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(Drug information on 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 maturation.
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(Drug information on doxorubicin) and cisplatin(Drug information on cisplatin) (Platinol), resulted in enhanced antitumor activity compared to either agent alone.
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(Drug information on 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(Drug information on irinotecan) (CPT-11, Camptosar), 5-FU, and leucovorin with or without bevacizumab as first-line therapy for metastatic colorectal cancer.
The combination of bevacizumab with carboplatin(Drug information on carboplatin) (Paraplatin) plus paclitaxel(Drug information on 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 cardiovascular events.
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 (firstname.lastname@example.org), (301) 496-8798.