Trastuzumab deruxtecan

Identification

Summary

Trastuzumab deruxtecan is an antibody used to treat certain types of unresectable or metastatic HER2 positive breast cancer.

Brand Names

Enhertu

Generic Name

Trastuzumab deruxtecan

DrugBank Accession Number

DB14962

Background

Trastuzumab deruxtecan is a HER2-directed antibody attached to a topoisomerase inhibitor that is approved for use in certain types of treatment-resistant HER2-positive cancers.⁶ It is classified as an antibody-drug conjugate. The cleavable peptide linker used to bind the antibody and drug in this product distinguishes it from other members of its class.⁴

Trastuzumab deruxtecan was developed by Daiichi Sankyo in collaboration with AstraZeneca and was first approved by the FDA in 2019.⁶

Type

Biotech

Groups

Approved, Investigational

Biologic Classification

Protein Based Therapies
Monoclonal antibody (mAb)

Protein Chemical Formula

Not Available

Protein Average Weight

Not Available

Sequences

Not Available

Synonyms

• fam-trastuzumab deruxtecan-nxki
• Trastuzumab deruxtecan

External IDs

• DS-8201
• DS-8201A
• WHO 10516

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Pharmacology

Indication

In the US, trastuzumab deruxtecan is indicated for the treatment of adult patients 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.⁶ It is also indicated to treat adults with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.⁶ Trastuzumab deruxtecan is also indicated to treat adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.⁶

In Canada, trastuzumab deruxtecan is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have previously been treated with trastuzumab emtansine, or who have received at least one prior anti-HER2-based regimen either in the metastatic setting or in the adjuvant/neoadjuvant setting who have experienced disease recurrence during or within 6 months of adjuvant/neoadjuvant therapy.⁸ Trastuzumab deruxtecan is also indicated in Canada for the treatment of adult patients with unresectable or metastatic HER2-low breast cancer who have received at least one prior line of chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.⁸

In Europe, trastuzumab deruxtecan is indicated as monotherapy for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received one or more prior anti-HER2-based regimens and unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.⁹ It is also indicated for the treatment of adult patients with advanced HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.⁹ It is also indicated as a monotherapy for the treatment of adult patients with advanced non-small cell lung cancer whose tumors have an activating HER2 mutation and who require systemic therapy following platinum-based chemotherapy with or without immunotherapy.⁹

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Advanced gastric adenocarcinoma		••••••••••••	•••••	•••••••••• ••••••• •••• •••••••••••	•••••••••• ••••••• •••••••••••• ••• ••••••••
Treatment of	Advanced gastroesophageal adenocarcinoma		••••••••••••	•••••	•••••••••• ••••••• •••• •••••••••••	•••••••••• ••••••• •••••••••••• ••• ••••••••
Treatment of	Advanced non-small cell lung cancer (nsclc)		••••••••••••	•••••		•••••••••• ••••••• •••••••••••• ••• ••••••••
Treatment of	Metastatic breast cancer		••••••••••••	•••••		•••••••••• ••••••• •••••••••••• ••• ••••••••
Treatment of	Unresectable breast cancer		••••••••••••	•••••		•••••••••• ••••••• •••••••••••• ••• ••••••••

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Pharmacodynamics

Trastuzumab demonstrates antitumor activity against certain types of HER2 positive breast cancer, however, clinical trials are still ongoing to confirm its efficacy.^3,6,7 By exploiting both targeted antibody and cytotoxic effects, trastuzumab deruxtecan can effectively destroy tumors.⁴

The FDA label warns of a potential risk for neutropenia, interstitial lung disease/pneumonitis, and left ventricular dysfunction following the use of this drug.⁶

Mechanism of action

Trastuzumab deruxtecan is a humanized anti-HER2 IgG1 antibody, targeting cancer cause by mutation of the HER2 gene. In addition, the small molecule portion of this drug, deruxtecan (DXd), is a topoisomerase I inhibitor.^1,6 It is attached to the antibody by a peptide linker. After trastuzumab deruxtecan binds to HER2 found on malignant cells, it is internalized and linker cleavage occurs through the actions of lysosomal enzymes. After it is released through cleavage, DXd causes targeted DNA damage and apoptosis in cancer cells, due to the ability to cross cell membranes.^4,6

Normally, drugs in this class (antibody-drug conjugates) present a challenge. The monoclonal antibody accurately targets cancer cells, however exert limited killing action. The addition of a cytotoxic agent (a topoisomerase I inhibitor in this case) effectively kills dividing cancer cells, including those in the healthy tissues, leading to various adverse effects. The peptide linker used to formulate this drug is cleavable, which is unique to other antibody-drug conjugates, allowing for increased efficacy and reduced drug resistance to topoisomerase.⁴

Target	Actions	Organism
AHigh affinity immunoglobulin gamma Fc receptor I	antibody	Humans
ADNA topoisomerase 1	inhibitor	Humans

Absorption

The Cmax of trastuzumab deruxtecan at normal therapeutic doses was 122 μg/mL (20%). The AUC of trastuzumab deruxtecan was 735 μg·day/mL (31%).⁶

