Genentech is a leader in research and development in angiogenesis, the process of forming new blood vessels. While angiogenesis normally occurs during certain stages of human development, the adult body produces new blood vessels infrequently — for example, once a month in women during menstruation, and as a part of wound healing in both men and women. In the context of cancer, tumor angiogenesis is the creation of a network of blood vessels that supplies tumors with essential nutrients and oxygen, and removes waste products.1
In 1989, Napoleone Ferrara, M.D., and a team of scientists at Genentech first isolated human vascular endothelial growth factor (VEGF), a protein now believed to be one of the most potent sources of angiogenesis.2, 3 The need for oxygen and nutrients triggers tumor cells to produce and release the VEGF protein, which leads to the formation of new blood vessels to feed the tumor. In addition to supporting tumor growth, these new vessels provide a "highway" along which tumor cells can travel through the bloodstream to other parts of the body. This may lead to the formation of new tumors and spread of cancer (metastasis). Sustained angiogenesis is a hallmark of most, if not all cancers.4 Without angiogenesis, a tumor would not likely grow beyond a few millimeters, the size of an average pencil eraser.3
Anti-Angiogenesis As researchers gained a greater understanding of VEGF and its role in angiogenesis, they turned their focus to creating therapies that could interfere with angiogenesis by targeting the VEGF protein, one of the most potent and predominant regulators of angiogenesis.
Therapies that inhibit VEGF may have multiple effects on angiogenesis, tumor growth and delivery of other types of therapy.5,6 These effects may include:
- Reducing the tumor's blood supply by potentially causing existing small blood vessels in the tumor to die.
- Preventing the development of new blood vessels in the tumor.
- Facilitating the delivery of chemotherapy to the tumor cells by potentially making mature tumor vessels, which tend to be leaky, behave more like normal vessels.
By inhibiting the VEGF protein, the blood supply to a tumor may be gradually reduced.
Avastin: The First Anti-Angiogenesis Treatment For Cancer In 1993, Dr. Ferrara and his team at Genentech produced a monoclonal antibody that specifically binds to the VEGF protein, preventing it from promoting new blood vessel growth.7 In 2004, after seven years of human clinical trials, the U.S. Food and Drug Administration (FDA) approved the antibody, known as Avastin® (bevacizumab), in combination with intravenous 5-fluorouracil (FU)-based chemotherapy for the first-line treatment of patients with metastatic colorectal cancer. Avastin is the first approved anti-angiogenesis treatment for cancer.
Avastin was initially approved based on the results of a Phase III study of the drug plus chemotherapy in previously untreated metastatic colorectal cancer patients. This study provided the first Phase III clinical validation of the long-standing hypothesis that targeting a tumor's blood supply via angiogenesis could be used as a cancer therapy.
In June 2006, the FDA approved Avastin in combination with intravenous 5-FU-based chemotherapy for the second-line treatment of patients with metastatic colorectal cancer. In October 2006, the FDA approved Avastin in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer (NSCLC).
In July 2009, Avastin was approved for the treatment of people with metastatic renal cell carcinoma in combination with interferon alfa.
BOXED WARNINGS and Additional Important Safety Information People receiving Avastin may experience side effects. In clinical trials, some people treated with Avastin experienced serious and sometimes fatal side effects, including:
Gastrointestinal (GI) perforation: Treatment with Avastin can result in the development of a potentially serious side effect called GI perforation, which is the development of a hole in the stomach, small intestine, or large intestine. In clinical trials, this event occurred in more people who received Avastin than in the comparison group (0.3% to 2.4%). In some cases, GI perforation resulted in fatality. Avastin therapy should be permanently stopped if GI perforation occurs.
Surgery and wound healing problems: Treatment with Avastin can lead to slow or incomplete wound healing (for example, when a surgical incision has trouble healing or staying closed). In some cases, this event resulted in fatality. Surgery and wound healing problems occurred more often in people who received Avastin than in the comparison group. Avastin therapy should not be started for at least 28 days after surgery and until the surgical wound is fully healed. The length of time between stopping Avastin and having voluntary surgery without the risk of having surgery and wound healing problems has not been determined. Treatment with Avastin should be stopped at least 28 days before voluntary surgery and in people with surgery and wound healing problems that require medical treatment.
Severe bleeding: Treatment with Avastin can result in serious bleeding, including coughing up blood, bleeding in the stomach, vomiting of blood, bleeding in the brain, nosebleeds, and vaginal bleeding. These events occurred up to 5 times more often in people who received Avastin. Across cancer types, 1.2% to 4.6% of people who received Avastin experienced severe to fatal bleeding. People who have recently coughed up blood (greater than or equal to a half teaspoon of red blood) or have serious bleeding should not receive Avastin. Treatment with Avastin should be permanently stopped if serious bleeding occurs (i.e., requiring medical attention).
