MET exon 14 skipping non-small cell lung cancer (NSCLC) is a molecularly-defined lung cancer subtype driven by splice site mutations that cause exon 14 skipping in the MET receptor tyrosine kinase. MET exon 14 (METex14) alterations occur in approximately 3-4% of NSCLC and are more common in older patients. Exon 14 encodes a juxtamembrane domain containing a CBL binding site required for receptor ubiquitination and degradation. Skipping this exon leads to prolonged MET signaling. Capmatinib and tepotinib are selective MET inhibitors approved for this indication.
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name: MET Exon 14 Skipping Non-Small Cell Lung Cancer
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-04-22T20:13:21Z'
description: >-
MET exon 14 skipping non-small cell lung cancer (NSCLC) is a molecularly-defined
lung cancer subtype driven by splice site mutations that cause exon 14 skipping
in the MET receptor tyrosine kinase. MET exon 14 (METex14) alterations occur
in approximately 3-4% of NSCLC and are more common in older patients. Exon 14
encodes a juxtamembrane domain containing a CBL binding site required for
receptor ubiquitination and degradation. Skipping this exon leads to prolonged
MET signaling. Capmatinib and tepotinib are selective MET inhibitors approved
for this indication.
categories:
- Molecularly-Defined Cancer
- Lung Cancer Subtype
- Solid Tumor
parents:
- non-small cell lung carcinoma
has_subtypes:
- name: METex14 Splice Site Mutation
description: >-
Point mutations at splice donor or acceptor sites flanking exon 14 are the
most common mechanism, causing exon 14 exclusion during mRNA splicing.
- name: METex14 Whole Exon Deletion
description: >-
Genomic deletion of the entire exon 14 region, a less common mechanism of
exon 14 loss.
- name: METex14 with MET Amplification
description: >-
A subset of METex14-positive tumors also harbor MET gene amplification,
which may increase oncogenic drive and affect inhibitor sensitivity.
pathophysiology:
- name: MET Exon 14 Splice Mutations
description: >-
MET exon 14 skipping results from splice site mutations that cause exclusion
of exon 14 during pre-mRNA splicing. Exon 14 encodes a juxtamembrane regulatory
domain containing a CBL E3 ubiquitin ligase binding site (Y1003). Loss of this
domain prevents receptor ubiquitination and degradation, leading to prolonged
MET signaling after ligand stimulation.
evidence:
- reference: PMID:26729443
reference_title: "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."
supports: PARTIAL
snippet: MET exon 14 mutations were identified in 28 of 933 nonsquamous NSCLCs (3.0%) and were not seen in other cancer types in this study.
explanation: This abstract documents MET exon 14 mutations in NSCLC, supporting the presence of exon 14 alterations in this subtype.
cell_types:
- preferred_term: type II pneumocyte
term:
id: CL:0002063
label: pulmonary alveolar type 2 cell
biological_processes:
- preferred_term: transmembrane receptor protein tyrosine kinase signaling pathway
modifier: INCREASED
term:
id: GO:0007169
label: cell surface receptor protein tyrosine kinase signaling pathway
downstream:
- target: Prolonged MET Signaling
description: Loss of CBL-mediated ubiquitination and degradation
- name: Prolonged MET Signaling
description: >-
METex14 skipping results in prolonged receptor activation and downstream signaling
through RAS-MAPK, PI3K-AKT, and STAT3 pathways. HGF (hepatocyte growth factor)
ligand binding triggers signaling, but receptor downregulation is impaired.
biological_processes:
- preferred_term: MAPK cascade
modifier: INCREASED
term:
id: GO:0000165
label: MAPK cascade
- preferred_term: phosphatidylinositol 3-kinase signaling
modifier: INCREASED
term:
id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
downstream:
- target: Cell Proliferation and Migration
description: Sustained HGF-MET signaling promotes tumor growth
- name: Cell Proliferation and Migration
description: >-
MET signaling promotes cell proliferation, survival, motility, and invasion.
The HGF-MET axis is particularly important for epithelial-mesenchymal transition
and metastasis.
biological_processes:
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
- name: MET Inhibitor Resistance
description: >-
Resistance to MET inhibitors can develop through secondary MET kinase mutations
(D1228N/V, Y1230C/H), MET amplification increase, or bypass pathway activation
(KRAS, EGFR, HER3). On-target resistance mutations affect drug binding.
biological_processes:
- preferred_term: response to drug
modifier: ABNORMAL
term:
id: GO:0009410
label: response to xenobiotic stimulus
histopathology:
- name: Adenocarcinoma Predominance
finding_term:
preferred_term: Lung Adenocarcinoma
term:
id: NCIT:C3512
label: Lung Adenocarcinoma
frequency: VERY_FREQUENT
description: Adenocarcinoma is the most common histologic subtype in NSCLC.
evidence:
- reference: PMID:32657049
reference_title: "Genetic profile of non-small cell lung cancer (NSCLC): A hospital-based survey in Jinhua."
supports: PARTIAL
snippet: "Of 256 patients with NSCLC, 219 were adenocarcinoma"
explanation: Abstract reports a NSCLC cohort dominated by adenocarcinoma.
phenotypes:
- category: Neoplastic
name: Lung Adenocarcinoma
frequency: VERY_FREQUENT
description: >-
METex14 NSCLC is predominantly adenocarcinoma histology, though can occur in
sarcomatoid carcinoma with higher frequency than other molecular subtypes.
phenotype_term:
preferred_term: Lung adenocarcinoma
term:
id: HP:0030078
label: Lung adenocarcinoma
- category: Clinical
name: Older Age at Diagnosis
frequency: VERY_FREQUENT
description: >-
Unlike ALK/ROS1-positive patients, METex14 patients are typically older
(median age ~70s), reflecting a distinct demographic profile.
