T-DXd Breakthrough Designation Signals New Era for HER2-Positive Metastatic Breast Cancer

The FDA has granted breakthrough therapy designation to the combination of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and pertuzumab (Perjeta) for the first-line treatment of adult patients with unresectable or metastatic HER2-positive breast cancer.¹ This significant designation, the ninth for T-DXd from Daiichi Sankyo and AstraZeneca, underscores the compelling preliminary clinical results from the phase 3 DESTINY-Breast09 trial (NCT04784715), suggesting a substantial improvement over existing therapies for this aggressive disease.

Breakthrough therapy designation is a mechanism designed by the FDA to expedite the development and regulatory review of investigational medicines that address serious conditions and demonstrate preliminary clinical evidence of substantial improvement over available therapies on a clinically significant endpoint. The designation for T-DXd combined with pertuzumab highlights the urgency and potential impact of this regimen for patients facing a poor prognosis with current standard-of-care treatments.

The basis for this designation stems from pivotal data presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.² The DESTINY-Breast09 trial, a global, multicenter, randomized, open-label, phase 3 study, evaluated the efficacy and safety of T-DXd either as monotherapy or in combination with pertuzumab vs the current standard of care, taxane, trastuzumab (Herceptin), and pertuzumab, in treatment-naive patients with HER2-positive metastatic breast cancer. Patients were randomized 1:1:1 across the 3 treatment arms. The primary end point of the study is progression-free survival (PFS) as assessed by blinded independent central review (BICR). Secondary end points include investigator-assessed PFS, overall survival (OS), objective response rate (ORR), duration of response (DOR), pharmacokinetics, and safety. The trial enrolled 1157 patients across various sites globally.

“This breakthrough therapy designation provides further recognition of the potential benefit of [T-DXd] in combination with pertuzumab in the first-line setting of HER2-positive metastatic breast cancer,” said Ken Takeshita, MD, global head of research and development at Daiichi Sankyo, in a press release.¹ “If approved, [T-DXd] will continue to redefine the treatment of metastatic breast cancer, as these latest results from DESTINY-Breast09 demonstrate a median progression-free survival of more than three years when using [T-DXd] plus pertuzumab in this disease setting, which is an improvement over the current standard of care that has been in place for more than a decade.”

HER2-positive metastatic breast cancer represents a critical unmet medical need. Approximately 1 in 5 breast cancer cases are HER2-positive, an aggressive subtype characterized by the overexpression of the HER2 growth-promoting protein. Despite advancements in HER2-targeted therapies, metastatic disease remains challenging, with only about 30% of patients diagnosed with or progressing to this stage expected to survive 5 years postdiagnosis. Furthermore, approximately 1 in 3 do not receive subsequent lines of therapy after first-line treatment due to rapid disease progression or death. The potential for a new first-line option offering extended progression-free survival is therefore of immense clinical importance.

T-DXd is a specifically engineered HER2-directed antibody-drug conjugate (ADC) developed using Daiichi Sankyo's proprietary DXd ADC Technology. It comprises a HER2 monoclonal antibody linked to a topoisomerase I inhibitor payload via a cleavable tetrapeptide-based linker. This design allows for targeted delivery of the cytotoxic payload to HER2-expressing cancer cells, minimizing systemic toxicity. The drug has already received multiple prior BTDs and approvals across various HER2-expressing cancers, including different lines of therapy for HER2-positive and HER2-low metastatic breast cancer, non–small cell lung cancer, metastatic gastric or gastroesophageal junction adenocarcinoma, and solid tumors.

REFERENCES:

1. Enhertu® plus pertuzumab granted breakthrough therapy designation in the U.S. as first-line therapy for patients with HER2-positive metastatic breast cancer. News release. Daiichi Sankyo. July 17, 2025. Accessed July 21, 2025. https://tinyurl.com/2f5wepd8

2. Tolaney S, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): interim results from DESTINY-Breast09. J Clin Oncol. 2025;43(suppl 17):LBA1008.