Potential use of lenvatinib for patients with unresectable hepatocellular carcinoma including after treatment with sorafenib: Real-world evidence and in vitro assessment via protein phosphorylation array.

Takahiro Tanaka,Yasushi Sato,Masahiro Sogabe,Naoki Muguruma,Yasuhiro Mitsui,Tatsuya Taniguchi,Masashi Kitazawa,Hironori Tanaka,Katsuhisa Horimoto,Yasuteru Fujino,Hiroshi Miyamoto,Tetsu Tomonari,Akihiro Hirao,Tetsuji Takayama,Koichi Okamoto,Harumi Kagiwada,Kazuhiko Fukui

doi:10.18632/oncotarget.27640

Takahiro Tanaka, Yasushi Sato + Show 15 more

Open Access

https://doi.org/10.18632/oncotarget.27640

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Abstract

The efficacy and safety of lenvatinib (LEN) as a second/third-line treatment for unresectable hepatocellular carcinoma (HCC) after sorafenib (SOR) therapy remains unknown. We evaluated the outcomes of second/third-line LEN treatment, investigated the sensitivity of a SOR-resistant HCC cell line (PLC/PRF5-R2) to LEN, and assessed their signal transduction pathways by protein array analysis. We retrospectively enrolled 57 patients with unresectable HCC. Fifty-three radiologically evaluated patients comprised 34 molecular-targeted agent (MTA)-naive (first-line), nine intolerant to SOR (second-line), and 10 resistant to regorafenib (third-line). The objective response rates (ORRs) were 61.8% in first-line, 33.3% in second-line, and 20.0% in third-line groups. The overall survival (OS) in the first-line was significantly longer than that in the third-line group (p < 0.05). Patients with better liver functional reserves (child score, ALBI grade) exhibited higher ORR and longer OS. The IC50 of LEN against PLC/PRF5-R2 was significantly higher than that against PLC/PRF5. LEN significantly inhibited more LEN-related signal transduction pathways in PLC/PRF5 than in PLC/PRF5-R2 cells. This suggests that LEN is active and safe as a second/third-line treatment for unresectable HCC. LEN seems more effective for patients with HCC with better hepatic reserve functions or before MTA-resistance is acquired because of the partial cross-resistance to SOR.

Highlights

Hepatocellular carcinoma (HCC) is reportedly the fifth most commonly-diagnosed malignancy and the second leading cause of cancer-related death worldwide [1]
Of these, four patients were excluded from the analysis because they could not be evaluated using modified Response Evaluation Criteria in Solid Tumors measurements due to renal failure
We demonstrated the therapeutic efficacy and safety of LEN as a second- and third-line treatment, for patients intolerant to SOR and as a first-line treatment for HCC

Summary

Introduction

Hepatocellular carcinoma (HCC) is reportedly the fifth most commonly-diagnosed malignancy and the second leading cause of cancer-related death worldwide [1]. A randomized, placebocontrolled, phase III RESORCE trial reported that regorafenib (REG), an oral MTA, resulted in survival benefits for patients with advanced HCC who were progressing while on SOR. In this trial, REG showed a 2.8-month improvement in mOS, with a 38% reduction in the risk of death [4]. A phase III REACH-2 trial demonstrated that ramucirumab (RAM) in advanced HCC patients with baseline α-fetoprotein levels ≥ 400 ng/ml after SOR failure showed significant improvements in mOS [8.5 vs 7.3 months; hazard ratio: 0.710; 95% confidence interval (CI): 0.531–0.949]. The patients for whom RAM is indicated are limited to a proportion of only 23.3% [9]

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