T-DXd/Pertuzumab Combo Earns FDA Approval in Advanced HER2+ Breast Cancer

The FDA has approved fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) in combination with pertuzumab (Perjeta) for the first-line treatment of adults with unresectable or metastatic HER2-positive breast cancer, as confirmed by an FDA-approved diagnostic assay. The agency simultaneously approved the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and the HER2 Dual ISH DNA Probe Cocktail as companion diagnostic devices to identify patients eligible for therapy with this combination, according to a news release from the regulatory agency.

The approval was based on results from the phase 3 DESTINY-Breast09 trial (NCT04784715), a randomized, three-arm, multicenter global study that enrolled 1,157 adults with HER2-positive advanced or metastatic breast cancer. Eligible patients had either not received prior chemotherapy or HER2-targeted therapy or had completed neoadjuvant or adjuvant HER2-targeted therapy more than 6 months prior to the diagnosis of advanced disease. One prior line of endocrine therapy for advanced or metastatic disease was permitted.

Patients were assigned to receive the investigative therapy of T-DXd or trastuzumab (Herceptin), pertuzumab, and a taxane (THP). Treatment with the combination of T-DXd and pertuzumab (n = 383) demonstrated a median progression-free survival (PFS) of 40.7 months (95% CI, 36.5-not estimable [NE]) by blinded independent review committee (BICR) assessment vs 26.9 months (95% CI, 21.8-NE) for treatment with THP (n = 387; HR, 0.56; 95% CI, 0.44-0.71; P <.0001).

Confirmed objective response rates (ORR) were 87% (95% CI, 83%-90% versus 81% (95% CI, 77%-85%) with THP and the investigative combination, respecitvely. Overall survival (OS) data were not yet mature at the time of the PFS analysis, and 16% of patients have died across both treatment arms.

Trial Design and Patient Population

This phase 3 trial enrolled adults with HER2-positive advanced or metastatic breast cancer who were either treatment-naïve to chemotherapy and HER2-targeted therapy or had completed neoadjuvant or adjuvant HER2-targeted therapy more than 6 months prior to the diagnosis of advanced or metastatic disease. Patients with advanced or metastatic disease were permitted to have received a single prior line of endocrine therapy.

Participants were randomized in a 1:1:1 ratio to receive T-DXd (5.4 mg/kg) in combination with pertuzumab, THP, or an investigational regimen. Treatments were administered intravenously every 3 weeks and continued until disease progression or unacceptable toxicity. For the combination of T-DXd plus pertuzumab, the recommended dosing for the first cycle is 5.4 mg/kg of T-DXd followed by 840 mg of pertuzumab. For subsequent cycles, T-DXd is maintained at 5.4 mg/kg, with pertuzumab reduced to 420 mg every three weeks. The prescribing information shared by the FDA highlights neutropenia and left ventricular dysfunction as key precautions for this regimen.

The trial’s primary end point was PFS assessed by BICR using RECIST 1.1 criteria. Key secondary end points included OS and confirmed ORR by BICR.

Enhertu is an antibody-drug conjugate that combines a monoclonal antibody targeting HER2 on cancer cells with deruxtecan, a topoisomerase I inhibitor. The drug is internalized into tumor cells, where deruxtecan induces DNA damage and cell death. Perjeta is a HER2-directed monoclonal antibody that inhibits HER2 signaling, suppresses tumor cell proliferation, and induces apoptosis. The combination leverages complementary mechanisms to improve clinical outcomes in HER2-positive advanced breast cancer.

Subgroup Analysis Supports Broad Benefit

Notably, additional, data presented at the 2025 European Society for Medical Oncology Congress demonstrated that T-DXd in combination with pertuzumab provided a consistent PFS benefit compared with THP across key subgroups of patients with HER2-positive advanced or metastatic breast cancer, regardless of hormone receptor status, prior therapy, or PIK3CA mutation status, reinforcing the FDA approval.

References

1. FDA approves fam-trastuzumab deruxtecan-nxki with pertuzumab for unresectable or metastatic HER2-positive breast cancer. FDA. December 15, 2025. 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
2. Loibl S, Jiang Z, Barroso-Sousa R, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab vs taxane + trastuzumab + pertuzumab (THP) for patients with HER2+ advanced/metastatic breast cancer: additional analyses of DESTINY-Breast09 in key subgroups of interest. Presented at: European Society for Medical Oncology Congress 2025; October 17-21, 2025; Berlin, Germany. LBA18.