Lung Cancer
Volume 67, Issue 3 , Pages 257-274 , March 2010

Targeted therapies for non-small cell lung cancer

  • Wolfram C.M. Dempke

      Affiliations

    • University of Munich, University Hospital of Grosshadern (Hematology and Oncology), D-81377 Munich, Germany
    • Corresponding Author InformationCorresponding author at: Industriestrasse 41, D-81245 Munich, Germany. Tel.: +49 89 37912 632; fax: +49 89 37912 633.
  • ,
  • Tamas Suto

      Affiliations

    • Amgen Europe GmbH Dammstrasse 23, CH-6301 Zug, Switzerland
  • ,
  • Martin Reck

      Affiliations

    • Thoraxklinik Grosshansdorf, Wöhrendamm 80, D-22927 Grosshansdorf, Germany

Received 3 September 2009 ,Revised 13 October 2009 ,Accepted 19 October 2009.

References 

  1. Ramalingam S, Belani C. Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions. Oncologist. 2008;15:5–13
  2. Shepherd FA. Second-line chemotherapy for non-small cell lung cancer. Expert Rev Anticancer Ther. 2003;3:435–442
  3. Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker S, et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol. 2003;21:330–353
  4. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimes for advanced non-small cell lung cancer. N Engl J Med. 2002;346:92–98
  5. Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol. 2009;27:3277–3283
  6. Rudd RM, Gower NH, Spiro SG, Eisen JM, Harper PG, Littler JA, et al. Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non small cell lung cancer. A phase III randomized study of the London Cancer Group. J Clin Oncol. 2005;23:142–153
  7. Martoni A, Marino A, Sperandi F, Giaquinta F, Di Fabio F, Melloti B, et al. Multicentre randomized phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer. Eur J Cancer. 2005;41:81–92
  8. Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ. 1995;311:899–909
  9. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000;6:443–446
  10. Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhason A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–1417
  11. Gridelli C, Maione P, Luciana M, Rossi A. Cetuximab and other anti-epidermal growth factor receptor monoclonal antibodies in the treatment of non-small cell lung cancer. Oncologist. 2009;14:601–611
  12. Rosell R, Robinet G, Szczesna A, Ramlau R, Constenla M, Mennecier BC, et al. Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer. Ann Oncol. 2008;19:362–369
  13. Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomized phase III trial. Lancet. 2009;373:1525–1531
  14. Lynch TJ, Patel T, Dreisbach L, Neuberg DS. A randomized multicenter phase III study of cetuximab (Erbitux®) in combination with taxane/carboplatin versus taxane/carboplatin alone as first-line treatment for patients with advanced/metastatic non-small cell lung cancer (NSCLC). J Thorac Oncol. 2007;2(8 Suppl. 4):340
  15. Thatcher N, Lynch T, Butts C, Scott DA, Woods BS. Cetuximab plus platinum-based chemotherapy as 1st-line treatment in patients with non-small cell lung cancer (NSCLC): a meta-analysis of randomized phase II/III trials. 13th WCLC 2009; #A3.7.
  16. Lynch TJ, Blumenschein GR, Engelman JA, Espindoza-Delgado I, Govindan R, Hanke J, et al. Summary statement novel agents in the treatment of lung cancer. J Thorac Oncol. 2008;6(6 Suppl. 2):107–112
  17. Katzel JA, Fanucchi MP, Li Z. Recent advances of novel targeted therapy in non-small cell lung cancer. J Hema Oncol. 2009;2:2–20
  18. 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;22:2184–2191
  19. 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;355:2542–2550
  20. 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;27:1227–1234
  21. Brahmer JR, Gray R, Schiller JH, Hann CL. ECOG 4599 phase III trial of carboplatin and paclitaxel±bevacizumab: subset analysis of survival by gender. J Clin Oncol. 2006;24(Suppl.):7036
