The FDA Grants Priority Review to T-DXd/Pertuzumab in 1L Metastatic Breast Cancer

Results from the phase 3 DESTINY-Breast09 trial will support the FDA’s decision on whether to approve T-DXd plus pertuzumab in frontline metastatic breast cancer.

The FDA has accepted and granted priority review to a supplemental biologics license application (sBLA) for fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) plus pertuzumab (Perjeta) as a frontline therapy for adult patients with unresectable or metastatic HER2-positive breast cancer, according to a press release from AstraZeneca.1

The Prescription Drug User Fee Act date is anticipated to be in Q1 of 2026.

Notably, the sBLA was reviewed under the Real-Time Oncology Review program, which permitted the FDA to review aspects of the application before it was submitted. Previously, in July 2025, the FDA granted breakthrough therapy designation to the regimen in the same indication.2

The approval of the sBLA was based on results from the phase 3 DESTINY-Breast09 trial (NCT04784715), which evaluated T-DXd with or without pertuzumab compared with standard of care treatment in the first-line treatment of patients with HER2-positive breast cancer. Most recently, interim results from the trial were shared at the 2025 American Society of Clinical Oncology Annual Meeting.3

At the data cutoff of February 26, 2025, 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 standard of care (HR, 0.56; 95% CI, 0.44-0.71; P <.00001). The 6-month PFS rates were 93.0% (95% CI, 89.9%-95.2%) vs 87.8% (95% CI, 84.0%-90.7%), respectively, the 12-month PFS rates were 85.9% (95% CI, 81.9%-89.1%) vs 72.4% (95% CI, 67.4%-76.8%), and the 24-month PFS rates were 70.1% (95% CI, 64.8%-74.8%) vs 52.1% (95% CI, 46.4%-57.5%).

Across all prespecified subgroups, T-DXd demonstrated a consistent PFS improvement vs standard of care, including patients with de novo treatment status (HR, 0.49; 95% CI, 0.35-0.70), hormone receptor–negative status (HR, 0.52; 95% CI, 0.37-0.73), and a PIK3CA mutation (HR, 0.52; 95% CI, 0.35-0.77).

The objective response rate (ORR) with the T-DXd regimen was 85.1% (95% CI, 81.2%-88.5%), with 15.1% of patients achieving a complete response (CR), compared with an ORR of 78.6% (95% CI, 74.1%-82.5%), with 8.5% CRs, with standard of care. The median duration of response was 39.2 months (95% CI, 35.1-NC) vs 26.4 months (95% CI, 22.3-NC), respectively; 73.3% and 54.9% remained in response at 24 months, respectively, and 9.9% and 14.5% had stable disease.

Additionally, though overall survival (OS) was at approximately 16% maturity at data cutoff, a favorable trend for the T-DXd regimen has been observed (HR, 0.84; 95% CI, 0.59-1.19).

“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,” stated Susan Galbraith, executive vice president of Oncology Haematology R&D at AstraZeneca, in the press release.1 “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.”

DESTINY-Breast09 included 1157 patients who were randomly assigned, in a 1:1:1 ratio, to receive T-DXd plus pertuzumab (n = 383), standard of care consisting of a taxane, trastuzumab (Herceptin), and pertuzumab (n = 387), and T-DXd plus placebo (n = 387). T-DXd was administered at 5.4 mg/kg once every 3 weeks, and pertuzumab was given as an 840 mg loading dose, then 420 mg once every 3 weeks.

Eligible patients had HER2-positive advanced or metastatic breast cancer, no other prior systemic treatment for metastatic breast cancer, and a disease-free interval of at least 6 months from last chemotherapy or HER2-targeted therapy in the neoadjuvant/adjuvant setting; asymptomatic or inactive brain metastases, and one prior line of endocrine therapy for metastatic breast cancer were permitted.

The primary end point of the trial was PFS per BICR. A key secondary end point was OS; other secondary end points included ORR, DOR, and safety. Results from the T-DXd plus placebo arm have been blinded until the final PFS analysis.

Any treatment-emergent adverse event (TEAE) occurred in 99.7% of the T-DXd plus pertuzumab arm and 99.0% of the standard of care arm; possibly treatment-related TEAEs of grade 3 or higher occurred in 54.9% vs 52.4%.

TEAEs were associated with treatment discontinuation, dose interruptions, and dose reductions in 20.7%, 68.8%, and 45.9% of the T-DXd group, and 28.3%, 49.0%, and 19.9% of the standard of care group; TEAEs led to death in 3.4% and 0.8%, respectively, with 1.3% and 0.3% possibly being treatment-related.

AEs of special interest were adjudicated drug-related interstitial lung disease/pneumonitis, which occurred in 12.1% of the T-DXd arm and 1.0% of the standard of care arm, and left ventricular dysfunction, which occurred in 11.0% and 7.1%, respectively.

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/2256m25p
2. 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://tinyurl.com/yyvfzskc
3. 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.LBA1008