Efficacy of Hepatic Artery Infusion Chemotherapy Combined With Regorafenib and Sintilimab Versus Regorafenib Alone in <scp>MSS</scp> / <scp>pMMR</scp> Colorectal Cancer Liver Metastases After Second‐Line Treatment Failure

BACKGROUND: Microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer liver metastases (CRCLM) have limited treatment options after failure of second-line systemic therapies. Hepatic artery infusion chemotherapy (HAIC) combined with targeted therapy and immunotherapy may offer improved outcomes. METHODS: This retrospective single-center study compared the efficacy and safety of HAIC (oxaliplatin, 5-fluorouracil, leucovorin) combined with regorafenib and sintilimab (HAIC-R-S) versus regorafenib monotherapy in MSS/pMMR CRCLM patients refractory to ≥ 2 lines of systemic therapy. Propensity score matching was used to balance baseline characteristics, resulting in 45 matched pairs (n = 90). Survival outcomes, tumor response, and adverse events (AEs) were analyzed. RESULTS: The HAIC-R-S group showed significantly improved median progression-free survival (PFS) (6.5 vs. 3.4 months; p < 0.001) and overall survival (OS) (14.1 vs. 8.1 months; p < 0.001) compared to regorafenib alone. Objective response rate (ORR) (37.8% vs. 2.2%; p < 0.001) and disease control rate (71.1% vs. 42.2%; p = 0.006) were also superior. Grade ≥ 3 AEs were more frequent in the combination group (26.7% vs. 13.3%), primarily hematologic toxicities. CONCLUSION: In this retrospective, hypothesis-generating study, HAIC (oxaliplatin, 5-fluorouracil, leucovorin) combined with regorafenib and sintilimab showed improved PFS, OS, and ORRs compared with regorafenib monotherapy in refractory MSS/pMMR CRCLM, albeit with increased hematologic toxicity. These findings require validation in prospective, multicenter randomized trials before clinical implementation.