Cancer Chemotherapy and Pharmacology

, Volume 73, Issue 5, pp 1063–1070

Is there any predictor for clinical outcome in EGFR mutant NSCLC patients treated with EGFR TKIs?

  • Ji Yun Lee
  • Sung Hee Lim
  • Moonjin Kim
  • Sungmin Kim
  • Hyun Ae Jung
  • Won Jin Chang
  • Moon Ki Choi
  • Jung Yong Hong
  • Su Jin Lee
  • Jong-Mu Sun
  • Jin Seok Ahn
  • Keunchil Park
  • Myung-Ju Ahn
Original Article

Abstract

Background

Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) have demonstrated some dramatic response rate and prolonged progression-free survival (PFS) in advanced non-small-cell lung cancer (NSCLC) patients with activating EGFR mutation. However, PFS and overall survival (OS) among those patients who were treated with EGFR TKIs are inconsistent and unpredictable. In this study, we evaluated predictors of clinical outcome in EGFR mutant NSCLC patients treated with EGFR TKIs.

Methods

A total of 148 patients who had metastatic or recurrent NSCLC with activating EGFR mutation treated with either erlotinib or gefitinib as a first-line (n = 10) and a second-line or more treatment (n = 138) were retrospectively reviewed.

Results

The median follow-up duration was 21.9 months (range, 1.1–62.5). The median PFS and OS for a total 148 patients were 10.6 months (95 % CI 9.0–12.2) and 21.8 months (95 % CI 18.5–25.1), respectively. The survival outcomes were similar between the first-line and second-line or more line of treatment of EGFR TKIs (P = 0.512 for PFS, P = 0.699 for OS). Although a high number of metastasis sites (3–6 vs. 1–2) were associated with shorter PFS and OS (median PFS 9.9 vs. 11.9 months, P = 0.019; median OS 16.4 vs. 22.2 months, P = 0.021, respectively) in univariate analysis, but not in multivariate analysis. According to the clinical and molecular markers by multivariate analysis, there were no significant differences in PFS. When PFS was dichotomized by median 11 months for 105 patients treated with EGFR TKIs as second-line therapy, no significant differences in any clinical or molecular features were found between longer PFS and shorter PFS groups.

Conclusions

Despite the inconsistencies in PFS among EGFR mutant patients treated with EGFR TKIs, no significant differences of clinical features were noted, thereby suggesting a need for more understanding of the heterogeneity of underlying biology.

Keywords

Epidermal growth factor receptor Tyrosine kinase inhibitors Non-small-cell lung cancer Predictor 

Supplementary material

280_2014_2442_MOESM1_ESM.docx (17 kb)
Supplementary material 1 (DOCX 17 kb)

