Author of

• 35930

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  MA13 - Tumor Biology: Focus on EGFR Mutation, DNA Repair and Tumor Microenvironment (ID 214)

  • Event: WCLC 2020
  • Type: Mini Oral
  • Track: Tumor Biology and Systems Biology - Basic and Translational Science
  • Presentations: 1
  • Moderators:
  • Coordinates: 1/31/2021, 16:45 - 17:45, Scientific Program Auditorium

  • 35936

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    MA13.07 - Structural Classification of Atypical EGFR Mutations Identifies 4 Major Subgroups with Distinct Patterns of Drug Sensitivity (ID 3760)

    16:45 - 17:45  |  Presenting Author(s): Jacqulyne Ponville Robichaux
    • Abstract
    • Slides

    Introduction
    

    While osimertinib has resulted in striking improvements in outcomes for patients with NSCLC harboring classical EGFR mutations (Ex19del, L858R, and/or T790M), patients with atypical EGFR mutations have shown heterogeneous and in some cases inferior responses to EGFR inhibitors. The frequency, structural and clinical implications of atypical EGFR mutations are less understood.

    Methods
    

    We characterized the mutational landscape (N=16,715 patients with EGFR mutations), in vitro sensitivity (N=70 Ba/F3 cell lines), and in silico structure of primary and co-occurring acquired EGFR mutations to determine functional groups. Clinical outcomes in patients with atypical EGFR mutations treated with EGFR TKIs were evaluated through a retrospective analysis from the MD Anderson GEMINI database and Moffitt Cancer Center.

    Results
    

    Among EGFR mutant NSCLC patients, 67% had classical mutations, 31% had atypical EGFR mutations, and 3% had a tertiary mutation including Ex19del/L858R with T790M plus an atypical mutation. Atypical mutations included exon 20 insertions (9%), other primary atypical mutations (13%), and complex mutations including an atypical mutation (9%). EGFR mutations could be separated into four distinct functional subgroups: 1) classical-like, 2) T790M-like including a subset of tertiary mutations, 3) exon 20 insertions, and 4) ATP-Binding Pocket Volume-Reducing (PVR) mutations. The classical-like were broadly sensitive to 1^st, 2^nd, and 3^rd-generation inhibitors with a drug binding pocket similar to classical mutations. T790M-like mutations were sensitive to 3^rd-generation EGFR inhibitors, but resistant to first- and second-generation inhibitors irrespective of co-occurring mutations. Tertiary mutations were generally resistant to EGFR inhibitors, but a drug repurposing screen identified select PKC and ALK inhibitors as having activity. The exon 20 insertion mutations, which cause significant reduction in drug binding pocket volume, were highly resistant to the majority of EGFR inhibitors but sensitive to novel exon 20 specific inhibitors. Lastly, we found a fourth group of mutations, ATP-Binding Pocket Volume Reducing (PVR) mutations that were associated with resistance to 1st- and 3rd-generation inhibitors, but selectively sensitive to quinazoline-based, 2nd-generation inhibitors such as afatinib and poziotinib preclinically. These mutations were primary located in the P-loop (exon 18), the c-terminal loop of the αc-helix (exon 20), and the A-loop (exon 21) of EGFR. Retrospective analysis of patients with PVR mutations revealed that patients had a significantly longer median progression free survival (mPFS) when treated with a 2nd-generation inhibitor (mPFS = 24mo) versus a 1^st-generation (mPFS = 9.5mo, p = 0.013, HR = 4.2) or 3^rd-generation inhibitor (mPFS = 6.4mo, p <0.0001, HR = 3.4). Three patients with NSCLC, who acquired PVR mutations after first-line osimertinib treatment had clinical benefit after receiving 2^nd-generation EGFR inhibitors.

    Conclusion
    

    EGFR mutations can be separated into four distinct subgroups based on the structural changes caused by the mutation and differential sensitivity to EGFR inhibitors. The PVR subgroup, largely comprised of exon 18 or 20 point mutations, had greater relative sensitivity to 2^nd-generation drugs with a quinazoline core than 3rd-generation drugs such as osimertinib in vitro, and improved outcomes in patients treated with these agents compared with osimertinib. These findings define subgroups of EGFR mutations that may better guide future treatment approaches for atypical EGFR mutations.

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