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EGFR Targeted Therapy

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Targeted Therapies for Lung Cancer

Part of the book series: Current Cancer Research ((CUCR))

Abstract

The identification of sensitizing mutations in the epidermal growth factor receptor (EGFR) gene in patients with non-small cell lung cancer (NSCLC) and the development of EGFR-tyrosine kinase inhibitors (EGFR TKIs) to target these mutations have dramatically improved outcomes for this subset of patients. For patients with EGFR-mutated NSCLC, the use of EGFR TKIs is associated with improved efficacy and quality of life compared to chemotherapy. The latest generation EGFR TKI, osimertinib, is highly effective in treating acquired resistance due to the T790M mutation as well as treating central nervous system metastases. As first-line treatment, its use has led to the longest median progression-free survival to date for patients with EGFR-mutated NSCLC. Acquired resistance to osimertinib is caused by multiple mechanisms, and numerous trials are currently underway to address this. Future studies should also aim to address the historically refractory EGFR exon 20 insertions, and current agents under study are promising.

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References

  1. Rotow J, Bivona TG. Understanding and targeting resistance mechanisms in NSCLC. Nat Rev Cancer. 2017;17(11):637–58. https://doi.org/10.1038/nrc.2017.84.

    Article  CAS  PubMed  Google Scholar 

  2. Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97(5):339–46. https://doi.org/10.1093/jnci/dji055.

    Article  CAS  PubMed  Google Scholar 

  3. Tsao AS, Tang XM, Sabloff B, Xiao L, Shigematsu H, Roth J, et al. Clinicopathologic characteristics of the EGFR gene mutation in non-small cell lung cancer. J Thorac Oncol. 2006;1(3):231–9.

    Article  PubMed  Google Scholar 

  4. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):958–67. https://doi.org/10.1056/NEJMoa0904554.

    Article  CAS  PubMed  Google Scholar 

  5. Zhang YL, Yuan JQ, Wang KF, Fu XH, Han XR, Threapleton D, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7(48):78985–93. https://doi.org/10.18632/oncotarget.12587.

    Article  PubMed  PubMed Central  Google Scholar 

  6. 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 U S A. 2004;101(36):13306–11. https://doi.org/10.1073/pnas.0405220101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39. https://doi.org/10.1056/NEJMoa040938.

    Article  CAS  PubMed  Google Scholar 

  8. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–500. https://doi.org/10.1126/science.1099314.

    Article  CAS  PubMed  Google Scholar 

  9. Cohen S. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J Biol Chem. 1962;237:1555–62.

    CAS  PubMed  Google Scholar 

  10. Burgess AW, Cho H-S, Eigenbrot C, Ferguson KM, Garrett TPJ, Leahy DJ, et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell. 2003;12(3):541–52. https://doi.org/10.1016/S1097-2765(03)00350-2.

    Article  CAS  PubMed  Google Scholar 

  11. Carpenter G, Lembach KJ, Morrison MM, Cohen S. Characterization of the binding of 125-I-labeled epidermal growth factor to human fibroblasts. J Biol Chem. 1975;250(11):4297–304.

    CAS  PubMed  Google Scholar 

  12. Yarden Y, Schlessinger J. Epidermal growth factor induces rapid, reversible aggregation of the purified epidermal growth factor receptor. Biochemistry. 1987;26(5):1443–51.

    Article  CAS  PubMed  Google Scholar 

  13. de Larco JE, Todaro GJ. Epithelioid and fibroblastic rat kidney cell clones: epidermal growth factor (EGF) receptors and the effect of mouse sarcoma virus transformation. J Cell Physiol. 1978;94(3):335–42. https://doi.org/10.1002/jcp.1040940311.

    Article  PubMed  Google Scholar 

  14. Mendelsohn J, Masui H, Goldenberg A. Anti-epidermal growth factor receptor monoclonal antibodies may inhibit A431 tumor cell proliferation by blocking an autocrine pathway. Trans Assoc Am Phys. 1987;100:173–8.

    CAS  PubMed  Google Scholar 

  15. Dokala A, Thakur SS. Extracellular region of epidermal growth factor receptor: a potential target for anti-EGFR drug discovery. Oncogene. 2017;36(17):2337–44. https://doi.org/10.1038/onc.2016.393.

    Article  CAS  PubMed  Google Scholar 

  16. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127–37. https://doi.org/10.1038/35052073.

    Article  CAS  PubMed  Google Scholar 

  17. Ullrich A, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam AW, et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature. 1984;309:418. https://doi.org/10.1038/309418a0.

    Article  CAS  PubMed  Google Scholar 

  18. Lemmon MA, Schlessinger J, Ferguson KM. The EGFR family: not so prototypical receptor tyrosine kinases. Cold Spring Harb Perspect Biol. 2014;6(4):a020768. https://doi.org/10.1101/cshperspect.a020768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Garrett TPJ, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO, et al. Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor α. Cell. 2002;110(6):763–73. https://doi.org/10.1016/S0092-8674(02)00940-6.

    Article  CAS  PubMed  Google Scholar 

  20. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2000;103(2):211–25.

    Article  CAS  PubMed  Google Scholar 

  21. Hirsch FR, Varella-Garcia M, Cappuzzo F. Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer. Oncogene. 2009;28:S32. https://doi.org/10.1038/onc.2009.199.

    Article  CAS  PubMed  Google Scholar 

  22. Prabhakar CN. Epidermal growth factor receptor in non-small cell lung cancer. Transl Lung Cancer Res. 2015;4(2):110–8. https://doi.org/10.3978/j.issn.2218-6751.2015.01.01.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Testa JR, Siegfried JM. Chromosome abnormalities in human non-small cell lung cancer. Cancer Res. 1992;52(9 Suppl):2702s–6s.

    CAS  PubMed  Google Scholar 

  24. Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7(3):169–81. https://doi.org/10.1038/nrc2088.

    Article  CAS  PubMed  Google Scholar 

  25. Yasuda H, Park E, Yun CH, Sng NJ, Lucena-Araujo AR, Yeo WL, et al. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med. 2013;5(216):216ra177. https://doi.org/10.1126/scitranslmed.3007205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang Y, Li RQ, Ai YQ, Zhang J, Zhao PZ, Li YF, et al. Exon 19 deletion was associated with better survival outcomes in advanced lung adenocarcinoma with mutant EGFR treated with EGFR-TKIs as second-line therapy after first-line chemotherapy: a retrospective analysis of 128 patients. Clin Transl Oncol. 2015;17(9):727–36. https://doi.org/10.1007/s12094-015-1300-4.

