CaboNivo (cabozantinib VEGFR/MET/AXL TKI + nivolumab PD-1) drives 43% ORR in metastatic non–clear cell RCC—chromophobe remains refractory

Cabozantinib (a multikinase VEGFR/MET/AXL inhibitor) plus nivolumab (PD-1 antibody) was evaluated in an investigator-initiated Phase 2 study in advanced/metastatic non–clear cell RCC with 0–1 prior systemic therapies (excluding prior ICI) across two histology cohorts (NCT03635892). In Cohort 1 (papillary/unclassified/translocation-associated; n=53; 74% 1L), ORR was 43% (95% CI 30–58) with mPFS 11 months (95% CI 8–14) and median OS 28 months (95% CI 21–37); FH-deficient RCC stood out with ORR 88% (7/8 PRs), while tRCC was lower (ORR 20%; 1/5). Cohort 2 (chromophobe; n=7) had no objective responses (5 SD); cabozantinib and nivolumab were discontinued for toxicity in 42% and 38% of Cohort 1 patients—higher discontinuation than typically reported with 1L pembrolizumab+lenvatinib in nccRCC (ORR ~51% overall; chromophobe ORR ~33%; median PFS ~17.9 months), suggesting CaboNivo’s activity is competitive in some nccRCC subsets but tolerability and histology selection are key.