Background: Cabo is an anti-VEGFR2/MET/AXL drug with broad multi-kinase inhibitory spectrum. Preclinical and clinical studies in various solid tumors demonstrated favorable immune modulatory activity of Cabo with clinical synergy seen when combined with PD-1/ PD-L1 inhibitors like Durva. Upon completion of phase Ib gastrointestinal (GI) basket CAMILLA trial evaluating Cabo + Durva in 30 patients (pts) demonstrating favorable safety & efficacy, the trial was expanded to phase 2 multi-cohort, multi-center trial of 117 pts. Herein, we report results of the phase 2 CRC cohort, the first evaluation of cabo + IO in this population. Methods: Pts enrolled in this cohort were administered Cabo + Durva at the RP2D of 40mg QD and 1500mg IV Q4W respectively. Enrolled pts must have progressed on 2 or more lines of therapy. Primary outcome measure was investigator assessed overall response rate (ORR) and secondary outcomes were rate of treatment related adverse events (TRAE), investigator assessed disease control rate (DCR), progression free survival (PFS), and overall survival (OS). Subgroup analysis was done in pts with RAS wild type tumors. Exploratory analysis of pathogenic molecular tumor alterations using next generation sequencing (NGS) was done in pts who achieved confirmed partial response (PRc)/ stable disease (SD) > 6 months. Results: Of the 36 pts enrolled, 29 (16F, 13M) were evaluable for efficacy. Median age 57 years (27-76). 90% (26) had ECOG of 1. All had pMMR/MSS, 41% (12) had RAS wild type tumors, and 6.9% (2) had HER2 amplification. 52% (15) had received ≥ 3 lines of therapy. All had metastases at ≥ 3 sites and 79% (23) metastases in the liver. Among 36 pts evaluable for safety, treatment related serious adverse events (SAEs) occurred in 31% (11/36). Most common TRAEs were grade 1-2 fatigue (53%), nausea (42%), diarrhea (36%), anorexia (31%), hand-foot syndrome (22%), & hypertension (16%). Grade ≥ 3 immune-related adverse events (IRAE) occurred in 16.6% (6/36). Efficacy analysis revealed an ORR 27.6% (8/29); PRc 21% (6/29); DCR 86.2% (25/29); median DOR was not reached (NR); median PFS 4.4 months; 6-month PFS 28% & median OS 9.1 months. In the RAS wild type subgroup, ORR (PRc) was 50.0%; DCR 83.3%; median PFS 6.3 months and median OS was NR. Of the 7 pts who achieved PRc/SD > 6 months, one had KRAS G12V tumor mutation along with mutations in ARID1A & IDH1. Remaining pts had RAS wild type tumors & among those, the following NGS alterations were detected: 1 HER-2 amplification, 1 MET amplification, & 2 alterations in ATM. Conclusions: Cabo + Durva demonstrated promising efficacy and was fairly tolerated without new safety signals in heavily treated pMMR/MSS CRC pts. These encouraging results warrant further evaluation of this regimen in a randomized setting as salvage therapy in pMMR/MSS CRC. Clinical trial information: NCT03539822.