Remarkable preclinical activity of trastuzumab-deruxtecan (T-DXd) in FISH-negative, HER2 IHC 1+ and 2+ expressing primary endometrial cancer cell lines and xenografts.

OBJECTIVE: Antibody-drug conjugates (ADCs) targeting the human epidermal growth factor receptor 2 (HER2) such as trastuzumab deruxtecan (T-DXd) may offer a novel therapeutic option for endometrial cancer patients with HER2-overexpressing tumors. However, the activity of T-DXd in endometrial cancer patients with low HER2 expression (IHC 2+ or 1+, FISH negative) remains unreported. Accordingly, the objectives of this study were to evaluate T-DXd preclinical activity both in-vitro and in-vivo against primary FISH-negative endometrial endometrioid cancer (EEC) cell lines with IHC 1+ to 2+ HER2 expressions.

METHODS: Primary FISH-negative EEC cell lines with low HER2 expression were characterized by immunohistochemistry (IHC), flow cytometry (mean fluorescence intensity, MFI) and FISH assays. T-DXd efficacy was investigated in vitro by evaluating cell viability, DNA damage, antibody-dependent cell cytotoxicity and bystander killing. In vivo activity was assessed in HER2 2+ and 1+ FISH-negative EEC xenograft mouse model.

RESULTS: T-DXd demonstrated significant in-vitro cytotoxicity in HER2 FISH-negative, IHC 2+ and 1+ cell lines. By contrast, in the HER2 IHC 0 cell line, no significant difference in cell death was observed between T-DXd and Control ADC. In vivo, T-DXd was highly effective in tumor growth suppression and significantly prolonged overall survival in both HER2 IHC 2+ and 1+ xenograft mouse models.

CONCLUSIONS: T-DXd showed remarkable preclinical activity against HER2 FISH-negative, IHC-low EEC both in-vitro and in-vivo. These findings support its use beyond HER2-high expression and may represent a novel and effective treatment option for patients with HER2-low EEC who have progressed on standard chemotherapy and immunotherapy.