Targeted therapies for non-small cell lung cancer

Lung Cancer

Volumn 67, Issue 3, 2010, Pages 257-274

  Dempke, Wolfram C M ^a   Suto, Tamas ^b   Reck, Martin ^c  

^a LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^b AMGEN INC   (United States)

^c Thoraxklinik Grosshansdorf   (Germany)

Author keywords

Mechanisms of action; New drugs; NSCLC; Targeted therapy; Treatment

Indexed keywords

3 [1 (2,6 DICHLORO 3 FLUOROPHENYL)ETHOXY] 5 [1 (4 PIPERIDINYL) 1H PYRAZOL 4 YL] 2 PYRIDINYLAMINE; BEVACIZUMAB; BIBF 1120; BMS 690514; CARBOPLATIN; CEDIRANIB; CETUXIMAB; CISPLATIN; CYTOKINE RECEPTOR ANTAGONIST; DOCETAXEL; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; ERLOTINIB; FIGITUMUMAB; GEFITINIB; GEMCITABINE; LAPATINIB; N [4 (3 CHLORO 4 FLUOROANILINO) 7 (TETRAHYDRO 3 FURYLOXY) 6 QUINAZOLINYL] 4 DIMETHYLAMINO 2 BUTENAMIDE; NAVELBINE; PACLITAXEL; PANITUMUMAB; PEMETREXED; PLACEBO; PLATINUM COMPLEX; QUINAZOLINE DERIVATIVE; SCATTER FACTOR RECEPTOR INHIBITOR; SOMATOMEDIN C DERIVATIVE; TRASTUZUMAB; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANDETANIB; VASCULOTROPIN INHIBITOR;

ACNE; ADENOCARCINOMA; ADVANCED CANCER; ANOREXIA; ASTHENIA; BLEEDING; BRAIN HEMORRHAGE; BRAIN METASTASIS; CLINICAL TRIAL; COLORECTAL CANCER; COUGHING; DEHYDRATION; DIARRHEA; DOSE RESPONSE; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG DOSE REDUCTION; DRUG HALF LIFE; DRUG STRUCTURE; DRUG WITHDRAWAL; DYSPNEA; FATIGUE; FEBRILE NEUTROPENIA; GASTROINTESTINAL SYMPTOM; HAND FOOT SYNDROME; HEADACHE; HUMAN; HYPERGLYCEMIA; HYPERTENSION; HYPONATREMIA; LUNG CANCER; LUNG HEMORRHAGE; LUNG NON SMALL CELL CANCER; METASTASIS; MOLECULAR THERAPY; MULTIPLE CYCLE TREATMENT; NAUSEA; NEUTROPENIA; PATIENT CARE; PATIENT SELECTION; PRIORITY JOURNAL; PROTEINURIA; RASH; RECOMMENDED DRUG DOSE; REVIEW; SIDE EFFECT; SINGLE DRUG DOSE; SQUAMOUS CELL CARCINOMA; THORAX PAIN; THROMBOCYTOPENIA; TREATMENT OUTCOME; VOMITING;

ANTINEOPLASTIC AGENTS; CARCINOMA, NON-SMALL-CELL LUNG; FEMALE; HUMANS; INDIVIDUALIZED MEDICINE; LUNG NEOPLASMS; MALE; RECEPTOR, EPIDERMAL GROWTH FACTOR; RECEPTORS, VASCULAR ENDOTHELIAL GROWTH FACTOR;

EID: 75749097259     PISSN: 01695002     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.lungcan.2009.10.012     Document Type: Review

References (150)

