FDA Approves Erbitux for Advanced Colon Ca

ROCKVILLE, Maryland—The US Food and Drug Administration (FDA) has granted accelerated approval to Erbitux (cetuximab for injection, ImClone Systems and Bristol-Myers Squibb) for two indications in patients with epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer. The agency approved use of the monoclonal antibody in combination with irinotecan (Camptosar) in patients who are refractory to irinotecan-based chemotherapy, and as a single agent in patients who are intolerant to irinotecan-based chemotherapy.

ImClone originally sought approval for Erbitux in 2001, but FDA medical officers concluded that its application could not be reviewed because 94 pa-tients, about half of those then studied, had not failed approved treatments for colon cancer, and safety and efficacy data for some of the remaining patients were missing. In August 2003, ImClone again sought Erbitux’s approval, this time backed by a 329-patient study and new results from two smaller studies submit-ted earlier.

FDA approved Erbitux on the basis of its objective response rates but emphasized that the sponsors did not provide evidence that the drug improves survival. FDA can grant accelerated approval to drugs that are intended to treat serious or life-threatening diseases on the basis of early evidence of effectiveness. How-ever, under the FDA rules, the sponsor of an agent receiving such approval must conduct further studies to demonstrate that it truly provides a benefit to patients. Toward this end, two studies involving approximately 2,000 patients are in progress to determine whether Erbitux can stop the progression of colorectal cancer and extend survival.

Erbitux is a recombinant, human-mouse monoclonal antibody that binds specifically to the human EGFR on the surfaces of normal and cancer cells. The antibody competitively inhibits the binding of epidermal growth factor and other ligands, including TGF (transforming growth factor)-alpha, and thus pre-vents phosphorylation and the activation of receptor-associated kinases. As a result, Erbitux inhibits cell growth, induces cell death, and decreases matrix metalloproteinase and vascular endothelial growth factor (VEGF) production.

Three Studies

Before Erbitux’s approval, FDA medical officers evaluated results from three studies: a randomized phase II trial of 329 patients who received Erbitux plus irinotecan or Erbitux alone, an open-label, single-arm trial of 138 patients, and data from 111 patients treated with Erbitux as a single agent.

The controlled, multicenter phase II study randomized 218 patients to Erbitux/irinotecan and 57 patients to Erbitux alone. In both study arms, patients received an initial dose of Erbitux at 400 mg/m², followed by 250 mg/m² weekly until disease progression or unacceptable toxicity. All patients were given a 20-mg test dose of Erbitux on the first day of treatment. The patients getting both drugs received the same dose of irinotecan as the one on which they had failed treatment. Two subgroups were also analyzed: irinotecan-refractory patients and those who had failed irinotecan and oxaliplatin (Eloxatin).

Researchers found a significant difference in objective response rates between the Erbitux/irinotecan and Erbitux-only arms—22.9% vs 10.8%, respectively (P = .007). The response rate favored the two-drug combination in both the failure group and the refractory arm, but the differences were not significant (P = .09 and .07, respectively). The median duration of response was significant in the total study population at 5.7 months in the combination arm and 4.2 months in the monotherapy group.

Median time to disease progression for all patients was 4.1 months vs 1.5 months. Among the failure patients, it was 2.9 months vs 1.5 months; and in the refractory arm, 4.0 months vs 1.5 months (P < .001 for all three patient groups).

In the 138-patient, single-arm, multi-center, open-label trial, patients received the same Erbitux dosage schedule as used in the phase II study. Seventy-four of the participants had documented progression on irinotecan. The response rate was 15% for the overall population and 12% for the failure group, and the median duration of response was 6.5 and 6.7 months, respectively.

Of the 57 patients enrolled in the multicenter, open-label, single-arm trial of Erbitux monotherapy, 28 patients had documented progression on irinotecan. Overall, the response rate was 9%, but it was 14% for the failure group. The median time to progression was 1.4 months for all patients, and 1.3 months for the failure arm. The median duration of response for both groups was 4.2 months.

Safety Data

An analysis of safety data from 633 patients treated with Erbitux found three adverse reactions serious enough to warrant warnings in the labeling: infusion reactions, interstitial lung disease, and dermatologic toxicity.

"Caution must be exercised with every Erbitux infusion," the labeling warns. "Severe infusion reactions require the immediate interruption of Erbitux therapy and permanent discontinuation from further treatment."