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Efficacy of platinum combination chemotherapy after first-line gefitinib treatment in non-small cell lung cancer patients harboring sensitive EGFR mutations

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Abstract

Purpose

Gefitinib is an effective first-line chemotherapy for advanced non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, whether second-line platinum combination chemotherapy after first-line gefitinib treatment shows similar effects to first-line platinum combination chemotherapy in these patients remains unclear. Therefore, we here aimed to investigate the efficacy of platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations.

Methods/patients

We retrospectively evaluated the clinical effects of second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations (exon 19 deletion or exon 21 L858R mutation) at five institutions. All patients were initially treated with gefitinib (250 mg/day) followed by platinum combination chemotherapy as second-line chemotherapy.

Results

Between January 2006 and December 2012, 42 patients [8 men, 34 women; median age, 63 years (range 39–75 years)] were enrolled. The overall response rate, disease control rate, and median progression-free survival (PFS) were 26.2, 61.9 %, and 5.1 months, respectively, after the second-line treatment. The corresponding values for first-line gefitinib treatment were 69.0, 95.2 %, and 11.1 months, respectively. Moreover, second-line platinum combination chemotherapy with pemetrexed or bevacizumab-containing regimens was independently associated with improved PFS.

Conclusions

Second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations was effective and showed equivalent outcomes to first-line platinum combination chemotherapy. After failure of first-line gefitinib therapy, second-line platinum combination chemotherapy with pemetrexed or bevacizumab might result in improved PFS.

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Abbreviations

CR:

Complete response

EGFR:

Epidermal growth factor receptor

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

PD:

Progressive disease

PFS:

Progression-free survival

PPS:

Post-progression survival

PR:

Partial response

RR:

Response rate

SD:

Stable disease

TKI:

Tyrosine kinase inhibitor

References

  1. Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62:220–41.

    Article  PubMed  Google Scholar 

  2. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ. 1995;311:899–909.

    Article  Google Scholar 

  3. Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker S Jr, et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol. 2004;22:330–53.

    Article  PubMed  Google Scholar 

  4. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–57.

    Article  CAS  PubMed  Google Scholar 

  5. 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. 2010;11:121–8.

    Article  CAS  PubMed  Google Scholar 

  6. 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. 2010;362:2380–8.

    Article  CAS  PubMed  Google Scholar 

  7. Inoue A, Kobayashi K, Usui K, Maemondo M, Okinaga S, Mikami I, et al. First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. J Clin Oncol. 2009;27:1394–400.

    Article  CAS  PubMed  Google Scholar 

  8. Morita S, Okamoto I, Kobayashi K, Yamazaki K, Asahina H, Inoue A, et al. Combined survival analysis of prospective clinical trials of gefitinib for non-small cell lung cancer with EGFR mutations. Clin Cancer Res. 2009;15(13):4493–8.

    Article  CAS  PubMed  Google Scholar 

  9. Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012;30:1122–8.

    Article  CAS  PubMed  Google Scholar 

  10. Yoshino R, Imai H, Mori K, Takei K, Tomizawa M, Kaira K, et al. Surrogate endpoints for overall survival in advanced non-small-cell lung cancer patients with mutations of the epidermal growth factor receptor gene. J Clin Oncol. 2014;2:731–6.

    Google Scholar 

  11. 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-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol. 2013;24:54–9.

    Article  CAS  PubMed  Google Scholar 

  12. 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;17:5530–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Mariano C, Bosdet I, Karsan A, Ionescu D, Murray N, Laskin JJ, et al. A population-based review of the feasibility of platinum-based combination chemotherapy after tyrosine kinase inhibition in EGFR mutation positive non-small cell lung cancer patients with advanced disease. Lung Cancer. 2014;83:73–7.

    Article  PubMed  Google Scholar 

  14. Tseng JS, Yang TY, Chen KC, Hsu KH, Yu CJ, Liao WY, et al. Prior EGFR tyrosine-kinase inhibitor therapy did not influence the efficacy of subsequent pemetrexed plus platinum in advanced chemonaive patients with EGFR-mutant lung adenocarcinoma. Onco Targets Ther. 2014;7:799–805.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol. 2007;2:706–14.

    Article  PubMed  Google Scholar 

  16. Nagai Y, Miyazawa H, Huqun, Tanaka T, Udagawa K, Kato M, et al. Genetic heterogeneity of the epidermal growth factor receptor in non-small cell lung cancer cell lines revealed by a rapid and sensitive detection system, the peptide nucleic acid-locked nucleic acid PCR clamp. Cancer Res. 2005;65:7276–82.

    Article  CAS  PubMed  Google Scholar 

  17. Yatabe Y, Hida T, Horio Y, Kosaka T, Takahashi T, Mitsudomi T. A rapid, sensitive assay to detect EGFR mutation in small biopsy specimens from lung cancer. J Mol Diagn. 2006;8:335–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.

    Article  CAS  PubMed  Google Scholar 

  19. Chang GC, Tsai CM, Chen KC, Yu CJ, Shih JY, Yang TY, et al. Predictive factors of gefitinib antitumor activity in East Asian advanced non-small cell lung cancer patients. J Thorac Oncol. 2006;1:520–5.

    Article  PubMed  Google Scholar 

  20. Bai H, Wang Z, Chen K, Zhao J, Lee JJ, Wang S, et al. Influence of chemotherapy on EGFR mutation status among patients with non-small-cell lung cancer. J Clin Oncol. 2012;30:3077–83.

    Article  PubMed  Google Scholar 

  21. 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. J Clin Oncol. 2012;30:3002–11.

