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Brand name(s): Avastin®

• Approved for First-Line Treatment of Metastatic Colorectal Cancer
• Approved for Second-Line Treatment of Metastatic Colorectal Cancer
• Approved for First-Line Treatment of Non-Small Cell Lung Cancer (NSCLC)
• Approved for Metastatic HER2 Negative Breast Cancer
• Drug Warnings Issued

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. Bevacizumab, 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.

Bevacizumab 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.

Bevacizumab 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 bevacizumab, it cannot stimulate the growth of blood vessels, thus denying tumors blood, oxygen and other nutrients needed for growth.

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

Overall, patients given bevacizumab 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 bevacizumab 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.

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 bevacizumab 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 bevacizumab alone (n=244), bevacizumab plus FOLFOX4 (n=293), and FOLFOX4 alone (n=292). Following a planned interim analysis, the bevacizumab monotherapy arm was closed to accrual based on evidence of decreased survival in patients treated with bevacizumab 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, bevacizumab 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, bevacizumab 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 bevacizumab 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 bevacizumab combination were reported by investigator assessment to have significantly longer progression-free survival and higher overall response rate.

The most serious, and sometimes fatal, bevacizumab toxicities are gastrointestinal perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome and congestive heart failure. The monthst common adverse events in patients receiving bevacizumab 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 bevacizumab 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 bevacizumab in this study included CNS hemorrhage, gastrointestinal hemorrhage, and gastrointestinal perforation with sepsis.

First-Line Treatment of Non-Small Cell Lung Cancer (NSCLC)

On October 11, 2006, the FDA granted approval for a labeling extension for bevacizumab (Avastin®, Genentech, Inc.), administered in combination with carboplatin and paclitaxel, for the initial systemic treatment of patients with unresectable, locally advanced, recurrent, or metastatic, non-squamous, non-small cell lung cancer. This recommendation is based on the demonstration of a statistically significant improvement in overall survival (OS) in patients receiving bevacizumab with carboplatin and paclitaxel compared to those receiving carboplatin and paclitaxel alone.

The primary trial (E4599) supporting this approval was a randomized, active controlled, open label, multi-center clinical trial evaluating bevacizumab plus carboplatin and paclitaxel (n=434) versus carboplatin and paclitaxel alone (n=444). (See the protocol summary.)

Among the 878 randomized patients, the median age was 63, 46 percent were female, no patients had received prior chemotherapy, 76 percent had stage IV disease, 12 percent had stage IIIB disease with malignant pleural effusion, 11 percent had recurrent disease, and 40 percent had an ECOG performance status of 0.

OS, the primary endpoint, was significantly longer in patients receiving bevacizumab in combination with paclitaxel and carboplatin as compared to those receiving paclitaxel and carboplatin alone (median OS 12.3 vs 10.3 mos; hazard ratio 0.80, p=0.013 stratified log rank test). Although a consistent effect was observed across most subgroups, in an exploratory analysis, evidence of a survival benefit was not observed in women (HR 0.99; 95 percent CI 0.79, 1.25).

In E4599, data collection was limited to NCI-CTC grade 3-5 adverse events. Severe and life-threatening adverse events occurring more frequently in patients receiving bevacizumab and chemotherapy were

• neutropenia (27 percent vs. 17 percent)
• fatigue (16 percent vs. 13 percent)
• hypertension (8 percent vs. 0.7 percent)
• infection without neutropenia (7 percent vs. 3 percent)
• thrombosis/embolism (5 percent vs. 3 percent)
• pneumonitis or pulmonary infiltrate (5 percent vs. 3 percent)
• infection with grade 3 or 4 neutropenia (5 percent vs. 2 percent)
• febrile neutropenia (5 percent vs. 2 percent)
• hyponatremia (4 percent vs. 1 percent)
• proteinuria (3 percent vs. 0)
• headache (3 percent vs. 0.5 percent)

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

Metastatic HER2-Negative Breast Cancer

On February 22, 2008, the FDA granted accelerated approval for bevacizumab (Avastin®, made by Genentech) to be used in combination with paclitaxel (Taxol®) for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer.

