Skip to main content

Advertisement

Log in

A phase II trial of erlotinib in patients with EGFR wild-type advanced non-small-cell lung cancer

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

There is as yet no optimal treatment regimen for patients with epidermal growth factor receptor (EGFR) gene wild-type non-small-cell lung cancer (NSCLC) that has progressed despite cytotoxic chemotherapy. This trial was performed to evaluate the efficacy and toxicity of erlotinib, a tyrosine kinase inhibitor of EGFR, in Japanese patients with EGFR wild-type tumors.

Methods

Patients with stage III/IV or postoperative recurrence of NSCLC whose tumors have wild-type EGFR were eligible. Erlotinib (150 mg/day) was administered until disease progression or unacceptable toxicity occurred. The primary end point was disease control rate (DCR).

Results

Thirty-one patients (23 men and 8 women; median age, 71 years; range, 31–89) were enrolled between January 2008 and June 2011. Twenty-one had adenocarcinoma, nine had squamous cell carcinoma, and one had large cell carcinoma. Ten, nine, eight, and four patients showed performance status 0, 1, 2, and 3, respectively. Erlotinib was administered following the median 3.1 regimens of cytotoxic chemotherapies. One patient achieved complete response, four showed partial response, and eight had stable disease. Thus, response rate was 17.2%, and DCR was 44.8%. Skin rash was the most common side effect (80.6%). Two patients developed interstitial lung disease. Nevertheless, all of these events were reversible, and there were no treatment-related deaths. The median progression-free survival and survival times were 2.1 and 7.7 months, respectively.

Conclusion

Erlotinib might be an alternative option for patients resistant to cytotoxic chemotherapy even in those with EGFR wild-type NSCLC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Matsuda T, Marugame T, Kamo K, Katanoda K, Ajiki W, Sobue T, The Japan Cancer Surveillance Research Group (2011) Cancer incidence and incidence rates in Japan in 2005: based on data from 12 population-based cancer registries in the monitoring of cancer incidence in Japan (MCIJ) project. Jpn J Clin Oncol 41:139–147

    Article  PubMed  Google Scholar 

  2. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300

    Article  PubMed  Google Scholar 

  3. Azzoli CG, Baker S Jr, Temin S, Pao W, Aliff T, Brahmer J, Johnson DH, Laskin JL, Masters G, Milton D, Nordquist L, Pfister DG, Piantadosi S, Schiller JH, Smith R, Smith TJ, Strawn JR, Trent D, Giaccone G, American Society of Clinical Oncology (2009) American society of clinical oncology clinical practice guideline update on chemotherapy for stage IV non-small cell lung cancer. J Clin Oncol 27:6251–6266

    Article  PubMed  CAS  Google Scholar 

  4. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH, Eastern Cooperative Oncology Group (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92–98

    Article  PubMed  CAS  Google Scholar 

  5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L, National Cancer Institute of Canada Clinical Trials Group (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132

    Article  PubMed  CAS  Google Scholar 

  6. Johnson JR, Cohen M, Sridhara R, Chen YF, Williams GM, Duan J, Gobburu J, Booth B, Benson K, Leighton J, Hsieh LS, Chidambaram N, Zimmerman P, Pazdur R (2005) Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res 11:6414–6421

    Article  PubMed  CAS  Google Scholar 

  7. 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, North-East Japan Study Group (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380–2388

    Article  PubMed  CAS  Google Scholar 

  8. 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

    Article  PubMed  CAS  Google Scholar 

  9. Inoue A, Suzuki T, Fukuhara T, Maemondo M, Kimura Y, Morikawa N, Watanabe H, Saijo Y, Nukiwa T (2006) Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol 24:3340–3346

    Article  PubMed  CAS  Google Scholar 

  10. Mitsudomi T, Yatabe Y (2007) Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci 98:1817–1824

    Article  PubMed  CAS  Google Scholar 

  11. 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

    Article  PubMed  CAS  Google Scholar 

  12. Asami K, Koizumi T, Hirai K, Ameshima S, Tsukadaira A, Morozumi N, Morikawa A, Atagi S, Kawahara M (2011) Gefitinib as first-line treatment in elderly epidermal growth factor receptor-mutated patients with advanced lung adenocarcinoma: results of a Nagano Lung Cancer Research Group Study. Clin Lung Cancer 12:387–392

    Article  PubMed  CAS  Google Scholar 

  13. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS (2011) Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 29:2866–2874

    Article  PubMed  CAS  Google Scholar 

  14. Wu JY, Wu SG, Yang CH, Chang YL, Chang YC, Hsu YC, Shih JY, Yang PC (2011) Comparison of gefitinib and erlotinib in advanced NSCLC and the effect of EGFR mutations. Lung Cancer 72:205–212

