MET
Mesenchymal-epithelial transition proto-oncogene (MET)
MET Biology
The MET gene, located on chromosome 7q21-q31, encodes the tyrosine kinase receptor c-MET.1,2 Under normal physiological conditions, hepatocyte growth factor binds to the c-MET receptor initiating activation of the MET signaling pathway. This pathway is involved in cell proliferation, survival, and growth, and plays an important role in embryonic development, wound healing, and tissue regeneration. MET mutations, gene amplification, and protein overexpression, can drive oncogenic MET signaling, thereby contributing to carcinogenesis and tumor progression.1,3-5 In non–small cell lung cancer (NSCLC), MET exon 14 skipping mutations (METex14) are the most common oncogenic MET alterations and generally occur independently of other driver mutations.3,6,7 METex14 may coincide with MET amplification, with a co-occurrence rate of 0% to 40.5%.5,7-14 MET amplification, marked by increased MET gene copy numbers, is a known resistance mechanism in EGFR-mutated NSCLC.3,9,14-16 The incidence of METex14 varies by histology with approximate rates of 2% in adenocarcinoma, 1% in squamous cell carcinoma, 6% in adenosquamous cell carcinoma, and 13% in pulmonary sarcomatoid carcinoma (PSC).17 Patients with METex14 mutations are typically older, predominantly female, and less likely to be smokers compared with those without such mutations.
METex14 Testing
The National Comprehensive Cancer Network (NCCN) NSCLC Panel recommends screening eligible patients with metastatic NSCLC for METex14 skipping mutations, guided by the efficacy of several agents and FDA approvals for capmatinib and tepotinib.18-20 Next-generation sequencing (NGS) is the preferred method for detecting METex14 skipping mutations, with RNA-based NGS possibly offering enhanced detection.17,18 Liquid biopsy may be employed when tissue biopsy is challenging, but negative results should be followed up with tissue-based testing. Amplicon-based NGS methods, though widely used, may have low detection rates for METex14 mutations due to allele dropout, leading to false negatives.21 Hybrid capture-based NGS methods offer better detection rates but may have increased off-target sequencing.17,22
METex14 Targeted Therapy
The US Food & Drug Administration (FDA) has approved 2 oral medications for treating METex14-positive metastatic NSCLC. Both approved agents are MET kinase inhibitors that act by inhibiting hepatocyte growth factor (HGF)-dependent and -independent MET phosphorylation and MET-dependent downstream signaling pathways.23,24 Capmatinib received accelerated approval in 2020 for use in adult patients with METex14-positve metastatic NSCLC, as detected by an FDA-approved test.23,25 The FoundationOne CDx assay (Foundation Medicine, Inc.) received concurrent approval as a companion diagnostic. Full FDA approval for capmatinib was subsequently granted in August of 2022.26 More recently in February 2024, tepotinib received full approval for treating adult patients with METex14-positve metastatic NSCLC, following its initial accelerated approval in 2021.27,28
References
1. Smyth EC, Sclafani F, Cunningham D. Emerging molecular targets in oncology: clinical potential of MET/hepatocyte growth-factor inhibitors. Onco Targets Ther. 2014;7:1001-1014. doi:10.2147/OTT.S44941
2. Spitaleri G, Trillo Aliaga P, Attili I, et al. MET in non-small-cell lung cancer (NSCLC): cross 'a long and winding road' looking for a target. Cancers (Basel). 2023;15(19):4779. doi:10.3390/cancers15194779
3. Frampton GM, Ali SM, Rosenzweig M, 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):850-859. doi:10.1158/2159-8290.CD-15-0285
4. Sadiq AA, Salgia R. MET as a possible target for non-small-cell lung cancer. J Clin Oncol. 2013;31(8):1089-1096. doi:10.1200/JCO.2012.43.9422
5. Tong JH, Yeung SF, Chan AW, 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):3048-3056. doi:10.1158/1078-0432.CCR-15-2061
6. Awad MM, Lee JK, Madison R, et al. Characterization of 1,387 NSCLCs with MET exon 14 (METex14) skipping alterations (SA) and potential acquired resistance (AR) mechanisms. J Clin Oncol. 2020;38(15):9511. doi: 10.1016/j.jtocrr.2022.100381
7. Reungwetwattana T, Ou SH. MET exon 14 deletion (METex14): finally, a frequent-enough actionable oncogenic driver mutation in non-small cell lung cancer to lead MET inhibitors out of "40 years of wilderness" and into a clear path of regulatory approval. Transl Lung Cancer Res. 2015;4(6):820-824. doi:10.3978/j.issn.2218-6751.2015.12.03
8. Schrock AB, Frampton GM, Suh J, et al. Characterization of 298 patients with lung cancer harboring MET exon 14 skipping alterations. J Thorac Oncol. 2016;11(9):1493-1502. doi:10.1016/j.jtho.2016.06.004
9. Mignard X, Ruppert A, Antoine M, et al: c-MET overexpression as a poor predictor of MET amplifications or exon 14 mutations in lung sarcomatoid carcinomas. J Thorac Oncol. 2020;13(12):1962-1967. doi:10.1016/j.jtho.2018.08.008
10. Baldacci S, Figeac M, Antoine M, et al. High MET overexpression does not predict the presence of MET exon 14 splice mutations in NSCLC: Results from the IFCT PREDICT.amm study. J Thorac Oncol. 2020;12020;15(1):120-124. doi:10.1016/j.jtho.2019.09.196
11. Noonan SA, Berry L, Lu X, et al. Identifying the appropriate FISH criteria for defining MET copy number-driven lung adenocarcinoma through oncogene overlap analysis. J Thorac Oncol. 2016;11(8):1293-1304. doi:10.1016/j.jtho.2016.04.033
12. Wolf J, Seto T, Han JY, et al. Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. N Engl J Med. 2020;383(10):944-957. doi:10.1056/NEJMoa2002787
13. Le X, Kowalski D, Cho BC, et al. Liquid biopsy to detect MET exon 14 skipping (METex14) and MET amplification in patients with advanced NSCLC: Biomarker analysis from VISION study. Cancer Res. 2020;80(suppl 16):3385 doi:10.1158/1538-7445.AM2020-3385
14. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19(8):2240-2247. doi:10.1158/1078-0432.CCR-12-2246
15. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039-1043.