    Article  CAS  PubMed  Google Scholar 

  22. Wu JY, Shih JY, Yang CH, Chen KY, Ho CC, Yu CJ, et al. Second-line treatments after first-line gefitinib therapy in advanced nonsmall cell lung cancer. Int J Cancer. 2010;126:247–55.

    Article  CAS  PubMed  Google Scholar 

  23. Hattori Y, Satouchi M, Shimada T, Urata Y, Yoneda T, Mori M, et al. A phase 2 study of bevacizumab in combination with carboplatin and paclitaxel in patients with non-squamous non-small-cell lung cancer harboring mutations of epidermal growth factor receptor (EGFR) after failing first-line EGFR-tyrosine kinase inhibitors (HANSHIN Oncology Group 0109). Lung Cancer. 2015;87:136–40.

    Article  PubMed  Google Scholar 

  24. Deng QF, Su B, Zhao YM, Zhou CC. Sensitivity of two cell lines with acquired resistance to gefitinib to several chemotherapeutic drugs. Zhonghua Shong Liu Za Xhi. 2008;30:813–6 (article in Chinese).

    CAS  Google Scholar 

  25. Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, et al. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol. 2007;18:317–23.

    Article  CAS  PubMed  Google Scholar 

  26. Takeuchi S, Yano S. Clinical significance of epidermal growth factor receptor tyrosine kinase inhibitors: sensitivity and resistance. Respir Invest. 2014;52:348–56.

    Google Scholar 

  27. Wu SG, Yang CH, Yu CJ, Lee JH, Hsu YC, Chang YL, et al. Good response to pemetrexed in patients of lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Lung Cancer. 2011;72:333–9.

    Article  PubMed  Google Scholar 

  28. Sigmond J, Backus HH, Wouters D, Temmink OH, Jansen G, Peters GJ. Induction of resistance to the multitargeted antifolate Pemetrexed (ALIMTA) in WiDr human colon cancer cells is associated with thymidylate synthase overexpression. Biochem Pharmacol. 2003;66:431–8.

    Article  CAS  PubMed  Google Scholar 

  29. Giovannetti E, Mey V, Nannizzi S, Pasqualetti G, Marini L, Del Tacca M, et al. Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells. Mol Pharmacol. 2005;68:110–8.

    CAS  PubMed  Google Scholar 

  30. Gomez HL, Santillana SL, Vallejos CS, Velarde R, Sanchez J, Wang X, et al. A phase II trial of pemetrexed in advanced breast cancer: clinical response and association with molecular target expression. Clin Cancer Res. 2006;12:832–8.

    Article  CAS  PubMed  Google Scholar 

  31. Bepler G, Sommers KE, Cantor A, Li X, Sharma A, Williams C, et al. Clinical efficacy and predictive molecular markers of neoadjuvant gemcitabine and pemetrexed in resectable non-small cell lung cancer. J Thorac Oncol. 2008;3:1112–8.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Ceppi P, Volante M, Saviozzi S, Rapa I, Novello S, Cambieri A, et al. Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer. 2006;107:1589–96.

    Article  CAS  PubMed  Google Scholar 

  33. Giovannetti E, Lemos C, Tekle C, Smid K, Nannizzi S, Rodriguez JA, et al. Molecular mechanisms underlying the synergistic interaction of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, with the multitargeted antifolate pemetrexed in non-small-cell lung cancer cells. Mol Pharmacol. 2008;73:1290–300.

    Article  CAS  PubMed  Google Scholar 

  34. Naumov GN, Nilsson MB, Cascone T, Briggs A, Straume O, Akslen LA, et al. Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance. Clin Cancer Res. 2009;15:3484–94.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Mok TSK, Wu Y, Nakagawa K, Kim S, Yang JC, Ahn M, et al. Gefitinib/chemotherapy vs chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) after progression on first-line gefitinib: the Phase III, randomised IMPRESS study. Ann Oncol. 2014; doi:410.1093/annonc/mdu438.45.

  36. Matikas A, Mistriotis D, Georgoulias V, Kotsakis A. Current and future approaches in the management of non-small-cell lung cancer patients with resistance to EGFR TKIs. Clin Lung Cancer. 2015;. doi:10.1016/j.cllc.2014.12.013.

    PubMed  Google Scholar 

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Acknowledgments

We thank Ms. Keiko Kogure and Drs. Takashi Osaki, Mie Kotake, Yosuke Kamide, Akihiro Ono, and Yasuhiko Koga for their assistance in preparing this manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

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    Authors and Affiliations

    1. Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15, Showa-machi, Maebashi, Gunma, 371-8511, Japan

      T. Masuda, H. Imai, T. Kuwako, N. Sunaga, T. Hisada & M. Yamada

    2. Department of Respiratory Medicine, Gunma Prefectural Cancer Center, Ohta, Gunma, Japan

      Y. Miura & K. Minato

    3. Division of Respiratory Medicine, National Hospital Organization Nishigunma Hospital, Shibukawa, Gunma, Japan

      R. Yoshino, Y. Tomizawa & R. Saito

    4. Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

      K. Kaira

    5. Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

      K. Shimizu

    6. Division of Internal Medicine, Isesaki Municipal Hospital, Isesaki, Gunma, Japan

      S. Ishihara

    7. Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

      A. Mogi

    8. Division of Respiratory Medicine, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan

      A. Takise

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    1. T. Masuda
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    Correspondence to H. Imai.

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    T. Masuda and H. Imai contributed equally to this work.

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    Masuda, T., Imai, H., Kuwako, T. et al. Efficacy of platinum combination chemotherapy after first-line gefitinib treatment in non-small cell lung cancer patients harboring sensitive EGFR mutations. Clin Transl Oncol 17, 702–709 (2015). https://doi.org/10.1007/s12094-015-1297-8

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