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

René J. Boosman*, Merel Jebbink, Wouter B. Veldhuis, Stefanie L. Groenland, Bianca A.M.H. van Veggel, Pim Moeskops, Adrianus J. de Langen, Jos H. Beijnen, Egbert F. Smit, Alwin D.R. Huitema, Neeltje Steeghs

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: 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.

METHODS: A retrospective observational cohort study was performed, including patients receiving 40 - 80 mg osimertinib as ≥ 2 line therapy and from whom pharmacokinetic samples were collected during routine care. Trough plasma concentrations (C min,pred) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166 µg/L was taken to explore the exposure-efficacy relationship.

RESULTS: 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 C min,pred  < 166 µg/L and C min,pred  ≥ 166 µg/L, respectively (p = 0.03). In the multivariate analysis, a C min,pred  < 166 µg/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).

CONCLUSION: 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.

Original languageEnglish
Pages (from-to)2507-2514
Number of pages8
JournalPharmaceutical Research
Volume39
Issue number10
DOIs
Publication statusPublished - Oct 2022

Keywords

  • exposure–response analysis
  • NSCLC
  • osimertinib
  • pharmacokinetics-pharmacodynamics
  • Acrylamides
  • Aniline Compounds
  • Humans
  • Antineoplastic Agents/therapeutic use
  • ErbB Receptors/genetics
  • Pyrimidines
  • Lung Neoplasms/drug therapy
  • Carcinoma, Non-Small-Cell Lung/drug therapy
  • Protein Kinase Inhibitors/therapeutic use
  • Retrospective Studies
  • Indoles
  • Mutation

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