Covariate-adjusted analysis of the Phase 3 REFLECT study of lenvatinib versus sorafenib in the treatment of unresectable hepatocellular carcinoma

Br J Cancer. 2020 Jun;122(12):1754-1759. doi: 10.1038/s41416-020-0817-7. Epub 2020 Apr 8.


Background: In the Phase 3 REFLECT trial in patients with unresectable hepatocellular carcinoma (uHCC), the multitargeted tyrosine kinase inhibitor, lenvatinib, was noninferior to sorafenib in the primary outcome of overall survival. Post-hoc review revealed imbalances in prognostic variables between treatment arms. Here, we re-analyse overall survival data from REFLECT to adjust for the imbalance in covariates.

Methods: Univariable and multivariable adjustments were undertaken for a candidate set of covariate values that a physician panel indicated could be prognostically associated with overall survival in uHCC. The values included baseline variables observed pre- and post-randomisation. Univariable analyses were based on a stratified Cox model. The multivariable analysis used a "forwards stepwise" Cox model.

Results: Univariable analysis identified alpha-fetoprotein (AFP) as the most influential variable. The chosen multivariable Cox model analysis resulted in an estimated adjusted hazard ratio for lenvatinib of 0.814 (95% CI: 0.699-0.948) when only baseline variables were included. Adjusting for post-randomisation treatment variables further increased the estimated superiority of lenvatinib.

Conclusions: Covariate adjustment of REFLECT suggests that the original noninferiority trial likely underestimated the true effect of lenvatinib on overall survival due to an imbalance in baseline prognostic covariates and the greater use of post-treatment therapies in the sorafenib arm.

Trial registration: Trial number: NCT01761266 (Submitted January 2, 2013).

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Hepatocellular / drug therapy*
  • Female
  • Humans
  • Liver Neoplasms / drug therapy*
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Phenylurea Compounds / therapeutic use*
  • Prognosis
  • Quinolines / therapeutic use*
  • Risk Factors
  • Sorafenib / therapeutic use*


  • Antineoplastic Agents
  • Phenylurea Compounds
  • Quinolines
  • Sorafenib
  • lenvatinib

Associated data