Background: Despite aggressive therapy with concurrent chemoradiation, fewer than 25% of patients with stage 3 NSCLC achieve 5-year survival and are presumably cured. To date, treatment modifications—including consolidation chemotherapy, maintenance therapy with molecularly targeted agents, concomitant administration of monoclonal antibodies, and escalation of radiation therapy (RT) dose—have not improved these outcomes. Immune checkpoint inhibitors represent an effective treatment for advanced NSCLC and may enhance RT-associated anti-tumor immunity. RTOG 3505 will test whether the addition of the anti-programmed death 1 (PD1) antibody nivolumab after chemoradiation improves overall survival (OS) and progression-free survival (PFS) in this population. Methods: Key eligibility criteria include surgically unresectable stage 3 NSCLC, ECOG 0-1, adequate organ function, available archival tissue, and absence of active autoimmune disease. Patients will receive thoracic RT to 60 Gy with concurrent cisplatin 50 mg/m² IV on Days 1, 8, 29, and 36, and etoposide 50 mg/m² IV on Days 1-5 and 29-33. This regimen was selected to (1) minimize risk of pulmonary toxicity and steroid requirements, and (2) optimize timing of immunotherapy. Between 4 and 12 weeks after completion of chemoradiation, eligible patients will be randomized to nivolumab 240 mg IV or placebo every 2 weeks for 1 year. Stratification factors include performance status, histology, and tumor PD-L1 status. Co-primary endpoints are OS and PFS, as determined by central radiology review. Secondary objectives include toxicity assessment, patient-reported outcomes and quality of life, and OS and PFS according to PD-L1 expression. Exploratory objectives include biomarkers to predict treatment efficacy and toxicity. A total of 660 patients will be enrolled to provide ≥90% power to detect (1) a hazard ratio (HR) of 0.7 for OS with two-sided type I error of 0.04, and (2) HR of 0.667 for PFS two-sided type I error of 0.01, allowing a 16.7% drop-out rate before randomization. Clinical trial information: NCT02768558