Cabozantinib plus atezolizumab for the treatment of advanced hepatocellular carcinoma: shedding light on the preclinical rationale and clinical trials.

Combining multikinase inhibitors (MKIs) with immune checkpoint inhibitors (ICIs) in advanced hepatocellular carcinoma (HCC) has a strong biological rationale. Among MKIs, cabozantinib seems an ideal partner for ICIs, playing a potentially synergistic role via a spectrum of immunomodulatory actions. This paper discusses the preclinical rationale for combining cabozantinib and atezolizumab in advanced HCC. It examines the mechanism of action of these agents and highlights their synergistic activities The eventual approval of novel combinations for advanced HCC will require careful patient selection and a refinement of study design for future trials. Regarding the search for predictive biomarkers, etiology and extent of disease may predict response to therapy. Moving cabozantinib to first-line, treatment sequencing should consider possible cross-resistance not only to ICIs but also to other MKIs. Finally, the response rates of such combinations may pave the way for their evaluation as peri-operative therapies.