Until recently, there were no standard therapeutic options in the setting of acquired resistance to initial EGFR TKIs and, outside clinical trials with investigational drugs, EGFR-mutated NSCLC patients generally received platinum-based or single-agent chemotherapy upon progression. Osimertinib has led to a paradigm shift in the management of lung cancer patients progressing to first- or second-generation TKIs, thus supporting the need in clinical practice for tumor genotyping at the time of disease progression on or after EGFR TKI therapy for biomarker evaluation of EGFR T790M. Osimertinib has also demonstrated activity in patients with CNS and leptomeningeal metastasis, which is particularly relevant, given the possibility to potentially spare these patients from radiotherapy or delay its use, including WBRT, that can ultimately compromise the cognitive function and QoL. Other novel, mutant-selective EGFR TKIs produced by different pharmaceutical companies, including EGF816, naquotinib (ASP8273), avitinib (AC0010) and PF-06747775, are in clinical development (Table 2) and have shown promising activity with manageable safety profile in early phase studies.133–139 More data from ongoing studies are eagerly awaited to confirm these preliminary results. Despite the evolving therapeutic landscape for EGFR-mutated NSCLC patients, there are still several issues to be addressed, such as the optimal therapeutic sequence of different generation EGFR TKIs. Osimertinib is being tested in the first-line setting, compared with standard EGFR TKI therapy, to see whether upfront use of an irreversible inhibitor could be a more effective strategy to improve clinical outcome and delay the resistance. Another possible strategy to prevent or delay the occurrence of resistance could be the upfront combination of EGFR inhibitors with other targeted agents. Indeed, the combination of erlotinib and bevacizumab results in a long PFS in EGFR-mutated NSCLC patients and, in the BELIEF trial, this combination was effective in presence of the T790M mutation, identified in 35% of patients, who attained a PFS of 16 months.16 The assessment of T790M mutation in ctDNA by using highly sensitive blood-based assays has already proven to be feasible in clinical practice and useful to identify those patients who are candidates for osimertinib. Moreover, a combined analysis of EGFR genotyping in matched blood and urine by a highly sensitive and quantitative assay using next-generation sequencing, as performed in the TIGER-X study of rociletinib, could further improve the chance of T790M mutation detection.140 Despite the high efficacy of osimertinib in T790M-mutant NSCLC, similar to other oncogene-addicted tumors, patients may ultimately progress due to acquisition of additional mechanism of resistance by tumor cells under the selective pressure of the EGFR TKI, including the C797S mutation. A novel EGFR inhibitor, EAI045, has shown to be able to overcome T790M and C797S resistance in in vitro and in vivo studies, although its clinical efficacy still needs to be investigated. Profiling of tumors at progression remains crucial in order to unravel the complex and heterogeneous resistance mechanisms to first-, second- and third-generation EGFR TKIs. The detection of new mechanisms of resistance to third-generation EGFR TKIs is feasible through ctDNA genotyping and suggests the need for new therapeutic approaches for these patients. Liquid biopsy, including not only ctDNA but also other tumor sources such as CTCs and exosomes, appears to be the most appealing strategy to study the dynamic evolution of oncogene-addicted tumor cells during treatment with different EGFR TKIs, thereby giving an early warning about possible recurrence and helping to establish novel, potentially targetable molecular alterations.
(To view a larger version of Table 2, click here.)
The authors report no conflicts of interest in this work.
Mariacarmela Santarpia,1 Alessia Liguori,1 Niki Karachaliou,2 Maria Gonzalez-Cao,3 Maria Grazia Daffinà,1 Alessandro D’Aveni,1 Grazia Marabello,1 Giuseppe Altavilla,1 Rafael Rosell3–5
1Medical Oncology Unit, Department of Human Pathology “G. Barresi”, University of Messina, Messina, Italy; 2Institute of Oncology Rosell (IOR), University Hospital Sagrat Cor, 3Department of Oncology, Institute of Oncology Rosell (IOR), Quirón-Dexeus University Institute, Barcelona, 4Cancer Biology and Precision Medicine Program, Germans Trias i Pujol Research Institute, 5Catalan Institute of Oncology, Germans Trias i Pujol University Hospital, Badalona, Spain
1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–E386.
