Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor used for the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and head and neck cancer. It is used to treat a certain type of cancer of the colon (large intestine) or rectum that has spread to other parts of the body. This medication is also used to treat head and neck cancer. Cetuximab works by slowing or stopping the growth of cancer cells. Cetuximab is an epidermal growth factor receptor binding FAB. Cetuximab is composed of the Fv (variable; antigen-binding) regions of the 225 murine EGFr monoclonal antibody specific for the N-terminal portion of human EGFr with human IgG1 heavy and kappa light chain constant (framework) regions.
Mechanism of Action of Cetuximab
Cetuximab binds to the epidermal growth factor receptor (EGFr) on both normal and tumor cells. EGFr is over-expressed in many colorectal cancers. Cetuximab competitively inhibits the binding of epidermal growth factor (EGF) and TGF alpha, thereby reducing their effects on cell growth and metastatic spread. Cetuximab is a monoclonal antibody that binds to and blocks the binding of ligands (e.g., epidermal growth factor and tissue growth factor-a) to the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) on the surface of normal and tumor cells. The binding of cetuximab to EGFR leads to internalization of the receptor preventing further activation and blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor (VEGF) production. In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth and survival of cancer cells that over-express EGFR. No anti-tumor effects of cetuximab were noted in human tumor xerographs lacking EGFR expression. In addition, signal tranduction through the EGFR results in activation of wild-type RAS protein. In cells with activating RAS somatic mutations, the mutant RAS protein is continually active and appears independent of EGFR regulation. Cetuximab may make cancer cells more vulnerable to other cancer chemotherapy agents and radiation therapy. Preclinical trials have suggested synergy between cetuximab and irinotecan, gemcitabine, and doxorubicin. The addition of cetuximab to irinotecan or irinotecan/5-fluorouracil chemotherapy in animal studies increased anti-tumor effects compared to chemotherapy alone. The mechanism of this synergy has not been established. It is thought that the blockage of EGFR signaling, which alone may be cytotoxic in some cell lines, may increase the vulnerability of cells to the cytotoxic effects of chemotherapy that may have only have been slightly effective without EGFR blockade. Although considered a cytostatic agent, cetuximab can cause tumor regression when given as a single agent. In some cancers, such as colorectal cancer, cells can activate the EGFR receptor through autocrine or paracrine mechanisms. These autocrine and paracrine mechanisms are necessary for cells to survive in a less than hospitable microenvironment around the tumor with low pH and pO2 tension. These tumor cells may experience apoptosis when the autocrine and paracrine EGFR-activation is inhibited.
Indications of Cetuximab
- Squamous Cell Carcinoma
- Colorectal Cancer
- Head and Neck Cancer
- Non-Small Cell Lung Cancer
- Pancreatic Cancer
- Metastatic Colorectal Cancers
- Metastatic Squamous Cell Carcinoma of the Head and Neck
- Advanced squamous cell carcinoma of the head and neck
- Locally or regionally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy.
- Recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck in combination with platinum-based therapy with 5-FU.
- Recurrent or metastatic squamous cell carcinoma of the head and neck progressing after platinum-based therapy.
- K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer as determined by approved tests.
- In combination with FOLFIRI for first-line treatment.
- In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy.
- As a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan.
Contra-Indications of Cetuximab
- Low amount of magnesium in the blood
- Low amount of calcium in the blood
- Low amount of potassium in the blood
- Coronary artery disease
- Abnormal heart rhythm
- Chronic Heart Failure
- Interstitial pneumonitis
- Lung fibrosis
- Skin infection due to a bacteria
- Skin rash resembling acne
- A Mother who is Producing Milk and Breastfeeding
- Allergies to Cetuximab, Galactose-Alpha-1, 3-Galactose (Alpha-Gal)
Dosages of Cetuximab
- Strengths: 2 mg/mL ; 1mL, 2mg
- 400 mg/m2 IV for the initial dose; 250 mg/m2 IV per week for subsequent doses.
- 400 mg/m2 IV for the initial dose; 250 mg/m2 IV per week for subsequent doses.
