Trastuzumab deruxtecan

Last updated

Trastuzumab deruxtecan
Trastuzumab deruxtecan.svg
Monoclonal antibody
Type Whole antibody
Source Humanized
Target HER2
Clinical data
Trade names Enhertu
Other namesDS-8201a, fam-trastuzumab deruxtecan-nxki
AHFS/Drugs.com Monograph
MedlinePlus a620006
License data
Pregnancy
category
Routes of
administration 		Intravenous
Drug class Antineoplastic
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem SID
DrugBank
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C6460H9972N1724O2014S44.(C52H57F1N9O13)8

Trastuzumab deruxtecan, sold under the brand name Enhertu, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the topoisomerase I inhibitor deruxtecan (a derivative of exatecan). [11] [12] It is licensed for the treatment of breast cancer or gastric or gastroesophageal adenocarcinoma. [12] [13] Trastuzumab binds to and blocks signaling through epidermal growth factor receptor 2 (HER2/neu) on cancers that rely on it for growth. Additionally, once bound to HER2 receptors, the antibody is internalized by the cell, carrying the bound deruxtecan along with it, where it interferes with the cell's ability to make DNA structural changes and replicate its DNA during cell division, leading to DNA damage when the cell attempts to replicate itself, destroying the cell. [13]

Contents

Trastuzumab deruxtecan was approved for medical use in the United States in December 2019, [12] in Japan in March 2020, [14] in the European Union in January 2021, [8] [10] and in Australia in October 2021. [1] It is the first approved therapy by the US Food and Drug Administration (FDA) targeted to people with the HER2-low breast cancer subtype subset of HER2-negative breast cancer. [15]

Medical uses

Trastuzumab deruxtecan is indicated for the treatment of adults with unresectable (unable to be removed with surgery) or metastatic (when cancer cells spread to other parts of the body) HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting and for adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen. [12] [13]

In May 2022, the US Food and Drug Administration (FDA) expanded the indication to include the treatment of adults with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. [16] [17]

In August 2022, the FDA expanded the indication to include the treatment of unresectable or metastatic HER2-low breast cancer. [15]

In April 2024, the FDA expanded the indication to include the treatment of unresectable or metastatic HER2-positive (IHC3+) solid tumors for adults who have received prior systemic treatment and have no satisfactory alternative treatment options. [18]

Side effects and label warnings

The most common side effects are nausea, fatigue, vomiting, alopecia (hair loss), constipation, decreased appetite, anemia (hemoglobin in blood is below the reference range), decreased neutrophil count (white blood cells that help lead your body's immune system response to fight infection), diarrhea, leukopenia (other white blood cells that help the immune system), cough and decreased platelet count (component of blood whose function is to react to bleeding from blood vessel injury by clumping, thereby initiating a blood clot). [12]

The prescribing information for trastuzumab deruxtecan includes a boxed warning about the risk of interstitial lung disease (a group of lung conditions that causes scarring of lung tissues) and embryo-fetal toxicity. [12] Interstitial lung disease and pneumonitis, including cases resulting in death, have been reported with trastuzumab deruxtecan. [12]

History

The US Food and Drug Administration (FDA) approved trastuzumab deruxtecan based on the results of one clinical trial enrolling 184 female participants with HER2-positive, unresectable and/or metastatic breast cancer who had received two or more prior anti-HER2 therapies in the metastatic setting. [12] These participants were heavily pretreated in the metastatic setting, receiving between two and 17 therapies prior to receiving trastuzumab deruxtecan. [12] Participants in the clinical trial received trastuzumab deruxtecan every three weeks and tumor imaging was obtained every six weeks. [12] The overall response rate was 60.3%, which reflects the percentage of participants who had a certain amount of tumor shrinkage with a median duration of response of 14.8 months. [12]

Efficacy was evaluated in a multicenter, open-label, randomized trial (DESTINY-Gastric01, NCT03329690) in participants with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma who had progressed on at least two prior regimens, including trastuzumab, a fluoropyrimidine- and a platinum-containing chemotherapy. [13] A total of 188 participants were randomized (2:1) to receive trastuzumab deruxtecan 6.4 mg/kg intravenously every three weeks or physician's choice of either irinotecan or paclitaxel monotherapy. [13]

