Antiangiogenic agents in the management of non-small cell lung cancer: Where do we stand now and where are we headed?

Cancer Biology and Therapy

Volumn 13, Issue 5, 2012, Pages 247-263

  Aggarwal, Charu ^a   Somaiah, Neeta ^b   Simon, George R ^b  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b MEDICAL UNIVERSITY OF SOUTH CAROLINA   (United States)

Author keywords

Angiogenesis; Antiangiogenic therapy; Chemotherapy; Monoclonal antibody; Non small cell lung cancer; Tyrosine kinase inhibitor; Vascular endothelial growth factor

Indexed keywords

AFLIBERCEPT; ANGIOGENESIS INHIBITOR; ANTINEOPLASTIC AGENT; AXITINIB; BEVACIZUMAB; BNC 105 P; BRIVANIB; CARBOPLATIN; CEDIRANIB; CISPLATIN; DOCETAXEL; ERLOTINIB; GEFITINIB; GEMCITABINE; IRINOTECAN; LINIFANIB; MOTESANIB; N [2 [(4 HYDROXYPHENYL)AMINO] 3 PYRIDINYL] 4 METHOXYBENZENESULFONAMIDE; NAVELBINE; NINTEDANIB; PACLITAXEL; PAZOPANIB; PEMETREXED; PLINABULIN; RAMUCIRUMAB; SORAFENIB; SUNITINIB; UNCLASSIFIED DRUG; UNINDEXED DRUG; VADIMEZAN; VANDETANIB;

ABDOMINAL PAIN; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ANEMIA; ANOREXIA; ANTIANGIOGENIC THERAPY; ANTINEOPLASTIC ACTIVITY; ARTERY THROMBOSIS; ASTHENIA; BLEEDING; BRAIN HEMORRHAGE; CANCER COMBINATION CHEMOTHERAPY; CANCER MORTALITY; CANCER STAGING; CANCER SURVIVAL; CELL CYCLE ARREST; CEREBROVASCULAR DISEASE; CHOLECYSTITIS; DEHYDRATION; DIARRHEA; DIVERTICULITIS; DRUG EFFICACY; DRUG ERUPTION; DRUG INDUCED HEADACHE; DRUG SAFETY; DYSPNEA; FATIGUE; FEBRILE NEUTROPENIA; GAMMA GLUTAMYL TRANSFERASE BLOOD LEVEL; GASTROINTESTINAL DISEASE; HAND FOOT SYNDROME; HEART MUSCLE ISCHEMIA; HUMAN; HYPERTENSION; HYPONATREMIA; INFECTION; INTERSTITIAL LUNG DISEASE; LEUKOPENIA; LUNG HEMORRHAGE; LUNG NON SMALL CELL CANCER; LYMPHOCYTOPENIA; META ANALYSIS; MONOTHERAPY; MULTIPLE CYCLE TREATMENT; MYALGIA; NAUSEA; NEUTROPENIA; OVERALL SURVIVAL; PAIN; PROGRESSION FREE SURVIVAL; PROTEINURIA; QUALITY OF LIFE; REVIEW; SIDE EFFECT; STOMATITIS; THROMBOCYTOPENIA; THROMBOEMBOLISM; TREATMENT DURATION; TREATMENT OUTCOME; UNSPECIFIED SIDE EFFECT; VASCULAR DISEASE; VEIN THROMBOSIS; VOMITING;

EID: 84857882376     PISSN: 15384047     EISSN: 15558576     Source Type: Journal    
DOI: 10.4161/cbt.19594     Document Type: Review

References (91)

