The U.S. Food and Drug Administration (FDA) has granted approval to Enhertu (trastuzumab deruxtecan) for the treatment of adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-low or HER2-ultralow breast cancer, as determined by an FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic setting. This decision marks Enhertu as the first HER2-directed therapy approved for this specific patient population, offering a new treatment option beyond chemotherapy. The approval was supported by data from the DESTINY-Breast06 Phase III trial.
DESTINY-Breast06 Trial Results
The DESTINY-Breast06 trial demonstrated a significant 36% reduction in the risk of disease progression or death in patients treated with Enhertu compared to those receiving chemotherapy (HR 0.64; 95% CI: 0.54-0.76; p<0.0001). The trial included patients with chemotherapy-naive HER2-low or HER2-ultralow metastatic breast cancer. Patients treated with Enhertu experienced a median progression-free survival (PFS) of 13.2 months (95% CI: 12.0-15.2), compared to 8.1 months (95% CI: 7.0-9.0) for those treated with chemotherapy. The confirmed objective response rate (ORR) was 62.6% (95% CI: 57.6-67.4) in the Enhertu arm versus 34.4% (95% CI: 29.7-39.4) in the chemotherapy arm.
Aditya Bardia, MD, MPH, Program Director of Breast Oncology at UCLA Health Jonsson Comprehensive Cancer Center, highlighted the potential of Enhertu as a new standard of care, noting that the median progression-free survival exceeded one year with a response rate of more than 60 percent.
HER2-Ultralow Expression Analysis
An exploratory analysis of patients with HER2-ultralow expression showed results consistent with those observed in patients with HER2-low expression. This suggests that Enhertu may provide clinical benefit across the spectrum of HER2 expression in HR-positive metastatic breast cancer. Approximately 85-90% of patients with HR-positive, HER2-negative metastatic breast cancer were found to have actionable levels of HER2 expression. Furthermore, nearly two-thirds of patients previously assessed as IHC 0 at a local laboratory were reclassified as HER2-low or HER2-ultralow upon central analysis of the tumor sample.
Safety Profile
The safety profile of Enhertu in the DESTINY-Breast06 trial was consistent with previous clinical trials, with no new safety concerns identified. However, Enhertu carries boxed warnings for interstitial lung disease (ILD)/pneumonitis and embryo-fetal toxicity. Common adverse reactions (≥20%) included decreased white blood cell count, nausea, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, fatigue, decreased platelet count, alopecia, increased alanine aminotransferase, increased blood alkaline phosphatase, increased aspartate aminotransferase, decreased blood potassium, diarrhea, vomiting, constipation, decreased appetite, COVID-19, and musculoskeletal pain. Serious adverse reactions occurred in 20% of patients, with fatalities due to adverse reactions reported in 2.8% of patients.
Clinical Significance
This approval expands the treatment options for patients with HR-positive, HER2-low or HER2-ultralow metastatic breast cancer who have progressed on endocrine therapy. Prior to this approval, chemotherapy was the standard of care following endocrine therapy, which is associated with poor response rates and outcomes. Enhertu offers a targeted approach with the potential to improve outcomes for this patient population.
Dave Fredrickson, Executive Vice President of AstraZeneca's Oncology Hematology Business Unit, emphasized that this approval brings Enhertu to an earlier treatment setting and a broader patient population with HER2-expressing metastatic breast cancer. Ken Keller, Global Head of Oncology Business at Daiichi Sankyo, noted that Enhertu continues to redefine the classification and treatment of HR-positive metastatic breast cancer.
Following the approval, AstraZeneca is due to pay Daiichi Sankyo $175 million as a milestone payment for the HER2-low and HER2-ultralow chemotherapy-naïve breast cancer indication.