    Article  CAS  PubMed  Google Scholar 

  27. Yang JC-H, Wu Y-L, 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. https://doi.org/10.1016/S1470-2045(14)71173-8.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang Y, Sheng J, Kang S, Fang W, Yan Y, Hu Z, et al. Patients with exon 19 deletion were associated with longer progression-free survival compared to those with L858R mutation after first-line EGFR-TKIs for advanced non-small cell lung cancer: a meta-analysis. PLoS One. 2014;9(9):e107161. https://doi.org/10.1371/journal.pone.0107161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ichihara E, Hotta K, Nogami N, Kuyama S, Kishino D, Fujii M, et al. Phase II trial of gefitinib in combination with bevacizumab as first-line therapy for advanced non-small cell lung cancer with activating EGFR gene mutations: the Okayama Lung Cancer Study Group Trial 1001. J Thorac Oncol. 2015;10(3):486–91. https://doi.org/10.1097/jto.0000000000000434.

    Article  CAS  PubMed  Google Scholar 

  30. 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. https://doi.org/10.1016/s1470-2045(14)70381-x.

    Article  CAS  PubMed  Google Scholar 

  31. Qu J, Wang YN, Xu P, Xiang DX, Yang R, Wei W, et al. Clinical efficacy of icotinib in lung cancer patients with different EGFR mutation status: a meta-analysis. Oncotarget. 2017;8(20):33961–71. https://doi.org/10.18632/oncotarget.15475.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Moyer JD, Barbacci EG, Iwata KK, Arnold L, Boman B, Cunningham A, et al. Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor Tyrosine Kinase. Cancer Res. 1997;57(21):4838–48.

    CAS  PubMed  Google Scholar 

  33. Barker AJ, Gibson KH, Grundy W, Godfrey AA, Barlow JJ, Healy MP, et al. Studies leading to the identification of ZD1839 (IRESSA): an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer. Bioorg Med Chem Lett. 2001;11(14):1911–4.

    Article  CAS  PubMed  Google Scholar 

  34. Ward WH, Cook PN, Slater AM, Davies DH, Holdgate GA, Green LR. Epidermal growth factor receptor tyrosine kinase. Investigation of catalytic mechanism, structure-based searching and discovery of a potent inhibitor. Biochem Pharmacol. 1994;48(4):659–66.

    Article  CAS  PubMed  Google Scholar 

  35. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, 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(12):2237–46. https://doi.org/10.1200/jco.2003.10.038.

    Article  CAS  PubMed  Google Scholar 

  36. 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(16):2149–58. https://doi.org/10.1001/jama.290.16.2149.

    Article  CAS  PubMed  Google Scholar 

  37. Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa survival evaluation in lung cancer). Lancet. 2005;366(9496):1527–37. https://doi.org/10.1016/s0140-6736(05)67625-8.

    Article  CAS  PubMed  Google Scholar 

  38. Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008;372(9652):1809–18. https://doi.org/10.1016/s0140-6736(08)61758-4.

    Article  CAS  PubMed  Google Scholar 

  39. Kazandjian D, Blumenthal GM, Yuan W, He K, Keegan P, Pazdur R. FDA approval of Gefitinib for the treatment of patients with metastatic EGFR mutation-positive non-small cell lung cancer. Clin Cancer Res. 2016;22(6):1307–12. https://doi.org/10.1158/1078-0432.Ccr-15-2266.

    Article  CAS  PubMed  Google Scholar 

  40. Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 2. J Clin Oncol. 2004;22(5):785–94. https://doi.org/10.1200/jco.2004.07.215.

    Article  CAS  PubMed  Google Scholar 

  41. Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 1. J Clin Oncol. 2004;22(5):777–84. https://doi.org/10.1200/jco.2004.08.001.

    Article  CAS  PubMed  Google Scholar 

  42. Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva lung cancer investigation trial. J Clin Oncol. 2007;25(12):1545–52. https://doi.org/10.1200/jco.2005.05.1474.

    Article  CAS  PubMed  Google Scholar 

  43. 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. https://doi.org/10.1200/jco.2005.02.840.

    Article  CAS  PubMed  Google Scholar 

  44. Mok TS, Wu Y-L, Thongprasert S, Yang C-H, Chu D-T, Saijo N, et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57. https://doi.org/10.1056/NEJMoa0810699.

    Article  CAS  PubMed  Google Scholar 

  45. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, 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. https://doi.org/10.1200/jco.2010.33.4235.

    Article  CAS  PubMed  Google Scholar 

  46. 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. https://doi.org/10.1038/bjc.2013.721.

    Article  CAS  PubMed  Google Scholar 

  47. Shen YW, Zhang XM, Li ST, Lv M, Yang J, Wang F, et al. Efficacy and safety of icotinib as first-line therapy in patients with advanced non-small-cell lung cancer. Onco Targets Ther. 2016;9:929–35. https://doi.org/10.2147/ott.S98363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bria E, Milella M, Cuppone F, Novello S, Ceribelli A, Vaccaro V, et al. Outcome of advanced NSCLC patients harboring sensitizing EGFR mutations randomized to EGFR tyrosine kinase inhibitors or chemotherapy as first-line treatment: a meta-analysis. Ann Oncol. 2011;22(10):2277–85. https://doi.org/10.1093/annonc/mdq742.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Petrelli F, Borgonovo K, Cabiddu M, Barni S. Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small-cell lung cancer: a meta-analysis of 13 randomized trials. Clin Lung Cancer. 2012;13(2):107–14. https://doi.org/10.1016/j.cllc.2011.08.005.

    Article  CAS  PubMed  Google Scholar 

  50. Gao G, Ren S, Li A, Xu J, Xu Q, Su C, et al. Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: a meta-analysis from six phase III randomized controlled trials. Int J Cancer. 2012;131(5):E822–9. https://doi.org/10.1002/ijc.27396.

    Article  CAS  PubMed  Google Scholar 

  51. Lee CK, Davies L, Wu YL, Mitsudomi T, Inoue A, Rosell R, et al. Gefitinib or Erlotinib vs chemotherapy for EGFR mutation-positive lung cancer: individual patient data meta-analysis of overall survival. J Natl Cancer Inst. 2017;109(6) https://doi.org/10.1093/jnci/djw279.

  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. https://doi.org/10.1038/bjc.2016.456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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. https://doi.org/10.1200/jco.2015.63.4154.

    Article  CAS  PubMed  Google Scholar 

  54. Lee CK, Brown C, Gralla RJ, Hirsh V, Thongprasert S, Tsai CM, et al. Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis. J Natl Cancer Inst. 2013;105(9):595–605. https://doi.org/10.1093/jnci/djt072.

    Article  CAS  PubMed  Google Scholar 

  55. Paz-Ares L, Soulieres D, Moecks J, Bara I, Mok T, Klughammer B. Pooled analysis of clinical outcome for EGFR TKI-treated patients with EGFR mutation-positive NSCLC. J Cell Mol Med. 2014;18(8):1519–39. https://doi.org/10.1111/jcmm.12278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Thongprasert S, Duffield E, Saijo N, Wu YL, Yang JC, Chu DT, et al. Health-related quality-of-life in a randomized phase III first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients from Asia with advanced NSCLC (IPASS). J Thorac Oncol. 2011;6(11):1872–80. https://doi.org/10.1097/JTO.0b013e31822adaf7.

