Dataset Information

Mechanisms of resistance to osimertinib.

ABSTRACT: The introduction of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has significantly improved the prognosis of advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. The most common mechanism of acquired resistance to first- and second-generation EGFR TKIs is represented by the secondary T790M mutation. Osimertinib, a third-generation TKI designed to target both EGFR sensitizing mutations and T790M, was first approved for the treatment of EGFR T790M mutation-positive NSCLC patients in progression after EGFR TKI therapy. The FLAURA study demonstrated that first-line treatment of EGFR mutant patients with osimertinib significantly improved progression free survival (PFS) over first-generation EGFR-TKIs, thus leading to its approval also in this setting. Moreover, osimertinib has shown significant central nervous system (CNS) activity and a favorable safety profile. The current review focuses on the clinical development of osimertinib, the mechanisms of acquired resistance identified in patients receiving osimertinib and the strategies currently under evaluation to overcome resistance.

SUBMITTER: Lazzari C

PROVIDER: S-EPMC7330330 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mechanisms of resistance to osimertinib.

Lazzari Chiara C Gregorc Vanesa V Karachaliou Niki N Rosell Rafael R Santarpia Mariacarmela M

Journal of thoracic disease 20200501 5

The introduction of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has significantly improved the prognosis of advanced non-small cell lung cancer (NSCLC) patients with <i>EGFR</i> mutations. The most common mechanism of acquired resistance to first- and second-generation EGFR TKIs is represented by the secondary <i>T790M</i> mutation. Osimertinib, a third-generation TKI designed to target both EGFR sensitizing mutations and T790M, was first approved for the treatment of ...[more]

PMID: 32642198

Similar Datasets

Project description:ImportanceOsimertinib 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.ObjectiveTo understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior.Design, setting, and participantsPatients 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 measuresMechanisms of resistance and their association with time to treatment discontinuation on osimertinib.ResultsOf 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 relevanceAcquired 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.

Dataset Information

Mechanisms of resistance to osimertinib.

Publications

Mechanisms of resistance to osimertinib.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets