Background: sRCC is an aggressive histologic growth pattern in RCC with a poor prognosis and limited therapeutic options. First-line N+I provided efficacy benefits over S in patients (pts) with sRCC and intermediate/poor (I/P)-risk disease at 42 months follow-up. Here, we report an exploratory post hoc analysis of N+I vs S in pts with I/P-risk and sRCC with long-term follow-up of 5 years. Methods: Pts with clear cell advanced RCC were randomized 1:1 to N 3 mg/kg plus I 1 mg/kg every 3 weeks × 4, then N 3 mg/kg every 2 weeks vs S 50 mg once daily (4 weeks; 6-week cycles). Pts with sRCC were identified via independent central pathology review of archival tumor tissue or histological classification per local pathology. Outcomes in pts with sRCC were not prespecified. Endpoints in pts with sRCC and IMDC I/P risk included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Outcomes were also assessed per baseline tumor PD-L1 expression level (≥1% vs <1%). Safety outcomes used descriptive statistics. Results: Of 1096 randomized pts in CheckMate 214, 139 I/P-risk pts with sRCC were identified (N+I, n = 74; S, n = 65). Of all treated pts, 9 of 73 (12%) in the N+I arm vs zero of 65 in the S arm remained on treatment. The primary reason for discontinuation was disease progression (N+I, 37%; S, 71%). OS continued to favor N+I vs S (HR 0.46 [95% CI 0.29–0.71]; P = 0.0004; table). PFS benefit with N+I vs S was similarly maintained (HR 0.50 [95% CI 0.32–0.80; P = 0.0036]). Additionally, ORR was higher (61% vs 23%; P < 0.0001), median duration of response was longer (NR vs 25 months), and more pts had complete responses (23% vs 6%) with N+I vs S, respectively. Efficacy was better with N+I vs S regardless of PD-L1 expression, yet the degree of OS, PFS, and ORR benefits with N+I was greater for pts with PD-L1 ≥ 1% (Table). No new safety signals emerged in either arm. Conclusions: N+I showed clinically meaningful benefits in long-term OS, PFS, and the frequency and depth of response vs S in previously untreated pts with sRCC and I/P-risk disease, supporting N+I as a preferred first-line therapy in this population. Clinical trial information: NCT02231749.

^aMinimum follow-up NR; zero pts at risk at 5 y. m, median; NE, not estimable; NR, not reached.