Avastin® (bevacizumab) in Metastatic Colorectal Cancer
Full Prescribing Information, including Boxed Warnings.
Avastin was the first anti-angiogenesis therapy approved by the U.S. Food and Drug Administration (FDA). It was approved in combination with intravenous (IV) 5-fluorouracil (FU)-based chemotherapy for first-line treatment of patients with metastatic carcinoma of the colon or rectum in February 2004, and for second-line treatment in June 2006.
Avastin "Firsts" in Metastatic Colorectal Cancer Avastin, in combination with chemotherapy, is the first and only FDA-approved biologic therapy proven to extend overall survival in first- and second-line metastatic colorectal cancer (mCRC). In the pivotal Phase III study, Avastin showed the longest reported overall survival in any first-line clinical trial of patients with mCRC.1
Proposed Mechanism of Action Avastin is a therapeutic antibody (not chemotherapy) specifically designed to bind to and inhibit the vascular endothelial growth factor (VEGF) protein, a potent source of angiogenesis. Angiogenesis is a process that connects tumors to the blood supply.3 By inhibiting VEGF, Avastin may interfere with the blood supply to a tumor, which is thought to be critical to a tumor's ability to grow and spread in the body (metastasize). The effects of Avastin on tumor blood vessels may also enhance the delivery of chemotherapy drugs to the cancer.4-6
Clinical Trial Data First-Line Treatment in Metastatic Colorectal Cancer The Avastin FDA approval for first-line treatment of patients with metastatic carcinoma of the colon or rectum is based on data from two trials. The pivotal trial was a large, placebo-controlled, randomized study that demonstrated a prolongation in the median survival of patients treated with Avastin plus the IFL (IV 5-FU/Leucovorin/CPT-11) chemotherapy regimen by approximately five months, compared to patients treated with the IFL chemotherapy regimen alone (20.3 months versus 15.6 months). The study showed that Avastin-treated patients had a 52 percent improvement in overall survival compared to chemotherapy alone (based on a hazard ratio of 0.66). In addition, this study demonstrated an improvement in progression-free survival (PFS) of more than four months (10.6 months in the Avastin/IFL arm compared to 6.2 months in the IFL-alone arm).1
Second-Line Treatment in Metastatic Colorectal Cancer The second-line approval for Avastin is based on results of a randomized, controlled, multicenter Phase III trial (E3200) of 829 patients with advanced or metastatic colorectal cancer who had received previous treatment with irinotecan and IV 5-FU as initial therapy for metastatic disease or as adjuvant therapy. The study showed that patients who received Avastin plus the IV 5-FU-based chemotherapy regimen known as FOLFOX4 (oxaliplatin/5-FU/leucovorin) had a 25 percent reduction in the risk of death (based on a hazard ratio of 0.75), the primary endpoint, which is equivalent to a 33 percent improvement in overall survival, compared to patients who received FOLFOX4 alone. Median survival for patients receiving Avastin plus FOLFOX4 was 13.0 months, compared to 10.8 months for those receiving FOLFOX4 alone.1
The National Comprehensive Cancer Network (NCCN) recommends Avastin plus intravenous 5FU-based chemotherapy as a first-line treatment option for advanced colorectal cancer, the second leading cause of cancer deaths in the U.S.7
Avastin Safety First-Line Metastatic Colorectal Cancer The most serious adverse events associated with Avastin across all trials were GI perforation, wound healing complication, hemorrhage, non-GI fistula formation, arterial thromboembolic events, hypertensive crisis, reversible posterior leukoencephalopathy syndrome, neutropenia and infection, nephrotic syndrome, and congestive heart failure. The most common grade 3-4 events in Study 2107, which occurred at a higher incidence (≥2%) in the Avastin plus IFL vs IFL groups, were asthenia, abdominal pain, pain, hypertension, deep vein thrombosis, intra-abdominal thrombosis, syncope, diarrhea, constipation, leukopenia, and neutropenia.
Second-Line Metastatic Colorectal Cancer The most serious adverse events associated with Avastin across all trials were GI perforation, wound healing complication, hemorrhage, non-GI fistula formation, arterial thromboembolic events, hypertensive crisis, reversible posterior leukoencephalopathy syndrome, neutropenia and infection, nephrotic syndrome, and congestive heart failure. The most common grade 3-5 (non-hematologic) and 4-5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea, nausea, vomiting, dehydration, ileus, neuropathy-sensory, neurologic-other, fatigue, abdominal pain, headache, hypertension, and hemorrhage.
View full prescribing information, including Boxed WARNINGS. For more information on Avastin, visit http://www.avastin.com.
Avastin Development Program Based on data showing that VEGF may play a broad role in a range of cancers, a global development program for Avastin currently includes more than 300 clinical trials in 20 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 Hurwitz, et. al. Bevacizumab in combination with fluorouracil and leucovorin: An active regimen for first-line metastatic colorectal cancer. Jour Clin Onc. 2005;23:3502-3508.
2 American Cancer Society. "Leading Sites of New Cancer Cases and Deaths - 2007 Estimates." Available at http://www.cancer.org/downloads/stt/CFF2007LeadingSites.pdf. Accessed May 7, 2007.
3 Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted antiogenic mitogen. Science. 1989;246:1306-1309.
4 Rosen LS. Clinical experience with angiogenesis signaling inhibitors: focus on vascular endothelial growth factor (VEGF) blockers. Cancer Control. 2002;9:36-44.
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 Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun M. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43-66.