Bevacizumab (Avastin™) was the first U.S. Food and Drug Administration (FDA)-approved biological therapy designed to inhibit the formation of new blood vessels to tumors. It is manufactured by Genentech, South San Francisco, Calif. The National Cancer Institute (NCI), part of the National Institutes of Health, has been involved in the clinical development of bevacizumab in several tumor types under a cooperative research and development agreement (CRADA) with Genentech.

Tumor cells require a constant supply of blood to receive the oxygen and nutrients they need to survive. As a tumor grows, it signals the need for more blood by secreting growth factors that trigger the formation of new blood vessels, a process called angiogenesis. Of the many growth factors implicated in the formation of new blood vessels, vascular endothelial growth factor (VEGF) has been identified as one of the most potent proteins supporting tumor growth. In addition to affecting tumor growth, VEGF promotes formation of new capillaries surrounding the tumor, providing increased nutrients for growth and a convenient route for tumor cells to spread throughout the body.

Bevacizumab was developed to inhibit VEGF. It was designed to cause the destruction of the blood vessel networks that feed cancer cells, as the lack of a constant source of blood may slow tumor growth. Bevacizumab is an antibody—a type of targeting device produced by the immune system that can locate and bind to a specific protein. In the case of bevacizumab, it is a monoclonal (cells derived from a single common ancestor) antibody that binds to and inhibits VEGF.

History of Development

Bevacizumab is one of many angiogenesis inhibitors that have been developed based on a hypothesis of angiogenesis action published in 1971 by Judah Folkman, M.D., Harvard Medical School, Boston, Mass. By 1983, scientists had demonstrated that tumors secrete VEGF and by 1989, VEGF had been cloned for investigational purposes. The first clinical trials to examine the efficacy of anti-angiogenic agents for cancer patients began in the 1990s.

In February 2004, the FDA approved the use of bevacizumab based on a Phase III clinical trial sponsored by Genentech that showed benefit in first-line treatment of metastatic colorectal cancer when the drug was added to standard chemotherapy (Hurwitz H, Fehrenbach L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New England Journal of Medicine 2004; 350:2335-42). The results of this trial demonstrated that, when compared to the standard chemotherapy being prescribed for untreated metastatic colon cancer at the time, bevacizumab in combination with standard chemotherapy:

• Increased median overall survival by 30 percent (20.3 months vs. 15.6 months).
• Increased median progression-free survival, or the time that a patient's cancer was not growing, by 71 percent (10.6 months vs. 6.2 months).
• Increased response rate (45 percent vs. 35 percent) and duration of response to bevacizumab (10.4 months vs. 7.1 months).

Recent Trial Results

Bevacizumab has been investigated for efficacy in treatment in a number of cancers. The NCI, in collaboration with a network of investigators led by the Eastern Cooperative Oncology Group (ECOG), recently sponsored three key randomized clinical trials of bevacizumab, the first of which was a trial of metastatic colorectal cancer:

Preliminary results from a large, randomized clinical trial for patients with advanced colorectal cancer who had previously received treatment were released in November 2004 (http://www.nci.nih.gov/newscenter/pressreleases/BevacizumabOxaliplatin). This trial is different from the Genentech trial in February 2004 in several respects, particularly because it offered a different choice of chemotherapy. Researchers in this trial (known as E3200) found that the patients who received bevacizumab in combination with FOLFOX4 (a regimen of oxaliplatin, 5-fluorouracil and leucovorin) had a median overall survival of 12.5 months compared to patients treated with FOLFOX4 alone, who had a median overall survival of 10.7 months. This difference is statistically significant and corresponds to a 17 percent improvement in median overall survival. There was a 26 percent reduction in the risk of death for patients in this study who received bevacizumab plus FOLFOX4 compared to those who received FOLFOX4 alone.

A breast cancer clinical trial, which released initial results in April 2005 (http://www.nci.nih.gov/newscenter/pressreleases/AvastinBreast), demonstrated that bevacizumab, in combination with standard chemotherapy, delayed the progression of disease by an average of approximately 5 months. From December 2001 to May 2004, this randomized study enrolled 722 women who had recurrent or metastatic breast cancer, or cancer that had spread to other organs, that had not been previously treated with chemotherapy. The women were treated with bevacizumab in combination with paclitaxel, or paclitaxel alone. Those women receiving combination therapy showed a delay in development of their breast cancer that was statistically significant. This was the first study to show the benefit of anti-angiogenic therapy for breast cancer and was a major advance in the treatment of patients with metastatic disease.

