Population Pharmacokinetics of Trastuzumab Deruxtecan in Patients With HER2‐Positive Breast Cancer and Other Solid Tumors

Abstract

Trastuzumab deruxtecan (T-DXd; DS-8201) is a HER2-targeting antibody-drug conjugate with a novel enzymecleavable linker, a topoisomerase I inhibitor payload, and a drug-to-antibody ratio of ≈ 8. We have characterized the population pharmacokinetics (PK) of T-DXd and released drug (free DXd) in patients with HER2-positive breast cancer or other solid tumor malignancies. This analysis includes pooled data from 5 clinical studies with 639 patients. T-DXd doses ranged from 0.8 to 8.0 mg/kg every 3 weeks. Serum concentrations of T-DXd and released drug were analyzed using a sequential 2-step approach, with the nonlinear mixed-effects modeling methods. Covariate assessment was based upon stepwise forward-addition and backward-elimination process, followed by both univariate and multivariate analysis quantifying their impact on steady-state exposure of T-DXd and released drug. A 2-compartment model with linear elimination best described PK profiles of intact T-DXd, while a 1-compartment model with time-varying release-rate constant and linear elimination described released-drug PK profiles. Statistically significant covariates (country, tumor size, sex, formulation, age, body weight, albumin, total bilirubin, and aspartate aminotransferase [AST]) resulted in < 20% change in steady-state AUC of T-DXd and released drug, except for increased body weight (95th percentile, 86 kg) and decreased albumin (5th percentile, 31 g/L). Analysis of patients stratified by country, race, renal function, and hepatic function found no clinically meaningful differences in steady-state exposure of intact T-DXd or released drug. Overall, results suggest that no dose adjustment based on tested covariates or in specific patient populations is warranted.

Exatecan Antibody Drug Conjugates Based on a Hydrophilic Polysarcosine Drug-Linker Platform

“…DS-8201a showed a favorable rat PK profile despite its relatively high overall hydrophobicity level. This observation is in accordance with previously reported primate PK studies of this ADC, even though a comparison with the native antibody was not provided [ 39 , 55 ]. A possible explanation could be that the PK profile of DS-8201a is favored by the progressive deruxtecan drug-linker deconjugation in plasma over time.…”

“…To address this issue, we investigated the in vitro cytotoxicity of Tra-Exa-PSAR10 in HER2+ breast (MDA-MB-361) and esophageal (OE-19) cancer cell lines that were rendered resistant to T-DM1. The characterization of T-DM1 resistance mechanisms of these two models demonstrated no alteration of HER2 expression in resistant OE-19 cells, whereas resistant MDA-MB-361 cells demonstrated heterogeneity in HER2 expression when compared to the parental cell line [ 55 , 56 ]. Our results showed that Tra-Exa-PSAR10 circumvented T-DM1-resistance in both cancer models.…”

Exposure‐Response Relationships in Patients With HER2‐Positive Metastatic Breast Cancer and Other Solid Tumors Treated With Trastuzumab Deruxtecan

“…Statistically significant covariates (country, tumor size, sex, formulation, age, body weight, albumin, total bilirubin, and aspartate aminotransferase (AST)) resulted in a < 20% change in steady‐state area under the concentration‐time curve (AUC) of intact T‐DXd and released drug, except for increased body weight (95th percentile, 86 kg) and decreased albumin (5th percentile, 31 g/L). Analysis of patients stratified by country, race, renal function, and hepatic function found no clinically meaningful differences in steady‐state exposure of intact T‐DXd or released drug 12 …”

“…Analysis of patients stratified by country, race, renal function, and hepatic function found no clinically meaningful differences in steady-state exposure of intact T-DXd or released drug. 12 Here, we characterize T-DXd exposure-response relationships with respect to key efficacy and safety end points to further support dose justification of T-DXd in patients with HER2-positive metastatic breast cancer.…”

“…T‐DXd was initially evaluated in the 2‐part, phase I J101 trial (NCT02564900) in patients with HER2‐expressing solid tumors 1,7 . In the dose‐escalation phase, no dose‐limiting toxicities were observed and the maximum tolerated dose was not reached (with a highest tested dose of 8.0 mg/kg); 5.4 and 6.4 mg/kg every 3 weeks (Q3W) were selected as the recommended doses for expansion on the basis of the observed clinical activity and safety profile, as well as pharmacokinetic (PK)‐pharmacodynamic (PD) modeling suggesting that intact T‐DXd trough concentration at steady‐state would exceed the target exposure derived from mouse xenograft studies (4,260 ng/mL) in > 90% of patients 8 . In addition, clinical observation showed a numerical increase in hematologic adverse events (i.e., decreased platelet count and decreased neutrophil count) in the high doses compared with the doses of 3.2 mg/kg or lower.…”