Abstract IA25: Targeted therapies for hepatocellular carcinoma

Abstract

Abstract In 2008, the multikinase inhibitor Sorafenib consistently proved to extend the survival of patients with Hepatocellular Carcinoma (HCC) that were treated in the advanced stage and had a good liver function, and it became the first agent to be specifically approved for this indication (ref). Although Sorafenib was a paradigm shift in the field, systemic therapy of HCC remains a major unmet need. The mechanism of action of Sorafenib is still poorly understood and the same is true for the mechanism of resistance after initial response, which usually reveals as disease stabilization for a few months. Molecular biomarkers predicting response and resistance to Sorafenib are also hardly defined. Furthermore, all subsequent novel targeted agents or regimens tested in large randomized controlled trials both in the first-line and second-line setting have been unable to reach or improve the magnitude of benefit obtained with Sorafenib. Strategies under study have included the blockade of other pro-angiogenic signals such as the FGFR pathway using Brivanib, proliferative signals such as the EGFR pathway using Erlotinib, or cell growth, proliferation, angiogenesis and apoptosis signals arising from the PI3K-Akt-mTOR pathway using Everolimus. The relevance of targeting these pathways is still not completely understood since biomarker data have not been reported, including EGFR and FGFR expression in tumor specimens. Besides, a number of trials have definitively shown the lack of efficacy of Doxorubicin, used for decades as a systemic therapy for HCC patients without formal scientific evidence. And no survival benefit was proven for combination chemotherapy based on 5-fluorouracil and oxaliplatin. The door was then opened to a more focused approach in which only patients with an altered targeted pathway are deemed candidates for a given agent. The anticancer activity of the c-met tyrosine kinase inhibitor Tivantinib was suggested in a randomized, placebo-controlled trial in the second-line setting where patients with high c-met expression survived significantly longer if they received Tivantinib. Patient enrichment based on molecular targets has been incorporated into the clinical development of other agents such as a monoclonal antibody that binds to glypican-3 or Refametinib a tyrosine kinase inhibitor that targets the MAPK (Ras-Raf-MEK-ERK) pathway. Agents targeting novel signaling pathways including TGF-β and FGF19, but also less explored pathways such as Wntβ-catenin, Hedgehog or Notch are being studied for the treatment of HCC. We will soon learn whether or not this more selective approach translates into positive results. Identification of driver molecular events in an individual patient using markers from tumor biopsies has proven successful in other tumors including breast or lung cancer. However, the reliability of this strategy has been challenged by studies showing intratumoural heterogeneity in various malignancies at advanced stages. HCC needs to be explored in this regard. Citation Format: Bruno Sangro. Targeted therapies for hepatocellular carcinoma [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA25.