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Trastuzumab deruxtecan gains FDA Approval: expanding treatment options for HER2-low breast cancer

On January 27, 2025, the U.S. Food and Drug Administration (FDA) recently approved trastuzumab deruxtecan (T-DXd) for patients with human epidermal growth factor receptor 2 (HER2)-low and HER2-ultralow metastatic breast cancer.1 This approval reflects a growing understanding of HER2 expression as a spectrum rather than a strict binary classification, where patients previously classified as HER2-negative (Immunohistochemistry [IHC] scores of 0 or 1+) are now considered for T-DXd treatment following endocrine therapy. This marks an improvement on the standard of care of chemotherapy, which provides suboptimal response rates.2,3

This decision was based on findings from the Phase III, randomized, open-label DESTINY-Breast06 trial (NCT04494425), which evaluated the efficacy and safety of T-DXd versus chemotherapy (investigator’s choice of capecitabine, paclitaxel or nab-paclitaxel) in 866 patients. The primary endpoint, progression-free survival (PFS), was met, where PFS was significantly improved in the T-DXd arm (13.2 months versus 8.1 months, 95% CI, 0.51, 0.74). Furthermore, no new safety concerns have been identified and the safety profile of T-DXd remains consistent across trials.4 The findings build upon results from the DESTINY-Breast04 trial (NCT03734029), which demonstrated the initial superiority of T-DXd in terms of PFS (10.1 months versus 5.4 months, 95% CI, 0.40 to 0.64) and overall survival (23.9 months versus 17.5 months, CI, 0.48 to 0.86) compared to chemotherapy.5

We recently spoke with Giuseppe Viale, MD, FRCPath, University of Milan, Milan, Italy, who commented on the significance of T-DXd in this setting, stating that:

“So my take home lesson is that since T-DXd has proven to be effective both in the HER2 low and in the ultra low [settings], it is very important that patients whose tumors have been scored zero in the past will be retested in order to see whether actually they are eligible for the treatment”

While T-Dxd has demonstrated substantial clinical benefit, ongoing research is essential to refine patient selection criteria and optimize treatment sequencing. Beyond breast cancer, T-Dxd is being evaluated across multiple tumor types with low HER2 expression; including gastric, colorectal, and lung cancers.1 This approval represents a therapeutic milestone for patients previously ineligible for HER2-directed therapy, where they can now be considered for T-DXd following endocrine therapy.

References:

  1. Enhertu approved in the US as first HER2-directed therapy for patients with HER2-low or HER2-ultralow metastatic breast cancer following disease progression after one or more endocrine therapies [Internet]. AstraZeneca; [cited 2025 Jan 29]. Available from: https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-approved-in-us-for-breast-cancer-post-et.html
  2. ‌National Cancer Institute. Female Breast Cancer Subtypes – Cancer Stat Facts [Internet]. SEER; [cited 2025 Jan 29]. Available from: https://seer.cancer.gov/statfacts/html/breast-subtypes.html
  3. Manohar PM and Davidson NE. Updates in endocrine therapy for metastatic breast cancer. Cancer biology & medicine. 2021 Oct 19(2):202–212. doi:10.20892/j.issn.2095-3941.2021.0255
  4. Curigliano G, Hu X, Dent RA, Yonemori K, Barrios CH, O’Shaughnessy J, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): Primary results from DESTINY-Breast06 (DB-06). Journal of clinical oncology. 2024 Jun;42. doi:10.1200/JCO.2024.42.17_suppl.LBA1000
  5. Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. New England Journal of Medicine. 2022 Jun 387(1):9-20. doi:10.1056/NEJMoa2203690