Qian et al.

BMC Cancer 2014, 14:683

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RESEARCH ARTICLE Open Access

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
Haili Qian1†, Feng Gao3†, Haijuan Wang1 and Fei Ma2*

Abstract
Background: Crizotinib was granted accelerated approval by the Food and Drug Administration in 2011 for the
treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). To evaluate the efficacy
and safety of crizotinib, we performed a meta-analysis of published clinical trials using the random effect model.
Methods: The efficacy and safety of crizotinib was evaluated based on 1-year overall survival (OS), progression-free
survival (PFS), overall response rate (ORR), partial response, complete response, stable disease, and dose reduction
or cessation because of crizotinib toxicity.
Results: Six clinical trials were included in the meta-analysis. Crizotinib treatment demonstrated a 1-year OS of 66.8%
(95% CI, 52.2–78.8%) and a PFS of 8.6 months (95% CI, 7.3–9.9 months). The aggregate ORR, partial response and
complete response rates were 61.2%, 59.8% and 1.5%, respectively. The proportion of patients achieving stable disease
was 42.6% (95% CI, 17.3–72.5%). The most frequently reported adverse effects of crizotinib were mild visual disturbances,
nausea, vomiting, diarrhea, constipation, edema, reduction in glomerular filtration rate, and generally reversible
but sometimes severe elevations in aspartate aminotransferase and alanine aminotransferase. The proportion of
patients who required dose reduction or cessation because of crizotinib toxicity was 6.5% (95% CI, 4.1–10.1%).
Conclusions: This meta-analysis revealed extended survival and improved response rates in patients treated with
crizotinib. As a novel, targeted anticancer agent, crizotinib appears to be a favorable treatment option for patients
with locally advanced or metastatic ALK-positive NSCLC.
Keywords: Meta-analysis, Crizotinib, Anaplastic lymphoma kinase (ALK), Non-small cell lung cancer (NSCLC)

Background based chemotherapy is 7.4–9.9 months, and the median

Lung cancer, of which approximately 85–90% of cases OS with combined chemotherapy and bevacizumab is
are non-small cell lung cancer (NSCLC), is the most 12.5 months. Median progression-free survival (PFS)
common fatal malignancy among all cancers worldwide, with second-line chemotherapy, such as pemetrexed and
and its incidence has gradually increased over recent de- docetaxel, is approximately 2.2–2.9 months. Although
cades, [1,2]. Patients usually present with unresectable associated with a higher response rate, OS with gefitinib
locally advanced (stage IIIB) or distant metastases (stage is similar to that of standard carboplatin plus paclitaxel
IV) NSCLC. For patients newly diagnosed with advanced chemotherapy [3]. The 5-year survival rate of NSCLC is
NSCLC, the median overall survival (OS) with platinum- lower than 20% [4,5]. However, despite the relatively
poor prognosis for NSCLC patients, the development of
treatments for NSCLC has not yet kept pace [6].
* Correspondence: [email protected]
†
Equal contributors
In recent years, the identification of genetic abnormal-
2
Department of Medical Oncology, Cancer Institute/Hospital, Peking Union ities that may underlie oncogenic development and pro-
Medical College & Chinese Academy of Medical Sciences, Beijing, China gression have revolutionized oncology research [7]. A
Full list of author information is available at the end of the article

