Developmental antiangiogenic agents for the treatment of Non-Small Cell Lung Cancer (NSCLC)

Investigational New Drugs

Volumn 30, Issue 4, 2012, Pages 1802-1811

  Blumenschein Jr , George R ^a  

^a UNIVERSITY OF TEXAS   (United States)

Author keywords

Angiogenesis inhibitor; Biological marker; Carcinoma; Non small cell lung; Protein tyrosine kinase; Receptor; Vascular endothelial growth factor

Indexed keywords

AFLIBERCEPT; ANGIOGENESIS INHIBITOR; ANTINEOPLASTIC AGENT; AXITINIB; BEVACIZUMAB; BEXAROTENE; CARBOPLATIN; CEDIRANIB; CISPLATIN; DOCETAXEL; ERLOTINIB; FIBROBLAST GROWTH FACTOR; GEMCITABINE; MOTESANIB; NINTEDANIB; PACLITAXEL; PAZOPANIB; PEMETREXED; PLACEBO; PLATELET DERIVED GROWTH FACTOR; RAMUCIRUMAB; SORAFENIB; SUNITINIB; TUMOR MARKER; VANDETANIB; VASCULOTROPIN; VASCULOTROPIN RECEPTOR;

ABDOMINAL PAIN; ADVANCED CANCER; ANOREXIA; ANTIANGIOGENIC ACTIVITY; APPETITE; ARTERIAL THROMBOEMBOLISM; ASTHENIA; BLEEDING DISORDER; BLOOD TOXICITY; BRAIN HEMORRHAGE; CANCER INHIBITION; CHEMOTHERAPY INDUCED EMESIS; CHEMOTHERAPY INDUCED NAUSEA AND VOMITING; DEEP VEIN THROMBOSIS; DEHYDRATION; DIARRHEA; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG ERUPTION; DRUG FATALITY; DRUG INDUCED HEADACHE; DRUG SAFETY; DRUG TARGETING; DRUG WITHDRAWAL; DYSPHONIA; DYSPNEA; EPISTAXIS; FATIGUE; FEBRILE NEUTROPENIA; GASTROINTESTINAL TOXICITY; HAND FOOT SYNDROME; HEMOPTYSIS; HUMAN; HYPERTENSION; HYPONATREMIA; INFECTION; LUNG CARCINOGENESIS; LUNG EMBOLISM; LUNG HEMORRHAGE; LUNG NON SMALL CELL CANCER; MONOTHERAPY; MYALGIA; NAUSEA; NEUTROPENIA; OVERALL SURVIVAL; PAIN; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHASE 4 CLINICAL TRIAL (TOPIC); PNEUMOTHORAX; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PROTEINURIA; REVIEW; SIDE EFFECT; SIGNAL TRANSDUCTION; STOMATITIS; THROMBOCYTOPENIA; TREATMENT OUTCOME; WEIGHT;

ANGIOGENESIS INHIBITORS; CARCINOMA, NON-SMALL-CELL LUNG; HUMANS; LUNG NEOPLASMS; MOLECULAR TARGETED THERAPY; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 84866734165     PISSN: 01676997     EISSN: 15730646     Source Type: Journal    
DOI: 10.1007/s10637-011-9750-1     Document Type: Review

References (79)

