Systemic Therapy and Sequencing Options in Advanced Hepatocellular Carcinoma: A Systematic Review and Network Meta-analysis

JAMA Oncol. 2020 Dec 1;6(12):e204930. doi: 10.1001/jamaoncol.2020.4930. Epub 2020 Dec 10.


Importance: The treatment landscape for advanced hepatocellular carcinoma (HCC) has recently changed and become relatively confusing. Head-to-head comparisons between most of the available agents have not been performed and are less likely to be examined in a prospective fashion in the future. Therefore, a network meta-analysis (NMA) is helpful to compare different agents from across different trials.

Objective: To evaluate comparative effectiveness of different systemic treatments in advanced patients with HCC across lines of therapy.

Data sources: We searched various databases for abstracts and full-text articles published from database inception through March 2020.

Study selection: We included phase 3 trials evaluating different vascular endothelial growth factor inhibitors (VEGFis), checkpoint inhibitors (CPIs), or their combinations in advanced HCC, in the first-line or refractory setting.

Data extraction and synthesis: The reporting of this systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. The overall effect was pooled using the random effects model.

Main outcomes and measures: Outcomes of interest included overall (OS) and progression-free survival (PFS).

Findings: Fourteen trials (8 in the first-line setting and 6 in the second-line setting) at low risk of bias were included. The 8 trials in the first-line setting encompassed a total of 6290 patients, with an age range of 18 to 89 years. The 5 trials included in the second-line analysis encompassed a total of 2653 patients, with an age range of 18 to 91 years. Network meta-analysis showed the combination of atezolizumab and bevacizumab was superior in patients with HCC treated in the first-line setting compared with lenvatinib (HR, 0.63; 95% CI, 0.44-0.89), sorafenib (HR, 0.58; 95% CI, 0.42-0.80), and nivolumab (HR, 0.68; 95% CI, 0.48-0.98). In the refractory setting, NMA showed that all studied drugs had PFS benefit compared with placebo. However, this only translated into OS benefit with regorafenib (HR, 0.62; 95% CI, 0.51-0.75) and cabozantinib (HR, 0.76; 95% CI, 0.63-0.92) compared with placebo. In the NMA of patients with α-fetoprotein (AFP) levels of 400 ng/mL or greater, regorafenib, cabozantinib, and ramucirumab showed PFS and OS benefit compared with placebo with no superiority of an active drug compared with any others.

Conclusions and relevance: This systematic review and NMA of 14 trials found that atezolizumab and bevacizumab in combination is now considered the standard of care in the first-line setting in patients with advanced HCC. Regorafenib and cabozantinib are preferred options in refractory patients, with ramucirumab as an additional option in those with levels of AFP of 400 ng/mL or higher. Future trials should focus on other potential combinations and best treatment strategy in patients with prior VEGFi/CPI exposure.

Publication types

  • Comparative Study
  • Systematic Review

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / economics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / pathology
  • Clinical Trials, Phase III as Topic
  • Female
  • Humans
  • Immune Checkpoint Inhibitors / economics
  • Immune Checkpoint Inhibitors / therapeutic use*
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / pathology
  • Male
  • Middle Aged
  • Network Meta-Analysis
  • Protein Kinase Inhibitors / economics
  • Protein Kinase Inhibitors / therapeutic use*
  • Randomized Controlled Trials as Topic
  • Survival Analysis
  • Treatment Outcome
  • Young Adult


  • Immune Checkpoint Inhibitors
  • Protein Kinase Inhibitors