Trastuzumab Deruxtecan Dosing in Human Epidermal Growth Factor Receptor 2-Positive Gastric Cancer: Population Pharmacokinetic Modeling and Exposure-Response Analysis.

This study evaluated the benefit/risk of trastuzumab deruxtecan (T-DXd) 6.4 mg/kg in patients with HER2-positive gastric cancer using pharmacometrics. A population pharmacokinetic (PopPK) model was developed using data from patients with gastric cancer, breast cancer, or other tumors in T-DXd clinical trials primarily conducted in Asia. Post hoc model-estimated pharmacokinetic metrics were used in exposure-efficacy (objective response rates [ORRs]) and exposure-safety analyses. The PopPK analysis included 808 patients (217 with gastric cancer, 512 with breast cancer, 79 with other cancers). In gastric cancer, T-DXd 6.4 mg/kg steady-state exposure metrics were lower vs 6.4 mg/kg in breast cancer but similar to 5.4 mg/kg in breast cancer. Tumor type was selected as a significant covariate on T-DXd clearance. In exposure-efficacy analysis among 160 patients with gastric cancer, T-DXd steady-state minimum concentration was associated with confirmed ORR in univariate logistic regression analysis (P = 0.023). Model-predicted confirmed ORR in gastric cancer was 36.0% (90% CI, 29.3-43.7) with 5.4 mg/kg and 40.0% (90% CI, 33.1-47.6) with 6.4 mg/kg. Among 808 patients in exposure-safety analyses, model-predicted estimates of any-grade interstitial lung disease (ILD) over 180 days were 10.2 (90% CI, 8.7-12.8) with 6.4 mg/kg in gastric cancer and 9.7 (90% CI, 8.2-11.8) with 5.4 mg/kg in breast cancer. In gastric cancer, T-DXd efficacy was higher at 6.4 mg/kg than 5.4 mg/kg. Exposure and ILD rates were comparable between 6.4 mg/kg in gastric cancer and 5.4 mg/kg in breast cancer. This study identified T-DXd 6.4 mg/kg as the recommended dose in HER2-positive gastric cancer. This article is protected by copyright. All rights reserved.