Immune checkpoint (IC) inhibitors are effective in mismatch repair-deficient or microsatellite instability-high colorectal cancer (CRC). However, for mismatch repair-proficient (pMMR) mCRC, which account for 95% of mCRC tumors, treatment options are limited. In patients with CRC, LAG-3 is overexpressed on colorectal immune cells and correlated with poor differentiation, advanced stage, lymph node involvement and invasion depth (Chen J, Zihua C. Med Oncol. 2014; 31:82). As such, LAG-3 represents a rational target for IC inhibition in CRC. IC inhibitor combination therapy with MK4280A, a coformulation of anti–LAG3 antibody favezelimab and pembrolizumab, has shown promising antitumor activity and a manageable safety profile in patients with PD-L1 CPS≥1 microsatellite stable mCRC and may be efficacious in pMMR mCRC (Garralda E et al. J Clin Oncol. 2021;39. Abstract 3584). In this ongoing phase 3 study (NCT05064059), we will evaluate the efficacy and safety of MK-4280A in patients with PD-L1–positive pMMR mCRC. The open-label, parallel group, active-controlled study plans to enroll approximately 432 patients aged ≥18 years with histologically confirmed unresectable mCRC, pMMR and PD-L1 CPS ≥1 tumors, and measurable disease per RECIST v1.1 by investigator review. All patients must have experienced progressive disease after: 1) fluoropyrimidine, irinotecan and oxaliplatin, with or without anti-VEGF antibody, anti–EGFR antibody for patients with left-sided tumors that are RAS WT, and 2) RAF inhibitor with or without binimetinib in patients with BRAF v600E mutations. Key eligibility criteria include ECOG status 0 or 1, adequate organ function, and availability of archival or newly obtained tissue sample to assess PD-L1 and MMR status. Patients will be randomly assigned to MK-4280A (coformulated favezelimab 800 mg/pembrolizumab 200 mg; Arm A) IV Q3W or standard of care (Arm B) (regorafenib 160 mg PO Q4W [QD on days 1-21; no dose on days 22-28] or TAS-102 35mg/m2 PO Q4W [BID on days 1-5 and 8-12; no dose on days 6, 7, and 13-28]). Patients will be stratified by geographic region (Asia Pacific, EMEA/Americas), presence of liver metastases (yes, no) and time from initial diagnosis of mCRC to randomization (≥18 mo, < 18 mo). Treatment will continue for ≤35 cycles of MK-4280A or unacceptable toxicity, disease progression, confirmed CR with MK-4280A must have been treated for ≥8 cycles and have received 2 cycles after the initial CR was observed (Arm A), or withdrawal from study. Disease assessment by CT or MRI will be performed Q9W during the study. Primary end point is overall survival (OS). Secondary end points are progression free survival (PFS), objective response rate (ORR) and duration of response (by blinded independent central review per RECIST v1.1), patient-reported outcomes on health-related quality of life, and safety graded per NCI CTCAE v5.0. OS and PFS will be estimated by Kaplan-Meier methods. ORR with 95% CI will be estimated using the Clopper-Pearson method. ClinicalTrials.gov, NCT05064059. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.