  22. Eberhardt W, Reck M, von Pawel J, Betticher D. Subgroup results from a randomised, double-blind, multicentre phase III study of bevacizumab in combination with cisplatin-gemcitabine in chemotherapy-naïve patients with advanced or recurrent non-squamous nonsmall cell lung cancer (NSCLC): study BO17704. Eur J Cancer. 2007;5(Suppl.):362
  23. Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, et al. 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;26:60–65
  24. Crinò L, Mezger J, Griesinger F, Zhou C, Reck M. MO19390 (SAiL): safety and efficacy of first-line bevacizumab (BV)-based therapy in advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2009;27(Suppl.):8043
  25. Fischbach N, Spigel D, Brahmer J, Garst J, Robles R, Chung C, et al. Preliminary safety and effectiveness of bevacizumab (BV) based treatment in subpopulations of patients (pts) with non-small cell lung cancer (NSCLC) from the ARIES study: a bevacizumab (BV) treatment observational cohort study (OCS). J Clin Oncol. 2009;27(Suppl.):8040
  26. Akerley WL, Langer CJ, Oh Y, Strickland DK, Royer SJ, Xia Q, et al. Acceptable safety of bevacizumab therapy in patients with brain metastases due to non-small cell lung cancer. J Clin Oncol. 2008;26(Suppl.):8043
  27. Miller VA, O’Connor 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(Suppl.):8002
  28. Hainsworth J, Herbst R. A phase III multicenter, placebo-controlled, double-blind, randomized clinical trial to evaluate the efficacy of bevacizumab (Avastin®) in combination with erlotinib (Tarceva®) compared with erlotinib alone for treatment of advanced non-small cell lung cancer after failure of standard first-line chemotherapy (BETA). J Thorac Oncol. 2008;3(Suppl. 4):S302
  29. Dempke WCM, Heinemann V. Resistance to EGF-R (erbB-1) and VEGF-R modulating agents. Eur J Cancer. 2009;45:1117–1128
  30. Guix M, Faber RC, Wang SE, Olivares MG, Song Y, Qu S, et al. Acquired resistance to EGFR-tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest. 2008;118:2609–2619
  31. Hewish M, Chau I, Cunningham D. Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine. Recent Pat Anticancer Drug Discov. 2009;4:54–72
  32. Haluska P, Shaw HM, Batzel GN, Yin D, Molina JR, Molife LR, et al. Phase I dose escalation trial of the anti insulin-like growth factor-I receptor monoclonal antibody CP-751,871 in patients with refractory solid tumors. Clin Cancer Res. 2007;13:5834–5840
  33. Lacy MQ, Alsina M, Fonseca R, Paccagnella ML, Melvin CL, Yin D, et al. Phase I, pharmacokinetic and pharmacodynamic study of the anti-insulin like growth factor type 1 receptor monoclonal antibody CP-751,871 in patients with multiple myeloma. J Clin Oncol. 2008;26:3196–3202
  34. Karp DD, Paz-Ares LG, Novello S, Haluska P, Garland L, Cardenal F, et al. Phase II study of the anti-insulin-like growth factor type 1 receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer. J Clin Oncol. 2009;27:2515–2522
  35. Han JY, Choi BG, Choi JY, Lee SY, Ju SY. The prognostic significance of pretreatment plasma levels of insulin-like growth factor (IGF)-1, IGF-2, and IGF binding protein-3 in patients with advanced non-small cell lung cancer. Lung Cancer. 2006;54:227–234
  36. Sequist LV, Martins RG, Spigel D, Grunberg SM, Spira A, Jänne PA, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol. 2008;26:2442–2449
  37. Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinoma with acquired resistance to kinase inhibitors. Clin Cancer Res. 2006;12:6494–6501
  38. Fukui T, Mitsudomi T. Mutations in the epidermal growth factor receptor gene and effects of EGFR-tyrosine kinase inhibitors on lung cancer. Gen Thorac Cardiovasc Surg. 2008;56:97–103
  39. Kosaka T, Yatabe Y, Endoh H, Yoshida K, Hida T, Tsuboi M, et al. Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Clin Cancer Res. 2006;12:5764–5769
  40. Fukuoda M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, et al. Multi-Institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol. 2003;21:2237–2246
  41. Bailey R, Janas M. Getting the grips with gefitinib. Lancet Oncol. 2003;4:719–720
