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The Oncologist, Vol. 10, No. 6, 382-391, June 2005; doi:10.1634/theoncologist.10-6-382
© 2005 AlphaMed Press

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VEGF-Targeted Therapy: Therapeutic Potential and Recent Advances

Lee S. Rosen

John Wayne Cancer Institute and St. John’s Health Center, Santa Monica, California, USA

Correspondence: Correspondence: Lee S. Rosen, M.D., 2020 Santa Monica Boulevard, Suite 510, Santa Monica, California 90404, USA. Telephone: 310-633-8400; Fax: 310-633-8419; e-mail: lrosen{at}premiereoncology.com


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Key Regulators of Angiogenesis
 Antiangiogenic Strategies
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Conclusion
 References
 
After completing this course, the reader will be able to:

  1. Compare and contrast the mechanism of action for angiogenesis inhibitors currently being explored for the treatment of cancer.
  2. Compare the efficacy of standard chemotherapy alone to that of chemotherapy combined with an antiangiogenic agent for the treatment of metastatic colorectal cancer.
  3. Describe the rationale for the use of angiogenesis inhibitors in the treatment of breast cancer.
  4. Assess recent data describing the efficacy of angiogenesis inhibitors in the treatment of NSCLC.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Key Regulators of Angiogenesis
 Antiangiogenic Strategies
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Conclusion
 References
 
After over 30 years of theorizing, the use of angiogenesis inhibitors as anticancer therapy has finally moved from the realm of research to reality. Normal adult vasculature is generally quiescent in nature, with endothelial cells dividing approximately every 10 years. In contrast, the growth of tumors requires constant vascular growth and remodeling in order for solid tumors to grow beyond 1–2 mm3 in size. Vascular endothelial growth factor (VEGF) and its receptors are key regulators of the process of angiogenesis, which makes them attractive therapeutic targets. A multitude of VEGF-targeted inhibitory agents are currently being investigated for the treatment of cancer. This review article focuses on recent developments in the use of angiogenesis inhibitors for the treatment of breast, lung, and colorectal cancers.

Key Words. Angiogenesis • Lung cancer • VEGF • Vascular endothelial growth factor • Colorectal cancer • Breast cancer • Bevacizumab • Vatalanib • PTK787


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Key Regulators of Angiogenesis
 Antiangiogenic Strategies
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Conclusion
 References
 
Recent advances in the development of targeted therapies for the treatment of cancer have provided new hope and improved patient outcomes in a wide variety of tumor types. Much excitement and research has been focused on the development of agents that inhibit tumor angiogenesis. While the vasculature of a normal adult is generally quiescent, with endothelial cells dividing approximately every 10 years, tumors require constant vascular growth and remodeling [1]. Generally, tumors cannot grow beyond 1–2 mm3 in diameter without the development of a vascular supply [2]. The process of angiogenesis is regulated by a delicate balance between local proangiogenic and antiangiogenic factors, which are released by both tumor and host cells, including endothelial cells, pericytes, and cells of the immune system. To date, a multitude of both pro- and antiangiogenic factors have been described, the most potent of which is vascular endothelial growth factor (VEGF) [3].


   KEY REGULATORS OF ANGIOGENESIS
Top
 Learning Objectives
 Abstract
 Introduction
 Key Regulators of Angiogenesis
Antiangiogenic Strategies
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Conclusion
 References
 
VEGF
VEGF is the prototypical proangiogenic molecule, and it has been implicated in several steps throughout the angiogenesis process [4]. The VEGF family of molecules currently consists of six growth factors, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor, and three receptors, including VEGF receptor (VEGFR)-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4). VEGF-A is currently the most well-characterized member of the VEGF family and is composed of at least six isoforms due to alternative gene splicing [5]. One of the most striking characteristics of VEGF is its ability to induce vascular permeability [3]. This enhanced permeability leads to subsequent fibrin deposition in the extracellular matrix that can then serve as a scaffold for migrating endothelial cells. The three VEGFRs are transmembrane tyrosine kinases that are predominantly found on endothelial cells. The activation of VEGFR-2 by its ligands results in enhanced permeability of the vasculature and increased migration and proliferation of endothelial cells, making it also a major target for therapy [4].

