Given the well-established role of
angiogenesis (or new blood vessel formation) in tumor growth and metastasis,
antiangiogenic therapy, a concept first proposed by Dr. Judah Folkman, has
become increasingly recognized as a promising new anticancer strategy. As the
angiogenic switch in tumors reflects the net balance of a diverse group of
endogenous angiogenic promoters and inhibitors, a multitude of agents have been
developed to target different factors and pathways. Over 20 antiangiogenic drugs
are currently undergoing evaluation in phase I, II, and III trials.
Of known proangiogenic factors, vascular endothelial growth
factor (VEGF; also known as the vascular permeability factor) is one of the most
potent and specific, and has been identified as a crucial regulator of both
normal and pathologic angiogenesis. VEGF is a secreted, heparin-binding protein
that exists in multiple isoforms due to alternative splicing. The action of VEGF
is mainly mediated through binding of the circulating VEGF peptides to receptor
tyrosine kinases on endothelial cells, VEGFR-1 (Flt-1), and VEGFR-2
(KDR/Flk-1).The biological effects of VEGF include endothelial cell mitogenesis
and migration, induction of proteinases leading to remodeling of the
extracellular matrix, increased vascular permeability, maintenance of survival
for newly formed blood vessels, and possibly suppression of dendritic cell
Overexpression of VEGF has been demonstrated in most human
cancers examined to date. In breast cancer, increased levels of VEGF, as
measured in the circulation or in tumor tissues, correlated with an increase in
microvessel density and advanced disease stages, and in some cases,
independently predicted reduced relapse-free and overall survival.[3,4] A
similar correlation was also implicated in a variety of other solid tumors.
More recently, the importance of endothelial cells and angiogenesis has also
been suggested in hematologic malignancies, such as aggressive lymphoma,
myelogenous leukemia, multiple myeloma, myelodysplasia, and others.
The apparent significance of VEGF in cancer pathogenesis
supports the rationale for VEGF-targeting therapeutics. Anti-VEGF agents
currently in clinical trials include monoclonal antibodies targeting the VEGF
ligand (eg, bevacizumab) and inhibitors directed at the receptors (eg, SU5416).
Bevacizumab (rhuMAb VEGF, Genentech, Inc) is a recombinant
humanized anti-VEGF monoclonal antibody (MAb) that recognizes all biologically
active isoforms of VEGF and blocks their binding to the VEGF receptors.[6,7]
Bevacizumab is composed of the antigen-binding complementarity-determining
regions from a murine anti-VEGF MAb (A.4.6.1) and the human immunoglobulin G1
framework. Anti-VEGF MAbs have shown potent growth inhibition in vivo in a
variety of human cancer xenograft[7,8] and metastasis models, including
rhabdomyosarcoma, glioblastoma, breast, lung, colon cancer, and others. Such a
growth inhibitory effect was accompanied by a reduction in vascular
permeability, decrease in tumor vessel density, and in some cases, complete
suppression of angiogenesis.[11,12] Furthermore, the combination of anti-VEGF
MAb and chemotherapeutic agents, such as doxorubicin and cisplatin
(Platinol), resulted in enhanced antitumor activity compared to either agent
Several clinical trials have evaluated bevacizumab at different
doses and schedules.[13,14] Pharmacokinetics appeared to be linear at doses
above 1 mg/kg, with a half-life of ~15 days. Recommended doses for further
studies are 5 or 10 mg every 2 weeks or 15 mg every 3 weeks. Evidence of
single-agent activity has been demonstrated in a phase II study in patients with
previously treated metastatic breast cancer, where objective tumor
responses, including one complete response, were documented.
