The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients

Shang-Gin Wu, Yi-Nan Liu, Meng-Feng Tsai, Yih-Leong Chang, Chong-Jen Yu, Pan-Chyr Yang, James Chih-Hsin Yang, Yueh-Feng Wen, Jin-Yuan Shih, Shang-Gin Wu, Yi-Nan Liu, Meng-Feng Tsai, Yih-Leong Chang, Chong-Jen Yu, Pan-Chyr Yang, James Chih-Hsin Yang, Yueh-Feng Wen, Jin-Yuan Shih

Abstract

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are associated with favorable response in EGFR mutant lung cancer. Acquired resistance to reversible EGFR TKIs remains a significant barrier, and acquired EGFR T790M-mutation is the major mechanism. Second-generation irreversible EGFR TKI, afatinib, had also been approved for treating EGFR mutant lung cancer patients, but the mechanism of acquired resistance to afatinib has not been well studied.

Results: Forty-two patients had tissue specimens taken after acquiring resistance to afatinib. The sensitizing EGFR mutation were all consistent between pre- and post-afatinib tissues. Twenty patients (47.6%) had acquired T790M mutation. T790M rate was not different between first-generation EGFR TKI-naïve patients (50%) and first-generation EGFR TKI-treated patients (46.4%) (p = 0.827). No clinical characteristics or EGFR mutation types were associated with the development of acquired T790M. No other second-site EGFR mutations were detected. There were no small cell or squamous cell lung cancer transformation. Other genetic mutations were not identified in PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2.

Methods: Afatinib-prescription record of our department of pharmacy from January 2007 and December 2014 was retrieved. We investigated patients with tissue specimens available after acquiring resistance to afatinib. Enrolled patients should have partial response or durable stable disease of treatment response to afatinib. Various mechanisms of acquired resistance to first-generation EGFR TKIs were evaluated. Histology and cytology were reviewed. EGFR, PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2 genetic alterations were evaluated by sequencing. Statistical analysis was performed using Chi-square test and Kaplan-Meier method.

Conclusions: T790M was detected in half of the lung adenocarcinoma after acquiring resistance to afatinib. T790M is still the major acquired resistance mechanism. First-generation EGFR TKI exposure did not influence the prevalence of T790M in lung cancer acquired resistance to afatinib.

Keywords: EGFR TKI; T790M; acquired resistance; afatinib; lung adenocarcinoma.

Conflict of interest statement

CONFLICTS OF INTEREST

Dr. Yu, Dr. C-H Yang and Dr. Shih received honoraria for speeches from Astra Zeneca, Boehringer Ingelheim and Roche.

Figures

Figure 1. Patient collection flow chart
Figure 1. Patient collection flow chart
Figure 2. Kaplan–meier curve of afatinib progression-free…
Figure 2. Kaplan–meier curve of afatinib progression-free survival in patients with acquired resistance to afatinib
(A) The difference in progression-free survival of afatinib treatment between patients with (solid line, n = 20) and without acquired T790M-mutations (dashed line, n = 22) did not reach statistically significant (median, 8.9 months vs. 8.2 months; p = 0.938, by the log-rank test). (B) The difference in progression-free survival of afatinib treatment between first-generation EGFR TKI-naïve (solid line, n = 14) and first-generation EGFR TKI-treated patients (dash line, n = 28) reached statistically significant (median, 21.0 months vs. 7.0 months; p < 0.001, by the log-rank test).
Figure 3. Kaplan–meier curve of post-afatinib-progression survival…
Figure 3. Kaplan–meier curve of post-afatinib-progression survival in 14 first-generation EGFR TKI-naïve patients who acquired resistance to afatinib
(A) The difference in progression-free survival between patients with (solid line, n = 7) and without T790M-mutations (dashed line, n = 7) did not reach statistically significant (median, 21.0 months vs. 33.8 months; p = 0.648, by the log-rank test). (B) Patients with acquired T790M had a longer median post-afatinib-progression survival than patients without acquired T790M mutations, but the difference did not reach statistical significance (median, 35.3 months vs. 17.8 months; p = 0.616, by the log-rank test).

