Skip to main content
SpringerLink
Log in

Characteristics and Response to Crizotinib in ALK-Rearranged, Advanced Non-Adenocarcinoma, Non-Small Cell Lung Cancer (NA-NSCLC) Patients: a Retrospective Study and Literature Review

  • Original Research Article
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

Background

Oncogenic fusion genes consisting of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) can be detected in 5–7% of lung adenocarcinoma cases. The prevalence of ALK rearrangement in non-adenocarcinoma, non-small cell lung cancers (NA-NSCLC) is currently unknown. In addition, the efficacy of crizotinib in these patients has not been well established.

Objectives

The aim of this study was to investigate the prevalence of ALK rearrangement in NA-NSCLC patients and the therapeutic efficacy of crizotinib in these patients.

Methods

We included NA-NSCLC patients who were tested for the presence of ALK rearrangement in our institution from January 2013 to May 2018. The effectiveness of crizotinib in ALK-positive patients was retrospectively analyzed. A literature review was performed and eligible previously published cases were analyzed in combination with our data.

Results

A total of 4662 patients were screened and 1696 NA-NSCLC patients were tested for the presence of ALK rearrangement during the study period. Thirty-two positive patients were identified (1.9%, 95% CI, 1.2–2.5%). A statistically higher percentage of younger (58.0 vs. 63.0, p = 0.01), female patients (53.1% vs. 10.8%, p < 0.01) who were non-smokers (71.9% vs. 40.6%, p < 0.01) and whose tumors contained adenocarcinoma components (34.4% vs. 6.1%, p < 0.01) were observed in the ALK-positive group. Eighteen patients were excluded from the study and 14 eligible patients were included for survival analysis. The median duration of crizotinib treatment (MDT) as a proxy for progression-free survival of the 14 eligible patients in our institution was 6.0 months (95% CI, 1.2–10.8 months). We combined our data with sporadic cases from 16 previous publications (total n = 37) and found that the MDT was 7.0 months (95% CI, 6.0–8.0 months).

Conclusions

Our study suggests the opportunity to test ALK rearrangement in NA-NSCLC patients, especially in younger, female, non-smoking patients containing adenocarcinoma components. Crizotinib provides an option for the treatment of NA-NSCLC patients who have an ALK rearrangement.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561–6.

    Article  CAS  Google Scholar 

  2. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27(26):4247–53.

    Article  CAS  Google Scholar 

  3. Childress MA, Himmelberg SM, Chen H. et al. ALK fusion partners impact response to ALK inhibition: differential effects on sensitivity, cellular phenotypes, and biochemical properties. Mol Cancer Res. 2018. https://doi.org/10.1158/1541-7786.MCR-18-0171.

  4. Woo CG, Seo S, Kim SW, et al. Differential protein stability and clinical responses of EML4-ALK fusion variants to various ALK inhibitors in advanced ALK-rearranged non-small cell lung cancer. Ann Oncol. 2017;28(4):791–7.

    CAS  PubMed  Google Scholar 

  5. Golding B, Luu A, Jones R, et al. The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC). Mol Cancer. 2018;17(1):52.

    Article  Google Scholar 

  6. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385–94.

    Article  CAS  Google Scholar 

  7. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167–77.

    Article  Google Scholar 

  8. Shaw AT, Kim TM, Crinò L, et al. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017;18(7):874–86.

    Article  CAS  Google Scholar 

  9. Kim DW, Tiseo M, Ahn MJ, et al. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol. 2017;35(22):2490–8.

    Article  Google Scholar 

  10. Ou SH, Ahn JS, De Petris L, et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase II global study. J Clin Oncol. 2016;34(7):661–8.

    Article  CAS  Google Scholar 

  11. Soria JC, Tan DSW, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017;389(10072):917–29.

    Article  CAS  Google Scholar 

  12. Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017;390(10089):29–39.

    Article  CAS  Google Scholar 

  13. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377(9):829–38.

    Article  CAS  Google Scholar 

  14. Wang J, Shen Q, Shi Q, et al. Detection of ALK protein expression in lung squamous cell carcinomas by immunohistochemistry. J Exp Clin Cancer Res. 2014;33:109.

    Article  CAS  Google Scholar 

  15. Vergne F, Quéré G, Andrieu-Key S, et al. ALK-rearranged squamous cell lung carcinoma responding to crizotinib: a missing link in the field of non-small cell lung cancer? Lung Cancer. 2016;91:67–9.

    Article  Google Scholar 

  16. Chaft JE, Rekhtman N, Ladanyi M, et al. ALK-rearranged lung cancer: adenosquamous lung cancer masquerading as pure squamous carcinoma. J Thorac Oncol. 2012;7(4):768–9.

    Article  Google Scholar 

  17. Zhang Q, Wang J, Zhang S. ALK-rearranged squamous cell lung cancer: a case report. Int J Clin Exp Pathol. 2015;8(2):2195–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen X, Zhang Y, Lu J, et al. Pulmonary sarcomatoid carcinoma with ALK rearrangement: frequency, clinical-pathologic characteristics, and response to ALK inhibitor. Transl Oncol. 2017;10(2):115–20.

    Article  Google Scholar 

  19. Murakami Y, Saka H, Oki M. Response to crizotinib and clinical outcome in ALK-rearranged pulmonary pleomorphic carcinoma. J Thorac Oncol. 2015;10(5):e28–9.