phenotype_term:
preferred_term: Neoplasm of the lung
term:
id: HP:0100526
label: Neoplasm of the lung
- category: Clinical
name: Variable Smoking History
frequency: FREQUENT
description: >-
METex14 alterations occur in both smokers and never-smokers, with
approximately 50% having smoking history.
phenotype_term:
preferred_term: Neoplasm of the lung
term:
id: HP:0100526
label: Neoplasm of the lung
- category: Clinical
name: Brain Metastases
frequency: FREQUENT
description: >-
Brain metastases occur in METex14 NSCLC. CNS penetration of MET inhibitors
varies; capmatinib and tepotinib have shown intracranial activity.
phenotype_term:
preferred_term: Neoplasm of the nervous system
term:
id: HP:0004375
label: Neoplasm of the nervous system
biochemical:
- name: MET Exon 14 Testing
notes: >-
METex14 testing requires RNA-based NGS or comprehensive DNA-based NGS that
covers splice sites. Standard DNA sequencing may miss some splice mutations.
IHC for MET overexpression is not reliable for detecting exon 14 skipping.
PCR-based assays and RNA sequencing can detect the aberrant splice product.
genetic:
- name: MET
association: Somatic Splice Site Mutation
inheritance:
- name: Somatic
notes: >-
MET (7q31.2) encodes the hepatocyte growth factor receptor. Exon 14 skipping
results from mutations at splice donor (3') or acceptor (5') sites, or within
the exon itself. Over 100 different METex14 mutations have been identified.
MET amplification can co-occur and may affect inhibitor sensitivity. MET is
also a resistance mechanism in EGFR-mutant NSCLC.
treatments:
- name: Capmatinib
description: >-
Selective MET inhibitor approved for METex14 NSCLC based on GEOMETRY mono-1
trial. Active in both treatment-naive and previously treated patients.
Demonstrated intracranial activity.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: capmatinib
term:
id: CHEBI:231693
label: capmatinib
- name: Tepotinib
description: >-
Selective MET inhibitor approved for METex14 NSCLC based on VISION trial.
Once-daily dosing. Shown activity in CNS metastases.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: tepotinib
term:
id: NCIT:C88314
label: Tepotinib
- name: Crizotinib
description: >-
Multi-kinase inhibitor (ALK/ROS1/MET) with activity against METex14.
Less potent and selective than capmatinib/tepotinib but may be used
off-label where specific MET inhibitors unavailable.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: crizotinib
term:
id: CHEBI:64310
label: crizotinib
- name: Immunotherapy
description: >-
Checkpoint inhibitors may be used for METex14 NSCLC, though response rates
appear lower than in smoking-associated NSCLC. Often used after MET inhibitor
progression.
treatment_term:
preferred_term: immunotherapy
term:
id: NCIT:C15262
label: Immunotherapy
- name: Chemotherapy
description: >-
Platinum-based chemotherapy used at progression or in combination with
immunotherapy. Standard option when targeted therapy fails.
treatment_term:
preferred_term: chemotherapy
term:
id: MAXO:0000647
label: chemotherapy
disease_term:
preferred_term: lung adenocarcinoma
term:
id: MONDO:0005061
label: lung adenocarcinoma
classifications:
icdo_morphology:
classification_value: Carcinoma
harrisons_chapter:
- classification_value: cancer
- classification_value: solid tumor
references:
- reference: DOI:10.1007/s11523-023-00976-4
title: 'Real-World Treatment Outcomes of MET Exon14 Skipping in Non-small Cell Lung Cancer: GFPC 03-18 Study'
found_in:
- MET_Exon_14_Skipping_NSCLC-deep-research-falcon.md
findings:
- statement: 'Real-World Treatment Outcomes of MET Exon14 Skipping in Non-small Cell Lung Cancer: GFPC 03-18 Study'
supporting_text: 'Real-World Treatment Outcomes of MET Exon14 Skipping in Non-small Cell Lung Cancer: GFPC 03-18 Study'
- reference: DOI:10.1038/s41416-024-02615-9
title: Efficacy and safety of tepotinib in Asian patients with advanced NSCLC with MET exon 14 skipping enrolled in VISION
found_in:
- MET_Exon_14_Skipping_NSCLC-deep-research-falcon.md
findings:
- statement: Efficacy and safety of tepotinib in Asian patients with advanced NSCLC with MET exon 14 skipping enrolled in VISION
supporting_text: 'Tepotinib, a MET inhibitor approved for the treatment of MET exon 14 (METex14) skipping NSCLC, demonstrated durable clinical activity in VISION (Cohort A + C; N = 313): objective response rate (ORR) 51.4% (95% CI: 45.8, 57.1); median duration of response (mDOR) 18.0 months (95% CI: 12.4, 46.4).'
evidence:
- reference: DOI:10.1038/s41416-024-02615-9
reference_title: Efficacy and safety of tepotinib in Asian patients with advanced NSCLC with MET exon 14 skipping enrolled in VISION
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Tepotinib, a MET inhibitor approved for the treatment of MET exon 14 (METex14) skipping NSCLC, demonstrated durable clinical activity in VISION (Cohort A + C; N = 313): objective response rate (ORR) 51.4% (95% CI: 45.8, 57.1); median duration of response (mDOR) 18.0 months (95% CI: 12.4, 46.4).'
explanation: Deep research cited this publication as relevant literature for MET Exon 14 Skipping NSCLC.
