Cabozantinib in the treatment of advanced hepatocellular carcinoma patients

Abstract

Hepatocellular carcinoma (HCC) is the sixth most frequently diagnosed malignancy in the world, with the number of cases steadily increasing. Currently, around 850,000 new cases are diagnosed annually. In the majority of patients, HCC is diagnosed at an advanced stage mainly due to the lack of early symptoms. Risk factors for HCC are well known. HCC usually develops in cirrhotic liver; the exception is a form of fibrolamellar carcinoma arising in healthy liver. Hepatocarcinogenesis is a multistage process in which many pathways of intracellular signal transduction are disturbed, which leads to various biological characteristics of the disease. During foetal life, liver cells produce multiple factors, e.g. epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), or platelet-derived growth factor (PDGF), which play a significant role in organogenesis. In adults, the production of many of the factors decreases or does not exist. As a result of organ damage (e.g. after injury), hepatocytes start the synthesis again, but only temporarily. In a chronically damaged liver, a dysregulation of the production of these factors takes place, it is continuous and leads to hepatocarcinogenesis. Understanding the HCC pathogenesis has allowed the synthesis of compounds that can directly interfere with the molecular pathways associated with the growth and progression of tumours. Cabozantinib (an oral tyrosine kinase inhibitor) targets VEGF, MET, and AXL receptors. It may be an option in patients with HCC with disease progression after one or two lines of systemic treatment (e.g. after sorafenib therapy). The use of cabozantinib in the treatment of patients with advanced HCC was evaluated in a prospective phase III study, which demonstrated prolongation of overall survival (OS) and progression-free survival (PFS) compared to patients receiving placebo. Based on the results of the study, the use of cabozantinib provides an opportunity to further improve treatment outcomes in patients with advanced HCC.