Abstract 6761: Antitumor activity of datopotamab deruxtecan in a co-clinical trial with patient derived xenografts

Abstract Trophoblast cell-surface antigen-2 (TROP2) is expressed in multiple cancers. Datopotamab deruxtecan (Dato-DXd) is an antibody drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload. Dato-DXd is FDA approved for hormone receptor-positive, HER2-negative breast cancer and EGFR-mutated non-small cell lung cancer following EGFR-directed therapy and platinum based chemotherapy. However, determinants of response and optimal combinations need further study. We performed a co-clinical trial, to determine the concordance of anti-tumor activity of Dato-DXd in patient derived xenografts (PDX) and matched patients treated with Dato-DXd (TP01) and to assess potential of combinations.We generated 23 PDX models of different cancer types: breast invasive ductal carcinoma, lung adenocarcinoma, urothelial carcinoma, esophageal adenocarcinoma, head and neck carcinoma and pancreatic adenocarcinoma (PDAC). Nineteen models were created from biopsies performed just before Dato-DXd treatment of patients and 4 models were generated after the patients acquired resistance to Dato-DXd. The antitumor efficacy of Dato-DXd and the isotype control-DXd (IgG-DXd) were tested. Antitumor activity was assessed by objective response and event-free survival (time to tumor doubling) per PDXNET metrics. Based on our results from a previous synergy screen in vitro, four PDAC cell lines were also treated with a combination of Dato-DXd and gemcitabine. A total of 49 models were implanted, and 23 PDX models generated across 6 tumor types (PDX take rate of 47%). Of 13 pretreatment PDXs tested for Dato-DXd efficacy: 5 (38.5%) had a partial response, 3 (23%) had stable disease, and 5 (38.5%) had progressive disease. Antitumor activity in PDXs was concordant with matched patients treated with Dato-DXd and assessed by RECIST V1.1. in 10 out of 13 (77%) models. Ten of 13 (77%) PDXs had significant prolongation of event-free survival (EFS). Among 4 PDAC PDXs tested 2 (50%) had prolongation of EFS. We sought to identify chemotherapy combinations that enhance activity of Dato-DXd in PDAC cell lines in vitro, and determined that the combination of Dato-DXd and gemcitabine was synergistic. A pretreatment PDX model was generated from a patient with PDAC who had received topoisomerase inhibitor treatment (FOLFIRINOX) as well as gemcitabine/abraxane, and had PD as best response to Dato-DXd. The PDX model progressed on both Dato-DXd and gemcitabine monotherapy, but the combination therapy showed tumor regression, and significantly prolonged event-free survival compared to monotherapy (p = 0.0067 for both comparisons). Dato-DXd has antitumor activity in several tumor types. Combinations may further enhance antitumor activity. Further studies are needed to explore the mechanisms of resistance and potential combinations. Citation Format: Dhruv Chachad, Kurt W. Evans, Ming Zhao, Erkan Yuca, Ran Zhang, Yasmeen Rizvi, Gabriela Raso, Argun Akcakanat, Stephen Scott, Justin M. Roberts, Ming Sun, Nakul Shah, Hong Zebger-Gong, Gunnar Klauss, Yui Tanaka, Daisuke Okajima, Funda Meric-Bernstam. Antitumor activity of datopotamab deruxtecan in a co-clinical trial with patient derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6761.