Background: A subset of colorectal carcinomas (CRCs) are characterized by mismatch repair (MMR) deficiency resulting in microsatellite instability (MSI). MSI-high tumors contain high levels of lymphocyte infiltrates and express the PD-1 immune checkpoint receptor and its ligand, PD-L1. In the phase 2 KEYNOTE-016 study, the anti–PD-1 antibody pembrolizumab demonstrated antitumor activity against MMR-deficient tumors in patients with treatment-refractory metastatic CRC. KEYNOTE-177 (ClinicalTrials.gov, NCT02563002) is an international, randomized, open-label, phase 3 study of pembrolizumab versus standard-of-care (SOC) chemotherapy in first-line MMR-deficient or MSI-high metastatic CRC. Methods: Key eligibility criteria include age ≥18 years, confirmed MSI-high or MMR-deficient metastatic CRC, ECOG PS 0-1, no active autoimmune disease or brain metastases, and no prior therapy for metastatic disease. ~270 patients will be randomly assigned 1:1 to receive either pembrolizumab 200 mg every 3 weeks or investigator's choice of SOC chemotherapy (mFOLFOX6 or FOLFIRI alone or in combination with bevacizumab or cetuximab, chosen before randomization). Treatment is to continue until progressive disease (PD), unacceptable toxicity, patient/investigator decision, or completion of 35 cycles (pembrolizumab only). Response is to be assessed every 9 weeks per RECIST v1.1 by central imaging vendor review and per RECIST adapted for immunotherapy response patterns. Eligible patients may continue pembrolizumab beyond initial RECIST-defined progression. Patients in the SOC arm who have PD and meet crossover criteria may be eligible to receive pembrolizumab for up to 17 treatment cycles. AEs are to be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Patients are to be followed up for survival every 9 weeks. The primary end point is PFS per RECIST v1.1; key secondary end points include OS and ORR. Enrollment in KEYNOTE-177 is ongoing. Clinical trial information: NCT02563002