Trastuzumab Deruxtecan and Pertuzumab Approved for HER2-Positive Breast Cancer
Expert Perspectives · Keira Smith · 2026-01-28
The FDA has approved fam-trastuzumab deruxtecan-nxki (Enhurtu®, Daiichi Sankyo) in combination with pertuzumab for first-line treatment of patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)–positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-approved test.
In addition, the FDA approved the PATHWAY anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody and HER2 Dual ISH DNA Probe Cocktail as companion diagnostic devices for selection of patients who are eligible for treatment with the approved combination.
Why This Approval Matters
“Trastuzumab deruxtecan has shown efficacy in patients with previously treated HER2-positive advanced or metastatic breast cancer,” wrote Sara M. Tolaney, MD, MPH, Chief of the Division of Breast Oncology at Dana-Farber Cancer Institute, and colleagues, in their published results of the DESTINY-Breast09 trial (NCT04784715) on which the approval was based. “We conducted a phase 3 trial involving patients with HER2-positive advanced or metastatic breast cancer and no previous chemotherapy or HER2-directed therapy for metastatic disease.”
Breaking Down DESINTY-Breast09
Efficacy was studied in DESTINY-Breast09, a randomized, three-arm, multicenter, global trial that enrolled 1,157 patients with HER2-positive advanced or metastatic breast cancer who had not previously received chemotherapy or HER2-targeted therapy or who had received neoadjuvant or adjuvant HER2-targeted therapy more than six months before their advanced or metastatic disease diagnosis. They were allowed to have received a single line of prior endocrine therapy for advanced or metastatic disease.
Patients were randomized 1:1:1 to receive either fam-trastuzumab deruxtecan-nxki 5.4 mg/kg in combination with one of the following:
- Pertuzumab
- THP (taxane—docetaxel or paclitaxel), trastuzumab, and pertuzumab
- An investigational therapy
Treatment was given by intravenous infusion every three weeks until unacceptable toxicity or disease progression. The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR), based on RECIST v1.1 Secondary end points included overall survival (OS) and confirmed objective response rate (ORR) assessed by BICR.
Median PFS was 40.7 months in patients receiving fam-trastuzumab deruxtecan-nxki plus pertuzumab versus 26.9 months in patients receiving THP. Confirmed ORR was 87% and 81% in the respective arms. The OS data was immature at the time of PFS analysis, with 126 (16%) of patients who died in the overall population across both study arms.
Managing Adverse Events
The prescribing information includes warnings and precautions for neutropenia and left ventricular dysfunction.
Dosing and Administration
The recommended dose for Cycle 1, Day 1, is fam-trastuzumab deruxtecan-nxki 5.4 mg/kg followed by pertuzumab 840 mg. The recommended dose for subsequent cycles in fam-trastuzumab deruxtecan-nxki 5.4 mg/kg followed by pertuzumab 420 mg by intravenous infusion, every three weeks.
Conclusion
“Trastuzumab deruxtecan plus pertuzumab led to a significantly lower risk of progression or death than THP when used as first-line treatment for HER2-positive advanced or metastatic breast cancer, with no new safety signals,” concluded Dr. Tolaney and colleagues.
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