Lung Cancer 83 (2014) 109–111
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Case report
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 Richard Schwab a , Istvan Petak a,b,∗ , Mihaly Kollar a , Ferenc Pinter a , Edit Varkondi a , Andrea Kohanka a , Helga Barti-Juhasz a , Julia Schönleber c , Diana Brauswetter b , Laszlo Kopper d , Laszlo Urban e a
KPS Medical Biotechnology and Healthcare Services Ltd., Budapest, Hungary Hungarian Academy of Sciences, Pathobiochemistry Research Group, Budapest, Hungary c Semmelweis University, Ist Department of Gynecology, Budapest, Hungary d Semmelweis University, Ist Institute of Pathology and Experimental Cancer Research, Budapest, Hungary e Matrahaza Healthcare Center and University Teaching Hospital, Matrahaza, Hungary b
a r t i c l e
i n f o
Article history: Received 2 July 2013 Received in revised form 4 October 2013 Accepted 8 October 2013 Keywords: c-MET Crizotinib Squamous cell lung cancer Non-small cell lung cancer Targeted therapy Predictive biomarker Receptor tyrosine kinase Personalized medicine Pharmacogenomics
a b s t r a c t The initial radiotherapy of a 73 years old Caucasian male patient with advanced squamous cell lung carcinoma was terminated due to severe pericarditis. Subsequently, the tumor sample was analyzed for possible targets with comprehensive molecular diagnostics. EGFR, KRAS and PIK3CA genes were wild type, ALK and ROS1 were negative for rearrangement, but c-MET was amplified by fluorescent in situ hybridization. The kinase inhibitor crizotinib is already in clinical use for the treatment of ALK positive non-small cell lung cancers, but it is also known to be a potent c-MET inhibitor. The patient was treated with the standard dose of twice a day 250 mg crizotinib as a monotherapy. Major partial response to therapy was confirmed by chest CT and PET/CT after 8 weeks on therapy. C-MET expression is associated with poor prognosis and resistance to EGFR inhibitors. This case may indicate that c-MET tyrosine kinase inhibitors can be an effective targeted treatment option for squamous cell carcinoma patients, and future clinical trials should be expanded for this patient group as well. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
2. Case report
Crizotinib is a dual tyrosine kinase inhibitor of ALK and c-MET kinases [1]. Rapid clinical development and fast track registration of crizotinib has been based on the high response rate of lung adenocarcinomas with ALK rearrangement [2]. Here we report the successful treatment with crizotinib of a non-small cell lung carcinoma patient with squamous cell histology, which was negative for ALK rearrangement but had amplification of c-MET oncogene.
The 73 years old Caucasian male patient was diagnosed with the central stage IV lung cancer by PET-CT in the March of 2012 (Fig. 1A). Bronchoscopy confirmed the tumor and the histological evaluation of the biopsy indicated squamous cell lung cancer. The patient received one local irradiation (20 Gy), which was followed within two weeks by pericarditis and cardiac tamponed, which required surgical intervention. The patient refused chemotherapy. The tissue sample of a pretreatment biopsy taken with bronchoscopy was analyzed extensively to identify potential molecular targets of targeted therapies. DNA extracted from the specimen was used for DNA sequencing. Exons 19 and 21 of EGFR, exon 2 of KRAS and exons 9 and 20 of PIK3CA were PCR amplified and directly sequenced. All exons were wild types. For fluorescent in situ hybridization (FISH) analysis of MET gene copy number, C-MET (Kreatech) and ALK break apart and ALK/AML4 (Kreatech), ROS1 (ZytoLight) break apart probes were hybridized on sections from paraffin-embedded tissue of the
∗ Corresponding author at: KPS Medical Biotechnology and Healthcare Services Ltd., 34 Retek, 1024, Budapest, Hungary. Tel.: +36 70 967 10 32; fax: +36 1 700 1720; mobile: +36 30 541 10 63. E-mail address: [email protected] (I. Petak). 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.10.006
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R. Schwab et al. / Lung Cancer 83 (2014) 109–111
Fig. 1. PET-CT scan of the chest before crizotinib treatment (A) and after treatment (B).
