|Angiogenesis Inhibitors: VEGF|
|Neha Vapiwala, MD|
|The Abramson Cancer Center of the University of Pennsylvania|
In Part Two of our series on biologic therapies, we are performing an in-depth review of the major targeted therapies that are currently making headlines around the world.
Here, we will address the main anti-angiogenesis drug: bevacizumab. Please feel free to refer as needed to Part One, which presented the basic science principles behind targeted therapies and outlined the major classes of molecular inhibitors, including angiogenesis inhibitors. Remember that the drugs have both generic and trade names, but we will use primarily the generic name in the following discussions.I) Bevacizumab (AvastinTM, anti-VEGF)
Bevacizumab is a targeted therapy against the vascular endothelial growth factor (VEGF), a signaling protein that leads to the birth of new blood vessels, ie: vascular growth. Like cetuximab and trastuzumab, bevacizumab is a monoclonal antibody that binds to its specific target, in this case VEGF.
Endothelial cells are the cells that line the insides of blood vessels; they contain receptors which bind VEGF. In the presence of VEGF-binding, these endothelial cells multiply and new blood vessels are formed. Active tumors secrete VEGF because they need more blood supply in order to get nutrients to maintain their growth. By blocking VEGF, bevacizumab prevents the interaction of VEGF with its receptors on the surface of endothelial cells.
Bevacizumab was developed by Genentech, Inc., and in February 2004 became the first and only drug of its class (angiogenesis inhibitors) to receive US FDA approval in the treatment of cancer. Furthermore, and more importantly, it is the first and only anti-angiogenic agent proven to significantly extend the survival time of patients in a phase III trial. The benefit was demonstrated in advanced colorectal cancer patients.
Colorectal cancer is a tumor of the colon or rectum, and is the third most common cancer affecting men and women in the U.S. Approximately 147,500 new cases were diagnosed in 2003. According to the Centers for Disease Control and Prevention (CDC), it is the second leading cause of cancer-related death, behind lung cancer.
Current FDA-Approved Indications
Bevacizumab is indicated for the first-line treatment of patients with metastatic carcinoma of the colon or rectum, when used in combination with intravenous 5-fluorouracil-based chemotherapy.
Details of dose, administration, and duration of bevacizumab therapy
The recommended dose of bevacizumab is 5 mg/kg, given once every 14 days as an intravenous (IV) infusion. It should be continued unless and until disease progression is detected.
So what are the side effects of bevacizumab?
Possible adverse side effects of bevacizumab include:
Serious, but rarer, side-effects include:
Review of the Pivotal Clinical Trials
The FDA's approval of bevacizumab for colorectal cancer was largely based on the following trial which looked at the combination of anti-angiogenesis therapy with intravenous 5-fluorouracil-based chemotherapy. The results were first presented at the ASCO conference in June, 2003.
1) Bevacizumab (a monoclonal antibody to vascular endothelial growth factor) prolongs survival in first-line colorectal cancer (CRC): Results of a phase III trial of bevacizumab in combination with bolus IFL (irinotecan, 5-fluorouracil, leucovorin) as first-line therapy in subjects with metastatic CRC
Materials & Methods
2) Bevacizumab in the Treatment of Other Solid TumorsBreast cancer:
Current Areas of Cancer Research with Bevacizumab: Open Clinical Trials
Now that bevacizumab has a well-established role in colorectal cancer and an increasingly promising one in some other solid tumors, researchers are focusing more than ever on bevacizumab. Their primary goal is to optimize the use of bevacizumab in order to obtain improved patient outcomes for a long list of tumor types. At the present time, remember that bevacizumab is not approved for use in tumor types other than colorectal cancer.
Listed below are some of the latest clinical trials that are currently enrolling patients, along with the study sponsors. Note that while bevacizumab continues to be investigated as a single agent therapy, it is increasingly being incorporated as an adjunctive agent within a whole treatment regimen. Depending on the tumor type, this regimen may contain varying combinations of chemotherapy, radiation therapy, surgery, hormonal agents, and even other targeted therapies.Breast:
For further information, please see Targeted Therapy Basics.