Efficacy and Safety of HAIC Plus Regorafenib and Icaritin in Advanced Hepatocellular Carcinoma After First-Line Lenvatinib Failure: A Retrospective Analysis.

INTRODUCTION

We evaluated the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with regorafenib and icaritin in patients with advanced hepatocellular carcinoma (HCC) progressing after first-line lenvatinib therapy, based on retrospective observational data, with the goal of proposing a novel second-line strategy to improve survival outcomes.

MATERIALS AND

METHODS

A retrospective analysis included 79 advanced HCC patients treated at Union Hospital between January 2022 and October 2023, all with confirmed progression after first-line lenvatinib. Participants were divided into two groups: HAIC + regorafenib + icaritin (n=38) and regorafenib monotherapy (n=41). Primary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS). Secondary endpoints covered changes in blood biomarkers and treatment-related adverse events (AEs).

RESULTS

The triple-therapy group demonstrated superior ORR (44.7% vs. 19.5%, P<0.05) and DCR (73.7% vs. 48.8%, P<0.05) compared to monotherapy. Median PFS (6.7 vs. 3.9 months, P<0.05) and median OS (12.4 vs. 9.2 months, P<0.05) were significantly prolonged with combination therapy. Although all-grade abdominal pain, fever, and vomiting were more frequent in the triple-therapy group (P<0.05), the incidence of grade 3/4 AEs did not differ significantly between groups. Notably, all-grade fatigue was less common in the combination group (P<0.05).

DISCUSSION: The survival benefit with triplet therapy likely reflects complementary mechanisms: HAIC delivers high intratumoral drug concentrations, thereby bypassing local resistance; regorafenib blocks bypass signaling pathways upregulated after lenvatinib failure; and icaritin reduces fatigue through immunomodulation. While safety is manageable, the retrospective design limits causal inference, highlighting the need for prospective validation.

CONCLUSION

HAIC combined with regorafenib and icaritin shows enhanced efficacy and manageable toxicity in lenvatinib-refractory advanced HCC, with improved physical tolerance evidenced by reduced fatigue. The observed benefits of this triplet regimen warrant further prospective validation as a potential personalized secondline approach for Barcelona Clinic Liver Cancer stage C (BCLC-C) patients, pending confirmation in randomized controlled trials.