FDA Approves New Use of Avastin Plus Chemotherapy for People with Metastatic
SOUTH SAN FRANCISCO, Calif. -- January 23, 2013
Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today
announced that the U.S. Food and Drug Administration (FDA) has approved a new
use of Avastin^® (bevacizumab) in combination with fluoropyrimidine-based
irinotecan or oxaliplatin chemotherapy for people with metastatic colorectal
cancer (mCRC). The new indication will allow people who received Avastin plus
an irinotecan or oxaliplatin containing chemotherapy as an initial treatment
(first-line) for mCRC to continue to receive Avastin plus a different
irinotecan or oxaliplatin containing chemotherapy after their cancer worsens
“The majority of people diagnosed with metastatic colorectal cancer receive
Avastin plus chemotherapy as their initial treatment,” said Hal Barron, M.D.,
chief medical officer and head of Global Product Development. “These people
now have the option to continue with Avastin plus a new chemotherapy after
their cancer worsens, which may help them live longer than changing to the new
Avastin in combination with fluoropyrimidine-irinotecan or
fluoropyrimidine-oxaliplatin based chemotherapy is now indicated for the
second-line treatment of patients with metastatic colorectal cancer who have
progressed on a first-line Avastin containing regimen. The approval is based
on positive results from the Phase III ML18147 study, which were presented at
the 2012 American Society of Clinical Oncology annual meeting and showed that
people who continued to receive an Avastin-based regimen after their cancer
worsened lived longer than people who switched to chemotherapy alone.
*The risk of death was reduced by 19 percent for people who received
Avastin in combination with standard chemotherapy in both the first- and
second-line compared to those who received chemotherapy alone (HR=0.81,
p=0.0057). Median overall survival was 11.2 months compared to 9.8 months.
*The risk of the cancer worsening or death (progression-free survival; PFS)
was reduced by 32 percent (HR=0.68, p<0.0001). Median PFS was 5.7 months
compared to 4.1 months.
*Overall survival and PFS were calculated from the time patients were
randomized to the second-line treatment.
*There was no significant difference in response rate between treatment
*Adverse events (AEs) in ML18147 were consistent with those seen in
previous pivotal trials of Avastin in mCRC.
Avastin is the only biologic medicine approved by the FDA to treat people with
mCRC in combination with intravenous 5FU-based chemotherapy as an initial
treatment, as treatment for people whose cancer worsened after chemotherapy
alone, and now as a treatment for people whose cancer has worsened after
initial treatment with an Avastin-based regimen. This is the third approval
for Avastin in mCRC based on improved overall survival. Avastin is not
indicated for adjuvant treatment of colon cancer.
Avastin is approved in Europe in combination with fluoropyrimidine-based
chemotherapy for the treatment of adult patients with metastatic carcinoma of
the colon or rectum. The European product information has been updated based
on the positive results of the Phase III ML18147 study with an implementation
date of December 12, 2012, allowing people with mCRC who received Avastin plus
chemotherapy as a first-line treatment to continue to receive Avastin plus
chemotherapy after their cancer worsens as part of their second-line
About the ML18147 Study
ML18147 was a randomized, open-label, Phase III multicenter, multinational
trial evaluating the efficacy and safety profile of Avastin plus standard
second-line chemotherapy in 820 patients with mCRC whose disease had
progressed following Avastin plus standard first-line chemotherapy (irinotecan
or oxaliplatin-based). Patients were randomized at progression to one of two
*Arm A: Chemotherapy* plus Avastin (equivalent of 2.5 mg/kg i.v. per week)
*Arm B: Chemotherapy* alone
*Depending on the first-line chemotherapy backbone
(fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based), the
chemotherapy backbone was switched in the second-line setting.
The primary endpoint of the study was overall survival measured from the time
patients were randomized to the second-line treatment. The secondary efficacy
endpoints of the study included PFS, overall response rate and safety profile.
