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1.  Aflibercept 
Aflibercept, an intravenously administered anti-VEGF and antiplacental growth factor (PlGF) agent, has recently been approved by the U.S. Food and Drug Administration in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer who have previously received an oxaliplatin-containing chemotherapy regimen. In the phase III VELOUR trial, aflibercept plus FOLFIRI statistically significantly prolonged both progression-free survival (PFS; median PFS for the aflibercept plus FOLFIRI arm was 6.90 vs. 4.67 months for the placebo-plus-FOLFIRI arm) and overall survival (median overall survival for the aflibercept-plus-FOLFIRI arm was 13.50 vs. 12.06 months for the placebo plus FOLFIRI arm), but grade 3 or 4 adverse events were more common with the addition of aflibercept. However, the addition of aflibercept to 5-fluorouracil, leucovorin, and oxaliplatin (mFOL-FOX6) in the phase II AFFIRM trial of first-line treatment of mCRC failed to improve PFS or response rate. As a decoy VEGF receptor, aflibercept (VEGF-Trap) has binding affinity for VEGF-A, VEGF-B, PlGF-1, and PlGF-2, and this is a mechanism of significant interest. Optimal strategies for incorporating aflibercept into treatment regimens that include other anti-VEGF and cytotoxic chemotherapeutic agents, as well as development of predictive biomarkers for treatment response, have yet to be defined.
PMCID: PMC3710732  PMID: 23444216
2.  Aflibercept in wet AMD: specific role and optimal use 
Vascular endothelial growth factor (VEGF) is a naturally occurring glycoprotein in the body that acts as a growth factor for endothelial cells. It regulates angiogenesis, enhances vascular permeability, and plays a major role in wet age-related macular degeneration. The consistent association between choroidal neovascularization and increased VEGF expression provides a strong reason for exploring the therapeutic potential of anti-VEGF agents in the treatment of this disorder. Blockade of VEGF activity is currently the most effective strategy for arresting choroidal angiogenesis and reducing vascular permeability, which is frequently the main cause of visual acuity deterioration. In recent years, a number of other molecules have been developed to increase the efficacy and to prolong the durability of the anti-VEGF effect. Aflibercept (EYLEA®; Regeneron Pharmaceutical Inc and Bayer), also named VEGF Trap-eye, is the most recent member of the anti-VEGF armamentarium that was approved by the US Food and Drug Administration in November 2011. Because of its high binding affinity and long duration of action, this drug is considered to be a promising clinically proven anti-VEGF agent for the treatment of wet maculopathy.
This article reviews the current literature and clinical trial data regarding the efficacy and the pharmacological properties of VEGF-Trap eye and describes the possible advantages of its use over the currently used “older” anti-VEGF drugs.
For this review, a search of PubMed from January 1989 to May 2013 was performed using the following terms (or combination of terms): vascular endothelial growth factors, VEGF, age-related macular degeneration, VEGF-Trap eye in wet AMD, VEGF-Trap eye in diabetic retinopathy, VEGF-Trap eye in retinal vein occlusions, aflibercept. Studies were limited to those published in English.
Results and conclusion
Two Phase III clinical trials, VEGF Trap-eye Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and 2, comparing VEGF Trap-eye to ranibizumab demonstrated the noninferiority of this novel compound. The clinical equivalence of this compound against ranibizumab is maintained even when the injections are administered at 8-week intervals, which indicates the potential to reduce the risk of monthly intravitreal injections and the burden of monthly monitoring.
PMCID: PMC3749085  PMID: 23990705
aflibercept; AMD; neovascularization; VEGF; VEGF inhibition; VEGF-Trap eye
3.  Phase 1 Study of VEGF Trap (Aflibercept) Administered Subcutaneously to Patients with Advanced Solid Tumors 
To determine the maximum tolerated dose (MTD) or maximal administered dose (MAD) and pharmacokinetic and safety profiles of subcutaneously administered VEGF Trap (aflibercept), a novel anti-angiogenic agent.
Experimental Design
In this open-label, dose-escalation study, patients with advanced solid tumors were treated with subcutaneous doses of aflibercept at seven dose levels. Patients received a single dose of aflibercept and then underwent safety and pharmacokinetic assessments over the next 4 weeks. Patients then received weekly or bi-weekly treatment over the subsequent 6 weeks. Patients tolerating and benefiting could continue on aflibercept at the same dose and schedule until progression of disease.
Thirty-eight patients received at least one dose of aflibercept. MTD was not reached. Due to solubility/dosing limits with the subcutaneous formulation, 1600mcg/kg/week was the MAD. The most common toxicities were proteinuria (37%), fatigue (32%), injection site reactions (18%), nausea (17%), myalgia and anorexia (16% each), hypertension (13%), and voice hoarseness (11%). Drug-related grade 3–4 toxicity was uncommon (7%) and reversible: dehydration, cerebral ischemia, proteinuria, hypertension, leukopenia, and pulmonary embolism. We identified dose-proportional increases in plasma concentrations of aflibercept bound to VEGF with a t1/2 of 18 days. No anti-aflibercept antibodies were detected. Stable disease was maintained for at least 10 weeks in 18 patients (47%), and 2 patients maintained on study for more than 1 year.
Subcutaneous aflibercept was well-tolerated and had manageable side effects. Its favorable pharmacokinetic profile and potential antitumor activity warrants further evaluation.
PMCID: PMC4211604  PMID: 20028764
angiogenesis; aflibercept; phase 1; VEGF inhibitors; cancer
4.  Effects of a Single Intravitreal Injection of Aflibercept and Ranibizumab on Glomeruli of Monkeys 
PLoS ONE  2014;9(11):e113701.
It is known that endothelial cells in the kidney are also strongly VEGF-dependent. Whether intravitreal drugs can be detected within the glomeruli or affect VEGF in glomerular podocytes is not known. Therefore, the aim of this pilot study was to investigate the effects of a single intravitreal injection of aflibercept and ranibizumab on glomeruli of monkeys.
