Bevacizumab (Avastin) for Treatment of Solid Tumors: Questions and Answers
Bevacizumab (Avastin) was the first U.S. Food and Drug Administration (FDA)-
approved biological therapy designed to inhibit the formation of new blood
vessels to tumors. It is manufactured by Genentech, South San Francisco, Calif.
The National Cancer Institute (NCI), part of the National Institutes of Health,
has been involved in the clinical development of bevacizumab in several tumor
types under a cooperative research and development agreement (CRADA) with
Genentech.
Tumor cells require a constant supply of blood to receive the oxygen and
nutrients they need to survive. As a tumor grows, it signals the need for more
blood by secreting growth factors that trigger the formation of new blood
vessels, a process called angiogenesis. Of the many growth factors implicated
in the formation of new blood vessels, vascular endothelial growth factor
(VEGF) has been identified as one of the most potent protein supporting tumor
growth. In addition to affecting tumor growth, VEGF promotes formation of new
capillaries surrounding the tumor, providing increased nutrients for growth and
a convenient route for tumor cells to spread throughout the body.
Bevacizumab was developed to inhibit VEGF. It was designed to cause the
destruction of the blood vessel networks that feed cancer cells as the lack of
a constant source of blood may slow tumor growth. Bevacizumab is an antibody --
a type of targeting device produced by the immune system that can locate and
bind to a specific protein. In the case of bevacizumab, it is a monoclonal
(cells derived from a single common ancestor) antibody that binds to and
inhibits VEGF.
History of Development
Bevacizumab is one of many angiogenesis inhibitors that have been
developed based on a hypothesis of angiogenesis action published in 1971 by
Judah Folkman, M.D., Harvard Medical School, Boston, Mass. By 1983, scientists
had demonstrated that tumors secrete VEGF and by 1989, VEGF had been cloned for
investigational purposes. The first clinical trials to examine the efficacy of
anti-angiogenic agents for cancer patients began in the 1990s.
In February 2004, the FDA approved the use of bevacizumab based on a Phase III
clinical trial sponsored by Genentech that showed benefit in first-line
treatment of metastatic colorectal cancer when the drug was added to standard
chemotherapy (Hurwitz H, Fehrenbach L, Novotny W et al. Bevacizumab plus
irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer, New
England Journal of Medicine 2004; 350:2335-42). The results of this trial demonstrated that,
when compared to the standard chemotherapy being prescribed for untreated
metastatic colon cancer at the time, bevacizumab in combination with standard
chemotherapy:
-
Increased median overall survival by 30 percent (20.3 months vs. 15.6 months)
-
Increased median progression-free survival, or the time that a patient's cancer
was not growing, by 71 percent (10.6 months vs. 6.2 months)
-
Increased response rate (45 percent vs. 35 percent) and duration of response to
bevacizumab (10.4 months vs. 7.1 months)
Recent Trial Results
Bevacizumab has been investigated for efficacy in treatment in a number of
cancers. The NCI, in collaboration with a network of investigators led by the
Eastern Cooperative Oncology Group (ECOG), recently sponsored three key
randomized clinical trials of bevacizumab, the first of which was a trial of
metastatic colorectal cancer:
Preliminary results from a large, randomized clinical trial for patients with
advanced colorectal cancer who had previously received treatment were released
in November 2004
(http://www.nci.nih.gov/newscenter/pressreleases/BevacizumabOxaliplatin). This
trial is different from the Genentech trial in February 2004 in several
respects, particularly because it offered a different choice of chemotherapy.
Researchers in this trial (known as E3200) found that the patients 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 for patients in this study who
received bevacizumab plus FOLFOX4 compared to those who received FOLFOX4 alone.
A breast cancer clinical trial, which released initial results in April 2005
(http://www.nci.nih.gov/newscenter/pressreleases/AvastinBreast), demonstrated
that bevacizumab, in combination with standard chemotherapy, delayed the
progression of disease by an average of approximately 5 months. From December
2001 to May 2004, this randomized study enrolled 722 women who had recurrent or
metastatic breast cancer, or cancer that had spread to other organs, that had
not been previously treated with chemotherapy. The women were treated with
bevacizumab in combination with paclitaxel, or paclitaxel alone. Those women
receiving combination therapy showed a delay in development of their breast
cancer that was statistically significant. This was the first study to show the
benefit of anti-angiogenic therapy for breast cancer and was a major advance in
the treatment of patients with metastatic disease.
A lung cancer study, which released its preliminary results in March 2005
(http://www.nci.nih.gov/newscenter/pressreleases/AvastinLung), showed that
those patients receiving a combination therapy of bevacizumab and chemotherapy
were living longer than patients receiving only standard chemotherapy. The
interim results of this study were made public because the primary endpoint of
improving overall survival had been achieved. Patients receiving a regimen of
chemotherapy (paclitaxel and carboplatin) and bevacizumab had a median overall
survival of 12.5 months compared to the control group, receiving only
paclitaxel and carboplatin, who survived an average of 10.2 months. The
improved survival of 2.3 months was statistically significant. The results of
this randomized study were noteworthy because they revealed the potential for
improved survival rates with the addition of an anti-angiogeneic therapy. It
should be noted, however, that these results apply only to patients in the
study (those with advanced non-squamous, non-small cell lung cancer who had not
previously received systemic chemotherapy) and that the most significant
adverse event observed in this study was life-threatening or fatal bleeding,
primarily from the lungs.
NCI, in collaboration with Genentech, is currently evaluating the potential use
of bevacizumab in a number of different cancers. NCI is sponsoring more than 30
trials using this drug, including Phase III clinical trials in advanced or
metastatic renal cell carcinoma, pancreatic cancer, and ovarian cancer. NCI
also is conducting a Phase III trial evaluating the use of the drug for
colorectal cancer patients who have undergone potentially curative surgery. For
current information about ongoing clinical trials using bevacizumab, please go
to http://www.cancer.gov/clinicaltrials/search.
It is important to note that there are general toxicities associated with
bevacizumab therapy, including bleeding, arterial clots (which could lead to
stroke and heart attack), bowel perforation, wound healing difficulties, and
hypertension.
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