MET alterations in Lung Cancer

by Matthew Cecchini, MD PhD FRCPC
March 20, 2026

MET (also called c-MET or HGFR — hepatocyte growth factor receptor) is a protein found on the surface of cells that receives signals from a molecule called hepatocyte growth factor (HGF). When HGF binds to MET, it activates signalling pathways that promote cell growth, survival, and movement — processes that are tightly regulated in normal tissue but can become dangerously uncontrolled in cancer. In non-small cell lung cancer, the MET gene can be altered in several distinct ways, each with different implications for treatment. The most therapeutically important is a specific change called MET exon 14 skipping, found in approximately 3–4% of non-small cell lung cancers, which qualifies patients for targeted MET inhibitor therapy. MET gene amplification — extra copies of the MET gene — is also clinically relevant, both as a primary driver in a small subset of lung cancers and as one of the most common mechanisms by which EGFR-mutated lung cancers develop resistance to EGFR inhibitors. Understanding which type of MET alteration is present is essential because the implications for treatment differ substantially depending on the specific change identified.

What the test looks for

The MET gene can be altered in lung cancer through three distinct mechanisms, and it is important to understand that these are not interchangeable — they have different causes, different clinical significance, and different therapeutic implications.

MET exon 14 skipping mutations

This is the most therapeutically important MET alteration in lung cancer. Exon 14 of the MET gene encodes a region of the protein that contains a regulatory site — the juxtamembrane domain — responsible for marking the MET protein for degradation after it has been activated. When mutations occur at the splice sites flanking exon 14 (the boundaries where the genetic message is edited during processing), exon 14 is skipped during the production of messenger RNA. The resulting MET protein lacks the juxtamembrane degradation signal, so instead of being broken down after activation, it remains present and active for much longer than normal — continuously driving growth signals. MET exon 14 skipping is not a simple point mutation at a single location; rather, it can result from multiple underlying DNA changes at the splice sites, all of which have the same effect.

MET exon 14 skipping is found in approximately 3–4% of lung adenocarcinomas and in a higher proportion — up to 20–30% — of a specific subtype called pulmonary sarcomatoid carcinoma, one of the rarer and more aggressive forms of non-small cell lung cancer. It tends to occur in older patients and, unlike EGFR mutations and ALK rearrangements, is not specifically enriched in never-smokers.

MET gene amplification

MET amplification refers to an increase in the number of copies of the MET gene in cancer cells — from the normal two copies to many additional copies — leading to overproduction of MET protein and increased MET signalling. MET amplification occurs in two distinct clinical contexts in lung cancer:

Primary (de novo) MET amplification. Present in the original tumour before any treatment. High-level primary MET amplification (many extra gene copies) in the absence of other driver mutations is considered an actionable alteration that may predict response to MET inhibitors. However, the evidence is less robust than for MET exon 14 skipping. Low-level amplification has uncertain significance.
Acquired MET amplification. One of the most common mechanisms by which EGFR-mutated lung cancers develop resistance to EGFR tyrosine kinase inhibitors (TKIs), including osimertinib. When a cancer that was initially controlled by an EGFR inhibitor progresses, MET amplification is found in approximately 15–25% of cases, depending on the specific EGFR TKI used. In this setting, MET amplification bypasses EGFR inhibition by activating downstream signalling through an alternative route.

MET protein overexpression

Some lung cancers produce abnormally large amounts of MET protein without a gene-level change — a finding detected by immunohistochemistry. MET overexpression is common in lung cancer generally and, by itself, does not currently have established clinical significance as a predictive biomarker for MET-targeted therapy. It is mentioned here because it may appear on pathology reports, but it should not be confused with MET exon 14 skipping or high-level gene amplification.

Why is the test done

To identify MET exon 14 skipping and determine eligibility for MET inhibitor therapy. Capmatinib (Tabrecta) and tepotinib (Tepmetko) are both approved for advanced NSCLC harbouring MET exon 14 skipping alterations, including in the first-line setting. These drugs achieve clinically meaningful response rates in this population — particularly in treatment-naive patients — and testing is the only way to identify who qualifies.
To detect acquired MET amplification at the time of progression on EGFR TKI therapy. In patients whose EGFR-mutated lung cancer is progressing on an EGFR inhibitor, identifying MET amplification as the resistance mechanism opens the possibility of combining an EGFR TKI with a MET inhibitor to overcome resistance. This is an active area of clinical investigation, and several trials have demonstrated meaningful benefit from such combinations.
To characterise the complete molecular landscape of the tumour. Comprehensive molecular profiling identifies all actionable alterations simultaneously — including MET, EGFR, ALK, KRAS, and others — ensuring that no targetable finding is missed and that the full biological picture is available for treatment planning.
To provide prognostic context. MET exon 14 skipping-positive lung cancers have historically had a less favourable prognosis than some other driver-positive subtypes, in part because they tend to occur in older patients and because effective targeted therapies were not available until recently. With approved MET inhibitors, outcomes are improving.