A lung cancer study, which released its preliminary results in March 2005 (http://www.nci.nih.gov/newscenter/pressreleases/AvastinLung), showed that those patients receiving a combination therapy of bevacizumab and chemotherapy were living longer than patients receiving only standard chemotherapy. The interim results of this study were made public because the primary endpoint of improving overall survival had been achieved. Patients receiving a regimen of chemotherapy (paclitaxel and carboplatin) and bevacizumab had a median overall survival of 12.5 months compared to the control group, receiving only paclitaxel and carboplatin, who survived an average of 10.2 months. The improved survival of 2.3 months was statistically significant. The results of this randomized study were noteworthy because they revealed the potential for improved survival rates with the addition of an anti-angiogenic therapy. It should be noted, however, that these results apply only to patients in the study (those with advanced non-squamous, non-small cell lung cancer who had not previously received systemic chemotherapy) and that the most significant adverse event observed in this study was life-threatening or fatal bleeding, primarily from the lungs.

NCI, in collaboration with Genentech, is currently evaluating the potential use of bevacizumab in a number of different cancers. NCI is sponsoring more than 30 trials using this drug, including Phase III clinical trials in advanced or metastatic renal cell carcinoma, pancreatic cancer, and ovarian cancer. NCI also is conducting a Phase III trial evaluating the use of the drug for colorectal cancer patients who have undergone potentially curative surgery. For current information about ongoing clinical trials using bevacizumab, please go to http://www.cancer.gov/clinicaltrials/search.

It is important to note that there are general toxicities associated with bevacizumab therapy, including bleeding, arterial clots (which could lead to stroke and heart attack), bowel perforation, wound healing difficulties, and hypertension.

# # #

• National Cancer Institute Fact Sheet 7.2, Biological Therapies for Cancer: Questions and Answers ¹
  (http://www.cancer.gov/cancertopics/factsheet/Therapy/biological)
• National Cancer Institute Fact Sheet 7.42, Angiogenesis Inhibitors Therapy ²
  (http://www.cancer.gov/cancertopics/factsheet/Therapy/angiogenesis-inhibitors)
• Bevacizumab (Avastin™) for Metastatic Colorectal Cancer ³
  (http://www.cancer.gov/newscenter/pressreleases/bevacizumab)
• Bevacizumab (Avastin™) for Treatment of Solid Tumors: Questions and Answers ⁴
  (http://www.cancer.gov/cancertopics/factsheet/AvastinFactSheet)

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Glossary Terms

A drug used to treat symptoms of cancer of the colon, breast, stomach, and pancreas. It is also used in a cream to treat certain skin conditions. 5-fluorouracil stops cells from making DNA and it may kill cancer cells. It is a type of antimetabolite. Also called 5-FU and fluorouracil.

An unexpected medical problem that happens during treatment with a drug or other therapy. Adverse events do not have to be caused by the drug or therapy, and they may be mild, moderate, or severe. Also called adverse effect.

Blood vessel formation. Tumor angiogenesis is the growth of new blood vessels that tumors need to grow. This is caused by the release of chemicals by the tumor.

A substance that may prevent the formation of blood vessels. In anticancer therapy, an angiogenesis inhibitor may prevent the growth of new blood vessels that tumors need to grow.

A protein made by plasma cells (a type of white blood cell) in response to an antigen (a substance that causes the body to make a specific immune response). Each antibody can bind to only one specific antigen. The purpose of this binding is to help destroy the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen.

A drug used to treat several types of cancer, including certain types of colorectal, lung, breast, and kidney cancers and glioblastoma. It is also being studied in the treatment of other types of cancer. Avastin binds to vascular endothelial growth factor (VEGF) and may prevent the growth of new blood vessels that tumors need to grow. It is a type of antiangiogenesis agent and a type of monoclonal antibody. Also called bevacizumab.

A drug used to treat several types of cancer, including certain types of colorectal, lung, breast, and kidney cancers and glioblastoma. It is also being studied in the treatment of other types of cancer. Bevacizumab binds to vascular endothelial growth factor (VEGF) and may prevent the growth of new blood vessels that tumors need to grow. It is a type of antiangiogenesis agent and a type of monoclonal antibody. Also called Avastin.

Treatment to boost or restore the ability of the immune system to fight cancer, infections, and other diseases. Also used to lessen certain side effects that may be caused by some cancer treatments. Agents used in biological therapy include monoclonal antibodies, growth factors, and vaccines. These agents may also have a direct antitumor effect. Also called biological response modifier therapy, biotherapy, BRM therapy, and immunotherapy.