- reference: DOI:10.1200/jco.23.02363
title: 'Vebreltinib for Advanced Non–Small Cell Lung Cancer Harboring c-Met Exon 14 Skipping Mutation: A Multicenter, Single-Arm, Phase II KUNPENG Study'
found_in:
- MET_Exon_14_Skipping_NSCLC-deep-research-falcon.md
findings:
- statement: 'Vebreltinib for Advanced Non–Small Cell Lung Cancer Harboring c-Met Exon 14 Skipping Mutation: A Multicenter, Single-Arm, Phase II KUNPENG Study'
supporting_text: The KUNPENG study aimed to evaluate the efficacy and safety of vebreltinib (also known as bozitinib, APL-101, PLB-1001, and CBT-101), a potent and highly selective inhibitor of c-mesenchymal-epithelial transition ( MET ), in patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring c-Met alterations.
evidence:
- reference: DOI:10.1200/jco.23.02363
reference_title: 'Vebreltinib for Advanced Non–Small Cell Lung Cancer Harboring c-Met Exon 14 Skipping Mutation: A Multicenter, Single-Arm, Phase II KUNPENG Study'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The KUNPENG study aimed to evaluate the efficacy and safety of vebreltinib (also known as bozitinib, APL-101, PLB-1001, and CBT-101), a potent and highly selective inhibitor of c-mesenchymal-epithelial transition ( MET ), in patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring c-Met alterations.
explanation: Deep research cited this publication as relevant literature for MET Exon 14 Skipping NSCLC.
- reference: DOI:10.21037/tlcr-24-93
title: 'Diagnosis and treatment of non-small cell lung cancer (NSCLC) harboring MET Ex14 skipping: have we met the desired drug?'
found_in:
- MET_Exon_14_Skipping_NSCLC-deep-research-falcon.md
findings:
- statement: 'Diagnosis and treatment of non-small cell lung cancer (NSCLC) harboring MET Ex14 skipping: have we met the desired drug?'
supporting_text: 'Diagnosis and treatment of non-small cell lung cancer (NSCLC) harboring MET Ex14 skipping: have we met the desired drug?'
- reference: DOI:10.21203/rs.3.rs-4520709/v1
title: 'MET Exon 14 Skipping Mutations in Non–Small-Cell Lung Cancer: Testing Considerations and Clinical Outcomes a 3 years screening experience'
found_in:
- MET_Exon_14_Skipping_NSCLC-deep-research-falcon.md
findings:
- statement: MET exon 14 skipping is an oncogenic driver observed in 1 to 4% of non-small cell lung cancer (NSCLC).
supporting_text: MET exon 14 skipping is an oncogenic driver observed in 1 to 4% of non-small cell lung cancer (NSCLC).
evidence:
- reference: DOI:10.21203/rs.3.rs-4520709/v1
reference_title: 'MET Exon 14 Skipping Mutations in Non–Small-Cell Lung Cancer: Testing Considerations and Clinical Outcomes a 3 years screening experience'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: MET exon 14 skipping is an oncogenic driver observed in 1 to 4% of non-small cell lung cancer (NSCLC).
explanation: Deep research cited this publication as relevant literature for MET Exon 14 Skipping NSCLC.
- reference: DOI:10.3389/fonc.2023.1113696
title: 'Survival outcomes and prognostic factors of lung cancer patients with the MET exon 14 skipping mutation: A single-center real-world study'
found_in:
- MET_Exon_14_Skipping_NSCLC-deep-research-falcon.md
findings:
- statement: The MET exon 14 skipping (METex14) mutation is an important oncogenic driver in lung cancer.
supporting_text: The MET exon 14 skipping (METex14) mutation is an important oncogenic driver in lung cancer.
evidence:
- reference: DOI:10.3389/fonc.2023.1113696
reference_title: 'Survival outcomes and prognostic factors of lung cancer patients with the MET exon 14 skipping mutation: A single-center real-world study'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The MET exon 14 skipping (METex14) mutation is an important oncogenic driver in lung cancer.
explanation: Deep research cited this publication as relevant literature for MET Exon 14 Skipping NSCLC.
- reference: DOI:10.3390/ijms241210119
title: 'Targeting MET in Non-Small Cell Lung Cancer (NSCLC): A New Old Story?'
found_in:
- MET_Exon_14_Skipping_NSCLC-deep-research-falcon.md
findings:
- statement: In recent years, we have seen the development and approval for clinical use of an increasing number of therapeutic agents against actionable oncogenic drivers in metastatic non-small cell lung cancer (NSCLC).
supporting_text: In recent years, we have seen the development and approval for clinical use of an increasing number of therapeutic agents against actionable oncogenic drivers in metastatic non-small cell lung cancer (NSCLC).
evidence:
- reference: DOI:10.3390/ijms241210119
reference_title: 'Targeting MET in Non-Small Cell Lung Cancer (NSCLC): A New Old Story?'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In recent years, we have seen the development and approval for clinical use of an increasing number of therapeutic agents against actionable oncogenic drivers in metastatic non-small cell lung cancer (NSCLC).
explanation: Deep research cited this publication as relevant literature for MET Exon 14 Skipping NSCLC.
- reference: DOI:10.3390/ijms252413715
title: 'MET Exon 14 Skipping and Novel Actionable Variants: Diagnostic and Therapeutic Implications in Latin American Non-Small-Cell Lung Cancer Patients'
found_in:
- MET_Exon_14_Skipping_NSCLC-deep-research-falcon.md
findings:
- statement: Targeted therapy indications for actionable variants in non-small-cell lung cancer (NSCLC) have primarily been studied in Caucasian populations, with limited data on Latin American patients.
supporting_text: Targeted therapy indications for actionable variants in non-small-cell lung cancer (NSCLC) have primarily been studied in Caucasian populations, with limited data on Latin American patients.
evidence:
- reference: DOI:10.3390/ijms252413715
reference_title: 'MET Exon 14 Skipping and Novel Actionable Variants: Diagnostic and Therapeutic Implications in Latin American Non-Small-Cell Lung Cancer Patients'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Targeted therapy indications for actionable variants in non-small-cell lung cancer (NSCLC) have primarily been studied in Caucasian populations, with limited data on Latin American patients.
explanation: Deep research cited this publication as relevant literature for MET Exon 14 Skipping NSCLC.
