奥西默替尼
Cmin公司
肺癌
医学
内科学
危险系数
肿瘤科
置信区间
药代动力学
表皮生长因子受体
药效学
毒性
药理学
胃肠病学
癌症
最大值
埃罗替尼
作者
R. Boosman,M. 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
标识
DOI:10.1007/s11095-022-03355-2
摘要
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 - 80 mg 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 166 µg/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 < 166 µg/L and Cmin,pred ≥ 166 µg/L, respectively (p = 0.03). In the multivariate analysis, a Cmin,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).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.
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