anti-VEGF Monoclonal Antibody Research Articles

Ambiguous effects of anti-VEGF monoclonal antibody (bevacizumab) for POEMS syndrome

ObjectiveVascular endothelial growth factor (VEGF) plays an essential role in the pathophysiology of polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome. Anti-VEGF antibody (bevacizumab) appears to be an attractive...

Mechanisms of action of the anti-VEGF monoclonal antibody bevacizumab on chronic lymphocytic leukemia cells

Chronic lymphocytic leukemia (CLL) remains incurable; therefore searching for new therapeutic strategies in this disease is necessary. An important mechanism of tumor development is neoangiogenesis. A potent antiangiogenic factor, bevacizumab (Avastin, AVA), has been poorly explored in CLL so far. In the current study we assessed cytotoxic activity of AVA alone or in combinations with drugs routinely used in this disease. Cells isolated from 60 CLL patients were treated with AVA alone or in combination with anti-CD20 monoclonal antibody (MoAb), rituximab (RIT), anti-CD52 MoAb, alemtuzumab (ALT), 2-CdA (2-chlorodeoxyadenosine), FA (fludarabine), MAF (mafosfamide) or RAPA (rapamycin). Cytotoxicity was assessed by propidium iodide staining. Apoptosis was evaluated using annexin-V and TUNEL assays. Additionally, a drop of mitochondrial potential (DYm) as well as expression of apoptosis-regulating proteins Bax, Bak, Bid, Bad, Bcl-2, Mcl-2, XIAP, FLIP, Akt and Bcl-2-A1 were determined by flow cytometry. At the dose of 40 μg/ml, after 48 hours of incubation, AVA induced significant cytotoxicity against CLL cells. The drug triggered apoptosis, with activation of caspase-3 and -9, but not caspase-8, along with a drop of DYm. Incubation with AVA induced significant overexpression of proapoptotic Bak and Bad as well as downregulation of antiapoptotic Mcl-2 and Akt proteins. Combination of AVA with RIT, ALT or RAPA significantly increased cytotoxicity when compared with the effects of single drugs. In conclusion, this is the first report showing proapoptotic activity of AVA against CLL cells. Combination of AVA with RIT, ALT or RAPA may be a promising therapeutic strategy, which requires confirmation in further studies.

Combined use of Anti-VEGF and Anti-EGFR Monoclonal Antibodies with Photodynamic Therapy Suppresses Tumor Growth in an In vivo Tumor Model

Photodynamic therapy (PDT) is a promising treatment option for cancer. It can be used for drug-resistant and inoperable tumors. However, one of the unsolved problems in PDT is tumor recurrence. The aim of this study is to suppress tumor regrowth by including angiogenesis inhibitors that target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways, to the PDT protocol. Human bladder cancer (MGH cell line) xenografts were induced in Balb/c nude mice. The animals treated with PDT received an intravenous injection of hypericin followed by irradiation after 6 hours, with a broadband light source through a 560-640 NM bandpass filter. A light dosage of 120 J/cm2 and 100 mW/cm2 was administered. Angiogenesis inhibitors, bevacizumab and cetuximab were administered at a dose of 10 mg/kg. Treatment efficacy was assessed by monitoring the tumor growth inhibition of xenograft tumors. Immunohistochemistry was performed to evaluate the expression of VEGF and EGFR. Expression of the major proteins in the VEGF and EGFR pathways was investigated by immunoblotting. One-way ANOVA with Bonferroni correction was performed to analyze the data. Tumors treated with the combination of PDT and inhibitors exhibited significantly greater treatment response compared to control and PDT groups. Downregulation of VEGF and EGFR observed in tumors treated with PDT + bevacizumab and cetuximab respectively. Our results show that blocking VEGF or/and EGFR pathways along with PDT can effectively suppress tumor growth.