The approval was based on the demonstration of an improvement in progression-free survival (PFS) in patients receiving bevacizumab with paclitaxel compared to those receiving paclitaxel alone as a first-line treatment for metastatic breast cancer. No data are currently available that demonstrate an improvement in disease-related symptoms or increased overall survival with bevacizumab in breast cancer.

The efficacy and safety of bevacizumab as first-line treatment of patients with metastatic breast cancer was studied in a single, open-label, randomized, multicenter study (Study 7 or E2100). Patients who had not received chemotherapy for locally recurrent or metastatic breast cancer were randomized to receive either paclitaxel (N=354 patients) alone at 90 mg/m2 weekly for three doses with one week rest (28-day cycle) or in combination with bevacizumab 10 mg/kg every 14 days (N=368 patients). Patients with HER2-overexpressing breast cancer were not eligible unless they had received prior therapy with trastuzumab (Herceptin®).

The addition of bevacizumab to paclitaxel resulted in an improvement in PFS with no significant improvement in overall survival. The median PFS was 11.3 months (95 percent CI 10.5,13.3) and 5.8 months (95 percent CI 5.4, 8.2) months for the bevacizumab plus paclitaxel arms versus the paclitaxel alone, respectively (p<0.0001, HR 0.48, 95 percent CI 0.39, 0.61) Partial response rates in patients with measurable disease were higher with bevacizumab plus paclitaxel: 48.9 percent versus 22.2 percent (p<0.001). No complete responses were observed.

The efficacy and safety of bevacizumab as a second and third line treatment of patients with metastatic breast cancer were studied in a single open-label randomized study (Study 8 or AVF2119). Patients who had received prior anthracycline and taxane therapy in the adjuvant setting or for their metastatic breast cancer were randomized to receive either capecitabine alone or in combination with bevacizumab. The study enrolled 462 patients. The study failed to demonstrate a statistically significant effect on PFS or overall survival. The product labeling specifies that bevacizumab is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

Data collection in Trial 7 was limited to NCI-CTC grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events. A 20 percent increase in grade 3-5 adverse events was observed in the bevacizumab plus paclitaxel arm compared to paclitaxel alone. Severe and life-threatening adverse events occurring more frequently on the bevacizumab-containing arm included sensory neuropathy, hypertension, fatigue, infection without neutropenia, neutropenia, vomiting, diarrhea, bone pain, headache, proteinuria, and cerebrovascular ischemia. Fatal adverse reactions occurred in 6 of 363 (1.7 percent) of patients who received paclitaxel plus bevacizumab. Causes of death were gastrointestinal perforation (two patients), myocardial infarction (two patients), diarrhea/abdominal pain/weakness/hypotension (two patients).

The most serious, and sometimes fatal, bevacizumab adverse events have been previously described in product labeling and include gastrointestinal perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome, congestive heart failure, and neutropenic sepsis. The most common bevacizumab adverse events previously described in product labeling include asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis, and proteinuria.

Drug Warnings Issued

On August 12, 2004, the FDA and Genentech, Inc. issued an important drug warning 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 bevacizumab. 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 bevacizumab, with an estimated overall rate of up to 5 percent.

On September 27, 2006, the FDA and Genentech, Inc. issued another important drug warning to healthcare providers that, for patients taking bevacizumab, there is evidence of an increased risk of reversible posterior leukoencephalopathy syndrome (RPLS), a rare brain-capillary leak syndrome associated with hypertension, fluid retention, and cytotoxic effects of immunosuppressive drugs on the vascular endothelium. There is also an increased risk of nasal septum perforation, so prescribing information has been revised to include that serious adverse effect.

On September 24, 2007, the FDA issued a safety labeling update. The updated prescribing information notes that non-gastrointestinal fistula formation has been reported in patients treated with bevacizumab in controlled clinical studies (with an incidence of < 0.3%) and in post-marketing experience, in some cases with fatal outcome. Fistula formation involving the following areas of the body other than the gastrointestinal tract has been reported: tracheo-esophageal, bronchopleural, biliary, vaginal, and bladder. Events were reported throughout treatment with bevacizumab, with most events occurring within the first six months. Physicians are instructed to permanently discontinue bevacizumab in patients with fistula formation involving an internal organ.

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

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