The salvage therapy in lung adenocarcinoma initially harbored susceptible EGFR mutation and acquired resistance occurred to the first-line gefitinib and second-line cytotoxic chemotherapy

Chih-Jen Yang, Jen-Yu Hung, Ming-Ju Tsai, Kuan-Li Wu, Ta-Chih Liu, Shah-Hwa Chou, Jui-Ying Lee, Jui-Sheng Hsu, Ming-Shyan Huang, Inn-Wen Chong, Chih-Jen Yang, Jen-Yu Hung, Ming-Ju Tsai, Kuan-Li Wu, Ta-Chih Liu, Shah-Hwa Chou, Jui-Ying Lee, Jui-Sheng Hsu, Ming-Shyan Huang, Inn-Wen Chong

Abstract

Background: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib can provide better efficacy and prolonged progression free survival (PFS) than cytotoxic chemotherapy for metastatic lung non-squamous cell carcinoma harboring susceptible EGFR mutations when used as first-line therapy. Cytotoxic chemotherapy is regarded as being the standard therapy to overcome acquired resistance to an initial EGFR TKI. However, there is currently no consensus on how best to treat patients who develop resistance to both an initial EGFR TKI and chemotherapy.

Methods: We enrolled stage IV lung adenocarcinoma patients with an EGFR mutation and who had developed acquired resistance to gefitinib and cytotoxic chemotherapy from two university-affiliated hospitals in Taiwan from June 2011 to December 2014. Basic demographic data, included Eastern Cooperative Oncology Group (ECOG) performance status were collected, and the response rate, progression-free survival (PFS) and overall survival (OS) were analyzed.

Result: Two hundred and nine patients with mutated EGFR and who took gefitinib as the first-line therapy were identified in the study period, of whom 86 received second-line cytotoxic chemotherapy, and 60 who received third-line therapy were eligible for this study. The patients who received cytotoxic chemotherapy had a significantly higher disease control rate than those who received erlotinib (73% vs. 46%, p = 0.0363), however there were no significant differences in PFS (2.9 months vs. 3.1 months, p = 0.9049) and OS (8.9 months vs. 7.9 months, p = 0.4956). Platinum- or pemetrexed-based chemotherapy provided similar PFS and OS as others did. The only significant poor prognostic factors for OS were old age (≥65 years) (HR = 5.97 [2.65-13.44], p < 0.0001) and poor performance status (ECOG ≥2) (HR = 5.84 [2.61-13.09], p < 0.0001).

Conclusion: Retreatment with an EGFR TKI is not inferior to cytotoxic chemotherapy when used as salvage therapy for patients with adenocarcinoma with an EGFR mutation, especially if a third-generation EGFR TKI is not available, or if the reason for resistance is unknown or is not related to the T790M mutation. Old age and poor ECOG score were both poor prognostic factors in the salvage therapy.

Keywords: Acquired resistance; Chemotherapy; Epidermal growth factor receptor; Erlotinib; Gefitinib.

Figures

Fig. 1
Fig. 1
Kaplan-Meier curves of progression-free survival (PFS3; A,C,E) and overall survival (OS3; B,D,F) with the third-line treatment. a, b Analyses of the whole study cohort showed that patients receiving chemotherapy and those receiving erlotinib had similar PFS3 (MST of PFS3: 2.9 vs. 3.1 months, log-rank p = 0.8945) and OS3 (MST of OS3: 8.9 vs. 7.9 months, log-rank p = 0.4956). c, d Analyses of the patients receiving chemotherapy showed that patients receiving platinum-based doublet had a similar PFS3 and a trend for better OS3 as compared with those receiving chemotherapy without platinum (MST of PFS3: 3.2 vs. 2.8 months, log-rank p = 0.5760; MST of OS3: 10.6 vs. 7.5 months, log-rank p = 0.0545). e, f Analyses of the patients receiving chemotherapy showed that patients receiving pemetrexed had a similar PFS3 and a trend for better OS3 as compared with those receiving chemotherapy without pemetrexed (MST of PFS3: 2.9 vs. 3.0 months, log-rank p = 0.2045; MST of OS3: undefined vs. 7.7 months, log-rank p = 0.0795). Abbreviation: MST = median survival time

