Skip to main content

Advertisement

Log in

“Who Should Receive Epidermal Growth Factor Receptor Inhibitors for Non-Small Cell Lung Cancer and When?”

  • Lung Cancer
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Inhibition of the epidermal growth factor receptor (EGFR) pathway in non-small cell lung cancer (NSCLC) is an exciting and rapidly evolving field. Erlotinib and gefitinib, two tyrosine kinase inhibitors (TKIs) of EGFR, have demonstrated activity in advanced NSCLC in the second- and third-line settings. Subset analyses of phase II and phase III clinical trials lead to the recognition that these two agents had more activity in certain subsets of NSCLC patients including never smokers, people of Asian descent and patients with EGFR FISH-positive or mutation-positive tumors. In particular, never smokers had statistically significant improvements in survival with either erlotinib or gefitinib therapy. Patients with EGFR FISH- or mutation-positive tumors had improved response rates to TKI therapy while those with KRAS mutant tumors did not derive any benefit. In the BR.21 trial treatment with erlotinib resulted in statistically significant improvements in overall survival and quality of life. Thus, while the question of who should receive EGFR TKI therapy is still not completely answered, all patients should be considered for erlotinib therapy in the second- or third-line setting. In daily clinical practice, there is currently no data to support the use of EGFR mutation or FISH status in this decision making process. Prospective trials are ongoing to determine which patient and tumor characteristics are predictive of a clinical benefit from TKI therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: •Of importance ••Of major importance

  1. American Cancer Society (2006) Cancer Facts and Figures 2006. American Cancer Society.

  2. Drugs @ FDA (2006).

  3. 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 2003, 290:2149–2158

    Article  PubMed  CAS  Google Scholar 

  4. 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 2003, 21:2237–2246

    Article  PubMed  CAS  Google Scholar 

  5. Perez-Soler R, Chachoua A, Hammond LA, 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

    Article  PubMed  CAS  Google Scholar 

  6. 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 2005, 366:1527–1537

    Article  PubMed  CAS  Google Scholar 

  7. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al.: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005, 353:123–132

    Article  PubMed  CAS  Google Scholar 

  8. 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 2004, 22:777–784

    Article  PubMed  CAS  Google Scholar 

  9. Gatzemeier U, Pluzanska A, Szczesna A, et al.: Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC). J Clin Oncol, 2004 ASCO Annual Meeting Proceedings 2004, 22, 7010.

  10. 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 2004, 22:785–794

    Article  PubMed  CAS  Google Scholar 

  11. 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 2005, 23:5892–5899

    Article  PubMed  CAS  Google Scholar 

  12. Scaltriti M, Baselga J: The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res 2006, 12:5268–5272

    Article  PubMed  CAS  Google Scholar 

  13. Hirsch FR, Varella-Garcia M, Bunn PA Jr., et al.: Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 2003, 21:3798–3807

    Article  PubMed  CAS  Google Scholar 

  14. Kaneda H, Kurata T, Tamura K, et al.: A phase I study of irinotecan in combination with amrubicin for advanced lung cancer patients. Anticancer Res 2006, 26:2479–2485

    PubMed  CAS  Google Scholar 

  15. Bezjak A, Tu D, Seymour L, 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

    Article  PubMed  CAS  Google Scholar 

  16. Gatzemeier U, Heller A, Foernzler D, et al.: Exploratory analyses of HER1/EGFR, K-ras mutations and other molecular markers in tumors of patients with NSCLC treated with chemotherapy with or without erlotinib (Tarceva) (TALENT-phase III). J Clin Oncol, 2005 ASCO Annual Meeting Proceedings 2005, 23, 7028. http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=34&abstractID=31779

  17. Giaccone G, Gallegos Ruiz M, Le Chevalier T, et al.: Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study. Clin Cancer Res 2006, 12:6049–6055

    Article  PubMed  CAS  Google Scholar 

  18. Lilenbaum R, Axelrod R, Thoas S, et al.: Randomized phase II trial of single agent erlotinib vs. standard chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2. J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I 2006, 24, 7022.

