Primary and secondary therapeutic strategies for EGF receptor pathway inhibition in non-small-cell lung cancer

Expert Review of Anticancer Therapy

Volumn 10, Issue 10, 2010, Pages 1589-1599

  Batus, Marta ^a   Fidler, Mary Jo ^a   Bonomi, Philip D ^a  

^a RUSH UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

EGFR inhibition; epidermal growth factor receptor; human epidermal growth factor receptor 2; non small cell lung cancer; resistance; targeted therapy; tyrosine kinase inhibitor

Indexed keywords

3 [1 (2,6 DICHLORO 3 FLUOROPHENYL)ETHOXY] 5 [1 (4 PIPERIDINYL) 1H PYRAZOL 4 YL] 2 PYRIDINYLAMINE; ANAPLASTIC LYMPHOMA KINASE; BEVACIZUMAB; CARBOPLATIN; CETUXIMAB; CISPLATIN; CRIZOTINIB; DOCETAXEL; ECHINODERM MICROTUBULE ASSOCIATED PROTEIN LIKE 4; EPIDERMAL GROWTH FACTOR RECEPTOR; ERLOTINIB; GEFITINIB; HYBRID PROTEIN; N [4 (3 CHLORO 4 FLUOROANILINO) 7 (TETRAHYDRO 3 FURYLOXY) 6 QUINAZOLINYL] 4 DIMETHYLAMINO 2 BUTENAMIDE; NAVELBINE; PACLITAXEL; PANITUMUMAB; PEMETREXED; PF 299804; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PLACEBO; PROTEIN TYROSINE KINASE INHIBITOR; SOMATOMEDIN; TAXANE DERIVATIVE; UNCLASSIFIED DRUG; VANDETANIB;

ADD ON THERAPY; CANCER COMBINATION CHEMOTHERAPY; CLINICAL TRIAL; DIARRHEA; DRUG DOSE ESCALATION; DRUG WITHDRAWAL; EPITHELIAL MESENCHYMAL TRANSITION; GENE AMPLIFICATION; HUMAN; IN VITRO STUDY; LUNG NON SMALL CELL CANCER; MUTATION; NAUSEA AND VOMITING; PREDICTION; REVIEW; SIGNAL TRANSDUCTION; SKIN TOXICITY; SOLID TUMOR; STOMATITIS; TREATMENT FAILURE; TREATMENT WITHDRAWAL; VOMITING;

ANTIBODIES, MONOCLONAL; ANTINEOPLASTIC AGENTS; CARCINOMA, NON-SMALL-CELL LUNG; CLINICAL TRIALS AS TOPIC; DRUG RESISTANCE, NEOPLASM; FEMALE; GENE AMPLIFICATION; HUMANS; LUNG NEOPLASMS; MALE; MOLECULAR TARGETED THERAPY; MUTATION; PROGNOSIS; PROTEIN KINASE INHIBITORS; RECEPTOR, EPIDERMAL GROWTH FACTOR; TREATMENT OUTCOME;

EID: 77958067346     PISSN: 14737140     EISSN: 17448328     Source Type: Journal    
DOI: 10.1586/era.10.104     Document Type: Review

References (110)

