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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Journal ArticleDOI
A randomized, double-blind, placebo-controlled, phase 3 study of tivantinib in Japanese patients with MET-high hepatocellular carcinoma.
Masatoshi Kudo,Manabu Morimoto,Michihisa Moriguchi,Namiki Izumi,Tetsuji Takayama,Hitoshi Yoshiji,Keisuke Hino,Takayoshi Oikawa,Tetsuhiro Chiba,Kenta Motomura,Junko Kato,Kentaro Yasuchika,Akio Ido,Takashi Sato,Daisuke Nakashima,Kazuomi Ueshima,Masafumi Ikeda,Takuji Okusaka,Kazuo Tamura,Junji Furuse +19 more
TL;DR: This study did not confirm the significant efficacy of tivantinib as a second‐line treatment for Japanese patients with MET‐high hepatocellular carcinoma and the most common tivaninib‐related grade ≥3 adverse events were neutropenia, leukocytopenia and anemia.
Journal ArticleDOI
Antiangiogenic treatment in hepatocellular carcinoma: the balance of efficacy and safety.
TL;DR: A critical overview of antiangiogenic drugs and strategies in intermediate- and advanced-stage HCC is given, with a special focus on safety, as well as promising Phase II data have been reported with MET inhibitors in this hard-to-treat population.
Journal ArticleDOI
Phase I study of tivantinib in Japanese patients with advanced hepatocellular carcinoma: Distinctive pharmacokinetic profiles from other solid tumors
Takuji Okusaka,Takeshi Aramaki,Yoshitaka Inaba,Shinichiro Nakamura,Manabu Morimoto,Michihisa Moriguchi,Takashi Sato,Yuta Ikawa,Masafumi Ikeda,Junji Furuse +9 more
TL;DR: 115 mg BID of tivantinib is recommended among Japanese patients with HCC regardless of CYP2C19 phenotype, and at this dose, the pharmacokinetic profiles of tavantinIB did not remarkably differ between EM and PM.
Journal ArticleDOI
Prognostic value of the neutrophil-to-lymphocyte ratio in the ARQ 197-215 second-line study for advanced hepatocellular carcinoma
Nicola Personeni,Laura Giordano,Giovanni Abbadessa,Camillo Porta,Ivan Borbath,Bruno Daniele,Jean-Luc Van Laethem,Hans Van Vlierberghe,Jörg Trojan,Enrico N. De Toni,Antonio Gasbarrini,Monica Lencioni,Maria Lamar,Yunxia Wang,Dale Shuster,Brian Schwartz,Armando Santoro,Lorenza Rimassa +17 more
TL;DR: Baseline NLR is an independent prognostic biomarker in patients with HCC and compensated liver function who are candidate for second-line treatments and independently predicted survival in both the placebo and the tivantinib cohort.
Journal ArticleDOI
Management of patients with intermediate stage hepatocellular carcinoma.
TL;DR: The classifications and current management for patients with intermediate stage HCC are summarized as well as recent key developments in this space are highlighted.
References
More filters
Journal ArticleDOI
New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)
Elizabeth Eisenhauer,P. Therasse,Jan Bogaerts,Lawrence H. Schwartz,Daniel J. Sargent,Robert Ford,Janet Dancey,S. Arbuck,S. Gwyther,Margaret M. Mooney,Larry Rubinstein,Lalitha K. Shankar,Lori E. Dodd,Robert M. Kaplan,Denis Lacombe,Jaap Verweij +15 more
TL;DR: The revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions, and a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included.
Journal ArticleDOI
Sorafenib in Advanced Hepatocellular Carcinoma
Josep M. Llovet,Sergio Ricci,Vincenzo Mazzaferro,Philip Hilgard,Edward Gane,Jean-Frédéric Blanc,André Cosme de Oliveira,Armando Santoro,Jean-Luc Raoul,Alejandro Forner,Myron Schwartz,Camillo Porta,Stefan Zeuzem,Luigi Bolondi,Tim F. Greten,Peter R. Galle,Jean Francois Seitz,Ivan Borbath,Dieter Häussinger,Tom Giannaris,Minghua Shan,M. Moscovici,D. Voliotis,Jordi Bruix +23 more
TL;DR: In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.
Journal ArticleDOI
Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.
Ann-Lii Cheng,Yoon-Koo Kang,Zhendong Chen,Chao Jung Tsao,Shukui Qin,Jun Suk Kim,Rongcheng Luo,Jifeng Feng,Sheng-Long Ye,Tsai Sheng Yang,Jianming Xu,Yan Sun,Houjie Liang,Jiwei Liu,Jiejun Wang,Won Young Tak,Hongming Pan,Karin Burock,Jessie Zou,D. Voliotis,Zhongzhen Guan +20 more
TL;DR: Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated.
Journal Article
[New response evaluation criteria in solid tumours-revised RECIST guideline (version 1.1)].
Hirokazu Watanabe,Morihito Okada,Yasushi Kaji,Miyako Satouchi,Yozo Sato,Yuichiro Yamabe,Hiroaki Onaya,Masahiro Endo,Miyuki Sone,Yasuaki Arai +9 more
TL;DR: This paper is an overview of the new response evaluation criteria in solid tumours: revised RECIST guideline (version 1. 1), with a focus on updated contents.
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