Acquired resistance to EGFR targeted therapy in non-small cell lung cancer: Mechanisms and therapeutic strategies

Cancer Treatment Reviews

Volumn 65, Issue , 2018, Pages 1-10

  Lim, Sun Min ^a   Syn, Nicholas L ^b   Cho, Byoung Chul ^c   Soo, Ross A ^b  

^a Bundang CHA Hospital   (South Korea)

^b NATIONAL UNIVERSITY HEALTH SYSTEM   (Singapore)

^c Yonsei University College of Medicine   (South Korea)

Author keywords

Drug resistance; EGFR targeted therapies; Epidermal growth factor receptor; Non small cell lung cancer; Osimertinib

Indexed keywords

AC 0010; AVITINIB; BIOLOGICAL MARKER; BRIGATINIB; BUPARLISIB; CABOZANTINIB; CAPMATINIB; DACOMITINIB; EF 816; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 2; ERLOTINIB; FIBROBLAST GROWTH FACTOR RECEPTOR 1; GEFITINIB; MAVELERTINIB; METHIONINE; NAQUOTINIB; NAZARTINIB; OLMUTINIB; OSIMERTINIB; PHOSPHATIDYLINOSITOL KINASE; PHOSPHATIDYLINOSITOL KINASE 3CA; PROTEIN AXL; PROTEIN TYROSINE KINASE INHIBITOR; ROCILETINIB; SOMATOMEDIN RECEPTOR; THREONINE; TYROSINE KINASE RECEPTOR; UNCLASSIFIED DRUG; EGFR PROTEIN, HUMAN; PROTEIN KINASE INHIBITOR;

AMINO ACID SUBSTITUTION; AREA UNDER THE CURVE; CANCER CHEMOTHERAPY; CANCER IMMUNOTHERAPY; CONTROLLED STUDY; CYTOTOXICITY; DIARRHEA; DISEASE CONTROL; DISEASE COURSE; DISEASE EXACERBATION; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; DRY SKIN; GENE AMPLIFICATION; GENE MUTATION; HUMAN; HUMAN TISSUE; IN VITRO STUDY; LIQUID BIOPSY; MAJOR CLINICAL STUDY; MAXIMUM CONCENTRATION; MOLECULARLY TARGETED THERAPY; MOUSE; MULTICENTER STUDY; NON SMALL CELL LUNG CANCER; NONHUMAN; ONCOGENE; ONCOGENE MET; PARONYCHIA; PHARMACODYNAMICS; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; RANDOMIZED CONTROLLED TRIAL; REVIEW; SYSTEMIC ACQUIRED RESISTANCE; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG RESISTANCE; ENZYMOLOGY; GENETICS; LUNG TUMOR; RANDOMIZED CONTROLLED TRIAL (TOPIC);

ANIMALS; CARCINOMA, NON-SMALL-CELL LUNG; DRUG RESISTANCE, NEOPLASM; HUMANS; LUNG NEOPLASMS; MOLECULAR TARGETED THERAPY; PROTEIN KINASE INHIBITORS; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RECEPTOR, EPIDERMAL GROWTH FACTOR;

EID: 85042385721     PISSN: 03057372     EISSN: 15321967     Source Type: Journal    
DOI: 10.1016/j.ctrv.2018.02.006     Document Type: Review

References (104)