1. American Cancer Society (2009) Cancer facts & figures, 2009. American Cancer Society, Atlanta
2. World Health Organization (2008) Fact sheet No. 310: the top ten causes of death. November 2008. http://www.who.int/mediacentre/factsheets/fs310-2008. pdf. Accessed 8 October 2009
3. National Comprehensive Cancer Network (2011) NCCN clinical practice guidelines in oncology™. Non-Small Cell Lung Cancer. V.3.2011. http://www.nccn.org/professionals/physician-gls/PDF/nscl.pdf. Accessed 21 May 11 A.D.
4. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98
5. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26:3543-3551
6. AVASTIN® (bevacizumab) (2011) Solution for intravenous infusion [package insert]. South San Francisco, CA: Genentech, Inc
7. Iressa® (gefitinib tablets) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP
8. Tarceva® (erlotinib tablets) [package insert]. South San Franscisco, CA: Genentech, Inc
9. Kerbel RS (2006) Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science 312:1171-1175
10. Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438:932-936
11. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182-1186
12. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669-676
13. Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249-257
14. Folkman J, Klagsbrun M (1987) Vascular physiology. A family of angiogenic peptides. Nature 329:671-672
15. Folkman J, Shing Y (1992) Angiogenesis. J Biol Chem 267:10931-10934
16. Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011-27
17. Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 8:579-591
18. Korpanty G, Smyth E, Sullivan LA, Brekken RA, Carney DN (2010) Antiangiogenic therapy in lung cancer: focus on vascular endothelial growth factor pathway. Exp Biol Med (Maywood) 235:3-9
19. Jain RK, Booth MF (2003) What brings pericytes to tumor vessels? J Clin Invest 112:1134-1136
20. Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18:4-25
21. Toi M, Matsumoto T, Bando H (2001) Vascular endothelial growth factor: its prognostic, predictive, and therapeutic implications. Lancet Oncol 2:667-673
22. Yuan A, Yu C-J, Kuo S-H, Chen W-J, Lin F-Y, Luh K-T, Yang PC, Lee Y-C (2001) Vascular endothelial growth factor 189 mRNA isoform expression specifically correlates with tumor angiogenesis, patient survival, and postoperative relapse in non-small-cell lung cancer. J Clin Oncol 19:432-441
23. Millauer B, Longhi MP, Plate KH, Shawver LK, Risau W, Ullrich A, Strawn LM (1996) Dominant-negative inhibition of Flk-1 suppresses the growth of many tumor types in vivo. Cancer Res 56:1615-1620
24. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF III, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F (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 22:2184-2191
25. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542-2550
26. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C (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 27:1227-1234
27. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C (2010) Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-smallcell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol 21:1804-1809
28. Crino L, Dansin E, Garrido P, Griesinger F, Laskin J, Pavlakis N, Stroiakovski D, Thatcher N, Tsai CM, Wu YL, Zhou C (2010) Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study. Lancet Oncol 11:733-740
29. Wozniak AJ, Garst J, Jahanzeb M, Kosty MP, Vidaver R, Beatty S, Teng S, Flick ED, Sing A, Lynch TJ, for the ARIES Investigators (2010) Clinical outcomes (CO) for special populations of patients (pts) with advanced non-small cell lung cancer (NSCLC): results from ARIES, a bevacizumab (BV) observational cohort study (OCS). J Clin Oncol 28: Abstract 7618
30. Dowlati A, Gray R, Sandler AB, Schiller JH, Johnson DH (2008) Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumaban Eastern Cooperative Oncology Group Study. Clin Cancer Res 14:1407-1412
31. Socinski MA, Langer CJ, Huang JE, Kolb MM, Compton P, Wang L, Akerley W (2009) Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. J Clin Oncol 27:5255-5261
32. Herbst RS, Ansari R, Bustin F, Flynn P, Hart L, Otterson GA, Vlahovic G, Soh CH, O'Connor P, Hainsworth J (2011) Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet 377:1846-1854
