Targeted Oncology

, Volume 13, Issue 2, pp 141–156 | Cite as

Treatment of EGFR T790M-Positive Non-Small Cell Lung Cancer

  • Joan Rou-En Choo
  • Chee-Seng Tan
  • Ross A. Soo
Review Article


The treatment of lung cancer has changed dramatically with the development of tyrosine kinase inhibitors (TKIs) that target sensitizing somatic mutations of the epidermal growth factor receptor (EGFR). Despite remarkable initial responses, patients eventually develop progressive disease, with the most common cause of resistance to first-line EGFR TKIs being the acquired T790M mutation. Various third-generation EGFR TKIs have been developed to specifically target this acquired mutation, of which osimertinib is currently the only approved agent. In addition, the eagerly anticipated data from the FLAURA study recently found improved efficacy with increased progression-free survival (PFS) with osimertinib compared to standard of care first-generation EGFR TKIs in the first-line setting. Of note, osimertinib has also demonstrated promising efficacy in patients with known brain metastases. However, as patients invariably develop resistance during treatment with osimertinib, most commonly with the development of triple mutated EGFR (sensitizing mutations/T790M/C797S), which is resistant to all existing EGFR TKIs, efforts are currently ongoing to develop new strategies or novel compounds to specifically target this resistance mechanism.


Compliance with Ethical Standards



Conflict of interest

Ross Soo has received honoraria from AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Taiho, and a research grant from AstraZeneca.

Chee-Seng Tan has received honoraria from AstraZeneca, Merck, Boehringer Ingelheim, Novartis, Eli Lilly, Eisai, and Bristol-Myers Squibb.

Joan Choo declares no conflict of interests.


