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Trastuzumab; Uses, Dosage, Side Effects, Drug Interactions

Trastuzumab is recombinant IgG1 kappa, a humanized monoclonal antibody that selectively binds with high affinity in a cell-based assay (Kd = 5 nM) to the extracellular domain of the human epidermal growth factor receptor protein. Produced in CHO cell culture. In December 2017, FDA approved Ogivri (trastuzumab-dust) as a biosimilar to Herceptin (trastuzumab) for the treatment of patients with breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma) whose tumors overexpress the HER2 gene (HER2+).

Mechanism of Action of Trastuzumab

The HER2 gene (also known as HER2/neu and ErbB2 gene) is amplified in 20–30% of early-stage breast cancers. Trastuzumab is a monoclonal antibody targeting HER2, inducing an immune-mediated response that causes internalization and downregulation of HER2. It may also upregulate cell cycle inhibitors such as p21^Waf1 and p27^Kip1.In some types of cancer, HER2 may send signals despite the absence of growth factors arriving and binding to the receptor, making its effect in the cell constitutive; however, trastuzumab is not effective in this case.

The HER2 pathway promotes cell growth and division when it is functioning normally; however, when it is overexpressed, cell growth accelerates beyond its normal limits. In some types of cancer, the pathway is exploited to promote rapid cell growth and proliferation and hence tumor formation. The EGF pathway includes the receptors HER1 (EGFR), HER2, HER3, and HER4; the binding of EGF to HER is required to activate the pathway. The pathway initiates the MAP kinase pathway as well as the PI3 kinase/AKT pathway, which in turn activates the NF-κB pathway. In cancer cells, the HER2 protein can be expressed up to 100 times more than in normal cells (2 million versus 20,000 per cell). This overexpression leads to strong and constant proliferative signaling and hence tumor formation. Overexpression of HER2 also causes deactivation of checkpoints, allowing for even greater increases in proliferation.

The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell (molecules called EGFs) to inside the cell and turn genes on and off. The HER (human epidermal growth factor receptor) protein, binds to human epidermal growth factor and stimulates cell proliferation. In some cancers, notably certain types of breast cancer, HER2 is over-expressed and causes cancer cells to reproduce uncontrollably.

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HER2 extends across the cell membrane and carries signals from outside the cell to the inside. Signaling compounds called mitogens (specifically EGF in this case) arrive at the cell membrane, and bind to the extracellular domain of the HER family of receptors. Those bound proteins then link (dimerize), activating the receptor. HER2 sends a signal from its intracellular domain, activating several different biochemical pathways. These include the PI3K/Akt pathway and the MAPK pathway. Signals on these pathways promote cell proliferation and the growth of blood vessels to nourish the tumor (angiogenesis).

Normal cell division — mitosis — has checkpoints that keep cell division under control. Some of the proteins that control this cycle are called cdk2 (CDKs). Overexpression of HER2 sidesteps these checkpoints, causing cells to proliferate in an uncontrolled fashion. This is caused by phosphorylation by Akt.

Trastuzumab binds to domain IV of the extracellular segment of the HER2/neu receptor. Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferation. It has been suggested that trastuzumab does not alter HER-2 expression, but downregulates activation of AKT.In addition, trastuzumab suppresses angiogenesis both by induction of antiangiogenic factors and repression of proangiogenic factors. It is thought that a contribution to the unregulated growth observed in cancer could be due to proteolytic cleavage of HER2/neu that results in the release of the extracellular domain. One of the most relevant proteins that trastuzumab activates is the tumor suppressor p27 (kip1), also known as CDKN1B. Trastuzumab has been shown to inhibit HER2/neu ectodomain cleavage in breast cancer cells. Experiments in laboratory animals indicate that antibodies, including trastuzumab, when bound to a cell, induce immune cells to kill that cell, and that such antibody-dependent cell-mediated cytotoxicity is another important mechanism of action.

Indications of Trastuzumab

Cancer, breast
Metastatic breast cancer
Metastatic gastroesophageal junction adenocarcinoma
Breast cancer, adjuvant
Esophageal carcinoma
Breast cancer
Breast cancer, metastatic
Gastric cancer
Salivary gland cancer
Trastuzumab is used to treat metastatic (spread) breast cancer. It is effective against tumors that overexpress the HER2/neu protein.
As part of chemotherapy regimen for adjuvant treatment of lymph-node positive, HER2/neu protein positive breast cancer.
Treatment of gastric (stomach) cancer.
It is not known whether or not trastuzumab may be effective in other cancers that may also have this HER-2/neu protein, including ovarian, colon, endometrial, lung, bladder, prostate, and salivary gland tumors.

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Contra-Indications of Trastuzumab

Anemia
Decreased Neutrophils a Type of White Blood Cell
High blood pressure
Disease of the Muscle of the Heart with Enlargement
Heart Failure
Obstruction of a Blood Vessel by a Blood Clot
Abnormally low blood pressure
Interstitial Pneumonitis
Acute Respiratory Distress Syndrome
Lung Disease
Pregnancy

Dosage of Trastuzumab

Strengths: 150 mg; 440 mg

Breast Cancer

Metastatic Breast Cancer

Initial dose: 4 mg/kg IV over 90 minutes, alone or with paclitaxel
Maintenance dose: 2 mg/kg IV over 30 minutes once weekly

Breast Cancer – Adjuvant

Adjuvant Treatment of Breast Cancer

If given with, or following, paclitaxel, docetaxel, or docetaxel/carboplatin

Initial dose: 4 mg/kg IV over 90 minutes, then 2 mg/kg IV over 30 minutes weekly for 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin)
Maintenance dose: 6 mg/kg IV over 30 to 90 minutes every 3 weeks, starting one week after completion of weekly dosing

If used as a single agent within 3 weeks after multi-modality anthracycline-based regimens

Initial dose: 8 mg/kg IV over 90 minutes
Maintenance dose: 6 mg/kg IV over 30 to 90 minutes every 3 weeks
Duration of therapy: 52 weeks

Esophageal Carcinoma

Metastatic Gastric Cancer

Initial dose: 8 mg/kg IV over 90 minutes
Maintenance dose: 6 mg/kg IV over 30 to 90 minutes every 3 weeks
Duration of therapy: Until disease progression

Gastric Cancer

Metastatic Gastric Cancer

Initial dose: 8 mg/kg IV over 90 minutes
Maintenance dose: 6 mg/kg IV over 30 to 90 minutes every 3 weeks
Duration of therapy: Until disease progression

Side Effects of Trastuzumab

The most common

More common

Fast or irregular heartbeat
appetite loss
changes in nails
constipation
fatigue
fever
Back pain
dizziness
headache
increased cough
Acid or sour stomach
decreased appetite
Agitation
chest congestion
chest pain
cold sweats
confusion
decreased sexual ability or desire
stomach or abdominal cramps, gas, or pain
trouble sleeping

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Less common

bleeding gums
blood in the urine or stools
chest pain
diarrhea
Burning, crawling, itching, numbness, prickling, “pins and needles“, or tingling feelings
difficulty in moving
feeling of warmth
muscle stiffness
redness of the face, neck, arms and occasionally, upper chest
sudden sweating
lack or loss of strength
muscle spasm
difficult or labored breathing
difficulty in swallowing
dry mouth
fever
headache
hoarseness
increased blood pressure

Drug Interactions of Trastuzumab

Trastuzumab may interact with following drugs ,suppliments & may decrease the efficacy of drug

azathioprine
belimumab
corticosteroids (e.g., budesonide, dexamethasone, hydrocortisone, fluticasone, prednisone)
cyclosporine
infliximab
mycophenolate
other medications to treat cancer (e.g., carboplatin, cyclophosphamide, doxorubicin, ifosfamide, vincristine)
sirolimus
tacrolimus
beclomethasone, inhaled
cholera vaccine
daclizumab
denosumab
dichlorphenamide
fingolimod
paclitaxel
paclitaxel protein bound

Pregnancy & Lactation of Trastuzumab

Pregnancy

This medication can cause harm to the fetus if used during pregnancy. Women who could become pregnant should use effective contraception while receiving this medication and for 7 months after stopping it. If you become pregnant while taking this medication, contact your doctor immediately.

Lactation

It is not known if trastuzumab passes into breast milk. If you are a breast-feeding mother and are receiving this medication, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding.