FDA Approves AstraZeneca and Daiichi Sankyo’s Enhertu for Treating HER2-low or HER2-ultralow Breast Cancer

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AstraZeneca and collaboration partner Daiichi Sankyo announced on Jan. 27, 2025 that FDA has approved their jointly developed antibody-drug conjugate (ADC), Enhertu (fam-trastuzumab deruxtecan-nxki), for treating adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by a FDA-approved test. Specifically, the treatment is for those patients who have progressed on one or more endocrine therapies in the metastatic setting. The approval makes fam-trastuzumab deruxtecan-nxki the first HER2-directed therapy in the United States for treating this type of breast cancer, according to a company press release (1).

In a Phase III trial (DESTINY-Breast06), fam-trastuzumab deruxtecan-nxki demonstrated a 36% reduction in disease-progression risk or death compared to chemotherapy in the overall patient population involved in the trial. The median progression-free survival (PFS) was 13.2 months, which was seen in patients randomized to the therapy, compared to a PFS of 8.1 months in patients randomized to chemotherapy. A confirmed objective response rate (ORR) of 62.6% was seen in the patients treated with fam-trastuzumab deruxtecan-nxki versus an ORR of 34.4% for the patients treated with chemotherapy (1).

“Endocrine therapy is typically used in the initial treatment of HR-positive metastatic breast cancer, and, following progression, subsequent chemotherapy is associated with poor outcomes. With a median progression-free survival exceeding one year and a response rate of more than 60%, [fam-trastuzumab deruxtecan-nxki] offers a potential new standard of care for patients with HR-positive, HER2-low, or HER2-ultralow metastatic breast cancer following endocrine therapy,” said Aditya Bardia, MD, program director of Breast Oncology and director of Translational Research Integration, UCLA Health Jonsson Comprehensive Cancer Center, US, and investigator in the DESTINY-Breast06 trial, in the press release (1).

FDA granted the approval after the fam-trastuzumab deruxtecan-nxki application received priority review and breakthrough therapy designation. Approval was based on results from the Phase III trial, which were presented at the 2024 American Society of Clinical Oncology Meeting and published in The New England Journal of Medicine (2).

“Building on the practice-changing previous approvals for Enhertu, this new approval brings this important medicine to an earlier treatment setting and a broader patient population with HER2-expressing metastatic breast cancer. The approval also highlights the importance of testing metastatic breast cancer tumors for detectable staining with a standard IHC test to identify those who may be eligible for treatment with Enhertu following endocrine therapy,” said Dave Fredrickson, executive vice-president, Oncology Hematology Business Unit, AstraZeneca, in the release.

Ken Keller, global head of Oncology Business, and president and CEO, Daiichi Sankyo, added in the release, “Enhertu continues to redefine the classification and treatment of HR-positive metastatic breast cancer with important new data across the spectrum of HER2 expression. Today’s approval underscores our ongoing commitment to realizing the full potential of this innovative antibody drug conjugate and represents another paradigm shift in how certain breast cancers can be treated.”

Fam-trastuzumab deruxtecan-nxki is approved in more than 70 countries, including the US, for patients with HER2-low metastatic breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy (based on the results from the DESTINY-Breast04 trial). The companies also have regulatory applications under review in the European Union, Japan, and several other countries.

Enhertu was discovered by Daiichi Sankyo and is being jointly developed and commercialized with AstraZeneca under a March 2019 collaboration (3). This FDA approval triggers a milestone payment of $175 million by AstraZeneca to Daiichi Sankyo for the HER2-low and HER2-ultralow chemotherapy-naïve breast cancer indication (1). US sales of the ADC are recognized by Daiichi Sankyo.

References

1. 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. Press Release. Jan. 27, 2025.
2. 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
3. AstraZeneca. AstraZeneca and Daiichi Sankyo Enter Collaboration for Novel HER2-Targeting Antibody-Drug Conjugate. Press Release. March 28, 2019.