1. American Cancer Society. Cancer Facts & Figures, 2009. American Cancer Society, Inc., Atlanta, GA, USA (2009).
2. Ramalingam S, Belani C. Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions. Oncologist 13(Suppl. 1), 5-13 (2008).
3. Sandler A, Gray R, Perry MC et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 355(24), 2542-2550 (2006).
4. Avastin® (bevacizumab) (package insert). Genentech Inc., CA, USA (2009).
5. Reck M, von Pawel J, Zatloukal P 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(8), 1227-1234 (2009).
6. No authors listed. Erlotinib (Tarceva) for advanced non-small cell lung cancer. Med. Lett. Drugs Ther. 47(1205), 25-26 (2005).
7. Shepherd FA, Rodrigues PJ, Ciuleanu T et al. Erlotinib in previously treated non-small-cell lung cancer. N. Engl. J. Med. 353(2), 123-132 (2005).
8. Fukuoka M, Yano S, Giaccone G et al. Multi-institutional randomized Phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (the IDEAL 1 trial) [corrected]. J. Clin. Oncol. 21(12), 2237-2246 (2003).
9. Kris MG, Natale RB, Herbst RS et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290(16), 2149-2158 (2003).
10. Thatcher N, Chang A, Parikh P 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 Survival Evaluation in Lung Cancer). Lancet 366(9496), 1527-1537 (2005).
11. Iressa® (gefitinib tablets), package insert. AstraZeneca Pharmaceuticals LP, DE, USA (2005).
12. Kim ES, Hirsh V, Mok T et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised Phase III trial. Lancet 372(9652), 1809-1818 (2008).
13. Maruyama R, Nishiwaki Y, Tamura T 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(26), 4244-4252 (2008).
14. Pirker R, Pereira JR, Szczesna A et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised Phase III trial. Lancet 373(9674), 1525-1531 (2009).
15. Lynch TJ, Patel T, Dreisbach L et al. Overall survival (OS) results from the Phase III trial BMS 099: cetuximab+taxane/carboplatin as 1st-line treatment for advanced NSCLC. J. Thorac. Oncol. 3(11 Suppl. 4), S305 (2008).
16. Giaccone G, Herbst RS, Manegold C et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a Phase III trial - INTACT 1. J. Clin. Oncol. 22(5), 777-784 (2004). (Pubitemid 41103588)
17. Herbst RS, Giaccone G, Schiller JH 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(5), 785-794 (2004). (Pubitemid 41103589)
18. Gatzemeier U, Pluzanska A, Szczesna A et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J. Clin. Oncol. 25(12), 1545-1552 (2007).
19. Herbst RS, Prager D, Hermann R et al. TRIBUTE: a Phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J. Clin. Oncol. 23(25), 5892-5899 (2005).
20. Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361(10), 947-957 (2009).
21. Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat. Rev. Cancer 7(3), 169-181 (2007).
22. Tsao MS, Sakurada A, Cutz JC et al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N. Engl. J. Med. 353(2), 133-144 (2005).
23. Rosell R, Moran T, Queralt C et al. Screening for epidermal growth factor receptor mutations in lung cancer. N. Engl. J. Med. 361(10), 958-967 (2009).
24. Pan Q, Pao W, Ladanyi M. Rapid polymerase chain reaction-based detection of epidermal growth factor receptor gene mutations in lung adenocarcinomas. J. Mol. Diagn. 7(3), 396-403 (2005).
25. Lynch TJ, Bell DW, Sordella R et al. 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 (2004).
26. Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304(5676), 1497-1500 (2004).
27. Inoue A, Suzuki T, Fukuhara T et al. Prospective Phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J. Clin. Oncol. 24(21), 3340-3346 (2006).
28. Wu YL, Zhong WZ, Li LY et al. Epidermal growth factor receptor mutations and their correlation with gefitinib therapy in patients with non-small cell lung cancer: a meta-analysis based on updated individual patient data from six medical centers in mainland China. J. Thorac. Oncol. 2(5), 430-439 (2007).
29. Jackman DM, Miller VA, Cioffredi LA et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin. Cancer Res. 15(16), 5267-5273 (2009).
30. Mitsudomi T, Morita S, Yatabe Y et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised Phase 3 trial. Lancet Oncol. 11(2), 121-128 (2010).
31. Lee JS, Ignacio J, Yu C et al. FAST-ACT: a Phase II randomized double-blind trial of sequential erlotinib and chemotherapy as first-line treatment in patients (pts) with stage IIIB/IV non-small cell lung cancer (NSCLC). J. Clin. Oncol. 26(Suppl.) (2008) (Abstract 8031).
