Skip to main content

Advertisement

SpringerLink
Log in

Targeting EGFR in Lung Cancer: Current Standards and Developments

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

Abstract

Lung cancer is the second most common malignant tumor and the leading cause of cancer death. Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is a distinct subtype of lung cancer comprising approximately 15–40% of non-squamous tumors. The development of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) has been a significant step forward in the treatment of patients with EGFR-mutant tumors, and over the last few years has been the therapy of choice in the initial management of patients with activating mutations in EGFR, with some differences in efficacy and toxicity profile. Up to 50% of patients treated with first- and second-generation TKIs develop an EGFR exon 20 T790M mutation at the time of progression. In this context, osimertinib has shown a great benefit in terms of progression-free survival (PFS) in the second-line setting, including central nervous system metastasis control. The FLAURA trial, which compared osimertinib to first-generation inhibitors as first-line therapy, showed a clear PFS advantage for osimertinib and a trend towards an increased overall survival (OS) assessed by investigator review. Although T790M mutation is the most common mechanism of resistance to first- and second-generation EGFR TKIs, other EGFR-dependent and -independent mechanisms have been described, such as HER2 and MET amplifications or BRAF and MEK mutations. Some mechanisms of resistance to osimertinib and other third-generation TKIs have also been described. Several fourth-generation TKIs, targeted drug combinations and immunotherapy strategies are under investigation to overcome resistance to EGFR TKIs in order to improve EGFR-mutant NSCLC patient outcomes.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2017;67(1):7–30.

    Article  PubMed  Google Scholar 

  2. Ettinger DS, Akerley W, Borghaei H, Chang AC, Cheney RT, Chirieac LR, et al. Non-small cell lung cancer. JNCCN. 2012;10(10):1236–71.

    PubMed  CAS  Google Scholar 

  3. Janssen-Heijnen ML, Coebergh JW, Klinkhamer PJ, Schipper RM, Splinter TA, Mooi WJ. Is there a common etiology for the rising incidence of and decreasing survival with adenocarcinoma of the lung? Epidemiol Camb Mass. 2001;12(2):256–8.

    Article  CAS  Google Scholar 

  4. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543–50.

    Article  CAS  Google Scholar 

  5. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367–80.

    Article  PubMed  CAS  Google Scholar 

  6. Luo J, Solimini NL, Elledge SJ. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell. 2009;136(5):823–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. 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(2):92–8.

    Article  PubMed  CAS  Google Scholar 

  8. 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(2):123–32.

    Article  PubMed  CAS  Google Scholar 

  9. 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 Lond Engl. 2005;366(9496):1527–37.

    Article  CAS  Google Scholar 

  10. 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 Off J Am Soc Clin Oncol. 2004;22(5):785–94.

    Article  CAS  Google Scholar 

  11. 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 Off J Am Soc Clin Oncol. 2004;22(5):777–84.

    Article  CAS  Google Scholar 

  12. 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(25):5892–9.

    Article  PubMed  CAS  Google Scholar 

  13. Sequist LV, Martins RG, Spigel D, Grunberg SM, Spira A, Jänne PA, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol. 2008;26(15):2442–9.

    Article  PubMed  CAS  Google Scholar 

  14. Schuette W, Schirmacher P, Eberhardt WEE, Fischer JR, von der Schulenburg J-MG, Mezger J, et al. EGFR mutation status and first-line treatment in patients with stage III/IV non-small cell lung cancer in Germany: an observational study. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2015;24(8):1254–61.

    Article  CAS  Google Scholar 

  15. 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(36):13306–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Sekine A, Kato T, Hagiwara E, Shinohara T, Komagata T, Iwasawa T, et al. Metastatic brain tumors from non-small cell lung cancer with EGFR mutations: distinguishing influence of exon 19 deletion on radiographic features. Lung Cancer Amst Neth. 2012;77(1):64–9.

    Article  Google Scholar 

  17. Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001;37(4):3–8.

