# EGFR mutation and resistance of non-small-cell lung cancer to gefitinib

Source: https://onco.cc/key-papers/paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005/  
OnCo record `paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

A 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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Tags: lung-evidence
- Journal: New England Journal of Medicine
- Year: 2005
- DOI: 10.1056/NEJMoa044238
- Authors: Kobayashi S, Boggon TJ, Dayaram T, et al.
- 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.
- What it means: 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.

## Sources

- N Engl J Med 2005: https://doi.org/10.1056/NEJMoa044238
- PubMed: https://pubmed.ncbi.nlm.nih.gov/15728811/
- Kobayashi et al., N Engl J Med 2005: EGFR T790M and resistance of non-small-cell lung cancer to gefitinib: https://doi.org/10.1056/NEJMoa044238

## Connected records

- key papers: [Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib](https://onco.cc/key-papers/paper-lynch-egfr-activating-mutations-gefitinib-nejm-2004/), [Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors](https://onco.cc/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/), [Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer](https://onco.cc/key-papers/paper-osimertinib-nsclc-n-engl-j-med-2017/)
- biomarkers: [EGFR T790M](https://onco.cc/biomarkers/egfr-t790m/)
- cancers: [EGFR-mutated non-small-cell lung cancer](https://onco.cc/cancers/egfr-mutant-nsclc/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- fronts: [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- terms: [Driver mutation](https://onco.cc/terms/driver-mutation/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [EGFR mutation subtypes (exon 19 deletion, L858R, exon 20 insertion, T790M)](https://onco.cc/terms/egfr-mutation-subtypes/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/)
- technologies: [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [EGFR](https://onco.cc/targets/egfr/)
- drugs: [Gefitinib](https://onco.cc/drugs/gefitinib/), [Osimertinib](https://onco.cc/drugs/osimertinib/)
- institutions: [Dana-Farber Brigham Cancer Center](https://onco.cc/institutions/dana-farber/)
- pathways: [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/), [Resistance routes: how a blocked pathway comes back](https://onco.cc/pathways/resistance-routes-map/)
- people: [Matthew Meyerson](https://onco.cc/people/matthew-meyerson/), [Pasi A. Jänne](https://onco.cc/people/pasi-janne/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)
- roadmaps: [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](https://onco.cc/roadmaps/lung-cancer-evidence-roadmap/)
- ideas: [Make resistance a diagnosis: sequence at every progression and choose the next line from what the tumour became](https://onco.cc/ideas/idea-lung-resistance-directed-sequencing-at-every-progression/)

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