A tube through which the blood circulates in the body. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins.

The long, tube-shaped organ in the abdomen that completes the process of digestion. The bowel has two parts, the small bowel and the large bowel. Also called intestine.

Cancer that forms in tissues of the breast, usually the ducts (tubes that carry milk to the nipple) and lobules (glands that make milk). It occurs in both men and women, although male breast cancer is rare.

A term for diseases in which abnormal cells divide without control and can invade nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymph systems. There are several main types of cancer. Carcinoma is a cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is a cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is a cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the blood. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system. Central nervous system cancers are cancers that begin in the tissues of the brain and spinal cord. Also called malignancy.

The smallest type of blood vessel. A capillary connects an arteriole (small artery) to a venule (small vein) to form a network of blood vessels in almost all parts of the body. The wall of a capillary is thin and leaky, and capillaries are involved in the exchange of fluids and gases between tissues and the blood.

A drug that is used to treat advanced ovarian cancer that has never been treated or symptoms of ovarian cancer that has come back after treatment with other anticancer drugs. It is also used together with other drugs to treat advanced, metastatic, or recurrent non-small cell lung cancer and is being studied in the treatment of other types of cancer. Carboplatin is a form of the anticancer drug cisplatin and causes fewer side effects in patients. It attaches to DNA in cells and may kill cancer cells. It is a type of platinum compound. Also called Paraplatin.

The individual unit that makes up the tissues of the body. All living things are made up of one or more cells.

Treatment with drugs that kill cancer cells.

A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called clinical study.

Cancer that develops in the colon (the longest part of the large intestine) and/or the rectum (the last several inches of the large intestine before the anus).

In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works.

To heal or restore health; a treatment to restore health.

An object that has a specific use. In medicine, wheelchairs, pumps, and artificial limbs are examples of devices.

Any substance, other than food, that is used to prevent, diagnose, treat or relieve symptoms of a disease or abnormal condition. Also refers to a substance that alters mood or body function, or that can be habit-forming or addictive, especially a narcotic.

Effectiveness. In medicine, the ability of an intervention (for example, a drug or surgery) to produce the desired beneficial effect.

A drug used to treat symptoms of cancer of the colon, breast, stomach, and pancreas. It is also used in a cream to treat certain skin conditions. Fluorouracil stops cells from making DNA and it may kill cancer cells. It is a type of antimetabolite. Also called 5-fluorouracil and 5-FU.

An agency in the U.S. federal government whose mission is to protect public health by making sure that food, cosmetics, and nutritional supplements are safe to use and truthfully labeled. The Food and Drug Administration also makes sure that drugs, medical devices, and equipment are safe and effective, and that blood for transfusions and transplant tissue are safe. Also called FDA.

A substance made by the body that functions to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy.

A blood pressure of 140/90 or higher. Hypertension usually has no symptoms. It can harm the arteries and cause an increase in the risk of stroke, heart attack, kidney failure, and blindness. Also called high blood pressure.

A tentative proposal made to explain certain observations or facts that requires further investigation to be verified.

The complex group of organs and cells that defends the body against infections and other diseases.

In clinical trials, refers to a drug (including a new drug, dose, combination, or route of administration) or procedure that has undergone basic laboratory testing and received approval from the U.S. Food and Drug Administration (FDA) to be tested in human subjects. A drug or procedure may be approved by the FDA for use in one disease or condition, but be considered investigational in other diseases or conditions. Also called experimental.

The active ingredient in a drug used alone or in combination with other drugs to treat colon cancer or rectal cancer that has spread to other parts of the body or has come back after treatment with fluorouracil. It is also being studied in the treatment of other types of cancer. Irinotecan blocks certain enzymes needed for cell division and DNA repair, and it may kill cancer cells. It is a type of topoisomerase inhibitor and a type of camptothecin analog.

The active ingredient in a drug used to lessen the toxic effects of substances that block the action of folic acid, especially the anticancer drug methotrexate. Leucovorin is used to treat some types of anemia and is also used together with fluorouracil to treat colorectal cancer. It is also being studied in the treatment of other types of cancer and other conditions. Leucovorin is a form of folic acid. It is a type of chemoprotective agent and a type of chemosensitizing agent. Also called folinic acid.

Cancer that forms in tissues of the lung, usually in the cells lining air passages. The two main types are small cell lung cancer and non-small cell lung cancer. These types are diagnosed based on how the cells look under a microscope.

A statistics term. The middle value in a set of measurements.