The kidneys of eight cynomolgus monkeys, which were intravitreally injected either with 2 mg of aflibercept or with 0.5 mg of ranibizumab, were investigated one and seven days after injection. Two animals served as controls. The distribution of aflibercept, ranibizumab and VEGF was evaluated using anti-Fc- or anti-F(ab)-fragment and anti-VEGF antibodies respectively. The ratio of stained area/nuclei was calculated using a semi-quantitative computer assisted method. Glomerular endothelial cell fenestration was quantified in electron microscopy using a systematic uniform random sampling protocol and estimating the ratio of fenestrae per µm.
Compared to the controls, the anti-VEGF stained area/nuclei ratio of the ranibizumab-treated animals showed no significant changes whereas the stained areas of the aflibercept-treated monkeys showed a significant decrease post-treatment. Immune reactivity (IR) against aflibercept or ranibizumab was detected in aflibercept- or ranibizumab treated animals respectively. The number of fenestrations of the glomerular endothelial cells has shown no significant differences except one day after aflibercept injection in which the number was increased.
Surprisingly, both drugs could be detected within the capillaries of the glomeruli. After a single intravitreal injection of aflibercept, VEGF IR in the podocytes was significantly reduced compared to controls. Ranibizumab injection had no significant effect on the glomeruli's VEGF level. Whether this is caused by aflibercept's higher affinity to VEGF or because it is used in a higher stoichiometric concentration compared to ranibizumab remains to be investigated.
PMCID: PMC4240650  PMID: 25415380
5.  Aflibercept: a Potent Vascular Endothelial Growth Factor Antagonist for Neovascular Age-Related Macular Degeneration and Other Retinal Vascular Diseases 
Biologics in Therapy  2012;2(1):3.
In the western hemisphere, age-related macular degeneration (AMD) is the leading cause of visual loss in the elderly. Currently approved therapies for AMD include argon laser, photodynamic therapy, and antivascular endothelial growth factor (VEGF) therapy. The index review discusses aflibercept (VEGF Trap-Eye) in the context of current anti-VEGF therapies for neovascular AMD and other retinal vascular diseases. It highlights important differences between VEGF Trap-Eye and currently used anti-VEGF therapies for neovascular AMD; and discusses the efficacy of these treatments utilizing information from landmark clinical trials.
A systematic search of literature was conducted on PubMed, Science Direct, and Scopus with no limitations of language or years of publication.
Preclinical studies have shown that VEGF Trap-Eye binds to VEGF-A with a higher affinity than other anti-VEGF molecules; and that it also binds to placental growth factor (PlGF). In clinical trials, VEGF Trap-Eye has been shown to be as effective in the treatment of neovascular AMD as other anti-VEGF therapies and possibly to have a longer duration of drug activity.
VEGF Trap-Eye has enhanced the treatment options currently available for the management of neovascular AMD. The comparable efficacy of VEGF Trap-Eye (to other anti-VEGF agents) coupled with its longer dosing interval may decrease the number of annual office visits for patients with AMD and their caregivers.
PMCID: PMC3873045  PMID: 24392297
Aflibercept; Age-related macular degeneration; Antivascular endothelial growth factor; Neovascular age-related macular degeneration; Vascular endothelial growth factor Trap-Eye
6.  Aflibercept: a Potent Vascular Endothelial Growth Factor Antagonist for Neovascular Age-Related Macular Degeneration and Other Retinal Vascular Diseases 
Biologics in Therapy  2012;2(1):3.
In the western hemisphere, age-related macular degeneration (AMD) is the leading cause of visual loss in the elderly. Currently approved therapies for AMD include argon laser, photodynamic therapy, and antivascular endothelial growth factor (VEGF) therapy. The index review discusses aflibercept (VEGF Trap-Eye) in the context of current anti-VEGF therapies for neovascular AMD and other retinal vascular diseases. It highlights important differences between VEGF Trap-Eye and currently used anti-VEGF therapies for neovascular AMD; and discusses the efficacy of these treatments utilizing information from landmark clinical trials.
A systematic search of literature was conducted on PubMed, Science Direct, and Scopus with no limitations of language or years of publication.
Preclinical studies have shown that VEGF Trap-Eye binds to VEGF-A with a higher affinity than other anti-VEGF molecules; and that it also binds to placental growth factor (PlGF). In clinical trials, VEGF Trap-Eye has been shown to be as effective in the treatment of neovascular AMD as other anti-VEGF therapies and possibly to have a longer duration of drug activity.
VEGF Trap-Eye has enhanced the treatment options currently available for the management of neovascular AMD. The comparable efficacy of VEGF Trap-Eye (to other anti-VEGF agents) coupled with its longer dosing interval may decrease the number of annual office visits for patients with AMD and their caregivers.
PMCID: PMC3873045  PMID: 24392297
Aflibercept; Age-related macular degeneration; Antivascular endothelial growth factor; Neovascular age-related macular degeneration; Vascular endothelial growth factor Trap-Eye
7.  Development of a Preclinical PK/PD Model to Assess Antitumor Response of a Sequential Aflibercept and Doxorubicin-Dosing Strategy in Acute Myeloid Leukemia 
The AAPS Journal  2013;15(3):662-673.
Timing of the anti-angiogenic agent with respect to the chemotherapeutic agent may be crucial in determining the success of combination therapy in cancer. We investigated the effects of sequential therapy with the potent VEGF inhibitor, aflibercept, and doxorubicin (DOX) in preclinical acute myeloid leukemia (AML) models. Mice were engrafted with human HL-60 and HEL-luciferase leukemia cells via S.C. and/or I.V. injection and treated with two to three doses of aflibercept (5–25 mg/kg) up to 3–7 days prior to doxorubicin (30 mg/kg) administration. Leukemia growth was determined by local tumor measurements (days 0–16) and systemic bioluminescent imaging (days 0–28) in animals receiving DOX (3 mg/kg) with or without aflibercept. A PK/PD model was developed to characterize how prior administration of aflibercept altered intratumoral DOX uptake. DOX concentration–time profiles were described using a four-compartment PK model with linear elimination. We determined that intratumoral DOX concentrations were 6-fold higher in the aflibercept plus DOX treatment group versus DOX alone in association with increased drug uptake rates (from 0.125 to 0.471 ml/h/kg) into tumor without affecting drug efflux. PD modeling demonstrated that the observed growth retardation was mainly due to the combination of DOX plus TRAP group; 0.00794 vs. 0.0043 h−1. This PK/PD modeling approach in leukemia enabled us to predict the effects of dosing frequency and sequence for the combination of anti-VEGF and cytotoxic agents on AML growth in both xenograft and marrow, and may be useful in the design of future rational combinatorial dosing regimens in hematological malignancies.
