Comparative efficacy of novel combination strategies for unresectable hepatocellular carcinoma: A network metanalysis of phase III trials

Eur J Cancer. 2022 Oct:174:57-67. doi: 10.1016/j.ejca.2022.06.058. Epub 2022 Aug 12.

Abstract

Background: Dual programmed cell death-1 and vascular endothelial growth factor pathway inhibition is the novel standard of care for patients with unresectable hepatocellular carcinoma. Direct comparisons between first-line treatments are lacking.

Method: We conducted a literature search in MEDLINE (https://pubmed.ncbi.nlm.nih.gov), the Cochrane library (https://www.cochranelibrary.com) and Embase (www.embase.com) between January 2007 and February 2022. We included phase III randomised controlled trials that tested immune-checkpoint inhibitors or tyrosine kinase inhibitors, including sorafenib, lenvatinib and donafenib, and evaluated as primary end-point overall survival (OS) or progression-free survival (PFS). Studies testing loco-regional therapies were excluded. The primary end-point was to compare the efficacy of first-line options in terms of OS and PFS. We extracted Hazard ratios (HR) and 95% confidence intervals (95% CI) for OS and PFS and performed a frequentist network meta-analysis with fixed effect multivariable meta-regression models. The research protocol was registered in PROSPERO, an international prospective register of systematic reviews (registration code CRD42022312489).

Findings: Literature review yielded 13709 results, after duplicates removal and exclusion of not relevant studies, 70 papers were available for screening. After full-text review, 9 studies were eligible for analysis. Atezolizumab plus bevacizumab reduced the risk of death compared to placebo (HR 0·40; 95% CI 0·28-0·57), sorafenib (HR 0·58; 95% CI 0·42-0·80), lenvatinib (HR 0·63; 95% CI 0·44-0·89), atezolizumab plus cabozantinib (HR 0·64; 95% CI 0·43-0·97), nivolumab (HR 0·68; 95% CI 0·48-0·98) and donafenib (HR 0·69; 95% CI 0·48-0·99). Atezolizumab plus bevacizumab was not statistically superior to durvalumab plus tremelimumab (HR 0·74; 95% CI 0·52-1·06) and sintilimab plus IBI305 (HR 1·02; 95% CI 0·67-1·55) in reducing the risk of death. Efficacy was associated with a higher risk of grade 3 adverse events.

Keywords: CTLA-4; Clinical trials; Hepatocellular cancer; Immunotherapy; PD-1; Survival; VEGF.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / therapeutic use
  • Bevacizumab / therapeutic use
  • Carcinoma, Hepatocellular* / drug therapy
  • Clinical Trials, Phase III as Topic
  • Humans
  • Immune Checkpoint Inhibitors
  • Liver Neoplasms* / drug therapy
  • Nivolumab / therapeutic use
  • Phenylurea Compounds
  • Protein Kinase Inhibitors / therapeutic use
  • Quinolines
  • Sorafenib / therapeutic use
  • Systematic Reviews as Topic
  • Vascular Endothelial Growth Factor A

Substances

  • Antineoplastic Agents
  • Immune Checkpoint Inhibitors
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Quinolines
  • Vascular Endothelial Growth Factor A
  • Bevacizumab
  • Nivolumab
  • Sorafenib
  • lenvatinib