2. Santarpia M, Karachaliou N, Rosell R. Beyond platinum treatment for NSCLC: what does the future hold? Expert Rev Anticancer Ther. 2017;17(4):293–295.
3. Rosell R, Karachaliou N. Large-scale screening for somatic mutations in lung cancer. Lancet. 2016;387(10026):1354–1356.
4. Lazzari C, Spitaleri G, Catania C, et al. Targeting ALK in patients with advanced non small cell lung cancer: biology, diagnostic and therapeutic options. Crit Rev Oncol Hematol. 2014;89(3):358–365.
5. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–957.
6. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380–2388.
7. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11(2):121–128.
8. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;1(3):239–246.
9. Han JY, Park K, Kim SW, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012;30(10):1122–1128.
10. Inoue A, Kobayashi K, Maemondo M, et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol. 2013;24(1):54–59.
11. Sequist LV, Yang JCH, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327–3334.
12. Wu YL, Zhou C, Hu CP, 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):213–222.
13. Blackhall F, Cappuzzo F. Crizotinib: from discovery to accelerated development to front-line treatment. Ann Oncol. 2016;27(Suppl 3):iii35–iii41.
14. Novello S, Barlesi F, Califano R, Cufer T, et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(Suppl 5):v1–v27.
15. Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236–1244.
16. Rosell R, Dafni U, Felip E, et al. Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial. Lancet Respir Med. 2017;5(5):435–444.
17. Wu J, Savooji J, Liu D. Second- and third-generation ALK inhibitors for non-small cell lung cancer. J Hematol Oncol. 2016;9(1):19.
18. Santarpia M, Daffinà MG, D’Aveni A, et al. Spotlight on ceritinib in the treatment of ALK+ NSCLC: design, development and place in therapy. Drug Des Dev Ther. 2017;11:2047–2063.
19. Santarpia M, Altavilla G, Rosell R. Alectinib: a selective, next-generation ALK inhibitor for treatment of ALK-rearranged non-small-cell lung cancer. Expert Rev Respir Med. 2015;9(3):255–268.
20. Planchard D, Besse B, Groen HJ, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17(7):984–993.
21. Santarpia M, Giovannetti E, Rolfo C, et al. Recent developments in the use of immunotherapy in non-small cell lung cancer. Expert Rev Respir Med. 2016;10(7):781–798.
22. Karachaliou N, Sosa AE, Barron FB, et al. Pharmacological management of relapsed/refractory NSCLC with chemical drugs. Expert Opin Pharmacother. 2017;18(3):295–304.
23. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823–1833.
24. Dholaria B, Hammond W, Shreders A, Lou Y. Emerging therapeutic agents for lung cancer. J Hematol Oncol. 2016;9(1):138.
25. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005;5(5):341–354.
26. Ciardiello F, Tortora G. EGFR antagonist in cancer treatment. N Engl J Med. 2008;358(11):1160–1174.
27. Cancer Genome Atlas Research N. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489(7417):519–525.
28. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol. 2003;21(20):3798–3807.
29. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998–2006.
30. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New Engl J Med. 2004;350(21):2129–2139.
31. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–1500.
32. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101(36):13306–13311.
33. Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7(3):169–181.
34. Zhang YL, Yuan JQ, Wang KF, 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):78985–78993.
35. Greenhalgh J, Dwan K, Boland A, et al. First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer. Cochrane Database Syst Rev. 2016;(5):CD010383.
36. Yang JC, Wu YL, Schuler M, 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):141–151.
37. Ettinger DS, Wood DE, Aisner DL, et al. Non-small cell lung cancer, version 5.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2017;15(4):504–535.