The combination of bevacizumab and chemotherapy was also
evaluated. In a phase II trial of bevacizumab and fluorouracil (5-FU) plus
leucovorin, 104 patients with untreated metastatic colorectal cancer were
randomized to either chemotherapy alone, or in combination with two dose levels
of bevacizumab.[15,16] Although the study was not designed and powered to
compare efficacy, the combination arms suggested a trend toward a higher
response rate and longer time to tumor progression. Genentech is currently
sponsoring a phase III trial comparing irinotecan (CPT-11, Camptosar), 5-FU, and
leucovorin with or without bevacizumab as first-line therapy for metastatic
The combination of bevacizumab with carboplatin (Paraplatin)
plus paclitaxel (Taxol) was also tested for safety and feasibility in a small
randomized phase II trial in patients with advanced non-small-cell lung cancer
(NSCLC).[17,18] There appeared to be an advantage for the higher dose of
bevacizumab (15 mg/kg every 2 weeks), but the results were not statistically
significant. In this trial, several major hemorrhagic events were reported in
the bevacizumab arm, as indicated below.
A variety of side effects have been reported in the clinical
studies of bevacizumab. Most significant were hemorrhagic events in the NSCLC
study of the bevacizumab and carboplatin/paclitaxel combination, in which 6 of
the 66 patients developed life-threatening pulmonary hemorrhage (4 of which were
fatal); most patients had tumors of squamous cell histology or central
location. Life-threatening hemorrhage was not observed in other bevacizumab
trials, although bleeding graded as serious has been reported. Hypertension
attributable to bevacizumab was common (about 20%) but in most cases, was mild
or controllable with medication. Proteinuria of varying severity has been
reported. In the study of bevacizumab with 5-FU and leucovorin, there also
appeared to be an increase in thromboembolic events in the combination arm
compared to chemotherapy alone. Other events less clinically significant
included epistaxis, headache, diarrhea, fever, and rash.
The mechanisms and risk factors for bevacizumab-related
toxicities remain unknown. At present, all ongoing clinical trials have
implemented specific exclusion criteria and early stopping rules to minimize
risk to patients, with special attention to bleeding, thrombosis, and
In view of the critical role of VEGF in tumor pathogenesis and
the preliminary efficacy data of bevacizumab, the Cancer Therapy Evaluation
Program (CTEP) of the National Cancer Institute (NCI) has established an
agreement to develop bevacizumab in collaboration with Genentech, Inc. The CTEP
is currently sponsoring a number of clinical trials of bevacizumab, ranging from
phase I to phase III.
The general goals of these trials include: (1) assessing the
activity of bevacizumab in various solid tumors and hematologic malignancies,
(2) evaluating the safety and efficacy of combining bevacizumab with
conventional chemotherapy and radiation, or with other targeted and biological
agents, (3) exploring the surrogate and predictive markers of anti-VEGF therapy,
and (4) understanding the mechanism of action and treatment failure. A list of
currently open or approved NCI-sponsored trials is provided below. Information
about these trials can be obtained from the contact listed for each trial or
from Helen Chen, MD, at the NCI’s CTEP (email@example.com),
1. Folkman J: Angiogenesis in cancer, vascular, rheumatoid and
other disease. Nat Med 1:27-31, 1995.
2. Ferrara N, Davis-Smyth T: The biology of vascular endothelial
growth factor. Endocr Rev 18:4-25, 1997.
3. Linderholm B, Grankvist K, Wilking N, et al: Correlation of
vascular endothelial growth factor content with recurrences, survival, and first
relapse site in primary node-positive breast carcinoma after adjuvant treatment.
J Clin Oncol 18:1423-31, 2000.
4. Gasparini G: Clinical significance of determination of
surrogate markers of angiogenesis in breast cancer. Crit Rev Oncol Hematol
5. Poon RT, Fan ST, Wong J: Clinical implications of circulating
angiogenic factors in cancer
patients. J Clin Oncol 19:1207-25, 2001.
6. Kim KJ, Li B, Houck K, et al: The vascular endothelial growth
factor proteins: identification of biologically relevant regions by neutralizing
monoclonal antibodies. Growth Factors 7:53-64, 1992.
