Drug/Small Molecule:
trastuzumab emtansine

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PharmGKB gathers information regarding PGx on FDA drug labels from the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels", and from FDA-approved FDA and EMA-approved (European Medicines Agency) EMA labels brought to our attention. Excerpts from the label and downloadable highlighted label PDFs are manually curated by PharmGKB.

Please note that some drugs may have been removed from or added to the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" without our knowledge. We periodically check the table for additions to this table and update PharmGKB accordingly.

There is currently no such list for European drug labels - we are working with the EMA to establish a list of European Public Assessment Reports (EPAR)s that contain PGx information. We are constructing this list by initially searching for drugs for which we have PGx-containing FDA drug labels - of these 44 EMA EPARs were identified and are being curated for pgx information.

We welcome any information regarding drug labels containing PGx information approved by the FDA, EMA or other Medicine Agencies around the world - please contact feedback.



last updated 10/25/2013

FDA Label for trastuzumab emtansine and ERBB2

This label is on the FDA Biomarker List
Genetic testing required

Summary

The FDA-approved label requires test results demonstrating HER2 protein overexpression prior to initiating therapy with trastuzumab emtansine using FDA-approved tests by laboratories with demonstrated proficiency.

Annotation

HER2 (ERBB2) overexpression can be detected through an immnohistochemistry (IHC) test, which measures HER2 protein levels, or through fluorescence in situ hybridization (FISH), which assays gene amplification. In the randomized study discussed in the label, patients were required to have evidence of HER2 overexpression defined as 3+ IHC by Dako Herceptest™, or evidence of overexpression defined as FISH amplification ratio greater than or equal to 2.0 by Dako HER2 FISH PharmDx™ test.

The drug label also recommends avoiding the concomitant use of strong CYP3A4 inhibitors.

Excerpts from the trastuzumab emtansine (KADCYLA) drug label:

Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA therapy because these are the only patients studied for whom benefit has been shown.

Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized.

In vitro studies indicate that DM1, the cytotoxic component of KADCYLA, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 inhibitors...with KADCYLA should be avoided due to a potential for increase in DM1 exposure and toxicity. Consider an alternate medication with no or minimal potential to inhibit CYP3A4.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the trastuzumab emtansine drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Genes and/or phenotypes found in this label

  • CYP3A4
    • Clinical pharmacology section, Pharmacokinetics section, Use in specific populations section, metabolism/PK
    • source: FDA Label
  • CYP3A5
    • Drug interactions section, Pharmacokinetics section, Use in specific populations section, metabolism/PK
    • source: FDA Label
  • ERBB2
    • Indications & usage section, Description section, Clinical pharmacology section, Clinical studies section, Warnings and precautions section, efficacy
    • source: FDA Label

last updated 07/10/2014

European Medicines Agency (EMA) Label for trastuzumab emtansine and ERBB2

Genetic testing required

Summary

The EMA European Public Assessment Report (EPAR) for trastuzumab emtansine (Kadcyla) contains information regarding indication of the drug in patients with HER2-positive (encoded by the ERBB2 gene) breast cancer due to its mechanism of action, and HER2 positive status should be tested for by a validated method.

Annotation

Trastuzumab emtansine is a HER2-targeted antibody linked to a microtubule inhibitor. It is designed to selectively target HER2-overexpressing tumor cells, internalize and release the inhibitor in the cell, resulting in cell death.

Excerpts from the trastuzumab emtansine (Kadcyla) EPAR:

Kadcyla, as a single agent, is indicated for the treatment of adult patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:

  • Received prior therapy for locally advanced or metastatic disease, or
  • Developed disease recurrence during or within six months of completing adjuvant therapy.

Patients treated with trastuzumab emtansine should have HER2 positive tumour status, defined as a score of 3+ by immunohistochemistry (IHC) or a ratio of 2.0 or more by in situ hybridization (ISH) assessed by a CE-marked In Vitro Diagnostic (IVD) medical device. If a CE-marked IVD is not available, the HER2-status should be assessed by an alternate validated test.

Conjugation of DM1 to trastuzumab confers selectivity of the cytotoxic agent for HER2-overexpressing tumour cells, thereby increasing intracellular delivery of DM1 directly to malignant cells. Upon binding to HER2, trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in release of DM1-containing cytotoxic catabolites (primarily lysine-MCC-DM1).

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the trastuzumab emtansine (Kadcyla) EMA drug label.

*Disclaimer: The contents of this page have not been endorsed by the EMA and are the sole responsibility of PharmGKB.

Genes and/or phenotypes found in this label

  • Breast Neoplasms
    • Indications & usage section, Dosage & administration section, Information for patients section, Pharmacodynamics section, Pharmacokinetics section, Warnings and precautions section, efficacy
    • source: European Medicines Agency (EMA) Label
  • CYP3A4
    • Drug interactions section, Pharmacokinetics section, metabolism/PK
    • source: European Medicines Agency (EMA) Label
  • ERBB2
    • Indications & usage section, Information for patients section, Pharmacodynamics section, efficacy
    • source: European Medicines Agency (EMA) Label

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

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This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Gene?
2D structure from PubChem
provided by PubChem

Overview

Generic Names
  • T-DM1
  • Trastuzumab-DM1
  • Trastuzumab-MCC-DM1
  • Trastuzumab-MCC-DM1 antibody-drug conjugate
Trade Names
Brand Mixture Names

PharmGKB Accession Id:
PA165958441

Description

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab and DM1, a microtubule polymerization inhibitor, covalently bound via a stable thioether linker [Article:22271209].

Source: PharmGKB

Indication

Trastuzumab emtansine is targeted toward HER2 (ERBB2) positive breast cancer, and has gone through phase I and II trials for patients with HER2-positive metastatic breast cancer [Article:21506905].

Source: PharmGKB

Other Vocabularies

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

EvidenceGene
No Dosing Guideline available DL No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
CYP3A4
No Dosing Guideline available DL No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
CYP3A5
No Dosing Guideline available DL No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
ERBB2
No related drugs are available.
No related diseases are available

Publications related to trastuzumab emtansine: 1

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Drug Interaction Potential of Trastuzumab Emtansine Combined With Pertuzumab in Patients With HER2-Positive Metastatic Breast Cancer. Current drug metabolism. 2012. Lu Dan, et al. PubMed

LinkOuts

PubChem Substance:
135353969
FDA Drug Label at DailyMed:
23f3c1f4-0fc8-4804-a9e3-04cf25dd302e

Clinical Trials

These are trials that mention trastuzumab emtansine and are related to either pharmacogenetics or pharmacogenomics.

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Sources for PharmGKB drug information: DrugBank, Open Eye Scientific Software.