Trastuzumab deruxtecan (DS-8201a), a HER2-Targeting Antibody-Drug Conjugate with Topoisomerase I Inhibitor Payload, Shows Antitumor Activity in Uterine and Ovarian Carcinosarcoma with HER2/neu Expression (046)

Objectives: Carcinosarcomas (CSs) are highly aggressive gynecologic malignancies containing both carcinomatous and sarcomatous elements with heterogeneous HER2/neu expression. We evaluated the preclinical in vitro and in vivo activity of trastuzumab deruxtecan (DS-8201a), a novel HER2/neu-targeting antibody-drug conjugate (ADC) against primary uterine and ovarian CSs overexpressing HER2/neu. Methods: Twelve primary uterine and ovarian CS cell lines were evaluated for HER2/neu surface expression by immunohistochemistry (IHC) and by flow cytometry, and gene amplification by ¹³cytotoxicity, viability, and bystander killing effect assays. In vivo activity was studied in mouse CS xenograft models. Results: DS-8201a, as compared to MAAA-9199 control ADC, was found to be highly effective against uterine and ovarian CS cell lines demonstrating 3+ HER2/neu expression. Specifically, the mean half-maximal inhibitory concentrations (IC50's) were 0.02931 μg/mL and 9.75 μg/mL (p<0.0001) against 3+ HER2/neu uterine cell line, and 0.0285 μg/mL and 20.9 μg/mL (p<0.0001) against 3+ ovarian HER2/neu cell lines for DS-8201a versus MAAA-9199, respectively. There was no significant difference between DS-8201a and MAAA-9199 against CS cell lines with low/negligible HER2/neu expression. Importantly, DS-8201a induced an efficient bystander killing effect of HER2/neu negative tumor cells when admixed with 3+ HER2/neu cells. In vivo studies confirmed that DS-8201a was significantly more effective than MAAA-9199 in decreasing tumor volume and prolonging life in 3+ HER2/neu-expressing CS xenografts (attached Figure). There was no significant toxicity demonstrated between treatment and control groups. Conclusions: Trastuzumab deruxtecan (DS-8201a) is a novel ADC with remarkable activity against CS with strong (3+) HER2/neu expression. Clinical studies with DS-8201a in patients harboring chemotherapy-resistant CS with high HER2/neu expression are warranted. DS-8201a showing significant tumor growth inhibition in 3+ HER2/neu expression mice. Day 8 mean tumor volumes in treated mice with DS-8201a (0.271 cm3) versus ADC isotope control (0.859 cm3, p=0.0011) and vehicle control (0.804 cm3, p=0.0047). Day 11 mean tumor volumes in treated mice with DS-8201a (0.179 cm3) versus ADC isotope control (1.166 cm3, p <0.0001) and vehicle control (1.151 cm3, p <0.0001).Fig. 1