primary NSCLC as described previously. Analysis of the number of c-MET and control probes demonstrated the intra-chromosomal amplification of the c-MET gene, while break-apart of the ALK probe was not observed. The cut-off for MET amplification (MET/CEN7) was 2.2. Two months after the cessation of radiotherapy – after obtaining the informed consent of the patient and approval by the national drug authority – the patient was treated with crizotinib monotherapy at the normal dose of two times 250 mg. Almost complete response of tumors in the left lung and major response in the central tumor to therapy was confirmed by chest CT and PET/CT after 8 weeks on therapy (Fig. 1B). The paralysis of the left diaphragm ceased. The general condition of the patient improved, coughing was diminished and patient even returned to work as an ER doctor. Three weeks later pneumonia and pneumonitis developed and the hemoculture, revealed MRSA+ sepsis, had high temperature, which was not controllable and the patient died. During the MRSA pneumonia the absolute neutrophil count was in the normal range. Autopsy confirmed all original diagnosis.
3. Discussion This is the first report of clinical response to crizotinib in cMET positive squamous cell lung carcinoma. Previously, similar responses to crizotinib have been reported in case reports of c-MET copy number gain positive lung adenocarcinoma [3], glioblastoma [4], gastric cancer [5], and esophageal cancer [6]. These clinical observations are in line with previous preclinical investigations, which found increased sensitivity of cancer cells with c-MET amplification to small molecule tyrosine kinase inhibitors due to ligand independent activation auto-activation of c-MET [7]. The frequency of c-MET amplification has been reported to be between 3.9% and 21% of squamous cell lung carcinoma cases [8–10]. High c-MET copy number has been found to be associated with worse prognosis and shorter survival [6,10]. De novo c-MET amplification was found to be mutually exclusive with KRAS and HER-2 mutations, but frequently concomitant with EGFR amplification [9,11]. No c-MET amplification was found in case of ALK translocation [12]. Secondary c-MET amplification has been identified as an important mechanism of EGFR inhibitor resistance of EGFR mutant lung adenocarcinomas [13]. PIK3CA mutations may lead to the c-MET independent activation of the AKT/mTOR pathway, and has been found to be a negative predictive biomarker of receptor tyrosine kinase inhibitors, but on the other hand PI3K pathway is an attractive target for novel targeted therapies [14]. In summary, the case report is another example of targetderived decision in the treatment of lung cancer similarly to the previous report on the treatment of a ROS1 positive patient with
crizotinib [15]. C-MET amplification may define a subset of cancers in which c-MET is the major driver oncogene. The ligand independent activation of c-MET in these tumors may lead to higher sensitivity to tyrosine kinase inhibitors (TKI). Although, we cannot completely rule out that this tumor had mixed pathology of adenocarcinoma and squamous carcinoma, but the biopsy we analyzed by FISH was confirmed to be squamous cell carcinoma by two independent pathologists. Thus, clinical trials with c-MET-TKI are warranted in c-MET amplified cancers including squamous cell lung cancer. Conflict of interest None declared. Acknowledgements This work was supported by grants OTKA-T046665NKFP 07 A2NANODRUG OM-00080/2008, TECH 08 A2-STEMKILL OM-00107/2008 References [1] Gandhi L, Jänne PA. Crizotinib for ALK-rearranged non-small cell lung cancer: a new targeted therapy for a new target. Clin Cancer Res 2012;15(18(14)):3737–42. [2] Shaw AT, Solomon B, Kenudson MM. Crizotinib and testing for ALK. J Natl Compr Canc Netw 2011;9(12):1335–41. [3] 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(May (5)): 942–6. [4] Chi AS, Batchelor TT, Kwak EL, Clark JW, Wang DL, Wilner KD, et al. Rapid radiographic and clinical improvement after treatment of a MET-amplified recurrent glioblastoma with a mesenchymal-epithelial transition inhibitor. J Clin Oncol 2012;30(January 20 (3)):e30–3. [5] Okamoto W, Okamoto I, Arao T, Kuwata K, Hatashita E, Yamaguchi H, et al. Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification. Mol Cancer Ther 2012;11(July (7)):1557–64. [6] Lennerz JK, Kwak EL, Ackerman A, Michael M, Fox SB, Bergethon K, et al. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J Clin Oncol 2011;29(December 20 (36)):4803–10. [7] Smolen GA, Sordella R, Muir B, Mohapatra G, Barmettler A, Archibald H, et al. Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proc Natl Acad Sci U S A 2006;103(February 14 (7)):2316–21. [8] Chen YT, Chang JW, Liu HP, Yu TF, Chiu YT, Hsieh JJ, et al. Clinical implications of high MET gene dosage in non-small cell lung cancer patients without previous tyrosine kinase inhibitor treatment. Thorac Oncol 2011;6(December (12)):2027–35. [9] Beau-Faller M, Ruppert AM, Voegeli AC, Neuville A, Meyer N, Guerin E, et al. MET gene copy number in non-small cell lung cancer: molecular analysis in a targeted tyrosine kinase inhibitor naïve cohort. J Thorac Oncol 2008;3(April (4)):331–9.