    Article  Google Scholar 

  18. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358(11):1160–74.

    Article  PubMed  CAS  Google Scholar 

  19. Singh B, Carpenter G, Coffey RJ. EGF receptor ligands: recent advances. F1000Research. 2016. https://doi.org/10.12688/f1000research.9025.1.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell. 2006;125(6):1137–49.

    Article  PubMed  CAS  Google Scholar 

  21. Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Gazdar AF, Minna JD. Deregulated EGFR signaling during lung cancer progression: mutations, amplicons, and autocrine loops. Cancer Prev Res Phila Pa. 2008;1(3):156–60.

    Article  CAS  Google Scholar 

  23. Massarelli E, Johnson FM, Erickson HS, Wistuba II, Papadimitrakopoulou V. Uncommon epidermal growth factor receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance. Lung Cancer Amst Neth. 2013;80(3):235–41.

    Article  Google Scholar 

  24. Li K, Yang M, Liang N, Li S. Determining EGFR-TKI sensitivity of G719X and other uncommon EGFR mutations in non-small cell lung cancer: Perplexity and solution (Review). Oncol Rep. 2017;37(3):1347–58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Chabon JJ, Simmons AD, Lovejoy AF, Esfahani MS, Newman AM, Haringsma HJ, et al. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun. 2016;7:11815.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Rosell R, Molina MA, Serrano MJ. EGFR mutations in circulating tumour DNA. Lancet Oncol. 2012;13(10):971–3.

    Article  PubMed  CAS  Google Scholar 

  27. Perez-Soler R. The role of erlotinib (Tarceva, OSI 774) in the treatment of non-small cell lung cancer. Clin Cancer Res. 2004;10(12):4238–40.

    Article  Google Scholar 

  28. Tsao M-S, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J, et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med. 2005;353(2):133–44.

    Article  PubMed  CAS  Google Scholar 

  29. 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(10):947–57.

    Article  PubMed  CAS  Google Scholar 

  30. Greenhalgh J, Dwan K, Boland A, Bates V, Vecchio F, Dundar Y, et al. First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer. Cochrane Database Syst Rev. 2016;5:CD010383.

  31. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong S-S, Sriuranpong V, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011;29(21):2866–74.

    Article  PubMed  CAS  Google Scholar 

  32. Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol. 2013;24(1):54–9.

    Article  PubMed  CAS  Google Scholar 

  33. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, 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(2):121–8.

    Article  PubMed  CAS  Google Scholar 

  34. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380–8.

    Article  PubMed  CAS  Google Scholar 

  35. Douillard JY, Ostoros G, Cobo M, Ciuleanu T, McCormack R, Webster A, et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer. 2014;110(1):55–62.

    Article  PubMed  CAS  Google Scholar 

  36. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735–42.

    Article  PubMed  CAS  Google Scholar 

  37. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239–46.

    Article  PubMed  CAS  Google Scholar 

  38. Wu YL, Zhou C, Liam CK, Wu G, Liu X, Zhong Z, et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol. 2015;26(9):1883–9.

    Article  PubMed  Google Scholar 

  39. Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, et al. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 2013;14(10):953–61.

    Article  PubMed  CAS  Google Scholar 

  40. Shi YK, Wang L, Han BH, Li W, Yu P, Liu YP, et al. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol. 2017;28(10):2443–50.

    Article  PubMed  CAS  Google Scholar 

  41. Sequist LV, Yang JCH, Yamamoto N, O’Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327–34.

    Article  PubMed  CAS  Google Scholar 

  42. Yang JCH, Hirsh V, Schuler M, Yamamoto N, O’Byrne KJ, Mok TSK, et al. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3342–50.

    Article  PubMed  CAS  Google Scholar 

  43. Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(2):213–22.

