Skip to main content

Advertisement

Log in

Efficacy and tolerability of crizotinib in the treatment of ALK-positive, advanced non-small cell lung cancer in Chinese patients

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Crizotinib has been reported to be particularly effective and to have acceptable toxicity in advanced anaplastic lymphoma kinase (ALK)-positive, non-small cell lung cancer (NSCLC). In this study, we analyzed the efficacy and tolerability of crizotinib in the treatment of 72 Chinese patients with ALK-positive, advanced NSCLC. All patients received oral crizotinib 250 mg twice daily in 28-day cycles during the period June 1, 2013, to October 15, 2014. The tumor response was assessed after the first cycle of crizotinib and then after every two cycles using the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. Tolerability was assessed at least twice per cycle until crizotinib was discontinued. The patients tended to be young (mean age 55 years, range 31–83 years), never or light smokers (smoking index <400), and to have an adenocarcinoma histology. Most (49/72; 68.1 %) had received previous anticancer treatment before crizotinib therapy. Sixty-seven patients (93 %) were able to be assessed for efficacy. The objective response rate and disease control rate were 52.2 % (95 % CI 40.5–63.9 %) and 64.2 % (95 % CI 52.75–75.7 %), respectively. The estimated median progression-free survival for all 67 patients was 10.3 months (95 % CI 8.6–12.0 months). Mild visual disturbances, nausea, vomiting, diarrhea and constipation were the most commonly reported adverse effects. Thus, crizotinib was well tolerated and showed promising efficacy in Chinese patients with ALK-positive, advanced NSCLC. Further prospective, multicenter studies with a larger sample size are needed to confirm these findings.

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.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Shibuya K, Mathers CD, Boschi-Pinto C, Lopez AD, Murray CJ. Global and regional estimates of cancer mortality and incidence by site. II. Results for the global burden of disease 2000. BMC Cancer. 2002;2:36.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.

    Article  PubMed  Google Scholar 

  3. Jackson SE, Chester JD (2014) Personalised cancer medicine. Int J Cancer May 2, 2014 [Epub ahead of print].

  4. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472–80.

    Article  CAS  PubMed  Google Scholar 

  5. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031–7.

    Article  CAS  PubMed  Google Scholar 

  6. Fan Y, Xu X, Xie C. EGFR-TKI therapy for patients with brain metastases from non-small-cell lung cancer: a pooled analysis of published data. Onco Targets Ther. 2014;7:2075–84.

    PubMed Central  PubMed  Google Scholar 

  7. Metro G, Finocchiaro G, Toschi L, Bartolini S, Magrini E, Cancellieri A, Trisolini R, Castaldini L, Tallini G, Crino L, Cappuzzo F. Epidermal growth factor receptor (EGFR) targeted therapies in non-small cell lung cancer (NSCLC). Rev Recent Clin Trials. 2006;1:1–13.

    Article  CAS  PubMed  Google Scholar 

  8. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561–6.

    Article  CAS  PubMed  Google Scholar 

  9. Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, Stokes M, Sullivan L, Mitchell J, Wetzel R, Macneill J, Ren JM, Yuan J, Bakalarski CE, Villen J, Kornhauser JM, Smith B, Li D, Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush J, Comb MJ. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131:1190–203.

    Article  CAS  PubMed  Google Scholar 

  10. Gridelli C, Peters S, Sgambato A, Casaluce F, Adjei AA, Ciardiello F. ALK inhibitors in the treatment of advanced NSCLC. Cancer Treat Rev. 2014;40:300–6.

    Article  CAS  PubMed  Google Scholar 

  11. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Jänne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, Iafrate AJ. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693–703.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Takahashi T, Sonobe M, Kobayashi M, Yoshizawa A, Menju T, Nakayama E, Mino N, Iwakiri S, Sato K, Miyahara R, Okubo K, Manabe T, Date H. Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene. Ann Surg Oncol. 2010;17:889–97.