    Article  PubMed  Google Scholar 

  57. Chen G, Feng J, Zhou C, Wu YL, Liu XQ, Wang C, et al. Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). Ann Oncol. 2013;24(6):1615–22. https://doi.org/10.1093/annonc/mdt012.

    Article  CAS  PubMed  Google Scholar 

  58. 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. https://doi.org/10.1016/s1470-2045(15)00121-7.

    Article  CAS  PubMed  Google Scholar 

  59. 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. https://doi.org/10.1200/jco.2017.73.9250.

    Article  CAS  PubMed  Google Scholar 

  60. Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008;27:4702. https://doi.org/10.1038/onc.2008.109. https://www.nature.com/articles/onc2008109#supplementary-information.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Engelman JA, Zejnullahu K, Gale CM, Lifshits E, Gonzales AJ, Shimamura T, 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(24):11924–32. https://doi.org/10.1158/0008-5472.Can-07-1885.

    Article  CAS  PubMed  Google Scholar 

  62. Gonzales AJ, Hook KE, Althaus IW, Ellis PA, Trachet E, Delaney AM, et al. Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2008;7(7):1880–9. https://doi.org/10.1158/1535-7163.Mct-07-2232.

    Article  CAS  PubMed  Google Scholar 

  63. Yonesaka K, Kudo K, Nishida S, Takahama T, Iwasa T, Yoshida T, et al. The pan-HER family tyrosine kinase inhibitor afatinib overcomes HER3 ligand heregulin-mediated resistance to EGFR inhibitors in non-small cell lung cancer. Oncotarget. 2015;6(32):33602–11. https://doi.org/10.18632/oncotarget.5286.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012;13(5):528–38. https://doi.org/10.1016/s1470-2045(12)70087-6.

    Article  CAS  PubMed  Google Scholar 

  65. Reckamp KL, Giaccone G, Camidge DR, Gadgeel SM, Khuri FR, Engelman JA, et al. A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non-small cell lung cancer after failure of prior chemotherapy and erlotinib. Cancer. 2014;120(8):1145–54. https://doi.org/10.1002/cncr.28561.

    Article  CAS  PubMed  Google Scholar 

  66. Takeda M, Okamoto I, Nakagawa K. Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer. Lung Cancer. 2015;88(1):74–9. https://doi.org/10.1016/j.lungcan.2015.01.026.

    Article  PubMed  Google Scholar 

  67. Wang LY, Cui JJ, Guo AX, Yin JY. Clinical efficacy and safety of afatinib in the treatment of non-small-cell lung cancer in Chinese patients. Onco Targets Ther. 2018;11:529–38. https://doi.org/10.2147/ott.S136579.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Califano R, Tariq N, Compton S, Fitzgerald DA, Harwood CA, Lal R, et al. Expert consensus on the management of adverse events from EGFR Tyrosine Kinase inhibitors in the UK. Drugs. 2015;75(12):1335–48. https://doi.org/10.1007/s40265-015-0434-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yang CJ, Tsai MJ, Hung JY, Lee MH, Tsai YM, Tsai YC, et al. The clinical efficacy of Afatinib 30 mg daily as starting dose may not be inferior to Afatinib 40 mg daily in patients with stage IV lung adenocarcinoma harboring exon 19 or exon 21 mutations. BMC Pharmacol Toxicol. 2017;18(1):82. https://doi.org/10.1186/s40360-017-0190-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Park K, Tan E-H, 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. https://doi.org/10.1016/S1470-2045(16)30033-X.

    Article  CAS  PubMed  Google Scholar 

  71. Sequist LV, Yang JC, 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. https://doi.org/10.1200/jco.2012.44.2806.

    Article  CAS  PubMed  Google Scholar 

  72. 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. https://doi.org/10.1016/s1470-2045(13)70604-1.

    Article  CAS  PubMed  Google Scholar 

  73. 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. https://doi.org/10.1093/annonc/mdw611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 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. https://doi.org/10.1016/s1470-2045(17)30608-3.

    Article  CAS  PubMed  Google Scholar 

  75. Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, 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. https://doi.org/10.1200/JCO.2018.78.7994.

    Article  CAS  PubMed  Google Scholar 

  76. FDA. VIZIMPRO (dacomitinib) tablets, for oral use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211288s000lbl.pdf.

  77. Addeo A. Dacomitinib in NSCLC: a positive trial with little clinical impact. Lancet Oncol. 2018;19(1):e4. https://doi.org/10.1016/S1470-2045(17)30923-3.

    Article  PubMed  Google Scholar 

  78. Ou SHI, Soo RA. Dacomitinib in lung cancer: a “lost generation” EGFR tyrosine-kinase inhibitor from a bygone era? Drug Des Devel Ther. 2015;9:5641–53. https://doi.org/10.2147/dddt.S52787.

    Article  PubMed  PubMed Central  Google Scholar 

  79. 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. https://doi.org/10.1056/NEJMoa044238.

    Article  CAS  PubMed  Google Scholar 

  80. Yun C-H, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong K-K, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci. 2008;105(6):2070–5. https://doi.org/10.1073/pnas.0709662105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Cross DAE, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4(9):1046–61. https://doi.org/10.1158/2159-8290.Cd-14-0337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Oxnard GR, Arcila ME, Sima CS, Riely GJ, Chmielecki J, Kris MG, et al. Acquired resistance to EGFR Tyrosine Kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 2011;17(6):1616–22. https://doi.org/10.1158/1078-0432.Ccr-10-2692.

    Article  CAS  PubMed  Google Scholar 

  83. 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. https://doi.org/10.1158/1078-0432.Ccr-12-2246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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. https://doi.org/10.1126/scitranslmed.3002003.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Gaut D, Sim MS, Yue Y, Wolf BR, Abarca PA, Carroll JM, et al. Clinical implications of the T790M mutation in disease characteristics and treatment response in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). Clin Lung Cancer. 2018;19(1):e19–28. https://doi.org/10.1016/j.cllc.2017.06.004.

    Article  CAS  PubMed  Google Scholar 

  86. 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. https://doi.org/10.1056/NEJMoa1413654.

    Article  PubMed  Google Scholar 

  87. Sequist LV, Soria J-C, Camidge DR. Update to Rociletinib data with the RECIST confirmed response rate. N Engl J Med. 2016;374(23):2296–7. https://doi.org/10.1056/NEJMc1602688.

