In historic FDA nod, AstraZeneca, Daiichi's Enhertu snags ultrafast approval in broad HER2-low breast cancer use

A new era of HER2-low treatment is upon us.

Thanks to a landmark FDA approval Friday, AstraZeneca and Daiichi Sankyo’s Enhertu has become the first therapy targeted to treat unresectable or metastatic breast cancer expressing low levels of HER2, a brand-new category that was once part of the HER2-negative group.

The decision comes four months ahead of schedule, the FDA noted, apparently impressed with the benefits Enhertu has shown. The agency is also giving the HER2-targeted antibody-drug conjugate a broad range of use.

Patients with HER2-low breast cancer can get Enhertu after just one prior chemotherapy in the metastatic setting, or if their cancer returned rapidly in six months after postsurgery adjuvant chemotherapy during the non-metastatic phase. No hormone receptor (HR) status is required, meaning both HR-positive and triple-negative breast cancer patients may be eligible for the drug.

The HER2-low setting marks a large category. According to data from the National Cancer Institute cited by the FDA, about 80% to 85% of 287,850 new breast cancer cases that will be diagnosed in the U.S. this year are considered HER2-negative by the old definition. Now, among them, about 60% fit the description of HER2-low.

Based on the huge patient population, SVB Securities analyst Andrew Berens, M.D., previously projected that Enhertu could reach $4.6 billion sales in HER2-low patients by 2030. 

Currently, tumors with HER2 immunohistochemical (IHC) score of at least 3, or a score of 2 accompanied by a positive in situ hybridization (ISH) test, are called HER2-positive. HER2-low covers patients with IHC 1+ or IHC 2+ with a negative ISH score. Before Enhertu, these patients weren’t eligible for HER2-targeted therapies; instead, they mostly receive either endocrine therapy if they have HR-positive disease or chemotherapy.

Enhertu uses a HER2-directed antibody component included in Roche’s Herceptin to locate the tumor and then release a toxic payload to kill it off.

In the groundbreaking Destiny-Breast04 trial, Enhertu cut the risk of disease progression or death by 50% and the risk of death by 36% over the physician’s choice of chemo in patients with previously treated HER2-low metastatic breast cancer. The drug showed similar benefits in both HR-negative and HR-positive patients, although the HR-negative population is rather small. Improvements in the lower boundary of HER2 expression—IHC 1+—were also consistent with those among higher expressers.

AstraZeneca and Daiichi Sankyo are also exploring earlier and even wider use of Enhertu. For one thing, because Enhertu also showed remarkable data in the lower expressers within the HER2-low group, the two companies are trying to figure out the lowest HER2 expression requirement where Enhertu could still work.

They also aim to move Enhertu to earlier treatment. The Destiny-Breast06 trial is testing Enhertu in patients right after disease progression on endocrine therapy before chemo.