T-DXd in HR-Positive, HER2-Ultralow Breast Cancer: DESTINY-Breast06
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T-DXd in HR+ HER2-Low/Ultralow Breast Cancer: DESTINY-Breast06 Findings at SABCS 2025
HR-positive, HER2-negative metastatic breast cancer accounts for approximately 70% of patients. Options after endocrine therapy and CDK4/6 inhibitors are limited. At SABCS 2025, researchers presented DESTINY-Breast06 , a Phase 3 trial of trastuzumab deruxtecan (T-DXd) , which outperformed chemotherapy in both HER2-low and HER2-ultralow disease.
1) What Did DESTINY-Breast06 Change?
Earlier studies established T-DXd activity in HER2-low disease (IHC 1+ or 2+/ISH-). This trial extended the approach to HER2-ultralow (IHC >0 but <1+). It tested whether treatment could outperform standard chemotherapy, such as paclitaxel or capecitabine, after endocrine resistance.
2) Study Design and Arms
The trial included 866 patients whose disease progressed after at least one endocrine treatment line. Randomization was 1:1:
• T-DXd (Enhertu): 5.4 mg/kg (IV every 3 weeks)
• Chemotherapy: Investigator's choice (Paclitaxel, Nab-paclitaxel, Capecitabine)
40% had ultralow HER2 expression. Median follow-up was 13.8 months.
3) Primary Result: PFS Difference in Months
BICR AssessmentClinical Significance
T-DXd extended median progression-free survival (PFS) over chemotherapy by more than 5 months . HR 0.62 represents a clear 38% reduction in progression or death risk. The difference is highly significant statistically (p<0.001).
4) Summary Results
| Parameter | T-DXd | Chemotherapy | Difference/Interpretation |
|---|---|---|---|
| PFS (Median) | 13.2 Months | 8.1 Months | HR 0.62 (38% Risk Reduction) |
| ORR (Response) | 52% | 31% | Substantially greater tumor shrinkage |
| Duration of Response (DOR) | 14.5 Months | 7.8 Months | Longer-lasting responses |
| Overall Survival (OS) | HR 0.71 | Reference | Immature data (favorable trend) |
5) What About the Ultralow Group?
Results were consistent in HER2-ultralow disease (IHC >0 <1+), with HR 0.58 . Even nearly negative tumors with minimal staining benefited more from T-DXd than chemotherapy.
Safety and Side Effects
The profile resembled earlier T-DXd studies, but serious adverse effects were more frequent than with chemotherapy (88% vs chemotherapy).
Key Concerns:
- ILD (Interstitial Lung Disease): The main risk. Grade 3+ rate: 12%; fatal cases: 0.5%. Early detection and management are crucial.
- Neutropenia: 20% Grade 3+.
- Nausea: Common in the T-DXd arm.
Despite this, patient-reported outcomes (PROs) indicated maintained quality of life.
Frequently Asked Questions
DROZDOGAN Academy Commentary
DESTINY-Breast06 nearly eliminates the concept of HER2 negativity: even minimal HER2 expression becomes a target. It strengthens T-DXd's potential as a new treatment standard in endocrine-resistant disease. ILD risk requires multidisciplinary patient selection and monitoring.
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