The summaries are free for public
use. The Chronic Liver Disease
Foundation will continue to add and
archive summaries of articles deemed
relevant to CLDF by the Board of
Trustees and its Advisors.
Abstract Details
Hepatocellular Carcinoma: Reasons for Phase III Failure and Novel Perspectives on Trial Design
Llovet JM1, Hernandez-Gea V. Clin Cancer Res. 2014 Mar 3. [Epub ahead of print]
Author information
1HCC Translational Research Laboratory, Barcelona Clinic Liver Group, Insitut d'Investigacions Biomediques Sugust Pi i Sunyer.
Abstract
Hepatocellular carcinoma (HCC) is a major health problem. Most HCC patients recur after resection/ablation or are diagnosed at advanced stages. Sorafenib remains the only approved systemic drug for these patients. Molecular therapies targeting signaling cascades involved in hepatocarcinogenesis have been explored in phase III clinical trials. However, none of the druags tested have shown positive results in first (brivanib, sunitinib, erlotinib and linifanib) or second line (brivanib, everolimus) after sorafenib progression. Reasons for failure are heterogeneous and include lack of understanding of critical drivers of tumor progression/dissemination, liver toxicity, flaws in trial design or marginal antitumoral potency. These trials are also challenging time to progression as a surrogate end-point of survival. Trials ongoing testing drugs head-to-head vs. sorafenib in "all comers" might have difficulties in achieving superior results in first line. Novel trials are currently designed testing drugs in biomarker-based subpopulations of HCC patients. Two types of studies are emerging. 1) Phase II pivotal proof-of-concept studies testing drugs blocking potential oncogenic addiction loops, and 2) Phase II-III studies using biomarker-based trial enrichment for defining activation of signalling pathways in HCC subgroups. These strategies have deemed successful in breast, melanoma and lung cancer, and are expected to change the landscape of trial design and management of HCC patients.