Strategy of anti-angiogenesis and antiangiogenic drugs in NSCLC

Development and metastasis of NSCLC are closely related to angiogenesis.Several distinct groups of vascular-targeted therapies have evolved:anti-VEGF monoclonal antibody,small molecules inhibitors,vascular disrupting agents,endothelial cell growth inhibitors,et al.Antiangiogenic treatment could make longer survival than conventional treatment.The strategy of anti-angiogenic drugs combined conventional treatment is being studied. Key words: Carcinoma,non-small-cell lung; Angiogenesis inhibitors; Molecular targeted therapy

Constitutional Genetic Variants as Predictors of Antiangiogenic Therapy Outcome in Renal Cell Carcinoma

The development of specific angiogenesis inhibitors has drastically improved renal cancer treatment in recent years. Currently, four VEGF receptor inhibitors (sorafenib, sunitinib, pazopanib and axitinib), one anti-VEGF monoclonal antibody (bevacizumab) and two inhibitors of the mTOR pathway (temsirolimus and everolimus) have been approved to treat renal cell carcinoma (RCC), and several other molecules are under investigation. However, lack of response to antiangiogenic drugs and adverse drug reactions leading to treatment suspension are critical clinical problems that need to be solved. Because antiangiogenic drugs act on nonmalignant endothelial cells, the genetic background of the patient may play a crucial role determining the efficacy of these drugs. This article focuses on the identification of polymorphisms associated with antiangiogenic drugs outcome in RCC patients. It reviews and summarizes our current knowledge on this area and discusses future strategies to identify new biomarkers that could be used to personalize RCC management.

Bevacizumab Diminishes Experimental Autoimmune Encephalomyelitis by Inhibiting Spinal Cord Angiogenesis and Reducing Peripheral T-Cell Responses

Angiogenesis in the animal model of multiple sclerosis experimental autoimmune encephalomyelitis (EAE) is regulated by vascular endothelial growth factor (VEGF) and angiopoietin-2. We determined whether VEGF blockade with the anti-VEGF monoclonal antibody bevacizumab could inhibit angiogenesis and affect peripheral pathogenic immune responses in EAE. Mice treated with bevacizumab from the time of onset of clinical signs showed reduced clinical and pathologic scores. Bevacizumab suppressed angiogenesis and reduced angiopoietin-2 expression at Day 21 but had no effect on VEGF upregulation at Day 14. Messenger RNA levels for the angiogenesis-related protein CD105 were increased at Day 14. Bevacizumab reduced vascular permeability in the spinal cord at Day 14 and Day 21. In peripheral lymph nodes, it induced retention of CD4-positive T cells and inhibited T-cell proliferation. It also reduced mononuclear cell infiltration into spinal cord and the relative proportion of T cells. Isolated lymphoid cells showed reduced secretion of the T-helper 17 (Th-17) cell cytokine interleukin 17 and the Th-1 cytokine interferon-γ. When bevacizumab was added to naive T cells or to antigen-stimulated T cells from mice with untreated EAE in vitro, it had no effect on proliferation or the secretion of interleukin 17 or interferon-γ. These data indicate that bevacizumab ameliorates vascular and T-cell responses during EAE, but its effects on T cells may be indirect, possibly by suppressing angiogenesis.

IS6-2 - Molecular Targeted Therapies: How Can Biomarker Improve Outcome?

ABSTRACT For physicians facing patients with organ-limited metastases from colorectal cancer, tumor shrinkage and sterilization of micro-metastatic disease is the main goal, giving the opportunity for secondary surgical resection. At the same time, for the majority of patients who will not achieve a sufficient tumor response, disease control remains the predominant objective. Since FOLFOX or FOLFIRI have similar efficacies, the challenge is to define which could be the most effective targeted agent to achieve these goals. The a priori molecular identification of patients who could benefit from anti-EGFR or anti-VEGF monoclonal antibodies (i.e. the targeted therapies up to now available for mCRC) is of critical importance. In this setting, the KRAS mutational status is the first identified predictive marker of response to anti-EGFR therapy and is required prior treatment with anti-EGFR therapy. For KRAS wild-type patients, the choice is in between anti-VEGF and anti-EGFR. In the future, in addition to clinical considerations, molecular markers may provide critical information for selecting patients who might benefit preferentially from one of these drugs. Indeed, the tumor's pathology and patient's metabolism is driven by genetic make-up, influencing the individual response and toxicity. A great amount of exploratory data has been delivered. The challenge of treatments' optimization through specific biomarkers gain special value for a potentially curable disease as mCRC with metastases confined to the liver, and it is even more important if we consider that we do really have the opportunity of mutually exclusive therapeutic choices in this setting. The high degree of complexity of the biological systems we are dealing with makes the discovery of determinant biomarkers a demanding endeavor per se. On the other hand, researchers have to face with all the difficulties of prospective verification and clinical validation of the most promising factors. In the future, to make translational research productive, affordable and more concrete, it will be necessary to have a worldwide effort from the scientific community (from medical oncologists to surgeons and basic researchers, but also of national health systems, industries, regulatory agencies and academies).

