Oncotarget

Research Papers:

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

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

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Oncotarget. 2020; 11:2531-2542. https://doi.org/10.18632/oncotarget.27640

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Abstract

Tetsu Tomonari1,*, Yasushi Sato2,*, Hironori Tanaka1, Takahiro Tanaka1, Yasuteru Fujino1, Yasuhiro Mitsui1, Akihiro Hirao1, Tatsuya Taniguchi1, Koichi Okamoto1, Masahiro Sogabe1, Hiroshi Miyamoto1, Naoki Muguruma1, Harumi Kagiwada3, Masashi Kitazawa4, Kazuhiko Fukui3,4, Katsuhisa Horimoto3,4 and Tetsuji Takayama1

1 Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan

2 Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan

3 Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan

4 SOCIUM, Inc., Tokyo, Japan

* These authors contributed equally to this work

Correspondence to:

Tetsuji Takayama,email: takayama@tokushima-u.ac.jp

Keywords: hepatocellular carcinoma; lenvatinib; sorafenib; hepatic reserve function; FGFR

Received: April 02, 2020     Accepted: June 01, 2020     Published: June 30, 2020

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.


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