c-MET

  • Mesenchymal–epithelial transition (MET), also called hepatocyte growth factor receptor (HGF receptor)
  • Gene Location: Chromosome 7 (7q21-31)

 

Biology

  • The MET proto-oncogene, located on chromosome 7q31, encodes a receptor tyrosine kinase (RTK) known as the hepatocyte growth factor receptor (HGFR) or cMET.1,2
  • c-MET is localized to the epithelial cells of the lungs, liver, pancreas, prostate, bone marrow, muscle, and kidneys. It is characterized as a heterodimer with a three-domain extracellular portion.3
  • The primary ligands for c-METare hepatocyte growth factor (HGF) and its isoform NK1.1,3
  • Under normal conditions, MET promotes processes such as cell proliferation, motility, scattering, survival, differentiation, and morphogenesis via interaction with HGF. Additionally, it is linked to protective roles against lung fibrosis and liver cirrhosis.3

Etiology and Epidemiology

  • There are various etiologies of oncogenesis in the MET pathway, including amplification, exon 14 skipping mutations, gene fusions, and c-MET protein overexpression.2
  • MET exon 14 skipping mutations occur in approximately 3% to 4% of adenocarcinoma non–small cell lung cancer (NSCLC) cases and 1% to 2% of other NSCLC histologies, with higher prevalence observed in older, never-smoking women.4-6
  • MET amplification, defined by an increase in MET gene copy number, occurs in about 1% to 5% of NSCLC cases and may also arise as a mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs).7-8
  • c-METoverexpression in NSCLC ranges from 13.7% to 63.7% for the incidence of primary overexpression and 30.4% to 37.0% for the incidence of secondary overexpression.2
  • MET alterations generally occur independently of other actionable drivers, including EGFR, ALK, ROS1, and BRAF, although co-occurrence of MET amplification and MET exon 14 skipping has been documented in select cases.9

 

Biomarker Testing

When to Test:

  • Testing for c-MET overexpression via immunohistochemistry (IHC) should be included at diagnosis alongside broad-panel next-generation sequencing (NGS) testing, including MET exon 14 skipping (METex14) mutations.9 
  • Repeat c-MET IHC testing may also be considered at the time of disease progression, based on clinical context and tissue availability.9

Available Testing Methods:

  • c-MET overexpression should be assessed via IHC, as it results from a variety of mechanisms—such as transcriptional upregulation or posttranslational modification—rather than a single, defined genomic alteration.2,9,10 
  • RNA-based NGS is the preferred method for detecting METex14given the heterogeneity of splicing alterations. DNA-based NGS may miss a subset of these alterations and should be interpreted with caution or supplemented with RNA analysis when available.2,9
  • MET amplification can be evaluated using either fluorescence in situ hybridization (FISH), which allows quantification of MET gene copy number and MET/CEP7 ratio, or NGS-based copy number analysis, which can provide complementary information when part of a comprehensive molecular profiling panel.2,7,8

Guideline Recommendations for Testing:

  • Updated guidelines from the National Comprehensive Cancer Network (NCCN) recommend testing for c-MET and HER2 overexpression via IHC in patients with advanced or metastatic NSCLC along side broad panel testing for EGFR, ALK, KRAS, ROS1, BRAF, NTRK, METex14 skipping mutations, RET, HER2 mutations, NRG1, and PD-L1.9 
  • Testing for HER2 IHC or c-MET/MET IHC is also recommended upon disease progression, with timing carefully considered to optimize tissue utilization.9

Targeted Therapy

Approved Agents

  • On May 14, 2025, the FDA granted accelerated approval to telisotuzumabvedotin-tllv (Teliso-V) for the treatment of adults with locally advanced or metastatic NSCLC who have high c-MET protein overexpression (defined as ≥50% of tumor cells with strong [3+] staining) and who have received prior systemic therapy.11,12
  • Approval was based on data from the LUMINOSITY study (NCT03539536), a multicenter, open-label, multicohort trial that evaluated 84 patients with EGFR wild-type, nonsquamous NSCLC and high c-METprotein overexpression.12 
  • In conjunction with the drug approval, the FDA also approved the VENTANA MET (SP44) RxDx Assay (Roche Diagnostics) as a companion diagnostic to identify patients eligible for treatment with Teliso-V.12 

Telisotuzumab vedotin-tllv11 

  • FDA-Approved Indication:
    • Teliso-V is approved for the treatment of adult patients with locally advanced or metastatic NSCLC with high c-METprotein overexpression [≥50% of tumor cells with strong (3+) staining], as determined by an FDA-approved test, who have received a prior systemic therapy.
    • This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
  • Mechanism of Action:
    • Teliso-Vis an antibody-drug conjugate (ADC) that targets c-MET, the cell surface receptor for hepatocyte growth factor (HGF).
    • It consists of a humanized IgG1κ antibody linked to the microtubule inhibitor monomethyl auristatin E (MMAE) via a protease-cleavable linker.
    • Upon binding to c-MET-expressing cells, the ADC is internalized and the linker is cleaved intracellularly, releasing MMAE.
    • MMAE then disrupts the microtubule network, leading to cell cycle arrest and apoptosis in actively dividing tumor cells.
  • Drug Information:
  • Patient Resources:

References

  1. Uchikawa E, Chen Z, Xiao G-Y, Zhang X, Bai X-C. Structural basis of the activation of c-MET receptor. Nat Commun. 2021;12:4074. doi:10.1038/s41467-021-24367-3
  2. Zhan S, Li J, Cheng B, et al. Landscape of C-MET overexpression in non-small cell lung cancer: a large-scale study of clinicomolecular features and prognosis based on Chinese data. Ther Adv Med Oncol. 2024;16:17588359241279715. doi:10.1177/17588359241279715
  3. Organ SL, Tsao MS. An overview of the c-MET signaling pathway. Ther Adv Med Oncol. 2011;3(suppl 1):S7-S19. doi:10.1177/1758834011422556
  4. 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-15-028
  5. Paik PK, Drilon A, Fan PD, 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):842-849.doi:10.1158/2159-8290.CD-14-1467
  6. Vuong HG, Ho ATN, Altibi AMA, et al. Clinicopathological implications of MET exon 14 mutations in non-small cell lung cancer - asystematic review and meta-analysis. Lung Cancer. 2018;123:76-82.doi:10.1016/j.lungcan.2018.07.006
  7. Camidge DR, Otterson GA, Clark JW, et al. Crizotinib in patients with MET-amplified NSCLC.J Thorac Oncol. 2021;16(11):1017-1029.doi:10.1016/j.jtho.2021.02.010
  8. Piotrowska Z, Isozaki H, Lennerz JK, et al. Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion.Cancer Discov. 2018;8(12):1529-1539. doi:10.1158/2159-8290
  9. National Comprehensive Cancer Network. NCCN guidelines version 5.2025: Non-small cell lung cancer. Accessed July 14, 2025. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
  10. MET IHC Testing - EMRELISTM. AbbVie. 2025. Accessed June 27, 2025. https://www.emrelishcp.com/met-ihc-testing
  11. EMRELIS (telisotuzumabVedotin-Tllv). Prescribing information.AbbVie. 2025.https://www.rxabbvie.com/pdf/emrelis_pi.pdf
  12. FDA.gov. FDA grants accelerated approval to telisotuzumabvedotin-tllv for NSCLC with high c-Met protein overexpression. Updated May 14, 2025. Accessed July 9, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-telisotuzumab-vedotin-tllv-nsclc-high-c-met-protein-overexpression