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Targeted Oncology
Published in: Targeted Oncology 4/2010

01-12-2010 | Review

Examining the safety profile of angiogenesis inhibitors: implications for clinical practice

Author: Martin Reck

Published in: Targeted Oncology | Issue 4/2010

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Abstract

Dysregulation of angiogenesis in solid tumors enables tumor growth and metastasis. Receptors that mediate angiogenesis, and their ligands, have been identified; among these, vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase play a central role. In non-small cell lung cancer (NSCLC), clinical benefit has been shown with bevacizumab, which blocks VEGF binding to its receptors. In addition, small-molecule tyrosine kinase inhibitors are currently in clinical practice or development in several indications. The potential clinical benefit of antiangiogenic agents is accompanied by the need to understand their safety profiles, seek suitable combination regimens and identify patients able to tolerate one treatment over another. This is particularly relevant in cancers for which patients often present with advanced disease and suffer co-morbidities, requiring an agent that is both efficacious and well tolerated over long-term continuous treatment. Using literature from peer-reviewed journals, this review considers different antiangiogenic agents and their safety profiles, focusing on the potential impact of these data on the treatment of patients with NSCLC.
Literature
1.
Ferrara N (1999) Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int 56(3):794–814CrossRefPubMed
2.
Andrae J, Gallini R, Betsholtz C (2008) Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22(10):1276–1312CrossRefPubMed
3.
Nissen LJ, Cao R, Hedlund EM et al (2007) Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis. J Clin Invest 117(10):2766–2677CrossRefPubMed
4.
5.
Presta LG, Chen H, O'Connor SJ et al (1997) Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57(20):4593–4599PubMed
6.
Sandler A, Gray R, Perry MC et al (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355(24):2542–2550CrossRefPubMed
7.
Reck M, von Pawel J, Zatloukal P et al (2009) Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non–small-cell lung cancer: AVAiL. J Clin Oncol 27(8):1227–1234CrossRefPubMed
8.
Reck M, von Pawel J, Zatloukal P et al (2010) Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. doi:10.​1093/​annonc/​mdq020
9.
Miller V, O'connor P, Soh J et al (2009) A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 27(18(supp)):abstr LBA8002
10.
Kwaan HC, Vicuna B (2007) Incidence and pathogenesis of thrombosis in hematologic malignancies. Semin Thromb Hemost 33(4):303–312CrossRefPubMed
11.
Johnson DH, Fehrenbacher L, Novotny WF et al (2004) Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22(11):2184–2191CrossRefPubMed
12.
Sandler AB, Hirsch V, Reck M et al (2008) Retrospective study of clinical and radiographic risk factors associated with early-onset, severe pulmonary hemorrhage in bevacizumab-treated patients with advanced non-small cell lung cancer. J Clin Oncol 26(15S)
13.
Ramalingam SS, Dahlberg SE, Langer CJ et al (2008) Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol 26(1):60–65CrossRefPubMed
14.
Leighl NB, Zatloukal P, Mezger J et al (2009) Efficacy and safety of first-line bevacizumab (Bv) and cisplatin/gemcitabine (CG) in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC) in the BO17704 study (AVAiL). J Clin Oncol 27:15s (suppl; abstr 8050)
15.
Griesinger F, Pavlakis N, Garrido P et al (2009) MO19390 (SAIL): safety and efficacy of first-line bevacizumab plus chemotherapy in elderly patients with a advanced or recurrent non-squamous non-small cell lung cancer (NSCLC). Presented at 13th World Conference on Lung Cancer, July 31–August 4, 2009, San Francisco, CA, USA
