|Source||Humanized (from mouse)|
|Pregnancy cat.||D (US)|
|Legal status||℞-only (US)|
|Protein binding||93% (in vitro)|
|Mol. mass||148.5 kDa|
|(what is this?)|
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 mertansine (DM1). Trastuzumab alone stops growth of cancer cells by binding to the HER2/neu receptor, whereas mertansine enters cells and destroys them by binding to tubulin. Because the monoclonal antibody targets HER2, and HER2 is only over-expressed in cancer cells, the conjugate delivers the toxin specifically to tumor cells.
In the EMILIA clinical trial of women with advanced HER2 positive breast cancer who were already resistant to trastuzumab alone, it improved survival by 5.8 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.
In the United States, trastuzumab emtansine (T-DM1) 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.
As of 2013[update], several clinical studies of trastuzumab emtansine for other indications are planned or ongoing:
- 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;
- 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.
- a phase III trial for HER2+ gastric cancer compares T-DM1 to physician's choice of taxane (docetaxel or paclitaxel).
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 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 (after the codename for mertansine) or trastuzumab-MCC-DM1 (after the codename for emtansine), both abbreviated T-DM1, and by the codename PRO132365.
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 bound to several molecules of mertansine, a cytotoxic maytansinoid containing a sulfhydryl group, through a crosslinking reagent known as SMCC. 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 mertansine, forming a covalent bond between the antibody and mertansine. Each trastuzumab molecule may be linked to zero to eight mertansine molecules (3.5 on average).
Several other linker structures were tested during preclinical development, all containing disulfide bonds, which can undergo reduction within the body, separating the antibody from the maytansinoid and releasing the latter into the circulation. The SMCC linker forms a thioether bond instead of a disulfide bond, and is thus nonreducible (cannot undergo cleavage by reduction within the cell). The fact that mertansine is only released after the antibody-drug conjugate has been taken up by a tumor cell reduces toxic effects while maintaining antitumor efficacy. Indeed, trastuzumab-MCC-DM1 was found to have better efficacy and pharmacokinetics and less toxicity than conjugates built with other linkers, and was thus selected for further development as trastuzumab emtansine.
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