On December 15, 2025, the U.S. Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki with pertuzumab for the first-line treatment of adults with unresectable or metastatic HER2-positive breast cancer, defined as HER2 IHC 3+ or ISH-positive by an FDA-approved test. Fam-trastuzumab deruxtecan-nxki is marketed as Enhertu® by Daiichi Sankyo, Inc.
This approval establishes fam-trastuzumab deruxtecan-nxki with pertuzumab as a new frontline option for patients with advanced HER2-positive disease, expanding the role of antibody–drug conjugates earlier in the treatment paradigm (FDA, 2025).
Read About Fam-trastuzumab deruxtecan-nxki (Enhertu) on OncoDaily
Companion Diagnostic Approval
Alongside the therapeutic approval, the FDA also approved two companion diagnostic devices to identify eligible patients for treatment with fam-trastuzumab deruxtecan-nxki with pertuzumab:
- PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody
- HER2 Dual ISH DNA Probe Cocktail
These diagnostics confirm HER2 IHC 3+ or ISH-positive status, ensuring accurate patient selection for this regimen (FDA, 2025). Full prescribing information for Enhertu will be available on Drugs@FDA.
Efficacy Results From DESTINY-Breast09
The FDA approval of fam-trastuzumab deruxtecan-nxki with pertuzumab was based on results from the DESTINY-Breast09 trial (NCT04784715), a randomized, three-arm, multicenter, global Phase III study enrolling 1,157 adults with HER2-positive advanced or metastatic breast cancer.
Eligible patients had not received prior chemotherapy or HER2-targeted therapy for metastatic disease, or had received neoadjuvant or adjuvant HER2-targeted therapy more than six months before diagnosis of advanced disease. A single prior line of endocrine therapy for metastatic disease was permitted.
Patients were randomized 1:1:1 to receive:
- Fam-trastuzumab deruxtecan-nxki 5.4 mg/kg plus pertuzumab (n=383)
- THP regimen (taxane, trastuzumab, pertuzumab) (n=387)
- An investigational therapy (n=387)
Treatment was administered intravenously every three weeks until disease progression or unacceptable toxicity.
Read About DESTINY-Breast09 Trial on OncoDaily
Progression-Free Survival Benefit
The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR) using RECIST v1.1.
Median PFS was:
- 40.7 months (95% CI: 36.5, not estimable) with fam-trastuzumab deruxtecan-nxki with pertuzumab
- 26.9 months (95% CI: 21.8, not estimable) with THP
This corresponded to a 44% reduction in the risk of disease progression or death (hazard ratio 0.56, 95% CI: 0.44–0.71; p <0.0001) in favor of fam-trastuzumab deruxtecan-nxki with pertuzumab (DESTINY-Breast09; FDA, 2025).
Objective Response and Overall Survival
Confirmed objective response rate (ORR) by BICR was:
- 87% (95% CI: 83–90) in the fam-trastuzumab deruxtecan-nxki with pertuzumab arm
- 81% (95% CI: 77–85) in the THP arm
At the time of the PFS analysis, overall survival data were not mature, with 126 deaths (16%) reported across both study arms in the overall population. Continued follow-up is ongoing to evaluate long-term survival outcomes (FDA, 2025).
Safety Profile
The prescribing information for fam-trastuzumab deruxtecan-nxki with pertuzumab includes key warnings and precautions for:
- Neutropenia
- Left ventricular dysfunction
Patients receiving this regimen require routine monitoring of blood counts and cardiac function, consistent with the known safety profiles of HER2-targeted therapies and antibody–drug conjugates (FDA, 2025).
Recommended Dosing
For Cycle 1, Day 1, the recommended doses are:
- Fam-trastuzumab deruxtecan-nxki 5.4 mg/kg
- Pertuzumab 840 mg
For subsequent cycles, the recommended regimen is:
- Fam-trastuzumab deruxtecan-nxki 5.4 mg/kg
- Pertuzumab 420 mg
Both agents are administered by intravenous infusion every three weeks until disease progression or unacceptable toxicity.
Clinical Significance
The FDA approval of fam-trastuzumab deruxtecan-nxki with pertuzumab marks a significant shift in the frontline management of HER2-positive metastatic breast cancer. By delivering a substantial improvement in progression-free survival compared with the established THP regimen, this combination introduces a new standard-setting option that integrates next-generation HER2-directed therapy earlier in the disease course.