Background: RAS-mutant and microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients have an immunosuppressive microenvironment and show a low response rate to immunotherapy. Sintilimab plus bevacizumab and CapeOX (BBCAPX) has proved its efficacy and safety in above unresectable mCRC patients (Xuefeng Fang et al. ASCO 2022). Here, we report updated efficacy, safety, progression-free survival (PFS) data and biomarker analyses from this single arm, open-label, phase 2 trial (NCT05171660). Methods: RAS-mutant and MSS mCRC patients received sintilimab (200 mg, day 1) plus bevacizumab (7.5mg/kg, day 1) and oxaliplatin (135 mg/m², day 1) and capecitabine (1g/m², bid, day 1-14) of each 21-day cycle. Clinical response was assessed every 2 cycles via RECIST 1.1 criteria. Whole exome sequencing (WES) and 289 NanoString panel RNA sequencing was performed for tumor mutational burden, genomic alteration, immune microenvironment and other biomarker analysis. Results: 25 patients with unresectable metastases were enrolled after the assessment of CRC multidisciplinary team. 2 (8.0%) patients showed complete response (CR), 19 (76.0%) patients had a partial response (PR) and 4 (16.0%) had stable disease. Objective response rate (ORR) reached 84.0% and disease control rate was 100.0%. The median PFS was 18.2 months for the full analysis set. The most common treatment-related adverse events (TRAEs) in all grades were anemia (21/25, 84.0%), neutropenia (20/25, 80.0%) and hand-foot syndrome (14/25, 56.0%). The most frequent grade 3 or 4 TRAEs were neutropenia (3/25, 12.0%) and alanine transaminase increased (2/25, 8.0%). No grade 5 adverse events occurred. In biomarker exploration, after treatment, as compared with the baseline, the results of WES suggested 5 patients appeared TTN/OBSCN “double-hit” and copy number variants burden was significantly decreased in tumor tissues. Nanostring panel RNA sequencing analysis found that there was a better tumor immune microenvironment cell infiltration in CR/PR patients compared with non-CR/PR patients tumors as well as PFS-long group (＜12.5 months) compared with PFS-short group (≥12.5 months). Conclusions: Combination treatment of sintilimab plus bevacizumab and CapeOX as first-line treatment demonstrated a high ORR (84.0%) and a manageable safety profile in RAS-mutant, MSS unresectable mCRC. Exploratory biomarker assessment analysis showed some patients changed into “immune-hot” subtype after the treatment. We are launching a phase 3, randomized, open-label, multicentric clinical trial (NCT04194359) to further evaluate the effect, safety and prognostic biomarkers of this combination in RAS mutant, MSS mCRC patients when compared with that of bevacizumab and CapeOX. Clinical trial information: NCT05171660.