R. Schwab et al. / Lung Cancer 83 (2014) 109–111 [10] 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(March (3)):305–13. [11] Onozato R, Kosaka T, Kuwano H, Sekido Y, Yatabe Y, Mitsudomi T. Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary resected lung cancers. J Thorac Oncol 2009;4(January (1)):5–11. [12] Boland JM, Jang JS, Li J, Lee AM, Wampfler JA, Erickson-Johnson MR, et al. MET and EGFR Mutations Identified in ALK-rearranged pulmonary adenocarcinoma: molecular analysis of 25 ALK-positive cases. J Thorac Oncol 2013;8(May (5)):574–81.
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[13] 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(May 18 (5827)):1039–43. [14] Petak I, Schwab R, Orfi L, Kopper L, Keri G. Integrating molecular diagnostics into anticancer drug discovery. Nat Rev Drug Discov 2010;9(July (7)): 523–35. [15] Bos M, Gardizi M, Schildhaus HU, Heukamp LC, Geist T, Kaminsky B, et al. Complete metabolic response in a patient with repeatedly relapsed non-small cell lung cancer harboring ROS1 gene rearrangement after treatment with crizotinib. Lung Cancer 2013;81(July (1)):142–3.
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Case report
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 Richard Schwab a , Istvan Petak a,b,∗ , Mihaly Kollar a , Ferenc Pinter a , Edit Varkondi a , Andrea Kohanka a , Helga Barti-Juhasz a , Julia Schönleber c , Diana Brauswetter b , Laszlo Kopper d , Laszlo Urban e a
KPS Medical Biotechnology and Healthcare Services Ltd., Budapest, Hungary Hungarian Academy of Sciences, Pathobiochemistry Research Group, Budapest, Hungary c Semmelweis University, Ist Department of Gynecology, Budapest, Hungary d Semmelweis University, Ist Institute of Pathology and Experimental Cancer Research, Budapest, Hungary e Matrahaza Healthcare Center and University Teaching Hospital, Matrahaza, Hungary b
a r t i c l e
i n f o
Article history: Received 2 July 2013 Received in revised form 4 October 2013 Accepted 8 October 2013 Keywords: c-MET Crizotinib Squamous cell lung cancer Non-small cell lung cancer Targeted therapy Predictive biomarker Receptor tyrosine kinase Personalized medicine Pharmacogenomics
a b s t r a c t The initial radiotherapy of a 73 years old Caucasian male patient with advanced squamous cell lung carcinoma was terminated due to severe pericarditis. Subsequently, the tumor sample was analyzed for possible targets with comprehensive molecular diagnostics. EGFR, KRAS and PIK3CA genes were wild type, ALK and ROS1 were negative for rearrangement, but c-MET was amplified by fluorescent in situ hybridization. The kinase inhibitor crizotinib is already in clinical use for the treatment of ALK positive non-small cell lung cancers, but it is also known to be a potent c-MET inhibitor. The patient was treated with the standard dose of twice a day 250 mg crizotinib as a monotherapy. Major partial response to therapy was confirmed by chest CT and PET/CT after 8 weeks on therapy. C-MET expression is associated with poor prognosis and resistance to EGFR inhibitors. This case may indicate that c-MET tyrosine kinase inhibitors can be an effective targeted treatment option for squamous cell carcinoma patients, and future clinical trials should be expanded for this patient group as well. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
2. Case report
Crizotinib is a dual tyrosine kinase inhibitor of ALK and c-MET kinases [1]. Rapid clinical development and fast track registration of crizotinib has been based on the high response rate of lung adenocarcinomas with ALK rearrangement [2]. Here we report the successful treatment with crizotinib of a non-small cell lung carcinoma patient with squamous cell histology, which was negative for ALK rearrangement but had amplification of c-MET oncogene.
