Skip to main content
SpringerLink
Log in

Resistance to epidermal growth factor receptor tyrosine kinase inhibitors in mutated non-small cell lung cancer: new avenues and strategies to overcome resistance

  • short review
  • Published:
memo - Magazine of European Medical Oncology Aims and scope Submit manuscript

Summary

The most common driver mutation in non-small cell lung cancer (NSCLC) is found within the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). It commonly affects younger, female, and non-smoking patients. To date, there are five approved tyrosine kinase inhibitors (TKIs) for the treatment of EGFR-mutated NSCLC: erlotinib, gefitinib, the second-generation TKI afatinib and dacomitinib, and the third-generation TKI osimertinib. Sequencing TKI treatment or starting with osimertinib first are reasonable treatment strategies. Nevertheless, patients develop resistance to these TKIs, which can be primary or acquired. Primary resistance includes resistance mutations such as EGFR insertion 20, acquired resistance comprises the development of resistance mutations, activation of bypass signaling, or histological transformation into small cell lung cancer.

This article summarizes the current landscape of treatment in EGFR-mutated lung cancer and discusses the different resistance mechanisms. It gives a perspective on novel EGFR TKIs and potential combination strategies to overcome resistance.

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Planchard D, Popat S, Kerr K, Novello S, et al. Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(suppl 4):iv192–iv237.

    Article  CAS  PubMed  Google Scholar 

  2. Westover D, Zugazagoitia J, Cho B, et al. Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Ann Oncol. 2018;29(suppl 1):i10–i9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kerr KM, Bubendorf L, Edelman MJ, et al. Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer. Ann Oncol. 2014;25(9):1681–90.

    Article  CAS  PubMed  Google Scholar 

  4. 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(25):2380–8.

    Article  CAS  PubMed  Google Scholar 

  5. 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(2):121–8.

    Article  CAS  PubMed  Google Scholar 

  6. Rosell R, Carcereny E, Gervais R, 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  CAS  PubMed  Google Scholar 

  7. Sequist LV, Yang JC, Yamamoto N, 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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wu YL, Cheng Y, Zhou X, 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  CAS  PubMed  Google Scholar 

  10. Mok TS, Cheng Y, Zhou X, et al. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. J Clin Oncol. 2018;36(22):2244–50.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Hochmair MJ, Morabito A, Hao D, et al. Sequential treatment with afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: an observational study. Future Oncol. 2018;14(27):2861–74.

    Article  CAS  PubMed  Google Scholar 

  13. Gainor JF, Shaw AJ. Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J Clin Oncol. 2013;31(31):3987–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Maione P, Sacco PC, Casaluce F, et al. Overcoming resistance to EGFR inhibitors in NSCLC. Rev Recent Clin Trials. 2016;11(2):99–105.

    Article  CAS  PubMed  Google Scholar 

  15. Lim SM, Syn NL, Cho BC, Soo RA. Acquired resistance to EGFR targeted therapy in non-small cell lung cancer: mechanisms and therapeutic strategies. Cancer Treat Rev. 2018;65:1–10.

    Article  CAS  PubMed  Google Scholar 

  16. Heigener DF, Schumann C, Sebastian M, et al. Afatinib in non-small cell lung cancer harboring uncommon EGFR mutations pretreated with reversible EGFR inhibitors. Oncologist. 2015;20(10):1167–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cho JH, Sun J, Lee S, et al. OA10.05 an open-label, multicenter, phase II single arm trial of Osimertinib in NSCLC patients with uncommon EGFR mutation(KCSG-LU15-09). J Thorac Oncol. 2018;13(10):s344. https://doi.org/10.1016/j.jtho.2018.08.291.

    Article  Google Scholar 

  18. Heymach M, Negrao J, Robichaux B, et al. OA02.06 A Phase II Trial of Poziotinib in EGFR and HER2 exon 20 Mutant Non-Small Cell Lung Cancer (NSCLC). J Thorac Oncol. 2018;13(10):323–4. https://doi.org/10.1016/j.jtho.2018.08.243.