33. Kabbinavar FF, Miller VA, Johnson BE, O'Connor PG, Soh C, TLAS I (2010) Overall survival (OS) in ATLAS, a phase IIIb trial comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy (chemo) with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 28: Abstract 7526
34. Patel JD, Bonomi P, Socinski MA, Govindan R, Hong S, Obasaju C, Pennella EJ, Girvan AC, Guba SC (2009) Treatment rationale and study design for the pointbreak study: a randomized, openlabel phase III study of pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/ bevacizumab versus paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-smallcell lung cancer. Clin Lung Cancer 10:252-256
35. Wakelee HA, Dahlberg SE, Keller SM, Gandara DR, Graziano S, Leighl NB, Adjei AA, Schiller J (2011) Interim report of on-study demographics and toxicity from Eastern Cooperative Oncology Group (ECOG) E1505, a phase III randomized trial of adjuvant chemotherapy with or without bevacizumab for completely resected early stage non-small cell lung cancer. J Thorac Oncol 6: Abstract O42.03
36. Levitzki A (2004) PDGF receptor kinase inhibitors for the treatment of PDGF driven diseases. Cytokine Growth Factor Rev 15:229-235
37. Murakami M, Zheng Y, Hirashima M, Suda T, Morita Y, Ooehara J, Ema H, Fong GH, Shibuya M (2008) VEGFR1 tyrosine kinase signaling promotes lymphangiogenesis as well as angiogenesis indirectly via macrophage recruitment. Arterioscler Thromb Vasc Biol 28:658-664
38. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D (2003) Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111:1287-1295
39. Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes HP, Menger MD, Ullrich A, Vajkoczy P (2004) Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 18:338-340
40. 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 8:15-27
41. Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8:299-309
42. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (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 64:7099-7109
43. Scagliotti G, Novello S, von Pawel J, Reck M, Pereira JR, Thomas M, brao Miziara JE, Balint B, de Marinis F, Keller A, Aren O, Csollak M, Albert I, Barrios CH, Grossi F, Krzakowski M, Cupit L, Cihon F, DiMatteo S, Hanna N (2010) Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol 28:1835-1842
44. Gatzemeier U, Eisen T, Santoro A, Paz-Ares L, Bennouna J, Liao M, Strauss UP, Montegriffo E, Ong TJ, Biesma B (2010) Sorafenib (S) + gemcitabine/ cisplatin (GC) vs GC alone in the first-line treatment of advanced non-small cell lung cancer (NSCLC): Phase III NSCLC research experience utilizing sorafenib (NEXUS) trial. Ann Oncol 21:viii7.
45. Schiller JH, Lee JW, Hanna NH, Traynor AM, Carbone DP (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: Abstract 8014
46. Molina JR, Dy GK, Foster NR, Allen Ziegler KL, Adjei A, Rowland KM, Aubry M, Flynn PJ, Mandrekar SJ, Schild SE, Adjei AA (2011) A randomized phase II study of pemetrexed (PEM) with or without sorafenib (S) as second-line therapy in advanced non-small cell lung cancer (NSCLC) of nonsquamous histology: NCCTG N0626 study. J Clin Oncol 29: Abstract 7513
47. Spigel DR, Burris HA III, Greco FA, Shipley DL, Friedman EK, Waterhouse DM, Whorf RC, Mitchell RB, Daniel DB, Zangmeister J, Bass JD, Hainsworth JD (2011) Randomized, double-blind, placebo-controlled, phase II trial of sorafenib and erlotinib or erlotinib alone in previously treated advanced non-small-cell lung cancer. J Clin Oncol 29:2582-2589
48. Vroling L, Lind JS, de Haas RR, Verheul HM, van Hinsbergh V, Broxterman HJ, Smit EF (2010) CD133+ circulating haematopoietic progenitor cells predict for response to sorafenib plus erlotinib in non-small cell lung cancer patients. Br J Cancer 102:268-275
49. Kim ES, Herbst RS, Lee JJ, Blumenschein GR, Jr., Tsao A, Alden CM, Tang X, Liu S, Stewart DJ, Heymach JV, Tran HT, Hicks ME, Erasmus J, Jr., Gupta S, Powis G, Lippman SM, Wistuba II, Hong WK (2010) The BATTLE trial (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination): personalizing therapy for lung cancer. Presented at: the 101st Annual Meeting of the American Association for Cancer Research; April 17-21, 2010; Washington, DC
50. Herbst RS, Blumenschein GR, Jr., Kim ES, Lee J, Tsao AS, Alden CM, Liu S, Stewart DJ, Wistuba II, Hong WK (2010) Sorafenib treatment efficacy and KRAS biomarker status in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. J Clin Oncol (Meeting Abstracts) 28:7609.
