1 Department of Health Services Research & Policy, London School of Hygiene and Tropical Medicine, 15-17 Tavistock Place, London, WC1H 9SH, UK. firstname.lastname@example.org.
2 Oncology Unit, Ospedale del Mare, Napoli, Italy.
3 Avalon Health Economics LLC, Morristown, NJ, USA.
4 University of Glasgow, Glasgow, UK.
5 Medical Department, University Medical Center Mainz, Mainz, Germany.
6 The Christie NHS Foundation Trust, Manchester, UK.
7 Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Cantabria, Spain.
8 Department of Public Health, Health Services Research and Health Technology Assessment, UMIT - University for Health Sciences, Medical Informatics, and Technology, Hall i.T., Hall in Tirol, Austria.
9 Department of Health Policy and Management, Harvard Chan School of Public Health and Dept of Radiology, Harvard Medical School, Boston, MA, USA.
10 Division of HTA, ONCOTYROL-Center for Personalized Cancer Medicine, Innsbruck, Austria.
11 Department of Health Economics and HTA, Purple Squirrel Economics, New York, NY, USA.
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).