Difference between revisions of "Trastuzumab emtansine (Kadcyla)"

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Also known as TDM1, T-DM1, trastuzumab emtansine.
 
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==General information==
 
==General information==
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Class: Antibody-cytotoxic agent conjugate consisting of the HER2 humanized IgG1 kappa monoclonal antibody [[Trastuzumab (Herceptin)]] linked with a small molecule microtubule inhibitor and maytansine derivative, emtansine (DM1).  The humanized monoclonal antibody binds to subdomain IV of the HER2 receptor, is subjected to receptor-mediated endocytosis, and lysosomal degradation leads to the intracellular release of DM1.  DM1 binds to tubulin at the rhizoxin binding site, inhibits the assembly of microtubules, and leads to cell cycle arrest and cell death via apoptosis.  Similar to [[Trastuzumab (Herceptin)]], ado-trastuzumab emtansine inhibits HER2 receptor signaling, facilitates antibody-dependent cell-mediated cytotoxicity (ADCC), and inhibits shedding of the HER2 extracellular domain in HER2-overexpressing human breast cancer cells.<ref name="insert">[http://www.gene.com/download/pdf/kadcyla_prescribing.pdf Ado-trastuzumab emtansine (Kadcyla) package insert]</ref><ref>[[Media:Adotrastuzumabemtansine.pdf|Ado-trastuzumab emtansine (Kadcyla) package insert (locally hosted backup)]]</ref><ref>[http://www.kadcyla.com/ Kadcyla manufacturer's website]</ref><ref>[http://www.immunogen.com/wt/page/trastuzumab_DM1 ImmunoGen product site]</ref><ref>http://www.immunogen.com/img/T-DM1%20+%20pertuzumab%20at%20SABCS.pdf A Phase Ib/II Trial of Trastuzumab-DM1 (T-DM1) with Pertuzumab for Patients with HER2-Positive,
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Class/mechanism: Antibody-cytotoxic agent conjugate consisting of the HER2 humanized IgG1 kappa monoclonal antibody [[Trastuzumab (Herceptin)]] linked with a small molecule microtubule inhibitor and maytansine derivative, emtansine (DM1).  The humanized monoclonal antibody binds to subdomain IV of the HER2 receptor, is subjected to receptor-mediated endocytosis, and lysosomal degradation leads to the intracellular release of DM1.  DM1 binds to tubulin at the rhizoxin binding site, inhibits the assembly of microtubules, and leads to cell cycle arrest and cell death via apoptosis.  Similar to [[Trastuzumab (Herceptin)]], ado-trastuzumab emtansine inhibits HER2 receptor signaling, facilitates antibody-dependent cell-mediated cytotoxicity (ADCC), and inhibits shedding of the HER2 extracellular domain in HER2-overexpressing human breast cancer cells.<ref name="insert">[http://www.gene.com/download/pdf/kadcyla_prescribing.pdf Ado-trastuzumab emtansine (Kadcyla) package insert]</ref><ref>[[:File:Adotrastuzumabemtansine.pdf|Ado-trastuzumab emtansine (Kadcyla) package insert (locally hosted backup)]]</ref><ref>[http://www.kadcyla.com/ Kadcyla manufacturer's website]</ref><ref>[http://www.immunogen.com/our-adc-technology/kadcyla ImmunoGen product site]</ref><ref>http://www.immunogen.com/img/T-DM1%20+%20pertuzumab%20at%20SABCS.pdf A Phase Ib/II Trial of Trastuzumab-DM1 (T-DM1) with Pertuzumab for Patients with HER2-Positive,
 
Locally Advanced or Metastatic Breast Cancer: Interim Efficacy and Safety Results</ref><ref>[http://ecancer.org/tv/pubdate/1087 Dr. Sara Hurvitz's 2011 European Society for Medical Oncology (ESMO) Presentation]</ref>
 
Locally Advanced or Metastatic Breast Cancer: Interim Efficacy and Safety Results</ref><ref>[http://ecancer.org/tv/pubdate/1087 Dr. Sara Hurvitz's 2011 European Society for Medical Oncology (ESMO) Presentation]</ref>
 
<br>Route: IV
 
<br>Route: IV
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<br>Extravasation: no information
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<br>Extravasation: [[irritant]]
  
