Chidamide combined with serplulimab and regorafenib or fruquintinib as third-line therapy for advanced colorectal cancer (C-ooperate/SCOG-C001): A single-arm, exploratory, multicenter, phase 2 trial.

Abstract

e15583 Background: Despite established first- and second-line standards with chemotherapy plus anti-VEGF or anti-EGFR agents, third-line options remain limited in colorectal cancer (CRC). Subtype-selective histone deacetylase (HDAC) inhibition may enhance tumor immunogenicity, supporting synergy with PD-1 inhibition plus VEGF-pathway blockade. We therefore conducted a proof-of-concept, single-arm, phase II trial evaluating chidamide plus serplulimab with regorafenib or fruquintinib as third-line therapy for advanced CRC; preliminary findings are presented. Methods: This single-arm, phase Ⅱ study (ChiCTR2300077213) enrolled adults (≥18 years) with pathologically confirmed CRC, ECOG performance status 0-1, measurable disease per iRECIST, and progression after ≥2 lines of systemic therapy. Patients(pts) received chidamide 20 mg orally twice weekly and serplulimab 3 mg/kg intravenously every two weeks, combined with either regorafenib 120 mg or fruquintinib 5 mg orally once daily for three weeks followed by one week off. Treatment continued until disease progression, intolerable toxicity, withdrawal of consent, or up to 2 years. The primary endpoints were safety and objective response rate (ORR) determined by investigators. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), PFS and OS rates at 6- and 12-month, quality of life (QoL), and nutritional score PG-SGA. Results: As of Jan 6, 2026, thirty pts had been enrolled, with a median age of 62.0 years. Most pts had a left-sided primary tumor (86.7%), and all were pMMR/MSS. Liver metastases were present in 22 pts (73.3%) and lung metastases in 13 pts (43.3%). Previous treatment lines ranged from 2 to 4, with 33.3% pts having received more than third-line treatment before. The incidence of ≥3 grade adverse events was 53.3% (n = 16). A total of 26 patients were evaluable for efficacy analysis at a median follow-up of 11.9 months. The ORR was 11.5% (95% CI: 2.4-30.2%) and DCR was 42.3% (95% CI: 23.4-63.1%), including 3 pts achieved partial response and 8 achieved stable disease. The median PFS was 3.0 months (95% CI: 2.3-5.9), and the 6-month PFS rate was 20.5% (95% CI: 9.1-46.3%). The median OS was 7.7 months (95% CI: 5.5-NA), with a 6-month OS rate of 65.9% (95% CI: 49.2-88.4%). Conclusions: Preliminary results indicated that chidamide plus serplulimab with regorafenib or fruquintinib is a feasible and promising third-line treatment option for advanced CRC, alongside manageable toxicity. Clinical trial information: ChiCTR2300077213.