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Eliezer M Van Allen



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    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA09.05 - Genomic Correlates of Differential Response to EGFR-Directed Tyrosine Kinase Inhibitors (Now Available) (ID 1169)

      15:15 - 16:45  |  Author(s): Eliezer M Van Allen

      • Abstract
      • Presentation
      • Slides

      Background

      Oncogenic mutations in EGFR are powerful biomarkers of response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, there remains significant heterogeneity in duration of response to therapy and overall survival, and the molecular determinants of this differential response have been incompletely characterized.

      Method

      We identified NSCLC patients at our institution with sensitizing oncogenic EGFR mutations who had been treated with EGFR TKI(s) and who had at least one tumor specimen profiled via targeted next generation sequencing (OncoPanel). Duration of therapy (DOT) on first-line EGFR TKI and overall survival (OS) were assessed. Mutations associated with differential benefit to therapy were identified by comparing mutation rates in outliers with DOT or OS ≥75th percentile vs ≤25th percentile. Fisher’s exact test was used to calculate statistical significance, and the Benjamini-Hochberg method was used to correct for false discovery rate (FDR). Time to event outcomes were assessed with the Kaplan-Meier method.

      Result

      We identified 270 patients for inclusion in our cohort. 70% were female (190/270), 60% were never smokers (163/270), and median age was 62 (range 29-93). Sensitizing EGFR mutations were predominantly exon 19 deletion (51%, 138/270) or L858R (38%, 103/270). 94% of patients were treated with first-line erlotinib (253/270), and 30% received second-line osimertinib (82/270). The median DOT on first-line TKI was 12 months (range 0-72 months) and median OS was 28 months (range 1-133 months). Pre-treatment sequencing was available for 188 patients, 65 of whom also had documented assessment of resistance mechanism (T790M 78%, other 22%). Pre-existing concurrent TP53 mutations were associated with shorter DOT (median 10 vs 16 mo, p=0.0017), but there was no significant difference in OS (median 25 vs 36 mo, p=0.2) and no association with resistance mechanism (p=0.674). In addition to TP53, BCOR and SMARCA4 mutations were enriched in patients with shorter DOT, whereas MTOR mutations were enriched in patients with DOT in the top quartile, though these analyses did not pass FDR correction. Pre-treatment SMARCA4 mutations were more frequent in patients with survival in the bottom quartile (Fisher’s p=0.01), and were associated with decreased OS (median 32 vs 12 mo, log-rank p<0.0001).

      Conclusion

      Genomic features may contribute to differential outcomes in patients with EGFR-mutated NSCLC. In addition to TP53 mutations, pre-treatment SMARCA4 mutations may associate with worse outcomes in these patients.

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