{"entity":{"id":"met-altered-nsclc","kind":"cancer","name":"MET exon 14 and MET-amplified non-small-cell lung cancer","aka":["MET exon 14 skipping lung cancer","METex14 NSCLC","MET-amplified lung cancer","c-Met overexpressing NSCLC"],"tldr":"MET-driven lung cancer comes in three forms: an exon 14 skipping mutation treated with the pills capmatinib or tepotinib, MET amplification that often arises as an escape route from EGFR drugs, and high c-Met protein levels that the antibody-drug conjugate telisotuzumab vedotin targets.","summary":"MET exon 14 skipping mutations remove the domain that marks the receptor for degradation, so it accumulates and signals persistently; they were shown to be targetable in 2015 when patients responded to crizotinib. Capmatinib (GEOMETRY mono-1, 2020) produced response rates of 68 percent in treatment-naive and 41 percent in previously treated patients and received accelerated approval in May 2020, and tepotinib (VISION, 2020) a 46 percent response rate with approval in February 2021; both are brain-penetrant and cause peripheral oedema. Savolitinib is approved in China for the same mutation, including sarcomatoid tumours. Checkpoint inhibitors work poorly despite frequent PD-L1 expression, and exon 14 patients who are fit and untreated are usually given the MET inhibitor first.\n\nMET amplification behaves differently by context. De novo high-level amplification (gene copy number 10 or more) responds to capmatinib in about a third of patients; low-level amplification does not. As acquired resistance to osimertinib, MET amplification is treated by adding a MET inhibitor to osimertinib: the SAVANNAH and SACHI trials of osimertinib plus savolitinib showed high response rates in patients selected by MET testing, and SACHI led to approval of the combination in China in 2025. Amivantamab, the EGFR-MET bispecific antibody, covers MET-mediated resistance in EGFR-mutated disease as well.\n\nc-Met protein overexpression without a MET genomic alteration is the target of telisotuzumab vedotin, an antibody-drug conjugate with a microtubule payload: LUMINOSITY reported a 35 percent response rate in non-squamous EGFR wild-type tumours with high c-Met expression, and the drug received accelerated approval in May 2025, with TeliMET NSCLC-01 comparing it with docetaxel. Open questions are the best MET inhibitor sequence, whether MET inhibitors should be combined with chemotherapy or immunotherapy first line, and how to define MET amplification consistently across assays.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/C-Met","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/C-Met"},{"label":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}],"tags":["subtype-page","lung"],"related":[],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","adc","bispecific-antibody","cgp"],"targets":["met","egfr"],"drugs":["capmatinib","tepotinib","capmatinib-tepotinib","savolitinib","telisotuzumab-vedotin","telisotuzumab-adizutecan","amivantamab","crizotinib"],"companies":["novartis","merck-kgaa","astrazeneca","abbvie","hengrui"],"institutions":[],"pathways":["nsclc-signalling","rtk-activation"],"terms":["met-amplification","resistance","driver-mutation","tki-term"],"trials":["geometry-mono-1","nct02864992","luminosity","telimet-nsclc-01","nct03778229"],"people":["ross-camidge","alexander-drilon"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"MET exon 14 skipping mutations occur in 3 to 4 percent of non-small-cell lung cancers, typically in older patients and enriched in sarcomatoid tumours; de novo high-level MET amplification in 1 to 2 percent; and MET amplification appears as a resistance mechanism in about 15 percent of EGFR-mutated cancers after osimertinib. About a quarter of non-squamous lung cancers overexpress the c-Met protein.","subtypes":["MET exon 14 skipping adenocarcinoma or sarcomatoid carcinoma (capmatinib, tepotinib)","De novo high-level MET amplification (gene copy number 10 or more)","MET amplification as acquired resistance in EGFR-mutated adenocarcinoma (osimertinib plus savolitinib, amivantamab)","c-Met protein overexpression without a genomic alteration (telisotuzumab vedotin)"],"biomarkers":["MET exon 14 skipping by RNA or DNA sequencing (DNA panels miss some intronic variants)","MET gene copy number by fluorescence in situ hybridisation or sequencing","c-Met immunohistochemistry (3+ in 50 percent or more of cells for telisotuzumab vedotin)","MET amplification in plasma or tissue at progression on osimertinib","Peripheral oedema and creatinine on MET inhibitors"],"standardOfCare":[{"setting":"Advanced MET exon 14, first line or later","approach":"Capmatinib (GEOMETRY mono-1) or tepotinib (VISION); platinum-pemetrexed with or without pembrolizumab if the inhibitor is not tolerated or after it.","refs":["capmatinib","geometry-mono-1","tepotinib","nct02864992","capmatinib-tepotinib","pemetrexed","carboplatin"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"MET amplification after osimertinib in EGFR-mutated disease","approach":"Osimertinib plus savolitinib (SAVANNAH, SACHI) where available; amivantamab plus chemotherapy; platinum-pemetrexed.","refs":["osimertinib","savolitinib","nct03778229","amivantamab","nct04988295","met-amplification"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"c-Met overexpression, previously