Other Proangiogenic Factors
The platelet-derived growth factor (PDGF) family of molecules is structurally related to the VEGF family and has been demonstrated to have significant angiogenic properties in vitro and in vivo [6]. It is believed that the major role of PDGF in the regulation of angiogenesis is control of pericyte function. There are four currently known PDGF family members that are able to form homo- and heterodimers. One homodimer, PDGF-BB, has been shown to upregulate VEGF in vascular smooth muscle cells, which in turn, enhances endothelial cell survival [7]. Additional data have shown that PDGF-BB results in enhanced proliferation of endothelial cells [8]. Platelet-derived endothelial-cell growth factor (PD-ECGF), also known as thymidine phosphorylase, is produced by stromal cells, tumor cells, and infiltrating macrophages [9]. PD-ECGF has been shown to have angiogenic activity in vivo and is associated with high vessel counts despite low VEGF staining in colorectal tumors [10]. In addition to these, several other angiogenic factors have been described, including angiogenin, angiopoietins, Tie-2, integrins, and fibroblast growth factor (FGF)-1 and FGF-2.


   ANTIANGIOGENIC STRATEGIES
Top
 Learning Objectives
 Abstract
 Introduction
 Key Regulators of Angiogenesis
 Antiangiogenic Strategies
Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Conclusion
 References
 
Targeting VEGF is thought to prevent the formation of new tumor vasculature, thus inhibiting tumor growth. However, it also has been suggested that anti-VEGF therapy may produce vascular normalization [11,12]. As a result of high VEGF expression, the vasculature in tumors is inefficient, chaotic, and abnormal. As a result of neutralizing local VEGF, anti-VEGF agents can induce normalization of these vessels, resulting in a potential decrease in vascular volume and interstitial fluid pressure within the tumor allowing enhanced delivery of oxygen and cytotoxic therapies to the tumor. This mechanism of action has important implications in combining anti-VEGF agents with chemotherapy, as they may improve the efficacy of these regimens. Many agents that target VEGF function are currently in development, including those targeting VEGF (e.g., VEGF antibodies and soluble VEGFRs) and those that target VEGFRs (e.g., VEGFR antibodies and small-molecule kinase inhibitors; Table 1Go).


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  		Table 1. VEGF-targeted therapies currently in development
 
Bevacizumab (Avastin®; Genentech, Inc., South San Francisco, CA, http://www.gene.com) is a humanized monoclonal antibody directed against VEGF-A. This antibody maintains the high specificity and affinity of the parental antibody for human VEGF-A, while reducing immunogenicity and providing a longer biologic half-life [13]. Bevacizumab is believed globally to prevent binding of all VEGF isoforms to all VEGFRs [4]. In preclinical mouse models, anti-VEGF monoclonal antibodies inhibit VEGF, block the growth of human tumor xenografts, and dramatically reduce the size and number of liver tumors [14]. Additionally, the combination of this anti-VEGF antibody and chemotherapy in nude mice with human cancer xenografts has greater activity than chemotherapy alone or antibody alone [15].

Another class of angiogenesis inhibitors currently in development is the small-molecule tyrosine kinase inhibitors (TKIs). These agents act by inhibiting receptor signaling and associated downstream events. VEGFR TKIs currently in development include vatalanib (PTK787/ZK-222584), SU11248, and ZD6474. Vatalanib is an orally available small-molecule TKI that is a potent inhibitor of VEGFR-1 and VEGFR-2 [16]. SU11248 inhibits VEGFR-2 and PDGF [17], while ZD6474 inhibits VEGFR-2, VEGFR-3, and, to some extent, the epidermal growth factor receptor (EGFR) [18].