1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics 2010. CA Cancer J Clin 2010; 60:277-300; PMID:20610543; http://dx.doi.org/10.3322/caac.20073.
2. Carmeliet P. Angiogenesis in life, disease and medicine. Nature 2005; 438:932-6; PMID:16355210; http://dx.doi.org/10.1038/nature04478.
3. Kerbel RS. Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science 2006; 312:1171-5; PMID:16728631; http://dx.doi.org/10.1126/science.1125950.
4. Gridelli C, Rossi A, Maione P, Rossi E, Castaldo V, Sacco PC, et al. Vascular disrupting agents: a novel mechanism of action in the battle against nonsmall cell lung cancer. Oncologist 2009; 14:612-20; PMID:19474164; http://dx.doi.org/10.1634/theoncologist.2008-0287.
5. Jenab-Wolcott J, Giantonio BJ. Bevacizumab: current indications and future development for management of solid tumors. Expert Opin Biol Ther 2009; 9:507-17; PMID:19344286; http://dx.doi.org/10.1517/14712590902817817.
6. AVASTIN® (bevacizumab) Solution for intravenous infusion [package insert]. South San Francisco, CA: Genentech, Inc. 2011.
7. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, et al. 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 2004; 22:2184-91; PMID:15169807; http://dx.doi.org/10.1200/JCO.2004.11.022.
8. Hapani S, Sher A, Chu D, Wu S. Increased risk of serious hemorrhage with bevacizumab in cancer patients: a meta-analysis. Oncology 2010; 79:27-38; PMID:21051914; http://dx.doi.org/10.1159/000314980.
9. Besse B, Lasserre SF, Compton P, Huang J, Augustus S, Rohr UP. Bevacizumab safety in patients with central nervous system metastases. Clin Cancer Res 2010; 16:269-78; PMID:20028762; http://dx.doi.org/10.1158/1078-0432. CCR-09-2439.
10. Socinski MA, Langer CJ, Huang JE, Kolb MM, Compton P, Wang L, et al. Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. J Clin Oncol 2009; 27:5255-61; PMID:19738122; http://dx.doi.org/10. 1200/JCO.2009.22.0616.
11. Crinò L, Dansin E, Garrido P, Griesinger F, Laskin J, Pavlakis N, et al. 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 2010; 11:733-40; PMID:20650686; http://dx.doi.org/10.1016/S1470-2045(10) 70151-0.
12. Leighl NB, Bennouna J, Yi J, Moore N, Hambleton J, Hurwitz H. Bleeding events in bevacizumab-treated cancer patients who received full-dose anticoagulation and remained on study. Br J Cancer 2011; 104:413-8; PMID:21245868; http://dx.doi.org/10.1038/sj.bjc.6606074.
13. Kano MR, Morishita Y, Iwata C, Iwasaka S, Watabe T, Ouchi Y, et al. VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFRbeta signaling. J Cell Sci 2005; 118:3759-68; PMID:16105884; http://dx.doi.org/10.1242/jcs.02483.
14. Nissen LJ, Cao R, Hedlund EM, Wang Z, Zhao X, Wetterskog D, et al. Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis. J Clin Invest 2007; 117:2766-77; PMID:17909625; http://dx.doi.org/10.1172/JCI32479.
15. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003; 111:1287-95; PMID:12727920; http://dx.doi.org/10.1172/JCI17929
16. Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes HP, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 2004; 18:338-40; PMID:14657001; http://dx.doi.org/10.1096/fj.03-0271fje
17. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355:2542-50; PMID:17167137; http://dx.doi.org/10.1056/ NEJMoa061884.
18. Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, et al. Eastern Cooperative Oncology Group. 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 2008; 26:60-5; PMID:18165641; http://dx.doi.org/10.1200/JCO. 2007.13.1144.
19. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. 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 2009; 27:1227-34; PMID:19188680; http://dx.doi.org/10.1200/ JCO.2007.14.5466.
20. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. BO17704 Study Group. 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 2010; 21:1804-9; PMID:20150572; http://dx.doi.org/10.1093/annonc/mdq020.
21. Leighl NB, Zatloukal P, Mezger J, Ramlau R, Moore N, Reck M, et al. Efficacy and safety of bevacizumabbased therapy in elderly patients with advanced or recurrent nonsquamous non-small cell lung cancer in the phase III BO17704 study (AVAiL). J Thorac Oncol 2010; 5:1970-6; PMID:20978447; http://dx.doi.org/10.1097/JTO.0b013e3181f49c22.
