Sintilimab in combination with cetuximab and chemotherapy as first-line treatment for microsatellite stable/pMMR and RAS/BRAF wild-type metastatic colorectal cancer (CALLIOPSIS): An open-label, non-comparative, phase Ib/II dose escalation and expansion trial.

e15537 Background: Immunotherapy offers limited therapeutic benefit in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Priorstudies indicate that anti- epidermal growth factor receptor (EGFR) antibody combined with chemotherapy might enhance malignant tumor immunogenicity. This study aims to evaluate the safety and efficacy of Sintilimab, a PD-1 inhibitor, combined with Cetuximab and chemotherapy, as a first-line treatment for pMMR/MSS and RAS/BRAF wild-type mCRC. Methods: A phase Ib/II dose escalation and expansion trial was conducted. Patients received 6 cycles of Sintilimab 200mg ivgtt q3w, cetuximab and chemotherapy q2w for at least 8 cycles, followed by maintenance therapy with capecitabine ±cetuximab for those whose best response is complete response (CR), partial response (PR) or stabel disease (SD) until disease progression or intolerable toxicity. Primary endpoints included safety and objective response rate (ORR). In the dose escalation phase (3+3 design), patients received cetuximab (500 mg/m², Q2W) and investigator-chosen chemotherapy regimens (mFOLFOX6, CAPEOX), with Sintilimab tested at 100 mg, 150 mg, and 200 mg (Q3W). The recommended phase II dose was 200 mg Q3W. Results: Between December 26, 2023, and December 31, 2025, 25 eligible patients were enrolled (72.0% male, 16.0% ECOG PS 0, median age 54 years， 60 % liver metastasis, 48% peritoneal metastasis, 24% PD-L1 CPS≥5 ). In the dose escalation phase, 88.9% of patients experienced grade 3/4 treatment-related adverse events, with 55.6% requiring dose adjustments for chemotherapy-related issues. No immune-related grade 3/4 adverse events were observed. The overall ORR was 76.0%, with 68.4% for the 200 mg Sintilimab cohort. The median progression-free survival (PFS) was not reached. Surgical resection was feasible in 10 patients (40.0%, 1 planned ,9 R0 resection, including 1 ypT0N0). Treatment was well tolerated, with 72.0% of patients experiencing ≥ grade 3 adverse events, most commonly neutropenia (36.0%), rash (8.0%). Conclusions: The combination of Sintilimab with cetuximab and chemotherapy shows manageable safety and efficacy in advanced pMMR/MSS and RAS/BRAF wild-type mCRC. The overall ORR was 76.0%% and 40.0% of patients achieved surgical resectability. Further clinical data are needed to confirm these findings. Clinical trial information: NCT06776757 . Treatment outcomes and surgical conversion outcomes. Therapeutic outcome N=25(%) ORR (Objective response rate) 19(76) DCR (Disease Control Rate) 25(100) SCR (Surgical conversion rate) 8(32) Surgical outcome N=9(%) Complete resection rate R0 9(100) R1 0(0) R2 0(0) Tumor regression grade TRG1 3(34) TRG2 2(22) TRG3 3(33) TRG4 1(11)