Indian Journal of Cancer
Home  ICS  Feedback Subscribe Top cited articles Login 
Users Online :354
Small font sizeDefault font sizeIncrease font size
Navigate here
Resource links
 »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
 »  Article in PDF (1,101 KB)
 »  Citation Manager
 »  Access Statistics
 »  Reader Comments
 »  Email Alert *
 »  Add to My List *
* Registration required (free)  

  In this article
 »  Abstract
 » Introduction
 » Case Report
 » Discussion
 » Conclusion
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    PDF Downloaded128    
    Comments [Add]    

Recommend this journal


  Table of Contents  
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 178-181

Role of crizotinib in c-mesenchymal-epidermal transition-positive nonsmall cell lung cancer patients

Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. U Batra
Rajiv Gandhi Cancer Institute and Research Centre, New Delhi
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-509X.219592

Rights and Permissions

 » Abstract 

The increasing cases of NSCLC and improved understanding of its molecular biology has lead to identification of its varied driver mutations. cMET amplification has an important role as resistance mechanism for EGFR TKIs. Crizotinib is a drug which shows its anti-tumoral effect in cMET positive cases. Here we present a case series of three such patients who achieved were cMET amplified and showed partial response on Crizotinib.

Keywords: Brain metastasis, c-mesenchymal-epidermal transition, crizotinib, nonsmall cell lung cancer

How to cite this article:
Batra U, Jain A, Sharma M, Bajaj R, Suryavanshis M. Role of crizotinib in c-mesenchymal-epidermal transition-positive nonsmall cell lung cancer patients. Indian J Cancer 2017;54:178-81

How to cite this URL:
Batra U, Jain A, Sharma M, Bajaj R, Suryavanshis M. Role of crizotinib in c-mesenchymal-epidermal transition-positive nonsmall cell lung cancer patients. Indian J Cancer [serial online] 2017 [cited 2020 Mar 29];54:178-81. Available from:

 » Introduction Top

Nonsmall cell lung cancer (NSCLC) accounts for 80%–85% of all lung cancers and majority of the patients have advance disease at the time of initial presentation.[1] Worldwide, 1.8 million new cases of lung cancer were diagnosed, and nearly 1.6 million people died of this grave disease in the year 2012.[2] The survival of patients with advanced NSCLC had reached a plateau with the conventional chemotherapy. However, with the understanding of molecular pathology and advent of targeted therapies, the survival of patients with advanced NSCLC is increasing. Nearly 40% of NSCLC patients harbor at least one activated pathway with mutations in either KRAS gene or epidermal growth factor receptor (EGFR) gene or fusion gene of echinoderm microtubule-associated protein-like 4 (EML4) and the intracellular domain of anaplastic lymphoma kinase (ALK), named as EML4-ALK or ROS1 gene or c-mesenchymal-epidermal transition (c-MET) gene.[3],[4] Studies have demonstrated that mutations in various growth-regulating proteins such as KRAS, EGFR, EML4-ALK, MEK-1, B-RAF, and KIF5B-RET as well as inactivation of growth-inhibiting pathways such as TP53, PTEN, p16, and LKB-1 are responsible for the disruption of critical cell signaling pathways in NSCLC. Mutations in tyrosine kinase domain of the EGFR gene have shown a good response to personalized treatment with EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, afatinib, and gefitinib in NSCLC.[5],[6] Similarly, inhibition of EML4 ALK fusion protein by ALK and c-MET inhibitors such as crizotinib has shown a very high response rate in advanced NSCLC.[7],[8],[9]

Studies have reported that c-mesenchymal-epidermal transition (c-Met) receptor belonging to tyrosine kinase family plays a key role in the survival of cancer cell. The expression of this receptor kinase induces cell migration and invasion which are crucial steps for metastasis in various cancers.[10] An oral ATP-competitive TKI of ALK and c-MET, crizotinib has shown promising evidence in the treatment of patients with NSCLC.[11] Moreover, crizotinib has also demonstrated its antitumoral effect in c-MET-positive patients in several clinical trials. Here, we report a case series of three patients with c-MET-amplified NSCLC treated with crizotinib therapy.

