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Management of Non-small Cell Lung Cancer Patients with MET Exon 14 Skipping Mutations

  • Lung Cancer (HA Wakelee and TA Leal, Section Editors)
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Opinion statement

The MET exon 14 skipping mutation is found in approximately 3% of lung adenocarcinomas and slightly more than 2% of lung squamous cell carcinomas. In recent years, more and more evidence has shown that MET inhibitors have achieved good anti-tumor effect in patients with MET exon 14 skipping mutation, suggesting that MET exon 14 skipping mutation may be a new target for NSCLC patients. Patients with positive MET exon 14 skipping mutation are recommended to be administered MET inhibitors, and crizotinib is recommended by the NCCN guideline. Due to the presence of gene amplification, second site mutation, bypass activation, and pathological type transformation, one of the inevitable problems of targeted therapy is drug resistance. If type I MET inhibitors (crizotinib, capmatinib, tepotinib, savolitinib) drug resistance is developed, type II MET inhibitors (cabozantinib, glesatinib, merestinib) can be considered.

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  1. Organ SL, Tsao MS. An overview of the c-MET signaling pathway. Ther Adv Med Oncol. 2011;3(1 Suppl):S7–19. https://doi.org/10.1177/1758834011422556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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(1):5–11. https://doi.org/10.1097/JTO.0b013e3181913e0e.

    Article  PubMed  Google Scholar 

  3. Drilon A, Cappuzzo F, Ou SI, Camidge DR. Targeting MET in lung cancer: will expectations finally be MET? J Thorac Oncol. 2017;12(1):15–26. https://doi.org/10.1016/j.jtho.2016.10.014.

    Article  PubMed  Google Scholar 

  4. Ma PC, Jagadeeswaran R, Jagadeesh S, Tretiakova MS, Nallasura V, Fox EA, et al. Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer. Cancer Res. 2005;65(4):1479–88. https://doi.org/10.1158/0008-5472.CAN-04-2650.

    Article  CAS  PubMed  Google Scholar 

  5. The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543–50. https://doi.org/10.1038/nature13385.

    Article  CAS  PubMed Central  Google Scholar 

  6. 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(8):842–9. https://doi.org/10.1158/2159-8290.CD-14-1467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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(8):850–9. https://doi.org/10.1158/2159-8290.CD-15-0285.

    Article  CAS  PubMed  Google Scholar 

  8. Liu X, Jia Y, Stoopler MB, Shen Y, Cheng H, Chen J, et al. Next-generation sequencing of pulmonary sarcomatoid carcinoma reveals high frequency of actionable MET gene mutations. J Clin Oncol. 2016;34(8):794–802. https://doi.org/10.1200/JCO.2015.62.0674.

    Article  CAS  PubMed  Google Scholar 

  9. Awad MM, Oxnard GR, Jackman DM, Savukoski DO, Hall D, Shivdasani P, et al. MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression. J Clin Oncol. 2016;34(7):721–30. https://doi.org/10.1200/JCO.2015.63.4600.

    Article  CAS  PubMed  Google Scholar 

  10. Tong JH, Yeung SF, Chan AWH, Chung LY, Chau SL, Lung RWM, et al. MET amplification and exon 14 splice site mutation define unique molecular subgroups of non-small cell lung carcinoma with poor prognosis. Clin Cancer Res. 2016;22(12):3048–56. https://doi.org/10.1158/1078-0432.CCR-15-2061.

  11. Saito M, Shiraishi K, Kunitoh H, Takenoshita S, Yokota J, Kohno T. Gene aberrations for precision medicine against lung adenocarcinoma. Cancer Sci. 2016;107(6):713–20. https://doi.org/10.1111/cas.12941.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zheng D, Wang R, Ye T, Yu S, Hu H, Shen X, et al. MET exon 14 skipping defines a unique molecular class of non-small cell lung cancer. Oncotarget. 2016;7(27):41691. https://doi.org/10.18632/oncotarget.9541.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Liu S, Gou L, Li A, Lou N, Gao H, Su J, et al. The unique characteristics of MET exon 14 mutation in Chinese patients with NSCLC. J Thorac Oncol. 2016;11(9):1503–10. https://doi.org/10.1016/j.jtho.2016.05.016.