In clinical trials for different cancer types, there were additional serious and sometimes fatal side effects that occurred in more people who received Avastin than in those in the comparison group. The formation of an abnormal passage from parts of the body to another part (non-GI fistula formation) was seen in 0.3% or less of people. Severe to life threatening stroke or heart problems were seen in 2.4% of people. Too much protein in the urine, which led to kidney problems, was seen in less than 1% of people. Additional serious side effects that occurred in more people who received Avastin than those in the comparison group included severe to life-threatening high blood pressure, which was seen in 5% to 18% of people, and nervous system and vision disturbances (reversible posterior leukoencephalopathy syndrome), which was seen in less than 0.1% of people. Infusion reactions with the first dose of Avastin were uncommon and occurred in less than 3% of people, and severe reactions occurred in 0.2% of people.
Common side effects that occurred in more than 10% of people who received Avastin for different cancer types, and at least twice the rate of the comparison group, were nosebleeds, headache, high blood pressure, inflammation of the nose, too much protein in the urine, taste change, dry skin, rectal bleeding, tear production disorder, back pain, and inflammation of the skin (exfoliative dermatitis). Across all trials, treatment with Avastin was permanently stopped in 8.4% to 21% of people because of side effects.
Avastin may impair fertility. Patients who are pregnant or thinking of becoming pregnant should talk with their doctor about the potential risk of loss of the pregnancy or the potential risk of Avastin to the fetus during and following Avastin therapy, and the need to continue an effective birth control method for at least 6 months following the last dose of Avastin.
First-line Metastatic Colorectal Cancer In the first-line metastatic colorectal cancer trial, the most common severe to life-threatening side effects that increased by 2% or more in people who received Avastin plus IFL (chemotherapy) vs IFL (chemotherapy) alone were weakness (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), high blood pressure (12% vs 2%), blood clots in the veins of the body (9% vs 5%), blood clots inside the abdomen (3% vs 1%), a brief loss of consciousness (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), reduced white blood cell counts (37% vs 31%), and reduced white blood cell counts that may increase the chance of infection (21% vs 14%).
Second-line Metastatic Colorectal Cancer In the second-line metastatic colorectal cancer trial, the most common severe to life-threatening and fatal side effects that increased by 2% or more in people who received Avastin plus FOLFOX4 (chemotherapy) vs FOLFOX4 (chemotherapy) alone were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), blockage of the bowel (4% vs 1%), numbness and tingling in fingers and toes (17% vs 9%), nervous system disturbances (5% vs 3%), tiredness (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), high blood pressure (9% vs 2%), and severe bleeding (5% vs 1%).
Metastatic Kidney Cancer In the metastatic kidney cancer trial, the most common severe to fatal side effects that increased by 2% or more in people who received Avastin vs those in the comparison group included tiredness (13% vs 8%), weakness (10% vs 7%), too much protein in the urine (7% vs 0%), high blood pressure (6% vs 1%), and severe bleeding (3% vs 0.3%).
Non-small Cell Lung Cancer In the non-small cell lung cancer trial, the most common life-threatening to fatal side effects that increased by 2% or more in people who received Avastin vs those in the comparison group were reduced white blood cell counts (27% vs 17%), tiredness (16% vs 13%), high blood pressure (8% vs 0.7%), infection without reduced white blood cell counts (7% vs 3%), blood clots in the veins of the body (5% vs 3%), fever with reduced white blood cell counts (5% vs 2%), inflammation of the lungs (5% vs 3%), infection with severe or life-threatening reduced white blood cell counts (4% vs 2%), low sodium levels in the blood that could lead to seizure or coma.
For full Prescribing Information and Boxed WARNINGS on Avastin, please visit http://www.avastin.com.
For more information about angiogenesis, visit our Research section.
Avastin Development Program Based on data showing that the VEGF protein may play a broad role in a range of cancers, a global development program for Avastin currently includes more than 450 clinical trials in more than 30 different tumor types, including early-stage cancers. It is also being studied in combination with other targeted therapy agents in the absence of chemotherapy.
References
1 Rosen LS. Clinical experience with angiogenesis signaling inhibitors: focus on vascular endothelial growth factor (VEGF) blockers. Cancer Control. 2002;9:36-44.
2 Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted antiogenic mitogen. Science. 1989;246:1306-1309.
3 Ranieri G, Patruno R, Ruggieri E, Montemurro S, Valerio P, Ribatti D, Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Curr Med Chem. 2006;13:1845-1857
4 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.
5 Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer . 2002;2:727-739.
6 Jain RK. Normalizing tumor vasculature with antiangiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001;7:987-989.
7 Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo . Nature. 1993;362:841-844.