Outcomes by IMDC risk in the COSMIC-313 phase 3 trial evaluating cabozantinib (C) plus nivolumab (N) and ipilimumab (I) in first-line advanced RCC (aRCC) of IMDC intermediate or poor risk.

605 Background: In COSMIC-313 (NCT03937219), C+N+I significantly improved progression-free survival (PFS) compared with N+I in first-line aRCC of IMDC intermediate or poor risk (Choueiri ESMO 2022). Here, outcomes are analyzed by IMDC risk group. Methods: A total of 855 patients (pts) with clear cell aRCC of IMDC intermediate or poor risk 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 for up to 2 years. The primary endpoint was PFS by blinded independent radiology review (BIRC) per RECIST 1.1 in the first 550 randomized pts (PITT population). The secondary endpoint was overall survival (OS) in all randomized pts; objective response rate (ORR) and safety were additional endpoints. Results: Overall, 75% of pts were IMDC intermediate and 25% were poor risk. Meaningful differences in baseline characteristics for intermediate vs poor risk in the PITT population were observed for KPS ≥90 (67% vs 47%), prior nephrectomy (71% vs 44%), and ≥2 target/non-target lesions per BIRC (68% vs 83%); characteristics were balanced across treatment arms for intermediate risk but some imbalances were seen for poor risk (42% for C+N+I vs 52% for P+N+I had KPS ≥90 and 37% vs 50% had prior nephrectomy). In intermediate risk pts, PFS was improved with C+N+I (HR 0.63, 95% CI 0.47–0.85), and ORR and DCR (PITT population) were numerically higher (Table). For poor risk pts, no difference in PFS and ORR was apparent, but DCR was numerically higher with C+N+I. PD as best response was lower with C+N+I vs P+N+I in both risk groups. Duration of response was not reached (NR) in each treatment group. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 74% with C+N+I vs 42% with P+N+I for intermediate risk and 67% vs 38% for poor risk. TRAEs led to discontinuation of all treatment components in 14% vs 5% for intermediate risk and 5% vs 4% for poor risk. Additional analyses relevant to IMDC risk group will be presented. Conclusions: In COSMIC-313, C+N+I improved PFS vs P+N+I in first-line aRCC of IMDC intermediate or poor risk; subgroup analysis suggested that the benefit was primarily in intermediate risk pts. Follow-up for OS is ongoing. Clinical trial information: NCT03937219 . [Table: see text]