Key Highlights:
- The FDA has approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for adult patients with unresectable or metastatic, hormone receptor-positive (HR+), HER2-low (IHC 1+ or 2+/ISH-negative), or HER2-ultralow (IHC 0 with membrane staining) breast cancer.
- This approval applies to patients whose disease has progressed after at least one prior endocrine therapy in the metastatic setting.
Clinical Trial Findings: DESTINY-Breast06
The FDA’s decision was based on results from the phase 3 DESTINY-Breast06 trial (NCT04494425), which compared T-DXd with chemotherapy in chemotherapy-naïve patients with metastatic HR+, HER2-low or HER2-ultralow breast cancer.
- Progression-Free Survival (PFS):
- Overall Population: T-DXd reduced the risk of disease progression or death by 36% compared to chemotherapy (HR, 0.64; 95% CI, 0.54-0.76; P < .0001).
- HER2-Low Patients (n = 713): Median PFS was 13.2 months with T-DXd vs 8.1 months with chemotherapy (HR, 0.62; 95% CI, 0.52-0.75; P < .001).
- HER2-Ultralow Patients (n = 153): Median PFS was 13.2 months with T-DXd vs 8.3 months with chemotherapy (HR, 0.78; 95% CI, 0.50-1.21).
- Overall Response Rate (ORR):
- 62.6% with T-DXd vs 34.4% with chemotherapy.
- Overall Survival (OS): Data remain immature at this time.
Safety Profile
- Grade 3 or higher adverse events were reported in 52.8% of T-DXd-treated patients vs 44.4% in the chemotherapy group.
- Interstitial Lung Disease (ILD): 11.3% of patients in the T-DXd arm developed ILD, including three fatal cases (Grade 5).
Expert Insights
Dr. Aditya Bardia, lead author of DESTINY-Breast06 and director of Translational Research Integration at UCLA Health, emphasized that T-DXd represents a “potential new standard of care” for HR+, HER2-low or HER2-ultralow metastatic breast cancer following endocrine therapy.
Krissa Smith, Vice President of Education at Susan G. Komen, highlighted the importance of knowing HER2 status to guide treatment decisions, stating that “patients now have more personalized options.”
Conclusion
With this approval, T-DXd becomes the first HER2-targeted therapy for HER2-low and HER2-ultralow metastatic breast cancer, offering a significant treatment advancement for patients who have progressed on endocrine therapy.
References:
- AstraZeneca. Enhertu approved in the US as first HER2-directed therapy for patients with HER2-low or HER2-ultralow metastatic breast cancer following disease progression after one or more endocrine therapies. News Release. January 27, 2025. Link
- Bardia A, Hu X, Dent R, et al. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med. 2024;391(22):2110-2122. doi:10.1056/NEJMoa2407086