Efficacy and Safety of Aflibercept and Its Role in the Treatment of Metastatic Colorectal Cancer
Vascular endothelial growth factor (VEGF) and related pathway elements are critically important in the pathogenesis, growth, and development of solid tumors. Inhibiting the VEGF signaling pathway is being investigated as a therapeutic strategy for cancer, either by blockade of VEGF ligand binding or inhibition of the VEGF receptor. Aflibercept is a VEGF inhibitor that has been approved by the US Food and Drug Administration for the treatment of macular degeneration and metastatic colorectal cancer (mCRC).
A search of PubMed and MEDLINE from January 2000 to August 2013 was performed using the following terms (or combination of terms): VEGF, colorectal cancer, mCRC, aflibercept, ziv-aflibercept. Studies were limited to those published in English.
Phase 1 and 2 clinical trials of aflibercept in advanced non-hematological cancer showed acceptable safety and provided justification for further investigation. Four phase 3 clinical trials were conducted to evaluate aflibercept for the treatment of different cancers. The VELOUR trial evaluated aflibercept with FOLFIRI in patients with mCRC. The addition of aflibercept resulted in improved median overall survival (OS, 13.5 vs. 12.1 months, p = 0.0032). The VITAL trial evaluated docetaxel plus aflibercept vs. docetaxel plus placebo in patients with non-small cell lung cancer (NSCLC) who had progressed after first-line platinum-based chemotherapy; there was no significant difference between the two treatment groups in terms of OS. The VANILLA trial in patients with metastatic pancreatic adenocarcinoma was terminated because addition of aflibercept to gemcitabine failed to demonstrate improved OS in an interim analysis. In patients with metastatic androgen-independent prostate cancer, the VENICE trial also failed to demonstrate an increase in OS when aflibercept was combined with standard first-line chemotherapy. The most common adverse events associated with aflibercept in these trials were hypertension, venous and arterial thromboembolic events, hemorrhage, and proteinuria.
In patients with mCRC, aflibercept demonstrated an improvement in OS when added to FOLFIRI. However, it has failed to show similar benefits in other tumor types. Further investigation is needed to improve patient selection and to distinguish patients who may benefit best from aflibercept from those who will require other anti-angiogenic agents.
- Cook KM, Figg WD. Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin. 2010;60(4):222–43. CrossRef
- Tonini T, Rossi F, Claudio PP. Molecular basis of angiogenesis and cancer. Oncogene. 2003;22:6549–56. CrossRef
- Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011–27. CrossRef
- Galiano RD, Tepper OM, Pelo CR, et al. Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells. Am J Pathol. 2004;164:1935–47. CrossRef
- Papetti M, Herman IM. Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol. 2002;282:C947–70. CrossRef
- Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 1995;55:3964–8.
- Takahashi Y, Tucker SL, Kitadai Y, et al. Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer. Arch Surg. 1997;132:541–6. CrossRef
- Cascinu S, Staccioli MP, Gasparini G, et al. Expression of vascular endothelial growth factor can predict event-free survival in stage II colon cancer. Clin Cancer Res. 2000;6:2803–7.
- United States Food and Drug Administration. FDA approves Eylea for eye disorder in older people. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm280601.htm. Updated Nov 18, 2011. Accessed Feb 19, 2013.
- United States Food and Drug Administration. Ziv-aflibercept. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm314438.htm. Updated Aug 3, 2012. Accessed Feb 19, 2013.
- United States Food and Drug Administration. FDA approves Zaltrap for metastatic colorectal cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm314372.htm. Accessed Feb 18, 2013.
- Ramlau R, Gorbunova V, Ciuleanu TE, et al. Aflibercept and docetaxel versus docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer: a randomized, controlled phase III trial. J Clin Oncol. 2012;30:3640–7. CrossRef
- Fischer C, Jonckx B, Mazzone M, et al. Anti-PLGF inhibits growth of VEGF®-inhibitor-resistant tumors without affecting healthy vessels. Cell. 2007;131(3):463–75. CrossRef
- Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA. 2002;99:11393–8. CrossRef
- Huang J, Frischer JS, Serur A, et al. Regression of established tumors and metastases by potent vascular endothelial growth factor blockade. Proc Natl Acad Sci USA. 2003;100:7785–90. CrossRef
- Byrne AT, Ross L, Holash J, et al. Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res. 2003;9:5721–8.
