Background: We hypothesize that a correlation may exist between the number of somatic mutations in individual tumors and the response to immune checkpoint inhibitors since each protein-coding mutation has the potential to serve as a novel antigen for an immune response. This may explain why lung cancers and melanomas, which harbor hundreds of somatic tumors, respond so well to these agents. Microsatellite unstable (MSI) tumors are deficient in DNA mismatch repair which leads to hundreds to thousands of spontaneous mutations. Furthermore, similar to melanoma, MSI positive colon cancers, there is often prominent lymphocyte infiltration. PD-1 is upregulated on activated T cells and provides inhibitory signals to T cells undergoing activation. MK-3475 is a humanized monoclonal IgG4 antibody against PD-1 and is showing activity in multiple tumor types. This study aims to establish the treatment benefit and evaluate MSI as a predictive marker of response to anti-PD-1 blockade. Methods: This is an open-label, 2-stage, phase 2 study to evaluate the clinical activity of MK-3475 in 3 cohorts of patients: MSI positive colorectal cancer (CRC); MSI negative CRC; and MSI positive solid tumors but not CRC. MK-3475 will be administered at 10 mg/kg every 14 days. The co-primary endpoints for CRC cohorts are immune-related progression-free survival (irPFS) rate at 20 weeks and objective response rate assessed using immune related response criteria. The primary endpoint for the cohort with other solid tumors is irPFS at 20 weeks. Secondary endpoints include disease control rate, progression-free survival, overall survival and safety. Each MSI positive and MSI negative CRC cohort will evaluate up to 25 patients, and the cohort with MSI positive solid tumors but not CRC will enroll up to 21 patients. Results from exome sequencing and PD-L1 expression using IHC on tumor tissue will be correlated with response. Clinical trial information: NCT01876511.