| Bevacizumab Combined With Oxaliplatin-Based Chemotherapy
Prolongs Survival for Previously Treated Patients With Advanced Colorectal
Preliminary results from a large, randomized clinical trial for
patients with advanced colorectal cancer who had previously received
treatment show that those who received bevacizumab (Avastin)
in combination with an oxaliplatin (Eloxatin) regimen known
as FOLFOX4 lived longer than patients who received FOLFOX4 alone.
The Data Monitoring Committee overseeing the trial (known as E3200)*
recommended that the results of a recent interim analysis be made
public because the study had met its primary endpoint of demonstrating
improved overall survival. Researchers found that the patients in
the trial who received bevacizumab in combination with FOLFOX4 (a
regimen of oxaliplatin, 5-fluorouracil and leucovorin) had a median
overall survival of 12.5 months compared to patients treated with
FOLFOX4 alone, who had a median overall survival of 10.7 months.
This difference is statistically significant and corresponds to
a 17 percent improvement in median overall survival. There was a
26 percent reduction in the risk of death (hazard ratio of 0.74)
for patients in this study who received bevacizumab plus FOLFOX4
compared to those who received FOLFOX4 alone.
The clinical trial was sponsored by the National Cancer Institute
(NCI), part of the National Institutes of Health, and conducted
by a network of researchers led by the Eastern Cooperative Oncology
Group. Genentech, Inc., which manufactures bevacizumab, provided
bevacizumab for the trial under the Cooperative Research and Development
Agreement (CRADA) with NCI for the clinical development of bevacizumab.
Sanofi-Synthelabo, a member of the Sanofi-Aventis Group and manufacturer
of oxaliplatin, provided that drug for the trial under its CRADA
"These results are simply more good news for people with colorectal
cancer," said Study Chair Bruce J. Giantonio, M.D., of the
University of Pennsylvania's Abramson Cancer Center in Philadelphia.
"We now know that bevacizumab added to second-line chemotherapy
with FOLFOX4 improves survival. With these findings, we can now
more confidently expect survival for people with advanced disease
to be more than double what it was just a few years ago." According
to Giantonio, preliminary results of the E3200 trial will be presented
at the ASCO Gastrointestinal Cancers Symposium to be held in Hollywood,
Fla., on Jan.27-29, 2005.
"This trial highlights benefits of the public-private collaborations
that NCI has spearheaded over the last several years," said
James H. Doroshow, M.D., director of NCI's Division of Cancer Treatment
and Diagnosis and leader of NCI's Clinical Trials Working Group.
"Working with the biotechnology and pharmaceutical companies,
NCI was able to coordinate the drug development of these two new
agents (bevacizumab and oxaliplatin) in combination and, through
the dedication and commitment of the patients and physicians who
participated in the study, provide an important advance for patients."
A total of 829 patients were enrolled in the study between October
2001 and April 2003. Patients previously had received a fluorouracil-based
therapy and irinotecan (Camptosar), either alone or at the
same time, for advanced disease or if their disease had relapsed
within six months of concluding adjuvant (post-surgical) treatment
with these chemotherapy agents. Patients were randomized to one
of three treatment groups. One patient group received the standard
FOLFOX4 treatment plus bevacizumab. The second group received the
standard FOLFOX4 treatment only, and the third group received bevacizumab
alone. In March 2003, the study investigators suspended randomization
to the third treatment arm, bevacizumab alone, on the recommendation
of the Data Monitoring Committee when review of early results suggested
that overall survival for patients in that group might be lower
than that of patients treated in the other two groups.
Treatment toxicities observed in this study were consistent with
those side effects observed in other clinical trials in which bevacizumab
was combined with chemotherapy. Side effects included neuropathy
(problems with nerve function) for FOLFOX4 and high blood pressure
and bleeding for bevacizumab.
Bevacizumab is designed to bind to and inhibit Vascular Endothelial
Growth Factor (VEGF), a protein that plays a critical role in tumor
angiogenesis, the formation of new blood vessels to the tumor. Oxaliplatin
is a novel platinum-based anticancer drug that destroys cancer cells.
"The results of this study are very important for all those
living with advanced colorectal cancer," said NCI Director
Andrew C. von Eschenbach, M.D. "They provide further confirmation
that a biologic agent that targets a tumor's blood supply can prolong
survival when combined with chemotherapy, even for patients who
have previously received therapy for advanced disease."
An estimated 106,370 people will be diagnosed with colon cancer
and an estimated 40,570 people will be diagnosed with rectal cancer
in the United States in 2004. Colorectal cancer is the third most
commonly diagnosed cancer in this country both in men and in women.
An estimated 56,730 deaths from colorectal cancer will occur in
2004 in the United States, accounting for about 10 percent of all
cancer deaths in the nation.
For more information about cancer, visit the NCI Web site at http://www.cancer.gov
or call NCI's Cancer Information Service at 1-800-4 CANCER (1-800-422-6237).
* E3200: Phase III Trial of Bevacizumab,
Oxaliplatin, Fluorouracil and Leucovorin Versus Oxaliplatin, Fluorouracil
and Leucovorin Versus Bevacizumab Alone in Previously Treated Patients
With Advanced Colorectal Cancer