title: Tivantinib  in hepatocellular carcinoma.
abstract: BACKGROUND
  Tivantinib (ARQ 197) is a selective, oral MET receptor tyrosine kinase inhibitor with broad-spectrum antitumor activity as single agent and in combination in preclinical studies including several MET overexpressing cell lines.
  
  
  METHODS
  This paper covers the preclinical data, the Phase I studies as monotherapy or in combination with sorafenib, and a Phase II study as second-line systemic treatment in patients with advanced hepatocellular carcinoma (HCC). The analysis of MET expression as companion diagnostic and the safety profile of tivantinib in HCC are discussed.
  
  
  CONCLUSIONS
  Tivantinib, a novel MET inhibitor with an ATP-independent binding mechanism, stabilizes the inactive conformation of the MET receptor tyrosine kinase, thus disrupting constitutive and ligand-mediated activation. MET overexpression was shown as a negative prognostic factor in HCC after sorafenib failure. Tivantinib demonstrated a nearly doubling of progression free and overall survival in the MET high group compared to placebo in a Phase II study in patients with advanced HCC as second-line treatment. The activity of tivantinib in combination with sorafenib is also promising. Adverse events include hematological toxicity, asthenia and loss of appetite. The initially high incidence of neutropenia in patients with HCC lead to dose reduction from 360 mg b.i.d. to 240 mg b.i.d. Currently, a pivotal Phase III study in advanced, MET-high HCC after sorafenib failure is planned.
authors.affiliation: Klinikum der Johann-Wolfgang Goethe-Universität, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. trojan@em.uni-frankfurt.de
authors.forename: Jörg
authors.initials: J
authors.lastname: Trojan
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011760:Pyrrolidinones / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*
chemical_list: C551661:ARQ 197; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011760:Pyrrolidinones; D011804:Quinolines; D019859:Proto-Oncogene Proteins c-met