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T790M is the gatekeeper mutation that lung cancers acquire to escape first- and second-generation EGFR inhibitors. Finding it, in tissue or blood, is the historic gate for osimertinib after an earlier EGFR drug.
The c.2369C>T (T790M) substitution in exon 20 enlarges the ATP-binding pocket's affinity for ATP and confers resistance to erlotinib, gefitinib and afatinib; it arose in about half of patients progressing on those drugs. Osimertinib's 2015 accelerated approval (AURA) was for metastatic EGFR T790M-positive NSCLC after an EGFR TKI, detected by the cobas EGFR Mutation Test v2 in tissue or plasma, the first plasma companion diagnostic. That indication remains on the label, though first-line osimertinib has made acquired T790M uncommon. FoundationOne CDx and Guardant360 CDx also list T790M in their EGFR claims.
In plain words · A growth receptor that is mutated in some lung cancers and overproduced in others; the first great success of targeted pills.
If your lung cancer grew on erlotinib, gefitinib or afatinib and a T790M mutation is found, osimertinib is the on-label next step. The mutation can often be detected in a blood sample; if the blood test is negative the tumour should be biopsied, because blood misses it in a fair share of patients.
Written only from the label or guideline text cited on this page. Not medical advice; your own report and the reading your team gives it come first.
The EGFR exon 20 c.2369C>T (p.T790M) substitution detected in tumour tissue or plasma cell-free DNA; a negative plasma result should prompt tissue testing.
“EGFR exon 19 deletions, EGFR exon 21 L858R, and T790M”
FDA: List of FDA-Authorized Companion Diagnostic Devices| Threshold | Drug | Cancer | Regulator | Source |
|---|---|---|---|---|
| EGFR T790M after prior EGFR TKI Indication 1.4 of the osimertinib label: metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR TKI therapy. | Osimertinib | Non-small-cell lung cancer | FDA | label |
| Device | Maker | Indication and sample | Drug | PMA / 510(k) |
|---|---|---|---|---|
| cobas EGFR Mutation Test v2 | Roche Molecular Systems | Non-Small Cell Lung Cancer (NSCLC) - Plasma | Osimertinib | P150044 (09/28/2016) |
Matched on the name and aliases of the readout in the title, setting and summary of each trial; a match is a mention, not proof the readout was an entry criterion.
It is the practical guide to what to do after transformation: treat it as small-cell lung cancer with platinum and etoposide, expect central nervous system disease, and do not expect a checkpoint inhibitor to help.
It changed how resistance is investigated: the first question at progression on osimertinib is whether T790M is still there, because losing it means the tumour is no longer EGFR-driven in the growing compartment and another EGFR inhibitor will not help.
It is the document that defines what a complete lung cancer molecular report looks like, and its asymmetry about plasma, rule in but never rule out, is the single most useful sentence in it.
One term page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
It is the reference frequency table for resistance to first-generation EGFR inhibitors, and it made rebiopsy at progression standard rather than exceptional, because the mechanism decides the next treatment and cannot be guessed.
The case for re-biopsy at progression, for treating resistance as a diagnosis rather than an endpoint, and for the idea of a drug holiday. It is also the origin of resistance-directed sequencing: what you give next should depend on what the tumour became.
It generalised the single-patient finding and made the point that drug-resistant subclones are selected by treatment rather than created by it, which is the model the whole field now works with.
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.
Shares EGFR exon 19 deletion, EGFR mutation subtypes (exon 19 deletion, L858R, exon 20 insertion, T790M), Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors, EGFR and the tags biomarker, egfr.
Shares Non-small-cell lung cancer and the tags biomarker, resistance.
Shares the tags biomarker, resistance.
Shares the tags biomarker, resistance.
Shares the tags biomarker, resistance.
Shares On-target resistance mutations (gatekeeper, solvent-front, compound) and the tags biomarker, resistance.
Shares the tags biomarker, resistance.
Shares the tags biomarker, resistance.