669PD - Met as prognostic factor and therapeutic target in pretreated hepatocellular carcinoma (HCC): final results of a randomized controlled phase 2 trial...

Date 01 October 2012
Event ESMO Congress 2012
Session Gastrointestinal tumors, non-colorectal
Topics Biomarkers
Hepatobiliary Cancers
Presenter Bruno Daniele
Authors B. Daniele1, L. Rimassa2, C. Porta3, I. Borbath4, S. Salvagni5, J. van Laethem6, H. van Vlierberghe7, R. von Roemeling8, G. Abbadessa9, A. Santoro10
  • 1Clinical Oncology, G. Rummo Hospital, 82100 - Benevento/IT
  • 2Oncology Hematology, Humanitas Cancer Center, Istituto Clinico Humanitas IRCCS, Rozzano/IT
  • 3Oncologia Medica, Ospedale San Matteo, IT-27100 - Pavia/IT
  • 4Gastro-enterology, Cliniques Universitaires St. Luc, BE-1200 - Brussels/BE
  • 5Oncology, Azienda Ospedaliera Parma, Parma/IT
  • 6Gastroenterology, Erasme University Hospital, Brussels/BE
  • 7Gastroenterology, Gent University Hospital, Gent/BE
  • 8Clinical Deveopment Oncology, Daiichi Sankyo Pharma Development, US-08837 - Edison/US
  • 9Medical Administration, ArQule, Inc, 01801 - Woburn/US
  • 10Humanitas Cancer Center, Istituto Clinico Humanitas, IT-20089 - Rozzano/IT

Abstract

Background

Tivantinib (T), a selective, oral inhibitor of MET, the hepatocyte growth factor (HGF) receptor, was tolerated in HCC as monotherapy and with sorafenib.

Methods

Multi center RCT; key selection criteria: unresectable HCC, 1 prior systemic therapy, PS <2; no Chld-Pugh B-C. Randomization: 2:1 to T or placebo (P); dose: 360mg BID (TA), then 240 mg BID (TB) in all patients (pts) due to G ≥ 3 neutropenia; stratification: PS, vascular invasion. Tumor evaluation: by CT / MRI every 6 weeks; central radiology review by RECIST 1.1. Crossover to open label T allowed after PD. Endpoints include: time to tumor progression (TTP) in the intent-to-treat (ITT) population; disease control rate (DCR), progression free survival (PFS), overall survival (OS), efficacy in MET+ (MET ≥2+ in ≥50% of tumor cells by immunohistochemistry) pts, safety.

Results

107 enrolled HCC pts, 71 on T (TA: 38; TB: 33), 36 on P. Pt characteristics were generally well balanced. In ITT, median TTP: 1.6 vs 1.4 mos (HR 0.64, 90%CI 0.43-0.94; P = 0.04). Most promising results were obtained in MET+ group, TTP: 2.7 vs 1.4 mos (HR 0.43, 95%CI 0.19-0.97; P = 0.03), DCR (95%CI): 50% (28-72%) vs 20% (4-48%), OS 7.2 vs 3.8 mos (HR 0.38, 95%CI 0.18-0.81, P < 0.02). Prognostic role of several factors was evaluated in the P group. MET+ pts had a 60% higher risk of progression and a 195% higher risk of death; high HGF (cutoff: median value of 2307 pg/mL) pts showed a similar trend in terms of TTP and OS. in MET+ pts on T, the most common AEs were fatigue (7, 31.7%) and asthenia (6, 27.3%). Blood levels (PK) of T were higher than in non HCC studies. No relation between MET and HBV/HCV, HGF or PK was observed. Strict dose reduction guidelines and the TB starting dose dramatically reduced the G ≥ 3 neutropenia rate without changing efficacy.

Conclusions

In this study, MET is an independent, negative prognostic factor in pretreated HCC pts; T shows pronounced activity in the MET+ patients with a manageable safety profile at TB. Larger studies are warranted.

Disclosure

R. von Roemeling: The Author is an employee of Daiichi-Sankyo and holds company stocks.

G. Abbadessa: The Author is an employee of ArQule and holds ArQule's stock options.

A. Santoro: The Author serves on the advisory board at ArQule.

All other authors have declared no conflicts of interest.