An update on molecularly targeted therapies in secondand third-line treatment in non-small cell lung cancer: Focus on EGFR inhibitors and anti-angiogenic agents

Clinical and Translational Oncology

Volumn 15, Issue 5, 2013, Pages 343-357

  Majem, M ^a   Pallares C ^a  

^a HOSPITAL DE LA SANTA CREU I SANT PAU   (Spain)

Author keywords

Anti angiogenic agents; ErbB Family Blocker; Multityrosine kinase inhibitors; NSCLC; Pretreated patients

Indexed keywords

AFATINIB; ANGIOGENESIS INHIBITOR; AXITINIB; CANERTINIB; CEDIRANIB; DACOMITINIB; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; LAPATINIB; LINIFANIB; MOTESANIB; NERATINIB; NINTEDANIB; PAZOPANIB; PELITINIB; SORAFENIB; SUNITINIB; VANDETANIB; AMINOQUINOLINE DERIVATIVE; ANILINE DERIVATIVE; EPIDERMAL GROWTH FACTOR RECEPTOR; N (4 (3 CHLORO 4 (2 PYRIDINYLMETHOXY)ANILINO) 3 CYANO 7 ETHOXY 6 QUINOLYL) 4 (DIMETHYLAMINO) 2 BUTENAMIDE; N-(4-(3-CHLORO-4-(2-PYRIDINYLMETHOXY)ANILINO)-3-CYANO-7-ETHOXY-6-QUINOLYL)-4-(DIMETHYLAMINO)-2-BUTENAMIDE; PROTEIN KINASE INHIBITOR; QUINAZOLINE DERIVATIVE; QUINOLINE DERIVATIVE;

ANTIANGIOGENIC THERAPY; ARTICLE; CANCER CHEMOTHERAPY; HUMAN; LUNG NON SMALL CELL CANCER; MOLECULARLY TARGETED THERAPY; MULTICENTER STUDY (TOPIC); PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); DRUG ANTAGONISM; LUNG TUMOR; REVIEW; VASCULARIZATION;

AMINOQUINOLINES; ANGIOGENESIS INHIBITORS; ANILINE COMPOUNDS; CARCINOMA, NON-SMALL-CELL LUNG; HUMANS; LUNG NEOPLASMS; MOLECULAR TARGETED THERAPY; PROTEIN KINASE INHIBITORS; QUINAZOLINES; QUINOLINES; RECEPTOR, EPIDERMAL GROWTH FACTOR;

EID: 84886296148     PISSN: 1699048X     EISSN: 16993055     Source Type: Journal    
DOI: 10.1007/s12094-012-0964-2     Document Type: Article

References (100)

