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:
Deep vein thrombosis (clot)
High blood pressure
Decreased blood counts
Serious, but rarer, side-effects include:
Formation of holes in the colon (gastrointestinal perforation), generally requiring surgery and sometimes leading to intra-abdominal infections
Slower wound healing
Internal bleeding (lungs, etc)
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
Randomized, phase III, double-blind trial
Enrolled 923 patients with previously untreated metastatic colorectal cancer (first-line treatment)
Patients randomized to:
Arm 1 (411 patients) = bolus-IFL plus placebo
Arm 2 (402 patients) = bolus-IFL plus bevacizumab
Arm 3 (110 patients) = 5-FU/LV plus bevacizumab
Bolus-IFL = Irinotecan 125 mg/m2 IV, 5-fluorouracil 500 mg/m2 IV, and Leucovorin 20 mg/m2 IV, given once a week x 4 weeks, repeated every 6 weeks
Bevacizumab = 5 mg/kg every 2 weeks
Arm 3 was discontinued once the safety and tolerability of arm 2 was established
Overall survival was 20.3 months in Arm 2 with bevacizumab vs. 15.6 months in Arm 1 with placebo
Median progression-free survival was 10.6 months with bevacizumab compared with 6.4 months with placebo.
Data showed that median overall survival in Arm 3 was 18.3 months, median progression-free survival was 8.8 months, overall response rate was 39%, and median duration of response was 8.5 months.
Bevacizumab resulted in a 30% increase in median overall survival in combination with IFL, compared to IFL alone.
The survival benefit associated with bevacizumab was observed early in treatment and persisted throughout the course of the trial.
It is the first and only anti-angiogenic agent proven to significantly extend survival in a phase III trial.
2) Bevacizumab in the Treatment of Other Solid Tumors
A phase I/II trial studied bevacizumab monotherapy in patients with previously treated metastatic breast cancer, and found an overall response rate of 6.7% with a median duration of response of 5.5 months. Also, a study of 486 patients with anthracycline- and taxane-refractory breast cancer investigated bevacizumab in combination with capecitabine (Xeloda, oral 5-FU), and showed a better response rate compared with capecitabine alone (19.8% vs 9.1%).
A phase II study of bevacizumab in combination with gemcitabine showed a response rate of 38% and a remarkable 54% 1-year survival rate.
Renal cell/kidney cancer:
A phase 2 study of single-agent bevacizumab compared with placebo in patients with metastatic renal carcinoma was stopped early because there was a significant increase in the time to progression of disease with high-dose bevacizumab compared to placebo (hazard ratio, 2.55; p<0.001). Although there were no significant differences in overall survival between groups, the authors concluded that bevacizumab can significantly prolong the time to progression of disease in patients with metastatic renal-cell 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.
A Pilot Study to Evaluate Angiogenesis after Treatment with Bevacizumab in Previously Untreated Patients with Inflammatory Breast Cancer or Locally Advanced Breast Cancer. NCI
Head and Neck:
Bevacizumab and Erlotinib in Treating Patients With Recurrent or Metastatic Head and Neck Cancer. University of Chicago Cancer Research Center
Irinotecan, Cisplatin, and Bevacizumab in Treating Patients With Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma. Memorial Sloan-Kettering Cancer Center
Bevacizumab With or Without Docetaxel in Treating Patients With Previously Treated Metastatic Pancreatic Cancer. Fox Chase Cancer Center
Bevacizumab and Low-Dose Cyclophosphamide in Treating Patients With Recurrent Ovarian Epithelial or Primary Peritoneal Cancer. California Cancer Consortium
Phase II Study of Bevacizumab in Patients With Persistent or Recurrent Squamous Cell Carcinoma of the Cervix. Gynecologic Oncology Group
Phase II Study of Bevacizumab in Patients With Relapsed Aggressive Non-Hodgkin's Lymphoma. SWOG
Renal Cell (Kidney):
Interferon alfa-2b With or Without Bevacizumab in Treating Patients With Advanced Renal Cell Carcinoma (Kidney Cancer). Cancer and Leukemia Group B
Bevacizumab With or Without Interferon alpha in Treating Patients With Metastatic Malignant Melanoma. Arthur G. James Cancer Hospital & Richard J. Solove Research Institute
Combination Chemotherapy With or Without Bevacizumab in Treating Patients With Malignant Mesothelioma. University of Chicago Cancer Research Center
Bevacizumab With or Without Thalidomide in Treating Patients With Relapsed or Refractory Multiple Myeloma. California Cancer Consortium