Chimeric monoclonal antibody targets EGFR for the treatment of colon cancer

Over-expression of the human epidermal growth factor receptor (EGFR) is detected in many cancers, including those of the colon and rectum. Cetuximab, a recombinant, human/mouse chimeric monoclonal antibody, binds specifically to the extracellular domain of EGFR on both normal and tumor cells, thereby inhibiting cell growth and inducing apoptosis. Cetuximab was approved on February 12, 2004, in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The monoclonal antibody was also approved as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma in patients who are intolerant to irinotecan-based chemotherapy.

Efficacy. Cetuximab was evaluated alone or in combination with irinotecan in a randomized, controlled trial (N=329). Cetuximab was also evaluated in combination with irinotecan in an open-label, single-arm trial (N=138) and as a single agent in another clinical trial (N=57). All of the trials enrolled patients with EGFR-expressing metastatic colorectal cancer whose disease had progressed after receiving an irinotecan-containing regimen. In the randomized, controlled trial, patients received either cetuximab or cetuximab plus irinotecan, with an initial cetuximab dose of 400 mg/m2 followed by weekly doses of 250 mg/m2 until disease progression or unacceptable toxicity. Patients who received irinotecan as part of their regimen were continued at the same dose and schedule of irinotecan as they had previously failed. Disease progression was assessed by an Independent Radiographic Review Committee blinded to the treatment arms. The objective response rates were 22.9% and 10.8% in the cetuximab plus irinotecan and cetuximab monotherapy groups, respectively (P=.007; 95% CI, 4.1­20.2). The mean duration of response was 5.7 months in the combination arm and 4.2 months in the monotherapy arm.

Safety. Severe infusion reactions, characterized by the rapid onset of airway obstruction, urticaria, and/or hypotension, have been reported with the administration of cetuximab. Most severe infusion reactions were associated with the first infusion of cetuximab despite the use of prophylactic antihistamines. These reactions require immediate interruption of cetuximab therapy and permanent discontinuation from further treatment. At the time of infusion, appropriate medical therapy (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen) should be available for use in the treatment of such reactions. Interstitial lung disease (ILD) has been reported in patients receiving cetuximab. Therapy should be interrupted and a prompt investigation should be performed in the event of acute onset or worsening pulmonary symptoms. Dermatologic toxicities, including acneform rash, skin drying and fissuring, and inflammatory and infectious sequelae, have been associated with cetuximab therapy. Patients receiving cetuximab therapy should wear sunscreen and hats, as well as limit total sun exposure, during the course of their treatment. The most serious adverse reactions associated with cetuximab are infusion reactions, dermatologic toxicity, interstitial lung disease, fever, sepsis, kidney failure, pulmonary embolus, dehydration, and diarrhea. The most common adverse events associated with cetuximab are acneform rash, asthenia/malaise, diarrhea, nausea, abdominal pain, fever, constipation, and vomiting.

Dosing. Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in the specific technology being used prior to initiation of cetuximab therapy. The recommended initial loading dose of cetuximab is 400 mg/m2 (first infusion) administered as a 120-minute IV infusion (maximum infusion rate 5 mL/min). The recommended weekly maintenance dose (all other infusions) is 250 mg/m2 infused over 60 minutes (maximum infusion rate 5 mL/min). The dose of cetuximab is the same regardless of whether it is being administered as monotherapy or in combination with irinotecan. Patients who experience a mild-to-moderate infusion reaction shoud have their infusion rate permanently reduced by 50%, while patients experiencing a severe infusion reaction should have their therapy immediately and permanently discontinued.

Cost. According to the company, cetuximab will be priced at roughly $2,400/dose, which translates into an approximate monthly cost of $10,000.