Datopotamab deruxtecan

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Datopotamab deruxtecan
Deruxtecan ADCs.svg
Monoclonal antibody
Type Whole antibody
Source Humanized
Target Trop-2
Clinical data
Pronunciationda" toe poe' tah mab der" ux tee' kan
Trade names Datroway
Other namesDS-1062a, Dato-DXd, datopotamab deruxtecan-dlnk
AHFS/Drugs.com Multum Consumer Information
License data
Routes of
administration 		Intravenous
Drug class Antibody-drug conjugate
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
UNII
KEGG
Chemical and physical data
Formula C6464H10008N1708O2012S44
Molar mass 145251.75 g·mol−1

Datopotamab deruxtecan, sold under the brand name Datroway, is an anti-cancer medication used for the treatment of breast cancer. [1] [4] It is a Trop-2-directed antibody and topoisomerase inhibitor antibody-drug conjugate. [1] [4]

Contents

The most common adverse reactions, including laboratory abnormalities, include stomatitis, nausea, fatigue, decreased leukocytes, decreased calcium, alopecia, decreased lymphocytes, decreased hemoglobin, constipation, decreased neutrophils, dry eye, vomiting, increased ALT, keratitis, increased AST, and increased alkaline phosphatase. [4]

Datopotamab deruxtecan was approved for medical use in the United States in January 2025, [4] [5] and in the European Union in April 2025. [2] [3]

Medical uses

Datopotamab deruxtecan is indicated for the treatment of adults with unresectable or metastatic, hormone receptor positive, human epidermal growth factor receptor 2-negative (IHC 0, IHC1+ or IHC2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease. [4]

Side effects

Datopotamab deruxtecan is associated with a range of adverse events. [6] [7] The most common side effects are stomatitis, nausea, fatigue, alopecia (hair loss), constipation, vomiting, dry eye, keratitis, anemia, decreased appetite, increased aspartate transferase (AST), rash, diarrhea, neutropenia, and increased alanine aminotransferase (ALT). [2]

Pharmacology

Mechanism of action

As a antibody-drug conjugate (ADC), datopatomab deruxtecan binds to Trop-2 and undergoes receptor internalization, allowing the payload (i.e., the active anti-cancer drug) to be transported into the cell. It is transported into lysosomes. Inside the cell, it is split by selective cleaving of the tetrapeptide linker (Gly-Gly-Phe-Gly) by enzymes specific to tumor cells, such as cathepsins. It results in the release of exatecan, which acts on topoisomerase, an enzyme essential to DNA replication that controls coiling of the DNA helix, leading to DNA damage, cell replication arrest and, consequently, apoptosis. Then, exatecan is able to penetrate into neighboring cells, thereby causing a cascade of cell death. The minimum ihibitory concentration (MIC) of exatecan in vitro was shown to be equal to 0.31 μM. [8] Exatecan is a derivative of camptothecin, a substance found in Camptotheca acuminata. [9]

Pharmacokinetics

Datopatamab deruxtecan pharmacokinetic parameters after the first dose of 6 mg/kg [1] [10]
ParameterDatopatamab deruxtecanDeruxtecan
Cmax 154 μg/mL2.8 ng/mL
AUC 671 μg*day/mL18 ng*day/mL
mean steady state volume3.5n/d
plasma protein binding n/a98%
blood-to-plasma concentration ration/d0.6 (in vitro)
half life (t1/2)4.8 days5.5 days
clearance0.6 L/dayn/d

Metabolism and interactions

Deruxtecan is metabolised by CYP3A4, without notable glucuronidation. Moreover, it is a substrate of several transporter systems, i.e. OATP1B1, OATP1B3, MATE2-K, P-gp, MRP1 and BCRP. Therefore, use with itraconazole (CYP3A inhibitor) and ritonavir (OATP1B/CYP3A inhibitor) is contraindicated. [1]

History

Efficacy was evaluated in TROPION-Breast01 (NCT05104866), a multicenter, open-label, randomized trial. [4] Participants must have experienced disease progression, been deemed unsuitable for further endocrine therapy, and have received one or two lines of prior chemotherapy for unresectable or metastatic disease. [4] Participants were excluded for a history of ILD/pneumonitis requiring steroids, ongoing ILD/pneumonitis, clinically active brain metastases, or clinically significant corneal disease. [4] Participants also were excluded for ECOG performance status >1. [4] Randomization was stratified by previous lines of chemotherapy, prior CDK4/6 inhibitor treatment, and geographical region. [4] A total of 732 patients were randomized (1:1) to datopotamab deruxtecan-dlnk (n=365) or investigator's choice of chemotherapy (n=367); eribulin (60%), capecitabine (21%), vinorelbine (10%), or gemcitabine (9%). [4]

