Kadcyla (ado-trastuzumab emtansine) was recently approved for the treatment of breast cancer. It is targeted against HER2. HER2, a protein which drives normal cell growth, is found in different cancer types, including breast cancers. Kadcyla is a compound drug. Kadcyla, previously called T-DM1, is trastuzumab connected to a drug called DM1 that interferes with cancer cell growth.
The approval was based on the EMILIA study. The EMILIA study involving 991 patients who were randomly assigned into two groups:
The Kadcyla group
The lapatinib plus capecitabine group (capecitabine is also a chemotherapy drug)
The trial results showed that:
Those in the Kadcyla group survived progression-free for 9.6 months whereas those in the lapatinib plus capecitabine group survived 6.4 months progression-free. Patients in the Kadcyla group had a median overall survival of 30.9 months while In the lapatinib plus capecitabine group, median overall survival was 25.1 months.
Because the HER2 receptor is expressed so widely in other cancers and not only breast, the temptation is to use it whenever HER expression is found. However, all recommendations to use a drug outside of its indication should be based on clinical studies. It is not an innocuous drug, and gastrointestinal effects, such as vomiting, diarrhea, and stomatitis, were more common than with lapatinib/capecitabine. Kadcyla carries black box warnings for liver toxicity, heart damage (reduction in left ventricular ejection fraction), and fetal harm if given to pregnant women.
However, in the most recent trial, Kadcyla dissapointed.
Results of the anticipated phase III MARIANNE trial found that HER2-positive metastatic breast cancer patients treated with ado-trastuzumab emtansine (T-DM1) plus pertuzumab had similar progression-free survival (PFS) compared with those treated with trastuzumab plus a taxane-based chemotherapy.
Though the trial met its noninferiority endpoint, showing a similar PFS in the first-line setting between the two combination therapies along with T-DM1 alone, it failed to demonstrate that T-DM1 performs better than trastuzumab plus chemotherapy.
The trial randomized 1,095 patients 1:1:1 to three treatment arms. The primary endpoint was PFS. Secondary endpoints included overall survival, response rate, and the incidence of adverse events. Each of the T-DM1 treatment arms—either with placebo or pertuzumab—were compared with trastuzumab plus either docetaxel or paclitaxel.
(ado-trastuzumab emtansine) for Injection
HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY
- Do Not Substitute KADCYLA for or with trastuzumab (see DOSAGE AND ADMINISTRATION).
- Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin (see DOSAGE AND ADMINISTRATIONand WARNINGS AND PRECAUTIONS).
- Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function (see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS.
- Embryo-Fetal Toxicity: Exposure to KADCYLA during pregnancy can result in embryo-fetal harm. Advise patients of these risks and the need for effective contraception. (see WARNINGS AND PRECAUTIONS and Use in Specific Populations)
KADCYLA (ado-trastuzumab emtansine) is a HER2-targeted antibody-drug conjugate (ADC) which contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitory drug DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). Emtansine refers to the MCC-DM1 complex.
The antibody trastuzumab, is a well characterized recombinant monoclonal antibody product produced by mammalian (Chinese hamster ovary) cells, and the small molecule components (DM1 and MCC) are produced by chemical synthesis. Ado-trastuzumab emtansine contains an average of 3.5 DM1 molecules per antibody. Ado-trastuzumab emtansine has the following chemical structure:
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.
One question remains: When they came up with this name, did they think of Godzila? Does size matter?
Gianni L, et al. Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. N Engl J Med. 2012; 367(19):1783-91.
Niculescu-Duvaz I (June 2010). “Trastuzumab emtansine, an antibody-drug conjugate for the treatment of HER2+ metastatic breast cancer”. Curr. Opin. Mol. Ther. 12 (3): 35060.
Kadcyla, Prescribing Information, 2015
For Lay version see here