treated non-squamous","approach":"Telisotuzumab vedotin (LUMINOSITY) after platinum chemotherapy; TeliMET NSCLC-01 versus docetaxel is confirmatory.","refs":["telisotuzumab-vedotin","luminosity","telimet-nsclc-01","docetaxel"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}}],"stateOfArt":["Two approved brain-penetrant MET inhibitors for exon 14 skipping with response rates of 40 to 70 percent.","Osimertinib plus savolitinib for MET-amplified resistance in EGFR-mutated disease (SACHI, approved in China).","Telisotuzumab vedotin, the first antibody-drug conjugate for a lung cancer selected by protein expression, approved in 2025."],"history":[{"year":2015,"title":"MET exon 14 skipping shown to be a targetable driver with crizotinib responses","refs":["met","crizotinib"]},{"year":2020,"title":"GEOMETRY mono-1: capmatinib approved; VISION: tepotinib reported","refs":["geometry-mono-1","capmatinib","nct02864992","tepotinib"]},{"year":2021,"title":"Tepotinib approved; savolitinib approved in China","refs":["tepotinib","savolitinib"]},{"year":2024,"title":"LUMINOSITY: telisotuzumab vedotin response rate 35 percent in c-Met high tumours","refs":["luminosity","telisotuzumab-vedotin"]},{"year":2025,"title":"Telisotuzumab vedotin approved; SACHI: osimertinib plus savolitinib for MET-amplified resistance","refs":["telisotuzumab-vedotin","savolitinib","osimertinib"]}],"pipeline":["telimet-nsclc-01","telisotuzumab-adizutecan","savolitinib","nct03778229","amivantamab"],"openProblems":["MET amplification has no agreed threshold and results differ between assays.","Peripheral oedema limits the dose of every MET inhibitor and has no good treatment.","Whether MET inhibitors should be combined with chemotherapy or immunotherapy first line in exon 14 disease is untested."],"parent":"nsclc"},"route":"/cancers/met-altered-nsclc/","neighbours":{"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"bispecific-antibody","kind":"technology","name":"Bispecific antibodies","route":"/technologies/bispecific-antibody/"},{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"met","kind":"target","name":"MET","route":"/targets/met/"}],"drug":[{"id":"amivantamab","kind":"drug","name":"Amivantamab","route":"/drugs/amivantamab/"},{"id":"capmatinib","kind":"drug","name":"Capmatinib","route":"/drugs/capmatinib/"},{"id":"capmatinib-tepotinib","kind":"drug","name":"Capmatinib & tepotinib","route":"/drugs/capmatinib-tepotinib/"},{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/"},{"id":"crizotinib","kind":"drug","name":"Crizotinib","route":"/drugs/crizotinib/"},{"id":"docetaxel","kind":"drug","name":"Docetaxel","route":"/drugs/docetaxel/"},{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"pemetrexed","kind":"drug","name":"Pemetrexed","route":"/drugs/pemetrexed/"},{"id":"savolitinib","kind":"drug","name":"Savolitinib","route":"/drugs/savolitinib/"},{"id":"telisotuzumab-adizutecan","kind":"drug","name":"Telisotuzumab adizutecan","route":"/drugs/telisotuzumab-adizutecan/"},{"id":"telisotuzumab-vedotin","kind":"drug","name":"Telisotuzumab vedotin","route":"/drugs/telisotuzumab-vedotin/"},{"id":"tepotinib","kind":"drug","name":"Tepotinib","route":"/drugs/tepotinib/"}],"company":[{"id":"abbvie","kind":"company","name":"AbbVie (incl. ImmunoGen, Capstan)","route":"/companies/abbvie/"},{"id":"astrazeneca","kind":"company","name":"AstraZeneca","route":"/companies/astrazeneca/"},{"id":"hengrui","kind":"company","name":"Jiangsu Hengrui Pharmaceuticals","route":"/companies/hengrui/"},{"id":"merck-kgaa","kind":"company","name":"Merck KGaA (EMD Serono)","route":"/companies/merck-kgaa/"},{"id":"novartis","kind":"company","name":"Novartis","route":"/companies/novartis/"}],"pathway":[{"id":"nsclc-signalling","kind":"pathway","name":"Non-small cell lung cancer (KEGG map)","route":"/pathways/nsclc-signalling/"},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"}],"term":[{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"met-amplification","kind":"term","name":"MET amplification (bypass resistance)","route":"/terms/met-amplification/"},{"id":"tki-term","kind":"term","name":"Tyrosine kinase inhibitor (TKI)","route":"/terms/tki-term/"}],"trial":[{"id":"nct04988295","kind":"trial","name":"A Study of Amivantamab and Lazertinib in Combination With Platinum-Based Chemotherapy Compared With Platinum-Based Chemotherapy in Patients With Epidermal Growth Factor Receptor (EGFR)-Mutated Locally Advanced or Metastatic Non- Small Cell Lung Cancer After Osimertinib Failure","route":"/trials/nct04988295/"},{"id":"geometry-mono-1","kind":"trial","name":"GEOMETRY mono-1","route":"/trials/geometry-mono-1/"},{"id":"luminosity","kind":"trial","name":"LUMINOSITY","route":"/trials/luminosity/"},{"id":"nct03778229","kind":"trial","name":"Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib","route":"/trials/nct03778229/"},{"id":"telimet-nsclc-01","kind":"trial","name":"TeliMET NSCLC-01","route":"/trials/telimet-nsclc-01/"},{"id":"nct02864992","kind":"trial","name":"Tepotinib Phase II in NSCLC Harboring MET Alterations (VISION)","route":"/trials/nct02864992/"}],"person":[{"id":"alexander-drilon","kind":"person","name":"Alexander Drilon","route":"/people/alexander-drilon/"},{"id":"ross-camidge","kind":"person","name":"D. Ross Camidge","route":"/people/ross-camidge/"}],"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}]}}