Disitamab vedotin in preclinical models of HER2-positive breast and gastric cancers resistant to trastuzumab emtansine and trastuzumab deruxtecan

Background: Most HER2-positive breast or gastric cancers eventually become resistant to the approved anti-HER2 antibody-drug conjugates (ADC) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). Disitamab vedotin (DV) is a novel anti-HER2 ADC that binds to a different epitope on HER2 compared to trastuzumab. We assessed the efficacy of DV in breast and gastric cancer cell lines and xenografts, including tumor models resistant to T-DM1 and T-DXd. Additionally, we investigated whether combining two anti-HER2 ADCs could enhance the efficacy of the individual ADCs. Methods: The efficacy of DV, T-DM1, and T-DXd, both as single agents and in combinations, was assessed using an AlamarBlue cell proliferation assay in HER2-positive breast and gastric cancer cell lines, including those resistant to T-DM1 and T-DXd. The efficacy of DV was evaluated also in breast and gastric cancer SCID mouse xenografts that had progressed on T-DM1 and/or T-DXd. ADC combinations were tested in breast and gastric cancer xenografts. Results: DV was effective in cell lines resistant to T-DM1 and/or T-DXd, and it inhibited the growth of breast and gastric cancer xenografts that had progressed on T-DM1 and/or T-DXd. The combinations of DV plus T-DM1 and DV plus T-DXd showed greater efficacy than the corresponding single agents in both breast and gastric cancer cell lines and xenografts. Conclusions: DV was effective in treating breast and gastric cancer xenograft tumors resistant to T-DM1 and/or T-DXd. The combination of DV with T-DM1 or T-DXd demonstrated promising activity.