Sintilimab in combination with cetuximab and chemotherapy as first-line treatment for RAS/BRAF wild-type advanced colorectal cancer (CALLIOPSIS): An open-label, non-comparative, phase 1b/2 dose escalation and expansion trial.

Abstract

e15531 Background: Immunotherapy offers limited therapeutic benefit in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Mechanistic studies indicate that adding epidermal growth factor receptor (EGFR) antibodies to chemotherapy may enhance immune responses. This study aims to evaluate the safety and efficacy of Sintilimab, combined with Cetuximab and chemotherapy, as a first-line treatment for pMMR/MSS and RAS/BRAF wild-type mCRC. Methods: We conducted a phase 1b/2, open-label, uncontrolled dose-escalation and expansion trial evaluating six cycles of Sintilimab combined with Cetuximab and chemotherapy, followed by maintenance therapy with Cetuximab and chemotherapy until disease progression or intolerable toxicity. The primary endpoints were safety and objective response rate (ORR). In the dose-escalation phase (3+3 design), patients received Cetuximab (500 mg/m², Q2W) with investigator-chosen chemotherapy regimens (mFOLFOX6, CAPEOX). Sintilimab was administered at three doses (100 mg, 150 mg, 200 mg; Q3W), with 200 mg Q3W determined as the recommended dose for the expansion phase. In the dose expansion phase, patients received 200 mg Q3W of Sintilimab alongside the same cetuximab and chemotherapy regimens. Results: Between December 26, 2023, and January 4, 2025, 15 eligible patients (67% male, 20% ECOG PS 0, median age 54 years) were enrolled. 9 patients participated in the dose escalation phase, and 6 in the dose expansion phase. In the dose escalation phase, 8 patients (88.9%) experienced Grade 3/4 treatment-related adverse events, with 5 patients (55.6%) requiring dose modifications due to chemotherapy-related issues but no immune-related Grade 3/4 adverse events were observed, and the maximum tolerated dose of Sintilimab was not reached. The overall ORR in the study was 86.7%, with the Sintilimab 200 mg dose group showing an ORR of 77.8%. Of these, 6 patients (40%) became eligible for surgical resection (5 patients of R0 resection, including one with ypT0N0, one patient declined surgery and opted for further observation). Conclusions: The combination of sintilimab and cetuximab demonstrated manageable safety and efficacy in advanced pMMR/MSS and RAS/BRAF wild-type mCRC, with 40% of patients achieving conversion to surgical resection. However, additional clinical data are required to validate these findings. Clinical trial information: NCT06776757 . The therapeutic and surgical outcomes. Therapeutic outcome n=15 ORR (Objective response rate) 13(86.7%) DCR (Disease Control Rate) 15(100%) SCR (Surgical conversion rate) 6(40%) Surgical outcome N=5 Complete resection rate R0 5(100%) R1 0(0%) R2 0(0%) Tumor regression grade TRG1 2(40%) TRG2 1(20%) TRG3 1(20%) TRG4 1(20%)