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 In clinical trials for MCRC, the following side effects occurred more often in people receiving Avastin plus chemotherapy than in people receiving chemotherapy alone: nosebleeds, hypertension (high blood pressure), proteinuria (too much protein in the urine, a possible sign of kidney malfunction). Additional side effects included weakness, pain, diarrhea, and leukopenia (a reduced white blood cell count).
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 People who took Avastin with chemotherapy had a higher risk of stroke or heart problems (blood clots) compared with people taking chemotherapy alone. Additional serious side effects seen in patients who took Avastin with chemotherapy include severe hypertension, kidney malfunction, and nervous system and vision disturbances, and neutropenia (a reduced white blood cell count that may increase the chance of developing an infection).
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
BOXED WARNINGS and Additional Important Safety Information People receiving Avastin may experience side effects. In clinical trials, some people treated with Avastin experienced serious and sometimes fatal side effects, including:
Gastrointestinal (GI) perforation: Treatment with Avastin can result in the development of a potentially serious side effect called GI perforation, which is the development of a hole in the stomach, small intestine, or large intestine. In clinical trials, this event occurred in more people who received Avastin than in the comparison group (0.3% to 2.4%). In some cases, GI perforation resulted in fatality. Avastin therapy should be permanently stopped if GI perforation occurs.
Surgery and wound healing problems: Treatment with Avastin can lead to slow or incomplete wound healing (for example, when a surgical incision has trouble healing or staying closed). In some cases, this event resulted in fatality. Surgery and wound healing problems occurred more often in people who received Avastin than in the comparison group. Avastin therapy should not be started for at least 28 days after surgery and until the surgical wound is fully healed. The length of time between stopping Avastin and having voluntary surgery without the risk of having surgery and wound healing problems has not been determined. Treatment with Avastin should be stopped at least 28 days before voluntary surgery and in people with surgery and wound healing problems that require medical treatment.
Severe bleeding: Treatment with Avastin can result in serious bleeding, including coughing up blood, bleeding in the stomach, vomiting of blood, bleeding in the brain, nosebleeds, and vaginal bleeding. These events occurred up to 5 times more often in people who received Avastin. Across cancer types, 1.2% to 4.6% of people who received Avastin experienced severe to fatal bleeding. People who have recently coughed up blood (greater than or equal to a half teaspoon of red blood) or have serious bleeding should not receive Avastin. Treatment with Avastin should be permanently stopped if serious bleeding occurs (i.e., requiring medical attention).
In clinical trials for different cancer types, there were additional serious and sometimes fatal side effects that occurred in more people who received Avastin than in those in the comparison group. The formation of an abnormal passage from parts of the body to another part (non-GI fistula formation) was seen in 0.3% or less of people. Severe to life threatening stroke or heart problems were seen in 2.4% of people. Too much protein in the urine, which led to kidney problems, was seen in less than 1% of people. Additional serious side effects that occurred in more people who received Avastin than those in the comparison group included severe to life-threatening high blood pressure, which was seen in 5% to 18% of people, and nervous system and vision disturbances (reversible posterior leukoencephalopathy syndrome), which was seen in less than 0.1% of people. Infusion reactions with the first dose of Avastin were uncommon and occurred in less than 3% of people, and severe reactions occurred in 0.2% of people.
Common side effects that occurred in more than 10% of people who received Avastin for different cancer types, and at least twice the rate of the comparison group, were nosebleeds, headache, high blood pressure, inflammation of the nose, too much protein in the urine, taste change, dry skin, rectal bleeding, tear production disorder, back pain, and inflammation of the skin (exfoliative dermatitis). Across all trials, treatment with Avastin was permanently stopped in 8.4% to 21% of people because of side effects.
Avastin may impair fertility. Patients who are pregnant or thinking of becoming pregnant should talk with their doctor about the potential risk of loss of the pregnancy or the potential risk of Avastin to the fetus during and following Avastin therapy, and the need to continue an effective birth control method for at least 6 months following the last dose of Avastin.
In the first-line metastatic colorectal cancer trial, the most common severe to life-threatening side effects that increased by 2% or more in people who received Avastin plus IFL (chemotherapy) vs IFL (chemotherapy) alone were weakness (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), high blood pressure (12% vs 2%), blood clots in the veins of the body (9% vs 5%), blood clots inside the abdomen (3% vs 1%), a brief loss of consciousness (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), reduced white blood cell counts (37% vs 31%), and reduced white blood cell counts that may increase the chance of infection (21% vs 14%).
In the second-line metastatic colorectal cancer trial, the most common severe to life-threatening and fatal side effects that increased by 2% or more in people who received Avastin plus FOLFOX4 (chemotherapy) vs FOLFOX4 (chemotherapy) alone were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), blockage of the bowel (4% vs 1%), numbness and tingling in fingers and toes (17% vs 9%), nervous system disturbances (5% vs 3%), tiredness (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), high blood pressure (9% vs 2%), and severe bleeding (5% vs 1%).
For full Prescribing Information and Boxed WARNINGS on Avastin, please 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 450 clinical trials in more than 30 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.