  19. Miller VA, Kris MG, Shah N, et al.: Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 2004, 22:1103–1109

    Article  PubMed  CAS  Google Scholar 

  20. Janne PA, Gurubhagavatula S, Yeap BY, et al.: Outcomes of patients with advanced non-small cell lung cancer treated with gefitinib (ZD1839, “Iressa”) on an expanded access study. Lung Cancer 2004, 44:221–230

    Article  PubMed  Google Scholar 

  21. Haringhuizen A, van Tinteren H, Vaessen HF, et al.: Gefitinib as a last treatment option for non-small-cell lung cancer: durable disease control in a subset of patients. Ann Oncol 2004, 15:786–792

    Article  PubMed  CAS  Google Scholar 

  22. Simon GR, Ruckdeschel JC, Williams C, et al.: Gefitinib (ZD1839) in previously treated advanced non-small-cell lung cancer: experience from a single institution. Cancer Control 2003, 10:388–395

    PubMed  Google Scholar 

  23. Argiris A, Mittal N: Gefitinib as first-line, compassionate use therapy in patients with advanced non-small-cell lung cancer. Lung Cancer 2004, 43:317–322

    Article  PubMed  Google Scholar 

  24. Park J, Park BB, Kim JY, et al.: Gefitinib (ZD1839) monotherapy as a salvage regimen for previously treated advanced non-small cell lung cancer. Clin Cancer Res 2004, 10:4383–4388

    Article  PubMed  CAS  Google Scholar 

  25. Tsao MS, Sakurada A, Cutz JC, et al.: Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med 2005, 353:133–144

    Article  PubMed  CAS  Google Scholar 

  26. 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 2004, 350:2129–2139

    Article  PubMed  CAS  Google Scholar 

  27. Paez JG, Janne PA, Lee JC, et al.: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004, 304:1497–1500

    Article  PubMed  CAS  Google Scholar 

  28. Pao W, Miller V, Zakowski M, 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

    Article  PubMed  CAS  Google Scholar 

  29. Huang SF, Liu HP, Li LH, et al.: High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res 2004, 10:8195–8203

    Article  PubMed  CAS  Google Scholar 

  30. Kosaka T, Yatabe Y, Endoh H, et al.: Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res 2004, 64:8919–8923

    Article  PubMed  CAS  Google Scholar 

  31. Shigematsu H, Lin L, Takahashi T, et al.: Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005, 97:339–346

    Article  PubMed  CAS  Google Scholar 

  32. Janne PA, Johnson BE: Effect of epidermal growth factor receptor tyrosine kinase domain mutations on the outcome of patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors. Clin Cancer Res 2006, 12:4416s–4420s

    Article  PubMed  Google Scholar 

  33. Han SW, Kim TY, Hwang PG, et al.: Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 2005, 23:2493–2501

    Article  PubMed  CAS  Google Scholar 

  34. Mitsudomi T, Kosaka T, Endoh H, et al.: Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol 2005, 23:2513–2520

    Article  PubMed  CAS  Google Scholar 

  35. Takano T, Ohe Y, Sakamoto H, et al.: Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol 2005, 23:6829–6837

    Article  PubMed  CAS  Google Scholar 

  36. Cortes-Funes H, Gomez C, Rosell R, et al.: Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients. Ann Oncol 2005, 16:1081–1086

    Article  PubMed  CAS  Google Scholar 

  37. Taron M, Ichinose Y, Rosell R, et al.: Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. Clin Cancer Res 2005, 11:5878–5885

    Article  PubMed  CAS  Google Scholar 

  38. Bell DW, Lynch TJ, Haserlat SM, et al.: Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol 2005, 23:8081–8092

    Article  PubMed  CAS  Google Scholar 

  39. Eberhard DA, Johnson BE, Amler LC, 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

    Article  PubMed  CAS  Google Scholar 

  40. Riely GJ, Politi KA, Miller VA, Pao W: Update on epidermal growth factor receptor mutations in non-small cell lung cancer. Clin Cancer Res 2006, 12:7232–7241

    Article  PubMed  CAS  Google Scholar 

  41. Shigematsu H, Gazdar AF: Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer 2006, 118:257–262

    Article  PubMed  CAS  Google Scholar 

  42. Shih JY, Gow CH, Yang PC: EGFR mutation conferring primary resistance to gefitinib in non-small-cell lung cancer. N Engl J Med 2005, 353:207–208