1. Ettinger DS, Akerley W, Bepler G, Blum MG, Chang A, Cheney RT, Chirieac LR, D'Amico TA, Demmy TL, Ganti AK, Govindan R, Grannis FW Jr, Jahan T, Jahanzeb M, Johnson DH, Kessinger A, Komaki R, Kong FM, Kris MG, Krug LM, Le QT, Lennes IT, Martins R, O'Malley J, Osarogiagbon RU, Otterson GA, Patel JD, Pisters KM, Reckamp K, Riely GJ, Rohren E, Simon GR, Swanson SJ, Wood DE, Yang SC (2010) Non-small cell lung cancer. J Natl Compr Cancer Netw 8(7): 740-801
2. 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(2): 92-98
3. Felip E, Gridelli C, Baas P, Rosell R, Stahel R (2011)Metastatic non-small-cell lung cancer: consensus on pathology and molecular tests, first-line, secondline, and third-line therapy: 1st ESMO consensus conference in lung cancer, Lugano, 2010. Ann Oncol 22(7): 1507-1519. doi:10.1093/annonc/ mdr150
4. Syrigos KN, Saif MW, Karapanagiotou EM, Oikonomopoulos G, De Marinis F (2011) The need for third-line treatment in non-small cell lung cancer: an overview of new options. Anticancer Res 31(2): 649-659
5. von Pawel J, Papai-Szekely Z, Viñolas N, Sederholm C, Klima M, Desaiah D, Leschinger M, Dittrich C (2011) A randomized phase II study of pemetrexed versus pemetrexed plus erlotinib in second-line treatment for locally advanced or metastatic, nonsquamous NSCLC. J Clin Oncol 29(suppl):abstr7526
6. Chang MH, Ahn JS, Lee J, Kim KH, Park YH, Han J, Ahn MJ, Park K (2010) The efficacy of pemetrexed as a third- or fourth-line therapy and the signifi- cance of thymidylate synthase expression in patients with advanced non-small cell lung cancer. Lung Cancer 69(3): 323-329. doi:10.1016/j.lungcan. 2009.12.002
7. Scartozzi M, Mazzanti P, Giampieri R, Berardi R, Galizia E, Gasparini S, Zuccatosta L, Cascinu S (2010) Clinical predictive factors for advanced nonsmall cell lung cancer (NSCLC) patients receiving third-line therapy: selecting the unselectable? Lung Cancer 68(3): 433-437. doi:10.1016/j.lungcan. 2009.07.008
8. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez- Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba II, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis WD, Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, Lander ES, Gibbs RA, Meyerson M, Wilson RK (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455(7216): 1069-1075. doi:10.1038/nature07423
9. Herbst RS, Heymach JV, Lippman SM (2008) Lung cancer. N Engl J Med 359(13): 1367-1380. doi:10.1056/NEJMra0802714
10. Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, Stokes M, Sullivan L, Mitchell J, Wetzel R, Macneill J, Ren JM, Yuan J, Bakalarski CE, Villen J, Kornhauser JM, Smith B, Li D, Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush J, Comb MJ (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131(6): 1190-1203. doi:10.1016/j.cell.2007.11.025
11. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350(21): 2129-2139
12. Sharma SV, Bell DW, Settleman J, Haber DA (2007) Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7(3): 169-181. doi:10.1038/nrc2088
13. Garassino M, Martelli O, Bettini A, Floriani I, Copreni E, Lauricella C, Ganzinelli M, Marabese M, Broggini M, Veronese S, Gherardi G, Longo F, Fabbri M, Tomirotti M, Alabiso O, Sarobba M, Labianca R, Marsoni S, Farina G, Scanni A (2012) TAILOR: a phase III trial comparing erlotinib with docetaxel as the second-line treatment of NSCLC patients with wild-type (wt) EGFR. J Clin Oncol 30(15S):abstr LBA7501
14. Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, Chiang A, Yang G, Ouerfelli O, Kris MG, Ladanyi M, Miller VA, Pao W (2006) Novel D761Y and common secondary T790 M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 12(21): 6494-6501. doi:10.1158/1078-0432.CCR- 06-1570
15. Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, Inserra E, Diederichs S, Iafrate AJ, Bell DW, Digumarthy S, Muzikansky A, Irimia D, Settleman J, Tompkins RG, Lynch TJ, Toner M, Haber DA (2008) Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 359(4): 366-377. doi:10.1056/NEJMoa0800668