1. Ramalingam S., and Belani C. Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions. Oncologist 15 (2008) 5-13
2. Shepherd F.A. Second-line chemotherapy for non-small cell lung cancer. Expert Rev Anticancer Ther 3 (2003) 435-442
3. Pfister D.G., Johnson D.H., Azzoli C.G., Sause W., Smith T.J., Baker S., et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 21 (2003) 330-353
4. Schiller J.H., Harrington D., Belani C.P., Langer C., Sandler A., Krook J., et al. Comparison of four chemotherapy regimes for advanced non-small cell lung cancer. N Engl J Med 346 (2002) 92-98
5. Soon Y.Y., Stockler M.R., Askie L.M., and Boyer M.J. Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol 27 (2009) 3277-3283
6. Rudd R.M., Gower N.H., Spiro S.G., Eisen J.M., Harper P.G., Littler J.A., 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 23 (2005) 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 41 (2005) 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 311 (1995) 899-909
9. Clynes R.A., Towers T.L., Presta L.G., and Ravetch J.V. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med 6 (2000) 443-446
10. Van Cutsem E., Köhne C.H., Hitre E., Zaluski J., Chang Chien C.R., Makhason A., et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360 (2009) 1408-1417
11. Gridelli C., Maione P., Luciana M., and Rossi A. Cetuximab and other anti-epidermal growth factor receptor monoclonal antibodies in the treatment of non-small cell lung cancer. Oncologist 14 (2009) 601-611
12. Rosell R., Robinet G., Szczesna A., Ramlau R., Constenla M., Mennecier B.C., 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 19 (2008) 362-369
13. Pirker R., Pereira J.R., 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 373 (2009) 1525-1531
14. ®) 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 2 8 Suppl. 4 (2007) 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 T.J., Blumenschein G.R., Engelman J.A., Espindoza-Delgado I., Govindan R., Hanke J., et al. Summary statement novel agents in the treatment of lung cancer. J Thorac Oncol 6 6 Suppl. 2 (2008) 107-112
17. Katzel J.A., Fanucchi M.P., and Li Z. Recent advances of novel targeted therapy in non-small cell lung cancer. J Hema Oncol 2 (2009) 2-20
18. Johnson D.H., Fehrenbacher L., Novotny W.F., Herbst R.S., Nemunaitis J.J., Jablons D.M., 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 22 (2004) 2184-2191
19. Sandler A., Gray R., Perry M.C., Brahmer J., Schiller J.H., Dowlati A., et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355 (2006) 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 27 (2009) 1227-1234
21. Brahmer J.R., Gray R., Schiller J.H., and Hann C.L. ECOG 4599 phase III trial of carboplatin and paclitaxel ± bevacizumab: subset analysis of survival by gender. J Clin Oncol 24 Suppl. (2006) 7036
22. Eberhardt W., Reck M., von Pawel J., and 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 5 Suppl. (2007) 362
23. Ramalingam S.S., Dahlberg S.E., Langer C.J., Gray R., Belani C.P., Brahmer J.R., 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 26 (2008) 60-65
24. Crinò L., Mezger J., Griesinger F., Zhou C., and 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 27 Suppl. (2009) 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 27 Suppl. (2009) 8040
26. Akerley W.L., Langer C.J., Oh Y., Strickland D.K., Royer S.J., Xia Q., et al. Acceptable safety of bevacizumab therapy in patients with brain metastases due to non-small cell lung cancer. J Clin Oncol 26 Suppl. (2008) 8043
27. Miller V.A., O'Connor P., Soh C., and 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 27 Suppl. (2009) 8002
28. ®) compared with erlotinib alone for treatment of advanced non-small cell lung cancer after failure of standard first-line chemotherapy (BETA). J Thorac Oncol 3 Suppl. 4 (2008) S302
29. Dempke W.C.M., and Heinemann V. Resistance to EGF-R (erbB-1) and VEGF-R modulating agents. Eur J Cancer 45 (2009) 1117-1128