16.
Cabebe E, Wakelee H (2007) Role of anti-angiogenesis agents in treating NSCLC: focus on bevacizumab and VEGFR tyrosine kinase inhibitors. Curr Treat Options Oncol 8(1):15–27CrossRefPubMed
17.
Somer RA, Sherman E, Langer CJ (2008) Restrictive eligibility limits access to newer therapies in non-small-cell lung cancer: the implications of Eastern Cooperative Oncology Group 4599. Clin Lung Cancer 9(2):102–105CrossRefPubMed
18.
Lynch T, Brahmer J, Fischbach N et al (2008) Preliminary treatment patterns and safety outcomes for non-small cell lung cancer (NSCLC) from ARIES, a bevacizumab treatment observational cohort study (OCS). Journal of Clinical Oncology 26(15S)
19.
20.
Gridelli C, Maione P, Rossi A et al (2007) The role of bevacizumab in the treatment of non-small cell lung cancer: current indications and future developments. Oncologist 12(10):1183–1193CrossRefPubMed
21.
Akerley WL, Langer CJ, Oh Y et al (2008) Acceptable safety of bevacizumab therapy in patients with brain metastases due to non-small cell lung cancer. J Clin Oncol 26(15S):abstract 8043
22.
Jaeger E, Wu Y, Mezger J et al. Safety of first-line bevacizumab (bv) plus chemotherapy in elderly patients (pts) with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC): MO19390 (SAiL) study group. Ann Oncol 19(Supplement 8):abstract 240P
23.
Pereg D, Lishner M (2008) Bevacizumab treatment for cancer patients with cardiovascular disease: a double edged sword? Eur Heart J 29(19):2325–2326CrossRefPubMed
24.
Scappaticci FA, Skillings JR, Holden SN et al (2007) Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 99(16):1232–1239CrossRefPubMed
25.
Kilickap S, Abali H, Celik I (2003) Bevacizumab, bleeding, thrombosis, and warfarin. J Clin Oncol 21(18):3542, author reply 3543CrossRefPubMed
26.
Griesinger F, Laskin JJ, Pavlakis N et al (2008) Safety of first-line bevacizumab-based therapy with concomitant cardiovascular or anticoagulation medication in advanced or recurrent non-squamous non-small cell lung cancer in MO19390 (SAiL). J Clin Oncol 26(15S):abstract 8049
27.
28.
Shen BQ, Lee DY, Zioncheck TF (1999) Vascular endothelial growth factor governs endothelial nitric-oxide synthase expression via a KDR/Flk-1 receptor and a protein kinase C signaling pathway. J Biol Chem 274(46):33057–33063CrossRefPubMed
29.
Granger JP, Alexander BT (2000) Abnormal pressure-natriuresis in hypertension: role of nitric oxide. Acta Physiol Scand 168(1):161–168CrossRefPubMed
30.
de Graaf JC, Banga JD, Moncada S et al (1992) Nitric oxide functions as an inhibitor of platelet adhesion under flow conditions. Circulation 85(6):2284–2290PubMed
31.
Yao SK, Ober JC, Krishnaswami A et al (1992) Endogenous nitric oxide protects against platelet aggregation and cyclic flow variations in stenosed and endothelium-injured arteries. Circulation 86(4):1302–1309PubMed
32.
Mourad JJ, des Guetz G, Debbabi H et al (2008) Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. Ann Oncol 19(5):927–934CrossRefPubMed
33.
Chow LQ, Eckhardt SG (2007) Sunitinib: from rational design to clinical efficacy. J Clin Oncol 25(7):884–896CrossRefPubMed
34.
Socinski MA, Novello S, Brahmer JR et al (2008) Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer. J Clin Oncol 26(4):650–656CrossRefPubMed
35.
Brahmer J, Govindan R, Novello S et al (2007) Efficacy and safety of continuous daily sunitinib dosing in previously treated advanced non-small cell lung cancer (NSCLC): Results from a phase II study. J Clin Oncol 25(18S):abstract 7542
36.
37.