16. Hirsh V (2011) Afatinib (BIBW 2992) development in non-small-cell lung cancer. Future Oncol 7(7): 817-825. doi:10.2217/fon.11.62
17. Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, Padera RF, Shapiro GI, Baum A, Himmelsbach F, Rettig WJ, Meyerson M, Solca F, Greulich H, Wong KK (2008) BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27(34): 4702-4711. doi:10.1038/onc.2008.109
18. Solca F, Dahl G, Zoephel A, Bader G, Sanderson M, Klein C, Kraemer O, Himmelsbach F, Haaksma E, Adolf GR (2012) Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB Family Blocker. J Pharmacol Exp Ther. doi:10.1124/jpet.112.197756
19. Eskens FA, Mom CH, Planting AS, Gietema JA, Amelsberg A, Huisman H, van Doorn L, Burger H, Stopfer P, Verweij J, de Vries EG (2008) A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours. Br J Cancer 98(1): 80-85. doi:10.1038/sj.bjc.6604108
20. Yap TA, Vidal L, Adam J, Stephens P, Spicer J, Shaw H, Ang J, Temple G, Bell S, Shahidi M, Uttenreuther-Fischer M, Stopfer P, Futreal A, Calvert H, de Bono JS, Plummer R (2010) Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol 28(25): 3965-3972
21. Awada A, Dumez H, Wolter P, Hendlisz A, Beese-Hammer T, Piccart M, Uttenreuther-Fischer M, Stopfer P, Taton M, Schöffski P (2011) A phase I dose finding study of the 3-day administration of BIBW 2992, an irreversible dual EGFR/HER-2 inhibitor, in combination with three-weekly docetaxel in patients with advanced solid tumors. J Clin Oncol 29(15S):abstr3556
22. Spicer J, Harris D, Ang J, Chau M, Vizor S, Shahidi M, Uttenreuther-Fischer M, Southey K, Chambers J, de Bono JS (2008) A phase I study of daily BIBW2992, an irreversible EGFR/HER2 dual kinase inhibitor, in combination with paclitaxel (abstract 474P). Ann Oncol 19(Suppl8):abstr474P (viii-157)
23. Marshall J, Shapiro G, Terlizzi E, Stopfer P, Amelsberg A, Gordon M (2008) A phase I dose escalation trial of BIBW2992, an irreversible EGFR/HER2 kinase inhibitor, for 20 and 13 days in combination with docetaxel every 21 day. Ann Oncol 19(8):viii158
24. Yang JC, Shih JY, Su WC, Hsia TC, Tsai CM, Ou SH, Yu CJ, Chang GC, Ho CL, Sequist LV, Dudek AZ, Shahidi M, Cong XJ, Lorence RM, Yang PC, Miller VA (2012) Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol 13(5): 539-548
25. Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, Crino L, Tan EH, Chao TY, Shahidi M, Cong XJ, Lorence RM, Yang JC (2012) Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 13(5): 528-538
26. Hirsch V, Cadranel J, Cong J, Fairclough D, Finnern H, Lorence R, Miller V, Palmer M, Yang C-H (2011) Symptom and health-related quality of life benefit of afatinib (BIBW 2992) in advanced NSCLC patients previously treated with erlotinib or gefitinib: results of a randomized Phase III Trial (LUX-Lung 1). J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 6(62):S324 (abstr O311.307)
27. Sequist LV, Yang JC-H, Yamamoto N, O'Byrne K, Hirsh V, Mok K, Geater SL, Orlov S, Tsai C-M, Boyer M, Su W-C, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M (2012) Phase III study of afatinib or cisplatin/pemetrexed in metastatic lung adenocarcinoma patients with epidermal growth factor receptor mutations. J Clin Oncol 29(suppl):abstr LBA 7512
28. Yamamoto N, Katakami N, Atagi S, Hida T, Goto K, Horai T, Inoue A, Ichinose Y, Kobayashi K, Takeda K, Kiura K, Saka H, Tamura T, Okamoto I, Nigami N, Morinaga R, Nishio K, Seki Y, Lorence R, Shahidi M (2011) A phase II trial of afatinib (BIBW 2992) in patients (pts) with advanced nonsmall cell lung cancer previously treated with erlotinib (E) or gefitinib (G). J Clin Oncol 29(suppl):abstr7524
29. Janjigian Y, Groen H, Horn L, Smit E, Fu Y, Wang F, Shahidi M, Denis L, Pao W, Miller V (2011) Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib. J Clin Oncol 29(suppl):abstr7525
30. Nunes M, Shi C, Greenberger LM (2004) Phosphorylation of extracellular signal-regulated kinase 1 and 2, protein kinase B, and signal transducer and activator of transcription 3 are differently inhibited by an epidermal growth factor receptor inhibitor, EKB-569, in tumor cells and normal human keratinocytes. Mol Cancer Ther 3(1): 21-27
