New Opportunities in the Systemic Treatment of Hepatocellular Carcinoma-Today and Tomorrow

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Liver cirrhosis, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease represent major risk factors of HCC. Multiple different treatment options are available, depending on the Barcelona Clinic Liver Cancer (BCLC) algorithm. Systemic treatment is reserved for certain patients in stages B and C, who will not benefit from regional treatment methods. In the last fifteen years, the arsenal of available therapeutics has largely expanded, which improved treatment outcomes. Nevertheless, not all patients respond to these agents and novel combinations and drugs are needed. In this review, we aim to summarize the pathway of trials investigating the safety and efficacy of targeted therapeutics and immunotherapies since the introduction of sorafenib. Furthermore, we discuss the current evidence regarding resistance mechanisms and potential novel targets in the treatment of advanced HCC.

Keywords: hepatocellular carcinoma; immunotherapy; monoclonal antibodies; targeted therapy; tyrosine kinase inhibitors.

Figure 1

A simplified representation of mechanism of action of targeted therapeutics. AKT—protein kinase B; ERK—extracellular signal-regulated kinase; FGFR—fibroblast growth factor receptor; FLT-3—FMS-like tyrosine kinase 3; MEK—mitogen-activated protein kinase; mTOR—mammalian target of rapamycin; PDGFR—platelet-derived growth factor receptor; PI3K—phosphatidylinositol 3-kinase; RAF—rapidly accelerated fibrosarcoma; RAS—rat sarcoma virus; VEGFR—vascular endothelial growth factor receptor.

Figure 2

A timeline of selected phase 2/3 HCC trials published after 2015.