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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0b013e31821528d3
Brief Reports

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

Ou, Sai-Hong Ignatius MD, PhD*; Kwak, Eunice L. MD, PhD†; Siwak-Tapp, Christina PhD*; Dy, Joni RN, OCN*; Bergethon, Kristin BA†; Clark, Jeffrey W. MD†; Camidge, D. Ross MD, PhD‡; Solomon, Benjamin J. MBBS, PhD§; Maki, Robert G. MD, PhD∥; Bang, Yung-Jue MD, PhD¶; Kim, Dong-Wan MD, PhD¶; Christensen, James PhD#; Tan, Weiwei PhD#; Wilner, Keith D. PhD#; Salgia, Ravi MD, PhD**; Iafrate, A. John MD, PhD††

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*Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange, California; †Massachusetts General Hospital Cancer Center, Boston, Massachusetts; ‡University of Colorado Cancer Center, Aurora, Colorado; §Peter MacCallum Cancer Center, Melbourne, Australia; ∥Melanoma Sarcoma oncology, Memorial Sloan Kettering Cancer Center, New York City, New York; ¶Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; #Pfizer Global Research and Development, La Jolla, California; **University of Chicago, University of Chicago Medical Center, Chicago, Illinois; and ††Department of Pathology. Massachusetts General Hospital, Boston, Massachusetts.

Disclosure: James Christensen, PhD, Weiwei Tan, PhD, and Keith D. Wilner, PhD, are employees of Pfizer.

Address for correspondence: Sai-Hong Ignatius Ou, MD, PhD, Division of Hematology/Oncology, Department of Internal Medicine, Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, 101 the City Drive, Bldg 56, RT 81, Rm 241, Orange, CA 92868-3298. E-mail:

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Crizotinib is a dual MET and ALK inhibitor. Currently, clinical development of crizotinib is focused primarily on ALK rearranged non-small cell lung cancer (NSCLC). Here we report an NSCLC patient with de novo MET amplification but no ALK rearrangement who achieved a rapid and durable response to crizotinib indicating is also a bona fide MET inhibitor.

Mutations in the mesenchymal-epithelial transition (MET) gene or increases in MET gene copy number have been reported and implicated in the pathogenesis of non-small cell lung cancer (NSCLC).1,2 Recently, MET gene amplification has been identified as one of the acquired secondary resistance mechanisms in patients with activating epidermal growth factor receptor (EGFR) mutations who progress on EGFR tyrosine kinase inhibitors.3,4 Nevertheless, true de novo MET amplification as determined by fluorescence in situ hybridization (FISH) or quantitative polymerase chain reaction is rare in NSCLC.5–11 De novo MET amplification has been associated with poor outcome,5,6,9,12 but its significance as a primary oncogenic driver has never been established in patients with NSCLC. Crizotinib (PF-02341066) has recently emerged as a potent anaplastic lymphoma kinase (ALK) inhibitor; however, it also has significant in vitro MET inhibitory activity (IC50 of 8 nm).13

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Patient is a 77-year-old white female with a 45 pack year of smoking history who quit 20 years ago. In October 2008, after a routine chest x-ray, she was noted to have a mass in the left lung. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)/computed tomography (CT) imaging revealed an FDG-PET-avid 4.0 cm left upper lobe mass, an FDG-PET-avid 1.3 cm right upper lobe mass, and additional FDG-PET uptake in the precarinal, aortopulmonary, and left hilar lymph nodes. CT-guided biopsy of the left upper lobe mass revealed moderately differentiated adenocarcinoma. Complete staging workup revealed that she had stage IV NSCLC and was treated with carboplatin/gemcitabine/bevacizumab combination chemotherapy every 3 weeks for five cycles. She achieved a partial response and was switched to maintenance bevacizumab. In March 2010, she developed a new cough, fatigue, and chest tightness. A repeat 18F-FDG-PET/CT scan revealed evidence of progression with enlarging PET-avid subcarinal and left hilar lymphadenopathy compared with September 2009. Patient then decided to seek access to crizotinib through a clinical trial (A8081001, identifier: NCT00585195).

