Background: The majority of NSCLC patients (pts) present at the time of diagnosis with advanced disease. Subsets of pts are eligible for therapies targeted at mutated oncogene drivers; however, the majority of pts have few effective options beyond standard platinum-based chemotherapy. Preclinical data suggest that immune dysfunction, including T-cell downregulation through increased tumor expression of programmed death-1 ligand (PD-L1), plays a role in NSCLC. Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has shown clinical activity against several solid tumors including NSCLC. Preliminary data suggest that nivolumab’s activity in first-line NSCLC is accentuated in pts with positive tumor PD-L1 expression (PD-L1+). This phase III, randomized, open-label trial will compare the clinical activity of first-line nivolumab monotherapy vs ICC in treatment-naïve pts with stage IV or recurrent NSCLC with PD-L1+ tumor expression. Methods: Chemotherapy-naïve pts with ECOG performance status ≤1 and without known EGFR mutations or ALK translocations will be randomized 1:1 to nivolumab (3 mg/kg IV Q2W) or ICC, and stratified by tumor PD-L1 expression level (Dako immunohistochemistry assay) and NSCLC histology. Pts randomized to ICC (maximum of six 3-week cycles) will receive gemcitabine 1250 mg/m² + cisplatin 75 mg/m², gemcitabine 1000 mg/m² + carboplatin AUC 5, or paclitaxel 200 mg/m² + carboplatin AUC 6 (squamous [sq]), or pemetrexed 500 mg/m² + either cisplatin 75 mg/m² or carboplatin AUC 6 (non-sq); with optional crossover to nivolumab. The primary objective is to assess progression-free survival (PFS) with nivolumab vs ICC in pts with strong PD-L1 expression. Secondary objectives are objective response rate and overall survival in strongly PD-L1+ pts, PFS in pts with any PD-L1 expression level, and disease-related symptom improvement. Exploratory objectives include safety, correlation of PD-L1 expression with PFS, pharmacokinetics, pharmacodynamics, pt-reported outcomes, and potential biomarkers. Clinical trial information: NCT02041533.