Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: final analysis of efficacy and safety from the phase III CheckMate 214 trial

BACKGROUND: Nivolumab plus ipilimumab (NIVO + IPI) demonstrated significant long-term survival and response benefits in patients with previously untreated advanced renal cell carcinoma (aRCC) in the phase III CheckMate 214 trial (NCT02231749). We report final efficacy and safety results with 9.3 years median follow-up. PATIENTS AND METHODS: Patients (N = 1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg every 3 weeks × four doses, followed by NIVO (3 mg/kg or 240 mg every 2 weeks or 480 mg every 4 weeks); or sunitinib (SUN) (50 mg) once daily (4 weeks on, 2 weeks off). ENDPOINTS: overall survival (OS), and independent radiology review committee-assessed progression-free survival and objective response rate in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate/poor-risk (primary), intention-to-treat (secondary), and IMDC favorable-risk (exploratory) patients. RESULTS: With a median (range) follow-up of 9.3 years (8.6-9.9 years), the hazard ratio (95% confidence interval) for OS with NIVO + IPI versus SUN was 0.71 (0.62-0.82) in intention-to-treat patients, 0.69 (0.59-0.81) in intermediate/poor-risk patients, and 0.80 (0.59-1.09) in favorable-risk patients; 108-month OS probabilities were 31.4% versus 19.5%, 30.2% versus 18.7%, and 35.3% versus 21.8%, respectively. Progression-free survival probabilities at 96 months were 22.7% versus 9.0% (intention-to-treat), 25.4% versus 8.5% (intermediate/poor risk), and 12.5% versus 11.3% (favorable risk). Probabilities of remaining in response at 96 months with NIVO + IPI versus SUN were 48.0% versus 19.0% (intention-to-treat), 50.0% versus 23.0% (intermediate/poor risk), and 36.0% versus not estimable (favorable risk). Incidence of any-grade (grade 3-4) treatment-related adverse events (AEs) was 94.1% (48.6%) with NIVO + IPI versus 97.6% (64.1%) with SUN. Exploratory post hoc analyses reported include descriptive analyses of OS by immune-mediated AE discontinuation status. CONCLUSIONS: In the longest phase III follow-up of a first-line checkpoint inhibitor combination in aRCC (>9 years), NIVO + IPI maintained a substantial survival benefit with durable responses versus SUN. Grade 3-4 treatment-related AEs were lower with NIVO + IPI versus SUN at 9 years. NIVO + IPI remains a first-line standard of care in aRCC.