Efficacy and Safety of Regorafenib with or without Immune Checkpoint Inhibitors as Second-Line Treatment for Advanced Hepatocellular Carcinoma: A Systematic Review and Arm-Level Synthesis of Real-World Comparative Cohorts.

Background: Regorafenib is a standard second-line therapy for advanced hepatocellular carcinoma (HCC), but its efficacy as a monotherapy is limited. Combining regorafenib with immune checkpoint inhibitors (ICIs) may enhance antitumor activity through synergistic modulation of the tumor microenvironment. This study synthesizes real-world evidence from comparative cohorts by summarizing arm-level efficacy and safety outcomes reported for regorafenib plus ICIs and for regorafenib monotherapy. Methods: A systematic search of PubMed, Embase, The Cochrane Library, and Web of Science was conducted up to January 10, 2026, to identify comparative real-world studies. Outcomes were synthesized primarily at the arm level: ORR was pooled as a single-arm proportion, and mPFS/mOS were summarized using reported medians. Random-effects models and exploratory meta-regression were used to examine differences in pooled arm-level summaries across cohort types rather than within-study head-to-head comparative effect estimates. Results: Six studies involving 921 patients were included. Because adjusted within-study comparative estimates were inconsistently reported, findings should be interpreted as non-comparative arm-level summaries. In arm-level pooling, cohorts receiving regorafenib plus ICIs had a higher pooled ORR (0.28, 95% CI: 0.23-0.32) than cohorts receiving regorafenib monotherapy (0.10, 95% CI: 0.06-0.14). The pooled mPFS summary was longer in the combination cohorts (7.34 months; 95% CI: 6.09-8.59) than in the monotherapy cohorts (3.97 months; 95% CI: 3.16-4.77). The pooled mOS summary was numerically longer with the combination (16.87 months) versus monotherapy (11.07 months). The incidence of grade ≥3 adverse events was broadly similar between cohort types. Conclusion: In this arm-level synthesis of real-world comparative cohorts, regorafenib plus ICIs was associated with numerically higher pooled response and longer pooled mPFS summaries than regorafenib monotherapy, while severe adverse event incidence appeared broadly similar across cohort types. Because these results are based on non-comparative pooled arm-level estimates and heterogeneous observational cohorts, they should be considered hypothesis-generating rather than definitive evidence of superiority. Prospective comparative trials and well-adjusted real-world analyses are needed to clarify comparative effectiveness and identify patients most likely to benefit. Registration: PROSPERO CRD 420261290236.