Supplementary Material for: Relationship between Pulmonary Adverse Events and Everolimus Exposure in Japanese and Non-Japanese Patients: A Meta-Analysis of Oncology Trials

<i>Aims:</i> This meta-analysis explores the relationship between the everolimus minimum (Cmin) and maximum (Cmax) exposure and the risk for pulmonary adverse events (AEs) in Japanese versus non-Japanese patients. <i>Methods:</i> Patient-level data from patients treated with daily everolimus in advanced solid tumor trials were evaluated using a Cox regression model, stratified by cancer type or treatment arm, with log-transformed time-averaged Cmin or Cmax as a time-varying covariate. Kaplan-Meier analysis was used to evaluate the relationship between pulmonary AEs and pharmacokinetic parameters. <i>Results:</i> Thirty studies were identified. In the Cmin population (<i>n = </i>1,962), all-grade pulmonary AE incidence was significantly higher in Japanese versus non-Japanese patients (19.9 vs. 9.4%). Pharmacokinetic parameters were similar between Japanese and non-Japanese patients. A 2-fold increase in everolimus Cmin significantly increased the risk for the first any-grade pulmonary AE in Japanese (risk ratio: 1.824; 95% CI: 1.141-2.918) and non-Japanese patients (risk ratio: 1.406; 95% CI: 1.156-1.710). <i>Conclusions:</i> The risk for pulmonary AEs is related to everolimus exposure. Local monitoring and reporting differences might account for the significantly higher reported incidence of low-grade everolimus-associated pulmonary AEs in Japanese versus non-Japanese patients. Patients should be carefully monitored for early signs of pulmonary AEs, and appropriate medical management should be implemented.

研究目的：本荟萃分析旨在探讨依维莫司（everolimus）最低血药浓度（Cmin）与峰浓度（Cmax）的暴露水平，与日本患者及非日本患者发生肺部不良事件（AEs）的风险之间的关联。研究方法：本研究收集晚期实体瘤临床试验中接受每日依维莫司治疗的患者的患者个体水平数据，采用Cox回归模型按癌症类型或治疗组进行分层分析，以对数转换后的时间平均谷浓度（Cmin）或峰浓度（Cmax）作为时变协变量；同时采用Kaplan-Meier分析评估肺部不良事件与药代动力学参数之间的关联。研究结果：本研究共纳入30项相关研究。在谷浓度队列（n=1962）中，日本患者的全级别肺部不良事件发生率显著高于非日本患者（19.9% vs. 9.4%）。日本患者与非日本患者的药代动力学参数水平无显著差异。依维莫司谷浓度每升高2倍，日本患者首次发生任意级别肺部不良事件的风险显著升高（风险比：1.824；95%置信区间：1.141~2.918），非日本患者亦呈现相似的风险升高趋势（风险比：1.406；95%置信区间：1.156~1.710）。研究结论：肺部不良事件的发生风险与依维莫司的暴露水平密切相关。日本患者报告的低级别依维莫司相关性肺部不良事件发生率显著高于非日本患者，该差异可能源于地区间监测与报告标准的不同。临床实践中应密切监测患者肺部不良事件的早期体征，并采取恰当的医疗干预措施。