© 2014 Qian et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
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translocation in the gene encoding the receptor tyrosine considered eligible for the analysis. The inclusion criteria
kinase anaplastic lymphoma kinase (ALK), leading to the were as follows: (i) articles were clinical trials investigat-
expression of ALK fusion proteins, was first reported in ing the efficacy and/or safety of crizotinib in the treat-
NSCLC patients in 2007 [8,9]. The activated ALK fusion ment of ALK-positive NSCLC; (ii) a standardized effect
proteins result in aberrant ALK signaling and oncogenic size could be calculated on the evaluations of 1-year
transformation through several molecular signaling path- overall survival (OS), progression-free survival (PFS),
ways, including PI3K/AKT/mTOR, JAK/STAT, and RAS/ overall response rate (ORR), partial response, complete
MEK/ERK [10]. Constitutive ALK signaling mediates en- response, stable disease, and/or dose reduction or cessa-
hanced cell proliferation, cell survival, and metabolism. tion because of adverse effects of crizotinib were re-
ALK gene rearrangements are found in approximately 2– ported; (iii) articles were in English; and (iv) full text was
7% of unselected patients with NSCLC [11]. Because of available. Two investigators (MF and WH) independ-
the role of ALK in oncogenesis, tyrosine kinase inhibition ently assessed the articles for relevancy.
has been investigated as a therapeutic approach [11]. Cri-
zotinib is a small-molecule selective inhibitor of ALK and Data extraction
mesenchymal epithelial growth factor (c-Met)/hepatocyte All articles were first de-identified (article title, author
growth factor receptor (HGFR) kinases [12]. It was ap- names, journal name and year of publication) before se-
proved via accelerated drug approval by the US Food and lection. The abstracts of the articles were independently
Drug Administration in 2011, based on the findings of reviewed by two authors (MF and WH). Outcomes were
two early phase clinical trials demonstrating prolonged pooled for 1-year OS (defined as the percentage of pa-
progression-free survival (PFS; 6–10 months) and high re- tients who remained alive 1 year after crizotinib treat-
sponse rates (50–57%) in patients with ALK-positive ment), ORR (defined as the observed alive rate of
NSCLC [13,14]. A further phase 3 clinical trial in patients patients since the date of crizotinib treatment), partial
with ALK-positive NSCLC confirmed the advantage of cri- response (defined as the percentage of patients who had
zotinib in survival, response rates, and duration of re- a decrease in the size of tumor, or in the extent of can-
sponse in ALK-positive patients with NSCLC, although cer in the body, in response to crizotinib treatment),
mild to severe adverse effects, commonly reported as complete response (defined as the percentage of pa-
gastrointestinal disturbances (nausea, diarrhea, vomiting, tients who had the disappearance of all signs of cancer
and constipation), visual disturbances and fatigue, were in response to crizotinib treatment), dose reduction or
noted [15,16]. cessation because of adverse effects of crizotinib, and
This study systematically combines data from published mean duration of PFS and stable disease. Data were fil-
clinical trials to evaluate the efficacy and safety of crizotinib tered and transferred into a standard electronic form.
in the treatment of ALK-positive NSCLC using a random Any discrepancies were resolved by discussion until a
effect model following the Preferred Reporting Items for consensus was reached. If not, the principal investigator
Systematic Reviews and Meta-Analyses (PRISMA) guide- (QH) made the final decision on the eligibility of the
lines [17]. study and data extraction.

