Translation of Pro-Angiogenic and Anti-Angiogenic Therapies into Clinical Use - Mechanical and Chemical Signaling in Angiogenesis - page 264

4.1 Bevacizumab: the First Clinical Anti-Angiogenic Therapy
As the key regulator of angiogenesis, VEGF has been the prime focus of anti-
angiogenic drug development for cancer. One of the first biologic VEGF-targeting
agents was a mouse anti-VEGF antibody [ 58 ]. A recombinant humanized anti-
VEGF antibody was then developed by Genentech. This antibody, named
bevacizumab, targets all isoforms of human VEGF-A [ 59 ]. A phase III clinical trial
was conducted in 813 patients with previously untreated metastatic colorectal
cancer; patients were randomized to receive either combination chemotherapy plus
bevacizumab, or combination chemotherapy alone [ 60 ]. The addition of
bevacizumab to combination chemotherapy resulted in clinically significant
improvements in progression-free survival and overall survival; bevacizumab
boosted overall survival by a median time of 4.5 months when added to combination
chemotherapy. In 2004, bevacizumab (Avastin ) gained Food and Drug Adminis-
tration (FDA) approval as a first-line treatment for metastatic colorectal cancer,
becoming the first FDA-approved anti-angiogenic treatment for cancer [ 61 ].
Bevacizumab has been evaluated for treatment of metastatic renal cell
carcinoma. A multi-center, randomized, double-blind phase III trial was conducted
in 649 patients with previously untreated renal cell carcinoma; patients were
randomized to receive either interferon alfa plus bevacizumab, or interferon alfa
alone [ 62 ]. Again, the results were clinically significant. The addition of
bevacizumab to interferon alfa boosted progression-free survival by a median time
of 4.8 months. Bevacizumab raised overall survival by a median time of 2 months
when added to interferon alfa [ 63 ]. The combination of bevacizumab and inter-
feron alfa is now FDA-approved as first-line treatment for metastatic renal cell
carcinoma. Bevacizumab has also shown promise for treating a brain cancer,
glioblastoma multiforme. A phase II clinical trial of bevacizumab plus irinotecan
was conducted in 35 patients with recurrent glioblastome multiforme [ 64 ]. The
prognosis for these patients has historically been very poor, but twenty of 35
patients in the bevacizumab trial had at least a partial response. Bevacizumab now
carries FDA approval for recurrent glioblastoma multiforme.
The anti-VEGF antibody has demonstrated similar success for non-small-cell
lung cancer. A randomized phase III clinical trial was conducted, to investigate
whether the addition of bevacizumab to first-line chemotherapy with paclitaxel and
carboplatin improves survival in patients with metastatic non-small-cell lung
cancer [ 65 ]. The trial enrolled 878 patients with recurrent or advanced non-small-
cell lung cancer; patients were randomized to receive either bevacizumab plus
paclitaxel and carboplatin, or paclitaxel and carboplatin alone. The results were
significant and clinically meaningful. Adding bevacizumab to first-line chemo-
therapy improved response rate and progression-free survival. Bevacizumab
increased overall survival time by a median time of 2 months when added to first-
line chemotherapy. The anti-VEGF antibody, in combination with carboplatin and
paclitaxel, is FDA-approved for treatment of advanced non-squamous, non-small-
cell lung cancer.