The antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization–negative) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by a FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic setting.
The approval was granted by the FDA after securing Priority Review and Breakthrough Therapy Designation and was based on results from the DESTINY-Breast06 Phase III trial, which were presented by Curigliano et al at the 2024 ASCO Annual Meeting (LBA1000) and published in December 2024 by Bardia et al in The New England Journal of Medicine.
Aditya Bardia, MD, MPH
Aditya Bardia, MD, MPH, Program Director of Breast Oncology and Director of Translational Research Integration at UCLA Health Jonsson Comprehensive Cancer Center, and investigator in the DESTINY-Breast06 trial, said: “Endocrine therapy is typically used in the initial treatment of HR-positive metastatic breast cancer and following progression, subsequent chemotherapy is associated with poor outcomes. With a median progression-free survival exceeding 1 year and a response rate of more than 60%, trastuzumab deruxtecan offers a potential new standard of care for patients with HR-positive, HER2-low or HER2-ultralow metastatic breast cancer following endocrine therapy.”
DESTINY-Breast 06 Findings
In the trial, T-DXd showed a 36% reduction in the risk of disease progression or death vs chemotherapy (hazard ratio = 0.64, 95% confidence interval = 0.54-0.76, P < .0001) in the overall trial population of patients with chemotherapy-naive HER2-low or HER2-ultralow metastatic breast cancer. A median progression-free survival of 13.2 months was seen in patients assigned to receive T-DXd compared to 8.1 months in those receiving chemotherapy. The confirmed objective response rate in the overall trial population was 62.6% for T-DXd vs 34.4% for chemotherapy.
In an exploratory analysis of patients with HER2-ultralow expression, results were seen to be consistent between patients with HER2-low expression and HER2-ultralow expression.
HER2 status in the trial was confirmed by a central laboratory and was performed on a tumor sample obtained at the time of initial metastatic diagnosis or later. Approximately 85% to 90% of patients with HR-positive, HER2-negative metastatic breast cancer were determined to have actionable levels of HER2 expression. Further, nearly two-thirds of patients previously assessed as IHC 0 at a local laboratory were classified as HER2-low or HER2-ultralow upon central analysis of the tumor sample.
The safety profile of T-DXd in DESTINY-Breast06 was consistent with previous clinical trials of the agent in patients with breast cancer, with no new safety concerns identified.
T-DXd is a specifically engineered HER2-directed DXd antibody-drug conjugate that is already approved in more than 75 countries, including the United States, for patients with HER2-low metastatic breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial. Regulatory applications are under review in the European Union, Japan, and several other countries based on the DESTINY-Breast06 results.