Methods Statistical analysis

Search strategy for the identification of studies Data management and analysis were performed using
To evaluate the efficacy and safety of crizotinib in the treat- Comprehensive Meta-analysis Version 2 (Biostat, Englewood,
ment of ALK-positive NSCLC, PubMed, Embase, and the NJ, USA). Data were pooled statistically using the event
Cochrane Library (all from 1980 to Nov 2013) were rates calculated for primary (the 1-year OS, ORR, partial
searched to identify clinical trials in English-language jour- response, complete response) and secondary endpoints
nals. The search terms used were “crizotinib”, “non-small (dose reduction or cessation because of crizotinib ad-
cell lung cancer”, “carcinoma”, “anaplastic lymphoma kin- verse effects, and mean duration of PFS and stable
ase”, and “clinical trial” in various combinations. We also disease).
manually searched the related references from the bibliog- A random effect meta-analysis was conducted to investi-
raphy of the selected articles. Only eligible original studies gate the efficacy and safety of crizotinib in the treatment
with full text available were selected, and meeting abstracts of ALK-positive NSCLC in this study. Because fixed ef-
were excluded. The corresponding authors of some studies fects models in meta-analysis assume that one true effect
were contacted for further information if necessary. exists, which all studies are estimating, they increase the
risk of a Type I error and create overly narrow confidence
Article selection criteria intervals. In contrast, random effects models assume that
All clinical trials exploring the efficacy and safety of cri- true effects are different across studies owing to hetero-
zotinib in the treatment of ALK-positive NSCLC were geneity of patients, treatments or other factors. Random
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effects models create wider confidence intervals and five had the same data presented in other studies, six did
minimize the risk of Type I error. Therefore, random ef- not provide sufficient information to calculate an effect
fects models are recommended to be routinely employed size, and seven studies were case reports. The article
in meta-analysis, particularly when study heterogeneity is selection process is shown in Figure 1, and details of
expected or found [18]. the six articles [14,19-23] selected for our analysis are
The measure of heterogeneity was evaluated using shown in Table 1.
Cochran’s Q-test. Additionally, heterogeneity was assessed In these 6 studies, the efficacy and toxicity of crizo-
using the I2 statistic. A high value for I2 indicates het- tinib was investigated in the treatment of ALK-positive
erogeneity. Publication bias was evaluated using Egger’s NSCLC. Analysis of pooled data revealed a 1-year OS of
test. 66.8% (95% CI, 52.2–78.8%; Figure 2A) and a PFS of
8.6 months (95% CI, 7.3–9.9 months; Figure 2B). In
Ethical approval terms of response rates, the aggregate ORR (Figure 3A),
The study was approved by the Ethics Committee of partial response (Figure 3B) and complete response
the Cancer Hospital of Chinese Academy of Medical (Figure 3C) were 61.2% (95% CI, 57.4–64.8%), 59.8%
Sciences. (95% CI, 56.0–63.5%) and 1.5% (95% CI, 0.8–2.8%), re-
spectively. The proportion of patients achieving stable
Results disease (Figure 3D) was 42.6% (95% CI, 17.3–72.5%).
A total of 87 abstracts were initially selected through data- The proportion of patients who required dose reduction
base searching, and 63 articles were excluded because they or cessation because of crizotinib toxicity was 6.5%
failed to meet the criteria. For the remaining 24 articles, (95% CI, 4.1–10.1%, Figure 4).

Figure 1 Flow chart describing the article selection process.

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Table 1 Main characteristics of the selected studies

Citation Mean age Number of Duration of Dose and frequency of Trial Tumor histologic type Extent of
(years) patients follow up crizotinib phase (Adenocarcinoma, %) disease
(month) administration (Metastatic, %)
Shaw et al. [21] 50.0 173 12.2 250 mg twice daily Phase 3 95 95
Brosnan et al. [22] 54.7 38 16.3 250 mg twice daily NA NA NA
Riely [23] 53.0 261 12.0 250 mg twice daily Phase 2 92 NA
Camidge et al. [19] 52.0 149 16.3 250 mg twice daily Phase 1 97 NA
Shaw et al. [20] 51.0 56 18.0 250 mg twice daily Phase 1 96 89
Kwak et al. [14] 51.0 82 6.4 250 mg twice daily Phase 1 96 NA
NA = not applicable.

