Bevacizumab

Bevacizumab (trade name Avastin, Genentech/Roche) is a drug that blocks angiogenesis, the growth of new blood vessels. It is used to treat various cancers, including colorectal, lung, and kidney cancer, and eye disease.

Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor A (VEGF-A). VEGF-A is a chemical signal that stimulates angiogenesis in a variety of diseases, especially in cancer, retinal proliferation of diabetes in the eye. Bevacizumab was the first clinically available angiogenesis inhibitor in the United States.

Bevacizumab is currently approved by the U.S. Food and Drug Administration (FDA) for cancers that are metastatic (have spread to other parts of the body). It received its first approval in 2004 for combination use with standard chemotherapy for metastatic colon cancer and non-small cell lung cancer.

In 2008, the FDA approved bevacizumab for use in metastatic breast cancer. This was controversial, because the FDA's advisory panel recommended against approval, since it only slowed tumor growth but failed to extend survival. In July 2010, the FDA revoked the indication for advanced breast cancer, although the drug is still approved for use in Australia. FDA approval is only required for Genentech to market a drug for that indication. Doctors can still prescribe it for that indication, although insurance companies are less likely to pay for it.

It is prescribed off-label -on the basis of clinical studies- for treatment of macular degeneration, an eye disease also characterized by proliferation of blood vessels in the retina.

Clinical studies are underway in non-metastatic breast cancer, renal cell carcinoma, glioblastoma multiforme, ovarian cancer, castrate-resistant (formally called hormone refractory) prostate cancer, non-metastatic unresectable liver cancer and metastatic or unresectable locally advanced pancreatic cancer. A study released in April 2009 found that bevacizumab is not effective at preventing recurrences of non-metastatic colon cancer following surgery. In May 2009, it received FDA approval for treatment of recurring glioblastoma multiforme, while treatment for initial growth is still in phase III clinical trial.

Background
Bevacizumab is a humanized monoclonal antibody, and was the first commercially available angiogenesis inhibitor. It stops tumor growth by preventing the formation of new blood vessels by targeting and inhibiting the function of a natural protein called vascular endothelial growth factor (VEGF) that stimulates new blood vessel formation.

The drug was first developed as a genetically engineered version of a mouse antibody that contains both human and mouse components. Genentech is able to produce the antibody in production-scale quantities.

Colorectal cancer
Bevacizumab was approved by the FDA in February 2004 for use in metastatic colorectal cancer when used with standard chemotherapy treatment (as first-line treatment) and with 5-fluorouracil-based therapy for second-line metastatic colorectal cancer. This recommendation was based on E3200 trial - addition of bevacizumab to oxaliplatin/5-FU/leucovorin (FOLFOX4) therapy. It was approved by the EMEA in January 2005 for use in colorectal cancer.

Lung cancer
The overall data shows that bevacizumab has no effect on survival but has been shown to improve progression free survival time in some lung cancer types [Reck M, von PJ, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Reck M, von PJ, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann.Oncol. 2010 Sep;21(9):1804-9.}]

In 2006, the FDA approved bevacizumab for use in lung cancer in combination with standard first-line chemotherapy. A study conducted by the Eastern Cooperative Oncology Group (ECOG) demonstrated a 2-month improvement in overall survival in patients with Stage IIIb/IV non-small cell lung cancer (NSCLC). However, other studies have unfortunately not mirrored this finding and overall data shows that bevacizumab has no effect on survival. Due to the observance of severe pulmonary hemorrhage in patients with NSCLC with squamous histology in an earlier study, patients with such histology were excluded from the pivotal ECOG trial.

Breast cancer
In December 2010, the FDA removed the breast cancer indication from bevacizumab, saying that it had not been shown to be safe and effective in breast cancer patients. The combined data from four different clinical trials showed that bevacizumab neither prolonged overall survival nor slowed disease progression sufficiently to outweigh the risk it presents to patients. This only prevented Genentech from marketing bevacizumab for breast cancer. Doctors are free to prescribe bevacizumab off label, although insurance companies are less likely to approve off-label treatments. In June 2011, an FDA panel unanimously rejected an appeal by Roche. A panel of cancer experts has ruled for a second time that Avastin, the best-selling cancer drug in the world, should no longer be used in breast cancer patients, clearing the way for the U.S. government to remove its endorsement from the drug. The June 2011 meeting of the FDA's oncologic drug advisory committee was the last step in an appeal by the drug's maker. The committee concluded that breast cancer clinical studies of patients taking Avastin have shown no advantage in survival rates, no improvement in quality of life, and significant side effects. Patient support groups were disappointed by the committee's decision.

Assuming the FDA follows through on the withdrawal, drugmaker Roche could lose up to $1 billion in revenue for its best-selling product, which generates over $6 billion per year. Avastin is FDA-approved for various types of colon, lung, kidney and brain cancer, which are not part of the debate. Doctors will still be allowed to prescribe Avastin for breast cancer, though insurers may not pay for it. When administration fees are included, a year's treatment of Avastin can cost $90,000.

