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| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Humanized (frommouse) |
| Clinical data | |
| Trade names | Kadcyla |
| Other names | ado-trastuzumab emtansine, trastuzumab-DM1, T-DM1 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a613031 |
| License data | |
| Pregnancy category | |
| Routes of administration | Intravenous infusion |
| Drug class | Antineoplastic agent |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | N/A |
| Protein binding | 93% (in vitro) |
| Metabolism | Liver (CYP3A4/3A5-mediated) |
| Eliminationhalf-life | 4 days |
| Identifiers | |
| CAS Number | |
| PubChem SID | |
| DrugBank |
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| ChemSpider |
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| UNII | |
| KEGG |
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| ChEMBL | |
| Chemical and physical data | |
| Formula | C6448H9948N1720O2012S44·(C47H62ClN4O13S)n[citation needed] |
| Molar mass | 148.5 kg/mol[citation needed] |
 N Y (what is this?) (verify) | |
Trastuzumab emtansine,[6][7] sold under the brand nameKadcyla, is anantibody-drug conjugate consisting of the humanizedmonoclonal antibodytrastuzumab (Herceptin) covalently linked to thecytotoxic agentDM1.[8][9][10][11] Trastuzumab alone stops growth of cancer cells by binding to theHER2 receptor, whereas trastuzumab emtansine undergoes receptor-mediated internalization into cells, is catabolized in lysosomes where DM1-containing catabolites are released and subsequently bindtubulin to cause mitotic arrest and cell death.[12] Trastuzumab binding to HER2 prevents homodimerization or heterodimerization (HER2/HER3) of the receptor, ultimately inhibiting the activation ofMAPK andPI3K/AKT cellular signalling pathways. Because the monoclonal antibody targets HER2, and HER2 is only over-expressed in cancer cells, the conjugate delivers the cytotoxic agent DM1 specifically to tumor cells.[13] The conjugate is abbreviatedT-DM1.
In the EMILIA clinical trial[14] of women with advancedHER2 positivebreast cancer who were already resistant to trastuzumab alone, it improved medianoverall survival by 5.8 months (30.9 months vs. 25.1 months) compared to the combination oflapatinib andcapecitabine.[13] Based on that trial, the U.S.Food and Drug Administration (FDA) approved marketing on 22 February 2013.[15][16][17]
Trastuzumab emtansine was developed byGenentech, and is manufactured byLonza.[18]
In the United States, trastuzumab emtansine was approved specifically for treatment of HER2-positivemetastatic breast cancer (mBC) in patients who have been treated previously with trastuzumab and ataxane (paclitaxel ordocetaxel), and who have already been treated for mBC or developed tumorrecurrence within six months ofadjuvant therapy.[19][4]
Approval was based on the EMILIA study,[14] a phase IIIclinical trial that compared trastuzumab emtansine versuscapecitabine (Xeloda) pluslapatinib (Tykerb) in 991 people with unresectable, locally advanced or metastatic HER2-positive breast cancer who had previously been treated with trastuzumab and taxanechemotherapy.[14] This trial showed improvedprogression-free survival in patients treated with trastuzumab emtansine (median 9.6 vs. 6.4 months), along with improvedoverall survival (median 30.9 vs. 25.1 months) and safety.[13]
During clinical trials, the most commonadverse effects of trastuzumab emtansine were fatigue, nausea, musculoskeletal pain,thrombocytopenia (lowplatelet counts), headache,increased liver enzyme levels, and constipation.[4]
Severe adverse events identified during the EMILIA trial includedhepatotoxicity (liver damage), including rare cases ofliver failure,hepatic encephalopathy, andnodular regenerative hyperplasia; heart damage (dysfunction of theleft ventricle);interstitial lung disease, includingacute interstitial pneumonitis; thrombocytopenia; andperipheral neuropathy.[4] Overall, trastuzumab emtansine was better tolerated than the control treatment, a combination oflapatinib (Tykerb) andcapecitabine (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.[4]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, andstomatitis, were more common with lapatinib/capecitabine.[4]
In the United States, trastuzumab emtansine carriesblack box warnings for liver toxicity, heart damage (reduction in left ventricularejection fraction), andfetal harm if given to pregnant women.[4][17]
Trastuzumab emtansine is anantibody-drug conjugate (ADC), a combination between amonoclonal antibody and asmall-molecule drug. Each molecule of trastuzumab emtansine consists of a single trastuzumab molecule with several molecules of DM1, acytotoxicmaytansinoid, attached.[20] SMCC, or succinimidyltrans-4-(maleimidylmethyl)cyclohexane-1-carboxylate, is aheterobifunctional crosslinker, a type ofchemical reagent that contains two reactivefunctional groups, asuccinimideester and amaleimide. The succinimide group of SMCC reacts with the freeamino group of alysine residue in the trastuzumab molecule[failed verification] and the maleimide moiety of SMCC links to the free sulfhydryl group of DM1, forming acovalent bond between the antibody and the DM1. Each trastuzumab molecule may be linked to zero to eight DM1 molecules (3.5 on average).[20][21] DM1 binds at plus ends of cellularmicrotubules and thereby inhibitscell division in the target tumor cells.[22]
In 2013, trastuzumab emtansine was approved in the United States for the treatment of adults with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination.[17][19]
Referred to as T-DM1 during clinical research, trastuzumab emtansine was reviewed under the FDA'spriority review program.[17]
The safety and effectiveness of trastuzumab emtansine were evaluated in a clinical study of 991 patients randomly assigned to receive trastuzumab emtansine or lapatinib plus capecitabine, another chemotherapy drug.[17] Patients received treatment until either the cancer progressed or the side effects became intolerable.[17] The study was designed to measure progression-free survival, the length of time patients lived without the cancer progressing, and overall survival, the length of time patients lived before death.[17]
Results showed that patients treated with trastuzumab emtansine had a median progression-free survival of 9.6 months compared to 6.4 months in patients treated with lapatinib plus capecitabine.[17] The median overall survival was 30.9 months in the trastuzumab emtansine group and 25.1 months in the lapatinib plus capecitabine group.[17]
The U.S.Food and Drug Administration (FDA) approved trastuzumab emtansine in February 2013, and granted the application for Kadcyla to Genentech.[17] The FDA granted the application for trastuzumab emtansinepriority review andbreakthrough therapy designations.[23]
In 2013, trastuzumab emtansine was approved in the UK,[3] and the EU.[5]
In 2019, trastuzumab emtansine was approved in the United States 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.[23]
Approval was based on KATHERINE (NCT01772472[24]), a randomized, multicenter, open-label trial of 1486 patients with HER2-positive EBC.[23] Breast tumor samples were required to demonstrate HER2 overexpression defined as 3+ IHC or ISH amplification ratio ≥ 2.0 determined at a central laboratory using Ventana's PATHWAY anti-HER2-/neu (4B5) Rabbit Monoclonal Primary Antibody or INFORM HER2 Dual ISH DNA Probe Cocktail assays.[23] Patients were required to have had neoadjuvant taxane and trastuzumab-based therapy with residual invasive tumor in the breast and/or axillary lymph nodes.[23] Patients received radiotherapy and/or hormonal therapy concurrent with study treatment per local guidelines.[23] Patients were randomized (1:1) to receive trastuzumab emtansine 3.6 mg/kg intravenously or trastuzumab 6 mg/kg intravenously on day 1 of a 21-day cycle for 14 cycles.[23]
The trial's primary endpoint was invasive disease-free survival (IDFS), defined as the time from the date of randomization to first occurrence of ipsilateral invasive breast tumor recurrence, ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause.[23] After a median follow-up of 40 months, the trial demonstrated a statistically significant improvement in IDFS in patients who received trastuzumab emtansine compared with those who received trastuzumab (HR 0.50; 95% CI: 0.39, 0.64; p<0.0001).[23] Overall survival data were not mature at the time of the IDFS analysis.[23]
In the UK, trastuzumab emtansine was not recommended for use by theNational Health Service by advisory bodyNICE, reportedly because an acceptable pricing agreement could not be reached withRoche.[25] Originally it cost £5,900 a month.[26] and NICE estimated it cost £166,000 perQALY[27] (well over the usual maximum). It has been funded by the English NHSCancer Drugs Fund but in January 2015 it was proposed to remove it from the approved list.[28] After a secret discount was agreed by Roche the Cancer Drugs Fund will continue to fund it.[26]
In June 2017, the NHS Confederation and NHS Chief Executive Simon Stevens announced that the NHS would be offering trastuzumab emtansine to a limited number of women after striking a deal with Roche on the price.[29]
In 2013, trastuzumab emtansine was approved in the United States with the generic name "ado-trastuzumab emtansine",[17][19] rather than the originalUnited States Adopted Name (USAN) issued in 2009, "trastuzumab emtansine".[19] Trastuzumab is the anti-HER2 antibody; emtansine refers to the linker-drug (SMCC-DM1). The "ado-" prefix was added at the request of the FDA to help preventdispensing errors.[30][19][31] Duringpreclinical development and clinical trials, the drug was also known as trastuzumab-DM1 or trastuzumab-MCC-DM1 (after the codename foremtansine), both abbreviated T-DM1, and by the codename PRO132365.[10]
Since 2013 there have been some more clinical trials:
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