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World J Gastroenterol. Feb 21, 2019; 25(7): 789-807
Published online Feb 21, 2019. doi: 10.3748/wjg.v25.i7.789
Targeted and immune therapies for hepatocellular carcinoma: Predictions for 2019 and beyond
Masatoshi Kudo
Masatoshi Kudo, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka 589-8511, Japan
Author contributions: Kudo M designed the research and wrote the paper.
Conflict-of-interest statement: Masatoshi Kudo received lecture fees from Bayer, Eisai, MSD, and Ajinomoto, research grants from Chugai, Otsuka, Takeda, Taiho, Sumitomo Dainippon, Daiichi Sankyo, MSD, Eisai, Bayer, AbbVie, Medico’s Hirata, Astellas Pharma, and Bristol-Myers Squibb, and advisory consulting fees from Kowa, MSD, Bristol-Myers Squibb, Bayer, Chugai, Taiho, Eisai, and Ono Pharmaceutical.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Masatoshi Kudo, MD, PhD, Director, Full Professor, Professor and Chairman, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2, Ohno-Higashi, Osaka 589-8511, Japan. m-kudo@med.kindai.ac.jp
Telephone: +81-723660221-3149 Fax: +81-723672880
Received: December 7, 2018
Peer-review started: December 8, 2018
First decision: December 28, 2018
Revised: January 10, 2019
Accepted: January 14, 2019
Article in press: January 14, 2019
Published online: February 21, 2019
Processing time: 77 Days and 5.3 Hours
Abstract

Systemic therapy for hepatocellular carcinoma (HCC) has markedly advanced since the survival benefit of a molecular targeted agent, sorafenib, were demonstrated in the SHARP and Asia Pacific trials in 2007. Treatment options for patients with advanced HCC increased by sorafenib, and long-term survival for patients with advanced stage HCC has become possible to some extent. However, development of a more potent first-line novel molecular targeted agent replacing sorafenib and a potent second-line agent after disease progression on or intolerant to sorafenib has been warranted because sorafenib lacks tumor shrinking/necrotizing effects and induces relatively severe adverse events such as hand foot skin reaction. Many agents in the 1st line and 2nd line setting were attempted to develop between 2007 and 2016, but all of these clinical trials failed. On the other hand, clinical trials of 4 agents (regorafenib, lenvatinib, cabozantinib, and ramucirumab) succeeded in succession in 2017 and 2018, and their use in clinical practice is possible (regorafenib and lenvatinib) or underway (cabozantinib and ramucirumab). Furthermore, all of 5 clinical trials of combination therapy with transcatheter chemoembolization (TACE) plus a molecular targeted agent failed to date, however, the combination of TACE and sorafenib (TACTICS trials) was reported to be successful and presented at ASCO in 2018. Phase 3 clinical trials of immune checkpoint inhibitors and a combination therapy of immune checkpoint inhibitors and molecular targeted agents are also ongoing, which suggests treatment paradigm of HCC in all stages from early, intermediate and advanced stage, is expected to be changed drastically in the very near future.

Keywords: Hepatocellular carcinoma; Molecular targeted agent; Immune checkpoint inhibitor; Sorafenib; Lenvatinib

Core tip: Systemic therapy for hepatocellular carcinoma (HCC) has markedly advanced since sorafenib was approved in 2007. Since then, there was no active drug for 10 years that prolong overall survival, however, in 2017 and 2018, clinical trials of 4 more molecular targeted agents including lenvatinib as first line agent, regorafenib, cabozantinib and ramucirumab as second line agent have shown their survival benefit. In addition, immune check point inhibitors, nivolumab and pembrolizumab, were approved by Food and Drug Administration. Combination cancer immunotherapy, that combines immune checkpoint inhibitors and molecular targeted agents show great promise in the treatment of HCC.