Kadcyla (Trastuzumab)

Uses

Adjuvant Breast Cancer: Kadcyla (Trastuzumab) is used for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature) breast cancer

• As part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
• As part of a treatment regimen with docetaxel and carboplatin
• As a single agent following multi-modality anthracycline based therapy. Select patients for therapy based on an FDA-approved companion diagnostic for Kadcyla (Trastuzumab)

Metastatic Breast Cancer: Kadcyla (Trastuzumab) is used for:

• In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
• As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.

Select patients for therapy based on an FDA-approved companion diagnostic for Kadcyla (Trastuzumab)

Metastatic Gastric Cancer: Kadcyla (Trastuzumab) is used, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease. Select patients for therapy based on an FDA-approved companion diagnostic for Kadcyla (Trastuzumab)

Kadcyla (Trastuzumab) is also used to associated treatment for these conditions: Breast Cancer, Early Breast Cancer, Inflammatory Breast Cancer (IBC), Locally Advanced Breast Cancer (LABC), Metastatic Adenocarcinoma of the Gastro-Esophageal Junction, Metastatic Adenocarcinoma of the Stomach, Metastatic Breast Cancer, Metastatic Gastric Adenocarcinoma, Metastatic Gastroesophageal Junction Adenocarcinoma

How Kadcyla (Trastuzumab) works

Kadcyla (Trastuzumab) is a recombinant humanized IgG1 monoclonal antibody against the HER-2 receptor, a member of the epidermal growth factor receptors which is a photo-oncogene. Over-expressed in breast tumour cells, HER-2 overamplifies the signal provided by other receptors of the HER family by forming heterodimers . The HER-2 receptor is a transmembrane tyrosine kinase receptor that consists of an extracellular ligand-binding domain, a transmembrane region, and an intracellular or cytoplasmic tyrosine kinase domain. It is activated by the formation of homodimers or heterodimers with other EGFR proteins, leading to dimerization and autophosphorylation and/or transphosphorylation of specific tyrosine residues in EGFR intracellular domains . Further downstream molecular signaling cascades are activated, such as the Ras/Raf/mitogen-activated protein kinase (MAPK), the phosphoinositide 3-kinase/Akt, and the phospholipase Cγ (PLCγ)/protein kinase C (PKC) pathways that promote cell growth and survival and cell cycle progression . Due to upregulation of HER-2 in tumour cells, hyperactivation of these signaling pathways and abnormal cell proliferation is observed. Kadcyla (Trastuzumab) binds to the extracellular ligand-binding domain and blocks the cleavage of the extracellular domain of HER-2 to induce its antibody-induced receptor downmodulation , and subsequently inhibits HER-2-mediated intracellular signaling cascades. Inhibition of MAPK and PI3K/Akt pathways lead to an increase in cell cycle arrest, and the suppression of cell growth and proliferation . Kadcyla (Trastuzumab) also mediates the activation of antibody-dependent cell-mediated cytotoxicity (ADCC) by attracting the immune cells, such as natural killer (NK) cells, to tumor sites that overexpress HER-2 . While the drug alone has a minimal potential to induce complement-dependent cytotoxicity (CDC), one study demonstrated increased therapeutic effectiveness and a synergistic effect on uterine serous carcinoma cells in vitro when used in combination with pertuzumab, which also has minor effects on CDC alone. This study showed that only the combination of both cell-bound antibodies would be sufficient to bind and activate the complement component 1q (C1q) required to initiate the complement cascade reaction.

Intrinsic trastuzumab resistance has been noted for some patients with HER-2 positive breast cancer. Mechanisms involving trastuzumab resistance include deficiency of phosphatase and tensin homologue and activation of phosphoinositide 3-kinase, and the overexpression of other surface receptors, such as insulin-like growth factor .

Dosage

Kadcyla (Trastuzumab) dosage

Intravenous (Adult)-

Early breast cancer: For treatment after chemotherapy, radiotherapy or surgery. Initially, 4 mg/kg via infusion over 90 min followed by 2 mg/kg via infusion over 30 min wkly for 1 yr or until disease recurrence, whichever occurs 1st. Alternatively, initial dose of 8 mg/kg via infusion over 90 min followed by 6 mg/kg via infusion over 30-90 min at 3-wkly interval for 1 yr or until disease recurrence, whichever occurs 1st.

