Trastuzumab deruxtecan in breast cancer
Miguel Martín, Atanasio Pandiella, Emilio Vargas, Elena Díaz‐Rodríguez, Teresa Iglesias-Hernangómez, Concha Martínez Cano, Inés Fernández-Cuesta, Elena Winkow, Maria Perelló
Abstract
Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) consisting of a humanised, anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody covalently linked to a topoisomerase I inhibitor cytotoxic payload (DXd). The high drug-to-antibody ratio (8:1) ensures a high DXd concentration is delivered to target tumour cells, following internalisation of T-DXd and subsequent cleavage of its tetrapeptide-based linker. DXd’s membrane-permeable nature enables it to cross cell membranes and potentially exert antitumour activity on surrounding tumour cells regardless of HER2 expression. T-DXd’s unique mechanism of action is reflected in its efficacy in clinical trials in patients with HER2-positive advanced breast cancer (in heavily pretreated populations and in those previously treated with a taxane and trastuzumab), as well as HER2-low metastatic breast cancer. Thus, ADCs such as T-DXd have the potential to change the treatment paradigm of targeting HER2 in metastatic breast cancer, including eventually within the adjuvant/neoadjuvant setting. • Antibody-drug conjugates have significantly improved breast cancer (BC) treatment. • Trastuzumab deruxtecan’s (T-DXd) structure allows large payload delivery to targets. • T-DXd has demonstrated unprecedented efficacy in patients with HER2+ advanced BC. • T-DXd has significantly improved survival rates in heavily pretreated BC patients. • T-DXd may change the treatment paradigm of targeting HER2 in metastatic BC.