38. Santarpia M, Gil N, Rosell R. Strategies to overcome resistance to tyrosine kinase inhibitors in non-small-cell lung cancer. Expert Rev Clin Pharmacol. 2015;8(4):461–477.
39. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786–792.
40. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2(3):e73.
41. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.
42. Yu HA, Arcila ME, Rekhtman N, 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):2240–2247.
43. Tan CS, Gilligan D, Pacey S. Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer. Lancet Oncol. 2015;16(9):e447–e459.
44. Koch H, Busto ME, Kramer K, et al. Chemical proteomics uncovers EPHA2 as a mechanism of acquired resistance to small molecule EGFR kinase inhibition. J Proteome Res. 2015;14(6):2617–2625.
45. Bivona TG, Hieronymus H, Parker J, et al. FAS and NF-kappaB signalling modulate dependence of lung cancers on mutant EGFR. Nature. 2011;471(7339):523–526.
46. Karachaliou N, Codony-Servat J, Teixidó C, et al. BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer. Sci Rep. 2015;5:17499.
47. Lee HJ, Zhuang G, Cao Y, et al. Drug resistance via feedback activation of stat3 in oncogene-addicted cancer cells. Cancer Cell. 2014;26(2):207–221.
48. Gandara DR, Li T, Lara PN, et al. Acquired resistance to targeted therapies against oncogene-driven non-small-cell lung cancer: approach to subtyping progressive disease and clinical implications. Clin Lung Cancer. 2014;15(1):1–6.
49. Yu HA, Sima CS, Huang J, et al. Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. J Thorac Oncol. 2013;8(3):346–351.
50. Conforti F, Catania C, Toffalorio F, et al. EGFR tyrosine kinase inhibitors beyond focal progression obtain a prolonged disease control in patients with advanced adenocarcinoma of the lung. Lung Cancer. 2013;81(3):440–444.
51. Soria JC, Wu YL, Nakagawa K, 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):990–998.
52. Soria JC, Kim SW, Wu YL, et al. Gefitinib/chemotherapy vs chemotherapy in EGFR mutation-positive NSCLC after progression on 1st line gefitinib (IMPRESS study): final overall survival (OS) analysis. Ann Oncol. 2016;27(Suppl 6):vi416–vi454.
53. Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA. 2008;105(6):2070–2075.
54. Engelman JA, Zejnullahu K, Gale CM, et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res. 2007;67(24):11924–11932.
55. Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008;27(34):4702–4711.
56. Kwak E. The role of irreversible HER family inhibition in the treatment of patients with non-small cell lung cancer. Oncologist. 2011;16(11):1498–1507.
57. Miller VA, Hirsh V, Cadranel J, 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):528–538.
58. Katakami N, Atagi S, Goto K, et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013;31(27):3335–3341.
59. Ellis PM, Shepherd FA, Millward M, et al. Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial. Lancet Oncol. 2014;15(12):1379–1388.
60. Sequist LV, Besse B, Lynch TJ, et al. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2010;28(18):3076–3083.
61. Janjigian YY, Smit EF, Groen HJ, 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):1036–1045.
62. Zhou WJ, Ercan D, Chen L, et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature. 2009;462(7276):1070–1074.
63. Riely GJ, Yu HA. EGFR: the paradigm of an oncogene-driven lung cancer. Clin Cancer Res. 2015;21(10):2221–2226.
64. Walter AO, Sjin RT, Haringsma HJ, et al. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov. 2013;3(12):1404–1415.
65. Cross DA, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4(9):1046–1061.
66. Sequist LV, Soria JC, Goldman JW, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2015;372(18):1700–1709.
67. Jänne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689–1699.
68. Van Der Steen N, Caparello C, Rolfo C, et al. New developments in the management of non-small-cell lung cancer, focus on rociletinib: what went wrong? Onco Targets Ther. 2016;9:6065–6074.