31. Erlichman C, Hidalgo M, Boni JP, Martins P, Quinn SE, Zacharchuk C, Amorusi P, Adjei AA, Rowinsky EK (2006) Phase I study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in patients with advanced solid tumors. J Clin Oncol 24(15): 2252-2260. doi:10.1200/JCO.2005.01. 8960
32. Yoshimura N, Kudoh S, Kimura T, Mitsuoka S, Matsuura K, Hirata K, Matsui K, Negoro S, Nakagawa K, Fukuoka M (2006) EKB-569, a new irreversible epidermal growth factor receptor tyrosine kinase inhibitor, with clinical activity in patients with non-small cell lung cancer with acquired resistance to gefitinib. Lung Cancer 51(3): 363-368. doi:10.1016/j.lungcan.2005.10.006
33. Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD, Nilakantan R, Overbeek E, Reich MF, Shen R, Shi X, Tsou HR, Wang YF, Wissner A (2004) Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res 64(11): 3958-3965. doi:10.1158/0008-5472.CAN-03-2868
34. Wong KK, Fracasso PM, Bukowski RM, Lynch TJ, Munster PN, Shapiro GI, Janne PA, Eder JP, Naughton MJ, Ellis MJ, Jones SF, Mekhail T, Zacharchuk C, Vermette J, Abbas R, Quinn S, Powell C, Burris HA (2009) A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin Cancer Res 15(7): 2552-2558. doi:10.1158/1078-0432.CCR-08-1978
35. Sequist LV, Besse B, Lynch TJ, Miller VA, Wong KK, Gitlitz B, Eaton K, Zacharchuk C, Freyman A, Powell C, Ananthakrishnan R, Quinn S, Soria JC (2010) Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer. J Clin Oncol 28(18): 3076-3083. doi:10.1200/JCO.2009.27.9414
36. Allen LF, Eiseman IA, Fry DW, Lenehan PF (2003) CI-1033, an irreversible pan-erbB receptor inhibitor and its potential application for the treatment of breast cancer. Semin Oncol 30(5 Suppl 16): 65-78
37. Chiappori AA, Ellis PM, Hamm JT, Bitran JD, Eiseman I, Lovalvo J, Burnett D, Olson S, Lenehan P, Zinner RG (2006) A phase I evaluation of oral CI- 1033 in combination with paclitaxel and carboplatin as first-line chemotherapy in patients with advanced non-small cell lung cancer. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 1(9): 1010-1019
38. Janne PA, von Pawel J, Cohen RB, Crino L, Butts CA, Olson SS, Eiseman IA, Chiappori AA, Yeap BY, Lenehan PF, Dasse K, Sheeran M, Bonomi PD (2007) Multicenter, randomized, phase II trial of CI-1033, an irreversible pan- ERBB inhibitor, for previously treated advanced non small-cell lung cancer. J Clin Oncol 25(25): 3936-3944. doi:10.1200/JCO.2007.11.1336
39. Ross HJ, Blumenschein GR Jr, Aisner J, Damjanov N, Dowlati A, Garst J, Rigas JR, Smylie M, Hassani H, Allen KE, Leopold L, Zaks TZ, Shepherd FA (2010) Randomized phase II multicenter trial of two schedules of lapatinib as first- or second-line monotherapy in patients with advanced or metastatic nonsmall cell lung cancer. Clin Cancer Res 16(6): 1938-1949. doi:10.1158/1078-0432.CCR-08-3328
40. Engelman JA, Zejnullahu K, Gale CM, Lifshits E, Gonzales AJ, Shimamura T, Zhao F, Vincent PW, Naumov GN, Bradner JE, Althaus IW, Gandhi L, Shapiro GI, Nelson JM, Heymach JV, Meyerson M, Wong KK, Janne PA (2007) PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 67(24): 11924-11932. doi:10.1158/0008-5472.CAN-07-1885
41. Bello CL, LaBadie RR, Ni G, Boutros T, McCormick C, Ndongo MN (2012) The effect of dacomitinib (PF-00299804) on CYP2D6 activity in healthy volunteers who are extensive or intermediate metabolizers. Cancer Chemother Pharmacol 69(4): 991-997. doi:10.1007/s00280-011-1793-7
42. Janne P, Schellens J, Engelman J et al (2008) Preliminary activity and safety results from a phase I clinical trial of PF-00299804, an irreversible pan-HER inhibitor, in patients (pts) with NSCLC. J Clin Oncol 26(18S):abstr8027
43. Janne PA, Boss DS, Camidge DR, Britten CD, Engelman JA, Garon EB, Guo F, Wong S, Liang J, Letrent S, Millham R, Taylor I, Eckhardt SG, Schellens JH (2011) Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clin Cancer Res 17(5): 1131-1139. doi:10.1158/1078-0432.CCR-10-1220
