(Avastin) with standard chemotherapy
prolonged survival of patients
with metastatic colorectal cancer by nearly
5 months in the first major randomized
trial to validate the promise of an antiangiogenesis
agent against human cancer.
"The addition of bevacizumab to standard
first-line chemotherapy for metastatic
colorectal cancer results in a clinically
meaningful and statistically
significant improvement in survival," lead
investigator Herbert Hurwitz, MD, of
Duke University Medical Center,
Durham, North Carolina, announced
(ASCO abstract 3646).
Extended Median Survival
The combination of bevacizumab and
IFL (bolus irinotecan [CPT-11, Camptosar],
fluorouracil [5-FU], and leucovorin)
extended median survival by 4.7
months and delayed cancer progression
by 4.4 months in comparison to the same
three agents with a placebo, according to
Dr. Hurwitz. Median survival increased
from 15.6 months to 20.3 months, and
progression-free survival from 6.24
months to 10.6 months.
Both arms of the study had a few complete
responders, Dr. Hurwitz noted, but
overall response favored the bevacizumab/
IFL combination. The response rate rose from 34.7% of 403 patients who received
standard therapy plus placebo, to
44.9% of 412 patients given bolus IFL
plus the novel agent. Duration of response
increased from 7.1 months to 10.4 months.
"An improvement in all subgroups
was noted," Dr. Hurwitz said, including
patients with variable performance status,
number of metastatic sites, sex and
age, as well as baseline characteristics such
as albumin levels.
Inhibits VEGF Signaling
Bevacizumab is a recombinant, humanized
monoclonal antibody that interferes
with the flow of blood to tumors
by inhibiting signaling from a key regulator,
the vascular endothelial growth factor
(VEGF). VEGF is overexpressed in
most human tumors. Judah Folkman,
MD, of Harvard University proposed in
the 1970s that cutting blood supply to
tumors could stop cancers by starving
them, and Napoleone Ferrara, MD, of
Genentech, cloned VEGF and played a
key role in the preclinical biology leading
to the development of bevacizumab.
While antiangiogenic drugs have
shown promise in preclinical and phase II
studies, until now none had succeeded in
a phase III trial. That included bevacizumab.
A randomized study of patients
with metastatic breast cancer refractory
to doxorubicin and paclitaxel showed a
higher response rate, but no change in
time to progression or overall survival,
when bevacizumab was added to singleagent capecitabine.
One initial concern about bevacizumab
in the colorectal trial, Dr. Hurwitz said,
was that inhibiting VEGF would lead to a
substantial increase in bleeding or thromboembolytic
complications. This did not
happen. The toxicity rate for grade 3/4
bleeding was 2.5% for the placebo arm vs
3.1% for the bevacizumab arm. For thromboembolism,
the grade 3/4 toxicity rate
was 16.1% for the placebo arm vs 19.3%
for the bevacizumab arm. Dr. Hurwitz
noted that the patients on bevacizumab
were on therapy an average of 4.5 months
longer, a differential that is not reflected
in the reported data.
'Remarkably Well Tolerated'
Although he described bevacizumab
as "remarkably well tolerated," Dr. Hurwitz
reported that grade 3 hypertension
increased from 2.3% in the placebo arm
to 10.9% in the bevacizumab arm. The
hypertension was easily controlled with
oral medication, he said.
Of more concern were six cases of
gastrointestinal perforations in the bevacizumab
cohort. One event led to a patient
death, and two caused patients to
discontinue treatment. Three patients
stopped treatment, but were able to resume
therapy with bevacizumab, according
to Dr. Hurwitz.
"An uncommon but serious complication
of bevacizumab may have been
identified in this study," he said.
The trial enrolled about 900 patients
from September 7, 2000 to May 6, 2002.
Dr. Hurwitz did not report on a third arm
of about 100 patients who only received 5-
FU and leucovorin as standard chemotherapy.
This arm was stopped after bolus
IFL became standard treatment for colorectal
cancer. The Arm 3 data was reported
separately at the annual meeting of
the American Association for Cancer Research.
See the following page for another report
on bevacizumab (ASCO abstract