  42. Natale RB. Quantitative gene expression in non-small cell lung cancer from paraffin-embedded tissue specimen: predicting response to gefitinib, an EGFR kinase inhibitor. Lung Cancer. 2003;41(Suppl. 2):S71–S72
  43. Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–1500
  44. Sequist LV, Bell DW, Lynch TJ, Haber DA. Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol. 2007;25:587–595
  45. Herbst R, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol. 2004;22:785–794
  46. Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survial Evaluation in Lung Cancer). Lancet. 2005;366:1527–1537
  47. Chang A, Parikh P, Thongprasert S, Tan EH, Perng RP, Ganzon D, et al. Gefitinib (IRESSA) in patients of Asian origin with refractory advanced non-small cell lung cancer: subset analysis from the ISEL trial. J Thorac Oncol. 2006;1:847–855
  48. Mitsudomi T, Kosaka T, Yatebe Y. Biological and clinical implications of EGFR mutations in lung cancer. Int J Clin Oncol. 2006;11:190–198
  49. Cufer T, Vrdoljak E, Gaafar R, Erensoy I, Pemberton K. Phase II, open-label, randomized study (SIGN) of single-agent gefitinib (IRESSA) or docetaxel as second-line therapy in patients with advanced (stage IIIb or IV) non-small-cell lung cancer. Anticaner Drugs. 2006;17:401–409
  50. Maruyama R, Nishiwak Y, Tamura T, Yamamoto N, Tsuboi M, Nakagawa K, et al. Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J Clin Oncol. 2008;26:4244–4252
  51. Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008;372:1809–1818
  52. Inoue A, Kobayashi K, Usui K, Maemondo M, Okinaga S, Mikami I, et al. First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. J Clin Oncol. 2009;27:1394–1400
  53. Mok T, Wu YP, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:1018–1020
  54. Fukuoka M, Wu YP, Thongprasert S, Yang D, Chu N, Saijo C, et al. Biomarker analyses from a phase III, randomized, open-label, first-line study of gefitinib (G) versus carboplatin/paclitaxel (C/P) in clinically selected patients (pts) with advanced non-small cell lung cancer (NSCLC) in Asia (IPASS). J Clin Oncol. 2009;27(Suppl.):15
  55. Kobayashi K, Inoue A, Maemondo M, Sugawara S, Isobe H, Oizumi S, et al. First-line gefitinib versus first-line chemotherapy by carboplatin (CBDCA) plus paclitaxel (TXL) in non-small cell lung cancer (NSCLC) patients with EGFR mutations: a phase III study (002) by North east Japan Gefitinib Study Group. J Clin Oncol. 2009;27(Suppl.):15s
  56. Pérez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D, et al. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol. 2004;22:3238–3247
  57. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123–132
  58. Bezjak A, Tu D, Seymour L, Clark G, Trajkovic A, Zukin M, et al. Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol. 2006;24:3831–3837
  59. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960–1966
  60. Reck M, Mali P, Arrieta O, von Pawels J. Global efficacy and safety results from the TRUST study of erlotinib monotherapy in >7000 patients (pts) with non-small cell lung cancer (NSCLC). ESMO. 2008;262P
  61. Clark GM, Cameron T, Das-Gupta A. Clinical benefit of erlotinib in male smokers with squamous-cell carcinoma. J Clin Oncol. 2006;24(Suppl.):7166
  62. Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, et al. Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res. 2006;12:2166–2171
  63. Zhu CQ, da Cunha Santos G, Ding K, Sakurada A, Cutz JC, Liu N, et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol. 2008;26:4268–4275
  64. Rosell R, Moran T, Queralt T, Porta R, Cardenal F, Camps C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361:958–967
  65. Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczesna A, Juhasz E, et al. SATURN: a double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. J Clin Oncol. 2009;27(Suppl.):8001
