Background: The majority of mCRC pts are microsatellite stable (MSS), have poor intratumoral CD8⁺ T cell infiltration, and no clinical response to immunotherapy checkpoint inhibitors. Preclinical studies suggest that chemotherapy may synergize with anti-PD-1. In non-small cell lung cancer (NSCLC), the combination of pembrolizumab (PemB), pemetrexed (PemT), + carboplatin demonstrated synergistic activity. This study will combine PemB with PemT, then that combination + oxaliplatin (Ox). The rationale for addition of Ox to PemT is that enhanced immunogenic cell death may induce CD8⁺ T cell infiltration into CRC tumors and model the mechanism of cytotoxicity seen in NSCLC. Thus, the combination of PemB+ PemT + Ox may induce synergistic antitumor immune activity. Methods: This multi-center phase Ib trial is actively enrolling pts with incurable mCRC with prior treatment for mCRC including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and if RAS wild-type, anti-EGFR therapy. Measurable disease by imaging (RECIST 1.1) is required. Standard ineligibility includes active infections, systemic steroid use, or other conditions contraindicating immunotherapy. Cohort 1 will receive PemB + PemT; Cohort 2 will receive PemB + PemT + dose-escalated Ox. Imaging will be performed every 6 wks. The primary aim of Cohort 1: to evaluate for safety and efficacy using doses of PemB and PemT that have been studied in NSCLC. The primary aim of Cohort 2: to evaluate the safety, tolerability, and efficacy of PemB in combination with PemT + Ox. The RP2D of the 3-drug combination will be at the MTD taking into account toxicity profiles of study therapy agents. Secondary aims: to evaluate the clinical benefit rate of the doublet and triplet combinations in pts with chemo-refractory MSS mCRC and to estimate progression-free survival and overall survival in pts with MSS mCRC treated with these combinations. The cohorts will be analyzed separately with descriptive intent only. Maximum enrollment is 33 pts. Support: Merck; Lilly; NSABP Foundation, Inc. Clinical trial information: NCT03626922