The main inclusion and exclusion criteria include but are not limited to the following:

Inclusion Criteria include, but are not limited to:

• Has a histologically confirmed diagnosis of colorectal adenocarcinoma that is at stage IV (as defined by American Joint Committee on Cancer eighth edition) [National Comprehensive Cancer Network 2018]
• Has centrally confirmed Microsatellite Instability-High/Mismatch Repair Deficient (MSI-H/dMMR) status
• Has centrally confirmed RAS and BRAF mutation status
• A woman of child-bearing potential (WOCBP) must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours for urine or within 72 hours for serum before the first dose of study intervention.
• Has measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 as assessed by the local site investigator/radiology
• Must provide an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 3 days before randomization
• Has a life expectancy of at least 3 months
• Has received Hepatitis B Virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable hepatitis B virus (HBV) viral load prior to randomization if hepatitis B surface antigen (HBsAg) positive
• Has an undetectable Hepatitis C Virus (HCV) viral load if HCV infected
• Has well controlled Human Immunodeficiency Virus (HIV) on antiretroviral therapy (ART) if HIV infected

Exclusion Criteria include, but are not limited to:

• Has received prior systemic therapy for stage IV colorectal cancer (CRC). Participants may have received prior adjuvant/neoadjuvant chemotherapy for CRC as long as it was completed at least 6 months prior to randomization
• Has undergone major operation within 4 weeks of randomization or has not adequately recovered from major surgery or has ongoing surgical complications
• Has received prior therapy with an anti-programmed cell death 1 protein (anti-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), or anti-programmed cell death ligand 2 (anti PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], tumor necrosis factor receptor superfamily, member 4 [OX 40], tumor necrosis factor receptor superfamily member 9 [CD137])
• Has received prior radiotherapy within 2 weeks of start of study intervention or has radiation-related toxicities, requiring corticosteroids
• Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication
• Has a known additional malignancy that is progressing or has required active treatment within the past 5 years, with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
• Has an active autoimmune disease that has required systemic treatment in past 2 years
• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• Has an active infection requiring systemic therapy (eg, tuberculosis, known viral or bacterial infection)
• Has HIV-infection with a history of Kaposi's sarcoma or Multicentric Castleman's Disease
• Has had an allogenic tissue/solid organ transplant