- Baffert F, Le T, Sennino B, et al. Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. Am J Physiol Heart Circ Physiol. 2006;290:H547–59. CrossRef
- Williams JL, Cartland D, Rudge JS, Egginton S. VEGF trap abolishes shear stress- and overload-dependent angiogenesis in skeletal muscle. Microcirculation. 2006;13:499–509. CrossRef
- Gaya A, Tse V. A preclinical and clinical review of aflibercept for the management of cancer. Cancer Treat Rev. 2012;38:484–93. CrossRef
- Le XF, Mao W, Lu C, et al. Specific blockade of VEGF and HER2 pathways results in greater growth inhibition of breast cancer xenografts that overexpress HER2. Cell Cycle. 2008;7:3747–58. CrossRef
- Hu L, Hofmann J, Holash J, et al. Vascular endothelial growth factor trap combined with paclitaxel strikingly inhibits tumor and ascites, prolonging survival in a human ovarian cancer model. Clin Cancer Res. 2005;11(19 Pt. 1):6966–71. CrossRef
- Lejeune P, Chiron M, Le Moigne R, et al. Combination of the antiangiogenic agent aflibercept results in greater antitumor activity. In: Proceedings from the 99th American association for cancer research annual meeting. April 12–16, 2008; San Diego. Abstract 1107.
- Abrahams C, Li B, Parveen A, Thurston G. Combination of aflibercept (VEGF trap) and docetaxel produces increased anti-tumor effects associated with enhanced changes to tumor vasculature. In: Proceedings from the 101st American association for cancer research annual meeting. April 17–21, 2010; Washington, DC. Abstract 5427.
- Wachsberger PR, Burd R, Cardi C, et al. VEGF trap in combination with radiotherapy improves tumor control in u87 glioblastoma. Int J Radiat Oncol Biol Phys. 2007;67:1526–37. CrossRef
- Chiron M, Vrignaud P, Lejeune P, et al. Synergistic activity of aflibercept (VEGF trap) in combination with 5-fluorouracil and irinotecan in preclinical tumor models. In: Proceedings from the AACR-NCIEORTC: molecular targets and cancer therapeutics. October 22–26, 2007; San Francisco. Abstract A13.
- Freyer G, Isambert N, You B, et al. Phase I dose-escalation study of aflibercept in combination with docetaxel and cisplatin in patients with advanced solid tumors. Br J Cancer. 2012;107:598–603. CrossRef
- Isambert N, Freyer G, Zanetta S, et al. Phase I dose-escalation study of intravenous aflibercept in combination with docetaxel in patients with advanced solid tumors. Clin Cancer Res. 2012;18:1743–50. CrossRef
- Limentani SA, Just R, Purdham A, et al. A phase I dose escalation and pharmacokinetic (PK) study of intravenous (iv) aflibercept (VEGF trap) plus FOLFOX4 in patients (pts) with advanced solid tumors: preliminary results [abstract]. J Clin Oncol. 2008;26(Suppl):3556.
- Patnaik A, Pipas M, Rosen L, et al. A phase I dose escalation and pharmacokinetic (PK) study of intravenous (iv) aflibercept (VEGF trap) plus weekly gemcitabine (Gem) in patients (pts) with advanced solid tumors: preliminary results [abstract]. J Clin Oncol. 2008;26(Suppl):3558.
- Van Cutsem E, Khayat D, Verslyp C, et al. Phase I dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumors. Eur J Cancer. 2013;49:17–24. CrossRef
- Kuhnowski F, Thieblemont C, Jardin F, et al. A phase I study of IV aflibercept (Afl) in combination with R-CHOP in untreated patients (pts) with B-cell lymphoma [abstract]. J Clin Oncol. 2010;28(15S):8010.
- Tew WP, Gordon M, Murren J, et al. Phase 1 study of aflibercept administered subcutaneously to patients with advanced solid tumors. Clin Cancer Res. 2010;16:358–66. CrossRef
- Lockhart AC, Rothenberg ML, Dupont J, et al. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol. 2010;28:207–14. CrossRef
- Diaz-Padilla I, Siu LL, San Pedro-Salcedo M, et al. A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours. Br J Cancer. 2012;107:604–11. CrossRef
- Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. CrossRef
- Massarelli E, Miller VA, Leighl NB, et al. Phase II study of the efficacy and safety of intravenous (IV) AVE0005 (VEGF trap) given every 2 weeks in patients (Pts) with platinum- and erlotinib-resistant adenocarcinoma of the lung (NSCLA) [abstract]. J Clin Oncol. 2007;25(18S):7627.
