ROCKVILLE, Maryland-In February 2004, the US Food and Drug Administration (FDA) approved two agents that work by different mechanisms to slow tumor growth in patients with colorectal cancer. The decisions represent the first FDA approval of targeted therapy in colorectal cancer with a monoclonal antibody or an antiangiogenesis drug. Both products- cetuximab (Erbitux, ImClone) and bevacizumab (Avastin, Genentech, Inc.)-are genetically engineered versions of a mouse antibody that contain both human and mouse components, and both showed good tumor response rates in clinical trials. On February 12, cetuximab was approved to treat advanced metastatic colorectal cancer, in combination intravenously with irinotecan (Camptosar), or given alone for patients who cannot tolerate irinotecan. According to the FDA, cetuximab "is the first monoclonal antibody approved to treat this type of cancer." It is believed to work by targeting the epidermal growth factor receptor (EGFR) on the surface of cancer cells, interfering with their growth. On the heels of that announcement, the FDA approved on February 26 use of bevacizumab as first-line treatment for patients with metastatic colorectal cancer, representing "the first [antiangiogenesis] product that has been proven to delay tumor growth and more importantly, significantly extend the lives of patients," the agency said. Bevacizumab is thought to work by targeting and inhibiting the function of vascular endothelial growth factor (VEGF), in turn preventing new blood vessel formation essential for tumor cell growth. Erbitux Shrank Tumors, Delayed Growth
Treatment with Erbitux, approved under FDA's accelerated-approval program, has not been shown to extend patients' lives, but it shrank tumors in some patients and delayed tumor growth, especially when used as a combination treatment. For patients with tumors that express EGFR and who no longer re- sponded to irinotecan alone or in combination with other chemotherapy drugs, combination treatment with Erbitux and irinotecan shrank tumors in 22.9% of patients and delayed tumor growth by approximately 4.1 months. For patients who received Erbitux alone, the tumor response rate was 10.8%, and tumor growth was delayed by 1.5 months. Efficacy and safety of Erbitux alone or in combination with irinotecan were studied in a randomized, controlled trial in 329 patients, and in a 138- patient combination study in which all patients received both drugs. It was further evaluated as a single agent in a third clinical trial with 57 patients. Safety data from an additional 111 patients treated only with Erbitux were also evaluated. All trials included patients with EGFR-expressing metastatic colorectal cancer whose disease had progressed after receiving irinotecan. Severe infusion reactions have occurred in 3% of patients and were characterized by rapid onset of airway obstruction, rash, and hypotension; they were rarely fatal, and 90% were associated with the first infusion, according to a boxed warning in the package insert. Interstitial lung disease has been reported infrequently, but the association is unclear. Besides the acneiform rash often seen with Erbitux, more common side-effects include dry skin, tiredness or weakness, fever, constipation, and abdominal pain. Avastin: Result of Years of R&D
"The approval of Avastin is the result of many years of research and development exploring a promising new approach to fighting cancer, and it is one of a number of recent new treatments for colorectal cancer that, taken together, have significantly improved the armamentarium for fighting this disease," said FDA Commissioner Mark B. McClellan, MD, PhD. Safety and efficacy of Avastin was primarily shown in a randomized, double-blind clinical trial of more than 800 patients with metastatic colorectal cancer that was designed to assess whether it extended survival duration. Half of the patients received the new standard chemotherapy, IFL (irinotecan, 5-FU, and leucovorin) and half received Avastin once every 2 weeks in addition to IFL. Patients given Avastin/ IFL survived about 5 months longer and the average time to tumor regrowth or appearance or new tumors was 4 months longer than with IFL alone. Overall response rate to the treatment was 45% vs 35% for the control arm of the trial. Serious, but uncommon, side-effects include gastrointestinal perforation, generally requiring surgery and sometimes leading to intra-abdominal infections; impaired wound healing; and pulmonary or internal hemorrhage. More common side-effects include hypertension, tiredness, thrombosis, diarrhea, decreased leukocytes, headache, loss of appetite, and mouth sores.