There were statistically significant differences for 1-year NSCLC treatments (docetaxel or pemetrexed as a single
OS (Q = 14.903, p = 0.002, I2 = 79.870) and stable disease agent, n = 174) in ALK-positive patients with advanced
(Q = 122.520, p <0.001, I2 = 97.551). No significant differ- NSCLC previously treated with one platinum-containing
ence was observed for other outcomes (p >0.05). Funnel regimen in a Phase 3 trial [21]. Results showed that PFS
plots and Egger’s regression test revealed no significant was prolonged in the crizotinib-treated group (7.7 months
publication bias (p >0.05). vs. 3.3 months, p <0.0001). Patients in the crizotinib arm
completed more treatment cycles than those in the
Discussion standard chemotherapy arm. Response was significantly
The goal of this meta-analysis was to evaluate the efficacy improved (65% vs. 20%, p <0.0001). Thus, crizotinib
and safety of crizotinib in the treatment of ALK-positive treatment demonstrated an improvement in survival
NSCLC. The aggregated effect size revealed that crizotinib and response rates, which were superior to standard-of-
treatment shows generally extended survival (1-year OS: care chemotherapy. As a novel targeted anticancer
66.8%; PFS: 8.6 months) and improved response rates agent, crizotinib appears to be a favorable treatment
(ORR: 61.2%; partial response: 59.8%; complete response: option for patients with locally advanced or metastatic
1.5%; stable disease: 42.6%). These findings strongly indi- ALK-positive NSCLC.
cate the effectiveness of crizotinib treatment in patients Notably, 6.5% of patients have to reduce the dose or dis-
with ALK-positive NSCLC. In a retrospective analysis of a continue crizotinib treatment because of toxicity. In the
phase 1 trial [20], ALK-positive patients who received cri- studies included in this meta-analysis, the most frequently
zotinib (n = 82) showed improved survival compared to reported adverse effects were mild visual disturbances,
ALK-positive control patients (n = 36) who did not receive nausea, vomiting, diarrhea, constipation, edema, reduction
crizotinib. In the second- and third-line settings, 1-year in glomerular filtration rate, and generally reversible but
OS was 70% versus 44%, respectively; and 2-year OS was sometimes severe elevations in aspartate aminotransferase
55% versus 12%, respectively. The effect of crizotinib treat- and alanine aminotransferase. Shaw et al. [21] found that
ment (n = 173) was also compared with standard-of-care adverse events reported with crizotinib treatment of ALK-

A B

Figure 2 Forest plot for the aggregate survival data of crizotinib in the treatment of patients with locally advanced or metastatic
anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). (A) 1-year overall survival (OS); (B) progression-free
survival (PFS).
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A B

C D

Figure 3 Forest plot for the aggregate response data of crizotinib in the treatment of patients with locally advanced or metastatic
anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). (A) overall response rate (ORR); (B) partial response;
(C) complete response; (D) stable disease.

positive NSCLC patients were comparable to docetaxel or conclusions from this study to all patients with ALK-
pemetrexed, with similar severe (grade 3 or 4) reactions positive NSCLC should be cautious.
across the treatment groups. Discontinuation rates were
slightly higher in the chemotherapy arm (10%) compared
with the crizotinib arm (6%). Although generally tolerated, Conclusions
the toxicity of crizotinib should be monitored in order to In conclusion, the meta-analysis investigated the efficacy
maximize its safety [24,25], and the dose of crizotinib and safety of crizotinib in the treatment of patients with
needs to be adjusted when necessary [26]. locally advanced or metastatic ALK-positive NSCLC. Clin-
As a newly approved medication, evidence of the effi- ical trials with crizotinib treatment show extended survival
cacy and safety of crizotinib in the treatment of ALK- and improved response rates, along with tolerable toxicity.
positive NSCLC is relatively incomplete. The findings As a novel targeted anticancer agent, crizotinib appears to
from this meta-analysis are therefore valuable for physi- be a favorable treatment option for patients with locally
cians and public health policy makers in formulating strat- advanced or metastatic ALK-positive NSCLC. Further
egies to maximize the efficacy and minimize crizotinib blinded, placebo-controlled studies with larger sample
toxicity. However, given the relatively small numbers of sizes are needed to compare the efficacy and safety of
cases included into the trials, generalization of the crizotinib with other NSCLC treatments.

