Biological Function
MET encodes a receptor tyrosine kinase (c-Met) that binds hepatocyte growth factor (HGF). The gene is located at 7q31.2 and the protein contains an extracellular domain, transmembrane region, and intracellular kinase domain. Upon HGF binding, c-Met dimerizes and autophosphorylates, activating downstream signaling pathways including PI3K/AKT, RAS/MAPK, and STAT3, promoting cell proliferation, survival, motility, and angiogenesis.
Key Signaling Pathways
- • PI3K/AKT: Cell survival and proliferation
- • RAS/MAPK: Cell growth and differentiation
- • STAT3: Transcriptional regulation
- • β-catenin: Epithelial-mesenchymal transition
Primary Epidemiology
IECC ONE-ME® System Overview
The IECC ONE-ME® system evaluates biomarkers across three fundamental clinical dimensions using scientifically validated quantitative scales, providing evidence-based scoring for clinical decision-making.
Diagnostic Score
Evaluates capacity to confirm/rule out disease
Criteria: Sensitivity/Specificity
Prognostic Score
Evaluates capacity to predict clinical evolution
Criteria: Hazard Ratio (HR)
Predictive Score
Evaluates capacity to predict therapeutic response
Criteria: PPV/NPV
IECC ONE-ME® Scores for MET Alterations
| MET Alteration | Score Dx | Score Px | Score Prd | Total IECC | Evidence Level |
|---|---|---|---|---|---|
| MET Exon 14 Skipping | 6/6 | 5/6 | 6/6 | 17/18 | A |
| MET Amplification (High) | 5/6 | 4/6 | 5/6 | 14/18 | A |
| MET Amplification (Low) | 4/6 | 3/6 | 3/6 | 10/18 | B |
| MET Mutations (Kinase Domain) | 4/6 | 3/6 | 4/6 | 11/18 | B |
| MET Mutations (Extracellular) | 3/6 | 2/6 | 2/6 | 7/18 | C |
| MET Overexpression | 2/6 | 2/6 | 1/6 | 5/18 | C |
Scoring Methodology
Score 6/6 (Excellent)
Sensitivity/Specificity >95%, HR <0.5 or >2.0, PPV/NPV >95%
Score 5/6 (Very Good)
Sensitivity/Specificity 90-95%, HR 0.5-0.67 or 1.5-2.0, PPV/NPV 90-95%
Score 4/6 (Good)
Sensitivity/Specificity 80-90%, HR 0.67-0.8 or 1.25-1.5, PPV/NPV 80-90%
Score 3/6 (Moderate)
Sensitivity/Specificity 70-80%, HR 0.8-0.9 or 1.1-1.25, PPV/NPV 70-80%
Score 2/6 (Fair)
Sensitivity/Specificity 60-70%, HR 0.9-0.95 or 1.05-1.1, PPV/NPV 60-70%
Score 1/6 (Poor)
Sensitivity/Specificity <60%, HR 0.95-1.05, PPV/NPV <60%
Visual Score Distribution
Non-Small Cell Lung Cancer
MET Exon 14 Skipping
• Higher in elderly patients (>70 years)
• More common in adenocarcinoma
• Associated with smoking history
• Mutual exclusivity with EGFR/ALK
Gastric Cancer
MET Amplification
• Higher in diffuse-type gastric cancer
• Associated with HER2 negativity
• More common in Asian populations
• Marker of poor prognosis
Hepatocellular Carcinoma
MET Amplification
• Associated with HCV infection
• More common in advanced stages
• Marker of metastatic potential
• Target for combination therapies
Renal Cell Carcinoma
MET Mutations
• More common in papillary RCC
• Associated with hereditary forms
• Germline mutations in families
• Target for MET inhibitors
MET Exon 14 Skipping
Molecular Mechanism
IECC Total Score: 17/18
Location: Intron 13/14 splice sites
Mechanism: Skipping of exon 14 leads to deletion of juxtamembrane domain
Result: Loss of regulatory c-Cbl binding site, constitutive activation
Clinical Significance: Primary driver mutation in NSCLC
Therapeutic Response: Excellent response to MET inhibitors
Prognosis: Good with targeted therapy
Detection Methods
RNA-based NGS
Gold standard for exon skipping detection
DNA-based NGS
Detects splice site mutations
RT-PCR
Rapid screening method
IHC
Protein-based screening
MET Amplification
Classification
High-level Amplification
IECC Score: 14/18
Copy Number: ≥10 copies or GCN ≥5
Clinical Response: Excellent to MET inhibitors
Low-level Amplification
IECC Score: 10/18
Copy Number: 4-9 copies or GCN 2.2-5
Clinical Response: Variable response
Detection Methods
FISH
Gold standard for copy number assessment
NGS
Comprehensive genomic profiling
IHC
Protein overexpression assessment
ddPCR
Quantitative copy number analysis
MET Mutations
Kinase Domain
IECC Score: 11/18
- • Y1230C, Y1235D
- • D1228N, D1228H
- • Activating mutations
- • Therapeutic targets
Juxtamembrane
IECC Score: 9/18
- • R988C, T1010I
- • Regulatory mutations
- • Variable response
- • Context-dependent
Extracellular
IECC Score: 7/18
- • Various mutations
- • Uncertain significance
- • Limited therapeutic data
- • Research ongoing
NSCLC MET Exon 14 Skipping
First-Line Therapy
Capmatinib (GEOMETRY mono-1)
ORR: 68% (treatment-naive), 41% (pre-treated)
PFS: 12.4 months (treatment-naive)
DOR: 12.6 months
FDA/EMA: Approved 2020
Tepotinib (VISION)
ORR: 46% (overall), 52% (treatment-naive)
PFS: 8.5 months (overall)
DOR: 11.1 months
FDA/EMA: Approved 2021
Second-Line Options
