Exposure-Response Analysis of Osimertinib in EGFR Mutation Positive Non-Small Cell Lung Cancer Patients in a Real-Life Setting.

Abstract

Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung cancer (NSCLC). Clinical trials with osimertinib could not demonstrate an exposure-efficacy relationship, while a relationship between exposure and toxicity has been found. In this study, we report the exposure-response relationships of osimertinib in a real-life setting. A retrospective observational cohort study was performed, including patients receiving 40-80mg osimertinib as ≥ 2 line therapy and from whom pharmacokinetic samples were collected during routine care. Trough plasma concentrations (Cmin,pred) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166µg/L was taken to explore the exposure-efficacy relationship. A total of 145 patients and 513 osimertinib plasma concentration samples were included. Median progression free survival (PFS) was 13.3 (95% confidence interval (CI):10.3-19.1) months and 9.3 (95% CI: 7.2-11.1) months for patients with Cmin,pred < 166µg/L and Cmin,pred ≥ 166µg/L, respectively (p = 0.03). In the multivariate analysis, a Cmin,pred < 166µg/L resulted in a non-statistically significant hazard ratio of 1.10 (95% CI: 0.60-2.01;p = 77). Presence of a EGFR driver-mutation other than the exon 19 del or L858R mutations, led to a shorter PFS with a hazard ratio of 2.89 (95% CI: 1.18-7.08;p = 0.02). No relationship between exposure and toxicity was observed (p = 0.91). In our real-life cohort, no exposure-response relationship was observed for osimertinib in the current dosing scheme. The feasibility of a standard lower fixed dosing of osimertinib in clinical practice should be studied prospectively.