Targeting TROP2 Across Solid Tumors: The Clinical Profile and Role of Datopotamab Deruxtecan

OBJECTIVE: To evaluate the pharmacology, efficacy, safety, and clinical use of datopotamab deruxtecan (Dato-DXd), a recently approved trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate (ADC), in the treatment of advanced solid tumors. DATA SOURCES: . STUDY SELECTION AND DATA EXTRACTION: Evidence was gathered from clinical trials, relevant articles, guidelines, abstracts, and package inserts. DATA SYNTHESIS: Dato-DXd received accelerated approval by the Food and Drug Administration (FDA) in 2025 for hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer, and epidermal growth factor receptor (EGFR)-mutant nonsmall cell lung cancer (NSCLC). In the TROPION-Breast01 trial, Dato-DXd demonstrated superior efficacy with a response rate of 36.4% versus 22.9% for chemotherapy and median progression-free survival of 6.9 versus 4.9 months. In NSCLC, TROPION-Lung01 showed a response rate of 26.4% with Dato-DXd compared with 12.8% with docetaxel. For the approved EGFR-mutant NSCLC indication, the TROPION-Lung05 trial demonstrated a response rate of 35.8% with Dato-DXd. Treatment-related adverse events included stomatitis, nausea, alopecia, and ocular events, with interstitial lung disease/pneumonitis representing the most clinically significant safety concern. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The TROP2-directed ADC appears to be a viable therapeutic alternative for select patients with previously treated HR+/HER2- breast cancer or EGFR-mutant NSCLC after progression on targeted therapy. CONCLUSIONS: Dato-DXd offers a promising treatment option for heavily pretreated patients with HR+/HER2- breast cancer and EGFR-mutant NSCLC, providing meaningful clinical benefit with a manageable safety profile. Optimal sequencing and positioning within the rapidly shifting ADC landscape requires further investigation.