Trastuzumab deruxtecan: Redefining precision oncology across HER2-driven cancers

Trastuzumab deruxtecan is a novel antibody-drug conjugate (ADC) that has redefined the therapeutic landscape of HER2-driven cancers. Built upon a humanized anti-HER2 monoclonal antibody linked to a potent topoisomerase I inhibitor via a cleavable tetrapeptide linker, T-DXd uniquely combines high drug-to-antibody ratio with a robust bystander effect, enabling efficacy even in tumors with heterogeneous or low HER2 expression. Clinical trials have demonstrated remarkable activity across a spectrum of malignancies, including breast, gastric, non-small cell lung, colorectal, and other solid tumors. In HER2-positive breast cancer, T-DXd significantly outperformed trastuzumab emtansine (T-DM1), with substantial improvements in progression-free and overall survival, while also showing benefit in HER2-low disease. In gastric cancer, T-DXd became the first ADC approved for HER2-positive tumors and demonstrated activity in HER2-low subgroups. Moreover, in HER2-mutant NSCLC and HER2-positive colorectal cancer, T-DXd achieved clinically meaningful responses, validating its role as a precision oncology agent beyond traditional HER2 amplification. The recent tumor-agnostic FDA approval highlights its broad clinical potential across solid tumors. This review summarizes the mechanism of action, pivotal clinical evidence, and emerging applications of T-DXd, underscoring its transformative role in modern oncology and outlining future prospects for combination strategies, biomarker-driven patient selection, and expanded global access.