Novel Perspectives in Immune Checkpoint Inhibitors and the Management of Non-Alcoholic Steatohepatitis-Related Hepatocellular Carcinoma

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is a huge worldwide healthcare burden. The incidence of non-viral causes of hepatocellular carcinoma, such as non-alcoholic steatohepatitis (NASH), is rising. The introduction of immune checkpoint inhibitors (ICI) has led to a paradigm shift in the systemic treatment of HCC. However, not all patients can benefit from ICI. Recent studies have suggested that the response to ICI may allude to the underlying aetiology of HCC, such as NASH. Our review aims to summarise the latest evidence of ICI in advanced HCC, elaborates on the controversy surrounding the use of ICI in NASH-HCC, and discusses potential biomarkers that can be used to predict responses to ICI in advanced HCC. ABSTRACT: Immune checkpoint inhibitors have revolutionised the systemic treatment of advanced hepatocellular carcinoma. Although phase III trials, testing single agent nivolumab and pembrolizumab, failed to meet their primary endpoints, the combination of atezolizumab and bevacizumab has demonstrated a remarkable objective response and unprecedented survival benefits, replacing sorafenib as the standard first-line treatment for advanced hepatocellular carcinoma. Despite these successes observed in immune checkpoint inhibitors in the management of advanced hepatocellular carcinoma, not all patients responded to treatment, which has led to the search of risk factors and biomarkers that could predict the response to immune checkpoint inhibitors. Recent translational studies have begun to shed light on the impact of an underlying liver disease, namely NASH, which might affect the response to immune checkpoint inhibitors. In addition, antidrug-antibody and gene expression assays have demonstrated promises in predicting the response to immune checkpoint inhibitors. In this article, we will provide an overview of the use of ICI in the management of advanced HCC, review the evidence that surrounds the recent controversy regarding NASH-HCC, and discuss potential biomarkers that predict the response to immune checkpoint inhibitors.