The U.S. Food and Drug Administration (FDA) has approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in combination with pertuzumab (Perjeta) as a first-line treatment for patients with newly diagnosed HER2-positive breast cancer that is either metastatic or cannot be surgically removed.
Alongside this approval, the FDA also authorized two diagnostic tests—PATHWAY and VENTANA—to assess a tumor’s HER2 status, helping clinicians identify patients eligible for this therapy.
How the Therapy Works
T-DXd is an antibody-drug conjugate (ADC) that specifically targets HER2, a protein overexpressed on cancer cells. The drug binds to these cells, enters them, and releases a cytotoxic agent that kills the cancer cells. Pertuzumab, a monoclonal antibody, works by binding to HER2 and blocking its signaling, enhancing the treatment’s anti-cancer effect.
This new approval provides a first-line alternative for patients with untreated metastatic or unresectable HER2-positive breast cancer. It may offer improved outcomes compared to the current standard regimen, which combines taxane chemotherapy with HER2-targeted monoclonal antibodies. Experts highlighted the significance of this therapy at the San Antonio Breast Cancer Symposium 2025, noting its potential to reshape the treatment landscape for advanced breast cancer.
Clinical Trial Evidence
The approval is based on results from the phase III DESTINY-Breast09 trial, a multicenter, randomized study involving 1,157 adults with advanced HER2-positive breast cancer. Participants had not previously received chemotherapy or HER2-targeted therapy, except if treatment occurred more than six months before metastasis.
Patients were assigned to one of three treatment groups:
- T-DXd plus pertuzumab
- Taxane plus trastuzumab and pertuzumab (THP)
- Investigational therapy
During a follow-up of approximately 45 months, patients treated with T-DXd were 44% less likely to experience disease progression compared to those receiving THP. Median progression-free survival (PFS) was 40.7 months for T-DXd versus 26.9 months for THP. Additionally, the overall tumor response rate was higher in the T-DXd group (87% vs. 81%).
Safety and Dosage
T-DXd carries a boxed warning for potentially fatal interstitial lung disease (ILD) and pneumonitis, as well as risks of embryo-fetal harm.
The recommended dosing schedule is:
- Initial dose: T-DXd 5.4 mg/kg + pertuzumab 840 mg
- Subsequent doses (every three weeks): T-DXd 5.4 mg/kg + pertuzumab 420 mg
Treatment should continue until disease progression or unacceptable toxicity occurs.
The Impact on Breast Cancer Patients
Breast cancer remains the most common non-skin cancer in women, with federal statistics projecting 316,950 new cases and 42,170 deaths in 2025. HER2-positive breast cancer represents roughly 13% of all cases, highlighting the critical need for effective therapies in this subgroup.
With the approval of T-DXd plus pertuzumab, patients now have a promising new first-line option that may extend survival and improve quality of life for those facing advanced HER2-positive breast cancer.