Vascular-targeting agents (VTAs) are another class of agents currently under development that target tumor vasculature. VTAs are acute-acting agents that produce vascular shutdown within a few hours of administration. Unlike classic angiogenesis inhibitors that inhibit new vessel formation, VTAs selectively target endothelial cells in the existing vasculature of tumors [19–21]. This class of agents is in the early stages of development; the microtubule inhibitors ZD6126 and combretastatin A-4 phosphate prodrug are currently the farthest along in development.


   ANGIOGENESIS INHIBITORS IN THE TREATMENT OF COLORECTAL CANCER
Top
 Learning Objectives
 Abstract
 Introduction
 Key Regulators of Angiogenesis
 Antiangiogenic Strategies
 Angiogenesis Inhibitors in the...
Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Conclusion
 References
 
In 2004, Hurwitz and colleagues first reported the first efficacy analysis of a placebo-controlled randomized trial of irinotecan (Camptosar®; Pfizer Inc., New York, http://www.pfizer.com)/5-fluorouracil (5-FU)/leucovorin (LV) (IFL) with or without bevacizumab for the first-line therapy of metastatic colorectal cancer [22]. Treatment with bevacizumab plus IFL resulted in a significantly longer survival time than with chemotherapy alone. This study provided definitive proof that angiogenesis inhibitors could be effective in the treatment of cancer, and based on the results of this study, the U.S. Food and Drug Administration approved bevacizumab in combination with i.v. 5-FU-based chemotherapy for the first-line treatment of patients with metastatic colorectal cancer.

More recently, the results from a phase II study investigating the use of 5-FU/LV/bevacizumab were reported (AVF2192g; Table 2Go) [23,24]. This trial, which was completed parallel to the pivotal phase III study, enrolled patients who were not considered to be candidates for irinotecan therapy because they possessed at least one pre-treatment characteristic predictive of lack of response to irinotecan or a greater risk of toxicity (age ≥65 years, Eastern Cooperative Oncology Group [ECOG] performance status of 1 or 2, serum albumin ≤3.5 g/dl, or prior radiation therapy of the abdomen or pelvis). The results of this study were consistent with those seen in prior studies; progression-free survival (PFS) was 9.2 months for patients who received 5-FU/LV/bevacizumab, compared with 5.5 months for those who received 5-FU/LV alone (p = .0002; Table 2Go). Median overall survival was 16.6 months in the arm containing bevacizumab, which was not statistically greater than the survival rate observed with 5-FU/LV alone (12.9 months; p = .160). However, overall survival rates did fall within the range previously reported in phase III studies of bolus infusional IFL [22,25]. Thus, this patient population, which cannot tolerate irinotecan or would not derive full survival benefit from irinotecan-based therapy, was able to achieve comparable survival with the less toxic 5-FU/LV/bevacizumab regimen [23].


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  		Table 2. Phase II trial of bevacizumab in metastatic colorectal cancer patients not eligible for irinotecan (AVF2192g): efficacy
 
Subsequent safety analyses of the AVF2107g study have demonstrated a small, but consistent, greater risk of gastrointestinal (GI) perforation in patients who received bevacizumab [11,22]. Among the 392 patients treated with 5-FU/LV/bevacizumab, 1.5% experienced a GI perforation event. Furthermore, an analysis of the patients who underwent surgery while on therapy revealed that 4 of the 40 patients who received bevacizumab combined with bolus IFL and 1 of the 15 patients who received bevacizumab plus 5-FU/LV experienced wound healing and bleeding complications during the 60-day postoperative period; however, none of the patients who received IFL plus placebo experienced similar complications [26]. Wound healing and bleeding complications included anastomotic bowel dehiscence (two patients), thoracotomy wound dehiscence (one patient), hemothorax following lung resection (one patient), and ecchymosis and bleeding along the surgical incision following revision of colostomy (one patient). Prior to the occurrence of these complications, these patients had not received treatment with bevacizumab therapy for 13–89 days. These data suggest that physicians should consider the potential risks and benefits of surgery in patients who are receiving or have recently been treated with bevacizumab-based therapy.