PMCID: PMC3691438  PMID: 23550025
acute myeloid leukemia; aflibercept; doxorubicin; pharmacokinetics/pharmacodynamics; VEGF TRAP
8.  Aflibercept in wet age-related macular degeneration: a perspective review 
In the treatment of neovascular age-related macular degeneration (AMD), vascular endothelial growth factor (VEGF) has emerged as a key target of therapy. Currently, patients with neovascular AMD are treated with monthly intravitreal injections of anti-VEGF medications. Aflibercept is a novel recombinant fusion protein engineered to bind all isoforms of VEGF-A, VEGF-B, and placental growth factor. It is the latest medication to receive US Federal Drug Administration (FDA) approval for the treatment of neovascular AMD. Theoretical models suggest this molecule may have a longer duration of action compared with current treatments. The results of the VEGF Trap-Eye: Investigation of Efficacy and Safety in wet Age-related Macular Degeneration studies (VIEW 1 and VIEW 2) support this by demonstrating that aflibercept, dosed every 2 months after a monthly loading dose for 3 months, was noninferior in the proportion of patients who maintained or improved vision at 52 weeks compared with monthly injections of ranibizumab. These results were maintained over the 2 years of the studies. Aflibercept (Eylea; Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA and Bayer, Basel, Switzerland) was approved by the FDA for the treatment of neovascular AMD on 18 November 2011.
PMCID: PMC3539286  PMID: 23342231
aflibercept; neovascular age-related macular degeneration; ranibizumab; vascular endothelial growth factor; wet age-related macular degeneration
9.  Comparative effectiveness of aflibercept for the treatment of patients with neovascular age-related macular degeneration 
Wet age-related macular degeneration (AMD) is the most common reason for vision loss in the United States. Many treatments, such as laser therapy and photodynamic therapies, have been used but their efficacy is limited. Emerging anti-vascular endothelial growth factor (VEGF) therapies are now considered the standard of care. Anti-VEGF agents inhibit angiogenesis in the eye by suppressing abnormal blood vessel growth, leading to vision improvement. Ranibizumab and bevacizumab are two examples of anti-VEGF drugs that have been approved; both showed promise based on the visual acuity scale. Aflibercept, another new therapy known to trap VEGF and inhibit multiple growth factors, is promising not only because it can be taken bimonthly based on year 1 of the VIEW trials, but it can also be extended, as demonstrated in year 2 of the VIEW trials. Based on a cost–effect analysis, aflibercept is comparable to other leading therapies. This is a review of relevant clinical trials that have proven the non-inferiority and safety of aflibercept compared to the standard of care and its unique role in the current management of wet AMD.
PMCID: PMC3595183  PMID: 23503202
aflibercept; VEGF; anti-VEGF; pegatanib; bevacizumab; ranibizumab; VIEW trials
10.  Safety profiles of anti-VEGF drugs: bevacizumab, ranibizumab, aflibercept and ziv-aflibercept on human retinal pigment epithelium cells in culture 
The British Journal of Ophthalmology  2014;98(Suppl 1):i11-i16.
To compare the safety profiles of antivascular endothelial growth factor (VEGF) drugs ranibizumab, bevacizumab, aflibercept and ziv-aflibercept on retinal pigment epithelium cells in culture.
Human retinal pigment epithelium cells (ARPE-19) were exposed for 24 h to four anti-VEGF drugs at 1/2×, 1×, 2× and 10× clinical concentrations. Cell viability and mitochondrial membrane potential assay were performed to evaluate early apoptotic changes and rate of overall cell death.
Cell viability decreased at 10× concentrations in bevacizumab (82.38%, p=0.0001), aflibercept (82.68%, p=0.0002) and ziv-aflibercept (77.25%, p<0.0001), but not at lower concentrations. However, no changes were seen in cell viability in ranibizumab-treated cells at all concentrations including 10×. Mitochondrial membrane potential was slightly decreased in 10× ranibizumab-treated cells (89.61%, p=0.0006) and 2× and 10× aflibercept-treated cells (88.76%, 81.46%; p<0.01, respectively). A larger reduction in mitochondrial membrane potential was seen at 1×, 2× and 10× concentrations of bevacizumab (86.53%, 74.38%, 66.67%; p<0.01) and ziv-aflibercept (73.50%, 64.83% and 49.65% p<0.01) suggestive of early apoptosis at lower doses, including the clinical doses.
At clinical doses, neither ranibizumab nor aflibercept produced evidence of mitochondrial toxicity or cell death. However, bevacizumab and ziv-aflibercept showed mild mitochondrial toxicity at clinically relevant doses.
PMCID: PMC4033208  PMID: 24836865
Macula; Treatment Medical; Angiogenesis
11.  Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab 
Angiogenesis  2012;15(2):171-185.
Pharmacological inhibition of VEGF-A has proven to be effective in inhibiting angiogenesis and vascular leak associated with cancers and various eye diseases. However, little information is currently available on the binding kinetics and relative biological activity of various VEGF inhibitors. Therefore, we have evaluated the binding kinetics of two anti-VEGF antibodies, ranibizumab and bevacizumab, and VEGF Trap (also known as aflibercept), a novel type of soluble decoy receptor, with substantially higher affinity than conventional soluble VEGF receptors. VEGF Trap bound to all isoforms of human VEGF-A tested with subpicomolar affinity. Ranibizumab and bevacizumab also bound human VEGF-A, but with markedly lower affinity. The association rate for VEGF Trap binding to VEGF-A was orders of magnitude faster than that measured for bevacizumab and ranibizumab. Similarly, in cell-based bioassays, VEGF Trap inhibited the activation of VEGFR1 and VEGFR2, as well as VEGF-A induced calcium mobilization and migration in human endothelial cells more potently than ranibizumab or bevacizumab. Only VEGF Trap bound human PlGF and VEGF-B, and inhibited VEGFR1 activation and HUVEC migration induced by PlGF. These data differentiate VEGF Trap from ranibizumab and bevacizumab in terms of its markedly higher affinity for VEGF-A, as well as its ability to bind VEGF-B and PlGF.
