Exposure-response analysis of osimertinib in EGFR mutation positive non-small cell lung cancer patients in a real-life setting

Boosman, R.J.; Jebbink, M.; Veldhuis, W.B.; Groenland, S.L.; Veggel, B.A.M.H. van; Moeskops, P.; Langen, A.J. de; Beijnen, J.H.; Smit, E.F.; Huitema, A.D.R.; Steeghs, N.

doi:doi:10.1007/s11095-022-03355-2

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,C-pred) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166 mu g/L was taken to explore the exposure-efficacy relationship. Results: A total of 145 patients and 513 osimertinib plasma concentration samples were...Show moreBackground: 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,C-pred) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166 mu g/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,C-pred < 166 mu g/L and C-min,C-pred >= 166 mu g/L, respectively (p = 0.03). In the multivariate analysis, a C-min,C-pred < 166 mu g/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.Show less

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Exposure-response analysis of osimertinib in EGFR mutation positive non-small cell lung cancer patients in a real-life setting