Next-Generation HER2-Targeted Antibody-Drug Conjugates in Breast Cancer

Simple Summary Human epidermal growth factor receptor 2 (HER2) is amplified or overexpressed in approximately 20% of breast cancer cases. This overexpression is correlated with a more aggressive form of the disease and predicts a less favorable prognosis. Historically, the standard treatment for patients with HER2-positive breast cancer has involved chemotherapy in combination with monoclonal antibodies that target the HER2 receptor, notably trastuzumab and pertuzumab. However, resistance to these drugs has been ubiquitous, presenting challenges in the management of the disease. Antibody-drug conjugates (ADCs) represent a promising therapeutic category for the treatment of breast cancer. Trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) are currently approved ADCs. These molecules have been pivotal, demonstrating superior clinical outcomes over previous conventional treatments in HER2-positive breast cancer (T-DM1, T-DXd) and HER2-Low (T-DXd). However, drug resistance remains an unresolved problem, and there is interest in developing better-tolerated and more effective therapeutics for breast cancer. This review focuses on the emergence of innovative HER2-targeted ADCs, including those currently undergoing investigation in clinical trials.Abstract Human epidermal growth factor receptor 2 (HER2) tyrosine kinase is overexpressed in 20% of breast cancers and associated with a less favorable prognosis compared to HER2-negative disease. Patients have traditionally been treated with a combination of chemotherapy and HER2-targeted monoclonal antibodies such as trastuzumab and pertuzumab. The HER2-targeted antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) represent a novel class of therapeutics in breast cancer. These drugs augment monoclonal antibodies with a cytotoxic payload, which is attached by a linker, forming the basic structure of an ADC. Novel combinations and sequential approaches are under investigation to overcome resistance to T-DM1 and T-DXd. Furthermore, the landscape of HER2-targeted therapy is rapidly advancing with the development of ADCs designed to attack cancer cells with greater precision and reduced toxicity. This review provides an updated summary of the current state of HER2-targeted ADCs as well as a detailed review of investigational agents on the horizon. Clinical trials are crucial in determining the optimal dosing regimens, understanding resistance mechanisms, and identifying patient populations that would derive the most benefit from these treatments. These novel ADCs are at the forefront of a new era in targeted cancer therapy, holding the potential to improve outcomes for patients with HER2-positive and HER2-Low breast cancer.