    Article  PubMed  Google Scholar 

  88. Park K, Jänne PA, Yu CJ, Bazhenova L, Paz-Ares L, Baek E, et al. 412OA global phase II study of olmutinib (HM61713) in patients with T790M-positive NSCLC after failure of first-line EGFR-TKI. Ann Oncol. 2017;28(suppl_10):mdx671.001. https://doi.org/10.1093/annonc/mdx671.001.

    Article  Google Scholar 

  89. Kim D-W, Tan DS-W, Ponce Aix S, Sequist LV, Smit EF, Hida T, et al. Preliminary phase II results of a multicenter, open-label study of nazartinib (EGF816) in adult patients with treatment-naïve EGFR-mutant non-small cell lung cancer (NSCLC). J Clin Oncol. 2018;36(15_suppl):9094. https://doi.org/10.1200/JCO.2018.36.15_suppl.9094.

    Article  Google Scholar 

  90. Wang H, Zhang L, Zheng X, Zhang X, Si X, Wang M. The ability of avitinib to penetrate the blood brain barrier and its control of intra−/extra- cranial disease in patients of non-small cell lung cancer (NSCLC) harboring EGFR T790M mutation. J Clin Oncol. 2017;35(15_suppl):e20613. https://doi.org/10.1200/JCO.2017.35.15_suppl.e20613.

    Article  Google Scholar 

  91. Murakami H, Nokihara H, Hayashi H, Seto T, Park K, Azuma K, et al. Clinical activity of ASP8273 in Asian patients with non-small-cell lung cancer with EGFR activating and T790M mutations. Cancer Sci. 2018;109(9):2852–62. https://doi.org/10.1111/cas.13724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Husain H, Martins RG, Goldberg SB, Senico P, Ma W, Masters J, et al. 1358PFirst-in-human phase I study of PF-06747775, a third-generation mutant selective EGFR tyrosine kinase inhibitor (TKI) in metastatic EGFR mutant NSCLC after progression on a first-line EGFR TKI. Ann Oncol. 2017;28(suppl_5):mdx380.060. https://doi.org/10.1093/annonc/mdx380.060.

    Article  Google Scholar 

  93. Wu YL, Ahn MJ, Garassino MC, Han JY, Katakami N, Kim HR, et al. CNS efficacy of Osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3). J Clin Oncol. 2018:Jco2018779363. https://doi.org/10.1200/jco.2018.77.9363.

    Article  CAS  PubMed  Google Scholar 

  94. Gao X, Le X, Costa DB. The safety and efficacy of osimertinib for the treatment of EGFR T790M mutation positive non-small-cell lung cancer. Expert Rev Anticancer Ther. 2016;16(4):383–90. https://doi.org/10.1586/14737140.2016.1162103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 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. https://doi.org/10.1056/NEJMoa1612674.

    Article  CAS  PubMed  Google Scholar 

  96. Osimertinib (TAGRISSO). U.S. Food and Drug Administration (FDA). https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm549683.htm. Accessed 12 Oct 2018.

  97. Bertranou E, Bodnar C, Dansk V, Greystoke A, Large S, Dyer M. Cost-effectiveness of osimertinib in the UK for advanced EGFR-T790M non-small cell lung cancer. J Med Econ. 2018;21(2):113–21. https://doi.org/10.1080/13696998.2017.1377718.

    Article  PubMed  Google Scholar 

  98. Ramalingam SS, Yang JC, Lee CK, Kurata T, Kim DW, John T, et al. Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J Clin Oncol. 2018;36(9):841–9. https://doi.org/10.1200/jco.2017.74.7576.

    Article  CAS  PubMed  Google Scholar 

  99. 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. https://doi.org/10.1056/NEJMoa1713137.

    Article  CAS  PubMed  Google Scholar 

  100. FDA approves osimertinib for first-line treatment of metastatic NSCLC with most common EGFR mutations. U.S. Food & Drug Administation (FDA). https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm605113.htm. Accessed 13 Oct 2018.

  101. Sundaresan TK, Sequist LV, Heymach JV, Riely GJ, Janne PA, Koch WH, et al. Detection of T790M, the acquired resistance EGFR mutation, by Tumor Biopsy versus noninvasive blood-based analyses. Clin Cancer Res. 2016;22(5):1103–10. https://doi.org/10.1158/1078-0432.ccr-15-1031.

    Article  CAS  PubMed  Google Scholar 

  102. Vanderlaan PA, Yamaguchi N, Folch E, Boucher DH, Kent MS, Gangadharan SP, et al. Success and failure rates of tumor genotyping techniques in routine pathological samples with non-small-cell lung cancer. Lung Cancer. 2014;84(1):39–44. https://doi.org/10.1016/j.lungcan.2014.01.013.

    Article  PubMed  Google Scholar 

  103. Folch E, Yamaguchi N, VanderLaan PA, Kocher ON, Boucher DH, Goldstein MA, et al. Adequacy of lymph node transbronchial needle aspirates using convex probe endobronchial ultrasound for multiple tumor genotyping techniques in non-small-cell lung cancer. J Thorac Oncol. 2013;8(11):1438–44. https://doi.org/10.1097/JTO.0b013e3182a471a9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Overman MJ, Modak J, Kopetz S, Murthy R, Yao JC, Hicks ME, et al. Use of research biopsies in clinical trials: are risks and benefits adequately discussed? J Clin Oncol. 2013;31(1):17–22. https://doi.org/10.1200/jco.2012.43.1718.

    Article  PubMed  Google Scholar 

  105. Sacher AG, Paweletz C, Dahlberg SE, Alden RS, O’Connell A, Feeney N, et al. Prospective validation of rapid plasma genotyping for the detection of EGFR and KRAS mutations in advanced lung cancer. JAMA Oncol. 2016;2(8):1014–22. https://doi.org/10.1001/jamaoncol.2016.0173.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Lokhandwala T, Bittoni MA, Dann RA, D’Souza AO, Johnson M, Nagy RJ, et al. Costs of diagnostic assessment for lung cancer: a medicare claims analysis. Clin Lung Cancer. 2017;18(1):e27–34. https://doi.org/10.1016/j.cllc.2016.07.006.

    Article  PubMed  Google Scholar 

  107. Piotrowska Z, Niederst MJ, Mino-Kenudson M, Morales-Oyarvide V, Fulton L, Lockerman E, et al. Variation in mechanisms of acquired resistance among EGFR-mutant NSCLC patients with more than 1 Postresistant Biopsy. Int J Radiat Oncol Biol Phys. 90(5):S6–7. https://doi.org/10.1016/j.ijrobp.2014.08.032.

    Article  Google Scholar 

  108. Goldman JW, Noor ZS, Remon J, Besse B, Rosenfeld N. Are liquid biopsies a surrogate for tissue EGFR testing? Ann Oncol. 2018;29(suppl_1):i38–46. https://doi.org/10.1093/annonc/mdx706.

