ROCKVILLE, Maryland-In
February 2004, the US Food and Drug
Administration (FDA) approved two
agents that work by different mechanisms
to slow tumor growth in patients
with colorectal cancer. The decisions
represent the first FDA approval
of targeted therapy in colorectal cancer
with a monoclonal antibody or an
antiangiogenesis drug. Both products-
cetuximab (Erbitux, ImClone)
and bevacizumab (Avastin, Genentech,
Inc.)-are genetically engineered versions
of a mouse antibody that contain
both human and mouse components,
and both showed good tumor response
rates in clinical trials.
On February 12, cetuximab was approved
to treat advanced metastatic
colorectal cancer, in combination intravenously
with irinotecan (Camptosar),
or given alone for patients who
cannot tolerate irinotecan. According
to the FDA, cetuximab "is the first
monoclonal antibody approved to
treat this type of cancer." It is believed
to work by targeting the epidermal
growth factor receptor (EGFR) on the
surface of cancer cells, interfering with
their growth.
On the heels of that announcement,
the FDA approved on February
26 use of bevacizumab as first-line
treatment for patients with metastatic
colorectal cancer, representing "the
first [antiangiogenesis] product that
has been proven to delay tumor growth
and more importantly, significantly
extend the lives of patients," the agency
said. Bevacizumab is thought to
work by targeting and inhibiting the
function of vascular endothelial
growth factor (VEGF), in turn preventing
new blood vessel formation
essential for tumor cell growth.
Erbitux Shrank Tumors,
Delayed Growth
Treatment with Erbitux, approved
under FDA's accelerated-approval
program, has not been shown to extend
patients' lives, but it shrank tumors
in some patients and delayed
tumor growth, especially when used
as a combination treatment.
For patients with tumors that express
EGFR and who no longer re-
sponded to irinotecan alone or in combination
with other chemotherapy
drugs, combination treatment with
Erbitux and irinotecan shrank tumors
in 22.9% of patients and delayed tumor
growth by approximately 4.1
months. For patients who received
Erbitux alone, the tumor response rate
was 10.8%, and tumor growth was
delayed by 1.5 months.
Efficacy and safety of Erbitux alone
or in combination with irinotecan were
studied in a randomized, controlled
trial in 329 patients, and in a 138-
patient combination study in which
all patients received both drugs. It was
further evaluated as a single agent in a
third clinical trial with 57 patients.
Safety data from an additional 111
patients treated only with Erbitux were
also evaluated. All trials included patients
with EGFR-expressing metastatic
colorectal cancer whose disease had
progressed after receiving irinotecan.
Severe infusion reactions have occurred
in 3% of patients and were
characterized by rapid onset of airway
obstruction, rash, and hypotension;
they were rarely fatal, and 90% were
associated with the first infusion, according
to a boxed warning in the
package insert. Interstitial lung disease
has been reported infrequently,
but the association is unclear. Besides
the acneiform rash often seen with
Erbitux, more common side-effects
include dry skin, tiredness or weakness,
fever, constipation, and abdominal
pain.
Avastin: Result of
Years of R&D
"The approval of Avastin is the
result of many years of research and
development exploring a promising
new approach to fighting cancer, and
it is one of a number of recent new
treatments for colorectal cancer that,
taken together, have significantly improved
the armamentarium for fighting
this disease," said FDA Commissioner
Mark B. McClellan, MD, PhD.
Safety and efficacy of Avastin was
primarily shown in a randomized,
double-blind clinical trial of more than
800 patients with metastatic colorectal
cancer that was designed to assess
whether it extended survival duration.
Half of the patients received the new
standard chemotherapy, IFL (irinotecan,
5-FU, and leucovorin) and half
received Avastin once every 2 weeks in
addition to IFL. Patients given Avastin/
IFL survived about 5 months longer
and the average time to tumor regrowth
or appearance or new tumors
was 4 months longer than with IFL
alone. Overall response rate to the treatment
was 45% vs 35% for the control
arm of the trial.
Serious, but uncommon, side-effects
include gastrointestinal perforation,
generally requiring surgery and
sometimes leading to intra-abdominal
infections; impaired wound healing;
and pulmonary or internal hemorrhage.
More common side-effects
include hypertension, tiredness,
thrombosis, diarrhea, decreased leukocytes,
headache, loss of appetite, and
mouth sores.