Anti-tumor activity and biomarker analysis for TROP2-antibody drug conjugate Datopotamab deruxtecan in patient-derived breast cancer xenograft models.

Autor:	Meric-Bernstam F; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Yuca E; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Evans KW; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Zhao M; The University of Texas MD Anderson Cancer Center, Houston, United States., Maejima T; Daiichi Sankyo, Inc., Basking Ridge, NJ, United States., Karibe T; Daiichi Sankyo Co., Ltd., Tokyo, Japan., Raso MG; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Tang X; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Zheng X; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Rizvi YQ; The University of Texas MD Anderson Cancer Center, United States., Akcakanat A; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Scott SS; The University of Texas MD Anderson Cancer Center, Houston, United States., Wang B; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Byers LA; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Tripathy D; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Okajima D; Daiichi-Sankyo (Japan), Tokyo, Japan., Damodaran S; The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Nov 25. Date of Electronic Publication: 2024 Nov 25.
DOI:	10.1158/1078-0432.CCR-24-1948
Abstrakt:	Background: Datopotamab deruxtecan (Dato-DXd), is a humanized anti-TROP2 IgG1 monoclonal antibody 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 (BCXs) varying in TROP2 expression. Methods: The antitumor activity of Dato-DXd and isotype-control-DXd (IgG-DXd) was assessed against 11 BCXs varying in TROP2 expression, 10 representing tumors post-neoadjuvant chemotherapy. Pharmacodynamic effects were assessed at 24 and 72 hours. The effects of TROP2 expression on Dato-DXd activity was assessed in vitro and in vivo using viral overexpression in BCX-derived cell lines. Results: 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 (EFS) in 8 (73%) models while IgG-DXd (10 mg/kg) led to response in 1 (9%) and prolonged EFS in 3 (27%) models. TROP2 RNA and protein was 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 in vitro and in vivo. Dato-DXd increased γH2AX and phospho-KAP1 in the 2 Dato-DXd-sensitive BCXs but not in a Dato-DXd-resistant BCX. In Dato-DXd-sensitive models, antitumor activity was enhanced in combination with PARP inhibitor, olaparib. Conclusion: 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.
Databáze:	MEDLINE
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