FDA Grants Breakthrough Therapy Designation for Trastuzumab Deruxtecan in HER2-Low Metastatic Breast Cancer

Trastuzumab deruxtecan has been granted breakthrough therapy designation by the FDA for the treatment for HER2-low metastatic breast cancer.

The FDA has granted breakthrough therapy designation to fam-trastuzumab deruxtecan-nxki (Enhertu) for adults with unresectable HER2-low metastatic breast cancer and who have received prior treatment in the metastatic setting or developed disease recurrence within 6 months of adjuvant chemotherapy completion, according to a press release from AstraZeneca.1

The breakthrough therapy designation was based on results from the phase 3 DESTINY-Breast04 trial (NCT03734029). Previously reported results indicated that patients saw a statistically significant and clinically meaningful improvement in progression-free survival (PFS) and overall survival (OS) following treatment with trastuzumab deruxtecan.2

“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. [Trastuzumab deruxtecan] 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,” Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, said in the press release.

About 540 patients were enrolled in the trial across Asia, Europe, and North America. Patients were randomized 2:1 to receive either trastuzumab deruxtecan at 5.4 mg/kg or physicians’ choice of chemotherapy. In total, 480 patients were hormone receptor (HR)–positive, and 60 were HR-negative.

The primary end point was PFS and the secondary end points included PFS via investigator assessment, OS, objective response rate, and duration of response.

Patients were eligible for treatment if they had pathologically documented breast cancer. This included those with unresectable or metastatic disease, low HER2 expression, HR-positive or HR-negative disease, and had progressed on and would no longer benefit from endocrine therapy. Additionally, patients needed to have 1 measurable lesion and had adequate cardiac, bone marrow, renal, hepatic, and blood clotting functions.

Exclusion criteria included being ineligible for physician’s choice of therapy, having high-HER2 expression, and having previously been treated with anti-HER2 therapy.

Trastuzumab deruxtecan was previously granted priority review by the FDAin January 2022.3 This was based on results of the DESTINY-Breast03 trial (NCT03529110) for patients with HER2-positive unresectable or metastatic breast cancer.

“Historically, only patients with HER2-positive metastatic breast cancer were shown to benefit from HER2-directed therapy. 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 for these patients. This breakthrough therapy designation acknowledges the potential of [trastuzumab deruxtecan] to fulfill an unmet medical need and we look forward to working closely with the FDA to bring the first HER2-directed therapy to patients with metastatic breast cancer whose tumors have lower levels of HER2 expression,” Ken Takeshita, global head of R&D at Daiichi Sankyo, concluded.


  1. 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. https://bit.ly/3KkJjts
  2. Enhertu significantly improved both progression-free and overall survival in DESTINY-Breast04 trial in patients with HER2 low metastatic breast cancer. News Release. Daiichi-Sankyo. February 21, 2022. Accessed April 27, 2022. https://bwnews.pr/3KqNVhn
  3. Correcting and replacing Enhertu granted priority review in the US for patients with HER2-positive metastatic breast cancer treated with a prior anti-HER2-based regimen. News Release. AstraZeneca and Daiichi Sankyo. January 17, 2022. Accessed April 27, 2022. https://bwnews.pr/3y19dzJ
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