title: Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib.
abstract: ARQ 197-215 was a randomized placebo-controlled phase II study testing the MET inhibitor tivantinib in second-line hepatocellular carcinoma (HCC) patients. It identified tumor MET as a key biomarker in HCC.Aim of this research was to study the prognostic and predictive value of tumor (MET, the receptor tyrosine kinase encoded by the homonymous MNNG-HOS transforming gene) and circulating (MET, hepatocyte growth factor [HGF], alpha-fetoprotein [AFP], vascular endothelial growth factor [VEGF]) biomarkers in second-line HCC. Tumor MET-High status was centrally assessed by immunohistochemistry. Circulating biomarkers were centrally analyzed on serum samples collected at baseline and every 4-8 weeks, using medians as cut-off to determine High/Low status. Tumor MET, tested in 77 patients, was more frequently High after (82%) versus before (40%) sorafenib. A significant interaction (p = 0.04) between tivantinib and baseline tumor MET in terms of survival was observed. Baseline circulating MET and HGF (102 patients) High status correlated with shorter survival (HR 0.61, p = 0.03, and HR 0.60, p = 0.02, respectively), while the association between AFP (104 patients) or VEGF (103 patients) status and survival was non-significant.
  
  
  CONCLUSIONS
  Tumor MET levels were higher in patients treated with sorafenib. Circulating biomarkers such as MET and HGF may be prognostic in second-line HCC. These results need to be confirmed in larger randomized clinical trials.
authors: Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors: Lorenza
authors: L
authors: Rimassa
authors: ArQule, Burlington, MA, USA.
authors: Giovanni
authors: G
authors: Abbadessa
authors: Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.|Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Milan, Italy.
authors: Nicola
authors: N
authors: Personeni
authors: Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors: Camillo
authors: C
authors: Porta
authors: Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors: Ivan
authors: I
authors: Borbath
authors: G Rummo Hospital, Benevento, Italy.
authors: Bruno
authors: B
authors: Daniele
authors: Azienda Ospedaliera Universitaria Sant'Orsola-Malpighi, Bologna, Italy.
authors: Stefania
authors: S
authors: Salvagni
authors: Erasme University Hospital, Brussels, Belgium.
authors: Jean-Luc
authors: JL
authors: Van Laethem
authors: Ghent University Hospital, Ghent, Belgium.
authors: Hans
authors: H
authors: Van Vlierberghe
authors: J W Goethe-University Hospital, Frankfurt, Germany.
authors: Jörg
authors: J
authors: Trojan
authors: Klinikum der Universitaet Muenchen-Grosshadern, Munich, Germany.
authors: Enrico N
authors: EN
authors: De Toni
authors: Vancouver General Hospital, British Columbia Cancer Clinic, Vancouver, Canada.
authors: Alan
authors: A
authors: Weiss
authors: Cedar Sinai, Los Angeles, CA, USA.
authors: Steven
authors: S
authors: Miles
authors: Policlinico Universitario Agostino Gemelli, Rome, Italy.
authors: Antonio
authors: A
authors: Gasbarrini
authors: Azienda Ospedaliero-Universitaria di Pisa, Pisa, Italy.
authors: Monica
authors: M
authors: Lencioni
authors: ArQule, Burlington, MA, USA.
authors: Maria E
authors: ME
authors: Lamar
authors: ArQule, Burlington, MA, USA.
authors: Yunxia
authors: Y
authors: Wang
authors: Daiichi Sankyo, Edison, NJ, USA.
authors: Dale
authors: D
authors: Shuster
authors: ArQule, Burlington, MA, USA.
authors: Brian E
authors: BE
authors: Schwartz
authors: Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.|Humanitas University, Rozzano, Milan, Italy.
authors: Armando
authors: A
authors: Santoro
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019859:Proto-Oncogene Proteins c-met / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis
chemical_list: C551661:ARQ 197; D014408:Biomarkers, Tumor; D011760:Pyrrolidinones; D011804:Quinolines; D019859:Proto-Oncogene Proteins c-met
keywords: AFP; HCC; HGF; MET; sorafenib