  66. Brugger W, Triller N, Blasinska-Morawiec M, Curescu S, Sakalauskas R, Manikhas G, et al. Biomarker analyses from the phase III placebo-controlled SATURN study of maintenance erlotinib following first-line chemotherapy for advanced NSCLC. J Clin Oncol. 2009;27(Suppl.):8020
  67. Brugger W, Kim JH, Hansen O, Triller N. Molecular markers and clinical outcome with erlotinib: results from the phase III placebo-controlled SATURN study of maintenance therapy for advanced NSCLC. WCLC. 2009;B9.1
  68. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359:1367–1380
  69. Minkovsky N, Berezov A. BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors. Curr Opin Investig Drugs. 2008;9:1336–1346
  70. Eskens FA, Mom CH, Planting AST, Gietema JA, Amelsberg A, Huisman H, et al. A phase I dose escalation study of BIBW 29992, an irreversible dual inhibitor of epidermal growth factor receptor I (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours. Br J Cancer. 2008;98:80–85
  71. Yang C, Hirsh V, Cadranel J, Chen Y, Park K, Kim S, et al. Phase IIb/III double-blind randomized trial of BIBW 2992, an irreversible, dual inhibitor of EGFR and HER2 plus best supportive care (BSC) versus placebo plus BSC in patients with NSCLC failing 1–2 lines of chemotherapy (CT) and erlotinib or gefitinib (LUX-Lung 1): a preliminary report. J Clin Oncol. 2009;27(Suppl.):422s
  72. http://www.boehringer-ingelheim.com
  73. Eder JP, Woude FV, Boerner SC, Boerner SA, LoRusso PM. Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res. 2009;15:2207–2214
  74. Puri N, Salgia R. Synergism of EGFR and c-Met pathways, cross-talk and inhibition, in non-small cell lung cancer. J Carcinogenesis. 2008;7:1–8
  75. Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, et al. MET amplification occurs with or without T790M mutation in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. PNAS. 2007;52:20932–20937
  76. Kim ES, Salgia R. Met pathway as a therapeutic target. J Thorac Oncol. 2009;4:444–447
  77. Kwak EL, Camidge DR, Clark J, Shapiro GI, Maki RG, Ratain MJ, et al. Clinical activity observed in a phase 1 dose-escalation trial of an oral MET and ALK inhibitor, PF-02341066. J Clin Oncol. 2009;27(Suppl.):3509
  78. Youssoufian H, Hicklin DJ, Rowinsky EK. Review: monoclonal antibodies to the vascular endothelial growth factor receptor-2 in cancer therapy. Clin Cancer Res. 2007;18(Suppl.):5544s–5548s
  79. Alitalo K, Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell. 2002;3:219–227
  80. Kerbel RS. Tumor angiogenesis. New Engl J Med. 2008;358:2039–2049
  81. 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;65:4389–4400
  82. Laurie SA, Gauthier I, Arnold A, Shepherd FA, Ellis PM, Chen E, et al. 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. 2008;26:1871–1878
  83. Laurie SA, Arnold A, Shepherd FA, Ellis PM, Chen E, Seymour L. Randomizes, double-blind phase II trial of carboplatin+paclitaxel (C+P) with either daily oral cediranib, an inhibitor of vascular endothelial growth factor receptor [VEGFR] tyrosine kinases. Ann Oncol. 2009;19(Suppl. 8):90–91
  84. Wells SA, Gosnell JE, Gagel RF, Moley JF, Pfister DG, Sosa JA, et al. Vandetanib in metastatic hereditary medullary thyroid cancer: follow-up results of an open-label phase II trial. J Clin Oncol. 2007;25(Suppl.):6018
  85. Heymach JV, Johnson BE, Prager D, Csada E, Roubec J, Pesek M, et al. Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer. J Clin Oncol. 2007;25:4270–4277
  86. Herbst RS, Sun Y, Korfee P, Germonpre P, Naijo N, Zhou C, et al. 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. 2009;27(Suppl.):407s
  87. De Boer R, Arrieta O, Gottfired M, Blackhall FH, Raats J, Yang CH, et al. 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. 2009;27(Suppl.):8010
  88. Natale RB, Thongprasert S, Greco FA, Thomas M, Tsai CM, Sunpawerawong P, et al. 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. 2009;27(Suppl.):8009