About Colorectal Cancer
According to the American Cancer Society, colorectal cancer is the third most
commonly diagnosed cancer in both men and women in the United States and the
third leading cause of cancer deaths. In 2012, more than 143,000 people were
diagnosed and nearly 52,000 individuals were projected to die from the disease
in the United States. If colorectal cancer spreads (metastasizes) to distant
organs, such as the lungs or the liver, five-year survival declines to 12
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Avastin is a prescription-only medicine that is a solution for intravenous
infusion. It is a biologic antibody designed to specifically bind to a protein
called vascular endothelial growth factor (VEGF) that plays an important role
throughout the lifecycle of the tumor to develop and maintain blood vessels, a
process known as angiogenesis. Avastin is designed to interfere with the tumor
blood supply by directly binding to the VEGF protein to prevent interactions
with receptors on blood vessel cells. The tumor blood supply is thought to be
critical to a tumor's ability to grow and spread in the body (metastasize).
Avastin Indications in Metastatic Colorectal Cancer:
*Avastin is indicated for the first- or second-line treatment of patients
with metastatic carcinoma of the colon or rectum in combination with
intravenous 5-fluorouracil-based chemotherapy.
*Avastin in combination with fluoropyrimidine-irinotecan or
fluoropyrimidine-oxaliplatin based chemotherapy is indicated for the
second-line treatment of patients with metastatic colorectal cancer who
have progressed on a first-line Avastin containing regimen.
*Avastin is not indicated for adjuvant treatment of colon cancer.
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
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 (2.4 percent to 0.3 percent). 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
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, 1.2 percent
to 4.6 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
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 percent or less 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 less than one 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
high blood pressure, which was seen in five percent to 18 percent of people,
and nervous system and vision disturbances (reversible posterior
leukoencephalopathy syndrome), which was seen in less than 0.1 percent 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.
Common side effects that occurred in more than 10 percent 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 percent to 21 percent 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.
First-line Metastatic Colorectal Cancer
In the first-line metastatic colorectal cancer trial, the most common severe
to life threatening side effects that increased by two percent or more in
people who received Avastin plus IFL chemotherapy vs. IFL alone were weakness
(10 percent vs. 7 percent), abdominal pain (8 percent vs. 5 percent), pain (8
percent vs. 5 percent), high blood pressure (12 percent vs. 2 percent), blood
clots in the veins of the body (9 percent vs. 5 percent), blood clots inside
the abdomen (3 percent vs. 1 percent), a brief loss of consciousness (3
percent vs. 1 percent), diarrhea (34 percent vs. 25 percent), constipation (4
percent vs. 2 percent), reduced white blood cell counts (37 percent vs. 31
percent), and reduced white blood cell counts that may increase the chance of
infection (21 percent vs. 14 percent).
Second-line Metastatic Colorectal Cancer
In the second-line metastatic colorectal cancer trial, the most common severe
to life threatening and fatal side effects that increased by two percent or
more in people who received Avastin plus FOLFOX4 chemotherapy vs. FOLFOX4
alone were diarrhea (18 percent vs. 13 percent), nausea (12 percent vs. 5
percent), vomiting (11 percent vs. 4 percent), dehydration (10 percent vs. 5
percent), blockage of the bowel (4 percent vs. 1 percent), numbness and
tingling in fingers and toes (17 percent vs. 9 percent), nervous system
disturbances (5 percent vs. 3 percent), tiredness (19 percent vs. 13 percent),
abdominal pain (8 percent vs. 5 percent), headache (3 percent vs. 0 percent),
high blood pressure (9 percent vs. 2 percent), and severe bleeding (5 percent
vs. 1 percent).
Second-line Metastatic Colorectal Cancer in Patients who Have Progressed on an
Avastin Containing Regimen in First-line mCRC
In this second-line trial, nonew safety signals were observed when Avastin
was administered in second-line mCRC patients who progressed on an Avastin
containing regimen in first-line mCRC. The safety data was consistent with the
known safety profile established in first and second-line mCRC.
For full Prescribing Information and Boxed WARNINGS on Avastin, please visit
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