{"entity":{"id":"paper-wolf-geometry-mono-1-capmatinib-nejm-2020","kind":"paper","name":"Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer","aka":[],"tldr":"MET exon 14 skipping is found in 3 to 4 percent of lung cancers. Untreated patients given capmatinib responded 68 percent of the time; those already treated, 41 percent. Order of treatment mattered more than usual.","summary":"The GEOMETRY mono-1 investigators, reported by Wolf, Seto, Han and colleagues, assigned 364 patients with MET-dysregulated advanced non-small-cell lung cancer to cohorts by previous lines of therapy and MET status (exon 14 skipping mutation, or amplification by gene copy number), all receiving capmatinib 400 mg twice daily. The primary endpoint was overall response by independent review.\n\nIt is the trial that separated the two ways MET goes wrong. Exon 14 skipping behaves like a classical driver; amplification only behaves like one above a gene copy number of 10, and below that threshold the drug barely works. Few targets in lung cancer have so clear a dose-of-target effect.","asOf":"2026-09-25","links":[{"label":"N Engl J Med 2020","url":"https://doi.org/10.1056/NEJMoa2002787"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/32877583/"},{"label":"ClinicalTrials.gov NCT02414139","url":"https://clinicaltrials.gov/study/NCT02414139"}],"tags":["lung-evidence"],"related":["paper-frampton-met-exon-14-cancer-discov-2015","paper-cho-mariposa-amivantamab-lazertinib-nejm-2024"],"cancers":["lung-cancer","nsclc","met-altered-nsclc"],"sections":["targeted-therapy","diagnostics"],"technologies":["ngs","kinase-inhibitors"],"targets":["met"],"drugs":["capmatinib","tepotinib"],"companies":["novartis"],"institutions":[],"pathways":[],"terms":["driver-mutation"],"trials":["geometry-mono-1"],"people":[],"bottlenecks":["b-biomarker-validation","b-rare-cancers","b-dose-optimisation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2020,"doi":"10.1056/NEJMoa2002787","pmid":"32877583","authors":"Wolf J, Seto T, Han JY, et al.","paperType":"rct","findings":["In MET exon 14 skipping disease, overall response 68 percent (95 percent confidence interval 48 to 84) in 28 previously untreated patients and 41 percent (29 to 53) in 69 previously treated patients.","Median duration of response 12.6 months in the untreated group and 9.7 months (5.6 to 13.0) in the previously treated group.","In MET amplification with a gene copy number of 10 or higher, response was 40 percent (16 to 68) in untreated and 29 percent (19 to 41) in previously treated patients.","In previously treated patients with MET amplification and a gene copy number below 10, response was 7 to 12 percent.","MET exon 14 skipping mutations occur in 3 to 4 percent of non-small-cell lung cancer and MET amplifications in 1 to 6 percent.","The commonest adverse events were peripheral oedema (51 percent) and nausea (45 percent), mostly grade 1 or 2."],"whatItMeans":"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.","caveats":["Single-arm cohort study with response as the primary endpoint; no randomised comparison against chemotherapy or immunotherapy.","Heavily cohort-dependent results, and the untreated cohorts are small (28 patients for the headline 68 percent).","MET exon 14 skipping is detected differently by DNA and RNA assays, and the false-negative rate of DNA-only panels is a live problem."],"changedPractice":true,"participants":364},"route":"/key-papers/paper-wolf-geometry-mono-1-capmatinib-nejm-2020/","neighbours":{"paper":[{"id":"paper-cho-mariposa-amivantamab-lazertinib-nejm-2024","kind":"paper","name":"Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC","route":"/key-papers/paper-cho-mariposa-amivantamab-lazertinib-nejm-2024/"},{"id":"paper-frampton-met-exon-14-cancer-discov-2015","kind":"paper","name":"MET exon 14 splicing alterations across tumour types and their sensitivity to MET inhibitors","route":"/key-papers/paper-frampton-met-exon-14-cancer-discov-2015/"}],"cancer":[{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"met-altered-nsclc","kind":"cancer","name":"MET exon 14 and MET-amplified non-small-cell lung cancer","route":"/cancers/met-altered-nsclc/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"section":[{"id":"diagnostics","kind":"section","name":"Diagnostics & Biomarkers","route":"/fronts/diagnostics/"},{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"term":[{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"}],"technology":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"met","kind":"target","name":"MET","route":"/targets/met/"}],"drug":[{"id":"capmatinib","kind":"drug","name":"Capmatinib","route":"/drugs/capmatinib/"},{"id":"tepotinib","kind":"drug","name":"Tepotinib","route":"/drugs/tepotinib/"}],"company":[{"id":"novartis","kind":"company","name":"Novartis","route":"/companies/novartis/"}],"trial":[{"id":"geometry-mono-1","kind":"trial","name":"GEOMETRY mono-1","route":"/trials/geometry-mono-1/"}],"bottleneck":[{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"},{"id":"b-dose-optimisation","kind":"bottleneck","name":"Wrong doses","route":"/bottlenecks/b-dose-optimisation/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}],"roadmap":[{"id":"lung-cancer-evidence-roadmap","kind":"roadmap","name":"Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch","route":"/roadmaps/lung-cancer-evidence-roadmap/"}]}}