History relating to breast cancer
In 2010, before the FDA announcement, The National Comprehensive Cancer Network (NCCN) updated the NCCN Clinical Practice Guidelines for Oncology (NCCN Guidelines) for Breast Cancer to affirm the recommendation regarding the use of bevacizumab (Avastin, Genentech/Roche) in the treatment of metastatic breast cancer.

In 2008, the FDA approved Bevacizumab for use in breast cancer. A panel of outside advisers voted 5 to 4 against approval, but their recommendations were overruled. The panel expressed concern that data from the clinical trial did not show any increase in quality of life or prolonging of life for patients - two important benchmarks for late-stage cancer treatments. The clinical trial did show that bevacizumab reduced tumor volumes and showed an increase in progression free survival time. It was based on this data that the FDA chose to overrule the recommendation of the panel of advisers. This decision was lauded by patient advocacy groups and some oncologists. Other oncologists felt that granting approval for late-stage cancer therapies that did not prolong or increase the quality of life for patients would give license to pharmaceutical companies to ignore these important benchmarks when developing new late-stage cancer therapies.

On March 28, 2007, the European Commission approved bevacizumab in combination with paclitaxel for the first-line treatment of metastatic breast cancer.

Other cancers
In certain renal (kidney) cancers, Bevacizumab improves the progression free survival time but not survival time. In 2009, the FDA approved Bevacizumab for use in metastatic renal cell cancer (a form of kidney cancer) , following earlier reports of activity and EU approval in 2007. Also in 2009, an FDA advisory committee unanimously recommended Bevacizumab for treatment of glioblastoma multiforme, a type of brain cancer.

In the September 2009 issue of the Journal of Clinical Oncology, UCLA researchers reported that Avastin improves response and survival in patients with recurrent glioblastoma in comparison to historical controls. Avastin may also be useful in the treatment of radiation necrosis, since it reduces edema and mass effect and diminishes blood-brain-barrier leakage.

Bevacizumab did not meet its primary endpoint of extending overall survival (OS) in a recent phase III trial in unresectable gastric cancer (in combination with paclitaxel / Taxol), but it did demonstrate a positive result in treatment of ovarian cancer.

Drug administration
Bevacizumab is usually given intravenously every 14 days. In colon cancer, it is given in combination with the chemotherapy drug 5-FU (5-fluorouracil), leucovorin, and oxaliplatin or irinotecan.

Investigational
Bevacizumab has also demonstrated activity in ovarian cancer, and glioblastoma multiforme, a type of brain tumour, when used as a single agent. The FDA granted accelerated approval of Avastin for the treatment of recurrent glioblastoma multiforme in May 2009.

In 2010 two phase III trials showed a 27% and 54% increase in progression-free survival in ovarian cancer.

Bevacizumab has been investigated as a possible treatment of pancreatic cancer, as an addition to chemotherapy, but studies have shown no improvement in survival. It may also cause higher rates of high blood pressure, bleeding in the stomach and intestine, and intestinal perforations.

The drug is also undergoing initial trials as an addition to established chemotherapy protocols and surgery in the treatment of pediatric osteosarcoma.

Uses in eye disease
Many diseases of the eye, such as age-related macular degeneration (AMD) and diabetic retinopathy, damage the retina and cause blindness when blood vessels around the retina grow abnormally and leak fluid, causing the layers of the retina to separate. This abnormal growth is caused by VEGF, so bevacizumab has been successfully used to inhibit VEGF and slow this growth.

Bevacizumab has recently been used by ophthalmologists as an intravitreal agent in the treatment of proliferative (neovascular) eye diseases, particularly for choroidal neovascular membrane (CNV) in AMD. Although not currently approved by the FDA for such use, the injection of 1.25-2.5 mg of bevacizumab into the vitreous cavity has been performed without significant intraocular toxicity Many retina specialists have noted impressive results in the setting of CNV, proliferative diabetic retinopathy, neovascular glaucoma, diabetic macular edema, retinopathy of prematurity and macular edema secondary to retinal vein occlusions.

Ranibizumab, a Fab fragment derived from the same parent molecule as bevacizumab, has been developed by Genentech (by the same scientist Napoleone Ferrara) for intraocular use. This drug, under the trade name Lucentis, now has FDA approval. It has undergone extensive clinical trials. Reports indicate substantially better outcomes in patients treated with intravitreal Lucentis than conventional treatments in people with choroidal neovascularization (wet age related macular degeneration). Most patients with choroidal neovascularization lose vision or at best maintain vision despite treatment with laser, photodynamic therapy or Macugen. A much larger proportion (up to 70%) gained vision with Lucentis.

When bevacizumab is used in the treatment of macular degeneration, only tiny and relatively inexpensive doses (compared to amounts used in colon and other cancers) are required. Some investigators believe that bevacizumab at a cost of around $42 a dose is as effective as ranibizumab at a cost of over $1,593 a dose.

