Aflibercept in the treatment of metastatic colorectal cancer

Tzu-Fei Wang, Albert Craig Lockhart, Tzu-Fei Wang, Albert Craig Lockhart

Abstract

Colorectal cancer is the third most common cancer in the US. In recent decades, an improved understanding of the role of the angiogenesis pathway in colorectal cancer has led to advancements in treatment. Bevacizumab has been shown to improve the progression-free survival and overall survival when combined with cytotoxic chemotherapy in patients with metastatic colorectal cancer, and at present is the only antiangiogenesis agent approved for the treatment of this cancer. Aflibercept is a novel angiogenesis-targeting agent, and has demonstrated efficacy in treating metastatic colorectal cancer in a recent randomized Phase III trial. Here we review the role of angiogenesis in the tumorigenesis of colorectal cancer, strategies for targeting angiogenesis, and the clinical development of aflibercept.

Keywords: VEGF; VEGFR; aflibercept; angiogenesis; colorectal cancer; targeted therapy.

Figures

Figure 1
Figure 1
Schematic illustration of the family of VE GF receptors, ligands and their functions. There are six VE GF ligands, VE GF-A, VE GF-B, VE GF-C, VE GF-D, VEGF-E, and PIGF and three main VEGF receptors, VEGFR-1, VEGFR-2, and VEGFR-3. Each VEGF ligand has specific affinity to different receptors as illustrated. Binding of ligands to the extramembrane domain of the receptors trigger dimerization of the receptor, autophosphorylation of the tyrosine kinase domain of the receptor, and initiate multiple downstream signal transduction pathways that result in endothelial cell proliferation, migration, survival, and more. (The figure is modified from Salmon, Cross, and Kerbel10). Abbreviations: VEGF, vascular endothelial growth factor; PIGF, placenta growth factors; FAK, focal adhesion kinase; PI3K, phosphatidylinositol 3-kinase.
Figure 2
Figure 2
Grade 3/4 adverse events with >5% differe nce in incidence between aflibercept and placebo arms in the VELOUR trial. Notes: *FN: Febrile neutropenia. Difference in incidence of febrile neutropenia did not exceed 5% (3.9%), but was included due to its clinical significance.