    Article  PubMed  Google Scholar 

  15. Schneider CP, Heigener D, Schott-von-Römer K, Gütz S, Laack E, Digel W, Guschall WR, Franke A, Bodenstein H, Schmidtgen C, Reck M (2008) Epidermal growth factor receptor-related tumor markers and clinical outcomes with erlotinib in non-small cell lung cancer: an analysis of patients from german centers in the TRUST study. J Thorac Oncol 3:1446–1453

    Article  PubMed  Google Scholar 

  16. Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K (2005) Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366:1527–1537

    Article  PubMed  CAS  Google Scholar 

  17. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L, National Cancer Institute of Canada Clinical Trials Group (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132

    Article  PubMed  CAS  Google Scholar 

  18. Cho BC, Im CK, Park MS, Kim SK, Chang J, Park JP, Choi HJ, Kim YJ, Shin SJ, Sohn JH, Kim H, Kim JH (2007) Phase II study of erlotinib in advanced non-small-cell lung cancer after failure of gefitinib. J Clin Oncol 25:2528–2533

    Article  PubMed  CAS  Google Scholar 

  19. Lee DH, Kim SW, Suh C, Yoon DH, Yi EJ, Lee JS (2008) Phase II study of erlotinib as a salvage treatment for non-small-cell lung cancer patients after failure of gefitinib treatment. Ann Oncol 19:2039–2042

    Article  PubMed  CAS  Google Scholar 

  20. Moyer JD, Barbacci EG, Iwata KK, Arnold L, Boman B, Cunningham A, DiOrio C, Doty J, Morin MJ, Moyer MP, Neveu M, Pollack VA, Pustilnik LR, Reynolds MM, Sloan D, Theleman A, Miller P (1997) Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 57:4838–4848

    PubMed  CAS  Google Scholar 

  21. Paz-Ares L, Soulières D, Melezínek I, Moecks J, Keil L, Mok T, Rosell R, Klughammer B (2010) Clinical outcomes in non-small-cell lung cancer patients with EGFR mutations: pooled analysis. J Cell Mol Med 14:51–69

    Article  PubMed  CAS  Google Scholar 

  22. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2010) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216

    Google Scholar 

  23. Common terminology criteria for adverse events (CTCAE) Version 3.0. National Cancer Institute Web site. 22 May 2003. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Accessed 1 March 2011

  24. Reck M, van Zandwijk N, Gridelli C, Baliko Z, Rischin D, Allan S, Krzakowski M, Heigener D (2010) Erlotinib in advanced non-small cell lung cancer: efficacy and safety findings of the global phase IV Tarceva Lung Cancer Survival Treatment study. J Thorac Oncol 5:1616–1622

    Article  PubMed  Google Scholar 

  25. Yoshioka H, Hotta K, Kiura K, Takigawa N, Hayashi H, Harita S, Kuyama S, Segawa Y, Kamei H, Umemura S, Bessho A, Tabata M, Tanimoto M, Okayama Lung Cancer Study Group (2010) A phase II trial of erlotinib monotherapy in pretreated patients with advanced non-small cell lung cancer who do not possess active EGFR mutations: Okayama Lung Cancer Study Group trial 0705. J Thorac Oncol 5:99–104

    Article  PubMed  Google Scholar 

  26. Bozzetti C, Tiseo M, Lagrasta C, Nizzoli R, Guazzi A, Leonardi F, Gasparro D, Spiritelli E, Rusca M, Carbognani P, Majori M, Franciosi V, Rindi G, Ardizzoni A (2008) Comparison between epidermal growth factor receptor (EGFR) gene expression in primary non-small cell lung cancer (NSCLC) and in fine-needle aspirates from distant metastatic sites. J Thorac Oncol 3:18–22

    Article  PubMed  Google Scholar 

  27. Ushiki A, Koizumi T, Kobayashi N, Kanda S, Yasuo M, Yamamoto H, Kubo K, Aoyagi D, Nakayama J (2009) Genetic heterogeneity of EGFR mutation in pleomorphic carcinoma of the lung: response to gefitinib and clinical outcome. Jpn J Clin Oncol 39:267–270

    Article  PubMed  Google Scholar 

  28. Chang MH, Ahn HK, Lee J, Jung CK, Choi YL, Park YH, Ahn JS, Park K, Ahn MJ (2011) Clinical impact of amphiregulin expression in patients with epidermal growth factor receptor (EGFR) wild-type nonsmall cell lung cancer treated with EGFR-tyrosine kinase inhibitors. Cancer 117:143–151

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

None declared.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Takashi Kobayashi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kobayashi, T., Koizumi, T., Agatsuma, T. et al. A phase II trial of erlotinib in patients with EGFR wild-type advanced non-small-cell lung cancer. Cancer Chemother Pharmacol 69, 1241–1246 (2012). https://doi.org/10.1007/s00280-012-1831-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-012-1831-0

Keywords

Navigation