Who should be tested

Current guidelines recommend MET testing — specifically for MET exon 14 skipping — for:

All patients with advanced or metastatic non-small cell lung cancer undergo comprehensive molecular profiling at diagnosis.
Patients with pulmonary sarcomatoid carcinoma, in particular, have a substantially higher prevalence of MET exon 14 skipping in this subtype.
Patients with EGFR-mutated lung cancer progressing on EGFR TKI therapy, where MET amplification testing is an essential part of the resistance mechanism workup.

MET amplification testing at diagnosis — as a primary driver — is also increasingly performed as part of comprehensive NGS panels, though the therapeutic implications of primary MET amplification without exon 14 skipping are less well defined and should be interpreted in the clinical context.

How the test is performed

Because MET exon 14 skipping is caused by splice site mutations that affect RNA processing, the most sensitive testing approach depends on the platform used.

Next-generation sequencing (NGS)

Comprehensive next-generation sequencing (NGS) is the preferred testing approach. RNA-based NGS is particularly well suited to detecting MET exon 14 skipping because it directly sequences the messenger RNA and can confirm that exon 14 is absent from the transcript — the definitive evidence of the alteration. DNA-based NGS can also detect underlying splice-site mutations that cause exon 14 skipping. However, it may miss some cases in which the causative variant lies outside the sequenced regions or is not well captured by the panel design. Laboratories that use DNA-based NGS alone may have lower sensitivity for MET exon 14 skipping than those using RNA-based or combined approaches.

MET gene amplification is assessed on DNA-based NGS panels by measuring the copy number of the MET gene relative to a reference standard. The degree of amplification (low, intermediate, or high) is typically reported alongside the exon 14 skipping result.

Fluorescence in situ hybridization (FISH)

FISH is the standard method for assessing MET gene copy number and amplification. It directly visualises the number of MET gene copies per cell and calculates the ratio of MET signals to chromosome 7 centromere signals (since MET resides on chromosome 7). High-level amplification (MET/CEP7 ratio ≥ 2, or average MET copy number ≥ 6 per cell) is generally considered potentially clinically significant. FISH cannot detect exon 14 skipping — it only assesses gene copy number.

Liquid biopsy

Cell-free circulating tumour DNA testing can detect MET exon 14 skipping mutations and, to a more limited degree, MET amplification. Liquid biopsy is particularly useful for monitoring patients on EGFR TKI therapy and detecting emerging MET amplification at the time of progression, when repeat tissue biopsy may not always be feasible. Sensitivity for detecting exon 14 skipping on liquid biopsy is moderate, and a negative result does not rule out the alteration — tissue testing should follow when liquid biopsy is negative. The alteration is clinically important to exclude.

How results are reported

MET results on a comprehensive NGS report may include several components, which are reported separately:

MET exon 14 skipping: Reported as detected or not detected, with notation of the specific underlying splice site variant identified (e.g., “MET splice site mutation c.3028+1G>T causing exon 14 skipping”) or, on RNA-based panels, confirmation that exon 14 is absent from the transcript.
MET copy number/amplification: Reported as the estimated copy number or amplification ratio, often categorised as low-level (2–4 copies above baseline), intermediate, or high-level amplification.
MET protein overexpression (IHC): If immunohistochemistry was performed, the staining intensity and extent will be noted — but as described above, this finding alone does not currently determine treatment eligibility.

The variant allele frequency (VAF) of any detected mutation will also be reported, providing a sense of the proportion of tumour cells that carry the alteration.