Efficacy was based on DESTINY-Breast03 (NCT03529110), a multicenter, open-label, randomized trial that enrolled 524 participants with HER2-positive, unresectable, and/or metastatic breast cancer who received prior trastuzumab and taxane therapy for metastatic disease or developed disease recurrence during or within six months of completing neoadjuvant or adjuvant therapy. [16] Participants were randomized 1:1 to receive either trastuzumab deruxtecan or trastuzumab emtansine by intravenous infusion every three weeks until unacceptable toxicity or disease progression. [16] Randomization was stratified by hormone receptor status, prior treatment with pertuzumab, and history of visceral disease. [16]

The FDA approved trastuzumab deruxtecan for the treatment of HER2-low breast cancer based on DESTINY-Breast04, a randomized, multicenter, open label clinical trial that enrolled 557 adult participants with unresectable or metastatic HER2-low breast cancer. [15] The trial included two cohorts: 494 hormone receptor positive (HR+) participants and 63 hormone receptor negative (HR-) participants. [15] Of these participants, 373 randomly received trastuzumab deruxtecan by intravenous infusion every three weeks and 184 randomly received physician's choice of chemotherapy (eribulin, capecitabine, gemcitabine, nab paclitaxel, or paclitaxel). [15] The results showed improvement in both progression-free survival and overall survival in people with unresectable or metastatic HER2-low breast cancer. [15]

In September 2023, the UK's National Institute for Heath and Care Excellence (NICE) published guidance that it would not recommend Trastuzumab deruxtecan, specifically under the brand name Enhertu, to be used for treatment of breast cancer by the UK's National Heath Service (NHS), citing the cost of the drug being too high in comparison to its benefits. After talks with drug manufacturers AstraZeneca and Daiichi Sankyo, the NHS failed to negotiate a supply at what it deemed to be an acceptable price, and announced in March 2024 that the treatment would not be available to NHS patients. Roughly 1000 patients in the UK would have qualified for free treatment, had a supply been negotiated. Enhertu was however approved by The Scottish Medicines Consortium for use by NHS Scotland in December 2023 [19]

Society and culture

The US Food and Drug Administration (FDA) approved trastuzumab deruxtecan in December 2019. [12] [20] The application for trastuzumab deruxtecan was granted accelerated approval, fast track designation, and breakthrough therapy designation. [12] The FDA granted the approval of Enhertu to Daiichi Sankyo. [12]

In December 2020, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Enhertu, intended for the treatment of metastatic HER2-positive breast cancer. [21] [22] Trastuzumab deruxtecan was reviewed under EMA's accelerated assessment program. The applicant for this medicinal product is Daiichi Sankyo Europe GmbH. Trastuzumab deruxtecan was approved for medical use in the European Union in January 2021. [8] [10]

In January 2021, the FDA granted accelerated approval to trastuzumab deruxtecan for the treatment of adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen. [13] [23]

In October 2021, the Australian Therapeutic Goods Administration approved trastuzumab deruxtecan for provisional registration indicated for the treatment of adults with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti HER2-based regimens. [1]

Related Research Articles

<span class="mw-page-title-main">Trastuzumab</span> Medication

Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer and stomach cancer. It is specifically used for cancer that is HER2 receptor positive. It may be used by itself or together with other chemotherapy medication. Trastuzumab is given by slow injection into a vein and injection just under the skin.

<span class="mw-page-title-main">HER2</span> Mammalian protein found in humans

Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently referred to as HER2 or CD340.

<span class="mw-page-title-main">Lapatinib</span> Cancer medication

Lapatinib (INN), used in the form of lapatinib ditosylate (USAN) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).

<span class="mw-page-title-main">Daiichi Sankyo</span> Japanese pharmaceutical company

Daiichi Sankyo Company, Limited is a global pharmaceutical company and the second-largest pharmaceutical company in Japan. It achieved JPY 1,278 billion in revenue in 2022. The company owns the American pharmaceutical company American Regent.

<span class="mw-page-title-main">Pertuzumab</span> Pharmaceutical drug

Pertuzumab, sold under the brand name Perjeta, is a monoclonal antibody used in combination with trastuzumab and docetaxel for the treatment of metastatic HER2-positive breast cancer; it also used in the same combination as a neoadjuvant in early HER2-positive breast cancer.

<span class="mw-page-title-main">Neratinib</span> Chemical compound

Neratinib (INN), sold under the brand name Nerlynx, is a tyrosine kinase inhibitor anti-cancer medication used for the treatment of breast cancer.

