A phase 2 study of fruquintinib combined with sintilimab and chidamide in refractory MSS metastatic colorectal cancer: Preliminary efficacy and safety.

Abstract

2631 Background: Microsatellite stable (MSS) metastatic colorectal cancer (mCRC) has limited response to immune checkpoint inhibitors. Preliminary evidence from preclinical studies and the CAPability-01 trial suggest that combining anti-angiogenic therapy with epigenetic drugs such as histone deacetylase inhibitors can favorably remodel the tumor immune microenvironment and enhance the efficacy of PD-1 immune checkpoint blockade for advanced MSS-type mCRC. This study evaluates the efficacy and safety of the triple combination of fruquintinib, sintilimab, and chidamidein patients with refractory MSS mCRC. Methods: This is a single-arm, open-label phase 2 study. Eligible patients had histologically confirmed MSS-type mCRC, disease progression after ≥2 prior lines of therapy, ≥1 measurable lesion (RECIST v1.1), and ECOG 0–1. Patients received fruquintinib (5 mg orally on days 1–14, Q3w), sintilimab (200 mg IV on day 1, Q3w), and chidamide (30 mg orally twice weekly). The primary endpoint was mPFS. Secondary endpoints included ORR, DCR, mOS, DOR and safety. Tumor assessments were performed every 9 weeks. With a statistical hypothesis of improving the median PFS from 3.7 (historical control) to 6.0 m, a sample size of 46 patients was planned. Results: From January to December 2025, a total of 9 patients were enrolled. The median age was 60.0 years (39–72). All patients had MSS-type tumors, with a median of 2 prior lines of therapy (range: 2–4). Preliminary efficacy analysis showed that 4 patients achieved PR and 2 achieved SD, resulting in an ORR rate of 44.4% and a DCR rate of 66.7%. Given the limited sample size and relatively short follow-up of 9.1m at this preliminary analysis, mPFS and mOS were not yet reached. Treatment was generally tolerable. TRAEs of any grade occurred in all 9 patients. The most common TRAEs included hematological toxicities such as thrombocytopenia (66.7%), neutropenia (44.4%), and leukopenia (33.3%); hepatic laboratory abnormalities including elevated ALT 33.3%), and elevated AST (33.3%); as well as proteinuria (66.7%), hyperlipidemia (55.6%), increased blood creatine kinase (55.6%), and fatigue (1/9 with Grade 3). Grade ≥3 TRAEs were observed in 5 patients (55.6%), including Grade 3 neutropenia (2 patients), fatigue (1 patient), cutaneous adverse reactions (1 patient), and cholecystitis (1 patient). No treatment-related deaths occurred. Conclusions: Preliminary results indicate that the triple therapy of fruquintinib, sintilimab, and chidamide demonstrates promising response rate, disease control and a manageable safety profile in patients with refractory MSS-type mCRC. This combination strategy represents a potential therapeutic option for this population, who currently have limited treatments available. Further follow-up with a larger sample size and longer duration is needed to confirm its survival benefit. Clinical trial information: NCT06979908 .