44. Mok TS, Spigel DR, Park K, Socinski MA, Tung S, Kim D-W, Ou S-HI, Zhang H, O'Connell J, Jänne P (2010) Efficacy and safety of PF299804 as first-line treatment (TX) of patients (PTS) with advanced (ADV) NSCLC selected for activating mutation (MU) of epidermal growth factor receptor (EGFR). Ann Oncol 21(suppl8):vii8 (abstr LBA18)
45. Boyer M, Blackhall FH, Park K, Barrios CH, Krzakowski M, Taylor I, Liang J, Denis L, O'Connell J, Ramalingam S (2010) Efficacy and safety of PF299804 versus erlotinib (E): a global, randomized phase II trial in patients (pts) with advanced non-small cell lung cancer (NSCLC) after failure of chemotherapy (CT). J Clin Oncol 28(18S):abstrLBA7523
46. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21): 1182-1186
47. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3): 353-364
48. Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25(4): 581-611
49. Hellberg C, Ostman A, Heldin CH (2010) PDGF and vessel maturation. Recent Results Cancer Res 180: 103-114. doi:10.1007/978-3-540-78281-0-7
50. Appelmann I, Liersch R, Kessler T, Mesters RM, Berdel WE (2010) Angiogenesis inhibition in cancer therapy: platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) and their receptors: biological functions and role in malignancy. Recent Results Cancer Res 180: 51-81. doi:10.1007/978-3-540-78281-0-5
51. Stefanou D, Batistatou A, Arkoumani E, Ntzani E, Agnantis NJ (2004) Expression of vascular endothelial growth factor (VEGF) and association with microvessel density in small-cell and non-small-cell lung carcinomas. Histol Histopathol 19(1): 37-42
52. Donnem T, Al-Saad S, Al-Shibli K, Busund LT, Bremnes RM (2010) Coexpression of PDGF-B and VEGFR-3 strongly correlates with lymph node metastasis and poor survival in non-small-cell lung cancer. Ann Oncol 21(2): 223-231. doi:10.1093/annonc/mdp296
53. Donnem T, Andersen S, Al-Saad S, Al-Shibli K, Busund LT, Bremnes RM (2011) Prognostic impact of angiogenic markers in non-small-cell lung cancer is related to tumor size. Clin Lung Cancer 12(2): 106-115. doi:10.1016/j.cllc. 2011.03.005
54. Bremnes RM, Camps C, Sirera R (2006) Angiogenesis in non-small cell lung cancer: the prognostic impact of neoangiogenesis and the cytokines VEGF and bFGF in tumours and blood. Lung Cancer 51(2): 143-158. doi:10.1016/j.lungcan.2005. 09.005
55. Yuan A, Yu CJ, Kuo SH, Chen WJ, Lin FY, Luh KT, Yang PC, Lee YC (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(2): 432-441
56. Hanrahan EO, Lin HY, Kim ES, Yan S, Du DZ, McKee KS, Tran HT, Lee JJ, Ryan AJ, Langmuir P, Johnson BE, Heymach JV (2010) Distinct patterns of cytokine and angiogenic factor modulation and markers of benefit for vandetanib and/or chemotherapy in patients with non-small-cell lung cancer. J Clin Oncol 28(2): 193-201. doi:10.1200/JCO.2009.22.4279
57. Hanrahan EO, Ryan AJ, Mann H, Kennedy SJ, Langmuir P, Natale RB, Herbst RS, Johnson BE, Heymach JV (2009) Baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from vandetanib in non-small cell lung cancer. Clin Cancer Res 15(10): 3600-3609. doi:10.1158/1078-0432.CCR-08-2568
58. Fontanini G, Vignati S, Boldrini L, Chine S, Silvestri V, Lucchi M, Mussi A, Angeletti CA, Bevilacqua G (1997) Vascular endothelial growth factor is associated with neovascularization and influences progression of non-small cell lung carcinoma. Clin Cancer Res 3(6): 861-865
59. Fontanini G, Lucchi M, Vignati S, Mussi A, Ciardiello F, De Laurentiis M, De Placido S, Basolo F, Angeletti CA, Bevilacqua G (1997) Angiogenesis as a prognostic indicator of survival in non-small-cell lung carcinoma: a prospective study. J Natl Cancer Inst 89(12): 881-886
60. Kerbel RS (2006) Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science 312(5777): 1171-1175. doi:10.1126/science. 1125950
61. 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(24): 2542-2550. doi:10.1056/NEJMoa061884
62. Wedge SR, Ogilvie DJ, Dukes M, Kendrew J, Chester R, Jackson JA, Boffey SJ, Valentine PJ, Curwen JO, Musgrove HL, Graham GA, Hughes GD, Thomas AP, Stokes ES, Curry B, Richmond GH, Wadsworth PF, Bigley AL, Hennequin LF (2002) ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 62(16): 4645-4655