    Article  CAS  PubMed  Google Scholar 

  109. Zhang J, Fujimoto J, Zhang J, Wedge DC, Song X, Zhang J, et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science. 2014;346(6206):256–9. https://doi.org/10.1126/science.1256930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. de Bruin EC, McGranahan N, Mitter R, Salm M, Wedge DC, Yates L, et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science (New York, NY). 2014;346(6206):251–6. https://doi.org/10.1126/science.1253462.

    Article  CAS  Google Scholar 

  111. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214–8. https://doi.org/10.1038/nature12213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, et al. Tracking the evolution of non-small-cell lung cancer. N Engl J Med. 2017;376(22):2109–21. https://doi.org/10.1056/NEJMoa1616288.

    Article  CAS  PubMed  Google Scholar 

  113. 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. https://doi.org/10.1093/annonc/mdx017.

    Article  CAS  PubMed  Google Scholar 

  114. 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. https://doi.org/10.1038/nm.3854.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. de Bruin EC, McGranahan N, Mitter R, Salm M, Wedge DC, Yates L, et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science. 2014;346(6206):251–6. https://doi.org/10.1126/science.1253462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Guibert NM, Paweletz C, Hu Y, Feeney NB, Plagnol V, Poole V, et al. Early detection of competing resistance mutations using plasma next-generation sequencing (NGS) in patients (pts) with EGFR-mutant NSCLC treated with osimertinib. J Clin Oncol. 2017;35(15_suppl):11529. https://doi.org/10.1200/JCO.2017.35.15_suppl.11529.

    Article  Google Scholar 

  117. Oxnard GR, Thress KS, Alden RS, Lawrance R, Paweletz CP, Cantarini M, et al. Association between plasma genotyping and outcomes of treatment with Osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol. 2016;34(28):3375–82. https://doi.org/10.1200/jco.2016.66.7162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Goldman JW, Karlovich C, Sequist LV, Melnikova V, Franovic A, Gadgeel SM, et al. EGFR genotyping of matched urine, plasma, and tumor tissue in patients with non–small-cell lung cancer treated with Rociletinib, an EGFR Tyrosine Kinase inhibitor. JCO Precis Oncol. 2018;(2):1–13. https://doi.org/10.1200/po.17.00116.

  119. Ge M, Zhuang Y, Zhou X, Huang R, Liang X, Zhan Q. High probability and frequency of EGFR mutations in non-small cell lung cancer with brain metastases. J Neuro-Oncol. 2017;135(2):413–8. https://doi.org/10.1007/s11060-017-2590-x.

    Article  CAS  Google Scholar 

  120. Shin DY, Na II, Kim CH, Park S, Baek H, Yang SH. EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol. 2014;9(2):195–9. https://doi.org/10.1097/jto.0000000000000069.

    Article  CAS  PubMed  Google Scholar 

  121. Hsiao SH, Chou YT, Lin SE, Hsu RC, Chung CL, Kao YR, et al. Brain metastases in patients with non-small cell lung cancer: the role of mutated-EGFRs with an exon 19 deletion or L858R point mutation in cancer cell dissemination. Oncotarget. 2017;8(32):53405–18. https://doi.org/10.18632/oncotarget.18509.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Mak KS, Gainor JF, Niemierko A, Oh KS, Willers H, Choi NC, et al. Significance of targeted therapy and genetic alterations in EGFR, ALK, or KRAS on survival in patients with non–small cell lung cancer treated with radiotherapy for brain metastases. Neuro-Oncology. 2015;17(2):296–302. https://doi.org/10.1093/neuonc/nou146.

    Article  CAS  PubMed  Google Scholar 

  123. Martínez P, Mak RH, Oxnard GR. Targeted therapy as an alternative to whole-brain radiotherapy in egfr-mutant or alk-positive non–small-cell lung cancer with brain metastases. JAMA Oncol. 2017;3(9):1274–5. https://doi.org/10.1001/jamaoncol.2017.1047.

    Article  PubMed  Google Scholar 

  124. 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. https://doi.org/10.1200/JCO.2016.69.7144.

    Article  CAS  PubMed  Google Scholar 

  125. Yang JC, Cho BC, Kim CH, Kim S, Lee J, Su W, et al. Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): updated results from the BLOOM study. J Clin Oncol. 2017;35(15_suppl):2020. https://doi.org/10.1200/JCO.2017.35.15_suppl.2020.

    Article  Google Scholar 

  126. Ahn M-J, Kim D-W, Cho BC, Kim S-W, Lee J-S, Ahn JS, et al. Phase I study (BLOOM) of AXD3759, a BBB penetrable EGFR inhibitor, in TKI naïve EGFRm NSCLC patients in CNS metastases. J Clin Oncol. 2017;35(suppl 18):abst 2006.

    Article  Google Scholar 

  127. Corre R, Gervais R, Guisier F, Tassy L, Vinas F, Lamy R, et al. Octogenarians with EGFR-mutated non-small cell lung cancer treated by tyrosine-kinase inhibitor: a multicentric real-world study assessing tolerance and efficacy (OCTOMUT study). Oncotarget. 2018;9(9):8253–62. https://doi.org/10.18632/oncotarget.23836.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Yoshioka H, Komuta K, Imamura F, Kudoh S, Seki A, Fukuoka M. Efficacy and safety of erlotinib in elderly patients in the phase IV POLARSTAR surveillance study of Japanese patients with non-small-cell lung cancer. Lung Cancer. 2014;86(2):201–6. https://doi.org/10.1016/j.lungcan.2014.09.015.

    Article  PubMed  Google Scholar 

  129. Roviello G, Zanotti L, Cappelletti MR, Gobbi A, Dester M, Paganini G, et al. Are EGFR tyrosine kinase inhibitors effective in elderly patients with EGFR-mutated non-small cell lung cancer? Clin Exp Med. 2018;18(1):15–20. https://doi.org/10.1007/s10238-017-0460-7.

    Article  CAS  PubMed  Google Scholar 

  130. Morikawa N, Minegishi Y, Inoue A, Maemondo M, Kobayashi K, Sugawara S, et al. First-line gefitinib for elderly patients with advanced NSCLC harboring EGFR mutations. A combined analysis of North-East Japan Study Group studies. Expert Opin Pharmacother. 2015;16(4):465–72. https://doi.org/10.1517/14656566.2015.1002396.

    Article  CAS  PubMed  Google Scholar 

  131. Spigel DR, Hainsworth JD, Burkett ER, Burris HA, Yardley DA, Thomas M, et al. Single-agent gefitinib in patients with untreated advanced non-small-cell lung cancer and poor performance status: a Minnie pearl cancer research network phase II trial. Clin Lung Cancer. 2005;7(2):127–32. https://doi.org/10.3816/CLC.2005.n.028.