    Article  PubMed  CAS  Google Scholar 

  44. Yang JCH, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015;16(2):141–51.

    Article  PubMed  CAS  Google Scholar 

  45. Ramalingam SS, Jänne PA, Mok T, O’Byrne K, Boyer MJ, Von Pawel J, et al. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15(12):1369–78.

    Article  PubMed  CAS  Google Scholar 

  46. Ellis PM, Shepherd FA, Millward M, Perrone F, Seymour L, Liu G, et al. Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial. Lancet Oncol. 2014;15(12):1379–88.

    Article  PubMed  CAS  Google Scholar 

  47. Ramalingam SS, O’Byrne K, Boyer M, Mok T, Jänne PA, Zhang H, et al. Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): pooled subset analyses from two randomized trials. Ann Oncol. 2016;27(3):423–9.

    Article  PubMed  CAS  Google Scholar 

  48. Ramalingam SS, Blackhall F, Krzakowski M, Barrios CH, Park K, Bover I, et al. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2012;30(27):3337–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Zugazagoitia J, Díaz A, Jimenez E, Nuñez JA, Iglesias L, Ponce-Aix S, et al. Second-line Treatment of Non-Small Cell Lung Cancer: focus on the Clinical Development of Dacomitinib. Front Med. 2017;4:36.

    Article  Google Scholar 

  50. Mok T, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, et al. Dacomitinib versus gefitinib for the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer (ARCHER 1050): A randomized, open-label phase III trial. J Clin Oncol. 2017;35(15):LBA9007.

  51. Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(11):1454–66.

    Article  PubMed  CAS  Google Scholar 

  52. Yang JJ, Zhou Q, Yan HH, Zhang XC, Chen HJ, Tu HY, et al. A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations. Br J Cancer. 2017;116(5):568–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Park K, Tan EH, O’Byrne K, Zhang L, Boyer M, Mok T, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17(5):577–89.

    Article  PubMed  CAS  Google Scholar 

  54. Paz-Ares L, Tan EH, O’Byrne K, Zhang L, Hirsh V, Boyer M, et al. Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial. Ann Oncol. 2017;28(2):270–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Urata Y, Katakami N, Morita S, Kaji R, Yoshioka H, Seto T, et al. Randomized Phase III Study Comparing Gefitinib With Erlotinib in Patients With Previously Treated Advanced Lung Adenocarcinoma: WJOG 5108L. J Clin Oncol. 2016;34(27):3248–57.

    Article  PubMed  CAS  Google Scholar 

  56. Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015;16(8):897–907.

    Article  PubMed  CAS  Google Scholar 

  57. Takeda M, Okamoto I, Nakagawa K. Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer. Lung Cancer Amst Neth. 2015;88(1):74–9.

    Article  Google Scholar 

  58. Takeda M, Nakagawa K. Toxicity profile of epidermal growth factor receptor tyrosine kinase inhibitors in patients with epidermal growth factor receptor gene mutation-positive lung cancer. Mol Clin Oncol. 2017;6(1):3–6.

    Article  PubMed  CAS  Google Scholar 

  59. Li J, Karlsson MO, Brahmer J, Spitz A, Zhao M, Hidalgo M, et al. CYP3A phenotyping approach to predict systemic exposure to EGFR tyrosine kinase inhibitors. J Natl Cancer Inst. 2006;98(23):1714–23.

    Article  PubMed  CAS  Google Scholar 

  60. Tan AR, Yang X, Hewitt SM, Berman A, Lepper ER, Sparreboom A, et al. Evaluation of biologic end points and pharmacokinetics in patients with metastatic breast cancer after treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22(15):3080–90.

    Article  CAS  Google Scholar 

  61. Takimoto T, Kijima T, Otani Y, Nonen S, Namba Y, Mori M, et al. Polymorphisms of CYP2D6 gene and gefitinib-induced hepatotoxicity. Clin Lung Cancer. 2013;14(5):502–7.