 » Case Report Top

The clinical, histopathologic, and molecular characteristics of these patients are summarized in [Table 1]. There were two males and one female with metastatic adenocarcinoma NSCLC. Repeat biopsy for all the three patients showed c-MET amplification during the course of treatment. All patients were treated with crizotinib with minimal side effects.
Table 1: The clinicopathologic features of patients

Click here to view

The first patient was a 58-year-old male reformed smoker who was diagnosed as Stage IV NSCLC adenocarcinoma with multiple bony metastases [Figure 1]a. He received four cycles of palliative chemotherapy with carboplatin and pemetrexed. Post four cycles of chemotherapy patient showed a partial response [Figure 1]b. EGFR mutation L858R was detected in exon 21 and patient was started on an oral TKI (erlotinib). One month post erlotinib, the patient developed brain seizures and hematuria. Repeat positron emission tomography (PET) showed disease progression with renal lesion whereas brain metastasis was detected on magnetic resonance imaging [Figure 1]c. A repeat biopsy was done from renal lesion which revealed the presence of thyroid transcription factor-1 (TTF-1)-positive adenocarcinoma and also showed c-MET amplification in addition to L858R mutation. The patient received whole brain radiotherapy followed by c-MET inhibitor crizotinib. One month post crizotinib therapy, the patient showed a significant response to treatment [Figure 1]d followed by a stable disease after 3 months. However, he had progressive brain lesions.
Figure 1: (a) PET-CT shows multiple bone metastasis (b) Partial response post chemotherapy (c) Progressive disease (d) Significant response to Crizotinib

Click here to view

The second patient was a 50-year-old female with poorly differentiated carcinoma histology, favoring adenocarcinoma. Initial PET-computed tomography showed metabolically active right lung mass with lymph nodal and bony involvement. Molecular testing revealed EGFR wild type and no rearrangement of ALK was found. Patient received three cycles of carboplatin and pemetrexed combination as palliative systemic chemotherapy. Post three cycles of chemotherapy, patient showed disease progression. Patient was put on single-agent docetaxel therapy, and post three cycles, there was a disease progression [Figure 2]a. Further molecular testing by fluorescence in situ hybridization (FISH) revealed ROS1 not amplified but c-MET amplification. Hence, she was started on crizotinib. Two months post crizotinib therapy, patient showed a partial response to treatment. The patient continues to take crizotinib [Figure 2]b.
Figure 2: (a) Progressive disease after chemotherapy (b) Partial response after Crizotinib

Click here to view

The third patient was a 78-year-old male who presented with massive left-sided pleural effusion, for which he underwent medical thoracoscopy [Figure 3]a. The biopsy revealed the presence of TTF-1-positive adenocarcinoma. Further molecular testing revealed EGFR wild type, ALK not rearranged, ROS1 not amplified, c-MET amplified by FISH. In view of old age, he was not willing for chemotherapy, therefore, started on crizotinib therapy. Revaluation after 2 months revealed a partial response to treatment [Figure 3]b. He tolerated crizotinib well without any major side effect and at present continues to take crizotinib and has stable disease [Figure 3]c.
Figure 3: (a) Disease at presentation (b) Partial response after Crizotinib for 2 months (c) Stable disease after 4 months

Click here to view

 » Discussion Top

Several molecular epidemiological studies of NSCLC from India have reported the incidence of EGFR mutation and ALK gene rearrangement in the range of 23.2%–35% and 2.7%–3%, respectively.[12],[13],[14],[15],[16] However, with the increasing use of Next-generation sequencing (NGS), more targetable alternatives are being determined. c-MET is found in 3%–4% of patients based on FISH analysis, usually exclusive of other mutations.[17],[18],[19],[20]

Data from recent studies indicate that activating mutations and genomic amplification in the MET gene could potentially act as an important therapeutic target in NSCLC.[21],[22],[23],[24],[25] c-MET is the tyrosine kinase receptor for hepatocyte growth factor (HGF) that contains an intracellular juxtamembrane domain encoded in part by MET exon 14 which may respond to treatment with c-MET inhibitors such as crizotinib and cabozantinib. Around 4% of NSCLC cases have amplification of the MET gene resulting in a poor prognosis.[20],[26] Binding of HGF induces dimerization of MET that induces activation of tyrosine kinase by phosphorylation of the residues Y1230, Y1234, and Y1235 and promotes tumor angiogenesis, cell invasion, and metastasis.[27],[28] Studies have reported that amplification of c-MET pathway might play a critical role in tumor aggressiveness. MET amplification in lung cancer patients also leads to resistance to oral TKI such as gefitinib or erlotinib due to the lack of point mutation T790M in exon 20 of EGFR.[29]

