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

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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. TRIAL REGISTRATION: NCT02404584, registered 26 March 2015.