FDA Approval for CetuximabBrand name(s): Erbitux®
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interaction, and contraindications.
Head and Neck Cancer
On March 1, 2006, the U.S. Food and Drug Administration granted approval to cetuximab (Erbitux®, made by 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 III 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 (six to seven weeks), starting one week before RT. RT was administered for six to seven 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 percent 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 percent CI (0.52, 0.89)]. The observed effect was primarily confined to patients enrolled in sites in the United States.
Additional data were derived from a single-arm trial of cetuximab monotherapy in103 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 percent (95 percent CI 7 percent to 21 percent). Median response duration was 5.8 months (95 percent 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 percent 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.
 Back to Top
_________________________________________________
Colorectal Cancer
On February 12, 2004, the U.S. Food and Drug Administration approved cetuximab (Erbitux®, made by Imclone Systems, Inc.), a monoclonal antibody directed against the epidermal growth factor receptor (EGFR). Cetuximab is approved for use, in combination with irinotecan, for the treatment of EGFR-expressing, metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy.
Cetuximab is also approved for use as a single agent for the treatment of EGFR-expressing, recurrent metastatic colorectal carcinoma in patients who are intolerant to irinotecan-based chemotherapy.
Cetuximab is a recombinant, human/mouse chimeric IgG1 monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). Cetuximab binds specifically to the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor–alpha.
Binding of cetuximab to the EGFR 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 production. The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Over-expression of EGFR is also detected in many human cancers including those of the colon and rectum.
The recommended dose of cetuximab, in combination with irinotecan or as monotherapy, is 400 mg/m2 as an initial loading dose (first infusion only) administered as a 120-minute IV infusion. The recommended weekly maintenance dose is 250 mg/m2 infused over 60 minutes.
Premedication with an H1 antagonist is recommended. Appropriate medical resources for the treatment of severe infusion reactions should be available during cetuximab infusions. The rate of cetuximab infusion should be reduced for mild or moderate infusion reactions; cetuximab should be discontinued for severe infusion reactions. Dose reductions are also recommended for moderate or severe skin toxicity.
The data establishing the efficacy and safety of cetuximab were derived mainly from the results of a multicenter, randomized, controlled clinical trial conducted in 329 patients; patients were randomized to receive either cetuximab plus irinotecan (218 patients) or cetuximab monotherapy (111 patients).
Supporting data were derived from an open-label, single-arm trial (138 patients) of cetuximab plus irinotecan and an open-label single-arm trial (57 patients) of cetuximab as a single agent. All studies enrolled patients with EGFR-expressing (75-82 percent of those screened were positive), recurrent, metastatic colorectal cancer. All patients had received prior irinotecan; two-thirds of the patients in the randomized study and half of those in the supportive study had progressed during or within 30 days of receiving an adequate course of irinotecan.
In the randomized trial, 38 percent had also received prior oxaliplatin. Determination of clinical benefit was based on evidence of durable responses without evidence of an effect on survival. In the randomized trial, the overall response rate was 23 percent with a median duration of response of 5.7 months in the cetuximab plus irinotecan arm. The overall response rate was 12 percent with a median duration of response of 4.1 months in the cetuximab monotherapy arm.
The median time to progression was significantly longer for patients receiving combination therapy (4.1 vs. 1.5 months). Comparable results were observed in the single arm studies of cetuximab plus irinotecan (15 percent ORR, 6.5 months median response duration) and cetuximab monotherapy (9 percent ORR, 1.4 months median response duration).
The most serious adverse reactions observed in clinical trials of cetuximab, alone or in combination with irinotecan, were infusion reactions (3 percent), dermatologic toxicity (1 percent), interstitial lung disease (0.5 percent), fever (5 percent), sepsis (3 percent); renal dysfunction (2 percent), pulmonary embolism (1 percent), dehydration (5 percent in patients receiving cetuximab plus irinotecan; 2 percent in patients receiving cetuximab monotherapy), and diarrhea (6 percent in patients receiving cetuximab plus irinotecan, 0 percent in patients receiving cetuximab monotherapy).
Thirty-seven (10 percent) patients receiving cetuximab plus irinotecan and 14 (5 percent) patients receiving cetuximab monotherapy discontinued treatment primarily because of adverse events.
The most common adverse events seen in 354 patients receiving cetuximab plus irinotecan were acneform rash (88 percent), asthenia/malaise (73 percent), diarrhea (72 percent), nausea (55 percent), abdominal pain (45 percent), and vomiting (41 percent).
The most common adverse events seen in 279 patients receiving cetuximab monotherapy were acneform rash (90 percent), asthenia/malaise (49 percent), fever (33 percent), nausea (29 percent), constipation (28 percent), and diarrhea (28 percent).
On October 2, 2007, the FDA expanded labeling and granted regular approval for single-agent cetuximab for the treatment of patients with EGFR-expressing metastatic colorectal cancer (mCRC) after failure of both irinotecan- and oxaliplatin-based chemotherapy regimens. Cetuximab was initially approved in 2004 under accelerated approval regulations and the study described below verifies the clinical benefit of single-agent cetuximab in this patient population.
The study supporting conversion to regular approval was an open-label, multinational study conducted by the NCI-Canada (NCIC) in patients with EGFR-expressing, progressive mCRC following both irinotecan- and oxaliplatin-containing regimens.
Five hundred seventy-two patients were randomized (1:1) to best supportive palliative care (BSC) or palliative care plus cetuximab administered as an intravenous infusion of 400 mg/m2 on the first dose, then 250 mg/m2 weekly until disease progression. Patients randomized to cetuximab demonstrated a statistically significant improvement in overall survival (OS) compared to those randomized to best supportive care (median OS: 6.1 vs. 4.6 months; hazard ratio 0.766, p=0.0048, stratified log-rank test). All documented tumor responses (evaluated centrally by NCIC) occurred in patients randomized to cetuximab (6.6 percent); the median response duration was 5.5 months and all were partial responses.
Back to Top
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products, or Patricia Keegan, M.D., director of the FDA's Division of Clinical Trials Design and Analysis.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other
products. (See "Understanding the Approval Process for New Cancer Treatments.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.
For further information related to oncology drug approvals, regulatory information and other oncology resources, please refer to the FDA's Oncology Tools Web site.
Back to Top |