    Article  Google Scholar 

  19. Neal J, Doebele R, Riely G, et al. Safety, PK, and preliminary antitumor activity of the oral EGFR/HER2 Exon 20 inhibitor TAK-788 in NSCLC. J Thorac Oncol. 2018;13(10, suppl):s599. https://doi.org/10.1016/j.jtho.2018.08.901.

    Article  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yun CH, Mengwasser KE, Toms AV, 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  CAS  PubMed  PubMed Central  Google Scholar 

  22. Thress KS, Brant R, Carr TH, et al. EGFR mutation detection in ctDNA from NSCLC patient plasma: a cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer. 2015;90(3):509–15.

    Article  PubMed  Google Scholar 

  23. Oxnard GR, Hu Y, Mileham KF, et al. Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M–positive lung cancer and acquired resistance to osimertinib. JAMA Oncol. 2018;4(11):1527–34.

    Article  PubMed  Google Scholar 

  24. Wang S, Song Y, Liu D. EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance. Cancer Lett. 2017;385:51–4.

    Article  CAS  PubMed  Google Scholar 

  25. Chic N, Mayo-de-las-Casas C, Reguart N. Successful treatment with Gefitinib in advanced non-small cell lung cancer after acquired resistance to osimertinib. J Thorac Oncol. 2017;12(6):e78–e80.

    Article  PubMed  Google Scholar 

  26. Wang Z, Yang JJ, Huang J, et al. Lung adenocarcinoma harboring EGFR T790M and in trans C797S responds to combination therapy of first- and third-generation EGFR TKIs and shifts allelic configuration at resistance. J Thorac Oncol. 2017;12(11):1723–7.

    Article  PubMed  Google Scholar 

  27. Arulananda S, Do H, Musafer A, Mitchell P, Dobrovic John AT. Combination osimertinib and gefitinib in C797S and T790M EGFR-mutated non-small cell lungcancer. J Thorac Oncol. 2017;12(11):1728–32.

    Article  PubMed  Google Scholar 

  28. Niederst MJ, Hu H, Mulvey HE, et al. The allelic context of the C797S mutation acquired upon treatment with third-generation EGFRinhibitors impacts sensitivity to subsequent treatment strategies. Clin Cancer Res. 2015;21(17):3924–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ou SH, Kwak EL, Siwak-Tapp C, et al. Activity of crizotinib (PF02341066), a dual mesenchymalepithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thorac Oncol. 2011;6(5):942–6.

    Article  PubMed  Google Scholar 

  30. Camidge RD, Ou S‑HI, Shapiro G, et al. Efficacy and safety of crizotinib in patients with advanced MET-amplified non-small cell lung cancer. J Clin Oncol. 2014;32(suppl 5):abstract 8001.

    Article  Google Scholar 

  31. Frampton GM, Ali SM, Rosenzweig M, et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 2015;5(8):850–9.

    Article  CAS  PubMed  Google Scholar 

  32. Paik PK, Drilon A, Fan PD, et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov. 2015;5(8):842–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Awad MM, Oxnard GR, Jackman DM, et al. MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and cMET overexpresion. J Clin Oncol. 2016;34(7):721–30.

    Article  CAS  PubMed  Google Scholar 

  34. Takezawa K, Pirazzoli V, Arcila ME, et al. HER2 amplification: a potent mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancer that lack the second-side EGFRT790M mutation. Cancer Discov. 2012;2(19):922–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Stewart EL, Tan SZ, Lui G, Tsae MS. Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC with EGFR mutations—a review. Tranl Lung Cancer Res. 2015;4(1):67–81.

