FDA

Enhertu plus pertuzumab OK’d for HER2-positive breast cancer

December 24, 2025

On December 15, 2025, FDA approved Enhertu (fam-trastuzumab deruxtecan-nxki) in combination with pertuzumab for the first-line treatment of adults with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer as determined by an FDA-approved test.

FDA also approved the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and HER2 Dual ISH DNA Probe Cocktail as companion diagnostic devices for selecting HER2-positive (HER2 IHC3+ or ISH+) breast cancer patients for treatment with fam-trastuzumab deruxtecan-nxki in combination with pertuzumab.

Efficacy

Efficacy was evaluated in the randomized, three-arm, multicenter DESTINY-Breast09 trial (NCT04784715) that enrolled 1157 adults with HER2-positive advanced or metastatic breast cancer who hadn’t received prior chemotherapy or HER2-targeted therapy or had received neoadjuvant or adjuvant HER2-targeted therapy ≥6 months before the diagnosis of advanced or metastatic disease. A single line of prior endocrine therapy was permitted for advanced or metastatic breast cancer. Patients were randomized (1:1:1) to receive either, fam-trastuzumab deruxtecan-nxki 5.4 mg/kg plus pertuzumab (n = 383), or THP (taxane [docetaxel or paclitaxel], trastuzumab, and pertuzumab) (n = 387), or an investigational therapy (n = 387) by IV infusion every three weeks until unacceptable toxicity or disease progression.

The major efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Additional efficacy outcome measures were overall survival (OS) and confirmed objective response rate (ORR) assessed by BICR. Median PFS was 40.7 months (95% confidence interval [CI], 36.5, not estimable [NE]) in the fam-trastuzumab deruxtecan-nxki plus pertuzumab arm and 26.9 months (95% CI, 21.8, NE) in the THP arm (hazard ratio, 0.56; 95% CI, 0.44-0.71; p-value <0.0001). Confirmed ORR was 87% (95% CI, 83- 90) and 81% (95% CI, 77-85) in the respective arms. At the time of the PFS analysis, OS data wasn’t mature with 126 (16%) of patients who died across both study arms in the overall population.

Safety

The most common adverse reactions with trastuzumab deruxtecan plus pertuzumab were decreased WBC count, decreased hemoglobin, decreased neutrophil count, nausea, increased ALT and AST, diarrhea, decreased lymphocyte count, decreased platelet count, increased alkaline phosphatase, decreased blood potassium, fatigue, alopecia, vomiting, upper respiratory tract infection, constipation, decreased appetite, decreased weight, COVID-19, musculoskeletal pain, abdominal pain, and increased blood bilirubin.

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

Recommended dose

The recommended dosage of Enhertu for cycle 1, day 1 is 5.4 mg/kg, followed by pertuzumab 840 mg. For subsequent cycles, the recommended fam-trastuzumab deruxtecan-nxki dose is 5.4 mg/kg, followed by pertuzumab 420 mg by intravenous infusion every three weeks.

Sources:

FDA approves fam-trastuzumab deruxtecan-nxki with pertuzumab for unresectable or metastatic HER2-positive breast cancer. [News release]. 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-fam-trastuzumab-deruxtecan-nxki-pertuzumab-unresectable-or-metastatic-her2-positive

Enhertu (fam-trastuzumab deruxtecan-nxki) [package insert]. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761139s038s042lbl.pdf Revised December 2025. Accessed December 20, 2025.

Enhertu® plus pertuzumab approved in the US as first new treatment in more than a decade for first-line treatment of patients with HER2 positive metastatic breast cancer. [News release]. 2025. daiichisankyo.com/files/news/pressrelease/pdf/202512/20251216_E2.pdf