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U.S. Department of Health and Human Services

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Erbitux (ceuximab) Approved for Use in Combination with Radiation Therapy

On March 1, 2006, the U.S. Food and Drug Administration granted approval to cetuximab (Erbitux, ImClone Systems, Inc.) for use in combination with radiation therapy (RT) for the treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN) or as a single agent for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed. This approval is based on a statistically significant improvement in overall survival and duration of locoregional disease control for RT plus cetuximab when compared to RT alone. Evidence of cetuximab safety and efficacy is also supported by demonstration of durable objective tumor responses with cetuximab when administered as a single-agent in second- or third-line treatment of advanced SCCHN.

The safety and efficacy of cetuximab in combination with RT were demonstrated in a phase 3 randomized trial of 424 patients with Stage III/IV SCC of the oropharynx, hypopharynx or larynx who had no prior therapy. Patients were randomized to receive either cetuximab plus RT (211 patients) or RT alone (213 patients). Cetuximab was administered as a 400 mg/m2 initial dose, followed by 250 mg/m2 weekly for the duration of RT(6-7 weeks), starting one week before RT. RT was administered for 6-7 weeks as once daily, twice daily or concomitant boost.

The median survival time was 49 months on the cetuximab plus RT versus 29.3 months observed in patients receiving RT alone [p=0.03, stratified log-rank test; hazard ratio 0.74, (95% CI 90.56, 0.97). The median duration of locoregional control was 24.4 months in patients receiving cetuximab plus RT versus 14.9 months for those receiving RT alone [p=0.005, stratified log-rank test; hazard ratio 0.68, 95 % CI (0.52, 0.89). The observed effect was primarily confined to patients enrolled in sites in the US.

Additional data were derived from a single-arm trial of cetuximab monotherapy in 103 patients with recurrent or metastatic SCCHN after failure of platinum-based therapy. Eighty percent had metastatic disease. Patients received cetuximab as a 400 mg/m2 loading dose, followed by 250 mg/m2 weekly. The objective response rate of cetuximab monotherapy was 12.6% (95% CI 7%–21%). Median response duration was 5.8 months (95% CI 2.9; 5.8).

The most common adverse events reported for both treatment arms were mucositis and radiation dermatitis. The incidence of serious mucositis, radiation dermatitis and allergic/anaphylatoid reaction were > 2% higher in the RT + cetuximab arm when compared with RT alone. The following serious adverse reactions, some with fatal outcome were observed in the cetuximab plus RT arm: infusion reactions, cardiopulmonary arrest and/or sudden death and acneform rash.

The overall incidence of late radiation toxicity (any grade) was higher in the cetuximab plus RT arm compared with RT alone. However, the incidence of Grade 3 or 4 late radiation toxicities were generally similar between the two treatment groups.

Death and serious cardiotoxicity were observed in a single arm trial combining cisplatin with cetuximab and RT conducted in patients with locally advanced squamous cell cancer of the head neck. The cetuximab, RT and cisplatin combination should be reserved for controlled clinical trials where toxicity can be clearly evaluated.

Adverse events associated with cetuximab monotherapy in patients with SCCHN were generally consistent with the adverse reactions previously described for cetuximab. The following serious adverse reactions, some with fatal outcomes, have been reported in the cetuximab safety data base: infusion reactions, interstitial lung disease, acneform rash and hypomagnesemia.

Full prescribing information including clinical trial information, safety, dosing, drug-drug interaction and contraindications is available at Drugs@FDA.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by phone at 1-800-FDA-1088; by facsimile 1-800-FDA-0178 by mail using the Form 3500