32. Khambata-Ford S, Harbison CT, Hart LL et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a Phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J. Clin. Oncol. 28(6), 918-927 (2010).
33. John T, Liu G, Tsao MS. Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors. Oncogene 28(Suppl. 1), S14-S23 (2009).
34. Hirsch FR, Varella-Garcia M, Bunn PA Jr et al. Molecular predictors of outcome with gefitinib in a Phase III placebo-controlled study in advanced non-small-cell lung cancer. J. Clin. Oncol. 24(31), 5034-5042 (2006).
35. Cappuzzo F, Hirsch FR, Rossi E et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J. Natl Cancer Inst. 97(9), 643-655 (2005). (Pubitemid 40812628)
36. Hirsch FR, Herbst RS, Olsen C et al. Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy. J. Clin. Oncol. 26(20), 3351-3357 (2008).
37. Balak MN, Gong Y, Riely GJ et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin. Cancer Res. 12(21), 6494-6501 (2006).
38. Maheswaran S, Sequist LV, Nagrath S et al. Detection of mutations in EGFR in circulating lung-cancer cells. N. Engl. J. Med. 359(4), 366-377 (2008).
39. Inukai M, Toyooka S, Ito S et al. Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res. 66(16), 7854-7858 (2006).
40. Bean J, Riely GJ, Balak M et al. Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clin. Cancer Res. 14(22), 7519-7525 (2008).
41. Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305(5687), 1163-1167 (2004).
42. Tsao MS, Liu N, Chen JR et al. Differential expression of MET/hepatocyte growth factor receptor in subtypes of non-small cell lung cancers. Lung Cancer 20(1), 1-16 (1998).
43. Ma PC, Jagadeeswaran R, Jagadeesh S et al. Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer. Cancer Res. 65(4), 1479-1488 (2005).
44. Bean J, Brennan C, Shih JY et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc. Natl Acad. Sci. USA 104(52), 20932-20937 (2007).
45. Quinlan MP, Settleman J. Isoform-specific ras functions in development and cancer. Future Oncol. 5(1), 105-116 (2009).
46. Lievre A, Bachet JB, Le CD et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66(8), 3992-3995 (2006).
47. Karapetis CS, Khambata-Ford S, Jonker DJ et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 359(17), 1757-1765 (2008).
48. Miller VA, Zakowski M, Riley GJ et al. EGFR mutation and copy number EGFR protein expression and KRAS mutation as predictors of outcome with erlotinib in bronchioloalveolar cell carcinoma (BAC): results of a prospective Phase II trial. J. Clin. Oncol. 24(Suppl. 18) (2006) (Abstract 7003).
49. Pao W, Wang TY, Riely GJ et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2(1), e17 (2005).
50. Tsao M, Zhu C, Sakurada A et al. An analysis of the prognostic and predictive importance of K-ras mutation status in the National Cancer Institute of Canada Clinical Trials Group BR.21 study of erlotinib versus placebo in the treatment of non-small cell lung cancer. J. Clin. Oncol. 24(Suppl. 18) (2006) (Abstract 7005).
51. Zhu CQ, da Cunha SG, Ding K 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(26), 4268-4275 (2008).
52. Hirsch FR, Dziadziuszko R, Varella-Garcia L et al. Randomized Phase II study of erlotinib (E) or intercalated E with carboplatin/paclitaxel (CP) in chemotherapy-naive advanced NSCLC: correlation of biomarker status and clinical benefit. J. Clin. Oncol. 27(Suppl. 15) (2009) (Abstract 8026).
53. Miller VA, Wakelee HA, Lara PN et al. Activity and tolerance of XL647 in NSCLC patients with acquired resistance to EGFR-TKIs: preliminary results of a Phase II trial. J. Clin. Oncol. 26(Suppl. 15) (2008) (Abstract 8028).
54. O'Byrne KJ, Bondarenko I, Barrios C et al. Molecular and clinical predictors of outcome for cetuximab in non-small cell lung cancer (NSCLC): data from the FLEX study. J. Clin. Oncol. 27(Suppl. 15) (2009) (Abstract 8007).
55. Solomon B, Varella-Garcia M, Camidge DR. ALK gene rearrangements: a new therapeutic target in a molecularly defined subset of non-small cell lung cancer. J. Thorac. Oncol. 4(12), 1450-1454 (2009).
56. Shaw AT, Yeap BY, Mino-Kenudson M et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J. Clin. Oncol. 27(26), 4247-4253 (2009).
57. Tam IY, Chung LP, Suen WS et al. Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features. Clin. Cancer Res. 12(5), 1647-1653 (2006).
58. Camp ER, Summy J, Bauer TW, Liu W, Gallick GE, Ellis LM. Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor. Clin. Cancer Res. 11(1), 397-405 (2005).
59. Chakravarti A, Loeffler JS, Dyson NJ. Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res. 62(1), 200-207 (2002).