Her tumor tested negative for ALK rearrangement by break-apart FISH but positive for high-level MET amplification (MET/CEP7 ratio >5.0) (Figure 1), thus meeting the eligibility criteria for enrollment in the MET-enriched molecular cohort of the A8081001 trial (required to have MET mutations or MET amplification) (MET/CEP7 ratio >2.2; not polysomy). The patient started crizotinib 250 mg by mouth twice a day (the recommended phase II dose) in late May 2010. Her symptoms before starting crizotinib included persistent cough, fatigue, and chest tightness. Within a week of starting crizotinib, her cough disappeared and her fatigue decreased. A 18F-FDG-PET/CT scan performed 25 days after starting crizotinib revealed a dramatic 49.3% decrease in SUVmax from baseline (Figures 2A, B) with a corresponding 35.7% decrease in the maximum aggregate tumor measurement by RECIST (version 1.1) (Figures 3A, B). A follow-up 8-week PET/CT revealed continual response to crizotinib with a 67.6% decrease in the SUVmax from baseline with a corresponding 45.2% decrease in tumor measurement by RECIST (version 1.1). She achieved maximum reduction in aggregate tumor measurement of 54.8% on September 2010, and she continues on study with partial response. The only side effect attributed to crizotinib experienced by the patient was asymptomatic grade 1 sinus bradycardia and transient grade 1 visual disturbances characterized by intermittent flashing lights in the peripheral visual fields. Follow-up visual acuity and slit-lamp examination revealed no specific retinal abnormality.

Figure 1
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Figure 2
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Figure 3
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Criteria Determining MET Amplification in A8081001 Trial

The MET copy number was determined by laboratory-developed test using a bacterial artificial chromosome probe containing MET sequence (CTB-13N12) labeled in SpectrumOrange and a commercial centromere 7 probe (Vysis/Abbott Molecular, IL) labeled in SpectrumGreen. Five-micron sections of formalin-fixed paraffin-embedded tumor material were prepared and an hematoxylin and eosin section reviewed to select regions for hybridization that contained a majority of tumor cells. For each specimen, individual cell MET and CEP7 signals were analyzed in a total of 50 tumor cells. FISH-positive groups include (1) high-level amplification (presence of loose or tight clusters of MET signals too numerous to count) or a MET/CEP7 ratio more than 5.0 and (2) low-level amplification (tumors with MET/CEP7 ratio ≥2.2 and ≤5.0).

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This is the first report of rapid and durable clinical response with single-agent crizotinib in a NSCLC patient with de novo MET amplification. Furthermore, given this patient was negative for ALK rearrangement, the beneficial clinical effect observed in this patient can likely be attributed to crizotinib's MET inhibitory property.13 The rapid and significant clinical response to crizotinib in this patient with NSCLC with de novo MET amplification mirrored what has been described for crizotinib's activity in patients with NSCLC with ALK rearrangement14,15 and strongly suggests that de novo MET amplification in NSCLC is likely a primary oncogenic driver in some NSCLC and is a valid clinical target. Matsubara et al.16 have shown that MET amplification alone is a strong predictor of sensitivity to another MET inhibitor (PHA665752) in NSCLC cell lines.

Going forward, two major challenges exist in exploring the clinical activity of MET inhibitors in patients with NSCLC with de novo MET amplification. First, the clinicopathologic profile of these patients remains largely unknown. Review of the literature suggests that in NSCLC, de novo MET amplification is not specific to any given gender, age group, histologic subtype, smoking status, or ethnicity.6,7,10,12 As the screening result from A8081001 demonstrates, de novo MET amplification in NSCLC is rare.3,5,6–11 As of July 25, 2010, we have identified only two patients with NSCLC with de novo MET amplification out of 94 patients with NSCLC who had enrolled onto the screening portion of A8081001 and who had adequate tumor tissue to be successfully screened simultaneously for MET amplification and ALK rearrangement at University of California Irvine. The other patient with MET amplified (MET/CEP7 ratio 2.5) NSCLC was a male white never smoker who presented with stage IIIB squamous cell carcinoma and who has not started treatment with crizotinib due to response to initial chemoradiation treatment. For comparison purpose, 15 patients with ALK-positive NSCLC were identified from the same 94 patients with NSCLC who were screened. Similarly, University of Colorado screened 66 patients with NSCLC (from June 2008 to October 2009) for both ALK rearrangement and de novo MET amplification. No patient was positive for MET amplification, whereas 13 patients were positive for ALK rearrangement.11 Granted the strategy used by many A8081001 investigators to screen mostly never smokers with adenocarcinoma may have skewed the chance of finding more patients with de novo MET amplification.