Colorectal Cancer
Either as monotherapy or in combination with irinotecan or FOLFIRI (irinotecan, 5-fluorouracil, leucovorin):
- Initial Dose: 400 mg/m2 administered as a 2 hour IV infusion (maximum infusion rate 10 mg /min)
- Maintenance Dose: 250 mg/m2 infused over 1 hour (maximum infusion rate 10 mg/min) once a week
Squamous Cell Carcinoma
In combination with radiation therapy or in combination with platinum-based therapy with 5-FU:
- Initial dose: 400 mg/m2 administered as a 2 hour IV infusion (maximum infusion rate 10 mg/min) 1 week prior to initiation of a course of radiation therapy or 1 hour before the initiation of platinum-based therapy with 5-FU
- Maintenance dose: 250 mg/m2 infused over 1 hour (maximum infusion rate 10 mg/min) once a week for the duration of radiation therapy (6 to 7 weeks) or until disease progression or unacceptable toxicity when administered in combination with platinum-based therapy with 5-FU (complete the administration 1 hour prior to radiation therapy or platinum-based therapy with 5-FU)
Monotherapy
- Initial dose: 400 mg/m2 administered as a 2 hour IV infusion (maximum infusion rate 10 mg/min)
- Maintenance dose: 250 mg/m2 administered as a 1 hour IV infusion (maximum infusion rate 10 mg/min) until disease progression or unacceptable toxicity
Side Effects of Cetuximab
The most common
- chest pain
- certainly hair loss
- headache
- joint painPain
- dizziness
- nausea and vomiting
- Severe stomach ache
- epigastric pain,
- diarrhoea,
- anorexia,
- flatulence,
- headache,
- dizziness,
- fainting, fast or pounding heartbeats.
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
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
- muscle stiffness
- redness of the face, neck, arms and occasionally, upper chest
- lack or loss of strength
- muscle spasm
- difficult or labored breathing
- dry mouth
- headache
- irritability
- lack or loss of strength
- loose stools
- loss of interest or pleasure
- muscle stiffness
- night sweats
- passing gas
- stomach discomfort, upset, or pain
- swollen joints
- trouble concentrating
- increased blood pressure
Drug Interactions of Cetuximab
Cetuximab may interact with following drugs, supplements & may decrease the efficacy of the drug
- alpha blockers (e.g., alfuzosin, doxazosin, silodosin, tamsulosin)
- anticancer medications (e.g., cabazitaxel, docetaxel, doxorubicin, etoposide, ifosfamide, irinotecan, vincristine)
- “azole” antifungal medications (e.g., fluconazole, itraconazole, ketoconazole)
- beta-blockers (e.g., atenolol, propranolol, metoprolol)
- barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
- benzodiazepines (e.g., chlordiazepoxide, clonazepam, diazepam, lorazepam)
- calcium channel blockers (e.g., nifedipine, diltiazem, verapamil, amlodipine, felodipine)
- carbamazepine
- chloroquine
- corticosteroids (e.g., dexamethasone, prednisone, methylprednisolone)
- cyclosporine
- dantrolene
- “gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
- losartan
- macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
- metronidazole
- mirtazapine
- modafinil
- montelukast
- norfloxacin
- ondansetron
- carbamazepine
- phenytoin
- progestins (e.g., dienogest, levonorgestrel, medroxyprogesterone, norethindrone)
- proton pump inhibitors (PPIs; e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)
- selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine,paroxetine, sertraline)
- sildenafil
- “statin” anticholesterol medications (e.g., atorvastatin, lovastatin, simvastatin)
- tadalafil
- tetracycline
- theophylline
- tocilizumab
- tolterodine
- tramadol
- other selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, fluoxetine, sertraline)
- 5-HT3 antagonists (e.g., granisetron, ondansetron)
- tamsulosin
- tapentadol
- thiazide diuretics (e.g., hydrochlorothiazide, indapamide)
- tramadol
- tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine,
- trimethoprim
- other tyrosine kinase inhibitors (e.g., dasatinib, imatinib, nilotinib, sunitinib)
- tetracycline
- tocilizumab
- vandetanib
- vemurafenib
- vitamin C
Pregnancy & Lactation of Cetuximab
FDA Pregnancy Category C
It is not known whether cetuximab is secreted in human breast milk; however, IgG is secreted in human milk. The potential for absorption of cetuximab and harm to the infant after ingestion is unknown. It is advised that women avoid breastfeeding during cetuximab therapy and for 60 days after the last dose of cetuximab.
Lactation
It is not known if cetuximab passes into breast milk. If you are a breastfeeding mother and are taking this medication, it may affect your baby. Breastfeeding should be stopped while you are being treated with cetuximab and should not be restarted until at least 60 days after the last dose of medication. The safety and effectiveness of using this medication have not been established for children.
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