Treatments for EGFR-mutant non-small cell lung cancer (NSCLC): The road to a success, paved with failures

Pharmacology and Therapeutics

Volumn 174, Issue , 2017, Pages 1-21

  Lee, Dae Ho ^a  

^a University of Ulsan College of Medicine   (South Korea)

Author keywords

Epidermal growth factor receptor mutation; Non small cell lung cancer; Resistance mechanism; Tyrosine kinase inhibitor

Indexed keywords

AFATINIB; EPIDERMAL GROWTH FACTOR RECEPTOR; ERLOTINIB; GEFITINIB; OSIMERTINIB; PROTEIN TYROSINE KINASE INHIBITOR; ANTINEOPLASTIC AGENT; EGFR PROTEIN, HUMAN; PROTEIN KINASE INHIBITOR;

CANCER CHEMOTHERAPY; CLINICAL OUTCOME; EXON; HUMAN; MOLECULAR DIAGNOSTICS; MONITORING; MUTANT; MUTATION; NEXT GENERATION SEQUENCING; NON SMALL CELL LUNG CANCER; PRIORITY JOURNAL; REVIEW; TREATMENT RESPONSE; ANIMAL; DRUG RESISTANCE; GENETICS; LUNG TUMOR; MOLECULARLY TARGETED THERAPY;

ANIMALS; ANTINEOPLASTIC AGENTS; CARCINOMA, NON-SMALL-CELL LUNG; DRUG RESISTANCE, NEOPLASM; HUMANS; LUNG NEOPLASMS; MOLECULAR TARGETED THERAPY; MUTATION; PROTEIN KINASE INHIBITORS; RECEPTOR, EPIDERMAL GROWTH FACTOR;

EID: 85013755437     PISSN: 01637258     EISSN: 1879016X     Source Type: Journal    
DOI: 10.1016/j.pharmthera.2017.02.001     Document Type: Review

References (210)

1. Ahn, M.J., Kim, D.W., Kim, T.M., Lin, C.C., Rathnayake, J., Carlie, D.J., 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). Journal of Clinical Oncology, 34, 2016, abstr 9003 (suppl.).
2. Ahn, M.J., Yang, J., Yu, H., Saka, H., Ramalingam, S., Goto, K., Kim, S.W., et al. 136O: Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: Results from the TATTON phase Ib trial. Journal of Thoracic Oncology, 11, 2016, S115 (suppl.).
3. Akbay, E.A., Koyama, S., Carretero, J., Altabef, A., Tchaicha, J.H., Christensen, C.L., et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discovery 3 (2013), 1355–1363.
4. Alexandrova, E.M., Yallowitz, A.R., Li, D., Xu, S., Schulz, R., Proia, D.A., et al. Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment. Nature 523 (2015), 352–356.
5. Arcila, M.E., Nafa, K., Chaft, J.E., Rekhtman, N., Lau, C., Reva, B.A., et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: Prevalence, molecular heterogeneity, and clinicopathologic characteristics. Molecular Cancer Therapeutics 12 (2013), 220–229.
6. Arcila, M.E., Oxnard, G.R., Nafa, K., Riely, G.J., Solomon, S.T., Zakowski, Z., et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clinical Cancer Research 17 (2011), 1169–1180.
7. Azuma, K., Kawahara, A., Sonoda, K., Nakashima, K., Tashiro, K., Watari, K., et al. FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor. Oncotarget 5 (2014), 5908–5919.
8. Barber, L.J., Davies, M.N., Gerlinger, M., Dissecting cancer evolution at the macro-heterogeneity and micro-heterogeneity scale. Current Opinion in Genetics & Development 30 (2014), 1–6.
9. Barlesi, F., Besse, B., Chu, Q., Gandhi, L., Griesinger, F., Felip, E., et al. Phase II activity of the HSP90 inhibitor AUY922 in patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). Journal of Thoracic Oncology, 8(Suppl. 2), 2013, abstr 1.11-037.
10. Bean, J., Brennan, C., Shih, J.Y., Riely, G., Viale, A., Wang, L., et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proceedings of the National Academy of Sciences of the United States of America 104 (2007), 20932–20937.
11. Beau-Faller, M., Prim, N., Ruppert, A.M., Nanni-Metéllus, I., Lacave, R., Lacroix, L., et al. Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: A randomized observational study by the French ERMETIC-IFCT network. Annals of Oncology 25 (2014), 126–131.
12. Borghaei, H., Paz-Ares, L., Horn, L., Spigel, D.R., Steins, M., Ready, N.E., et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. The New England Journal of Medicine 373 (2015), 1627–1639.
13. Brahmer, J., Reckamp, K.L., Baas, P., Crino, L., Eberhardt, W.E., Poddubskaya, E., Antonia, S., et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. The New England Journal of Medicine 373 (2015), 123–135.
14. Bria, E., Pilotto, S., Amato, E., Fassan, M., Novello, S., Peretti, U., et al. Molecular heterogeneity assessment by next-generation sequencing and response to gefitinib of EGFR mutant advanced lung adenocarcinoma. Oncotarget 6 (2015), 12783–12795.
15. Camidge, D.R., Pao, W., Sequist, L.V., Acquired resistance to TKIs in solid tumors: Learning from lung cancer. Nature Reviews. Clinical Oncology 11 (2014), 473–481.
16. Cappuzzo, F., Janne, P.A., Skokan, M., Finocchiaro, G., Rossi, E., Ligorio, C., et al. MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients. Annals of Oncology 20 (2009), 298–304.
17. Carcereny, E., Molina, M.A., Sanchez, J.J., Betran-Alamillo, J., Mayo, C., Aldeguer, E., et al. Mutations of the catalytic subunit a of PI3K (PIK3CA) in erlotinib-treated non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations. Journal of Clinical Oncology, 29, 2011, abstr 7588 (suppl.).
18. Carpenter, G., Cohen, S., Epidermal growth factor. Annual Review of Biochemistry 48 (1979), 193–216.
19. Chabon, J.J., Simmons, A., Newman, A.M., Lovejoy, A.F., Esfahani, M.S., Haringsma, H., et al. Inter- and intra-patient heterogeneity of resistance mechanisms to the mutant EGFR selective inhibitor rociletinib. Journal of Clinical Oncology, 34, 2016, abstr 9000 (suppl.).
20. Chaft, J.E., Arcila, M.E., Paik, P.K., Lau, C., Riely, G.J., Pietanza, M.C., et al. Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling. Molecular Cancer Therapeutics 11 (2012), 489–491.
21. Chaft, J.E., Oxnard, G.F., Sima, C.S., Kris, M.G., Miller, V.A., Riely, G.J., Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clinical Cancer Research 17 (2011), 6298–6303.
22. Chen, N., Fang, W., Zhan, J., Hong, S., Tang, Y., Kang, S., et al. Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation. Journal of Thoracic Oncology 10 (2015), 910–923.
23. Cheng, Y., Murakami, H., Yang, P.C., He, J., Nakagawa, K., Kang, J.H., 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. Journal of Clinical Oncology 34 (2016), 3258–3266.
24. Cortot, A.B., Repellin, C.E., Shimamura, T., Capelletti, Z.K., Ercan, D., et al. Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway. Cancer Research 73 (2013), 834–843.
25. Costa, D.B., Halmos, B., Kumar, A., Schumer, S.T., Huberman, M.S., Boggon, T.J., et al. BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Medicine 4 (2007), 1669–1679.
26. Costa, C., Molina, M.A., Drozdowskyj, A., Giménez-Capitán, A., Bertran-Alamillo, J., Karachaliou, N., 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. Clinical Cancer Research 20 (2014), 2001–2010.
27. Cragg, M.S., Kuroda, J., Puthalakath, H., Huang, D.C., Strasser, A., Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. PLoS Medicine 4 (2007), 1681–1689.
28. Cross, D.A., Ashton, S.E., Ghiorghiu, S., Eberlaein, C., Nebhab, C.A., Spitzler, P.J., et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discovery 4 (2014), 1046–1061.
29. Dempke, W.C., Edvardsen, K., Lu, S., Reinmuth, N., Reck, M., Inoue, A., Brain metastases in NSCLC - are TKIs changing the treatment strategy?. Anticancer Research 35 (2015), 5797–5806.
30. Dhingra, K., Rociletinib: Has the TIGER lost a few of its stripes?. Annals of Oncology 27 (2016), 1116–1164.
31. Ellis, P.M., Shepherd, F.A., Millward, M., Perrone, F., Seymour, L., Liu, G., et al. Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): A double-blind, randomized, phase 3 trial. The Lancet Oncology 15 (2014), 1379–1388.
32. Engelman, J.A., Zejnullahu, K., Gale, C.M., Lifshits, E., Gonzales, A.J., 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 Research 67 (2007), 11924–11932.
33. Engelman, J.A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J.O., et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316 (2007), 1039–1043.
34. Engelman, J.A., Mukohara, T., Zejnullahu, K., Lifshits, E., Borrás, A.M., Gale, C.M., et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. The Journal of Clinical Investigation 116 (2006), 2695–2706.
35. Faber, A.C., Corcoran, R.B., Ebi, H., Sequist, L.V., Waltman, B.A., Chung, E., et al. BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. Cancer Discovery 1 (2011), 352–365.
36. Fehrenbacher, L., Spira, A., Ballinger, M., Kowanetz, M., Vansteenkiste, J., Mazlieres, J., et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): A multicentre, open-label, phase 2 randomised controlled trial. Lancet 387 (2016), 1837–1846.
37. Food and Drug Administration, Cobas EGFR Mutation Test v2 for in vitro diagnostic use. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf12/P120019S007c.pdf, 2016.
38. Fujita, Y., Suda, K., Kimura, H., Matsumoto, K., Arao, T., Nagai, T., et al. Highly sensitive detection of EGFR T790M mutation using colony hybridization predicts favorable prognosis of patients with lung cancer harboring activating EGFR mutation. Journal of Thoracic Oncology 7 (2012), 1640–1644.
39. Fukuoka, M., Yano, S., Giaccone, G., Tamura, T., Nakagawa, K., Douillard, J.Y., 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). Journal of Clinical Oncology 21 (2003), 2237–2246.
40. Gainor, J.F., Shaw, A.T., Sequist, L.V., Fu, X., Azzoli, C.G., Piotrowska, Z., et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: A retrospective analysis. Clinical Cancer Research 22 (2016), 4585–4593.
41. Gandara, D.R., Li, T., Lara, P.N., Kelly, K., Riess, J.W., Redman, M.W., et al. Acquired resistance to targeted therapies against oncogene-driven non-small-cell lung cancer: Approach to subtyping progressive disease and clinical implications. Clinical Lung Cancer 15 (2014), 1–6.
42. 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 trial. International Journal of Cancer 131 (2012), E822–E829.
43. Garon, E.B., Rizvi, N.A., Hui, R., Leighl, N., Balmanoukian, A.S., Eder, J.P., et al. Pembrolizumab for the treatment of non-small-cell lung cancer. The New England Journal of Medicine 372 (2015), 2018–2028.
44. Garon, E., Wolf, B., Lisberg, A., Kim, K., Horton, J., Kamranpour, N., et al. Prior TKI therapy in NSCLC EGFR mutant patients associates with lack of response to anti-PD-1 treatment. Journal of Thoracic Oncology, 10, 2015, S269.
45. 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. Journal of Clinical Oncology 25 (2007), 1545–1552.
46. Gelsomino, F., Facchinetti, F., Haspinger, E.R., et al. Targeting the MET gene for the treatment of non-small-cell lung cancer. Critical Reviews in Oncology/Hematology 89 (2014), 284–299.
47. Gerlinger, M., Rowan, A.J., Horswell, S., Larkin, J., Endefelder, D., Gronroos, E., et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The New England Journal of Medicine 366 (2012), 883–892.
48. Giaccone, G., Herbst, R.S., 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. Journal of Clinical Oncology 22 (2004), 777–784.
49. Gibbons, D.L., Chow, L.Q., Kim, D., Kim, S.W., Yeh, T., Song, X., et al. 57O efficacy, safety and tolerability of MEDI4736 (durvalumab [D]), a human IgG1 anti-programmed cell death-ligand-1 (PD-L1) antibody, combined with gefitinib (G): A phase I expansion in TKI-naïve patients (pts) with EGFR mutant NSCLC. Journal of Thoracic Oncology, 11, 2016, S79.