Figure 4 Forest plot for the aggregate proportion of patients who required dose reduction or cessation because of crizotinib
toxicity in the treatment of locally advanced or metastatic anaplastic lymphoma kinase (ALK)-positive non-small cell lung
cancer (NSCLC).
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Competing interests mutant non-small-cell lung cancer cells. Anticancer Drugs 2013,
The authors declare that they have no competing interests. 24(10):1039–1046.
13. Berge EM, Lu X, Maxson D, Baron AE, Gadgeel SM, Solomon BJ, Doebele RC,
Authors’ contributions Varella-Garcia M, Camidge DR: Clinical benefit from pemetrexed before
FM carried out the study and drafted the manuscript. HW participated in the and after crizotinib exposure and from crizotinib before and after
extraction and analysis of data. HQ and FG conceived of the study, and pemetrexed exposure in patients with anaplastic lymphoma kinase-
participated in its design and coordination and helped to draft the positive non-small-cell lung cancer. Clin Lung Cancer 2013, 14(6):636–643.
manuscript. All authors read and approved the final manuscript. 14. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH,
Dezube BJ, Janne 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,
Acknowledgements
Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA,
This manuscript was reviewed by Dr. Tao Wen for design and language
Wilner K, Salgia R, Shapiro GI, Clark JW, et al: Anaplastic lymphoma kinase
preparation. We greatly appreciate his support.
inhibition in non-small-cell lung cancer. N Engl J Med 2010,
363(18):1693–1703.
Author details
1 15. Frampton JE: Crizotinib: a review of its use in the treatment of anaplastic
State Key Laboratory of Molecular Oncology, Cancer Institute/Hospital,
lymphoma kinase-positive, advanced non-small cell lung cancer. Drugs
Peking Union Medical College & Chinese Academy of Medical Sciences,
2013, 73(18):2031–2051.
Beijing, China. 2Department of Medical Oncology, Cancer Institute/Hospital,
16. Casaluce F, Sgambato A, Maione P, Rossi A, Ferrara C, Napolitano A,
Peking Union Medical College & Chinese Academy of Medical Sciences,
Palazzolo G, Ciardiello F, Gridelli C: ALK inhibitors: a new targeted therapy
Beijing, China. 3Health Division of Guard Bureau, General Staff Department of
in the treatment of advanced NSCLC. Target Oncol 2013, 8(1):55–67.
Chinese PLA, Beijing, China.
17. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF: Improving the
quality of reports of meta-analyses of randomised controlled trials: the
Received: 25 April 2014 Accepted: 9 September 2014
QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 1999,
Published: 19 September 2014
354(9193):1896–1900.
18. Hunter JE, Schmidt FL: Fixed effects vs. random effects meta-analysis
References models: implications for cumulative research knowledge. Int J Sel Assess
1. Weinmann M, Jeremic B, Toomes H, Friedel G, Bamberg M: Treatment of 2000, 8(4):275–292.
lung cancer in the elderly. Part I: non-small cell lung cancer. Lung Cancer 19. Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, Riely GJ,
2003, 39(3):233–253. Solomon B, Ou SH, Kim DW, Salgia R, Fidias P, Engelman JA, Gandhi L, Jänne
2. Roberts PJ: Clinical use of crizotinib for the treatment of non-small cell PA, Costa DB, Shapiro GI, Lorusso P, Ruffner K, Stephenson P, Tang Y, Wilner
lung cancer. Biologics 2013, 7:91–101. K, Clark JW, Shaw AT: Activity and safety of crizotinib in patients with
3. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, ALK-positive non-small-cell lung cancer: updated results from a phase 1
Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, study. Lancet Oncol 2012, 13(10):1011–1019.
Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS: 20. Shaw AT, Yeap BY, Solomon BJ, Riely GJ, Gainor J, Engelman JA, Shapiro GI,
Biomarker analyses and final overall survival results from a phase III, Costa DB, Ou SH, Butaney M, Salgia R, Maki RG, Varella-Garcia M, Doebele
randomized, open-label, first-line study of gefitinib versus carboplatin/ RC, Bang YJ, Kulig K, Selaru P, Tang Y, Wilner KD, Kwak EL, Clark JW, Iafrate
