Abstract 1840: Potent antitumor efficacy of Dato-DXd compared with sacituzumab govitecan in brain metastases mouse model of triple negative breast cancer

Background: Metastatic brain tumors are common, especially in patients with triple-negative breast cancer (TNBC) and lead to poor prognosis. Current drug therapies are unsatisfactory, and the development of new drugs is needed. TROP2 is overexpressed in various cancers and an attractive target molecule in breast cancer. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) targeting TROP2 and designed to selectively release the payload in the tumor cell via a cleavable tetrapeptide-based linker. Dato-DXd has demonstrated preliminary intracranial activity in patients, but its pharmacodynamics in brain metastases is not yet clarified. Here, we evaluated the efficacy and payload distribution of Dato-DXd and sacituzumab govitecan (SG), another TROP2-directed ADC that was designed to be cleaved by hydrolysis which may result in gradual payload release in blood circulation and the tumor, in a mouse brain metastasis model of TNBC. Methods: We prepared a brain metastasis model by transplanting luciferase-expressing TROP2-positive TNBC cells into the brains of nude mice. To characterize ADC in treatment against intracranially transplanted tumors, the antitumor activity by measuring chemiluminescence and the concentration of the payload in tumors after intravenous administration of Dato-DXd were compared with those of SG. Results: Chemiluminescence showed that Dato-DXd administered at 10 mg/kg on Day 1 significantly reduced tumor size in the brain metastasis model compared with SG administered at 10 mg/kg on Days 1 (average -99.5% vs. -1.8%, p=0.02). Median survival was 18 days (95% confidence interval [CI]; 14-not assessed [NA] days) in control group, 48 days (15-NA days) in SG group, and 83 days (49-NA days) in Dato-DXd group. The DXd payload from Dato-DXd was rarely detected in the serum (Lower limit of quantification [LLOQ] of DXd: 0.01 ng/mL), while the SN-38 payload from SG was gradually increased (LLOQ of SN38: 0.015ng/mL). After administration of Dato-DXd, the payload in the tumor was accumulated and maintained, whereas the payload concentration gradually decreased in SG group (the area under the concentration-time curve [AUC] of the payload: 320.9 vs. 161.8 ng*hr/g). In contrast, the AUC of the payload in normal brain after administration of Dato-DXd was significantly lower than that after administration of SG (13.7 vs. 48.5 ng*hr/g). Conclusion: In this mouse model of brain metastases, Dato-DXd showed more potent antitumor activity against intracranially transplanted tumors of TNBC with higher accumulation of the payload in tumors compared with SG. The dosing utilized in this model does not directly correlate with human dosages, necessitating caution in interpreting the study results. This study warrants further clinical evaluation of Dato-DXd in TNBC patients with brain metastases. Citation Format: Chikako Funasaka, Hiroki Takashima, Daisuke Okajima, Tsuyoshi Karibe, Takanori Maejima, Satoru Yasuda, Toru Mukohara, Toshihiko Doi, Masahiro Yasunaga. Potent antitumor efficacy of Dato-DXd compared with sacituzumab govitecan in brain metastases mouse model of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1840.