Electronic supplementary material
The online version of this article (doi:10.1007/s10456-011-9249-6) contains supplementary material, which is available to authorized users.
PMCID: PMC3338918  PMID: 22302382
VEGF receptor; Aflibercept; Affinity; Age-related macular degeneration; Placental growth factor; Biomedicine; Cardiology; Biomedicine general; Ophthalmology; Cancer Research; Cell Biology; Oncology
12.  Compartment Model Predicts VEGF Secretion and Investigates the Effects of VEGF Trap in Tumor-Bearing Mice 
Frontiers in Oncology  2013;3:196.
Angiogenesis, the formation of new blood vessels from existing vasculature, is important in tumor growth and metastasis. A key regulator of angiogenesis is vascular endothelial growth factor (VEGF), which has been targeted in numerous anti-angiogenic therapies aimed at inhibiting tumor angiogenesis. Systems biology approaches, including computational modeling, are useful for understanding this complex biological process and can aid in the development of novel and effective therapeutics that target the VEGF family of proteins and receptors. We have developed a computational model of VEGF transport and kinetics in the tumor-bearing mouse, which includes three-compartments: normal tissue, blood, and tumor. The model simulates human tumor xenografts and includes human (VEGF121 and VEGF165) and mouse (VEGF120 and VEGF164) isoforms. The model incorporates molecular interactions between these VEGF isoforms and receptors (VEGFR1 and VEGFR2), as well as co-receptors (NRP1 and NRP2). We also include important soluble factors: soluble VEGFR1 (sFlt-1) and α-2-macroglobulin. The model accounts for transport via macromolecular transendothelial permeability, lymphatic flow, and plasma clearance. We have fit the model to available in vivo experimental data on the plasma concentration of free VEGF Trap and VEGF Trap bound to mouse and human VEGF in order to estimate the rates at which parenchymal cells (myocytes and tumor cells) and endothelial cells secrete VEGF. Interestingly, the predicted tumor VEGF secretion rates are significantly lower (0.007–0.023 molecules/cell/s, depending on the tumor microenvironment) than most reported in vitro measurements (0.03–2.65 molecules/cell/s). The optimized model is used to investigate the interstitial and plasma VEGF concentrations and the effect of the VEGF-neutralizing agent, VEGF Trap (aflibercept). This work complements experimental studies performed in mice and provides a framework with which to examine the effects of anti-VEGF agents, aiding in the optimization of such anti-angiogenic therapeutics as well as analysis of clinical data. The model predictions also have implications for biomarker discovery with anti-angiogenic therapies.
PMCID: PMC3727077  PMID: 23908970
systems biology; mathematical model; computational model; angiogenesis; tumor xenograft model; anti-angiogenic therapy; cancer
13.  Phase I Study of Intravenous Vascular Endothelial Growth Factor Trap, Aflibercept, in Patients With Advanced Solid Tumors 
Journal of Clinical Oncology  2009;28(2):207-214.
Vascular endothelial growth factor (VEGF) Trap (aflibercept) is an angiogenesis inhibitor comprising portions of the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G. This phase I study was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of VEGF Trap administered intravenously (IV) every 2 weeks.
Patients and Methods
Patients with refractory solid tumors or non-Hodgkin's lymphoma with adequate organ function were eligible. Pharmacokinetic/pharmacodynamic markers included measurement of plasma VEGF bound to VEGF Trap and free VEGF Trap. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was incorporated to measure the biologic effects of the drug on tumor vascularity and permeability.
The study enrolled 47 patients at doses ranging from 0.3 to 7.0 mg/kg IV every 2 weeks. Dose-limiting toxicities were rectal ulceration and proteinuria at the 7.0 mg/kg dose. Other mechanism-specific toxicities included hypertension. On the basis of these observations and on pharmacokinetics, the recommended phase II dose of VEGF Trap as a single agent is 4 mg/kg every 2 weeks. Three RECIST (Response Evaluation Criteria in Solid Tumors) –defined partial responses were observed, one at the 3.0 mg/kg and two at the 7.0 mg/kg dose level. Maximum plasma concentration of free VEGF Trap increased proportionally with dose. Maximal VEGF-bound VEGF Trap complex levels were reached at doses ≥ 2.0 mg/kg. Changes in volume transfer constant measured by DCE-MRI at baseline and at 24 hours after administration indicate a possible dose-related change in this pharmacodynamic marker.
IV VEGF Trap was well tolerated at the dose levels tested. Pharmacodynamic and pharmacokinetic markers were indicative of VEGF blockade.
PMCID: PMC2815710  PMID: 19949018
14.  Clinical and differential utility of VEGF inhibitors in wet age-related macular degeneration: focus on aflibercept 
Age-related macular degeneration (AMD) has become a major public health problem and a leading cause of blindness in industrialized nations. AMD results from the ageing eye’s inability to metabolize and dispose completely of photoreceptor outer segments and other waste products. As a result, lipids, particularly apolipoproteins, accumulate within Bruch’s membrane, leading to chronic ischemia and inflammation. The subsequent upregulation of inflammatory cytokines and growth factors, including vascular endothelial growth factor (VEGF), induces the growth of neovascular membranes from the choriocapillaris into the subretinal or subretinal pigment epithelium spaces. To counter this, intravitreally administered drugs (pegaptanib, bevacizumab, ranibizumab) that specifically target VEGF have become the standard treatment for exudative AMD. Aflibercept, a recently approved fusion protein, binds to all isoforms of both VEGF-A and placental growth factor with high affinity. Phase III trials showed that monthly or every other month injections of aflibercept prevent vision loss (fewer than 15 letters) in 95% of patients. Additionally, aflibercept injections every 4 or 8 weeks produce average vision gains of 6.9 letters to 10.9 letters, comparable with those achieved with monthly ranibizumab. After one year of regularly administered aflibercept injections, patients required an average of only 4.2 injections during the second year. Aflibercept promises to decrease the injection frequency required for many patients and appears to serve as an effective “salvage” therapy for patients who respond poorly to other anti-VEGF drugs.
