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
Citations
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Journal ArticleDOI
c-MET receptor tyrosine kinase as a molecular target in advanced hepatocellular carcinoma.
TL;DR: The role of activated HGF/MET signaling in hepatocellular carcinoma, its prognostic relevance, and the implications for therapeutic approaches in HCC were summarized in this article. But, no evidence for a c-MET oncogenic addiction exists in patients with HCC.
Journal ArticleDOI
Treatment options after sorafenib failure in patients with hepatocellular carcinoma.
TL;DR: The most relevant to date published literature on treatment options beyond sorafenib, reported studies, ongoing investigational efforts, and possibilities for future studies in advanced hepatocellular carcinoma are reviewed.
Journal ArticleDOI
A Highly Potent and Specific MET Therapeutic Protein Antagonist with Both Ligand-Dependent and Ligand-Independent Activity
Shane A. Olwill,Christian Joffroy,Hendrik Gille,Elisa Vigna,Gabriele Matschiner,Andrea Allersdorfer,Bradley Lunde,Jakub Jaworski,James F. Burrows,Cristina Chiriaco,Hans Jürgen Christian,Martin Hülsmeyer,Stefan Trentmann,Kristian Jensen,Andreas Hohlbaum,Laurent P. Audoly +15 more
TL;DR: Analysis of MET protein levels on xenograft biopsy samples and data indicate that the MET inhibitor PRS-110 has potentially broad anticancer activity that warrants evaluation in patients, suggesting its ligand-independent mechanism of action.
Journal ArticleDOI
Hepatocellular Carcinoma: Review of Targeted and Immune Therapies.
TL;DR: Despite the toxicity and low response rate, sorafenib had shown a significant survival benefit in phase III clinical trials, thus encouraging clinical research aimed at advancing the field of molecular therapy.
Journal ArticleDOI
Phase I study of PF-03446962, a fully human monoclonal antibody against activin receptor-like kinase-1, in patients with hepatocellular carcinoma
Matteo Simonelli,Paolo Andrea Zucali,Armando Santoro,Melanie B. Thomas,F. de Braud,Hossein Borghaei,Jordan Berlin,Crystal S. Denlinger,Cristina Noberasco,Lorenza Rimassa,Tae Yong Kim,Patricia A. English,Antonello Abbattista,C. Gallo Stampino,Marina Carpentieri,J. A. Williams +15 more
TL;DR: The observed safety, tolerability, pharmacokinetic profile, and clinical activity support further evaluation of PF-03446962 in patients with HCC and other solid malignancies, as single agent or in combination with other antiangiogenic, chemotherapeutic, or immunotherAPEutic agents.
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