A Systematic Review and Network Meta-Analysis of Second-Line Therapy in Hepatocellular Carcinoma

Background: In patients with advanced hepatocellular carcinoma (HCC) following sorafenib failure, it is unclear which treatment is most efficacious, as treatments in the second-line setting have not been directly compared and no standard therapy exists. This systematic review and network meta-analysis (NMA) aimed to compare the clinical benefits and toxicities of these treatments. Methods: A systematic review of randomized controlled trials (RCTs) was conducted to identify phase iii RCTs in advanced HCC following sorafenib failure. Baseline characteristics and outcomes of placebo were examined for heterogeneity. Primary outcomes of interest were extracted for results, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), grade 3/4 toxicities, and subgroups. An nma was conducted to compare both drugs through the intermediate placebo. Comparisons were expressed as hazard ratios (HRs) for os and PFS, and as risk difference (RD) for ORR and toxicities. Subgroup analyses for OS and PFS were also performed. Results: Two RCTs were identified (1280 patients) and compared through an indirect network; CELESTIAL (cabozantinib vs. placebo) and RESORCE (regorafenib vs. placebo). Baseline characteristics of patients in both trials were similar. Both trials also had similar placebo outcomes. Cabozantinib, compared with regorafenib, showed similar os [hazard ratio (HR): 1.21; 95% confidence interval (CI): 0.90 to 1.62], pfs (HR: 1.02; 95% ci: 0.78 to 1.34) and ORR (−3.0%; 95% ci: −7.6% to 1.7%). Both treatments showed similar toxicities, but there were marginally higher risks of grade 3/4 hand–foot syndrome (5%; 95% ci: 0.1% to 9.8%), diarrhea (4.8%; 95% ci: 1.1% to 8.5%), and anorexia (4.4%; 95% ci: 0.8% to 8.0%) for cabozantinib. Subgroup results for os and pfs were consistent with overall results. Conclusions: Overall, this nma determined that cabozantinib and regorafenib have similar clinical benefits and toxicities for second-line HCC.