Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma

Abstract

Molecular targeted therapy for advanced hepatocellular carcinoma (HCC) has changed markedly. Although sorafenib was used in clinical practice as the first molecular targeted agent in 2007, the SHARPE and Asian-Pacific trials demonstrated that sorafenib only improved overall survival (OS) by approximately 3 months in patients with advanced HCC compared with placebo. Molecular targeted agents were developed during the 10-year period from 2007 to 2016, but every test of these agents from phase II or phase III clinical trial failed due to a low response rate and high toxicity. In the 2 years after, 2017 through 2018, four successful novel drugs emerged from clinical trials for clinical use. As recommended by updated Barcelona Clinical Liver cancer (BCLC) treatment algorithms, lenvatinib is now feasible as an alternative to sorafenib as a first-line treatment for advanced HCC. Regorafenib, cabozantinib, and ramucirumab are appropriate supplements for sorafenib as second-line treatment for patients with advanced HCC who are resistant, show progression or do not tolerate sorafenib. In addition, with promising outcomes in phase II trials, immune PD-1/PD-L1 checkpoint inhibitors nivolumab and pembrolizumab have been applied for HCC treatment. Despite phase III trials for nivolumab and pembrolizumab, the primary endpoints of improved OS were not statistically significant, immune PD-1/PD-L1 checkpoint therapy remains to be further investigated. This review summarizes the development and progression of molecular targeted and immune-based checkpoint therapies in HCC.

Keywords: Hepatocellular carcinoma; Immunotherapy; Molecular targeted therapy.

Fig. 1

Important target molecules and signal transduction pathways in hepatocarcinogenesis and progression. Drug-targeting receptors are present on the cell membrane of hepatoma cells and endothelial cells. EGFR: epidermal growth factor receptor; Tie2: angiopoietin receptor; FGFR: fibroblast growth factor receptor; PDGFR: platelet-derived growth factor receptor; VEGFR: vascular endothelial growth factor receptor; RET: glial cell-derived neurotrophic factor receptor; C-MET: hepatocyte growth factor receptor; KIT: stem cell factor receptor. Two signal transduction pathways, Ras/Raf/MEK/ERK and PI3K/Akt/mTOR/HIF, affect the proliferation and survival of HCC cells by regulating gene expression

Fig. 2

Development and clinical trials of molecular target and immune checkpoint medicines of HCC from 2007 to 2019. Orange: trials with positive results; blue: trials with negative results