Volume of distribution

The estimated volume of distribution of trastuzumab deruxtecan in the central compartment is 2.77 L, according to a population based pharmacokinetic study.⁶ Pharmacokinetic studies found that the unchanged drug is distributed in the blood and is not significantly retained in tissues.²

Protein binding

The Dxd portion of the drug has a plasma protein binding estimated at 97%.⁶

Metabolism

Trastuzumab deruxtecan is likely broken down into small peptides and amino acids through catabolism, just as the metabolism of endogenous IgG.^5,6 Cathepsin B and L enzymes are thought to be involved in the cleavage of the peptide linker that joins the topoisomerase I inhibitor and the antibody.⁴ In vitro, DXd, the topoisomerase inhibitor portion of the drug, is found to be metabolized by CYP3A4.⁶

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• Trastuzumab deruxtecan
  • Dxd + Trastuzumab

Route of elimination

A pharmacokinetic study revealed that this drug was mainly excreted in the feces. Another study determined that 67% of a dose was excreted in the feces.^2,4 Unmetabolized DXd was found in the urine during a pharmacokinetic study.²

Half-life

In a pharmacokinetic study, the median elimination half-life of trastuzumab deruxtecan was about 5.8 days.⁶

Clearance

Trastuzumab deruxtecan is rapidly cleared from systemic circulation.² Estimated systemic clearance of trastuzumab deruxtecan is 0.42 L/day, according to a population pharmacokinetic analysis. DXd showed a systemic clearance of about 19.2 L/h.⁶

Adverse Effects

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Toxicity

LD50 and overdose information are not currently available, but effects of an overdose are likely to impact the lungs, heart, and circulatory system, leading to significant toxicity.⁶

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Trastuzumab deruxtecan.
Adalimumab	The risk or severity of adverse effects can be increased when Adalimumab is combined with Trastuzumab deruxtecan.
Aducanumab	The risk or severity of adverse effects can be increased when Aducanumab is combined with Trastuzumab deruxtecan.
Alemtuzumab	The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Trastuzumab deruxtecan.
Alirocumab	The risk or severity of adverse effects can be increased when Alirocumab is combined with Trastuzumab deruxtecan.

Food Interactions

No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Enhertu	Injection, powder, for solution	100 mg	Intravenous	Daiichi Sankyo Europe, Gmb H	2021-03-03	Not applicable
Enhertu	Powder, for solution	100 mg / vial	Intravenous	Astra Zeneca	2021-07-09	Not applicable
Enhertu	Injection, powder, lyophilized, for solution	100 mg/5mL	Intravenous	Daiichi Sankyo Inc.	2019-12-20	Not applicable

Categories

ATC Codes

L01FD04 — Trastuzumab deruxtecan

• L01FD — HER2 (Human Epidermal Growth Factor Receptor 2) inhibitors
• L01F — MONOCLONAL ANTIBODIES AND ANTIBODY DRUG CONJUGATES
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Amino Acids, Peptides, and Proteins
• Antibodies
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antibody-drug Conjugates
• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• BCRP/ABCG2 Substrates
• Blood Proteins
• Cancer immunotherapy
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Globulins
• HER2 (Human Epidermal Growth Factor Receptor 2) inhibitors
• HER2 Receptor Antagonists
• Immunoglobulins
• Immunologic Factors
• Immunoproteins
• Immunotherapy
• MATE 2 Substrates
• MATE substrates
• MONOCLONAL ANTIBODIES AND ANTIBODY DRUG CONJUGATES
• Noxae
• OATP1B3 substrates
• P-glycoprotein substrates
• Proteins
• Serum Globulins
• Topoisomerase Inhibitors
• Toxic Actions

Chemical TaxonomyProvided by Classyfire

Description

Not Available

Kingdom

Organic Compounds

Super Class

Organic Acids

Class

Carboxylic Acids and Derivatives

Sub Class

Amino Acids, Peptides, and Analogues

Direct Parent

Peptides

Alternative Parents

Not Available

Substituents

Not Available

Molecular Framework

Not Available

External Descriptors

Not Available

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

5384HK7574

CAS number

1826843-81-5

References

Synthesis Reference

Nakada T, Masuda T, Naito H, Yoshida M, Ashida S, Morita K, Miyazaki H, Kasuya Y, Ogitani Y, Yamaguchi J, Abe Y2, Honda T2. (2016).Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads. Bioorg Med Chem Lett.,Mar 15;26(6):1542-1545

