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by Dr. C.H. Weaver M.D. updated 1/2022

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. 

Enhertu is a HER2-targeting antibody drug conjugate (ADC) used for the treatment of patients with advanced HER2-positive cancer. Data released in September 2021 confirms that Enhertu is an effective treatment but is associated with significant lung toxicity in 16% of patients.7,8

Breast CancerConnect 490

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.

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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.

Trial Confirms Enhertu Superior to Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer

The DESTINY-Breast03 Phase III clinical trial evaluated the safety and effectiveness of Enhertu versus trastuzumab emtansine (T-DM1) in ~500 patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane. At a planned interim analysis an Independent Data Monitoring Committee concluded that Enhertu delayed cancer progression better than T-DM1 and also showed a strong trend toward improved overall survival compared to T-DM1.7,10

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Follow up data was released in December 2021, and showed that the  median survival duration without cancer progression was 6.8 months with T-DM1 and had not been reached in the group receiving Enhertu. The objective response rate for patients on Enhertu was 79%, compared to 34% for those on T-DM1.8

The phase 2 DESTINY-Breast01 clinical trial results were updated at San Antonio Breast Cancer Symposium in December 2021. 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. 

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Interstitial Lung Disease

The most common reported side effects of Enhertu 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. 

Interstitial lung disease related to Enhertu occurred in 16% of  participants, including 5 (2.7%) whose deaths were attributed to ILD in the initial trial.9 ILD occurred in a smaller proportion of patients (8.2%) in DESTINY-Breast03 than in DESTINY-Breast01 and only 2 participants (0.8%) experienced grade 3 ILD and no grade 4 or 5 ILD occurred.10

References:

  1. Doi T, et al. J Clin Oncol. 2017;35(15):108
  2. 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.
  3. American Cancer Society. Breast Cancer Overview. 2016.
  4. NCCN Guidelines. Breast Cancer. Version 2.2017.
  5. [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)
  6. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies
  7. https://www.astrazeneca.com/media-centre/press-releases/2021/enhertu-head-to-head-trial-meets-primary-endpoint.html
  8. https://oncologypro.esmo.org/meeting-resources/esmo-congress-2021/trastuzumab-deruxtecan-t-dxd-vs-trastuzumab-emtansine-t-dm1-in-patients-pts-with-her2-metastatic-breast-cancer-mbc-results-of-the-randomi

  9. Saura, C., Modi, S., Krop, I., Park, B. W., Kim, S. B., Tamura, K., Andre, F., Iwata, H., Ito, Y., Tsurutani, J., Sohn, J., Lee, C., Liu, Y., Cathcart, J., Singh, J., & Yamashita, T. (2021, Septembe 16-21, 2021). Trastuzumab Deruxtecan (T-DXd) in Patients with HER2-Positive Metastatic Breast Cancer: Updated Survival Results from a Phase 2 Trial (DESTINY-Breast01). European Society for Medical Oncology Annual Meeting, Lugano, Switzerland.

  10. Cortes, J., Kim, S., Chung, W., Im, S., Park, Y. H., Hegg, R., Kim, M. H., Tseng, L., Petry, V., Chung, C., Iwata, H., Hamilton, E., Curigliano, G., Xu, B., Lee, C., Liu, Y., Cathcart, J., Bako, E., Verma, S., & Hurvitz, S. A. (2021, September 16-21, 2021). Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase III DESTINY-Breast03 study. European Society of Medical Oncology, Lugano, Switzerland.