What each result means

MET exon 14 skipping detected. This is the most actionable MET result. The cancer harbors a splice-site alteration that removes the regulatory exon 14 from the MET protein, leaving MET constitutively active. Capmatinib (Tabrecta) and tepotinib (Tepmetko) are both approved for this alteration in advanced NSCLC. They can be used in the first-line setting — a meaningful advance, since many other targeted therapies require prior treatment before approval. Response rates in treatment-naive patients have been approximately 65–70% in clinical trials, and durable responses of a year or more are seen in a meaningful proportion of patients. Your oncologist will discuss which drug is appropriate for your situation and what side effects to expect.
High-level primary MET amplification (no exon 14 skipping). High-level MET gene amplification without an accompanying exon 14 skipping mutation is considered potentially targetable, though the evidence base is less mature than for exon 14 skipping. Some clinical trial data support the use of MET inhibitors in this setting, and several ongoing trials are specifically studying high-level MET-amplified NSCLC. Your oncologist may discuss MET inhibitor therapy or clinical trial participation as options, depending on whether other actionable alterations are present and what prior treatments have been received.
Low-level MET amplification. Low-level increases in MET copy number are common in lung cancer and are generally not considered clinically actionable as a standalone finding. They do not currently predict benefit from MET inhibitor therapy. Low-level amplification may appear as an incidental finding on comprehensive NGS panels and should not be confused with high-level, therapeutically significant amplification.
Acquired MET amplification at progression on EGFR TKI. If you have EGFR-mutated lung cancer and your cancer is progressing on an EGFR inhibitor, detection of MET amplification on repeat testing identifies a bypass resistance mechanism. This finding supports the strategy of combining a MET inhibitor with continued EGFR inhibitor therapy to re-establish disease control. Several clinical trials have demonstrated meaningful response rates with EGFR plus MET inhibitor combinations — including amivantamab (which targets both EGFR and MET) combined with lazertinib in the MARIPOSA trial — and this is an active and evolving area of clinical practice. Your oncologist will discuss whether a combination approach or clinical trial is appropriate.
No MET alteration detected. No MET exon 14 skipping or significant amplification was identified. Based on this result, MET-targeted therapy is not indicated. The full molecular profile will guide treatment decisions.

MET alterations and other lung cancer biomarkers

MET exon 14 skipping mutations occur largely independently of other major driver alterations — they are rarely found alongside EGFR mutations, ALK rearrangements, or KRAS mutations in treatment-naive patients. This mutual exclusivity supports the conclusion that MET exon 14 skipping is itself a primary driver of the cancer’s growth, rather than a secondary change.

Acquired MET amplification, by contrast, occurs specifically in the context of prior EGFR TKI therapy and co-exists with the original EGFR mutation — it is a secondary change that arises under the selective pressure of treatment. The distinction between primary and acquired MET alteration is therefore not just biological but directly shapes the treatment approach.

PD-L1 expression is also tested in all NSCLC patients and reported separately. In MET exon 14 skipping-positive lung cancers, targeted MET inhibitor therapy is generally preferred over immunotherapy as the initial treatment. However, the interaction between MET status and immunotherapy benefit is an active area of study.

MET alterations: germline vs. somatic

MET alterations found in lung cancer — including exon 14 skipping and amplification — are somatic, arising within the cancer cells during the patient’s lifetime and not inherited. Germline MET mutations are associated with a rare hereditary condition called hereditary papillary renal cell carcinoma, but this is entirely distinct from the somatic MET alterations found in lung cancer. Patients with a somatic MET alteration in their lung tumour do not need to worry about passing it to their children, and family members do not require MET screening on this basis.

What happens next

If MET exon 14 skipping is found: Your oncologist will discuss MET inhibitor therapy — capmatinib or tepotinib — as a first-line option for advanced disease. Both are taken as daily oral tablets. Your oncologist will review expected side effects, monitoring requirements, and what to watch for. Brain imaging may be recommended, as brain metastases occur in a meaningful proportion of patients with MET exon 14 skipping-positive NSCLC.
If high-level primary MET amplification is found: Your oncologist will assess whether MET inhibitor therapy or clinical trial participation is appropriate based on your full molecular profile and treatment history.
If acquired MET amplification is identified at progression on an EGFR TKI, A combination strategy targeting both EGFR and MET will be discussed. Clinical trial options should be explored, as this is an active area of drug development with multiple studies currently enrolling.
If no MET alteration is found, the full molecular panel results will guide treatment. If no targetable alteration is identified, treatment will be based on PD-L1 expression and may include immunotherapy, chemotherapy, or a combination of both.

Questions to ask your doctor

Has my tumour been tested for MET exon 14 skipping, and what method was used?
Does my tumour have MET gene amplification, and if so, is it high-level or low-level?
If I have MET exon 14 skipping, which drug — capmatinib or tepotinib — is recommended for me, and why?
Do I have brain metastases, and how does that affect my treatment plan?
If my cancer previously progressed on an EGFR inhibitor, was MET amplification tested as a possible resistance mechanism?
Are there clinical trials studying MET-targeted treatments that I might be eligible for?
What other biomarkers have been tested, and were any other actionable alterations found?
If my cancer progresses on a MET inhibitor, will re-testing be done to identify the resistance mechanism?