69. US Food and Drug Administration. FDA approves new pill to treat certain patients with non-small cell lung cancer; 2015. Available from: http://www.fda.gov/News Events /News room/PressAnnouncements/ucm472525.htm. Accessed May 15, 2017.
70. Hirano T, Yasuda H, Tani T, et al. In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer. Oncotarget 2015;6(36):38789–38803.
71. Planchard D, Brown KH, Kim D-W, et al. Osimertinib Western and Asian clinical pharmacokinetics in patients and healthy volunteers: implications for formulation, dose, and dosing frequency in pivotal clinical studies. Cancer Chemother Pharmacol. 2016;77(4):767–776.
72. Goss G, Tsai CM, Shepherd FA, 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):1643–1652.
73. TAGRISSO® (osimertinib) tablets, for oral use. US prescribing information; 2015. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208065s006lbl.pdf. Accessed May 15, 2017.
74. Yang JC, Ahn MJ, Kim DW, 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):1288–1296.
75. Yang J, Ramalingam SS, Jänne PA, et al. LBA2_PR: osimertinib (AZD9291) in pre-treated pts with T790M-positive advanced NSCLC: updated Phase 1 (P1) and pooled Phase 2 (P2) results. J Thorac Oncol. 2016;11(4):S152–S153.
76. Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376(7):629–640.
77. Park SJ, Kim HT, Lee DH, et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer. 2012;77(3):556–560.
78. Hoffknecht P, Tufman A, Wehler T, et al. Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated nonsmall-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol. 2015;10(1):156–163.
79. Altavilla G, Arrigo C, Santarpia MC, et al. Erlotinib therapy in a patient with non-small-cell lung cancer and brain metastases. J Neurooncol. 2008;90(1):31–33.
80. Proto C, Imbimbo M, Gallucci R, et al. Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future. Transl Lung Cancer Res. 2016;5(6):563–578.
81. Clarke JL, Pao W, Wu N, et al. High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J Neurooncol. 2010;99(2):283–286.
82. Grommes C, Oxnard GR, Kris MG, et al. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol. 2011;13(12):1364–1369.
83. Togashi Y, Masago K, Fukudo M, et al. Efficacy of increased-dose erlotinib for central nervous system metastases in non-small cell lung cancer patients with epidermal growth factor receptor mutation. Cancer Chemother Pharmacol. 2011;68(4):1089–1092.
84. Milton DT, Azzoli GC, Heelan RT, et al. A phase I/II study of weekly high-dose erlotinib in previously treated patients with nonsmall cell lung cancer. Cancer. 2006;107(5):1034–1041.
85. Heon S, Yeap BY, Britt GJ, et al. Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clin Cancer Res. 2010;16:5873–5882.
86. Zimmermann S, Dziadziuszko R, Peters S. Indications and limitations of chemotherapy and targeted agents in non-small cell lung cancer brain metastases. Cancer Treat Rev. 2014;40(6):716–722.
87. Ballard P, Yates JW, Yang Z, 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):5130–5140.
88. Goss G, Tsai C, Shepherd F, et al. CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. IALSC Congress; 2016:MA16.11.
89. Pareek V, Welch M, Ravera E, et al. Marked differences in CNS activity among EGFR inhibitors: case report and mini-review. J Thorac Oncol. 2016;11(11):e135–e139.
90. Yang JCH, Kim DW, Kim SW, 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(Suppl):abstr9002.
91. Ahn MJ, Kim DW, Kim TM, et al. Phase I study of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningeal metastasis (LM). J Clin Oncol. 2016;34:abstr 9003.
92. Santarpia M, Karachaliou N, González-Cao M, et al. Feasibility of cell-free circulating tumor DNA testing for lung cancer. Biomark Med. 2016;10(4):417–430.
93. Taniguchi K, Uchida J, Nishino K, et al. Quantitative detection of EGFR mutations in circulating tumor DNA derived from lung adenocarcinomas. Clin Cancer Res. 2011;17(24):7808–7815.
