Cabozantinib: An evolving therapy for hepatocellular carcinoma

Abstract

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.

AXL Knock-Out in SNU475 Hepatocellular Carcinoma Cells Provides Evidence for Lethal Effect Associated with G2 Arrest and Polyploidization

“…AXL is one of the several receptor kinases inhibited by Cabozantinib, a drug recently approved for the treatment of advanced HCCs [5]. The role of AXL inhibition in the efficacy of Cabozantinib treatment is not known.…”

“…A newly approved drug for second-line therapy, Cabozantinib, inhibits the activity of several receptor tyrosine kinases, including VEGFR, MET, and AXL, a member of the TAM (TYRO3, AXL, MER) family [5]. TAM family of receptors are expressed selectively in different normal cells, in particular, macrophages, and mediate the clearance of dead cells by efferocytosis [6,7].…”

A 10-Gene Signature Identified by Machine Learning for Predicting the Response to Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma

“…TSPAN8, S100A8, TYRO3, LOX, and PEG10, which were upregulated in nonresponders in our study, have been identified as indicators of a poor prognosis in HCC and could promote HCC progression by multiple mechanisms, such as proliferation, invasion, and metastasis [ 16 – 18 ]. Additionally, the overexpression of TYRO3 mediates sorafenib resistance and could serve as a potential target of cabozantinib [ 19 , 20 ]. LOX, as an extracellular matrix (ECM) remodeling enzyme, might stiffen the ECM and support angiogenesis surrounding the tumor tissue, thereby contributing to the TACE nonresponse phenotype [ 21 ].…”

A Novel Microcrystalline BAY-876 Formulation Achieves Long-Acting Antitumor Activity Against Aerobic Glycolysis and Proliferation of Hepatocellular Carcinoma

“…Among them, Sorafenib is the most widely used (75)(76)(77). In order to overcome the shortcomings of Sorafenib, newly molecular targeted drugs including Regorafenib, Lenvatinib and Cabozantinib have been approved for marketing one after another (78)(79)(80). Although it is currently believed that these drugs are generally superior to Sorafenib, these agents (lenvatinib, regorafenib, and carbozantinib) have the same chemical core structure (1-(4-(pyridin-4-yloxy)phenyl) urea) with sorafenib (81).…”