22. Patel JD, Hensing TA, Rademaker A, Hart EM, Blum MG, Milton DT, et al. Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer. J Clin Oncol 2009; 27:3284-9; PMID:19433684; http://dx.doi.org/10. 1200/JCO.2008.20.8181.
23. Miller VA, O'Conner P, Soh C, Kabbinavar F. 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 2009; 27:8002.
24. Kabbinavar FF, Miller VA, Johnson BE, O'Connor PG, Soh C. TLAS I. 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). [Abstract 7526]. J Clin Oncol 2010; 28.
25. Herbst RS, Ansari R, Bustin F, Flynn P, Hart L, Otterson GA, et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced nonsmall-cell lung cancer after failure of standard firstline chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet 2011; 377:1846-54; PMID:21621716; http://dx.doi.org/10.1016/S0140-6736(11)60545-X.
26. Wozniak AJ, Garst J, Jahanzeb M, Kosty MP, Vidaver R, Beatty S, et al. 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). [Abstract 7618]. J Clin Oncol 2010; 28.
27. Patel JD, Bonomi P, Socinski MA, Govindan R, Hong S, Obasaju C, et al. Treatment rationale and study design for the pointbreak study: a randomized, open-label 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-small-cell lung cancer. Clin Lung Cancer 2009; 10:252-6; PMID:19632943; http://dx.doi.org/10.3816/CLC.2009.n.035.
28. Dahlberg SE, Ramalingam SS, Belani CP, Schiller JH. A randomized phase III study of maintenance therapy with bevacizumab (B), pemetrexed (Pm), or a combination of bevacizumab and pemetrexed (BPm) following carboplatin, paclitaxel and bevacizumab (PCB) for advanced nonsquamous NSCLC: ECOG trial 5508 (NCT01107626). J Clin Oncol 2011; 29; [abstract TBS 218].
29. Zinner RG, Saxman SB, Peng G, Monberg MJ, Ortuzar WI. Treatment rationale and study design for a randomized trial of pemetrexed/carboplatin followed by maintenance pemetrexed versus paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab in patients with advanced non-small-cell lung cancer of nonsquamous histology. Clin Lung Cancer 2010; 11:352-7; PMID:20837462; http://dx.doi.org/10.3816/CLC.2010.n.045.
30. Wakelee HA, Dahlberg SE, Keller SM, Gandara DR, Graziano S, Leighl NB, et al. 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 2011; 6; [abstract 042.03].
31. 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 2010; 28:780-7; PMID:20048182; http://dx.doi.org/10.1200/JCO.2009.23.7537.
32. Camidge DR, Ballas MS, Dubey S, Haigentz M, Rosen PJ, Spicer JF, et al. 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). [Abstract 7588]. J Clin Oncol 2010; 28.
33. National Cancer Institute. NCI Drug Dictionary. http://www.cancer.gov/ drugdictionary/. Accessed January 5, 2011.
34. Leighl NB, Raez LE, Besse B, Rosen PJ, Barlesi F, Massarelli E, et al. A multicenter, phase 2 study of vascular endothelial growth factor trap (Aflibercept) in platinum- and erlotinib-resistant adenocarcinoma of the lung. J Thorac Oncol 2010; 5:1054-9; PMID:20593550; http://dx.doi.org/10.1097/JTO. 0b013e3181e2f7fb
35. th Biennial World Conference on Lung Cancer; July 3-7, 2011; Amsterdam, Netherlands 2011; [abstract O43.06].
36. Natale RB. Dual targeting of the vascular endothelial growth factor receptor and epidermal growth factor receptor pathways with vandetinib (ZD6474) in patients with advanced or metastatic non-small cell lung cancer. J Thorac Oncol 2008; 3:128-30; PMID:18520295; http://dx.doi.org/10.1097/JTO. 0b013e318174e95a.
37. Wedge SR, Ogilvie DJ, Dukes M, Kendrew J, Chester R, Jackson JA, et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis and tumor growth following oral administration. Cancer Res 2002; 62:4645-55; PMID:12183421.
38. Natale RB, Bodkin D, Govindan R, Sleckman BG, Rizvi NA, Capó A, et al. 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 2009; 27:2523-9; PMID:19332730; http://dx.doi.org/10.1200/JCO.2008.18. 6015.
