Background: Most pts with mCRC have microsatellite stable (MSS) disease (95%) which is unresponsive to checkpoint inhibition. Chemotherapy activity is mediated through both cytotoxicity as well as immunological effects including reduced T-regulatory cell activity, enhanced tumor antigen presentation, and induced PD-L1 tumor cell expression. Chemotherapy with checkpoint inhibitors can potentially activate T cells and alter the microenvironment to improve outcomes. Our purpose was to evaluate pembro plus pem in a safety run-in (cohort 1) and the same with dose-escalated oxali (cohort 2). Methods: Eligible pts with MSS mCRC had ECOG PS of 0-1, measurable metastatic disease, adequate organ function, and prior treatment with fluoropyrimidine-, oxali-, and irinotecan-based therapies (plus an anti-EGFR agent, if apropos). Cohort 1 treatment was pem 500 mg/m² IV plus pembro 200 mg IV every 3 wks. Cohort 2 treatment was the same, plus oxali at an escalating dose of 85-120 mg/m² utilizing a 3+3 design with expansion of 6 additional pts at the RP2D. Imaging was performed every 3 cycles; response was determined by RECIST 1.1. Primary endpoint (EP) of each cohort: safety and best ORR with cohort 2 also to establish the RP2D. Secondary EPs: Clinical benefit rate (CBR), PFS, OS at 1 year, and exploratory assessments of circulating immunologic profiles and molecular predictors of response. Descriptive statistics were planned as a signal-seeking study. Results: From Jul 2019-Apr 2021, 34 pts enrolled from 4 different centers. In cohort 1 (n=15), one pt was taken off study due to LFT elevation and orchitis attributed to pembro with reduced lymphadenopathy upon withdrawal. There was 1 PR (duration 686 days) and 4 SDs (61, 66, 124, 128 days) among 11 evaluable for response. There were no unexpected nor grade 5 toxicities. In cohort 2 (n=19), 2 pts achieved a PR (127 and 185 days), with SDs in 5 (59, 63, 69, 115, 437), among 13 evaluable for response. At oxali dose of 85 mg/m², 1/6 pts had DLT (grade 4 neutropenia ≥7 days); another 1/6 pts had DLT at 120 mg/m² (grade 3 AST/ALT). The RP2D was 120 mg/m². Common grade 3/4 AEs included: neutropenia (24%), anemia (9%), fatigue (9%), abdominal pain (6%), nausea (6%), and ALT/AST (6%). There was no febrile neutropenia nor any grade 5 events. Combined cohort rates of PR/CBR were 3/24 (12.5%) and 12/24 (50%), respectively. Conclusions: In this study of heavily pretreated pts with MSS mCRC, combining pembro plus pem or pem+oxali was well tolerated. Overall CBR was 50%, with objective responses (PRs) in 3/24 (12.5%) evaluable pts. This compares favorably with KEYNOTE 016, in which pembro in MSS mCRC pts had 0/18 objective responses and CBR=11% (2/18). Further studies testing these agents in earlier lines of treatment with robust correlative analyses is supported. Support: NSABP Foundation; Merck; Lilly. Clinical trial information: NCT03626922.