Exposure-Response Analyses of Datopotamab Deruxtecan (Dato-DXd), a TROP2-Directed Antibody-Drug Conjugate, in...

Datopotamab deruxtecan (Dato-DXd) is a trophoblast cell-surface antigen-2 (TROP2)-directed antibody-drug conjugate (ADC) that has demonstrated clinical activity in patients with NSCLC who have received prior therapies. Exposure-response (ER) analyses were conducted using Phase 1-3 clinical data from patients with NSCLC (efficacy and safety) or breast cancer (BC) (only safety). Parametric time-to-event models were developed for overall survival (OS), progression-free survival (PFS), and adverse events of special interest (AESI). Logistic regression models were used for overall response rate (ORR), Grade ≥ 3 treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs associated dose reduction. Covariate effects were assessed using stepwise selection. A significant linear ER relationship was found between Dato-DXd AUC in the first cycle (AUC₁) and OS. Drug effect on PFS and ORR was respectively described by a maximum effect (E_max) relationship with Dato-DXd AUC during a dosing interval (AUC_τ) and Dato-DXd average concentration (C_av), indicating near-maximal efficacy at 6 mg/kg. Baseline liver metastasis, squamous histology, and lower albumin (28.0 g/L, 5th percentile) were identified as significant risk factors of shortened OS and PFS, predicted to increase mortality risk by 52%, 48%, and 84%, respectively. The exposure-safety analysis identified Dato-DXd or DXd exposures as statistically significant predictors for safety endpoints except adjudicated drug-related interstitial lung disease (ILD)/pneumonitis for which no ER relationship was observed. These ER analyses support that the 6 mg/kg Q3W Dato-DXd regimen optimized the benefit-risk profile for patients with advanced nonsquamous NSCLC and identified clinically relevant factors that influence both survival and safety outcomes.