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For conciseness and simplicity, HemOnc.org currently will focus on treatment regimens and not list information such as: renal/hepatic dose adjustments, metabolism (including CYP450), excretion, monitoring parameters (although this will be considered for checklists), or manufacturer. Instead, for the most current information, please refer to your preferred pharmacopeias such as [http://www.thomsonhc.com/home/dispatch Micromedex], [http://online.lexi.com/ Lexicomp], [http://www.utdol.com/online/content/search.do UpToDate (courtesy of Lexicomp)], or the prescribing information.
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For conciseness and simplicity, HemOnc.org currently will focus on treatment regimens and not list information such as: renal/hepatic dose adjustments, metabolism (including CYP450), excretion, monitoring parameters (although this will be considered for checklists), or manufacturer. Instead, for the most current information, please refer to your preferred pharmacopeias such as [http://www.thomsonhc.com/home/dispatch Micromedex], [http://online.lexi.com/ Lexicomp], [http://reference.medscape.com/drug/kadcyla-ado-trastuzumab-emtansine-999820 Medscape],[http://www.utdol.com/online/content/search.do UpToDate (courtesy of Lexicomp)], or the prescribing information.<ref name="insert"></ref>
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 +
==Resistance mechanisms==
 +
* Hunter FW, Barker HR, Lipert B, Rothé F, Gebhart G, Piccart-Gebhart MJ, Sotiriou C, Jamieson SMF. Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer. Br J Cancer. 2020 Mar;122(5):603-612. Epub 2019 Dec 16. [https://doi.org/10.1038/s41416-019-0635-y link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7054312/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31839676/ PubMed]
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==Diseases for which it is established==
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*[[Breast_cancer,_HER2-positive|HER2+ breast cancer]]
  
 
==Diseases for which it is used==
 
==Diseases for which it is used==
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*[[Breast cancer]]
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*[[Malignant solid neoplasm, ERBB2-mutated|HER2+ tumors (site-agnostic)]]
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==Clinical trials==
 
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*[http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=84883 EMILIA: A phase III, randomized, multicenter study of trastuzumab-DM1 (T-DM1) compared with lapatinib (L) plus capecitabine (X) in patients with HER2-positive locally advanced or metastatic breast cancer (MBC) and previously treated with a trastuzumab-based regimen.]<ref>S. Verma, V. Dieras, L. Gianni, D. Miles, M. Welslau, M. D. Pegram, J. Baselga, E. Guardino, L. Fang, C. M. Linehan, K. L. Blackwell. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=84883 EMILIA: A phase III, randomized, multicenter study of trastuzumab-DM1 (T-DM1) compared with lapatinib (L) plus capecitabine (X) in patients with HER2-positive locally advanced or metastatic breast cancer (MBC) and previously treated with a trastuzumab-based regimen.] 2011 ASCO Annual Meeting abstract TPS116.</ref><ref>[http://clinicaltrials.gov/ct2/show/NCT00829166 EMILIA at ClinicalTrials.gov]</ref>
 
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*[http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=84827 MARIANNE: A phase III, randomized study of trastuzumab-DM1 (T-DM1) with or without pertuzumab (P) compared with trastuzumab (H) plus taxane for first-line treatment of HER2-positive, progressive, or recurrent locally advanced or metastatic breast cancer (MBC).]<ref>P. A. Ellis, C. H. Barrios, Y. Im, M. Patre, F. Branle, E. A. Perez. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=84827 MARIANNE: A phase III, randomized study of trastuzumab-DM1 (T-DM1) with or without pertuzumab (P) compared with trastuzumab (H) plus taxane for first-line treatment of HER2-positive, progressive, or recurrent locally advanced or metastatic breast cancer (MBC).] 2011 ASCO Annual Meeting abstract TPS102.</ref><ref>[http://clinicaltrials.gov/ct2/show/NCT01120184 MARIANNE at ClinicialTrials.gov]</ref>
 
  
 
==Patient drug information==
 
==Patient drug information==
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*Patient counseling information can be found on [http://www.gene.com/download/pdf/kadcyla_prescribing.pdf#page=22 page 22 of the Ado-trastuzumab emtansine (Kadcyla) package insert]<ref name="insert"></ref>
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*[https://chemocare.com/druginfo/ado-trastuzumab-emtansine.aspx Ado-trastuzumab emtansine (Kadcyla) patient drug information (Chemocare)]<ref>[https://chemocare.com/druginfo/ado-trastuzumab-emtansine.aspx Ado-trastuzumab emtansine (Kadcyla) patient drug information (Chemocare)]</ref>
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*Patient counseling information can be found in [http://www.gene.com/download/pdf/kadcyla_prescribing.pdf the Ado-trastuzumab emtansine (Kadcyla) package insert]<ref name="insert"></ref>
 +
*[http://www.uptodate.com/contents/ado-trastuzumab-emtansine-patient-drug-information Ado-trastuzumab emtansine (Kadcyla) patient drug information (UpToDate)]<ref>[http://www.uptodate.com/contents/ado-trastuzumab-emtansine-patient-drug-information Ado-trastuzumab emtansine (Kadcyla) patient drug information (UpToDate)]</ref>
  