General References

1. Tamura K, Tsurutani J, Takahashi S, Iwata H, Krop IE, Redfern C, Sagara Y, Doi T, Park H, Murthy RK, Redman RA, Jikoh T, Lee C, Sugihara M, Shahidi J, Yver A, Modi S: Trastuzumab 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 Jun;20(6):816-826. doi: 10.1016/S1470-2045(19)30097-X. Epub 2019 Apr 29. [Article]
2. Nagai Y, Oitate M, Shiozawa H, Ando O: Comprehensive preclinical pharmacokinetic evaluations of trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate, in cynomolgus monkeys. Xenobiotica. 2019 Sep;49(9):1086-1096. doi: 10.1080/00498254.2018.1531158. Epub 2019 Jan 4. [Article]
3. Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, Andre F, Iwata H, Ito Y, Tsurutani J, Sohn J, Denduluri N, Perrin C, Aogi K, Tokunaga E, Im SA, Lee KS, Hurvitz SA, Cortes J, Lee C, Chen S, Zhang L, Shahidi J, Yver A, Krop I: Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2019 Dec 11. doi: 10.1056/NEJMoa1914510. [Article]
4. Xu Z, Guo D, Jiang Z, Tong R, Jiang P, Bai L, Chen L, Zhu Y, Guo C, Shi J, Yu D: Novel HER2-Targeting Antibody-Drug Conjugates of Trastuzumab Beyond T-DM1 in Breast Cancer: Trastuzumab Deruxtecan(DS-8201a) and (Vic-)Trastuzumab Duocarmazine (SYD985). Eur J Med Chem. 2019 Dec 1;183:111682. doi: 10.1016/j.ejmech.2019.111682. Epub 2019 Sep 6. [Article]
5. Kendrick F, Evans ND, Arnulf B, Avet-Loiseau H, Decaux O, Dejoie T, Fouquet G, Guidez S, Harel S, Hebraud B, Javaugue V, Richez V, Schraen S, Touzeau C, Moreau P, Leleu X, Harding S, Chappell MJ: Analysis of a Compartmental Model of Endogenous Immunoglobulin G Metabolism with Application to Multiple Myeloma. Front Physiol. 2017 Mar 17;8:149. doi: 10.3389/fphys.2017.00149. eCollection 2017. [Article]
6. FDA Approved Drug Products: Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use [Link]
7. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies [Link]
8. Health Canada Approved Drug Products: Enhertu (trastuzumab deruxtecan) powder for concentrate for intravenous infusion [Link]
9. EMA Approved Drug Products: Enhertu (Trastuzumab deruxtecan) Powder for concentrate for solution for infusion. [Link]

External Links

RxNav

2267574

Wikipedia

Trastuzumab_deruxtecan

FDA label

Download (590 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Not Yet Recruiting	Treatment	Breast Cancer	1
4	Recruiting	Diagnostic	Anatomic Stage IV Breast Cancer AJCC v8 / Brain Metastases / Metastatic Breast Carcinoma	1
3	Active Not Recruiting	Treatment	Advanced or Metastatic Breast Cancer	1
3	Active Not Recruiting	Treatment	Breast Cancer	3
3	Active Not Recruiting	Treatment	HER2-Positive Primary Breast Cancer / Residual Invasive Breast Cancer	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, powder, for solution	Intravenous	100 MG
Injection, powder, lyophilized, for solution	Intravenous	100 mg/5mL
Powder, for solution	Intravenous	100 mg / vial
Solution	Intravenous	100 mg

Prices

Not Available

Patents

Not Available

Properties

State

Not Available

Experimental Properties

Not Available

Targets

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Details1. High affinity immunoglobulin gamma Fc receptor I

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Antibody

General Function

Receptor signaling protein activity

Specific Function

High affinity receptor for the Fc region of immunoglobulins gamma. Functions in both innate and adaptive immune responses.

Gene Name

FCGR1A

Uniprot ID

P12314

Uniprot Name

High affinity immunoglobulin gamma Fc receptor I

Molecular Weight

42631.525 Da

References

1. Tamura K, Tsurutani J, Takahashi S, Iwata H, Krop IE, Redfern C, Sagara Y, Doi T, Park H, Murthy RK, Redman RA, Jikoh T, Lee C, Sugihara M, Shahidi J, Yver A, Modi S: Trastuzumab 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 Jun;20(6):816-826. doi: 10.1016/S1470-2045(19)30097-X. Epub 2019 Apr 29. [Article]
2. Nagai Y, Oitate M, Shiozawa H, Ando O: Comprehensive preclinical pharmacokinetic evaluations of trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate, in cynomolgus monkeys. Xenobiotica. 2019 Sep;49(9):1086-1096. doi: 10.1080/00498254.2018.1531158. Epub 2019 Jan 4. [Article]
3. FDA Approved Drug Products: Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use [Link]

Details2. DNA topoisomerase 1

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Poly(a) rna binding

Specific Function

Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a singl...

Gene Name

TOP1

Uniprot ID

P11387

Uniprot Name

DNA topoisomerase 1

Molecular Weight

90725.19 Da

References

1. Tamura K, Tsurutani J, Takahashi S, Iwata H, Krop IE, Redfern C, Sagara Y, Doi T, Park H, Murthy RK, Redman RA, Jikoh T, Lee C, Sugihara M, Shahidi J, Yver A, Modi S: Trastuzumab 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 Jun;20(6):816-826. doi: 10.1016/S1470-2045(19)30097-X. Epub 2019 Apr 29. [Article]
2. FDA Approved Drug Products: Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use [Link]

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Drug created at May 20, 2019 14:38 / Updated at December 22, 2023 19:51