30. Guix M., Faber R.C., Wang S.E., Olivares M.G., 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 118 (2008) 2609-2619
31. Hewish M., Chau I., and Cunningham D. Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine. Recent Pat Anticancer Drug Discov 4 (2009) 54-72
32. Haluska P., Shaw H.M., Batzel G.N., Yin D., Molina J.R., Molife L.R., 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 13 (2007) 5834-5840
33. Lacy M.Q., Alsina M., Fonseca R., Paccagnella M.L., Melvin C.L., 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 26 (2008) 3196-3202
34. Karp D.D., Paz-Ares L.G., 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 27 (2009) 2515-2522
35. Han J.Y., Choi B.G., Choi J.Y., Lee S.Y., and Ju S.Y. 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 54 (2006) 227-234
36. Sequist L.V., Martins R.G., Spigel D., Grunberg S.M., Spira A., Jänne P.A., et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 26 (2008) 2442-2449
37. Balak M.N., Gong Y., Riely G.J., Somwar R., Li A.R., Zakowski M.F., 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 12 (2006) 6494-6501
38. Fukui T., and Mitsudomi T. Mutations in the epidermal growth factor receptor gene and effects of EGFR-tyrosine kinase inhibitors on lung cancer. Gen Thorac Cardiovasc Surg 56 (2008) 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 12 (2006) 5764-5769
40. Fukuoda M., Yano S., Giaccone G., Tamura T., Nakagawa K., Douillard J.Y., et al. Multi-Institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21 (2003) 2237-2246
41. Bailey R., and Janas M. Getting the grips with gefitinib. Lancet Oncol 4 (2003) 719-720
42. Natale R.B. Quantitative gene expression in non-small cell lung cancer from paraffin-embedded tissue specimen: predicting response to gefitinib, an EGFR kinase inhibitor. Lung Cancer 41 Suppl. 2 (2003) S71-S72
43. Paez J.G., Jänne P.A., Lee J.C., Tracy S., Greulich H., Gabriel S., et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304 (2004) 1497-1500
44. Sequist L.V., Bell D.W., Lynch T.J., and Haber D.A. Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol 25 (2007) 587-595
45. Herbst R., Giaccone G., Schiller J.H., Natale R.B., 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 22 (2004) 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 366 (2005) 1527-1537
47. Chang A., Parikh P., Thongprasert S., Tan E.H., Perng R.P., 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 1 (2006) 847-855
48. Mitsudomi T., Kosaka T., and Yatebe Y. Biological and clinical implications of EGFR mutations in lung cancer. Int J Clin Oncol 11 (2006) 190-198
49. Cufer T., Vrdoljak E., Gaafar R., Erensoy I., and 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 17 (2006) 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 26 (2008) 4244-4252
51. Kim E.S., Hirsh V., Mok T., Socinski M.A., Gervais R., Wu Y.L., et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 372 (2008) 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 27 (2009) 1394-1400
53. Mok T., Wu Y.P., Thongprasert S., Yang C.H., Chu D.T., Saijo N., et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361 (2009) 1018-1020
54. Fukuoka M., Wu Y.P., 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 27 Suppl. (2009) 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 27 Suppl. (2009) 15s
56. Pérez-Soler R., Chachoua A., Hammond L.A., Rowinsky E.K., 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 22 (2004) 3238-3247
57. Shepherd F.A., Rodrigues Pereira J., Ciuleanu T., Tan E.H., Hirsh V., Thongprasert S., et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353 (2005) 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 24 (2006) 3831-3837
59. Moore M.J., Goldstein D., Hamm J., Figer A., Hecht J.R., 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 25 (2007) 1960-1966
