Daiichi Sankyo and AstraZeneca’s ENHERTU® (trastuzumab deruxtecan) has been recommended for approval 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 who have received at least one endocrine therapy in the metastatic setting and who are not considered suitable for endocrine therapy as the next line of treatment.

ENHERTU is a specifically engineered HER2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca.

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) based its positive opinion on results from the DESTINY-Breast06 phase 3 trial presented at the 2024 American Society of Clinical Oncology (#ASCO24) Annual Meeting and published in The New England Journal of Medicine. The recommendation will now be reviewed by the European Commission, which has the authority to grant marketing authorizations for medicines in the EU.

In the DESTINY-Breast06 trial, ENHERTU demonstrated a 38 percent reduction in the risk of disease progression or death versus chemotherapy in patients with chemotherapy-naïve HR positive, HER2 low metastatic breast cancer (n=713; hazard ratio [HR] 0.62; 95 percent confidence interval [CI]: 0.52-0.75; p<0.0001) as assessed by blinded independent review (BICR). Median progression-free survival (PFS) was 13.2 months (95 percent CI: 11.4-15.2) in the ENHERTU arm compared to 8.1 months (95 percent CI: 7.0-9.0) in the chemotherapy arm.

Confirmed objective response rate (ORR) in the HER2 low population was 56.5 percent (95 percent CI: 51.2-61.7) in the ENHERTU arm versus 32.2 percent in the chemotherapy arm (95 percent CI: 27.4-37.3). There were nine complete responses (CRs) and 194 partial responses (PRs) seen in the ENHERTU arm, compared to zero CRs and 114 PRs in the chemotherapy arm. Median duration of response (DOR) was 14.1 months in the ENHERTU arm versus 8.6 months in the chemotherapy arm.

In the overall trial population of patients with chemotherapy-naïve HR positive, HER2 low or HER2 ultralow metastatic breast cancer (n=866), ENHERTU achieved a similar 36 percent reduction in the risk of disease progression or death versus chemotherapy (HR 0.64; 95 percent CI: 0.54-0.76; p<0.0001). A median PFS of 13.2 months (95 percent CI: 12.0-15.2) was seen in patients treated with ENHERTU compared to 8.1 months (95 percent CI: 7.0-9.0) in patients treated with chemotherapy.

Confirmed ORR in the overall trial population was 57.3 percent (95 percent CI: 52.5-62.0) in the ENHERTU arm versus 31.2 percent (95 percent CI: 26.8-35.8) in the chemotherapy arm. There were 13 CRs and 237 PRs seen in the ENHERTU arm, compared to zero CRs and 134 PRs in the chemotherapy arm. Median DOR was 14.3 months in the ENHERTU arm versus 8.6 months in the chemotherapy arm.

An exploratory analysis of the HER2 ultralow population (n=153; HR 0.78; 95 percent CI: 0.50-1.21) showed the clinically meaningful improvement in PFS was consistent between patients with HER2 low and HER2 ultralow expression, with 13.2 months (95 percent CI: 9.8-17.3) in patients treated with ENHERTU compared to 8.3 months (95 percent CI: 5.8-15.2) in those treated with chemotherapy. Confirmed ORR was 61.8 percent (95 percent CI: 50.0-72.8) in the ENHERTU arm versus 26.3 percent in the chemotherapy arm (95 percent CI: 16.9-37.7). There were four CRs and 43 PRs seen in the ENHERTU arm, compared to zero CRs and 20 PRs in the chemotherapy arm. Median DOR was 14.3 months in the ENHERTU arm versus 14.1 months in the chemotherapy arm.

“ENHERTU is the first HER2 directed treatment and antibody drug conjugate to show 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,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo.

“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 is limited and subsequent 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, which would mark an important shift in how patients in this setting are treated,” said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology Hematology R&D, AstraZeneca.