Avastin® (bevacizumab) in Metastatic Colorectal Cancer
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 is not indicated for adjuvant treatment of colon cancer.
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
- Gastrointestinal (GI) perforation: Avastin can result in the development of a potentially serious, and sometimes fatal side effect called GI perforation, which is the development of a hole in the stomach, small intestine or large intestine. Symptoms may include abdominal pain, nausea, vomiting, constipation, and fever. Patients must stop Avastin for at least 28 days before voluntary surgery.
- 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.
- Severe bleeding: Treatment with Avastin can result in serious and sometimes fatal bleeding. This includes coughing up blood, bleeding in the stomach, vomiting blood, bleeding in the brain, nosebleeds and vaginal bleeding. People who have recently coughed up blood or have serious bleeding should not receive Avastin.
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
Possible serious side effects
Everyone reacts differently to Avastin therapy. So it’s important to know what the side effects are. Although some people may have a life-threatening side effect, most do not. Your doctor will stop treatment if any serious side effects occur. Be sure to contact your health care team if there are any signs of these side effects.
Most serious side effects (not common, but sometimes fatal):
- GI perforation. A hole that develops in your stomach or intestine. Symptoms include pain in your abdomen, nausea, vomiting, constipation, or fever
- Wounds that don’t heal. A cut made during surgery can be slow to heal or may not fully heal. Avastin should not be used for at least 28 days before or after surgery and until surgical wounds are fully healed
- Serious bleeding. This includes vomiting or coughing up blood; bleeding in the stomach, brain, or spinal cord; nosebleeds; and vaginal bleeding. If you recently coughed up blood or had serious bleeding, be sure to tell your doctor
Other possible serious side effects
- Abnormal passage in the body. This type of passage—known as a fistula—is an irregular connection from one part of the body to another and can sometimes be fatal
- Severe high blood pressure. Blood pressure that severely spikes or shows signs of affecting the brain. Blood pressure should be monitored every 2 to 3 weeks while on Avastin and after stopping treatment
- Kidney problems. These may be caused by too much protein in the urine and can sometimes be fatal
- Infusion reactions. These were uncommon with the first dose (less than 3% of patients). 0.2% of patients had severe reactions. Infusion reactions include high blood pressure or severe high blood pressure that may lead to stroke, trouble breathing, decreased oxygen in red blood cells, a serious allergic reaction, chest pain, headache, tremors, and excessive sweating. Your doctor or nurse will monitor you for signs of infusion reactions
- Severe stroke or heart problems. These may include blood clots, mini-stroke, heart attack, and chest pain. These can sometimes be fatal
- Nervous system and vision problems. Signs include headache, seizure, high blood pressure, sluggishness, confusion, and blindness
Side effects seen most often
In clinical studies across different types of cancer, some patients experienced the following side effects:
- High blood pressure
- Too much protein in the urine
- Rectal bleeding
- Back pain
- Taste change
- Dry skin
- Inflammation of the skin
- Inflammation of the nose
- Watery eyes
Avastin is not for everyone
Talk to your doctor if you are:
- Undergoing surgery. Avastin should not be used for 28 days before or after surgery and until surgical wounds are fully healed
- Pregnant or think you are pregnant. Data have shown that Avastin may harm your unborn baby. Use birth control while on Avastin. If you stop Avastin, you should keep using birth control for 6 months before trying to become pregnant
- Planning to become pregnant. Taking Avastin could cause a woman’s ovaries to stop working and may impair her ability to have children.
- Breastfeeding. Breastfeeding while on Avastin may harm your baby and is therefore not recommended
If you have any questions about your condition or treatment, talk to your doctor.
You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.
Please see full Product Information, including Serious Side Effects, for additional important safety information.
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.
2 American Cancer Society. "Leading Sites of New Cancer Cases and Deaths - 2007 Estimates." Available at http://www.cancer.org/acs/groups/content/@nho /documents/document/globalfactsandfigures2007rev2p.pdf. Accessed May 7, 2007.