 
==History of changes in FDA indication==
 
==History of changes in FDA indication==
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*2/22/2013: [http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm340704.htm FDA approved] for "patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination."
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*2013-02-22: [http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm340704.htm Initial approval] for patients with [[Biomarkers#HER2|HER2]]-[[Biomarkers#Overexpression|positive]], metastatic [[breast cancer]] who previously received [[Trastuzumab (Herceptin) | trastuzumab]] and a [[:Category:Taxanes|taxane]], separately or in combination. ''(Based on EMILIA)''
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*2019-05-03: Approval expanded for the adjuvant treatment of patients with [[Biomarkers#HER2|HER2]]-[[Biomarkers#Overexpression|positive]] early [[breast cancer]] (EBC) who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment. ''(Indication extended to the adjuvant setting; based on KATHERINE)''
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 +
==History of changes in EMA indication==
 +
*2013-11-15: Initial marketing authorization as Kadcyla. 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 received prior therapy for locally advanced or metastatic disease.
 +
*2013-11-15: Initial marketing authorization as Kadcyla. 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 developed disease recurrence during or within six months of completing adjuvant therapy.
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*2019-12-16: Extension of indication to include the use of Kadcyla as a single agent for the adjuvant treatment of adult patients with HER2-positive early [[breast cancer]] who have invasive residual disease, in the breast and/or lymph nodes, after neoadjuvant taxane-based and HER2-targeted therapy.
 +
 
 +
==History of changes in Health Canada indication==
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*2013-09-11: Initial notice of compliance as monotherapy for the treatment of HER2-positive metastatic [[breast cancer]] patients who received both prior treatment with trastuzumab and a taxane, separately or in combination. Patients should have received prior therapy for metastatic disease.
 +
*2013-09-11: Initial notice of compliance as monotherapy for the treatment of HER2-positive metastatic [[breast cancer]] patients who received both prior treatment with trastuzumab and a taxane, separately or in combination. Patients should have developed disease recurrence during or within 6 months of completing adjuvant therapy.
 +
*2019-11-25: New indication as monotherapy for the adjuvant treatment of HER-2 positive early [[breast cancer]] patients who have residual invasive disease following neoadjuvant taxine and trastuzumab based treatment.
 +
 
 +
==History of changes in PMDA indication==
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*2013-09-20: Initial approval for the treatment of unresectable or recurrent HER2-positive [[breast cancer]].
 +
*2020-08-21: New indication and a new dosage for the postoperative adjuvant treatment for HER2-positive [[breast cancer]].
 +
==Also known as==
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*'''Code name:''' PRO-132365
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*'''Generic names:''' ado-trastuzumab emtansine, TDM1, T-DM1
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*'''Brand name:''' Kadcyla, Ujvira
  
 
==References==
 
==References==
 
<references/>
 
<references/>
  
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[[Category:Drug index]]
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[[Category:Drugs]]
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[[Category:Chemotherapy]]
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[[Category:Intravenous medications]]
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[[Category:Antibody medications]]
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[[Category:Irritant]]
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[[Category:Antibody-drug conjugates]]
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[[Category:Protein expression-specific medications]]
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[[Category:Anti-HER2 medications]]
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[[Category:Anti-HER2 antibody-drug conjugates]]
 
[[Category:Microtubule inhibitors]]
 
[[Category:Microtubule inhibitors]]
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[[Category:Breast cancer medications]]
 
[[Category:Breast cancer medications]]
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[[Category:Drugs FDA approved in 2013]]
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[[Category:Malignant solid neoplasm, ERBB2-mutated medications]]
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[[Category:EMA approved in 2013]]
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[[Category:FDA approved in 2013]]
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[[Category:Health Canada approved in 2013]]
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[[Category:PMDA approved in 2013]]