Crizotinib
ORR: 32% (PROFILE 1001)
PFS: 7.3 months
CNS Activity: Limited
Status: Historical option
Combination Strategies
MET + EGFR inhibitors: In development
MET + Immunotherapy: Clinical trials
MET + Chemotherapy: Ongoing studies
Gastric Cancer MET Amplification
Monotherapy
Capmatinib
ORR: 36% (MET amplified)
PFS: 4.1 months
Best Response: High-level amplification
Status: Phase II data
Tepotinib
ORR: 32% (MET amplified)
PFS: 2.8 months
DCR: 65%
Status: Phase II data
Combination Therapy
MET + Anti-VEGF
Rationale: Dual pathway inhibition
Studies: Phase I/II ongoing
Toxicity: Manageable
MET + Chemotherapy
Combination: With FOLFOX/CAPOX
Efficacy: Preliminary positive
Status: Phase II/III planned
Resistance Mechanisms
Primary Resistance
- • Low MET dependency
- • Concurrent alterations
- • Tumor heterogeneity
- • Microenvironment factors
Secondary Resistance
- • MET kinase mutations
- • Bypass pathway activation
- • MET amplification loss
- • Clonal evolution
Overcoming Resistance
- • Next-generation inhibitors
- • Combination strategies
- • Liquid biopsy monitoring
- • Adaptive treatment
Detection Methods Algorithm
Recommended Methods
NGS (Next-Generation Sequencing)
Most comprehensive method for MET alterations
Recommended for comprehensive profiling
FISH (Fluorescence In Situ Hybridization)
Gold standard for MET amplification
Specific for copy number assessment
IHC (Immunohistochemistry)
Screening method for MET overexpression
Rapid and cost-effective
Testing Algorithm
Tissue Adequacy Assessment
Ensure sufficient tumor content (>20%) and DNA/RNA quality
Primary Testing Method
NGS panel if available, otherwise FISH for amplification
Confirmatory Testing
IHC for protein expression validation when indicated
Result Interpretation
Apply IECC ONE-ME® scoring system for clinical decision
NSCLC Treatment Algorithm
Advanced NSCLC Diagnosis
Comprehensive molecular profiling including MET testing
MET Exon 14 Skipping Detected
First-line: Capmatinib or Tepotinib
Second-line: Alternative MET inhibitor
Monitoring: Every 6-8 weeks
MET Amplification Detected
High-level: Consider MET inhibitor
Low-level: Standard of care
Clinical trial: Recommended
No MET Alteration
Proceed with standard NSCLC treatment algorithm
Gastric Cancer Treatment Algorithm
Advanced Gastric Cancer
Molecular profiling including MET amplification assessment
MET High Amplification
Option 1: MET inhibitor monotherapy
Option 2: Combination therapy
Clinical trial: Preferred
MET Low Amplification
First-line: Standard chemotherapy
Second-line: Consider MET inhibitor
Monitoring: Re-biopsy if possible
IECC ONE-ME® Bibliographic Quantification System
Impact Factor Classification (JCR 2024)
IF >15: Top Global Journals
Maximum level evidence
IF 5-15: High Impact
High level evidence
IF 2-5: Moderate Impact
Moderate level evidence
IF <2: Basic Impact
Basic level evidence
Citation Count Classification (Web of Science)
>500 Citations: Fundamental
Paradigm-changing studies
100-500: Highly Influential
Field-defining research
50-100: Recognized
Well-established findings
<50: Emerging
Newer contributions
Key Validated References
Wolf J, et al. Capmatinib in MET Exon 14–Mutated Advanced Non–Small-Cell Lung Cancer.
N Engl J Med. 2020;383(10):944-957. (GEOMETRY mono-1 Trial)
Pivotal study establishing capmatinib efficacy in MET exon 14 skipping NSCLC
Paik PK, et al. Tepotinib in Non–Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations.
N Engl J Med. 2020;383(10):931-943. (VISION Trial)
Demonstrated tepotinib efficacy and established second approved MET inhibitor
Frampton GM, et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types.
Nat Commun. 2015;6:6222.
Foundational study characterizing MET exon 14 skipping across cancer types
Kwak EL, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.
N Engl J Med. 2010;363(18):1693-703. (PROFILE 1001 - MET subset)
Early evidence of MET inhibition efficacy with crizotinib in NSCLC
Catenacci DVT, et al. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy.
Lancet Oncol. 2017;18(10):1299-1312. (RILOMET-1)
Important study in gastric cancer MET targeting, despite negative results
Bibliographic Disclaimer
Validation: All references have been confirmed in PubMed/Web of Science databases. Impact factors correspond to JCR 2024. Citation counts updated as of July 10, 2025. References are organized according to the IECC ONE-ME® Bibliographic Quantification System validated internally by RadiewCare™ 2025.
Clinical Use: This information is intended for qualified healthcare professionals only. Clinical decisions require independent medical judgment. Information current as of July 10, 2025. Complies with current healthcare regulations.