Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib

// Lorenza Rimassa 1 , Giovanni Abbadessa 2 , Nicola Personeni 1,3 , Camillo Porta 4 , Ivan Borbath 5 , Bruno Daniele 6 , Stefania Salvagni 7 , Jean-Luc Van Laethem 8 , Hans Van Vlierberghe 9 , Jörg Trojan 10 , Enrico N. De Toni 11 , Alan Weiss 12 , Steven Miles 13 , Antonio Gasbarrini 14 , Monica Lencioni 15 , Maria E. Lamar 2 , Yunxia Wang 2 , Dale Shuster 16 , Brian E. Schwartz 2 and Armando Santoro 1,17 1 Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy 2 ArQule, Burlington, MA, USA 3 Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Milan, Italy 4 Fondazione IRCCS Policlinico San Matteo, Pavia, Italy 5 Cliniques Universitaires Saint-Luc, Brussels, Belgium 6 G Rummo Hospital, Benevento, Italy 7 Azienda Ospedaliera Universitaria Sant’Orsola-Malpighi, Bologna, Italy 8 Erasme University Hospital, Brussels, Belgium 9 Ghent University Hospital, Ghent, Belgium 10 J W Goethe-University Hospital, Frankfurt, Germany 11 Klinikum der Universitaet Muenchen-Grosshadern, Munich, Germany 12 Vancouver General Hospital, British Columbia Cancer Clinic, Vancouver, Canada 13 Cedar Sinai, Los Angeles, CA, USA 14 Policlinico Universitario Agostino Gemelli, Rome, Italy 15 Azienda Ospedaliero-Universitaria di Pisa, Pisa, Italy 16 Daiichi Sankyo, Edison, NJ, USA 17 Humanitas University, Rozzano, Milan, Italy Correspondence to: Lorenza Rimassa, email: // Keywords : HCC, MET, HGF, AFP, sorafenib Received : August 02, 2016 Accepted : August 20, 2016 Published : August 25, 2016 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.