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

INTRODUCTION: 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. AREA COVERED: . 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. EXPERT OPINION: 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.