Background: Programmed death-1 receptor ligand (PD-L1) is a key therapeutic target in the reactivation of the immune response against multiple cancers. Avelumab* is a fully human anti-PD-L1 IgG1 antibody that has shown promising efficacy and an acceptable safety profile in multiple tumor types, including non-small-cell lung cancer (NSCLC). This open-label phase 3 trial (NCT02576574) compares single-agent avelumab vs platinum-based doublet chemotherapy as first-line treatment for patients (pts) with PD-L1-positive (+) recurrent or stage IV NSCLC negative for activating EGFR mutation and ALK translocation. Methods: The primary objective of this global, multicenter, randomized trial is to demonstrate superiority of avelumab in improving progression-free survival (PFS) according to RECIST 1.1 and as assessed by an Independent Review Committee (IRC) vs platinum-based doublet chemotherapy. Approximately 420 pts with PD-L1+ tumors, as determined by companion diagnostic assay, will be randomized. Eligibility criteria include: histologically confirmed metastatic or recurrent NSCLC, ECOG PS 0-1, no prior systemic treatment for recurrent/metastatic NSCLC, no prior therapy with any drug targeting T cell coregulatory proteins, no concurrent anticancer treatment or immunosuppressive agents, and known EGFR mutation/ALK translocation-negative tumor. Pts receive either avelumab 10 mg/kg as a 1h intravenous (IV) infusion Q2W or a platinum-based doublet (non-squamous histology: pemetrexed 500 mg/m² + cisplatin 75 mg/m² or carboplatin AUC 6; squamous histology: paclitaxel 200 mg/m² + carboplatin AUC 6, gemcitabine 1250 mg/m² + cisplatin 75 mg/m², or gemcitabine 1000 mg/m² + carboplatin AUC 5) by IV infusion. Treatment is given until disease progression, unacceptable toxicity, or consent withdrawal, with a maximum of 6 cycles of chemotherapy. Secondary endpoints include objective response rate, overall survival, quality of life (assessed via EQ-5D, EORTC QLQ-C30, and EORTC QLQ-LC13), safety as per NCI-CTCAE v4.03, and tumor biomarkers. Trial enrollment began in Oct 2015. *Proposed INN. Clinical trial information: NCT02576574