Trastuzumab Emtansine

Metastatic Breast Cancer (MBC): Trastuzumab Emtansine, as a single agent, is indicated for the treatment of patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who have received prior treatment with trastuzumab and a taxane.

Trastuzumab Emtansine is a HER2-targeted antibody-drug conjugate 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. An average of 3.5 DM1 molecules are conjugated to each molecule of trastuzumab.

Conjugation of DM1 to trastuzumab confers selectivity of the cytotoxic agent for HER2-overexpressing tumor cells, thereby increasing intracellular delivery of DM1 directly to malignant cells. Upon binding to HER2, trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in release of DM1-containing cytotoxic catabolites (primarily lysine-MCC-DM1).

Trastuzumab Emtansine has the mechanisms of action of both trastuzumab and DM1.

Trastuzumab emtansine, like trastuzumab, binds to domain IV of the HER2 extracellular domain (ECD), as well as to Fcγ receptors and complement C1q. In addition, Trastuzumab Emtansine, like trastuzumab, inhibits shedding of the HER2 ECD, inhibits signaling through the phosphatidylinositol 3-kinase (PI3-K) pathway, and mediates antibody-dependent cell-mediated cytotoxicity (ADCC) in human breast cancer cells that overexpress HER2.

DM1, the cytotoxic drug component of Trastuzumab Emtansine, binds to tubulin. By inhibiting tubulin polymerization, both DM1 and Trastuzumab Emtansine cause cells to arrest in the G2/M phase of the cell cycle, ultimately leading to apoptotic cell death. Results from in vitro cytotoxicity assays show that DM1 is 20–200 times more potent than taxanes and vinca alkaloids.

The MCC linker is designed to limit systemic release and increase targeted delivery of DM1, as demonstrated by detection of very low levels of free DM1 in plasma.

Recommended Doses And Schedules: The recommended dose of Trastuzumab Emtansine is 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. Do not administer Trastuzumab Emtansine at doses greater than 3.6 mg/kg. Do not substitute Trastuzumab Emtansine for or with trastuzumab. Closely monitor the infusion site for possible subcutaneous infiltration during drug administration

First Infusion: Administer infusion over 90 minutes. Patients should be observed during the infusion and for at least 90 minutes following the initial dose for fever, chills, or other infusionrelated reactions 

Subsequent Infusions: Administer over 30 minutes if prior infusions were well tolerated. Patients should be observed during the infusion and for at least 30 minutes after infusion.

No formal drug-drug interaction studies with trastuzumab emtansine in humans have been conducted. In vitro metabolism studies in human liver microsomes suggest that DM1, a component of trastuzumab emtansine, is metabolized mainly by CYP3A4 and, to a lesser extent, by CYP3A5. DM1 does not induce or inhibit P450-mediated metabolism in vitro. Caution should be taken when trastuzumab emtansine is co-administered with potent CYP3A inhibitors.

Trastuzumab Emtansine is contraindicated in patients with a known hypersensitivity to Trastuzumab Emtansine or any of its excipients.

Pregnancy: There are no clinical studies of trastuzumab emtansine in pregnant women. No reproductive and developmental toxicology studies have been conducted with trastuzumab emtansine.

Trastuzumab, a component of trastuzumab emtansine, can cause fetal harm or death when administered to a pregnant woman. In the postmarketing setting, cases of oligohydramnios, some associated with fatal pulmonary hypoplasia, have been reported in pregnant women receiving trastuzumab. Animal studies of maytansine, a closely related chemical entity of the same maytansinoid class as DM1, suggest that DM1, the microtubule inhibiting cytotoxic drug component of trastuzumab emtansine, is expected to be teratogenic and potentially embryotoxic.

Administration of trastuzumab emtansine to pregnant women is not recommended. Women who become pregnant must contact their doctor and should be advised of the possibility of harm to the fetus. If a pregnant woman is treated with trastuzumab emtansine, close monitoring by a multidisciplinary team is recommended.

Nursing Mothers: It is not known whether trastuzumab emtansine is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Kadcyla, women should discontinue nursing prior to initiating treatment with trastuzumab emtansine. Women may begin nursing 7 months after concluding treatment.

Patients treated with Trastuzumab Emtansine must have confirmed HER2-positive tumor status as assessed by either HER2 protein overexpression or gene amplification.

Anti neoplastic preparations.

Pediatric Use: The safety and efficacy of Trastuzumab Emtansine in children below 18 years of age have not been established.

Geriatric Use: There are insufficient data to establish the safety and efficacy of Trastuzumab Emtansine in patients 75 years of age or older.

Store vials at 2°C-8°C.