16. Bean J, Brennan C, Shih JY, 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(52):20932-20937. doi:10.1073/pnas.0710370104
17. Socinski MA, Pennell NA, Davies KD. MET Exon 14 skipping mutations in non-small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerations. JCO Precis Oncol. 2021;5:PO.20.00516. doi:10.1200/PO.20.00516
18. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 3.2024. Accessed March 13, 2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
19. Wolf J, Neal J, Mansfield A, et al. Comparison of clinical outcomes of patients with METΔex14 NSCLC treated with first-line capmatinib in the GEOMETRY mono-1 study with those of a cohort of real-world patients. Poster presented at: The European Society for Medical Oncology Virtual Meeting, September 19-21, 2020. Poster 1246P.
20. Drilon A, Clark JW, Weiss J, et al. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration. Nat Med. 2020;26(1):47-51. doi:10.1038/s41591-019-0716-8
21. Poirot B, Doucet L, Benhenda S, et al. MET exon 14 alterations and new resistance mutations to tyrosine kinase inhibitors: Risk of inadequate detection with current amplicon-based NGS panels. J Thorac Oncol. 2017;12(10):1582-1587. doi:10.1016/j.jtho.2017.07.026
22. Jennings LJ, Arcila ME, Corless C, et al. Guidelines for validation of next-generation sequencing-based oncology panels: a joint consensus recommendation of the Association for Molecular Pathology and College of American Pathologists. J Mol Diagn. 2017;19(3):341-365. doi:10.1016/j.jmoldx.2017.01.011
23. TABRECTA (capmatinib). Package insert. East Hanover, NJ,USA: Novartis Pharmaceuticals Corporation; 03/2023.
24. TEPMETKO (tepotinib). Package insert. Darmstadt, Germany.Merck KGaA; 02/2024.
25. FDA grants accelerated approval to capmatinib formetastatic non-small cell lung cancer. US FDA. Updated May 6, 2020.Accessed March 13, 2024.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-capmatinib-metastatic-non-small-cell-lung-cancer
26. FDA approves capmatinib for metastatic non-small cell lung cancer. US FDA. Updated August 11, 2022. Accessed March 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capmatinib-metastatic-non-small-cell-lung-cancer
27. FDA grant accelerated approval to tepotinib for metastatic non-small cell lung cancer. US FDA. Updated February 3, 2021. Accessed March 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tepotinib-metastatic-non-small-cell-lung-cancer
28. FDA approves tepotinib for metastatic non-small cell lung cancer. US FDA. Updated February 16, 2024. Accessed March 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tepotinib-metastatic-non-small-cell-lung-cancer
Additional Reading
Liang H, Wang M. MET oncogene in non-small cell lung cancer: mechanism of MET dysregulation and agents targeting the HGF/c-Met Axis. Onco Targets Ther. 2020;13:2491-2510. doi:10.2147/OTT.S231257
Salgia R. Role of c-Met in cancer: emphasis on lung cancer. Semin Oncol. 2009;36(2 suppl 1):S52-S58. doi:10.1053/j.seminoncol.2009.02.008
Titmarsh HF, O'Connor R, Dhaliwal K, Akram AR. The emerging role of the c-MET-HGF axis in non-small cell lung cancer tumor immunology and immunotherapy. Front Oncol. 2020;10:54. doi:10.3389/fonc.2020.00054
Zucali PA, Ruiz MG, Giovannetti E, et al. Role of cMET expression in non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors. Ann Oncol. 2008;19(9):1605-1612. doi:10.1093/annonc/mdn240
