PII-136 - PHARMACOKINETICS OF TRASTUZUMAB DERUXTECAN (T-DXD) IN SUBJECTS WITH HER2-LOW METASTATIC BREAST CANCER

Z. Lu¹, S. Hennig², L. Li¹, E. Kamiyama³, P. Vaddady¹, M. Abutarif¹, T. Garimella¹, A. Khatri¹; ¹Quantitative Clinical Pharmacology, Daiichi-Sankyo, Inc, ²Certara, Inc., ³Quantitative Clinical Pharmacology, Daiichi Sankyo Co., Ltd..

Background: Pharmacokinetic (PK) characterization of T-DXd, a HER2-targeting antibody-drug conjugate, and DXd, a topoisomerase I inhibitor payload in HER2-low metastatic breast cancer (mBC) population was conducted using data across tumor types from 10 Phase 1 to 3 clinical trials.

Methods: A population PK (PopPK) analysis was performed using nonlinear mixed effects modeling approach using NONMEM® (version 7.4.3), similar to previous analysis in HER2-positive mBC [Yin O et al. Clin Pharmacol Ther. 2021 ;109(5):1314-1325].

Results: Data across T-DXd doses of 0.8 to 8 mg/kg from 1675 subjects, including1128 BC subjects, of which 485 were HER2-low BC, were included. The PK was adequately described by a two-compartment model with linear elimination for T-DXd with production of DXd modeled using a time-varying release rate from T-DXd [1]. T-DXd elimination clearance and volume of distribution of central and peripheral compartments were estimated at 0.410 L/day, 2.68 L and 6.64 L, respectively. DXd elimination clearance was estimated at 19.6 L/hour.

All covariates identified showed < 20% change in T-DXd and DXd steady-state area under the concentration-time curve at steady-state (AUCss), indicating no clinically meaningful effect, except for subjects with high body weight (90 kg; 95th percentile) showing a 30% T-DXd and a 36% higher DXd AUCss, respectively, relative to a 59 kg typical BC subject. These differences in T-DXd or DXd exposures were not considered clinically meaningful based on exposure-response analyses. T-DXd and DXd AUCss was comparable across HER2-low and HER2-positive mBC subjects. In HER2-low BC subjects T-DXd and DXd AUCss were similar across subgroups of interests: mild hepatic or mild or moderate renal impairment (vs. normal counterparts), region (Asia, North America, Europe, and rest of the world), and race-country (Asian-Japan, Asian-Non-Japan, and Non-Asian).

Conclusion: T-DXd and DXd exposures were comparable across subjects with HER2-low and HER2-positive mBC, and across different hepatic and renal function, region, and race-country groups within HER2-low mBC, supporting the dosing recommendation of 5.4 mg/kg in HER2-low mBC from PK perspective.