Thromboembolic events were also greater for patients who received bevacizumab, with arterial events reported in 3.3% of patients compared with 1% of patients receiving placebo [27]. These data suggest that it may be efficacious for patients who receive treatment with bevacizumab therapy to also receive low-dose aspirin therapy, if they are ≥65 years of age, have experienced a heart attack or stroke, and exhibit no contraindications for the use of aspirin therapy (hypersensitivity, active peptic ulcer disease, bleeding disorder, or qualitative platelet dysfunction) [28]. It should be noted that low-dose aspirin therapy is a standard recommendation for patients with cardiac risk factors. Further studies can determine if low-dose aspirin truly affects the clotting risks of antiVEGF therapy. These patients should also be monitored for potential bleeding complications.

While bevacizumab has proven efficacy in colorectal cancer, the optimal chemotherapy regimen to use in combination with bevacizumab is still unknown. Due to numerous clinical studies, the 5-FU/LV/oxaliplatin (Eloxatin®; Sanofi-Synthelabo Inc., New York, http://www.sanofi-synthelabo.us) (FOLFOX) and infusional 5-FU/LV/irinotecan (FOLFIRI) regimens are now more widely used than IFL in the U.S. A phase III ECOG trial, E3200, sought to determine if bevacizumab would be active in combination with the FOLFOX regimen. Patients with previously treated metastatic colorectal cancer (one prior regimen, usually containing irinotecan) were randomized to receive either FOLFOX-4/bevacizumab, FOLFOX-4 alone, or bevacizumab alone. The preliminary safety analysis showed that there was no apparent greater toxicity with the FOLFOX-4/bevacizumab regimen than with FOLFOX alone [29]. Around the same time, the bevacizumab-alone arm was dropped because of inferior results. And recently, it was announced that patients who received the combination of FOLFOX-4/bevacizumab had a statistically significant survival advantage [30]. The study results should be presented at the 2005 Annual Meeting of the American Society of Clinical Oncology. One can conclude that bevacizumab augments the effectiveness of 5-FU-, irinotecan-, or oxali-platin-based chemotherapy. And, one can certainly extrapolate from the N9741 and ECOG 3200 studies that a FOLFOX/bevacizumab combination is the best available therapy for first-line metastatic colorectal cancer. However, without formal randomized and prospective studies, it is still reasonable to use a 5-FU- or FOLFIRI-based regimen along with bevacizumab instead.

Several studies are also under way to evaluate the use of capecitabine (Xeloda®; Hoffmann-La Roche Inc., Nutley, NJ, http://www.rocheusa.com), an oral fluoropyrimidine, in combination with bevacizumab; these studies include the TREE-2 trial comparing FOLFOX/bevacizumab, bFOL/bevacizumab, and XELOX/bevacizumab in the first-line setting and the NO16966 trial comparing FOLFOX-4 with XELOX with or without bevacizumab (Table 3Go).


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  		Table 3. Ongoing trials of bevacizumab in colorectal cancer
 
Among the other antiangiogenic agents currently being tested for use in the treatment of colorectal cancer, vatalanib (PTK787) is the farthest along in clinical development. In three phase I/II studies, vatalanib produced overall response rates (ORRs) of 44%–54% when given at doses ranging from 300–2,000 mg/day and combined with chemotherapy for the treatment of colorectal cancer (Table 4Go) [31–33]. The most common severe adverse events included ataxia, dyspnea, and hypertension. Two large phase III trials (CONFIRM-1 [Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases in First Line] and CONFIRM-2 [Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases in Second Line]) are currently under way to assess the efficacy of this agent in both the first- and second-line settings. The CONFIRM-1 trial has enrolled 1,090 patients for treatment with FOLFOX-4 with or without vatalanib for the first-line therapy of metastatic colorectal cancer. Enrollment for this study was completed in June of 2004. The CONFIRM-2 trial completed enrollment in October, 2004, and randomized 830 patients to receive FOLFOX-4 with or without vatalanib for the second-line treatment of metastatic colorectal cancer.


