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Outcomes in patients with non-small-cell lung cancer and acquired Thr790Met mutation treated with osimertinib: a genomic study
Abstract
Background Osimertinib is approved for the treatment of non-small-cell lung cancer in patients who develop the EGFR Thr790Met mutation after treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs). We assessed outcomes in patients with non-small-cell lung cancer and the EGFR Thr790Met mutation who were treated with osimertinib, a third-generation EGFR TKI, after previous treatment failure with one or more other EGFR TKIs.Methods Eligible patients had been enrolled at one centre in the AURA study, had shown resistance to a previous EGFR TKI, and had EGFR-activating mutations and acquired Thr790Met mutation detectable in tumour tissue or plasma. Patients took 20-240 mg osimertinib per day until disease progression or development of intolerable side-effects. Plasma samples were collected every 6 weeks and tumour tissue biopsy was done at study entry and was optional after disease progression. We tested samples for resistance mechanisms, including EGFR-activating, Thr790Met, and Cys797Ser mutations, and assessed associations with overall survival, progression-free survival, and survival after disease progression.Findings Of 71 patients enrolled in AURA, 53 were eligible for this analysis. Median progression-free survival was 11·1 months (95% CI 8·4-13·9) and overall survival was 16·9 months (11·7-29·1). 47 patients had disease progression. Median overall survival after osimertinib progression was 5·4 months (95% CI 4·1-10·0). Plasma samples were available for 40 patients after disease progression. 12 (30%) of these had the Thr790Met mutation (four of whom also had Cys797Ser mutations). Patients without detectable EGFR-activating mutations in plasma before treatment had the best overall and post-progression survival (22·4 months, 95% CI 15·6-not reached, and 10·8 months, 7·2-not reached, respectively). Loss of the Thr790Met mutation but presence of EGFR-activating mutations in plasma were associated with the shortest progression-free survival (median 2·6 months, 95% CI 1·3-not reached). In 22 post-progression tumour samples, we found one squamous cell and two small-cell transformations. We detected Thr790Met in nine (50%) of 18 samples, Cys797Ser in two (17%) of 12, cMET amplification in five (50%) of ten, BRAF mutation in one (8%) of 13, and KRAS mutation in one (8%) of 13.Interpretation Heterogeneous resistance mechanisms developed in patients receiving osimertinib. Differences in resistance mechanisms might dictate future development strategies for osimertinib in clinical trials.Funding AstraZeneca, Taiwan Ministry of Science and Technology.
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“Most recently, several groups reported that a subset of cases lost T790M at the time of progression[6, 12–14]”
From Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR -Mutant NSCLC (2018) · cites this paper as [14]
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Metadata
- Authors
- Lin, C.-C., Shih, J.-Y., Yu, C.-J., Ho, C.-C., Liao, W.-Y., Lee, J.-H., Tsai, T.-H., Su, K.-Y., Hsieh, M.-S., Chang, Y.-L., Bai, Y.-Y., Huang, D. D.-R., Thress, K. S., & Yang, J. C.-H.
- Affiliations
- National Taiwan University Hospital (TW)
- National Taiwan University (TW)
- AstraZeneca (United States) (US)
- Corresponding author
- Yang, James Chih-Hsin
- ORCID
- Venue
- The Lancet Respiratory Medicine
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 6
- Issue
- 2
- Pages
- 107-116
- ISSN
- 2213-2600 (ISSN-L)
- OpenAlex
- W2772237551
- Cited by
- 145
- References
- 23
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 13 · 2023: 16 · 2022: 15 · 2021: 29 · 2020: 20 · 2019: 24 · 2018: 16
- FWCI
- 13.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet Respiratory Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AstraZeneca
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- non-small cell lung cancer, osimertinib, acquired resistance, EGFR tyrosine kinase inhibitors, EGFR activating mutations, plasma biomarkers, resistance mechanisms, progression-free survival, overall survival, post-progression survival, third-generation EGFR-TKI
- MeSH terms
- Acrylamides, Adult, Aged, Aged, 80 and over, Aniline Compounds, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Female, Humans, Indoles, Lung Neoplasms, Male, Middle Aged, Mutation, Piperazines, Pyrimidines, Retrospective Studies, Genomics, ErbB Receptors
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