  1. 1.
    World Health Organization (WHO). Cancer fact sheet no. 297. 2017. Accessed 9 Aug 2017.
  2. 2.
    Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol. 2014;9(2):154–62. Scholar
  3. 3.
    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. Scholar
  4. 4.
    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. Scholar
  5. 5.
    Paez JG, Jänne 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. Scholar
  6. 6.
    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. Scholar
  7. 7.
    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. Scholar
  8. 8.
    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. Scholar
  9. 9.
    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. Scholar
  10. 10.
    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(18_suppl):LBA9007. Scholar
  11. 11.
    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. Scholar
  12. 12.
    Corallo S, D’Argento E, Strippoli A, Basso M, Monterisi S, Rossi S, et al. Treatment options for EGFR T790M-negative EGFR tyrosine kinase inhibitor-resistant non-small cell lung cancer. Target Oncol. 2017;12(2):153–61. Scholar
  13. 13.
    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. Scholar
  14. 14.
    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. Scholar
  15. 15.
    Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor–mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res. 2006;12(21):6494–501. Scholar
  16. 16.
    Bean J, Riely GJ, Balak M, Marks JL, Ladanyi M, Miller VA, et al. Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clin Cancer Res. 2008;14(22):7519–25. Scholar
  17. 17.
    Costa DB, Halmos B, Kumar A, Schumer ST, Huberman MS, Boggon TJ, et al. BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med. 2007;4(10):1669–79. Scholar
  18. 18.
    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. Scholar
  19. 19.
    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. Scholar
  20. 20.
    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. Scholar
  21. 21.
    Ohashi K, Sequist LV, Arcila ME, Moran T, Chmielecki J, Lin YL, et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci U S A. 2012;109(31):E2127–33. Scholar
  22. 22.
    Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet. 2012;44(8):852–60. Scholar
  23. 23.
    Tan DSW, Lee DH, Soo R, Michels S, Barlesi F, Sangha R, et al. P3.02b-117 phase Ib results from a study of Capmatinib (INC280) + EGF816 in patients with EGFR-mutant non-small cell lung cancer (NSCLC). J Thorac Oncol. 2017;12(1):S1264–5. Scholar
  24. 24.
    McCoach CE, Yu A, Gandara DR, Riess J, Li T, Lara P, et al. Phase I study of INC280 plus erlotinib in patients with MET expressing adenocarcinoma of the lung. J Clin Oncol. 2015;33(15_suppl):2587. Scholar
  25. 25.
    Scagliotti G, von Pawel J, Novello S, Ramlau R, Favaretto A, Barlesi F, et al. Phase III multinational, randomized, double-blind, placebo-controlled study of tivantinib (ARQ 197) plus erlotinib versus erlotinib alone in previously treated patients with locally advanced or metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015;33(24):2667–74. Scholar
  26. 26.
    Zakowski MF, Ladanyi M, Kris MG. EGFR mutations in small-cell lung cancers in patients who have never smoked. N Engl J Med. 2006;355(2):213–5. Scholar
  27. 27.
    Royal College of Physicians (RCP). National Lung Cancer Audit (NLCA) annual report 2016 (for the audit period 2015). 2016. Accessed 11 Aug 2017.
  28. 28.
    Hata A, Katakami N, Yoshioka H, Kaji R, Masago K, Fujita S, et al. Spatiotemporal T790M heterogeneity in individual patients with EGFR-mutant non-small-cell lung cancer after acquired resistance to EGFR-TKI. J Thorac Oncol. 2015;10(11):1553–9. Scholar
  29. 29.
    U.S. Food and Drug Administration (FDA). Summary of safety and effectiveness data (SSED) for cobas® EGFR Mutation Test. 2013. Accessed 11 Aug 2017.
  30. 30.
    U.S. Food and Drug Administration (FDA). Summary of safety and effectiveness data (SSED) for therascreen® EGFR RGQ PCR Kit. 2013. Accessed 11 Aug 2017.
  31. 31.
    U.S. Food and Drug Administration (FDA). Summary of safety and effectiveness data (SSED) for cobas® EGFR Mutation Test v2. 2015. Accessed 11 Aug 2017.
  32. 32.
    Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch RD, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 2001;61(4):1659–65.PubMedGoogle Scholar
  33. 33.
    Wang Z, Chen R, Wang S, Zhong J, Wu M, Zhao J, et al. Quantification and dynamic monitoring of EGFR T790M in plasma cell-free DNA by digital PCR for prognosis of EGFR-TKI treatment in advanced NSCLC. PLoS One. 2014;9(11):e110780. Scholar
  34. 34.
    Kukita Y, Uchida J, Oba S, Nishino K, Kumagai T, Taniguchi K, et al. Quantitative identification of mutant alleles derived from lung cancer in plasma cell-free DNA via anomaly detection using deep sequencing data. PLoS One. 2013;8(11):e81468. Scholar
  35. 35.
    Nagai Y, Miyazawa H, Huqun, Tanaka T, Udagawa K, Kato M, et al. Genetic heterogeneity of the epidermal growth factor receptor in non-small cell lung cancer cell lines revealed by a rapid and sensitive detection system, the peptide nucleic acid-locked nucleic acid PCR clamp. Cancer Res. 2005;65(16):7276–82. Scholar
  36. 36.
    Bai H, Mao L, Wang HS, Zhao J, Yang L, An TT, et al. Epidermal growth factor receptor mutations in plasma DNA samples predict tumor response in Chinese patients with stages IIIB to IV non-small-cell lung cancer. J Clin Oncol. 2009;27(16):2653–9. Scholar
  37. 37.
    Forshew T, Murtaza M, Parkinson C, Gale D, Tsui DW, Kaper F, et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med. 2012;4(136):136ra68. Scholar
  38. 38.
    Newman AM, Bratman SV, To J, Wynne JF, Eclov NC, Modlin LA, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20(5):548–54. Scholar
  39. 39.
    Thress KS, Brant R, Carr TH, Dearden S, Jenkins S, Brown H, 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. Scholar
  40. 40.
    Karlovich C, Goldman JW, Sun JM, Mann E, Sequist LV, Konopa K, et al. Assessment of EGFR mutation status in matched plasma and tumor tissue of NSCLC patients from a phase I study of rociletinib (CO-1686). Clin Cancer Res. 2016;22(10):2386–95. Scholar
  41. 41.
    Wang W, Song Z, Zhang Y. A comparison of ddPCR and ARMS for detecting EGFR T790M status in ctDNA from advanced NSCLC patients with acquired EGFR-TKI resistance. Cancer Med. 2017;6(1):154–62. Scholar
  42. 42.
    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. Scholar
  43. 43.
    Jenkins S, Yang JC, Ramalingam SS, Yu K, Patel S, Weston S, et al. Plasma ctDNA analysis for detection of the EGFR T790M mutation in patients with advanced non-small cell lung cancer. J Thorac Oncol. 2017;12(7):1061–70. Scholar
  44. 44.
    Sundaresan TK, Sequist LV, Heymach JV, Riely GJ, Jänne 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. Scholar
  45. 45.
    Reckamp KL, Melnikova VO, Karlovich C, Sequist LV, Camidge DR, Wakelee H, et al. A highly sensitive and quantitative test platform for detection of NSCLC EGFR mutations in urine and plasma. J Thorac Oncol. 2016;11(10):1690–700. Scholar
  46. 46.
    Wakelee HA, Gadgeel SM, Goldman JW, Reckamp KL, Karlovich CA, Melnikova V, et al. Epidermal growth factor receptor (EGFR) genotyping of matched urine, plasma and tumor tissue from non-small cell lung cancer (NSCLC) patients (pts) treated with rociletinib. J Clin Oncol. 2016;34(15_suppl):9001. Scholar
  47. 47.
    Wei F, Lin CC, Joon A, Feng Z, Troche G, Lira ME, et al. Noninvasive saliva-based EGFR gene mutation detection in patients with lung cancer. Am J Respir Crit Care Med. 2014;190(10):1117–26. Scholar
  48. 48.
    Satouchi M, Tanaka H, Yoshioka H, Shimokawaji T, Mizuno K, Takeda K, et al. Detection of epidermal growth factor receptor gene T790M mutation in cytology samples using the cobas® EGFR mutation test. Lung Cancer. 2017;111:190–4. Scholar
  49. 49.
    Théoleyre S, Masson I, Herbreteau G, Vallée A, Sénellart H, Denis MG. Treatment of a NSCLC patient with osimertinib based on the detection of the EGFR T790M resistance mutation in cerebrospinal fluid. Lung Cancer. 2017;114:111–2. Scholar
  50. 50.
    Vallée A, Audigier-Valette C, Herbreteau G, Merrien J, Tessonnier L, Théoleyre S, et al. Rapid clearance of circulating tumor DNA during treatment with AZD9291 of a lung cancer patient presenting the resistance EGFR T790M mutation. Lung Cancer. 2016;91:73–4.
  51. 51.
    Gautschi O, Aebi S, Heukamp LC. Successful AZD9291 therapy based on circulating T790M. J Thorac Oncol. 2015;10(12):e122–4. Scholar
  52. 52.
