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Current Colorectal Cancer Reports
Published in: Current Colorectal Cancer Reports 5/2016

01-10-2016 | Therapeutic Approaches to Metastatic Colorectal Cancers (V Ricci, Section Editor)

Ramucirumab: a Novel Anti-Angiogenic Agent in the Treatment of Metastatic Colorectal Cancer

Authors: Gaurav Goel, Aman Chauhan, Peter J. Hosein

Published in: Current Colorectal Cancer Reports | Issue 5/2016

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Abstract

Angiogenesis is a multistep process that plays a key role in cancer growth and metastases. It is mediated through multiple vascular endothelial growth factor receptors (VEGFRs) and their ligands. The expression of VEGFR-2 is upregulated in tumor endothelial cells, and it is considered to be the primary receptor driving malignant angiogenesis. Ramucirumab (IMC-1121B, LY3009806) is a fully human monoclonal antibody that directly binds to VEGFR-2 with high affinity and specificity. It is also the most recent addition to our armamentarium of anti-angiogenic drugs approved for the treatment of metastatic colorectal cancer (CRC). The aim of this review is to summarize the pre-clinical and clinical development of ramucirumab and discuss its place in the current treatment paradigm for metastatic CRC.
Literature
1.
2.
Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 1999;13(1):9–22.PubMed
3.
4.
Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1(1):27–31.CrossRefPubMed
5.
6.
Sawano A, Iwai S, Sakurai Y, Ito M, Shitara K, Nakahata T, et al. Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood. 2001;97(3):785–91.CrossRefPubMed
7.
Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med. 1996;2(10):1096–103.CrossRefPubMed
8.
Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood. 1996;87(8):3336–43.PubMed
9.
Zhang HT, Craft P, Scott PA, Ziche M, Weich HA, Harris AL, et al. Enhancement of tumor growth and vascular density by transfection of vascular endothelial cell growth factor into MCF-7 human breast carcinoma cells. J Natl Cancer Inst. 1995;87(3):213–9.CrossRefPubMed
10.
Amini A, Masoumi Moghaddam S, Morris DL, Pourgholami MH. The critical role of vascular endothelial growth factor in tumor angiogenesis. Curr Cancer Drug Targets. 2012;12(1):23–43.CrossRefPubMed
11.
12.
Gille H, Kowalski J, Li B, LeCouter J, Moffat B, Zioncheck TF, et al. Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. J Biol Chem. 2001;276(5):3222–30. doi:10.​1074/​jbc.​M002016200.CrossRefPubMed
13.
Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246(4935):1306–9.CrossRefPubMed
14.
Witte L, Hicklin DJ, Zhu Z, Pytowski B, Kotanides H, Rockwell P, et al. Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy. Cancer Metastasis Rev. 1998;17(2):155–61.CrossRefPubMed
15.
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(18):3964–8.PubMed
16.
Ellis LM, Staley CA, Liu W, Fleming RY, Parikh NU, Bucana CD, et al. Down-regulation of vascular endothelial growth factor in a human colon carcinoma cell line transfected with an antisense expression vector specific for c-src. J Biol Chem. 1998;273(2):1052–7.CrossRefPubMed
17.
18.
Prewett M, Huber J, Li Y, Santiago A, O’Connor W, King K, 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(20):5209–18.PubMed
19.
Bruns CJ, Liu W, Davis DW, Shaheen RM, McConkey DJ, Wilson MR, et al. Vascular endothelial growth factor is an in vivo survival factor for tumor endothelium in a murine model of colorectal carcinoma liver metastases. Cancer. 2000;89(3):488–99.CrossRefPubMed
20.
Tonra JR, Deevi DS, Corcoran E, Li H, Wang S, Carrick FE, et al. Synergistic antitumor effects of combined epidermal growth factor receptor and vascular endothelial growth factor receptor-2 targeted therapy. Clin Cancer Res. 2006;12(7 Pt 1):2197–207. doi:10.​1158/​1078-0432.​ccr-05-1682.CrossRefPubMed
21.
Posey JA, Ng TC, Yang B, Khazaeli MB, Carpenter MD, Fox F, et al. A phase I study of anti-kinase insert domain-containing receptor antibody, IMC-1C11, in patients with liver metastases from colorectal carcinoma. Clin Cancer Res. 2003;9(4):1323–32.PubMed
22.
Lu D, Jimenez X, Zhang H, Bohlen P, Witte L, Zhu Z. Selection of high affinity human neutralizing antibodies to VEGFR2 from a large antibody phage display library for antiangiogenesis therapy. Int J Cancer. 2002;97(3):393–9.CrossRefPubMed
23.
Lu D, Shen J, Vil MD, Zhang H, Jimenez X, Bohlen P, et al. Tailoring in vitro selection for a picomolar affinity human antibody directed against vascular endothelial growth factor receptor 2 for enhanced neutralizing activity. J Biol Chem. 2003;278(44):43496–507. doi:10.​1074/​jbc.​M307742200.CrossRefPubMed
24.
Miao HQ, Hu K, Jimenez X, Navarro E, Zhang H, Lu D, et al. Potent neutralization of VEGF biological activities with a fully human antibody Fab fragment directed against VEGF receptor 2. Biochem Biophys Res Commun. 2006;345(1):438–45. doi:10.​1016/​j.​bbrc.​2006.​04.​119.CrossRefPubMed
25.
