Abstract 5642: Datopotomab deruxtecan (Dato-DXd), a TROP2 directed antibody-drug conjugate, demonstrates remarkable antitumor activity in uterine serous carcinoma

Abstract Objective: Uterine serous carcinoma is a rare biologically aggressive type of endometrial cancer associated with a high rate of mortality. Datopotamab deruxtecan (Dato-DXd) is a novel ADC composed of the humanized anti-TROP2 IgG1 monoclonal antibody, a cleavable tetrapeptide linker, and a topoisomerase I inhibitor payload. TROP2 expression is detected in up to 95% of uterine serous carcinoma (USC) cases, making it an excellent target for therapy. We evaluated the preclinical activity of Dato-DXd in vitro against primary USC cell lines with various TROP2 expression and in vivo in TROP2 overexpressing cell-line derived xenografts in mice. Methods: Primary USC cell lines were established from chemotherapy-naïve patients at time of surgery and analyzed by flow cytometry for TROP2 expression. USC cell lines with varying TROP2 expression levels were treated with scalar concentrations of Dato-DXd or a non-targeting ADC isotype control (CTL ADC). Flow cytometry-based assays were used to evaluate viability. RepresentativeTROP2 expressing USC were co-cultured with a TROP2 non-expressing USC cell line to evaluate bystander effect. Four-hour chromium release assays were used to evaluate Dato-DXd ability to induce antibody dependent cell cytotoxicity (ADCC) in vitro. Finally, mice xenograft models were established from a selected TROP2 3+ cell line (ie, USC-ARK2) to evaluate the in vivo activity of Dato-DXd vs treatment with vehicle, datopotomab (unconjugated antibody), or control (CTL) ADC with an endpoint of overall survival. Results: In vitro, TROP2 overexpressing cell lines demonstrated remarkable sensitivity to Dato-DXd compared to CTL ADC. When high TROP2 USC cells were admixed with TROP2 low-expression cells, significant bystander cytotoxicity was observed (p=0.03). Mechanistically, double stranded DNA breakage was demonstrated by increased phosphorylation of the histone H2AX in TROP2 positive cell lines after DATO-DXd exposure vs CTL ADC. In the TROP2 selected cell lines, both Dato-DXd and datopotomab were effective in inducing significant ADCC when challenged with heterologous peripheral blood lymphocytes (p= ≤ 0.05 ). In vivo, Dato-DXd demonstrated a significant survival advantage in mice xenografted with ARK2 compared to the other treatment groups (p<0.0001). By day 10, ARK-2 xenografted mice treated with Dato-DXd had significantly decreased growth when compared to the other three treatments which experienced continued linear growth. The median survival for Dato-DXd was not reached as all mice were still alive at the conclusion of the study on day 60 (p<0.0001). Conclusions: Dato-DXd demonstrates remarkable preclinical activity both in vitro as well as in vivo against biologically aggressive USC primary cell lines and xenografts. Clinical trials are warranted. Citation Format: Michelle Greenman, Cem Demirkiran, Stefania Bellone, Tobias Hartwich, Blair McNamara, Victoria Ettorre, Niccolo G. Santin, Namrata Sethi, Luca Palmieri, Yang Yang-Hartwich, Katyayani Papatla, Elena Ratner, Alessandro D. Santin. Datopotomab deruxtecan (Dato-DXd), a TROP2 directed antibody-drug conjugate, demonstrates remarkable antitumor activity in uterine serous carcinoma [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 5642.