Enhertu (Trastuzumab Deruxtecan) Treatment of HER2+ Breast Cancer

Enhertu is an effective treatment option for HER2-positive Breast Cancer and for many patients with very low levels of HER2 expression.

Charles H. Weaver, MD
5–7 minutes
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Enhertu (fam-trastuzumab deruxtecan-nxki) was first approved in 2019 for adults with unresectable or metastatic HER2-positive breast cancer and has since received multiple label expansions across breast, lung, gastric/GEJ, and other HER2-positive solid tumors.​

Current FDA-approved indications

  • Unresectable or metastatic HER2-positive breast cancer after prior anti‑HER2–based regimens in the metastatic setting.​
  • Unresectable or metastatic HER2‑low (IHC 1+ or IHC 2+/ISH–) breast cancer after prior chemotherapy in the metastatic setting or recurrence within 6 months of completing adjuvant chemotherapy.​
  • Unresectable or metastatic HR‑positive HER2‑low or HER2‑ultralow breast cancer that has progressed on one or more endocrine therapies in the metastatic setting (DESTINY‑Breast06; January 27, 2025 approval).​
  • Unresectable or metastatic HER2‑mutant non‑small cell lung cancer after at least one prior systemic therapy.​
  • Locally advanced or metastatic HER2‑positive gastric or gastroesophageal junction adenocarcinoma after a prior trastuzumab‑based regimen.​
  • Adult patients with unresectable or metastatic HER2‑positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options (tumor‑agnostic indication; April 5, 2024 accelerated approval).​

Mechanism and clinical activity

Enhertu is a HER2‑directed antibody–drug conjugate linking a humanized anti‑HER2 monoclonal antibody to a topoisomerase I inhibitor (DXd) via a cleavable tetrapeptide linker, designed for high drug-to-antibody ratio and bystander antitumor effect. Clinical trials across breast, gastric, lung, and other HER2‑expressing solid tumors have shown high objective response rates and durable disease control, including in CNS involvement and in HER2‑low and HER2‑mutant disease.​

Safety and ILD considerations

Across DESTINY trials, Enhertu is associated with interstitial lung disease (ILD)/pneumonitis, including fatal cases, leading to a boxed warning in the prescribing information. Reported ILD rates vary by study (approximately 10–15% overall with lower rates in later trials), underscoring the need for early recognition of pulmonary symptoms, prompt imaging, and treatment interruption or discontinuation per label guidance.

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 trial in very advanced breast cancer reported that an objective response rate of 60%, a disease control rate of 94%, and an average survival duration of 21 was attained at the recommended dose of Enhertu4  in patients treated with and average of seven prior lines of treatment.

Enhertu Superior to Kadcyla in patients with HER2-positive metastatic breast cancer

The DESTINY-Breast 03 Phase III clinical trial evaluated the safety and effectiveness of Enhertu versus Kadcyla (trastuzumab emtansine (T-DM1) in ~500 patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane. Data released in December 2022 showed that the  median survival duration without cancer progression was improved from 7 months with T-DM1 to 29 months for individuals treated with Enhertu. The objective response rate for patients on Enhertu was 79%, compared to 34% for those on T-DM1.4,7,8,10

The phase 2 DESTINY-Breast 01 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.

Enhertu Superior to Chemotherapy

Enhertu demonstrated a 34% reduction in the risk of death and a 13-month increase in overall survival compared with chemotherapy treatment of physician’s choice in patients with advanced HER2-positive unresectable and/or metastatic breast cancer who received prior treatment with Kadcyla according to results reported from the phase 3 DESTINY-Breast02 trial in 608 patients.13

HER2 “low” Disease

Data presented at the American Society of Clinical Oncology 2022 Annual Meeting showed the potential to improve survival for metastatic breast cancer patients and define a new segment of patients with “HER2-low disease”. This led to FDA approval for adult patients with unresectable, or metastatic HER2-low (IHC 1+ or IHC 2+/ISH‑) breast cancer.

In the DESTINY-Breast04 clinical trial HER2-low expression was defined as IHC 1+ or IHC 2+/ISH. In these patients the median duration of survival without recurrence was approximately 10 months with Enhertu compared to 5 months for those receiving chemotherapy for both HR positive and negative patients. Enhertu also improved average survival duration to 24 months and from 17 months with chemotherapy.12

Interstitial Lung Disease

The most common reported side effects of Enhertu include decreased appetite, fatigue, anemia, diarrhea and constipation. Drug-related interstitial lung disease (ILD) and pneumonitis is of concern and nausea and hair loss occur in a majority of individuals.

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

The prescribing information includes a Boxed Warning advising health professionals of the risk of interstitial lung disease and embryo-fetal toxicity. ILD is a “late” complication of treatment occurring on average 5-7 months after beginning therapy. Individuals experiencing shortness of breath or any respiratory symptoms should bring them to the attention of their treating physician.

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, September 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.
  11. Hamilton EP, Bragaia VPH, Yeo W, et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients (pts) with HER2-positive (HER2+) unresectable and/or metastatic breast cancer (mBC): Safety follow-up of the randomized, phase 3 study DESTINY-Breast03. Presented at: the 2022 ASCO Annual Meeting; June 3-7, 2022; Chicago, IL. Abstract 1000.
  12. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-low-breast-cancer/
  13. Krop, Ian et al T-DXd yields superior outcomes over chemotherapy-based regimens in patients previously treated with T-DM1 participating in the phase III DESTINY-Breast02 trial. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS2-01.
  14. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-fam-trastuzumab-deruxtecan-nxki-pertuzumab-unresectable-or-metastatic-her2-positive?utm_medium=email&utm_source=govdelivery
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