Cabozantinib plus nivolumab and ipilimumab in previously untreated, advanced renal cell carcinoma: final results and biomarker analyses from the phase III COSMIC-313 study

• With longer follow-up, cabozantinib + nivolumab + ipilimumab continued to show improved PFS versus nivolumab + ipilimumab • OS was comparable between the two arms and there were no new safety signals • Adding cabozantinib to nivolumab + ipilimumab may overcome M2-like macrophage-mediated immune suppression • Molecular correlates of response differ markedly by treatment regimen With longer follow-up, cabozantinib + nivolumab + ipilimumab continued to show improved PFS versus nivolumab + ipilimumab OS was comparable between the two arms and there were no new safety signals Adding cabozantinib to nivolumab + ipilimumab may overcome M2-like macrophage-mediated immune suppression Molecular correlates of response differ markedly by treatment regimen Primary results from COSMIC-313 demonstrated significantly longer progression-free survival (PFS) with first-line cabozantinib plus nivolumab and ipilimumab versus placebo plus nivolumab and ipilimumab in patients with advanced renal-cell carcinoma (RCC). Final efficacy and safety results, as well as data from exploratory biomarker analyses, are reported here. The design, participants, and primary-endpoint PFS outcomes have been reported previously for this phase III, double-blind, randomized (1:1) study of cabozantinib or placebo plus nivolumab and ipilimumab in adults with previously untreated, advanced clear cell RCC. The secondary endpoint was overall survival (OS) in the intention-to-treat population. Exploratory biomarker analyses investigated the potential association between immune cell types and gene signatures with clinical outcomes. After a median follow-up of 45.0 months, the updated median PFS in the cabozantinib (triplet) arm was longer than in the placebo (doublet) arm (16.6 versus 11.2 months; hazard ratio HR 0.82, 95% confidence interval CI 0.69-0.98]). There was no significant difference in median OS (HR 1.02, 95% CI 0.85-1.23, P = 0.84), and the safety profile was consistent with the earlier analysis (grade 3/4 treatment-related adverse events occurred in 75% and 43% of patients in the triplet and doublet arms, respectively). In patients with higher levels of M2-like macrophages, the triplet regimen was associated with significantly improved PFS and OS compared with the doublet regimen. Responders in the triplet arm exhibited elevated angiogenic signatures and reduced immune-related pathways, while responders in the doublet arm had robust immune activation. Long-term results from COSMIC-313 continue to demonstrate a PFS benefit with the addition of cabozantinib to nivolumab and ipilimumab. There was no OS benefit and no new safety signals were observed. Exploratory biomarker analyses suggest adding cabozantinib to nivolumab and ipilimumab improves survival in patients with high levels of M2-like macrophages.