As Genentech has developed both drugs it has little interest in seeing Bevacizumab use in the eye and it is likely to remain off label. Off-label use of this medication has created significant controversy in medical retina and vitreo-retinal surgery. On October 11, 2007, Genentech issued a letter to Physicians that they would no longer sell bevacizumab to compounding pharmacies. This would have effectively stopped its use for macular degeneration patients who had no insurance coverage for Ranibizumab (Lucentis) and for any patient who had other vision threatening conditions where Bevacizumab has been shown to work.

However, the ophthalmic community, led by the American Academy of Ophthalmology (AAO) and the American Society of Retinal Specialists (ASRS), fought back and managed to get Genentech to agree to continue providing bevacizumab to retinal surgeons, who in turn could get compounding pharmacies to "cut" the dosage to the appropriate ophthalmic dosage for continued use.

The National Eye Institute (NEI) of the National Institutes of Health (NIH) announced in October 2006 that it would fund a comparative study trial of ranibizumab (Lucentis) and bevacizumab (Avastin) to assess the relative safety and effectiveness in treating AMD. This study, called the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT Study), enrolled about 1,200 patients with newly diagnosed wet AMD, randomly assigning the patients to one of four treatment groups:

(Group1) Lucentis with four-week dosing, and after one year, re-randomization to Lucentis every four weeks or variable dosing as required based on diagnostic findings;

(Group 2) Bevacizumab with four-week dosing, and after one year, re-randomization to bevacizumab every four weeks or variable dosing as required based on diagnostic findings;

(Group 3) Lucentis on a variable dosing schedule for 2 years; after initial treatment, with monthly evaluation and re-treatment based on signs of lesion activity; and

(Group 4) Bevacizumab on a variable dosing schedule for 2 years; after initial treatment, with monthly evaluation and re-treatment based on signs of lesion activity.

The CATT Study will be conducted at 47 clinical sites throughout the United States, and will follow the patients for two years and is expected to take four years to complete. Enrollment began on February 22, 2008, with fifteen sites beginning recruiting. One-year follow-up data will be reported in 2009.

The primary goals of the study are to better understand the safety and efficacy of intravitreal bevacizumab and to develop better dosing and re-treatment guidelines for both bevacizumab and Lucentis.

Results of the study were released on April 29, 2011. The benefits of both Avastin and Lucentis are essentially identical after one year. This has a significant impact because the price difference between the two medications means insurance providers and Medicare will fund treatment with Avastin in preference to the higher priced Lucentis.

As of July 2010, Avastin is being used successfully in a case study of Familial Exudative Vitreoretinopathy in Buffalo, New York.

Adverse effects
Bevacizumab inhibits the growth of blood vessels, which is part of the body's normal healing and maintenance. The body grows new blood vessels in wound healing, and as collateral circulation around blocked or atherosclerotic blood vessels. One concern is that bevacizumab will interfere with these normal processes, and worsen conditions like coronary artery disease or peripheral artery disease.

The main side effects are hypertension and heightened risk of bleeding. Bowel perforation has been reported. In advanced lung cancer, less than half of patients qualify for treatment. nasal septum perforation, and renal thrombotic microangiopathy have been reported. In December 2010, the FDA warned of the risk of developing perforations in the body, including in the nose, stomach, and intestines.

These effects are largely avoided in ophthalmological use since the drug is introduced directly into the eye thus minimizing any effects on the rest of the body.

Costs
Bevacizumab is one of the most expensive drugs widely marketed. In 2008, sales of Avastin generated nearly $2.7 billion for Genentech. Both physicians and the media have criticized the high cost of a drug that doesn't cure cancer but only prolongs life. In the U.S., many insurance companies have refused to pay for all or part of the costs of bevacizumab. In countries with national health care systems (such as the UK and Canada), many of those national health services have restricted its use because of its extraordinarily lop-sided cost-benefit ratio; in the U.K., for example, the National Institute for Health and Clinical Excellence has taken the public position that bevacizumab should not be funded by the NHS because it costs nearly £21,000 per patient but has only limited usage in cancer treatment because it merely extends life rather than providing a cure.

In 2006 the Scottish Medicines Consortium recommended against the NHS funding Avastin, for first-line treatment of metastatic carcinoma of the colon or rectum, due to estimated costs of £24,000 to £93,000 per Quality-adjusted life year (QALY).

Though Genentech has adjusted the price for patients in certain situations, Genentech continues to insist that the benefit is worth the cost, and the medication's high cost helps cover the cost of the expensive and risky research needed to develop new drugs.

The addition of bevacizumab to standard treatment can prolong the lives of breast and lung cancer patients by several months, at a cost of $100,000 a year in the United States. For colorectal cancer, Robert J. Mayer wrote in the New England Journal of Medicine that bevacizumab extended life by 4.7 months (20.3 months vs. 15.6 months) in the initial study, at a cost of $42,800 to $55,000. Costs in other countries vary; in Canada it is reported to cost $40,000 CAD per year.