Optimal First- and Second-Line Treatment Regimens in Patients with Advanced Hepatocellular Carcinoma: A Systematic Review and Network Meta-Analysis

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.

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Comparison of systemic therapy efficacy in advanced hepatocellular carcinoma: Systematic review and frequentist network meta-analysis of randomized controlled trials.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.293 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 293-293

Author(s):

Robin Park ◽

Laércio Lopes da Silva ◽

Voravech Nissaisorakarn ◽

Ivy Riano ◽

Anwaar Saeed

Keyword(s):

Hepatocellular Carcinoma ◽

Systematic Review ◽

Meta Analysis ◽

Objective Response ◽

Indirect Comparison ◽

Advanced Hepatocellular Carcinoma ◽

Second Line ◽

First Line ◽

Line Setting ◽

Systemic Agents

293 Background: Several systemic agents are approved for use in the first line and second line treatment settings for advanced hepatocellular carcinoma (aHCC). However, choosing among available options in both first and second line settings remain difficult due to the paucity of head-to-head comparative trials. Therefore, we have conducted a systematic review and network meta-analysis for the indirect comparison of the systemic agents in the first line and second line settings. Methods: Published clinical trials that have evaluated systemic agents in the first line and second line settings in advanced HCC from inception to April 2020 were identified by searching PubMed, EMBASE, and Cochrane Databases and abstracts presented in the main annual ASCO and ESMO conferences from 2017 to 2020. Studies published in English providing clinical outcomes data including overall survival (OS), progression free survival (PFS) and objective response rate (ORR) were included in the analysis. The primary outcomes of interest were pooled hazard ratios (HR) of OS and OR of ORR in first line studies and HR of PFS and OR of ORR for second line studies. OS for second line agents were synthesized in a qualitative analysis. Results: Overall, 8,335 patients (13 studies) and 4,612 patients (11 studies) were analyzed in phase II/III trials for first line and second line settings respectively. In the first line setting, atezolizumab plus bevacizumab and lenvatinib were ranked highest as the regimens associated with the greatest OS (A+B, HR 0.58, 95% CI, 0.42-0.80; P-score 0.993) and ORR (lenva, OR 3.34, 95% CI, 2.17-5.14; P-score 0.080) respectively. In the second line setting, cabozantinib showed the highest probability of greatest PFS benefit (HR 0.44, 95% CI, 0.29-0.66; P-score 0.854) as well as the highest probability of greatest ORR benefit (cabo, OR 9.40, 95% CI, 1.25-70.83, P-score, 0.266). Conclusions: In the first line setting, atezolizumab plus bevacizumab may be the superior regimen whereas lenvatinib may be considered as the initial option when robust tumor responses are preferred. In the second line setting, cabozantinib may be the preferred option including in cases when robust tumor responses are favored.

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