1. Pao, W., Miller, V., Zakowski, M., Doherty, J., Politi, K., Sarkaria, I., et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101 (2004), 13306–13311.
2. 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. N Engl J Med 350 (2004), 2129–2139.
3. 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. N Engl J Med 361 (2009), 947–957.
4. 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 362 (2010), 2380–2388.
5. 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 13 (2012), 239–246.
6. Sequist, L.V., Yang, J.C., 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 31 (2013), 3327–3334.
7. 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. Lancet Oncol 15 (2014), 213–222.
8. 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. Lancet Oncol 11 (2010), 121–128.
9. Neel DS, Bivona TG. Resistance is futile: overcoming resistance to targeted therapies in lung adenocarcinoma. NPJ precision oncology 2017;1.
10. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology non-small cell lung cancer. 2017.
11. 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. J Natl Cancer Inst 105 (2013), 595–605.
12. 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.
13. Solca, F., Dahl, G., Zoephel, A., Bader, G., Sanderson, M., Klein, C., et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther 343 (2012), 342–350.
14. 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 Res 67 (2007), 11924–11932.
15. Paz-Ares, L., Tan, E.H., O'Byrne, K., Zhang, L., Hirsh, V., Boyer, M., et al. Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial. Ann Oncol 28 (2017), 270–277.
16. 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. Lancet Oncol 16 (2015), 141–151.
17. Park, K., Tan, E.H., O'Byrne, K., Zhang, L., Boyer, M., Mok, T., et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol 17 (2016), 577–589.
18. Mok, T., Cheng, Y., Zhou, X., Lee, K.H., Nakagawa, K., 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. ASCO Annual Meeting. J Clin Oncol, 35(abstr LBA9007), 2017, 2017.
19. 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. J Clin Oncol 28 (2010), 357–360.
20. 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. Clin Lung Cancer 15 (2014), 1–6.
21. Yang, J.J., Chen, H.J., Yan, H.H., Zhang, X.C., Zhou, Q., Su, J., et al. Clinical modes of EGFR tyrosine kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer. Lung Cancer 79 (2013), 33–39.
22. Tan, C.S., Cho, B.C., Soo, R.A., Treatment options for EGFR mutant NSCLC with CNS involvement-can patients BLOOM with the use of next generation EGFR TKIs?. Lung Cancer 108 (2017), 29–37.
23. Ni, Y., Bi, J., Ye, X., Fan, W., Yu, G., Yang, X., et al. Local microwave ablation with continued EGFR tyrosine kinase inhibitor as a treatment strategy in advanced non-small cell lung cancers that developed extra-central nervous system oligoprogressive disease during EGFR tyrosine kinase inhibitor treatment: a pilot study. Medicine (Baltimore), 95, 2016, e3998.
24. Weickhardt, A.J., Scheier, B., Burke, J.M., Gan, G., Lu, X., Bunn, P.A., et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol 7 (2012), 1807–1814.
25. Yu, H.A., Sima, C.S., Huang, J., Solomon, S.B., Rimner, A., Paik, P., 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 8 (2013), 346–351.
26. 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. Lancet Oncol 16 (2015), 990–998.
27. Soria, J.C., Kim, S.W., Wu, Y.L., Gefitinib/chemotherapy vs chemotherapy in EGFR mutation-positive NSCLC after progression on 1st line gefitinib (IMPRESS study): final overall survival (OS) analysis. Ann Oncol 27 (2016), 416–454.
28. Park, K., Yu, C.J., Kim, S.W., Lin, M.C., Sriuranpong, V., Tsai, C.M., et al. First-line erlotinib therapy until and beyond response evaluation criteria in solid tumors progression in Asian patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer: the ASPIRATION study. JAMA Oncol 2 (2016), 305–312.
29. 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. Clin Cancer Res 19 (2013), 2240–2247.
30. Oxnard, G.R., Arcila, M.E., Chmielecki, J., Ladanyi, M., Miller, V.A., Pao, W., New strategies in overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer. Clin Cancer Res 17 (2011), 5530–5537.
