Background: Approximately 5% of mCRCs are dMMR, leading to high levels of MSI. CRCs with MSI-H have abundant lymphocyte infiltrates and strong expression of immune checkpoints. In the phase 2 KEYNOTE-016 study, the anti–programmed death 1 (PD-1) antibody pembro provided an ORR of 40% in patients (pts) with progressive dMMR mCRC vs 0% in pts with MMR-proficient mCRC. KEYNOTE-177 (ClinicalTrials.gov, NCT02563002) is an international, randomized, open-label, phase 3 study to evaluate the efficacy and safety of pembro vs standard-of-care (SOC) chemotherapy as first-line therapy for dMMR or MSI-H mCRC. Methods: Pts aged ≥18 years with locally confirmed dMMR or MSI-H stage IV CRC, measurable disease per RECIST v1.1 by local site assessment, ECOG performance status 0-1, adequate organ function, no active autoimmune disease or brain metastases, and no prior systemic therapy for mCRC are eligible. Pts will be randomized 1:1 to receive pembro 200 mg every 3 weeks (Q3W) or investigator’s choice of SOC chemotherapy (options include mFOLFOX6 or FOLFIRI alone or in combination with bevacizumab or cetuximab; must be chosen prior to randomization). Treatment will continue until disease progression, unacceptable toxicity, pt/investigator decision to withdrawal, or completion of 35 cycles (pembro only). Response will be evaluated Q9W per RECIST v1.1 by central imaging vendor review and per immune-related RECIST. Pts in the SOC arm who have disease progression and meet crossover criteria may be eligible to receive pembro for up to 17 treatment cycles. Eligible pts may continue pembro after initial RECIST-defined progression. AEs will be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Pts are to be followed up for survival Q9W. Primary end point is PFS per RECIST v1.1 by central imaging vendor review. Secondary end points include ORR per RECIST v1.1 by central imaging vendor review, OS, and safety and tolerability. Other end points include DOR and HRQoL. Planned enrollment in KEYNOTE-177 is 270 pts across 23 countries. Clinical trial information: NCT02563002