FDA approval summary
On December 15, 2025, the U.S. Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo, Inc.) in combination with pertuzumab for the first-line treatment of adults with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-approved test.
At the same time, the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and the HER2 Dual ISH DNA Probe Cocktail were approved as companion diagnostic devices for selecting HER2-positive breast cancer patients for this regimen.
Full prescribing information for Enhertu will be posted on Drugs@FDA.
DESTINY-Breast09 trial (NCT04784715)
Efficacy was evaluated in DESTINY-Breast09 (NCT04784715), a randomized, three-arm, multicenter, global phase 3 trial in patients with HER2-positive advanced or metastatic breast cancer who had not received prior chemotherapy or HER2-targeted therapy for advanced or metastatic disease, or who had completed neoadjuvant/adjuvant HER2-targeted therapy more than six months before the diagnosis of advanced or metastatic disease. A single line of endocrine therapy for advanced or metastatic breast cancer was allowed.
- Design: Randomized, three-arm, multicenter, global trial
- Patients: 1,157 adults with HER2-positive advanced or metastatic breast cancer
- Treatment arms (1:1:1 randomization):
- Fam-trastuzumab deruxtecan-nxki 5.4 mg/kg plus pertuzumab (n = 383)
- THP (taxane [docetaxel or paclitaxel], trastuzumab, and pertuzumab) (n = 387)
- An investigational therapy arm (n = 387)
- All treatments were administered by intravenous infusion every three weeks until disease progression or unacceptable toxicity.
The major efficacy outcome was progression-free survival (PFS) as assessed by blinded independent central review (BICR) using RECIST v1.1. Additional efficacy outcomes included overall survival (OS) and confirmed objective response rate (ORR) by BICR.
Efficacy: substantial PFS benefit vs THP
In the primary comparison, fam-trastuzumab deruxtecan-nxki plus pertuzumab was superior to THP (taxane + trastuzumab + pertuzumab) in terms of PFS. The investigational arm was not part of this approval.
- PFS (BICR):
- Enhertu + pertuzumab: median 40.7 months (95% CI: 36.5, not estimable)
- THP: median 26.9 months (95% CI: 21.8, not estimable)
- Hazard ratio (HR): 0.56 (95% CI: 0.44, 0.71); p < 0.0001
- Confirmed ORR:
- Enhertu + pertuzumab: 87% (95% CI: 83, 90)
- THP: 81% (95% CI: 77, 85)
At the time of the PFS analysis, OS data were not mature: 126 deaths (16% of patients across the relevant study arms) had occurred in the overall population. Longer follow-up will be needed to clarify the impact on OS.
Safety profile and key warnings
The prescribing information for Enhertu in combination with pertuzumab includes warnings and precautions for:
- Neutropenia
- Left ventricular dysfunction
Given the known cardiac risks of HER2-directed antibodies and the hematologic toxicity associated with antibody–drug conjugates (ADCs), careful monitoring of left ventricular ejection fraction and blood counts is essential. In patients with baseline cardiac comorbidities, collaborative management with cardiology may be important.
Recommended dosing
The recommended dosing schedule is:
- Cycle 1, Day 1:
- Fam-trastuzumab deruxtecan-nxki 5.4 mg/kg IV
- Followed by pertuzumab 840 mg IV
- Subsequent cycles (every 3 weeks):
- Fam-trastuzumab deruxtecan-nxki 5.4 mg/kg IV
- Followed by pertuzumab 420 mg IV
Treatment is continued every three weeks until disease progression or unacceptable toxicity.
Regulatory considerations: Project Orbis, RTOR, and expedited programs
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence that enables concurrent submission and review of oncology drugs among international partners. For this application, FDA collaborated with Switzerland’s Swissmedic (SMC); reviews at other regulatory agencies are ongoing.
- The Real-Time Oncology Review (RTOR) pilot program was used to streamline data submission and review prior to the complete application.
- The Assessment Aid, a voluntary submission from the applicant, was used to facilitate FDA’s assessment.
- The application received priority review, and the combination of fam-trastuzumab deruxtecan-nxki with pertuzumab was granted breakthrough therapy designation.
FDA’s expedited programs for serious conditions (Fast Track, Breakthrough Therapy, Priority Review, Accelerated Approval) are outlined in the guidance “Expedited Programs for Serious Conditions – Drugs and Biologics.”
Editorial perspective (Morningglorysciences)
For more than a decade, THP (taxane + trastuzumab + pertuzumab) has been the standard first-line backbone for HER2-positive metastatic breast cancer. DESTINY-Breast09 now positions Enhertu, an ADC, together with pertuzumab as a potential new first-line standard, delivering a median PFS of 40.7 months versus 26.9 months with THP and a numerically higher ORR.
However, moving a highly potent ADC into the first-line setting raises several strategic and practical questions:
- How to balance deeper and more durable disease control upfront against the loss of Enhertu as a later-line option
- How long-term exposure to ADC plus dual HER2 blockade will affect cumulative hematologic and cardiac toxicity
- How cost and resource utilization will compare with current standards in different healthcare systems
For younger patients or those with a long anticipated survival, sequencing decisions will likely require nuanced, shared decision-making that weighs early intensification with Enhertu against preserving therapeutic options for subsequent lines.
Future work will need to address:
- Subgroup analyses by hormone receptor status, visceral disease burden, and prior neoadjuvant/adjuvant HER2 therapy
- Real-world safety data, particularly regarding cardiac events and ADC-related interstitial lung disease, in broader practice settings
- Optimal positioning of ADCs relative to other emerging HER2-targeted agents and immunotherapies in the first- and later-line landscape
Overall, this approval represents a major step toward ADC-based intensification in the first-line management of HER2-positive metastatic breast cancer and will likely reshape treatment algorithms globally as additional survival and safety data accumulate.
*This article is based on the AACR “FDA Approval Alert” and FDA source documents, summarized and edited by Morningglorysciences.*
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