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  		Table 4. Phase I/II trials with vatalanib (PTK787) in colorectal cancer
 

   ANGIOGENESIS INHIBITORS IN THE TREATMENT OF BREAST CANCER
Top
 Learning Objectives
 Abstract
 Introduction
 Key Regulators of Angiogenesis
 Antiangiogenic Strategies
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
Angiogenesis Inhibitors in the...
 Conclusion
 References
 
Primary breast tumors exhibit a high level of angiogenic activity, and both primary tumors and metastases in the breast are dependent on angiogenesis for their growth [34]. In recent studies, tumor angiogenesis has been shown to act as an independent prognostic indicator in primary breast cancer [35]. Microvessel density (MVD), a surrogate marker of tumoral angiogenesis, has been suggested to predict recurrence, particularly in node-negative patients, for over 10 years. Many studies have concluded that MVD is prognostic in invasive breast cancer; however, this conclusion remains controversial, and others have found no correlation between MVD and prognosis. In a 2004 meta-analysis examining data from a total of 87 published studies, a high MVD was found to significantly predict poor survival (risk ratio, 1.54; 95% confidence interval [CI], 1.29–1.84) [36]. When node-negative patients were analyzed, similar results were observed with a risk ratio of 1.99 for relapse-free survival (95% CI, 1.33–2.98) and 1.54 for overall survival (95% CI, 1.01–2.33). However, standardization in the methods of MVD assessment is needed, as measurements are poorly reproducible, making the clinical utility of this method questionable. Nevertheless, it is clear that angiogenesis can be a potential therapeutic target in breast cancer.

Bevacizumab has been tested in a phase II trial in patients with previously treated metastatic breast cancer [37]. Among the 75 patients enrolled, an ORR of 9.3% was observed. Seventeen percent of patients responded or maintained stable disease at 22 weeks. In a pivotal phase III study, 462 patients with anthracycline- or taxane-refractory disease were randomized to receive capecitabine with or without bevacizumab [38]. Patients who received bevacizumab experienced a significantly greater ORR (9.1% versus 19.8%; p = .001). However, PFS rates were similar between the two study arms (4.17 months versus 4.86 months). A phase III study (E2100) to compare paclitaxel (Taxol®; Bristol-Myers Squibb Company, New York, NY, http://www.bms.com) with or without bevacizumab in previously untreated patients with metastatic disease recently closed to accrual in May, 2004, and results are awaited.

Sandra Swain, M.D., of the National Cancer Institute, recently presented the preliminary results of a pilot study designed to evaluate changes in parameters of angiogenesis (including endothelial proliferation, tumor VEGF levels, and vascular permeability, as measured by dynamic magnetic resonance imaging [MRI]) after treatment with bevacizumab in previously untreated patients with inflammatory breast cancer [39]. Dynamic MRI is a noninvasive imaging technique that allows visualization of the micro-circulation using extracellular low molecular-weight contrast agents. This technique is helpful in visualizing vascular changes; however, controversy remains as to the optimal way to report the results. Using dynamic MRI, a decrease in vascular permeability was observed on treatment with bevacizumab (median change in K21 was –0.82; p = .002 after cycle 4). Furthermore, a trend of decreased tumor VEGF expression after therapy with bevacizumab alone was observed in responding patients.

Efforts have also been made to combine VEGF-targeted therapies with human EGFR (HER-2)-targeted therapies in breast cancer. These studies are based on preclinical models demonstrating that HER-2 gene amplification is associated with an increase in VEGF gene amplification [40]. Furthermore, HER-2 activation resulted in an upregulation of VEGF expression. These studies indicate that increased expression of VEGF may, in part, mediate the biologically aggressive phenotype of HER-2/neu-overexpressing human breast cancer. In a study aimed at analyzing the combined effects of HER-2/neu and VEGF on clinical outcome, VEGF expression was found to be predictive of survival [41]. Furthermore, when HER-2 and VEGF were combined for analysis, additional prognostic information for survival was obtained, supporting the use of combination therapy with HER-2- and VEGF-targeted agents. A phase I/II study of bevacizumab combined with trastuzumab (Herceptin®; Genentech, Inc.) is currently ongoing in an effort to determine if this combination can improve patient outcome.