60. Jones HE, Gee JM, Taylor KM et al. Development of strategies for the use of anti-growth factor treatments. Endocr. Relat. Cancer 12(Suppl. 1), S173-S182 (2005).
61. Noro R, Gemma A, Miyanaga A et al. PTEN inactivation in lung cancer cells and the effect of its recovery on treatment with epidermal growth factor receptor tyrosine kinase inhibitors. Int. J. Oncol. 31(5), 1157-1163 (2007).
62. Jhawer M, Goel S, Wilson AJ et al. PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res. 68(6), 1953-1961 (2008).
63. Buckingham LE, Coon JS, Morrison LE et al. The prognostic value of chromosome 7 polysomy in non-small cell lung cancer patients treated with gefitinib. J. Thorac. Oncol. 2(5), 414-422 (2007).
64. Cappuzzo F, Varella-Garcia M, Shigematsu H et al. Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients. J. Clin. Oncol. 23(22), 5007-5018 (2005).
65. Viloria-Petit A, Crombet T, Jothy S et al. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res. 61(13), 5090-5101 (2001).
66. Grandal MV, Madshus IH. Epidermal growth factor receptor and cancer: control of oncogenic signalling by endocytosis. J. Cell. Mol. Med. 12(5A), 1527-1534 (2008).
67. TYKERB® (lapatinib) tablets, package insert. GlaxoSmithKline, NC, USA (2008).
68. Smylie M, Blumenschein G, Dowlati A et al. A Phase II multicenter trial comparing two schedules of lapatinib (LAP) as first or second line monotherapy in subjects with advanced or metastatic non-small cell lung cancer (NSCLC) with either bronchioloalveolar carcinoma (BAC) or no smoking history. J. Clin. Oncol. 25(Suppl. 18), 412S (2007) (Abstract 7611).
69. Suda K, Onozato R, Yatabe Y, Mitsudomi T. EGFR T790M mutation: a double role in lung cancer cell survival? J. Thorac. Oncol. 4(1), 1-4 (2009).
70. Riely GJ. Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. J. Thorac. Oncol. 3(6 Suppl. 2), S146-S149 (2008).
71. Li D, Ambrogio L, Shimamura T et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27(34), 4702-4711 (2008).
72. Kwak EL, Sordella R, Bell DW et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc. Natl Acad. Sci. USA 102(21), 7665-7670 (2005).
73. Eskens FA, Mom CH, Planting AS et al. 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 (2008).
74. Shaw H, Plummer R, Vidal L et al. A Phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in patients with advanced solid tumours. J. Clin. Oncol. 24(Suppl.) (2006) (Abstract 3027).
75. Yang C-H, Shih J-Y, Su W-C et al. BIBW 2992, a novel irreversible EGFR/HER2 tyrosine kinase inhibitor, in chemonaive patients with adenocarcinoma of the lung and activating EGFR mutations (LUX-Lung 2). Presented at: 13th World Conference on Lung Cancer of the International Association for the Study of Lung Cancer. San Francisco, CA, USA, 31 July-4 August 2009.
76. Engelman JA, Zejnullahu K, Gale CM et al. 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 (2007).
77. Janne PA, Reckamp K, Koczywas M et al. A Phase 2 trial of PF-00299804 (PF299), an oral irreversible HER tyrosine kinase inhibitor (TKI), in patients (pts) with advanced NSCLC after failure of prior chemotherapy and erlotinib: preliminary efficacy and safety results. J. Thorac. Oncol. 4(9 Suppl. 1), S293-S294 (2009) (Abstract A3.1).
78. Tabernero J. The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents. Mol. Cancer Res. 5(3), 203-220 (2007).
79. Natale RB, Thongprasert S, Greco FA 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. 15), 409S (2009) (Abstract 8009).
80. Herbst RS, Sun Y, Korfee S 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.), 807S (2009) (Abstract CRA8003).
81. De Boer R, Arrieta O, Gottfried M 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.), 409S (2009) (Abstract 8010).
82. 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). Proceedings of: 2008 Chicago Multidisciplinary Symposium in Thoracic Oncology. Chicago, IL, USA, 13-15 November 2008 (Abstract 189).
83. Auberger J, Loeffler-Ragg J, Wurzer W, Hilbe W. Targeted therapies in non-small cell lung cancer: proven concepts and unfulfilled promises. Curr. Cancer Drug Targets 6(4), 271-294 (2006).
84. Ramalingam S, Belani CP. Recent advances in targeted therapy for non-small cell lung cancer. Expert Opin. Ther. Targets 11(2), 245-257 (2007).
85. Haber DA, Bell DW, Sordella R et al. Molecular targeted therapy of lung cancer: EGFR mutations and response to EGFR inhibitors. Cold Spring Harb. Symp. Quant. Biol. 70, 419-426 (2005).