PMCID: PMC3422153  PMID: 22973088
age-related macular degeneration; choroidal neovascularization; vascular endothelial growth factor; aflibercept; ranibizumab; bevacizumab; VEGF trap
15.  Retrospective Analysis of First-Line Anti-Vascular Endothelial Growth Factor Treatment Patterns in Wet Age-Related Macular Degeneration 
Advances in Therapy  2013;30(12):1111-1127.
This study compared the number of, and expenditures on, first-line intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections between patients who were treated with aflibercept or ranibizumab for wet age-related macular degeneration (AMD).
This was a retrospective cohort study based on U.S. administrative claims data. Selected patients had initiated first-line intravitreal anti-VEGF treatment with ranibizumab or aflibercept (index date) between November 18, 2011 and April 30, 2013, were aged ≥18 years on the index date, had 12 months of continuous insurance enrollment prior to the index date (baseline period), were diagnosed with wet AMD during the baseline period or on the index date, and had at least 6 or 12 months of follow-up enrollment after the index date without switching to a different anti-VEGF agent (follow-up periods). Outcomes measured within the 6 and 12 month follow-up periods included the number of, and healthcare expenditures on, intravitreal anti-VEGF injections. Multivariable regressions compared the outcomes between aflibercept and ranibizumab.
The 6 months analyses included 319 aflibercept patients and 1,054 ranibizumab patients (12 month analyses: 57 and 374, respectively). Over the first 6 months after the index date, neither the number of injections (aflibercept mean = 3.8 ± 1.6; ranibizumab mean = 3.9 ± 1.9) nor the expenditures on injections (aflibercept mean = $7 468 ± $4 211; ranibizumab mean = $7 816 ± $4 834) differed significantly between aflibercept patients and ranibizumab patients (in multivariable regression treating ranibizumab as reference: incidence rate ratio = 0.97, 95% confidence interval [CI] 0.91–1.03, P = 0.277; cost ratio = 0.96, 95% CI 0.89–1.04, P = 0.338). Differences were also insignificant in the 12 month analyses. The overall mean days between injections differed by only 1.8 (95% CI 1.3–2.3) days between the aflibercept patients and ranibizumab patients (42.4 and 40.6, respectively).
Aflibercept and ranibizumab were used at a similar frequency resulting in similar intravitreal anti-VEGF injection healthcare expenditures among wet AMD patients initiating first-line intravitreal anti-VEGF treatment.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-013-0078-4) contains supplementary material, which is available to authorized users.
PMCID: PMC3906738  PMID: 24310208
Anti-vascular endothelial growth factor; Healthcare expenditures; Healthcare utilization; Intravitreal; Ophthalmology; Retrospective wet age-related macular degeneration
16.  Hemorrhagic Pseudoaneurysm in a Patient Receiving Aflibercept for Metastatic Thyroid Cancer 
Thyroid  2012;22(5):552-555.
Agents such as aflibercept, which target the angiogenic pathway, are of great interest as candidates for the management of metastatic differentiated thyroid cancer. Here, we report a patient who developed a hemorrhagic abdominal pseudoaneurysm shortly after being started on this drug.
Patient Findings
The patient was a 67-year-old woman being treated with single agent aflibercept (VEGF-Trap) for metastatic thyroid cancer. She had no history of intra-abdominal pathology or vascular disease but had been previously treated with sorafenib. Twelve days after receiving her second dose of aflibercept, she developed vague abdominal pain, which increased in severity and was accompanied by nausea and vomiting. Her symptoms progressed along with a decline in her hematocrit and signs of internal hemorrhaging. An angiogram identified an occluded celiac artery with increased collaterals and a bleeding pseudoaneurysm in the inferior pancreaticoduodenal artery. After the pseudoaneurysm was coiled, the patient stabilized.
Summary and Conclusions
Anti-angiogenic agents, usually well tolerated, can disrupt the delicate balance of normal endothelium, leading to hemorrhagic and thrombotic complications. The hemorrhage of aberrant vasculature should be included in the differential diagnosis in patients presenting with vague complaints while being treated with anti-angiogenic agents.
PMCID: PMC3338952  PMID: 22510046
17.  Rapid decrease in tumor perfusion following VEGF blockade predicts long-term tumor growth inhibition in preclinical tumor models 
Angiogenesis  2012;16(2):429-441.
Vascular endothelial growth factor (VEGF) is a key upstream mediator of tumor angiogenesis, and blockade of VEGF can inhibit tumor angiogenesis and decrease tumor growth. However, not all tumors respond well to anti-VEGF therapy. Despite much effort, identification of early response biomarkers that correlate with long-term efficacy of anti-VEGF therapy has been difficult. These difficulties arise in part because the functional effects of VEGF inhibition on tumor vessels are still unclear. We therefore assessed rapid molecular, morphologic and functional vascular responses following treatment with aflibercept (also known as VEGF Trap or ziv-aflibercept in the United States) in preclinical tumor models with a range of responses to anti-VEGF therapy, including Colo205 human colorectal carcinoma (highly sensitive), C6 rat glioblastoma (moderately sensitive), and HT1080 human fibrosarcoma (resistant), and correlated these changes to long-term tumor growth inhibition. We found that an overall decrease in tumor vessel perfusion, assessed by dynamic contrast-enhanced ultrasound (DCE-US), and increases in tumor hypoxia correlated well with long-term tumor growth inhibition, whereas changes in vascular gene expression and microvessel density did not. Our findings support previous clinical studies showing that decreased tumor perfusion after anti-VEGF therapy (measured by DCE-US) correlated with response. Thus, measuring tumor perfusion changes shortly after treatment with VEGF inhibitors, or possibly other anti-angiogenic therapies, may be useful to predict treatment efficacy.
PMCID: PMC3595479  PMID: 23238831
VEGF blockade; Tumor perfusion; Tumor growth response; Preclinical model; Response biomarker
18.  Phase I dose-escalation study of aflibercept in combination with docetaxel and cisplatin in patients with advanced solid tumours 
British Journal of Cancer  2012;107(4):598-603.
This phase I cohort study investigated aflibercept (vascular endothelial growth factor (VEGF) trap) plus docetaxel and cisplatin in patients with advanced solid tumours.