References

    1. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–1500. doi: 10.1126/science.1099314.
    1. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, de Marinis F, Corre R, Bover I, Illiano A, Dansin E, De Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Munoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239–246. doi: 10.1016/S1470-2045(11)70393-X.
    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, Yoshioka H, Shibata K, Kudoh S, Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121–128. doi: 10.1016/S1470-2045(09)70364-X.
    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, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–957. doi: 10.1056/NEJMoa0810699.
    1. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–2388. doi: 10.1056/NEJMoa0909530.
    1. Tan CS, Gilligan D, Pacey S. Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer. Lancet Oncol. 2015;16:e447–e459. doi: 10.1016/S1470-2045(15)00246-6.
    1. Oxnard GR, Arcila ME, Chmielecki J, Ladanyi M, Miller VA, Pao W. New strategies in overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer. Clin Cancer Res. 2011;17:5530–5537. doi: 10.1158/1078-0432.CCR-10-2571.
    1. Planchard D, Loriot Y, Andre F, Gobert A, Auger N, Lacroix L, Soria JC. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol. 2015;26:2073–2078. doi: 10.1093/annonc/mdv319.
    1. Yver A. Osimertinib (AZD9291) - a science-driven, collaborative approach to rapid drug design and development. Ann Oncol. 2016;27(6):1167–1170. doi: 10.1093/annonc/mdw129.
    1. Chuang JC, Salahudeen AA, Wakelee HA: Rociletinib, a third generation EGFR tyrosine kinase inhibitor: current data and future directions. Expert Opin Pharmacother. 2016;17:989–93.
    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, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372:1689–1699. doi: 10.1056/NEJMoa1411817.
    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, Garon EB, Heist RS, Logan J, Neal JW, Mendenhall MA, Nichols S, Piotrowska Z, Wozniak AJ, Raponi M, Karlovich CA, Jaw-Tsai S, Isaacson J, Despain D, Matheny SL, Rolfe L, Allen AR, Camidge DR. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2015;372:1700–1709. doi: 10.1056/NEJMoa1413654.
    1. Jiang T, Ren S, Zhou C. Role of circulating-tumor DNA analysis in non-small cell lung cancer. Lung Cancer. 2015;90:128–134. doi: 10.1016/j.lungcan.2015.09.013.
    1. Yang CJ, Tsai MJ, Hung JY, Liu TC, Chou SH, Lee JY, Hsu JS, Tsai YM, Huang MS, Chong IW. Pemetrexed had significantly better clinical efficacy in patients with stage IV lung adenocarcinoma with susceptible EGFR mutations receiving platinum-based chemotherapy after developing resistance to the first-line gefitinib treatment. Onco Targets Ther. 2016;9:1579–1587. doi: 10.2147/OTT.S100164.
    1. Becker A, Crombag L, Heideman DA, Thunnissen FB, van Wijk AW, Postmus PE, Smit EF. Retreatment with erlotinib: Regain of TKI sensitivity following a drug holiday for patients with NSCLC who initially responded to EGFR-TKI treatment. Eur J Cancer. 2011;47:2603–2606. doi: 10.1016/j.ejca.2011.06.046.
    1. Song T, Yu W, Wu SX. Subsequent treatment choices for patients with acquired resistance to EGFR-TKIs in non-small cell lung cancer: restore after a drug holiday or switch to another EGFR-TKI? Asian Pac J Cancer Prev. 2014;15:205–213. doi: 10.7314/APJCP.2014.15.1.205.
    1. Hata A, Katakami N, Yoshioka H, Fujita S, Kunimasa K, Nanjo S, Otsuka K, Kaji R, Tomii K, Iwasaku M, Nishiyama A, Hayashi H, Morita S, Ishida T. Erlotinib after gefitinib failure in relapsed non-small cell lung cancer: clinical benefit with optimal patient selection. Lung Cancer. 2011;74:268–273. doi: 10.1016/j.lungcan.2011.03.010.