    CAS  Google Scholar 

  36. Li BT, Shen R, Buonocore D, et al. Ado-trastuzumab emtansine in patients with HER2 mutant lung cancers: results from a phase II basket trial. J Clin Oncol. 2018;36(24):2532–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Oser MG, Niederst MJ, Sequist LV, Engelman JA. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol. 2015;16(4):e165–e72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tan DS, Yang JC, Leighl NB, et al. Updated results of a phase 1 study of EGF816, a third-generation, mutant-selective EGFR tyrosine kinase inhibitor (TKI), in advanced non-small cell lung cancer (NSCLC) harboring T790M. J Clin Oncol. 2016;34(15_suppl):9044.

    Article  Google Scholar 

  40. Tan DS, Kim SW, Sequist LV, et al. Phase II results for single-agent nazartinib (EGF816) in adult patients (pts) with treatment-naive EGFR-mutant non-small cell lung cancer (NSCLC). ESMO, abstract LBA61. 2018.

    Google Scholar 

  41. Cho BC, et al. Lazertinib, a third generation EGFR TKI in patients with EGFR resistant NSCLC: updated results of a phase I/II trial. WCLC 2018, AbstractOA05.07. 2018.

    Google Scholar 

  42. Rizvi NA, Chow LQ, Borghaei H, et al. Safety and response with nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus erlotinib in patients (pts) with epidermal growth factor receptor mutant (EGFR MT) advanced NSCLC. J Clin Oncol. 2014;32(suppl 15):abstr 8022. https://doi.org/10.1200/jco.2014.32.15.

    Article  Google Scholar 

  43. Ahn MJ, Yang J, Yu H, et al. Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: results from the TATTON phase Ib trial. J Thorac Oncol. 2016;11(suppl 4):s115. https://doi.org/10.1016/S1556-0864(16)30246-5.

    Article  Google Scholar 

  44. Gibbons DL, Chow LQ, Kim DW, et al. Efficacy, safety and tolerability of MEDI4736 (durvalumab [D]), a human IgG1 anti-programmed cell death-ligand-1 (PD-L1) antibody, combined with gefitinib (G): A phase I expansion in TKI-naive patients (pts) with EGFR mutant NSCLC. J Thorac Oncol. 2016;11(suppl 4):s79. https://doi.org/10.1016/S1556-0864(16)30171-X.

    Article  Google Scholar 

  45. Seike M, Inoue A, Sugawara S, et al. Phase III study of gefitinib (G) versus gefitinib+carboplatin+pemetrexed (GCP) as first-line treatment for patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009). Ann Oncol. 2018;29(suppl 8):viii493–viii547. https://doi.org/10.1093/annonc/mdy292.005.

    Article  Google Scholar 

  46. Seto T, Kato T, Nishio M, 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  CAS  PubMed  Google Scholar 

  47. Furuya N, Fukuhara T, Saito H, et al. Phase III study comparing bevacizumab plus erlotinib to erlotinib in patients with untreated NSCLC harboring activating EGFR mutations: NEJ026. J Clin Oncol. 2018;36(suppl 15):s9006. https://doi.org/10.1200/JCO.2018.36.15_suppl.9006.

    Article  Google Scholar 

  48. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288–301.

    Article  CAS  PubMed  Google Scholar 

  49. Cappuzzo F, McCleod M, Hussein M, et al. IMpower130: Progression-free survival (PFS) and safety analysis from a randomised phase III study of carboplatin + nab-paclitaxel (CnP) with or without atezolizumab (atezo) as first-line (1L) therapy in advanced non-squamous NSCLC. Ann Oncol. 2018;29(suppl 1):LBA53. https://doi.org/10.1093/annonco/mdy424.065.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Clinical Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria

    Gudrun Absenger

Authors
  1. Gudrun Absenger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gudrun Absenger.

Ethics declarations

Conflict of interest

G. Absenger declares that she has no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Absenger, G. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors in mutated non-small cell lung cancer: new avenues and strategies to overcome resistance. memo 12, 128–135 (2019). https://doi.org/10.1007/s12254-019-0488-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12254-019-0488-3

Keywords

Search

Navigation