    Remon J, Caramella C, Joelet C, Lacroix L, Lawson A, Smalley S, et al. P3.02b-102 osimertinib benefit in ctDNA T790M positive, EGFR-mutant NSCLC patients. J Thorac Oncol. 2017;12(1):S1254–5. Scholar
  53. 53.
    Cross DA, 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. Scholar
  54. 54.
    Sequist LV, Rolfe L, Allen AR. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2015;373(6):578–9. Scholar
  55. 55.
    Park K, Lee JS, Han JY, Lee KH, Kim JH, Cho EK, et al. 1300: efficacy and safety of BI 1482694 (HM61713), an EGFR mutant-specific inhibitor, in T790M-positive NSCLC at the recommended phase II dose. J Thorac Oncol. 2016;11(4 Suppl):S113. Scholar
  56. 56.
    Yu HA, Spira AI, Horn L, Weiss J, West HJ, Giaccone G, et al. Antitumor activity of ASP8273 300 mg in subjects with EGFR mutation-positive non-small cell lung cancer: interim results from an ongoing phase 1 study. J Clin Oncol. 2016;34(15_suppl):9050. Scholar
  57. 57.
    Tan DSW, Yang JCH, Leighl NB, Riely GJ, Sequist LV, Felip E, 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. Scholar
  58. 58.
    Husain H, Martins R, Goldberg S, Senico P, Ma W, Masters J, et al. P3.02b-001 phase 1 dose escalation of PF-06747775 (EGFR-T790M inhibitor) in patients with advanced EGFRm (del 19 or L858R+/−T790M) NSCLC. J Thorac Oncol. 2017;12(1):S1185. Scholar
  59. 59.
    Zhang L, Zhao H, Hu B, Jiang J, Zheng X, Zhang Y, et al. First-in-human study of AC0010, a novel irreversible, mutant-selective EGFR inhibitor in patients with 1st generation EGFR TKI-resistant non-small cell lung cancer (NSCLC). Ann Oncol. 2016;27(suppl_6):359O. Scholar
  60. 60.
    Jänne PA, Yang JC, 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. Scholar
  61. 61.
    Goss G, Tsai CM, Shepherd FA, Bazhenova L, Lee JS, Chang GC, et al. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2016;17(12):1643–52. Scholar
  62. 62.
    Yang JC-H, Ahn M-J, Kim D-W, Ramalingam SS, Sequist LV, Su W-C, et al. Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study phase II extension component. J Clin Oncol. 2017;35(12):1288–96. Scholar
  63. 63.
    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. Scholar
  64. 64.
    Ramalingam S, Reungwetwattana T, Chewaskulyong B, Dechaphunkul A, Lee KH, Imamura F, et al. 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. Scholar
  65. 65.
    Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, 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. Scholar
  66. 66.
    Mok T, Ahn MJ, Han JY, Kang JH, Katakami N, Kim HR, 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;35(15_suppl):9005. Scholar
  67. 67.
    Yang JCH, Kim DW, Kim SW, Cho BC, Lee JS, Ye X, et al. Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC): updated results from BLOOM, a phase I study. J Clin Oncol. 2016;34(15_suppl):9002. Scholar
  68. 68.
    Tan C-S, Cho BC, Soo RA. Treatment options for EGFR mutant NSCLC with CNS involvement—can patients BLOOM with the use of next generation EGFR TKIs? Lung Cancer. 2017;108:29–37. Scholar
  69. 69.
    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. Scholar
  70. 70.
    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. Scholar
  71. 71.
    Walter AO, Sjin RT, Haringsma HJ, Ohashi K, Sun J, Lee K, et al. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov. 2013;3(12):1404–15. Scholar
  72. 72.
    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. Scholar
  73. 73.
    Clovis Oncology announces regulatory update for rociletinib NDA filing. Business Wire. 2015. Accessed 27 Aug 2017.
  74. 74.
    Lee KO, Cha MY, Kim M, Song JY, Lee JH, Kim YH, et al. Discovery of HM61713 as an orally available and mutant EGFR selective inhibitor. Cancer Res. 2014;74(19 Supplement):LB-100.CrossRefGoogle Scholar
  75. 75.
    Park K, Lee J-S, Lee KH, Kim J-H, Min YJ, Cho JY, et al. Updated safety and efficacy results from phase I/II study of HM61713 in patients (pts) with EGFR mutation positive non-small cell lung cancer (NSCLC) who failed previous EGFR-tyrosine kinase inhibitor (TKI). J Clin Oncol. 2015;33(15_suppl):8084. Scholar
  76. 76.
    Boehringer Ingelheim returns development and commercial rights of olmutinib to Hanmi Pharmaceutical. 2016. Accessed 26 Aug 2017.
  77. 77.