    Article  PubMed  CAS  Google Scholar 

  62. Sequist LV, Heist RS, Shaw AT, Fidias P, Rosovsky R, Temel JS, et al. Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol. 2011;22(12):2616–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19(8):2240–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Kobayashi S, Boggon TJ, Dayaram T, Jänne 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(8):786–92.

    Article  PubMed  CAS  Google Scholar 

  65. 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. 2006;12(19):5764–9.

    Article  PubMed  CAS  Google Scholar 

  66. Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009;28(Suppl 1):S24–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. 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(6):2070–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Yu HA, Arcila ME, Hellmann MD, Kris MG, Ladanyi M, Riely GJ. Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing. Ann Oncol Off J Eur Soc Med Oncol. 2014;25(2):423–8.

    Article  CAS  Google Scholar 

  69. Nguyen K-SH, Kobayashi S, Costa DB. Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clin Lung Cancer. 2009;10(4):281–9.

  70. 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(52):20932–7.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Engelman JA, Mukohara T, Zejnullahu K, Lifshits E, Borrás AM, Gale C-M, et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest. 2006;116(10):2695–706.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316(5827):1039–43.

    Article  PubMed  CAS  Google Scholar 

  73. Godin-Heymann N, Bryant I, Rivera MN, Ulkus L, Bell DW, Riese DJ, et al. Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the T790M drug resistance mutation. Cancer Res. 2007;67(15):7319–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Takezawa K, Pirazzoli V, Arcila ME, Nebhan CA, Song X, de Stanchina E, et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov. 2012;2(10):922–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Uramoto H, Shimokawa H, Hanagiri T, Kuwano M, Ono M. Expression of selected gene for acquired drug resistance to EGFR-TKI in lung adenocarcinoma. Lung Cancer Amst Neth. 2011;73(3):361–5.

    Article  Google Scholar 

  76. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors. Sci Transl Med. 2011;3(75):75ra26.

  77. Chung JH, Rho JK, Xu X, Lee JS, Yoon HI, Lee CT, et al. Clinical and molecular evidences of epithelial to mesenchymal transition in acquired resistance to EGFR-TKIs. Lung Cancer. 2011;73(2):176–82.

    Article  PubMed  Google Scholar 

  78. Yano S, Wang W, Li Q, Matsumoto K, Sakurama H, Nakamura T, et al. Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res. 2008;68(22):9479–87.

    Article  PubMed  CAS  Google Scholar 

  79. Bivona TG, Hieronymus H, Parker J, Chang K, Taron M, Rosell R, et al. FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR. Nature. 2011;471(7339):523–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Ward RA, Anderton MJ, Ashton S, Bethel PA, Box M, Butterworth S, et al. Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR). J Med Chem. 2013;56(17):7025–48.

    Article  PubMed  CAS  Google Scholar 

  81. Yver A. Osimertinib (AZD9291)—a science-driven, collaborative approach to rapid drug design and development. Ann Oncol. 2016;27(6):1165–70.

    Article  PubMed  CAS  Google Scholar 

  82. Goss G, Tsai CM, Shepherd FA, Bazhenova L, Lee JS, Chang GC, et al. Osimertinib for pretreated EGFR Thr790 Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2016;17(12):1643–52.

    Article  PubMed  CAS  Google Scholar 

  83. Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum-pemetrexed in EGFR T790M—positive lung cancer. N Engl J Med. 2017;376(7):629–40.

    Article  PubMed  CAS  Google Scholar 

  84. Mok T, Ahn M-J, Han J-Y, Kang JH, Katakami N, Kim H, et al. CNS response to osimertinib in patients (pts) with T790M-positive advanced NSCLC: Data from a randomized phase III trial (AURA3). J Clin Oncol. 2017 May 20;35(15_suppl):9005–9005.

  85. Thress KS, Markovets A, Barrett JC, Chmielecki J, Goldberg SB, Shepherd FA, et al. Complete clearance of plasma EGFR mutations as a predictor of outcome on osimertinib in the AURA trial. J Clin Oncol. 2017;35:Abstract 9018.

