Pharmacology Update

Cetuximab Injection (Erbitux)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

In February, the FDA approved a new monoclonal antibody for the treatment of metastatic colorectal cancer. A genetically engineered human/mouse (chimeric) antibody, cetuximab targets the epidermal growth factor receptor (EGFR). The drug was approved under the FDA’s accelerated approval program. It is manufactured by ImClone Systems Incorporated and distributed and marketed by Bristol-Myers Squibb Company.

Indications

Cetuximab is approved for use in combination with irinotecan for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are refractory to irinotecan-based chemotherapy. It is also indicated as monotherapy in patients with ERFR-expressing metastatic colorectal cancer who are intolerant of irinotecan-based therapy.1

Dosage

The recommended dose of cetuximab is 400 mg/m2 initially, followed by 250 mg/m2 weekly. The initial dose is given by intravenous infusion over 120 minutes and maintenance dose over 60 minutes. Premedication with a histamine-1 receptor antagonist (eg, 50 mg of intravenous diphenhydramine) is recommended.1

Cetuximab is available as a 100 mg single-use vial.

Potential Advantages

Cetuximab has been reported to produce partial response or stabilization of disease in patients with irinotecan-refractory or irinotecan and oxaliplatin failure metastatic colorectal cancer expressing EGFR.1,2

Potential Disadvantages

Cetuximab has not been shown to improve disease-related symptoms or survival.1 The most common adverse events associated with cetuximab monotherapy are acneform rash (90%), asthenia/malaise (49%), fever (33%), nausea (29%), constipation (28%), and diarrhea (28%). Severe infusion reactions occurred in about 3% of patients. These were generally associated with the first infusion and were characterized by airway obstruction (eg, bronchospasm, stridor, hoarseness), urticaria, and hypotension. In rare instances (< 1 in 1000), death has resulted.1 Patients who experience an initial infusion reaction should be monitored closely in subsequent infusions. Interstitial lung disease has been reported rarely (< 0.5%). In clinical trials, 5% of patient on cetuximab monotherapy and 10% in combination with irinotecan discontinued therapy due to adverse events.

Comments

Cetuximab is a chimeric (mouse/human) monoclonal antibody produced in murine myeloma cell culture. It is a competitive inhibitor with high affinity for the EGFR and may enhance the antitumor effect of chemotherapeutic agents.2,3 EGFR is a commonly expressed transmembrane glycoprotein of the tyrosine kinase growth factor receptor family. EGFR is over-expressed by 25-80% of tumors and associated with advanced disease and poor prognosis.2,4 The drug’s efficacy has been evaluated in a randomized controlled study and in small single-arm open-label studies with the same dose of cetuximab (400 mg/m2 followed by weekly dose of 250 mg/m2).1,2,6 The primary end point was tumor response using WHO criteria. Partial response was defined as 50% or greater decrease in tumor size for 4 or more weeks. Stable disease was defined as less than a 50% decrease but less than a 25% increase in tumor size. In treatment naïve patients, partial response ranged from 43-58% and stable disease stable disease of 32-52%.2 In the largest study, in irinotecan refractory and irinotecan oxaliplatin resistant patients, a partial response of 22.9% was noted for cetuximab and irinotecan (n = 218) compared to 10.8% for cetuxumab alone (n = 111). Stable disease rates were 32.6% and 21.6% respectively (P = 0.007).1,2 In single-arm studies the overall response rate ranged 9-15%.1,6 Response to cetuximab did not appear to correlate with percent of intensity of EGFR expression and has not been shown to improve disease-related symptoms or survival.1 Improvement in disease-related symptoms or survival has not been demonstrated.1 The cost for the loading dose for a 1.8 m2 patient is about $3900 and about $2400 for each weekly dose.

Clinical Implications

The prognosis for patients with advanced metastatic colorectal cancer is poor. For tumors that express EGFR the combination of irinotecan and cetuximab offers an option in patients who are refractory to or intolerant of irinotecan. Currently there are no reliable predictive molecular or clinical markers for efficacy with cetuximab.5 Cetuximab joins another monoclonal antibody, bevacizumab, which was approved along with 5FU as first line treatment of metastatic colorectal cancer.

Cetuximab along with other drugs that target EGFR/tyrosine kinase is being evaluated for a variable of other tumors.

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Asst. Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are Associate Editors of Internal Medicine Alert.

References

1. ErbituxTM Product Information. ImClone System Incorported and Bristol-Myers Squibb Company. February 2004.

2. Reynolds NA, Wagstaf AJ. Drugs. 2004;64(1):109-118.

3. Herbst RS, Shin DM. Cancer. 2002;94(5):1593-1611.

4. Khalil MY, et al. Expert Rev Anticancer Ther. 2003; 3(3):367-80.

5. Ellis LM, et al. J Clin Oncol. 2004;22(7):1177-1179.

6. Saltz LB et al. J Clin Oncol. 2004;22 (7):1201-1208.