Patients received intravenous aflibercept 4, 5, or 6 mg kg−1 with docetaxel and cisplatin (75 mg m−2 each) on day 1 of a 3-week cycle until progressive disease or unacceptable toxicity. Primary objectives were determining cycle 1 dose-limiting toxicities (DLTs) and the aflibercept recommended phase II trial dose (RP2D) for this combination.
During the dose-escalation phase (n=16), there were two DLTs of febrile neutropenia (at 4 and 5 mg kg−1). Granulocyte colony-stimulating factor prophylaxis was subsequently recommended. The RP2D of aflibercept was established at 6 mg kg−1 and administered to 14 additional patients. The most frequent grade 3/4 adverse events (AEs) were neutropenia (43.3%), stomatitis (20.0%), asthenia/fatigue (20.0%), and hypertension (16.7%). All-grade AEs associated with VEGF blockade included epistaxis (83.3%), dysphonia (70.0%), proteinuria (53.3%), and hypertension (50.0%). There were five partial responses (16.7%) and 18 cases of stable disease (60.0%) (lasting >3 months in 10 patients). There were no pharmacokinetic (PK) interactions between the three drugs.
Aflibercept 6 mg kg−1 with docetaxel and cisplatin 75 mg m−2 every 3 weeks is the RP2D based on tolerability, antitumour activity, and PKs.
PMCID: PMC3419955  PMID: 22790797
aflibercept; VEGF trap; angiogenesis; anti-VEGF therapy
19.  Tumor surrogate blood vessel subtypes exhibit differential susceptibility to anti-VEGF therapy 
Cancer research  2011;71(22):7021-7028.
Anti-vascular therapy directed against VEGF or its receptors has been successful when administered at early stages of tumor vessel growth, but is less effective when administered later. Tumor blood vessels are heterogeneous, so vessel subpopulations may differ in their requirements for tumor cell-secreted VEGF and in their susceptibility to anti-VEGF/VEGFR therapy. Human cancers contain several distinct blood vessel types, including mother vessels (MV), glomeruloid microvascular proliferations (GMP), vascular malformations (VM), feeding arteries (FA) and draining veins (DV), all of which can be generated in mice in the absence of tumor cells using expression vectors for VEGF-A164. In this study, we investigated the sensitivity of each of these vessel types to anti-VEGF therapy with aflibercept ® (VEGF Trap), a potent inhibitor of VEGF-A164. Administering VEGF Trap treatment before or shortly after injection of a recombinant VEGF-A164 expressing adenovirus could prevent or regress tumor-free neovasculature, but it was progressively less effective if initiated at later times. Early-forming MVs and GMPs in which the lining endothelial cells expressed high levels of VEGFR-2 were highly susceptible to blockade by VEGF Trap. In contrast, late-forming VMs, FAs, and DVs that expressed low levels of VEGFR-2 were largely resistant. Together, our findings define the susceptibility of different blood vessel subtypes to anti-VEGF therapy, offering a possible explanation for the limited effectiveness of anti-VEGF-A/VEGFR treatment of human cancers, which are typically present for months to years before discovery and are largely populated by late-forming blood vessels.
PMCID: PMC3217088  PMID: 21937680
Angiogenesis; Arterio-venogenesis; Ad-VEGF-A164; VEGF; Aflibercept (VEGF Trap)
20.  The effect of anti-VEGF drugs (bevacizumab and aflibercept) on the survival of patients with metastatic colorectal cancer (mCRC) 
OncoTargets and therapy  2012;5:59-65.
Significant progression has been achieved in the treatment of metastatic colorectal cancer (mCRC) in recent years. This has been partly attributed to successfully incorporating new drugs into combination chemotherapy. In addition to the traditional cytotoxic chemotherapeutic agents, molecularly targeted agents began to play an important role in the treatment of advanced solid tumors. To date, two classes of molecularly targeted agents have been approved for treatment of patients with mCRC: (1) antivascular endothelial growth factor (anti-VEGF) agents (such as bevacizumab and aflibercept) and (2) antiendothelial cell growth factor receptor (anti-EGFR) agents (such as cetuximab and panitumumab). Aflibercept is a new member of anti-VEGF agents which has demonstrated efficacy for treatment of mCRC. With the commencement of clinical trials and basic research into aflibercept, more data from the bedside and the bench have been obtained. This review will outline the application of anti-VEGF agents by reviewing clinic experiences of bevacizumab and aflibercept, and try to add perspectives on the use of anti-VEGF agents in mCRC.
PMCID: PMC3345882  PMID: 22570554
chemotherapy; tumors; antiangiogenic
21.  Phase II Study of Aflibercept in Recurrent Malignant Glioma: A North American Brain Tumor Consortium Study 
Journal of Clinical Oncology  2011;29(19):2689-2695.
Antivascular endothelial growth factor (anti-VEGF) therapy is a promising treatment approach for patients with recurrent glioblastoma. This single-arm phase II study evaluated the efficacy of aflibercept (VEGF Trap), a recombinantly produced fusion protein that scavenges both VEGF and placental growth factor in patients with recurrent malignant glioma.
Patients and Methods
Forty-two patients with glioblastoma and 16 patients with anaplastic glioma who had received concurrent radiation and temozolomide and adjuvant temozolomide were enrolled at first relapse. Aflibercept 4 mg/kg was administered intravenously on day 1 of every 2-week cycle.
The 6-month progression-free survival rate was 7.7% for the glioblastoma cohort and 25% for patients with anaplastic glioma. Overall radiographic response rate was 24% (18% for glioblastoma and 44% for anaplastic glioma). The median progression-free survival was 24 weeks for patients with anaplastic glioma (95% CI, 5 to 31 weeks) and 12 weeks for patients with glioblastoma (95% CI, 8 to 16 weeks). A total of 14 patients (25%) were removed from the study for toxicity, on average less than 2 months from treatment initiation. The main treatment-related National Cancer Institute Common Terminology Criteria grades 3 and 4 adverse events (38 total) included fatigue, hypertension, and lymphopenia. Two grade 4 CNS ischemias and one grade 4 systemic hemorrhage were reported. Aflibercept rapidly decreases permeability on dynamic contrast enhanced magnetic resonance imaging, and molecular analysis of baseline tumor tissue identified tumor-associated markers of response and resistance.
