Dr. Pacheco on the Mechanism of Action of Trastuzumab Deruxtecan in HER2-Overexpressing Metastatic NSCLC

Jose Pacheco, MD, an assistant professor of Medicine-Medical Oncology at the University of Colorado Anschutz Medical Campus, discusses the mechanism of action of trastuzumab deruxtecan (Enhertu) in patients with HER2-overexpressing metastatic non–small cell lung cancer.

Trastuzumab deruxtecan consists of an antibody that targets HER2 proteins, Pacheco says. Eight topoisomerase I–inhibiting chemotherapy molecules are attached to the HER2 antibody via a cleavable linker, he continues.

The antibody-drug conjugate attaches to HER2 proteins on the outside of the cell and undergoes endocytosis, with the drug complex being taken into the cell. Within the cell's lysosome, cleavage from the linker occurs and the topoisomerase I inhibitor is released inside the cell, Pacheco says. However, the chemotherapy molecules are known to leave the cell and damage nearby cells that may not express HER2, Pacheco concludes.