Background: Docetaxel is a standard second line treatment for patients with advanced non-small cell lung cancer (NSCLC). It yields a low response rate (~10.5%), limited 1-year survival rate (~37%), and median overall survival (OS) of ~ 7.5 months. MK-3475 is a highly selective anti-PD-1 monoclonal antibody exerting dual ligand blockade (DLB) of the PD-1 pathway, a major pathway hijacked by tumors to suppress immune control. Preclinical and clinical data suggest that this pathway plays an important role in NSCLC. Upon interaction with its ligands, PD-L1 and PD-L2, the activation of PD-1 may lead to suppression of antitumor immunity. This randomized phase II/III trial was designed to assess the clinical activity of MK-3475 monotherapy compared with standard docetaxel in patients with advanced NSCLC whose disease has progressed after platinum-containing therapy. Methods: Eligibility stipulates minimum age of 18 years; ECOG performance status of 0-1, and diagnosis of advanced PD-L1-positive NSCLC with documented progression after platinum-containing systemic therapy. Patients are stratified by ECOG performance status, geographic location of the site, and degree of PD-L1 expression and randomized in a 1:1:1 ratio to receive intravenous MK-3475 (2 mg/kg, every 3 weeks [Q3W] or 10 mg/kg, Q3W) or docetaxel (75 mg/m², Q3W) for 2 years or until disease progression, unacceptable toxicity, intercurrent illness or investigator decision. Response to treatment will be evaluated every 9 weeks by investigators using the immune-related response criteria (irRC) and centrally by RECIST 1.1. Adverse events (AEs) will be monitored throughout the trial. Primary objectives include OS and PFS per RECIST 1.1 in patients with strong expression of PD-L1, and safety, including incidence and time to first Grade 3-5 AE. Secondary objectives include OS, PFS and ORR per RECIST 1.1 in patients with PD-L1 positive tumors. Fifty of approximately 920 pts targeted for accrual have enrolled. Clinical trial information: NCT01905657.