86. Fidler MJ, Argiris A, Patel JD et al. The potential predictive value of cyclooxygenase-2 expression and increased risk of gastrointestinal hemorrhage in advanced non-small cell lung cancer patients treated with erlotinib and celecoxib. Clin. Cancer Res. 14(7), 2088-2094 (2008).
87. Engelman JA, Zejnullahu K, Mitsudomi T et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316(5827), 1039-1043 (2007).
88. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Non-small cell lung cancer. V.2.2010 www.nccn.org/ professionals/physician-gls/PDF/nscl.pdf
89. Langer CJ, Demmy TL, Ettinger DS. NCCN clinical practice guidelines in oncology symposium: non-small cell lung cancer www.medscape.com/viewprogram/8178
90. Genentech Inc. FDA approves Tarceva as a maintenance therapy for advanced non-small cell lung cancer www.gene.com/gene/news/press-releases/display.do? method=detail&id=12727
91. Roche. Roche announces filing of Tarceva in EU as first-line maintenance therapy in advanced non-small cell lung cancer. 19 March 2009 www.roche.com/investors/ir-update/inv-update-2009-2003-19.htm
92. AstraZeneca. IRESSA (Gefitinib) receives marketing authorisation for the treatment of non-small cell lung cancer in Europe www.astrazeneca.com/media/ latest-press-releases/iressa-eu-approval?itemId=6346156
93. Merck KGaA. News Release. November 19, 2009. CHMP Opinion for Erbitux in Advanced Non-Small Cell Lung Cancer http://news.merck. de/N/0/ 95F233DCB18F57F1C125767300 3661FC/$File/CHMP-neg-En.pdf
94. BIBW 2992 and BSC versus placebo and bsc in non-small cell lung cancer patients failing erlotinib or gefitinib (LUX-LUNG 1) http://clinicaltrials.gov/ ct2/show/NCT00656136
95. BIBW 2992 versus chemotherapy as first line treatment in NSCLC with EGFR mutation http://clinicaltrials.gov/ct2/show/NCT00949650
96. PF-00299804 in treating patients with stage IIIB or stage IV non-small cell lung cancer that has not responded to standard therapy for advanced or metastatic cancer http://clinicaltrials.gov/ct2/show/NCT01000025
97. AstraZeneca Annual Report 2009. Therapy area review: oncology: cancer www.astrazeneca-annualreports. com/2009/directors-report/therapy-area- review/oncology/index.html
98. Carboplatin and paclitaxel with or without bevacizumab and/or cetuximab in treating patients with stage iv or recurrent non-small cell lung cancer http://clinicaltrials.gov/ct2/show/NCT00946712
99. Horner MJ, Ries LAG, Krapcho M et al. SEER Cancer Statistics Review, 1975- 2006, National Cancer Institute. Bethesda, MD, based on November 2008 SEER data submission, posted to the SEER website (2009) http://seer.cancer.gov/csr/ 1975-2006/
100. A study of ARQ 197 in combination with erlotinib http://clinicaltrials. gov/ct2/show/NCT01069757
101. A randomized Phase 2 study of erlotinib + ARQ 197 versus erlotinib + placebo in previously treated patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) http://clinicaltrials.gov/ct2/show/ NCT00777309
102. A study of XL184 with or without erlotinib in adults with non-small cell lung cancer http://clinicaltrials.gov/ct2/show/NCT00596648
103. A study of MetMAb administered to patients with advanced non-small cell lung cancer, in combination with tarceva (erlotinib) http://clinicaltrials.gov/ ct2/show/NCT00854308
104. A study of combined C-MET inhibitor and PAN-HER inhibitor (PF-02341066 and PF-00299804) in patients with non-small cell lung cancer http://clinicaltrials.gov/ct2/show/NCT01121575
105. An investigational drug, PF-02341066 is being studied versus standard of care in patients with advanced non-small cell lung cancer with a specific gene profile involving the anaplastic lymphoma kinase (ALK) gene http:// clinicaltrials.gov/ct2/show/NCT00932893
106. Combination study of CP-751,871 with paclitaxel and carboplatin in advanced lung cancer http://clinicaltrials.gov/ct2/show/NCT00147537
107. Phase 1b/2 study of AMG 479 in combination with paclitaxel and carboplatin for 1st line treatment of advanced squamous non-small cell lung cancer http://clinicaltrials.gov/ct2/show/NCT00807612
108. Gemcitabine hydrochloride and carboplatin with or without MK-0646 as first-line therapy in treating patients with stage IIIB or stage IV non-small cell lung cancer http://clinicaltrials.gov/ct2/show/NCT00951444
109. MK-0646 Insulin Growth Factor 1 Receptor Antibody in Stage IIIb or IV Metastatic Non-Squamous Lung Cancer (IMPACT) http://clinicaltrials.gov/ct2/show/ NCT00799240
110. Carboplatin and paclitaxel combined with cetuximab and/or cixutumumab in treating patients with stage IIIb or stage IV non-small cell lung cancer http://clinicaltrials.gov/ct2/show/NCT00986674