63. Heymach JV, Johnson BE, Prager D, Csada E, Roubec J, Pesek M, Spasova I, Belani CP, Bodrogi I, Gadgeel S, Kennedy SJ, Hou J, Herbst RS (2007) Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer. J Clin Oncol 25(27): 4270-4277. doi:10.1200/JCO.2006.10.5122
64. Heymach JV, Paz-Ares L, De Braud F, Sebastian M, Stewart DJ, Eberhardt WE, Ranade AA, Cohen G, Trigo JM, Sandler AB, Bonomi PD, Herbst RS, Krebs AD, Vasselli J, Johnson BE (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): 5407-5415. doi:10.1200/JCO. 2008.17.3138
65. Herbst RS, Sun Y, Eberhardt WE, Germonpre P, Saijo N, Zhou C, Wang J, Li L, Kabbinavar F, Ichinose Y, Qin S, Zhang L, Biesma B, Heymach JV, Langmuir P, Kennedy SJ, Tada H, Johnson BE (2010) 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 11(7): 619-626
66. Lee J, Hirsh V, Park K, Qin S, Blajman C, Perng R, Emerson L, Langmuir P, Manegold C (2010) Vandetanib versus placebo in patients with advanced nonsmall 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 28(15S):abstr7525
67. Natale RB, Thongprasert S, Greco FA, Thomas M, Tsai CM, Sunpaweravong P, Ferry D, Mulatero C, Whorf R, Thompson J, Barlesi F, Langmuir P, Gogov S, Rowbottom JA, Goss GD (2011) Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 29(8): 1059-1066. doi:10.1200/JCO.2010.28.5981
68. de Boer RH, Arrieta O, Yang CH, Gottfried M, Chan V, Raats J, de Marinis F, Abratt RP, Wolf J, Blackhall FH, Langmuir P, Milenkova T, Read J, Vansteenkiste JF (2011) 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 29(8): 1067-1074. doi:10.1200/JCO.2010.29.5717
69. Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM (2003) SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2(5): 471-478
70. 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(9): 1543-1548
71. 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 non-small-cell lung cancer. J Clin Oncol 26(4): 650-656. doi:10.1200/JCO.2007.13.9303
72. Novello S, Camps C, Grossi F, Mazieres J, Abrey L, Vernejoux JM, Thall A, Patyna S, Usari T, Wang Z, Chao RC, Scagliotti G (2011) Phase II study of sunitinib in patients with non-small cell lung cancer and irradiated brain metastases. J Thor Oncol Off Publ Int Assoc Study Lung Cancer 6(7): 1260-1266. doi:10.1097/JTO.0b013-318219a973
73. Scagliotti GV, Krzakowski M, Szczesna A, Strausz J, Makhson A, Reck M, Wierzbicki RF, Albert I, Thomas M, Miziara JE, Papai ZS, Karaseva N, Thongprasert S, Portulas ED, von Pawel J, Zhang K, Selaru P, Tye L, Chao RC, Govindan R (2012) Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non-small-cell lung cancer: a phase III trial. J Clin Oncol 30(17): 2070-2078. doi:10.1200/JCO.2011. 39.2993
74. 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(19): 7099-7109. doi:10.1158/0008-5472.CAN- 04-1443
75. Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, Santoro M (2006) BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst 98(5): 326-334. doi:10.1093/jnci/djj069
76. Iyer R, Fetterly G, Lugade A, Thanavala Y (2010) Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother 11(11): 1943-1955. doi:10.1517/14656566.2010.496453
77. Gatzemeier U, Eisen T, Santoro A, Paz-Ares L, Bennouna J, Liao M, Strauss U, Montegriffo E, Ong T, 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(suppl8):viii7 (abstr LBA16)
78. Scagliotti G, Novello S, von Pawel J, Reck M, Pereira JR, Thomas M, Miziara JEA, 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(11): 1835-1842. doi:10.1200/JCO.2009.26.1321
79. Schiller JHLJ, Hanna N 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. J Clin Oncol 26:abstr8014
80. Blumenschein GR Jr, Gatzemeier U, Fossella F, Stewart DJ, Cupit L, Cihon F, O'Leary J, Reck M (2009) Phase II, multicenter, uncontrolled trial of singleagent sorafenib in patients with relapsed or refractory, advanced non-smallcell lung cancer. J Clin Oncol 27(26): 4274-4280
81. Cho B, Kim D, Heo D, Kang S, Kim H, Lee D, Kim D, Jung M, Choi J, Kim J (2010) A multicenter phase II study of sorafenib in combination with erlotinib in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 28(15S):abstr7547
