Genetic polymorphisms of VEGFR2 and FGFR2 genes are associated with exposure to sunitinib and cardiovascular toxicity

Sunitinib is a multikinase inhibitor used to treat metastatic renal cell carcinoma (mRCC), with an inter-individual variability of pharmacokinetics and toxicity. Our goal was to assess associations between the pharmacogenetics, pharmacokinetics and toxicity of sunitinib. In this multi-center prospective study, 42 patients with mRCC were included. An NGS panel was used to identify variations in 19 genes involved in sunitinib pharmacokinetics and pharmacodynamics. Residual concentration of sunitinib and N-desethyl-sunitinib were used to estimate a composite AUC at steady-state. Fifty-seven percent of patients had a plasma exposure within the optimal therapeutic range. A higher composite AUC led to significantly greater risk of endocrine toxicity (p = 0.008) and neurologic toxicity (p = 0.024), and to a non-significantly greater risk of cardiovascular toxicity (p = 0.11). A alleles of FGFR2-rs2981582 and VEFGFR2-rs1870377 were associated with a lower risk of cardiovascular toxicity (OR = 0.22 [0.05-0.97], p = 0.04 and OR = 0.17 [0.04- 0.73], p = 0.01 respectively) and with a lower composite AUC (p = 0.02 and p = 0.0002 respectively). We demonstrated for the first time, an association between genetics polymorphisms in sunitinib targets and extent of exposure to this molecule as well as their association associated with the risk of cardiovascular toxicity. We described the concentration dependence of neurological and endocrine toxicity. NCT02404584, registered 26 March 2015. Sunitinib is a multikinase inhibitor used to treat metastatic renal cell carcinoma (mRCC) and gastro-intestinal stroma tumor. Inter-individual variability in the pharmacokinetics and toxicity of this molecule is not yet well understood. We conducted a multi-center prospective study to assess associations between variations in genes involved in pharmacokinetics and pharmacodynamics identified by NGS, the exposure to sunitinib and its active metabolite (composite AUC) and the adverse events of sunitinib. Fifty-seven percent of patients had a plasma exposure within the optimal therapeutic range. We observed significant associations between sunitinib AUC and both endocrine and neurologic toxicities, suggesting that these specific adverse events are concentration-dependent. We described for the first time, associations between genetics polymorphisms in sunitinib targets (A alleles of FGFR2–rs2981582 and VEFGFR2-rs1870377) and extent of exposure to this molecule. Interestingly, the same polymorphisms were significantly associated with the risk of cardiovascular toxicity. Our study opens up new insights into the links between genetic polymorphisms of VEGF receptors, concentrations of s-VEGFR (circulating form of the receptors), plasma exposure to sunitinib, axitinib or other VEGF-inhibiting TKIs and the toxicity of these molecules.