Journal ArticleDOI
Tivantinib for second-line treatment of advanced hepatocellular carcinoma: A randomised, placebo-controlled phase 2 study
Armando Santoro,Lorenza Rimassa,Ivan Borbath,Bruno Daniele,Stefania Salvagni,Jean-Luc Van Laethem,Hans Van Vlierberghe,Jörg Trojan,Frank T. Kolligs,Alan Weiss,Steven A. Miles,Antonio Gasbarrini,Monica Lencioni,Luca Cicalese,Morris Sherman,Cesare Gridelli,Peter Buggisch,Guido Gerken,Roland M. Schmid,Corrado Boni,Nicola Personeni,Ziad Hassoun,Giovanni Abbadessa,Brian Schwartz,Reinhard von Roemeling,Maria Lamar,Yinpu Chen,Camillo Porta +27 more
TLDR
Tivantinib could provide an option for second-line treatment of patients with advanced hepatocellular carcinoma and well-compensated liver cirrhosis, particularly for patients with MET-high tumours.Abstract:
Summary Background Tivantinib (ARQ 197), a selective oral inhibitor of MET, has shown promising antitumour activity in hepatocellular carcinoma as monotherapy and in combination with sorafenib. We aimed to assess efficacy and safety of tivantinib for second-line treatment of advanced hepatocellular carcinoma. Methods In this completed, multicentre, randomised, placebo-controlled, double-blind, phase 2 study, we enrolled patients with advanced hepatocellular carcinoma and Child-Pugh A cirrhosis who had progressed on or were unable to tolerate first-line systemic therapy. We randomly allocated patients 2:1 to receive tivantinib (360 mg twice-daily) or placebo until disease progression. The tivantinib dose was amended to 240 mg twice-daily because of high incidence of treatment-emergent grade 3 or worse neutropenia. Randomisation was done centrally by an interactive voice-response system, stratified by Eastern Cooperative Oncology Group performance status and vascular invasion. The primary endpoint was time to progression, according to independent radiological review in the intention-to-treat population. We assessed tumour samples for MET expression with immunohistochemistry (high expression was regarded as ≥2+ in ≥50% of tumour cells). This study is registered with ClinicalTrials.gov, number NCT00988741. Findings 71 patients were randomly assigned to receive tivantinib (38 at 360 mg twice-daily and 33 at 240 mg twice-daily); 36 patients were randomly assigned to receive placebo. At the time of analysis, 46 (65%) patients in the tivantinib group and 26 (72%) of those in the placebo group had progressive disease. Time to progression was longer for patients treated with tivantinib (1·6 months [95% CI 1·4–2·8]) than placebo (1·4 months [1·4–1·5]; hazard ratio [HR] 0·64, 90% CI 0·43–0·94; p=0·04). For patients with MET-high tumours, median time to progression was longer with tivantinib than for those on placebo (2·7 months [95% CI 1·4–8·5] for 22 MET-high patients on tivantinib vs 1·4 months [1·4–1·6] for 15 MET-high patients on placebo; HR 0·43, 95% CI 0·19–0·97; p=0·03). The most common grade 3 or worse adverse events in the tivantinib group were neutropenia (ten patients [14%] vs none in the placebo group) and anaemia (eight [11%] vs none in the placebo group). Eight patients (21%) in the tivantinib 360 mg group had grade 3 or worse neutropenia compared with two (6%) patients in the 240 mg group. Four deaths related to tivantinib occurred from severe neutropenia. 24 (34%) patients in the tivantinib group and 14 (39%) patients in the placebo group had serious adverse events. Interpretation Tivantinib could provide an option for second-line treatment of patients with advanced hepatocellular carcinoma and well-compensated liver cirrhosis, particularly for patients with MET-high tumours. Confirmation in a phase 3 trial is needed, with a starting dose of tivantinib 240 mg twice-daily. Funding ArQule, Daiichi Sankyo (Daiichi Sankyo Group).read more
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Angiopoietin-like protein 1 antagonizes MET receptor activity to repress sorafenib resistance and cancer stemness in hepatocellular carcinoma
Hsin An Chen,Tsang Chih Kuo,Chi Feng Tseng,Chi Feng Tseng,Jui Ti Ma,Shu Ting Yang,Chia Jui Yen,Ching-Yao Yang,Shian Ying Sung,Jen Liang Su +9 more
TL;DR: It is shown that ANGPTL1 expression positively correlates with sorafenib sensitivity in HCC cells and human HCC tissues and may serve as a novel MET receptor inhibitor for advanced HCC therapy.
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Roman L. Bogorad,Hao Yin,Anja Zeigerer,Hidenori Nonaka,Vera M. Ruda,Marino Zerial,Daniel G. Anderson,Victor Koteliansky +7 more
TL;DR: The data suggest that transformed proliferating cells from HCC are more sensitive to knockdown of integrins than normal quiescent hepatocytes, highlighting the potential of siRNA-mediated inhibition ofintegrins as an anti-cancer therapeutic approach.
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Xiao-Xiao Ding,Qing-Ge Zhu,Shi-Ming Zhang,Lei Guan,Ting Li,Lei Zhang,Shiyang Wang,Wanli Ren,Xue-Mei Chen,Jing Zhao,Song Lin,Zhi-Zhen Liu,Yanxia Bai,Bing He,Hu-Qin Zhang +14 more
TL;DR: This review summarized currently discovered driver mutations and corresponding signaling pathways, made an overview of identification methods ofDriver mutations and genes, and classified targeted drugs for HCC.
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