100% Human Monoclonal Antibodies in Oncology: Hype or Breakthrough?

Targeted therapies have dramatically modified treatment strategies in oncology since the early 2000's, especially for treating digestive cancers. These new biotherapies such as anti-VEGF (bevacizumab) or anti-EGFR (cetuximab) monoclonal antibodies have given oncologists new opportunities to use innovative treatment schedules or combinations with cytotoxics. Consequently, significant improvements in response rates, with trends to longer progression-free survival and/or overall survival have been achieved in patients with metastatic colorectal cancer (mCRC). Panitumumab is a novel, 100% human, anti-EGFR1 (HER1) antibody that has been approved in late 2007 for use as monotherapy in mCRC patients resistant to standard chemotherapy, provided that their tumor express EGFR and display wild-type K-Ras status. Panitumumab has been recently further approved in combination with chemotherapy in mCRC patients. However, owing to the fact that its mechanism of action for targeting EGFR is similar to that of chimeric cetuximab, picturing the specificities in pharmacological and pharmacokinetic properties of this 100% human antibody could help the oncologists to better define their strategies at the bedside.

292P - Serum Levels of VEGF Pre- and Post-Treatment With Bevacizumab (BEV) for Early Stage Breast Cancer (ESBC): ICORG 08-10

ABSTRACT Background Angiogenesis, partly mediated by vascular endothelial growth factor (VEGF), promotes metastases. BEV, an anti-VEGF monoclonal antibody which has some efficacy in metastatic BC is being studied as an adjuvant treatment for ESBC. However, there are no validated biomarkers, and the effects of BEV on VEGF levels in pts with ESBC is unknown. We studied VEGF serum concentration in ESBC receiving BEV. Methods 106 pts with HER-2 negative ESBC were included in this study. Patients received 4 cycles of docetaxel (75 mg/m2) + cyclophosphamide (600 mg/m2) with BEV (15 mg/kg) once every three weeks for one year. Serum samples were collected prior to commencement of treatment, at 6 months and 12 months. The VEGF levels in serum samples were determined, at each time point, using a VEGF enzyme-linked immunosorbent assay (ELISA). Results VEGF concentration was determined in serum samples from 65 patients. Serum VEGF was detectable in 62 of 65 patients and the median level in untreated patients was 325.4 pg/ml (range 0.1 - 924.8 pg/ml). All of the 62 patients showed a significant decrease in VEGF concentration after 6 and 12 months of treatment (median 9 ± 42.1 pg/ml, p Conclusion Adjuvant therapy with chemotherapy and BEV is associated with a significant reduction in VEGF levels at 6 months. Disclosure All authors have declared no conflicts of interest.

435TiP - A Dual Phase I/II Study of th-302 and Bevacizumab in Resectable Recurrent Glioblastoma Following Bevacizumab Failure

