nach oben

Current Oncology Reports

Erschienen in:

01.02.2014 | Evolving Therapies (R Bukowski, Section Editor)

Aflibercept—a Decoy VEGF Receptor

verfasst von: Kristen K. Ciombor, Jordan Berlin

Erschienen in: Current Oncology Reports | Ausgabe 2/2014

Einloggen, um Zugang zu erhalten

Abstract

Aflibercept (known as ziv-aflibercept in the USA and sold under the trade name Zaltrap®) is a human recombinant fusion protein with antiangiogenic effects that functions as a decoy receptor to bind vascular endothelial growth factors A and B and placental growth factor. Its unique mechanism of action with respect to other agents targeting angiogenesis led investigators to speculate that it may be more ubiquitously efficacious in tumors highly dependent on pathologic angiogenesis for their growth. Despite encouraging preclinical studies in various tumor types, aflibercept has not been proven efficacious in most later-phase clinical studies. In fact, its only currently held US Food and Drug Administration indication is in metastatic colorectal cancer in combination with 5-fluorouracil, leucovorin, and irinotecan for those patients previously treated with an oxaliplatin-containing chemotherapy regimen. Given aflibercept’s toxicity profile and cost, further investigation is needed to better understand its mechanism of action and to discover predictive biomarkers for optimization of its appropriate use in treatment of cancer patients.

Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6.PubMedCrossRef

Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298–307.PubMedCrossRef

Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003;9(6):685–93.PubMedCrossRef

Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer. 2008;8(8):579–91.PubMedCrossRef

Holash J et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science. 1999;284(5422):1994–8.PubMedCrossRef

Tsigkos S, Koutsilieris M, Papapetropoulos A. Angiopoietins in angiogenesis and beyond. Expert Opin Investig Drugs. 2003;12(6):933–41.PubMedCrossRef

Lohela M et al. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol. 2009;21(2):154–65.PubMedCrossRef

Fischer C et al. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat Rev Cancer. 2008;8(12):942–56.PubMedCrossRef

Jussila L, Alitalo K. Vascular growth factors and lymphangiogenesis. Physiol Rev. 2002;82(3):673–700.PubMed

10.

Park JE et al. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem. 1994;269(41):25646–54.PubMed

11.

Holash J et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A. 2002;99(17):11393–8.PubMedCentralPubMedCrossRef

12.

Willett CG et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol. 2009;27(18):3020–6.PubMedCrossRef

13.

Rini BI et al. Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol. 2008;26(22):3743–8.PubMedCrossRef

14.

Baffert F et al. Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. Am J Physiol Heart Circ Physiol. 2006;290(2):H547–59.PubMedCrossRef

15.

Fukasawa M, Korc M. Vascular endothelial growth factor-trap suppresses tumorigenicity of multiple pancreatic cancer cell lines. Clin Cancer Res. 2004;10(10):3327–32.PubMedCrossRef

16.

Verheul HM et al. Vascular endothelial growth factor trap blocks tumor growth, metastasis formation, and vascular leakage in an orthotopic murine renal cell cancer model. Clin Cancer Res. 2007;13(14):4201–8.PubMedCrossRef

17.

Le XF 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(23):3747–58.PubMedCentralPubMedCrossRef

18.

Hu L 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.PubMedCrossRef

19.

Cheron M VP, L.P., Demers B, Leopold D, Bissery MC. Synergistic activity of aflibercept (VEGF Trap) in combination with 5-fluorouracil and irinotecan in preclinical tumor models: abstract A13. In: Proceedings from the AACR-NCI-EORTC: molecular targets and cancer therapeutics, 2007

20.

Tew WP et al. Phase 1 study of aflibercept administered subcutaneously to patients with advanced solid tumors. Clin Cancer Res. 2010;16(1):358–66.PubMedCrossRef

21.•

Lockhart AC et al. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol. 2010;28(2):207–14. This phaseI trial of intravenously administered aflibercept established its safety and toxicity profile, as well as its recommended phase II dose.PubMedCrossRef

22.

