Abstract | Importance: 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: 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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Authors | Geoffrey R Oxnard, Yuebi Hu, Kathryn F Mileham, Hatim Husain, Daniel B Costa, Philip Tracy, Nora Feeney, Lynette M Sholl, Suzanne E Dahlberg, Amanda J Redig, David J Kwiatkowski, Michael S Rabin, Cloud P Paweletz, Kenneth S Thress, Pasi A Jänne |
Journal | JAMA oncology
(JAMA Oncol)
Vol. 4
Issue 11
Pg. 1527-1534
(11 01 2018)
ISSN: 2374-2445 [Electronic] United States |
PMID | 30073261
(Publication Type: Journal Article)
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Chemical References |
- Acrylamides
- Aniline Compounds
- osimertinib
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Topics |
- Acrylamides
(pharmacology, therapeutic use)
- Aniline Compounds
(pharmacology, therapeutic use)
- Drug Resistance, Neoplasm
- Female
- Humans
- Lung Neoplasms
(drug therapy, pathology)
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