References

    1. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics. CA Cancer J Clin. 2011;61:212–36.
    1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.
    1. American Cancer Society. Cancer Facts and Figures. 2011. [Accessed November 18, 2011]. Available from: .
    1. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.
    1. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.
    1. Chu E. An update on the current and emerging targeted agents in metastatic colorectal cancer. Clin Colorectal Cancer. 2011 Jul 11; [Epub ahead of print.]
    1. Tonini T, Rossi F, Claudio PP. Molecular basis of angiogenesis and cancer. Oncogene. 2003;22:6549–56.
    1. Salmon JS, Lockhart AC, Berlin J. Anti-angiogenic treatment of gastrointestinal malignancies. Cancer Invest. 2005;23:712–26.
    1. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L. VEGF-receptor signal transduction. Trends Biochem Sci. 2003;28:488–94.
    1. Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358:2039–49.
    1. Karkkainen MJ, Petrova TV. Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene. 2000;19:5598–605.
    1. Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature. 995(376):66–70.
    1. Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci U S A. 1998;95:9349–54.
    1. Zeng H, Dvorak HF, Mukhopadhyay D. Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) peceptor-1 down-modulates VPF/VEGF receptor-2-mediated endothelial cell proliferation, but not migration, through phosphatidylinositol 3-kinase-dependent pathways. J Biol Chem. 2001;276:26969–79.
    1. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011–27.
    1. Shalaby F, Rossant J, Yamaguchi TP, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995;376:62–6.
    1. Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M. Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet. 2000;67:295–301.
    1. Achen MG, Williams RA, Minekus MP, et al. Localization of vascular endothelial growth factor-D in malignant melanoma suggests a role in tumour angiogenesis. J Pathol. 2001;193:147–54.
    1. 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.
    1. 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.
    1. 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.
    1. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25:4779–86.
    1. Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–9.
    1. Sobrero A, Ackland S, Clarke S, et al. Phase IV study of bevacizumab in combination with infusional fluorouracil, leucovorin and irinotecan (FOLFIRI) in first-line metastatic colorectal cancer. Oncology. 2009;77:113–9.
    1. Van Cutsem E, Tabernero J, Lakomy R. Intravenous aflibercept versus placebo in combination with irinotecan/5-FU (FOLFIRI) for second-line treatment of metastatic colorectal cancer (MCRC): results of a multinational Phase III trial (EFC10262-VELOUR) Ann Oncol. 2011;22
    1. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–24.
    1. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–34.
    1. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.
    1. Hecht JR, Trarbach T, Jaeger E. A randomized, double-blind, placebo-controlled, phase III study in patients (Pts) with metastatic adenocarcinoma of the colon or rectum receiving first-line chemotherapy with oxaliplatin/5-fluorouracil/leucovorin and PTK787/ZK 222584 or placebo (CONFIRM- 1) J Clin Oncol. 2005;23(Suppl 2):Abstr LBA3.
    1. Kohne C, Bajetta E, Lin E. Final results of CONFIRM 2: A multinational, randomized, double-blind, phase III study in 2nd line patients (pts) with metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK787/ZK 222584 (PTK/ZK) or placebo. J Clin Oncol. 2007;25(Suppl 18S):4033.
    1. Prewett M, Huber J, Li Y, et al. Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. Cancer Res. 1999;59:5209–18.
    1. Spratlin JL, Mulder KE, Mackey JR. Ramucirumab (IMC-1121B): a novel attack on angiogenesis. Future Oncol. 2010;6:1085–94.
    1. Spratlin JL, Cohen RB, Eadens M, et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol. 2010;28:780–7.
    1. Grothey A, Galanis E. Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. Nat Rev Clin Oncol. 2009;6:507–18.
    1. Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001;7:987–9.
    1. Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004;10:145–7.
    1. Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A. 2002;99:11393–8.
    1. Kim ES, Serur A, Huang J, et al. Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. Proc Natl Acad Sci U S A. 2002;99:11399–404.
    1. 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.
    1. Townsley CA, Siu LL, Pedro-Salcedo MS. A Phase I study of aflibercept, pemetrexed, and cisplatin in patients with advanced solid tumors. J Clin Oncol. 2010;28(Suppl 15):Abstr 2536.
    1. De Groot JF, Cloughesy T, Lieberman FS. Phase I study of aflibercept and temozolomide in newly diagnosed, high-grade glioma. J Clin Oncol. 2011;(Suppl 29):Abstr 2043.
    1. Tang P, Cohen SJ, Bjarnason GA. Phase II trial of aflibercept (VEGF Trap) in previously treated patients with metastatic colorectal cancer (MCRC): a PMH phase II consortium trial. J Clin Oncol. 2008;(Suppl 26):Abstr 4027.
    1. Teng LS, Jin KT, He KF, Zhang J, Wang HH, Cao J. Clinical applications of VEGF-trap (aflibercept) in cancer treatment. J Chin Med Assoc. 2010;73:449–56.
    1. Dincer M, Altundag K. Angiotensin-converting enzyme inhibitors for bevacizumab- induced hypertension. Ann Pharmacother. 2006;40:2278–9.
    1. Izzedine H, Ederhy S, Goldwasser F, et al. Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol. 2009;20:807–15.
    1. US National Institutes of Health. Study of Aflibercept and Modified FOLFOX6 As First-line treatment in patients with metastatic colorectal cancer (AFFIRM) [Accessed September 21, 2011]. Available from: .
    1. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25:1539–44.
    1. Saltz LB, Lenz HJ, Kindler HL, et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol. 2007;25:4557–61.
    1. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360:563–72.
    1. Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009;27:672–80.
    1. Allegra CJ, Yothers G, O’Connell MJ, et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011;29:11–6.
    1. Investor update. [Accessed September 28, 2011]. Available from: .
    1. US National Institutes of Health. Aflibercept in Combination With Docetaxel in Metastatic Androgen Independent Prostate Cancer (VENICE) [Accessed September 21, 2011]. Available from: .
    1. US National Institutes of Health. A study of aflibercept versus placebo in patients with second-line docetaxel for locally advanced or metastatic non-small-cell lung cancer (VITAL) [Accessed September 21, 2011]. Available from: .
    1. Murukesh N, Dive C, Jayson GC. Biomarkers of angiogenesis and their role in the development of VEGF inhibitors. Br J Cancer. 2010;102:8–18.
    1. Hecht JR, Yoshino T, Mitchell EP, et al. A randomized, phase IIb study of sunitinib plus 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) versus bevacizumab plus mFOLFOX6 as first-line treatment for metastatic colorectal cancer (mCRC): Interim results. J Clin Oncol. 2010;28(Suppl 15):Abstr 3532.
    1. Samson B, Latreille J, Nguyen NT, Sperlich C, Berbiche D, Tournigand C. SUNCAP, a phase II study with sunitinib and capecitabine in patients with metastatic colorectal cancer (MCRC) refractory to previous treatment with 5FU/irinotecan/oxaliplatin. J Clin Oncol. 2011;29(Suppl 4):Abstr 545.
    1. Ychou M, Bouche O, Thézenas S, et al. Final results of a multicenter phase II trial assessing sorafenib (S) in combination with irinotecan (i) as second- or later-line treatment in metastatic colorectal cancer (mCRC) patients (pts) with KRAS-mutated tumors (mt; NEXIRI) J Clin Oncol. 2011;29(Suppl):Abstr e14002.
    1. Rixe O, Verslype C, Khayat D, et al. A phase I dose escalation (DE) and pharmacokinetics (PK) study of intravenous aflibercept (VEGF Trap) plus irinotecan, 5-fluorouracil, and leucovorin (I-LV5FU2) in patients with advanced solid tumors (STs) J Clin Oncol. 2008;26(Suppl):Abstr 3557.
    1. US National Institutes of Health. Aflibercept compared to placebo in term of eficacyin patients treatedwith gemcitabine for metastaticpancreatic cancer (VANILLA) [Accessed September 21, 2011]. Available from: .

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren