of nivolumab intravenously every four weeks for up to two years. A random forest model was used to determine immune subsets associated with improved OS with cabozantinib + nivolumab + ipilimumab (C+N+I) versus placebo + nivolumab + ipilimumab (P+N+I).

The C+N+I group consisted of 428 patients, and 427 patients were placed in the P+N+I group. A total of 75% of patients were classified as intermediate risk, and 25% classified as poor risk. At the median follow-up of 45 months, an improvement in PFS was maintained through the use of C+N+I. In the intent-to-treat (ITT) population and in each risk group, OS was not significantly different between the C+N+I and P+N+I treatment arms.

The overall response rate (ORR) was higher with C+N+I, with fewer patients experiencing progressive disease as their best response. Grade 3-4 treatment-emergent adverse events occurred in 81% of patients who received C+N+I and in 62% of patients who received P+N+I. The most common grade 3-4 events included increased alanine aminotransferase in 27% versus 6% of patients and aspartate aminotransferase in 20% versus 5% of patients, respectively.

Grade 5 treatment-related adverse events occurred in 1% of patients in both treatment arms. No significant differences in OS outcomes were identified based on baseline c-Met or programmed cell death ligand 1 (PD-L1) levels. Exploratory biomarker analyses indicated that higher M2 macrophage abundance was associated with improved OS in patients receiving C+N+I (hazard ratio, 0.51; 95% CI, 0.31-0.86), particularly in those with poor-risk disease, high baseline tumor burden, or visceral metastasis. Further biomarker studies focusing on angiogenic and immune signatures are ongoing.

The first-line treatment of aRCC with C+N+I continued to provide PFS and ORR benefits over P+N+I for patients with intermediate- or poor-risk disease. OS was similar in both treatment arms, and no new safety signals were seen. Notably, patients whose tumors have high M2 macrophage abundance had improved OS with C+N+I treatment.