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J. Chmielecki

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    MINI 10 - ALK and EGFR (ID 105)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI10.09 - Comprehensive Genomic Profiling Identifies EGFR Exon 19 Deletions in NSCLC Not Identified by Standard of Care Testing (ID 3042)

      16:45 - 18:15  |  Author(s): J. Chmielecki

      • Abstract
      • Presentation
      • Slides

      Non-small cell carcinoma (NSCLC) cases harboring deletions in exon 19 of EGFR typically respond to treatment with small molecule inhibitors of EGFR. Detection of EGFR deletions in routine clinical practice is performed using a large variety of assays and testing platforms, with varying performance characteristics that are often not readily available. Using a hybrid capture based comprehensive genomic profiling (CGP) assay we identified 250 consecutive NSCLC cases, obtained from a range of clinical institutions, harboring deletions in EGFR exon 19 and compared data from these cases with available prior EGFR testing results.

      DNA was extracted from 40 microns of FFPE sections and CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 678X for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. The results were evaluated for all classes of genomic alterations (GA). Clinically relevant genomic alterations (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials.

      Of the 250 cases with exon 19 deletions excluding the C-Helix, consisting primarily of 746-750, 71 (28%) had previous EGFR testing results obtained through standard of care testing at multiple different institutions available for review. Of these 71 cases, 12 (17%) were negative for EGFR alterations, but were identified by CGP as harboring an exon 19 deletion. Of 14 cases with deletions affecting the C-Helix (753-761), 6 had previous EGFR testing results available for review, with 5 (83%) cases having a prior negative result. For select cases clinical histories were reviewed, and the clinical benefit from treatment with small molecule inhibitors of EGFR was observed, consistent with historic norms, including EGFR 746-750 deleted patients responding to erlotinib and afatinib, a patient with EGFR T751_I759>N responding to afatinib, and a patient with EGFR S752_I759del having an ongoing 18 month response to erlotinib.

      CGP in the course of clinical care can identify EGFR exon 19 deletions in NSCLC that may be missed by standard of care testing, including both the canonical 746-750 deletion as well as the less characterized C- Helix deletions. Tumors with either of these alterations that go undetected by standard testing but are identified by CGP can respond to anti-EGFR therapy. Given the proven improved extent and duration of tumor response and patient survival benefit conferred by anti-EGFR targeted therapy in patients whose NSCLC harbor EGFR exon 19 deletions, the 17% false negative rate in patients tested by standard hot spot assays is a concern. Further evaluation of the impact of the increased range and sensitivity of CGP to uncover EGFR alterations in NSCLC that have been missed by non-hybrid capture assays appears warranted.

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