1. Disease Information

1.1 Overview / definition

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)

1.2 Synonyms / alternative names

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)

1.3 Key identifiers (ontology / coding systems)

• MeSH / ICD-10 / ICD-11 / OMIM / Orphanet / MONDO: Not explicitly provided in the retrieved evidence snippets for this run.
• Practically, this entity is captured clinically as NSCLC (often lung adenocarcinoma) with a molecular alteration (MET exon 14 skipping). (yuan2023metexon14 pages 1-2)

1.4 Evidence source type

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)

2. Etiology

2.1 Primary causal factors (genetic/mechanistic)

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)

2.2 Risk factors

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)

2.3 Protective factors

No genetic or environmental protective factors specific to developing METex14 NSCLC were identified in the retrieved evidence.

2.4 Gene–environment interactions

No METex14-specific gene–environment interaction evidence was retrieved.

3. Phenotypes (clinical presentation)

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.

3.1 Core clinical phenotypes

• Lung cancer symptoms/signs: cough, dyspnea, hemoptysis, chest pain, weight loss (general NSCLC phenotype; not explicitly quantified in retrieved sources).
• Advanced stage at detection in many cohorts: In the GFPC 03-18 cohort, 92.4% were stage IV. (babey2023realworldtreatmentoutcomes pages 1-2)
• Brain metastasis as prognostic/clinical feature: “Initial brain metastasis” was an independent poor prognostic factor in advanced METex14 lung adenocarcinoma in a real-world cohort. (gow2023survivaloutcomesand pages 1-2)

3.2 Biomarker phenotypes (tumor immune markers)

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)

3.3 Suggested HPO terms (examples)

(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.

4. Genetic / Molecular Information

4.1 Causal gene

• Gene: MET (MET proto-oncogene, receptor tyrosine kinase)
• Alteration class: Somatic splice-altering variants leading to MET exon 14 skipping (driver event). (spagnolo2023targetingmetin pages 2-3, yuan2023metexon14 pages 1-2)

4.2 Pathogenic variant classes that cause exon skipping

• Disrupted splice donor/acceptor sites near exon 14 due to point mutations, insertions, deletions, including larger deletions that may be missed by DNA-only NGS. (spagnolo2023targetingmetin pages 2-3, loyaux2024metexon14 pages 1-5)

4.3 Functional consequences (causal chain)

1. Genomic alteration disrupts exon 14 splicing →
2. Exon 14 is skipped in the mRNA →
3. MET protein lacks juxtamembrane regulatory sequence including CBL binding site (Tyr1003) →
4. Reduced ubiquitination/internalization/lysosomal degradation →
5. Increased MET receptor stability and signaling →
6. Activation of downstream oncogenic pathways promoting proliferation, survival, motility, EMT. (spagnolo2023targetingmetin pages 2-3, loyaux2024metexon14 pages 1-5)

Downstream pathways explicitly noted include RAS–RAF–MEK–MAPK and PI3K/AKT, as well as STAT and NF-κB. (spagnolo2023targetingmetin pages 2-3)

4.4 Co-mutations / potential modifiers

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)

4.5 Epigenetic information

No METex14-specific methylation/histone modification mechanism evidence was retrieved in the accessed texts.

4.6 Suggested GO terms (biological processes) and CL terms (cell types)

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.

5. Environmental Information

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.

6. Mechanism / Pathophysiology

6.1 Key molecular mechanism

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)

6.2 Tumor biology and signaling

MET activation propagates multiple growth and survival pathways (e.g., MAPK and PI3K/AKT), supporting proliferation, survival, motility, and EMT. (spagnolo2023targetingmetin pages 2-3)

6.3 Immune microenvironment considerations

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)

7. Anatomical Structures Affected

7.1 Primary organ/system

• Primary: Lung (respiratory system), typically NSCLC histologies including adenocarcinoma and sarcomatoid carcinoma enrichment. (gow2023survivaloutcomesand pages 1-2, babey2023realworldtreatmentoutcomes pages 1-2)

7.2 Secondary involvement

• Brain metastasis is clinically important and prognostic in advanced disease. (gow2023survivaloutcomesand pages 1-2)

7.3 Suggested UBERON terms (examples)

• UBERON:0002048 lung
• UBERON:0000955 brain

8. Temporal Development

8.1 Onset

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)

8.2 Progression/course

Many patients present with advanced/metastatic disease in real-world cohorts (e.g., stage IV predominance). (babey2023realworldtreatmentoutcomes pages 1-2)

9. Inheritance and Population

9.1 Inheritance

METex14 in NSCLC is generally a somatic (acquired) oncogenic driver, not a Mendelian inherited condition. (yuan2023metexon14 pages 1-2)

9.2 Epidemiology (prevalence)

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)

10. Diagnostics

10.1 Key diagnostic concept

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.

10.2 Testing modalities and pitfalls

• NGS (DNA and/or RNA): NGS is described as “the most useful method” for MET alterations but targeted DNA amplicon approaches may miss METex14 due to the high diversity of variants. (spagnolo2023targetingmetin pages 2-3)
• RT-PCR: Sensitive and low-cost, but can fail when nucleic acids are fragmented, especially in small/poor specimens. (spagnolo2023targetingmetin pages 2-3)
• IHC: Not adequate as a screening test for METex14 (false negatives reported). (spagnolo2023targetingmetin pages 2-3, makimoto2024diagnosisandtreatment pages 1-2)

10.3 Quantitative diagnostic performance (recent cohorts)

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)

10.4 Liquid biopsy

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)

11. Outcome / Prognosis

11.1 Prognostic factors (real-world)

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)

11.2 Real-world survival data

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)

12. Treatment

12.1 Current standard targeted therapies (real-world implementation)

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)

12.2 Tepotinib (VISION) — efficacy and safety

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)

12.3 Capmatinib (GEOMETRY mono-1) — efficacy

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)

12.4 Newer selective MET inhibitors (2024)

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)

12.5 Immunotherapy outcomes in METex14

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)

12.6 Suggested MAXO terms (examples)

• MAXO:0000757 targeted therapy
• MAXO:0000058 drug therapy
• MAXO:0000468 molecular targeted therapy
• For MET TKI administration, represent as targeted small molecule therapy (ontology mapping may require MAXO term resolution outside this run).

13. Prevention

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)

14. Other Species / Natural Disease

No naturally occurring METex14 skipping NSCLC analogs in other species were identified in the retrieved evidence.

15. Model Organisms / Experimental Models

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.

Summary Table of Key Quantitative Findings

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.

Expert synthesis / current understanding (2023–2024 emphasis)

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

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