50. Gong, Y., Somwar, R., Politi, K., Balak, M., Chmielecki, J., Jiang, X., et al. Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas. PLoS Medicine, 4, 2007, e294.
51. Gridelli, C., Ciardiello, F., Gallo, C., Feld, R., Butts, C., Gebbia, V., et al. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: The TORCH randomized trial. Journal of Clinical Oncology 30 (2012), 3002–3011.
52. Halmos, B., Pennell, N.A., Fu, P., Saad, S., Gadgeel, S., Otterson, G.A., et al. Randomized phase II trial of erlotinib beyond progression in advanced erlotinib-responsive non-small cell lung cancer. The Oncologist 20 (2015), 1298–1303.
53. Han, B., Jin, B., Zhang, Y., Chu, T., Gu, A., Xu, J., Combination of chemotherapy and gefitinib as first-line treatment of patients with advanced lung adenocarcinoma and sensitive EGFR mutations: A randomised controlled trial. Journal of Thoracic Oncology, 11(Suppl. 4S), 2016, S113.
54. Han, J.Y., Lee, S.H., Lee, G.K., Yun, T., Lee, Y.J., Hwang, K.H., et al. Phase I/II study of gefitinib (Iressa®) and vorinostat (IVORI) in previously treated patients with advanced non-small cell lung cancer. Cancer Chemotherapy and Pharmacology 75 (2015), 475–483.
55. Han, J.Y., Park, K., Kim, S.W., Lee, D.H., Kim, H.Y., Kim, H.T., et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. Journal of Clinical Oncology 30 (2012), 1122–1128.
56. Hata, A.N., Niederst, M.J., Archibald, H.L., Gomez-Caraballo, M., Siddiqui, F.M., Mulvey, H.E., et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nature Medicine 22 (2016), 262–269.
57. Hellmann, M.D., Gettinger, S.N., Goldman, J., Brahmer, J., Borghaei, H., Chow, L.Q., et al. CheckMate 012: Safety and efficacy of first-line nivolumab and ipilimumab in advanced NSCLC. Journal of Clinical Oncology, 35, 2016, abstr 3001 (suppl.).
58. Hendrickson, A.W., Haluska, P., Resistance pathways relevant to insulin-like growth factor-1 receptor-targeted therapy. Current Opinion in Investigational Drugs 10 (2009), 1032–1040.
59. Herbst, R.S., Baas, P., Kim, D.W., Felip, E., Perez-Gracia, J.L., Han, J.Y., et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 387 (2016), 1540–1550.
60. Herbst, R.S., Giaccone, G., Schiller, J.H., Natale, R.B., 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. Journal of Clinical Oncology 22 (2004), 785–794.
61. Herbst, R.S., Prager, D., Hermann, R., Fehrenbacher, L., Johnson, B.E., 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. Journal of Clinical Oncology 23 (2005), 5892–5899.
62. Hlinkova, K., Babal, P., Berzinec, P., Majer, I., Mikle-Barathova, Z., Piackova, B., et al. Evaluation of 2-year experience with EGFR mutation analysis of small diagnostic samples. Diagnostic Molecular Pathology 22 (2013), 70–75.
63. 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. Journal of Thoracic Oncology 10 (2015), 486–491.
64. Inoue, A., Kobayashi, K., Maemondo, M., Sugawara, S., Oizumi, S., Isobe, H., et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Annals of Oncology 24 (2013), 54–59.
65. Inukai, M., Toyooka, S., Ito, S., Asano, H., Ichihara, S., Soh, J., et al. Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Research 66 (2006), 7854–7858.
66. Jackman, D., Pao, W., Riely, G.J., Engelman, J.A., Kris, M.G., Janne, P.A., et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Journal of Clinical Oncology 28 (2010), 357–360.
67. Jain, A., Lim, C., Gan, E.M., Ng, D.Z., Ng, Q.S., Ang, M.K., et al. Impact of smoking and brain metastasis on outcomes of advanced EGFR mutation lung adenocarcinoma patients treated with first line epidermal growth factor receptor tyrosine kinase inhibitors. PloS One, 10, 2015, e0123587.
68. Janjigian, Y.Y., Smit, E.F., Groen, H.J., Horn, L., Gettinger, S., Camidge, D.R., et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discovery 4 (2014), 1036–1045.
69. Jänne, P.A., Wang, X., Socinski, M.A., Crawford, J., Stinchcombe, T.E., Gu, L., et al. Randomized phase II trial of erlotinib alone or with carboplatin and paclitaxel in patients who were never or light former smokers with advanced lung adenocarcinoma: CALGB 30406 trial. Journal of Clinical Oncology 30 (2012), 2063–2209.
70. Janne, P.A., Yang, J.C., Kim, D.W., Planchard, D., Ohe, Y., Ramalingam, S.S., et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. The New England Journal of Medicine 372 (2015), 1689–1699.
71. Johnson, B.E., The impact of next generation sequencing on the outcomes of patients with lung cancer. Plenary presentation O06.1 at: WIN 2016 Symposium; June 26-28, 2016; Paris, France, 2016.
72. Johnson, M.L., Yu, H.A., Hart, E.M., Weitner, B.B., Rademaker, A.W., Patel, J., 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. Journal of Clinical Oncology 33 (2015), 1666–1673.
73. Junttila, M.R., de Sauvage, F.J., Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 501 (2013), 346–354.
74. Kang, Y., Massagué, J., Epithelial-mesenchymal transitions: Twist in development and metastasis. Cell 118 (2004), 277–279.
75. Katakami, N., Atagi, S., Goto, K., Hida, T., Horai, T., Inoue, A., 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. Journal of Clinical Oncology 31 (2013), 3335–3344.
76. Kawakami, H., Okamoto, I., Okamoto, W., Tanizaki, J., Nakagawa, K., Nishio, K., Targeting MET amplification as a new oncogenic drive. Cancers (Basel) 6 (2014), 1540–1552.
77. Kim, T.M., 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. Journal of Thoracic Oncology 10 (2015), 1736–1744.
78. Klein, C.A., Selection and adaptation during metastatic cancer progression. Nature 501 (2013), 365–372.
79. Kobayashi, S., Boggon, T.J., Dayaram, T., Jänne, P.A., Kocher, O., Meyerson, M., et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. The New England Journal of Medicine 352 (2005), 786–792.
