First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial
Authors: Luis G. Paz-Ares, Suresh S. Ramalingam, Tudor-Eliade Ciuleanu, Jong-Seok Lee, Laszlo Urban, Reyes Bernabe Caro, Keunchil Park, Hiroshi Sakai, Yuichiro Ohe, Makoto Nishio, Clarisse Audigier-Valette, Jacobus A. Burgers, Adam Pluzanski, Randeep Sangha, Carlos Gallardo, Masayuki Takeda, Helena Linardou, Lorena Lupinacci, Ki Hyeong Lee, Claudia Caserta, Mariano Provencio, Enric Carcereny, Gregory A. Otterson, Michael Schenker, Bogdan Zurawski, Aurelia Alexandru, Alain Vergnenegre, Judith Raimbourg, Kynan Feeney, Sang-We Kim, Hossein Borghaei, Kenneth John O'Byrne, Matthew D. Hellmann, Arteid Memaj, Faith Ellen Nathan, Judith Bushong, Phuong Tran, Julie R. Brahmer, Martin Reck
Journal: Journal of Thoracic Oncology (2021)

IntroductionIn CheckMate 227, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with tumor programmed death-ligand 1 (PD-L1) greater than or equal to 1% (primary end point) or less than 1% (prespecified descriptive analysis). We report results with minimum 4 years' follow-up.MethodsAdults with previously untreated stage IV or recurrent NSCLC were randomized (1:1:1) to nivolumab plus ipilimumab, nivolumab, or chemotherapy (PD-L1 ≥1%); or to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1 <1%). Efficacy included OS and other measures. Safety included timing and management of immune-mediated adverse events (AEs). A post hoc analysis evaluated efficacy in patients who discontinued nivolumab plus ipilimumab due to treatment-related AEs (TRAEs).ResultsAfter 54.8 months' median follow-up, OS remained longer with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 greater than or equal to 1% (hazard ratio = 0.76; 95% confidence interval: 0.65–0.90) and PD-L1 less than 1% (0.64; 0.51–0.81); 4-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29% versus 18% (PD-L1 ≥1%); and 24% versus 10% (PD-L1 <1%). Benefits were observed in both squamous and nonsquamous histologies. In a descriptive analysis, efficacy was improved with nivolumab plus ipilimumab relative to nivolumab (PD-L1 ≥1%) and nivolumab plus chemotherapy (PD-L1 <1%). Safety was consistent with previous reports. The most common immune-mediated AE with nivolumab plus ipilimumab, nivolumab, and nivolumab plus chemotherapy was rash; most immune-mediated AEs (except endocrine events) occurred within 6 months from start of treatment and resolved within 3 months after, mainly with systemic corticosteroids. Patients who discontinued nivolumab plus ipilimumab due to TRAEs had long-term OS benefits, as seen in the all randomized population.ConclusionsAt more than 4 years' minimum follow-up, with all patients off immunotherapy treatment for at least 2 years, first-line nivolumab plus ipilimumab continued to demonstrate durable long-term efficacy in patients with advanced NSCLC. No new safety signals were identified. Immune-mediated AEs occurred early and resolved quickly with guideline-based management. Discontinuation of nivolumab plus ipilimumab due to TRAEs did not have a negative impact on the long-term benefits seen in all randomized patients.