- Tew WP, Colombo N, Ray-Coquard I, et al. VEGF-trap for patients (pts) with recurrent platinum-resistant epithelial ovarian cancer (EOC): preliminary results of a randomized, multicenter phase II study [abstract]. J Clin Oncol. 2007;25(18S):5508.
- Colombo N, Mangili G, Mammoliti S, et al. A phase II study of aflibercept in patients with advanced epithelial ovarian cancer and symptomatic malignant ascites. Gynecol Oncol. 2012;125:42–7. CrossRef
- Tang P, Cohen SJ, Kollmannsberger C, et al. Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer. Clin Cancer Res. 2012;18:6023–31. CrossRef
- Tarhini AA, Christensen S, Frankel P, et al. Phase II study of aflibercept (VEGF trap) in recurrent inoperable stage III or stage IV melanoma of cutaneous or ocular origin [abstract]. J Clin Oncol. 2009;27(15S):9028.
- Mackay HJ, Buckanovich RJ, Hirte H, et al. A phase II study single agent of aflibercept (VEGF trap) in patients with recurrent or metastatic gynecologic carcinosarcomas and uterine leiomyosarcoma. A trial of the Princess Margaret Hospital, Chicago and California Cancer Phase II Consortia. Gynecol Oncol. 2012;125:136–40. CrossRef
- Sherman EJ, Ho AL, Haque S, et al. A phase II study of VEGF trap (aflibercept) in patients with radioactive iodine-refractory, positron emission tomography (PET) positive thyroid carcinoma [abstract]. J Clin Oncol. 2010;28(15S):5587.
- Twardowski P, Stadler WM, Frankel P, et al. Phase II study of aflibercept (VEGF-trap) in patients with recurrent or metastatic urothelial cancer, a California cancer consortium trial. Urology. 2010;76:923–6. CrossRef
- Pericay CFG, Saunders M, Thomas A, et al. Phase 2 randomized, noncomparative open-label study of aflibercept and modified FOLFOX6 in the first line treatment of metastatic colorectal cancer (AFFIRM): abstract O-0024. Ann Oncol. 2012;23(Suppl 4):iv5–18.
- Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30:3499–506. CrossRef
- Riess H, Manges R, Karasek P, et al. Double-blind, placebo-controlled randomized phase III trial of aflibercept (A) plus gemcitabine (G) versus placebo (P) plus gemcitabine (G) in patients with metastatic pancreatic cancer: final results. In: Proceedings from the 12th world congress on gastrointestinal cancer. June 30–July 3, 2010; Barcelona. Abstract O-0006.
- Tannock IF, Fizazi K, Ivanov S, et al. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet Oncol. 2013;14(8):760–8
- Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomized phase 3 trial. Lancet Oncol. 2013;14:29–37. CrossRef
- Gruppo Oncologico Nord Ovest. Continuation of bevacizumab beyond progression improves outcome in patients with metastatic colorectal cancer (BEBYP). Late breaking abstract #17; ESMO 2012 congress of the European society for medical oncology in Vienna. http://abstracts.webges.com/viewing/view.php?congress=esmo2012&congress_id=370&publication_id=2734. Accessed Sept 25, 2013.
- Allegra CJ, Tabernero J, Rougier P, et al. Meta-analysis of anti-VEGF class adverse events from three double-blind (Db) placebo (Pbo)-controlled phase III trials with IV aflibercept (Afl). J Clin Oncol. 2012;(suppl 4: abstr 561).
- Piao Y, Heymach JV, Bekele B, et al. Circulating cytokine and angiogenic factors as predictive biomarkers of glioblastoma response to aflibercept (VEGF trap) [abstract]. J Clin Oncol. 2009;27(15S):2029.
- de Groot JF, Piao Y, Tran H, et al. Myeloid biomarkers associated with glioblastoma response to anti-VEGF therapy with aflibercept. Clin Cancer Res. 2011;17:4872–81. CrossRef
- Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–65. CrossRef
- Efficacy and Safety of Aflibercept and Its Role in the Treatment of Metastatic Colorectal Cancer
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