FDA approves Avastin

Townsend Letter for Doctors and Patients,  May, 2004  by Ralph Moss, W.

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In February, the US Food and Drug Administration (FDA) approved Avastin (bevacizumab) for the treatment of advanced colorectal cancer. Avastin is an angiogenesis inhibitor. It works by targeting and inhibiting the functioning of vascular endothelial growth factor (VEGF), which stimulates new blood vessel formation. When bound by Avastin, VEGF can no longer stimulate the growth of blood vessels, thus denying tumors the blood, oxygen and other nutrients they need for growth. Avastin has been approved as a first-line treatment for patients with metastatic colorectal cancer. It thus will be highly competitive with another newly approved drug, Erbitux, which only received approval as a last-ditch therapy for advanced stages of this disease.

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Both Erbitux and Avastin are genetically engineered versions of a mouse antibody that contains both human and mouse components. Avastin is the first angiogenesis inhibitor ever approved to treat cancer. As such, it has generated a great deal of hope and excitement. It appears to work in accordance with a theory put forward 30 years ago by Professor Judah Folkman of Harvard, who suggested that by stopping the growth of new blood vessels one could stop the growth of cancer.

The FDA approved Avastin based on the results of a randomized, double-blind clinical trial of more than 800 patients with metastatic colorectal cancer. Avastin was found to extend colorectal cancer patients' lives by 4.7 months, when given intravenously along with a standard chemotherapy regimen known as IFL (aka the 'Saltz regimen'). IFL includes the already-approved drugs irinotecan (Camptosar or CPT 11), 5-fluorouracil (5FU) and leucovorin. Patients who received IFL alone lived on average 15.6 months. Those who also got Avastin survived on average 20.3 months. The average time before tumors started re-growing, or new tumors appeared, was four months longer in patients given Avastin than in patients who received IFL alone. The overall response rate to the IFL/Avastin treatment was 45% compared to 35% for the control arm of the trial. There is no mention of any complete responses or cures. (Responses are significant tumor shrinkages that last for one month or more.)

These positive results with Avastin came as a surprise. Just last year, its prospects did not look particularly promising. A 2003 clinical trial at the National Cancer Institute, for example, found that there were no significant differences in overall survival between those getting high-dose Avastin, low-dose Avastin, and no supplemental Avastin at all. (Yang 2003)

Yet Mark B. McClellan, MD, PhD, the departing FDA Commissioner, apparently sees things in a very different light. Both Avastin and Erbitux have "significantly improved the armamentarium for fighting this disease," he claimed. "These medical achievements [are] ... making a real difference in the lives of cancer patients." (FDA News, 2004)

Serious Side Effects

Angiogenesis inhibitors have been widely hailed as a benign form of treatment. According to an interview with Dr. Folkman, "... unlike chemotherapy, angiogenesis inhibitors will be used on a long-term basis for two important reasons: they will not generate drug resistance and they will be non-toxic." (Folkman, 2004)

However, in the current trials treatment with Avastin plus chemotherapy had many adverse consequences. At Genentech's website, www.avastin.com, the company states that "administration can result in the development of gastrointestinal perforation as well as wound dehiscence, in some instances resulting in fatality." (Dehiscence is the rupture or splitting open of a surgical wound, or of an organ or structure.) With Avastin, such perforations are sometimes associated with the formation of abscesses in the bowel. According to the FDA, this may be accompanied by internal bleeding. The incidence of this type of severe adverse event was 2%.

High Blood Pressure Crises

The Genentech website further states that "serious, and in some cases fatal, hemoptysis has occurred in patients with non-small cell lung cancer treated with chemotherapy and Avastin." Hemoptysis is the expectoration of blood or of blood-streaked sputum from the larynx, trachea, bronchi, or lungs. "In a small study," it continues, "the incidence of serious or fatal hemoptysis was 31% in patients with squamous histology (the microscopic structure of tissues, ed.) and 4% in patients with adenocarcinoma receiving Avastin...."

In the clinical trials just announced, the treatment was associated with high blood pressure in 60% of patients. In 7% this hypertension was severe enough to constitute a crisis (with a cuff reading of more than 200/110 mmHg), requiring emergency treatment. Despite palliative treatment, however, the hypertension was found to be long-lasting in a majority of cases. "Four months after discontinuation of therapy, persistent hypertension was present in 18 of 26 patients that received bolus-IFL plus Avastin and 8 of 10 patients that received bolus-IFL plus placebo." (A 'bolus' is a single relatively large dose of a drug.) In other words, the company is suggesting that severe hypertension is caused more by the IFL than by Avastin itself.