80. Kris, M.G., Natale, R.B., Herbst, R.S., Lynch, T.J. Jr., Prager, D., Belani, C.P., 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 290 (2003), 2149–2158.
81. Labbe, C., Korpanty, G., Tomasini, P., Doherty, M., Mascaux, C., Jao, K., et al. Prognostic and predictive effects of TP53 mutation in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Journal of Clinical Oncology, 34, 2016, abstr 11585 (suppl.).
82. Lanman, R.B., Mortimer, S.A., Zill, O.A., Sebisanovid, D., Lopez, R., Blau, S., et al. Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA. PloS One, 10, 2015, e0140712.
83. Leary, A.F., Castro, D.G., Nicholson, A.G., Ashley, S., Wortherspoon, A., O'Brien, M.E., et al. Establishing an EGFR mutation screening service for non-small cell lung cancer — Sample quality criteria and candidate histological predictors. European Journal of Cancer 48 (2012), 61–67.
84. Lee, C.K., Brown, C., Gralla, R.J., Hirsh, V., Thongprasert, S., Tsai, C.M., et al. Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival; a meta-analysis. Journal of the National Cancer Institute 105 (2013), 595–605.
85. Lee, Y., Lee, G.K., Lee, Y.S., Zhang, W., Hwang, J.A., Nam, B.H., 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 120 (2014), 2090–2098.
86. Lee, J.Y., Sun, J.M., Lim, S.H., Kim, H.A., Yoo, K.H., Jung, K.S., 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. Clinical Cancer Research 22 (2016), 2139–2145.
87. Li, D., Ambrogio, L., Shimamura, T., Kubo, S., Takahashi, M., Chirieac, L.R., et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27 (2008), 4702–4711.
88. Li, D., Marchenko, N.D., Moll, U.M., SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis. Cell Death and Differentiation 18 (2011), 1904–1913.
89. Lipinski, K.A., Barber, L.J., Davies, M.N., Ashenden, M., Sottoriva, A., Gerlinger, M., Cancer evolution and the limits of predictability in precision cancer medicine. Trends Cancer 2 (2016), 49–63.
90. Lynch, T.J., Bell, D.W., Sordella, R., Gurubhagavatula, S., Okimoto, R.A., Brannigan, B.W., et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. The New England Journal of Medicine 350 (2004), 2129–2139.
91. Ma, J.Y., Yan, H.J., Gu, W., Association between BIM deletion polymorphism and clinical outcome of EGFR-mutated NSCLC patient with EGFR-TKI therapy: A meta-analysis. Journal of Cancer Research and Therapeutics 11 (2015), 397–402.
92. 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. The New England Journal of Medicine 362 (2010), 2380–2388.
93. Marks, P.A., Discovery and development of SAHA as an anticancer agent. Oncogene 26 (2007), 1351–1356.
94. Master, G.A., Temin, S., Azzoli, C.G., Giaccone, G., Baker, S. Jr., Brahmer, J.R., et al. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical Oncology 33 (2015), 3488–3515.
95. Meacham, C.E., Morrison, S.J., Tumour heterogeneity and cancer cell plasticity. Nature 501 (2013), 328–337.
96. Mihda, A., Dearden, S., McCormack, R., EGFR mutation incidence in non-small cell lung cancer of adenocarcinoma histology: A systematic review and global map by ethnicity (mutMapII). American Journal of Cancer Research 5 (2015), 2892–2911.
97. Miller, V.A., Hirsh, V., Cadranel, J., Chen, Y.M., Park, K., Kim, S.W., 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. The Lancet Oncology 13 (2012), 528–538.
98. Mitsudomi, T., Morita, S., Yatabe, Y., Negoro, S., Okamoto, I., Tsurutani, J., et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. The Lancet Oncology 11 (2010), 121–128.
99. Mitsudomi, T., Tsai, C., Shepherd, F., Bazhenova, L., Lee, J.S., Chang, G., et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA2 Phase II study. Journal of Thoracic Oncology, 10(Suppl. 2), 2015, S320.
100. Mok, T.S., Nakagawa, K., Rosell, R., Wu, Y.L., Trygstad, C., Capizzi, R.L., et al. Phase III, randomized open label study (ARCHER 1050) of first-line dacomitinib versus gefitinib for advanced non-small cell lung cancer in patients with epidermal growth factor receptor activating mutations. Journal of Clinical Oncology, 31, 2013, abstr TPS8123 (suppl.).
101. Mok, T.S., Wu, Y.L., Thongprasert, S., Yang, C.H., Chu, D.T., Saijo, N., et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. The New England Journal of Medicine 361 (2009), 947–957.
102. Mok, T.S., Wu, Y., Ahn, M.J., Garassino, M.C., Kim, H.R., Ramalingam, S.S., et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. New Engl J Med., 2016, 10.1056/NEJMoa1612674.
103. Naidoo, J., Sima, C.S., Rodriguez, K., Busby, N., Nafa, K., Ladanyi, M., et al. Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib. Cancer 121 (2015), 3212–3220.
104. Nakagawa, T., Takeuchi, S., Yamada, T., Ebi, H., Sano, T., Nanjo, S., et al. EGFR-TKI resistance due to BIM polymorphism can be circumvented in combination with HDAC inhibition. Cancer Research 73 (2013), 2428–2434.
105. Nakagawa, T., Takeuchi, S., Yamada, T., Nanjo, S., Ishikawa, D., Sano, T., et al. Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer. Molecular Cancer Therapeutics 11 (2012), 2149–2157.
106. National Comprehensive Cancer Network, NCCN clinical practice guidelines in oncology non-small cell lung cancer, version 4. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf, 2016.
107. Ng, K.P., Hillmer, A.M., Chuah, C.T., Juan, W.C., Ko, T.K., Teo, A.S., et al. A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nature Medicine 18 (2012), 521–528.
108. Niederst, M.J., Hu, H., Mulvey, H.E., Lockerman, E.L., Garcia, A.R., 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. Clinical Cancer Research 21 (2015), 3924–3933.
109. Niederst, M.J., Sequist, L.V., Poirier, J.T., Mermel, C.H., Lockerman, E.L., Garcia, A.R., et al. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nature Communications, 6, 2015, 6377.
110. Novello, S., Barlesi, F., Califano, R., Cufer, T., Ekman, S., Levar, M.G., et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines. Annals of Oncology 27:Suppl. 5 (2016), v1–v27.
