Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M–Positive Lung Cancer and Acquired Resistance to Osimertinib
Open accessAbstract
Importance: Osimertinib mesylate is used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M mutation. Acquired resistance to osimertinib is a growing clinical challenge that is poorly understood. Objective: To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior. Design, Setting, and Participants: Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified from a multi-institutional cohort (n = 143) and a confirmatory trial cohort (NCT01802632) (n = 110). Next-generation sequencing of tumor biopsies after osimertinib resistance was performed. Genotyping of plasma cell-free DNA was studied as an orthogonal approach, including serial plasma samples when available. The study and analysis were finalized on November 9, 2017. Main Outcomes and Measures: Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib. Results: Of the 143 patients evaluated, 41 (28 [68%] women) had tumor next-generation sequencing after acquired resistance to osimertinib. Among 13 patients (32%) with maintained T790M at the time of resistance, EGFR C797S was seen in 9 patients (22%). Among 28 individuals (68%) with loss of T790M, a range of competing resistance mechanisms was detected, including novel mechanisms such as acquired KRAS mutations and targetable gene fusions. Time to treatment discontinuation was shorter in patients with T790M loss (6.1 vs 15.2 months), suggesting emergence of pre-existing resistant clones; this finding was confirmed in a validation cohort of 110 patients with plasma cell-free DNA genotyping performed after osimertinib resistance. In studies of serial plasma levels of mutant EGFR, loss of T790M at resistance was associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; P = .01). Conclusions and Relevance: Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance.
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Mechanisms of acquired resistance to osimertinib are more heterogeneous than those to first- and second-generation TKIs, including EGFR C797S, acquired KRAS, and targetable gene fusions.
“mechanisms of acquired resistance to osimertinib are more heterogeneous, and include EGFR C797S, acquired KRAS, and targetable gene fusions.”
From Afatinib for the treatment of <i>EGFR</i> mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [96]
The Abstract Results and Discussion describe heterogeneous resistance to osimertinib, including EGFR C797S, acquired KRAS mutations, and gene fusions. The paper does not establish the claim’s added comparison that these mechanisms are more heterogeneous than resistance to first- and second-generation TKIs. No page numbers are supplied in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredEGFR exon 20 tertiary mutations, MET amplification, HER2 amplification, small cell transformation, and EMT are possible drivers of resistance.
“Reports on individual cases or clinical series have demonstrated that EGFR exon 20 tertiary mutations, including C797S[5–7], MET amplification[8], HER2 amplification[9], small cell transformation[10], and epithelial-mesenchymal transition (EMT) [10, 11] are possible drivers of resistance.”
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Self-citation
- Authors
- Oxnard, G. R., Hu, Y., Mileham, K. F., Husain, H., Costa, D. B., Tracy, P., Feeney, N., Sholl, L. M., Dahlberg, S. E., Redig, A. J., Kwiatkowski, D. J., Rabin, M. S., Paweletz, C. P., Thress, K. S., & Jänne, P. A.
- Affiliations
- Brigham and Women's Hospital (US)
- Dana-Farber Cancer Institute (US)
- Carolinas Healthcare System (US)
- University of California San Diego (US)
- Beth Israel Deaconess Medical Center (US)
- Tufts University (US)
- AstraZeneca (United States) (US)
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Corresponding author
- Oxnard, Geoffrey R.
- ORCID
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2018-11-01
- Volume
- 4
- Issue
- 11
- Pages
- 1527
- ISSN
- 2374-2437 (ISSN-L)
- PMC
- PMC6240476
- OpenAlex
- W2885289995
- Cited by
- 686
- References
- 34
- Citations by year
- 2026: 41 · 2025: 49 · 2024: 84 · 2023: 81 · 2022: 105 · 2021: 129 · 2020: 100 · 2019: 88 · 2018: 9
- FWCI
- 61.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- National Cancer Institute (R01CA135257)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- osimertinib resistance, acquired drug resistance, C797S mutation, KRAS mutation, gene fusion, plasma cell-free DNA, liquid biopsy, time to treatment discontinuation, EGFR tyrosine kinase inhibitors, non-small cell lung cancer
- MeSH terms
- Acrylamides, Aniline Compounds, Female, Humans, Indoles, Lung Neoplasms, Pyrimidines, Drug Resistance, Neoplasm
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