Research Papers:

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

Lorenza Rimassa _, Giovanni Abbadessa, Nicola Personeni, Camillo Porta, Ivan Borbath, Bruno Daniele, Stefania Salvagni, Jean-Luc Van Laethem, Hans Van Vlierberghe, Jörg Trojan, Enrico N. De Toni, Alan Weiss, Steven Miles, Antonio Gasbarrini, Monica Lencioni, Maria E. Lamar, Yunxia Wang, Dale Shuster, Brian E. Schwartz and Armando Santoro

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Oncotarget. 2016; 7:72622-72633. https://doi.org/10.18632/oncotarget.11621

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Lorenza Rimassa1, Giovanni Abbadessa2, Nicola Personeni1,3, Camillo Porta4, Ivan Borbath5, Bruno Daniele6, Stefania Salvagni7, Jean-Luc Van Laethem8, Hans Van Vlierberghe9, Jörg Trojan10, Enrico N. De Toni11, Alan Weiss12, Steven Miles13, Antonio Gasbarrini14, Monica Lencioni15, Maria E. Lamar2, Yunxia Wang2, Dale Shuster16, Brian E. Schwartz2 and Armando Santoro1,17

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


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.

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