INTRODUCTION: In CheckMate 227, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with tumor programmed death ligand 1 (PD-L1) ≥1% (primary end point) or <1% (prespecified descriptive analysis). We report results with minimum 4 years' follow-up. METHODS: Adults with previously untreated stage IV/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). RESULTS: After 54.8 months' median follow-up, OS remained longer with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 ≥1% (HR 0.76; 95% CI: 0.65-0.90) and PD-L1 <1% (0.64; 0.51-0.81); 4-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29% versus 18% (PD-L1 ≥1%); 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 ≤6 months from start of treatment and resolved ≤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. CONCLUSIONS: At >4 years' minimum follow-up, with all patients off immunotherapy treatment for ≥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 guidelines-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.
- Paz-Ares, L. G.
- Ramalingam, S. S.
- Ciuleanu, T. E.
- Lee, J. S.
- Urban, L.
- Caro, R. B.
- Park, K.
- Sakai, H.
- Ohe, Y.
- Nishio, M.
- Audigier-Valette, C.
- Burgers, J. A.
- Pluzanski, A.
- Sangha, R.
- Gallardo, C.
- Takeda, M.
- Linardou, H.
- Lupinacci, L.
- Lee, K. H.
- Caserta, C.
- Provencio, M.
- Carcereny, E.
- Otterson, G. A.
- Schenker, M.
- Zurawski, B.
- Alexandru, A.
- Vergnenegre, A.
- Raimbourg, J.
- Feeney, K.
- Kim, S. W.
- Borghaei, H.
- O'Byrne, K. J.
- Hellmann, M. D.
- Memaj, A.
- Nathan, F. E.
- Bushong, J.
- Tran, P.
- Brahmer, J. R.
- Reck, M.
Keywords
- Ctla-4
- PD-1 checkpoint inhibitor
- first-line
- immunotherapy
- metastatic non-small cell lung cancer
