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

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.

A comprehensive English-language literature search was conducted on PubMed and ClinicalTrials.gov from January 2010 through September 2025 using the search terms datopotamab, datroway, breast cancer, or nonsmall cell lung cancer.

Evidence was gathered from clinical trials, relevant articles, guidelines, abstracts, and package inserts.

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.

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.

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.