    Article  PubMed  Google Scholar 

  14. Schrock AB, Frampton GM, Suh J, et al. Characterization of 298 lung cancer patients harboring MET exon 14 skipping (METex14) alterations. J Thorac Oncol. 2016;11(9):1493–502. https://doi.org/10.1016/j.jtho.2016.06.004.

    Article  PubMed  Google Scholar 

  15. Lee GD, Lee SE, Oh DY, et al. MET exon 14 skipping mutations in lung adenocarcinoma: clinicopathologic implications and prognostic values. J Thorac Oncol. 2017;12(8):1233–46. https://doi.org/10.1016/j.jtho.2017.04.031.

    Article  PubMed  Google Scholar 

  16. Kwon D, Koh J, Kim S, et al. MET exon 14 skipping mutation in triple-negative pulmonary adenocarcinomas and pleomorphic carcinomas: an analysis of intratumoral MET status heterogeneity and clinicopathological characteristics. Lung Cancer. 2017;106:131–7. https://doi.org/10.1016/j.lungcan.2017.02.008.

    Article  PubMed  Google Scholar 

  17. Saffroy R, Fallet V, Girard N, Mazieres J, Sibilot DM, Lantuejoul S, et al. MET exon 14 mutations as targets in routine molecular analysis of primary sarcomatoid carcinoma of the lung. Oncotarget. 2017;8(26):42428. https://doi.org/10.18632/oncotarget.16403.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Gow C, Hsieh M, Wu S, Shih J. A comprehensive analysis of clinical outcomes in lung cancer patients harboring a MET exon 14 skipping mutation compared to other driver mutations in an East Asian population. Lung Cancer. 2017;103:82–9. https://doi.org/10.1016/j.lungcan.2016.12.001.

    Article  PubMed  Google Scholar 

  19. Qiu T, Li W, Zhang T, Xing P, Huang W, Wang B, et al. Distinct MET protein localization associated with MET exon 14 mutation types in patients with non-small cell lung cancer. Clin Lung Cancer. 2018;19(4):e391–8. https://doi.org/10.1016/j.cllc.2017.12.006.

    Article  CAS  PubMed  Google Scholar 

  20. Yu Y, Zhang Q, Zhang J, Lu S. Prevalence of MET exon 14 skipping mutation in pulmonary sarcomatoid carcinoma patients without common targetable mutations: a single-institute study. J Cancer Res Ther. 2019;15(4):909–13. https://doi.org/10.4103/jcrt.JCRT_591_18.

    Article  PubMed  Google Scholar 

  21. Gherardi E, Birchmeier W, Birchmeier C, Woude GV. Targeting MET in cancer: rationale and progress. Nat Rev Cancer. 2012;12(2):89–103. https://doi.org/10.1038/nrc3205.

    Article  CAS  PubMed  Google Scholar 

  22. Reungwetwattana T, Liang Y, Zhu V, Ou SI. The race to target MET exon 14 skipping alterations in non-small cell lung cancer: the why, the how, the who, the unknown, and the inevitable. Lung Cancer. 2017;103:27–37. https://doi.org/10.1016/j.lungcan.2016.11.011.

    Article  PubMed  Google Scholar 

  23. Malik SM, Maher VE, Bijwaard KE, Becker RL, Zhang L, Tang SW, et al. U.S. Food and Drug Administration approval: crizotinib for treatment of advanced or metastatic non-small cell lung cancer that is anaplastic lymphoma kinase positive. Clin Cancer Res. 2014;20(8):2029–34. https://doi.org/10.1158/1078-0432.CCR-13-3077.

    Article  CAS  PubMed  Google Scholar 

  24. Kazandjian D, Blumenthal GM, Luo L, He K, Fran I, Lemery S, et al. Benefit-risk summary of crizotinib for the treatment of patients with ROS1 alteration-positive, metastatic non-small cell lung cancer. Oncologist. 2016;21(8):974–80. https://doi.org/10.1634/theoncologist.2016-0101.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Drilon A, Camidge DR, Ou SI, et al. Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC). J Clin Oncol. 2016;34(15):108. https://doi.org/10.1200/JCO.2016.34.15_suppl.108.