94. Oxnard GR, Paweletz CP, Kuang Y, et al. Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clin Cancer Res. 2014;20(6):1698–1705.
95. Sundaresan TK, Sequist LV, Heymach JV, et al. Detection of T790M, the acquired resistance EGFR mutation, by tumor biopsy versus noninvasive blood-based analyses. Clin Cancer Res. 2016;22(5):1103–1110.
96. Oxnard GR, Thress KS, Alden RS, 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):3375–3382.
97. Remon J, Caramella C, Jovelet C, et al. Osimertinib benefit in EGFR-mutant NSCLC patients with T790M-mutation detected by circulating tumour DNA. Ann Oncol. 2017;28(4):784–790.
98. Buder A, Hochmair M, Holzer S, et al. Association between EGFR T790M mutation copy numbers in cell-free plasma DNA and response to osimertinib in advanced NSCLC. J Thor Oncol. 2017;12(1S):S1206.
99. Sullivan I, Planchard D. Osimertinib in the treatment of patients with epidermal growth factor receptor T790M mutation-positive metastatic non-small cell lung cancer: clinical trial evidence and experience. Ther Adv Respir Dis. 2016;10(6):549–565.
100. Wang S, Song Y, Yan F, Liu D. Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors. Front Med. 2016;10(4):383–388.
101. Thress KS, Paweletz CP, Felip E, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015;21(6):560–562.
102. Wang S, Tsui ST, Liu C, Song Y, Liu D. EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancer. J Hematol Oncol. 2016;9(1):59.
103. Ercan D, Choi HG, Yun CH, et al. EGFR mutations and resistance to irreversible pyrimidine- based EGFR inhibitors. Clin Cancer Res. 2015;21(17):3913–3923.
104. Niederst MJ, Hu H, Mulvey HE, 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):3924–3933.
105. Rosell R, Karachaliou N. Lung cancer: using ctDNA to track EGFR and KRAS mutations in advanced-stage disease. Nat Rev Clin Oncol. 2016;13(7):401–402.
106. Song HN, Jung KS, Yoo KH, 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–e47.
107. Chabon JJ, Simmons AD, Lovejoy AF, et al. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun. 2016;7:11815.
108. Ou SI, Cui J, Schrock AB, 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; 108:228–231.
109. Nukaga S, Yasuda H, Tsuchihara K, et al. Amplification of EGFR wild-type alleles in non-small cell lung cancer cells confers acquired resistance to mutation-selective EGFR tyrosine kinase inhibitors. Cancer Res. 2017;77(8):2078–2089.
110. Chaib I, Karachaliou N, Pilotto S, et al. Co-activation of STAT3 and YES-associated protein 1 (YAP1) pathway in EGFR-mutant NSCLC. J Natl Cancer Inst. 2017;109(9).
111. Zhang J, Ji JY, Yu M, et al. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol. 2009;11(12):1444–1450.
112. Eberlein CA, Stetson D, Markovets AA, 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):2489–2500.
113. Tricker EM, Xu C, Uddin S, et al. Combined EGFR/MEK inhibition prevents the emergence of resistance in EGFR-mutant lung cancer. Cancer Discov. 2015;5(9):960–971.
114. Ho CC, Liao WY, Lin CA, et al. Acquired BRAF V600E mutation as resistant mechanism after treatment with osimertinib. J Thorac Oncol. 2017;12(3):567–572.
115. Planchard D, Loriot Y, Andre F, et al. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol. 2015;26(10):2073–2078.
116. Ou SH, 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.
117. Ortiz-Cuaran S, Scheffler M, Plenker D, et al. Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors. Clin Cancer Res. 2016;22(19):4837–4847.
118. Ham JS, Kim S, Kim HK, et al. Two cases of small cell lung cancer transformation from EGFR mutant adenocarcinoma during AZD9291 treatment. J Thorac Oncol. 2016;11(1):e1–e4.
