Skip to main content
SpringerLink
Log in

Optimal Management of Patients with Non-Small Cell Lung Cancer and Epidermal Growth Factor Receptor Mutations

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

In recent years, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, which have promising activity and a favourable toxicity profile, have been used in the management of advanced non-small cell lung cancer (NSCLC). The knowledge that EGFR- activating mutations confer sensitivity to EGFR TKIs has led to the design and analysis of phase II and III studies of gefitinib or erlotinib treatment in various clinical scenarios. We review the important NSCLC clinical trials of the efficacy of EGFR TKIs in the context of EGFR-activating mutations. Inall phase II single-arm studies or phase III randomized comparative studies, EGFR TKIs as monotherapy were superior to combination chemotherapy in terms of response rate and progression-free survival in patients with activating EGFR mutations. EGFR TKIs have contributed to the superior overall survival time in NSCLC patients with EGFR mutations compared with those patients without EGFR mutations. The results of these studies have led to a paradigm shift in the treatment of patients with advanced NSCLC. NSCLC with EGFR mutations constitutes a new entity requiring different personalized treatment strategies.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II

Similar content being viewed by others

References

  1. Yang CH, Yu CJ, Shih JY, et al. Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy. J Clin Oncol 2008; 26: 2745–53

    Article  PubMed  CAS  Google Scholar 

  2. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304: 1497–500

    Article  PubMed  CAS  Google Scholar 

  3. 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: 2129–39

    Article  PubMed  CAS  Google Scholar 

  4. 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 U S A 2004; 101: 13306–11

    Article  PubMed  CAS  Google Scholar 

  5. Politi K, Zakowski MF, Fan PD, et al. Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev 2006; 20: 1496–510

    Article  PubMed  CAS  Google Scholar 

  6. Ji H, Li D, Chen L, et al. The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell 2006; 9: 485–95

    Article  PubMed  CAS  Google Scholar 

  7. 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: 1527–37

    Article  PubMed  CAS  Google Scholar 

  8. Chang A, Parikh P, Thongprasert S, et al. Gefitinib (IRESSA) in patients of Asian origin with refractory advanced non-small cell lung cancer: subset analysis from the ISEL study. J Thorac Oncol 2006; 1: 847–55

    Article  PubMed  Google Scholar 

  9. Shepherd FA, Rodrigues PJ, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: 123–32

    Article  PubMed  CAS  Google Scholar 

  10. 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 2008; 372: 1809–18

    Article  PubMed  CAS  Google Scholar 

  11. 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 2008; 26: 4244–52

    Article  PubMed  CAS  Google Scholar 

  12. Lee DH, Park K, Kim JH, et al. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res 2010; 16: 1307–14

    Article  PubMed  CAS  Google Scholar 

  13. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947–57

    Article  PubMed  CAS  Google Scholar 

  14. Yang CH, Fukuoka M, Mok TS, et al. Final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib vs. carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS) [abstract]. Ann Oncol 2010; 21 Suppl. 8: viii1 (LBA2)

    Google Scholar 

  15. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010; 362: 2380–8

    Article  PubMed  CAS  Google Scholar 

  16. 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 2010; 11: 121–8

    Article  PubMed  CAS  Google Scholar 

  17. Ranson M, Hammond LA, Ferry D, et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol 2002; 20: 2240–50

    Article  PubMed  CAS  Google Scholar 

  18. Nakagawa K, Tamura T, Negoro S, et al. Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Japanese patients with solid malignant tumors. Ann Oncol 2003; 14: 922–30

    Article  PubMed  CAS  Google Scholar 

  19. Herbst RS, Maddox AM, Rothenberg ML, et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. J Clin Oncol 2002; 20: 3815–25

    Article  PubMed  CAS  Google Scholar 

  20. Baselga J, Rischin D, Ranson M, et al. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 2002; 20: 4292–302

    Article  PubMed  CAS  Google Scholar 

  21. 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). J Clin Oncol 2003; 21: 2237–46

    Article  PubMed  CAS  Google Scholar 

  22. 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: 2149–58

    Article  PubMed  CAS  Google Scholar 

  23. Morita S, Okamoto I, Kobayashi K, et al. Combined survival analysis of prospective clinical trials of gefitinib for non-small cell lung cancer with EGFR mutations. Clin Cancer Res 2009; 15: 4493–8

