Fam-trastuzumab deruxtecan-nxki is approved by the USFDA for unresectable or metastatic HR-positive, HER2-low or HER2-ultralow breast cancer

On January 27, 2025, the Food and Drug Administration sanctioned 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 identified by an FDA-approved assay, that has advanced following one or more endocrine therapies in the metastatic context.

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

Effectiveness and Safety

The efficacy was assessed in DESTINY-Breast06 (NCT04494425), a randomized, multicenter, open-label trial involving 866 adult patients with advanced or metastatic HR-positive breast cancer exhibiting 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 participants who had already undergone chemotherapy for advanced or metastatic illness.

Patients were randomized (1:1) to receive either fam-trastuzumab deruxtecan-nxki 5.4 mg/kg (N=436) via intravenous infusion every three weeks or a physician’s choice of single-agent chemotherapy (N=430, comprising capecitabine 60%, nab-paclitaxel 24%, or paclitaxel 16%).

The primary effectiveness endpoint was progression-free survival (PFS) in patients with HER2-low breast cancer, evaluated by blinded independent central review (BICR) according to RECIST v1.1 criteria. Supplementary effectiveness outcome measures included progression-free survival (PFS) evaluated by blinded independent central review (BICR) according to RECIST v1.1 in the entire population, overall survival (OS) in patients with HER2-low breast cancer, and OS in the overall population.

The trial showed a statistically significant enhancement in progression-free survival (PFS) among patients with HER2-low breast cancer (n=713). The median progression-free survival (PFS) was 13.2 months for the fam-trastuzumab deruxtecan-nxki group and 8.1 months for the chemotherapy group (Hazard ratio [HR] 0.62 [95% CI: 0.52, 0.75]; p-value <0.0001). The trial exhibited a statistically significant enhancement in progression-free survival within the whole population.

The median progression-free survival (PFS) was 13.2 months for the fam-trastuzumab deruxtecan-nxki group and 8.1 months for the chemotherapy group (hazard ratio 0.64 [95% confidence interval: 0.54, 0.76]; p-value <0.0001). At the time of the final analysis of the PFS, overall survival data was not yet mature, with a total of 335 (39%) patients deceased across both trial arms in the overall population.

In exploratory analyses of the HER2-ultralow subgroup (n=153 patients), the median progression-free survival (PFS) was 15.1 months in the fam-trastuzumab deruxtecan-nxki arm and 8.3 months in the chemotherapy arm, yielding a hazard ratio (HR) of 0.76 (95% CI: 0.49, 1.17).

In patients with detectable illness at baseline, the confirmed objective response rate (ORR) evaluated by BICR was 65.7% in the fam-trastuzumab deruxtecan-nxki arm and 30.8% in the chemotherapy arm.

The most prevalent adverse reactions (≥20%), encompassing laboratory abnormalities, included reduced white blood cell count, diminished neutrophil count, nausea, lowered hemoglobin, decreased lymphocyte count, fatigue, reduced platelet count, alopecia, elevated alanine aminotransferase, increased blood alkaline phosphatase, heightened aspartate aminotransferase, decreased blood potassium, diarrhea, vomiting, constipation, diminished appetite, COVID-19 infection, and musculoskeletal pain.

The advised dosage of fam-trastuzumab deruxtecan-nxki is 5.4 mg/kg administered via intravenous infusion once every three weeks (21-day cycle) until disease progression or intolerable toxicity occurs.