    Article  Google Scholar 

  20. Omachi N, Shimizu S, Kawaguchi T, et al. A case of large-cell neuroendocrine carcinoma harboring an EML4-ALK rearrangement with resistance to the ALK inhibitor crizotinib. J Thorac Oncol. 2014;9(6):e40–2.

    Article  Google Scholar 

  21. Wang Q, He Y, Yang X, et al. Extraordinary response to crizotinib in a woman with squamous cell lung cancer after two courses of failed chemotherapy. BMC Pulm Med. 2014;14:83.

    Article  Google Scholar 

  22. Wang W, Song Z, Zhang Y. Response to crizotinib in a squamous cell lung carcinoma patient harbouring echinoderm microtubule-associated protein-like 4-anaplastic lymphoma translocation: a case report. Thorac Cancer. 2016;7(3):355–7.

    Article  CAS  Google Scholar 

  23. Lin L, Huang F, Chen F, et al. Anaplastic lymphoma kinase (ALK)-rearranged pulmonary pleomorphic carcinoma successfully treated with crizotinib. J Int Med Res. 2018;46(8):3491–7.

    Article  Google Scholar 

  24. Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012;18(5):1472–82.

    Article  CAS  Google Scholar 

  25. Huang T, Engelmann BJ, Morgan RM, et al. EML4-ALK rearrangement in squamous cell carcinoma shows significant response to anti-ALK inhibitor drugs crizotinib and alectinib. Cancer Chemother Pharmacol. 2018;81(5):965–8.

    Article  Google Scholar 

  26. Watanabe J, Togo S, Sumiyoshi I, et al. Clinical features of squamous cell lung cancer with anaplastic lymphoma kinase (ALK)-rearrangement: a retrospective analysis and review. Oncotarget. 2018;9(35):24000–13.

    Article  Google Scholar 

  27. Song Z, Yu X, Zhang Y. Clinicopathological characteristics and survival of ALK, ROS1 and RET rearrangements in non-adenocarcinoma non-small cell lung cancer patients. Cancer Biol Ther. 2017;18(11):883–7.

    Article  CAS  Google Scholar 

  28. Mikes RE, Jordan F, Hutarew G, et al. First line crizotinib in anaplastic lymphoma kinase (ALK) rearranged squamous cell lung cancer. Lung Cancer. 2015;90(3):614–6.

    Article  Google Scholar 

  29. Li Q, Wu J, Yan LX, et al. ALK and ROS1 double-rearranged lung squamous cell carcinoma responding to crizotinib treatment: a case report. J Thorac Oncol. 2017;12(12):e193–7.

    Article  Google Scholar 

  30. Bolzacchini E, Tuzi A, Pinotti G, et al. ALK-rearranged squamous cell carcinoma of the lung treated with two lines of ALK inhibitors. J Thorac Oncol. 2017;12(5):e55–7.

    Article  Google Scholar 

  31. Xu J, Zhang Y, Jin B, 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.

    Article  CAS  Google Scholar 

  32. Forest F, Yvorel V, Karpathiou G, et al. Histomolecular profiling of pleomorphic, spindle cell, and giant cell carcinoma of the lung for targeted therapies. Hum Pathol. 2016;49:99–106.

    Article  Google Scholar 

  33. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13(10):1011–9.

    Article  CAS  Google Scholar 

  34. Solomon BJ, Kim DW, Wu YL, et al. Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in ALK-mutation-positive non-small-cell lung cancer. J Clin Oncol. 2018;36(22):2251–8.

    Article  Google Scholar 

  35. Liu L, Bi N, Ji Z, et al. Consolidation chemotherapy may improve survival for patients with locally advanced non-small-cell lung cancer receiving concurrent chemoradiotherapy--retrospective analysis of 203 cases. BMC Cancer. 2015;15:715.

    Article  Google Scholar 

  36. Wong DW, Leung EL, So KK, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer. 2009;115(8):1723–33.

    Article  CAS  Google Scholar 

  37. Travis WD, Brambilla E, Muller-Hermelink HK, et al. World Health Organization classification of tumours. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press; 2004.

    Google Scholar 

Download references

Acknowledgements

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

Author information

Author notes

  1. Bo Zhang and Yanwei Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Huaihai West Road No. 241, Shanghai, People’s Republic of China

    Bo Zhang, Yanwei Zhang, Jianlin Xu, Xueyan Zhang, Tianqing Chu, Shuyuan Wang, Jie Qian, Rong Qiao, Jun Lu, Lele Zhang & Baohui Han

Authors
  1. Bo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yanwei 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. Xueyan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tianqing Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shuyuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jie Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rong Qiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jun Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lele Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. 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

No external funding was used in the preparation of this manuscript.

Conflict of Interest

Bo Zhang, Yanwei Zhang, Jianlin Xu, Xueyan Zhang, Tianqing Chu, Shuyuan Wang, Jie Qian, Rong Qiao, Jun Lu, Lele Zhang, and Baohui Han declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

Electronic supplementary material

ESM 1

(PDF 161 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, B., Zhang, Y., Xu, J. et al. Characteristics and Response to Crizotinib in ALK-Rearranged, Advanced Non-Adenocarcinoma, Non-Small Cell Lung Cancer (NA-NSCLC) Patients: a Retrospective Study and Literature Review. Targ Oncol 13, 631–639 (2018). https://doi.org/10.1007/s11523-018-0592-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-018-0592-z

Search

Navigation