Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Department of Thoracic Oncology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek, Amsterdam, The Netherlands.
Pharm Res. 2022 Oct;39(10):2507-2514. doi: 10.1007/s11095-022-03355-2. Epub 2022 Aug 17.
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 (C) 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 C < 166 µg/L and C ≥ 166 µg/L, respectively (p = 0.03). In the multivariate analysis, a C < 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.
奥希替尼是一种不可逆的表皮生长因子受体（EGFR）抑制剂，是治疗 EGFR 突变阳性非小细胞肺癌（NSCLC）的重要药物。奥希替尼的临床试验未能证明暴露与疗效之间存在关系，而暴露与毒性之间存在关系。在这项研究中，我们报告了真实环境中奥希替尼的暴露-反应关系。
进行了一项回顾性观察队列研究，纳入了接受 40-80mg 奥希替尼作为二线治疗且在常规治疗期间采集了药代动力学样本的患者。估计了谷底血浆浓度（C）并将其用作奥希替尼暴露的衡量标准。采用先前定义的探索性药代动力学阈值 166μg/L 来探索暴露与疗效的关系。
共纳入 145 名患者和 513 个奥希替尼血浆浓度样本。C<166μg/L 和 C≥166μg/L 的患者中位无进展生存期（PFS）分别为 13.3（95%置信区间[CI]：10.3-19.1）个月和 9.3（95%CI：7.2-11.1）个月（p=0.03）。在多变量分析中，C<166μg/L 导致非统计学意义上的危险比为 1.10（95%CI：0.60-2.01；p=77）。除外显子 19 缺失或 L858R 突变以外的 EGFR 驱动突变的存在会导致 PFS 更短，其危险比为 2.89（95%CI：1.18-7.08；p=0.02）。未观察到暴露与毒性之间存在关系（p=0.91）。
在我们的真实队列中，在当前给药方案中未观察到奥希替尼的暴露-反应关系。应前瞻性研究临床实践中奥希替尼标准低固定剂量的可行性。
