Abstract

Introduction: In the phase 3 CheckMate 9LA study, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy alone. We report updated efficacy and safety (≥3 y of follow-up), clinical outcomes in patients with baseline brain metastases, and exploratory somatic mutation analyses. Methods: Adults with stage IV or recurrent NSCLC, no known sensitizing EGFR or ALK alterations, and Eastern Cooperative Oncology Group performance status less than or equal to 1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy alone (four cycles). Assessments included OS, progression-free survival (PFS), and objective response rate. Exploratory analyses included systemic and intracranial efficacy in patients with or without baseline brain metastases, in addition to OS and PFS by KRAS, TP53, STK11, and KEAP1 somatic mutation status in patients with nonsquamous NSCLC. Results: With a minimum follow-up of 36.1 months, nivolumab plus ipilimumab with chemotherapy continued to prolong OS versus chemotherapy alone in the intent-to-treat population (median [hazard ratio; 95% confidence interval] OS: 15.8 versus 11.0 mo [0.74; 0.62–0.87]; 3-y OS: 27% versus 19%). Efficacy outcomes were improved in patients with pretreated baseline brain metastases (median [hazard ratio; 95% confidence interval] OS: 19.3 versus 6.8 mo [0.45; 0.29–0.70]; systemic PFS: 9.7 versus 4.1 mo [0.44; 0.28–0.69]; intracranial PFS: 11.4 versus 4.6 mo [0.42; 0.26–0.68]). A trend of OS benefit was observed in patients treated with nivolumab plus ipilimumab with chemotherapy versus chemotherapy alone, despite KRAS, TP53, and STK11 tumor mutations. Extended follow-up revealed no new safety signals. Conclusions: With a 3-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy continued to have long-term, durable efficacy versus chemotherapy alone; a manageable safety profile; and survival benefit in patients with or without baseline brain metastases or select somatic mutations, further supporting the regimen as first-line treatment for patients with metastatic NSCLC.