  86. Ramalingam S, Yang JCH, Lee CK, Kurata T, Kim DW, John T, et al. LBA1_PR: osimertinib as first-line treatment for EGFR mutation-positive advanced NSCLC: updated efficacy and safety results from two Phase I expansion cohorts. J Thorac Oncol. 2016;11(Suppl 4):S152–3.

    Article  Google Scholar 

  87. Ramalingam S, Reungwetwattana T, Chewaskulyong B, Dechaphunkul A, Lee KH, Imamura F, et al. LBA2_PR-Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Ann Oncol. 2017;28(Suppl 5):mdx440.050-md.

  88. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113–25.

    Article  PubMed  Google Scholar 

  89. Jänne PA, Yang JCH, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689–99.

    Article  PubMed  Google Scholar 

  90. Sequist LV, Rolfe L, Allen AR. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2015;373(6):578–9.

    Article  PubMed  CAS  Google Scholar 

  91. Sequist LV, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM, Varga A, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2015;372(18):1700–9.

    Article  PubMed  Google Scholar 

  92. Sequist LV, Soria JC, Camidge DR. Update to rociletinib data with the RECIST confirmed response rate. N Engl J Med. 2016;374(23):2296–7.

    Article  PubMed  Google Scholar 

  93. Kim DW, Tiseo M, Ahn MJ, Reckamp KL, Hansen KH, Kim SW, et al. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol. 2017;35(22):2490–8.

    Article  PubMed  Google Scholar 

  94. Gettinger SN, Bazhenova LA, Langer CJ, Salgia R, Gold KA, Rosell R, et al. Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial. Lancet Oncol. 2016;17(12):1683–96.

    Article  PubMed  CAS  Google Scholar 

  95. Uchibori K, Inase N, Araki M, Kamada M, Sato S, Okuno Y, et al. Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer. Nat Commun. 2017;8:14768.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Liao BC, Lin CC, Lee JH, Yang JCH. Optimal management of EGFR-mutant non-small cell lung cancer with disease progression on first-line tyrosine kinase inhibitor therapy. Lung Cancer Amst Neth. 2017;110:7–13.

    Article  Google Scholar 

  97. Kim ES. Olmutinib: first global approval. Drugs. 2016;76(11):1153–7.

    Article  PubMed  CAS  Google Scholar 

  98. Park K, Lee JS, Lee KH, Kim JH, Cho BC, Min YJ, et al. BI 1482694 (HM61713), an EGFR mutant-specific inhibitor, in T790M + NSCLC: efficacy and safety at the RP2D. J Clin Oncol. 2016;34(Suppl 15):9055.

    Article  Google Scholar 

  99. Wang S, Cang S, Liu D. Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. J Hematol Oncol. 2016;9(1):34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Barnes TA, O’Kane GM, Vincent MD, Leighl NB. Third-generation tyrosine kinase inhibitors targeting epidermal growth factor receptor mutations in non-small cell lung cancer. Front Oncol. 2017;7:113.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Minari R, Bordi P, Tiseo M. Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance. Transl Lung Cancer Res. 2016;5(6):695–708.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Piotrowska Z, Niederst MJ, Karlovich CA, Wakelee HA, Neal JW, Mino-Kenudson M, et al. Heterogeneity underlies the emergence of EGFRT790 wild-type clones following treatment of T790M-positive cancers with a third-generation EGFR inhibitor. Cancer Discov. 2015;5(7):713–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Oxnard GR, Hu Y, Tracy P, Feeney N, Paweletz CP, Thress KS, et al. Abstract 4112: overgrowth of competing resistance mechanisms, such as an acquired KRAS mutation, underlies a poor prognosis subtype of acquired resistance to osimertinib in T790M-positive NSCLC. Cancer Res. 2017;77(Suppl 13):4112.