    Article  PubMed  Google Scholar 

  132. Lee SM, Khan I, Upadhyay S, Lewanski C, Falk S, Skailes G, et al. First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2012;13(11):1161–70. https://doi.org/10.1016/s1470-2045(12)70412-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Oxnard GR, Lo PC, Nishino M, Dahlberg SE, Lindeman NI, Butaney M, et al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol. 2013;8(2):179–84. https://doi.org/10.1097/JTO.0b013e3182779d18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol. 2012;13(1):e23–31. https://doi.org/10.1016/s1470-2045(11)70129-2.

    Article  CAS  PubMed  Google Scholar 

  135. Arcila ME, Nafa K, Chaft JE, Rekhtman N, Lau C, Reva BA, et al. EGFR Exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther. 2013;12(2):220–9. https://doi.org/10.1158/1535-7163.Mct-12-0620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Yang M, Xu X, Cai J, Ning J, Wery JP, Li QX. NSCLC harboring EGFR exon-20 insertions after the regulatory C-helix of kinase domain responds poorly to known EGFR inhibitors. Int J Cancer. 2016;139(1):171–6. https://doi.org/10.1002/ijc.30047.

    Article  CAS  PubMed  Google Scholar 

  137. Kobayashi Y, Mitsudomi T. Not all epidermal growth factor receptor mutations in lung cancer are created equal: perspectives for individualized treatment strategy. Cancer Sci. 2016;107(9):1179–86. https://doi.org/10.1111/cas.12996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Robichaux JP, Elamin YY, Tan Z, Carter BW, Zhang S, Liu S, et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer. Nat Med. 2018;24(5):638–46. https://doi.org/10.1038/s41591-018-0007-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Socinski MA, Goldman J, El-Hariry I, Koczywas M, Vukovic V, Horn L, et al. A multicenter phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer. Clin Cancer Res. 2013;19(11):3068–77. https://doi.org/10.1158/1078-0432.Ccr-12-3381.

    Article  CAS  PubMed  Google Scholar 

  140. Ramalingam S, Goss G, Rosell R, Schmid-Bindert G, Zaric B, Andric Z, et al. A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1). Ann Oncol. 2015;26(8):1741–8. https://doi.org/10.1093/annonc/mdv220.

    Article  CAS  PubMed  Google Scholar 

  141. Pillai R, Fennell D, Kovcin V, Ciuleanu T, Ramlau R, Kowalski D, et al. PL03.09: phase 3 study of Ganetespib, a heat shock protein 90 inhibitor, with Docetaxel versus Docetaxel in advanced non-small cell lung cancer (GALAXY-2). J Thorac Oncol. 2017;12(1):S7–8. https://doi.org/10.1016/j.jtho.2016.11.009.

    Article  Google Scholar 

  142. Johnson ML, Yu HA, Hart EM, Weitner BB, Rademaker AW, Patel JD, et al. Phase I/II study of HSP90 inhibitor AUY922 and Erlotinib for EGFR-mutant lung cancer with acquired resistance to epidermal growth factor receptor Tyrosine Kinase inhibitors. J Clin Oncol. 2015;33(15):1666–73. https://doi.org/10.1200/jco.2014.59.7328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Pillai RN, Ramalingam SS. Throwing more cold water on heat shock protein 90 inhibitors in NSCLC. J Thorac Oncol. 2018;13(4):473–4. https://doi.org/10.1016/j.jtho.2018.02.010.

    Article  PubMed  Google Scholar 

  144. Felip E, Barlesi F, Besse B, Chu Q, Gandhi L, Kim SW, et al. Phase 2 study of the HSP-90 inhibitor AUY922 in previously treated and molecularly defined patients with advanced non-small cell lung cancer. J Thorac Oncol. 2018;13(4):576–84. https://doi.org/10.1016/j.jtho.2017.11.131.

    Article  PubMed  Google Scholar 

  145. Noor Z, Goldman JW, Lawler W, Melancon D, Telivala B, Braiteh F, et al. P2.13-39 a phase Ib trial of the HSP90 inhibitor AUY922 in combination with Pemetrexed in metastatic non-squamous, non-small cell lung cancer patients. J Thorac Oncol. 2018;13(10, Supplement):S813–S4. https://doi.org/10.1016/j.jtho.2018.08.1434.

    Article  Google Scholar 

  146. Piotrowska Z, Costa DB, Huberman M, Oxnard GR, Gainor JF, Heist RS, et al. Activity of AUY922 in NSCLC patients with EGFR exon 20 insertions. J Clin Oncol. 2015;33(15_suppl):8015. https://doi.org/10.1200/jco.2015.33.15_suppl.8015.

    Article  Google Scholar 

  147. Heymach J, Negrao M, Robichaux J, 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:S323–S4.

    Article  Google Scholar 

  148. Doebele RC, Riely GJ, Spira AI, Horn L, Piotrowska Z, Costa DB, et al. First report of safety, PK, and preliminary antitumor activity of the oral EGFR/HER2 exon 20 inhibitor TAK-788 (AP32788) in non–small cell lung cancer (NSCLC). J Clin Oncol. 2018;36(15_suppl):9015. https://doi.org/10.1200/JCO.2018.36.15_suppl.9015.

    Article  Google Scholar 

  149. FDA. GILOTRIF (afatinib). FDA. 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf. Accessed 1 Nov 2018.

  150. Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015;16(7):830–8. https://doi.org/10.1016/s1470-2045(15)00026-1.

    Article  CAS  PubMed  Google Scholar 

  151. Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16(2):187–99. https://doi.org/10.1016/s1470-2045(14)71207-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009;373(9674):1525–31. https://doi.org/10.1016/s0140-6736(09)60569-9.

    Article  CAS  PubMed  Google Scholar 

  153. Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, et al. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol. 2010;28(6):911–7. https://doi.org/10.1200/jco.2009.21.9618.

    Article  CAS  PubMed  Google Scholar 

  154. Herbst RS, Redman MW, Kim ES, Semrad TJ, Bazhenova L, Masters G, et al. Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study. Lancet Oncol. 2018;19(1):101–14. https://doi.org/10.1016/s1470-2045(17)30694-0.

    Article  CAS  PubMed  Google Scholar 

  155. Sgambato A, Casaluce F, Maione P, Rossi A, Ciardiello F, Gridelli C. Cetuximab in advanced non-small cell lung cancer (NSCLC): the showdown? J Thorac Dis. 2014;6(6):578–80. https://doi.org/10.3978/j.issn.2072-1439.2014.06.14.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Nakamura H, Kawasaki N, Taguchi M, Kabasawa K. Survival impact of epidermal growth factor receptor overexpression in patients with non-small cell lung cancer: a meta-analysis. Thorax. 2006;61(2):140.

    Article  CAS  PubMed  Google Scholar 

  157. 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. https://doi.org/10.1056/NEJMoa050753.