119. Ramalingam S, Yang JC, Lee CK, et al. Osimertinib as first-line treatment for EGFR mutation-positive advanced NSCLC: updated efficacy and safety results from two Phase I expansion cohorts. J Thorac Oncol. 2016;11(4 Suppl):S152.
120. Denis MG, Vallée A, Théoleyre S. EGFR T790M resistance mutation in non small-cell lung carcinoma. Clin Chim Acta. 2015;444:81–85.
121. Su KY, Chen HY, Li KC, et al. Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. J Clin Oncol. 2012;30(4):433–440.
122. Yu HA, Arcila ME, Hellmann MD, et al. Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing. Ann Oncol. 2014;25(2):423–428.
123. Lee Y, Lee GK, Lee YS, et al. Clinical outcome according to the level of preexisting epidermal growth factor receptor T790M mutation in patients with lung cancer harboring sensitive epidermal growth factor receptor mutations. Cancer. 2014;120(14):2090–2098.
124. Costa C, Molina MA, Drozdowskyj A, et al. The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. Clin Cancer Res. 2014;20(7):2001–2010.
125. Diggs LP, Hsueh EC. Utility of PD-L1 immunohistochemistry assays for predicting PD-1/PD-L1 inhibitor response. Biomarker Res. 2017; 5(1):12.
126. Garassino M, Cho B, Gray JE, et al. Durvalumab in ≥ 3rd-line EGFR mutant/ALK+, locally advanced or metastatic NSCLC: results from the phase 2 ATLANTIC study. Ann Oncol. 2017;28 (Suppl 2):ii28–ii51.
127. Ahn MJ, Yang J, Yu H, et al. Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: results from the TATTON phase Ib trial. J Thorac Oncol. 2016;11(4):S115.
128. Planchard D, Kris M, Besse B, et al. Phase 1 study of ramucirumab or necitumumab in combination with osimertinib (AZD9291) in advanced T790M-positive EGFR-mutant NSCLC. J Thor Oncol. 2017;12(1):S1071(P2.06–005).
129. Hata AN, Niederst MJ, Archibald HL, et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med. 2016;22(3):262–269.
130. Jia Y, Yun CH, Park E, et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature. 2016;534(7605):129–132.
131. Wang S, Song Y, Liu D. EAI045: the fourth-generation EGFR inhibitor overcoming T790M and C797S resistance. Cancer Lett. 2017;385:51–54.
132. Uchibori K, Inase N, Araki M, et al. Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer. Nat Commun. 2017;8:14768.
133. Wang S, Cang S, Liu D. Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. J Hematol Oncol. 2016;9(1):34.
134. Barnes TA, O’Kane GM, Vincent MD, Leighl NB. Third-generation tyrosine kinase inhibitors targeting epidermal growth factor receptor mutations in non-small cell lung cancer. Front Oncol. 2017;7:113.
135. Tan DSW, Yang JCH, Leighl NB, et al. Updated results of a phase 1 study of EGF816, a third-generation, mutant-selective EGFR tyrosine kinase inhibitor (TKI), in advanced non-small cell lung cancer (NSCLC) harboring T790M. J Clin Oncol. 2016;34 (Suppl):abstr 9044.
136. Yu HA, Spira AI, Horn L, 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 (Suppl):abstr 9050.
137. Xu X, Mao L, Xu W, 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):2586–2597.
138. Husain H, Martins R, Goldberg S, et al. Phase 1 dose escalation of PF-06747775 (EGFR-T790M inhibitor) in patients with advanced EGFRm (Del 19 or L858R+/-T790M) NSCLC. J Thor Oncol. 2017;12(1): S1185.
139. Yu HA, Spira AI, Horn L, 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(Suppl):abstr 9050.
140. Reckamp KL, Melnikova VO, Karlovich C, 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):1690–1700.
<pSource: Lung Cancer: Targets and Therapy
Originally published August 18, 2017.</p