39. Lee J, Hirsh V, Park K, Qin S, Blajman CR, Perng R, et al. Vandetanib versus placebo in patients with advanced non-small cell lung cancer (NSCLC) after prior therapy with an EGFR tyrosine kinase inhibitor (TKI): A randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol 2010; 28; [abstract 7525].
40. Herbst RS, Sun Y, Eberhardt WE, Germonpré P, Saijo N, Zhou C, et al. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol 2010; 11:619-26; PMID:20570559; http://dx.doi.org/10.1016/S1470-2045(10)70132-7.
41. de Boer RH, Arrieta O, Yang CH, Gottfried M, Chan V, Raats J, et al. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol 2011; 29:1067-74; PMID:21282537; http://dx.doi.org/10.1200/JCO.2010.29. 5717.
42. Natale RB, Thongprasert S, Greco FA, Thomas M, Tsai CM, Sunpaweravong P, et al. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 2011; 29:1059-66; PMID:21282542; http://dx.doi.org/10.1200/JCO.2010.28.5981.
43. AstraZeneca. AstraZeneca withdraws regulatory submissions for Zactima (vandetanib) in combination with chemotherapy for advanced NSCLC. Available at: http://www.astrazeneca.com/media/latest-press-releases/zactima-adv-NSCLC?itemId= 317146. Accessed June 23, 2010.
44. Aisner J, Manola J, Dakhil SR, Stella PJ, Schiller JH. Randomized phase II study of vandetanib (V), docetaxel (D) and carboplatin (C) followed by maintenance V or placebo (P) in patients with stage IIIb IV, or recurrent non-small cell lung cancer (NSCLC): PrECOG PrE0501-Update on maintenance treatment, progression-free survival (PFS) and overall survival (OS). [Abstract 7560]. J Clin Oncol 2011; 29.
45. Nikolinakos P, Heymach JV. The tyrosine kinase inhibitor cediranib for non-small cell lung cancer and other thoracic malignancies. J Thorac Oncol 2008; 3:131-4; PMID:18520296; http://dx.doi.org/10.1097/JTO.0b013e318174e910.
46. Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR, et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 2005; 65:4389-400; PMID:15899831; http://dx.doi.org/10.1158/0008-5472.CAN- 04-4409.
47. Goss GD, Arnold A, Shepherd FA, Dediu M, Ciuleanu TE, Fenton D, et al. 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 2010; 28:49-55; PMID:19917841; http://dx.doi.org/10.1200/JCO.2009.22.9427.
48. NCIC Clinical Trials Group. Site Committee Open/Closed/Planned/On Hold/Withdrawn Studies. http://www.ctg.queensu.ca/public/Clinical-Trials/ph3- trial-accrual-closed.htm. Accessed August 11, 2011.
49. Gadgeel SM, Ruckdeschel JC, Wozniak AJ, Chen W, Hackstock D, Galasso C, et al. 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 2011; 29; [abstract 7564].
50. Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 2008; 68:4774-82; PMID:18559524; http://dx.doi.org/10.1158/0008-5472.CAN-07-6307.
51. Ellis PM, Kaiser R, Zhao Y, Stopfer P, Gyorffy S, Hanna N. Phase I open-label study of continuous treatment with BIBF 1120, a triple angiokinase inhibitor and pemetrexed in pretreated non-small cell lung cancer patients. Clin Cancer Res 2010; 16:2881-9; PMID:20460487; http://dx.doi.org/10.1158/1078-0432. CCR-09-2944.
52. Reck M, Kaiser R, Eschbach C, Stefanic M, Love J, Gatzemeier U, et al. 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 2011; 22:1374-81; PMID:21212157; http://dx.doi.org/10.1093/annonc/mdq618.
53. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. 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 2004; 64:7099-109; PMID:15466206; http://dx.doi.org/10.1158/0008-5472.CAN-04-1443.
54. Schiller JH, Lee JW, Hanna NH, Traynor AM, Carbone DP. A randomized discontinuation phase II study of sorafenib versus placebo in patients with nonsmall cell lung cancer who have failed at least two prior chemotherapy regimens: E2501. J Clin Oncol 2008; 26:26-31; [abstract 8014].
55. Scagliotti G, Novello S, von Pawel J, Reck M, Pereira JR, Thomas M, et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced nonsmall-cell lung cancer. J Clin Oncol 2010; 28:1835-42; PMID:20212250; http://dx.doi.org/10.1200/JCO.2009.26.1321.
56. Gatzemeier U, Eisen T, Santoro A, Paz-Ares L, Bennouna J, Liao M, et al. 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 2010; 21:viii.
