742TiP - Phase 3 randomized, double-blind, controlled study of cabozantinib (XL184) vs placebo in subjects with hepatocellular carcinoma who have received p...

Date 29 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Hepatobiliary Cancers
Presenter Ghassan Abou-Alfa
Citation Annals of Oncology (2014) 25 (suppl_4): iv210-iv253. 10.1093/annonc/mdu334
Authors G.K. Abou-Alfa1, A. Cheng2, T. Meyer3, A.B. El-Khoueiry4, M. Ikeda5, H.G. Chun6, J. Furuse7, J. Knox8, T. Okusaka9, M. Colombo10, P. Merle11, A. Santoro12, D. Gallagher13, E. Janczewska14, J. Trojan15, H.J. Klumpen16, I. Cicin17, J. Ping18, A.E. Borgman-Hagey18, R.K. Kelley19
  • 1Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, 10065 - New York/US
  • 2Internal Medicine, National Taiwan University Hospital, Taipei/TW
  • 3Medicine, Royal Free Hospital, London/GB
  • 4Medicine, University of Southern California, Keck School of Medicine, Los Angeles/US
  • 5Division Of Hepatobiliary And Pancreatic Oncology, National Cancer Center Hospital East, Chiba/JP
  • 6Catholic Comprehensive Cancer Institute, Seoul St. Mary's Hospital,of the Catholic University, KR-137-701 - Seoul/KR
  • 7Department Of Medical Oncology, Kyorin University School of Medicine, 181-8611 - Tokyo/JP
  • 8Dept. Of Medical Oncology And Hematology, Princess Margaret Hospital, M5G 2M9 - Toronto/CA
  • 9Division Of Hepatobiliary And Pancreatic Oncology, National Cancer Center Hospital, 104-0045 - Tokyo/JP
  • 10Medicine, University of Milan, Milan/IT
  • 11Medicine, Hospices Civils de Lyon, Lyon/FR
  • 12Medical Oncology, Istituto Clinico Humanitas, 20089 - Rozzano (Milano)/IT
  • 13Dept Medical Oncology, Mater Misercordiae University Hospital & Mater Private, Dublin /IE
  • 14Medicine, ŚLĄSKI MEDICAL UNIVERSITY, Katowice/PL
  • 15Gastrointestinal Oncology, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt/DE
  • 16Medical Oncology, Academic Medical Center (AMC), NL-1105AZ - Amsterdam/NL
  • 17Medical Oncology, Trakya University, 22030 - Edirne/TR
  • 18Oncology, Exelixis Inc, San Francisco/US
  • 19Medicine, University of California San Francisco, San Francisco/US

Abstract

Background

Currently, there are no approved systemic therapies for patients with advanced hepatocellular carcinoma (HCC) who fail sorafenib. Cabozantinib is an oral receptor tyrosine kinase inhibitor (TKI) with activity against tyrosine kinases including MET, RET and VEGFRs. MET and VEGFR signaling have been implicated in tumor neo-angiogenesis and invasion. MET is overexpressed in HCC compared with non-tumor liver tissue, with higher MET expression linked to poor prognosis. Cabozantinib prolonged survival in a MET-driven transgenic mouse model of HCC, and has demonstrated clinical activity in multiple solid tumor types, including 41 subjects with advanced HCC treated in a phase 2 randomized discontinuation study.

Trial design

This phase 3, randomized, double-blind study evaluates the efficacy and safety of cabozantinib compared with placebo in subjects with advanced HCC previously treated with sorafenib and have progressed following 1-2 prior systemic treatments for HCC. Subjects must be ≥ 18 year old, have Child-Pugh Score of A and ECOG PS ≤ 1. Subjects are randomized 2:1 to receive either cabozantinib or placebo. Stratification factors are etiology of disease, geographic region and the presence of extrahepatic spread of disease and/or macrovascular invasion. The primary endpoint is overall survival. Secondary endpoints are progression-free survival and objective response rate by RECIST 1.1. Additional endpoints include safety, tolerability, circulating tumor cells, serum bone markers and plasma biomarkers, effects on bony disease assessed by bone scan and health-related quality of life (HRQoL) using the EuroQol Health questionnaire (EQ-5D-5L). Enrollment was initiated in September 2013. Target recruitment is 760 subjects. A total of 621 events planned with 2 interim analyses (at 311 and 466 events) would provide 90% power to detect a 31.6% increase in OS (HR = 0.76). This abstract was accepted and previously presented at ASCO 2014ILCA 2014.

Disclosure

G.K. Abou-Alfa: Research Grants: Exelixis Consultancy: Exelixis; A. Cheng, T. Meyer, A.B. El-Khoueiry, M. Ikeda and T. Okusaka: Consultancy: Exelixis; H.G. Chun: Research grant: Exelixis Consultancy: Exelixiş E. Janczewska: Research grant: Exelixis; J. Ping: Employee: Exelixis Stock ownership: Exelixis; A.E. Borgman-Hagey: Employee: Exelixis Stock Ownership: Exelixis; R.K. Kelley: Research grant: Exelixis Consultancy: Exelixis. All other authors have declared no conflicts of interest.