Agents that inhibit the EGFR have been demonstrated to inhibit the synthesis of angiogenic proteins, including VEGF [42]. Thus, the dual inhibition of EGFR and VEGF may provide increased antitumor efficacy. Indeed, in pre-clinical studies, the combination of the EGFR small-molecule TKI erlotinib (Tarceva®; OSI Pharmaceuticals, Inc., Melville, NY, http://www.osip.com) and bevacizumab inhibited the growth of human colon cancer xenografts more effectively than either agent alone. In a phase II study combining erlotinib (150 mg/day) with bevacizumab (15 mg/kg) every 3 weeks for the treatment of metastatic or locally advanced breast cancer, 6 of 18 patients achieved stable disease, and one patient achieved a partial response [43]. The median duration of response was 8.8 months. It should be noted that several studies have recently identified various somatic mutations in the genomic sequence encoding the EGFR tyrosine kinase domain that are predictive of response to the small-molecule TKIs in patients with lung cancer. Thus, it is possible that specific breast cancer patient populations that are more likely to respond to this combination will be identified in the future.


   ANGIOGENESIS INHIBITORS IN THE TREATMENT OF LUNG CANCER
Top
 Learning Objectives
 Abstract
 Introduction
 Key Regulators of Angiogenesis
 Antiangiogenic Strategies
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
Conclusion
 References
 
Evidence supporting the use of angiogenesis inhibitors in the treatment of lung cancer includes altered expression of several angiogenic growth factors in lung tumors and studies demonstrating an unfavorable prognostic significance for these markers. Meta-analyses have demonstrated a poor prognosis associated with elevated VEGF expression [44] and increased MVD [45]. Activated VEGFR expression [46], elevated interleukin (IL)-8 [47], angiopoietin-2 [48], and PD-ECGF [49] have also been shown to correlate with a poor prognosis in lung cancer patients.

In a phase II study, the addition of bevacizumab to paclitaxel/carboplatin (Paraplatin®; Bristol-Myers Squibb Company) resulted in an impressive increase in response rate, particularly in patients with a nonsquamous histology (Table 5Go) [50]. Among the 99 previously untreated patients randomized, an ORR of 31.5% was observed for patients who received bevacizumab (15 mg/kg), compared with 18.8% for those who received chemotherapy alone. Furthermore, a longer time to progression (7.4 months versus 4.2 months) and overall survival time (17.7 months versus 14.9 months) were reported for patients who received bevacizumab (15 mg/kg).


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  		Table 5. Phase II study of carboplatin/paclitaxel ± bevacizumab in non-small cell lung cancer: efficacy
 
The addition of bevacizumab was generally well tolerated; however, a dose-related increase in leukopenia was observed [50]. Bleeding episodes (classified as hemoptysis/hematemesis) occurred in six patients, four of whom died. All six cases appeared to be tumor related and originated from centrally located pulmonary tumors found close to major blood vessels. Cavitation or necrosis of the tumor occurred in five patients.

Four of the cases of severe hemorrhages occurred in patients with squamous cell carcinomas [50]. Because squamous cell carcinoma is usually centrally located and has a greater tendency to cavitate than adenocarcinoma, it is possible that this histology may represent an increased risk factor for severe bleeding complications. In an exploratory subgroup analysis excluding patients with squamous cell carcinoma, a clinical benefit was observed, with only a 4% risk of severe bleeding. Further investigations are under way to clarify the relationship between squamous cell histology and these adverse events. In the meantime, patients with squamous cell lung cancers have been excluded from the large, ongoing, randomized clinical trials using bevacizumab.