57. rd, Greco FA, Shipley DL, Friedman EK, Waterhouse DM, et al. 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 2011; 29:2582-9; PMID:21576636; http://dx.doi.org/10.1200/JCO.2010.30.7678.
58. Molina JR, Dy GK, Foster NR, Allen Ziegler KL, Adjei A, Rowland KM, et al. 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. [Abstract 7513]. J Clin Oncol 2011; 29.
59. Sun L, Liang C, Shirazian S, Zhou Y, Miller T, Cui J, et al. Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole- 3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem 2003; 46:1116-9; PMID:12646019; http://dx.doi.org/ 10.1021/jm0204183.
60. Socinski MA, Novello S, Brahmer JR, Rosell R, Sanchez JM, Belani CP, et al. Multicenter, phase II trial of sunitinib in previously treated, advanced nonsmall-cell lung cancer. J Clin Oncol 2008; 26:650-6; PMID:18235126; http://dx.doi.org/10.1200/JCO.2007.13.9303.
61. Novello S, Scagliotti GV, Rosell R, Socinski MA, Brahmer J, Atkins J, et al. Phase II study of continuous daily sunitinib dosing in patients with previously treated advanced non-small cell lung cancer. Br J Cancer 2009; 101:1543-8; PMID:19826424; http://dx.doi.org/10.1038/sj.bjc.6605346.
62. Socinski MA, Scappaticci FA, Samant M, Kolb MM, Kozloff MF. Safety and efficacy of combining sunitinib with bevacizumab + paclitaxel/carboplatin in nonsmall cell lung cancer. J Thorac Oncol 2010; 5:354- 60; PMID:20032789; http://dx.doi.org/10.1097/JTO.0b013e3181c7307e.
63. Scagliotti GV, Krzakowski M, Szczesna A, Strausz J, Makhson A, Reck M, et al. 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 2010; 21:viii; [abstract LBA6].
64. Sloan B, Scheinfeld NS. Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. Curr Opin Investig Drugs 2008; 9:1324-35; PMID:19037839.
65. Kumar R, Knick VB, Rudolph SK, Johnson JH, Crosby RM, Crouthamel MC, et al. Pharmacokineticpharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 2007; 6:2012-21; PMID:17620431; http://dx.doi.org/10.1158/1535-7163.MCT-07-0193.
66. Altorki N, Lane ME, Bauer T, Lee PC, Guarino MJ, Pass H, et al. 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 2010; 28:3131-7; PMID:20516450; http://dx.doi.org/10.1200/JCO.2009.23.9749.
67. Jonker DJ, Rosen LS, Sawyer M, Wilding G, Noberasco C, Jayson G, et al. A phase I study of BMS-582664 (brivanib alaninate), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in patients (pts) with advanced/metastatic solid tumors: Safety, pharmacokinetic (PK) and pharmacodynamic (PD) findings. J Clin Oncol 2007; 25:25-31; [abstract 3559].
68. Huynh H, Ngo VC, Fargnoli J, Ayers M, Soo KC, Koong HN, et al. Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res 2008; 14:6146-53; PMID:18829493; http://dx.doi.org/10.1158/1078-0432.CCR-08-0509.
69. Mekhail T, Masson E, Fischer BS, Gong J, Iyer R, Gan J, et al. Metabolism, excretion and pharmacokinetics of oral brivanib in patients with advanced or metastatic solid tumors. Drug Metab Dispos 2010; 38:1962-6; PMID:20671097; http://dx.doi.org/10.1124/dmd.110.033951.
70. Albert DH, Tapang P, Magoc TJ, Pease LJ, Reuter DR, Wei RQ, et al. Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther 2006; 5:995-1006; PMID:16648571; http://dx.doi.org/ 10.1158/1535-7163.MCT-05-0410.
71. Shankar DB, Li J, Tapang P, Owen McCall J, Pease LJ, Dai Y, et al. ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia. Blood 2007; 109:3400-8; PMID:17209055; http://dx.doi.org/10.1182/blood-2006-06-029579.
72. Tan EH, Goss GD, Salgia R, Besse B, Gandara DR, Hanna NH, et al. Phase 2 trial of Linifanib (ABT-869) in patients with advanced non-small cell lung cancer. J Thorac Oncol 2011; 6:1418-25; PMID:21597387; http://dx.doi.org/10. 1097/JTO.0b013e318220c93e.
73. Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol 2005; 23:5474-83; PMID:16027439; http://dx.doi.org/10.1200/JCO.2005.04.192.
74. Schiller JH, Larson T, Ou SH, Limentani S, Sandler A, Vokes E, et al. Efficacy and safety of axitinib in patients with advanced non-small-cell lung cancer: results from a phase II study. J Clin Oncol 2009; 27:3836-41; PMID:19597027; http://dx.doi.org/10.1200/JCO.2008.20.8355.
