Background: Robust clinical activity has been observed with anti–PD-1 pembrolizumab (pembro) in patients (pts) with dMMR/MSI-H metastatic CRC tumors. However, given the response rate of 45% with first-line pembro demonstrated in KEYNOTE-177, there is room for improvement. Adding a second checkpoint inhibitor targeting a different pathway such as CTLA-4, LAG-3, TIGIT, or ILT4 may improve the efficacy of PD-1 inhibition. This ongoing, open-label, multicenter, multiarm, randomized, phase 2 trial (NCT04895722) will evaluate efficacy and safety of coformulated pembro and anti–CTLA-4 quavonlimab compared with pembro monotherapy in chemotherapy-refractory stage IV dMMR/MSI-H CRC in cohort A; the study will also evaluate the efficacy and safety of 4 pembro-based combinations (coformulation of pembro with either quavonlimab, anti–LAG-3 favezelimab, or anti-TIGIT vibostolimab; anti-ILT4 MK-4830 given sequentially with pembro) compared with pembro monotherapy in previously untreated stage IV dMMR/MSI-H CRC in cohort B. Methods: Pts aged ≥18 y with histologically confirmed stage IV dMMR/MSI-H CRC who have measurable disease per RECIST v1.1 by investigator and confirmed by blinded independent central review (BICR), will be enrolled. Pts in cohort A must have experienced PD after fluoropyrimidine, irinotecan, and oxaliplatin, with or without anti-VEGF antibody, and anti-EGFR antibody for pts with left-sided tumors that are RAS WT. Pts in cohort B will not have been previously treated for metastatic disease. Additional eligibility criteria include ECOG PS 0 or 1, adequate organ function, and availability of archival or newly obtained tissue sample. Pts with autoimmune disease, active CNS metastases, and those who received systemic therapy within 4 wks or radiotherapy within 2 wks before intervention will be excluded. Pts in cohort A will be randomly assigned 1:1 to receive either coformulated quavonlimab 25 mg/pembro 400 mg IV Q6W or pembro 400 mg IV Q6W. Pts in cohort B will be randomly assigned 1:1:1:1:1 to receive coformulated quavonlimab 25 mg/pembro 400 mg IV Q6W, favezelimab 800 mg/pembro 200 mg IV Q3W, vibostolimab 200 mg/pembro 200 mg IV Q3W, MK-4830 800 mg + pembro 200 mg IV Q3W (given sequentially), or pembro 400 mg IV Q6W. Pts will be stratified by RAS mutation (mutant vs WT). Treatment will continue for ≤2 y or until unacceptable toxicity, disease progression, confirmed CR (after ≥6 mo of study treatment and pts have received ≥6 wk of treatment after initial CR), or withdrawal from study. Disease assessment by CT or MRI will be performed Q9W. For both cohorts, primary end point is ORR by BICR per RECIST v1.1; secondary end points are ORR assessed by investigator, DOR and PFS assessed by BICR and by investigator per RECIST v1.1, OS, and safety and tolerability graded per NCI CTCAE v5.0. Enrollment in this trial is ongoing. Clinical trial information: NCT04895722.