Exposure-Response Analyses of Datopotamab Deruxtecan (Dato-DXd) in Patients with Hormone Receptor (HR) Positive, Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Cancer.

Dato-DXd (datopotamab deruxtecan) is an anti-TROP2 antibody-drug conjugate developed for the treatment of unresectable or metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer (HR+/HER2-BC) who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease. Associations between Dato-DXd or its payload DXd pharmacokinetics (PK) and various efficacy and safety endpoints were investigated in the current analysis. Exposure-efficacy analysis was conducted in a total of 352 patients with HR+/HER2-BC who received Dato-DXd at 6 mg/kg every 3 weeks (Q3W). Area under the curve in cycle 1 (AUC1) was identified as a significant covariate of overall survival (OS), with higher Dato-DXd exposure associated with longer OS. Progression-free survival (PFS) showed a positive trend with higher exposure, though baseline tumor size emerged as a more significant predictor in multivariable analyses. Exposure-safety analysis revealed correlations between higher Dato-DXd or DXd PK metrics and increased risk of selected safety events, including stomatitis and ocular surface events. PopPK analysis showed that Dato-DXd exposure increased with body weight, and implementing a capped dose of 540 mg for patients ≥90 kg helped normalize exposure across weight groups. Exposure-safety analysis further supported that this approach may reduce the potential associated safety risks. These results support the recommended Dato-DXd dosing regimen (6 mg/kg Q3W with dose capping for patients ≥90 kg) and highlight its favorable benefit-risk profile in patients with HR+/HER2-breast cancer.