  89. Shibuya K, Komaki R, Shintani T, Itasaka S, Ryan A, Jürgensmeier JM, et al. Targeted therapy against VEGFR and EGFR with ZD6474 enhances the therapeutic efficacy of irradiation in an orthotopic model of human non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2007;69:1534–1543
  90. Pennell PA, Lynch TJ. Combined inhibition of the VEGFR and the EGFR signalling pathways in treatment of the NSCLC. Oncologist. 2009;14:399–411
  91. Bahleda R, Felip E, Herbst RS, Hanna NH, Laurie SA, Shepherd SA, et al. Phase I multicenter trial of BMS-690514: safety, pharmacokinetic profile, biological effects, and early clinical evaluation in patients with advanced solid tumors and non-small cell lung cancer. J Clin Oncol. 2008;26(Suppl.):2564
  92. Bahleda R, Soria J, Harbison C, Park J, Felip E, Hanna N, et al. Tumor regression and pharmacodynamic (PD) biomarker validation in non-small cell lung cancer (NSCLC) patients treated with the ErbB/VEGFR inhibitor BMS-690514. J Clin Oncol. 2009;27(Suppl.):431s
  93. 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;68:4774–4782
  94. Camidge R, Conkling P, Stephenson JJ, Glassman PM, Zhao Y, Kaiser R, et al. Pharmacokinetic (PK) analysis of a phase I study of continuous oral treatment with the angiokinase inhibitor BIBF 1120, in combination with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2008;26(Suppl.):3567
  95. Freiwald M, Liesenfeld K, Bruno R, Hodge L, Stopfer P, Eschbach C, et al. Population pharmacokinetic analysis for BIBF 1120, an angiokinase inhibitor, in patients with advanced non-small-cell lung cancer (NSCLC). J Clin Oncol. 2008;26(Suppl.):14528
  96. Gridelli C, Maione P, Del Gaizo F, Colantuoni G, Guerriero C, Ferrara C, et al. Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer. Oncologist. 2007;12:191–200
  97. Socinski MA. The current status and evolving role of sunitinib in non-small cell lung cancer. J Thorac Oncol. 2008;3(6 Suppl. 2):119–123
  98. Gridelli C, Maione P, Rossi A, Falanga M, Bareschino M, Schettino C, et al. New avenues for second-line treatment of metastatic non-small cell lung cancer. Expert Rev Anticancer Ther. 2009;9:115–124
  99. Socinski MA, Novello S, Brahmer JR, Rosell R, Rosell R, Sanchez JM, et al Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer. J Clin Oncol. 2008;26:650–656
  100. Scagliotti GV, Novello S, Brahmer J, et al. A phase II study of continuous daily sunitinib dosing in patients with previously-treated advanced non-small cell lung cancer (NSCLC). J Thorac Oncol. 2007;2(Suppl. 4):S470
  101. http://www.suntrials.com
  102. Gatzemeier U, Blumenschein G, Fosella F, Simantov R, Elting J, Bigwood D, et al. Phase II trial of single-agent sorafenib in patients with advanced non-small cell lung carcinoma. J Clin Oncol. 2006;24(Suppl. 18):7002
  103. Schiller JH, Flaherty KT, Redlinger M, Binger K, Eun J, Petrenciuc O, et al. Sorafenib combined with carboplatin/paclitaxel for advanced non-small cell lung cancer: a phase I subset analysis. J Clin Oncol. 2006;24(Suppl. 18):7194
  104. Adjei AA, Molina JR, Hillman SL, Luyun RF, Reuter NF, Rowland KM, et al. A front-line window of opportunity phase II study of sorafenib in patients with advanced non-small cell lung cancer: a north central cancer treatment group study. J Clin Oncol. 2007;25(Suppl. 18):7547
  105. Coxon A, Bush T, Saafran D, Kaufman S, Belmontes B, Rex K, et al. Broad antitumor activity in breast cancer xenografts by motesanib, a highly selective, oral inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and KIT receptors. Clin Cancer Res. 2009;15:110–118
  106. Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2009;27:2278–2287
  107. Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour growth. Nature. 2006;441:424–430
  108. Yee KW, Zeng Z, Konopleva M, Verstovsek S, Ravandi F, Ferrajoli A, et al. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res. 2006;12:5165–5173
  109. Chan S, Scheulen ME, Johnston S, Mross K, Cardoso F, Dittrich C, et al. Phase II study with temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol. 2005;23:5314–5322
