Pharmaceutical Approval Update: Oncology
Manufacturer: ImClone Systems, Inc., Branchburg, NJ, and Bristol-Myers Squibb, Princeton, NJ
Indication: Cetuximab is indicated for use in combination with radiation therapy to treat patients with squamous cell cancer of the head and neck that cannot be removed by surgery. Cetuximab is also approved as monotherapy for patients whose head and neck cancer has metastasized despite the use of standard chemotherapy.
Drug Class: This recombinant, human/mouse (murine) chimeric monoclonal antibody binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). It is composed of Fv regions of a murine anti-EGFR antibody with human immunoglobulin G1 (IgG1) heavy-chain and kappa light-chain constant regions. Its approximate molecular weight is 152 kilodaltons.
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Uniqueness of Product: This is the first drug approved for head and neck cancer that has shown a survival benefit for patients.
Infusion Reactions. Severe infusion reactions have occurred after the administration of cetuximab in approximately 3% (17/633) of patients, although fatal outcomes have been rare (less than one subject in 1,000). Approximately 90% of these reactions were associated with the first infusion despite the use of prophylactic antihistamines. These reactions were characterized by the rapid onset of airway obstruction (bronchospasm, stridor, and hoarseness), urticaria, and hypotension.
Caution must be exercised with every infusion, because some patients have experienced their first severe reaction during later infusions. If a severe infusion reaction occurs, cetuximab therapy must be interrupted immediately and permanently. Appropriate medical therapy, including epinephrine, corticosteroids, intravenous (IV) antihistamines, broncho-dilators, and oxygen, should be on hand. Patients should be carefully observed until all signs and symptoms have completely resolved.
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Cardiopulmonary Arrest. Cardiopulmonary arrest or sudden death has occurred in 2% (4/208) of head and neck cancer patients who received radiation therapy and cetux-imab, although none of 212 patients treated with radiotherapy alone experienced this event. When combined with radiation, cetuximab should be used with caution in patients with known coronary artery disease, congestive heart failure, or cardiac arrhythmias.
Allergy. Severe allergic reactions, including difficulty breathing, rash, itching, low blood pressure, and heart attacks, have occurred in 3% of 1,485 patients receiving cetuximab.
These reactions, caused by the infusion, have resulted in death on rare occasions.
Skin Reactions. An acne-like rash, drying of the skin, cracking, redness, and swelling have been observed. Sun exposure may worsen these effects. Patients should wear sunscreen and hats to limit sun exposure. A related nail disorder, most often observed in the large toes and thumbs, has also been reported.
Dosage and Administration: The initial loading dose of cetuximab, when combined with radiation, is 400 mg/m2 as the first infusion, administered as a 120-minute IV infusion (maximum infusion rate, 5 ml/minute) one week before the initial course of radiation therapy. The recommended weekly maintenance dose is 250 mg/m2, infused over 60 minutes weekly, for the duration of radiation therapy (six to seven weeks). Cetuximab is administered 1 hour prior to radiation therapy.
The recommended regimen for cetuximab as a single agent is 400 mg/m2 initially, followed by 250 mg/m2 weekly, until disease progression or unacceptable toxicity.
Commentary: Cetuximab is combined with radiation therapy for locally or regionally advanced head and neck cancer and as a single agent in recurrent or metastatic head and neck cancer when prior platinum-based chemotherapy has failed. This is an important goal, because cetuximab is the first agent approved for this purpose in more than 30 years. For patients with locally or regionally advanced disease, cetuximab plus radiation has demonstrated significant improvements in survival and locoregional control. Nearly 40,000 diagnoses of head and neck cancer were confirmed in the U.S. in 2005, and more than 11,000 Americans died as a result of this disease.