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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.
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.
MET 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.
c-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.
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.
Central tumours arise in the large airways, peripheral ones in the alveoli; both drain to hilar then mediastinal nodes, and the pleural lining is a separate cancer site.
Same organ: Mediastinal germ cell tumour, Pleuropulmonary blastoma (types I, Ir, II and III), Type A and type AB thymoma, Type B1 and type B2 thymoma, Type B3 thymoma, Micronodular thymoma with lymphoid stroma, Adenocarcinoma of the lung, Squamous cell carcinoma of the lung, Large cell carcinoma of the lung, Sarcomatoid carcinoma of the lung, Adenosquamous carcinoma of the lung, Invasive mucinous adenocarcinoma of the lung, Adenocarcinoma in situ and minimally invasive adenocarcinoma of the lung, Basaloid squamous cell carcinoma of the lung, Lymphoepithelial carcinoma of the lung, Pulmonary blastoma (adult), Non-small-cell lung cancer, Lung cancer (all types), Small-cell lung cancer, Mesothelioma, Pleural mesothelioma, Thymoma and thymic carcinoma, Childhood lung and airway tumours (pleuropulmonary blastoma, tracheobronchial tumours), Inflammatory myofibroblastic tumour (IMT), EGFR-mutated non-small-cell lung cancer, ALK-positive non-small-cell lung cancer, KRAS G12C-mutant non-small-cell lung cancer, ROS1-positive non-small-cell lung cancer, RET fusion-positive non-small-cell lung cancer, BRAF V600E-mutant non-small-cell lung cancer, HER2-mutant non-small-cell lung cancer, NTRK fusion-positive non-small-cell lung cancer, PD-L1-high non-small-cell lung cancer without a driver mutation, Resectable stage I to III non-small-cell lung cancer, Unresectable stage III non-small-cell lung cancer, Limited-stage small-cell lung cancer, Extensive-stage small-cell lung cancer, Lung neuroendocrine tumours (typical and atypical carcinoid), Large cell neuroendocrine carcinoma of the lung, Thymoma (WHO types A, AB, B1, B2 and B3), Thymic carcinoma
Capmatinib (GEOMETRY mono-1) or tepotinib (VISION); platinum-pemetrexed with or without pembrolizumab if the inhibitor is not tolerated or after it.
Osimertinib plus savolitinib (SAVANNAH, SACHI) where available; amivantamab plus chemotherapy; platinum-pemetrexed.
Telisotuzumab vedotin (LUMINOSITY) after platinum chemotherapy; TeliMET NSCLC-01 versus docetaxel is confirmatory.
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A rare driver with a real drug, and a warning about biomarker thresholds: the same gene, tested the same way, predicts response or does not depending on a copy-number cut-off that has to be measured rather than assumed.
Tepotinib is an approved alternative to capmatinib for MET exon 14 lung cancer, and the trial validated circulating tumour DNA as a way to find the alteration.
The paper established MET exon 14 skipping as a bona fide lung cancer driver and showed why RNA-based or broad DNA testing is needed to detect it, paving the way for capmatinib and tepotinib.
Query for this cancer: (TITLE:"MET exon 14 and MET-amplified non-small-cell lung cancer" OR ABSTRACT:"MET exon 14 and MET-amplified non-small-cell lung cancer" OR TITLE:"MET exon 14 skipping lung cancer" OR ABSTRACT:"MET exon 14 skipping lung cancer" OR TITLE:"METex14 NSCLC" OR ABSTRACT:"METex14 NSCLC" OR TITLE:"MET-amplified lung cancer" OR ABSTRACT:"MET-amplified lung cancer" OR TITLE:"c-Met overexpressing NSCLC" OR ABSTRACT:"c-Met overexpressing NSCLC") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about MET exon 14 and MET-amplified non-small-cell lung cancer, not a curated reading list.
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Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
Temperature of 38 C or higher, or feeling shivery and unwell even without a fever. Antibody-drug conjugates suppress the bone marrow, and several carry a boxed warning for severe neutropenia.
No food effect (intravenous or subcutaneous antibody).
Capmatinib: photosensitivity, use sun protection. Tepotinib: take with food.
Known QT prolongation. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.
See all on the product pages:AmivantamabCapmatinibCapmatinib & tepotinibCarboplatinDocetaxelOsimertinibPemetrexedSavolitinibTelisotuzumab vedotinTepotinib·Printable cards in the navigator
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