Lung Cancer
Volume 69, Issue 3 , Pages 259-264 , September 2010

Lessons learnt from gefitinib and erlotinib: Key insights into small-molecule EGFR-targeted kinase inhibitors in non-small cell lung cancer

  • Eckart Laack

      Affiliations

    • Ambulantes Krebszentrum Hamburg, Hamburg, Germany
    • Corresponding Author InformationCorresponding author. Tel.: +49 40 889009860; fax: +49 40 889009866.
    • ,
  • Guido Sauter

      Affiliations

    • Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    • ,
  • Carsten Bokemeyer

      Affiliations

    • Department of Oncology, Hematology, and BMT with section Pneumology, Hubertus-Wald-Tumorzentrum, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Received 19 December 2009 ,Revised 7 May 2010 ,Accepted 13 May 2010.

References 

  1. WHO. Revised Global Burden of Disease (GBD) 2002 estimates: incidence, prevalence, mortality, YLL, YLD and DALYs by sex, cause and region, estimates for 2002 as reported in the World Health Report 2004. Geneva: World Health Organisation; 2004.
  2. Navada S, Lai P, Schwartz AG, Kalemkerian GP. Temporal trends in small cell lung cancer: analysis of the national Surveillance Epidemiology and End-Results (SEER) database. J Clin Oncol. 2006;24:384S
  3. Sher T, Dy GK, Adjei AA. Small cell lung cancer. Mayo Clin Proc. 2008;83:355–367
  4. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83:584–594
  5. BTS. Guidelines on the selection of patients with lung cancer for surgery. British Thoracic Society and Society of Cardiothoracic Surgeons of Great Britain and Ireland Working Party. Thorax 2001;56:89–108.
  6. 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. 2004;22:330–353
  7. Lin WC, Chiu CH, Liou JL, Chen YM, Perng RP, Tsai CM. Gefitinib as front-line treatment in Chinese patients with advanced non-small-cell lung cancer. Lung Cancer. 2006;54:193–199
  8. Yang CH, Yu CJ, Shih JY, Tsai MC, Chen KY, Lin ZZ et al. A prospective study assessing tumor response of gefitinib in chemonaive good performance advanced stage nonsmall cell lung cancer (NSCLC) patients with different types of Epidermal Growth Factor Receptor (EGFR) mutations:P3–158. J Thorac Oncol 2007 Aug;2(8 Suppl. 4):S137–852.
  9. Kimura H, Kasahara K, Shibata K, Sone T, Yoshimoto A, Kita T, et al. EGFR mutation of tumor and serum in gefitinib-treated patients with chemotherapy-naive non-small cell lung cancer. J Thorac Oncol. 2006;1:260–267
  10. Niho S, Kubota K, Goto K, Yoh K, Ohmatsu H, Kakinuma R, et al. First-line single agent treatment with gefitinib in patients with advanced non-small-cell lung cancer: a phase II study. J Clin Oncol. 2006;24:64–69
  11. Suzuki R, Hasegawa Y, Baba K, Saka H, Saito H, Taniguchi H, et al. A phase II study of single-agent gefitinib as first-line therapy in patients with stage IV non-small-cell lung cancer. Br J Cancer. 2006;94:1599–1603
  12. Lee DH, Han JY, Lee HG, Lee JJ, Lee EK, Kim HY, et al. Gefitinib as a first-line therapy of advanced or metastatic adenocarcinoma of the lung in never-smokers. Clin Cancer Res. 2005;11:3032–3037
  13. Mok T, Wu Y, Thongprasert S, Yang C, Chu D, Saijo N, et al. Phase III, randomized, open-label, first-line study of gefitinib vs. carboplatin/paclitaxel in clinically selected patients with advanced NSCLC (IPASS). Ann Oncolog. 2008;19:[abstract LBA2]
  14. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92–98
  15. Gettinger S. Targeted therapy in advanced non-small-cell lung cancer. Semin Respir Crit Care Med. 2008;29:291–301
  16. Li D, Shimamura T, Ji H, Chen L, Haringsma HJ, McNamara K, et al. Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy. Cancer Cell. 2007;12:81–93
  17. Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995;19:183–232
  18. Normanno N, Bianco C, Strizzi L, Mancino M, Maiello MR, De Luca A, et al. The ErbB receptors and their ligands in cancer: an overview. Curr Drug Targets. 2005;6:243–257
  19. Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19:3159–3167
  20. Scaltriti M, Baselga J. The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res. 2006;12:5268–5272
  21. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006;7:505–516
  22. Wieduwilt MJ, Moasser MM. The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell Mol Life Sci. 2008;65:1566–1584
