Regorafenib as Second-Line Versus Later-Line Therapy in Advanced Hepatocellular Carcinoma: A Multicenter Real-World Study with Exploratory Analysis of Prior Immune Checkpoint Inhibitor Exposure.

BACKGROUND: The therapeutic paradigm for advanced hepatocellular carcinoma has shifted with the global adoption of immune checkpoint inhibitor-based regimens, leading to the frequent use of multi-tyrosine kinase inhibitors in later treatment lines. OBJECTIVE: This study aimed to evaluate the real-world efficacy and safety of regorafenib as a later-line salvage therapy compared with its conventional second-line application within contemporary clinical practice. METHODS: This study included 255 patients with advanced hepatocellular carcinoma treated with regorafenib between 2017 and 2026. Clinical outcomes, including objective response rate, disease control rate, overall survival (OS), progression-free survival (PFS), and time to progression, were compared between patients receiving regorafenib as a second-line versus later-line therapy. RESULTS: Of the 255 enrolled patients, 209 received regorafenib as a second-line therapy and 46 as a later-line therapy. The mean maintained dose was significantly lower in the later-line group than in the second-line group. The overall objective response rate and disease control rate were 11.0% and 39.2%, with no significant differences between the second-line and later-line groups in the objective response rate or disease control rate. The median OS, PFS, and time to progression showed no significant difference between the second-line group and the later-line group. Within the later-line group, prior immune checkpoint inhibitor history was not significantly associated with OS or PFS. Discontinuation because of adverse events and liver dysfunction was more frequent in the later-line group than in the second-line group, whereas the rate due to cancer progression was lower. An association was observed between the development of hand-foot skin reaction (HFSR) and survival outcomes, with patients experiencing HFSR generally showing longer OS and PFS periods. Grade 3-4 HFSR was associated with the best outcomes for OS and PFS compared with the no HFSR group. On multivariate analysis, Child-Pugh class A, smaller tumor size, lower alpha-fetoprotein levels, and the absence of portal vein tumor thrombosis independently predicted longer OS. CONCLUSIONS: Regorafenib may remain a feasible salvage option in selected patients receiving later-line therapy, including those with prior immune checkpoint inhibitor exposure. Although the cumulative treatment burden leads to higher rates of toxicity-related discontinuation, observed OS and PFS did not differ significantly between treatment lines. However, the lack of significant differences in observed OS and PFS should be interpreted cautiously in the context of treatment-selection bias and small later-line subgroup size.