References

  1. 1.
    Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300. doi:10.3322/caac.20073 PubMedCrossRefGoogle Scholar
  2. 2.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917. doi:10.1002/ijc.25516 PubMedCrossRefGoogle Scholar
  3. 3.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (1995) Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311:899–909CrossRefGoogle Scholar
  4. 4.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2008) Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol 26:4617–4625. doi:10.1200/jco.2008.17.7162 CrossRefGoogle Scholar
  5. 5.
    Brabender J, Danenberg KD, Metzger R, Schneider PM, Park J, Salonga D, Holscher AH, Danenberg PV (2001) Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer Is correlated with survival. Clin Cancer Res 7:1850–1855PubMedGoogle Scholar
  6. 6.
    Sridhar SS, Seymour L, Shepherd FA (2003) Inhibitors of epidermal-growth-factor receptors: a review of clinical research with a focus on non-small-cell lung cancer. Lancet Oncol 4:397–406PubMedCrossRefGoogle Scholar
  7. 7.
    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, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139. doi:10.1056/NEJMoa040938 PubMedCrossRefGoogle Scholar
  8. 8.
    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 (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500. doi:10.1126/science.1099314 PubMedCrossRefGoogle Scholar
  9. 9.
    Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H (2004) 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 USA 101:13306–13311. doi:10.1073/pnas.0405220101 PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    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 (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957. doi:10.1056/NEJMoa0810699 PubMedCrossRefGoogle Scholar
  11. 11.
    Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, Ahn MJ, Yun T, Ahn JS, Suh C, Lee JS, Yoon SJ, Han JH, Lee JW, Jo SJ, Lee JS (2012) First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol 30:1122–1128. doi:10.1200/jco.2011.36.8456 PubMedCrossRefGoogle Scholar
  12. 12.
    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 (2010) 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 11:121–128. doi:10.1016/s1470-2045(09)70364-x PubMedCrossRefGoogle Scholar
  13. 13.
    Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Saijo Y, Hagiwara K, Morita S, Nukiwa T (2013) 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). Ann Oncol 24:54–59. doi:10.1093/annonc/mds214 PubMedCrossRefGoogle Scholar
  14. 14.
    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, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C (2011) 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. Lancet Oncol 12:735–742. doi:10.1016/s1470-2045(11)70184-x PubMedCrossRefGoogle Scholar
  15. 15.
    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 (2012) 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 13:239–246. doi:10.1016/s1470-2045(11)70393-x PubMedCrossRefGoogle Scholar
  16. 16.
    Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, Fong KM, Lee H, Toyooka S, Shimizu N, Fujisawa T, Feng Z, Roth JA, Herz J, Minna JD, Gazdar AF (2005) Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97:339–346. doi:10.1093/jnci/dji055 PubMedCrossRefGoogle Scholar
  17. 17.
    Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T, Mitsudomi T (2004) Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res 64:8919–8923. doi:10.1158/0008-5472.can-04-2818 PubMedCrossRefGoogle Scholar
  18. 18.
    Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, Inserra E, Diederichs S, Iafrate AJ, Bell DW, Digumarthy S, Muzikansky A, Irimia D, Settleman J, Tompkins RG, Lynch TJ, Toner M, Haber DA (2008) Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 359:366–377. doi:10.1056/NEJMoa0800668 PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, Kris MG, Miller VA, Ladanyi M, Riely GJ (2013) 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 19:2240–2247. doi:10.1158/1078-0432.ccr-12-2246 PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786–792. doi:10.1056/NEJMoa044238 PubMedCrossRefGoogle Scholar
  21. 21.
    Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73. doi:10.1371/journal.pmed.0020073 PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    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, Christensen JG, Wain JC, Lynch TJ, Vernovsky K, Mark EJ, Lanuti M, Iafrate AJ, Mino-Kenudson M, Engelman JA (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 3:75ra26. doi:10.1126/scitranslmed.3002003
  23. 23.
    Bai H, Wang Z, Wang Y, Zhuo M, Zhou Q, Duan J, Yang L, Wu M, An T, Zhao J, Wang J (2013) Detection and clinical significance of intratumoral EGFR mutational heterogeneity in Chinese patients with advanced non-small cell lung cancer. PLoS ONE 8:e54170. doi:10.1371/journal.pone.0054170 PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Su KY, Chen HY, Li KC, Kuo ML, Yang JC, Chan WK, Ho BC, Chang GC, Shih JY, Yu SL, Yang PC (2012) Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. J Clin Oncol 30:433–440. doi:10.1200/jco.2011.38.3224 PubMedCrossRefGoogle Scholar
  25. 25.
    Park JH, Kim TM, Keam B, Jeon YK, Lee SH, Kim DW, Chung DH, Kim YT, Kim YW, Heo DS (2013) Tumor burden is predictive of survival in patients with non-small-cell lung cancer and with activating epidermal growth factor receptor mutations who receive gefitinib. Clin Lung Cancer 14:383–389. doi:10.1016/j.cllc.2012.10.007 PubMedCrossRefGoogle Scholar
  26. 26.
    Goldie JH, Coldman AJ (1984) The genetic origin of drug resistance in neoplasms: implications for systemic therapy. Cancer Res 44:3643–3653PubMedGoogle Scholar
  27. 27.
    Foo J, Michor F (2009) Evolution of resistance to targeted anti-cancer therapies during continuous and pulsed administration strategies. PLoS Comput Biol 5:e1000557. doi:10.1371/journal.pcbi.1000557 PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, Majem M, Lopez-Vivanco G, Isla D, Provencio M, Insa A, Massuti B, Gonzalez-Larriba JL, Paz-Ares L, Bover I, Garcia-Campelo R, Moreno MA, Catot S, Rolfo C, Reguart N, Palmero R, Sanchez JM, Bastus R, Mayo C, Bertran-Alamillo J, Molina MA, Sanchez JJ, Taron M (2009) Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361:958–967. doi:10.1056/NEJMoa0904554 PubMedCrossRefGoogle Scholar
  29. 29.
    Morita S, Okamoto I, Kobayashi K, Yamazaki K, Asahina H, Inoue A, Hagiwara K, Sunaga N, Yanagitani N, Hida T, Yoshida K, Hirashima T, Yasumoto K, Sugio K, Mitsudomi T, Fukuoka M, Nukiwa T (2009) Combined survival analysis of prospective clinical trials of gefitinib for non-small cell lung cancer with EGFR mutations. Clin Cancer Res 15:4493–4498. doi:10.1158/1078-0432.ccr-09-0391 PubMedCrossRefGoogle Scholar
  30. 30.
    Di Leo A, Bleiberg H, Buyse M (2003) Overall survival is not a realistic end point for clinical trials of new drugs in advanced solid tumors: a critical assessment based on recently reported phase III trials in colorectal and breast cancer. J Clin Oncol 21:2045–2047. doi:10.1200/jco.2003.99.089 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Ji Yun Lee
    • 1
  • Sung Hee Lim
    • 1
  • Moonjin Kim
    • 1
  • Sungmin Kim
    • 1
  • Hyun Ae Jung
    • 1
  • Won Jin Chang
    • 1
  • Moon Ki Choi
    • 1
  • Jung Yong Hong
    • 1
  • Su Jin Lee
    • 1
  • Jong-Mu Sun
    • 1
  • Jin Seok Ahn
    • 1
  • Keunchil Park
    • 1
  • Myung-Ju Ahn
    • 1
  1. 1.Division of Hematology-Oncology, Department of Medicine, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulKorea

Personalised recommendations