Dr Bardia on the FDA Approval of T-DXd for HER2-Low/-Ultralow Metastatic Breast Cancer

“[T-DXd] works in HER2-expressing breast cancers, which are the majority of breast cancers. Even if there's just some expression of HER2, that sufficient for this drug to work.”

Aditya Bardia, MD, MPH, FASCO, professor, Department of Medicine, Division of Hematology/Oncology, director, Translational Research Integration, UCLA Health Jonsson Comprehensive Cancer Center, discusses the significance of the FDA approval of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for patients with pretreated HER2-low and -ultralow metastatic breast cancer.

On January 27, 2025, the FDA approved T-DXd for the treatment of adult patients with unresectable or metastatic, hormone receptor–positive, HER2-low or -ultralow breast cancer, as determined by an FDA-approved test, who have progressed on at least 1 endocrine therapy in the metastatic setting. This regulatory decision was backed by data from the phase 3 DESTINY-Breast06 trial (NCT04494425). In the trial, among all patients with chemotherapy-naive, HER2-low or -ultralow metastatic breast cancer. The median progression-free survival was 13.2 months (95% CI, 12.0-15.2) with T-DXd vs 8.1 months (95% CI, 7.0-9.0) with chemotherapy (HR, 0.64; 95% CI, 0.54-0.76; P < .0001). Furthermore, the confirmed overall response rates were 62.6% and 34.4% with T-DXd and chemotherapy, respectively.

The HER2-low and HER2-ultralow disease classifications are operationally defined based on HER2 expression levels, with HER2-ultralow indicating expression in 10% or fewer tumor cells and HER2-low indicating expression in more than 10% of tumor cells, Bardia explains. This approval underscores the drug’s efficacy in the overall group of HER2-expressing breast cancers, which constitute most breast cancer cases, he adds. As an antibody-drug conjugate, T-DXd binds to HER2-expressing tumor cells and delivers a cytotoxic payload, making even minimal HER2 expression sufficient for therapeutic activity, he says. This approval expands treatment options for patients with hormone receptor–positive metastatic breast cancer, allowing for its use in earlier lines of therapy than previously authorized, he concludes.