Aflibercept monotherapy has moderate toxicity and minimal evidence of single-agent activity in unselected patients with recurrent malignant glioma.
PMCID: PMC3139373  PMID: 21606416
22.  North Central Cancer Treatment Group (NCCTG) N0537: Phase II Trial of VEGF-Trap in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and/or a Taxane 
Clinical breast cancer  2012;12(6):387-391.
Angiogenesis is an established target for the treatment of MBC. Aflibercept (VEGF-Trap) is a humanized fusion protein, which binds VEGF-A, VEGF-B, and PIGF-1 and -2.
Patients and Methods
A 2-stage phase II study with primary end points of confirmed tumor response and 6-month progression-free survival (PFS). If either end point was promising after the initial 21 patients, an additional 20 patients would be enrolled. Measurable disease, <2 previous chemotherapy treatments, previous anthracycline or taxane therapy, and Eastern Cooperative Oncology Group performance status of 0 or 1 were required. Aflibercept was given at a dose of 4 mg/kg intravenous every 14 days.
Twenty-one patients were enrolled; 71% had visceral disease, 57% were estrogen receptor negative, 19% had HER2+ disease with previous trastuzumab treatment, and 33% had 2 previous chemotherapy regimens. Partial response rate was 4.8% (95% confidence interval [CI], 0.1%–23.8%) and 6-month PFS was 9.5% (95% CI, 1.2%–30.4%). Neither primary end point met efficacy goals and the study was terminated. A median of 3 cycles was given. Median PFS was 2.4 months. Common grade 3 or 4 adverse events were hypertension (33%), fatigue (19%), dyspnea (14%), and headache (14%). Two cases of severe left ventricular dysfunction were noted.
Aflibercept did not meet efficacy goals in patients previously treated with MBC. Toxicity was as expected for anti-VEGF therapy.
PMCID: PMC3586936  PMID: 23083501
Angiogenesis; Cooperative group; Monoclonal antibody; Breast cancer
23.  A Novel Tumor-Promoting Function Residing in the 5′ Non-coding Region of vascular endothelial growth factor mRNA 
PLoS Medicine  2008;5(5):e94.
Vascular endothelial growth factor-A (VEGF) is one of the key regulators of tumor development, hence it is considered to be an important therapeutic target for cancer treatment. However, clinical trials have suggested that anti-VEGF monotherapy was less effective than standard chemotherapy. On the basis of the evidence, we hypothesized that vegf mRNA may have unrecognized function(s) in cancer cells.
Methods and Findings
Knockdown of VEGF with vegf-targeting small-interfering (si) RNAs increased susceptibility of human colon cancer cell line (HCT116) to apoptosis caused with 5-fluorouracil, etoposide, or doxorubicin. Recombinant human VEGF165 did not completely inhibit this apoptosis. Conversely, overexpression of VEGF165 increased resistance to anti-cancer drug-induced apoptosis, while an anti-VEGF165-neutralizing antibody did not completely block the resistance. We prepared plasmids encoding full-length vegf mRNA with mutation of signal sequence, vegf mRNAs lacking untranslated regions (UTRs), or mutated 5′UTRs. Using these plasmids, we revealed that the 5′UTR of vegf mRNA possessed anti-apoptotic activity. The 5′UTR-mediated activity was not affected by a protein synthesis inhibitor, cycloheximide. We established HCT116 clones stably expressing either the vegf 5′UTR or the mutated 5′UTR. The clones expressing the 5′UTR, but not the mutated one, showed increased anchorage-independent growth in vitro and formed progressive tumors when implanted in athymic nude mice. Microarray and quantitative real-time PCR analyses indicated that the vegf 5′UTR-expressing tumors had up-regulated anti-apoptotic genes, multidrug-resistant genes, and growth-promoting genes, while pro-apoptotic genes were down-regulated. Notably, expression of signal transducers and activators of transcription 1 (STAT1) was markedly repressed in the 5′UTR-expressing tumors, resulting in down-regulation of a STAT1-responsive cluster of genes (43 genes). As a result, the tumors did not respond to interferon (IFN)α therapy at all. We showed that stable silencing of endogenous vegf mRNA in HCT116 cells enhanced both STAT1 expression and IFNα responses.
These findings suggest that cancer cells have a survival system that is regulated by vegf mRNA and imply that both vegf mRNA and its protein may synergistically promote the malignancy of tumor cells. Therefore, combination of anti-vegf transcript strategies, such as siRNA-based gene silencing, with anti-VEGF antibody treatment may improve anti-cancer therapies that target VEGF.
Shigetada Teshima-Kondo and colleagues find that cancer cells have a survival system that is regulated by vegf mRNA and that vegf mRNA and its protein may synergistically promote the malignancy of tumor cells.
Editors' Summary
Normally, throughout life, cell division (which produces new cells) and cell death are carefully balanced to keep the body in good working order. But sometimes cells acquire changes (mutations) in their genetic material that allow them to divide uncontrollably to form cancers—disorganized masses of cells. When a cancer is small, it uses the body's existing blood supply to get the oxygen and nutrients it needs for its growth and survival. But, when it gets bigger, it has to develop its own blood supply. This process is called angiogenesis. It involves the release by the cancer cells of proteins called growth factors that bind to other proteins (receptors) on the surface of endothelial cells (the cells lining blood vessels). The receptors then send signals into the endothelial cells that tell them to make new blood vessels. One important angiogenic growth factor is “vascular endothelial growth factor” (VEGF). Tumors that make large amounts of VEGF tend to be more abnormal and more aggressive than those that make less VEGF. In addition, high levels of VEGF in the blood are often associated with poor responses to chemotherapy, drug regimens designed to kill cancer cells.
Why Was This Study Done?
