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  6. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HR-positive, HER2-low or HER2-ultralow breast cancer
  1. Resources for Information | Approved Drugs

FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HR-positive, HER2-low or HER2-ultralow breast cancer

On January 27, 2025, the Food and Drug Administration approved fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo, Inc.) for unresectable or metastatic hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic setting.

FDA also approved the Ventana’s PATHWAY anti-HER-2 (4B5) Rabbit Monoclonal Primary Antibody assay as a companion diagnostic device to identify patients with HER2-ultralow (IHC 0 with membrane staining) breast cancer for treatment with Enhertu. This assay was previously approved to identify patients with HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer for treatment with Enhertu.  

Full prescribing information for Enhertu will be posted on Drugs@FDA. 

Efficacy and Safety

Efficacy was evaluated in DESTINY-Breast06 (NCT04494425), a randomized, multicenter, open-label trial in 866 adult patients with advanced or metastatic HR-positive breast cancer with HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) expression as determined by Ventana’s PATHWAY anti-HER-2 (4B5) Rabbit Monoclonal Primary Antibody assay and evaluated at a central laboratory. The trial excluded patients with prior chemotherapy for advanced or metastatic disease. Patients were randomized (1:1) to receive either fam-trastuzumab deruxtecan-nxki 5.4 mg/kg (N=436) by intravenous infusion every three weeks or physician’s choice of single agent chemotherapy (N=430, capecitabine 60%, nab-paclitaxel 24%, or paclitaxel 16%).

The major efficacy outcome measure was progression-free survival (PFS) in patients with HER2-low breast cancer assessed by blinded independent central review (BICR) based on RECIST v1.1. Additional efficacy outcome measures were PFS assessed by BICR based on RECIST v1.1 in the overall population, overall survival (OS) in patients with HER2-low breast cancer, and OS in the overall population. The trial demonstrated a statistically significant improvement in PFS in patients with HER2-low breast cancer (n=713). Median PFS was 13.2 months in the fam-trastuzumab deruxtecan-nxki arm and 8.1 months in the chemotherapy arm (Hazard ratio [HR] 0.62 [95% CI: 0.52, 0.75]; p-value <0.0001). The trial also demonstrated a statistically significant improvement in PFS in the overall population. Median PFS was 13.2 and 8.1 months in the fam-trastuzumab deruxtecan-nxki and chemotherapy arms, respectively (HR 0.64 [95% CI: 0.54, 0.76]; p-value <0.0001). At the time of the PFS final analysis, OS data was immature, and a total of 335 (39%) patients had died across both trial arms in the overall population.  

In exploratory analyses in the HER2-ultralow subgroup (n=153 patients), median PFS was 15.1 months in the fam-trastuzumab deruxtecan-nxki arm and 8.3 months in the chemotherapy arm with a HR of 0.76 (95% CI: 0.49, 1.17). In patients with measurable disease at baseline, confirmed objective response rate (ORR) assessed by BICR was 65.7% and 30.8% in the fam-trastuzumab deruxtecan-nxki and chemotherapy arms, respectively.  

The most common adverse reactions (≥20%), including laboratory abnormalities, were decreased white blood cell count, decreased neutrophil count, nausea, decreased hemoglobin, decreased lymphocyte count, fatigue, decreased platelet count, alopecia, increased alanine aminotransferase, increased blood alkaline phosphatase, increased aspartate aminotransferase, decreased blood potassium, diarrhea, vomiting, constipation, decreased appetite, COVID-19 infection, and musculoskeletal pain.

The recommended fam-trastuzumab deruxtecan-nxki dosage is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Expedited Programs

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review and breakthrough designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.

Follow the Oncology Center of Excellence on X: @FDAOncology.

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