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

Abstract

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).

Conflict of interest statement

Sponsorship for the study and analysis were funded by Eisai Inc., and Merck Sharp & Dohme Corporation, a subsidiary of Merck & Co., Inc., and study results were not contingent on the sponsors’ approvals nor did they conduct any censorship of the manuscript. A.B. is a director and shareholder of Avalon Health Economics and received compensation from Eisai as a consultant for this work. He has also been contracted by Bayer, Merck, Janssen, Novartis, Sword Health, Amgen, and Daichii Sankyo and received compensation outside of the submitted work. B.D. reports no conflicts of interest regarding the work at hand but has received personal fees and non-financial support for consultation for Ispen, Sanofi, and Bayer, and personal fees from Eisai, Eli Lilly, Astra Zeneca, and Incyte outside of the submitted work. K.D. is an employee of Avalon Health Economics. T.R.J.E. has received honoraria for advisory boards and/or speaker’s fees from Eisai, Celgene, Bristol-Myers Squibb, Bayer, Roche, Merck (MSD), Nucana, Karus Therapeutics, Modulate Therapeutics (all payable to the employing institution), research funding for clinical trials from multiple pharmaceutical and biotechnology companies including Eisai (all payable to the employing institution), and support to attend international scientific conferences from Bristol-Myers Squibb, Merck, Eisai, Bayer, Roche, Pierre Fabre, and Celgene. He is co-editor of the clinical study section of the British Journal of Cancer (honorarium payable to the employing institution). P.R.G. has received compensation from Eisai for this work and for adboards and lectures from Bayer, AstraZeneca, BMS, MSD, Roche, Sirtex, Ispen, and Lilly outside of the submitted work. R.A.H. received consultancy fees from Eisai for this work. He has also received compensation from Roche and Ispen and attended conferences for both Roche and BMS outside of the submitted work. C.L. has been paid honoraria for consultancy on this work. He has also received compensation for work from Ispen, Bayer, BMS, and Astra Zeneca, and has participated in a speaker’s bureau for Eisai, Ispen, Bayer, and BMS. Further, he has received research funding from Eisai, Ispen, BMS, MSD, Astra Zeneca, and Roche. U.S. has received honorarium for participating in an advisory board of Eisai and reports no other conflicts of interest. G.T. reports no conflicts of interest regarding the submitted work.

Figures

Fig. 1. Forest plot of univariate impact of candidate covariates on lenvatinib treatment effect.

BCLC Barcelona Clinic Liver Cancer, ECOG PS Eastern Cooperative Oncology Group Performance Status, EHS extrahepatic spread, HBV hepatitis B virus, HCV hepatitis C virus, MPVI macroscopic portal vein invasion.