J Clin Oncol. 2025 Aug 5:JCO2500812. doi: 10.1200/JCO-25-00812. Online ahead of print.
ABSTRACT
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.
PMID:40763319 | DOI:10.1200/JCO-25-00812
