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AstraZeneca’s Enhertu Gets FDA Approved as First Therapy for HER2-Low Breast Cancer

AstraZeneca’s Enhertu Gets FDA Approved as First Therapy for HER2-Low Breast Cancer

After blockbuster trial data showing that Enhertu could cut the risk of disease progression by 50 percent and deaths by 36 percent in patients with HER2-low metastatic breast cancer, the FDA has finally granted the AstraZeneca-Daiichi Sankyo cancer drug full approval for the indication. Photo: Daiichi Sankyo/AstraZeneca

The US Food and Drug Administration (FDA) has approved AstraZeneca and Daiichi Sankyo’s Enhertu (trastuzumab-deruxtecan) for the treatment of patients with unresectable or metastatic HER2-low breast cancer.

Enhertu is an antibody-drug conjugate (ADC) consisting of Roche’s Herceptin (trastuzumab), a monoclonal antibody against HER2 (human epidermal growth factor receptor 2), and the topoisomerase I inhibitor deruxtecan. The drug is being jointly developed and commercialized by AstraZeneca and Japan’s Daiichi Sankyo.

This is the first approved therapy for patients with the HER2-low breast cancer subtype, which is a newly defined subset of HER2-negative breast cancer.

HER2 is a tyrosine kinase receptor that is overexpressed and genetically amplified in approximately 20 percent of breast cancers. The receptor is involved in promoting cell growth.

HER2-low is characterized by the presence of some HER2 proteins on the cell surface, but not enough to be classified as HER2-positive.

In the US, it is estimated that 287,850 new cases of female breast cancer will be diagnosed in 2022, according to data from the National Cancer Institute (NCI) outlined by the FDA. Approximately 80 to 85 percent of these cases were previously considered to be the HER2-negative subtype (which includes hormone receptor positive and triple negative breast cancer), which means the tumors do not make higher than normal amounts of the HER2 protein.

Based on the new definitions, 60 percent of previously classified HER2-negative patients are now categorized as HER2-low.

Enhertu is indicated for patients with HER2-low breast cancer who have received even one prior chemotherapy in the metastatic setting, or their cancer returned during, or within six months of completing, adjuvant chemotherapy.


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As an ADC, Enhertu works by targeting tumor cells expressing HER2 and killing them with its drug payload.

HER2 positivity is currently classified as tumors with a HER2 immunohistochemical (IHC) score of at least 3, or a score of 2 accompanied by a positive in situ hybridization (ISH) test. The HER2-low subgroup covers patients with IHC 1+ or IHC 2+ with a negative ISH score. Prior to the approval of Enhertu, patients in the latter IHC/ISH category were not eligible for HER2-targeted therapies and mainly got endocrine therapy (if HR-positive disease) or chemotherapy.

“Today’s approval highlights the FDA’s commitment to be at the forefront of scientific advances, making targeted cancer treatment options available for more patients,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “Having therapies that are specially tailored to each patient’s cancer subtype is a priority to ensure access to safe and innovative treatments.”

Dave Fredrickson, executive vice president, Oncology Business Unit, AstraZeneca, said in a press release from the company that, “The rapid approval of ENHERTU in HER2-low metastatic breast cancer by the FDA underscores the urgency to bring this transformational medicine to patients as quickly as possible. Patients with HER2-low tumors, who are identified through existing HER2 testing methods, will now have the opportunity to be treated based upon their HER2 status.”

Enhertu Trial Data

Enhertu’s approval was based on the randomized, multicenter, open label Phase III DESTINY-Breast04 clinical trial that involved 557 adult patients with unresectable or metastatic HER2-low breast cancer.

The trial included 494 hormone receptor positive (HR+) patients and 63 hormone receptor negative (HR-) patients. Of these patients, 373 received Enhertu by intravenous infusion every three weeks and 184 received a chemotherapy (eribulin, capecitabine, gemcitabine, nab paclitaxel or paclitaxel).

Results from the trial showed that there was an improvement in both progression-free survival and overall survival in individuals with unresectable or metastatic HER2-low breast cancer. Specifically, Enhertu reduced the risk of disease progression by an impressive 50 percent and the risk of death by 36 percent in patients previously treated for HER2-low metastatic breast cancer.

Enhert showed similar benefits in both HR-negative and HR-positive patients, despite the HR-negative population being small.

Of the trial participants, females made up 99.6 percent of the group. The racial composition of the study group was reported to be as follows: 48 percent White, 40 percent Asian, two percent Black or African American and 3.8 percent Hispanic/Latino.


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Cancer Moonshot Program

The FDA said Enhertu’s approval highlights how the FDA’s efforts “align with the goals” of the federal administration’s Cancer Moonshot program, which aims to “target the right treatments to the right patients, speeding progress against the most deadly and rare cancers, and learning from the experience of all patients.”

As part of the Cancer Moonshot program, which US President Joe Biden launched in 2016 when he was Vice President, Biden “tapped federal agencies to develop ways to reduce the rate of cancer deaths and improve the lives of cancer patients and their families through advancements in cancer research and technology, and development of new programs.”

Enhertu received priority review and breakthrough therapy designations for the HER2-low indication. The FDA’s approval of Enhertu also came four months ahead of the Prescription Drug User Fee Act (PDUFA) deadline.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence, which provides a framework for concurrent submission and review of oncology drugs among international partners, according to the FDA. For Enhertu’s review, the FDA said it collaborated with the Australian Therapeutic Goods Administration, Health Canada and Swissmedic in Switzerland. Application reviews may be ongoing at the other regulatory agencies, the US federal agency added.

Enhertu Outlook

Enhertu was first approved in the US in 2019 and in addition to breast cancer, it is also indicated for the treatment of gastric or gastroesophageal adenocarcinoma.

AstraZeneca and Daiichi Sankyo are evaluating Enhertu for earlier and wider use, given that trial data also showed very promising results for Enhertu use even in low level expressers in the HER2-low group. As such, the companies are looking to determine what the lowest level of HER2 expression could be at which the drug could still effectively perform.

SVB Securities analyst Andrew Berens, MD, is projecting that Enhertu could reach $4.6 billion in sales from HER2-low patients alone by 2030 based on the strong trial data.