111. Ohashi, K., Sequist, L.V., Arcila, M.E., Moran, T., Chmielecki, J., Lin, Y.L., et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proceedings of the National Academy of Sciences of the United States of America 109 (2012), E2127–E2133.
112. Oser, M.G., Niederst, M.J., Sequist, L.V., Engelman, J.A., Transformation from non-small cell lung cancer to small cell lung cancer: molecular driver and cells of origin. The Lancet Oncology, 2015, e165–e172.
113. Oxnard, G.R., MINI30.06 Activity of AUY922 in NSCLC patients with EGFR exon 20 insertions. Journal of Thoracic Oncology, 10, 2015, abstr 1744 (suppl.).
114. Oxnard, G.R., ORAL17.07 mechanisms of acquired resistance to AZD9291 in EGFR T790M positive lung cancer. Journal of Thoracic Oncology, 10, 2015, abstr 1365 (suppl.).
115. Oxnard, G.R., Arcila, M.E., Sima, C.S., Riely, G.J., Chmielecki, J., Kris, M.G., 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. Clinical Cancer Research 17 (2011), 1616–1622.
116. Oxnard, G.R., Lo, P., Nishino, M., DahlberANg, S., Lindeman, N., Butaney, M., et al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. Journal of Thoracic Oncology 8 (2013), 179–184.
117. Oxnard, G.R., Ramalingam, S.S., Ahn, M.J., Kim, S.W., Yu, H.A., Saka, H., et al. Preliminary results of TATTON, a multi-arm phase Ib trial of AZD9291 combined with MEDI4736, AZD6094 or selumetinib in EGFR-mutant lung cancer. Journal of Clinical Oncology, 33, 2015, abstr 2509 (suppl.).
118. Oxnard, G.R., Thress, K.S., Alden, R.S., Lawrance, R., Paweletz, C.P., Cantarini, M., Yang, J.C., et al. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. Journal of Clinical Oncology 34 (2016), 3375–3382.
119. Paez, J.G., Jänne, P.A., Lee, J.C., Tracy, S., Greulich, H., Grabriel, S., et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304 (2004), 1497–1500.
120. Pan, Y., Zhang, Y., Li, Y., Hu, H., Wang, L., Hi, H., et al. Prevalence, clinicopathologic characteristics, and molecular association of EGFR exon 20 insertion mutations in East Asian patients with lung adenocarcinoma. Annals of Surgical Oncology 21:Suppl. 4 (2014), S490–S496.
121. Pao, W., Miller, V.A., Politi, K.A., Riely, G.J., Somwar, R., Zakowski, M.F., et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Medicine, 2, 2005, e73.
122. 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. Proceedings of the National Academy of Sciences of the United States of America 101 (2004), 13306–13311.
123. Park, K., Lee, J.S., Lee, K.H., Kim, J.H., Cho, B.C., Min, Y.J., et al. BI 1482694 (HM61713), an EGFR mutant-specific inhibitor, in T790M + NSCLC: Efficacy and safety at the RP2D. Journal of Clinical Oncology, 34, 2015, abstr 9055 (suppl.).
124. 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. The Lancet Oncology 17 (2016), 577–589.
125. Paz-Ares, L., Tan, E.H., Zhang, L., Hirsh, V., O'Bryne, K., Boyer, M., et al. Afatinib versus gefitinib in patients with EGFR mutation-positive non-small-cell lung cancer: Overall survival data from the phase IIb LUX-Lung 7 trial. Annals of Oncology, 27, 2016, abstr LBA43 (suppl.).
126. Peled, N., Wynes, M.W., Ikeda, N., Ohira, T., Yoshida, K., Qian, J., et al. Insulin-like growth factor-1 receptor (IGF-1R) as a biomarker for resistance to the tyrosine kinase inhibitor gefitinib in non-small cell lung cancer. Cellular Oncology 36 (2013), 277–288.
127. Piotrowska, Z., Niederst, M.J., Karlovich, C.A., Wakelee, H.A., Neal, J.W., 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 Discovery 5 (2015), 713–722.
128. Piotrowska, Z., Niederst, M.J., Mino-Kenudson, M., Morales-Oyarvide, V., Fulton, L., Locerman, E.J., et al. Variation in mechanisms of acquired resistance (AR) among EGFR-mutant NSCLC patients with more than one post-resistant biopsy. Journal of Clinical Oncology, 32, 2014, abstr 8053 (suppl.).
129. Planchard, D., Loriot, Y., Andre, F., Gobert, A., Auger, N., Lacroix, L., et al. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Annals of Oncology 26 (2015), 2073–2078.
130. Popat, S., Mok, T., Yang, J.C., Wu, Y.L., Lungershausen, J., Stammberger, U., et al. Afatinib in the treatment of EGFR mutation-positive NSCLC; a network meta-analysis. Lung Cancer 85 (2014), 230–286.
131. Qiu, M., Wang, J., Xu, Y., Ding, X., Li, M., Jiang, F., et al. Circulating tumor DNA is effective for the detection of EGFR mutation in non-small cell lung cancer: A meta-analysis. Cancer Epidemiology, Biomarkers & Prevention 24 (2015), 206–212.
132. Ramalingam, S.S., Rukazenkov, Y., Thomas, K., Soria, J.C., A randomized phase III study (FLAURA) of AZD9291, a novel EGFR TKI, versus gefitinib or erlotinib in treatment-naïve patients with advanced non-small cell lung cancer and an EGFR-TKI-sensitizing mutation. Journal of Clinical Oncology, 33, 2015, abstr TPS8102 (suppl.).
133. Ramalingam, S.S., Yang, J., Lee, C., Kurata, T., Kim, D.W., John, T., et al. AZD9291 in treatment-naïve EGFRm advanced NSCLC: AURA first-line cohort. Journal of Thoracic Oncology, 10(Suppl. 2), 2015, S319.
134. Ramalingam, S.S., Blackhall, F., Krzakowski, M., Barrios, C.H., Park, K., Bover, I., et al. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. Journal of Clinical Oncology 30 (2012), 3337–3344.
135. Ramalingam, S.S., Jänne, P.A., Mok, T., O'Byrne, K., Boyer, M.J., 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. The Lancet Oncology 15 (2014), 1369–1378.