    Article  Google Scholar 

  26. ClinicalTrials.gov. Available from: https://clinicaltrials.gov/. Accessed November 2019.

  27. Rotow JK, Woodard GA, Urisman A, McCoach CE, Bivona TG, Elicker BM, et al. Pathologic complete response to neoadjuvant crizotinib in a lung adenocarcinoma patient with a MET exon 14 skipping mutation. Clin Lung Cancer. 2019;20(2):e137–41. https://doi.org/10.1016/j.cllc.2018.11.003.

    Article  PubMed  Google Scholar 

  28. Baltschukat S, Engstler BS, Huang A, Hao H, Tam A, Wang HQ, et al. Capmatinib (INC280) Is Active against models of non-small cell lung cancer and other cancer types with defined mechanisms of MET activation. Clin Cancer Res. 2019;25(10):3164–75. https://doi.org/10.1158/1078-0432.CCR-18-2814.

    Article  CAS  PubMed  Google Scholar 

  29. Wolf J, Seto T, Han J-Y, et al. Capmatinib in MET exon 14 mutated advanced non-small lung cancer (NSCLC): efficacy data from the phase II GEOMETRY mono-1 study. IASLC 20th World Conference on Lung Cancer; 2019; Barcelona, Spain. 2019.

  30. Manja Friese-Hamim FBGL. The selective c-Met inhibitor tepotinib can overcome epidermal growth factor receptor inhibitor resistance mediated by aberrant c-Met activation in NSCLC models. Am J Cancer Res. 2017;7(4):962–72.

    PubMed  PubMed Central  Google Scholar 

  31. Paik PK. Phase II study of tepotinib in NSCLC patients with METex14 mutations. Proc Am Soc Clin Oncol 2019;Abstract 9005.

  32. Gu Y, Sai Y, Wang J, Yu M, Wang G, Zhang L, et al. Preclinical pharmacokinetics, disposition, and translational pharmacokinetic/pharmacodynamic modeling of savolitinib, a novel selective cMet inhibitor. Eur J Pharm Sci. 2019;136:104938. https://doi.org/10.1016/j.ejps.2019.05.016.

    Article  CAS  PubMed  Google Scholar 

  33. Lu S, Fang J, Cao LJ, et al. Preliminary efficacy and safety results of savolitinib treating patients with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations[R/OL].2019 AACR, abstract CT031.

  34. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298–308. https://doi.org/10.1158/1535-7163.MCT-11-0264.

  35. Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31(29):3639–46. https://doi.org/10.1200/JCO.2012.48.4659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Klempner SJ, Borghei A, Hakimian B, Ali SM, Ou SI. Intracranial activity of cabozantinib in MET exon 14–positive NSCLC with brain metastases. J Thorac Oncol. 2017;12(1):152–6. https://doi.org/10.1016/j.jtho.2016.09.127.

    Article  PubMed  Google Scholar 

  37. Engstrom LD, Aranda R, Lee M, Tovar EA, Essenburg CJ, Madaj Z, et al. Glesatinib Exhibits Antitumor activity in lung cancer models and patients harboring MET exon 14 mutations and overcomes mutation-mediated resistance to type I MET inhibitors in nonclinical models. Clin Cancer Res. 2017;23(21):6661–72. https://doi.org/10.1158/1078-0432.CCR-17-1192.

    Article  CAS  PubMed  Google Scholar 

  38. Bazhenova L, Kim D, Cavanna L, et al. P2.06-017 amethyst NSCLC trial: phase 2 study of MGCD265 in patients with advanced or metastatic NSCLC with activating genetic alterations in MET. J Thorac Oncol. 2017;12:S1080–1.

    Article  Google Scholar 

  39. Yan SB, Peek VL, Ajamie R, Buchanan SG, Graff JR, Heidler SA, et al. LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Investig New Drugs. 2013;31(4):833–44. https://doi.org/10.1007/s10637-012-9912-9.