  110. Gridelli C, Malone P, Rossi A. The potential role of mTOR inhibitors in non-small cell lung cancer. Oncologist. 2008;13:139–147
  111. La Monica S, Galetti M, Alfieri RR, Cavazzoni A, Ardizzoni A, Tiseo M, et al. Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines. Biochem Pharmacol. 2009;78:460–468
  112. Johnson BE, Jackman D, Jänne PA. Rationale for a phase I trial or erlotinib and the mammalian target of rapamycin inhibitor everolimus (RAD001) for patients with relapsed non-small cell lung cancer. Clin Cancer Res. 2007;13(Suppl. 15):4628s–4631s
  113. Milton DT, Riely GJ, Azzoli CG, Gomez JE, Heelan RT, Kris MG, et al. Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer. Cancer. 2007;110:599–605
  114. Khuri FR, Harvey D, Saba NF, Owonikoko TK, Kauh J, Shin DN, et al. Everolimus, an mTOR inhibitor, in combination with docetaxel for recurrent/refractory NSCLC: a phase I study. J Clin Oncol. 2009;27(Suppl.):421s
  115. Soria JC, Shepherd FA, Douillard JY, Wolf J, Giaccone G, Crino L, et al. Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. Ann Oncol. 2009;(published electronically (June 23))
  116. Drummond DC, Noble DO, Guo Z, Scott GK, Benz CC. Clinical development of histone deacetylase inhibitors as anticancer agents. Ann Rev Pharmacol Toxicol. 2005;45:495–528
  117. Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006;6:38–51
  118. Gridelli C, Rossi A, Malone P. The potential role of histone deacetylase inhibitors in the treatment of non-small-cell lung cancer. Crit Rev Oncol Hematol. 2008;68:29–36
  119. Vansteenkiste J, van Cutsem E, Dumez H, Chen C, Ricker JL, Randolph SS, et al. Early phase II trial of oral vorinostat in relapsed or refractory breast, colorectal, or non-small cell lung cancer. Invest New Drugs. 2008;26:483–488
  120. Traynor AM, Dubey S, Eickhoff JC, Kolesar JM, Schell K, Huie MS, et al. Vorinostat (NSC#701852) in patients with relapsed non-small cell lung cancer: a Wisconsin Oncology Network phase II study. J Thorac Oncol. 2009;4:522–526
  121. Ramalingam SS, Maitland M, Frankel P, Argiris AE, Koczywas EM, Gitlitz B, et al. Randomized, double-blind, placebo-controlled phase II study on carboplatin and paclitaxel with or without vorinostat, a histone deacetylase inhibitor (HDAC), for first-line therapy of advanced non-small cell lung cancer (NCI 7863). J Clin Oncol. 2009;27(Suppl.):408s
  122. Alghisi GC, Ruegg C. Vascular integrins in tumor angiogenesis: mediators and therapeutic targets. Endothelium. 2006;13:113–135
  123. Smith J. Cilgengitide (Merck). Curr Opin Investig Drugs. 2003;4:741–745
  124. Nabors LB, Mikkelsen T, Rosenfeld S, Hochberg F, Akella NS, Fisher JD, et al. Phase I and correlative biology study of cilengitide in patients with recurrent glioma. J Clin Oncol. 2007;25:1651–1657
  125. Manegold C, Vansteenkiste J, Cardenal F, Schütte W, Woll P, Ulsperger E, et al. Randomized phase II study of three doses of the integrin inhibitor cilengitide versus docetaxel as second-line treatment for patients with stage IV non-small cell lung cancer (NSCLC). J Clin Oncol. 2009;27(Suppl.):410s
  126. Abdollahi A, Griggs DW, Zieher H, Roth A, Lipson KE, Saffrich R, et al. Inhibition of alpha(v)beta3 integrin survival signaling enhances antiangiogenetic and antitumor effects of radiotherapy. Clin Cancer Res. 2005;11:6270–6279
  127. Albert JM, Cao C, Geng L, Leavitt L, Hallahan DE, Lu B. Integrin alpha v beta antagonist cilengitide enhances efficacy of radiotherapy in endothelial cell and non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2006;65:1536–1543
  128. Roodman GD. Biology of osteoclast activation in cancer. J Clin Oncol. 2001;19:3562–3571
  129. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423:337–342
  130. Nosaka K, Miyamoto T, Sakai T, Mitsuya H, Suda T, Matsuoka M. Mechanism of hypercalcemia in adult T-cell leukemia. Overexpression of receptor activator of nuclear factor κB ligand on adult T cell leukemia cells. Blood. 2002;99:634–640