Society and culture

Datopotamab deruxtecan was approved for medical use in the United States in January 2025. [4] [11] In December 2024, the US Food and Drug Administration granted the application for datopotamab deruxtecan breakthrough therapy designation. [12]

In January 2025, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Datroway, intended for the treatment of breast cancer. [2] The applicant for this medicinal product is Daiichi Sankyo Europe GmbH. [2] Datopotamab deruxtecan was authorized for medical use in the European Union in April 2025. [2] [3]

Names

Datopotamab deruxtecan is the international nonproprietary name, [13] and the United States Adopted Name. [14]

Datopotamab deruxtecan is sold under the brand name Datroway. [1]

References

  1. 1 2 3 4 5 6 "Datroway- datopotamab deruxtecan injection, powder, lyophilized, for solution". DailyMed. 28 January 2025. Retrieved 9 March 2025.
  2. 1 2 3 4 5 6 "Datroway EPAR". European Medicines Agency (EMA). 30 January 2025. Retrieved 16 February 2025. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. 1 2 3 "Datroway". Union Register of medicinal products. 8 April 2025. Retrieved 24 May 2025.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 "FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic, HR-positive, HER2-negative breast cancer". U.S. Food and Drug Administration (FDA). 17 January 2025. Archived from the original on 18 January 2025. Retrieved 19 January 2025.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  5. ↑ "Novel Drug Approvals for 2025". U.S. Food and Drug Administration (FDA). 21 February 2025. Archived from the original on 21 March 2025. Retrieved 9 March 2025.
  6. ↑ Heist RS, Sands J, Bardia A, Shimizu T, Lisberg A, Krop I, et al. (April 2024). "Clinical management, monitoring, and prophylaxis of adverse events of special interest associated with datopotamab deruxtecan". Cancer Treatment Reviews. 125: 102720. doi: 10.1016/j.ctrv.2024.102720 . PMID   38502995.
  7. ↑ Gadaleta-Caldarola G, Lanotte L, Infusino S, Gadaleta-Caldarola A, Schipilliti FM, Citrigno C, et al. (2023). "Safety evaluation of Datopotamab deruxtecan for triple-negative breast cancer: a meta-analysis". Cancer Treatment and Research Communications. 37: 100775. doi: 10.1016/j.ctarc.2023.100775 . PMID   37956525.
  8. ↑ Ogitani Y, Aida T, Hagihara K, Yamaguchi J, Ishii C, Harada N, et al. (October 2016). "DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1". Clinical Cancer Research. 22 (20): 5097–5108. doi: 10.1158/1078-0432.CCR-15-2822 . ISSN   1078-0432. PMID   27026201.
  9. ↑ Govindachari TR, Viswanathan N (January 1972). "Alkaloids of Mappia foetida". Phytochemistry. 11 (12): 3529–3531. Bibcode:1972PChem..11.3529G. doi:10.1016/S0031-9422(00)89852-0.
  10. ↑ Doi T, Shitara K, Naito Y, Shimomura A, Fujiwara Y, Yonemori K, et al. (November 2017). "Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody–drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study". The Lancet Oncology. 18 (11): 1512–1522. doi:10.1016/S1470-2045(17)30604-6. PMID   29037983.
  11. ↑ "Datroway Approved in the U.S. for Patients with Previously Treated Metastatic HR Positive, HER2 Negative Breast Cancer". Daiichi Sankyo US (Press release). 17 January 2025. Archived from the original on 18 January 2025. Retrieved 19 January 2025.
  12. ↑ "Datopotamab deruxtecan granted breakthrough therapy designation in US for patients with previously treated advanced EGFR-mutated non-small cell lung cancer". AstraZeneca US (Press release). 9 December 2024. Retrieved 20 January 2025.
  13. ↑ World Health Organization (2020). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 84". WHO Drug Information. 34 (3). hdl: 10665/340680 .
  14. ↑ "Datopotamab deruxtecan". American Medical Association. Retrieved 20 January 2025.
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