Author of

• 20127

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  OA 09 - EGFR TKI Resistance (ID 663)

  • Event: WCLC 2017
  • Type: Oral
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:Thanyanan Reungwetwattana, Lecia V Sequist
  • Coordinates: 10/17/2017, 11:00 - 12:30, Room 301 + 302

  • 23664

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    OA 09.02 - Osimertinib Resistance Mediated by Loss of EGFR T790M Is Associated with Early Resistance and Competing Resistance Mechanisms (ID 9000)

    11:10 - 11:20  |  Author(s): L.M. Sholl
    • Abstract
    • Presentation
    • Slides

    Background:
    Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) active in EGFR-mutant NSCLC with resistance to prior TKI. Improved understanding of the clinical and molecular characteristics of acquired resistance to osimertinib is needed.
    
    Method:
    We initially studied resistance biopsies and plasma specimens from an institutional cohort of 119 patients treated with osimertinib for T790M-positive NSCLC with resistance to prior TKI. For validation, we studied plasma from 157 patients treated with osimertinib on the AURA trial (NCT01802632).
    
    Result:
    45 of 119 patients underwent a resistance biopsy and 33 had resistance tumor genotyping available. 11 patients maintained T790M at resistance: 7 acquired EGFR C797S, 1 had a PIK3CA mutation. 22 patients had loss of T790M at resistance: 14 harbored a competing resistance mechanism, including histologic transformation to SCLC, MET amplification, mutations in BRAF, PIK3CA, or KRAS, or fusions in RET or FGFR. Median time to treatment failure (TTF) on osimertinib was 3 months in patients with loss of T790M and 15 months in patients with maintained T790M. In the validation cohort, 110 of 157 patients had detectable tumor DNA in plasma and were eligible for analysis. 58 patients (53%) maintained T790M at resistance; 24 (22%) also acquired a C797S mutation. 52 patients (47%) had loss of T790M at resistance and no C797S. Median TTF was shorter in patients with loss of T790M than in those with maintained T790M at resistance (5.7 vs 12.5 months). 50 patients had both pre- and post-osimertinib plasma genotyping. Studying the relative allelic fraction (AF) of T790M compared to driver EGFR mutation, patients with T790M loss had only slightly lower relative T790M AF pretreatment (29% vs. 38% median, p = 0.06). The ability of plasma response to predict subsequent resistance was studied in 19 patients from the initial cohort with baseline and follow-up plasma genotyping after 1-3 weeks on osimertinib. Studying the difference between the relative change in plasma levels of T790M and the EGFR driver, patients with T790M loss at time of resistance consistently had a greater T790M response than driver response (median difference 16%), suggesting incomplete suppression of the driver due to competing resistance mechanisms.
    
    Conclusion:
    In patients with acquired resistance to osimertinib, repeat testing for T790M could offer key insights into disease biology. Patients with early resistance on osimertinib are at risk of T790M loss with emergence of a complex variety of competing resistance mechanisms, and represent intuitive candidates for combination approaches such as combined EGFR & MET inhibition.
    
    

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