FDA Grants Priority Review to T-DXd for Post-Neoadjuvant HER2+ Early Breast Cancer

The FDA has accepted a supplemental biologics license application (sBLA) and granted priority review to trastuzumab deruxtecan (T-DXd; Enhertu) for the treatment of adult patients with HER2-positive (HER2+) early breast cancer who have residual invasive disease following neoadjuvant HER2-targeted therapy. The Prescription Drug User Fee Act target action date is set for the third quarter of 2026.¹

The sBLA is supported by results from the DESTINY-Breast05 trial (NCT04622319), a global, randomized, open-label phase 3 study in which T-DXd demonstrated a statistically significant 53% reduction in the risk of invasive disease recurrence or death compared with trastuzumab emtansine (T-DM1; Kadcyla) in patients with high-risk HER2+ early breast cancer with residual disease after neoadjuvant therapy (HR, 0.47; 95% CI, 0.34-0.66; P <.0001). The 3-year invasive disease-free survival (IDFS) rate was 92.4% with T-DXd vs 83.7% with T-DM1.

“While there has been significant progress in treating HER2-positive early breast cancer, managing patients at a higher risk of recurrence remains challenging. With this priority review, we move closer to bringing [T-DXd] to the post-neoadjuvant setting, offering more patients the opportunity for sustained long-term outcomes and a potential path to cure,” said Susan Galbraith, executive vice president, Oncology Hematology Research and Development, AstraZeneca, in a news release.

The FDA grants priority review designation to applications for medicines that, if approved, would represent a meaningful improvement in safety or efficacy over available treatments for serious conditions. The sBLA is also being reviewed under Project Orbis, a framework that enables concurrent regulatory evaluation of oncology medicines among international partner agencies. Regulatory submissions based on DESTINY-Breast05 data are additionally under review in the European Union and Japan.

T-DXd previously received breakthrough therapy designation from the FDA in this post-neoadjuvant setting, a designation intended to expedite development and review of investigational medicines that show preliminary evidence of substantial improvement over existing therapy for serious conditions with unmet need.²

Unmet Need in the Post-Neoadjuvant Setting

Approximately 1 in 5 breast cancers are classified as HER2+, a subtype associated with aggressive disease behavior and historically poor prognosis.¹ Despite multiagent neoadjuvant regimens, roughly half of patients with HER2+ early breast cancer do not achieve pathologic complete response (pCR) at the time of surgery, and failure to achieve pCR is associated with elevated risk of disease recurrence.

The current standard of care in the post-neoadjuvant setting—T-DM1—reduces recurrence risk compared with trastuzumab (Herceptin) alone; however, a substantial proportion of patients still experience disease recurrence or progression to metastatic disease. The 5-year survival rate for metastatic HER2+ breast cancer is approximately 30%, in contrast to nearly 90% for early-stage disease, underscoring the clinical importance of optimizing post-neoadjuvant therapy. Approximately 16,000 patients with HER2+ early breast cancer receive post-neoadjuvant therapy in the United States annually.

DESTINY-Breast05 Trial Design and Results

DESTINY-Breast05 enrolled 1635 patients across sites in Asia, Europe, North America, Oceania, and South America. Eligible patients had HER2+ breast cancer with residual invasive disease in the breast or axillary lymph nodes after neoadjuvant therapy, with high recurrence risk defined as presentation with inoperable disease prior to neoadjuvant treatment or pathologically positive axillary nodes at surgery. Patients were randomized to receive T-DXd (5.4 mg/kg) or T-DM1.

The primary end point was investigator-assessed IDFS, defined as time from randomization to first invasive local, axillary, or distant recurrence, or death from any cause. Results were published in The New England Journal of Medicine following presentation at the European Society for Medical Oncology (ESMO) 2025 Congress.

In addition to the primary end point, T-DXd significantly reduced the risk of disease recurrence or death by 53% vs T-DM1 (HR 0.47; 95% CI, 0.34-0.66; P <.0001). The drug also lowered risk of distant disease recurrence by 51% and reduced risk of brain metastasis events by 36% compared with T-DM1 (brain metastasis-free interval; HR 0.64; 95% CI, 0.35-1.17). IDFS findings were consistent across all prespecified subgroups. The safety profile of T-DXd in DESTINY-Breast05 was consistent with its established profile, with no new safety signals identified.

Mechanism of Action and Existing Approvals

T-DXd is a HER2-directed antibody-drug conjugate (ADC) comprising a HER2-targeting monoclonal antibody linked to a topoisomerase I inhibitor payload (DXd, an exatecan derivative) via a tetrapeptide-based cleavable linker. The drug is currently approved in more than 90 countries for the treatment of patients with unresectable or metastatic HER2+ breast cancer and has demonstrated clinical activity across a range of HER2-expressing tumor types, including HER2-low and HER2-ultralow breast cancer, HER2-mutant non–small cell lung cancer, and HER2+ gastric and gastroesophageal junction adenocarcinoma.

REFERENCES

1. Enhertu granted Priority Review in the US as post-neoadjuvant treatment for patients with HER2-positive early breast cancer. News release. AstraZeneca. March 9, 2026. Accessed March 9, 2026. https://tinyurl.com/t9e5r238

2. Enhertu granted Breakthrough Therapy Designation in the US as post-neoadjuvant therapy for patients with HER2-positive early breast cancer. News release. AstraZeneca. December 22, 2025. Accessed March 9, 2026. https://tinyurl.com/2y84hmyw