LBA8 Phase III study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313)

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C inhibits tyrosine kinases including MET, VEGFR, and TAM kinases (TYRO3, AXL, MER) and promotes an immune-permissive environment, which may enhance response to checkpoint inhibitors. C+N and N+I are both standards of care for first-line aRCC (N+I for intermediate or poor risk). COSMIC-313 (NCT03937219) is evaluating C in combination with N+I vs N+I in previously untreated aRCC of intermediate or poor risk and is the first study to evaluate a triplet therapy against a contemporary immuno-oncology doublet control. This global, double-blind, randomized phase III study enrolled previously untreated patients (pts) with clear cell aRCC of IMDC intermediate or poor risk. Pts were randomized to receive C 40 mg QD or matched placebo (P), stratified by region and IMDC risk. Both treatment groups received N (3 mg/kg IV Q3W) + I (1 mg/kg IV Q3W) for 4 cycles followed by N (480 mg IV Q4W); N was administered up to 2 y. The primary endpoint was progression-free survival (PFS) by blinded independent radiology review per RECIST 1.1 in the first 550 randomized pts (PITT population). The secondary endpoint was overall survival (OS) in all randomized pts (ITT population); objective response rate (ORR) and safety were additional endpoints. From Jun 2019 to Mar 2021, 855 pts were randomized (428, C+N+I; 427, P+N+I); IMDC risk was intermediate for 75% and poor for 25%. The study met the primary PFS endpoint (HR 0.73, 95% CI, 0.57–0.94; p=0.013); median PFS was not reached (NR; 95% CI, 14.0–not estimable) for C+N+I vs 11.3 mo (95% CI, 7.7–18.2) for P+N+I. Prespecified PFS subgroup analyses will be presented. ORR (PITT population) was 43% (95% CI, 37.2–49.2) for C+N+I vs 36% (95% CI, 30.1–41.8) for P+N+I; median duration of response was NR in either treatment group. Grade 3/4 TRAEs occurred in 73% with C+N+I vs 41% with P+N+I; 3 pts (1%) in each arm had grade 5 TRAEs, and a TRAE led to discontinuation of all treatment components in 12% vs 5%. C+N+I significantly improved PFS vs P+N+I in previously untreated aRCC of IMDC intermediate or poor risk. Safety was consistent with the known profiles of the treatment components. Follow-up for OS is ongoing.