References

    1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics 2014. CA: a cancer journal for clinicians. 2014;64:9–29.
    1. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, 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. 2004;350:2129–2139.
    1. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. The New England journal of medicine. 2009;361:947–957.
    1. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. The Lancet Oncology. 2011;12:735–742.
    1. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, 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. 2010;11:121–128.
    1. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato 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. 2013;31:3327–3334.
    1. Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee KY, Xu CR, Massey D, Kim M, 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. 2014;15:213–222.
    1. Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, 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. 2015;16:141–151.
    1. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK, Akhavanfard S, Heist RS, Temel J, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Science translational medicine. 2011;3:75ra26.
    1. Camidge DR, Pao W, Sequist LV. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nature reviews Clinical oncology. 2014;11:473–481.
    1. Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. The New England journal of medicine. 2015;372:1689–1699.
    1. Sequist LV, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM, Varga A, Papadimitrakopoulou V, Solomon BJ, Oxnard GR, Dziadziuszko R, Aisner DL, Doebele RC, Galasso C, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. The New England journal of medicine. 2015;372:1700–1709.
    1. Levin PA, Mayer M, Hoskin S, Sailors J, Oliver DH, Gerber DE. Histologic Transformation from Adenocarcinoma to Squamous Cell Carcinoma as a Mechanism of Resistance to EGFR Inhibition. J Thorac Oncol. 2015;10:e86–88.
    1. Costa DB, Halmos B, Kumar A, Schumer ST, Huberman MS, Boggon TJ, Tenen DG, Kobayashi S. BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS medicine. 2007;4:1669–1679. discussion 1680.
    1. Toyooka S, Date H, Uchida A, Kiura K, Takata M. The epidermal growth factor receptor D761Y mutation and effect of tyrosine kinase inhibitor. Clinical cancer research. 2007;13:3431. author reply 3431–3432.
    1. Ohashi K, Sequist LV, Arcila ME, Moran T, Chmielecki J, Lin YL, Pan Y, Wang L, de Stanchina E, Shien K, Aoe K, Toyooka S, Kiura K, 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. 2012;109:E2127–2133.
    1. Kim Y, Ko J, Cui Z, Abolhoda A, Ahn JS, Ou S-H, Ahn M-J, Park K. The EGFR T790M Mutation in Acquired Resistance to an Irreversible Second-Generation EGFR Inhibitor. Molecular Cancer Therapeutics. 2012;11:784–791.
    1. Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, Crino L, Tan EH, 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. 2012;13:528–538.
    1. Kim Y, Ko J, Cui Z, Abolhoda A, Ahn JS, Ou SH, Ahn MJ, Park K. The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor. Mol Cancer Ther. 2012;11:784–791.
    1. Azuma K, Kawahara A, Sonoda K, Nakashima K, Tashiro K, Watari K, Izumi H, Kage M, Kuwano M, Ono M, Hoshino T. FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor. Oncotarget. 2014;5:5908–5919. doi: 10.18632/oncotarget.1866.
    1. Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. The New England journal of medicine. 2005;352:786–792.
    1. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS medicine. 2005;2:e73.
    1. Kuiper JL, Heideman DA, Thunnissen E, Paul MA, van Wijk AW, Postmus PE, Smit EF. Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients. Lung cancer. 2014;85:19–24.
    1. Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, Chiang A, Yang G, Ouerfelli O, Kris MG, Ladanyi M, Miller VA, Pao W. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clinical cancer research. 2006;12:6494–6501.
    1. Bean J, Riely GJ, Balak M, Marks JL, Ladanyi M, Miller VA, Pao W. Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clinical cancer research. 2008;14:7519–7525.
    1. Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, Lai Z, Markovets A, Vivancos A, Kuang Y, Ercan D, Matthews SE, Cantarini M, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015;21:560–562.
    1. Solca F, Dahl G, Zoephel A, Bader G, Sanderson M, Klein C, Kraemer O, Himmelsbach F, Haaksma E, Adolf GR. Target Binding Properties and Cellular Activity of Afatinib (BIBW 2992), an Irreversible ErbB Family Blocker. Journal of Pharmacology and Experimental Therapeutics. 2012;343:342–350.
    1. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, Kris MG, Miller VA, Ladanyi M, Riely GJ. 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. 2013;19:2240–2247.
    1. Oser MG, Niederst MJ, Sequist LV, Engelman JA. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. The Lancet Oncology. 2015;16:e165–e172.
    1. Oxnard GR, Arcila ME, Sima CS, Riely GJ, Chmielecki J, Kris MG, Pao W, Ladanyi M, Miller VA. 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. 2011;17:1616–1622.
    1. Hata A, Katakami N, Yoshioka H, Takeshita J, Tanaka K, Nanjo S, Fujita S, Kaji R, Imai Y, Monden K, Matsumoto T, Nagata K, Otsuka K, et al. Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: Comparison between T790M mutation-positive and mutation-negative populations. Cancer. 2013;119:4325–4332.
    1. Wu SG, Yu CJ, Tsai MF, Liao WY, Yang CH, Jan IS, Yang PC, Shih JY. Survival of lung adenocarcinoma patients with malignant pleural effusion. The European respiratory journal. 2013;41:1409–1418.
    1. Centers for Disease C and Prevention Cigarette smoking among adults– United States, 2006. MMWR Morb Mortal Wkly Rep. 2007;56:1157–1161.
    1. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, Garg K, Austin JH, Asamura H, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6:244–285.
    1. Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Janne PA, Lynch T, Johnson BE, Miller VA. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Journal of clinical oncology. 2010;28:357–360.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) European journal of cancer. 2009;45:228–247.
    1. Tsai TH, Su KY, Wu SG, Chang YL, Luo SC, Jan IS, Yu CJ, Yu SL, Shih JY, Yang PC. RNA is favourable for analysing EGFR mutations in malignant pleural effusion of lung cancer. The European respiratory journal. 2012;39:677–684.
    1. Tsai TH, Yang CY, Ho CC, Liao WY, Jan IS, Chen KY, Wang JY, Ruan SY, Yu CJ, Yang JC, Yang PC, Shih JY. Multi-gene analyses from waste brushing specimens for patients with peripheral lung cancer receiving EBUS-assisted bronchoscopy. Lung cancer. 2013;82:420–425.
    1. Wu SG, Gow CH, Yu CJ, Chang YL, Yang CH, Hsu YC, Shih JY, Lee YC, Yang PC. Frequent epidermal growth factor receptor gene mutations in malignant pleural effusion of lung adenocarcinoma. The European respiratory journal. 2008;32:924–930.

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