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

The FDA has granted a breakthrough therapy designation to fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of adult patients with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in-situ hybridization [ISH]–negative) 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 additionally have received or be ineligible for endocrine therapy.¹

The designation is based on findings from the pivotal phase 3 DESTINY-Breast04 trial (NCT03734029), where trastuzumab deruxtecan led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) and overall survival (OS) vs physician’s choice of chemotherapy in patients with HER2-low unresectable and/or metastatic breast cancer, irrespective of HR status.

The positive topline results of DESTINY-Breast04 were announced in February 2022, and these data will be presented at an upcoming medical meeting.²

“Historically, only patients with HER2-positive metastatic breast cancer were shown to benefit from HER2-directed therapy. DESTINY-Breast04, in which [trastuzumab deruxtecan] 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,” Ken Takeshita, MD, global head of research and development at Daiichi Sankyo, stated in a press release. “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.”

DESTINY-Breast04 is a global, randomized, open-label, phase 3 trial evaluating the efficacy and safety of 5.4 mg/kg of trastuzumab deruxtecan vs physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel [Abraxane]).

In the study, patients with HR-positive (n = 480) or HR-negative (n = 60), unresectable and/or metastatic HER2-low breast cancer who had been previously treated with no more than 2 lines of chemotherapy were randomized 2:1 to receive trastuzumab deruxtecan or chemotherapy.

All patients in the trial received a HER2 test and the results were centrally confirmed. HER2-low disease was defined as an IHC score of 1+ or IHC2+ with a negative ISH score.

The primary end point of the study is PFS in patients with HR-positive disease based on blinded independent central review (BICR). Key secondary end points include PFS based on BICR in all randomized patients, OS in patients with HR-positive disease, and OS in all randomized patients. Other secondary end points include investigator-assessed PFS, objective response rate based on BICR and investigator assessment, duration of response based on BICR, and safety.

A total of approximately 540 patients were enrolled to the study across sites in Asia, Europe, and North America.

Per the press release, the safety profile of trastuzumab deruxtecan in DESTINY-Breast04 was consistent with prior studies, and no new safety concerns were reported. The rates of interstitial lung disease (ILD) were consistent with those observed in heavily pretreated HER2-positive breast cancer trials of trastuzumab deruxtecan, with a lower rate of reported grade 5 ILD, according to an independent adjudication committee.

“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,” Susan Galbraith, MBBChir, PhD, executive vice president of Oncology Research & Development at AstraZeneca, stated in a press release. “[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.”

Previously, in October 2021, the FDA granted a breakthrough therapy designation to trastuzumab deruxtecan for use in adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received 1 or more anti–HER2-based regimens.

References

1. ENHERTU granted breakthrough therapy designation in US for patients with HER2 low metastatic breast cancer. News release. Daiichi Sankyo. April 26, 2022. Accessed April 27, 2022. https://bit.ly/3MvIbEE
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://bit.ly/39eVCud