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• W2885289995 abstract "<h3>Importance</h3> Osimertinib mesylate is used globally to treat<i>EGFR</i>-mutant non–small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the<i>EGFR</i>T790M mutation. Acquired resistance to osimertinib is a growing clinical challenge that is poorly understood. <h3>Objective</h3> To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior. <h3>Design, Setting, and Participants</h3> 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. <h3>Main Outcomes and Measures</h3> Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib. <h3>Results</h3> 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,<i>EGFR</i>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<i>KRAS</i>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<i>EGFR</i>, loss of T790M at resistance was associated with a smaller decrease in levels of the<i>EGFR</i>driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease;<i>P</i> = .01). <h3>Conclusions and Relevance</h3> 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." @default.
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• W2885289995 date "2018-11-01" @default.
• W2885289995 modified "2023-10-17" @default.
• W2885289995 title "Assessment of Resistance Mechanisms and Clinical Implications in Patients With<i>EGFR</i>T790M–Positive Lung Cancer and Acquired Resistance to Osimertinib" @default.
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• W2885289995 doi "https://doi.org/10.1001/jamaoncol.2018.2969" @default.
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