    Article  PubMed  Google Scholar 

  13. Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, Solomon B, Stubbs H, Admane S, McDermott U, Settleman J, Kobayashi S, Mark EJ, Rodig SJ, Chirieac LR, Kwak EL, Lynch TJ, Iafrate AJ. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Fukui T, Yatabe Y, Kobayashi Y, Tomizawa K, Ito S, Hatooka S, Matsuo K, Mitsudomi T. Clinicoradiologic characteristics of patients with lung adenocarcinoma harboring EML4-ALK fusion oncogene. Lung Cancer. 2012;77:319–25.

    Article  PubMed  Google Scholar 

  15. Wang Y, Wang S, Xu S, Qu J, Liu B. Clinicopathologic features of patients with non-small cell lung cancer harboring the EML4-ALK fusion gene: a meta-analysis. PLoS One. 2014;9:e110617.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Wang J, Dong Y, Cai Y, Zhou L, Wu S, Liu G, Su D, Li X, Qin N, Nong J, Jia H, Zhang Q, Mu J, Zeng X, Zhang H, Zhang S, Zhang Z. Clinicopathologic characteristics of ALK rearrangements in primary lung adenocarcinoma with identified EGFR and KRAS status. J Cancer Res Clin Oncol. 2014;140:453–60.

    Article  CAS  PubMed  Google Scholar 

  17. Hong S, Fang W, Hu Z, Zhou T, Yan Y, Qin T, Tang Y, Ma Y, Zhao Y, Xue C, Huang Y, Zhao H, Zhang L. A large-scale cross-sectional study of ALK rearrangements and EGFR mutations in non-small-cell lung cancer in Chinese Han population. Sci Rep. 2014;4:7268.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Frampton JE. Crizotinib: a review of its use in the treatment of anaplastic lymphoma kinase-positive, advanced non-small cell lung cancer. Drugs. 2013;73:2031–51.

    Article  CAS  PubMed  Google Scholar 

  19. Ou SH, Kwak EL, Siwak-Tapp C, Dy J, Bergethon K, Clark JW, Camidge DR, Solomon BJ, Maki RG, Bang YJ, Kim DW, Christensen J, Tan W, Wilner KD, Salgia R, Iafrate AJ. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thorac Oncol. 2011;6:942–6.

    Article  PubMed  Google Scholar 

  20. Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, Massion PP, Siwak-Tapp C, Gonzalez A, Fang R, Mark EJ, Batten JM, Chen H, Wilner KD, Kwak EL, Clark JW, Carbone DP, Ji H, Engelman JA, Mino-Kenudson M, Pao W, Iafrate AJ. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30:863–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Qian H, Gao F, Wang H, Ma F. The efficacy and safety of crizotinib in the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer: a meta-analysis of clinical trials. BMC Cancer. 2014;14:683.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O’Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385–94.

    Article  CAS  PubMed  Google Scholar 

  23. Shaw AT, Yeap BY, Solomon BJ, Riely GJ, Gainor J, Engelman JA, Shapiro GI, Costa DB, Ou SH, Butaney M, Salgia R, Maki RG, Varella-Garcia M, Doebele RC, Bang YJ, Kulig K, Selaru P, Tang Y, Wilner KD, Kwak EL, Clark JW, Iafrate AJ, Camidge DR. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol. 2011;12:1004–12.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, Riely GJ, Solomon B, Ou SH, Kim DW, Salgia R, Fidias P, Engelman JA, Gandhi L, Jänne PA, Costa DB, Shapiro GI, Lorusso P, Ruffner K, Stephenson P, Tang Y, Wilner K, Clark JW, Shaw AT. 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;13:1011–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. 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. 2000;92:205–16.

    Article  CAS  PubMed  Google Scholar 

  26. Zhang X, Zhang S, Yang X, Yang J, Zhou Q, Yin L, An S, Lin J, Chen S, Xie Z, Zhu M, Zhang X, Wu YL. Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression. Mol Cancer. 2010;9:188.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Ou SH, Janne PA, Bartlett CH, Tang Y, Kim DW, Otterson GA, Crinò L, Selaru P, Cohen DP, Clark JW, Riely GJ. Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC. Ann Oncol. 2014;25:415–22.