ABSTRACT Introduction Bevacizumab, a recombinant human monoclonal anti-VEGF antibody, exhibits anti-tumor activity in recurrent glioblastoma; however, the median progression free survival (PFS) of patients who progress on bevacizumab and are subsequently started on a non-bevacizumab containing regimen is only 1.6 months. Pre-clinical studies have shown that anti-angiogenic treatment leads to an increase in hypoxia in the tumor microenvironment leading to increased invasiveness. Hypoxia upregulates survival mechanisms, inhibits apoptosis, and stimulates invasiveness. TH-302 is a hypoxia-activated prodrug that once activated releases the alkylating agent Br-IPM. This drug has shown to potentiate, in vivo, the anti-tumor efficacy of other anti-angiogenic agents. This dual phase I/II study enrolled subjects with recurrent glioblastoma following bevacizumab failure that were planned for repeat craniotomy. Methods Single center, dose-escalation, prospective study with TH-302 single dose at 575 mg/m2 or placebo administered pre-operatively, followed by postoperative combination therapy of bevacizumab at 10 mg/kg every 2 weeks and TH-302 dose escalated 240–480 mg/m2 every 2 weeks (4 week cycle) until disease progression. Resected tumor tissue was evaluated for hypoxia induced pimonidazole adducts, endogenous CAIX staining, double-strand DNA damage by gamma-H2AX and MGMT expression. Results Five patients underwent craniotomy and initiated TH-302 plus bevacizumab. No dose limiting toxicity was reported. There were no grade 3 or 4 adverse events (AEs) observed at 240mg/m2, and one grade 3 (skin ulceration) and no grade 4 AEs observed thus far in the second cohort at 340mg/m2. Of the initial 5 patients treated, one patient had a partial response (PR) and 3 patients had stable disease (SD) per RANO criteria. Histological assessment of resected tumors demonstrated extensive areas of hypoxia as measured by pimonidazole and a heterogeneous distribution of gamma-H2AX staining. Conclusions TH-302 demonstrates good tolerability when combined with bevacizumab. The MTD has not been reached and only one grade 3/4 toxicity was observed. Dose escalation is ongoing, with planned expansion at the MTD. Disclosure J. Sun: The author is an employee of pharmaceutical industry with a financial interest in the drug which is the subject of this abstract. C. Hart: The author is an employee of pharmaceutical industry with a financial interest in the drug which is the subject of this abstract. C. Eng: The author is an employee of pharmaceutical industry with a financial interest in the drug which is the subject of this abstract. All other authors have declared no conflicts of interest.

How to approach patients in relapse

How to approach patients in relapse

Targeted Therapies for Advanced Non-Small Cell Lung Cancer

The incorporation of targeted agents has considerably improved the management of patients with advanced non-small cell lung cancer (NSCLC) over the last years. The main targets include the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF). Currently available agents with established role in NSCLC include the anti-EGFR tyrosine-kinase inhibitors (TKIs) erlotinib/gefitinib and the anti-VEGF monoclonal antibody bevacizumab. Moreover, several other agents targeting critical pathways in lung carcinogenesis are currently under preclinical or clinical evaluation. This review presents an update on the role of targeted agents in advanced NSCLC. In addition, we present the main clinical studies investigating the activity of these agents in NSCLC and we provide recent data with respect to future therapeutic strategies.

Chemoprevention of age-related macular regeneration (AMD) with rapamycin

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness among people of 50 year or older. During AMD, vascular endothelial growth factor (VEGF) may become elevated, causing choroidal neovascularization (CNV) and vascular permeability and fragility. Choroidal neovascularization can break in Bruch's membrane, resulting in subretinal hemorrhage, fluid exudation, detachment of the retinal pigment epithelium from the choroid, and formation of fibrotic scars [1]. Patients with neovascular age-related macular degeneration could suffer sudden visual loss due to subretinal hemorrhage or fluid accumulation secondary to choroidal neovascularization. Although neovascular AMD only accounts for less than 15% of the overall age-related macular degeneration, it is responsible for over 80 percent of the severe vision loss cases. Current therapeutics for neovascular AMD are two closely related antibody drugs, ranibizumab (trade name Lucentis) and bevacizumab (trade name Avastin), both of which bind to and neutralize VEGF [2,3]. Bevacizumab is a humanized anti-VEGF monoclonal antibody while ranibizumab is a humanized monoclonal antibody fragment that is made based on the same murine monoclonal antibody as bevacizumab. Ranibizumab is an FDA-approved drug but bevacizumab is used off-label by ophthalmologists. Both agents are used for intravitreal injections, which is cumbersome for patients and is not suitable for preventive treatment. Therefore, new drugs are needed to prevent and treat this type of disease.

Update on novel therapies for pancreatic neuroendocrine tumors.

