Migrating Breast Cancer Cell
Credit: Christoph Burgstedt/Getty Images

AstraZeneca has established that targeting HER-2 low breast cancer works, and very well, by presenting striking Phase III results at the American Society of Clinical Oncology (ASCO) this week.

Enhertu (trastuzumab deruxtecan) demonstrated a 49% reduction in the risk of disease progression or death versus chemotherapy in patients with HER2-low metastatic breast cancer with hormone receptor (HR)-positive disease. Subjects who received the drug also showed a 36% reduction in the risk of death, with a median overall survival of 23.9 months versus 17.5 months for those on chemotherapy.

Results of the trial were simultaneously published in The New England Journal of Medicine.

“The results of DESTINY-Breast04 show for the first time that a HER2-directed therapy can provide a survival benefit to patients with low HER2 expression, indicating we must reconsider the way we categorize patients with metastatic breast cancer,” said Shanu Modi, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, US and Principal Investigator for the trial.

He added that, “The efficacy seen with Enhertu also reinforces the potential to establish a new standard of care for more than half of all patients with breast cancer currently categorized as having HER2-negative disease, but who actually have tumors with low HER2 expression.”

HER2 expression is currently defined as either positive or negative, and is determined by an immunohistochemistry (IHC) test that measures the amount of HER2 protein on a cancer cell, and/or an in situ hybridization (ISH) test which counts the copies of the HER2 gene in cancer cells. HER2-positive cancers are defined as IHC 3+ or IHC 2+/ISH+, and HER2-negative cancers are currently defined as IHC 0, IHC 1+ or IHC 2+/ISH-.

Approximately half of all patients with breast cancer have tumors with a HER2 IHC score of 1+, or 2+ in combination with a negative ISH test, a level of HER2 expression not currently eligible for HER2-targeted therapy. Low HER2 expression occurs in both HR-positive and HR-negative disease.

Enhertu is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialized by AstraZeneca and Daiichi Sankyo. DESTINY-Breast04 enrolled approximately 557 patients at multiple sites in Asia, Europe and North America.

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca said, “DESTINY-Breast04 validates targeting the lower end of the spectrum of HER2 expression, since Enhertu reduced the risk of disease progression or death across all types of patients in the trial by half, and reduced the risk of death by over a third. We must now evolve the way we classify and treat metastatic breast cancer to ensure these patients are effectively diagnosed and treated.”

In April 2022, the FDA granted Enhertu Breakthrough Therapy Designation in the US for the treatment of adults with unresectable or metastatic HER2-low breast cancer who have received a prior systemic therapy or developed disease recurrence during or within six months of completing adjuvant chemotherapy,

The drug has now received five Breakthrough Therapy Designations including three in breast cancer, one in lung and one in gastric cancer. It is currently under review in the US for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have a HER2 (ERBB2) mutation and in Europe for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma.

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