Enhertu (Trastuzumab Deruxtecan) Treatment of HER2+ Breast Cancer
by Dr. C.H. Weaver M.D. updated 12/2020
The United States Food and Drug Administration approved Enhertu (trastuzumab deruxtecan) (DS-8201) for the treatment of patients with HER2-positive metastatic breast cancer in 2019. A Lancet Oncology publication of the Phase I dose-expansion results in HER2-positive metastatic breast was initially reported in May 2019 and additional data was released at the San Antonio Breast Cancer Symposia in December 2020.
Enhertu is a HER2-targeting antibody drug conjugate (ADC) for the treatment of patients with HER2-positive cancer. Its initial application will be for the treatment of locally advanced or metastatic breast cancer patients who have been treated with Herceptin and Perjeta and have disease progression after ado-trastuzumab (T-DM1). (1)
About Enhertu (trastuzumab deruxtecan)
ADCs are a type of targeted cancer medicine that deliver cytotoxic chemotherapy (“payload”) to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Enhertu is a smart chemotherapy comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor (DXd) payload by a tetrapeptide linker. It is designed to deliver enhanced cell destruction upon release inside the cell and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.
About HER2-Positive Breast Cancer
About one in five patients with breast cancer over-express HER2 (make too much of), a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells, which is associated with aggressive disease.(2) Many tumors advance to the point where no currently approved HER2-targeting treatment continues to control the disease. Furthermore, there is no standard of care for HER2-positive tumors following treatment with Herceptin, Perjeta and T-DM1.(3)
The results of the initial breast cancer trial reported that an objective response rate of 60% and a disease control rate of 94% was attained at the recommended expansion dose of of DS-8201.(4) An average 20.7 months median duration of response in HER2-positive metastatic breast cancer patients previously treated with trastuzumab emtansine was reported. Patients enrolled in this part of the trial had a median of seven prior lines of treatment, including trastuzumab and trastuzumab emtansine, and in 86% of cases, pertuzumab.
The phase 2 DESTINY-Breast01 clinical trial results were updated at San Antonio Breast Cancer Symposium in December 2020. The trial included 253 patients with HER2-positive metastatic breast cancer previously treated with Kadcyla (ado-trastuzumab). The patients had received a median of six prior treatments for advanced disease, including HER2-targeted therapeutics.
With a median duration of follow-up of 20.5 months, patients treated with Enhertu achieved an objective response rate of 61.4% and a median duration of response of 21 months. The median progression-free survival was 19.4 months. The most common reported side effects include nausea, decreased appetite, vomiting, hair loss, fatigue, anemia, diarrhea and constipation. Cases of drug-related interstitial lung disease (ILD) and pneumonitis were also reported. According to the study authors “ILD was observed in 25 patients including 4 advanced cases resulting in ILD-related deaths. Because of this potential toxicity, close monitoring for signs and symptoms of ILD is recommended for early detection. If ILD is suspected, evaluations should include high-resolution CT, pulmonologist consultation, pulmonary function tests, and other tests. Although data on treatment for T-DXd-induced ILD are limited, if diagnosed, interruption of treatment and prompt intervention with glucocorticoids is recommended.”
Breakthrough Therapy designation is designed to expedite the development and review of medicines that may demonstrate substantial benefit over currently available treatments in order to ensure that patients with serious diseases have access to new treatments as soon as possible. Currently, there is no FDA-approved therapy for patients with HER2-positive metastatic breast cancer with disease progression following treatment with other HER2-targeting agents Herceptin, Perjeta and T-DM1.
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- Doi T, et al. J Clin Oncol. 2017;35(15):108
- Tamura, K, et al. Trastuzuamb deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Lancet Oncol. 2019;20(6):816-826.
- American Cancer Society. Breast Cancer Overview. 2016.
- NCCN Guidelines. Breast Cancer. Version 2.2017.
- [Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study](https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19%2930097-X/fulltext)
- FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies
Enhertu continues to demonstrate durable responses with new data from DESTINY-Breast01 in HER2-positive metastatic breast cancer
Updated results from the positive DESTINY-Breast01 Phase II trial showed AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo)’s Enhertu (trastuzumab deruxtecan) continued to demonstrate impressive efficacy and durable responses in patients with HER2-positive metastatic breast cancer following two or more prior HER2-based regimens.