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Original Investigation
October 22, 2020

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

Author Affiliations
  • 1Mayo Clinic Cancer Center, Phoenix, Arizona
  • 2Mayo Clinic Cancer Center, Rochester, Minnesota
  • 3Dow University of Health Sciences, Karachi, Pakistan
  • 4Department of Internal Medicine, Mayo Clinic, Arizona
  • 5Piedmont Athens Regional Hospital, Athens, Georgia
  • 6Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota
  • 7Mayo Clinic Alix School of Medicine, Scottsdale, Arizona
  • 8Mayo Clinic Libraries, Mayo Clinic, Phoenix, Arizona
  • 9Mayo Clinic Cancer Center, Mayo Clinic, Jacksonville, Florida
JAMA Oncol. 2020;6(12):e204930. doi:10.1001/jamaoncol.2020.4930
Key Points

Question  What is the most effective systemic treatment option in advanced hepatocellular carcinoma (HCC)?

Findings  In this network meta-analysis of 14 relevant phase 3 clinical trials, the combination of atezolizumab and bevacizumab was associated with superior results compared with other first-line agents including sorafenib and lenvatinib. In the refractory setting, both regorafenib and cabozantinib ranked highest compared with other agents including ramucirumab and pembrolizumab.

Meaning  The treatment landscape of advanced HCC is changing with the combination atezolizumab and bevacizumab now considered the standard of care in the first-line setting; regorafenib and cabozantinib are the preferred options in refractory patients.


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.

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