Bridging sunitinib exposure to time-to-tumor progression in hepatocellular carcinoma patients with mathematical modeling of an angiogenic biomarker

Hepatocellular carcinoma (HCC) is third in cancer-related causes of death worldwide and its treatment is a significant unmet medical need. Sunitinib is a selective tyrosine kinase inhibitor of the angiogenic biomarker: soluble vascular endothelial growth factor receptor-2 (sVEGFR₂). Sunitinib failed its primary overall survival endpoint in patients with advanced HCC in a phase III trial compared to sorafenib. In the present study, pharmacokinetic-pharmacodynamic modeling was used to link drug-exposure to tumor-growth-inhibition (TGI) and time-to-tumor progression (TTP) through sVEGFR₂ dynamics. The results suggest that 1) active drug concentration (i.e., sunitinib and its metabolite) inhibits the release of sVEGFR₂ and that such inhibition is associated with TGI, and 2) daily sVEGFR₂ exposure is likely a reliable predictor for the TTP in HCC patients. Moreover, the model quantitatively links the dynamics of an angiogenesis biomarker to TTP and accurately predicts observed literature-reported results of placebo treatment.