Cancer Medications : Avastin

by National Cancer Institute

(Page 4 of 18)

• Approval for First-Line Treatment of Metastatic Colorectal Cancer
• Drug Warning Issued
• Approval for Second-Line Treatment of Metastatic Colorectal Cancer

Approval for First-Line Treatment of Metastatic Colorectal Cancer

On February 26, 2004, the FDA approved bevacizumab (Avastin®, a trademark of Genentech, Inc.) as a first-line treatment for patients with metastatic colorectal cancer - cancer that has spread to other parts of the body. Avastin, a monoclonal antibody, is the first product to be approved that works by preventing the formation of new blood vessels, a process known as angiogenesis.

Avastin was shown to extend patients' lives by about five months when given intravenously as a combination treatment along with standard chemotherapy drugs for colon cancer (the "Saltz regimen" also known as IFL). IFL treatment includes ironotecan, 5-fluorouracil (5FU) and leucovorin.

Avastin is a genetically engineered version of a mouse antibody that contains both human and mouse components. (Antibodies are substances produced by the body's immune system to fight foreign substances.) Special technology also allows it to be produced in large quantities in the laboratory.

This new monoclonal antibody is believed to work by targeting and inhibiting the function of a natural protein called "vascular endothelial growth factor" (VEGF) that stimulates new blood vessel formation. When VEGF is targeted and bound to Avastin, it cannot stimulate the growth of blood vessels, thus denying tumors blood, oxygen and other nutrients needed for growth.

Angiogenesis inhibitors such as Avastin have been studied, first in the laboratory and then in patients, for three decades with the hope they might prevent the growth of cancer. This is the first such product that has been proven to delay tumor growth and more importantly, significantly extend the lives of patients.

"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 Mark B. McClellan, M.D., Ph.D., FDA Commissioner. "These medical achievements reflect the innovation of drug developers and the hard work of FDA's cancer review teams, and they are proof of the promise offered by biomedical innovation. The dedication of everyone involved in these efforts is making a real difference in the lives of cancer patients."

Colorectal cancer - cancer of the colon or rectum - is the third most common cancer affecting men and women in the U.S. and, according to the Centers for Disease Control and Prevention (CDC), is the second leading cause of cancer-related death. Colorectal cancer is also one of the most commonly diagnosed cancers in the U.S.; approximately 147,500 new cases were diagnosed in 2003.

The safety and efficacy of Avastin was primarily shown in a randomized, double-blind clinical trial of more than 800 patients with metastatic colorectal cancer designed to find out whether Avastin extended the lives of patients. Roughly half the patients received IFL, the standard chemotherapy combination, and the other half received Avastin once every two weeks in addition to IFL.

Overall, patients given Avastin in combination with IFL survived about five months longer and the average time before tumors started regrowing or new tumors appeared was four months longer than patients receiving IFL alone. The overall response rate to the treatment was 45 percent compared to 35 percent for the control arm of the trial.

Serious, but uncommon, side-effects of Avastin include formation of holes in the colon (gastrointestinal perforation) generally requiring surgery and sometimes leading to intra-abdominal infections, impaired wound healing, and bleeding from the lungs or internally. Other, more common, side-effects are high blood pressure, tiredness, blood clots, diarrhea, decreased white blood cells (lowering immunity to diseases) headache, appetite loss and mouth sores.

Drug Warning Issued

On August 12, 2004, the FDA and Genentech, Inc. issued an important drug warning 10 to healthcare providers that there is evidence of an increased risk of serious arterial thromboembolic events, including cerebrovascular accident, myocardial infarctions, transient ischemic attacks, and angina related to Avastin. The risk of fatal arterial thrombotic events is also increased. In randomized, active-controlled studies conducted in patients with metastatic colorectal cancer, the risks of a serious arterial thrombotic event was approximately two-fold higher in patients receiving infusional 5-FU based chemotherapy plus Avastin, with an estimated overall rate of up to 5 percent.