    Article  Google Scholar 

  104. Niederst MJ, Hu H, Mulvey HE, Lockerman EL, Garcia AR, Piotrowska Z, et al. The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin Cancer Res Off J Am Assoc Cancer Res. 2015;21(17):3924–33.

    Article  CAS  Google Scholar 

  105. Jia Y, Yun CH, Park E, Ercan D, Manuia M, Juarez J, et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature. 2016;534(7605):129–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015;21(6):560–2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Yosaatmadja Y, Silva S, Dickson JM, Patterson AV, Smaill JB, Flanagan JU, et al. Binding mode of the breakthrough inhibitor AZD9291 to epidermal growth factor receptor revealed. J Struct Biol. 2015;192(3):539–44.

    Article  PubMed  CAS  Google Scholar 

  108. Ercan D, Choi HG, Yun CH, Capelletti M, Xie T, Eck MJ, et al. EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors. Clin Cancer Res Off J Am Assoc Cancer Res. 2015;21(17):3913–23.

    Article  CAS  Google Scholar 

  109. Eberlein CA, Stetson D, Markovets AA, Al-Kadhimi KJ, Lai Z, Fisher PR, et al. Acquired resistance to the mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling in preclinical models. Cancer Res. 2015;75(12):2489–500.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Tricker EM, Xu C, Uddin S, Capelletti M, Ercan D, Ogino A, et al. Combined EGFR/MEK inhibition prevents the emergence of resistance in EGFR-mutant lung cancer. Cancer Discov. 2015;5(9):960–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Patel H, Pawara R, Ansari A, Surana S. Recent updates on third generation EGFR inhibitors and emergence of fourth generation EGFR inhibitors to combat C797S resistance. Eur J Med Chem. 2017;142:32–47.

    Article  PubMed  CAS  Google Scholar 

  112. Hayakawa H, Ichihara E, Ohashi K, Ninomiya T, Yasugi M, Takata S, et al. Lower gefitinib dose led to earlier resistance acquisition before emergence of T790M mutation in epidermal growth factor receptor-mutated lung cancer model. Cancer Sci. 2013;104(11):1440–6.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  113. Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236–44.

    Article  PubMed  CAS  Google Scholar 

  114. Yu H, Planchard D, Yang JC, Lee KH, Garrido P, Park K, et al. P1.04-001 osimertinib with ramucirumab or necitumumab in advanced T790M-positive EGFR-mutant NSCLC: preliminary Ph1 study results. J Thorac Oncol. 2017;12(11):S1972.

    Article  Google Scholar 

  115. Chen ZY, Zhong WZ, Zhang XC, Su J, Yang XN, Chen ZH, et al. EGFR mutation heterogeneity and the mixed response to EGFR tyrosine kinase inhibitors of lung adenocarcinomas. Oncologist. 2012;17(7):978–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Li T, Ling YH, Goldman ID, Perez-Soler R. Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in human non-small cell lung cancer cells. Clin Cancer Res. 2007;13(11):3413–22.

    Article  PubMed  CAS  Google Scholar 

  117. Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013;14(8):777–86.

    Article  PubMed  CAS  Google Scholar 

  118. Cheng Y, Murakami H, Yang PC, He J, Nakagawa K, Kang JH, et al. Randomized phase II trial of gefitinib with and without pemetrexed as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer with activating epidermal growth factor receptor mutations. J Clin Oncol. 2016;34(27):3258–66.

    Article  PubMed  CAS  Google Scholar 

  119. Soria JC, Wu YL, Nakagawa K, Kim SW, Yang JJ, Ahn MJ, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 2015;16(8):990–8.

    Article  PubMed  CAS  Google Scholar 

  120. Mok TSK, Kim SW, Wu YL, Nakagawa K, Yang JJ, Ahn MJ, et al. Gefitinib plus chemotherapy versus chemotherapy in epidermal growth factor receptor mutation-positive non-small-cell lung cancer resistant to first-line gefitinib (IMPRESS): overall survival and biomarker analyses. J Clin Oncol. 2017;35(36):4027–34.