    Article  CAS  Google Scholar 

  40. Wu W, Bi C, Credille KM, Manro JR, Peek VL, Donoho GP, et al. Inhibition of tumor growth and metastasis in non-small cell lung cancer by LY2801653, an inhibitor of several oncokinases, including MET. Clin Cancer Res. 2013;19(20):5699–710. https://doi.org/10.1158/1078-0432.CCR-13-1758.

    Article  CAS  PubMed  Google Scholar 

  41. Yan SB, Um SL, Peek VL, Stephens JR, Zeng W, Konicek BW, et al. MET-targeting antibody (emibetuzumab) and kinase inhibitor (merestinib) as single agent or in combination in a cancer model bearing MET exon 14 skipping. Investig New Drugs. 2018;36(4):536–44. https://doi.org/10.1007/s10637-017-0545-x.

    Article  CAS  Google Scholar 

  42. Kawada I, Hasina R, Arif Q, Mueller J, Smithberger E, Husain AN, et al. Dramatic antitumor effects of the dual MET/RON small-molecule inhibitor LY2801653 in non-small cell lung cancer. Cancer Res. 2014;74(3):884–95. https://doi.org/10.1158/0008-5472.CAN-12-3583.

    Article  CAS  Google Scholar 

  43. He AR, Cohen RB, Denlinger CS, Sama A, Birnbaum A, Hwang J, et al. First-in-human phase I study of merestinib, an oral multikinase inhibitor, in patients with advanced cancer. Oncologist. 2019. https://doi.org/10.1634/theoncologist.2018-0411.

  44. • Sabari JK, Leonardi GC, Shu CA, Umeton R, Montecalvo J, Ni A, et al. PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers. Ann Oncol. 2018;29(10):2085–91. It demonstrates occasional responses to PD-1 blockade can be achieved, but overall clinical efficacy is modest.

    Article  CAS  Google Scholar 

  45. Mayenga M, Monnet I, Massiani M-A, et al. Dramatic responses to immune checkpoint inhibitors in MET exon 14 skipping mutation (METex14mut) non-small cell lung cancers. 2019; 14(10): S259. https://doi.org/10.1016/j.jtho.2019.08.517.

  46. Dong H, Li P, Wu C, Zhou X, Lu H, Zhou T. Response and acquired resistance to crizotinib in Chinese patients with lung adenocarcinomas harboring MET exon 14 splicing alternations. Lung Cancer. 2016;102:118–21. https://doi.org/10.1016/j.lungcan.2016.11.006.

    Article  PubMed  Google Scholar 

  47. Ou SI, Young L, Schrock AB, Johnson A, Klempner SJ, Zhu VW, et al. Emergence of preexisting MET Y1230C mutation as a resistance mechanism to crizotinib in NSCLC with MET exon 14 skipping. J Thorac Oncol. 2017;12(1):137–40. https://doi.org/10.1016/j.jtho.2016.09.119.

    Article  PubMed  Google Scholar 

  48. Lu X, Peled N, Greer J, Wu W, Choi P, Berger AH, et al. MET exon 14 mutation encodes an actionable therapeutic target in lung adenocarcinoma. Cancer Res. 2017;77(16):4498–505. https://doi.org/10.1158/0008-5472.CAN-16-1944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Schrock AB, Lai A, Ali SM, Miller VA, Raez LE. Mutation of MET Y1230 as an acquired mechanism of crizotinib resistance in NSCLC with MET exon 14 skipping. J Thorac Oncol. 2017;12(7):e89–90. https://doi.org/10.1016/j.jtho.2017.02.017.

    Article  PubMed  Google Scholar 

  50. Zhang Y, Yin J, Peng F. Acquired resistance to crizotinib in advanced lung adenocarcinoma with MET exon 14 skipping. Lung Cancer. 2017;113:69–71. https://doi.org/10.1016/j.lungcan.2017.09.006.

    Article  PubMed  Google Scholar 

  51. Jiang W, Yang N, Zhang Y. Novel MET Exon 14 skipping treatment-naïve lung adenocarcinoma presented primary resistance to crizotinib. J Thorac Oncol. 2018;13(7):e124–6. https://doi.org/10.1016/j.jtho.2018.02.030.