- reference: DOI:10.3390/jmp4010006
title: 'MET Exon 14 Variants in Non-Small Cell Lung Carcinoma: Prevalence, Clinicopathologic and Molecular Features'
found_in:
- MET_Exon_14_Skipping_NSCLC-deep-research-falcon.md
findings:
- statement: Somatic MET exon 14 skipping mutations (MET ex14) are targetable driver mutations for non-small cell lung cancer (NSCLC), responsive to MET inhibitors.
supporting_text: Somatic MET exon 14 skipping mutations (MET ex14) are targetable driver mutations for non-small cell lung cancer (NSCLC), responsive to MET inhibitors.
evidence:
- reference: DOI:10.3390/jmp4010006
reference_title: 'MET Exon 14 Variants in Non-Small Cell Lung Carcinoma: Prevalence, Clinicopathologic and Molecular Features'
supports: SUPPORT
evidence_source: OTHER
snippet: Somatic MET exon 14 skipping mutations (MET ex14) are targetable driver mutations for non-small cell lung cancer (NSCLC), responsive to MET inhibitors.
explanation: Deep research cited this publication as relevant literature for MET Exon 14 Skipping NSCLC.
MET exon 14 skipping NSCLC is a subset of NSCLC in which heterogeneous genomic alterations at the MET exon 14 splice donor/acceptor region lead to RNA splicing that excludes exon 14 (“METex14”), producing an oncogenic MET receptor with impaired downregulation and sustained signaling. This is widely described as an actionable oncogenic driver in lung cancer. (gow2023survivaloutcomesand pages 1-2, loyaux2024metexon14 pages 1-5)
Common names used in the literature include: - “MET exon 14 skipping mutation” - “METex14” - “MET exon 14 skipping variant” - “METΔex14” (delta exon 14) (gow2023survivaloutcomesand pages 1-2, yuan2023metexon14 pages 1-2)
Most disease-characterization information in this report is derived from aggregated resources (reviews) and human clinical cohorts (retrospective real-world series, prospective/registrational clinical trials). Some mechanistic evidence is in vitro (cell line functional assays). (loyaux2024metexon14 pages 1-5, babey2023realworldtreatmentoutcomes pages 1-2, yang2024vebreltinibforadvanced pages 1-2, mazieres2023tepotinibtreatmentin pages 1-2)
Primary causal factor: Somatic genomic alterations disrupting MET exon 14 splicing (splice site point mutations, insertions, deletions, including larger deletions) that result in exon 14 skipping at the RNA level. The alterations are described as highly heterogeneous and can be missed by single-modality DNA-only assays. (loyaux2024metexon14 pages 1-5, spagnolo2023targetingmetin pages 2-3)
Key mechanistic definition: Exon 14 encodes a regulatory juxtamembrane region containing Tyr1003, which is required for binding of the E3 ubiquitin ligase CBL, enabling ubiquitination/internalization and degradation of MET. Exon 14 skipping removes this region, reducing receptor ubiquitination and degradation and increasing MET signaling. (spagnolo2023targetingmetin pages 2-3, loyaux2024metexon14 pages 1-5)
Risk factors in the strict sense (exposures causing METex14) are not established in the retrieved sources; however, demographic and clinicopathologic associations are consistently observed in cohorts: - METex14-positive lung cancer patients were reported to be “generally elderly individuals, never-smokers” in a real-world cohort. (gow2023survivaloutcomesand pages 1-2) - A large real-world French cohort had median age 73 and 62.7% female. (babey2023realworldtreatmentoutcomes pages 1-2)
Histology enrichment: METex14 is enriched in pulmonary sarcomatoid carcinoma (PSC). A single-center study reported 24.3% (9/37) METex14 in PSC. (gow2023survivaloutcomesand pages 1-2)
No genetic or environmental protective factors specific to developing METex14 NSCLC were identified in the retrieved evidence.
No METex14-specific gene–environment interaction evidence was retrieved.
Because METex14 NSCLC is a molecular subtype of NSCLC, phenotypes are largely those of lung cancer, with additional features related to metastatic pattern and biomarker profile.
High PD-L1 expression is common but not clearly predictive of immunotherapy benefit in available real-world evidence: - In a screening cohort, 67% of METex14 tumors had PD-L1 >50%. (loyaux2024metexon14 pages 1-5)
(Phenotypes are lung-cancer related; examples suitable for a knowledge base entry) - HP:0002094 Hemoptysis - HP:0002090 Dyspnea - HP:0012735 Cough - HP:0002664 Neoplasm of the lung - HP:0002662 Metastatic neoplasm (if applicable) - HP:0002133 Status epilepticus / HP:0001249 Intellectual disability are not typical; for CNS metastasis consider: - HP:0002893 Brain metastasis (term availability may vary; alternatively encode as “metastatic malignant neoplasm in brain” in SNOMED/ICD)
Note: Specific HPO term IDs for “brain metastasis” may require mapping via HPO/SNOMED resources not accessed in this run.
Downstream pathways explicitly noted include RAS–RAF–MEK–MAPK and PI3K/AKT, as well as STAT and NF-κB. (spagnolo2023targetingmetin pages 2-3)
In a screening series of METex14 tumors (n=46), 42% had co-occurring alterations, most commonly TP53 (24%) and PIK3CA (9%). (loyaux2024metexon14 pages 1-5)
No METex14-specific methylation/histone modification mechanism evidence was retrieved in the accessed texts.
