Trastuzumab emtansine

Trastuzumab emtansine

Monoclonal antibody
Type	Whole antibody
Source	Humanized (from mouse)
Clinical data
Trade names	Kadcyla, Kadccyla
Pregnancy category	US: D (Evidence of risk)
Legal status	US: ℞-only
Routes of administration	Intravenous infusion
Pharmacokinetic data
Bioavailability	N/A
Protein binding	93% (in vitro)
Metabolism	Hepatic (CYP3A4/3A5-mediated)
Biological half-life	4 days
Identifiers
CAS Number	1018448-65-1 N
ATC code	L01XC14 (WHO)
UNII	SE2KH7T06F N
KEGG	D09980 N
Chemical data
Formula	C6448H9948N1720O2012S44·(C47H62ClN4O13S)n
Molecular mass	148.5 kg/mol
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Trastuzumab emtansine (INN; in the United States, ado-trastuzumab emtansine, 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.

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.

Uses

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:

• First line treatment for metastatic breast cancer: the MARIANNE study compares taxane (docetaxel or paclitaxel) plus trastuzumab vs T-DM1 vs T-DM1 plus pertuzumab as first-line treatment for people with HER2 positive unresectable locally advanced or metastatic breast cancer; On December 19, 2014, Roche reported the results of the MARIANNE study. Neither Kadcyla-containing treatment significantly improved progression-free survival compared to Herceptin and chemotherapy.
• a phase III trial for HER2+ gastric cancer compares T-DM1 to physician's choice of taxane (docetaxel or paclitaxel). On October 22, 2015, Roche and co-developer ImmunoGen disclosed that Kadcyla had failed to meets its primary endpoint in the Phase II/III GATSBY trial investigating the second line treatment of HER2-positive advanced gastric cancer.
• the TH3RESA study is comparing T-DM1 vs treatment of physician's choice for people with HER2 positive metastatic breast cancer previously treated with trastuzumab and lapatinib. Interim results for TH3RESA suggest a doubling of progression-free survival from 3 months to 6 months.

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

Schematic representation of trastuzumab emtansine. The maytansine skeleton is shown in black at left. The thioether group that makes mertansine is shown in red. The linker group that makes emtansine is shown in blue at right, bound to the amino group (HN–) of a lysine residue in the trastuzumab molecule (–mab).

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.

External links

• Official U.S. website for Kadcycla