Resources for For Clinicians
The information on this page is limited to commercially available antibody-drug conjugates (ADCs) approved by the U.S. Food and Drug Administration (FDA) and intended for healthcare professionals (HCP) only. If you are not a U.S. healthcare professional, do not continue on this page.
| Always check the full Prescribing Information for additional Important Safety Information, including BOXED WARNINGS. Do not confuse ado-trastuzumab emtansine (Kadcyla®) with trastuzumab (Herceptin®). |
| International Nonproprietary Names (INN) | Ado-trastuzumab emtansine |
| Prescription Drug | Yes |
| Class | Antineoplastic Agents |
| US Brand Name | Kadcyla® |
| Other names | ado-trastuzumab emtansine, trastuzumab-DM1, T-DM1 |
| Available as a generic drug | No |
| Marketing Authorization | Genentech/Roche |
| United States Adopted Name (USAN) | Trastuzumab emtansine |
| FDA Approved | Yes |
| Initial U.S. Approval | February 22, 2013 |
| Indication | HER2-positive, metastatic breast and HER2-positive early breast cancer |
| Supplied as | NDC |
| One 100 mg vial, single-use vial | NDC 50242-088-01 |
| One 160 mg vial, single-use vial | NDC 50242-087-01 |
| Pregnancy Category | N (Not classified yet) |
| Route of Administration | Intravenous infusion |
| Biologic License Application (BLA) | 125427 |
General Description
Ado-trastuzumab emtansine also known as T-DM1 (Kadcyla®; Genentech/Roche) is a cancer medicine that contains the active substance trastuzumab emtansine. The agent is approved as a single agent in over 100 countries, including the United States and Europe (EMA) and is used to treat advanced or metastatic breast cancer in adults who previously received trastuzumab and a taxane.
Ado-trastuzumab emtansine is also used for the adjuvant treatment of patients with human epidermal growth factor 2 (HER2-) positive early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.
When to use?
Ado-trastuzumab emtansine can only be used when the cancer has been shown to ‘overexpress HER2’: this means that the cancer cell produces on its surface large quantities of a protein which stimulates the growth of the cancer cell and is called HER2.
Patients for therapy should be selected based on an US Food and drug Administration (FDA-) approved companion diagnostic for ado-trastuzumab emtansine.
What is ado-trastuzumab emtansine
Ado-trastuzumab emtansine is an antibody-drug conjugate engineered to deliver potent chemotherapy directly to HER2-positive cancer cells, potentially limiting damage to healthy tissues. It combines two anti-cancer properties joined together by a stable linker: the HER2-targeting properties of the humanized anti-HER2 IgG1 (antibody) trastuzumab linked to the anti-mitotic agent mertansine (a maytansine derivative; also known as the maytansinoid DM1).
The antibody-drug conjugate combines two strategies: the anti-HER2 activity of trastuzumab, and the targeted intracellular delivery of mertansine, a tubulin polymerisation inhibitor that interferes with mitosis and promotes apoptosis.
The linker in trastuzumab emtansine is a non-reducible thioether linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC, designated MCC after conjugation). Emtansine refers to the MCC-DM1 complex.
Trastuzumab is a well-characterized recombinant monoclonal antibody produced by mammalian (Chinese Hamster Ovary/CHO) cells. The small molecule cytotoxin, DM1, a microtubule inhibitor, and MCC linker are produced by chemical synthesis. Ado-trastuzumab emtansine contains an average drug-to-antibody ratio (DAR) of 3.5 DM1 molecules per antibody.
Appearance
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 ado-trastuzumab emtansine is administered by intravenous infusion following dilution.
| Click on the link to download the complete Full Prescribing Information for additional Important Safety Information, including BOXED WARNINGS. |
Logistics
Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of reconstitution. Do not freeze or shake.
Special Handling
Follow procedures for proper handling and disposal of anticancer drugs.
Clinical Pharmacology
Mechanism of Action The antibody used in ado-trastuzumab emtansine is the humanized anti-HER2 IgG1, trastuzumab which is conjugated to a 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 the intracellular release of DM1-containing cytotoxic catabolites. The 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.
Pharmacokinetics
The pharmacokinetics of ado-trastuzumab emtansine was evaluated in a phase I study and in a population pharmacokinetic analysis for the ado-trastuzumab emtansine conjugate (ADC) using pooled data from 5 trials in patients with breast cancer. A linear two-compartment model with first-order elimination from the central compartment adequately describes the ADC concentration-time profile. In addition to the ADC, the pharmacokinetics of total antibody (conjugated and unconjugated trastuzumab), DM1 were also determined.
