Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma

Kenji Ikeda,Hiromitsu Kumada,Yukio Osaki,Takashi Hisai,Toshiyuki Tamai,Seiji Kawazoe,Kiwamu Okita,Masafumi Ikeda,Takuji Okusaka,Takuya Suzuki,Seiichi Hayato,Masatoshi Kudo

doi:10.1007/s00535-016-1263-4

Abstract

BackgroundLenvatinib is an oral inhibitor of vascular endothelial growth factor receptor 1–3, fibroblast growth factor receptor 1–4, platelet-derived growth factor receptor alpha, RET, and KIT. This phase 2, single-arm, open-label multicenter study evaluated lenvatinib in advanced hepatocellular carcinoma (HCC).MethodsPatients with histologically/clinically confirmed advanced HCC who did not qualify for surgical resection or local therapies received lenvatinib at a dosage of 12 mg once daily (QD) in 28-day cycles. The primary efficacy endpoint was time to progression (TTP) per modified Response Evaluation Criteria in Solid Tumors v1.1; secondary efficacy endpoints included objective response rate (ORR), disease control rate (DCR), and overall survival (OS).ResultsBetween July 2010 and June 2011, 46 patients received lenvatinib at sites across Japan and Korea. The median TTP, as determined by independent radiological review, was 7.4 months [95 % confidence interval (CI): 5.5–9.4]. Seventeen patients (37 %) had partial response and 19 patients (41 %) had stable disease (ORR: 37 %; DCR: 78 %). Median OS was 18.7 months (95 % CI: 12.7–25.1). The most common any-grade adverse events (AEs) were hypertension (76 %), palmar-plantar erythrodysesthesia syndrome (65 %), decreased appetite (61 %), and proteinuria (61 %). Dose reductions and discontinuations due to AEs occurred in 34 (74 %) and 10 patients (22 %), respectively. Median body weight was lower in patients with an early (<30 days) dose withdrawal or reduction than in those without.ConclusionsLenvatinib 12-mg QD showed clinical activity and acceptable toxicity profiles in patients with advanced HCC, but early dose modification was necessary in patients with lower body weight. Further development of lenvatinib in HCC should consider dose modification by body weight.Trial registration IDwww.ClinicalTrials.gov NCT00946153.

Highlights

In hepatocellular carcinoma (HCC), which accounts for 85–90 % of primary liver cancers [1], increased expression of vascular endothelial growth factor (VEGF) levels hasJ Gastroenterol (2017) 52:512–519 been correlated with angiogenic activity, tumor progression, and poor prognosis [2, 3].Sorafenib is currently the only systemic VEGF-targeted therapy to have demonstrated a survival benefit in patients with advanced HCC [4, 5]
Background Lenvatinib is an oral inhibitor of vascular endothelial growth factor receptor 1–3, fibroblast growth factor receptor 1–4, platelet-derived growth factor receptor alpha, RET, and KIT
Lenvatinib 12-mg QD showed clinical activity and acceptable toxicity profiles in patients with advanced HCC, but early dose modification was necessary in patients with lower body weight

Summary

Introduction

In hepatocellular carcinoma (HCC), which accounts for 85–90 % of primary liver cancers [1], increased expression of vascular endothelial growth factor (VEGF) levels hasJ Gastroenterol (2017) 52:512–519 been correlated with angiogenic activity, tumor progression, and poor prognosis [2, 3].Sorafenib is currently the only systemic VEGF-targeted therapy to have demonstrated a survival benefit in patients with advanced HCC [4, 5]. The median overall survival (OS) and time to progression (TTP) with sorafenib are only *1 year and *4 months, respectively, with frequent dose reductions or discontinuations due to adverse events, including severe skin toxicity [6,7,8]. In a phase 1 study of lenvatinib in HCC, the maximum tolerable dose in patients with HCC and Child Pugh (CP) class A liver function was 12 mg QD [14]. Lenvatinib is an oral inhibitor of vascular endothelial growth factor receptor 1–3, fibroblast growth factor receptor 1–4, platelet-derived growth factor receptor alpha, RET, and KIT This phase 2, single-arm, open-label multicenter study evaluated lenvatinib in advanced hepatocellular carcinoma (HCC). Conclusions Lenvatinib 12-mg QD showed clinical activity and acceptable toxicity profiles in patients with advanced HCC, but early dose modification was necessary in patients with lower body weight.

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Conclusion