60. Reck M., Mali P., Arrieta O., and 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 G.M., Cameron T., and Das-Gupta A. Clinical benefit of erlotinib in male smokers with squamous-cell carcinoma. J Clin Oncol 24 Suppl. (2006) 7166
62. Hamilton M., Wolf J.L., Rusk J., Beard S.E., Clark G.M., Witt K., et al. Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res 12 (2006) 2166-2171
63. Zhu C.Q., da Cunha Santos G., Ding K., Sakurada A., Cutz J.C., 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 26 (2008) 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 361 (2009) 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 27 Suppl. (2009) 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 27 Suppl. (2009) 8020
67. Brugger W., Kim J.H., Hansen O., and 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 R.S., Heymach J.V., and Lippman S.M. Lung cancer. N Engl J Med 359 (2008) 1367-1380
69. Minkovsky N., and Berezov A. BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors. Curr Opin Investig Drugs 9 (2008) 1336-1346
70. Eskens F.A., Mom C.H., Planting A.S.T., Gietema J.A., 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 98 (2008) 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 27 Suppl. (2009) 422s
72. http://www.boehringer-ingelheim.com
73. Eder J.P., Woude F.V., Boerner S.C., Boerner S.A., and LoRusso P.M. Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res 15 (2009) 2207-2214
74. Puri N., and Salgia R. Synergism of EGFR and c-Met pathways, cross-talk and inhibition, in non-small cell lung cancer. J Carcinogenesis 7 (2008) 1-8
75. Bean J., Brennan C., Shih J.Y., 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 52 (2007) 20932-20937
76. Kim E.S., and Salgia R. Met pathway as a therapeutic target. J Thorac Oncol 4 (2009) 444-447
77. Kwak E.L., Camidge D.R., Clark J., Shapiro G.I., Maki R.G., Ratain M.J., et al. Clinical activity observed in a phase 1 dose-escalation trial of an oral MET and ALK inhibitor, PF-02341066. J Clin Oncol 27 Suppl. (2009) 3509
78. Youssoufian H., Hicklin D.J., and Rowinsky E.K. Review: monoclonal antibodies to the vascular endothelial growth factor receptor-2 in cancer therapy. Clin Cancer Res 18 Suppl. (2007) 5544s-5548s
79. Alitalo K., and Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 3 (2002) 219-227
80. Kerbel R.S. Tumor angiogenesis. New Engl J Med 358 (2008) 2039-2049
81. Wedge S.R., Kendrew J., Hennequin L.F., Valentine P.J., Barry S.T., Brave S.R., et al. AZD2171. A highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65 (2005) 4389-4400
82. Laurie S.A., Gauthier I., Arnold A., Shepherd F.A., Ellis P.M., 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 26 (2008) 1871-1878
83. Laurie S.A., Arnold A., Shepherd F.A., Ellis P.M., Chen E., and 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 19 Suppl. 8 (2009) 90-91
84. Wells S.A., Gosnell J.E., Gagel R.F., Moley J.F., Pfister D.G., Sosa J.A., et al. Vandetanib in metastatic hereditary medullary thyroid cancer: follow-up results of an open-label phase II trial. J Clin Oncol 25 Suppl. (2007) 6018
85. Heymach J.V., Johnson B.E., 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 25 (2007) 4270-4277
86. Herbst R.S., 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 27 Suppl. (2009) 407s
87. De Boer R., Arrieta O., Gottfired M., Blackhall F.H., Raats J., Yang C.H., 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 27 Suppl. (2009) 8010
88. Natale R.B., Thongprasert S., Greco F.A., Thomas M., Tsai C.M., 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 27 Suppl. (2009) 8009
89. Shibuya K., Komaki R., Shintani T., Itasaka S., Ryan A., Jürgensmeier J.M., 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 69 (2007) 1534-1543
90. Pennell P.A., and Lynch T.J. Combined inhibition of the VEGFR and the EGFR signalling pathways in treatment of the NSCLC. Oncologist 14 (2009) 399-411
91. Bahleda R., Felip E., Herbst R.S., Hanna N.H., Laurie S.A., Shepherd S.A., 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 26 Suppl. (2008) 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 27 Suppl. (2009) 431s
