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

Aims:  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.  Methods:  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.  Results:  Thirty studies were identified. In the Cmin population ( n =  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).  Conclusions:  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.