Latest revision as of 21:38, 21 September 2023

General information

Class/mechanism: Antibody-cytotoxic agent conjugate consisting of the HER2 humanized IgG1 kappa monoclonal antibody Trastuzumab (Herceptin) linked with a small molecule microtubule inhibitor and maytansine derivative, emtansine (DM1). The humanized monoclonal antibody binds to subdomain IV of the HER2 receptor, is subjected to receptor-mediated endocytosis, and lysosomal degradation leads to the intracellular release of DM1. DM1 binds to tubulin at the rhizoxin binding site, inhibits the assembly of microtubules, and leads to cell cycle arrest and cell death via apoptosis. Similar to Trastuzumab (Herceptin), ado-trastuzumab emtansine inhibits HER2 receptor signaling, facilitates antibody-dependent cell-mediated cytotoxicity (ADCC), and inhibits shedding of the HER2 extracellular domain in HER2-overexpressing human breast cancer cells.[1][2][3][4][5][6]
Route: IV
Extravasation: irritant

For conciseness and simplicity, HemOnc.org currently will focus on treatment regimens and not list information such as: renal/hepatic dose adjustments, metabolism (including CYP450), excretion, monitoring parameters (although this will be considered for checklists), or manufacturer. Instead, for the most current information, please refer to your preferred pharmacopeias such as Micromedex, Lexicomp, Medscape,UpToDate (courtesy of Lexicomp), or the prescribing information.[1]

Resistance mechanisms

  • Hunter FW, Barker HR, Lipert B, Rothé F, Gebhart G, Piccart-Gebhart MJ, Sotiriou C, Jamieson SMF. Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer. Br J Cancer. 2020 Mar;122(5):603-612. Epub 2019 Dec 16. link to original article link to PMC article PubMed

Diseases for which it is established

Diseases for which it is used

Patient drug information

History of changes in FDA indication

  • 2013-02-22: Initial approval for patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. (Based on EMILIA)
  • 2019-05-03: Approval expanded for the adjuvant treatment of patients with HER2-positive early breast cancer (EBC) who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment. (Indication extended to the adjuvant setting; based on KATHERINE)

History of changes in EMA indication

  • 2013-11-15: Initial marketing authorization as Kadcyla. 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 received prior therapy for locally advanced or metastatic disease.
  • 2013-11-15: Initial marketing authorization as Kadcyla. 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 developed disease recurrence during or within six months of completing adjuvant therapy.
  • 2019-12-16: Extension of indication to include the use of Kadcyla as a single agent for the adjuvant treatment of adult patients with HER2-positive early breast cancer who have invasive residual disease, in the breast and/or lymph nodes, after neoadjuvant taxane-based and HER2-targeted therapy.

History of changes in Health Canada indication

  • 2013-09-11: Initial notice of compliance as monotherapy for the treatment of HER2-positive metastatic breast cancer patients who received both prior treatment with trastuzumab and a taxane, separately or in combination. Patients should have received prior therapy for metastatic disease.
  • 2013-09-11: Initial notice of compliance as monotherapy for the treatment of HER2-positive metastatic breast cancer patients who received both prior treatment with trastuzumab and a taxane, separately or in combination. Patients should have developed disease recurrence during or within 6 months of completing adjuvant therapy.
  • 2019-11-25: New indication as monotherapy for the adjuvant treatment of HER-2 positive early breast cancer patients who have residual invasive disease following neoadjuvant taxine and trastuzumab based treatment.

History of changes in PMDA indication

  • 2013-09-20: Initial approval for the treatment of unresectable or recurrent HER2-positive breast cancer.
  • 2020-08-21: New indication and a new dosage for the postoperative adjuvant treatment for HER2-positive breast cancer.

Also known as

  • Code name: PRO-132365
  • Generic names: ado-trastuzumab emtansine, TDM1, T-DM1
  • Brand name: Kadcyla, Ujvira

References

  1. ↑ 1.0 1.1 1.2 Ado-trastuzumab emtansine (Kadcyla) package insert
  2. ↑ Ado-trastuzumab emtansine (Kadcyla) package insert (locally hosted backup)
  3. ↑ Kadcyla manufacturer's website
  4. ↑ ImmunoGen product site
  5. ↑ http://www.immunogen.com/img/T-DM1%20+%20pertuzumab%20at%20SABCS.pdf A Phase Ib/II Trial of Trastuzumab-DM1 (T-DM1) with Pertuzumab for Patients with HER2-Positive, Locally Advanced or Metastatic Breast Cancer: Interim Efficacy and Safety Results
  6. ↑ Dr. Sara Hurvitz's 2011 European Society for Medical Oncology (ESMO) Presentation
  7. ↑ Ado-trastuzumab emtansine (Kadcyla) patient drug information (Chemocare)
  8. ↑ Ado-trastuzumab emtansine (Kadcyla) patient drug information (UpToDate)
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