Additional Information
Mechanism of Action
What is ado-trastuzumab emtansine made of
The active substance of ado-trastuzumab emtansine, is made up of two active components which are linked together:
- Trastuzumab, a monoclonal antibody (a type of protein) that has been designed to recognize and attach to the protein HER2, which is found in large quantities on the surface of some cancer cells. By attaching to HER2, trastuzumab activates cells of the immune system, which then kill the cancer cells. Trastuzumab also stops HER2 from stimulating the growth of the cancer cells. About a quarter of breast cancers overexpress HER2.
- DM1, a toxic substance that kills cells when they attempt to divide and grow. DM1 becomes active once Kadcyla enters the cancer cell. It attaches to a protein in cells called ‘tubulin’, which is important in the formation of the internal ‘skeleton’ that cells need to assemble when they divide. By attaching to tubulin in cancer cells, DM1 stops the formation of this skeleton, preventing the division and growth of the cancer cells.
The cytotoxic effect of ado-trastuzumab emtansine varies depending on the intracellular concentration of DM1 accumulated in cancer cells, high intracellular levels resulting in rapid apoptosis, somewhat lower levels in impaired cellular trafficking and mitotic catastrophe, while the lowest levels lead to poor response to ado-trastuzumab emtansine.[2]
Binding of ado-trastuzumab emtansine to the extracellular domain of HER2 triggers entry of the antibody-drug conjugate complex into cancer cells via receptor-mediated endocytosis [3]. A high rate of internalization may result in high intracellular concentrations of DM1, and deceleration of the endocytosis rate might cause loss of sensitivity to ado-trastuzumab emtansine. [4]
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.
Approval and Indication of Usage
Ado-trastuzumab emtansine can only be obtained with a prescription and treatment should be prescribed by a doctor and given under the supervision of a healthcare professional who is experienced in the treatment of cancer patients.
Ado-trastuzumab emtansine is as a single agent, second-line mono therapy, for the treatment of patients with HER2+ metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients:
- Received prior therapy for metastatic disease, or
- Developed disease recurrence during or within six months of completing adjuvant therapy.
HER2+ metastatic breast cancer Over-expression or amplification of HER2 occurs in approximately 20% of breast cancers and is associated with more aggressive tumors and poorer prognosis in the absence of treatment. Although effective therapies for the initial management of HER2-positive metastatic breast cancer (MBC) exist, many patients will experience disease progression.
Patient selection
It is recommended to select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens. Assessment of HER2 protein overexpression and/or HER2 gene amplification should be performed using an FDA-approved companion diagnostic (tests) for breast cancer, specifically for the detection of HER2 protein overexpression and HER2 gene amplification by laboratories with demonstrated proficiency.*
Recommended Dosage, Administration, and Schedules
Ado-trastuzumab emtansine is for intravenous infusion only. Do not administer as an intravenous push or bolus. Do not use Dextrose (5%) solution.
The recommended dose of ado-trastuzumab emtansine is 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle; Q3W) until disease progression or unacceptable toxicity. Do not administer ado-trastuzumab emtansine at doses greater than 3.6 mg/kg.
Do not substitute ado-trastuzumab emtansine for or with trastuzumab.
- First infusion
- Administer infusion over 90 minutes. Physicians should observe patients during the infusion and for at least 90 minutes following the initial dose for fever, chills, or other infusion-related reactions
- Subsequent infusions
- Administer over 30 minutes if prior infusions were well tolerated. Observe patients during the infusion and for at least 30 minutes after infusion.
- In the treatment of patients with Metastatic Breast Cancer (MBC), patients should receive treatment until disease progression or unmanageable toxicity.
- In the treatment of patients with Early Breast Cancer (EBC), patients should receive treatment for a total of 14 cycles unless there is disease recurrence or unmanageable toxicity.
- Administer over 30 minutes if prior infusions were well tolerated. Observe patients during the infusion and for at least 30 minutes after infusion.
Do not re-escalate the ado-trastuzumab emtansine dose after a dose reduction is made.
- If a planned dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle. Adjust the schedule of administration to maintain a 3-week interval between doses. Administer the infusion at the dose and rate the patient tolerated in the most recent infusion.
