Targeted Oncology

, Volume 13, Issue 5, pp 631–639 | Cite as

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

  • Bo Zhang
  • Yanwei Zhang
  • Jianlin Xu
  • Xueyan Zhang
  • Tianqing Chu
  • Shuyuan Wang
  • Jie Qian
  • Rong Qiao
  • Jun Lu
  • Lele Zhang
  • Baohui HanEmail author
Original Research Article



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.


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.


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.


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).


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.



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

Compliance with Ethical Standards


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.

Supplementary material

11523_2018_592_MOESM1_ESM.pdf (161 kb)
ESM 1 (PDF 161 kb)


  1. 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.CrossRefGoogle Scholar
  2. 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.CrossRefGoogle Scholar
  3. 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.
  4. 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.PubMedGoogle Scholar
  5. 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.CrossRefGoogle Scholar
  6. 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.CrossRefGoogle Scholar
  7. 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.CrossRefGoogle Scholar
  8. 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.CrossRefGoogle Scholar
  9. 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.CrossRefGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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.CrossRefGoogle Scholar
  12. 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.CrossRefGoogle Scholar
  13. 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.CrossRefGoogle Scholar
  14. 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.CrossRefGoogle Scholar
  15. 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.CrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. 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.PubMedPubMedCentralGoogle Scholar
  18. 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.CrossRefGoogle Scholar
  19. 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.CrossRefGoogle Scholar
  20. 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.CrossRefGoogle Scholar
  21. 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.CrossRefGoogle Scholar
  22. 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.CrossRefGoogle Scholar
  23. 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.CrossRefGoogle Scholar
  24. 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.CrossRefGoogle Scholar
  25. 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.CrossRefGoogle Scholar
  26. 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.CrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 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.CrossRefGoogle Scholar
  30. 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.CrossRefGoogle Scholar
  31. 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.CrossRefGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 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.CrossRefGoogle Scholar
  35. 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.CrossRefGoogle Scholar
  36. 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.CrossRefGoogle Scholar
  37. 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

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Bo Zhang
    • 1
  • Yanwei Zhang
    • 1
  • Jianlin Xu
    • 1
  • Xueyan Zhang
    • 1
  • Tianqing Chu
    • 1
  • Shuyuan Wang
    • 1
  • Jie Qian
    • 1
  • Rong Qiao
    • 1
  • Jun Lu
    • 1
  • Lele Zhang
    • 1
  • Baohui Han
    • 1
    Email author
  1. 1.Department of Pulmonary, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiPeople’s Republic of China

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