93. Hilberg F., Roth G.J., 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 68 (2008) 4774-4782
94. Camidge R., Conkling P., Stephenson J.J., Glassman P.M., 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 26 Suppl. (2008) 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 26 Suppl. (2008) 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 12 (2007) 191-200
97. Socinski M.A. The current status and evolving role of sunitinib in non-small cell lung cancer. J Thorac Oncol 3 6 Suppl. 2 (2008) 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 9 (2009) 115-124
99. Socinski M.A., Novello S., Brahmer J.R., Rosell R., Rosell R., Sanchez J.M., Belani C.P., et al. Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer. J Clin Oncol 26 (2008) 650-656
100. Scagliotti G.V., 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 2 Suppl. 4 (2007) 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 24 Suppl. 18 (2006) 7002
103. Schiller J.H., Flaherty K.T., 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 24 Suppl. 18 (2006) 7194
104. Adjei A.A., Molina J.R., Hillman S.L., Luyun R.F., Reuter N.F., Rowland K.M., 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 25 Suppl. 18 (2007) 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 15 (2009) 110-118
106. Meric-Bernstam F., and Gonzalez-Angulo A.M. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 27 (2009) 2278-2287
107. Shaw R.J., and Cantley L.C. Ras, PI(3)K and mTOR signalling controls tumour growth. Nature 441 (2006) 424-430
108. Yee K.W., 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 12 (2006) 5165-5173
109. Chan S., Scheulen M.E., 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 23 (2005) 5314-5322
110. Gridelli C., Malone P., and Rossi A. The potential role of mTOR inhibitors in non-small cell lung cancer. Oncologist 13 (2008) 139-147
111. La Monica S., Galetti M., Alfieri R.R., Cavazzoni A., Ardizzoni A., Tiseo M., et al. Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines. Biochem Pharmacol 78 (2009) 460-468
112. Johnson B.E., Jackman D., and Jänne P.A. 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 13 Suppl. 15 (2007) 4628s-4631s
113. Milton D.T., Riely G.J., Azzoli C.G., Gomez J.E., Heelan R.T., Kris M.G., et al. Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer. Cancer 110 (2007) 599-605
114. Khuri F.R., Harvey D., Saba N.F., Owonikoko T.K., Kauh J., Shin D.N., et al. Everolimus, an mTOR inhibitor, in combination with docetaxel for recurrent/refractory NSCLC: a phase I study. J Clin Oncol 27 Suppl. (2009) 421s
115. Soria J.C., Shepherd F.A., Douillard J.Y., 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 D.C., Noble D.O., Guo Z., Scott G.K., and Benz C.C. Clinical development of histone deacetylase inhibitors as anticancer agents. Ann Rev Pharmacol Toxicol 45 (2005) 495-528
117. Minucci S., and Pelicci P.G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6 (2006) 38-51
118. Gridelli C., Rossi A., and Malone P. The potential role of histone deacetylase inhibitors in the treatment of non-small-cell lung cancer. Crit Rev Oncol Hematol 68 (2008) 29-36
119. Vansteenkiste J., van Cutsem E., Dumez H., Chen C., Ricker J.L., Randolph S.S., et al. Early phase II trial of oral vorinostat in relapsed or refractory breast, colorectal, or non-small cell lung cancer. Invest New Drugs 26 (2008) 483-488
120. Traynor A.M., Dubey S., Eickhoff J.C., Kolesar J.M., Schell K., Huie M.S., et al. Vorinostat (NSC#701852) in patients with relapsed non-small cell lung cancer: a Wisconsin Oncology Network phase II study. J Thorac Oncol 4 (2009) 522-526
121. Ramalingam S.S., Maitland M., Frankel P., Argiris A.E., Koczywas E.M., 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 27 Suppl. (2009) 408s
122. Alghisi G.C., and Ruegg C. Vascular integrins in tumor angiogenesis: mediators and therapeutic targets. Endothelium 13 (2006) 113-135
