Next-Generation HER2-Targeted ADCs: Comparative Mechanisms and Efficacy of T-DXd versus T-DM1 in Breast Cancer

Abstract

Breast cancer is widely regarded as the most prevalent cancer across populations worldwide, among which HER2-positive breast cancer represents a key subtype. A comparative analysis of two prominent HER2-directed antibody–drug conjugates (ADCs), namely trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), is presented in this study. Both take trastuzumab as the targeting basis, but they differ significantly in payload type, linker design and drug release mode. T-DM1 mainly acts on tumor cells with high HER2 expression and can effectively internalize the drug. Its released products have poor membrane permeability with relatively limited bystander effects. In contrast, T-DXd has a higher drug-toantibody ratio. The free toxins released by it can diffuse across cell membranes, generate effects on surrounding tumor cells and produce a bystander effect. Therefore, it also shows certain strengths in overcoming tumor heterogeneity and partial drug resistance. Existing clinical studies have shown that in advanced HER2-positive breast cancer, T-DXd presents superior disease control, survival benefits and remission effects compared with T-DM1. In HER2-low expression breast cancer, T-DXd also exhibits broader application potential, while the efficacy of T-DM1 is relatively limited. In general, nextgeneration ADCs have significantly improved the efficacy of HER2-targeting therapy through structural optimization. Further improvements are still needed in reducing toxicity, delaying drug resistance and promoting individualized treatment in the future.