On February 12, 2004, the FDA approved cetuximab (Erbitux®, made by Imclone Systems, Inc.), a monoclonal antibody directed against the epidermal growth factor receptor. Erbitux 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.

Erbitux 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.

Erbitux is a recombinant, human/mouse chimeric IgG1 monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). Erbitux 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 ERBITUX 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 Erbitux, 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 Erbitux infusions. The rate of Erbitux infusion should be reduced for mild or moderate infusion reactions; Erbitux 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 Erbitux were derived mainly from the results of a multicenter, randomized, controlled clinical trial conducted in 329 patients; patients were randomized to receive either Erbitux plus irinotecan (218 patients) or Erbitux monotherapy (111 patients).

Supporting data were derived from an open-label, single-arm trial (138 patients) of Erbitux plus irinotecan and an open-label single-arm trial (57 patients) of Erbitux 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 Erbitux plus irinotecan arm. The overall response rate was 12 percent with a median duration of response of 4.1 months in the Erbitux 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 Erbitux plus irinotecan (15 percent ORR, 6.5 months median response duration) and Erbitux monotherapy (9 percent ORR, 1.4 months median response duration).

The most serious adverse reactions observed in clinical trials of Erbitux, 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 Erbitux plus irinotecan; 2 percent in patients receiving Erbitux monotherapy), and diarrhea (6 percent in patients receiving Erbitux plus irinotecan, 0 percent in patients receiving Erbitux monotherapy).

Thirty-seven (10 percent) patients receiving Erbitux plus irinotecan and 14 (5 percent) patients receiving Erbitux monotherapy discontinued treatment primarily because of adverse events.

The most common adverse events seen in 354 patients receiving Erbitux 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 Erbitux monotherapy were acneform rash (90 percent), asthenia/malaise (49 percent), fever (33 percent), nausea (29 percent), constipation (28 percent), and diarrhea (28 percent).

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

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