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Andrew Wallace



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    P2.09 - Pathology (Not CME Accredited Session) (ID 958)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.09-15 - A Next Generation Sequencing (NGS) RNA-Scan Multiplex Panel (QIAseq) to Identify Gene-Rearranged Non-Small Cell Lung Cancer (ID 12777)

      16:45 - 18:00  |  Author(s): Andrew Wallace

      • Abstract
      • Slides

      Background

      Oncogenic fusion gene rearrangements are detected in up to 10% of advanced NSCLC with important therapeutic (eg. ALK, ROS1) or translational impact (eg. RET, NTRK1). The ‘QIAseq’ fusion panel is a 31-gene NGS multiplex assay that synchronously detects multiple oncogene fusion transcripts from formalin-fixed paraffin-embedded (FFPE) tissue derived RNA (Figure 1).qiaseq targets.jpg

      a9ded1e5ce5d75814730bb4caaf49419 Method

      QIAseq analysis was undertaken in 33 samples (31 NSCLC samples, 2 commercial controls). 12/31 NSCLC samples were positive controls with a known fusion genotype identified by Quantide X NGS or FISH +/- RT-PCR. The remaining 19/31 fusion negative NSCLC controls included 6 samples with EGFR/KRAS/NRAS mutations. Analysis required a minimum 2x 5ųM thick FFPE scrolls with >30% neoplastic cell content. Manual RNA extraction was undertaken in all samples except n=6 (ExScale automation extraction). NGS fusion breakpoints, crossing and spanning reads were calculated in QIAseq fusion-detected samples. An additional validation cohort of 40 NSCLC samples, including 20 with unknown fusion status will optimise QIAseq thresholds for fusion detection.

      4c3880bb027f159e801041b1021e88e8 Result

      48 QIAseq sequencing experiments was undertaken in 33 samples with ≥2 sequencing runs in 12 samples. QIAseq analysis detected a corresponding NGS fusion breakpoint in 14/14 (100%) positive controls including EML4-ALK (n=8), CLTC-ALK (n=1), CD74-ROS1 (n=3), CCDC6-RET (n=1) and 5-fusion control (n=1). QIAseq analysis was negative in 17/19 (89.4%) negative controls samples including all KRAS (n=4), NRAS (n=1) and EGFR (n=1) mutation samples. QIAseq detected novel fusion gene CD74 Exon 6-CAMK2A Exon 2 in n=1 sample subsequently confirmed on Sanger sequencing. Two separate runs detected TPM3 Exon 8-S100A7A Exon 2 fusion in n=1 sample not identified with Sanger sequencing. Both fusions have uncertain clinical significance. Validation cohort results will be presented.

      8eea62084ca7e541d918e823422bd82e Conclusion

      QIAseq detects NSCLC oncogenic fusions with high sensitivity and specificity. Future applications include optimising use of small biopsy specimens for synchronous gene rearrangement screening and identification of novel gene fusion targets.

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-33 - A Case Report of Exceptional Clinical Response to MEK Inhibition in a Patient with NRAS Mutation Positive NSCLC (ID 13275)

      16:45 - 18:00  |  Author(s): Andrew Wallace

      • Abstract

      Background

      NRAS mutation occurs in <1% patients with non-small cell lung cancer (NSCLC). Pre-clinical lung cancer models with NRAS mutation have demonstrated response to single agent MEK inhibition with activation of the PI3K-AKT-mTOR pathway as a putative resistance mechanism. There are a paucity of data for MEK inhibition in the clinical setting for NRAS positive disease. To our knowledge, this is the first report of an NRAS positive NSCLC patient to be treated with a MEK inhibitor.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A 51 year old female with advanced NSCLC was identified to have an NRAS Q61K mutation in both archival tumour and circulating tumour DNA (ctDNA) within the TARGET study. Tumour was analysed for a panel of 24 genes using an amplicon based NGS assay and circulating tumour DNA using a hybridisation capture technique of 650 genes. The patient was allocated in the Molecular Tumour Board to participate in the Phase I study of LNP3794, a first-in-human dose escalation study of a MEK inhibitor with primary endpoint of safety and tolerability. Serial plasma samples were acquired during treatment for ctDNA analysis and fresh tissue was acquired pre-treatment and on disease progression. A PDX model was implanted from the disease progression sample to explore functional mechanisms of resistance

      4c3880bb027f159e801041b1021e88e8 Result

      The patient was commenced on LNP3794 in Jun 2015 having previously progressed on first line chemotherapy with extensive lung metastases. Initially she exhibited G3 toxicity with LNP3794, managed by dose reduction and subsequently was well tolerated. Within 6 weeks the patient demonstrated an exceptional response with 44% reduction in tumour by RECIST 1.1, resolution of a number of lesions and with clear symptomatic benefit. She remained on study for 12 months with maintained PR. The NRAS mutant allele fraction in blood fell from 20% to not detectable within 6 months and subsequently started to rise 3 months prior to radiological progression. A PIK3CA Q546K mutation was identified by Foundation Medicine at progression. The PDX is currently growing at a slow rate and the hypothesis of re-sensitisation with a combination of an mTOR inhibitor with MEK inhibition will be explored.

      8eea62084ca7e541d918e823422bd82e Conclusion

      These data support further evaluation of MEK inhibitors in patients with NRAS positive NSCLC. As a rare population a multi-site study would be required. Combination with inhibitors of the PI3k-AKT-mTOR pathway, if tolerated, may further prolong response and clinical benefit and should also be explored.

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