FDA Approves Enhertu for HER2-Low and -Ultralow Breast Cancer

The Food and Drug Administration (FDA) approved Enhertu (fam-trastuzumab deruxtecan-nxki) for the treatment of adults with unresectable or metastatic HR-positive, HER2-low or -ultralow breast cancer whose disease progressed on one or more endocrine therapies in the metastatic setting.

A patient’s HER2 status would be determined by an FDA-approved test, as noted in a press release from Daiichi Sankyo and AstraZeneca, the manufacturers of Enhertu.

The approval of Enhertu, an antibody drug conjugate, was based on findings from the DESTINY-Breast06 trial presented in June 2024. In this trial, treatment with Enhertu resulted in a 36% reduction in the risk for disease progression or death compared with chemotherapy in 866patients with chemotherapy-naïve, HR-positive, HER2-low or -ultralow metastatic breast cancer. in addition, patients treated with Enhertu had a median progression-free survival of 13.2 months compared with 8.1 months in those treated with chemotherapy.

In the trial’s overall population, the objective response rate was 62.6% in the Enhertu group versus 34.4% in the chemotherapy group, according to the release. In particular, complete responses occurred in 2.5% of patients assigned Enhertu compared with none in those assigned chemotherapy. Partial responses were observed in 60.1% of patients in the Enhertu group versus 34.4% in the chemotherapy group.

This study also assessed outcomes in 713 patients with HER2-low breast cancer. In this subgroup of patients, the median progression-free survival was 13.2 months in the Enhertu group compared with 8.1 months in the chemotherapy group. Additionally, confirmed overall response rates were 62% in patients assigned Enhertu compared with 35.2% in those assigned chemotherapy. More patients in the Enhertu group had complete and partial responses to treatment (2.8% and 59.2%, respectively) compared with the chemotherapy group (0% and 35.2%). The median duration of response was longer in the Enhertu arm compared with the chemotherapy arm (14.1 months versus 8.6 months).

“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,” Dr. Aditya Bardia, Program Director of Breast Oncology and Director of Translational Research Integration, UCLA Health Jonsson Comprehensive Cancer Center, said in the release. “With a median progression-free survival exceeding one year and a response rate of more than 60%, [Enhertu] offers a potential new standard of care for patients with hormone receptor positive, HER2-low or HER2-ultralow metastatic breast cancer following endocrine therapy.”

The DESTINY-Breast-06 also analyzed data in 153 patients with HER2-ultralow metastatic breast cancer. The progression-free survival benefit continued in this subgroup of patients treated with Enhertu versus chemotherapy, with a median of 15.1 months and 8.3 months, respectively. Confirmed objective response rate for the Enhertu and chemotherapy arms was 65.7% and 30.8%, respectively. The Enhertu group had a median duration of response of 14.3 months compared with 14.1 months in the chemotherapy group.

“Including HER2-ultralow [disease], the proportion of patients who could benefit from [Enhertu] will be close to 85% in hormone receptor–positive, HER2-negative breast cancer,” lead study author Dr. Giuseppe Curigliano, of the University of Milan and European Institute of Oncology, said in a presentation of the data at the ASCO Annual Meeting.

Enhertu comes with boxed warning for embryo-fetal toxicity and interstitial lung disease, according to the release. The researchers who conducted the DESTINY-Breast06 trial assessed Enhertu’s safety in 434 patients with unresectable or metastatic HER2-low or -ultralow breast cancer. The most common side effects, occurring in at least 20% of patients, included were decreased neutrophil count, decreased white blood cell count, decreased hemoglobin, nausea, fatigue, decreased lymphocyte count, decreased platelet count, hair loss, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood alkaline phosphatase, diarrhea, decreased blood potassium, constipation, vomiting, COVID-19, decreased appetite and musculoskeletal pain.

Severe side effects occurring in 20% of patients treated with Enhertu, according to the press release. The serious side effects that occurred in at least 1% of patients in this group were interstitial lung disease/pneumonitis, febrile neutropenia, COVID-19 and hypokalemia. Side effects resulting in death were observed in 2.8% of patients.

“This new approval brings this important medicine to an earlier treatment setting and a broader patient population with HER2 expressing metastatic breast cancer,” said Dave Fredrickson, Executive Vice President of the Oncology Hematology Business Unit at AstraZeneca, said in the release. “The approval also highlights the importance of testing metastatic breast cancer tumors for detectable staining … to identify those who may be eligible for treatment with Enhertu following endocrine therapy.”

Ken Keller, Global Head of Oncology Business, and President and CEO of Daiichi Sankyo, also said 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.”

“We are excited to see more treatment options for these patients which enable more personalized care,” Krissa Smith, Vice President of Education for Susan G. Komen, said in the release. “It is critical for patients to understand the HER2 status of their metastatic breast cancer to help them make informed treatment decisions. Patients with tumors that are HER2 low or HER2 ultralow now have more options to consider with their health care team.”

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