Several trials are currently investigating angiogenesis inhibitors in non-small cell lung cancer (NSCLC; Table 6Go). An ongoing phase III trial of paclitaxel/carboplatin with or without bevacizumab is being conducted in previously untreated patients with stage IIIB or metastatic NSCLC by the ECOG (E4599; Table 6Go). This trial is now fully accrued, and the results are expected to help establish the role of bevacizumab in the treatment of NSCLC. A similar phase II study is currently investigating the use of this same regimen (paclitaxel/carboplatin with or without bevacizumab) in the neoadjuvant setting. Bevacizumab is also being evaluated in combination with the small-molecule EGFR TKI erlotinib in a phase I/II study in NSCLC.


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  		Table 6. Ongoing trials with angiogenesis inhibitors in non-small cell lung cancer
 
Other antiangiogenic agents currently being tested in NSCLC include small-molecule agents that target not only VEGF but other receptor tyrosine kinases found to be associated with NSCLC and activated vascular endothelial cells. SU11248 is an oral, multitargeted TKI that targets VEGFR, PDGFR, Kit, and Flt-3 [17]. In a murine small cell lung cancer xenograft model, SU11248 produced significant tumor growth inhibition. A phase II study of this agent is currently planned in NSCLC (Table 6Go). AG-013736 inhibits VEGFR-2, VEGFR-3, and VEGFR-1. In a phase I study in 36 patients with advanced solid tumors, the main dose-limiting toxicities observed were hypertension, proteinuria, and seizures [51]. Two durable partial remissions were observed, and seven patients achieved stable disease. A phase II study of AG-013736 is currently being planned for patients with metastatic or locally advanced NSCLC.

ZD6474 has been tested in combination with docetaxel (Taxotere®; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com) in a phase I/II study in patients with locally advanced or metastatic NSCLC who failed first-line platinum therapy [52]. Fifteen patients were treated with ZD6474, 100 mg/day or 300 mg/day, plus docetaxel, 75 mg/m2, every 21 days for the phase I, open-label portion of the study. The most common adverse event observed was rash (67% of patients experienced grade 3 rash). Seven patients experienced grade 3/4 myelosuppression. Preliminary pharmacokinetic analyses did not show any effects on docetaxel exposure of ZD6474 treatment. The double-blind, randomized phase of this study is ongoing. ZD6474 is also currently being tested alone or in combination with paclitaxel/carboplatin as first-line therapy for NSCLC.


   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 Key Regulators of Angiogenesis
 Antiangiogenic Strategies
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Conclusion
References
 
The success of bevacizumab in a randomized phase III setting for the treatment of colorectal cancer has raised hopes that antiangiogenic therapies will provide similar benefits for the treatment of other tumor types. However, these results follow the release of data from the pivotal phase III study in patients with breast cancer, which were disappointing. Why were these results so different? Both tumor types express high levels of VEGF; however, as has been reported for EGFR in lung cancer, high expression may not necessarily correlate with response to targeted agents. Yet, recent results in NSCLC have demonstrated genetic mutations in the EGFR that correlate with response to specific EGFR-targeted agents. It is possible that, with time, similar predictive markers may be identified for VEGF-based therapies as well. Currently, a wide array of antiangiogenic compounds are in development. The results of ongoing studies are needed to determine if improved response rates and survival can be achieved for specific tumor types by inhibiting different angiogenic factors. Although the concept of inhibiting angiogenesis as a treatment modality for cancer was first suggested over three decades ago, finding a place for these therapies in clinical practice has been a slow and challenging process. With the positive results of bevacizumab in colorectal cancer, enthusiasm for antiangiogenic agents has been renewed, and it appears that the time has finally come to include these agents among the therapeutic options for the treatment of cancer.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Key Regulators of Angiogenesis
 Antiangiogenic Strategies
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Conclusion
 References
 
Sponsored by the CBCETM(The Center for Biomedical Continuing Education). Supported by an educational grant from Genentech, Inc.

DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Dr. Rosen has received grants/research support from Amgen, Bristol-Myers Squibb, Genentech, ImClone Systems, Novartis Pharmaceuticals, and Pfizer.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Key Regulators of Angiogenesis
 Antiangiogenic Strategies
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Angiogenesis Inhibitors in the...
 Conclusion
 References
 

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Received December 13, 2004; accepted for publication March 31, 2005.




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