31. 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. Nat Med 22 (2016), 262–269.
32. 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.
33. 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. Proc Natl Acad Sci U S A 104 (2007), 20932–20937.
34. Wu, Y.L., Yang, J., Kim, D.W., Su, W.C., Ahn, M.J., Lee, D.H., et al. Safety and efficacy of INC280 in combination with gefitinib in patients with EGFR-mutated, MET-positive NSCLC: a single-arm phase 1B/II study. J Clin Oncol, 2014.
35. Neal Joel W, Dahlberg SE, Wakelee Heather A, Aisner Seena C., Bowden Michaela, et al. Cabozantinib (C), erlotinib (E) or the combination (E+C) as second- or third-line therapy in patients with EGFR wild-type (wt) non-small cell lung cancer (NSCLC): a randomized phase 2 trial of the ECOG-ACRIN Cancer Research Group (E1512). 2015 ASCO Annual Meeting. J Clin Oncol 2015. p. abstr 8003.
36. Zhang, Z., Lee, J.C., 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 44 (2012), 852–860.
37. Vuoriluoto, K., Haugen, H., Kiviluoto, S., Mpindi, J.P., Nevo, J., Gjerdrum, C., et al. Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene 30 (2011), 1436–1448.
38. Gay, C.M., Balaji, K., Byers, L.A., Giving AXL the axe: targeting AXL in human malignancy. Br J Cancer 116 (2017), 415–423.
39. Guix, M., Faber, A.C., Wang, S.E., Olivares, M.G., Song, Y., Qu, S., et al. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest 118 (2008), 2609–2619.
40. Cortot, A.B., Repellin, C.E., Shimamura, T., Capelletti, M., Zejnullahu, K., Ercan, D., et al. Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway. Cancer Res 73 (2013), 834–843.
41. Takezawa, K., Pirazzoli, 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 Discov 2 (2012), 922–933.
42. Sos, M.L., Koker, M., Weir, B.A., Heynck, S., Rabinovsky, R., Zander, T., et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 69 (2009), 3256–3261.
43. Tan DS, Lim KH, Tai WM, Ahmad A, Pan S, Ng QS. A phase 1b safety and tolerability study of a pan class I PI3K inhibitor buparlisib (BKM120) and gefitinib in EGFR TKI-resistant NSCLC. J Clin Oncol 2013;31:8107-.
44. 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;3:75ra26.
45. 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. Nat Commun, 6, 2015, 6377.
46. Capaccione, K.M., Hong, X., Morgan, K.M., Liu, W., Bishop, J.M., Liu, L., et al. Sox9 mediates Notch1-induced mesenchymal features in lung adenocarcinoma. Oncotarget 5 (2014), 3636–3650.
47. Yao, Z., Fenoglio, S., Gao, D.C., Camiolo, M., Stiles, B., Lindsted, T., et al. TGF-beta IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proc Natl Acad Sci U S A 107 (2010), 15535–15540.
48. Popat, S., Wotherspoon, A., Nutting, C.M., Gonzalez, D., Nicholson, A.G., O'Brien, M., Transformation to “high grade” neuroendocrine carcinoma as an acquired drug resistance mechanism in EGFR-mutant lung adenocarcinoma. Lung Cancer 80 (2013), 1–4.
49. Tan, C.S., Cho, B.C., Soo, R.A., Next-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor -mutant non-small cell lung cancer. Lung Cancer 93 (2016), 59–68.
50. Cross, D.A., Ashton, S.E., Ghiorghiu, S., Eberlein, C., Nebhan, C.A., Spitzler, P.J., et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 4 (2014), 1046–1061.
51. 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. N Engl J Med 372 (2015), 1689–1699.
52. Yang, J.C., Ahn, M.J., Kim, D.W., Ramalingam, S.S., Sequist, L.V., 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 35 (2017), 1288–1296.
53. Goss, G., Tsai, C.M., Shepherd, F.A., Bazhenova, L., Lee, J.S., Chang, G.C., 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 17 (2016), 1643–1652.
54. Mok, T.S., Wu, Y.L., Ahn, M.J., Garassino, M.C., Kim, H.R., Ramalingam, S.S., et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 376 (2017), 629–640.
55. Ballard, P., Yates, J.W., Yang, Z., Kim, D.W., Yang, J.C., 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 22 (2016), 5130–5140.
56. Goss G Tsai C-M, Shepherd F, Ahn Myung-Ju, Bazhenova L, Crino L, et al. CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. 2016 World Conference of Lung Cancer. J Thorac Oncol 2016: S440–S441.
57. Mok TS AM, 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). 2017 ASCO Annual Meeting. J Clin Oncol 2017. p. abstr 9005.
