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N. Marcoux



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    OA 09 - EGFR TKI Resistance (ID 663)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA 09.01 - Characterizing the Genomic Landscape of EGFR C797S in Lung Cancer Using ctDNA Next-Generation Sequencing (ID 10213)

      11:00 - 11:10  |  Author(s): N. Marcoux

      • Abstract
      • Presentation
      • Slides

      Background:
      Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) active in T790M-positive lung cancer. Acquired resistance to osimertinib is driven by EGFR C797S in ~20-30% of cases. Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) can be used to identify resistance mechanisms. The allelic configuration (cis vs. trans) of C797S with respect to T790M has therapeutic implications, but the relative frequency of each and other co-occurring genomic alterations are not well defined in clinical samples.

      Method:
      We queried the Guardant Health database for lung adenocarcinoma patients and an EGFR C797S mutation. All patients had comprehensive ctDNA testing using the Guardant360 NGS assay between June 2015 and June 2017. Cis/trans configuration for T790M and C797S was determined using Integrated Genomics Viewer software.

      Result:
      We identified 50 unique patients with a total of 66 samples which were C797S positive. All had a co-existent EGFR activating mutation (del19 74%, L858R 24%, other 2%). 60/66 (91%) C797S+ samples were also T790M+. In the 6 samples with C797S but without T790M in ctDNA, 4 were from patients who were T790M+ on a prior Guardant360 assay, 1 never had T790M in blood or tissue and developed C797S while on 1[st]-line afatinib, and 1 had no further clinical details available. T790M and C797S were on the same allele (cis configuration) in 44/46 evaluable patients (98%); 1 (2%) was in trans. One sample had two different C797S mutations, one cis and one trans to T790M. 13 C797S+/T790M+ samples (22%) had multiple C797X mutations detected and 12 samples carried other mutations in or adjacent to the EGFR ATP-binding pocket (e.g. L792, F795, G796, etc). The most common non-EGFR mutations co-occurring with C797S were BRAF amplification/mutation (20%), MET amplification (17%), PIK3CA mutation/amplification (15%), CCNE1 amplification 14% and MYC amplification (14%).

      Conclusion:
      Understanding EGFR TKI resistance mechanisms is critical to developing more effective therapies. ctDNA offers a non-invasive method to characterize the resistance landscape. Our data suggests C797S most commonly occurs with T790M in cis (98%), a state associated with resistance to all currently available EGFR TKIs. The trans configuration, which may respond to combined 1[st]/3[rd]-gen EGFR TKIs, is rare (2%). Moreover, C797S is frequently detected along with other resistance mechanisms in ctDNA, underscoring the heterogeneity of resistant cancers. New treatments targeting C797S/T790M are needed, as is a deeper understanding of therapeutic targeting of heterogeneity in resistant cancers.

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