Approval for Second-Line Treatment of Metastatic Colorectal Cancer

On June 20, 2006, the FDA granted approval for a labeling extension for bevacizumab (Avastin®, made by Genentech), administered in combination with intravenous 5-fluorouracil-based chemotherapy, for the second-line treatment of metastatic carcinoma of the colon or rectum. This recommendation is based on the demonstration of a statistically significant improvement in overall survival (OS) in patients receiving Avastin plus FOLFOX4 (5-flourouracil, leucovorin, and oxaliplatin) when compared to those receiving FOLFOX4 alone.

The trial (E3200) supporting this approval was an openlabel, randomized, three-arm, active-controlled, multicenter clinical trial evaluating Avastin alone (n=244), Avastin plus FOLFOX4 (n=293), and FOLFOX4 alone (n=292). Following a planned interim analysis, the Avastin monotherapy arm was closed to accrual based on evidence of decreased survival in patients treated with Avastin alone compared with FOLFOX4 alone.

Patients entered on the trial had progressive or recurrent disease following prior 5-FU and irinotecan-based therapy. Patients (99 percent) received irinotecan with or without 5-FU as initial therapy for metastatic disease; those who received adjuvant irinotecan-based chemotherapy were required to have recurred within six months of completing therapy.

In both the combination and monotherapy arms, Avastin was administered at a dose of 10 mg/kg every two weeks. The FOLFOX4 regimen, administered every two weeks, consisted of oxaliplatin 85 mg/m2 and leucovorin 200 mg/m2 administered concurrently as an intravenous infusion, then 5FU 400 mg/m2 IV bolus followed by 5FU 600 mg/m2 continuous intravenous infusion on Day 1. On Day 2, patients received leucovorin 200 mg/m2 IV, then 5FU 400 mg/m2 IV bolus followed by 5FU 600 mg/m2 continuous intravenous infusion. When given in combination with FOLFOX4, Avastin was administered on Day 1 prior to oxaliplatin and leucovorin.

Among the 829 randomized patients, the median age was 61 years and 49 percent had an ECOG performance status of 0. Twenty-six percent had received prior radiation therapy, 80 percent received prior adjuvant chemotherapy, and all received prior irinotecan therapy.

Overall survival, the trial's primary endpoint, was significantly longer in patients receiving Avastin in combination with FOLFOX4 as compared to those receiving FOLFOX4 alone (median overall survival was 13.0 months vs. 10.8 months; hazard ratio 0.75, p=0.001 stratified log rank test). The survival benefit was also observed in subgroups defined by age (<65 vs. >65 yrs) and gender. Patients treated with the Avastin combination were reported by investigator assessment to have significantly longer progression-free survival and higher overall response rate.

The most serious, and sometimes fatal, Avastin toxicities are gastrointestinal perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome and congestive heart failure. The most common adverse events in patients receiving Avastin are asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis, and proteinuria.

In Trial E3200, data were collected only for NCI-CTC grade 3-5 adverse events. Therefore, these data are likely to under-estimate the true adverse event rates. In addition, neither the time of onset nor the time to resolution of adverse events were collected.

NCI-CTC grade 3-5 adverse events that were more common in patients receiving the Avastin compared to FOLFOX4 alone were

• fatigue (19 percent vs. 13 percent)
• diarrhea (18 percent vs. 13 percent)
• sensory neuropathy (17 percent vs. 9 percent)
• nausea (12 percent vs. 5 percent)
• vomiting (11 percent vs. 4 percent)
• dehydration (10 percent vs. 5 percent)
• hypertension (9 percent vs. 2 percent)
• abdominal pain (8 percent vs. 5 percent)
• hemorrhage (5 percent vs. 1 percent)
• other neurologic toxicities (5 percent vs. 3 percent)
• ileus (4 percent vs. 1 percent)
• headache (3 percent vs. 0)

Fatal, treatment-related adverse events in patients receiving Avastin in this study included CNS hemorrhage, gastrointestinal hemorrhage, and gastrointestinal perforation with sepsis.

The current prescribing information 11 includes clinical trial information, safety, dosing, drug-drug interactions, and contraindications.

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