58. Aw DC, Tan EH, Chin TM, Lim HL, Lee HY, Soo RA. Management of epidermal growth factor receptor tyrosine kinase inhibitor-related cutaneous and gastrointestinal toxicities. Asia Pac J Clin Oncol 2017.
59. 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.
60. Chouaid, C., Dujon, C., Do, P., Monnet, I., Madroszyk, A., Le Caer, H., et al. Feasibility and clinical impact of re-biopsy in advanced non small-cell lung cancer: a prospective multicenter study in a real-world setting (GFPC study 12-01). Lung Cancer 86 (2014), 170–173.
61. de Bruin, E.C., McGranahan, N., Swanton, C., Analysis of intratumor heterogeneity unravels lung cancer evolution. Mol Cell Oncol, 2, 2015, e985549.
62. Sundaresan, T.K., Sequist, L.V., Heymach, J.V., Riely, G.J., Janne, P.A., Koch, W.H., et al. Detection of T790M, the acquired resistance EGFR mutation, by tumor biopsy versus noninvasive blood-based analyses. Clin Cancer Res 22 (2016), 1103–1110.
63. Novello, S., Barlesi, F., Califano, R., Cufer, T., Ekman, S., Levra, M.G., et al. Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 27 (2016), v1–v27.
64. Jenkins, S., Chy, J., Ramalingam, S.S., 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.
65. Wu, Y.L., Jenkins, S., Ramalingam, S., Han, J.Y., MA08.03 osimertinib vs platinum-pemetrexed for T790M -mutation positive advanced NSCLC (AURA3): Plama ctDNA Analysis. J Thorac Oncol, 12, 2017, S386.
66. Karlovich, C., Goldman, J.W., Sun, J.M., Mann, E., Sequist, L.V., 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 22 (2016), 2386–2395.
67. Thress, K.S., Brant, R., Carr, T.H., 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 90 (2015), 509–515.
68. Thress, K.S., Paweletz, C.P., Felip, E., Cho, B.C., 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 21 (2015), 560–562.
69. Yu, H.A., Tian, S.K., Drilon, A.E., Borsu, L., Riely, G.J., Arcila, M.E., et al. Acquired resistance of EGFR-mutant lung cancer to a T790M-specific EGFR inhibitor: emergence of a third mutation (C797S) in the EGFR tyrosine kinase domain. JAMA Oncol 1 (2015), 982–984.
70. Jia, Y., Yun, C.H., Park, E., Ercan, D., Manuia, M., Juarez, J., et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 534 (2016), 129–132.
71. Song, H.N., Jung, K.S., Yoo, K.H., Cho, J., Lee, J.Y., Lim, S.H., 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 11 (2016), e45–e47.
72. Chabon, J.J., Simmons, A.D., Lovejoy, A.F., Esfahani, M.S., Newman, A.M., Haringsma, H.J., et al. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun, 7, 2016, 11815.
73. Daniel Shao-Weng Tan D-WK, Natasha B. Leighl, Gregory J. Riely, James Chih-Hsin Yang, et al. Genomic profiling of resistant tumor samples following progression on EGF816, a third generation, mutant-selective EGFR tyrosine kinase inhibitor, in advanced non-smal cell lung cancer. 2017 ASCO Annual Meeting. J Clin Oncology; 2017.
74. 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. Clin Cancer Res 21 (2015), 3924–3933.
75. Wang, Z., Yang, J.J., Huang, J., Ye, J.Y., Zhang, X.C., Tu, H.Y., 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.
76. Menon, R., Muller, 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 11 (2016), e105–e107.
77. Oxnard Geoffrey R, Hu Y, Mileham Kathryn F, Tracy Philip, Feeney Nora, Sholl Lynette M, et al. Osimertinib resistance mediated by loss of EGFR T790M is associated with early resistance and competing resistance mechanisms. World Conference on Lung Cancer 2017.
78. Piotrowska Z, Nagy RJ, Fairclough S, Lanman RB, Marcoux N, Gettinger SN, et al. Characterizing the genomic landscape of EGFR C797S in lung cancer using ctDNA next-generation sequencing. IASLC World Conference on Lung Cancer 2017.
79. 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 11 (2016), e121–e123.
80. Chen, K., Zhou, F., Shen, W., Jiang, T., Wu, X., Tong, X., et al. Novel mutations on EGFR Leu792 potentially correlate to acquired resistance to osimertinib in advanced NSCLC. J Thorac Oncol 12 (2017), e65–e68.
81. Ou Q WX, Bao H, Tong X, Wang X, Zhang Z, et al. Investigating novel resistance mechanisms to third generation EGFR TKI osimertinib in non-small cell lung cancer pateints using next generation sequencing. J Clin Oncol. 2572-.
