Skip to main content

Clinical Outcomes of Different Generations of EGFR Tyrosine Kinase Inhibitors in Advanced Lung Adenosquamous Carcinoma

Molecular Diagnosis & Therapy volume 23, pages 773–779 (2019)Cite this article

Abstract

Objectives

The role of targeted therapy in patients with lung adenosquamous carcinoma (ASC) has been controversial and it was unclear whether a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) could improve outcomes. This study was designed to evaluate the efficacy of different generations of EGFR TKI therapy in ASC patients with sensitive EGFR mutations.

Methods

Patients with non-small cell lung cancer (NSCLC) diagnosed at the Shanghai Chest Hospital between January 2010 and December 2016 were retrospectively reviewed.

Results

A total of 10,037 NSCLC patients tested for EGFR mutations were screened, with primary ASC accounting for 1.4% (139/10,037). Positive EGFR mutations were found in 51.1% (71/139) of ASC patients, including 67 sensitive mutations (19del or 21L858R) and four uncommon mutations (19del + 20T790M, 21L858R + 20T790M, 19L747P + 20Q787Q, and 21L861Q). Sensitive EGFR mutations occurred more frequently in younger (62.0 vs 65.0, p = 0.010), non-smoking (83.6% vs 57.8%, p = 0.002) women (56.7% vs 34.4%, p = 0.014). Among the 36 ASC patients with eligible survival data for the first-generation TKIs, the median progression-free survival (PFS) was 9.3 months (95% CI 6.7–11.9), which was rather similar to the data of adenocarcinoma (9.3 vs 11.4 months, p = 0.294) in our institution as opposed to squamous cell carcinoma (9.3 vs 4.9 months, p < 0.001). The objective response rate (ORR) was 37.9% (11/29), and the disease control rate (DCR) was 86.2% (25/29). After progression on the initial EGFR TKIs, 42.1% of the cases (8/19) had an EGFR T790M mutation detected. A median PFS of 10.2 months (95% CI 5.8–14.5, n = 8) was achieved with treatment using the third-generation TKI. The ORR and DCR were 37.5% (3/8) and 100% (8/8), respectively. The median overall survival reached 38.3 months (95% CI 13.7–62.9).

Conclusions

Targeted therapy showed remarkable efficacy in ASC patients harboring sensitive EGFR mutations, comparable to adenocarcinoma. The application of the third-generation TKI provided an option to prolong survival.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

49,54 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

    PubMed  PubMed Central  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.

    Article  Google Scholar 

  3. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367–80.

    CAS  Article  Google Scholar 

  4. Travis WD, Burke AP. WHO classification of tumours of the lung, pleura, thymus and heart. 4th ed.

  5. Fitzgibbons PL, Kern WH. Adenosquamous carcinoma of the lung: a clinical and pathologic study of seven cases. Hum Pathol. 1985;16(5):463–6.

    CAS  Article  Google Scholar 

  6. Hsia JY, Chen CY, Hsu CP, Shai SE, Wang PY. Adenosquamous carcinoma of the lung. Surgical results compared with squamous cell and adenocarcinoma. Scand Cardiovasc J. 1999;33(1):29–32.

    CAS  Article  Google Scholar 

  7. Kamiyoshihara M, Hirai T, Kawashima O, Ishikawa S, Morishita Y, Maeshima A. A clinicopathologic study of the resected cases of adenosquamous carcinoma of the lung. Oncology reports. 1998;5(4):861–5.

    CAS  PubMed  Google Scholar 

  8. Shimizu J, Oda M, Hayashi Y, Nonomura A, Watanabe Y. A clinicopathologic study of resected cases of adenosquamous carcinoma of the lung. Chest. 1996;109(4):989–94.

    CAS  Article  Google Scholar 

  9. 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(2):121–8.

    CAS  Article  Google Scholar 

  10. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang 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. Lancet Oncol. 2011;12(8):735–42.