  131. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymphnode organogenesis. Nature. 1999;397:315–323
  132. Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Gene Dev. 1998;12:1260–1268
  133. Feeley BT, Liu NQ, Conduah AH, Krenek L, Roth K, Dougall WC, et al. Mixed metastatic lung cancer lesions in bone are inhibited by noggin overexpression and Rank:Fc administration. J Bone Miner Res. 2006;21:1571–1580
  134. Tometsko ME, Miller R, Dougall WC. RANK is expressed in human lung tumours and it functional on human lung cancer cells. Cancer Treat Rev. 2006;32(Suppl. 3):S45
  135. Miller R, Jones J, Tometsko M, Dougall WC. RANKL inhibition blocks lung cancer-induced osteolytic lesions and reduces skeletal tumor burden in both RANK-expression and RANK-negative lung cancers. ASBMR. 2007;22:S114
  136. Body JJ, Greipp P, Coleman RE, Facon T, Geurs F, Fermand JP, et al. A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastasis. Cancer. 2003;97:887–892
  137. Fizazi K, Lipton A, Mariette X, Body JJ, Rahim Y, Gralow JR, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol. 2009;27:1564–1571
  138. Davies AM, Lara PN, Mack PC. Incorporating bortezomib into the treatment of lung cancer. Clin Cancer Res. 2007;13(Suppl. 15):s4647–s4651
  139. Fanucchi MP, Fossella FV, Belt R, Natale R, Fidias P, Carbone DP, et al. Randomized phase II study of bortezomib alone and bortezomib in combination with docetaxel in previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2006;24:5025–5033
  140. Davies AM, Chansky K, Lara PN, Gumerlock PH, Crowley J, Albain KS, et al. Bortezomib plus gemcitabine/carboplatin as first-line treatment of advanced non-small cell lung cancer: a phase II Southwest Oncology Group Study (S0339). J Thorac Oncol. 2009;41:87–92
  141. Li T, Ho L, Piperdi B, Elrafei T, Elrafei T, Camacho FJ, et al Phase II study of the proteasome inhibitor bortezomib (PS-341, Velcade®) in chemotherapy-naïve patients with advanced stage no-small cell lung cancer (NSCLC). Lung Cancer. 2009;(published electronically (June 11))
  142. Jackson JR, Patrick DR, Dar MM, Huang PS. Targeted anti-mitotic therapies: can we improve on tubulin agents?. Nat Rev Cancer. 2007;7:107–117
  143. Garland LL, Taylor C, Pilkington DL, Cohen JL, Von Hoff DD. A phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with polo-like kinase-1 interacting properties, in patients with advanced solid tumors. Clin Cancer Res. 2006;12:5182–5189
  144. Rudolph D, Steegmaier M, Hoffmann M, Grauert M, Baum A, Quant J, et al. BI 6727, a polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin Cancer Res. 2009;15:3094–3102
  145. Schöffski P. Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist. 2009;14:559–570
  146. Steegmaier M, Hoffmann M, Baum A, Lénárt P, Petronczki M, Krssák M, et al. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol. 2007;17:316–322
  147. Von Pawel J, Reck M, Digel W, Kortsik C, Thomas M, Frickhofen N, et al. Randomized phase II trial of two dosing schedules of BI 2536, a novel Plk-1 inhibitor, in patients with relapsed advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2008;26(Suppl.):8030
  148. Ashkenazi A, Herbst RS. To kill a tumor cell: the potential of proapoptotic receptor agonists. J Clin Invest. 2008;118:1979–1990
  149. LoRusso P, Hong D, Heath E, Kurzrock R, Wang D, Hsu M, et al. First-in-human study of AMG655, a pro-apoptotic TRAIL receptor-2 agonist, in adult patients with advanced solid tumors. J Clin Oncol. 2007;25(Suppl.):3534
  150. Paz-Ares L, Sanchez-Torres JM, Diaz-Padilla I, Links M, Reguart N, Boyer M, et al. Safety and efficacy of AMG655 in combination with paclitaxel and carboplatin (PC) in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2009;27(Suppl.):19048

PII: S0169-5002(09)00543-1

doi: 10.1016/j.lungcan.2009.10.012

Lung Cancer
Volume 67, Issue 3 , Pages 257-274 , March 2010