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M. McKee

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    OA06 - Prognostic & Predictive Biomarkers (ID 452)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Biology/Pathology
    • Presentations: 1
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      OA06.07 - Evaluating Genomic Signatures Predicting Veliparib Sensitivity in Non-Small Cell Lung Cancer (NSCLC) (ID 5028)

      14:20 - 15:50  |  Author(s): M. McKee

      • Abstract
      • Presentation
      • Slides

      Veliparib is a potent poly(ADP-ribose) polymerase (PARP)-1 and PARP-2 inhibitor that has synthetic lethality interaction with cancers harboring homologous recombination deficiency. In preclinical models, it has also been shown to delay the repair of DNA damage induced by chemotherapeutics (platinum, alkylators, topoisomerase inhibitors). Clinically meaningful improvements in progression-free survival and overall survival were observed in a phase 2 trial of veliparib with carboplatin/paclitaxel in previously untreated metastatic or advanced NSCLC (M10-898 study). Intriguingly, smoking history had a major impact on veliparib effect—smokers benefited most from veliparib addition. The underlying mechanism for this observation remains unclear. The efficacy benefit of veliparib in smokers is not dependent on tobacco exposure during study treatment, but correlates with the duration of smoking history, suggesting a genetic basis.

      Genomic signatures in NSCLC associated with smoking status have been identified by The Cancer Genome Atlas (TCGA) Lung Cancer Project. Relevant observations were leveraged in the reported analysis. To comprehensively identify genes or genomic features that are associated with smoking status and veliparib response, patient tumor samples from the M10-898 trial were subjected to whole-exome (N = 38) and RNA sequencing (N = 75) analysis. Alexandrov somatic mutational signature was calculated from exome sequencing data.

      Data from TCGA show that cancer genomes in smokers harbor significantly more genetic alterations than those in non-smokers. These alterations include high mutational burden, high C>A transversion, high mutation frequency of key cancer genes (particularly TP53), and high homologous recombination defect signature. Similar observations were confirmed in the M10-898 study. Of the 38 patients with exome data, 26 were determined to be positive for a smoking-related signature—signature 4. Elevated mutational burden was observed among current and former smokers, with a mean of 199 somatic mutations in current or former smokers vs 60 in never-smokers (p = 0.004). The small sample size of our genomic cohort nevertheless precludes conclusive association of genomic signatures and veliparib benefits.

      Cancer genomes in smokers are enriched with genetic alterations associated with poor outcome using standard chemotherapy, as well as with vulnerability factors that can prime tumors to respond to veliparib. For further validation, a targeted sequencing assay to detect key DNA damage and repair genes as well as key genomic signatures has been established and will be used in all phase 3 veliparib trials.

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