Neuroendocrine tumors (NETs) describe a heterogeneous group of tumors with a wide range of morphologic, functional, and behavioral characteristics. Pancreatic neuroendocrine tumors (pNET) are a subset of NETs which are increasing in incidence and prevalence. These tumors are generally slow growing and behave in an indolent fashion. However, when these tumors spread they can be life threatening and difficult to treat with current modalities. In 2011, the landscape of treatment for pNET was changed with the approval of two targeted agents, sunitinib and everolimus, the first new therapies for this disease in over 20 years. Data from these clinical trials and extensive preclinical work into the underlying molecular pathways in neuroendocrine tumors has generated intense interest in the quest to identify additional effective agents in this challenging disease. At the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, several researchers presented updated data regarding the use of targeted agents, alternative chemotherapeutic agents and combinations of these in the treatment of pNET. Corrie et al. (Abstract #4121) reported data from a chemotherapy clinical trial replacing 5-FU with capecitabine and evaluating the addition of cisplatin in NETs. Several authors reviewed the addition of the anti VEGF monoclonal antibody bevacizumab into combination therapy. Ducreux et al (Abstract #4036) presented results from a trial of chemotherapy plus bevacizumab while Firdaus et al. (Abstract #4127) reported the results of combination therapy with octreotide, bevacizumab, and pertuzumab. Hobday et al. (Abstract #4048) reported positive results of an interim analysis of combination therapy with an mTOR inhibitor and bevacizumab. Kulke et al (Abstract #4125) reported the results of a clinical trial utilizing an antibody targeting the insulin growth factor receptor. Finally, Vinik et al. (Abstract #4118) provided updated survival data form the seminal phase III trial that led to approval of sunitinib in the treatment of pNET. The authors review and summarize these abstracts in this article.

Bevacizumab treatment of prostate cancer

Introduction: Angiogenesis plays an important role in the development and progression of prostate cancer. Vascular endothelial growth factor (VEGF) is a primary mediator of this process and is a target for novel therapies. Bevacizumab is a recombinant anti-VEGF monoclonal antibody that has demonstrated antitumor activity in a variety of cancers.Areas covered: In this review, we present the results of several clinical trials for bevacizumab in prostate cancer. Overall, these trials have shown improvements in progression-free survival but no changes in overall survival. Ongoing clinical trials are testing bevacizumab in combination with novel cytotoxic drugs and targeted therapies in metastatic and localized settings.Expert opinion: Bevacizumab has biological activity in prostate cancer. However, the mixed clinical trial results support the theory that prostate cancers may be driven only in part by angiogenesis. Questions remain about the future role of bevacizumab in the treatment of prostate cancer.

Anti‐VEGF antibody therapy does not promote metastasis in genetically engineered mouse tumour models

Resistance to anti-angiogenic therapy can occur via several potential mechanisms. Unexpectedly, recent studies showed that short-term inhibition of either VEGF or VEGFR enhanced tumour invasiveness and metastatic spread in preclinical models. In an effort to evaluate the translational relevance of these findings, we examined the consequences of long-term anti-VEGF monoclonal antibody therapy in several well-validated genetically engineered mouse tumour models of either neuroendocrine or epithelial origin. Anti-VEGF therapy decreased tumour burden and increased overall survival, either as a single agent or in combination with chemotherapy, in all four models examined. Importantly, neither short- nor long-term exposure to anti-VEGF therapy altered the incidence of metastasis in any of these autochthonous models, consistent with retrospective analyses of clinical trials. In contrast, we observed that sunitinib treatment recapitulated previously reported effects on tumour invasiveness and metastasis in a pancreatic neuroendocrine tumour (PNET) model. Consistent with these results, sunitinib treatment resulted in an up-regulation of the hypoxia marker GLUT1 in PNETs, whereas anti-VEGF did not. These results indicate that anti-VEGF mediates anti-tumour effects and therapeutic benefits without a paradoxical increase in metastasis. Moreover, these data underscore the concept that drugs targeting VEGF ligands and receptors may affect tumour metastasis in a context-dependent manner and are mechanistically distinct from one another.

Selecting the best targeted agent in first‐line treatment of unresectable liver metastases from colorectal cancer: does the bench have the answers?

For physicians facing patients with organ-limited metastases from colorectal cancer, tumor shrinkage and sterilization of micrometastatic disease is the main goal, giving the opportunity for secondary surgical resection. At the same time, for the majority of patients who will not achieve a sufficient tumor response, disease control remains the predominant objective. Since FOLFOX or FOLFIRI have similar efficacies, the challenge is to define which could be the most effective targeted agent (anti-EGFR or anti-VEGF) to reach these goals. Therefore, a priori molecular identification of patients that could benefit from anti-EGFR or anti-VEGF monoclonal antibodies (i.e. the currently approved targeted therapies for metastatic colorectal cancer) is of critical importance. In this setting, the KRAS mutation status was the first identified predictive marker of response to anti-EGFR therapy. Since it has been demonstrated that tumors with KRAS mutation do not respond to anti-EGFR therapy, KRAS status must be determined prior to treatment. Thus, for KRAS wild-type patients, the choices that remain are either anti-VEGF or anti-EGFR. In this review, we present the most updated data from translational research programs dealing with the identification of biomarkers for response to targeted therapies.

