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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

WARNINGS

  • 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

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 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 (up to 3.2%)
  • 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. In a controlled clinical trial, in patients with metastatic colorectal cancer who had surgery during the course of treatment, the incidence of wound healing complications, including serious and fatal complications, was 15 percent for patients who received Avastin and four percent for patients who did not receive Avastin
  • 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 wound healing problems following surgery has not been determined
  • Treatment with Avastin should be stopped at least 28 days before voluntary surgery and in people with wound healing problems following surgery that require medical treatment. Treatment with Avastin should be stopped in patients with slow or incomplete wound healing

Severe bleeding:

  • Treatment with Avastin can result in serious or fatal 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 five times more often in people who received Avastin compared to patients who received only chemotherapy
  • Across cancer types, 0.4 percent to 6.9 percent 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

Additional serious adverse events

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 in the body (GI and non-GI fistula formation) was seen in up to 2% of people. In a study of patients with cervical cancer, formation of an abnormal passage between the vagina and GI tract was seen in 8.3% of people
  • Severe to life-threatening stroke or heart problems were seen in 2.6 percent of people
  • Too much protein in the urine that led to kidney problems was seen in ≤1% percent 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 blood clots (VTE), up to 10.6%
    • severe to life threatening high blood pressure, which was seen in 5% to 18% of people
    • nervous system and vision disturbances (Posterior Reversible Encephalopathy Syndrome) which was seen in less than 0.5% of people
    • Infusion reactions with the first dose of Avastin were uncommon and occurred in less than three percent of people, and severe reactions occurred in 0.2 percent of people
  • Avastin can cause fertility issues for women. Avastin could cause a woman’s ovaries to stop working and may impair her ability to have children
  • Avoid use in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction

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.

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 six months following the last dose of Avastin.

Women should be advised to discontinue nursing or discontinue treatment with Avastin, taking into account the importance of Avastin to the mother.

Report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.
Report side effects to Genentech at (888) 835-2555.

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.

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