GO (examples): - GO:0007169 transmembrane receptor protein tyrosine kinase signaling pathway - GO:0038128 ERBB2 signaling pathway (not specific) vs more appropriate: - GO:0007173 epidermal growth factor receptor signaling pathway (not specific) - GO:0014068 positive regulation of phosphatidylinositol 3-kinase signaling - GO:0071902 positive regulation of protein serine/threonine kinase activity - GO:0001837 epithelial to mesenchymal transition
CL (examples): - CL:0000084 T cell (tumor immune microenvironment context) - CL:0000066 epithelial cell - CL:0002631 lung alveolar type II cell (a common inferred cell-of-origin for lung adenocarcinoma)
Note: GO/CL suggestions are ontology mappings; direct ontology annotations were not provided in the retrieved papers.
No METex14-specific environmental exposures were identified in the retrieved sources. General lung cancer risk factors (e.g., smoking, occupational exposures) apply at the NSCLC level but were not quantified in the provided evidence.
The defining mechanism is impaired MET downregulation due to loss of the exon 14–encoded juxtamembrane regulatory segment, increasing MET signaling output and driving oncogenesis. (spagnolo2023targetingmetin pages 2-3, loyaux2024metexon14 pages 1-5)
MET activation propagates multiple growth and survival pathways (e.g., MAPK and PI3K/AKT), supporting proliferation, survival, motility, and EMT. (spagnolo2023targetingmetin pages 2-3)
Although high PD-L1 expression is frequent (e.g., 67% with PD-L1 >50% in one cohort), real-world evidence suggests relatively limited immunotherapy efficacy in many patients, motivating prioritization of MET-targeted therapy when feasible. (loyaux2024metexon14 pages 1-5)
This is primarily an adult/older-adult cancer subtype. Cohort medians around early 70s were reported (median age 72–73 in VISION and a French real-world cohort). (mazieres2023tepotinibtreatmentin pages 1-2, babey2023realworldtreatmentoutcomes pages 1-2)
Many patients present with advanced/metastatic disease in real-world cohorts (e.g., stage IV predominance). (babey2023realworldtreatmentoutcomes pages 1-2)
METex14 in NSCLC is generally a somatic (acquired) oncogenic driver, not a Mendelian inherited condition. (yuan2023metexon14 pages 1-2)
Across sources, MET exon 14 skipping is described as a relatively rare but clinically significant NSCLC driver: - A clinical screening report describes published prevalence estimates of ~1–4% of NSCLC. (loyaux2024metexon14 pages 1-5) - A retrospective molecular pathology cohort found 1.9% MET exon 14 variants among 2296 NSCLCs (with most being exon 14 skipping). (yuan2023metexon14 pages 1-2)
Histology-specific enrichment: pulmonary sarcomatoid carcinoma shows markedly higher rates (e.g., 24.3% in one cohort). (gow2023survivaloutcomesand pages 1-2)
Because METex14 is defined by RNA exon skipping but caused by diverse DNA splice region alterations, optimal detection often requires strategies that can directly assess splicing (RNA) and/or cover diverse DNA events.
Latin American cohort (52-gene NGS panel, n=1560 biopsies): - Abstract quote: “RNA-based diagnosis detected 27% more cases of METex14 than DNA-based methods. Notably, 20% of METex14 cases with RNA reads below the detection threshold were confirmed using DNA analysis.” (Rivas et al., 2024; https://doi.org/10.3390/ijms252413715) (loyaux2024metexon14 pages 1-5)
Three-year screening experience (n=1143): 4 of 46 alterations were missed by DNA sequencing and “rescued” by fragment analysis or RNA sequencing, supporting a multimodal approach for large deletions. (loyaux2024metexon14 pages 1-5)
Liquid biopsy was used in pivotal tepotinib studies and demonstrated meaningful response rates in liquid-biopsy identified patients (see Treatment section). (mahrous2023…thediagnosis pages 6-7)
In a METex14-positive lung adenocarcinoma cohort, independent poor prognostic factors included: - Strong c-MET IHC staining - Initial brain metastasis - Supportive-care-only (gow2023survivaloutcomesand pages 1-2)
In a French real-world cohort (n=118), median overall survival was reported as 27.1 months (with median follow-up 16 months). (babey2023realworldtreatmentoutcomes pages 1-2)
Interpretation note: This cohort also reported treatment heterogeneity and did not demonstrate a clear median OS advantage in those who received anti-MET TKIs in their analyses, underscoring the complexity of real-world comparisons. (babey2023realworldtreatmentoutcomes pages 1-2)
Selective MET tyrosine kinase inhibitors (TKIs) have become standard targeted options in advanced METex14 NSCLC, with capmatinib and tepotinib established by pivotal phase II programs and incorporated into routine precision oncology testing pathways. (spagnolo2023targetingmetin pages 1-2, makimoto2024diagnosisandtreatment pages 1-2)