Second, guidelines need to be established to define MET amplification positivity similar to the guidelines established for EGFR amplification in NSCLC.17 Different studies have used different methods and criteria to detect and define MET amplification (Table 1). A recent retrospective subgroup analysis of a randomized phase II trial in unselected, EGFR tyrosine kinase inhibitor-naive patients with NSCLC, progression-free survival seemed to be most improved in patients with more than five MET copies by FISH when a MET inhibitor was combined with erlotinib compared with erlotinib alone.18 This current report provides further evidence that high-level MET amplification (MET/CEP7 ratio >5) is a good criterion to select a cohort of patients with molecularly enriched NSCLC for MET inhibitors in clinical trials. The significance of low MET amplification or MET high polysomy as a predictive marker of response to crizotinib or other MET inhibitors remains to be determined. One patient with NSCLC with high MET polysomy (mean MET copy number per cell, 9.02) but negative for ALK rearrangement or de novo MET amplification (MET/CEP7 ratio 1.14, 50 nuclei scored) was treated at University of California Irvine but experienced disease progression after two cycles (6 weeks) of crizotinib treatment (unpublished data). A recent clinical trial has demonstrated using immunohistochemistry (IHC) to stratify for MET protein expression level is another potential valid method to predict clinical response to a monoclonal antibody against MET in combination with erlotinib.19 The degree of concordance between IHC and FISH MET positivity and whether IHC will eventually be the preferred method for screening for MET amplification as it is less technically challenging and more cost-effective warrants further investigations.

Table 1
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Supported by (A8081001, identifier NCT00585195) Pfizer, Inc. Ravi Salgia, MD, PhD, is supported by grant 5RO1CA125541-05.

The authors thank Gina-Lee Emory for her assistance in managing this clinical trial.

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1. Cipriani NA, Abidoye OO, Vokes E, et al. MET as a target for treatment of chest tumors. Lung Cancer 2009;63:169–179.

2. Toschi L, Cappuzzo F. Clinical implications of MET gene copy number in lung cancer. Future Oncol 2010;6:239–247.

3. Bean J, Brennan C, Shin J-Y, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA 2007;104:20932–20937.

4. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer activating ERBB3 signaling. Science 2007;316:1039–1043.

5. Okuda K, Sasaki H, Yukiue H, et al. Met gene copy number predicts the prognosis for completely resected non-small cell lung cancer. Cancer Sci 2008;99:2280–2285.

6. Cappuzzo F, Marchetti A, Skokan M, et al. Increased MET gene copy number negatively affects survival of surgically resected non-small cell lung cancer patients. J Clin Oncol 2009;27:1667–1674.

7. Kubo T, Yamato H, Lockwood WW, et al. MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitors. Int J Cancer 2009;124:1778–1784.

8. Onozato R, Kosaka T, Kuwano H, et al. Activation of MET by gene amplification or by splice mutations deleting the juxtamembrance domain in primary resected lung cancers. J Thorac Oncol 2009;4:5–11.

9. Go H, Jeon YK, Park HJ, et al. High MET gene copy number leads to shorter survival in patients with non-small cell lung cancer. J Thorac Oncol 2010;5:305–313.

10. Onitsuka T, Uramoto H, Ono K, et al. Comprehensive molecular analyses of lung adenocarcinoma with regard to epidermal growth factor receptor, K-ras, MET, and hepatocyte growth factor status. J Thorac Oncol 2010;5:591–596.

11. Camidge DR, Kono SA, Flacco A, et al. Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment. Clin Cancer Res 2010;16:5581–5590.

12. Beau-Faller M, Ruppert A-M, Voegeli A-C, et al. MET copy number is in non-small cell lung cancer: molecular analysis in a tyrosine kinase inhibitor naive cohort. J Thorac Oncol 2008;3:331–339.

13. Zou HY, Li Q, Lee JH, et al. An orally available small-molecule inhibitor of c-MET, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res 2007;67:4408–4417.

14. Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:1693–1703.

15. Ou S-HI, Bazhenova L, Camidge DR, et al. Rapid and dramatic radiographic and clinical response to an ALK inhibitor (Crizotinib, PF02341066) in an ALK translocation-positive patient with non-small cell lung cancer. J Thorac Oncol 2010;5:2044–2046.

16. Matsubara D, Ishikawa S, Oguni S, et al. Molecular predictors of sensitivity to the MET inhibitor PHA665752 in lung carcinoma cells. J Thorac Oncol 2010;5:1317–1324.

17. Varella-Garcia M, Diebold J, Eberhard DA, et al. EGFR fluorescence in situ hybridization assay: guidelines for application to non-small-cell lung cancer. J Clin Pathol 2009;62:970–977.

18. Schiller JH, Akerley WL, Brugger W, et al. Results from ARQ 197–209: A global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naive patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 2010;28(18s):abstract LBA 7502.

19. Spigel D, Ervin T, Ramlau R, et al. Randomized phase multicenter double-blind placebo-controlled phase II study evaluating metmab, an antibody to MET receptor, in combination with erlotinib, in patients with advanced non-small-cell lung cancer. Ann Oncol 2010;21(Suppl 8):viii7 (LBA 15).

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Non-small cell lung cancer; De novo MET amplification NSCLC; 18F-FDG PET/CT; Crizotinib (PF02341066); MET polysomy; Anaplastic lymphoma kinase (ALK) re-arranged NSCLC

© 2011International Association for the Study of Lung Cancer


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