82. Ou, S.I., Cui, J., Schrock, A.B., Goldberg, M.E., Zhu, V.W., 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 108 (2017), 228–231.
83. Kong, L.L., Ma, R., Yao, M.Y., Yan, X.E., Zhu, S.J., Zhao, P., et al. Structural pharmacological studies on EGFR T790M/C797S. Biochem Biophys Res Commun 488 (2017), 266–272.
84. 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. Ann Oncol 26 (2015), 2073–2078.
85. Ou, S.I., Agarwal, N., Ali, S.M., 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 98 (2016), 59–61.
86. Shi, P., Oh, Y.T., Zhang, G., Yao, W., Yue, P., Li, Y., et al. Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment. Cancer Lett 380 (2016), 494–504.
87. Ortiz-Cuaran, S., Scheffler, M., Plenker, D., Dahmen, L., Scheel, A.H., Fernandez-Cuesta, L., et al. Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors. Clin Cancer Res 22 (2016), 4837–4847.
88. 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. J Thorac Oncol 10 (2015), 1736–1744.
89. Ho, C.C., Liao, W.Y., Lin, C.A., Shih, J.Y., Yu, C.J., Chih-Hsin, Yang J., Acquired BRAF V600E mutation as resistant mechanism after treatment with osimertinib. J Thorac Oncol 12 (2017), 567–572.
90. Ham, J.S., Kim, S., Kim, H.K., Byeon, S., Sun, J.M., Lee, S.H., et al. Two cases of small cell lung cancer transformation from egfr mutant adenocarcinoma during AZD9291 treatment. J Thorac Oncol 11 (2016), e1–e4.
91. Ichihara, E., Westover, D., Meador, C.B., Yan, Y., Bauer, J.A., Lu, P., et al. SFK/FAK signaling attenuates osimertinib efficacy in both drug-sensitive and drug-resistant models of egfr-mutant lung cancer. Cancer Res 77 (2017), 2990–3000.
92. Martinez-Marti, A., Felip, E., Matito, J., Mereu, E., Navarro, A., Cedres, S., et al. Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC). Ann Oncol 28 (2017), 2451–2457.
93. Ramalingam SS, Yang JC, Lee CK, Kurata T, Kim DW, John T, et al. Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 2017:JCO2017747576.
94. Oxnard GR. Mechanisms of acquired resistance to AZD9291 in EGFRT790 M positive lung cancer. IASLC 16th World Conf Lung Cancer. Denver, Colorado 2015.
95. 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 Discov 5 (2015), 713–722.
96. Li, L., Wang, H., Li, C., Wang, Z., Zhang, P., Yan, X., Transformation to small-cell carcinoma as an acquired resistance mechanism to AZD9291: A case report. Oncotarget 8 (2017), 18609–18614.
97. Eberlein, C.A., Stetson, D., Markovets, A.A., Al-Kadhimi, K.J., Lai, Z., Fisher, P.R., et al. Acquired resistance to the mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling in preclinical models. Cancer Res 75 (2015), 2489–2500.
98. Soria, J.C., Ohe, Y., Vansteenkiste, J., Reungwetwattana, T., Chewaskulyong, B., Lee, K.H., et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 378 (2018), 113–125.
99. Soo, R.A., Lim, S.M., Syn, N.L., Teng, R., Soong, R., Mok, T.S.K., et al. Immune checkpoint inhibitors in epidermal growth factor receptor mutant non-small cell lung cancer: current controversies and future directions. Lung Cancer 115 (2018), 12–20.
100. Lee, C.K., Man, J., Lord, S., Links, M., Gebski, V., Mok, T., et al. Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer-a meta-analysis. J Thorac Oncol 12 (2017), 403–407.
101. Rizvi, N., Chow, L., Borghaei, H., et al. Safety and response with nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus erlotinib in patients with epidermal growth factor receptor mutant advanced NSCLC. J Clin Oncol, 2014.
102. Ma, B.B.Y., Rudin, C.M., Cervantes, A., et al. Preliminary safety and clinical activity of erlotinib plus atezolizumab from a phase 1b study in advanced NSCLC. Ann Oncol, 27, 2016, S9.
103. Gibbons, D.L., Chow, L.Q., Kim, D.W., et al. Efficacy, safety and tolerability of MEDI4736 (durvalumab) a human IgG1 anti-programmed cell death-ligand-1 antibody, combined with gefitinib: a phase I expansion in TKI-naive patients with EGFR mutant NSCLC. J Thorac Oncol, 11, 2016, S79.
104. Ahn MJ Yang J, Yu H, Saka H, Ramalingam S, Goto K, et al., Oxnard GR. Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: Results from the TATTON phase Ib trial. European Lung Cancer Conference 2016. J Thorac Oncol 2016: S115.