title: Tivantinib: critical review with a focus on hepatocellular carcinoma.
abstract: BACKGROUND
  Sorafenib is the only approved agent for the treatment of advanced hepatocellular carcinoma (HCC). Sorafenib is an oral multikinase inhibitor that blocks several receptors involved in tumor cell proliferation and angiogenesis. The hepatocyte-growth factor/mesenchymal-epithelial transition (MET) factor pathway represents another emerging target in HCC. Tivantinib (ARQ 197) is an oral, selective small MET tyrosine kinase inhibitor with antitumor activity, especially in MET-high patients. Recent clinical data exhibit promising activity in HCC.
  
  
  METHODS
  This article reviews the preclinical and clinical data of tivantinib (published and ongoing trials), focusing on development in advanced HCC. Comments regarding the failure of trials with nonspecific drugs reported in the past 2 years are also included.
  
  
  CONCLUSIONS
  A randomized Phase II trial in second-line HCC showed a significant improvement in time to progression with tivantinib treatment in MET-high patients. Tivantinib remains in clinical development and has not yet been approved for any indication. A Phase III study in MET-high HCC is ongoing in a second-line setting, after sorafenib failure. In case of a survival benefit, tivantinib might become the first treatment for selected patients, based on MET status as a predictor. Therefore, there is a need for identifying HCC molecular subclasses and for developing a trial design based on molecular biomarkers.
authors.affiliation: Cancer Center Azienda Ospedaliera Papa Giovanni XXIII - Unit of Medical Oncology , Piazza OMS 1, 24127 Bergamo , Italy +39 035 267 3694, +39 035 267 3691 ; +39 035 267 4985 ; ecrota@hpg23.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Rota Caremoli
authors.forename: Roberto
authors.initials: R
authors.lastname: Labianca
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011760:Pyrrolidinones / Q000494:pharmacology / Q000627:therapeutic use*; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D012107:Research Design
chemical_list: C551661:ARQ 197; D000970:Antineoplastic Agents; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D011760:Pyrrolidinones; D011804:Quinolines; D019859:Proto-Oncogene Proteins c-met
keywords: c-MET inhibitor; hepatocellular carcinoma; hepatocyte growth factor receptor; tivantinib