Background: PD-1 blockade is particularly ineffective in patients with microsatellite stable (MSS) or mismatch repair (MMR)-proficient colorectal cancer (CRC). Regorafenib (R) has been shown to modulate anti-tumor immunity by different mechanisms including reduction of tumor-associated macrophages (TAMs) and the immunosuppressive cells. Synergy between Regorafenib and anti–PD-1/PD-L1 antibodies has been shown in pre-clinical models, as well as in several clinical studies, compared with either treatment alone. The purpose of this study was to evaluate the activity of regorafenib in combination with immune checkpoint inhibitors. Methods: This is a single-arm, open-label, phase II trial assessing the efficacy and safety of Regorafenib (80mg QD 3weeks/4) + Sintilimab (S) (200mg every 3 weeks) combination in non MSI-H mCRC patients (pts). The primary endpoint was the overall survival (OS). Secondary endpoints included progression free survival (PFS), objective response rate (ORR), disease control rate (DCR) and Safety. Results: As of February 1, 2023, a total of 103 patients with mCRC were enrolled and received R+S. Median age was 57 (range, 28-75). Male 59.2%, ECOG PS 0/1/2 20.4%/66.0%/13.6%, left-sided colon/right-sided colon/rectum 39.8%/15.5%/44.7%, RAS mutant 42.7%. The ORR was 21.4% and DCR was 63.1%, with complete response (cCR) in 1 (1.0%), partial response (PR) in 21 (20.4%) and stable disease (SD) in 43 (41.7%) patients. With a median follow up of 19.9 months (range, 0.1-41.4), the median PFS was 4.0 months (95% CI, 3.1-4.4 months) and median OS was 13.0 months (95% CI, 12.0-16.5 months). The patients who achieved ORR have significantly longer PFS (20.8 vs. 3.2 months, p＜0.001) and OS (not reach vs. 12.0 months, p＜0.001) than the non-ORR patients. The median PFS were similar regardless the KRAS mutation status, primary sidedness, or liver metastases. Multivariate analysis revealed that male, ECOG PS2, the number of metastatic sites ≥2, and RAS mutant were significantly associated with worse OS. The most common grade 3/4 adverse events were hand-foot syndrome (1.9%), stomatitis (1.9%), rash (1.0%), hypertension (1.0%), allergic reaction (1.0%), fatigue (1.0%) and fever (1.0%). 8(7.8%) patients experienced at least 1 dose modification or treatment interruption. No death was related to the treatment. Conclusions: In this study the R+S combination as salvage-line treatments in non-MSI-H mCRC achieved a promising clinical benefit, with a manageable safety profile. Female, ECOG PS0/1, single metastases, RAS wild type mCRC were associated with better OS. Clinical trial information: NCT04745130.