Associate Director, QCP Daiichi Sankyo, Inc. Somerville, New Jersey, United States
Background: Patritumab deruxtecan (HER3-DXd) is a HER3-targeting antibody-drug conjugate with a topoisomerase I inhibitor payload (DXd) with a drug-to-antibody ratio of approximately 8. HER3-DXd was well tolerated in phase 1 and 2 studies in adults showing promising anti-tumor activity and is being evaluated for non-small cell lung cancer at 5.6 mg/kg Q3W. The objective of this work was to use model-informed approach to support HER3-DXd dosing regimens in future pediatric development. Methods: A population PK (PPK) model was previously developed from a pooled dataset of phase 1-3 studies in adult cancer patients receiving doses from 1.6 to 8 mg/kg. A virtual pediatric population (vPop) was generated by nonparametric sampling of demographic variables (e.g. age, weight) and patient covariates (e.g. clinical chemistry, organ function) from NHANES database (1999 to 2020, n=24124) and the PPK dataset (n=733), respectively. The PPK model was used to simulate PK exposure in this vPop. Dosing based on weight and body surface area (BSA) were evaluated by comparing the simulated pediatric exposure metrics (AUC, Cmax, Ctrough) of the intact ADC and DXd with the simulated adult exposure at 5.6 mg/kg Q3W. Results: Weight-based dosing of 5.6 mg/kg Q3W in patients ≥6 years resulted in comparable exposure to adults with up to 22% difference in median AUC, Cmax, and Ctrough of intact ADC and DXd. In patients < 6 years dosed with 5.6 mg/kg, AUC and Ctrough of intact ADC and DXd were lower than adults by up to 30% and 51%, respectively. An age-corrected weight-based dosing, where this younger age group ( < 6 years) received a higher mg/kg dose, addressed the under-exposure in AUC and Ctrough, but led to an increased median Cmax of intact ADC and DXd by up to 38% and 60%, respectively. BSA-based dosing resulted in even higher exposure by increasing both median AUC and Cmax by up to 38% and 85%, respectively, for intact ADC and 61% and 122%, respectively, for DXd, which could increase the risk of DXd-related toxicities. Conclusion: The adult dose of 5.6 mg/kg Q3W is supported by the PK simulation as the initial starting dose for patients ≥6 years. Doses for patients < 6 years will be informed by data from patients ≥6 years of age. This approach provided a quantitative framework to support the dosing of HER3-DXd in pediatric cancer patients by leveraging the PPK model in adults and the NHANES database.
