FDA Approves Fam-Trastuzumab Deruxtecan-Nxki for Advanced HR-Positive, Low HER2 Breast Cancer

On January 27, 2025, the U.S. Food and Drug Administration (FDA) granted approval to fam-trastuzumab deruxtecan-nxki, marketed as Enhertu by Daiichi Sankyo, Inc. This drug is intended for patients with unresectable or metastatic hormone receptor-positive, HER2-low, or HER2-ultralow breast cancer. These patients have experienced cancer progression despite undergoing one or more endocrine therapies. Enhertu's approval was supported by an FDA-approved test to identify suitable candidates for the treatment.

Simultaneously, the FDA approved the Ventana PATHWAY anti-HER-2 (4B5) Rabbit Monoclonal Primary Antibody assay. This diagnostic tool is used to identify patients with HER2-ultralow breast cancer who can benefit from Enhertu. Previously, this assay was approved for identifying those with HER2-low breast cancer for Enhertu treatment.

The efficacy and safety of Enhertu were assessed in the DESTINY-Breast06 trial, a randomized, open-label, multicenter study involving 866 adults with advanced or metastatic HR-positive breast cancer. Participants had HER2-low or HER2-ultralow expression, as determined by the Ventana assay and confirmed in a central laboratory. Notably, individuals with prior chemotherapy for advanced or metastatic conditions were excluded from the trial.

Participants in the study were randomized into two groups: 436 received Enhertu at a dose of 5.4 mg/kg via intravenous infusion every three weeks, and 430 received a physician's choice of single-agent chemotherapy, which included capecitabine (60%), nab-paclitaxel (24%), or paclitaxel (16%).

The primary measure of efficacy was progression-free survival (PFS) in HER2-low breast cancer patients, evaluated by a blinded independent central review using RECIST v1.1 criteria. Secondary measures included overall survival (OS) and PFS in the overall study population.

Results from the trial revealed a significant improvement in PFS for HER2-low breast cancer patients treated with Enhertu. The median PFS was 13.2 months for those on Enhertu, compared to 8.1 months for those receiving chemotherapy. The hazard ratio for this improvement was 0.62, with a p-value of less than 0.0001, indicating statistical significance. The overall study population also showed similar improvements in PFS, with median values of 13.2 months for the Enhertu group and 8.1 months for the chemotherapy group, yielding a hazard ratio of 0.64.

At the final PFS analysis, the OS data was not fully mature, with 39% of participants having died across both study arms. An exploratory analysis of the HER2-ultralow subgroup showed a median PFS of 15.1 months for Enhertu and 8.3 months for chemotherapy, although the hazard ratio of 0.76 did not reach statistical significance.

In patients with measurable disease at baseline, the confirmed objective response rate (ORR) was notably higher in the Enhertu group at 65.7%, compared to 30.8% for those on chemotherapy.

Common adverse reactions observed in 20% or more of patients included decreased white blood cell and neutrophil counts, nausea, fatigue, hair loss, increased liver enzymes, and gastrointestinal issues such as diarrhea and vomiting. The recommended dosage of Enhertu is 5.4 mg/kg via intravenous infusion every three weeks, continuing until disease progression or intolerable toxicity occurs.

This FDA review incorporated the Assessment Aid, a voluntary submission to expedite the agency's assessment process. Enhertu's application received priority review and breakthrough designation, highlighting its potential impact on serious medical conditions.