FDA Grants Breakthrough Therapy Designation to T-DXd for HER2-Low Breast Cancer


Breakthrough therapy designation has been granted to trastuzumab deruxtecan by the FDA for patients with unresectable or metastatic HER2-low breast cancer.

The FDA has granted breakthrough therapy designation (BTD) to trastuzumab deruxtecan (Enhertu; T-DXd) for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-negative) breast cancer who have received prior systemic therapy in the metastatic setting or who have developed disease recurrence during or within 6 months of completing adjuvant chemotherapy, according to AstraZeneca.1

Results of the phase 3 DESTINY-Breast04 trial (NCT03734029) serve as basis for the BTD. In the study, T-DXd demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS) in this patient population.

“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,” stated Ken Takeshita, global head, R&D of Daiichi Sankyo, in the press release. “This Breakthrough Therapy Designation acknowledges the potential of Enhertu 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.”

The multicenter, global, open label DESTINY-Breast04 study enrolled a total of 557 patients with HER2-low, unresectable and/or metastatic breast cancer to determine the safety and efficacy of T-DXd in this patient population.2

Inclusion in the study was open to patients with pathologically confirmed disease who were aged 18 and older or who reached the age of maturity in their country. Other requirements included documented radiographic progression, at least 1 protocol-defined measurable lesion, adequate archival tumor samples available or the ability to provide fresh tissue, and protocol-defined adequate cardiac, bone marrow, renal, hepatic and blood clotting functions.

The primary end point of the study, which was met, was PFS with secondary end points including OS, objective response rate (ORR), and duration of response (DOR) among the study subjects.

Participants were randomized 2:1 and received either T-DXd at 5.4mg/kg or physician’s choice of chemotherapy which included capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel. Of those enrolled in the study, 480 were patients with HR-positive disease and 60 had HR-negative HER2-low unresectable and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy.

The safety profile of T-DXd was consistent with previous clinical trials and no new safety concerns were identified.

The agent has now been granted a total of 5 BTD’s including 3 in breast cancer, 1 in lung cancer, and 1 in gastric cancer.

“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. Enhertucontinues 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,” added Susan Galbraith, executive vice president, oncology R&D, in the press release.


1. Enhertu granted breakthrough therapy designation in the US for patients with HER2-low metastatic breast cancer. News release. April 27, 2022. Accessed April 27, 2022. https://bit.ly/3rVLBIR.

2. Trastuzumab deruxtecan (DS-8201a) versus investigator's choice for HER2-low breast cancer that has spread or cannot be surgically removed [DESTINY-Breast04]. Clinicaltrials.gov. Accessed April 27, 2022. https://bit.ly/3kfP29l.

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