Cabozantinib Triplet in Advanced RCC: Final COSMIC 313 Results
Key Takeaways
- Longer progression-free survival with cabozantinib, nivolumab, and ipilimumab persisted at final follow-up, while overall survival remained comparable between groups.
- Objective response was higher with the triplet, but treatment-related toxicity and discontinuation of study components were also more frequent.
- Subgroup and biomarker findings suggested variable benefit across disease subsets, and the authors described those signals as exploratory and hypothesis-generating.
COSMIC-313 was an international, multicenter, double-blind, randomized, placebo-controlled phase III trial in adults with previously untreated advanced or metastatic clear cell renal cell carcinoma who had IMDC intermediate- or poor-risk disease. Investigators randomly assigned 855 patients, in a 1:1 ratio, to cabozantinib 40 mg daily plus nivolumab and ipilimumab or placebo plus nivolumab and ipilimumab. Randomization was stratified by IMDC risk and geographic region, and median overall survival was 41.9 versus 42.0 months, with a hazard ratio of 1.02 and P = 0.84. Objective response rate was 46% versus 37%, and median duration of response was 31.1 months versus not estimable. These final results preserved response and progression-free survival advantages without separating overall survival.
IMDC intermediate-risk disease comprised 75% of the population, and in that subgroup median progression-free survival was 22.1 months with the triplet and 11.3 months with the doublet. Among poor-risk patients, the corresponding medians were 9.5 and 11.2 months. Progression-free survival probabilities at 12, 18, and 24 months were 57%, 48%, and 44% with the triplet and 48%, 41%, and 37% with the doublet. Overall survival probabilities at 24 and 36 months were 67% and 54% with the triplet and 65% and 54% with the doublet. The efficacy pattern was more favorable in intermediate-risk disease than in poor-risk disease.
Treatment-related toxicity remained substantially higher with the triplet, with grade 3 or 4 treatment-related adverse events in 75% of patients versus 43% with the doublet. Treatment-related adverse events led to discontinuation of at least one study component in 49% and 26%, respectively. Dose modification because of adverse events occurred in 92% versus 76%, and high-dose corticosteroids were used in 59% versus 37%. All treated patients had at least one treatment-emergent adverse event, and the most common grade 3 or 4 triplet toxicities were alanine aminotransferase and aspartate aminotransferase elevations. These events occurred in 26% and 19% of triplet-treated patients, while grade 5 treatment-related events occurred in three and five patients, with no new safety signals.
Exploratory biomarker analyses included RNA sequencing, molecular cluster assignment, immune cell deconvolution with CIBERSORT, and gene-signature response analyses. Among patients with M2-like macrophage levels in the top quartile, the triplet was associated with improved progression-free and overall survival versus the doublet; this benefit was not observed in the lower three quartiles.
The exploratory biomarker analyses also linked the angiogenic cluster to higher response with the triplet, while progression-free survival favored the triplet in angiogenic, proliferative, and T-effector/proliferative clusters. Among responders, angiogenic signatures were higher and immune-related pathways were lower with the triplet, whereas immune activation was stronger with the doublet. These retrospective findings were described as exploratory, hypothesis-generating, and in need of independent validation.