FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HR-positive, HER2-low or HER2-ultralow breast cancer
Regulatory approval: On Jan 27, 2025, the FDA approved fam-trastuzumab deruxtecan-nxki (Enhertu) for unresectable or metastatic 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, after progression on ≥1 endocrine therapy in the metastatic setting. Approval was supported by DESTINY-Breast06, which showed improved PFS versus physician’s choice chemotherapy; OS data were immature.
FDA approval (Jan 27, 2025)
The US FDA approved fam-trastuzumab deruxtecan-nxki (Enhertu; Daiichi Sankyo, Inc.) for unresectable or metastatic hormone receptor (HR)-positive, HER2-low or HER2-ultralow breast cancer, as determined by an FDA-approved test, after progression on one or more endocrine therapies in the metastatic setting.
The FDA also approved Ventana’s PATHWAY anti-HER-2 (4B5) Rabbit Monoclonal Primary Antibody assay as a companion diagnostic to identify patients with HER2-ultralow (IHC 0 with membrane staining) breast cancer for Enhertu; the assay was previously approved to identify HER2-low disease.
Key efficacy evidence: DESTINY-Breast06 (NCT04494425)
DESTINY-Breast06 was a randomized, multicenter, open-label trial in 866 adults with advanced/metastatic HR-positive breast cancer with HER2-low or HER2-ultralow expression (central lab). Patients with prior chemotherapy for advanced/metastatic disease were excluded. Participants received Enhertu 5.4 mg/kg IV q3w (n=436) or physician’s choice chemotherapy (n=430; capecitabine 60%, nab-paclitaxel 24%, paclitaxel 16%).
In HER2-low patients (n=713), median PFS was 13.2 vs 8.1 months (HR 0.62; 95% CI 0.52–0.75; p<0.0001). In the overall population, median PFS was 13.2 vs 8.1 months (HR 0.64; 95% CI 0.54–0.76; p<0.0001). OS was immature at PFS final analysis (335 deaths; 39%).
Exploratory HER2-ultralow subgroup (n=153): median PFS 15.1 vs 8.3 months (HR 0.76; 95% CI 0.49–1.17). In measurable disease at baseline, confirmed ORR was 65.7% vs 30.8% (BICR).
Safety and dosing
Common adverse reactions (≥20%; incl. labs) included cytopenias, nausea, fatigue, alopecia, transaminase/alkaline phosphatase elevations, GI events, decreased appetite, COVID-19 infection, and musculoskeletal pain. Recommended dose: 5.4 mg/kg IV every 3 weeks until progression or unacceptable toxicity.