Author of

• 25905

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  MA16 - Novel Mechanisms for Molecular Profiling (ID 917)

  • Event: WCLC 2018
  • Type: Mini Oral Abstract Session
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD

  • 26050

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    MA16.05 - MET Kinase Domain Rearrangements (KDRE) in Non-Small Cell Lung Cancer (NSCLC) Identified Through Comprehensive Genomic Profiling (CGP) (ID 13401)

    14:00 - 14:05  |  Author(s): Garrett M Frampton
    • Abstract
    • Presentation
    • Slides

    Background
    

    MET is a known oncogenic driver in NSCLC, and activation via various means including gene amplification, exon 14 skipping, and fusion has been reported to be targetable in the clinical setting. However, the prevalence and characteristics of NSCLCs harboring MET kinase fusions as well as diverse KDRE have not been comprehensively assessed.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    Hybrid-capture based CGP was performed on 32,643 FFPE or 3,076 blood-based ctDNA NSCLC specimens during the course of clinical care. Tumor mutational burden (TMB) was determined on 0.83-1.1 megabases (Mb) of sequenced DNA and is reported as mutations/Mb.

    4c3880bb027f159e801041b1021e88e8 Result
    

    In 35,719 unique NSCLC patient cases assayed, RE retaining the MET kinase domain were detected in 63 (0.2%) cases. These included MET fusions with an identified 5’ fusion partner (n=8, 12.7%), probable MET fusions with an unidentified fusion partner (n=32, 50.8%), MET kinase domain duplications (KDD, n=7, 11.1%), MET exon 14 skipping rearrangements (n=6, 9.5%), and MET rearrangements of the 5’ terminus (n=10, 15.9%). Fusion partners identified include CAPZA2 (2 cases), CAV2, CD47, INPPL1, LHFPL3, PRKAR2B and SPECC1. MET kinase-inactivating rearrangements were also detected in the larger cohort (n=10, 0.03%). MET KDRE cases harbored at least one targetable NSCLC NCCN guidelines driver alteration in 27.0% (n=17) of cases including EGFR activating subs (L858R, L861Q) or exon 19 deletions (n=8), MET exon 14 skipping short variants (n=6), ALK fusions (n=2), and a BRAF V600E mutation. KRAS short variants were detected in 6 additional cases. MET amplification also co-occurred in 36.5% of cases with MET KDRE (n=23, median copy number 16). The median TMB in cases with MET KDRE was 6.1 mut/Mb, as compared to a median of 7.0 mut/Mb for NSCLC samples overall. Clinical treatment information for a subset of cases will be presented, including paired cases in which the MET KDRE may represent an acquired mechanism of resistance to EGFR- or ALK-targeted therapy.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Potentially targetable MET rearrangements retaining the kinase domain were observed in 0.2% of NSCLCs, which may be an underestimate considering that these assays sequence all MET exons, but do not specifically bait MET intronic breakpoints. These data suggest that MET KDRE, including, but not limited to fusions and KDD, may represent a distinct subset of driver alterations and potential resistance mechanisms. The value of testing for and potentially targeting these alterations as part of routine clinical care in NSCLC warrants further investigation.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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• 25932

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  P1.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 944)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall

  • 27879

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    P1.12-15 - Distinctive Clinical Characteristics of SCLC in Never-Smokers (ID 13328)

    16:45 - 18:00  |  Author(s): Garrett M Frampton
    • Abstract
    • Slides

    Background
    

    Epidemiologic data suggest that 3% of patients with SCLCs are never-smokers. A large population study is required to describe the characteristics and outcomes of SCLC in never-smokers. Defining SCLC subgroups based on clinical characteristics, specifically smoking status, may lead to treatment advances in this historically recalcitrant cancer.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    We performed a multicenter analysis using the Flatiron Health electronic health record-derived database, a nationally representative database comprising patient-level structured and unstructured data curated via technology-enabled abstraction. The cohort consisted of patients with clinician confirmed SCLC diagnosed on or after January 1, 2013. Genomic data from a clinico-genomic database developed by Flatiron and Foundation Medicine was used for a subset of patients that had received next-generation sequencing on the FoundationOne panel. Clinical and genomic characteristics were compared between smokers and never-smokers using descriptive statistics while the presence of other cancers was confirmed via chart review for never-smokers. Association of patient characteristics with overall survival was assessed using a univariate Cox proportional hazards model.

    4c3880bb027f159e801041b1021e88e8 Result
    

    103 of 4655 (2.2%) SCLC patients were never-smokers. Characteristics of these patients were: female 65%, male 35%; Asian 4.85%, Black 4.85%, White 62.1%; extensive-stage (ES) 68.9%, limited-stage (LS) 20.4%, unknown 10.7%. Compared with smokers (n=4552), never-smokers were more likely to be 80+ years (p=0.040), female (p=0.013), Asian (p<0.001), and present with ES (p=0.038). Based on univariate analyses, poor prognostic factors in never-smokers included sodium < 140 mEql/L (HR=1.95; p=0.028) and ES (HR=2.62; p=0.013). 26 (25%) patients had confirmed history of multiple primary malignancies. Three patients had prior history of organ transplant and two patients had history of pulmonary fibrosis. Survival of never-smokers (8.0 months for ES and 20.6 months for LS) appeared similar to historical data from smokers with SCLC. In the subset of 251 SCLC patients where tumor mutation data was available, never-smokers (n=18, 7.2%) were less likely to have a detectable alteration in TP53 (44.4% vs 95.3%; p<0.001) or RB1 (27.8% vs 76.8%; p<0.001).

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    The never-smoker subgroup of SCLC patients has important clinical and genomic features that portend diagnostic, prognostic, and therapeutic opportunities. A high-frequency of other malignancies raises concern for neuroendocrine differentiation from other primary tumors. This series represents the largest reported data on SCLC in never-smokers.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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