FDA Approves T-DXd Plus Pertuzumab in Metastatic HER2+ Breast Cancer

The FDA approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) plus pertuzumab (Perjeta) as a frontline treatment for patients with unresectable or metastatic HER2-positive breast cancer as approved by an FDA-approved test, according to a press release from the agency.¹

Additionally, the FDA approved the PATHWAY anti-HER-2/neu (5B5) Rabbit Monoclonal Primary Antibody HER2 Dual ISH Probe Cocktail as a companion diagnostic for selecting patients with HER2-positive breast cancer for treatment with this newly approved regimen. HER2-positive was defined as immunohistochemistry 3+ or in situ hubridization-positive.

Supporting data came from the phase 3 DESTINY-Breast09 trial (NCT04784715), which evaluated T-DXd plus pertuzumab vs taxane, tastuzumab (Herceptin), and pertuzumab (THP) or an investigational therapy. Therein, the median progression-free survival (PFS) was 40.7 months (95% CI, 36.5-not estimable [NE]) with T-DXd plus pertuzumab and 26.9 months (95% CI, 21.8-NE) with THP (HR, 0.56; 95% CI, 0.44-0.71; P <.0001). The confirmed ORR was 87% (95% CI, 83%-90%) vs 81% (95% CI, 77%-85%), respectively. OS data was not mature at the time of PFS analysis.

A total of 1157 patients with HER2-positive advanced or metastatic breast cancer who had not received prior chemotherapy, targeted HER2-targeted therapy, or adjuvant HER2-targeted therapy more than 6 months before the diagnosis of advanced or metastatic disease. Those with advanced or metastatic disease were permitted a single line of endocrine therapy.

Safety data showed any treatment-emergent adverse event (TEAE) occurred in 99.7% of the T-DXd plus pertuzumab arm and 99.0% of the standard of care arm; possibly treatment-related TEAEs of grade 3 or higher occurred in 54.9% vs 52.4%.²

The recommended dosage for T-DXd is 5.4 mg/kg on cycle 1, day 1, followed by 840 mg of pertuzumab; for subsuquent cycles, the FDA recommends T-DXd at 5.4 mg/kg, then pertuzumab at 420 mg by intravenous infusion every 3 weeks.

The prescribing information includes warnings and precautions for neutropenia and left ventricular dysfunction.

Previously, in September 2025, the FDA granted priority review to this combination in the same indication.³

References

1. FDA approves fam-trastuzumab deruxtecan-nxki with pertuzumab for unresectable or metastatic HER2-positive breast cancer. News release. FDA. December 15, 2025. Accessed December 15, 2025. https://tinyurl.com/59n2f8bs
2. Tolaney SM, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): interim results from DESTINY-Breast09. J Clin Oncol. 2025;43(suppl_17):LBA1008. doi:10.1200/JCO.2025.43.17_suppl.LBA1008
3. ENHERTU® (fam-trastuzumab deruxtecan-nxki) plus pertuzumab granted priority review in the US as 1st-line treatment for patients with HER2-positive metastatic breast cancer. News release. AstraZeneca. September 24, 2025. Accessed December 15, 2025. https://tinyurl.com/2256m25p