Metastatic breast cancer: As monotherapy or combination therapy (with an aromatase inhibitor or taxane): Initially, 4 mg/kg via infusion over 90 min followed by 2 mg/kg via infusion over 30 min at wkly interval until progression of disease. As trastuzumab emtansine: 3.6 mg/kg as infusion 3 wkly (21-day cycle). Admin initial dose for 90 min. Subsequent doses may be administered as 30 min infusions.

Gastric cancer: For metastatic: Initially, 8 mg/kg via infusion over 90 min followed by 6 mg/kg via infusion over 30-90 min at 3-wkly interval until progression of disease.

Reconstitute with 20 mL of bacteriostatic sterile water for inj into a soln containing 21 mg/mL of trastuzumab. Swirl gently; do not shake. Dilute further prior to admin with appropriate vol of reconstituted trastuzumab soln in 250 mL of NaCl 0.9% inj.

Side Effects

Fever, headache, fatigue, nausea, vomiting, diarrhoea, infections, increased cough, dyspnoea, rash, neutropenia, anaemia, and myalgia; cardiac dysfunction, CHF.

Toxicity

There is no experience with overdosage of trastuzumab in clinical trials - single doses >8 mg/kg have not been tested in humans. Kadcyla (Trastuzumab) can contribute to the development of ventricular dysfunction and congestive heart failure, particularly when used in combination (or temporally adjacent) to other cardiotoxic chemotherapies such as anthracyclines.

Precaution

Patient with pre-existing CV and pulmonary disease; extensive pulmonary tumour involvement. Pregnancy and lactation.

Interaction

May increase cardiotoxicity of antineoplastic agents. May increase neutropenic effect of immunosuppressants. May increase serum level with paclitaxel.

Food Interaction

Kadcyla (Trastuzumab) Hypertension interaction

[Moderate] Decreases in left ventricular ejection fraction (LVEF) have been reported with agents that block HER2 activity.

Patients who have received prior anthracyclines, those who received anthracycline after stopping therapy with agents that block HER2 activity, or patients who received prior radiotherapy to the chest area may be at higher risk of decreased LVEF.

Therapy with these agents should be administered cautiously in patients with a previous history of heart conditions.

Evaluate cardiac function before, during, and upon completion of treatment.

Withhold or discontinue therapy with agents that block HER2 activity as appropriate, and for a confirmed clinically significant decrease in left ventricular function, or if the LVEF has not improved or has declined further.

It is recommended to monitor overall cardiac function and LVEF by echocardiogram or MUGA scan as appropriate.

Kadcyla (Trastuzumab) Drug Interaction

Major: doxorubicinModerate: paclitaxel protein-boundUnknown: aspirin, diphenhydramine, multivitamin with minerals, duloxetine, ethanol, ginkgo, arginine, esomeprazole, acetaminophen, pertuzumab, levothyroxine, docetaxel, tramadol, cyanocobalamin, ascorbic acid, cholecalciferol, phytonadione, alprazolam

Kadcyla (Trastuzumab) Disease Interaction

Major: pulmonary toxicityModerate: CHF, peripheral neuropathy, thrombocytopenia

Elimination Route

Peak and trough plasma concentrations at steady state (between weeks 16 and 32) were approximately 123 and 79 mcg/mL, respectively. At the highest weekly dose studied (500 mg), mean peak serum concentration was 377 mcg/mL.

Half Life

The terminal half-life is approximately 28 days, but may decrease with lower doses - at the 10mg and 500mg doses, half-lives averaged approximately 1.7 and 12 days, respectively.

Clearance

The predicted steady-state clearance of trastuzumab is 0.173 - 0.337 L/day, dependent primarily on the dosing regimen. The clearance rate for subcutaneously administered trastuzumab, formulated with hyaluronidase for improved subcutaneous absorption, is 0.11 L/day.

Elimination Route

Following metabolism, the complex elimination of trastuzumab in humans is mediated by epithelial cells in a dose-dependent (nonlinear) fashion. The renal excretion of trastuzumab is very low.

Pregnancy & Breastfeeding use

Pregnancy Category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Severe dyspnoea at rest.

Storage Condition

Store between 2-8° C.

Innovators Monograph

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