Khayat D et al. Intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours: results from the expansion cohort of a phase I study. Eur J Cancer. 2013;49(4):790–7.PubMedCrossRef

23.

Isambert N 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(6):1743–50.PubMedCrossRef

24.

Diaz-Padilla I 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(4):604–11.PubMedCentralPubMedCrossRef

25.

Van Cutsem E et al. Phase I dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours. Eur J Cancer. 2013;49(1):17–24.PubMedCrossRef

26.•

Gaya A, Tse V. A preclinical and clinical review of aflibercept for the management of cancer. Cancer Treat Rev. 2012;38(5):484–93. This excellent review comprehensively discusses the preclinical and clinical development of aflibercept.PubMedCrossRef

27.

Tang PA et al. Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer. Clin Cancer Res. 2012;18(21):6023–31.PubMedCrossRef

28.

Pericay CFG, Saunders M, Thomas A, Roh JK, Lopez R, 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.

29.

Ramlau R 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(29):3640–7.PubMedCrossRef

30.

Rougier P et al. Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. Eur J Cancer. 2013;49(12):2633–42.PubMedCrossRef

31.

Tannock IF 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.PubMedCrossRef

32.•

Van Cutsem E 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(28):3499–506. This pivotal phase III trial demonstrated a survival benefit of aflibercept in combination with FOLFIRI for patients with oxaliplatin-pretreated metastatic CRC and led to its FDA approval for this indication.PubMedCrossRef

33.

Hurwitz H et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.PubMedCrossRef

34.

Macedo LT, da Costa Lima AB, Sasse AD. Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups. BMC Cancer. 2012;12:89.PubMedCentralPubMedCrossRef

35.•

Bennouna J et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14(1):29–37. This phase III trial demonstrated the survival benefit of continuing bevacizumab therapy in the second-line setting beyond progression with bevacizumab therapy in the first-line setting for metastatic CRC.PubMedCrossRef

36.•

Grothey A et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–12. This phaseIII trial showed a survival benefit of single-agent regorafenib for patients with refractory metastatic CRC and led to its FDA approval for this indication.PubMedCrossRef

37.

Bach PB, Saltz LB, Wittes RE. In cancer care, cost matters. New York Times. 2012 Oct 15:A25.

Titel: Aflibercept—a Decoy VEGF Receptor
verfasst von: Kristen K. Ciombor
Jordan Berlin
Publikationsdatum: 01.02.2014
Verlag: Springer US
Erschienen in: Current Oncology Reports / Ausgabe 2/2014
Print ISSN: 1523-3790
Elektronische ISSN: 1534-6269
DOI: https://doi.org/10.1007/s11912-013-0368-7

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Aflibercept—a Decoy VEGF Receptor

Abstract

Neu im Fachgebiet Onkologie

Mehr Brustkrebs, aber weniger andere gynäkologische Tumoren mit Levonorgestrel-IUS

Bei seelischem Stress sind Checkpoint-Hemmer weniger wirksam

Antikörper mobilisiert Neutrophile gegen Krebs

Erhebliches Risiko für Kehlkopfkrebs bei mäßiger Dysplasie

Update Onkologie

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2014

Etirinotecan Pegol: Development of a Novel Conjugated Topoisomerase I Inhibitor

Naptumomab Estafenatox: Targeted Immunotherapy with a Novel Immunotoxin

Resectable, Borderline Resectable, and Locally Advanced Pancreatic Cancer: What Does It Matter?

Endoscopic Resection of Sinonasal Cancers

Endoglin for Targeted Cancer Treatment

Timing of Determining Axillary Lymph Node Status When Neoadjuvant Chemotherapy is Used

Neu im Fachgebiet Onkologie

Mehr Brustkrebs, aber weniger andere gynäkologische Tumoren mit Levonorgestrel-IUS

Bei seelischem Stress sind Checkpoint-Hemmer weniger wirksam

Antikörper mobilisiert Neutrophile gegen Krebs

Erhebliches Risiko für Kehlkopfkrebs bei mäßiger Dysplasie

Update Onkologie