Bevacizumab (trade name Avastin, Genentech/Roche) is a humanized monoclonal antibody that recognises and blocks vascular endothelial growth factor A (VEGF-A).[1] VEGF-A is a chemical signal that stimulates the growth of new blood vessels (angiogenesis).
Blood vessels grow uncontrollably in cancer, retinal proliferation of diabetes in the eye, and other diseases. Bevacizumab can block VEGF-A from creating new blood vessels. 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.[2] In 2008, it was approved by the FDA for use in metastatic breast cancer, a decision that generated some controversy as it went against the recommendation of its advisory panel,[3] who objected because it only slowed tumor growth but failed to extend survival.
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.[4] 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.[5]
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.
Indications
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.
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). 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.
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. The 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.[3]
Bevacizumab is usually given intravenously through the arm every 14 days. In colon cancer, it is given in combination with the chemotherapy drug 5-FU (5-fluorouracil), leucovorin, and oxaliplatin or irinotecan.
In 2009, the FDA approved Bevacizumab for use in metastatic renal cell cancer (a form of kidney cancer) which is the drug's sixth indication[6] [7], following earlier reports of activity[8] 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.[9]
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.[10] Avastin may also be useful in the treatment of radiation necrosis, since it reduces edema and mass effect and diminishes blood-brain-barrier leakage.
Investigational
Bevacizumab has also demonstrated activity in ovarian cancer[11], and glioblastoma multiforme[12], a type of brain tumour, when used as a single agent. The FDA granted accelerated approval[clarification needed] of Avastin for the treatment of recurrent glioblastoma multiforme in May, 2009.[citation needed]
Bevacizumab has been investigated as a possible treatment of pancreatic cancer, as an addition to chemotherapy, but studies have shown no improvement in survival.[13][14][15] It may also cause higher rates of high blood pressure, bleeding in the stomach and intestine, and intestinal perforations.
Non-oncologic uses
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 (although not studied in a controlled environment). Many retina specialists have noted impressive results in the setting of CNV, proliferative diabetic retinopathy, neovascular glaucoma, diabetic macular edema, retinopathy of prematurity[16] 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 inravitreal 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. Lucentis is however very expensive ($1500–2000 per injection, - the studies were done with monthly intravitreal injections). Bevacizumab is significantly cheaper (<$100 a shot versus >$1500) it appears to be safe (at least in the short term) and many doctors have noticed improvements in vision and outcomes similar to those seen with Lucentis. 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 will effectively stop its use for macular degeneration patients who have no insurance coverage for Ranibizumab (Lucentis) and for any patient who has 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 backand 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[1] 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), will enroll 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, which 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.
Side 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.[17]
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.[18] Posterior reversible encephalopathy syndrome,[19]nasal septum perforation, and renal thrombotic microangiopathy have been reported.[20]
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. Doctors and editorials have criticized the high cost, for a drug that doesn't cure cancer but only prolongs life. In the U.S., insurance companies have refused to pay for all or part of the costs of bevacizumab, and in countries with national health care systems, such as the UK and Canada, the health care systems have restricted its use because of the low ratio of benefits to cost. Genentech argues that the benefit is worth the cost, and the high cost pays for the expensive and risky research needed to develop new drugs. Genentech has adjusted the price for patients in certain circumstances. In 2008, sales of Avastin were nearly $2.7 billion.[21]
For colorectal cancer, Meyer 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[22]
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. [23] Costs in other countries vary; in Canada it is reported to cost $40,000 CAD per year. [24]
See also
References
- ^ Los M, Roodhart JM, Voest EE (April 2007). "Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer". The Oncologist 12 (4): 443–50. doi:10.1634/theoncologist.12-4-443. PMID 17470687.
- ^ Avastin Prescribing Information, Genentech Inc., October 2006, www.clinicaltrials.gov
- ^ a b "F.D.A. Approves Drug's Use for Breast Cancer". The New York Times. February 22, 2008. http://www.nytimes.com/2008/02/22/business/apee-drug.html.
- ^ Reed, Katie. "Roche drug Avastin fails cancer study, shares fall". Reuters 22 Apr 2009. Accessed 22 Apr 2009
- ^ Genentech, Inc. "FDA Grants Accelerated Approval of Avastin for Brain Cancer (Glioblastoma) That Has Progressed Following Prior Therapy". Market Watch 5 May 2009.
