Background: Immune surveillance is one of the primary mechanisms to prevent neoplastic growth. The PD-1 receptor-ligand pathway can be used by tumors to evade immune surveillance. MK-3475 is a potent, highly selective, humanized IgG4/kappa isotype mAb designed to block PD-1 interaction with its ligands PD-L1 and PD-L2, and can reactivate the immune system to eradicate the host tumor. Methods: This is a multi-center, non-randomized, multi-cohort trial of single agent MK-3475 in over 130 patients diagnosed with locally recurrent and/or distant metastatic 1) triple negative breast cancer, 2) head and neck cancer (both HPV and non-HPV associated), 3) urinary tract cancer or 4) gastric cancer. All enrolled patients must express PD-L1 within their tumor microenvironment. MK-3475 is given intravenously at 10 mg/kg every 2 weeks. Primary objectives are to determine (1) safety and tolerability and (2) anti-tumor activity of MK-3475 in patients with PD-L1 positive, advanced solid tumors. Secondary objectives include progression-free survival, overall survival and response duration in treated patients. Radiographic imaging will be obtained every 8 weeks to assess clinical response defined by RECIST 1.1. Tumor biopsies will be available both pre-treatment and during treatment to allow investigation of candidate biomarkers which may predict clinical response to immune checkpoint blockade. Treatment continues for 24 months or until complete response, disease progression, unacceptable toxicity, physician decision, or patient’s withdrawal of study consent. Retreatment for patients who progress after a complete response is allowed. AEs will be monitored and graded according to guidelines in the NCI CTCAE v. 4.0. Summary statistics for safety endpoints and the incidence rate of immune-related AEs and of Grade 3-5 AEs will be calculated. Efficacy will be evaluated in each cohort, in patients with baseline and with either ≥1 post-baseline evaluation or who discontinue the trial due to progressive disease or a drug-related AE. Overall response rate assessed by independent radiology review will be used as the primary endpoint for efficacy. Clinical trial information: NCT01848834.