ado-trastuzumab emtansine - Kadcyla; trastuzumab-DM1; T-DM1; trastuzumab-MCC-DM1; herceptin-DM1 conjuagate
Status: BLA approved in Feb. 2013; MAA approved in Sept. 2013
Organizations involved:
Genentech/Roche – Manuf.; R&D; Tech.; World mark.
Immunogen Inc. - R&D; Tech.
Cross ref.: See the entry for Herceptin, with this product involving the Herceptin active monoclonal antibody linked to a cytotoxin.
Description: Kadcyla is a lyophilized (freeze-dried) formulation of trastuzumab-DM1, an immunotoxin or antibody-drug conjugate (ADC), an antibody linked to a cytotoxin, composed of a recombinant humanized (chimeric human-mouse) IgG1k (IgG1-kappa) monoclonal antibody glycoprotein (trastuzumab) produced by a transformed Chinese hamster ovary (CHO) cell line covalently conjugated to DM1, a semisynthetic maytansinoid antimitotic drug, via a nonreducible thioether (4-[N-maleimidomethyl] cyclohexane-1-carboxylate) (MCC) linkage. Thus, it is essentially the active agent in Herceptin, trastuzumab, linked to DM-1. Emtansine refers to the MCC-DM1
complex. Ado-trastuzumab emtansine contains an average of 3.5 DM1 molecules per antibody.
KADCYLA (ado-trastuzumab emtansine) is a sterile, white to off-white preservative free
lyophilized powder in single-use vials. Each vial contains 100 mg or 160 mg ado-trastuzumab
emtansine. Following reconstitution, each single-use vial contains ado-trastuzumab emtansine
(20 mg/mL), polysorbate 20 [0.02% (w/v)], sodium succinate (10 mM), and sucrose [6% (w/v)]
with a pH of 5.0 and density of 1.026 g/mL. The resulting solution containing 20 mg/mL adotrastuzumab
emtansine is administered by intravenous infusion following dilution. Vials are stored in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of reconstitution.
Biological.: The trastuzumab moiety binds to HER2 on tumor cell surface surfaces. T-DM1 involves trastuzumab and the chemotherapy DM1 attached together using a stable linker, which is designed to keep T-DM1 in one piece until it reaches specific cancer cells. Upon internalization into HER2+ cells (tumor cells), the DM1 moiety is released and binds to tubulin, disrupting microtubule assembly/disassembly dynamics and inhibiting cell division and the proliferation of cancer cells that overexpress HER2.
DM-1 and other maytansinoids are derivatives of the antimitotic drug maytansine. These agents bind directly to microtubules in a manner similar to the Vinca alkaloids, including those commonly used as chemotherapy drugs.
Biological,/B>: Ado-trastuzumab emtansine is a HER2-targeted antibody-drug conjugate. The antibody is the
humanized anti-HER2 IgG1, trastuzumab. The small molecule cytotoxin, DM1, is a microtubule
inhibitor. Upon binding to sub-domain IV of the HER2 receptor, ado-trastuzumab emtansine
undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in
intracellular release of DM1-containing cytotoxic catabolites. Binding of DM1 to tubulin
disrupts microtubule networks in the cell, which results in cell cycle arrest and apoptotic cell
death. In addition, in vitro studies have shown that similar to trastuzumab, ado-trastuzumab
emtansine inhibits HER2 receptor signaling, mediates antibody-dependent cell-mediated
cytotoxicity and inhibits shedding of the HER2 extracellular domain in human breast cancer cells
that overexpress HER2.
Nomenclature: HER2 receptor Mab-DM1, rDNA [BIO]; Kadcyla [TR]; ado-trastuzumab emtansine [FDA]; trastuzumab-DM1 [SY]; trastuzumab-MCC-DM1 [SY];
T-DM1 [SY]; trastuzumab-MCC-DM1 [SY]; herceptin-DM1 conjuagate [SY]; NDC 50242-088-01;NDC 50242-087-01 [NDC]
Note, ado-trastuzumab emtansine is the USAN assigned in 2009. However, FDA selected ado-trastuzumab emtansine, presuambly to further differentiate Kadcyla from Herceptin (trastuzumab).
