ABSTRACT:
The clinical validation of second and third generation antibody-drug conjugates (ADCs) has significantly transformed the therapeutic approach to treating malignancies that express human epidermal growth factor receptor 2 (HER2). Trastuzumab emtansine (T-DM1), the first HER2-targeted ADC to receive approval, set a standard for delivering microtubule-inhibiting agents through a stable, non-cleavable linker. Nonetheless, its effectiveness is often limited by poor membrane permeability, which reduces its efficacy in tumours with varied HER2 expression. Trastuzumab deruxtecan (T-DXd) marks a pivotal advancement in engineering, featuring a cleavable peptide linker, a notably higher drug-to-antibody ratio of 8:1, and a membrane-permeable topoisomerase I inhibitor payload. This review offers an in-depth comparative analysis of these two agents, integrating data from key trials such as DESTINY-Breast03, DESTINY-Breast05, and DESTINY-Breast06. We assess the pharmacological strategies that enable T-DXd to overcome resistance to T-DM1, particularly focusing on the bystander killing effect and the induction of immunogenic cell death. Furthermore, the analysis explores the expansion of the therapeutic target into HER2-low and HER2-ultralow categories, a shift uniquely facilitated by T-DXd's architecture. Shifting safety paradigms, including the risk of interstitial lung disease for T-DXd versus the manageable hepatobiliary and hematologic toxicities of T-DM1, are assessed to provide a framework for optimal therapeutic sequencing in the modern ADC era.