Combination of bevacizumab and irradiation on uveal melanoma: an in vitro and in vivo preclinical study

Radiotherapy (RT) is the standard treatment for uveal melanoma. However it can cause damage to the retina and optic nerve. This study examined the in vitro and in vivo effects of the anti-VEGF monoclonal antibody bevacizumab associated with radiotherapy (RT) on tumor growth and tumor proliferation and vasculature on OCM-1 human uveal melanoma cell line. The anti-proliferative effects of bevacizumab, RT and their combination were tested both in vitro (OCM-1 cells co-cultured with HUVEC cells in Transwell plates) and in vivo (OCM-1 tumor xenografts in nude mice). In addition, treatment effects in vitro on VEGF secretion, as well as treatment effects in vivo on tumor proliferation (Ki67 labelling), tumor vasculature (VEGFR2 labelling) and VEGF tumoral concentration were analyzed. Bevacizumab given alone had a significant impact on tumor growth in vivo (and moderate effects in vitro). The bevacizumab-RT combination had additive effects in vitro (tumor cell proliferation) and in vivo (tumor growth), which translated into a significant decrease in Ki67 expression, VEGFR2 labelling and VEGF tumoral content. The bevacizumab-RT combination could be a promising clinical option to explore for the management of human uveal melanoma, since it may allow RT dose reduction without loss of antitumor efficacy.

Bevacizumab-Induced Alterations in Vascular Permeability and Drug Delivery: A Novel Approach to Augment Regional Chemotherapy for In-Transit Melanoma

To investigate whether the systemically administered anti-VEGF monoclonal antibody bevacizumab could improve regional chemotherapy treatment of advanced extremity melanoma by enhancing delivery and tumor uptake of regionally infused melphalan (LPAM). After treatment with systemic bevacizumab or saline, changes in vascular permeability were determined by spectrophotometric analysis of tumors infused with Evan's blue dye. Changes in vascular structure and tumor hemoglobin-oxygen saturation HbO(2) were determined by intravital microscopy and diffuse reflectance spectroscopy, respectively. Rats bearing the low-VEGF secreting DM738 and the high-VEGF secreting DM443 melanoma xenografts underwent isolated limb infusion (ILI) with melphalan (LPAM) or saline via the femoral vessels. The effect of bevacizumab on terminal drug delivery was determined by immunohistochemical analysis of LPAM-DNA adducts in tumor tissues. Single-dose bevacizumab given three days before ILI with LPAM significantly decreased vascular permeability (50.3% in DM443, P < 0.01 and 35% in DM738, P < 0.01) and interstitial fluid pressure (57% in DM443, P < 0.01 and 50% in DM738, P = 0.01). HbO(2) decreased from baseline in mice following treatment with bevacizumab. Systemic bevacizumab significantly enhanced tumor response to ILI with LPAM in two melanoma xenografts, DM443 and DM738, increasing quadrupling time 37% and 113%, respectively (P = 0.03). Immunohistochemical analyses of tumor specimens showed that pretreatment with systemic bevacizumab markedly increased LPAM-DNA adduct formation. Systemic treatment with bevacizumab before regional chemotherapy increases delivery of LPAM to tumor cells and represents a novel way to augment response to regional therapy for advanced extremity melanoma.

Targeting the blood vasculature

Blood vessels are essential for sustained growth of various malignant tumors including human non-small cell lung cancer (NSCLC). VEGF (vascular endothelial growth factor) is the key molecular regulator of new tumor blood capillary formation (i.e. angiogenesis) and its high expression is associated with poorer survival in NSCLC. Thus, it represents an attractive target for anticancer therapy. Bevacizumab, a humanized monoclonal anti-VEGF antibody, is currently approved for the first-line treatment of advanced stage non-squamous NSCLC in combination with chemotherapy.