51. Socinski MA, Novello S, Brahmer JR, Rosell R, Sanchez JM, Belani CP, Govindan R, Atkins JN, Gillenwater HH, Pallares C, Tye L, Selaru P, Chao RC, Scagliotti GV (2008) Multicenter, phase II trial of sunitinib in previously treated, advanced nonsmall-cell lung cancer. J Clin Oncol 26:650-656
52. Novello S, Scagliotti GV, Rosell R, Socinski MA, Brahmer J, Atkins J, Pallares C, Burgess R, Tye L, Selaru P, Wang E, Chao R, Govindan R (2009) Phase II study of continuous daily sunitinib dosing in patients with previously treated advanced non-small cell lung cancer. Br J Cancer 101:1543-1548
53. Reynolds C, Spira AI, Gluck WL, Pluenneke RE, Boehm KA, Zhan F, Asmar L (2011) Results of a phase II study of singleagent sunitinib in elderly non-small cell lung cancer patients. J Clin Oncol 29: Abstract 7549
54. Scagliotti GV, Krzakowski M, Szczesna A, Strausz J, Makhson A, Reck M, Tye L, Selaru P, Chao RC, Govindan R (2010) Sunitinib (SU) in combination with erlotinib (E) for the treatment of advanced/metastatic non-small cell lung cancer (NSCLC): a phase III study. Ann Oncol 21:viii3. Abstract LBA6
55. Thongprasert S, Tung Y, Kim J-H, Chang G-C, Park K, Su W-C, Kim S-W, Mok TSK, Sriuranpong V, Thall A, Tye L, Zhang K, Chao RC, Scagliotti GV, Govindan R (2011) Sunitinib plus erlotinib for the treatment of advanced NSCLC: subset analysis of East Asian patients participating in a phase III trial. J Thorac Oncol 6: Abstract MO09.02
56. Roth GJ, Heckel A, Colbatzky F, Handschuh S, Kley J, Lehmann-Lintz T, Lotz R, Tontsch-Grunt U, Walter R, Hilberg F (2009) Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120). J Med Chem 52:4466-4480
57. Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ (2008) BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 68:4774-4782
58. Reck M, Kaiser R, Eschbach C, Stefanic M, Love J, Gatzemeier U, Stopfer P, von Pawel J (2011) A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer. Ann Oncol 22:1374-1381
59. Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR, Smith NR, James NH, Dukes M, Curwen JO, Chester R, Jackson JA, Boffey SJ, Kilburn LL, Barnett S, Richmond GH, Wadsworth PF, Walker M, Bigley AL, Taylor ST, Cooper L, Beck S, Jurgensmeier JM, Ogilvie DJ (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65:4389-4400
60. Goss GD, Arnold A, Shepherd FA, Dediu M, Ciuleanu TE, Fenton D, Zukin M, Walde D, Laberge F, Vincent MD, Ellis PM, Laurie SA, Ding K, Frymire E, Gauthier I, Leighl NB, Ho C, Noble J, Lee CW, Seymour L (2010) Randomized, double-blind trial of carboplatin and paclitaxel with either daily oral cediranib or placebo in advanced non-small-cell lung cancer: NCIC Clinical Trials Group BR24 study. J Clin Oncol 28:49-55
61. NCIC Clinical Trials Group (2011) Site committee open/closed/planned/on hold/withdrawn studies. http://www.ctg.queensu.ca/public/Clinical-Trials/ph3- trial-accrual-closed.htm. Accessed 11 August 2011
62. Gadgeel SM, Ruckdeschel JC, Wozniak AJ, Chen W, Hackstock D, Galasso C, Burger A, Ivy SP, LoRusso P, Edelman MJ (2011) Cediranib, a VEGF receptor 1, 2, and 3 inhibitor, and pemetrexed in patients (pts) with recurrent non-small cell lung cancer (NSCLC). J Clin Oncol 29: Abstract 7564
63. Polverino A, Coxon A, Starnes C, Diaz Z, DeMelfi T, Wang L, Bready J, Estrada J, Cattley R, Kaufman S, Chen D, Gan Y, Kumar G, Meyer J, Neervannan S, Alva G, Talvenheimo J, Montestruque S, Tasker A, Patel V, Radinsky R, Kendall R (2006) AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res 66:8715-8721
64. Blumenschein GR Jr, Kabbinavar F, Menon H, Mok TS, Stephenson J, Beck JT, Lakshmaiah K, Reckamp K, Hei YJ, Kracht K, Sun YN, Sikorski R, Schwartzberg L (2011) A phase II, multicenter, open-label randomized study of motesanib or bevacizumab in combination with paclitaxel and carboplatin for advanced nonsquamous non-small-cell lung cancer. Ann Oncol. doi:10.1093
65. Amgen (2009) Independent data monitoring committee recommends resuming enrollment of non-squamous NSCLC patients in the motesanib MONET1 trial. http://www.amgen.com/media/media-pr-detail.jsp?year=2009&releaseID=1255738. Accessed 12 May 2010