    1. Zhao ZR, Li W, Long H. Readministration of EGFR tyrosine kinase inhibitor in non-small cell lung cancer patients after initial failure, what affects its efficacy? Sci Rep. 2014;4:5996.
    1. Zhao ZR, Wang JF, Lin YB, Wang F, Fu S, Zhang SL, Su XD, Jiang L, Zhang YG, Shao JY, Long H. Mutation abundance affects the efficacy of EGFR tyrosine kinase inhibitor readministration in non-small-cell lung cancer with acquired resistance. Med Oncol. 2014;31:810. doi: 10.1007/s12032-013-0810-6.
    1. Chang JW, Chou CL, Huang SF, Wang HM, Hsieh JJ, Hsu T, Cheung YC. Erlotinib response of EGFR-mutant gefitinib-resistant non-small-cell lung cancer. Lung Cancer. 2007;58:414–417. doi: 10.1016/j.lungcan.2007.05.018.
    1. Garfield DH. Modern treatment of lung cancer: case 2. Response to erlotinib after failure of gefitinib in a patient with advanced non-small-cell lung carcinoma. J Clin Oncol. 2005;23:7738–7740. doi: 10.1200/JCO.2005.02.4471.
    1. Wong AS, Soong R, Seah SB, Lim SW, Chuah KL, Nga ME, Chin TM, Soo RA. Evidence for disease control with erlotinib after gefitinib failure in typical gefitinib-sensitive Asian patients with non-small cell lung cancer. J Thorac Oncol. 2008;3:400–404. doi: 10.1097/JTO.0b013e318168c801.
    1. Watanabe S, Tanaka J, Ota T, Kondo R, Tanaka H, Kagamu H, Ichikawa K, Koshio J, Baba J, Miyabayashi T, Narita I, Yoshizawa H. Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: a retrospective analysis. BMC Cancer. 2011;11:1. doi: 10.1186/1471-2407-11-1.
    1. Lee DH, Kim SW, Suh C, Yoon DH, Yi EJ, Lee JS. Phase II study of erlotinib as a salvage treatment for non-small-cell lung cancer patients after failure of gefitinib treatment. Ann Oncol. 2008;19:2039–2042. doi: 10.1093/annonc/mdn423.
    1. Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S, McDermott U, Azizian N, Zou L, Fischbach MA, Wong KK, Brandstetter K, Wittner B, Ramaswamy S, Classon M, Settleman J. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010;141:69–80. doi: 10.1016/j.cell.2010.02.027.
    1. Viswanathan A, Pillot G, Govindan R. Lack of response to erlotinib after progression on gefitinib in patients with advanced non-small cell lung cancer. Lung Cancer. 2005;50:417–418. doi: 10.1016/j.lungcan.2005.07.004.
    1. Yang CJ, Tsai MJ, Hung JY, Tsai YM, Lee JY, Chou SH, Liu TC, Shen MC, Huang MS, Chong IW. Poorer prognosis in Taiwanese female ever smokers with stage IV lung adenocarcinoma who were readministered a tyrosine kinase inhibitor. Onco Targets Ther. 2016;9:1511–1518. doi: 10.2147/OTT.S100169.
    1. Sun JM, Lee KW, Kim JH, Kim YJ, Yoon HI, Lee JH, Lee CT, Lee JS. Efficacy and toxicity of pemetrexed as a third-line treatment for non-small cell lung cancer. Jpn J Clin Oncol. 2009;39:27–32. doi: 10.1093/jjco/hyn118.
    1. Chang MH, Ahn JS, Lee J, Kim KH, Park YH, Han J, Ahn MJ, Park K. The efficacy of pemetrexed as a third- or fourth-line therapy and the significance of thymidylate synthase expression in patients with advanced non-small cell lung cancer. Lung Cancer. 2010;69:323–329. doi: 10.1016/j.lungcan.2009.12.002.
    1. Chen YM, Shih JF, Fan WC, Wu CH, Chou KT, Tsai CM, Lee YC, Perng RP, Whang-Peng J. Third-line or fourth-line chemotherapy in non-small-cell lung cancer patients with relatively good performance status. J Chin Med Assoc. 2011;74:209–214. doi: 10.1016/j.jcma.2011.03.005.
    1. Shukuya T, Ko R, Mori K, Kato M, Yagishita S, Kanemaru R, Honma Y, Shibayama R, Koyama R, Shimada N, Takahashi K. Prognostic factors in non-small cell lung cancer patients who are recommended to receive single-agent chemotherapy (docetaxel or pemetrexed) as a second- or third-line chemotherapy: in the era of oncogenic drivers and molecular-targeted agents. Cancer Chemother Pharmacol. 2015;76:771–776. doi: 10.1007/s00280-015-2843-3.

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