Data from Antitumor Activity and Biomarker Analysis for TROP2 Antibody–Drug Conjugate Datopotamab Deruxtecan in Patient-Derived Breast Cancer Xenograft Models

<div>AbstractPurpose:<p>Datopotamab deruxtecan (Dato-DXd) is a humanized anti–trophoblast cell-surface antigen-2 (TROP2) IgG1 mAb linked to a potent topoisomerase I inhibitor payload (DXd). Dato-DXd has already shown antitumor activity in breast cancer; however, the determinants of response, including the importance of TROP2 expression, remain unclear. We tested the activity of Dato-DXd in a panel of breast cancer patient-derived xenografts (BCX) varying in TROP2 expression.</p>Experimental Design:<p>The antitumor activity of Dato-DXd and isotype-control-DXd (IgG-DXd) was assessed against 11 BCXs varying in TROP2 expression, 10 representing tumors postneoadjuvant chemotherapy. Pharmacodynamic effects were assessed at 24 and 72 hours. The effects of TROP2 expression on Dato-DXd activity was assessed <i>in vitro</i> and <i>in vivo</i> using viral overexpression in BCX-derived cell lines.</p>Results:<p>Models differed in their sensitivity to both Dato-DXd and IgG-DXd. Dato-DXd (10 mg/kg) led to objective response in 4 (36%) models and statistically significant prolongation of event-free survival in 8 (73%) models, whereas IgG-DXd (10 mg/kg) led to response in 1 (9%) and prolonged event-free survival in 3 (27%) models. TROP2 RNA and protein were significantly higher in Dato-DXd–sensitive models. In isogenic cell lines derived from Dato-DXd–resistant BCXs, overexpression of TROP2 conferred Dato-DXd antitumor activity <i>in vitro</i> and <i>in vivo</i>. Dato-DXd increased γH2AX and phospho-KAP1 in the two Dato-DXd–sensitive BCXs but not in a Dato-DXd–resistant BCX. In Dato-DXd–sensitive models, antitumor activity was enhanced in combination with a PARP inhibitor, olaparib.</p>Conclusions:<p>Dato-DXd is active in breast cancer models. Dato-DXd has TROP2-dependent and -independent mediators of activity; however, high TROP2 expression enhances Dato-DXd antitumor activity.</p></div>