66. Amgen Inc, Millenium Pharmaceuticals, Takeda Pharmaceutical Company Limited (2011) Top-line results announced of pivotal phase 3 motesanib trial in advanced non-squamous non-small cell lung cancer patients. http://www.takeda. com/press/article-40445. html. Accessed 18 April 2011
67. Scagliotti G, Vynnychenko I, Ichinose Y, Park K, Kubota K, Blackhall FH, Pirker R, Galiulin R, Ciuleanu T, Sydorenko O, Dediu M, Papai-Szekely Z, Martinez Banaclocha N, McCoy S, Yao B, Hei Y, Spigel DR (2011) An international, randomized, placebo-controlled, double-blind phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). J Clin Oncol 29: Abstract LBA7512
68. Choueiri TK (2008) Axitinib, a novel anti-angiogenic drug with promising activity in various solid tumors. Curr Opin Investig Drugs 9:658-671
69. Schiller JH, Larson T, Ou SH, Limentani S, Sandler A, Vokes E, Kim S, Liau K, Bycott P, Olszanski AJ, von Pawel J (2009) Efficacy and safety of axitinib in patients with advanced nonsmall-cell lung cancer: results from a phase II study. J Clin Oncol 27:3836-3841
70. Kumar R, Knick VB, Rudolph SK, Johnson JH, Crosby RM, Crouthamel MC, Hopper TM, Miller CG, Harrington LE, Onori JA, Mullin RJ, Gilmer TM, Truesdale AT, Epperly AH, Boloor A, Stafford JA, Luttrell DK, Cheung M (2007) Pharmacokineticpharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 6:2012-2021
71. Podar K, Tonon G, Sattler M, Tai YT, Legouill S, Yasui H, Ishitsuka K, Kumar S, Kumar R, Pandite LN, Hideshima T, Chauhan D, Anderson KC (2006) The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma. Proc Natl Acad Sci U S A 103:19478-19483
72. Altorki N, Lane ME, Bauer T, Lee PC, Guarino MJ, Pass H, Felip E, Peylan-Ramu N, Gurpide A, Grannis FW, Mitchell JD, Tachdjian S, Swann RS, Huff A, Roychowdhury DF, Reeves A, Ottesen LH, Yankelevitz DF (2010) Phase II proof-of-concept study of pazopanib monotherapy in treatment-naive patients with stage I/II resectable non-small-cell lung cancer. J Clin Oncol 28:3131-3137
73. Nikolinakos PG, Altorki N, Yankelevitz D, Tran HT, Yan S, Rajagopalan D, Bordogna W, Ottesen LH, Heymach JV (2010) Plasma cytokine and angiogenic factor profiling identifies markers associated with tumor shrinkage in early-stage non-small cell lung cancer patients treated with pazopanib. Cancer Res 70:2171-2179
74. Lockhart AC, Rothenberg ML, Dupont J, Cooper W, Chevalier P, Sternas L, Buzenet G, Koehler E, Sosman JA, Schwartz LH, Gultekin DH, Koutcher JA, Donnelly EF, Andal R, Dancy I, Spriggs DR, Tew WP (2010) Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol 28:207-214
75. Leighl NB, Raez LE, Besse B, Rosen PJ, Barlesi F, Massarelli E, Gabrail N, Hart LL, Albain KS, Berkowitz L, Melnyk O, Shepherd FA, Sternas L, Ackerman J, Shun Z, Miller VA, Herbst RS (2010) A multicenter, phase 2 study of vascular endothelial growth factor trap (Aflibercept) in platinum-and erlotinibresistant adenocarcinoma of the lung. J Thorac Oncol 5:1054-1059
76. (2011) Regeneron Pharmaceuticals, Inc. Sanofi-aventis and Regeneron report top-line results from phase III study with aflibercept (VEGF Trap) in second-line non-small cell lung cancer. Press release. March 10, 2011. http://newsroom.regeneron. com/releasedetail.cfm?ReleaseID=556162. Accessed 25 March 2011
77. Novello S, Ramlau R, Gorbunova VA, Ciuleanu TE, Ozguroglu M, Goksel T, Baldotto C, Bennouna J, Shepherd FA, Scagliotti G (2011) Aflibercept in combination with docetaxel for second-line treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC): Final results of a multinational placebocontrolled phase III trial (EFC10261-VITAL). Abstract associated with oral presentation at: the 14th Biennial World Conference on Lung Cancer; July 3-7, 2011; Amsterdam, Netherlands Abstract O43.06
78. Spratlin JL, Cohen RB, Eadens M, Gore L, Camidge DR, Diab S, Leong S, O'Bryant C, Chow LQ, Serkova NJ, Meropol NJ, Lewis NL, Chiorean EG, Fox F, Youssoufian H, Rowinsky EK, Eckhardt SG (2010) 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 28:780-787
79. Camidge DR, Ballas MS, Dubey S, Haigentz M, Rosen PJ, Spicer JF, West HJ, Shah GD, Youssoufian H, Mita AC (2010) A phase II, open-label study of ramucirumab (IMC-1121B), an IgG1 fully human monoclonal antibody (MAb) targeting VEGFR-2, in combination with paclitaxel and carboplatin as first-line therapy in patients (pts) with stage IIIb/IV non-small cell lung cancer (NSCLC). J Clin Oncol 28: Abstract 7588