Having to do with metastasis, which is the spread of cancer from the primary site (place where it started) to other places in the body.

The National Cancer Institute, part of the National Institutes of Health of the United States Department of Health and Human Services, is the Federal Government's principal agency for cancer research. The National Cancer Institute conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the National Cancer Institute Web site at http://www.cancer.gov. Also called NCI.

A federal agency in the U.S. that conducts biomedical research in its own laboratories; supports the research of non-Federal scientists in universities, medical schools, hospitals, and research institutions throughout the country and abroad; helps in the training of research investigators; and fosters communication of medical information. Access the National Institutes of Health Web site at http://www.nih.gov. Also called NIH.

A group of lung cancers that are named for the kinds of cells found in the cancer and how the cells look under a microscope. The three main types of non-small cell lung cancer are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. Non-small cell lung cancer is the most common kind of lung cancer.

A chemical compound (such as protein, fat, carbohydrate, vitamin, or mineral) contained in foods. These compounds are used by the body to function and grow.

The study of cancer.

A part of the body that performs a specific function. For example, the heart is an organ.

Cancer that forms in tissues of the ovary (one of a pair of female reproductive glands in which the ova, or eggs, are formed). Most ovarian cancers are either ovarian epithelial carcinomas (cancer that begins in the cells on the surface of the ovary) or malignant germ cell tumors (cancer that begins in egg cells).

A drug used together with other drugs to treat colorectal cancer that is advanced or has come back. It is also being studied in the treatment of other types of cancer. Oxaliplatin attaches to DNA in cells and may kill cancer cells. It is a type of platinum compound. Also called Eloxatin.

A colorless, odorless gas. It is needed for animal and plant life. Oxygen that is breathed in enters the blood from the lungs and travels to the tissues.

A drug used to treat breast cancer, ovarian cancer, and AIDS-related Kaposi sarcoma. It is also used together with another drug to treat non-small cell lung cancer. Paclitaxel is also being studied in the treatment of other types of cancer. It blocks cell growth by stopping cell division and may kill cancer cells. It is a type of antimitotic agent. Also called Taxol.

A disease in which malignant (cancer) cells are found in the tissues of the pancreas. Also called exocrine cancer.

A study to compare the results of people taking a new treatment with the results of people taking the standard treatment (for example, which group has better survival rates or fewer side effects). In most cases, studies move into phase III only after a treatment seems to work in phases I and II. Phase III trials may include hundreds of people.

The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins.

In medicine, the course of a disease, such as cancer, as it becomes worse or spreads in the body.

The length of time during and after treatment in which a patient is living with a disease that does not get worse. Progression-free survival may be used in a clinical study or trial to help find out how well a new treatment works. Also called PFS.

A molecule made up of amino acids that are needed for the body to function properly. Proteins are the basis of body structures such as skin and hair and of substances such as enzymes, cytokines, and antibodies.

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.

Cancer that has recurred (come back), usually after a period of time during which the cancer could not be detected. The cancer may come back to the same place as the original (primary) tumor or to another place in the body. Also called recurrence.

A treatment plan that specifies the dosage, the schedule, and the duration of treatment.

The most common type of kidney cancer. It begins in the lining of the renal tubules in the kidney. The renal tubules filter the blood and produce urine. Also called hypernephroma.

In medicine, an improvement related to treatment.

The percentage of patients whose cancer shrinks or disappears after treatment.

A person who has studied science, especially one who is active in a particular field of investigation.

Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. Also called significant.

In medicine, a loss of blood flow to part of the brain, which damages brain tissue. Strokes are caused by blood clots and broken blood vessels in the brain. Symptoms include dizziness, numbness, weakness on one side of the body, and problems with talking, writing, or understanding language. The risk of stroke is increased by high blood pressure, older age, smoking, diabetes, high cholesterol, heart disease, atherosclerosis (a build-up of fatty material and plaque inside the coronary arteries), and a family history of stroke.

A procedure to remove or repair a part of the body or to find out whether disease is present. An operation.

Affecting the entire body.

In medicine, a specific event that starts a process or that causes a particular outcome. For example, chemotherapy, painful treatments, or the smells, sounds, and sights that go with them may trigger anxiety and fear in a patient who has cancer. In allergies, exposure to mold, pollen or dust may trigger sneezing, watery eyes, and coughing.

An abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumors may be benign (not cancer), or malignant (cancer). Also called neoplasm.

A substance made by cells that stimulates new blood vessel formation. Also called VEGF.

A break in the skin or other body tissues caused by injury or surgical incision (cut).