    Article  CAS  PubMed  Google Scholar 

  158. Soria J-C, 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. https://doi.org/10.1016/S1470-2045(15)00006-6.

    Article  CAS  PubMed  Google Scholar 

  159. Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015;16(7):763–74. https://doi.org/10.1016/s1470-2045(15)00021-2.

    Article  CAS  PubMed  Google Scholar 

  160. FDA. PORTRAZZA (necitumumab) injection, for intravenous use – FDA. FDA. 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125547s000lbl.pdf. Accessed 30 Oct 2018.

  161. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, et al. Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer. N Engl J Med. 2018; https://doi.org/10.1056/NEJMoa1810865.

    Article  CAS  PubMed  Google Scholar 

  162. Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665–73. https://doi.org/10.1016/s0140-6736(14)60845-x.

    Article  CAS  PubMed  Google Scholar 

  163. Hirsch FR, Herbst RS, Gandara DR. EGFR tyrosine kinase inhibitors in squamous cell lung cancer. Lancet Oncol. 2015;16(8):872–3. https://doi.org/10.1016/S1470-2045(15)00126-6.

    Article  PubMed  Google Scholar 

  164. di Noia V, D’Argento E, Pilotto S, Grizzi G, Caccese M, Iacovelli R, et al. Necitumumab in the treatment of non-small-cell lung cancer: clinical controversies. Expert Opin Biol Ther. 2018;18(9):937–45. https://doi.org/10.1080/14712598.2018.1508445.

    Article  CAS  PubMed  Google Scholar 

  165. NCCN. NCCN Clinical practice guidelines in oncology – non-small cell lung cancer. NCCN.org. 2018. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed 30 Oct 2018.

  166. Janjigian YY, Smit EF, Groen HJ, Horn L, Gettinger S, Camidge DR, et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov. 2014;4(9):1036–45. https://doi.org/10.1158/2159-8290.Cd-14-0326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Smit E, Soria JC, Janjigian YY, Groen HJM, Pao W, Calvo E, et al. 86OAfatinib (A) plus cetuximab (C) in the treatment of patients (pts) with NSCLC: the story so far. Ann Oncol. 2017;28(suppl_2):mdx091.06-mdx.06. https://doi.org/10.1093/annonc/mdx091.006.

    Article  Google Scholar 

  168. Tang Z-H, Lu J-J. Osimertinib resistance in non-small cell lung cancer: mechanisms and therapeutic strategies. Cancer Lett. 2018;420:242–6. https://doi.org/10.1016/j.canlet.2018.02.004.

    Article  CAS  PubMed  Google Scholar 

  169. 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. https://doi.org/10.1200/jco.2016.66.9218.

    Article  CAS  PubMed  Google Scholar 

  170. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel–carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med. 2006;355(24):2542–50. https://doi.org/10.1056/NEJMoa061884.

    Article  CAS  PubMed  Google Scholar 

  171. Sandler A, Yi J, Dahlberg S, Kolb MM, Wang L, Hambleton J, et al. Treatment outcomes by tumor histology in Eastern Cooperative Group Study E4599 of bevacizumab with paclitaxel/carboplatin for advanced non-small cell lung cancer. J Thorac Oncol. 2010;5(9):1416–23. https://doi.org/10.1097/JTO.0b013e3181da36f4.

    Article  PubMed  Google Scholar 

  172. Herbst RS, Ansari R, Bustin F, Flynn P, Hart L, Otterson GA, et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet. 2011;377(9780):1846–54. https://doi.org/10.1016/s0140-6736(11)60545-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Furuya N, Fukuhara T, Saito H, Watanabe K, Sugawara S, Iwasawa S, 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(15_suppl):9006. https://doi.org/10.1200/JCO.2018.36.15_suppl.9006.

    Article  Google Scholar 

  174. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non–small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28. https://doi.org/10.1056/NEJMoa1501824.

    Article  PubMed  Google Scholar 

  175. Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378(22):2078–92. https://doi.org/10.1056/NEJMoa1801005.

    Article  CAS  PubMed  Google Scholar 

  176. Garassino MC, Gelibter AJ, Grossi F, Chiari R, Soto Parra H, Cascinu S, et al. Italian Nivolumab expanded access program in nonsquamous non-small cell lung cancer patients: results in never-smokers and EGFR-mutant patients. J Thorac Oncol. 2018;13(8):1146–55. https://doi.org/10.1016/j.jtho.2018.04.025.

    Article  PubMed  Google Scholar 

  177. Lee CK, Man J, Lord S, Links M, Gebski V, Mok T, et al. Checkpoint inhibitors in metastatic EGFR-Mutated non-small cell lung cancer-a meta-analysis. J Thorac Oncol. 2017;12(2):403–7. https://doi.org/10.1016/j.jtho.2016.10.007.

    Article  PubMed  Google Scholar 

  178. Ahn MJ, Yang J, Yu H, Saka H, Ramalingam S, Goto K, et al. 136O: Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: results from the TATTON phase Ib trial. J Thorac Oncol. 2016;11(4):S115. https://doi.org/10.1016/S1556-0864(16)30246-5.

    Article  Google Scholar 

  179. Mezquita L, Planchard D. Durvalumab for the treatment of non-small cell lung cancer. Expert Rev Respir Med. 2018;12(8):627–39. https://doi.org/10.1080/17476348.2018.1494575.

    Article  CAS  PubMed  Google Scholar 

  180. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288–301. https://doi.org/10.1056/NEJMoa1716948.

    Article  CAS  PubMed  Google Scholar 

  181. FDA. TECENTRIQ (atezolizumab) injection, for intravenous use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761034s009lbl.pdf. Accessed 14 Jan 2019.

  182. Ortiz-Cuaran S, Scheffler M, Plenker D, Dahmen L, Scheel AH, Fernandez-Cuesta L, et al. Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors. Clin Cancer Res. 2016;22(19):4837.

    Article  CAS  PubMed  Google Scholar 

  183. Yang Z, Yang N, Ou Q, Xiang Y, Jiang T, Wu X, et al. Investigating novel resistance mechanisms to third-generation EGFR Tyrosine Kinase inhibitor Osimertinib in non–small cell lung cancer patients. Clin Cancer Res. 2018;24(13):3097.

    Article  CAS  PubMed  Google Scholar 

  184. Yu HA, Tian SK, Drilon AE, Borsu L, Riely GJ, Arcila ME, et al. Acquired resistance of EGFR-mutant lung cancer to a T790M-specific EGFR inhibitor: emergence of a third mutation (C797S) in the EGFR Tyrosine Kinase domain. JAMA Oncol. 2015;1(7):982–4. https://doi.org/10.1001/jamaoncol.2015.1066.

    Article  PubMed  PubMed Central  Google Scholar 

  185. Kim TM, Song A, Kim D-W, Kim S, Ahn Y-O, Keam B, et al. Mechanisms of acquired resistance to AZD9291: a mutation-selective, irreversible EGFR inhibitor. J Thorac Oncol. 2015;10(12):1736–44. https://doi.org/10.1097/JTO.0000000000000688.

