FDA OKs New Antibody Drug Conjugate for HER2+ Breast Cancer

Nick Mulcahy

December 20, 2019

The US Food and Drug Administration (FDA) has granted accelerated approval to trastuzumab deruxtecan (Enhertu, AstraZeneca/Daiichi Sankyo) for the treatment of unresectable or metastatic HER2-positive breast cancer that has received two or more prior anti-HER2-based regimens in the metastatic setting.

Trastuzumab deruxtecan is a human epidermal growth factor receptor 2 (HER2)-directed antibody and topoisomerase inhibitor conjugate. The new drug targets the HER2 protein and is linked to a topoisomerase inhibitor, which is cytotoxic.

"There have been many advances in the development of drugs for HER2-positive breast cancer since the introduction of Herceptin (trastuzumab) in 1998. The approval of Enhertu represents the newest treatment option for patients who have progressed on available HER2-directed therapies," 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, said in a news release.

The approval is based on results from the pivotal phase 2 DESTINY-Breast01 trial. The open-label, single-arm study involved 184 women with metastatic HER2-positive breast cancer previously treated with two or more prior anti-HER2 therapies (median of six) in the metastatic setting including trastuzumab, trastuzumab emtansine, and pertuzumab.

Patients in the clinical trial received trastuzumab deruxtecan every 3 weeks and tumor imaging every 6 weeks. The overall response rate was 60.3%. There were 11 (6%) complete responses and 101 (54.9%) partial responses. Median duration of response was 14.8 months. 

Median progression-free survival was 16 months. "Those [results] are roughly double or triple what we've typically seen in other studies of this third- and later-line [treatment] population, where the median progression-free survival has been in the 4- to 5-month range," study investigator Ian Krop MD, PhD, Dana-Farber Cancer Institute, Boston, Massachusetts, said last week at the 2019 San Antonio Breast Cancer Symposium, where the data were presented, as reported by Medscape Medical News.

The results were also simultaneously published in the New England Journal of Medicine.

However, the new drug comes with a boxed warning about the risk of interstitial lung disease. Interstitial lung disease and pneumonitis, including cases resulting in death, have been reported with trastuzumab deruxtecan. Signs and symptoms include cough, dyspnea, fever, and other new or worsening respiratory symptoms. If these symptoms arise, trastuzumab deruxtecan may need to be withheld, have the dose reduced, or be permanently discontinued.

Treatment-emergent adverse events occurred in all but one study patient (99.5%), with 57.1% experiencing an adverse event of grade 3 or higher.

The FDA says that the most common side effects were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, decreased neutrophil count, diarrhea, leukopenia, cough, and decreased platelet count.

The FDA granted the application a Breakthrough Therapy designation and Fast Track designation. Trastuzumab deruxtecan was approved 4 months prior to the FDA goal date.

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