    Article  PubMed  CAS  Google Scholar 

  43. Bell DW, Gore I, Okimoto RA, et al.: Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nat Genet 2005, 37:1315–1316

    Article  PubMed  CAS  Google Scholar 

  44. 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 2006, 12:6494–6501

    Article  PubMed  CAS  Google Scholar 

  45. Sordella R, Bell DW, Haber DA, Settleman J: Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004, 305:1163–1167

    Article  PubMed  CAS  Google Scholar 

  46. Riely GJ, Pao W, Pham D, et al.: Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res 2006, 12:839–844

    Article  PubMed  CAS  Google Scholar 

  47. Jackman DM, Yeap BY, Sequist LV, et al.: Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res 2006, 12:3908–3914

    Article  PubMed  CAS  Google Scholar 

  48. Paz-Ares L, Sanchez M, Garcia-Velasco A, et al . A propective phase II trial of erlotinib in advanced non-small cell lung cancer (NSCLC) patients (p) with mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR). J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I 2006, 24, 7020.

  49. Nakagawa K: Clinical development of EGFR-tyrosine kinase inhibitors in Japan. Cancer Chemother Pharmacol 2006 58(Suppl 7):33–37

    Article  CAS  Google Scholar 

  50. Hirsch FR, Varella-Garcia M, McCoy J, et al.: Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study. J Clin Oncol 2005, 23:6838–6845

    Article  PubMed  CAS  Google Scholar 

  51. 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 2005, 97:643–655

    Article  PubMed  CAS  Google Scholar 

  52. Cappuzzo F, Toschi L, Trisolini R, et al . Clinical and biological effects of gefitinib in EGFR RISH+/Phospho-Akt+ or never smoker non-small cell lung cancer (NSCLC): preliminary results of the ONCOBELL trial J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I 2006, 24, 7023.

  53. Ahrendt SA, Decker PA, Alawi EA, et al.: Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer 2001, 92:1525–1530

    Article  PubMed  CAS  Google Scholar 

  54. Pao W, Wang TY, Riely GJ, et al.: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2005, 2:e17.

    Article  PubMed  CAS  Google Scholar 

  55. Thomas SK, Fossella FV, Liu D, et al.: Asian ethnicity as a predictor of response in patients with non-small-cell lung cancer treated with gefitinib on an expanded access program. Clin Lung Cancer 2006, 7:326–331

    PubMed  CAS  Google Scholar 

  56. Ho C, Murray N, Laskin J, et al.: Asian ethnicity and adenocarcinoma histology continues to predict response to gefitinib in patients treated for advanced non-small cell carcinoma of the lung in North America. Lung Cancer 2005, 49:225–231

    Article  PubMed  Google Scholar 

  57. Chen YM, Perng RP, Tsai CM: Gefitinib treatment is highly effective in non-small-cell lung cancer patients failing previous chemotherapy in Taiwan: a prospective phase II study. J Chemother 2005, 17:679–684

    PubMed  CAS  Google Scholar 

  58. Lee DH, Han JY, Kim HT, Lee JS: Gefitinib is of more benefit in chemotherapy-naive patients with good performance status and adenocarcinoma histology: retrospective analysis of 575 Korean patients. Lung Cancer 2006, 53:339–345

    Article  PubMed  Google Scholar 

  59. Clark GM, Zborowski DM, Santabarbara P, et al.: Smoking history and epidermal growth factor receptor expression as predictors of survival benefit from erlotinib for patients with non-small-cell lung cancer in the National Cancer Institute of Canada Clinical Trials Group study BR.21. Clin Lung Cancer, 2006, 7:389–394

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Julie R. Brahmer MD, MSc.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hann, C.L., Brahmer, J.R. “Who Should Receive Epidermal Growth Factor Receptor Inhibitors for Non-Small Cell Lung Cancer and When?”. Curr. Treat. Options in Oncol. 8, 28–37 (2007). https://doi.org/10.1007/s11864-007-0024-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11864-007-0024-2

Keywords

Navigation