Exposure‐Response Analyses of Datopotamab Deruxtecan (Dato‐ DXd ), a TROP2 ‐Directed Antibody‐Drug Conjugate, in Advanced Non‐small Cell Lung Cancer

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 (AUC 1 ) 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.