    Article  PubMed  Google Scholar 

  121. Chen N, Fang W, Zhan J, Hong S, Tang Y, Kang S, et al. Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation. J Thorac Oncol. 2015;10(6):910–23.

    Article  PubMed  CAS  Google Scholar 

  122. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–39.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet Lond Engl. 2016;387(10027):1540–50.

    Article  CAS  Google Scholar 

  124. Gettinger S, Politi K. PD-1 axis inhibitors in EGFR- and ALK-driven lung cancer: lost cause? Clin Cancer Res. 2016;22(18):4539–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Ahn MJ, Sun JM, Lee SH, Ahn JS, Park K. EGFR TKI combination with immunotherapy in non-small cell lung cancer. Expert Opin Drug Saf. 2017;16(4):465–9.

    Article  PubMed  CAS  Google Scholar 

  126. Zhi X, Wang Y, Yu J, Yu J, Zhang L, Yin L, et al. Potential prognostic biomarker CD73 regulates epidermal growth factor receptor expression in human breast cancer. IUBMB Life. 2012;64(11):911–20.

    Article  PubMed  CAS  Google Scholar 

  127. Turcotte M, Allard D, Mittal D, Bareche Y, Buisseret L, José V, et al. CD73 promotes resistance to HER2/ErbB2 antibody therapy. Cancer Res. 2017;77(20):5652–63.

    Article  PubMed  CAS  Google Scholar 

  128. Inoue Y, Yoshimura K, Kurabe N, Kahyo T, Kawase A, Tanahashi M, et al. Prognostic impact of CD73 and A2A adenosine receptor expression in non-small-cell lung cancer. Oncotarget. 2017;8(5):8738–51.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Antonioli L, Blandizzi C, Malavasi F, Ferrari D, Haskó G. Anti-CD73 immunotherapy: a viable way to reprogram the tumor microenvironment. Oncoimmunology. 2016;5(9):e1216292.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Sitkovsky MV, Hatfield S, Abbott R, Belikoff B, Lukashev D, Ohta A. Hostile, hypoxia-A2-adenosinergic tumor biology as the next barrier to overcome for tumor immunologists. Cancer Immunol Res. 2014;2(7):598.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Ceresoli GL, Cappuzzo F, Gregorc V, Bartolini S, Crinò L, Villa E. Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol. 2004;15(7):1042–7.

    Article  PubMed  CAS  Google Scholar 

  132. Wu C, Li YL, Wang ZM, Li Z, Zhang TX, Wei Z. Gefitinib as palliative therapy for lung adenocarcinoma metastatic to the brain. Lung Cancer Amst Neth. 2007;57(3):359–64.

    Article  Google Scholar 

  133. Porta R, Sánchez-Torres JM, Paz-Ares L, Massutí B, Reguart N, Mayo C, et al. Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J. 2011;37(3):624–31.

    Article  PubMed  CAS  Google Scholar 

  134. Wu YL, Zhou C, Cheng Y, Lu S, Chen GY, Huang C, et al. Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG-0803). Ann Oncol. 2013;24(4):993–9.

    Article  PubMed  Google Scholar 

  135. Welsh JW, Komaki R, Amini A, Munsell MF, Unger W, Allen PK, et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J Clin Oncol. 2013;31(7):895–902.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Schuler M, Wu YL, Hirsh V, O’Byrne K, Yamamoto N, Mok T, et al. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016;11(3):380–90.

    Article  PubMed  Google Scholar 

  137. Sperduto PW, Wang M, Robins HI, Schell MC, Werner-Wasik M, Komaki R, et al. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: radiation Therapy Oncology Group 0320. Int J Radiat Oncol Biol Phys. 2013;85(5):1312–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Magnuson WJ, Yeung JT, Guillod PD, Gettinger SN, Yu JB, Chiang VL. Impact of deferring radiation therapy in patients with epidermal growth factor receptor-mutant non-small cell lung cancer who develop brain metastases. Int J Radiat Oncol Biol Phys. 2016;95(2):673–9.

