Background: This Phase I study evaluated the safety, tolerability, and clinical activity of MK-3475, a selective anti-PD-1 antibody that blocks the interaction between programmed death-1 (PD-1) on T-cells and PD-L1 and PD-L2 on tumor cells in pts with previously-treated, progressive locally advanced or metastatic NSCLC. Methods: Previously-treated pts with NSCLC whose tumors expressed any detectable PD-L1 using a preliminary immunohistochemical assay were randomized to MK-3475 at 10 mg/kg every 2 weeks (Q2W) or 3 weeks (Q3W). Some pts with tumors without PD-L1 expression who had received ≥2 prior lines of therapy were treated with MK-3475 at 10 mg/kg Q2W. At least 1 measurable tumor lesion, ECOG performance status of 0-1, adequate organ function, and new tumor biopsy ≤60 days prior to study entry were required. Tumor response was assessed every 9 wks until disease progression by investigator review using immune-related response criteria (irRC) and independent central review using RECIST 1.1. Results: 450 pts provided tissue for PD-L1 assessment; 305 were eligible based on PD-L1 tumor staining. 221 pts (n=102, Q2W [including 43 whose tumors did not express PD-L1]; n=119, Q3W) began treatment between Feb 2013 and Oct 2013. 48% of pts experienced drug-related adverse events (AEs), usually grade 1-2 in severity, most commonly fatigue (13%), decreased appetite (6.5%), arthralgia (6.1%), pruritus (5.4%), rash (4.7%), and pyrexia (3.6%). The incidence of grade 3/4 drug-related AEs was 6%. There were 3 cases of drug-related grade 3/4 pneumonitis. The preliminary ORR (confirmed & unconfirmed by irRC/RECIST) in all pts was 15%/21% (16%/24% for pts with PD-L1 expressing tumors [19%/31% 10 mg/kg Q2W, 15%/22% 10 mg/kg Q3W], 10%/8% for pts without PD-L1 tumor expression. 40% of pts had <18 wks of follow-up and 69 pts (33%) remain on treatment. A mature dataset will be available for presentation, including correlation between level of tumor PD-L1 expression and response rates. Conclusions: In this cohort of over 200 pts, treatment with MK-3475 was generally well tolerated and provided robust antitumor activity in previously-treated pts with progressive locally advanced or metastatic NSCLC that expressed PD-L1. Clinical trial information: NCT01295827.