Potent antitumor efficacy of datopotamab deruxtecan compared with sacituzumab govitecan in an intracranial tumor model of triple-negative breast cancer.

Metastatic brain tumors are common in patients with triple-negative breast cancer (TNBC) and often lead to a poor prognosis. Trophoblast cell surface antigen 2 (TROP2) is overexpressed in TNBC cells and an attractive target molecule in breast cancer. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate targeting TROP2 that selectively releases payloads in tumors. We evaluated the efficacy and tumor concentration of payload of Dato-DXd and sacituzumab govitecan (SG), another TROP2-directed antibody-drug conjugate, in an intracranial TNBC xenograft model. We established the intracranial tumor model by orthotopically transplanting luciferase-expressing TROP2-positive TNBC cells into the brains of nude mice. Dato-DXd intravenously administered at 10 mg/kg on day 1 significantly reduced tumor size compared with SG administered at 10 mg/kg (average -99.5% vs. -1.8%, p = 0.02). The median survival was 18 days (95% confidence interval [CI]: 14 to not assessed [NA] days) in the control group, 48 days (15 to NA days) in the SG group, and 83 days (49 to NA days) in the Dato-DXd group. The payload released from Dato-DXd was rarely detected in the plasma (DXd: 0.09 ng/mL at maximum [at 6h postdose]), while the released payload of SG in the plasma was much higher than Dato-DXd and gradually decreased (SN-38: 10.8 ng/mL at maximum [at 0h postdose]). Dato-DXd showed greater antitumor activity in the intracranial TNBC model with higher payload accumulation in tumors compared with SG. Further clinical evaluation of Dato-DXd in patients with brain metastasis from TNBC is warranted.