Effects of Subsequent Systemic Anticancer Medication Following First-Line Lenvatinib: A Post Hoc Responder Analysis from the Phase 3 REFLECT Study in Unresectable Hepatocellular Carcinoma

Abstract

Introduction: Understanding the relationship between subsequent-line therapies and overall survival (OS) is important for maximizing OS for patients with hepatocellular carcinoma.

Objective: In this post hoc analysis, we investigated OS in lenvatinib- and sorafenib-treated patients from the REFLECT study, who then received subsequent anticancer medication during the survival follow-up period.

Methods: The follow-up period commenced at the first off-treatment visit after stopping the study medication and continued until study termination, withdrawal of consent, or death. OS and objective response rate were calculated for patients who did or did not receive poststudy anticancer medication for both treatment arms, as well as for the overall cohort. We investigated the subset of patients who responded to first-line treatment and subsequently received anticancer medication.

Results: The OS for patients initially randomized to first-line lenvatinib (versus first-line sorafenib) and who then received any subsequent anticancer medication was 20.8 vs. 17.0 months (hazard ratio [HR] 0.87; 95% CI 0.67-1.14). The OS for patients who initially received first-line lenvatinib (versus first-line sorafenib) and who did not receive any subsequent anticancer medication was 11.5 vs. 9.1 months (HR 0.90; 95% CI 0.75-1.09). Responders to first-line lenvatinib who received subsequent medication had a median OS of 25.7 months (95% CI 18.5-34.6); responders to first line-sorafenib who received subsequent medication had a median OS of 22.3 months (95% CI 14.6-not evaluable).

Conclusions: In this post hoc analysis of all patients in the REFLECT study who received subsequent anticancer medication, OS was increased compared with patients who did not receive any subsequent anticancer medication. In a subset analysis of responders who had received subsequent anticancer medication, use of first-line lenvatinib led to a slightly longer median OS; more research is needed on the benefits of using first-line lenvatinib compared with sorafenib.

Keywords: Lenvatinib; Overall survival; Response status; Second-line treatment; Sorafenib.

Conflict of interest statement

A.A.: reports honoraria, consulting or advisory fees, and speakers' bureau fees from Eisai. M.K.: reports honoraria and consulting or advisory fees from Bayer AG and Eisai Co., Ltd.; honoraria from Bayer AG, Bristol-Myers Squibb, EA Pharma Co., Ltd., Eisai Co., Ltd., and Merck Sharp & Dohme; research funding from Bayer AG, Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Merck Sharp & Dohme, Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., and Taiho Pharmaceutical and is the Editor-in-Chief of Liver Cancer. A.V.: reports consulting or advisory fees from Novartis International, Delcath Systems, Eli Lilly and Company, Roche Holding AG, Amgen Inc., Bayer AG, and Baxalta; honoraria from Novartis International, Roche Holding AG, Bayer AG, Sanofi S.A., Amgen Inc., Delcath Systems, Eli Lilly and Company, Bristol-Myers Squibb, and Merck Sharp & Dohme; personal fees from Bayer AG, Roche Holding AG, and Ipsen Corporate; and research funding from Novartis International. A.-L.C.: reports consulting or advisory fees from Bristol-Myers Squibb, Ono Pharmaceutical Co., Ltd., Novartis International AG, Bayer AG, Merck Group, and Merck Sharp & Dohme; and is an associate editor of Liver Cancer. W.Y.T.: reports consulting or advisory fees and speakers' bureau fees from Bayer HealthCare Pharmaceuticals, Korea-Gilead Sciences, Inc., AbbVie Korea, Samil Pharmaceutical Co., Yuhan Co., Ltd.; consulting or advisory fees from Bukwang Pharmaceutical Co., Ltd., Eisai Korea Inc., and Ono Pharma Korea Co., Ltd.; and speakers' bureau fees from Merck Sharp & Dohme Korea. B.-Y.R. and S.Q.: declare no conflicts of interest. T.R.J.E.: reports honoraria from Eisai Co., Ltd. for advisory boards and speaker's bureau; support from Eisai Co., Ltd. for sponsored clinical trials; honoraria for advisory boards and speakers' bureau fees from Bristol-Myers Squibb, Bayer AG, GlaxoSmithKline, and Roche/Genentech; honoraria for advisory boards from Celgene Corporation, Karus Therapeutics, Baxalta, TC BioPharm, and Immunova Therapeutics; support for sponsored clinical trials from Bristol-Myers Squibb, GlaxoSmithKIine, Roche/Genentech, Celgene Corporation, TC BioPharm, Merck Sharp & Dohme, Novartis, e-Therapeutics, Vertex, Verastem, Daiichi, AstraZeneca, Basilea, Immunocore, and Chugai; support to attend international scientific conferences from Bristol-Myers Squibb, Roche/Genentech, Bayer AG, Merck Sharp & Dohme, and Eisai Co., Ltd. C.L.L.: reports consulting or advisory fees and research funding from Bristol-Myers Squibb, Merck Sharp & Dohme, Eisai Co., Ltd., Merck Group, Servier, Sanofi S.A., Roche/Genentech, EXELISIS, Daiichi-Sankyo, Ipsen, and AstraZeneca; and consulting or advisory fees from Bayer AG, Amgen Inc., Novartis, and Pfizer Inc. B.D.: reports honoraria from Bristol-Myers Squibb and Bayer AG; consulting or advisory fees from Bayer AG, Eisai Co., Ltd., Eli Lilly and Company, Ipsen Corporate, and Merck Sharp & Dohme; and personal fees from Amgen Inc., Bayer AG, Bristol-Myers Squibb, Celgene Corporation, and Sanofi S.A. S.M.: employed by Eisai Inc., while this study was conducted and when the manuscript was first drafted. M.R.: employed by Eisai Inc. N.I.: reports being an associate editor of Liver Cancer. R.S.F.: reports consulting or advisory fees and research funding from Bayer AG, Bristol-Myers Squibb, Eisai Co., Ltd., Eli Lilly and Company, Merck Group, Novartis International AG, and Pfizer Inc.; consulting or advisory fees from AstraZeneca plc; and is on the editorial board Liver Cancer.

Copyright © 2019 by S. Karger AG, Basel.

Figures

Fig. 1

OS comparisons for patients receiving first-line lenvatinib or sorafenib for the overall REFLECT population and for patients who received subsequent anticancer medication during the survival follow-up period. OS, overall survival; REFLECT, A Multicenter, Randomized, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) Versus Sorafenib in First-Line Treatment of Subjects with Unresectable Hepatocellular Carcinoma; uHCC, unresectable hepatocellular carcinoma.

Fig. 2

Kaplan-Meier estimates of OS for (a) the overall REFLECT population by treatment arm (reprinted from Kudo et al. [6], Copyright 2018, with permission from Elsevier) and (b) patients from REFLECT who received subsequent anticancer medication by first-line treatment arm. HR, hazard ratio; REFLECT, A Multicenter, Randomized, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) Versus Sorafenib in First-Line Treatment of Subjects with Unresectable Hepatocellular Carcinoma; OS, overall survival.

Fig. 3

Kaplan-Meier estimates of OS for (a) lenvatinib responders and (b) sorafenib responders who received any subsequent anticancer medication. NE, not estimable; OS, overall survival.

Fig. 4

Kaplan-Meier estimate of OS for lenvatinib responders who received subsequent sorafenib. OS, overall survival.