Inclusion Criteria:  Has a histologically confirmed colorectal adenocarcinoma that is metastatic and unresectable. Has measurable disease per RECIST 1.1 as assessed by the local site investigator. Has been previously treated for the disease and radiographically progressed on or after or could not tolerate standard treatment. Submits an archival (≤ 5 years) or newly obtained tumor tissue sample or newly obtained tumor tissue sample that has not been previously irradiated. Has an Eastern Cooperative Oncology Group Performance Score (ECOG PS) of 0 to 1 within 10 days prior to first dose of study intervention. Has a life expectancy of at least 3 months, based on the investigator assessment. Has the ability to swallow and retain oral medication and not have any clinically significant gastrointestinal abnormalities that might alter absorption. Has adequate organ function.  Exclusion Criteria:  Has previously been found to have deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumor status. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis or leptomeningeal disease. Has a history of acute or chronic pancreatitis. Has neuromuscular disorders associated with an elevated creatine kinase (eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy). Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability. Has urine protein greater than or equal to 1g/24h. A woman of childbearing potential who has a positive urine/serum pregnancy test within 24/72 hours prior to the first dose of study intervention. Has received prior therapy with an anti-programmed cell death 1 (PD-1), anti-programmed death ligand 1 (PD-L1), or anti-programmed cell death ligand 2 (PD-L2), anti-lymphocyte activation gene 3 (LAG-3) antibody, with a tyrosine kinase inhibitor (TKI; eg, lenvatinib) other than rapidly accelerated fibrosarcoma (RAF) inhibitors (binimetinib is permitted if combined with a RAF inhibitor), or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4, OX-40, cluster of differentiation [CD] 137). Has previously received regorafenib or TAS-102. Has received prior systemic anticancer therapy including investigational agents within 28 days before randomization. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. 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 infections, etc.). Has a known history of human immunodeficiency virus (HIV) infection. Has known history of Hepatitis B or known active Hepatitis C virus infection. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. Has had an allogenic tissue/solid organ transplant.