VISION long-term follow-up (advanced/metastatic METex14 NSCLC): - Quantitative outcomes: ORR 51.4% (95% CI 45.8–57.1) and median DOR 18.0 months. (mazieres2023tepotinibtreatmentin pages 1-2) - Safety: peripheral edema was the most frequent treatment-related adverse event (67.1%; grade 3 edema 11.2%). (mazieres2023tepotinibtreatmentin pages 1-2)
Asian VISION subset (data cut-off Nov 20, 2022): - Abstract quote (Kato et al., 2024; https://doi.org/10.1038/s41416-024-02615-9): “ORR was 56.6%… mDOR 18.5 months… mPFS 13.8 months… mOS 25.5 months.” (yang2024vebreltinibforadvanced pages 1-2) - Safety: “TRAEs occurred in 95.3%… (39.6% Grade ≥3). Most common TRAEs: peripheral edema (62.3%), creatinine increase (38.7%).” (yang2024vebreltinibforadvanced pages 1-2)
Makimoto (2024) summarizes pivotal capmatinib outcomes: - Treatment-naïve cohort (n=28): ORR 68%, median DOR 12.6 months, median PFS 12.4 months. (makimoto2024diagnosisandtreatment pages 1-2) - Previously treated cohort (n=69): ORR 41%, median DOR 9.7 months, median PFS 5.4 months. (makimoto2024diagnosisandtreatment pages 1-2)
Vebreltinib (KUNPENG phase II; JCO 2024): - Efficacy: ORR 75% (95% CI 61.1–86), median DOR 15.9 months, median PFS 14.1 months, median OS 20.7 months; DCR 96.2%. (yang2024vebreltinibforadvanced pages 1-2) - Safety: common treatment-related adverse events included peripheral edema (82.7%), QT prolongation (30.8%), elevated serum creatinine (28.8%). (yang2024vebreltinibforadvanced pages 1-2)
In a 3-year testing/outcomes series, immunotherapy-treated patients (n=13) had ORR 30% and median PFS 4 months, while MET inhibitor-treated patients (n=15) had ORR 44% and median PFS 5.5 months (institutional real-world outcomes). (loyaux2024metexon14 pages 1-5)
Subtype-specific primary prevention for METex14 is not established. Prevention is largely that of lung cancer broadly: - Primary prevention: smoking cessation, reduction of occupational exposures (not quantified in retrieved sources). - Secondary prevention: lung cancer screening (e.g., LDCT) is NSCLC-level prevention and not METex14-specific. - Tertiary prevention: early identification of METex14 through comprehensive genomic profiling to enable effective targeted therapy and reduce morbidity. The need for mandatory MET testing in treatment decision-making is emphasized in diagnostic-focused work. (loyaux2024metexon14 pages 1-5)
No naturally occurring METex14 skipping NSCLC analogs in other species were identified in the retrieved evidence.
Evidence retrieved in this run includes in vitro functional modeling of MET variants: - In a Latin American cohort study, the functional impact of candidate MET variants (e.g., T992I, H1094Y) was evaluated in multiple cell lines (HEK293T, BEAS-2B, H1993), and effects on proliferation/migration through MET/AKT signaling were tested, alongside inhibitor sensitivity testing in 2D/3D culture. (loyaux2024metexon14 pages 1-5)
This supports the use of: - In vitro cell line models (human lung cancer lines; epithelial cell models) to study MET signaling output and drug sensitivity. - 3D culture models to approximate tumor-like behavior for drug testing.
No animal models (GEMMs/PDX) were described in the accessed evidence snippets.
| Finding | Numeric value(s) | Population/cohort | Source (DOI URL + publication year) | Evidence citation id |
|---|---|---|---|---|
| Prevalence in NSCLC (published range) | ~1–4%; also reported ~3% | General NSCLC across reviews/screening reports | Loyaux et al. 2024, https://doi.org/10.21203/rs.3.rs-4520709/v1; Makimoto 2024, https://doi.org/10.21037/tlcr-24-93 | (loyaux2024metexon14 pages 1-5, makimoto2024diagnosisandtreatment pages 1-2) |
| Prevalence in NSCLC (cohort-specific) | 1.9% (44/2296 MET exon 14 variants; 32/44 were MET exon 14 skipping) | Retrospective NSCLC cohort tested 2017–2019 | Yuan et al. 2023, https://doi.org/10.3390/jmp4010006 | (yuan2023metexon14 pages 1-2) |
| Prevalence in NSCLC (cohort-specific) | ~4.0% (46/1143 MET exon 14 alterations) | 3-year screening experience, consecutive NSCLC | Loyaux et al. 2024, https://doi.org/10.21203/rs.3.rs-4520709/v1 | (loyaux2024metexon14 pages 1-5) |
| Enrichment in pulmonary/sarcomatoid carcinoma | 24.3% (9/37) in pulmonary sarcomatoid carcinoma; literature 7.7–32% in sarcomatoid carcinomas; 8–17% noted in sarcomatoid carcinoma | Single-center real-world lung cancer cohort; literature summaries | Gow et al. 2023, https://doi.org/10.3389/fonc.2023.1113696; Yuan et al. 2023, https://doi.org/10.3390/jmp4010006; Makimoto 2024, https://doi.org/10.21037/tlcr-24-93 | (gow2023survivaloutcomesand pages 1-2, yuan2023metexon14 pages 1-2, makimoto2024diagnosisandtreatment pages 1-2) |
