In hormone receptor-positive breast cancer, chemotherapy is usually started after several lines of hormone treatment. This study looked at whether trastuzumab deruxtecan (Enhertu) could be used instead of usual chemotherapy, in patients whose cancer has low HER2 (HER2-low) or even very low HER2 (HER2-ultralow). The result was that with Enhertu the disease stayed under control for about 5 months longer on average (13.2 versus 8.1 months). Severe side effects were slightly more common, and lung inflammation is a side effect that must be taken seriously. It is not yet known whether this treatment helps people live longer overall.
HER2-positive after prior anti-HER2 therapy; HER2-low (IHC 1+ or 2+ with negative ISH) after prior chemotherapy; HR-positive HER2-low or HER2-ultralow (IHC 0 with membrane staining) after one or more lines of hormone therapy
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Trastuzumab deruxtecan (T-DXd) | 5.4 mg/kg | IV | Day 1 |
On the page “Breast cancer” · Advanced HER2-positive and HER2-low disease
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Trastuzumab deruxtecan (Enhertu) 5.4 mg per kg, IV infusion every 3 weeks, until disease progression or unacceptable toxicity.
Single-agent chemotherapy of the physician's choice: capecitabine (60%), nab-paclitaxel (24%) or paclitaxel (16%), at standard doses; the exact dose is not stated in the sources reviewed (label and ClinicalTrials.gov NCT04494425).
Source of the regimen details: FDA label for Enhertu (ENHERTU, 2026-05 version, sections 2 and 14); ClinicalTrials.gov NCT04494425.
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Adults with hormone receptor-positive metastatic breast cancer with low HER2 expression (HER2-low; IHC 1+ or 2+ with negative ISH) or very low HER2 expression (HER2-ultralow; IHC 0 with membrane staining) who had received one or more lines of endocrine-based therapy and no prior chemotherapy for metastatic disease. According to the FDA label, entry required progression after at least 2 lines of endocrine therapy in the metastatic setting, or 1 line with early progression (within 24 months of starting adjuvant endocrine therapy or within 6 months of starting first-line endocrine therapy with a CDK4/6 inhibitor).
Primary endpoint: progression-free survival (PFS) by blinded independent central review in HER2-low patients.
Secondary endpoints: progression-free survival in all randomised patients, overall survival and safety.
Grade 3 or higher adverse events: 52.8% in the trastuzumab deruxtecan group versus 44.4% in the chemotherapy group. Interstitial lung disease or pneumonitis (adjudicated) occurred in 49 patients (11.3%; three grade 5 events) in the trastuzumab deruxtecan group and in 1 patient (0.2%; grade 2) in the chemotherapy group. No new safety signals were observed.
In January 2025 the FDA approved trastuzumab deruxtecan for hormone receptor-positive, HER2-low or HER2-ultralow metastatic or unresectable breast cancer that has progressed after one or more endocrine therapies in the metastatic setting; this was the first approval of a treatment for the HER2-ultralow group. This study made it possible to use the drug before chemotherapy in this group.
The trial was open-label. At the time of reporting, overall survival data were immature. HER2-ultralow results are exploratory and based on limited numbers (153 patients). The control group did not include eribulin or combination regimens. Determining HER2-ultralow status requires careful immunohistochemistry assessment.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.
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