    Ministry of Food and Drug Safety (South Korea). Safety report on olmutinib (article in Korean). 2016. Accessed 27 Aug 2017.
  78. 78.
    Tan DS-W, Seto T, Leighl NB, Riely GJ, Sequist LV, Felip E, et al. First-in-human phase I study of EGF816, a third generation, mutant-selective EGFR tyrosine kinase inhibitor, in advanced non-small cell lung cancer (NSCLC) harboring T790M. J Clin Oncol. 2015;33(15_suppl):8013. Scholar
  79. 79.
    Kasibhatla S, Li J, Tompkins C, Vaillancourt M-T, Anderson J, Pferdekamper AC, et al. EGF816, a novel covalent inhibitor of mutant-selective epidermal growth factor receptor, overcomes T790M-mediated resistance in NSCLC. Cancer Res. 2014;74(19 Supplement):1733. Scholar
  80. 80.
    Tan DS-W, Kim D-W, Leighl NB, Riely GJ, Yang JC-H, Wolf J, et al. Genomic profiling of resistant tumor samples following progression on EGF816, a third generation, mutant-selective EGFR tyrosine kinase inhibitor (TKI), in advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2017;35(15_suppl):11506. Scholar
  81. 81.
    Sakagami H, Konagai S, Yamamoto H, Tanaka H, Matsuya T, Mori M, et al. ASP8273, a novel mutant-selective irreversible EGFR inhibitor, inhibits growth of non-small cell lung cancer (NSCLC) cells with EGFR activating and T790M resistance mutations. Cancer Res. 2014;74(19 Supplement):1728. Scholar
  82. 82.
    Goto Y, Nokihara H, Murakami H, Shimizu T, Seto T, Krivoshik AP, et al. ASP8273, a mutant-selective irreversible EGFR inhibitor in patients (pts) with NSCLC harboring EGFR activating mutations: preliminary results of first-in-human phase I study in Japan. J Clin Oncol. 2015;33(15_suppl):8014. Scholar
  83. 83.
    Astellas Announces Decision to Discontinue ASP8273 Treatment Arm and Close Randomization for Clinical Study Protocol 8273-CL-0302. Astellas News Release. 2017. Accessed 27 Aug 2017.
  84. 84.
    Husain H, Martins RG, Goldberg SB, Senico P, Ma W, Masters J, et al. 1358P. First-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. Scholar
  85. 85.
    Xu X, Mao L, Xu W, Tang W, Zhang X, Xi B, et al. AC0010, an irreversible EGFR inhibitor selectively targeting mutated EGFR and overcoming T790M-induced resistance in animal models and lung cancer patients. Mol Cancer Ther. 2016;15(11):2586–97. Scholar
  86. 86.
    Hong MH, Lee IY, Koh JS, Lee J, Suh B-C, Song H-J, et al. P3.02b-119 YH25448, a highly selective 3rd generation EGFR TKI, exhibits superior survival over osimertinib in animal model with brain metastases from NSCLC. J Thorac Oncol. 2017;12(1):S1265–6. Scholar
  87. 87.
    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. Scholar
  88. 88.
    Goldberg S, Moon J, Lilenbaum R, Politi K, Melnick MA, Stinchcombe T, et al. P3.02b-052 afatinib with or without cetuximab for first-line treatment of EGFR-mutant NSCLC: interim safety results of SWOG S1403. J Thorac Oncol. 2017;12(1):S1220–1. Scholar
  89. 89.
    Janjigian YY, Azzoli CG, Krug LM, Pereira LK, Rizvi NA, Pietanza MC, et al. Phase I/II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib. Clin Cancer Res. 2011;17(8):2521–7. Scholar
  90. 90.
    Lee JY, Sun J-M, Lim SH, Kim HS, Yoo KH, Jung KS, et al. A phase Ib/II study of afatinib in combination with nimotuzumab in non-small cell lung cancer patients with acquired resistance to gefitinib or erlotinib. Clin Cancer Res. 2016;22(9):2139–45. Scholar
  91. 91.
    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. Scholar
  92. 92.
    Ahn M-J, 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. Scholar
  93. 93.
    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. Scholar
  94. 94.
    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. Scholar
  95. 95.
    Ou Q, Wu X, Bao H, Tong X, Wang X, Zhang X, et al. Investigating novel resistance mechanisms to third generation EGFR TKI osimertinib in non-small cell lung cancer patients using next generation sequencing. J Clin Oncol. 2017;35(15_suppl):2572. Scholar
  96. 96.
    Song HN, Jung KS, Yoo KH, Cho J, Lee JY, Lim SH, et al. Acquired C797S mutation upon treatment with a T790M-specific third-generation EGFR inhibitor (HM61713) in non-small cell lung cancer. J Thorac Oncol. 2016;11(4):e45–7. Scholar
  97. 97.
    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. Scholar
  98. 98.
    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. Scholar
  99. 99.