    Article  PubMed  Google Scholar 

  52. Suzawa K, Offin M, Lu D, Kurzatkowski C, Vojnic M, Smith RS, et al. Activation of KRAS mediates resistance to targeted therapy in MET exon 14-mutant non-small cell lung cancer. Clin Cancer Res. 2019;25(4):1248–60. https://doi.org/10.1158/1078-0432.CCR-18-1640.

    Article  PubMed  Google Scholar 

  53. Ding G, Wang J, Ding P, Wen Y, Yang L. Case report: HER2 amplification as a resistance mechanism to crizotinib in NSCLC with MET exon 14 skipping. Cancer Biol Ther. 2019;20(6):837–42. https://doi.org/10.1080/15384047.2019.1566049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jin W, Shan B, Liu H, Zhou S, Li W, Pan J, et al. Acquired mechanism of crizotinib resistance in NSCLC with MET exon 14 skipping. J Thorac Oncol. 2019;14(7):e137–9. https://doi.org/10.1016/j.jtho.2019.04.021.

    Article  PubMed  Google Scholar 

  55. Han S, Fang J, Lu S, Wang L, Li J, Cheng M, et al. Response and acquired resistance to savolitinib in a patient with pulmonary sarcomatoid carcinoma harboring MET exon 14 skipping mutation: a case report. Onco Targets Ther. 2019;12:7323–8. https://doi.org/10.2147/OTT.S210365.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Bahcall M, Awad MM, Sholl LM, Wilson FH, Xu M, Wang S, et al. Amplification of wild-type KRAS imparts resistance to crizotinib in MET exon 14 mutant non-small cell lung cancer. Clin Cancer Res. 2018;24(23):5963–76. https://doi.org/10.1158/1078-0432.CCR-18-0876.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Fujino T, Kobayashi Y, Suda K, Koga T, Nishino M, Ohara S, et al. Sensitivity and Resistance of MET exon 14 mutations in lung cancer to eight MET tyrosine kinase inhibitors in vitro. J Thorac Oncol. 2019;14(10):1753–65. It showed sensitivity and resistance of eight METtyrosine kinase in MET exon 14 mutations.

  58. Rotow JK, Gui P, Wu W, Raymond VM, Lanman RB, Kaye FJ. Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment in MET exon 14 skipping mutation-positive lung cancer. Clin Cancer Res. 2019. https://doi.org/10.1158/1078-0432.CCR-19-1667.

  59. Heist RS, Sequist LV, Borger D, Gainor JF, Arellano RS, Le LP, et al. Acquired resistance to crizotinib in NSCLC with MET exon 14 skipping. J Thorac Oncol. 2016;11(8):1242–5. https://doi.org/10.1016/j.jtho.2016.06.013.

    Article  PubMed  Google Scholar 

  60. Guo R, Offin M, Brannon A R, et al. MET inhibitor resistance in patients with MET exon 14-altered lung cancers. Proc Am Soc Clin Oncol 2019; abstract 9006.

  61. Recondo G, Bahcall M, et al. Mechanisms of resistance to MET tyrosine kinase inhibitors in patients with MET exon 14 mutant non-small cell lung cancer. J Thoracic Oncol. 14(10):S285. https://doi.org/10.1016/j.jtho.2019.08.573.

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Correspondence to Yongbin Lin MD, PhD or Ying Liang MD, PhD.

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Caiwen Huang declares that there is no conflict of interest. Qihua Zou declares that there is no conflict of interest. Hui Liu declares that there is no conflict of interest. Bo Qiu declares that there is no conflict of interest. Qiwen Li declares that there is no conflict of interest. Yongbin Lin declares that there is no conflict of interest. Ying Liang declares that there is no conflict of interest.

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Huang, C., Zou, Q., Liu, H. et al. Management of Non-small Cell Lung Cancer Patients with MET Exon 14 Skipping Mutations. Curr. Treat. Options in Oncol. 21, 33 (2020). https://doi.org/10.1007/s11864-020-0723-5

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