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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  in vitro . Other MKI plus ICI combinations under investigation are evaluated. The results of the phase 1b COSMIC-021 study testing cabozantinib plus atezolizumab across numerous tumor types are presented along with the study design and the recent results of the phase 3 COSMIC-312 trial evaluating this combination as a front-line option for advanced HCC. 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.

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