7. Presta LG, Chen H, O’Connor SJ, et al: Humanization of an
antivascular endothelial growth factor monoclonal antibody for the therapy of
solid tumors and other disorders. Cancer Res 57:4593-4599, 1997.
8. Kim KJ, Li B, Winer J, et al: Inhibition of vascular
endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo.
Nature 362:841-844, 1993.
9. Warren RS, Yuan H, Matli MR, et al: Regulation by vascular
endothelial growth factor of human colon cancer tumorigenesis in a mouse model
of experimental liver metastasis. J Clin Invest 95:1789-1797, 1995.
10. Borgstrom P, Gold DP, Hillan KJ, et al: Importance of VEGF
for breast cancer angiogenesis in vivo: implications from intravital microscopy
of combination treatments with an anti-VEGF neutralizing monoclonal antibody and
doxorubicin. Anticancer Res 19:4203-4214, 1999.
11. Yuan F, Chen Y, Dellian M, et al: Time-dependent vascular
regression and permeability changes in established human tumor xenografts
induced by an antivascular endothelial growth factor/vascular permeability
factor antibody. Proc Natl Acad Sci U S A 93:14765-14770, 1996.
12. Borgstrom P, Hillan KJ, Sriramarao P, et al: Complete
inhibition of angiogenesis and growth of microtumors by antivascular endothelial
growth factor neutralizing antibody: novel concepts of angiostatic therapy from
intravital videomicroscopy. Cancer Res 56:4032-4039, 1996.
13. Gordon MS, Margolin K, Talpaz M, et al: Phase I safety and
pharmacokinetic study of recombinant human antivascular endothelial growth
factor in patients with advanced cancer. J Clin Oncol 19:843-850, 2001.
14. Sledge G, Miller K, Novotny W, et al: A Phase II trial of
single-agent rhumab VEGF (recombinant humanized monoclonal antibody to vascular
endothelial cell growth factor) in patients with relapsed metastatic breast
cancer (abstract 5c). Proc Am Soc Clin Oncol 19:3a, 2000.
15. Bergsland E, Hurwitz H, Fehrenbacher L, et al: A randomized
phase II trial comparing rhuMAb VEGF (recombinant humanized monoclonal cntibody
to vascular endothelial cell growth factor) plus 5-fluorouracil/leucovorin
(FU/LV) to FU/LV alone in patients with metastatic colorectal cancer (abstract
939). Proc Am Soc Clin Oncol 19:242a, 2000.
16. Bergsland EK, Fehrenbacher L, Novotny W, et al: Bevacizumab
(BV) + chemotherapy (CT) may improve survival in metastatic colorectal cancer
(MCRC) subjects with unfavorable prognostic indicators (abstract 2247). Proc Am
Soc Clin Oncol 19:124b, 2001.
17. DeVore RF, Fehrenbacher L, Herbst R, et al: A randomized
phase II trial comparing rhumab VEGF (recombinant humanized monoclonal antibody
to vascular endothelial cell growth factor) plus carboplatin/paclitaxel (CP) to
CP alone in patients with stage IIIB/IV NSCLC (abstract 1896). Proc Am Soc Clin
Oncol 19:485a, 2000.
18. Kabbinavar FF, Johnson D, Langmuir VK, et al: Patterns of
tumor progression during therapy with bevacizumab (BV) and chemotherapy (CT) for
metastatic colorectal cancer (MCRC) and advanced non-small-cell lung cancer
(NSCLC) (abstract 1105). Proc Am Soc Clin Oncol 19:277a, 2001.
19. Novotny W, Holmgren E, Griffing S, et al: Identification of
squamous cell histology and central, cavitary tumors as possible risk factors
for pulmonary hemorrhage in patients with advanced NSCLC receiving bevacizumab
(abstract 1318). Proc Am Soc Clin Oncol 19:330a, 2001.