Abstract No. 124 Systemic therapy in advanced hepatocellular carcinoma: where are we heading?

Abstract

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer in the world and third, in cancer related mortality. Only 20% HCC are early HCCs that are eligible for therapies such as resection, liver transplantation, and local ablation due to advanced stage, tumor burden, lack of liver donors and liver dysfunction. The majority of HCCs are treated with palliative therapy, which includes Transarterial chemoembolization (TACE) and systemic therapy, while transarterial radioembolization still struggles to find a place in evidence-based treatment. In this study we explore the advances made in systemic therapy for advanced HCC, especially since the approval of sorafenib, a tyrosine kinase inhibitor, including the evolution and emerging field of immunotherapy in the last decade through relevant literature. We reviewed recently published studies in PubMed and data presented in the last decade discussing both advances and failures in the systemic treatment of HCC. After Sorafenib demonstrated improved overall survival (OS) in SHARP and Asia Pacific trials over placebo many other phase III trials have been conducted with other multi kinase inhibitors like sunitinib, brivanib and linifanib; none of which yielded significant results compared to sorafenib. Lenvatinib has been approved as first-line therapy for advanced HCC due to increased response rate, progression free similar survival outcomes like sorafenib. Tyrosine kinase inhibitors Regorafenib and Cabozantinib have shown significant improvement in survival, in RESORCE and CELESTIAL trials, respectively, as second-line treatment after sorafenib failures, radiological progression or intolerance in patients. Ramucirumab an anti VEGF monoclonal IgG antibody, studied in REACH trial demonstrated a potential survival benefit for patients with AFP ≥ 400ng/dL and Immune checkpoint inhibitors, like nivolumab and pembrolizumab although showing promising response rates and minimal adverse effects in phase II trial failed to demonstrate an improved OS in phase III trial. Despite clinical trials where combination of TACE and molecular targeted agents have failed till date, combination of TACE with sorafenib indicated success in TACTICS trial and the outcome of various ongoing combination trials with molecular targeted agents and immune checkpoint inhibitors is eagerly awaited. While a lot of progress has been made in increasing survival of patients with advanced HCC, the ongoing trials will further change the treatment paradigm significantly for HCC.