123. Smith J. Cilgengitide (Merck). Curr Opin Investig Drugs 4 (2003) 741-745
124. Nabors L.B., Mikkelsen T., Rosenfeld S., Hochberg F., Akella N.S., Fisher J.D., et al. Phase I and correlative biology study of cilengitide in patients with recurrent glioma. J Clin Oncol 25 (2007) 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 27 Suppl. (2009) 410s
126. Abdollahi A., Griggs D.W., Zieher H., Roth A., Lipson K.E., Saffrich R., et al. Inhibition of alpha(v)beta3 integrin survival signaling enhances antiangiogenetic and antitumor effects of radiotherapy. Clin Cancer Res 11 (2005) 6270-6279
127. Albert J.M., Cao C., Geng L., Leavitt L., Hallahan D.E., and 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 65 (2006) 1536-1543
128. Roodman G.D. Biology of osteoclast activation in cancer. J Clin Oncol 19 (2001) 3562-3571
129. Boyle W.J., Simonet W.S., and Lacey D.L. Osteoclast differentiation and activation. Nature 423 (2003) 337-342
130. Nosaka K., Miyamoto T., Sakai T., Mitsuya H., Suda T., and 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 99 (2002) 634-640
131. Kong Y.Y., Yoshida H., Sarosi I., Tan H.L., Timms E., Capparelli C., et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymphnode organogenesis. Nature 397 (1999) 315-323
132. Bucay N., Sarosi I., Dunstan C.R., Morony S., Tarpley J., Capparelli C., et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Gene Dev 12 (1998) 1260-1268
133. Feeley B.T., Liu N.Q., Conduah A.H., Krenek L., Roth K., Dougall W.C., et al. Mixed metastatic lung cancer lesions in bone are inhibited by noggin overexpression and Rank:Fc administration. J Bone Miner Res 21 (2006) 1571-1580
134. Tometsko M.E., Miller R., and Dougall W.C. RANK is expressed in human lung tumours and it functional on human lung cancer cells. Cancer Treat Rev 32 Suppl. 3 (2006) S45
135. Miller R., Jones J., Tometsko M., and Dougall W.C. RANKL inhibition blocks lung cancer-induced osteolytic lesions and reduces skeletal tumor burden in both RANK-expression and RANK-negative lung cancers. ASBMR 22 (2007) S114
136. Body J.J., Greipp P., Coleman R.E., Facon T., Geurs F., Fermand J.P., 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 97 (2003) 887-892
137. Fizazi K., Lipton A., Mariette X., Body J.J., Rahim Y., Gralow J.R., 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 27 (2009) 1564-1571
138. Davies A.M., Lara P.N., and Mack P.C. Incorporating bortezomib into the treatment of lung cancer. Clin Cancer Res 13 Suppl. 15 (2007) s4647-s4651
139. Fanucchi M.P., Fossella F.V., Belt R., Natale R., Fidias P., Carbone D.P., 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 24 (2006) 5025-5033
140. Davies A.M., Chansky K., Lara P.N., Gumerlock P.H., Crowley J., Albain K.S., 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 41 (2009) 87-92
141. ®) in chemotherapy-naïve patients with advanced stage no-small cell lung cancer (NSCLC). Lung Cancer (2009) (published electronically (June 11))
142. Jackson J.R., Patrick D.R., Dar M.M., and Huang P.S. Targeted anti-mitotic therapies: can we improve on tubulin agents?. Nat Rev Cancer 7 (2007) 107-117
143. Garland L.L., Taylor C., Pilkington D.L., Cohen J.L., and Von Hoff D.D. 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 12 (2006) 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 15 (2009) 3094-3102
145. Schöffski P. Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist 14 (2009) 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 17 (2007) 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 26 Suppl. (2008) 8030
148. Ashkenazi A., and Herbst R.S. To kill a tumor cell: the potential of proapoptotic receptor agonists. J Clin Invest 118 (2008) 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 25 Suppl. (2007) 3534
150. Paz-Ares L., Sanchez-Torres J.M., 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 27 Suppl. (2009) 19048