| Demographics | Median age 73; 62.7% female; 83.9% adenocarcinoma; 92.4% stage IV; 27% had >3 metastatic sites | GFPC 03-18 real-world French cohort (n=118) | Babey et al. 2023, https://doi.org/10.1007/s11523-023-00976-4 | (babey2023realworldtreatmentoutcomes pages 1-2) |
| Demographics | Median age 72; 50.8% female; 33.9% Asian | VISION pooled Cohorts A+C (n=313) | Mazieres et al. 2023, long-term follow-up of VISION | (mazieres2023tepotinibtreatmentin pages 1-2) |
| Demographics/risk pattern | METex14-positive patients were generally elderly, never-smokers, and had poor performance scores | Single-center real-world lung cancer cohort (n=69 METex14+) | Gow et al. 2023, https://doi.org/10.3389/fonc.2023.1113696 | (gow2023survivaloutcomesand pages 1-2) |
| PD-L1 high expression | 67% with PD-L1 >50% | MET exon 14 tumors (n=46) | Loyaux et al. 2024, https://doi.org/10.21203/rs.3.rs-4520709/v1 | (loyaux2024metexon14 pages 1-5) |
| Co-mutations | 42% with co-occurring alterations; TP53 24%, PIK3CA 9% | MET exon 14 tumors (n=46) | Loyaux et al. 2024, https://doi.org/10.21203/rs.3.rs-4520709/v1 | (loyaux2024metexon14 pages 1-5) |
| Diagnostic performance (RNA vs DNA) | RNA-based diagnosis detected 27% more METex14 cases than DNA-based methods; 20% of RNA-low METex14 cases were confirmed by DNA analysis | Latin American NSCLC cohort, 1560 tumor biopsies | Rivas et al. 2024, https://doi.org/10.3390/ijms252413715 | (loyaux2024metexon14 pages 1-5) |
| Diagnostic performance (DNA-missed rescued) | 4/46 alterations missed by DNA sequencing and rescued by fragment analysis or RNA sequencing | 3-year NSCLC screening cohort | Loyaux et al. 2024, https://doi.org/10.21203/rs.3.rs-4520709/v1 | (loyaux2024metexon14 pages 1-5) |
| Tepotinib efficacy (VISION long-term) | ORR 51.4% (95% CI 45.8–57.1); median DOR 18.0 mo | Advanced/metastatic METex14 NSCLC, Cohorts A+C (n=313) | Mazieres et al. 2023, long-term follow-up of VISION | (mazieres2023tepotinibtreatmentin pages 1-2) |
| Tepotinib subgroup efficacy | Cohort C ORR 55.9%; treatment-naive ORR 57.3%, median DOR 46.4 mo; previously treated ORR 45.0%, median DOR 12.6 mo | VISION subgroup analyses | Mazieres et al. 2023, long-term follow-up of VISION | (mazieres2023tepotinibtreatmentin pages 1-2) |
| Tepotinib safety | Peripheral edema 67.1%; grade 3 edema 11.2% | VISION pooled Cohorts A+C | Mazieres et al. 2023, long-term follow-up of VISION | (mazieres2023tepotinibtreatmentin pages 1-2) |
| Tepotinib efficacy (Asian VISION subset) | ORR 56.6%; median DOR 18.5 mo; median PFS 13.8 mo; median OS 25.5 mo | Asian patients in VISION (n=106) | Kato et al. 2024, https://doi.org/10.1038/s41416-024-02615-9 | (yang2024vebreltinibforadvanced pages 1-2) |
| Tepotinib safety (Asian VISION subset) | TRAEs 95.3%; grade ≥3 TRAEs 39.6%; peripheral edema 62.3%; creatinine increase 38.7% | Asian patients in VISION (n=106) | Kato et al. 2024, https://doi.org/10.1038/s41416-024-02615-9 | (yang2024vebreltinibforadvanced pages 1-2) |
| Capmatinib efficacy (GEOMETRY mono-1, 1L) | ORR 68% (95% CI 48–84); median DOR 12.6 mo; median PFS 12.4 mo | Treatment-naive METex14 NSCLC (n=28) | Makimoto 2024, https://doi.org/10.21037/tlcr-24-93 | (makimoto2024diagnosisandtreatment pages 1-2) |
| Capmatinib efficacy (GEOMETRY mono-1, ≥2L) | ORR 41% (95% CI 29–53); median DOR 9.7 mo; median PFS 5.4 mo | Previously treated METex14 NSCLC (n=69) | Makimoto 2024, https://doi.org/10.21037/tlcr-24-93 | (makimoto2024diagnosisandtreatment pages 1-2) |
| Vebreltinib efficacy (KUNPENG) | ORR 75.0% (95% CI 61.1–86.0); DCR 96.2%; median DOR 15.9 mo; median PFS 14.1 mo; median OS 20.7 mo | Advanced METex14 NSCLC (n=52; 67.3% treatment-naive) | Yang et al. 2024, https://doi.org/10.1200/JCO.23.02363 | (yang2024vebreltinibforadvanced pages 1-2) |
| Vebreltinib subgroup efficacy | ORR 77.1% treatment-naive; 70.6% previously treated | KUNPENG subgroup analyses | Yang et al. 2024, https://doi.org/10.1200/JCO.23.02363 | (yang2024vebreltinibforadvanced pages 1-2) |
| Vebreltinib safety | Peripheral edema 82.7%; QT prolongation 30.8%; elevated serum creatinine 28.8% | KUNPENG phase II | Yang et al. 2024, https://doi.org/10.1200/JCO.23.02363 | (yang2024vebreltinibforadvanced pages 1-2) |
Table: This table compiles the main quantitative disease-characteristic, diagnostic, and treatment findings for MET exon 14 skipping NSCLC from the gathered evidence. It is useful for rapid knowledge-base population and side-by-side comparison of prevalence, testing yield, and MET inhibitor outcomes.
