FDA Grants Priority Review to First-Line T-DXd Plus Pertuzumab in Metastatic HER2+ Breast Cancer

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

The Prescription Drug User Fee Act target action date for the decision is expected during the first quarter of 2026.

The sBLA was supported by findings from the phase 3 DESTINY-Breast09 trial (NCT04784715), in which the combination of T-DXd and pertuzumab (n = 383) reduced the risk of disease progression or death by 44% compared with a taxane plus trastuzumab (Herceptin) and pertuzumab (THP; n = 387; HR, 0.56; 95% CI, 0.44-0.71; P < .00001).1,2 The median progression-free survival (PFS) by blinded independent central review (BICR) was 40.7 months (95% CI, 36.5-not calculable [NC]) with T-DXd plus pertuzumab vs 26.9 months (95% CI, 21.8-NC) with THP. The PFS benefit in the T-DXd arm was consistent across patient subgroups.

Additionally, the confirmed overall response rate (ORR) was 85.1% (95% CI, 81.2%-88.5%) in the T-DXd plus pertuzumab arm compared with 78.6% (95% CI, 74.1%-82.5%) in the THP arm. In total, 58 patients (15.1%) in the T-DXd plus pertuzumab arm achieved a complete response vs 33 (8.5%) of those in the THP arm.

“The DESTINY-Breast09 trial showed that treating patients with HER2-positive metastatic breast cancer with [T-DXd] in combination with pertuzumab until progression in the first-line setting produced a new landmark of more than 40 months for PFS and nearly doubled the number of patients with no evidence of disease on imaging,” Susan Galbraith, executive vice president of Oncology Haematology R&D at AstraZeneca, stated in a news release. “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.”

Previously, in July 2025, the FDA granted breakthrough therapy designation to the combination for this indication.3

“[T-DXd] in combination with pertuzumab delayed disease progression for more than 3 years compared to around 2 years with current standard of care [SOC] as a first-line treatment for patients with HER2-positive metastatic breast cancer,” Ken Takeshita, global head of R&D at Daiichi Sankyo, added in the news release.1 “Receiving priority review moves us closer to offering [T-DXd] to patients even earlier in the metastatic treatment pathway as a potential new first-line treatment option.”

What Was the Design of the DESTINY-Breast09 Trial?

The global, multicenter, randomized, open-label trial is investigating the efficacy and safety of T-DXd at 5.4 mg/kg as monotherapy or in combination with pertuzumab compared with SOC THP in the first-line setting in patients with HER2-positive metastatic breast cancer.1,2 Patients were randomly assigned 1:1:1 between the 3 arms and stratified by prior treatment (de novo metastatic disease vs progression from early-stage disease), hormone receptor status, and PIK3CA mutation status.

PFS by BICR is the primary end point in both T-DXd arms. Secondary end points include PFS by investigator assessment, overall survival, ORR, duration of response, pharmacokinetics, and safety. The portion of the trial investigating T-DXd monotherapy vs THP remains blinded to patients and is planned to continue to its final PFS analysis.

What Were the Safety Findings From DESTINY-Breast09?

The safety profile of T-DXd plus pertuzumab in the DESTINY-Breast09 trial was consistent with the known safety profiles of the individual agents. No new safety concerns were reported. Any treatment-emergent adverse effects (TEAEs) were reported in 99.7% of patients in the T-DXd/pertuzumab arm vs 99.0% of those in the THP arm.2 The most common possibly treatment-related any-grade TEAEs in the T-DXd/pertuzumab arm included nausea (71.1%), diarrhea (55.9%), neutropenia (48.8%), fatigue (48.3%), alopecia (46.2%), and vomiting (42.0%).

References

1. Enhertu 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://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-plus-pertuzumab-granted-priority-review-us-1st-line-treatment-patients-with-her2-positive-metastatic-breast-cancer.html
2. Tolaney SM, 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. doi:10.1200/JCO.2025.43.17_suppl.LBA100
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 September 24, 2025. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202507/20250717_E.pdf