The 73 years old Caucasian male patient was diagnosed with the central stage IV lung cancer by PET-CT in the March of 2012 (Fig. 1A). Bronchoscopy confirmed the tumor and the histological evaluation of the biopsy indicated squamous cell lung cancer. The patient received one local irradiation (20 Gy), which was followed within two weeks by pericarditis and cardiac tamponed, which required surgical intervention. The patient refused chemotherapy. The tissue sample of a pretreatment biopsy taken with bronchoscopy was analyzed extensively to identify potential molecular targets of targeted therapies. DNA extracted from the specimen was used for DNA sequencing. Exons 19 and 21 of EGFR, exon 2 of KRAS and exons 9 and 20 of PIK3CA were PCR amplified and directly sequenced. All exons were wild types. For fluorescent in situ hybridization (FISH) analysis of MET gene copy number, C-MET (Kreatech) and ALK break apart and ALK/AML4 (Kreatech), ROS1 (ZytoLight) break apart probes were hybridized on sections from paraffin-embedded tissue of the
∗ Corresponding author at: KPS Medical Biotechnology and Healthcare Services Ltd., 34 Retek, 1024, Budapest, Hungary. Tel.: +36 70 967 10 32; fax: +36 1 700 1720; mobile: +36 30 541 10 63. E-mail address: [email protected] (I. Petak). 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.10.006
110
R. Schwab et al. / Lung Cancer 83 (2014) 109–111
Fig. 1. PET-CT scan of the chest before crizotinib treatment (A) and after treatment (B).
primary NSCLC as described previously. Analysis of the number of c-MET and control probes demonstrated the intra-chromosomal amplification of the c-MET gene, while break-apart of the ALK probe was not observed. The cut-off for MET amplification (MET/CEN7) was 2.2. Two months after the cessation of radiotherapy – after obtaining the informed consent of the patient and approval by the national drug authority – the patient was treated with crizotinib monotherapy at the normal dose of two times 250 mg. Almost complete response of tumors in the left lung and major response in the central tumor to therapy was confirmed by chest CT and PET/CT after 8 weeks on therapy (Fig. 1B). The paralysis of the left diaphragm ceased. The general condition of the patient improved, coughing was diminished and patient even returned to work as an ER doctor. Three weeks later pneumonia and pneumonitis developed and the hemoculture, revealed MRSA+ sepsis, had high temperature, which was not controllable and the patient died. During the MRSA pneumonia the absolute neutrophil count was in the normal range. Autopsy confirmed all original diagnosis.
