ENHERTU® Approved in the EU for HER2-Low Metastatic Breast Cancer
Daiichi Sankyo (TSE: 4568) and AstraZeneca (LSE/STO/Nasdaq: AZN) announced the approval of ENHERTU® (trastuzumab deruxtecan) in the European Union (EU) as a monotherapy for the treatment of adult patients with unresectable or metastatic hormone receptor (HR) positive, HER2 low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (IHC 0 with membrane staining) breast cancer. This approval applies to patients who have already received at least one endocrine therapy in the metastatic setting and are not considered suitable for further endocrine treatment.
ENHERTU is a HER2-directed antibody-drug conjugate (ADC), developed by Daiichi Sankyo and co-commercialized with AstraZeneca. The European Commission’s approval follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). This decision is based on compelling data from the DESTINY-Breast06 phase 3 trial, which was presented at the 2024 American Society of Clinical Oncology (#ASCO24) Annual Meeting and published in The New England Journal of Medicine.
HER2 Low Metastatic Breast Cancer: A Common and Challenging Subtype
HR-positive, HER2-negative breast cancer is the most common subtype, accounting for approximately 70% of all breast cancers. While these cancers are classified as HER2-negative, many still express some level of HER2, complicating treatment strategies. Currently, endocrine therapies are the standard for HR-positive metastatic breast cancer, but many patients either discontinue treatment or transition to chemotherapy, which is often associated with lower response rates and poorer outcomes.
Trial Results: ENHERTU Demonstrates Superior Efficacy
The pivotal DESTINY-Breast06 trial demonstrated that ENHERTU significantly outperformed chemotherapy in patients with HR-positive, HER2 low or HER2 ultralow metastatic breast cancer. The trial enrolled 866 patients, with 713 patients in the HER2-low subgroup and 152 in the HER2-ultralow subgroup. In patients with chemotherapy-naïve HR-positive, HER2-low metastatic breast cancer, ENHERTU showed a 38% reduction in the risk of disease progression or death compared to chemotherapy, with a hazard ratio (HR) of 0.62 (95% confidence interval [CI]: 0.52-0.75, p<0.0001).
Median progression-free survival (PFS) was 13.2 months in the ENHERTU group, compared to 8.1 months in the chemotherapy arm. Additionally, the confirmed objective response rate (ORR) was 56.5% in the ENHERTU group, compared to 32.2% in the chemotherapy group. The median duration of response (DOR) was 14.1 months with ENHERTU versus 8.6 months with chemotherapy.
For the overall trial population, which included both HER2-low and HER2-ultralow subgroups, ENHERTU achieved a 36% reduction in the risk of disease progression or death versus chemotherapy (HR 0.64; 95% CI: 0.54-0.76; p<0.0001), with a median PFS of 13.2 months for ENHERTU versus 8.1 months for chemotherapy. The confirmed ORR in the overall population was 57.3% for ENHERTU compared to 31.2% for chemotherapy, and median DOR was 14.3 months for ENHERTU versus 8.6 months for chemotherapy.
HER2 Ultralow Population: Meaningful Clinical Benefit
An exploratory analysis of the HER2-ultralow subgroup also demonstrated consistent benefit. Patients treated with ENHERTU had a median PFS of 13.2 months, compared to 8.3 months in the chemotherapy group. The confirmed ORR was 61.8% for ENHERTU versus 26.3% for chemotherapy, and median DOR was 14.3 months versus 14.1 months, respectively.
Expanded Treatment Option for Patients
“This approval provides a new treatment option for HR-positive metastatic breast cancer with HER2 low or HER2 ultralow expression,” said Dr. Giuseppe Curigliano, Professor of Medical Oncology at the University of Milan and Principal Investigator of DESTINY-Breast06. “ENHERTU outperformed chemotherapy, providing patients with a progression-free survival of over one year, a significant improvement compared to current chemotherapy options.”
Ken Keller, President and CEO of Daiichi Sankyo, added, “ENHERTU continues to transform the treatment landscape by offering an innovative therapy for patients with HER2 low or ultralow metastatic breast cancer who have exhausted endocrine-based therapies. This approval extends the potential benefit of ENHERTU to a broader patient population.”
Safety Profile
The safety profile of ENHERTU in DESTINY-Breast06 was consistent with previous clinical trials. The most common grade 3 or 4 treatment-related adverse events included neutropenia (18.0%), anemia (10.5%), and fatigue (7.8%). Less common but serious adverse events, such as interstitial lung disease, occurred in 1.1% of patients. The overall safety profile continues to support the use of ENHERTU in the metastatic setting.
Financial Impact
Following this EU approval, AstraZeneca will make a milestone payment of $125 million to Daiichi Sankyo for the HER2 low and HER2 ultralow chemotherapy-naïve breast cancer indication. Sales of ENHERTU in most EU territories will be recognized by Daiichi Sankyo.
