Abstract 1704: Overcoming resistance in HER2-positive gastric and breast cancers: Efficacy of disitamab vedotin in preclinical models resistant to trastuzumab emtansine and trastuzumab deruxtecan

BACKGROUND: HER2-positive gastric and breast cancers often develop resistance to the approved antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). Disitamab vedotin (DV), a novel anti-HER2 ADC, binds to a distinct epitope on HER2 compared to trastuzumab. This study investigated the therapeutic potential of DV in preclinical models of gastric and breast cancer, including those resistant to T-DM1 and T-DXd and explored whether combining DV with these ADCs could enhance anti-tumor efficacy. METHODS: We evaluated the efficacy of DV, T-DM1, and T-DXd individually and in combination using AlamarBlue cell proliferation assays in HER2-positive gastric and breast cancer cell lines, including models resistant to T-DM1 and T-DXd. We assessed the in vivo efficacy of DV in SCID mouse xenograft models of gastric and breast cancer that had progressed on T-DM1 and/or T-DXd. We examined dual combinations of the three ADCs in xenograft models to evaluate potential synergistic effects. RESULTS: DV demonstrated significant anti-tumor activity in both in vitro and in vivo models, including cell lines and xenografts that were resistant to T-DM1 and T-DXd. In xenograft models, DV effectively inhibited tumor growth in cancers that had progressed following treatment with T-DM1 and/or T-DXd. Notably, combining DV with either T-DM1 or T-DXd resulted in superior anti-tumor effects compared to the use of single agents alone, both in cell culture and in xenograft studies. CONCLUSIONS: This study highlights the effectiveness of DV in overcoming resistance to T-DM1 and T-DXd in preclinical models of HER2-positive gastric and breast cancer. The combination of DV with these ADCs demonstrated enhanced efficacy, underscoring the potential of dual ADC strategies to improve outcomes in HER2-positive cancers. Citation Format: Negar Pourjamal, Vadim Le Joncour, György Vereb, Cilla Honkamaki, Jorma Isola, Jeffrey V Leyton, Pirjo Laakkonen, Heikki Joensuu, Mark Barok. Overcoming resistance in HER2-positive gastric and breast cancers: Efficacy of disitamab vedotin in preclinical models resistant to trastuzumab emtansine and trastuzumab deruxtecan [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 1704.