136. Reck, M., Rodríguez-Abreu, D., Robinson, A.G., Hui, R., Csőszi, T., Fülöp, A., et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. The New England Journal of Medicine 375 (2016), 1823–1833.
137. Reckamp, K.L., Giaccone, G., Camidge, D.R., Gadgeel, S.M., Khuri, F.R., Engelman, J.A., 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 120 (2014), 1145–1154.
138. Reckamp, K.L., Mack, P.C., Ruel, N., Frankel, P.H., Gitlitz, B.J., Li, T., et al. Biomarker analysis of a phase II trial of cabozantinib and erlotinib in patients (pts) with EGFR-mutant NSCLC with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance: A California Cancer Consortium Phase II Trial (NCI 9303). Journal of Clinical Oncology, 33, 2015, abstr 8087 (suppl.).
139. Redig, A.M., Taibi, M., Oxnard, G.R., Boucher, D., Rabin, M.S., Marcoux, J.P., et al. A phase II trial of erlotinib for EGFR mutant NSCLC to prospectively assess biopsy feasibility and acquired resistance at disease progression. Journal of Clinical Oncology, 33, 2015, abstr 8076 (suppl.).
140. Reguart, N., Rosell, R., Cardenal, F., Cardona, A.F., Isla, D., Palmero, R., et al. Phase I/II trial of vorinostat (SAHA) and erlotinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after erlotinib progression. Lung Cancer 84 (2014), 161–167.
141. Riely, G.J., Kris, M.G., Zhao, B., Akhurst, T., Milton, D.T., Moore, E., et al. Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus. Clinical Cancer Research 13 (2007), 5150–5155.
142. Rivlin, N., Koifman, G., Rotter, V., p53 orchestrates between normal differentiation and cancer. Seminars in Cancer Biology 32 (2015), 10–17.
143. Rizvi, N.A., Chow, L.Q.M., Borghaei, H., Shen, Y., Harbison, C., Alaparthy, S., et al. Safety and response with nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus erlotinib in patients (pts) with epidermal growth factor receptor mutant (EGFR MT) advanced NSCLC. Journal of Clinical Oncology, 32, 2014, abstr 8022 (suppl.).
144. 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. The Lancet Oncology 13 (2012), 239–246.
145. Sasaki, H., Endo, K., Takada, M., Kawahara, M., Kitahara, N., Tanaka, H., et al. EGFR exon 20 insertion mutation in Japanese lung cancer. Lung Cancer 58 (2007), 324–328.
146. Scagliotti, G.V., Bondarenko, I., Blackhall, F., Barlesi, F., Hsia, T.C., Jassem, J., et al. Randomized, phase III trial of figitumumab in combination with erlotinib versus erlotinib alone in patients with non adenocarcinoma non small-cell lung cancer. Annals of Oncology 26 (2015), 497–504.
147. Schuler, M., Yang, J.C., Park, K., Kim, J.H., Bennouna, J., Chen, Y.M., et al. Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial. Annals of Oncology 27 (2016), 417–423.
148. Sequist, L.V., Besse, B., Lynch, T.J., Miller, V.A., Wong, K.K., Gitlitz, B., 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. Journal of Clinical Oncology 28 (2010), 3076–3083.
149. Sequist, L.V., Martins, R.G., Spigel, D., Grunberg, S.M., Spira, A., Janne, P.A., et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. Journal of Clinical Oncology 26 (2008), 2442–2449.
150. Sequist, L.V., Soria, J.C., Goldman, J.W., Wakelee, H.A., Gadgeel, S.M., Varga, A., et al. Rociletinib in EGFR mutated non-small-cell lung cancer. The New England Journal of Medicine 372 (2015), 1700–1709.
151. Sequist, L.V., Waltman, B.A., Dias-Santagata, D., Digumarthy, S., Turke, A.B., Fidias, P., et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Science Translational Medicine, 3, 2011, 75ra26.
152. Sequist, L.V., Yang, J.C.-H., 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. Journal of Clinical Oncology 31 (2013), 3327–3334.
153. 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. The Lancet Oncology 15 (2014), 1236–1244.
154. Shepherd, F.A., Rodrigues Pereira, J., Ciuleanu, T., Tan, E.H., Hirsh, V., Thongprasert, S., et al. Erlotinib in previously treated non-small-cell lung cancer. The New England Journal of Medicine 353 (2005), 123–132.
155. Shiau, C.J., Babwah, J.P., de Cunha, S.G., Sykes, J.R., Boerner, S.L., Geddie, W.R., et al. Sample features associated with success rates in population-based EGFR mutation testing. Journal of Thoracic Oncology 9 (2014), 947–956.
156. Shigematsu, H., Lin, L., Takahashi, T., Nomura, M., Suzuki, M., Wistuba, I.I., et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. Journal of the National Cancer Institute 97 (2005), 339–346.
157. Socinski, M.A., 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. Clinical Cancer Research 19 (2013), 3068–3077.
158. Song, H.N., Jung, K.S., Yoo, K.H., Cho, J., Lee, J.Y., Lim, S.H., et al. Acquired C797S mutation upon treat-ment with a T790M-specific third-generation EGFR inhibitor (HM61713) in non-small cell lung cancer. Journal of Thoracic Oncology 11 (2016), e45–e47.
159. Soria, J.C., Kim, S.W., Wu, Y.L., Nakagawa, K., Yang, J.J., Ahn, M.J., et al. Gefitinib/chemotherapy vs chemotherapy in EGFR mutation-positive NSCLC resistant to first-line gefitinib: IMPRESS T790M subgroup. Journal of Thoracic Oncology, 10(Suppl. 2), 2015, S207.
160. Soria, J.C., Wu, Y.L., Nakagawa, K., Kim, S.W., Yang, J.J., Ahn, M.J., 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. The Lancet Oncology 16 (2015), 990–998.
161. Soucheray, M., Capelletti, M., Pulido, I., Kuang, Y., Paweletz, C.P., Becher, J.H., Kikuchi, E., et al. Intratumoral heterogeneity in EGFR-Mutant NSCLC results in divergent resistance mechanisms in response to EGFR tyrosine kinase inhibition. Cancer Research 75 (2015), 4372–4383.
