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Anna Minchom



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    FP07 - Pathology (ID 109)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP07.12 - Underdiagnosis of EGFR Exon 20 Insertion Mutation Variants: Estimates from NGS-based Real-World Datasets (ID 3399)

      00:00 - 00:00  |  Author(s): Anna Minchom

      • Abstract
      • Presentation

      Introduction

      Exon 20 insertion mutations (Exon20ins) account for up to 10% of all mutations in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers (NSCLCs). Exon20ins specific drugs are in development. Because Exon20ins are molecularly heterogenous, the ability to identify the range of variants is dependent on the test methods used. Real-time polymerase chain reaction (PCR) and next-generation sequencing (NGS) are two molecular tests widely used to identify mutations in the EGFR. We analyzed real-world genomic data to determine the frequency of Exon20ins variants and to assess the ability of PCR and NGS to comprehensively identify them.

      Methods

      Two US-based genomic databases were utilized for this analysis. NGS data from US institutions were extracted from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database, version 8.5 (The AACR Project GENIE Consortium. Cancer Discov. 2017;7(8):818-831). The FoundationInsights™ database (Foundation Medicine, Cambridge, MA) was used to obtain EGFR Exon20ins variants in real-world NSCLC samples. Coverage of Exon20ins from commercially available PCR tests (therascreen® and cobas®) was obtained from their instructions for use.

      Results

      The GENIE database included 12,497 patients with NSCLC. A total of 2,316 patients with EGFR mutant lung adenocarcinoma were identified and of these patients, 175 (7.6%) harbored Exon20ins. A total of 40 unique Exon20ins variants were identified. Of the 9 most common Exon20ins variants (≥5 patients), only 4 would have been identified at the protein level using commercially available PCR tests. PCR tests would have identified only 89 (50.9%) of the 175 patients with Exon20ins identified by NGS (Figure). The FoundationInsights™ database included 627 patients with lung adenocarcinomas who harbored Exon20ins and identified 102 unique Exon20ins variants. Of the 17 most common variants (≥5 patients), only 4 would have been identified at the protein level with commercially available PCR tests. PCR tests would have identified just 305 (48.6%) of the 627 patients with Exon20ins identified by NGS (Figure).

      Conclusion

      PCR methods are projected to miss 50% or more of Exon20ins. Reliance on commercially available PCR kit methods may provide insufficient information to support appropriate decision-making for emergent Exon20ins-directed therapies. The large number of insertion variants suggests that NGS platforms, academic or commercially available, would also improve their detection rate by capturing the full breadth of variants that have been identified.

      genie and fmi figure for submission.jpg

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    MA04 - Health Policy and the Real World (ID 217)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Health Services Research/Health Economics
    • Presentations: 1
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      MA04.07 - Comparative Clinical Outcomes for Patients with NSCLC Harboring EGFR Exon 20 Insertion Mutations and Common EGFR Mutations (ID 3390)

      16:45 - 17:45  |  Author(s): Anna Minchom

      • Abstract
      • Presentation
      • Slides

      Introduction

      Approximately 85–90% of the mutations seen in EGFR-mutant non-small cell lung cancers (NSCLCs) are common mutations (cEGFR), Exon 19 deletions and Exon 21 L858R. Up to 10% of EGFR-mutant NSCLC harbors Exon 20 insertion mutations (Exon20ins). We conducted a retrospective cohort study using real-world data to compare clinical outcomes between patients harboring Exon20ins and cEGFR.

      Methods

      This retrospective cohort study included patients from the Flatiron Health database (1 January 2011 through 31 May 2020) who had advanced NSCLC. The objectives of the study were to assess the prognostic value of Exon20ins compared with cEGFR (start date of first-line therapy as the index date) and the effect of tyrosine kinase inhibitor (TKI) treatment between the groups (start date of first TKI line as the index date). Analysis was stratified by line of TKI use. Endpoints included real-world overall survival (rwOS), progression-free survival (rwPFS), and time to next therapy (rwTTNT) and were analyzed using multivariable Cox proportional hazards model and summarized by Kaplan-Meier method.

      Results

      Among 62,464 patients with advanced NSCLC, 181 with Exon20ins and 2833 with cEGFR met eligibility criteria. Population demographics between the groups were comparable with minor exceptions. With median 34-month follow-up, Exon20ins was associated with a 75% increased risk of death (adjusted hazard ratio [adjHR] of 1.75 [95%CI, 1.45–2.13]; p˂0.0001); median rwOS was 16.23 (95%CI, 11.04–19.38) for Exon20ins and 25.49 months (95%CI, 24.48–27.04) for cEGFR (Table). The estimated 5-year survival rate for Exon20ins is 8% compared with 19% for cEGFR.

      The predictive value of TKI treatment, stratified by line, was assessed in 76 Exon20ins and 2749 cEGFR patients who were treated with TKIs. With median 20.6-month follow-up, there was a 170% increase in risk of progression or death associated with Exon20ins (adjHR of 2.7 [95% CI, 2.06–3.55]; p˂0.0001); median rwPFS was 2.86 months (95%CI, 2.14–3.91) compared with 10.45 months (95%CI: 10.05–10.94) for cEGFR. Furthermore, there was a 170% increased risk of death (adjHR of 2.70 [95% CI, 2.04–3.57]; p˂0.0001) associated with Exon20ins; median rwOS was 7.46 months (95%CI, 5.45–13.34) for Exon20ins and 25.49 months (95%CI, 24.28–26.81) for cEGFR (Table).

      Conclusion

      Patients with Exon20ins have a worse prognosis compared with patients with cEGFR. Furthermore, EGFR TKI treatment was substantially less effective for patients with Exon20ins, as the risk of disease progression and mortality was higher compared with patients with cEGFR. These findings highlight the need for new treatment options for Exon20ins.

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