75. Fujisaka Y, Yamada Y, Yamamoto N, Shimizu T, Fujiwara Y, Yamada K, et al. Phase 1 study of the investigational, oral angiogenesis inhibitor motesanib in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 2010; 66:935-43; PMID:20107802; http://dx.doi.org/10.1007/s00280-010-1243-y.
76. Polverino A, Coxon A, Starnes C, Diaz Z, DeMelfi T, Wang L, et al. 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 2006; 66:8715-21; PMID:16951187; http://dx.doi.org/10.1158/0008-5472. CAN-05-4665.
77. Blumenschein GR Jr, Kabbinavar F, Menon H, Mok TS, Stephenson J, Beck JT, et al. Motesanib NSCLC Phase II Study Investigators. 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 2011; 22:2057-67; PMID:21321086; http://dx.doi.org/10.1093/annonc/ mdq731.
78. Scagliotti G, Vynnychenko I, Ichinose Y, Park K, Kubota K, Blackhall FH, et al. 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 2012; 30:172-8. PMID:22124104; http://dx.doi.org/10.1200/JCO.2010.333.7089.
79. McKeage MJ, Von Pawel J, Reck M, Jameson MB, Rosenthal MA, Sullivan R, et al. Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced nonsmall cell lung cancer. Br J Cancer 2008; 99:2006-12; PMID:19078952; http://dx.doi.org/10.1038/sj.bjc. 6604808.
80. McKeage MJ, Reck M, Jameson MB, Rosenthal MA, Gibbs D, Mainwaring PN, et al. Phase II study of ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid/DMXAA) 1,800 mg/m(2) combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer. Lung Cancer 2009; 65:192-7; PMID:19409645; http://dx.doi.org/10.1016/j.lungcan.2009.03.027.
81. Antisoma plc. ATTRACT-1 phase III trial of ASA404 halted following interim analysis. Press release. March 29, 2010. http://www.antisoma.com/asm/ media/press/pr2010/2010-03-29/. Accessed July 27, 2010.
82. Antisoma plc. Antisoma announces outcome of ASA404 ATTRACT-2 trial. Press release. November 11, 2010. http://www.antisoma.com/asm/media/press/pr2010/ 2010-11-11/. Accessed November 24, 2010.
83. Lara PN Jr, Douillard JY, Nakagawa K, von Pawel J, McKeage MJ, Albert I, et al. Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer. J Clin Oncol 2011; 29:2965-71; PMID:21709202; http://dx.doi.org/10.1200/JCO.2011.35.0660.
84. Rudin CM, Mauer A, Smakal M, Juergens R, Spelda S, Wertheim M, et al. Phase I/II study of pemetrexed with or without ABT-751 in advanced or metastatic nonsmall-cell lung cancer. J Clin Oncol 2011; 29:1075-82; http://dx.doi.org/10. 1200/JCO.2010.32.5944.
85. Nicholson B, Lloyd GK, Miller BR, Palladino MA, Kiso Y, Hayashi Y, et al. NPI-2358 is a tubulin-depolymerizing agent: in-vitro evidence for activity as a tumor vascular-disrupting agent. Anticancer Drugs 2006; 17:25-31; PMID:16317287; http://dx.doi.org/10.1097/01.cad.0000182745.01612.8a.
86. st Annual Meeting of the American Association for Cancer Research; April 17-21, 2010; Washington DC.
87. Dahlberg SE, Sandler AB, Brahmer JR, Schiller JH, Johnson DH. Clinical course of advanced non-smallcell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. J Clin Oncol 2010; 28:949-54; PMID:20085937; http://dx.doi.org/ 10.1200/JCO.2009.25.4482.
88. Hurwitz H, Douglas PS, Middleton JP, Sledge GW, Johnson DH, Reardon DA, et al. Analysis of early hypertension (HTN) and clinical outcome with bevacizumab (BV). [Abstract 3039]. J Clin Oncol 2010; 28.
89. Goodwin R, Ding K, Seymour L, LeMaître A, Arnold A, Shepherd FA, et al.; NCIC Clinical Trials Group, Kingston, Ontario, Canada. Treatment-emergent hypertension and outcomes in patients with advanced non-small-cell lung cancer receiving chemotherapy with or without the vascular endothelial growth factor receptor inhibitor cediranib: NCIC Clinical Trials Group Study BR24. Ann Oncol 2010; 21:2220-6; PMID:20427348; http://dx.doi.org/10.1093/annonc/mdq221.
90. Nikolinakos PG, Altorki N, Yankelevitz D, Tran HT, Yan S, Rajagopalan D, et al. 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 2010; 70:2171-9; PMID:20215520; http://dx.doi.org/10.1158/0008-5472.CAN-09-2533.
91. National Institutes of Health. ClinicalTrials.gov. http://clinicaltrials. gov/.