Type Whole antibody Routes of
administration Intravenous infusion Bioavailability N/A Trade name Kadcyla, Kadccyla ATC code L01XC14 (WHO) Biological half-life 4 days | Trade names Kadcyla, Kadccyla Legal status US: ℞-only Molar mass 148.5 kg/mol Source Humanized (from mouse) Protein binding 93% (in vitro) | |
 | ||
Pregnancy
category US: D (Evidence of risk) | ||
Anti her2 mechanisms of approved her2 inhibitors
Trastuzumab emtansine also known as ado-trastuzumab emtansine and sold under the trade name Kadcyla, is an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent emtansine (DM1). Trastuzumab alone stops growth of cancer cells by binding to the HER2/neu receptor, whereas DM1 enters cells and destroys them by binding to tubulin. Trastuzumab binding to Her2 prevents homodimerization or heterodimerization (Her2/Her3) of the receptor, ultimately inhibiting the activation of MAPK and PI3K/Akt cellular signalling pathways. Because the monoclonal antibody targets HER2, and HER2 is only over-expressed in cancer cells, the conjugate delivers the toxin specifically to tumor cells. The conjugate is abbreviated T-DM1.
Contents
- Anti her2 mechanisms of approved her2 inhibitors
- Medical use
- Clinical trials
- Adverse effects
- UK pricing issues
- Nomenclature
- Chemical properties
- References
In the EMILIA clinical trial of women with advanced HER2 positive breast cancer who were already resistant to trastuzumab alone, it improved median overall survival by 5.8 months (30.9 months vs. 25.1 months) compared to the combination of lapatinib and capecitabine. Based on that trial, the U.S. Food and Drug Administration (FDA) approved marketing on February 22, 2013.
Trastuzumab emtansine was developed by Genentech, a subsidiary group of Roche, and is manufactured by Lonza. The planned cost is expected to be $9,800 a month, or $94,000 for a typical course of treatment.
Medical use
In the United States, ado-trastuzumab emtansine was approved specifically for treatment of HER2-positive metastatic breast cancer (mBC) in patients who have been treated previously with trastuzumab and a taxane (paclitaxel or docetaxel), and who have already been treated for mBC or developed tumor recurrence within six months of adjuvant therapy.
Approval was based on the EMILIA study, a phase III clinical trial that compared trastuzumab emtansine versus capecitabine (Xeloda) plus lapatinib (Tykerb) in 991 people with unresectable, locally advanced or metastatic HER2-positive breast cancer who had previously been treated with trastuzumab and taxane chemotherapy. This trial showed improved progression-free survival in patients treated with trastuzumab emtansine (median 9.6 vs. 6.4 months), along with improved overall survival (median 30.9 vs. 25.1 months) and safety.
Clinical trials
Since 2013 there have been some more clinical trials:
Adverse effects
During clinical trials, the most common adverse effects of trastuzumab emtansine were fatigue, nausea, musculoskeletal pain, thrombocytopenia (low platelet counts), headache, increased liver enzyme levels, and constipation.
Severe adverse events identified during the EMILIA trial included hepatotoxicity (liver damage), including rare cases of liver failure, hepatic encephalopathy, and nodular regenerative hyperplasia; heart damage (dysfunction of the left ventricle); interstitial lung disease, including acute interstitial pneumonitis; thrombocytopenia; and peripheral neuropathy. Overall, trastuzumab emtansine was better tolerated than the control treatment, a combination of lapatinib (Tykerb) and capecitabine (Xeloda), with 43% of patients in the trastuzumab emtansine group experiencing severe toxic effects, versus 59% of those who received lapatinib/capecitabine; furthermore, fewer patients had to stop treatment due to adverse effects than with lapatinib or capecitabine. Anemia, low platelet counts, and peripheral neuropathy were more common among patients who received trastuzumab emtansine, whereas heart damage and gastrointestinal effects, such as vomiting, diarrhea, and stomatitis, were more common with lapatinib/capecitabine.
In the United States, Kadcyla carries black box warnings for liver toxicity, heart damage (reduction in left ventricular ejection fraction), and fetal harm if given to pregnant women.
UK pricing issues
In the UK, Kadcyla was not recommended for use by the National Health Service by advisory body NICE, reportedly because an acceptable pricing agreement could not be reached with Roche. Originally it cost £5,900 a month. and NICE estimated it cost £166,000 per QALY (well over the usual maximum). It has been funded by the English NHS Cancer Drugs Fund but in January 2015 it was proposed to remove it from the approved list. After a secret discount was agreed by Roche the Cancer Drugs Fund will continue to fund it.
Nomenclature
In the United States, Kadcyla was approved with the generic name "ado-trastuzumab emtansine", rather than the original United States Adopted Name (USAN) issued in 2009, "trastuzumab emtansine". The "ado-" prefix was added at the request of the FDA to help prevent dispensing errors. During preclinical development and clinical trials, the drug was also known as trastuzumab-DM1 or trastuzumab-MCC-DM1 (after the codename for emtansine), both abbreviated T-DM1, and by the codename PRO132365.
Chemical properties
Trastuzumab emtansine is an antibody-drug conjugate (ADC), a combination between a monoclonal antibody and a small-molecule drug. Each molecule of trastuzumab emtansine consists of a single trastuzumab molecule with several molecules of DM1, a cytotoxic maytansinoid, attached. SMCC, or succinimidyl trans-4-(maleimidylmethyl)cyclohexane-1-carboxylate, is a heterobifunctional crosslinker, a type of chemical reagent that contains two reactive functional groups, a succinimide ester and a maleimide. The succinimide group of SMCC reacts with the free amino group of a lysine residue in the trastuzumab molecule and the maleimide moiety of SMCC links to the free sulfhydryl group of DM1, forming a covalent bond between the antibody and the DM1. Each trastuzumab molecule may be linked to zero to eight DM1 molecules (3.5 on average). DM1 binds at plus ends of cellular microtubules and thereby inhibits cell division in the target tumor cells.