Trastuzumab Deruxtecan Granted Breakthrough Therapy Designation for HER2-Low Metastatic Breast Cancer


Up to 50% of all patients with breast cancer have tumors with a HER2 immunohistochemistry level not currently eligible for HER2-targeted therapy.

The FDA has granted Breakthrough Therapy Designation to trastuzumab deruxtecan (Enhertu; AstraZeneca) for the treatment of human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. Patients with hormone receptor (HR)-positive breast cancer should also have received or be ineligible for endocrine therapy.

Trastuzumab deruxtecan is a HER2-directed antibody drug conjugate. The Breakthrough Therapy Designation will allow for accelerated development and regulatory review, based on its potential to treat a serious condition and address a significant unmet need.

“Historically, only patients with HER2-positive metatatic breast cancer were shown to benefit from HER2-directed therapy,” said Ken Takeshita, MD, global head of research and development at Daiichi Sankyo, in a press release. “DESTINY-Breast04, in which Enhertu showed a clinically meaningful survival benefit in patients with HER2-low metastatic breast cancer, is the first trial to demonstrate that selecting patients for treatment based on low expression of HER2 has the potential to change the diagnostic and treatment paradigms of these patients.”

The designation was based on data from the pivotal DESTINY-Breast04 phase 3 trial, which reported positive high-level results in February 2022. According to the study, trastuzumab deruxtecan demonstrated a statistically significant and clinically meaningful improvement in both progression-free survival and overall survival in patients with HER2-low unresectable and/or metastatic breast cancer in all randomized patients with HR-positive and HR-negative disease. The safety profile was consistent with previous clinical trials and no new safety concerns were identified.

According to the press release, up to 50% of all patients with breast cancer have tumors with a HER2 immunohistochemistry score of 1+ or 2+ in combination with a negative in-situ hybridization test, which is a level of HER2 expression not currently eligible for HER2-targeted therapy. Low HER2 expression occurs in both HR-positive and HR-negative disease.

Targeting this lower range in the HER2 expression spectrum could offer a new approach to delay disease progression and extend survival for patients with metastatic breast cancer. Chemotherapy is currently the only treatment option for HR-positive tumors following progression on endocrine therapy and few targeted options are available for individuals who are HR-negative.

“Today’s news is a significant validation of the potential we see for the historic DESTINY-Breast04 trial to enable a paradigm shift in how breast cancer is classified by targeting the full spectrum of HER2-expression,” said Susan Galbraith, MD, executive vice president of oncology research and development at AstraZeneca, in the press release. “Enhertu continues to show transformative potential, and this milestone represents an important advance for patients with HER2-low metastatic breast cancer who are in urgent need of new treatment options and better outcomes.”

This marks the third Breakthrough Therapy Designation for trastuzumab deruxtecan in breast cancer. The drug previously received the designation for the treatment of second line HER2-positive metastatic breast cancer in 2021 and later-line HER2-positive metastatic breast cancer in 2017. Two other Breakthrough Therapy Designations were granted for trastuzumab deruxtecan in 2020 for HER2-mutant metastatic non-small cell lung cancer and HER2-positive metastatic gastric cancer.


Enhertu granted Breakthrough Therapy Designation in the US for patients with HER2-low metastatic breast cancer. News release. AstraZeneca; April 27, 2022. Accessed April 27, 2022.

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