Rock EP, Goodman V, Jiang JX et al (2007) Food and Drug Administration drug approval summary: Sunitinib malate for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma. Oncologist 12(1):107–113CrossRefPubMed
38.
Rini BI, Tamaskar I, Shaheen P et al (2007) Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 99(1):81–83CrossRefPubMed
39.
Schoeffski P, Wolter P, Himpe U et al (2008) Sunitinib-related thyroid dysfunction: a single-center retrospective and prospective evaluation. J Clin Oncol 24(18S):3092
40.
Desai J, Yassa L, Marqusee E et al (2006) Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 145(9):660–664PubMed
41.
Motzer RJ, Hutson TE, Tomczak P et al (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356(2):115–124CrossRefPubMed
42.
Billemont B, Barete S, Meric JB et al (2008) Skin toxicity of sunitinib: prospective analysis in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 26(15S):16146
43.
Pouessel D, Culine S (2008) High frequency of intracerebral hemorrhage in metastatic renal carcinoma patients with brain metastases treated with tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor. Eur Urol 53(2):376–381CrossRefPubMed
44.
Witteles RM, Telli ML, Fischer GA et al (2008) Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate. J Clin Oncol 26(18S):abstract 9597
45.
Porta R, Szczylik C, Bracarda S et al (2008) Short- and long-term safety with sunitinib in an expanded access trial in metastatic renal cell carcinoma (mRCC). J Clin Oncol 26(15S):abstract 5114
46.
Wilhelm SM, Carter C, Tang L et al (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64(19):7099–7109CrossRefPubMed
47.
Gatzemeier U, Blumenschein G, Fosella F (2006) Phase II trial of single-agent sorafenib in patients with advanced non-small cell lung carcinoma. J Clin Oncol 24(18S):7002
48.
Gutierrez M, Kummar S, Allen D et al (2008) A phase II study of multikinase inhibitor sorafenib in patients with relapsed non-small cell lung cancer (NSCLC). J Clin Oncol 26:19084
49.
Liu B, Barret T, Choyke P et al (2006) A phase II study of BAY 43–9006 (Sorafenib) in patients with relapsed non-small cell lung cancer (NSCLC). J Clin Oncol 24(18S):17119
50.
Adjei AA, Molina JR, Mandrekar SJ et al (2007) Phase I trial of sorafenib in combination with gefitinib in patients with refractory or recurrent non-small cell lung cancer. Clin Cancer Res 13(9):2684–2691CrossRefPubMed
51.
Schiller JH, Lee JW, Hanna NH et al (2008) A randomized discontinuation phase II study of sorafenib versus placebo in patients with non-small cell lung cancer who have failed at least two prior chemotherapy regimens: E2501. J Clin Oncol 26(15S):abstract 8014
52.
Scagliotti G, von Pawel J, Reck M, Cupit L, Cihon F, DiMatteo S, O'Leary J, Hanna N (2008) Sorafenib plus carboplatin/paclitaxel in chemonaive patients with stage IIIB-IV non-small cell lung cancer (NSCLC): Interim analysis (IA) results from the Phase III, randomized, double-blind, placebo-controlled, ESCAPE (Evaluation of Sorafenib, Carboplatin, and Paclitaxel Efficacy in NSCLC) trial. J Thor Oncol 3(4):S97
53.
Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356(2):125–134CrossRefPubMed
54.
Riechelmann RP, Chin S, Wang L et al (2008) Sorafenib for metastatic renal cancer: the Princess Margaret experience. Am J Clin Oncol 31(2):182–187CrossRefPubMed
55.
Wedge SR, Ogilvie DJ, Dukes M et al (2002) ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 62(16):4645–4655PubMed
56.
Natale RB, Bodkin D, Govindan R et al (2009) Vandetanib versus gefitinib in patients with advanced non-small-cell lung cancer: results from a two-part, double-blind, randomized phase ii study. J Clin Oncol 27(15):2523–2529CrossRefPubMed
57.
Heymach JV, Paz-Ares L, De Braud F et al (2008) Randomized phase II study of vandetanib alone or with paclitaxel and carboplatin as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol 26(33):5407–5415CrossRefPubMed