Companies.: T-DM1 which was developed by Genentech and Immunogen Inc. Genentech manufactures T-DM1.
FDA approval of Kadcyla triggered a $10.5 million milestone payment to ImmunoGen, which also earns royalties on commercial sales of Kadcyla.
The product insert eports manufacture by Genentech, CBER/FDA lic. no. 1048.
FDA class: Biologic BLA
Indications: [full text of the "INDICATIONS AND USAGE" of the product insert, 8/2013]:
Status: On July 6, 2010, Genentech/Roche filed a BLA seeking accelerated approval of treatment of advanced HER2-positive breast cancer in patients having previously received multiple HER2-targeted medicines and chemotherapies (third-line therapy). This was based on the results of a single-arm Phase II study, which showed T-DM1 shrank tumors in one-third of women with advanced HER2-positive breast cancer, who had received on average seven prior medicines, including two HER2-targeted medicines.
On Aug. 27, 2010, FDA sent Genentech a Refuse to File letter. In its review of the BLA, the FDA stated the T-DM1 trials did not meet the standard for accelerated approval, because all available treatment choices approved for metastatic breast cancer, regardless of HER2 status, had not been exhausted in the study population.
Genentech expected to submit data from the amended Phase III randomized EMILIA study to the FDA to support a new T-DM1 BLA in mid-late 2012..
In Nov. 2012, FDA granted granted priority review status and assigned a PDUFA (target) date of Feb. 26, 2013 to the BLA filed by Novo Nordisk.
On Sept. 20, 2013, EMA recommended EU approval. Full approval was granted on Nov. 21, 2013.
Tech. transfer: In 2000, Immunogen granted Genentech the exclusive right to its maytansinoid TAP technology (such as DM1 and DM4) with antibodies that target HER2, including trastuzumab. Technologies licensed by Genentech include Immunogen's linker and methods for conjugation.
Essentially all of the patents and patent disputes concerning Herceptin can be assumed to be relevant to T-DM1.
Medical:
In the U.S., a boxed warning in the product insest warns of liver toxicity, heart toxicity and death. Kadcyla can also cause severe life-threatening birth defects, and pregnancy status should be verified prior to starting Kadcyla treatment.
The recommended dose of KADCYLA is 3.6 mg/kg given as an
intravenous infusion every 3 weeks (21-day cycle) until disease
progression or unacceptable toxicity.
Trials: The orignal BLA filing was based on the results of a Phase II study, which showed that T-DM1 shrank tumors in one-third of women who had received on average seven prior medicines for advanced HER2-positive breast cancer.
Upon BLA submission, patient enrollment was reported to be on track in the Phase III trial (EMILIA) evaluating T-DM1 for 2nd-line use. This 580-patient randomized trial began in February 2009 and compares T-DM1 – used as a single agent – to Tykerb (lapatinib) plus Xeloda (capecitabine). A Phase III 1st-line trial (MARIANNE) was planned to begin in mid-2010. A Phase II trial evaluating T-DM1 for this use has completed patient enrollment, with interim data expected to be reported in Oct. 2010. This trial compares T-DM1, given as a single agent, to Herceptin (trastuzumab) plus Taxotere (docetaxel). T rials to evaluate T-DM1 for early stage HER2+ breast cancer (adjuvant use) are being considered.
On March 29, 2012, topline results of EMILIA, the first randomized Phase III study of trastuzumab emtansine (T-DM1), were reported. The study enrolled people with HER2-positive metastatic breast cancer (mBC) who had previously received treatment with Herceptin (trastuzumab) and a taxane chemotherapy. EMILIA (TDM4370g/BO21977) was an international, Phase III, randomized, open-label study comparing trastuzumab emtansine alone to lapatinib in combination with Xeloda in 991 people with HER2-positive mBC whose disease progressed after initial treatment with Herceptin and a taxane chemotherapy. Participants in the trastuzumab emtansine arm received Trastuzumab emtansine 3.6 mg/kg every three weeks. Participants in the lapatinib and Xeloda arm received: Lapatinib 1250 mg daily and Xeloda 2000 mg/m2, days 1 – 14, every three weeks. The co-primary efficacy endpoints of the study were PFS (as assessed by an independent review committee) and OS. Other study endpoints included safety profile, one-year and two-year survival rates, PFS as assessed by investigator, overall response rate, duration of response and quality of life. The study showed patients who received trastuzumab emtansine lived significantly longer without their disease had worse (progression-free survival, or PFS) compared to those who received lapatinib plus Xeloda® (capecitabine). Final results for overall survival (OS), a co-primary efficacy endpoint of EMILIA, were not disclosed. The safety profile of trastuzumab emtansine was consistent with that seen in previous studies.
