# Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib

Source: https://onco.cc/key-papers/paper-oxnard-osimertinib-resistance-mechanisms-jama-oncol-2018/  
OnCo record `paper-oxnard-osimertinib-resistance-mechanisms-jama-oncol-2018` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

When the newest targeted pill stops working, what happens next depends on whether the tumour kept the mutation the pill was chosen for. Two thirds lost it, and those patients relapsed much sooner and by many different routes.

## Summary

Patients with advanced non-small-cell lung cancer who received osimertinib for T790M-positive acquired resistance to a prior EGFR inhibitor were identified from a multi-institutional cohort of 143 and a confirmatory trial cohort of 110, with next-generation sequencing of tumour biopsies after resistance and plasma cell-free DNA genotyping as an orthogonal approach. Of 41 patients with tumour sequencing after resistance, 13, 32%, maintained T790M, and EGFR C797S was seen in 9, 22%. Among the 28, 68%, with loss of T790M, a range of competing mechanisms was detected including acquired KRAS mutations and targetable gene fusions. Time to treatment discontinuation was shorter with T790M loss, 6.1 against 15.2 months, suggesting emergence of pre-existing resistant clones, a finding confirmed in the plasma validation cohort. In serial plasma, loss of T790M at resistance was associated with a smaller decrease in the driver EGFR mutation level after one to three weeks of therapy, 100% against 83% decrease.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: JAMA Oncology
- Year: 2018
- DOI: 10.1001/jamaoncol.2018.2969
- Authors: Oxnard GR, Hu Y, Mileham KF, et al.
- Findings: T790M maintained in 32% of resistant tumours, with C797S in 22%.; T790M lost in 68%, with heterogeneous competing mechanisms including KRAS mutation and new fusions.; Time to treatment discontinuation 6.1 months with T790M loss against 15.2 months when it was kept.; Early plasma kinetics separate the two groups within three weeks of starting treatment.
- What it means: 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.
- Caveats: Only 41 of 143 patients had tumour sequencing, so the mechanism frequencies rest on a subset.; Plasma and tissue detect partly different things.; Multi-institutional retrospective design.

## Sources

- Oxnard et al., JAMA Oncol 2018: resistance mechanisms after osimertinib in T790M-positive lung cancer (143 and 110 patients): https://doi.org/10.1001/jamaoncol.2018.2969
- PubMed: https://pubmed.ncbi.nlm.nih.gov/30073261/

## Connected records

- biomarkers: [EGFR C797S (and its phase with T790M)](https://onco.cc/biomarkers/egfr-c797s/), [EGFR T790M](https://onco.cc/biomarkers/egfr-t790m/)
- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Continuous and near-continuous ctDNA monitoring](https://onco.cc/technologies/continuous-ctdna-monitoring/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [KRAS](https://onco.cc/targets/kras/), [MET](https://onco.cc/targets/met/)
- drugs: [Guardant360 CDx](https://onco.cc/drugs/guardant360-cdx/), [Osimertinib](https://onco.cc/drugs/osimertinib/)
- institutions: [Dana-Farber Brigham Cancer Center](https://onco.cc/institutions/dana-farber/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [Drug-tolerant persister cells](https://onco.cc/pathways/drug-tolerant-persisters/), [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/)
- terms: [Biopsy](https://onco.cc/terms/biopsy/), [Cell-free DNA (cfDNA)](https://onco.cc/terms/cfdna/), [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [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/)
- people: [Pasi A. Jänne](https://onco.cc/people/pasi-janne/)
- journals: [JAMA Oncology](https://onco.cc/journals/jama-oncology/)

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