    CAS  Article  Google Scholar 

  11. Shi YK, Wang L, Han BH, Li W, Yu P, Liu YP, et al. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol. 2017;28(10):2443–50.

    CAS  Article  Google Scholar 

  12. Koo DH, Kim KP, Choi CM, Lee DH, Lee JC, Lee JS, et al. EGFR-TKI is effective regardless of treatment timing in pulmonary adenocarcinoma with EGFR mutation. Cancer Chemother Pharmacol. 2015;75(1):197–206.

    CAS  Article  Google Scholar 

  13. Zenke Y, Yoh K, Matsumoto S, Umemura S, Niho S, Ohmatsu H, et al. Clinical impact of gastric acid-suppressing medication use on the efficacy of erlotinib and gefitinib in patients with advanced non-small-cell lung cancer harboring EGFR mutations. Clin Lung Cancer. 2016;17(5):412–8.

    CAS  Article  Google Scholar 

  14. Fujiwara A, Yoshida M, Fujimoto H, Nakahara H, Ito K, Nishihama K, et al. A retrospective comparison of the clinical efficacy of gefitinib, erlotinib, and afatinib in Japanese patients with non-small cell lung cancer. Oncol Res. 2018;26(7):1031–6.

    Article  Google Scholar 

  15. Masters GA, Temin S, Azzoli CG, Giaccone G, Baker S Jr, Brahmer JR, et al. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015;33(30):3488–515.

    CAS  Article  Google Scholar 

  16. Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman J, Chirieac LR, et al. Non-small cell lung cancer, version 5.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Netw JNCCN. 2017;15(4):504–35.

    Article  Google Scholar 

  17. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. 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(3):239–46.

    CAS  Article  Google Scholar 

  18. 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(25):2380–8.

    CAS  Article  Google Scholar 

  19. Kang SM, Kang HJ, Shin JH, Kim H, Shin DH, Kim SK, et al. Identical epidermal growth factor receptor mutations in adenocarcinomatous and squamous cell carcinomatous components of adenosquamous carcinoma of the lung. Cancer. 2007;109(3):581–7.

    CAS  Article  Google Scholar 

  20. Jia XL, Chen G. EGFR and KRAS mutations in Chinese patients with adenosquamous carcinoma of the lung. Lung cancer (Amsterdam, Netherlands). 2011;74(3):396–400.

    Article  Google Scholar 

  21. Morodomi Y, Okamoto T, Takenoyama M, Takada K, Katsura M, Suzuki Y, et al. Clinical significance of detecting somatic gene mutations in surgically resected adenosquamous cell carcinoma of the lung in Japanese patients. Ann Surg Oncol. 2015;22(8):2593–8.

    Article  Google Scholar 

  22. Wang R, Pan Y, Li C, Zhang H, Garfield D, Li Y, et al. Analysis of major known driver mutations and prognosis in resected adenosquamous lung carcinomas. J Thor Oncol. 2014;9(6):760–8.

    CAS  Article  Google Scholar 

  23. Goss G, Tsai CM, Shepherd FA, Bazhenova L, Lee JS, Chang GC, et al. Osimertinib for pretreated EGFR Thr790 Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2016;17(12):1643–52.

    CAS  Article  Google Scholar 

  24. Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376(7):629–40.

    CAS  Article  Google Scholar 

  25. Shi X, Wu H, Lu J, Duan H, Liu X, Liang Z. Screening for major driver oncogene alterations in adenosquamous lung carcinoma using PCR coupled with next-generation and Sanger sequencing methods. Sci Rep. 2016;29(6):22297.

    Article  Google Scholar 

  26. Xu J, Jin B, Chu T, Dong X, Yang H, Zhang Y, et al. EGFR tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC) harboring uncommon EGFR mutations: a real-world study in China. Lung Cancer (Amsterdam, Netherlands). 2016;96:87–92.

    Article  Google Scholar 

  27. Song Z, Lin B, Shao L, Zhang Y. Therapeutic efficacy of gefitinib and erlotinib in patients with advanced lung adenosquamous carcinoma. J Chin Med Assoc JCMA. 2013;76(9):481–5.

