Sex-associated differences in osimertinib pharmacokinetics among Asian patients with non-small cell lung cancer.

3094 Background: Osimertinib is an oral, third-generation tyrosine kinase inhibitor (TKI) used in the treatment of epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancers (NSCLC). However, therein lies a high interindividual variability in osimertinib trough concentrations at steady state, which may in turn affect clinical outcomes. The study aimed to evaluate factors influencing osimertinib exposure and their potential impact on treatment response. Methods: This was a prospective single-institution study of Asian NSCLC patients receiving once daily 80mg osimertinib. Plasma concentrations of osimertinib and its metabolites, AZ5104 and AZ7550 were quantified at steady state using a validated LC-MS/MS method. Pharmacogenetic analysis was conducted using commercially available Taqman SNP genotyping assays. Results: A total of 177 Asian patients with Stage I-IV NSCLC tumors were enrolled. Median age was 65 (35-84) years old. Majority of patients were Chinese (90%), female (59%) and non-smokers (82%). Exon 19 deletions were present in 45% of patients. Subgroup analysis of 72 patients with available pharmacokinetic data showed no significant genotypic-phenotypic associations between CYP3A5*3, ABCB1 1236C>T, ABCB1 3435C>T, ABCB1 2677G>T/A and ABCG2 421C>A and osimertinib pharmacokinetics parameters. Sex was significantly associated with trough osimertinib levels and clearance, with females exhibiting 28% higher osimertinib levels and lower clearance compared with males ( P =0.0098). Similar trends were observed with AZ5104 and AZ7550 and osimertinib clearance ( P <0.001). No significant differences in overall survival and progression-free survival were observed between sexes. Analysis of best overall response showed that males were more likely to PD compared with females (OR=1.88, 95% CI; 0.54- 6.3) but this was not statistically significant ( P = 0.489). Conclusions: Our study showed that sex influences osimertinib pharmacokinetics, with females showing higher trough levels and lower clearance. These differences did not, however, translate into significant differences in survival or treatment response between males and females.