    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. Scholar
  100. 100.
    Menon R, Müller J, Schneider P, Lakis S, Thress K, Wolf J, et al. A novel EGFR(C797) variant detected in a pleural biopsy specimen from an osimertinib-treated patient using a comprehensive hybrid capture-based next-generation sequencing assay. J Thorac Oncol. 2016;11(9):e105–7. Scholar
  101. 101.
    Bersanelli M, Minari R, Bordi P, Gnetti L, Bozzetti C, Squadrilli A, et al. L718Q mutation as new mechanism of acquired resistance to AZD9291 in EGFR-mutated NSCLC. J Thorac Oncol. 2016;11(10):e121–3. Scholar
  102. 102.
    Ou S-H, 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. Scholar
  103. 103.
    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. Scholar
  104. 104.
    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):4837–47. Scholar
  105. 105.
    Ho C-C, Liao W-Y, Lin C-A, Shih J-Y, Yu C-J, Yang JC-H. Acquired BRAF V600E mutation as resistant mechanism after treatment with osimertinib. J Thorac Oncol. 2017;12(3):567–72. Scholar
  106. 106.
    Ou S-H, 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. Scholar
  107. 107.
    Piotrowska Z, Thress KS, Mooradian M, Heist RS, Azzoli CG, Temel JS, et al. MET amplification (amp) as a resistance mechanism to osimertinib. J Clin Oncol. 2017;35(15_suppl):9020. Scholar
  108. 108.
    Oxnard GR, Thress K, Paweletz C, Stetson D, Dougherty B, Markovets A, et al. ORAL17.07. Mechanisms of acquired resistance to AZD9291 in EGFR T790M positive lung cancer. J Thorac Oncol. 2015;10(9 Suppl.2):ORAL 17.07.Google Scholar
  109. 109.
    Ramalingam SS, Yang JC-H, Lee CK, Kurata T, Kim D-W, John T, et al. Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J Clin Oncol. 2017.
  110. 110.
    Kim TM, Song A, Kim DW, Kim S, Ahn YO, Keam B, et al. Mechanisms of acquired resistance to AZD9291: a mutation-selective, irreversible EGFR inhibitor. J Thorac Oncol. 2015;10(12):1736–44. Scholar
  111. 111.
    Ham JS, Kim S, Kim HK, Byeon S, Sun J-M, Lee SH, et al. Two cases of small cell lung cancer transformation from EGFR mutant adenocarcinoma during AZD9291 treatment. J Thorac Oncol. 2016;11(1):e1–4. Scholar
  112. 112.
    Lee JK, Lee J, Kim S, Kim S, Youk J, Park S, et al. Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas. J Clin Oncol. 2017;35(26):3065–74. Scholar
  113. 113.
    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):e78–80. Scholar
  114. 114.
    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. Scholar
  115. 115.
    Günther M, Juchum M, Kelter G, Fiebig H, Laufer S. Lung cancer: EGFR inhibitors with low nanomolar activity against a therapy-resistant L858R/T790M/C797S mutant. Angew Chem Int Ed Eng. 2016;55(36):10890–4. Scholar
  116. 116.
    Günther M, Lategahn J, Juchum M, Doring E, Keul M, Engel J, et al. Trisubstituted pyridinylimidazoles as potent inhibitors of the clinically resistant L858R/T790M/C797S EGFR mutant: targeting of both hydrophobic regions and the phosphate binding site. J Med Chem. 2017;60(13):5613–37. Scholar
  117. 117.
    Park H, Jung HY, Mah S, Hong S. Discovery of EGF receptor inhibitors that are selective for the d746-750/T790M/C797S mutant through structure-based de novo design. Angew Chem Int Ed Eng. 2017;56(26):7634–8. Scholar
  118. 118.
    Shi P, Oh YT, Deng L, Zhang G, Qian G, Zhang S, et al. Overcoming acquired resistance to AZD9291, a third-generation EGFR inhibitor, through modulation of MEK/ERK-dependent Bim and Mcl-1 degradation. Clin Cancer Res. 2017;23(21):6567–79 Scholar
  119. 119.
    Martin MJ, Eberlein C, Taylor M, Ashton S, Robinson D, Cross D. Inhibition of oxidative phosphorylation suppresses the development of osimertinib resistance in a preclinical model of EGFR-driven lung adenocarcinoma. Oncotarget. 2016;7(52):86313–25. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Joan Rou-En Choo
    • 1
  • Chee-Seng Tan
    • 1
  • Ross A. Soo
    • 1
    • 2
    • 3
  1. 1.Department of Haematology-OncologyNational University Cancer Institute of Singapore, National University Health SystemSingaporeSingapore
  2. 2.Cancer Science Institute of SingaporeNational University of SingaporeSingaporeSingapore
  3. 3.School of SurgeryThe University of Western AustraliaPerthAustralia

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