Abstract
BackgroundIn 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.MethodsUnivariable 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.ResultsUnivariable 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.ConclusionsCovariate 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 registrationTrial number: NCT01761266 (Submitted January 2, 2013).
Highlights
In the Phase 3 REFLECT trial in patients with unresectable hepatocellular carcinoma, the multitargeted tyrosine kinase inhibitor, lenvatinib, was noninferior to sorafenib in the primary outcome of overall survival
Superiority for lenvatinib in terms of overall survival cannot be shown based on the primary efficacy analysis, there are a number of reasons why lenvatinib may be superior to the standardof-care treatment, sorafenib
The baseline characteristics for REFLECT, which were considered by the clinical authors to have potential prognostic importance, are presented in Table 1 for the sorafenib and lenvatinib treatment groups
Summary
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. 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. 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. In a Phase 3 trial (REFLECT) in patients with unresectable hepatocellular carcinoma (uHCC), the multitargeted tyrosine kinase inhibitor, lenvatinib, was shown to be noninferior to the standard-of-care treatment, sorafenib, in terms of the primary outcome of overall survival.[1] The study reported that the median overall survival was longer for lenvatinib (13.6 months) compared to 12.3 months for sorafenib, but this difference was not statistically significant. There was a greater number of post-treatment therapies used after sorafenib compared with lenvatinib, leading the authors of the original study to speculate that: “If post-progression survival is prolonged by...post-study treatments, this could lead to a dilution of the observed overall survival treatment benefit”.1
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