Population Pharmacokinetics and Exposure-Response Analysis of First-Line Osimertinib Plus Chemotherapy in Patients with EGFR-Mutated Advanced NSCLC.

Osimertinib, a third-generation, central nervous system-active epidermal growth factor receptor-tyrosine kinase inhibitor, potently and selectively inhibits epidermal growth factor receptor-tyrosine kinase inhibitor sensitizing and T790M resistance mutations, with efficacy in epidermal growth factor receptor-mutated non-small cell lung cancer. In FLAURA2 (NCT04035486), first-line osimertinib plus platinum-pemetrexed chemotherapy showed significant improvement in progression-free survival over osimertinib monotherapy in patients with epidermal growth factor receptor-mutated advanced non-small cell lung cancer. A population pharmacokinetics analysis using cumulative pharmacokinetics data from 2,196 patients across six studies (AURA, AURA2, AURA3, ADAURA, FLAURA, and FLAURA2) assessed pharmacokinetics and its variability due to intrinsic and extrinsic factors. Upon a formal covariate search, none of the covariates retained in the final model had a clinically meaningful impact on the pharmacokinetics of osimertinib and its active metabolite, AZ5104. The osimertinib exposure derived from the population pharmacokinetics model was used to evaluate the relationship between osimertinib exposure and progression-free survival, as the efficacy primary end point, in the FLAURA2 combination arm. A Cox proportional hazard analysis indicated no exposure-progression-free survival relationship for osimertinib and its metabolite; the number of pemetrexed cycles was likely to be associated with progression-free survival. No exposure-safety relationship was observed between osimertinib exposure and the occurrence of adverse events, including those leading to osimertinib dose interruption/reduction/discontinuation, and other pre-determined adverse events. These results further reinforce the benefits of the FLAURA2 clinical data that establish osimertinib 80 mg once daily plus chemotherapy as a first-line treatment for patients with epidermal growth factor receptor-mutated advanced non-small cell lung cancer.