Introduction: The effectiveness and tolerability of triple therapy, which combines regorafenib, a programmed death 1 (PD-1) inhibitor, and transarterial chemoembolization (TACE), were compared to dual therapy consisting of regorafenib and a PD-1 inhibitor in patients with advanced hepatocellular carcinoma (HCC). Methods: A retrospective analysis was conducted on patients with advanced HCC who underwent second-line therapy from March 2019 to June 2022 at multiple centers. Patients were stratified into two groups: dual therapy (comprising regorafenib and a PD-1 inhibitor) and triple therapy (consisting of regorafenib, a PD-1 inhibitor, and TACE). Propensity score matching (PSM) was used to control for potential confounding variables. Results: After PSM, 112 eligible patients were included, with 56 in the triple therapy group and 56 in the dual therapy group. Median overall survival (OS) was significantly longer in the triple therapy group (15.4 vs. 8.9 months, p < 0.001), as was median progression-free survival (6.8 vs. 3.3 months, p < 0.001). The objective response rate (37.5% vs. 5.4%, p < 0.001) and disease control rate (73.2% vs. 44.6%, p = 0.002) were significantly higher in the triple therapy group compared to the dual therapy group. The incidence and severity of adverse events were similar between the two groups. Conclusion: Triple therapy demonstrated superior survival benefits compared to dual therapy in patients with advanced HCC. Additionally, the safety profiles of the two treatment regimens were comparable.

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