  23. Volm M, Rittgen W, Drings P. Prognostic value of ERBB-1, VEGF, cyclin A, FOS, JUN and MYC in patients with squamous cell lung carcinomas. Br J Cancer. 1998;77:663–669
  24. Ohsaki Y, Tanno S, Fujita Y, Toyoshima E, Fujiuchi S, Nishigaki Y, et al. Epidermal growth factor receptor expression correlates with poor prognosis in non-small cell lung cancer patients with p53 overexpression. Oncol Rep. 2000;7:603–607
  25. Garcia de Palazzo IE, Adams GP, Sundareshan P, Wong AJ, Testa JR, Bigner DD, et al. Expression of mutated epidermal growth factor receptor by non-small cell lung carcinomas. Cancer Res. 1993;53:3217–3220
  26. Pedersen MW, Meltorn M, Damstrup L, Poulsen HS. The type III epidermal growth factor receptor mutation. Biological significance and potential target for anti-cancer therapy. Ann Oncol. 2001;12:745–760
  27. Hynes NE, MacDonald G. ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol. 2009;21:177–184
  28. Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist. 2002;7(Suppl. 4):2–8
  29. Hidalgo M, Siu LL, Nemunaitis J, Rizzo J, Hammond LA, Takimoto C, et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol. 2001;19:3267–3279
  30. Blackhall F, Ranson M, Thatcher N. Where next for gefitinib in patients with lung cancer?. Lancet Oncol. 2006;7:499–507
  31. 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
  32. 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 Survival Evaluation in Lung Cancer). Lancet. 2005;366:1527–1537
  33. 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. Journal of Clinical Oncology. 2009;27(Suppl. 15):[abstract 8001]
  34. Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, 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. 2004;22:777–784
  35. Herbst RS, 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
  36. Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F, 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. 2007;25:1545–1552
  37. Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, 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. 2005;23:5892–5899
  38. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–2139
  39. Paez JG, Janne 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
  40. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA. 2004;101:13306–13311
  41. Sequist LV, Lynch TJ. EGFR tyrosine kinase inhibitors in lung cancer: an evolving story. Annu Rev Med. 2008;59:429–442
  42. Rosell R, Provencio M, Domine M, Pradas A, Salazar F, Reguart N, et al. Spanish Lung Adenocarcinoma Trial (SLAT) of customized treatment based on EGFR mutations (mut) and BRCA1 mRNA expression: Ancillary analyses of Abraxas and RAP80 expression. J Clin Oncol. 2008;26:[abstract 8037]
  43. 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
  44. Douillard JY, Shepherd FA, Hirsh V, Mok T, Socinski MA, Gervais R, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol. 2010;28:744–52.
  45. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–957
  46. Giaccone G, Rodriguez JA. EGFR inhibitors: what have we learned from the treatment of lung cancer?. Nat Clin Pract Oncol. 2005;2:554–561
  47. Kim TY, Han SW, Bang YJ. Chasing targets for EGFR tyrosine kinase inhibitors in non-small-cell lung cancer: Asian perspectives. Expert Rev Mol Diagn. 2007;7:821–836
  48. 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
  49. Sequist LV, Martins RG, Spigel D, Grunberg SM, Spira A, Janne 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
  50. Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med. 2008;359:366–377
  51. Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, 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. 2007;104:20932–20937
  52. Guix M, Faber AC, 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
  53. Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005;2:e17
  54. Eberhard DA, Johnson BE, Amler LC, Goddard AD, Heldens SL, Herbst RS, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005;23:5900–5909
  55. Massarelli E, Varella-Garcia M, Tang X, Xavier AC, Ozburn NC, Liu DD, et al. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin Cancer Res. 2007;13:2890–2896
  56. Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA. 2008;105:2070–2075
  57. Wong KK. Searching for a magic bullet in NSCLC: the role of epidermal growth factor receptor mutations and tyrosine kinase inhibitors. Lung Cancer. 2008;60(Suppl. 2):S10–S18