Across 2023–2024 sources, METex14 NSCLC is best understood as (i) a low-prevalence but clinically important NSCLC driver (~1–4%), (ii) strongly defined by a mechanistic loss of MET juxtamembrane negative regulation leading to sustained signaling, and (iii) a subtype where diagnostic modality matters—RNA-based approaches and multimodal workflows can recover clinically actionable cases missed by DNA-only assays. (spagnolo2023targetingmetin pages 2-3, loyaux2024metexon14 pages 1-5)
Therapeutically, the field has transitioned from proof-of-concept MET inhibition to routine use of selective MET TKIs (tepotinib/capmatinib) and emergence of additional selective inhibitors (e.g., vebreltinib), with consistently observed class toxicities including peripheral edema and creatinine elevations, and durable responses in substantial fractions of patients. (mazieres2023tepotinibtreatmentin pages 1-2, makimoto2024diagnosisandtreatment pages 1-2, yang2024vebreltinibforadvanced pages 1-2)
References
(gow2023survivaloutcomesand pages 1-2): Chien-Hung Gow, Min-Shu Hsieh, Yi-Lin Chen, Yi-Nan Liu, Shang-Gin Wu, and Jin-Yuan Shih. Survival outcomes and prognostic factors of lung cancer patients with the met exon 14 skipping mutation: a single-center real-world study. Frontiers in Oncology, Mar 2023. URL: https://doi.org/10.3389/fonc.2023.1113696, doi:10.3389/fonc.2023.1113696. This article has 11 citations.
(loyaux2024metexon14 pages 1-5): Romain Loyaux, Rym Ben Dhiab, Simon Garinet, Mathilda Bastide, Sophie Léonard-Goyet, Elizabeth Fabre, Audrey Mansuet-Lupo, Laure Gibault, Stéphane Jouveshomme, Etienne Giroux-Leprieur, Karen Leroy, Marie Wislez, and Hélène Blons. Met exon 14 skipping mutations in non–small-cell lung cancer: testing considerations and clinical outcomes a 3 years screening experience. Aug 2024. URL: https://doi.org/10.21203/rs.3.rs-4520709/v1, doi:10.21203/rs.3.rs-4520709/v1.
(yuan2023metexon14 pages 1-2): Lisi Yuan, Harshita Mehrotra, Xin He, and David Bosler. Met exon 14 variants in non-small cell lung carcinoma: prevalence, clinicopathologic and molecular features. Journal of Molecular Pathology, 4:46-56, Feb 2023. URL: https://doi.org/10.3390/jmp4010006, doi:10.3390/jmp4010006. This article has 2 citations.
(babey2023realworldtreatmentoutcomes pages 1-2): Hélène Babey, Philippe Jamme, Hubert Curcio, Jean Baptiste Assié, Remi Veillon, Hélène Doubre, Maurice Pérol, Florian Guisier, Eric Huchot, Chantal Decroisette, Lionel Falchero, Romain Corre, Alexis Cortot, Christos Chouaïd, and Renaud Descourt. Real-world treatment outcomes of met exon14 skipping in non-small cell lung cancer: gfpc 03-18 study. Targeted Oncology, 18:585-591, Jun 2023. URL: https://doi.org/10.1007/s11523-023-00976-4, doi:10.1007/s11523-023-00976-4. This article has 7 citations and is from a peer-reviewed journal.
(yang2024vebreltinibforadvanced pages 1-2): Jin-Ji Yang, Yan Zhang, Lin Wu, Jie Hu, Zhe-Hai Wang, Jing-Hua Chen, Yun Fan, Gen Lin, Qi-Ming Wang, Yu Yao, Jun Zhao, Yuan Chen, Jian Fang, Yong Song, Wei Zhang, Ying Cheng, Ren-Hua Guo, Xing-Ya Li, He-Peng Shi, Weizhe Xue, Dianqi Han, Peilong Zhang, and Yi‐Long Wu. Vebreltinib for advanced non–small cell lung cancer harboring c-met exon 14 skipping mutation: a multicenter, single-arm, phase ii kunpeng study. Journal of Clinical Oncology, 42:3680-3691, Nov 2024. URL: https://doi.org/10.1200/jco.23.02363, doi:10.1200/jco.23.02363. This article has 32 citations and is from a highest quality peer-reviewed journal.
(mazieres2023tepotinibtreatmentin pages 1-2): J Mazieres, PK Paik, MC Garassino, and X Le. Tepotinib treatment in patients with met exon 14–skipping non–small cell lung cancer: long-term follow-up of the vision phase 2 nonrandomized clinical trial. Unknown journal, 2023.
(spagnolo2023targetingmetin pages 2-3): Calogera Claudia Spagnolo, Giuliana Ciappina, Elisa Giovannetti, Andrea Squeri, Barbara Granata, Chiara Lazzari, Giulia Pretelli, Giulia Pasello, and Mariacarmela Santarpia. Targeting met in non-small cell lung cancer (nsclc): a new old story? International Journal of Molecular Sciences, 24:10119, Jun 2023. URL: https://doi.org/10.3390/ijms241210119, doi:10.3390/ijms241210119. This article has 42 citations.
(makimoto2024diagnosisandtreatment pages 1-2): Go Makimoto. Diagnosis and treatment of non-small cell lung cancer (nsclc) harboring met ex14 skipping: have we met the desired drug? Translational Lung Cancer Research, 13:1438-1443, Jun 2024. URL: https://doi.org/10.21037/tlcr-24-93, doi:10.21037/tlcr-24-93. This article has 2 citations and is from a peer-reviewed journal.
(mahrous2023…thediagnosis pages 6-7): M Mahrous, AO Jebriel, A Allehebi, A Shafik, and F El Karak. … the diagnosis, biomarker testing, and clinical management of advanced or metastatic non-small cell lung cancer with mesenchymal-epithelial transition exon 14 …. Unknown journal, 2023.
(spagnolo2023targetingmetin pages 1-2): Calogera Claudia Spagnolo, Giuliana Ciappina, Elisa Giovannetti, Andrea Squeri, Barbara Granata, Chiara Lazzari, Giulia Pretelli, Giulia Pasello, and Mariacarmela Santarpia. Targeting met in non-small cell lung cancer (nsclc): a new old story? International Journal of Molecular Sciences, 24:10119, Jun 2023. URL: https://doi.org/10.3390/ijms241210119, doi:10.3390/ijms241210119. This article has 42 citations.