Efficacy of regorafenib in the treatment of advanced hepatocellular carcinoma: A systematic review and meta-analysis

Abstract

BACKGROUND

Regorafenib is approved as a second-line treatment for advanced hepatocellular carcinoma (HCC), but its comparative efficacy remains under evaluation.

AIM

To evaluate the efficacy and safety of regorafenib vs other second-line therapies in advanced HCC.

METHODS

This systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. A comprehensive search of PubMed, EMBASE, Web of Science, and the Cochrane Library was performed on June 6, 2025. Studies were included if they reported at least one relevant clinical outcome: Overall survival, progression-free survival, objective response rate, or disease control rate. Data was extracted independently by two reviewers. Quality was assessed using the Cochrane Risk of Bias 2.0 tool for randomized controlled trials and the Newcastle-Ottawa Scale for cohort studies. Pooled effect estimates were calculated using random- or fixed-effects models depending on the degree of heterogeneity. Sensitivity analyses and Egger’s test were performed to evaluate the robustness of the results and potential publication bias.

RESULTS

Nine studies met inclusion criteria. Regorafenib significantly improved overall survival compared to controls [weighted mean difference = 2.54 months; 95% confidence interval (CI): 0.26-4.81; P < 0.05], but no significant benefit was observed for progression-free survival (weighted mean difference = 1.04; 95%CI: -1.27 to 3.36). The pooled objective response rate showed no overall difference, though regorafenib was inferior to nivolumab in subgroup analysis (odds ratio = 0.34; 95%CI: 0.20-0.58). Disease control rate did not differ significantly. No publication bias was detected.

CONCLUSION

Regorafenib offers a survival advantage in advanced HCC but does not significantly improve tumor response rates compared to alternative therapies.

Keywords: Regorafenib; Hepatocellular carcinoma; Second-line therapy; Overall survival; Meta-analysis

Core Tip: This study presents a comprehensive synthesis of current evidence regarding regorafenib’s clinical performance as a second-line treatment in patients with advanced hepatocellular carcinoma. Utilizing data from nine eligible studies, our meta-analysis provides an updated assessment of survival outcomes and tumor response metrics. Notably, regorafenib demonstrated a statistically significant improvement in overall survival compared to control groups, while objective tumor response rates did not show superiority, particularly when compared to immunotherapies such as nivolumab. Our results highlight regorafenib’s survival benefit and its role within a competitive therapeutic landscape.