    Article  PubMed  CAS  Google Scholar 

  24. 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 2009; 15: 5267–73

    Article  PubMed  CAS  Google Scholar 

  25. 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: 777–84

    Article  PubMed  CAS  Google Scholar 

  26. 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: 785–94

    Article  PubMed  CAS  Google Scholar 

  27. Hirsch FR, Varella-Garcia M, Bunn Jr PA, 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 2006; 24: 5034–42

    Article  PubMed  CAS  Google Scholar 

  28. Douillard JY, Shepherd FA, Hirsh V, 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

    Article  PubMed  CAS  Google Scholar 

  29. Hidalgo M, Siu LL, Nemunaitis J, 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: 3267–79

    PubMed  CAS  Google Scholar 

  30. 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: 3238–47

    Article  PubMed  CAS  Google Scholar 

  31. Kubota K, Nishiwaki Y, Tamura T, et al. Efficacy and safety of erlotinib monotherapy for Japanese patients with advanced non-small cell lung cancer: a phase II study. J Thorac Oncol 2008; 3: 1439–45

    Article  PubMed  Google Scholar 

  32. Uhm JE, Park BB, Ahn MJ, et al. Erlotinib monotherapy for stage IIIB/IV non-small cell lung cancer: a multicenter trial by the Korean Cancer Study Group. J Thorac Oncol 2009; 4: 1136–43

    Article  PubMed  Google Scholar 

  33. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009; 361: 958–67

    Article  PubMed  CAS  Google Scholar 

  34. 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: 5892–9

    Article  PubMed  CAS  Google Scholar 

  35. 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 2007; 25: 1545–52

    Article  PubMed  CAS  Google Scholar 

  36. 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 2008; 26: 4268–75

    Article  PubMed  CAS  Google Scholar 

  37. 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: 839–44

    Article  PubMed  CAS  Google Scholar 

  38. 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: 3908–14

    Article  PubMed  CAS  Google Scholar 

  39. Wu JY, Yu CJ, Yang CH, et al. First- or second-line therapy with gefitinib produces equal survival in non-small cell lung cancer. Am J Respir Crit Care Med 2008; 178: 847–53

    Article  PubMed  CAS  Google Scholar 

  40. Kancha RK, von BN, Peschel C, et al. Functional analysis of epidermal growth factor receptor (EGFR) mutations and potential implications for EGFR targeted therapy. Clin Cancer Res 2009; 15: 460–7

    Article  PubMed  CAS  Google Scholar 

  41. 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: 6494–501

    Article  PubMed  CAS  Google Scholar 

  42. Costa DB, Schumer ST, Tenen DG, et al. Differential responses to erlotinib in epidermal growth factor receptor (EGFR)-mutated lung cancers with acquired resistance to gefitinib carrying the L747S or T790M secondary mutations. J Clin Oncol 2008; 26: 1182–4

    Article  PubMed  Google Scholar 

  43. Wu JY, Wu SG, Yang CH, et al. Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clin Cancer Res 2008; 14: 4877–82

    Article  PubMed  CAS  Google Scholar 

  44. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005; 352: 786–92

    Article  PubMed  CAS  Google Scholar 

  45. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005; 2: e73

    Article  PubMed  Google Scholar 

  46. Kwak EL, Sordella R, Bell DW, et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A 2005; 102: 7665–70

    Article  PubMed  CAS  Google Scholar 

  47. Sequist LV, Besse B, Lynch TJ, et al. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer. J Clin Oncol 2010; 28: 3076–83

    Article  PubMed  CAS  Google Scholar 

  48. Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008; 27: 4702–11

    Article  PubMed  CAS  Google Scholar 

  49. Yang CH, Shih J, Chao T, et al. Use of BIBW 2992, a novel irreversible EGFR/HER2 TKI, to induce regression in patients with adenocarcinoma of the lung and activating EGFR mutations: preliminary results of a single-arm phase II clinical trial [abstract]. J Clin Oncol (Meeting Abstracts) 2008; 26: 8026

    Google Scholar 

  50. 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 2007; 67: 11924–32

    Article  PubMed  CAS  Google Scholar 

  51. Lin CC, Hsu HH, Sun CT, et al. Chemotherapy response in East Asian non-small cell lung cancer patients harboring wild-type or activating mutation of epidermal growth factor receptors. J Thorac Oncol 2010; 5: 1424–9

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

No sources of funding were used to assist with the preparation of this review. Dr Yang has received consultancy fees and honoraria from AstraZeneca and Roche; Dr Lin has no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Rd, Taipei, 10002, Taiwan

    Chia-Chi Lin &  James Chih-Hsin Yang

  2. Department of Urology, National Taiwan University College of Medicine, Taipei, Taiwan

    Chia-Chi Lin

  3. Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan

    Chia-Chi Lin &  James Chih-Hsin Yang

  4. Graduate Institute of Oncology and Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan

    James Chih-Hsin Yang

Authors
  1. Chia-Chi Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James Chih-Hsin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James Chih-Hsin Yang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lin, CC., Yang, J.CH. Optimal Management of Patients with Non-Small Cell Lung Cancer and Epidermal Growth Factor Receptor Mutations. Drugs 71, 79–88 (2011). https://doi.org/10.2165/11587560-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11587560-000000000-00000

Keywords

Search

Navigation