{"entity":{"id":"paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005","kind":"paper","name":"EGFR mutation and resistance of non-small-cell lung cancer to gefitinib","aka":[],"tldr":"One patient, two years in complete remission on gefitinib, then relapse. Sequencing the new biopsy found a second mutation in the same gene, at position 790, that stopped the drug binding.","summary":"Kobayashi, Boggon, Dayaram and colleagues at Beth Israel Deaconess and Dana-Farber reported a patient with EGFR-mutant, gefitinib-responsive advanced non-small-cell lung cancer who relapsed after two years of complete remission. The biopsy at relapse carried a second point mutation producing a threonine-to-methionine change at position 790 of EGFR, and structural modelling with biochemical studies showed this second mutation caused the resistance.\n\nA single case report that changed a field. T790M went on to account for roughly half of acquired resistance to first-generation EGFR inhibitors, and the drug built against it, osimertinib, is now the first-line standard. The chain from one re-biopsy to a global standard of care is the strongest argument in oncology for biopsying at progression.","asOf":"2026-09-25","links":[{"label":"N Engl J Med 2005","url":"https://doi.org/10.1056/NEJMoa044238"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/15728811/"},{"label":"Kobayashi et al., N Engl J Med 2005: EGFR T790M and resistance of non-small-cell lung cancer to gefitinib","url":"https://doi.org/10.1056/NEJMoa044238"}],"tags":["lung-evidence"],"related":["paper-lynch-egfr-activating-mutations-gefitinib-nejm-2004","paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011","paper-osimertinib-nsclc-n-engl-j-med-2017","egfr-t790m"],"cancers":["lung-cancer","nsclc","egfr-mutant-nsclc"],"sections":["targeted-therapy"],"technologies":["ngs","kinase-inhibitors"],"targets":["egfr"],"drugs":["gefitinib","osimertinib"],"companies":[],"institutions":["dana-farber"],"pathways":["rtk-activation","resistance-routes-map"],"terms":["resistance","driver-mutation","egfr-mutation-subtypes"],"trials":[],"people":["pasi-janne","matthew-meyerson"],"bottlenecks":["b-resistance","b-tumor-heterogeneity"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2005,"doi":"10.1056/NEJMoa044238","pmid":"15728811","authors":"Kobayashi S, Boggon TJ, Dayaram T, et al.","paperType":"translational","findings":["A second point mutation in EGFR, threonine to methionine at position 790, was present in the relapse biopsy of a patient who had a two-year complete remission on gefitinib.","Structural modelling and biochemical studies showed this second mutation led to gefitinib resistance.","A second EGFR mutation, T790M, appeared at relapse after two years of complete remission.","Structural and biochemical work showed the substitution blocks gefitinib binding.","The mutation was in the same gene as the sensitising one, on the same allele."],"whatItMeans":"Resistance to a targeted drug usually has a cause you can read off a sequence, which means it can be targeted in turn. Osimertinib exists because of this paper.","caveats":["A single patient; the frequency of T790M came from the case series that followed.","T790M is the commonest but not the only mechanism; MET amplification, small-cell transformation and others account for the rest.","Third-generation inhibitors select for their own resistance mutations, notably C797S, so the cycle continues.","A single patient.","It could not say how often T790M causes resistance, which took the later rebiopsy series.","Pre-existing low-level T790M was not measurable with the methods of the time."],"changedPractice":true,"participants":1},"route":"/key-papers/paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005/","neighbours":{"paper":[{"id":"paper-lynch-egfr-activating-mutations-gefitinib-nejm-2004","kind":"paper","name":"Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib","route":"/key-papers/paper-lynch-egfr-activating-mutations-gefitinib-nejm-2004/"},{"id":"paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011","kind":"paper","name":"Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors","route":"/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/"},{"id":"paper-osimertinib-nsclc-n-engl-j-med-2017","kind":"paper","name":"Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer","route":"/key-papers/paper-osimertinib-nsclc-n-engl-j-med-2017/"}],"biomarker":[{"id":"egfr-t790m","kind":"biomarker","name":"EGFR T790M","route":"/biomarkers/egfr-t790m/"}],"cancer":[{"id":"egfr-mutant-nsclc","kind":"cancer","name":"EGFR-mutated non-small-cell lung cancer","route":"/cancers/egfr-mutant-nsclc/"},{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"section":[{"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":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"egfr-mutation-subtypes","kind":"term","name":"EGFR mutation subtypes (exon 19 deletion, L858R, exon 20 insertion, T790M)","route":"/terms/egfr-mutation-subtypes/"},{"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":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"}],"drug":[{"id":"gefitinib","kind":"drug","name":"Gefitinib","route":"/drugs/gefitinib/"},{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}],"institution":[{"id":"dana-farber","kind":"institution","name":"Dana-Farber Brigham Cancer Center","route":"/institutions/dana-farber/"}],"pathway":[{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"}],"person":[{"id":"matthew-meyerson","kind":"person","name":"Matthew Meyerson","route":"/people/matthew-meyerson/"},{"id":"pasi-janne","kind":"person","name":"Pasi A. Jänne","route":"/people/pasi-janne/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/"}],"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/"}],"idea":[{"id":"idea-lung-resistance-directed-sequencing-at-every-progression","kind":"idea","name":"Make resistance a diagnosis: sequence at every progression and choose the next line from what the tumour became","route":"/ideas/idea-lung-resistance-directed-sequencing-at-every-progression/"}]}}