T-DXd Earns FDA Priority Review in First-Line HER2+ Breast Cancer

The FDA has granted priority review to the supplemental biologics license application (sBLA) of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for the first-line treatment of patients with unresectable or metastatic HER2-positive breast cancer.¹

The Prescription Drug User Fee Act target action date is anticipated during the first quarter of 2026. The sBLA is being reviewed under the FDA’s Real-Time Oncology Review program, which allows the FDA to review components of the application before the submission of the complete application.

The sBLA is supported by data from the phase 3 DESTINY-Breast09 study (NCT04784715) presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

“The DESTINY-Breast09 trial showed that treating patients with HER2-positive metastatic breast cancer with [T-DXd] in combination with pertuzumab [Perjeta] until progression in the first-line setting produced a new landmark of more than 40 months for progression-free survival [PFS] and nearly doubled the number of patients with no evidence of disease on imaging. This marks the first major evolution in treatment in this first-line setting in more than a decade—a setting where a strong response is crucial, as up to one third of patients may not receive second-line therapy,” said Susan Galbraith, executive vice president of Oncology Hematology Research and Development at AstraZeneca, in a press release.

The median PFS in DESTINY-Breast09 was 40.7 months (95% CI, 36.5–not calculable [NC]) with T-DXd plus pertuzumab vs 26.9 months (95%, 21.8–NC) with a taxane plus trastuzumab (Herceptin) and pertuzumab (THP; HR, 0.56; 95% CI, 0.44–0.71; P <.00001).²

In the T-DXd and THP arms, respectively, the PFS rates were 93.0% (95% CI, 89.9%–95.2%) vs 87.8% (95% CI, 84.0%–90.7%) at 6 months, 85.9% (95% CI, 81.9%–89.1%) vs 72.4% (95% CI, 67.4%–76.8%) at 12 months, and 70.1% (95% CI, 64.8%–74.8%) vs 52.1% (95% CI, 46.4%–52.3%) at 24 months.

The safety profile of T-DXd plus pertuzumab was comparable to prior reports of each individual agent. Any-grade treatment-emergent adverse effects (TEAEs) in the T-DXd and THP arms, respectively, included nausea (71.1% vs 28.8%), diarrhea (55.9% vs 54.2%), neutropenia (48.8% vs 44.5%), and fatigue (48.3% vs 34.6%). Additionally, the most common grade 3 or higher TEAEs in each arm included neutropenia (23.9% vs 33.2%), hypokalemia (10.2% vs 1.6%), and anemia (8.4% vs 3.7%).

In July, the FDA granted breakthrough therapy designation to T-DXd in the first-line setting, also supported by the DESTINY-Breast09 data, underscoring T-DXd’s substantial improvements over other therapies in the field.³

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 breakthrough therapy designations 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® (fam-trastuzumab deruxtecan-nxki) plus pertuzumab granted Priority Review in the US as 1st-line treatment for patients with HER2-positive metastatic breast cancer. News release. AstraZeneca. September 24, 2025. Accessed September 24, 2025. https://tinyurl.com/yc3ud2zm

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.

3. 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