  58. Greulich H, Chen TH, Feng W, Janne PA, Alvarez JV, Zappaterra M, et al. Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med. 2005;2:e313
  59. Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA. 2005;102:7665–7670
  60. Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786–792
  61. Kobayashi S, Ji H, Yuza Y, Meyerson M, Wong KK, Tenen DG, et al. An alternative inhibitor overcomes resistance caused by a mutation of the epidermal growth factor receptor. Cancer Res. 2005;65:7096–7101
  62. Shimamura T, Ji H, Minami Y, Thomas RK, Lowell AM, Shah K, et al. Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272. Cancer Res. 2006;66:6487–6491
  63. Yuza Y, Glatt KA, Jiang J, Greulich H, Minami Y, Woo MS, et al. Allele-dependent variation in the relative cellular potency of distinct EGFR inhibitors. Cancer Biol Ther. 2007;6:661–667
  64. Shimamura T, Gewulich H, Solca F, Wong K. Efficacy of BIBW 2992, a potent irreversible inhibitor of EGFR and HER2 in human NSCLC xenografts and in a transgenic mouse lung-cancer model. J Thorac Oncol. 2007;2:S380
  65. Suzuki T, Fujii A, Ohya J, Nakamura H, Fujita F, Koike M, et al. Antitumor activity of a dual epidermal growth factor receptor and ErbB2 kinase inhibitor MP-412 (AV-412) in mouse xenograft models. Cancer Sci. 2009;100:1526–1531
  66. Nelson MH, Dolder CR. Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors. Ann Pharmacother. 2006;40:261–269
  67. Janmaat ML, Giaccone G. Small-molecule epidermal growth factor receptor tyrosine kinase inhibitors. Oncologist. 2003;8:576–586
  68. Yoshimura N, Kudoh S, Kimura T, Mitsuoka S, Matsuura K, Hirata K, et al. EKB-569, a new irreversible epidermal growth factor receptor tyrosine kinase inhibitor, with clinical activity in patients with non-small cell lung cancer with acquired resistance to gefitinib. Lung Cancer. 2006;51:363–368
  69. Wong KK, Fracasso PM, Bukowski RM, Lynch TJ, Munster PN, Shapiro GI, et al. A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin Cancer Res. 2009;15:2552–2558
  70. Minkovsky N, Berezov A. BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors. Curr Opin Invest Drugs. 2008;9:1336–1346
  71. Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008;27:4702–4711
  72. Solca F, Schweifer N, Baum A, Rudolph D, Amelsberg A, Himmelsbach F, et al. BIBW 2992, an irreversible dual EGFR/HER2 kinase inhibitor, shows activity on L858R/T790 M EGFR mutants. Clinical Cancer Res. 2005;11:A242
  73. Perera SA, Li D, Shimamura T, Raso MG, Ji H, Chen L, et al. HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy. Proc Natl Acad Sci USA. 2009;106:474–479
  74. Plummer R, Vidal L, Perrett R, Spicer J, Stopfer P, Shahidi M, et al. A Phase I and pharmacokinetic (PK) study of BIBW 2992, an oral irreversible dual EGFR/HER2 inhibitor. Eur J Cancer Suppl. 2007;5:108
  75. Spicer J, Calvert H, Vidal L, Azribi F, Perrett R, Shahidi M, et al. Activity of BIBW 2992, an oral irreversible dual EGFR/HER2 inhibitor, in non-small cell lung cancer (NSCLC) with mutated EGFR. J Thorac Oncol. 2007;2:S410
  76. Shih JY, Yang CH, Su WC, Hsia TC, Tsai CM, Chen YM, et al. A Phase II study of BIBW 2992, a novel irreversible dual EGFR and HER2 tyrosine kinase inhibitor (TKI), in patients with adenocarcinoma of the lung and activating EGFR mutations after failure of 1 line of chemotherapy (LUX-Lung 2). J Clin Oncol. 2009;27(Suppl. 15):Abstract 8013
  77. Yang C, Shih J, Su W, Hsia T, Ho C, Dudek AZ, et al. BIBW 2992, a novel irreversible EGFR/HER2 tyrosine kinase inhibitor, in chemonaïve patients with adenocarcinoma of the lung and activating EGFR mutations. J Thorac Oncol. 2009;4(Suppl. 1):Abstract A3.3
  78. ClinicalTrials.gov. BIBW 2992 (TOVOK) and BSC versus placebo and BSC in non-small cell lung cancer patients failing erlotinib or gefitinib (LUX-LUNG 1), vol. 2008.
  79. De Greve J, Teugels E, Geers C, DeMey J, In’tveld P, Decoster L, et al. Activity of BIBW 2992, an irreversible inhibitor of EGFR and HER2, in adenocarcinoma of the lung with HER2neu kinase domain mutations. Eur J Cancer Suppl. 2009;7:555–556

PII: S0169-5002(10)00230-8

doi: 10.1016/j.lungcan.2010.05.015

Lung Cancer
Volume 69, Issue 3 , Pages 259-264 , September 2010

Article Tools

* Image Usage & Resolution