FDA Approves Fam-Trastuzumab Deruxtecan-nxki Plus Pertuzumab for First-Line Unresectable or Metastatic HER2-Positive Metastatic Breast Cancer
Key Clinical Summary
- Population and Design: On December 15, 2025, the US FDA approved fam-trastuzumab deruxtecan-nxki (T-DXd) + pertuzumab for unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer based on the phase 3 DESTINY-Breast09 trial (NCT04784715), which randomized 1,157 previously untreated adults across 3 treatment arms.
- Efficacy: Median PFS 40.7 vs 26.9 months with T-DXd + pertuzumab vs THP (HR 0.56; 95% CI 0.44 to 0.71; P < .0001); ORR 87% vs 81%, with OS data immature at analysis (16% deaths). Companion diagnostics (PATHWAY anti–HER2/neu 4B5 antibody and HER2 Dual ISH Probe Cocktail) were also FDA-approved to identify eligible patients.
- Clinical Relevance: T-DXd + pertuzumab demonstrated superior PFS and response rates over standard THP, establishing a new first-line HER2-targeted standard of care; key precautions include neutropenia and left ventricular dysfunction, with dosing every 3 weeks (T-DXd 5.4 mg/kg + pertuzumab 420 mg).
On December 15, 2025, the US Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki in combination with pertuzumab for first-line treatment of patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer as assessed by an FDA-approved test.
In tandem, the FDA has also approved tests PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and HER2 Dual ISH DNA Probe Cocktail as companion diagnostic devices for identifying HER2-positive (HER2 IHC3+ or ISH+) breast cancer patients eligible for treatment with fam-trastuzumab deruxtecan-nxki in combination with pertuzumab.
This approval was based on results from the DESTINY-Breast09 (NCT04784715) study, a randomized, 3-arm, global, multicenter trial which enrolled 1157 adults with HER2-positive advanced or metastatic breast cancer. Patients had not received prior chemotherapy or HER2-targeted therapy or had completed neoadjuvant or adjuvant HER2-targeted therapy more than 6 months before advanced disease diagnosis. A single line of prior endocrine therapy for advanced disease was permitted.
Patients were randomized 1:1:1 to receive either fam-trastuzumab deruxtecan-nxki (5.4 mg/kg) plus pertuzumab (n = 383), taxane (docetaxel or paclitaxel), trastuzumab, and pertuzumab (THP; n = 387), or an investigational therapy (n = 387). Treatments were administered intravenously every 3 weeks until unacceptable toxicity or disease progression.
The primary efficacy end point was progression-free survival (PFS) assessed by blinded independent central review (BICR) per RECIST v1.1. Secondary end points included overall survival (OS) and confirmed objective response rate (ORR).
The median PFS was 40.7 months (95% confidence interval [CI], 36.5 to not estimable [NE]) in the fam-trastuzumab deruxtecan-nxki plus pertuzumab arm and 26.9 months (95% CI, 21.8 to NE) in the THP arm (hazard ratio [HR], 0.56; 95% CI, 0.44 to 0.71; P < 0.0001). The confirmed ORR was 87% (95% CI, 83 to 90) and 81% (95% CI, 77 to 85), respectively.
At the time of the PFS analysis, OS data were not mature, and 126 deaths (16%) were observed across both study arms. In terms of safety, the prescribing information includes warnings and precautions for neutropenia and left ventricular dysfunction.
Source:
US Food and Drug Administration. FDA approves fam-trastuzumab deruxtecan-nxki with pertuzumab for unresectable or metastatic HER2-positive breast cancer. Accessed December 15, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-fam-trastuzumab-deruxtecan-nxki-pertuzumab-unresectable-or-metastatic-her2-positive