Spratlin JL, Cohen RB, Eadens M, Gore L, Camidge DR, Diab S, 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 Off J Am Soc Clin Oncol. 2010;28(5):780–7. doi:10.​1200/​jco.​2009.​23.​7537.CrossRef
26.•
Chiorean EG, Hurwitz HI, Cohen RB, Schwartz JD, Dalal RP, Fox FE, et al. Phase I study of every 2- or 3-week dosing of ramucirumab, a human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 in patients with advanced solid tumors. Ann Oncol. 2015;26(6):1230–7. doi:10.​1093/​annonc/​mdv144. Phase 1 study evaluating ramucirumab in two-weekly and three-weekly dosing regimen.
27.•
Yoshino T, Yamazaki K, Gotoh M, Nasroulah F, Gao L, Yoshizuka N, et al. Safety and pharmacokinetics of second-line ramucirumab plus FOLFIRI in Japanese patients with metastatic colorectal carcinoma. Anticancer Res. 2015;35(7):4003–7. Phase 1B study demonstrating safety of ramucirumab and FOLFIRI combination in metastatic colorectal cancer.
28.
29.
Chow LQM, Smith DC, Tan AR, Denlinger CS, Wang D, Shepard DR et al. Phase II study evaluating the effect of concomitant ramucirumab (IMC-1121B; RAM) on the pharmacokinetics (PK) of paclitaxel (PTX) and the PK of RAM as monotherapy in patients (pts) with advanced malignant solid tumors. ASCO Meeting Abstracts. 2014;32(15_suppl):e13554.
30.
Wang D, Braiteh FS, Lee JJ, Denlinger CS, Shepard DR, Chaudhary A et al. Phase II study evaluating the effect of concomitant ramucirumab (RAM) on the pharmacokinetics (PK) of irinotecan (IRI) and its metabolite SN-38 when coadministered with folinic acid (FA) and 5-fluorouracil (5-FU) (FOLFIRI) in patients (pts) with advanced malignant solid tumors. ASCO Meeting Abstracts. 2015;33(3_suppl):691.
31.
32.
Hochster HS, Catalano PJ, Mitchell EP, Cohen DJ, O’Dwyer PJ, Benson AB et al. E7208: A randomized phase II trial of irinotecan and cetuximab (IC) versus IC plus ramucirumab (ICR) in second-line therapy of KRAS wild-type colorectal cancer (CRC). ASCO Meeting Abstracts. 2014;32(15_suppl):TPS3665.
33.••
Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499–508. doi:10.​1016/​s1470-2045(15)70127-0. Phase 3 trial demonstrating the efficacy of ramucirumab in the second-line treatment of metastatic colorectal cancer.
34.••
Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31–9. doi:10.​1016/​s0140-6736(13)61719-5. Phase 3 trial demonstrating the efficacy of ramucirumab in the second-line treatment of metastatic gastric cancer.
35.••
Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224–35. doi:10.​1016/​s1470-2045(14)70420-6. Phase 3 trial demonstrating the efficacy of ramucirumab plus paclitaxel in the second-line treatment of metastatic gastric cancer.
36.••
Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665–73. doi:10.​1016/​s0140-6736(14)60845-x. Phase 3 trial demonstrating the efficacy of ramucirumab plus docetaxel in the second-line treatment of non-small-cell lung cancer.
37.
38.
Zhu AX, Finn RS, Mulcahy M, Gurtler J, Sun W, Schwartz JD, et al. A phase II and biomarker study of ramucirumab, a human monoclonal antibody targeting the VEGF receptor-2, as first-line monotherapy in patients with advanced hepatocellular cancer. Clin Cancer Res. 2013;19(23):6614–23. doi:10.​1158/​1078-0432.​ccr-13-1442.CrossRefPubMedPubMedCentral
39.
Goyal L, Ancukiewicz M, Jain RK, Zhu AX, Duda DG. A comparative study of circulating biomarkers of anti-VEGF therapy in phase II trials in advanced hepatocellular carcinoma (HCC) patients (pts). ASCO Meeting Abstracts. 2014;32(15_suppl):2543.
40.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42. doi:10.​1056/​NEJMoa032691.CrossRefPubMed
41.•
Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, 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. doi:10.​1016/​s1470-2045(12)70477-1. Phase 3 trial demonstrating the efficacy of bevacizumab in the second-line treatment of metastatic colorectal cancer.
42.
43.•
Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, 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 Off J Am Soc Clin Oncol. 2012;30(28):3499–506. doi:10.​1200/​jco.​2012.​42.​8201. Phase 3 trial demonstrating the efficacy of ziv-aflibercept in the second-line treatment of metastatic colorectal cancer.
44.
45.•
Goldstein DA, El-Rayes BF. Considering efficacy and cost, where does ramucirumab fit in the management of metastatic colorectal cancer? Oncologist. 2015;20(9):981–2. doi:10.​1634/​theoncologist.​2015-0028. Cost analysis of one month treatment with bevacizumab, ziv-aflibercept and ramucirumab found ramucirumab to be considerably more expensive than others.
Metadata
Title
Ramucirumab: a Novel Anti-Angiogenic Agent in the Treatment of Metastatic Colorectal Cancer
Authors
Gaurav Goel
Aman Chauhan
Peter J. Hosein
Publication date
01-10-2016
Publisher
Springer US
Published in
Current Colorectal Cancer Reports / Issue 5/2016
Print ISSN: 1556-3790
Electronic ISSN: 1556-3804
DOI
https://doi.org/10.1007/s11888-016-0329-2

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