Roche later reported a 32% reduction in the risk of death among patients in the pivotal Phase III study when compared to the standard-of-care arm. The median overall survival rate for T-DM1 patients was an impressive 30.9 months, while patients taking a combination of Tykerb and Xeloda achieved a 25.1-month OS rate. Also, fewer people who received Kadcyla experienced severe side effects compared to those receiving standard therapy (40.8 percent vs. 57.0 percent)
FDA initial approval included use in front-line HER-2 positive metastatic breast cancer (mBC)." This was based on the EMILIA trial including about 12% front-line mBC patients (about 60 1st-line mBC patients in the T-DM1 arm of the EMILIA trial).
KADCYLA was evaluated as single-agent in 884 patients with HER2-positive metastatic breast cancer. The most common (frequency ≥ 25%) adverse drug reactions (ADRs) seen in 884 patients treated with KADCYLA were fatigue, nausea, musculoskeletal
pain, thrombocytopenia, headache, increased transaminases, and constipation.
Market: Peak sales projections, based on expectations for approvals, are as high as $2-$5 billion/year.
Kadcyla costS $9,800 a month ,m(compared to the $4,500 for Herceptin),or about $94,000 for a 9.5-month course of therapy (in the U.S.).
Kadcyla is the 4th pharmaceutical targeting the Her receptor.
In April 2014, the U.K. National Institute for Health and Care Excellence (NICE) rejected NHS use of Kadcycla because the £90,000 per patient cost was considered far more than any comparable treatment. However, Kadcyla was already being paid for through the dedicated Cancer Drugs Fund set up by the
government. The Cancer Drugs Fund (CDF) provides
an additional £200m each year to enable patients to access drugs that are
not routinely funded by the NHS. So, some UK patients may receive the Kadcyla subsidized by the CDF.
Companies involvement:
Full monograph
179.1 HER2 receptor Mab-DM1, rDNA
KADCYLA™, as a single agent, is indicated for the treatment of patients with HER2-positive,
metastatic breast cancer who previously received trastuzumab and a taxane, separately or in
combination. Patients should have either:
Received prior therapy for metastatic disease, or
Developed disease recurrence during or within six months of completing adjuvant
therapy.
Nomenclature:
HER2 receptor Mab-DM1, rDNA [BIO]
ado-trastuzumab emtansine [FDA]
trastuzumab emtansine [USAN granted in 2009]
Kadcyla [TR]
trastuzumab-DM1 [SY]
trastuzumab-MCC-DM1 [SY]
T-DM1 [SY]
herceptin-DM1 conjuagate [SY]
NDC 50242-088-01;NDC 50242-087-01 [NDC]
FDA Class: Biologic BLA
Year of approval (FDA) = 2013
Date of 1st FDA approval = 20130222
(in format YYYYMMDD)
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
biopharmaceutical products
conjugates
exempt from CBER lot release requirements
hamster source materials
immunotoxins
monoclonal antibodies, recombinant
murine (mouse) materials used
recombinant DNA
4D5 murine hybridoma cells
4D5 murine hybridoma cells
Chinese hamster ovary (CHO) cells
glutamine synthetase (GS) expression system
mammalian cell culture
rodent cells <!-- rodentcells -->
suspension cell culture
C-127 (C127) murine tumor cells
divinyl sulfone (DVS)
lyophilized (freeze-dried)
thiocyanate
thiocyanate
transplants (see also rejection)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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