82. Spigel DR, Burris HA 3rd, 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(18): 2582-2589. doi:10.1200/JCO.2010.30.7678
83. Bayer (2012) http://www.press.bayer.com/baynews/baynews.nsf/id/Phase- III-MISSION-Trial-Nexavar-Patients-Non-Small-Cell-Lung-Cancer-Did-Not- Meet-Primary-Endpoint?OpenDocument&sessionID=1353666710. Accessed 22 May 2012
84. 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(12): 4774-4782
85. Okamoto I, Kaneda H, Satoh T, Okamoto W, Miyazaki M, Morinaga R, Ueda S, Terashima M, Tsuya A, Sarashina A, Konishi K, Arao T, Nishio K, Kaiser R, Nakagawa K (2010) Phase I safety, pharmacokinetic, and biomarker study of BIBF 1120, an oral triple tyrosine kinase inhibitor in patients with advanced solid tumors. Mol Cancer Ther 9(10): 2825-2833. doi:10.1158/1535-7163.MCT-10-0379
86. Reck M (2010) BIBF 1120 for the treatment of non-small cell lung cancer. Expert Opin Investig Drugs 19(6): 789-794. doi:10.1517/13543784.2010. 488220
87. Ellis PM, Kaiser R, Zhao Y, Stopfer P, Gyorffy S, Hanna N (2010) 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 16(10): 2881-2889. doi:10.1158/1078-0432.CCR-09-2944
88. Reck M, Kaiser R, Eschbach C, Stefanic M, Love J, Gatzemeier M, 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
89. Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, Pithavala YK, Reich SD, Freddo JL, Wilding G (2005) Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol 23(24): 5474-5483. doi:10.1200/JCO.2005.04.192
90. 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 non-small-cell lung cancer: results from a phase II study. J Clin Oncol 27(23): 3836-3841
91. 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(10): 4389-4400. doi:10.1158/0008-5472.CAN-04-4409
92. Goss G, Shepherd FA, Laurie S, Gauthier I, Leighl N, Chen E, Feld R, Powers J, Seymour L (2009) A phase I and pharmacokinetic study of daily oral cediranib, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with cisplatin and gemcitabine in patients with advanced nonsmall cell lung cancer: a study of the National Cancer Institute of Canada Clinical Trials Group. Eur J Cancer 45(5): 782-788. doi:10.1016/j.ejca.2008. 10.022
93. 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(1): 49-55. doi:10.1200/JCO.2009. 22.9427
94. van Cruijsen H, Voest EE, Punt CJ, Hoekman K, Witteveen PO, Meijerink MR, Puchalski TA, Robertson J, Saunders O, Jurgensmeier JM, van Herpen CM, Giaccone G (2010) Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours. Eur J Cancer 46(5): 901-911. doi:10.1016/j.ejca.2009.12.023
95. Gadgeel S, Ruckdeschel J, Wozniak A, Chen W, Hackstock D, Galasso C, Burger A, Ivy S, LoRusso M, Edelman M (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(suppl):abstr7564
96. Blumenschein GR Jr, Reckamp K, Stephenson GJ, O'Rourke T, Gladish G, McGreivy J, Sun YN, Ye Y, Parson M, Sandler A (2010) Phase 1b study of motesanib, an oral angiogenesis inhibitor, in combination with carboplatin/paclitaxel and/or panitumumab for the treatment of advanced non-small cell lung cancer. Clin Cancer Res 16(1): 279-290. doi:10.1158/1078- 0432.CCR- 09-1675
97. Scagliotti G, Vynnychenko I, Ichinose Y, Park K, Kubota K, Blackhall F, Pirker R, Galiulin R, Ciuleanu T, Sydorenko O, Dediu M, Papai-Szekely Z, Banaclocha NM, McCoy S, Yao B, Hei Y, Spigel D (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(suppl): 7512
98. Tan EH, Goss GD, Salgia R, Besse B, Gandara DR, Hanna NH, Yang JC, Thertulien R, Wertheim M, Mazieres J, Hensing T, Lee C, Gupta N, Pradhan R, Qian J, Qin Q, Scappaticci FA, Ricker JL, Carlson DM, Soo RA (2011) Phase 2 Trial of Linifanib (ABT-869) in Patients with Advanced Non-small Cell Lung Cancer. J Thorac Oncol Off Publ of the Int Assoc for the Study of Lung Cancer 6(6 suppl 2):S324 abstr O311.307
99. Sonpavde G, Hutson TE (2007) Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep 9(2): 115-119
100. Altorki N, Lane ME, Bauer T, Lee PC, Guarino MJ, Pass H, Felip E, Peylan-