<span class="mw-page-title-main">Olaparib</span> Chemical compound (cancer therapy drug)

Olaparib, sold under the brand name Lynparza, is a medication for the maintenance treatment of BRCA-mutated advanced ovarian cancer in adults. It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers.

<span class="mw-page-title-main">Trastuzumab emtansine</span> Pharmaceutical drug

Trastuzumab emtansine, sold under the brand name Kadcyla, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the cytotoxic agent DM1. Trastuzumab alone stops growth of cancer cells by binding to the HER2 receptor, whereas trastuzumab emtansine undergoes receptor-mediated internalization into cells, is catabolized in lysosomes where DM1-containing catabolites are released and subsequently bind tubulin to cause mitotic arrest and cell death. Trastuzumab binding to HER2 prevents homodimerization or heterodimerization (HER2/HER3) of the receptor, ultimately inhibiting the activation of MAPK and PI3K/AKT cellular signalling pathways. Because the monoclonal antibody targets HER2, and HER2 is only over-expressed in cancer cells, the conjugate delivers the cytotoxic agent DM1 specifically to tumor cells. The conjugate is abbreviated T-DM1.

<span class="mw-page-title-main">Nivolumab</span> Anticancer medication

Nivolumab, sold under the brand name Opdivo, is an anti-cancer medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colon cancer, esophageal squamous cell carcinoma, liver cancer, gastric cancer, and esophageal or gastroesophageal junction cancer. It is administered intravenously.

Margetuximab, sold under the brand name Margenza, is a chimeric IgG monoclonal antibody medication against HER2 used for the treatment of cancer.

<span class="mw-page-title-main">Pembrolizumab</span> Pharmaceutical drug used in cancer treatment

Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody, more specifically a PD-1 Inhibitor, used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is administered by slow intravenous injection.

Zolbetuximab, sold under the brand name Vyloy, is a monoclonal antibody used for the treatment of gastric cancer. It is a claudin 18.2-directed cytolytic antibody against isoform 2 of Claudin-18. Zolbetuximab was developed by Ganymed Pharmaceuticals. Astellas Pharma acquired the rights to zolbetuximab in December 2016, when it acquired Ganymed Pharmaceuticals.

<span class="mw-page-title-main">Sacituzumab govitecan</span> Antibody-drug conjugate

Sacituzumab govitecan, sold under the brand name Trodelvy by Gilead Sciences, is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate used for the treatment of metastatic triple-negative breast cancer and metastatic urothelial cancer.

<span class="mw-page-title-main">Alpelisib</span> Chemical compound

Alpelisib, sold under the brand name Piqray among others, is a medication used to treat certain types of breast cancer. It is used together with fulvestrant. It is taken by mouth. It is marketed by Novartis.

<span class="mw-page-title-main">Tucatinib</span> Chemical compound

Tucatinib, sold under the brand name Tukysa, is an anticancer medication used for the treatment of HER2-positive breast cancer. It is a small molecule inhibitor of HER2. It was developed by Array BioPharma and licensed to Cascadian Therapeutics.

Pertuzumab/trastuzumab/hyaluronidase, sold under the brand name Phesgo, is a fixed-dose combination medication to treat adults with HER2-positive breast cancer that has spread to other parts of the body, and for treatment of adults with early HER2-positive breast cancer. It contains pertuzumab, trastuzumab, and hyaluronidase–zzxf. It is injected under the skin via subcutaneous injection in the thigh. In the European Union, Phesgo contains the active ingredients pertuzumab and trastuzumab along with the enzyme vorhyaluronidase alfa.

Trastuzumab/hyaluronidase, sold under the brand name Herceptin SC among others, is a fixed-dose combination medication for the treatment of HER2-overexpressing breast cancer in adults. It is a combination of trastuzumab and hyaluronidase.

<span class="mw-page-title-main">Capivasertib</span> Medication

Capivasertib, sold under the brand name Truqap, is an anti-cancer medication used for the treatment of breast cancer. It is taken by mouth.

<span class="mw-page-title-main">Deruxtecan</span> Chemical compound

Deruxtecan is a chemical compound and a derivative of exatecan that acts as topoisomerase I inhibitor.

Zanidatamab, sold under the brand name Ziihera, is a humanized monoclonal antibody used for the treatment of HER2-positive biliary tract cancer. It is an IgG-like bispecific HER2-directed antibody. Zanidatamab is produced in Chinese hamster ovary cells.