    Article  PubMed  Google Scholar 

  139. Gerber NK, Yamada Y, Rimner A, Shi W, Riely GJ, Beal K, et al. Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. Int J Radiat Oncol Biol Phys. 2014;89(2):322–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Magnuson WJ, Lester-Coll NH, Wu AJ, Yang TJ, Lockney NA, Gerber NK, et al. Management of brain metastases in tyrosine kinase inhibitor-naïve epidermal growth factor receptor-mutant non-small-cell lung cancer: a retrospective multi-institutional analysis. J Clin Oncol. 2017;35(10):1070–7.

    Article  PubMed  CAS  Google Scholar 

  141. Park SJ, Kim HT, Lee DH, Kim KP, Kim SW, Suh C, et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer Amst Neth. 2012;77(3):556–60.

    Article  CAS  Google Scholar 

  142. Sakai M, Ishikawa S, Ito H, Ozawa Y, Yamamoto T, Onizuka M, et al. Carcinomatous meningitis from non-small-cell lung cancer responding to gefitinib. Int J Clin Oncol. 2006;11(3):243–5.

    Article  PubMed  Google Scholar 

  143. Yi HG, Kim HJ, Kim YJ, Han SW, Oh DY, Lee SH, et al. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for leptomeningeal metastasis from non-small cell lung cancer patients with sensitive EGFR mutation or other predictive factors of good response for EGFR TKI. Lung Cancer Amst Neth. 2009;65(1):80–4.

    Article  Google Scholar 

  144. Remon J, Caramella C, Jovelet C, Lacroix L, Lawson A, Smalley S, et al. Osimertinib benefit in EGFR-mutant NSCLC patients with T790M-mutation detected by circulating tumour DNA. Ann Oncol. 2017;28(4):784–90.

    PubMed  CAS  Google Scholar 

  145. Ballard P, Yates JWT, Yang Z, Kim DW, Yang JCH, Cantarini M, et al. Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res. 2016;22(20):5130–40.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain

    Asunción Díaz-Serrano, Elisabeth Jiménez, Jon Zugazagoitia & Luis Paz-Ares Rodríguez

  2. Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain

    Asunción Díaz-Serrano, Pablo Gella, Elisabeth Jiménez, Jon Zugazagoitia & Luis Paz-Ares Rodríguez

  3. Yale Comprehensive Cancer Center, Yale School of Medicine, 333 Cedar Street, WWW221, New Haven, CT, 06520, USA

    Jon Zugazagoitia

  4. Medicine School, Universidad Complutense de Madrid, Madrid, Spain

    Luis Paz-Ares Rodríguez

  5. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain

    Jon Zugazagoitia & Luis Paz-Ares Rodríguez

Authors
  1. Asunción Díaz-Serrano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pablo Gella
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elisabeth Jiménez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jon Zugazagoitia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luis Paz-Ares Rodríguez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luis Paz-Ares Rodríguez.

Ethics declarations

Funding

No external funding was used in the preparation of this manuscript.

Conflict of interest

Luis Paz-Ares has received consulting fees or honorarium from Roche, AstraZeneca, Pfizer, Boehringer Mannheim, Lilly, MSD, Merck, Novartis, and Astellas. Asunción Díaz-Serrano, Pablo Gella, Elisabeth Jiménez, and Jon Zugazagoitia declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

Additional information

This article is part of the topical collection on Lung Cancer.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Díaz-Serrano, A., Gella, P., Jiménez, E. et al. Targeting EGFR in Lung Cancer: Current Standards and Developments. Drugs 78, 893–911 (2018). https://doi.org/10.1007/s40265-018-0916-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-018-0916-4

Search

Navigation