Cabozantinib: An evolving therapy for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is rising in incidence and remains a leading cause of cancer-related death. After a decade of disappointing trials following the approval of sorafenib for patients with advanced HCC, a number of tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting angiogenesis and immune checkpoints have recently been approved. The phase 3 CELESTIAL trial demonstrated improved progression-free and overall survival with the TKI cabozantinib compared to placebo, supporting it as a treatment option for patients with advanced HCC previously treated with sorafenib. Cabozantinib blocks multiple key pathways of HCC pathogenesis, including VEGFR, MET, and the TAM (TYRO3, AXL, MER) family of receptor kinases, and promotes an immune-permissive tumor microenvironment. Here, we review the mechanisms of action of cabozantinib, including effects on tumor growth and its immunomodulatory properties, providing pre-clinical rationale for combination strategies with checkpoint inhibitors. We discuss the design and outcomes of CELESTIAL including improved survival across subgroups defined by age, disease etiology, baseline AFP level, prior therapies (including duration of prior sorafenib), and tumor burden. Cabozantinib had a manageable safety profile with dose modification. Studies combining cabozantinib with atezolizumab (COSMIC-312) and durvalumab (CAMILLA) in the first and second-line settings are ongoing, as well as a neoadjuvant study of cabozantinib with nivolumab. Future investigations are warranted to define the use of cabozantinib in patients with Child-Pugh B liver function and identify markers predictive of clinical benefit. The role of cabozantinib in HCC continues to evolve with an anticipated role in immunotherapy combinations.