Unraveling the Synergy between Atezolizumab and Bevacizumab for the Treatment of Hepatocellular Carcinoma

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is a highly prevalent cancer with increasing incidence and a high mortality rate. Recently, a combination of an antiangiogenic drug and an immune checkpoint inhibitor, atezolizumab/bevacizumab, has been adopted as a new standard of care to treat advanced HCC. This review discusses the mode of action, clinical efficacy and biomarker research for both drug classes and for the combination therapy with additional insights from the renal cell carcinoma field. Furthermore, a deeper understanding of the pathophysiological mechanisms responsible for the assumed synergy between atezolizumab and bevacizumab is provided. ABSTRACT: Tyrosine kinase inhibitors (TKIs) with antiangiogenic properties, such as sorafenib, have been the standard choice to systemically treat hepatocellular carcinoma for over a decade. More recently, encouraging results were obtained using immune checkpoint inhibitors, although head-to-head comparisons with sorafenib in phase 3 trials could not demonstrate superiority in terms of overall survival. The IMbrave150 was a breakthrough study that resulted in atezolizumab/bevacizumab, a combination of an antiangiogenic and an immune checkpoint inhibitor, as a new standard of care for advanced HCC. This review discusses the mode of action, clinical efficacy, and biomarker research for both drug classes and for the combination therapy. Moreover, the synergy between atezolizumab and bevacizumab is highlighted, unraveling pathophysiological mechanisms underlying an enhanced anticancer immunity by changing the immunosuppressed to a more immunoreactive tumor microenvironment (TME). This is achieved by upregulation of antigen presentation, upregulation of T-cell proliferation, trafficking and infiltration, impairing recruitment, and proliferation of immunosuppressive cells in the TME. However, more insights are needed to identify biomarkers of response that may improve patient selection and outcome.