There is very limited data on the role of the oral ATP-competitive TKI of c-MET, crizotinib in the treatment of patients with advanced or metastatic NSCLC. Studies have shown that crizotinib inhibits the tyrosine kinase activity of MET resulting in the inhibition of MET signaling in NSCLC.[30] In an eight-patient series of MET exon 14 mutations, Paik et al. reported a partial response in few patients with crizotinib therapy.[25] Another case report showed a partial response with crizotinib in an NSCLC patient with de novo MET amplification.[31] Similarly, Schwab et al. reported a major partial response to crizotinib in a squamous cell lung carcinoma patient with de novo c-MET amplification in the absence of ALK rearrangement.[32]

With all three patients showing a partial response to treatment, our study confirms the previous reports on crizotinib activity in NSCLC patients with MET amplification.

 » Conclusion Top

Due to the absence of novel and effective treatment strategy, reducing the Metastatic spread by using novel c-MET inhibitors is certainly one of the most promising approaches for the successful cancer treatment at present. Further studies seem warranted to evaluate the role of c-MET inhibitor in treating patients with metastatic NSCLC.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 » References Top

Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med 2008;359:1367-80.  Back to cited text no. 1
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-86.  Back to cited text no. 2
Sequist LV, Heist RS, Shaw AT, Fidias P, Rosovsky R, Temel JS, et al. Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol 2011;22:2616-24.  Back to cited text no. 3
Sholl LM(1), Aisner DL, Varella-Garcia M, Berry LD, Dias-Santagata D, Wistuba II et al. Multi-institutional Oncogenic Driver Mutation Analysis in Lung Adenocarcinoma: The Lung Cancer Mutation Consortium Experience. J Thorac Oncol. 2015;10:768-77.  Back to cited text no. 4
Okamoto I, Mitsudomi T, Nakagawa K, Fukuoka M. The emerging role of epidermal growth factor receptor (EGFR) inhibitors in first-line treatment for patients with advanced non-small cell lung cancer positive for EGFR mutations. Ther Adv Med Oncol 2010;2:301-7.  Back to cited text no. 5
Tsao AS, Papadimitrakopoulou VA. The future of NSCLC: Molecular profiles guiding treatment decisions. Oncology (Williston Park) 2011;25:607, 614.  Back to cited text no. 6
Kim D, Ahn M, Yang P. Updated results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC) Ann Oncol. 2012;23(suppl 9):ix402.  Back to cited text no. 7
Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:1693-703.  Back to cited text no. 8
Shaw AT, Yeap BY, Solomon BJ. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. The Lancet Oncology. 2011;12:1004-12.  Back to cited text no. 9
Lee SJ, Seol HJ, Lee HW, Kang WY, Kang BG, Jin J, et al. Gene silencing of c-Met leads to brain metastasis inhibitory effects. Clin Exp Metastasis 2013;30:845-54.  Back to cited text no. 10
Crinò L, Kim D, Riely GJ, Janne PA, Blackhall FH, Camidge DR. Initial phase II results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005. J Clin Oncol 29: 2011 (suppl; abstr 7514).  Back to cited text no. 11
Sahoo R, Harini VV, Babu VC, Patil Okaly GV, Rao S, Nargund A, et al. Screening for EGFR mutations in lung cancer, a report from India. Lung Cancer 2011;73:316-9.  Back to cited text no. 12
Chougule A, Prabhash K, Noronha V, Joshi A, Thavamani A, Chandrani P, et al. Frequency of EGFR mutations in 907 lung adenocarcioma patients of Indian ethnicity. PLoS One 2013;8:e76164.  Back to cited text no. 13
Doval DC, Azam S, Batra U, Choudhury KD, Talwar V, Gupta SK, et al. Epidermal growth factor receptor mutation in lung adenocarcinoma in India: A single center study. J Carcinog 2013;12:12.  Back to cited text no. 14
[PUBMED]  [Full text]  
