Sintilimab plus bevacizumab, oxaliplatin, and capecitabine as perioperative therapy in microsatellite-stable, resectable colorectal cancer liver metastases: An open-label, single-arm, phase II trial.

Abstract

3586 Background: Immunotherapy has revolutionized cancer treatment, yet its efficacy in proficient mismatch repair and/or microsatellite stable (pMMR/MSS) colorectal cancer liver metastases (CRLM) remains uncertain. Optimizing neoadjuvant regimens for such patients is crucial. Methods: A prospective, open-label, single-arm phase II clinical trial was conducted from June 2021 to January 2023. Patients with resectable pMMR/MSS CRLM were enrolled and received 4 cycles sintilimab combined with bevacizumab, oxaliplatin, and capecitabine preoperatively followed by 4 cycles oxaliplatin, and capecitabine postoperatively. The primary endpoints were safety and feasibility of neoadjuvant therapy and surgery. Secondary endpoints encompassed pathological response rates, objective response rate, progression-free survival (PFS), and overall survival (OS). Biomarker analyses were performed to identify potential predictors related to efficacy and prognosis. The study protocol was registered in ClinicalTrials.gov (NCT04940546). Results: Between June 2021 to January 2023, 36 patients were enrolled, and included in the safety analysis. The most common treatment-related adverse events (TRAEs) were fatigue (55.6%), peripheral neuritis (52.8%). Of the 36 patients, 30 received local treatment for liver metastases. 26 of them underwent CRLM surgery resection, and 7 of the 26 experienced surgery - related complications graded from 1-2 such as cholecystitis and pulmonary infection, one patient died from respiratory failure due to a pulmonary infection (immune pneumonia not excluded) a month after liver metastases resection. 34 were analyzed for efficacy. The objective response rate (ORR) was 67.6%, with a disease control rate (DCR) of 88.2%. 26 patients underwent surgery; the pathological complete response rate (pCR) was 11.5%, and the major pathological response rate (MPR) was 38.5%. After a median follow-up of 32.9 months, the median PFS was 14.2 months ( (95% CI: 11.6 - 29.0 months), and the median OS had not yet been reached. Biomarker analysis revealed that RAS wild-type (mPFS: 29.0 months (15.0 - NA) vs 11.5 months (9.8 - 15.7), log-rank P = 0.0087), SMAD4 wild-type population (mPFS: 20.2 months (12.3 - NA) vs 6.9 months (5.2 - NA), log-rank P < 0.0001) may benifit from immunotherapy combination treatment. The single cell RNA sequencing analysis revealed that higher intrafiltion of FIB_PLAG2A in the TME of CR/PR were associated with favorable prognosis, while higher intrafiltion of MPH_TREM2, FIB_POSTN in the TME of non CR/PR were linked to poor prognosis. Conclusions: The neoadjuvant regimen demonstrated acceptable safety and efficacy. RAS , SMAD4 wild-type patients may be a potential beneficiary population. Clinical trial information: NCT04940546 .