- ^ FDA clears Genentech drug for kidney cancer San Francisco Chronicle, August 2, 2009
- ^ http://www.genengnews.com/news/bnitem.aspx?name=59562374 "FDA Gives Roche's Avastin the Go-Ahead for Metastatic Renal Carcinoma "
- ^ Rini BI (February 2007). "Vascular endothelial growth factor-targeted therapy in renal cell carcinoma: current status and future directions". Clin Cancer Res 13 (4): 1098–106. doi:10.1158/1078-0432.CCR-06-1989. PMID 17317817.
- ^ Pollack, Andrew (2009-03-31). "F.D.A. Panel Supports Avastin to Treat Brain Tumor". New York Times. http://www.nytimes.com/2009/04/01/business/01avastin.html. Retrieved 2009-08-13.
- ^ OncoGenetics.Org (September 2009). "Avastin dramatically improves response, survival in deadly recurrrent glioblastomas". OncoGenetics.Org. http://www.oncogenetics.org/web/avastin-dramatically-improves-response-survival-in-deadly-recurrrent-glioblastomas. Retrieved 2009-09-02.
- ^ Konner JA et al. Proc ASCO 2007 (May 2008). A phase II study of intravenous (IV) and intraperitoneal (IP) paclitaxel (Tax), IP cisplatin (Cis), and IV bevacizumab (Bev) as first-line chemotherapy for optimal stage II or III ovarian, primary peritoneal, and fallopian tube cancer.. http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=31096.
- ^ T. F. Cloughesy, M. D. Prados, P. Y. Wen, T. Mikkelsen, L. E. Abrey, D. Schiff, W. K. Yung, Z. Maoxia, I. Dimery, and H. S. Friedman. A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM). J Clin Oncol (Meeting Abstracts) 2008 26: 2010b. [Abstract].
- ^ Saif MW (2008). "New developments in the treatment of pancreatic cancer. Highlights from the "44th ASCO Annual Meeting". Chicago, IL, USA. May 30 - June 3, 2008". JOP 9 (4): 391–7. PMID 18648128. http://www.joplink.net/prev/200807/27.html.
- ^ Rocha-Lima CM (June 2008). "New directions in the management of advanced pancreatic cancer: a review". Anticancer Drugs 19 (5): 435–46. doi:10.1097/CAD.0b013e3282fc9d11. PMID 18418211.
- ^ Riess H (2008). "Antiangiogenic strategies in pancreatic cancer". Recent Results Cancer Res 177: 123–9. doi:10.1007/978-3-540-71279-4_14. PMID 18084954.
- ^ Azad R, Chandra P (2007). "Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity". Indian journal of ophthalmology 55 (4): 319. doi:10.4103/0301-4738.33057. PMID 17595491.
- ^ New England Journal of Medicine, 8 May 2008, 358(19):2066, Clinical Implications of Basic Research: A New Weapon for Attacking Tumor Blood Vessels, Gregg L. Semenza.
- ^ Vamsidhar Velcheti, Avinash Viswanathan, Ramaswamy Govindan (2006). "The Proportion of Patients with Metastatic Non-small Cell Lung Cancer Potentially Eligible for Treatment with Bevacizumab: A Single Institutional Survey". Journal of Thoracic Oncology 1 (5): 501. doi:10.1097/01243894-200606000-00023. PMID 17409907. Full text
- ^ Reversible posterior leukoencephalopathy syndrome in cancer. Vaughn C, Zhang L, Schiff D. Curr Oncol Rep. 2008 Jan;10(1):86-91. Review. PMID: 18366965
- ^ Vera Eremina, J.Ashley Jefferson et al. (2008). "VEGF Inhibition and Renal Thrombotic Microangiopathy". The New England Journal of Medicine 358 (11): 1129. doi:10.1056/NEJMoa0707330. PMID 18337603. Full text
- ^ Genentech 2008 10-K Report,
- ^ Two Steps Forward in the Treatment of Colorectal Cancer, Robert J. Mayer, N Engl J Med, 350:2406-2408 June 3, 2004
- ^ A Cancer Drug Shows Promise, at a Price That Many Can't Pay, By ALEX BERENSON, New York Times, February 15, 2006
- ^ P.E.I. sole holdout on cancer drug CBC News, November 26, 2009
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