Desai SS, Shah AS, Prabhash K, Jambhekar NA. A year of anaplastic large cell kinase testing for lung carcinoma: Pathological and technical perspectives. Indian J Cancer 2013;50:80-6.  Back to cited text no. 15
  [Full text]  
Doval D, Prabhash K, Patil S, Chaturvedi H, Goswami C, Vaid A, et al. Clinical and epidemiological study of EGFR mutations and EML4-ALK fusion genes among Indian patients with adenocarcinoma of the lung. Onco Targets Ther 2015;8:117-23.  Back to cited text no. 16
Masuya D, Huang C, Liu D, Nakashima T, Kameyama K, Haba R, et al. The tumour-stromal interaction between intratumoral c-Met and stromal hepatocyte growth factor associated with tumour growth and prognosis in non-small-cell lung cancer patients. Br J Cancer 2004;90:1555-62.  Back to cited text no. 17
Nakamura Y, Niki T, Goto A, Morikawa T, Miyazawa K, Nakajima J, et al. c-Met activation in lung adenocarcinoma tissues: An immunohistochemical analysis. Cancer Sci 2007;98:1006-13.  Back to cited text no. 18
Zhao X, Weir BA, LaFramboise T, Lin M, Beroukhim R, Garraway L, et al. Homozygous deletions and chromosome amplifications in human lung carcinomas revealed by single nucleotide polymorphism array analysis. Cancer Res 2005;65:5561-70.  Back to cited text no. 19
Go H, Jeon YK, Park HJ, Sung SW, Seo JW, Chung DH. High MET gene copy number leads to shorter survival in patients with non-small cell lung cancer. J Thorac Oncol 2010;5:305-13.  Back to cited text no. 20
Camidge DR, Ou SH, Shapiro G, Otterson GA, Villaruz LC, Calero MA, et al. Efficacy and safety of crizotinib in patients with advanced c-Met-amplified non-small cell lung cancer (NSCLC). J Clin Oncol 2014;32:506s. [Suppl; Abstr 8001].  Back to cited text no. 21
Waqar SN, Morgensztern D, Sehn J. MET mutation associated with responsiveness to crizotinib. J Thorac Oncol 2015;10:e29-31.  Back to cited text no. 22
Mendenhall MA, Goldman JW. MET-Mutated NSCLC with major response to crizotinib. J Thorac Oncol 2015;10:e33-4.  Back to cited text no. 23
Frampton GM, Ali SM, Rosenzweig M, Chmielecki J, Lu X, Bauer TM, et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov 2015;5:850-9.  Back to cited text no. 24
Paik PK, Drilon A, Fan PD, Yu H, Rekhtman N, Ginsberg MS, et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov 2015;5:842-9.  Back to cited text no. 25
Cappuzzo F, Marchetti A, Skokan M, Rossi E, Gajapathy S, Felicioni L, et al. Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol 2009;27:1667-74.  Back to cited text no. 26
Furge KA, Zhang YW, Vande Woude GF. Met receptor tyrosine kinase: Enhanced signaling through adapter proteins. Oncogene 2000;19:5582-9.  Back to cited text no. 27
Agwa ES, Ma PC. Targeting the MET receptor tyrosine kinase in non-small cell lung cancer: Emerging role of tivantinib. Cancer Manag Res 2014;6:397-404.  Back to cited text no. 28
Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;316:1039-43.  Back to cited text no. 29
Timofeevski SL, McTigue MA, Ryan K, Cui J, Zou HY, Zhu JX, et al. Enzymatic characterization of c-Met receptor tyrosine kinase oncogenic mutants and kinetic studies with aminopyridine and triazolopyrazine inhibitors. Biochemistry 2009;48:5339-49.  Back to cited text no. 30
Ou SH, Kwak EL, Siwak-Tapp C, Dy J, Bergethon K, Clark JW, et al. 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.  Back to cited text no. 31
Schwab R, Petak I, Kollar M, Pinter F, Varkondi E, Kohanka A, et al. Major partial response to crizotinib, a dual MET/ALK inhibitor, in a squamous cell lung (SCC) carcinoma patient with de novo c-MET amplification in the absence of ALK rearrangement. Lung Cancer 2014;83:109-11.  Back to cited text no. 32


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1]


Print this article  Email this article


  Site Map | What's new | Copyright and Disclaimer
  Online since 1st April '07
  © 2007 - Indian Journal of Cancer | Published by Wolters Kluwer - Medknow