FDA Approves Enhertu for HR-Positive, HER2-Low and HER2-Ultralow Breast Cancer: A New Milestone in Treatment
Published: February 20, 2025
On January 27, 2025, the U.S. Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki—better known as Enhertu—for patients with unresectable or metastatic HR-positive, HER2-low, or HER2-ultralow breast cancer. This approval marks a significant step forward, offering new hope to those whose cancer has progressed after endocrine therapy. Developed by Daiichi Sankyo, Inc., Enhertu is the first therapy specifically approved for HER2-ultralow breast cancer, expanding treatment options for a previously underserved group.
Who Does Enhertu Help?
Enhertu targets adults with hormone receptor-positive (HR+) breast cancer that is either HER2-low (defined as IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining). Eligibility requires progression after at least one endocrine therapy in the metastatic setting, confirmed by an FDA-approved test. This precision ensures the right patients receive this innovative treatment.
A Game-Changing Diagnostic Tool
Alongside Enhertu, the FDA approved Ventana’s PATHWAY anti-HER-2 (4B5) assay as a companion diagnostic. Previously used to detect HER2-low expression, it’s now validated for HER2-ultralow cases, helping doctors accurately identify candidates for Enhertu. This dual approval underscores the importance of tailored medicine in oncology.
The Evidence: DESTINY-Breast06 Trial
The approval stems from the DESTINY-Breast06 trial, a randomized study of 866 patients with HR-positive, HER2-low or HER2-ultralow breast cancer. Participants had no prior chemotherapy for advanced disease. Half (436) received Enhertu at 5.4 mg/kg every three weeks via IV, while the other half (430) got physician’s choice of chemotherapy (capecitabine, nab-paclitaxel, or paclitaxel).
- Progression-Free Survival (PFS): For HER2-low patients (n=713), Enhertu extended median PFS to 13.2 months compared to 8.1 months with chemo—a 38% reduction in risk (hazard ratio 0.62, p<0.0001). The overall population saw similar gains.
- HER2-Ultralow Results: In an exploratory subgroup (n=153), PFS reached 15.1 months with Enhertu versus 8.3 months with chemo, hinting at broader potential.
- Response Rate: Among those with measurable disease, Enhertu achieved a 65.7% response rate, dwarfing chemo’s 30.8%.
Overall survival (OS) data remains immature, with 39% of patients deceased at the PFS analysis, but the trial’s PFS results are a strong foundation for this approval.
Safety and Side Effects
Enhertu isn’t without challenges. Common side effects (seen in ≥20% of patients) include low white blood cell and neutrophil counts, nausea, fatigue, anemia, hair loss, and elevated liver enzymes. Other frequent issues are diarrhea, vomiting, and musculoskeletal pain. Monitoring is critical to manage these risks, ensuring patient safety throughout treatment.
How It’s Administered
The recommended dose is 5.4 mg/kg, given as an IV infusion every three weeks (a 21-day cycle), continued until disease progression or unacceptable toxicity. Full prescribing details are available at Drugs@FDA.
Why This Matters
Enhertu’s approval is a breakthrough—especially for HER2-ultralow patients, who lacked targeted options until now. It builds on robust PFS improvements and a higher response rate, offering a lifeline for those with advanced HR-positive breast cancer. Looking ahead, ongoing OS data and wider adoption of the PATHWAY assay will shape its long-term impact.
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