Electroacupuncture combined with fruquintinib and sintilimab in microsatellite-stable metastatic colorectal cancer: A phase II study.

Microsatellite-stable metastatic colorectal cancer (MSS-mCRC) is generally unresponsive to immune checkpoint inhibitors (ICIs). Combining vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) with ICIs improves outcomes but often causes severe toxicities. Our previous preclinical work demonstrated that electroacupuncture (EA) potentiates anti-PD-1 therapy in MSS-CRC models by reprogramming the immunosuppressive microenvironment. Based on this rationale, we conducted a phase II trial to evaluate whether integrating EA with fruquintinib (a potent, selective small molecule inhibitor of VEGFR 1, 2, and 3) and sintilimab (a monoclonal antibody against PD-1) could improve tolerability and efficacy in MSS-mCRC. In this single-arm, investigator-initiated study, patients with histologically confirmed MSS-mCRC who had progressed through at least two prior regimens received 21-day cycles of EA (day 1-7), intravenous sintilimab (200 mg, day 8), and oral fruquintinib (5 mg/day, day 8-21). The primary endpoint was investigator-assessed objective response rate (ORR). From May 2024 to May 2025, 31 patients were enrolled and 28 were efficacy-evaluable. ORR was 21.4% [95% confidence interval (CI), 10.2-39.5] and DCR was 92.9% (95% CI, 77.4-98.0). Median PFS was 6.1 months (95% CI, 4.8-9.9) and median OS was 12.4 months (95% CI, 11.0-NA). TRAEs occurred in 80.6% of patients, with grade ≥3 in 29.0%, lower than rates reported for historical TKI-ICI combinations. No EA-related toxicity was observed. Overall, EA plus fruquintinib and sintilimab was feasible and showed an acceptable safety profile while maintaining antitumor activity in MSS-mCRC, warranting further evaluation in larger randomized trials.