Because VEGF is a key regulator of tumor development, several anti-VEGF therapies—drugs that target VEGF and its receptors—have been developed. These therapies strongly suppress the growth of tumor cells in the laboratory and in animals but, when used alone, are no better at increasing the survival times of patients with cancer than standard chemotherapy. Scientists are now looking for an explanation for this disappointing result. Like all proteins, cells make VEGF by “transcribing” its DNA blueprint into an mRNA copy (vegf mRNA), the coding region of which is “translated” into the VEGF protein. Other, “noncoding” regions of vegf mRNA control when and where VEGF is made. Scientists have recently discovered that the noncoding regions of some mRNAs suppress tumor development. In this study, therefore, the researchers investigate whether vegf mRNA has an unrecognized function in tumor cells that could explain the disappointing clinical results of anti-VEGF therapeutics.
What Did the Researchers Do and Find?
The researchers first used a technique called small interfering (si) RNA knockdown to stop VEGF expression in human colon cancer cells growing in dishes. siRNAs are short RNAs that bind to and destroy specific mRNAs in cells, thereby preventing the translation of those mRNAs into proteins. The treatment of human colon cancer cells with vegf-targeting siRNAs made the cells more sensitive to chemotherapy-induced apoptosis (a type of cell death). This sensitivity was only partly reversed by adding VEGF to the cells. By contrast, cancer cells engineered to make more vegf mRNA had increased resistance to chemotherapy-induced apoptosis. Treatment of these cells with an antibody that inhibited VEGF function did not completely block this resistance. Together, these results suggest that both vegf mRNA and VEGF protein have anti-apoptotic effects. The researchers show that the anti-apoptotic activity of vegf mRNA requires a noncoding part of the mRNA called the 5′ UTR, and that whereas human colon cancer cells expressing this 5′ UTR form tumors in mice, cells expressing a mutated 5′ UTR do not. Finally, they report that the expression of several pro-apoptotic genes and of an anti-tumor pathway known as the interferon/STAT1 tumor suppression pathway is down-regulated in tumors that express the vegf 5′ UTR.
What Do These Findings Mean?
These findings suggest that some cancer cells have a survival system that is regulated by vegf mRNA and are the first to show that a 5′UTR of mRNA can promote tumor growth. They indicate that VEGF and its mRNA work together to promote their development and to increase their resistance to chemotherapy drugs. They suggest that combining therapies that prevent the production of vegf mRNA (for example, siRNA-based gene silencing) with therapies that block the function of VEGF might improve survival times for patients whose tumors overexpress VEGF.
Additional Information.
Please access these Web sites via the online version of this summary at
This study is discussed further in a PLoS Medicine Perspective by Hughes and Jones
The US National Cancer Institute provides information about all aspects of cancer, including information on angiogenesis, and on bevacizumab, an anti-VEGF therapeutic (in English and Spanish)
CancerQuest, from Emory University, provides information on all aspects of cancer, including angiogenesis (in several languages)
Cancer Research UK also provides basic information about what causes cancers and how they develop, grow, and spread, including information about angiogenesis
Wikipedia has pages on VEGF and on siRNA (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC2386836  PMID: 18494554
24.  Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD 
The British Journal of Ophthalmology  2014;98(12):1636-1641.
Data comparing systemic exposure and systemic vascular endothelial growth factor (VEGF) suppression of ranibizumab, bevacizumab and aflibercept following intravitreal injection are lacking.
Fifty-six patients with wet age-related macular degeneration received intravitreal ranibizumab (0.5 mg), bevacizumab (1.25 mg), or aflibercept (2.0 mg). Serum pharmacokinetics and plasma free VEGF were evaluated after the first and third injections.
Following the first dose, systemic exposure to aflibercept was 5-, 37-, and 9-fold higher than ranibizumab, whereas, bevacizumab was 9-, 310-, and 35-fold higher than ranibizumab, based on geometric mean ratio of peak and trough concentrations and area under the curve, respectively. The third dose showed accumulation of bevacizumab and aflibercept but not ranibizumab. Aflibercept substantially suppressed plasma free VEGF, with mean levels below lower limit of quantitation (10 pg/mL) as early as 3 h postdose until ≥7 days postdose. Mean free (unbound) VEGF levels with ranibizumab were largely unchanged, with mean trough level of 14.4 pg/mL compared with baseline of 17 pg/mL.
There are notable differences in systemic pharmacokinetics and pharmacodynamics among anti-VEGF treatments after intravitreal administration. All three agents rapidly moved into the bloodstream, but ranibizumab very quickly cleared, whereas bevacizumab and aflibercept demonstrated greater systemic exposure and produced a marked reduction in plasma free VEGF.
Trial registration number
PMCID: PMC4251300  PMID: 25001321
25.  Effect of aflibercept in insufficient responders to prior anti-VEGF therapy in neovascular AMD 
Evaluation of three aflibercept injections at 4-week intervals in patients with neovascular AMD showing an “insufficient anatomic response” to prior anti-VEGF therapy with ranibizumab or bevacizumab.
The retrospective analysis included 96 eyes that had received at least three intravitreal 0.5 mg ranibizumab or 1.25 mg bevacizumab injections over a period of no more than 4 months prior to switching to aflibercept. In addition, the selected eyes had to have evidence of persisting or increasing sub- or intraretinal fluid, observed in optical coherence tomography (OCT). All patients received a loading dose of three intravitreal 2 mg aflibercept injections at 4-week intervals. Evaluation included central retinal thickness (CRT) and maximum pigment epithelium (PED) height measured by spectral domain OCT and best-corrected visual acuity (BCVA) prior to the switch of therapy and 4 weeks after the third aflibercept injection.
A significant reduction of mean CRT (−39 μm; p < 0.001) and maximum PED height (−46 μm; p < 0.001) as found 4 weeks after the third aflibercept injection. Eighty-two out of 96 eyes (85 %) had a PED just prior to switching to aflibercept. There was an improvement in BCVA of 1.9 letters 4 weeks after the last aflibercept injection; the vision gain, however, did not reach statistical significance (p = 0.061). The further analysis did not show any correlation of the change in CRT, maximum PED, and BCVA with the number of prior anti-VEGF treatments.
Retinal edema and PEDs regressed significantly after switching to aflibercept in patients insufficiently responding to prior therapy with ranibizumab or bevacizumab. No correlation could be found with regard to the number of prior treatments.
PMCID: PMC4218980  PMID: 24614949
Age-related macular degeneration; Aflibercept; Ranibizumab; Bevacizumab; Tolerance; Tachyphylaxis

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