- Slow or interrupt the infusion rate of ado-trastuzumab emtansine if the patient develops an infusion-related reaction. Permanently discontinue ado-trastuzumab emtansine for life-threatening infusion-related reactions.
- Management of increased serum transaminases, hyperbilirubinemia, left ventricular dysfunction, thrombocytopenia, pulmonary toxicity or peripheral neuropathy may require temporary interruption, dose reduction, or treatment discontinuation of ado-trastuzumab emtansine as per guidelines provided in Table 1.0 and Table 2.0.
- Hepatotoxicity. A reduction in the dose of KADCYLA is recommended in the case of hepatotoxicity exhibited as increases in serum transaminases and/or hyperbilirubinemia
Management of adverse events (infusion-related reactions, hepatotoxicity, left ventricular cardiac dysfunction, thrombocytopenia, pulmonary toxicity, or peripheral neuropathy) may require temporary interruption, dose reduction, or treatment discontinuation of ado-trastuzumab emtansine.
Closely monitor the infusion site for possible subcutaneous infiltration during drug administration [see Warnings and Precautions (5.10)]. 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 infusion-related 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.
| Click on the link to download the complete Full Prescribing Information for additional Important Safety Information, including BOXED WARNINGS. |
Dosage Forms and Strengths
Ado-trastuzumab emtansine is available as a lyophilized powder in single-use vials containing 100 mg per vial or 160 mg per vial.
Preparation for Administration
In order to prevent medication errors it is important to check the vial labels to ensure that the drug being prepared and administered is ado-trastuzumab emtansine and not trastuzumab.
Administration:
- Administer ado-trastuzumab emtansine as an intravenous infusion only with a 0.2 or 0.22 micron in-line polyethersulfone (PES) filter. Do not administer as an intravenous push or bolus.
- Do not mix ado-trastuzumab emtansine, or administer as an infusion, with other medicinal products.
- In order to improve traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded (or stated) in the patient file.
- Use aseptic technique for reconstitution and preparation of dosing solution. Appropriate procedures for the preparation of chemotherapeutic drugs should be used.
- Using a sterile syringe, slowly inject 5 mL of Sterile Water for Injection into the 100 mg ado-trastuzumab emtansine vial, or 8 mL of Sterile Water for Injection into the 160 mg ado-trastuzumab emtansine vial to yield a solution containing 20 mg/mL. Swirl the vial gently until completely dissolved. Do not shake. Inspect the reconstituted solution for particulates and discoloration.
- The reconstituted solution should be clear to slightly opalescent and free of visible particulates. The color of the reconstituted solution should be colorless to pale brown. Do not use if the reconstituted solution contains visible particulates or is cloudy or discolored.
- The reconstituted lyophilized vials should be used immediately following reconstitution with Sterile Water for Injection. If not used immediately, the reconstituted ado-trastuzumab emtansine vials can be stored for up to 24 hours in a refrigerator at 2oC to 8oC (36°F to 46°F); discard unused ado-trastuzumab emtansine after 24 hours. Do not freeze.
- The reconstituted product contains no preservative and is intended for single-use only.
Determine the correct dose (mg) of ado-trastuzumab emtansine
- Calculate the volume of the 20 mg/mL reconstituted ado-trastuzumab emtansine solution needed.
- Withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection. Do not use Dextrose (5%) solution.
- Gently invert the bag to mix the solution in order to avoid foaming
- The diluted ado-trastuzumab emtansine infusion solution should be used immediately. If not used immediately, the solution may be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours prior to use. This storage time is additional to the time allowed for the reconstituted vials. Do not freeze or shake.
Lyophilized powder in single-use vials: 100 mg per vial or 160 mg per vial of ado-trastuzumab emtansine.
Drug resistance
Despite favorable efficacy results of ado-trastuzumab emtansine, most treated patients eventually progress, and some HER2-positive breast cancers are primarily non-responsive or are only minimally responsive to ado-trastuzumab emtansine. [5]
Most second-line therapies are associated with either significant toxicities or limited improvements in overall survival (OS).
Clinical trials
In randomized clinical trials, efficacy has been demonstrated as the first line, second line, and later than the second-line treatment of advanced breast cancer.[2]
Manufacturing
Trastuzumab emtansine was developed by Genentech, and is manufactured by Lonza
