On August 5, 2022, the U.S. Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki (T-DXd, Enhertu), an intravenous infusion for the treatment of patients with unresectable or metastatic HER2-low breast cancer. This is the first approved therapy targeted to patients with the HER2-low breast cancer subtype, which is a newly defined subset of HER2-negative breast cancer.
It is estimated that 287,850 new cases of female breast cancer will be diagnosed in 2022 in the United States. Approximately 80% to 85% of those new cases were previously considered to be HER2-negative subtype (including hormone receptor–positive and triple-negative breast cancer), which means the tumors do not overexpress. Of that proportion of breast cancer diagnoses, about 60% of patients previously classified as having the HER2-negative subtype can now be considered as HER2-low. Prior to today’s approval, HER2-low patients received endocrine therapy 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.”
Patients with HER2-low breast cancer are eligible for T-DXd if they have received a prior chemotherapy in the metastatic setting, or their cancer returned during, or within 6 months of completing, adjuvant chemotherapy. This approval is based on DESTINY-Breast04, a randomized, multicenter, open label clinical trial that enrolled 557 adult patients with unresectable or metastatic HER2-low breast cancer. The trial included two cohorts: 494 hormone receptor–positive patients and 63 hormone receptor–negative patients. Of these patients, 373 randomly received T-DXd by intravenous infusion every 3 weeks and 184 randomly received physician’s choice of chemotherapy (eribulin, capecitabine, gemcitabine, nab-paclitaxel, or paclitaxel). The results showed improvement in both progression-free survival and overall survival in people with unresectable or metastatic HER2-low breast cancer.
The median age of trial participants was 57 years old, ranging from 28 to 81 years of age. Among the 557 patients, 24% were age 65 or older. Females comprised 99.6% of the trial population. Trial participants’ race was reported as 48% White, 40% Asian, 2% Black or African American, and 3.8% Hispanic/Latino.
The most common adverse reactions in patients receiving T-DXd in DESTINY-Breast04 are nausea, fatigue, alopecia, vomiting, constipation, decreased appetite, musculoskeletal pain, and diarrhea. The prescribing information includes a boxed warning to advise health care professionals of the risk of interstitial lung disease and embryofetal toxicity. Enhertu is not recommended for women who are pregnant.
T-DXd received Priority Review and Breakthrough Therapy designations for this indication. The FDA granted the approval of Enhertu to Daiichi Sankyo four months ahead of the Prescription Drug User Fee Act deadline. This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence.