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

Briggs, A. , Daniele, B., Dick, K., Evans, T. R. J. , Galle, P. R., Hubner, R. A., Lopez, C., Siebert, U. and Tremblay, G. (2020) Covariate-adjusted analysis of the Phase 3 REFLECT study of lenvatinib versus sorafenib in the treatment of unresectable hepatocellular carcinoma. British Journal of Cancer, 122(12), pp. 1754-1759. (doi: 10.1038/s41416-020-0817-7) (PMID:32265508) (PMCID:PMC7283323)

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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).

Item Type:Articles
Additional Information:This study was funded by Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corporation, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Evans, Professor Jeff and Briggs, Professor Andrew
Authors: Briggs, A., Daniele, B., Dick, K., Evans, T. R. J., Galle, P. R., Hubner, R. A., Lopez, C., Siebert, U., and Tremblay, G.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Health Economics and Health Technology Assessment
Journal Name:British Journal of Cancer
Publisher:Springer Nature
ISSN:0007-0920
ISSN (Online):1532-1827
Published Online:08 April 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in British Journal of Cancer 122(12): 1754-1759
Publisher Policy:Reproduced under a Creative Commons License

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