There have been lack of clinical studies on the role of drug treatment in patients who
develop progressive disease with immune checkpoint inhibitors. Amongst HCC patients who
become intolerant or refractory to sorafenib, cabozantinib has been shown by phase III
clinical trial (CELESTIAL) to prolong the overall survival of patients, as compared to
placebo. It is expected more patients will be treated with immune checkpoint inhibitors in
future, hence it is clinically important to study the efficacy and toxicity of cabozantinib
after treatment with immune checkpoint inhibitors.
Further, both MET activation and upregulation of regulatory T cells are implicated in
resistance mechanism to immune checkpoint inhibitors. Immuno-modulatory effects of
cabozantinib have been described in vitro and in murine models for several cancers. Moreover,
cabozantinib appears to exert its effect on regulatory T cells (Tregs) via the HGF/c-Met
pathway, where this receptor signaling cascade mediates multiple immune cell functions. HGF
was shown to suppress DC function and in turn induce Tregs (CD4+ CD25+ FoxP3) in a murine
central nervous system (CNS) autoimmunity model. HGF cultured monocytes differentiate into
monocytic cells that produce soluble factors that favor immune suppressive conditions ideal
for tumor progression. Above immunomodulatory effects could enable cabozantinib to reverse
the immunosuppressive phenotype in patients after failure with immune checkpoint inhibitors.
The starting dose of cabozantinib of 60mg once daily in the current study is chosen in
accordance with approved dose by FDA for treatment of advanced HCC
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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