US Food and Drug Administration Approval Summary: Trastuzumab Deruxtecan for the Treatment of Adult Patients With Hormone Receptor–Positive, Unresectable or Metastatic Human Epidermal Growth Factor Receptor 2–Low or Human Epidermal Growth Factor Receptor 2–Ultralow Breast Cancer

PURPOSE The US Food and Drug Administration (FDA) approved trastuzumab deruxtecan (T-DXd, DS-8201a) for patients with unresectable or metastatic breast cancer (MBC) who have tumor progression on previous endocrine therapy (ET) and have hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH]–) or HER2-ultralow (IHC 0 with membrane staining) tumors. PATIENTS AND METHODS Approval was based on DESTINY-Breast06, a randomized, open-label, multicenter trial of 866 patients with HR-positive breast cancer, including 713 patients with HER2-low and 153 with HER2-ultralow tumors. Patients were required to have progressed on previous ET and must not have received chemotherapy in the metastatic setting. Random assignment was 1:1 to T-DXd or investigator's choice of chemotherapy (paclitaxel, nab-paclitaxel, or capecitabine). Previous CDK4/6 inhibitor treatment, previous taxane use in the (neo)adjuvant setting, and HER2 status (IHC2+/ISH– v 1+ v IHC 0 with membrane staining) were stratification factors. RESULTS There was a statistically significant improvement in progression-free survival (PFS) by blinded independent central review (BICR) in the HER2-low population of 13.2 months (95% CI, 11.4 to 15.2) in the T-DXd arm and 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy arm (hazard ratio [HR], 0.62 [95% CI, 0.52 to 0.75], P < .0001). The trial also met its key secondary end point, PFS by BICR in the overall population, with a HR of 0.64 (95% CI, 0.54 to 0.76, P < .0001). CONCLUSION T-DXd is a new treatment option for patients with hormone receptor–positive, unresectable or MBC with HER2-low or HER2-ultralow tumors who have experienced progression on ET. This is the first indication specifying the category of HER2-ultralow expression in breast cancer, and an assay to select patients for this category was approved contemporaneously.