CHMP Recommends EU Approval of ENHERTU® for HER2 Low/Ultralow Metastatic Breast Cancer
Daiichi Sankyo (TSE: 4568) and AstraZeneca (LSE/STO/Nasdaq: AZN) have achieved a significant milestone with the recommendation for approval of their drug ENHERTU® (trastuzumab deruxtecan) in the European Union (EU). The drug has been endorsed by the Committee for Medicinal Products for Human Use (CHMP) as a monotherapy for 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 recommendation applies to patients who have received at least one endocrine therapy in the metastatic setting and are not considered suitable for endocrine therapy as their next line of treatment.
ENHERTU is a specially engineered HER2-directed DXd antibody-drug conjugate (ADC) that was developed by Daiichi Sankyo and is being co-developed and commercialized in collaboration with AstraZeneca. The positive opinion from the CHMP is based on compelling results from the DESTINY-Breast06 Phase 3 trial, which were presented at the 2024 American Society of Clinical Oncology (#ASCO24) Annual Meeting and subsequently published in The New England Journal of Medicine. The European Commission will now review the CHMP recommendation and make a final decision regarding market authorization in the EU.
The DESTINY-Breast06 trial demonstrated that ENHERTU significantly improved outcomes for patients. The drug reduced the risk of disease progression or death by 38% compared to chemotherapy in patients with chemotherapy-naïve HR-positive, HER2 low metastatic breast cancer (n=713; hazard ratio [HR] 0.62; 95% confidence interval [CI]: 0.52-0.75; p<0.0001). Median progression-free survival (PFS) was 13.2 months (95% CI: 11.4-15.2) in the ENHERTU group compared to 8.1 months (95% CI: 7.0-9.0) in the chemotherapy group.
The confirmed objective response rate (ORR) in the HER2 low population was 56.5% (95% CI: 51.2-61.7) in patients treated with ENHERTU, compared to 32.2% (95% CI: 27.4-37.3) in those receiving chemotherapy. The ENHERTU group saw nine complete responses (CRs) and 194 partial responses (PRs), while the chemotherapy group had zero CRs and 114 PRs. The median duration of response (DOR) was notably longer at 14.1 months in the ENHERTU arm compared to 8.6 months in the chemotherapy arm.
In the broader trial population, which included patients with chemotherapy-naïve HR-positive, HER2 low, or HER2 ultralow metastatic breast cancer (n=866), ENHERTU maintained similar benefits, reducing the risk of disease progression or death by 36% (HR 0.64; 95% CI: 0.54-0.76; p<0.0001). The median PFS was again 13.2 months (95% CI: 12.0-15.2) with ENHERTU versus 8.1 months (95% CI: 7.0-9.0) with chemotherapy.
The overall confirmed ORR in this expanded patient population was 57.3% (95% CI: 52.5-62.0) in the ENHERTU group compared to 31.2% (95% CI: 26.8-35.8) in the chemotherapy group. The ENHERTU arm recorded 13 CRs and 237 PRs, while the chemotherapy arm had zero CRs and 134 PRs. Median DOR was also superior in the ENHERTU arm at 14.3 months versus 8.6 months in the chemotherapy arm.
Additionally, an exploratory analysis of the HER2 ultralow population (n=153; HR 0.78; 95% CI: 0.50-1.21) indicated that the improvement in PFS was consistent with that observed in HER2 low patients. ENHERTU achieved a median PFS of 13.2 months (95% CI: 9.8-17.3) compared to 8.3 months (95% CI: 5.8-15.2) with chemotherapy. The confirmed ORR in the HER2 ultralow population was 61.8% (95% CI: 50.0-72.8) for ENHERTU versus 26.3% (95% CI: 16.9-37.7) for chemotherapy. The median DOR was 14.3 months for ENHERTU, comparable to 14.1 months for chemotherapy.
Ken Takeshita, MD, Global Head of R&D at Daiichi Sankyo, emphasized the importance of this advancement, stating, “ENHERTU is the first HER2-directed treatment and antibody-drug conjugate to demonstrate a progression-free survival of more than one year in patients with HER2 low or HER2 ultralow metastatic breast cancer following endocrine therapy. The CHMP recommendation is encouraging and supports our goal of further developing and advancing the way breast cancer is classified and treated.”
Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology Hematology R&D at AstraZeneca, echoed this sentiment, adding, “Endocrine therapy is typically used in the initial treatment of HR-positive metastatic breast cancer, but as the disease progresses, the benefit of continued endocrine therapy diminishes. Standard-of-care chemotherapy is associated with poor outcomes. ENHERTU has the potential to be the first HER2-directed treatment for patients in the EU with HR-positive, HER2 low, or HER2 ultralow metastatic breast cancer directly following endocrine therapy, marking a significant shift in treatment approaches.”
The safety profile of ENHERTU in the DESTINY-Breast06 trial was consistent with previous breast cancer studies, with no new safety concerns emerging. The most common grade 3 or higher treatment-related treatment-emergent adverse events (TEAEs) occurring in 5% or more of patients treated with ENHERTU included neutropenia (20.7%), leukopenia (6.9%), and anemia (5.8%). Interstitial lung disease (ILD) or pneumonitis was observed in 11.3% of patients receiving ENHERTU, with most cases being low grade (grade 1 [n=7; 1.6%] or grade 2 [n=36; 8.3%]). There were three grade 3 ILD events (0.7%) and three grade 5 events (0.7%), as determined by an independent adjudication committee.
ENHERTU is already approved in more than 75 countries, including the EU, for patients with HER2 low metastatic breast cancer who have received prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy. These approvals are based on the results from the earlier DESTINY-Breast04 trial.
The recommendation for approval by CHMP represents a crucial step toward making ENHERTU accessible to a broader patient population in the EU, potentially transforming treatment paradigms for those with HER2 low and HER2 ultralow metastatic breast cancer. The final decision by the European Commission is anticipated in the coming months, and if approved, ENHERTU will offer a new and effective therapeutic option for patients in need.
