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Vincent Miller

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    EP1.01 - Advanced NSCLC (ID 150)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.01-108 - EGFR Exon 18 Mutations in NSCLC: Frequent Co-Occurrence of Multiple EGFR Mutations and Assessment of Cis/Trans Status (ID 2747)

      08:00 - 18:00  |  Author(s): Vincent Miller

      • Abstract


      A subset of EGFR exon 18 (ex18) mutations including G719X are known drivers in NSCLC. However, the sensitivity profile of other ex18 mutations and frequently occurring dual ex18/ex18 and ex18/non-ex18 combinations has not been well described.


      Hybrid-capture based comprehensive genomic profiling was performed on 46,296 FFPE tissue samples from patients with NSCLC. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA and reported as mut/Mb. Configuration was determined by analyzing sequencing reads that spanned both loci. The number of reads that harbored mutations at one or both positions was tabulated and used to infer cis or trans status. Patient ancestry was determined by single nucleotide polymorphism (SNP) microarray data, ancestry informative markers, and principal component analysis (PCA)..


      EGFR ex18 mutations (point mutations and indels) were identified in 1.1% (522/46,296) of NSCLCs. The median patient age was 67 years (range 30-96) and 67% of patients were female. This subset was also enriched for patients of East Asian descent when compared to EGFR wildtype NSCLC (17% v 3.9%; p < 0.001), similar to ex19del and L858R populations (19% and 24%, respectively). Median TMB was 4.35 mut/mb (range 0-70). Co-occurring EGFR mutations were identified in 69% (362/522) of cases, including most commonly S768I (20%, 103/522) and L858R (12%,61/522). T790M was detected in 6.1% (32/522) of ex18 cases. Multiple EGFR ex18 mutations occurred in 15% (76/522) of cases including 2 cases with 3 and a single case with 4 such mutations. The most commonly observed missense pairs were E709A/G719S (17/76) and E709A/G719A (16/76). Other combinations of E709X/G719X made up an additional 42% (32/76), with the remaining 14% of cases consisting of rare combinations (n<4 for all). All ex18 mutations in all cases (76/76) were in cis. Preliminary evidence from paired cases and assessment of mutant allele frequencies suggests that ex18 mutations found together in cis arise de novo. Results of in vitro studies to determine the sensitivity of single ex18 mutations as well as common pairs to all generations of EGFR inhibitors will be presented.

      EGFR ex18 mutations co-occur at a high frequency with both ex18 and non-ex18 EGFR mutations, unlike classic EGFR mutations (L858R, ex19del). Female gender, East Asian ancestry, and low TMB were common in ex18 cases, similar to populations with classic EGFR mutations. In all cases with multiple EGFR ex18 mutations these mutations were always found to occur in cis. Further work to understand the evolution of these co-occurring EGFR mutations and to determine the best therapeutic strategy or strategies for this NSCLC patient population is warranted