162. Stahel, R., Dafni, U., Gautschi, G., Felip, E., Curioni-Fontecedro, A., Peters, S., et al. A phase II trial of erlotinib (E) and bevacizumab (B) in patients with advanced non-small-cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations with and without T790M mutation. The Spanish Lung Cancer Group (SLCG) and the European Thoracic Oncology Platform (ETOP) BELIEF trial. European Journal of Cancer, 51, 2015, S711.
163. Su, K.Y., Chen, H.Y., Li, K.C., Kuo, M.L., Yang, J.C., Chan, W.K., 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. Journal of Clinical Oncology 30 (2012), 433–440.
164. Suda, K., Murakami, I., Katayama, T., Tomizawa, K., Osada, H., Sekido, Y., et al. Reciprocal and complementary role of MET amplification and EGFR T790M mutation in acquired resistance to kinase inhibitors in lung cancer. Clinical Cancer Research 16 (2010), 5489–5498.
165. Suda, K., Murakami, I., Sakai, K., Mizuuch, H., Shimizu, S., Sato, K., et al. Small cell lung cancer transformation and T790M mutation: complementary roles in acquired resistance to kinase inhibitors in lung cancer. Scientific Reports, 5, 2015, 14447.
166. Sugawara, S., Oizumi, S., Minato, K., Harada, T., Inoue, A., Fujita, Y., et al. Randomized phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902. Annals of Oncology 26 (2015), 888–894.
167. Takezawa, K., Pirazzolli, V., Arcila, M.E., Nebhan, C.A., 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 Discovery 2 (2012), 922–933.
168. Tan, D.S., Mok, T.S., Rebbeck, T.R., Cancer genomics: Diversity and disparity across ethnicity and geography. Journal of Clinical Oncology 34 (2016), 91–101.
169. Tan, D.S., Yang, J.C., Leighl, N.B., Riely, G.J., Sequist, L.V., Felip, E., et al. Updated results of a phase I study of EGF816, a third generation mutant selective EGFR tyrosine kinase inhibitor, in advanced non-small cell lung cancer harboring T790M. Journal of Clinical Oncology, 34, 2016, abstr9044 (suppl.).
170. Tan, D.S., Lim, K.H., Tai, W.M., Ahmad, A., Pan, S., Ng, Q.S., et al. A phase Ib safety and tolerability study of a pan class I PI3K inhibitor buparlisib (BKM120) and gefitinib (gef) in EGFR TKI-resistant NSCLC. Journal of Clinical Oncology, 31, 2013, abstr 8107 (suppl.).
171. 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 366 (2005), 1527–1537.
172. Thress, K.S., Paweletz, C.P., Felip, E., Cho, B.C., Stetson, D., Dougherty, B., Lai, Z., et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nature Medicine 21 (2015), 560–562.
173. Turke, A.B., Zejnullahu, K., Wu, Y.L., Song, Y., Dias-Santagata, D., Lifthists, E., et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17 (2010), 77–88.
174. Uchida, J., Kato, K., Kukita, Y., Kumagai, T., Nishino, K., Daga, H., et al. Diagnostic accuracy of noninvasive genotyping of EGFR in lung cancer patients by deep sequencing of plasma cell-free DNA. Clinical Chemistry 61 (2015), 1191–1196.
175. Ulivi, P., Canale, M., Petracci, E., Chiadini, E., Dazzi, C., Capelli, L., et al. Role of TP53 mutations in predicting response to TKI treatment in EGFR-mutated NSCLC patients. Journal of Clinical Oncology, 34, 2016, abstr 9052 (suppl.).
176. Walter, A.O., Sjin, R.T., Harigsma, H.J., Ohashi, K., Sun, J., Lee, K., et al. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-meidated resistance in NSCLC. Cancer Discovery 3 (2013), 1404–1415.
177. Wang, L., Hu, H., Pan, Y., Wang, R., Li, Y., Shen, L., et al. PIK3CA mutations frequently coexist with EGFR/KRAS mutations in non-small cell lung cancer and suggest poor prognosis in EGFR/KRAS wildtype subgroup. PloS One, 9, 2014, e88291.
178. Wang, S.E., Narasanna, A., Perez-Torres, M., Xiang, B., Wu, F.Y., Yang, S., et al. HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell 10 (2006), 25–38.
179. Ware, K.E., Marshall, M.E., Heasley, L.R., Marek, L., Hinz, T.K., Hercule, P., et al. Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de repression of FGFR2 and FGFR3 expression. PloS One, 5, 2010, e14117.
180. Watanabe, M., Kawaguchi, T., Isa, S., Ando, M., Tamiya, A., Kubo, A., et al. Ultra-sensitive detection of the pretreatment EGFR T790M mutation in non-small cell lung cancer patients with an EGFR-activating mutation using droplet digital PCR. Clinical Cancer Research 21 (2015), 3552–3560.
181. Watanabe, S., Minegishi, Y., Yoshizawa, H., Maemondo, M., Inoue, A., Sugawara, S., et al. Effectiveness of gefitinib against non–small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q. Journal of Thoracic Oncology 9 (2014), 189–194.
182. Wu, Y.L., Kim, D.W., Felip, E., Zhang, L., Liu, X., Zhou, C., et al. Phase (Ph) II safety and efficacy results of a single-arm ph ib/II study of capmatinib (INC280) + gefitinib in patients (pts) with EGFR-mutated (mut), cMET-positive (cMET +) non-small cell lung cancer (NSCLC). Journal of Clinical Oncology, 34, 2016, abstr 9020 (suppl.).
183. Wu, Y.L., Lee, J.S., Thongprasert, S., Yu, C.J., Zhang, L., Ladrera, G., et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): A randomised, double-blind trial. The Lancet Oncology 14 (2013), 777–786.
184. Wu, Y.L., Soo, R., Kim, D.W., Yang, J., Stammberger, U., Chen, W., et al. Tepotinib plus gefitinib in patients with c-Met-positive/EGFR-mutant NSCLC: Recommended phase II dose (RP2D), tolerability, and efficacy. Annals of Oncology, 27(Suppl. 6), 2016, vi439, abstr 1257P.
185. Wu, J.Y., Wu, S.G., Yang, C.H., Gow, C.H., Chang, Y.L., Yu, C.J., et al. Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clinical Cancer Research 14 (2008), 4877–4882.
186. Wu, J.Y., Yu, C.J., Chang, Y.C., Yang, C.H., Shin, J.Y., Yang, P.C., Effectiveness of tyrosine kinase inhibitors on ‘uncommon’ epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clinical Cancer Research 17 (2011), 3812–3821.