3. Discussion This is the first report of clinical response to crizotinib in cMET positive squamous cell lung carcinoma. Previously, similar responses to crizotinib have been reported in case reports of c-MET copy number gain positive lung adenocarcinoma [3], glioblastoma [4], gastric cancer [5], and esophageal cancer [6]. These clinical observations are in line with previous preclinical investigations, which found increased sensitivity of cancer cells with c-MET amplification to small molecule tyrosine kinase inhibitors due to ligand independent activation auto-activation of c-MET [7]. The frequency of c-MET amplification has been reported to be between 3.9% and 21% of squamous cell lung carcinoma cases [8–10]. High c-MET copy number has been found to be associated with worse prognosis and shorter survival [6,10]. De novo c-MET amplification was found to be mutually exclusive with KRAS and HER-2 mutations, but frequently concomitant with EGFR amplification [9,11]. No c-MET amplification was found in case of ALK translocation [12]. Secondary c-MET amplification has been identified as an important mechanism of EGFR inhibitor resistance of EGFR mutant lung adenocarcinomas [13]. PIK3CA mutations may lead to the c-MET independent activation of the AKT/mTOR pathway, and has been found to be a negative predictive biomarker of receptor tyrosine kinase inhibitors, but on the other hand PI3K pathway is an attractive target for novel targeted therapies [14]. In summary, the case report is another example of targetderived decision in the treatment of lung cancer similarly to the previous report on the treatment of a ROS1 positive patient with
crizotinib [15]. C-MET amplification may define a subset of cancers in which c-MET is the major driver oncogene. The ligand independent activation of c-MET in these tumors may lead to higher sensitivity to tyrosine kinase inhibitors (TKI). Although, we cannot completely rule out that this tumor had mixed pathology of adenocarcinoma and squamous carcinoma, but the biopsy we analyzed by FISH was confirmed to be squamous cell carcinoma by two independent pathologists. Thus, clinical trials with c-MET-TKI are warranted in c-MET amplified cancers including squamous cell lung cancer. Conflict of interest None declared. Acknowledgements This work was supported by grants OTKA-T046665NKFP 07 A2NANODRUG OM-00080/2008, TECH 08 A2-STEMKILL OM-00107/2008 References [1] Gandhi L, Jänne PA. Crizotinib for ALK-rearranged non-small cell lung cancer: a new targeted therapy for a new target. Clin Cancer Res 2012;15(18(14)):3737–42. [2] Shaw AT, Solomon B, Kenudson MM. Crizotinib and testing for ALK. J Natl Compr Canc Netw 2011;9(12):1335–41. [3] 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(May (5)): 942–6. [4] Chi AS, Batchelor TT, Kwak EL, Clark JW, Wang DL, Wilner KD, et al. Rapid radiographic and clinical improvement after treatment of a MET-amplified recurrent glioblastoma with a mesenchymal-epithelial transition inhibitor. J Clin Oncol 2012;30(January 20 (3)):e30–3. [5] Okamoto W, Okamoto I, Arao T, Kuwata K, Hatashita E, Yamaguchi H, et al. Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification. Mol Cancer Ther 2012;11(July (7)):1557–64. [6] Lennerz JK, Kwak EL, Ackerman A, Michael M, Fox SB, Bergethon K, et al. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J Clin Oncol 2011;29(December 20 (36)):4803–10. [7] Smolen GA, Sordella R, Muir B, Mohapatra G, Barmettler A, Archibald H, et al. Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proc Natl Acad Sci U S A 2006;103(February 14 (7)):2316–21. [8] Chen YT, Chang JW, Liu HP, Yu TF, Chiu YT, Hsieh JJ, et al. Clinical implications of high MET gene dosage in non-small cell lung cancer patients without previous tyrosine kinase inhibitor treatment. Thorac Oncol 2011;6(December (12)):2027–35. [9] Beau-Faller M, Ruppert AM, Voegeli AC, Neuville A, Meyer N, Guerin E, et al. MET gene copy number in non-small cell lung cancer: molecular analysis in a targeted tyrosine kinase inhibitor naïve cohort. J Thorac Oncol 2008;3(April (4)):331–9.
R. Schwab et al. / Lung Cancer 83 (2014) 109–111 [10] 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(March (3)):305–13. [11] Onozato R, Kosaka T, Kuwano H, Sekido Y, Yatabe Y, Mitsudomi T. Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary resected lung cancers. J Thorac Oncol 2009;4(January (1)):5–11. [12] Boland JM, Jang JS, Li J, Lee AM, Wampfler JA, Erickson-Johnson MR, et al. MET and EGFR Mutations Identified in ALK-rearranged pulmonary adenocarcinoma: molecular analysis of 25 ALK-positive cases. J Thorac Oncol 2013;8(May (5)):574–81.
111
[13] 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(May 18 (5827)):1039–43. [14] Petak I, Schwab R, Orfi L, Kopper L, Keri G. Integrating molecular diagnostics into anticancer drug discovery. Nat Rev Drug Discov 2010;9(July (7)): 523–35. [15] Bos M, Gardizi M, Schildhaus HU, Heukamp LC, Geist T, Kaminsky B, et al. Complete metabolic response in a patient with repeatedly relapsed non-small cell lung cancer harboring ROS1 gene rearrangement after treatment with crizotinib. Lung Cancer 2013;81(July (1)):142–3.