paclitaxel in clinically selected patients with advanced non-small-cell AJ, Camidge DR: Effect of crizotinib on overall survival in patients with
lung cancer in Asia (IPASS). J Clin Oncol 2011, 29(21):2866–2874. advanced non-small-cell lung cancer harbouring ALK gene
4. Klastersky J, Paesmans M: Response to chemotherapy, quality of life rearrangement: a retrospective analysis. Lancet Oncol 2011,
benefits and survival in advanced non-small cell lung cancer: review of 12(11):1004–1012.
literature results. Lung Cancer 2001, 34(Suppl 4):S95–S101. 21. Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, De Pas T, Besse B,
5. American Cancer Society: Cancer Facts & Figures 2013. 2013. http://www. Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D,
cancer.org/research/cancerfactsstatistics/cancerfactsfigures2013/. Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD,
6. Bowles DW, Weickhardt AJ, Doebele RC, Camidge DR, Jimeno A: Crizotinib Jänne PA: Crizotinib versus chemotherapy in advanced ALK-positive lung
for the treatment of patients with advanced non-small cell lung cancer. cancer. N Engl J Med 2013, 368(25):2385–2394.
Drugs Today (Barc) 2012, 48(4):271–282. 22. Brosnan EM, Weickhardt AJ, Lu X, Maxon DA, Baron AE, Chonchol M,
7. Kanteti R, El-Hashani E, Dhanasingh I, Tretiakova M, Husain AN, Sharma S, Camidge DR: Drug-induced reduction in estimated glomerular filtration
Sharma J, Vokes EE, Salgia R: Role of PAX8 in the regulation of MET and rate in patients with ALK-positive non-small cell lung cancer treated with
RON receptor tyrosine kinases in non-small cell lung cancer. BMC Cancer the ALK inhibitor crizotinib. Cancer 2013, 120(5):664–674.
2014, 14:185. 23. Riely GJ, Evans TL, Salgia R, Ou SI, Gettinger SN, Otterson GA, Lanzalone S,
8. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Polli A, Shaw AT: Results of a global phase II study with crizotinib in
Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, advanced ALK-positive non-small cell lung cancer (NSCLC). Paper
Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H: Identification of the presented at: the 2012 Chicago Multidisciplinary Symposium in Thoracic
transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature Oncology. Chicago, IL: 2012. Abstract 3.
2007, 448(7153):561–566. 24. O’Bryant CL, Wenger SD, Kim M, Thompson LA: Crizotinib: a new
9. Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, treatment option for ALK-positive non-small cell lung cancer. Ann
Reeves C, Li Y, Hu Y, Tan Z, Stokes M, Sullivan L, Mitchell J, Wetzel R, Pharmacother 2013, 47(2):189–197.
Macneill J, Ren JM, Yuan J, Bakalarski CE, Villen J, Kornhauser JM, Smith B, Li 25. Ou SH: Crizotinib: a novel and first-in-class multitargeted tyrosine kinase
D, Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush J, Comb MJ: Global survey inhibitor for the treatment of anaplastic lymphoma kinase rearranged
of phosphotyrosine signaling identifies oncogenic kinases in lung non-small cell lung cancer and beyond. Drug Des Devel Ther 2011,
cancer. Cell 2007, 131(6):1190–1203. 5:471–485.
10. Steuer CE, Ramalingam SS: ALK-positive non-small cell lung cancer: 26. Curran MP: Crizotinib: in locally advanced or metastatic non-small cell
Mechanisms of resistance and emerging treatment options. Cancer 2014, lung cancer. Drugs 2012, 72(1):99–107.
120(16):2392–2402.
11. Miyanaga A, Shimizu K, Noro R, Seike M, Kitamura K, Kosaihira S, Minegishi
doi:10.1186/1471-2407-14-683
Y, Shukuya T, Yoshimura A, Kawamoto M, Tsuchiya S, Hagiwara K, Soda M,
Cite this article as: Qian et al.: The efficacy and safety of crizotinib in the
Takeuchi K, Yamamoto N, Mano H, Ishikawa Y, Gemma A: Activity of EGFR- treatment of anaplastic lymphoma kinase-positive non-small cell lung
tyrosine kinase and ALK inhibitors for EML4-ALK-rearranged non-small- cancer: a meta-analysis of clinical trials. BMC Cancer 2014 14:683.
cell lung cancer harbored coexisting EGFR mutation. BMC Cancer 2013,
13:262.
12. Chen X, Zhou JY, Zhao J, Chen JJ, Ma SN: Crizotinib overcomes
hepatocyte growth factor-mediated resistance to gefitinib in EGFR-