187. Wu, Y.L., Zhou, C., Hu, C.P., 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. The Lancet Oncology 15 (2014), 213–222.
188. Wu, Y.L., Zhou, C., Liam, C.K., Wu, G., Liu, X., Zhong, Z., et al. First-line erlotinib versus gemcitabine in patients with advanced EGFR mutation-positive non-small cell lung cancer; analyses from the phase III, randomized, open-label, ENSURE study. Annals of Oncology 26 (2015), 1883–1889.
189. Xie, M., Zhang, L., He, C.S., Xu, F., Liu, J.L., Hu, Z.H.,.. Tian, Y., Activation of Notch-1 enhances epithelial-mesenchymal transition in gefitinib-acquired resistant lung cancer cells. Journal of Cellular Biochemistry 113 (2012), 1501–1513.
190. Xu, L., Kikuchi, E., Xu, C., Ebi, H., Ercan, D., Cheng, K.A., et al. Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers codriven by mutant EGFR containing T790M and MET. Cancer Research 72 (2012), 3302–3311.
191. Yamamoto, C., Basaki, Y., Kawahara, A., Nakashima, K., Kage, M., Izumi, H., et al. Loss of PTEN expression by blocking nuclear translocation of EGR1 in gefitinib-resistant lung cancer cells harboring epidermal growth factor receptor-activating mutations. Cancer Research 70 (2010), 8715–8725.
192. Yang, J.C., Kim, D.W., Kim, S.W., Cho, B.C., Lee, J.S., 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. Journal of Clinical Oncology, 34, 2016, abstr 9002 (suppl.).
193. Yang, J.C., Ramalingam, S.S., Janne, P.A., Cantarini, M., Mitsudomi, T., Osimertinib (AZD9291) in pretreated patients with T790M positive advanced NSCLC: Updated phase I and pooled phase II results. Journal of Thoracic Oncology, 11(Suppl. 4), 2016, S57.
194. Yang, J.C., Sequist, L.V., Geater, S.L., Tsai, C.M., Mok, T.S., 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. The Lancet Oncology 16 (2015), 830–838.
195. Yang, J.C., 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. The Lancet Oncology 16 (2015), 141–151.
196. Yang, J.C., Ahn, M., Ramalingam, S.S., Sequist, L.V., Novello, S., Wu, W., Hirashima, T., et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA study phase II extension cohort. Journal of Thoracic Oncology, 10(Suppl. 2), 2015, S319.
197. Yang, J.J., Yang, L., Farnsworth, A., Handzel, A., Coleman, T., Morgan, S., et al. Preliminary results of a phase Ib trial of savolitinib combined with gefitinib in EGFR-mutant lung cancer. Journal of Clinical Oncology, 34, 2016, e20559 (suppl.).
198. Yano, S., Yamada, T., Takeuchi, S., Tachibana, K., Minami, Y., Yatabe, Y., et al. Hepatocyte growth factor expression in EGFR mutant lung cancer with intrinsic and acquired resistance to tyrosine kinase inhibitors in a Japanese cohort. Journal of Thoracic Oncology 6 (2011), 2011–2017.
199. Yasuda, H., Park, K., Yun, C.H., Sng, N.J., Lucena-Araujo, A.R., Weo, W.L., et al. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutation in lung cancer. Science Translational Medicine, 5, 2013, 216ra177.
200. Yatabe, Y., Kerr, K.M., Utomo, A., Rajadurai, P., Tran, V.K., Du, X., et al. EGFR mutation testing practices within the Asia Pacific region: results of a multicenter diagnostic survey. Journal of Thoracic Oncology 10 (2015), 438–445.
201. Yeo, C.D., Park, K.H., Park, C.K., Lee, S.H., Kim, S.J., Yoon, H.K., et al. Expression of insulin-like growth factor 1 receptor (IGF-1R) predicts poor responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer patients harboring activating EGFR mutations. Lung Cancer 87 (2015), 311–317.
202. Yoon, H.J., Lee, H.Y., Lee, K.S., Choi, Y.L., Ahn, M.J., Park, K., et al. Repeat biopsy for mutational analysis of non-small cell lung cancers resistant to previous chemotherapy: Adequacy and complications. Radiology 265 (2012), 939–948.
203. Yoshioka, H., Mitsudomi, T., Morita, S., Yatabe, Y., Negoro, S., Okamoto, I., et al. Final overall survival results of WJTOG3405, a randomized phase 3 trial comparing gefitinib with cisplatin plus docetaxel as the first-line treatment for patients with non-small cell lung cancer harboring mutations of the epidermal growth factor receptor. Journal of Clinical Oncology, 32, 2014, abstr 8117 (suppl.).
204. Yu, H.A., Jordan, E., Mi, A., Feldman, D., Rodriguez, C., Kim, H.R., et al. Concurrent genetic alterations identified by next-generation sequencing in pre-treatment, metastatic EGFR-mutant lung cancers. Journal of Clinical Oncology, 34, 2016, abstr 9053 (suppl.).
205. Yu, H.A., Spira, A.I., Horn, L., Weiss, J., West, H.J., 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 I study. Journal of Clinical Oncology, 34, 2016, abstr 9050 (suppl.).
206. Yu, H.A., Arcila, M.E., Hellmann, M.D., Kris, M.G., Ladanyi, M., Riely, G.J., Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing. Annals of Oncology 25 (2014), 423–428.
207. Yu, H.A., Arcila, M.E., Rekhtman, N., Sima, C.S., Zakowski, M.F., 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. Clinical Cancer Research 19 (2013), 2240–2247.
208. Zhang, Z., Lee, J.C., Lin, L., Olivas, V., Au, V., La Framboise, T., et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nature Genetics 44 (2012), 852–860.
209. Zhang, Y.W., Staal, B., Essenburg, C., Lewis, S., Kaufman, D., Vande Woude, G.F., Strengthening context-dependent anticancer effects on non-small cell lung carcinoma by inhibition of both MET and EGFR. Molecular Cancer Therapeutics 12 (2013), 1429–1941.
210. Zhou, C., Wu, Y.L., Chen, G., Feng, J., Liu, X.Q., Wang, C., et al. Final overall survival results from a randomized phase III study of erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802). Annals of Oncology 26 (2015), 1877–1883.