    CAS  Article  Google Scholar 

  28. Fan L, Yang H, Yao F, Zhao Y, Gu H, Han K, et al. Clinical outcomes of epidermal growth factor receptor tyrosine kinase inhibitors in recurrent adenosquamous carcinoma of the lung after resection. OncoTargets Ther. 2017;10:239–45.

    CAS  Article  Google Scholar 

  29. Xu J, Zhang Y, Jin B, Chu T, Dong X, Yang H, et al. Efficacy of EGFR tyrosine kinase inhibitors for non-adenocarcinoma lung cancer patients harboring EGFR-sensitizing mutations in China. J Cancer Res Clin Oncol. 2016;142(6):1325–30.

    CAS  Article  Google Scholar 

  30. Hata A, Katakami N, Yoshioka H, Kunimasa K, Fujita S, Kaji R, et al. How sensitive are epidermal growth factor receptor-tyrosine kinase inhibitors for squamous cell carcinoma of the lung harboring EGFR gene-sensitive mutations? J Thor Oncol. 2013;8(1):89–95.

    CAS  Article  Google Scholar 

  31. Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015;16(8):897–907.

    CAS  Article  Google Scholar 

  32. Wang Z, Shen Z, Li Z, Duan J, Fu S, Liu Z, et al. Activation of the BMP-BMPR pathway conferred resistance to EGFR-TKIs in lung squamous cell carcinoma patients with EGFR mutations. Proc Natl Acad Sci USA. 2015;112(32):9990–5.

    CAS  Article  Google Scholar 

  33. Nosaki K, Satouchi M, Kurata T, Yoshida T, Okamoto I, Katakami N, et al. Re-biopsy status among non-small cell lung cancer patients in Japan: a retrospective study. Lung cancer (Amsterdam, Netherlands). 2016;101:1–8.

    Article  Google Scholar 

  34. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. 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. 2013;19(8):2240–7.

    CAS  Article  Google Scholar 

  35. Oxnard GR, Thress KS, Alden RS, Lawrance R, Paweletz CP, Cantarini M, et al. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol. 2016;34(28):3375–82.

    CAS  Article  Google Scholar 

  36. Chouaid C, Dujon C, Do P, Monnet I, Madroszyk A, Le Caer H, et al. Feasibility and clinical impact of re-biopsy in advanced non small-cell lung cancer: a prospective multicenter study in a real-world setting (GFPC study 12-01). Lung cancer (Amsterdam, Netherlands). 2014;86(2):170–3.

    Article  Google Scholar 

  37. Greenhalgh J, Dwan K, Boland A, Bates V, Vecchio F, Dundar Y, et al. First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer. Cochrane Database Syst Rev. 2016;25(5):Cd010383.

    Google Scholar 

  38. Tan CS, Kumarakulasinghe NB, Huang YQ, Ang YLE, Choo JR, Goh BC, et al. Third generation EGFR TKIs: current data and future directions. Mol Cancer. 2018;17(1):29.

    Article  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge all the patients and their families for their contributions to this study.

Author information

Affiliations

  1. Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, People’s Republic of China

    Minjuan Hu, Bo Zhang, Jianlin Xu, Shuyuan Wang, Yiming Zhao, Lele Zhang & Baohui Han

Authors
  1. Minjuan Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jianlin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shuyuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yiming Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lele Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Baohui Han
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Baohui Han.

Ethics declarations

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest

The authors (MH, BZ, JX, SW, YZ, LZ, and BH) have no conflicts of interest to declare.

Ethical approval and informed consent

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee. Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hu, M., Zhang, B., Xu, J. et al. Clinical Outcomes of Different Generations of EGFR Tyrosine Kinase Inhibitors in Advanced Lung Adenosquamous Carcinoma. Mol Diagn Ther 23, 773–779 (2019). https://doi.org/10.1007/s40291-019-00425-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40291-019-00425-x