Background: DNA mismatch repair defect (dMMR) colorectal cancer (CRC) cells are highly immunogenic. Preclinical data showed that oxaliplatin-containing chemotherapy in combination with anti-VEGF enhances the antitumor activity of programmed cell death-1 (PD-1) pathway blockade in murine CRC models. Prior phase I study showed that mFOLFOX6/bevacizumab (bev) plus atezolizumab was well tolerated and enhanced intratumoral infiltration of CD8⁺ T cells. We hypothesize that the dMMR subset of CRC may be effectively targeted with the combination of PD-1 pathway blockade and mFOLFOX6/bev to promote tumor regression. Methods: This is a prospective randomized phase III open-label trial. Patients (pts) (N=347) with metastatic dMMR CRC will be randomized to 3 trial arms (1:1:1): mFOLFOX6/bev; atezolizumab monotherapy; or mFOLFOX6/bev plus atezolizumab. Stratification factors include BRAF status, metastatic site, and prior adjuvant therapy for CRC. Primary objective is to evaluate the efficacy of mFOLFOX6/bev/atezolizumab and atezolizumab monotherapy as compared to mFOLFOX6/bev. Primary endpoint is progression-free survival (PFS) assessed by study investigator. Secondary endpoints include overall survival, objective response rate, safety profile, surgical conversion rate, disease control rate, duration of response, and PFS by retrospective central review. Exploratory objective includes health-related quality of life. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: Metastatic CRC without prior chemotherapy for metastatic disease; Tumor determined to be dMMR by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2); Availability of archived tumor tissue for central confirmation of dMMR status; and measurable disease per RECIST. Activated as of Nov 7, 2017, the 1st of the planned 347 pts has been enrolled. Clinical trial #: NCT02997228. SUPPORT: U10CA180868, -180822, UGICA189867, U24CA196067 Clinical trial information: NCT02997228