LAUSR

Background: Capicua-double homeobox 4 (CIC-DUX4)-rearranged sarcomas (CDS) are extremely rare and highly aggressive sarcomas. There is no standard therapy for the patients with advanced CDS, and therapeutic development is needed. We evaluated preclinical efficacy of trastuzumab deruxtecan (T-DXd), a humanized monoclonal HER2-targeting antibody conjugated to a topoisomerase 1 inhibitor, DXd, in patient-derived xenograft (PDX) models with CDS. Methods: Patient-derived tumor tissue was transplanted into subcutaneous around the flank of female NOG mice, which were treated with vehicle or T-DXd (3 mg/kg, intravenous, Day0) when the mean tumor volume reached 200 mm3. Tumor volume was assessed twice weekly for 3 weeks to assess the efficacy of T-DXd. Results: This study included 3 CDS-derived PDXs. HER2 expression was low in one PDX and not expressed in two PDXs. One PDX was established from a specimen at initial diagnosis, two were established from specimens after prior-chemotherapy. T-DXd demonstrated significant tumor growth delay compared to vehicle in all PDX models investigated. One PDX with no efficacy was HER2-negative and had a treatment history of topoisomerase I inhibitor. In contrast, PDX of HER2-negative topoisomerase I inhibitor-resistant Ewing sarcoma was also administered T-DXd under the same conditions and was found to be refractory. Conclusion: The present study showed that a therapeutic potential of T-DXd in CDS patients, including HER2-negative. Citation Format: Yuki Kojima, Shigehiro Yagishita, Kazuki Sudo, Tatsunori Shimoi, Shintaro Iwata, Shun-ichi Watanabe, Chitose Ogawa, Akihiko Yoshida, Yasushi Yatabe, Kan Yonemori, Akinobu Hamada. Trastuzumab deruxtecan, antibody-drug conjugate targeting HER2, effectively inhibits growth of patient-derived xenograft model with CIC-rearranged sarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3995.