CLINICAL EFFICACY, SAFETY AND FUTURE HORIZONS OF TRASTUZUMAB DERUXTECAN (T-DXD) IN HER2 – DRIVEN TUMORS

Abstract

Trastuzumab deruxtecan (T-DXd, DS-8201, Enhertu®) is a next-generation antibody drug conjugate (ADC) that has transformed HER2-targeted therapy. It combines a humanized anti-HER2 monoclonal antibody with a potent topoisomerase I inhibitor payload via a cleavable linker enabling selective intracellular delivery and cytotoxicity while minimizing systemic exposure. The membrane permeable payload also produces a bystander killing effect allowing activity in tumors with heterogeneous or low HER2 expression. Preclinical studies demonstrated a high drug-to-antibody ratio, efficient linker cleavage and sustained tumor regression, supporting rapid clinical translation. Clinical trials and real world studies have confirmed the robust efficacy of T-DXd in HER2 positive and HER2 low breast and gastric cancers. Pivotal trials such as DESTINY-Breast01, DESTINY-Breast04 and DESTINY-Gastric01 showed significant improvements in progression free survival and objective response rates including in heavily pretreated patients. Real world evidence further validates the durable high objective response rates and meaningful survival benefits emphasizing its consistent effectiveness across diverse populations. Safety considerations include gastrointestinal toxicities, hematologic adverse events and a clinically significant risk of interstitial lung disease (ILD) highlighting the need for careful monitoring and early intervention. Challenges such as long term safety, resistance development and accessibility remain yet ongoing research aims to address these limitations. Future directions focus on combination strategies with immune checkpoint inhibitors or other HER2-targeted therapies, earlier-line use and biomarker guided patient selection to enhance efficacy, resistance and optimize safety. Overall, T-DXd represents a major advancement in ADC therapy, delivering potent targeted and durable anti tumor activity. Its proven clinical benefits, real world effectiveness and ongoing exploration in broader HER2 expressing malignancies underscore its evolving role as a versatile and personalized therapeutic option for patients with HER2 driven tumors.