References

  1. 1 2 3 4 "Enhertu". Therapeutic Goods Administration (TGA). 18 October 2021. Archived from the original on 23 October 2021. Retrieved 22 October 2021.
  2. ↑ "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 21 December 2022. Archived from the original on 3 April 2022. Retrieved 2 January 2023.
  3. ↑ "AusPAR: Trastuzumab deruxtecan". Therapeutic Goods Administration (TGA). 27 June 2022. Archived from the original on 18 July 2022. Retrieved 17 July 2022.
  4. ↑ "Enhertu (AstraZeneca Pty Ltd)". Therapeutic Goods Administration (TGA). 16 February 2023. Archived from the original on 18 March 2023. Retrieved 9 April 2023.
  5. ↑ "Summary Basis of Decision (SBD) for Enhertu". Health Canada. 23 October 2014. Archived from the original on 30 May 2022. Retrieved 29 May 2022.
  6. ↑ "Enhertu 100 mg powder for concentrate for solution for infusion - Summary of Product Characteristics (SmPC)". (emc). 1 July 2022. Archived from the original on 19 April 2021. Retrieved 1 July 2022.
  7. ↑ "Enhertu- fam-trastuzumab deruxtecan-nxki injection, powder, lyophilized, for solution". DailyMed. Archived from the original on 22 January 2021. Retrieved 15 January 2021.
  8. 1 2 3 "Enhertu EPAR". European Medicines Agency (EMA). 9 December 2020. Archived from the original on 23 March 2021. Retrieved 31 March 2021.
  9. ↑ "Enhertu Product information". Union Register of medicinal products. Archived from the original on 5 March 2023. Retrieved 3 March 2023.
  10. 1 2 3 "Enhertu approved in the EU for the treatment of HER2-positive metastatic breast cancer" (Press release). AstraZeneca. 20 January 2021. Archived from the original on 20 January 2021. Retrieved 21 January 2021.
  11. ↑ "A HER2-Targeting Antibody–Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model" (PDF). Archived (PDF) from the original on 24 September 2020. Retrieved 23 December 2019.
  12. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 "FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies". U.S. Food and Drug Administration (FDA) (Press release). 20 December 2019. Archived from the original on 20 December 2019. Retrieved 20 December 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  13. 1 2 3 4 5 6 "FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas". U.S. Food and Drug Administration (FDA). 15 January 2021. Archived from the original on 15 January 2021. Retrieved 15 January 2021.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  14. ↑ "Enhertu Approved in Japan for Treatment of Patients with HER2 Positive Unresectable or Metastatic Breast Cancer" (Press release). Daiichi Sankyo. 25 March 2020. Archived from the original on 28 January 2021. Retrieved 21 January 2021– via Business Wire.
  15. 1 2 3 4 5 6 "FDA Approves First Targeted Therapy for HER2-Low Breast Cancer". U.S. Food and Drug Administration (FDA) (Press release). 5 August 2022. Archived from the original on 6 August 2022. Retrieved 5 August 2022.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  16. 1 2 3 4 "FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer". U.S. Food and Drug Administration (FDA). 4 May 2022. Archived from the original on 4 May 2022. Retrieved 5 May 2022.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  17. ↑ "Cancer Accelerated Approvals". U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 6 December 2024.
  18. ↑ "FDA Roundup: April 9, 2024". U.S. Food and Drug Administration (FDA) (Press release). 9 April 2024. Archived from the original on 10 April 2024. Retrieved 12 April 2024.
  19. ↑ "Row as breast cancer drug which extends lives of patients blocked by NHS over cost". The Independent. 5 March 2024. Archived from the original on 5 March 2024. Retrieved 6 March 2024.
  20. ↑ "Drug Trials Snapshot: Enhertu". U.S. Food and Drug Administration (FDA). 20 December 2019. Archived from the original on 20 October 2020. Retrieved 24 January 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  21. ↑ "Enhertu: Pending EC decision". European Medicines Agency (EMA). 10 December 2020. Archived from the original on 12 December 2020. Retrieved 11 December 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  22. ↑ "Trastuzumab deruxtecan recommended for approval in the EU by CHMP for HER2-positive metastatic breast cancer" (Press release). AstraZeneca. 14 December 2020. Archived from the original on 20 January 2021. Retrieved 21 January 2021.
  23. ↑ "Enhertu approved in the US for the treatment of patients with previously treated HER2-positive advanced gastric cancer" (Press release). AstraZeneca. 18 January 2021. Archived from the original on 23 January 2021. Retrieved 22 January 2021.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.