58.
Herbst RS, Sun Y, Korfee S et al (2009) Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small cell lung cancer (NSCLC): A randomized, double-blind phase III trial (ZODIAC). J Clin Oncol 27:18s (suppl; abstract CRA8003)
59.
De Boer R, Arrieta Ó, Gottfried M et al (2009) Vandetanib plus pemetrexed versus pemetrexed as second-line therapy in patients with advanced non-small cell lung cancer (NSCLC): A randomized, double-blind phase III trial (ZEAL). J Clin Oncol 27:15s (suppl; abstract 8010)
60.
Natale RB, Thongprasert S, Greco FA et al (2009) Vandetanib versus erlotinib in patients with advanced non-small cell lung cancer (NSCLC) after failure of at least one prior cytotoxic chemotherapy: a randomized, double-blind phase III trial (ZEST). J Clin Oncol 27:15s (suppl; abstract 8009)
61.
Miller KD, Trigo JM, Wheeler C et al (2005) A multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer. Clin Cancer Res 11(9):3369–3376CrossRefPubMed
62.
Holden SN, Eckhardt SG, Basser R et al (2005) Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors. Ann Oncol 16(8):1391–1397CrossRefPubMed
63.
Veronese ML, Mosenkis A, Flaherty KT et al (2006) Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol 24(9):1363–1369CrossRefPubMed
64.
Wedge SR, Kendrew J, Hennequin LF et al (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65(10):4389–4400CrossRefPubMed
65.
Laurie SA, Gauthier I, Arnold A et al (2008) Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: the National Cancer Institute of Canada clinical trials group. J Clin Oncol 26(11):1871–1878CrossRefPubMed
66.
Laurie SA, Arnold A, Shepherd FA et al (2008) Randomized, double-blind Phase II trial of carboplatin plus paclitaxel (C + P) with either daily oral cediranib, an inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, or placebo, in advanced non-small cell lung cancer (NSCLC): a study of the national cancer institute of canada clinical trials group. Ann Oncol 19(8):abstract 231 PD
67.
Hirte H, Vidal L, Fleming G et al (2008) A phase II study of cediranib (AZD2171) in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: final results of a PMH, Chicago and California consortia trial. J Clin Oncol 26(18S):abstract 5521
68.
Matulonis UA, Berlin ST, Krasner CN et al (2008) Cediranib (AZD 2171) is an active agent in recurrent epithelial ovarian cancer. J Clin Oncol 26(18S):abstract 5501
69.
Riely GJ, Miller VA (2007) Vascular endothelial growth factor trap in non small cell lung cancer. Clin Cancer Res 13(15 Pt 2):s4623–46237CrossRefPubMed
70.
Massarelli E, Miller V, Leighl N et al (2007) 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). J Clin Oncol 25(18S):7627
71.
Rosen L, Kurzrock R, Jackson E et al (2005) Safety and pharmacokinetics of AMG 706 in patients with advanced solid tumors. J Clin Oncol 23(Supplement 16):abstract 3013
72.
73.
Hilberg F, Roth GJ, Krssak M et al (2008) BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 68(12):4774–4782CrossRefPubMed
74.
von Pawel J, Kaiser R, Eschbach C et al (2008) Efficacy, safety and pharmacokinetic (PK) results of a Phase II study with the triple angiokinase inhibitor BIBF 1120 in patients suffering from advanced non small cell lung cancer (NSCLC). J Thor Oncol 3(4):S61
75.
76.
Metadata
Title
Examining the safety profile of angiogenesis inhibitors: implications for clinical practice
Author
Martin Reck
Publication date
01-12-2010
Publisher
Springer-Verlag
Published in
Targeted Oncology / Issue 4/2010
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI
https://doi.org/10.1007/s11523-010-0159-0

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