    Article  CAS  PubMed  Google Scholar 

  186. Oxnard GR, Hu Y, Mileham KF, Husain H, Costa DB, Tracy P, 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; https://doi.org/10.1001/jamaoncol.2018.2969.

    Article  PubMed  Google Scholar 

  187. Ou SI, Cui J, Schrock AB, Goldberg ME, Zhu VW, Albacker L, et al. Emergence of novel and dominant acquired EGFR solvent-front mutations at Gly796 (G796S/R) together with C797S/R and L792F/H mutations in one EGFR (L858R/T790M) NSCLC patient who progressed on osimertinib. Lung Cancer. 2017;108:228–31. https://doi.org/10.1016/j.lungcan.2017.04.003.

    Article  PubMed  Google Scholar 

  188. Hidaka N, Iwama E, Kubo N, Harada T, Miyawaki K, Tanaka K, et al. Most T790M mutations are present on the same EGFR allele as activating mutations in patients with non-small cell lung cancer. Lung Cancer. 2017;108:75–82. https://doi.org/10.1016/j.lungcan.2017.02.019.

    Article  PubMed  Google Scholar 

  189. 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. 2015;21(17):3924–33. https://doi.org/10.1158/1078-0432.Ccr-15-0560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Wang Z, Yang JJ, Huang J, Ye JY, Zhang XC, Tu HY, 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. https://doi.org/10.1016/j.jtho.2017.06.017.

    Article  PubMed  Google Scholar 

  191. Arulananda S, Do H, Musafer A, Mitchell P, Dobrovic A, John T. Combination Osimertinib and Gefitinib in C797S and T790M EGFR-mutated non-small cell lung cancer. J Thorac Oncol. 2017;12(11):1728–32. https://doi.org/10.1016/j.jtho.2017.08.006.

    Article  PubMed  Google Scholar 

  192. Zhao P, Yao M-Y, Zhu S-J, Chen J-Y, Yun C-H. Crystal structure of EGFR T790M/C797S/V948R in complex with EAI045. Biochem Biophys Res Commun. 2018;502(3):332–7. https://doi.org/10.1016/j.bbrc.2018.05.154.

    Article  CAS  PubMed  Google Scholar 

  193. Jia Y, Yun C-H, Park E, Ercan D, Manuia M, Juarez J, et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature. 2016;534:129. https://doi.org/10.1038/nature17960.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Westover D, Qiao H, Ichihara E, Meador CB, Lovly CM. Mechanisms of Osimertinib resistance in EGFR mutant lung cancer. J Thorac Oncol. 2017;12(8):S1546. https://doi.org/10.1016/j.jtho.2017.06.063.

    Article  Google Scholar 

  195. Huang W-S, Liu S, Zou D, Thomas M, Wang Y, Zhou T, et al. Discovery of Brigatinib (AP26113), a phosphine oxide-containing, potent, orally active inhibitor of anaplastic lymphoma kinase. J Med Chem. 2016;59(10):4948–64. https://doi.org/10.1021/acs.jmedchem.6b00306.

    Article  CAS  PubMed  Google Scholar 

  196. 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. https://www.nature.com/articles/ncomms14768#supplementary-information. https://doi.org/10.1038/ncomms14768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. 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. https://doi.org/10.1016/s1470-2045(16)30392-8.

    Article  CAS  PubMed  Google Scholar 

  198. Planchard D, Loriot Y, André F, Gobert A, Auger N, Lacroix L, et al. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol. 2015;26(10):2073–8. https://doi.org/10.1093/annonc/mdv319.

    Article  CAS  PubMed  Google Scholar 

  199. Ou S-HI, Agarwal N, Ali SM. High MET amplification level as a resistance mechanism to osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment post-osimertinib progression. Lung Cancer. 2016;98:59–61. https://doi.org/10.1016/j.lungcan.2016.05.015.

    Article  PubMed  Google Scholar 

  200. York ER, Varella-Garcia M, Bang TJ, Aisner DL, Camidge DR. Tolerable and effective combination of full-dose crizotinib and osimertinib targeting MET amplification sequentially emerging after T790M positivity in EGFR-mutant non–small cell lung cancer. J Thorac Oncol. 2017;12(7):e85–8. https://doi.org/10.1016/j.jtho.2017.02.020.

    Article  PubMed  Google Scholar 

  201. Ahn M, Han J, Sequist L, Cho BC, Lee JS, Kim S, et al. OA 09.03 TATTON Ph Ib expansion Cohort: Osimertinib plus Savolitinib for Pts with EGFR-Mutant MET-Amplified NSCLC after progression on prior EGFR-TKI. J Thorac Oncol. 2017;12(11):S1768. https://doi.org/10.1016/j.jtho.2017.09.377.

    Article  Google Scholar 

  202. Patnaik A, Gordon M, Tsai F, Papadopoulous K, Rasco D, Beeram SM, et al. A phase I study of LY3164530, a bispecific antibody targeting MET and EGFR, in patients with advanced or metastatic cancer. Cancer Chemother Pharmacol. 2018;82(3):407–18. https://doi.org/10.1007/s00280-018-3623-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. La Monica S, Cretella D, Bonelli M, Fumarola C, Cavazzoni A, Digiacomo G, et al. Trastuzumab emtansine delays and overcomes resistance to the third-generation EGFR-TKI osimertinib in NSCLC EGFR mutated cell lines. J Exp Clin Cancer Res. 2017;36(1):174. https://doi.org/10.1186/s13046-017-0653-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Romaniello D, Mazzeo L, Mancini M, Marrocco I, Noronha A, Kreitman MS, et al. A combination of approved antibodies overcomes resistance of lung cancer to Osimertinib by blocking bypass pathways. Clin Cancer Res. 2018; https://doi.org/10.1158/1078-0432.Ccr-18-0450.

    Article  PubMed  Google Scholar 

  205. Janne PA, Yu HA, Johnson ML, Vigliotti M, Shipitofsky N, Guevara FM, et al. Phase 1 study of the anti-HER3 antibody drug conjugate U3-1402 in metastatic or unresectable EGFR-mutant NSCLC. J Clin Oncol. 2018;36(15_suppl):TPS9110–TPS. https://doi.org/10.1200/JCO.2018.36.15_suppl.TPS9110.

    Article  Google Scholar 

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    Zorawar S. Noor & Jonathan W. Goldman

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    Ravi Salgia

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Noor, Z.S., Goldman, J.W. (2019). EGFR Targeted Therapy. In: Salgia, R. (eds) Targeted Therapies for Lung Cancer. Current Cancer Research. Springer, Cham. https://doi.org/10.1007/978-3-030-17832-1_1

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