    Article  PubMed  Google Scholar 

  28. Nishino M, Jagannathan JP, Krajewski KM, O’Regan K, Hatabu H, Shapiro G, Ramaiya NH. Personalized tumor response assessment in the era of molecular medicine: cancer-specific and therapy-specific response criteria to complement pitfalls of RECIST. AJR Am J Roentgenol. 2012;198:737–45.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Choi H, Charnsangavej C, de Castro Faria S, Tamm EP, Benjamin RS, Johnson MM, Macapinlac HA, Podoloff DA. CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate treatment: a quantitative analysis correlated with FDG PET findings. AJR Am J Roentgenol. 2004;183:1619–28.

    Article  PubMed  Google Scholar 

  30. Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR, Chen LL, Podoloff DA, Benjamin RS. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007;25:1753–9.

    Article  PubMed  Google Scholar 

  31. Demidova I, Barinov A, Savelov N, Gagarin I, Grinevitch V, Stroiakovaski D, Popov M, Laktionov K, Gutorov S, Smolin A, Olshanskaya Y, Obukhova T. Immunohistochemistry, fluorescence in situ hybridization, and reverse transcription-polymerase chain reaction for the detection of anaplastic lymphoma kinase gene rearrangements in patients with non-small cell lung cancer: potential advantages and methodologic pitfalls. Arch Pathol Lab Med. 2014;138:794–802.

    Article  CAS  PubMed  Google Scholar 

  32. Selinger CI, Rogers TM, Russell PA, O’Toole S, Yip P, Wright GM, Wainer Z, Horvath LG, Boyer M, McCaughan B, Kohonen-Corish MR, Fox S, Cooper WA, Solomon B. Testing for ALK rearrangement in lung adenocarcinoma: a multicenter comparison of immunohistochemistry and fluorescent in situ hybridization. Mod Pathol. 2013;26:1545–53.

    Article  CAS  PubMed  Google Scholar 

  33. Martinez P, Hernández-Losa J, Montero MÁ, Cedrés S, Castellví J, Martinez-Marti A, Tallada N, Murtra-Garrell N, Navarro-Mendivill A, Rodriguez-Freixinos V, Canela M, Ramon y Cajal S, Felip E. Fluorescence in situ hybridization and immunohistochemistry as diagnostic methods for ALK positive non-small cell lung cancer patients. PLoS One. 2013;8(1):e52261.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Akiba J, Kawahara A, Abe H, Azuma K, Yamaguchi T, Taira T, Fukumitsu C, Takase Y, Yasumoto M, Umeno Y, Todoroki K, Kurita T, Yamaguchi R, Kage M, Yano H. Evaluation of immunohistochemistry using two different antibodies and procedures for primary lung adenocarcinoma harboring anaplastic lymphoma kinase rearrangement. Oncol Lett. 2014;8:2155–9.

    PubMed Central  PubMed  Google Scholar 

  35. Ali G, Proietti A, Pelliccioni S, Niccoli C, Lupi C, Sensi E, Giannini R, Borrelli N, Menghi M, Chella A, Ribechini A, Cappuzzo F, Melfi F, Lucchi M, Mussi A, Fontanini G. ALK rearrangement in a large series of consecutive non-small cell lung cancers: comparison between a new immunohistochemical approach and fluorescence in situ hybridization for the screening of patients eligible for crizotinib treatment. Arch Pathol Lab Med. 2014;138:1449–58.

    Article  PubMed  Google Scholar 

  36. Wang J, Cai Y, Dong Y, Nong J, Zhou L, Liu G, Su D, Li X, Wu S, Chen X, Qin N, Zeng X, Zhang H, Zhang Z, Zhang S. Clinical characteristics and outcomes of patients with primary lung adenocarcinoma harboring ALK rearrangements detected by FISH, IHC, and RT-PCR. PLoS One. 2014;9:e101551.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

Editorial assistance with the manuscript was provided by Content Ed Net, Shanghai Co. Ltd.

Conflict of interest

None of the authors has any conflict of interest to declare.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Liyan Jiang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cui, S., Zhao, Y., Gu, A. et al. Efficacy and tolerability of crizotinib in the treatment of ALK-positive, advanced non-small cell lung cancer in Chinese patients. Med Oncol 32, 180 (2015). https://doi.org/10.1007/s12032-015-0626-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-015-0626-7

Keywords

Navigation