Trastuzumab emtansine (Kadcyla)

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.
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.

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

• HER2+ breast cancer

Diseases for which it is used

• HER2+ tumors (site-agnostic)

Patient drug information

• Ado-trastuzumab emtansine (Kadcyla) patient drug information (Chemocare)
• Patient counseling information can be found in the Ado-trastuzumab emtansine (Kadcyla) package insert
• Ado-trastuzumab emtansine (Kadcyla) patient drug information (UpToDate)

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