Exposure‐Response Relationships in Patients With HER2‐Positive Metastatic Breast Cancer and Other Solid Tumors Treated With Trastuzumab Deruxtecan
Trastuzumab deruxtecan (T‐DXd) is a HER2‐targeting antibody‐drug conjugate composed of a novel enzyme‐cleavable linker and membrane‐permeable topoisomerase I inhibitor payload. T‐DXd has been approved for HER2‐positive metastatic breast cancer and for HER2‐positive metastatic gastric cancer. The app...
Gespeichert in:
Veröffentlicht in: | Clinical pharmacology and therapeutics 2021-10, Vol.110 (4), p.986-996 |
---|---|
Hauptverfasser: | , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | Trastuzumab deruxtecan (T‐DXd) is a HER2‐targeting antibody‐drug conjugate composed of a novel enzyme‐cleavable linker and membrane‐permeable topoisomerase I inhibitor payload. T‐DXd has been approved for HER2‐positive metastatic breast cancer and for HER2‐positive metastatic gastric cancer. The approval in breast cancer was based on results from the DESTINY‐Breast01 (U201; NCT03248492) and J101 (NCT02564900) trials. Here, we present dose justification for the approved 5.4 mg/kg every‐3‐weeks (Q3W) dose based on exposure‐efficacy evaluated in patients with HER2‐positive breast cancer (N = 337) from these 2 trials. Exposure‐safety was assessed in patients with all tumor types (N = 639, n = 512 with breast cancer) across 5 trials, including J101 and DESTINY‐Breast01. T‐DXd doses ranged from 0.8–8.0 mg/kg Q3W; most patients received 5.4 (n = 312) or 6.4 mg/kg (n = 291). For each end point, multivariate logistic or Cox regression analysis was performed using various exposure metrics of T‐DXd and released drug. A statistically significant association was observed between intact T‐DXd area under the concentration‐time curve (AUC) and confirmed objective response rate (ORR; P = 0.028). No significant exposure‐response relationships were observed between intact T‐DXd or released drug and duration of response or progression‐free survival; however, follow‐up was limited. All evaluated safety end points demonstrated a significant (P |
---|---|
ISSN: | 0009-9236 1532-6535 |
DOI: | 10.1002/cpt.2291 |