Author of

• 20186

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  P3.07 - Immunology and Immunotherapy (ID 723)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: Immunology and Immunotherapy
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 24118

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    P3.07-009 - PI3K/mTOR Pathway Altertions May Mediate PD-1/PD-L1 Blockade Resistance in Non-Small Cell Lung Cancer (ID 10489)

    09:30 - 09:30  |  Author(s): Z. Zhang
    • Abstract

    Background:
    Immune checkpoint inhibitors have changed the clinical practice for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) as the first line or second line therapies. Although PD-1/PD-L1 blockade has been demonstrated as a promising anti-tumor therapy with significant clinical benefits, the fact of acquired resistance after a response to PD-1/PD-L1 blockade has become a common concern. The mechanism underlying acquired resistance to immune checkpoint inhibitors have remained unclear.
    
    Method:
    FFPE samples from 127 Chinese NSCLC patients were collected, including 103 (81.1%) adenocarcinoma, 21 (16.5%) squamous cell carcinoma, 2 (1.6%) adenosquamous carcinoma and 1 (0.8%) large cell carcinoma. Comprehensive genomic profiling (CGP) assay with 450 genes whole exon region were performed for the analysis of genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, gene rearrangement in selected genes and also tumor mutation burden (TMB) calculated as total somatic substitutions and indels per megabase. We considered high TMB as over 80% of the 500 patient TMB distrbutions from our inhouse cancer database across solid tumor types.
    
    Result:
    32 patients with higher TMB values were collected from 127 Chinese NSCLC patients. Interestingly, we identified the frequency of PI3K/mTOR pathway genes (AKT1, FBXW7, PIK3CA, PTEN, TSC1/2, STK11 and mTOR) was significantly higher in patients with high TMB value (28.1% vs 10.5%, p=0.033). Moreover, PI3K/mTOR pathway alterations existed in 3 patients who initially responded to PD-1/PD-L1 blockade and then were resistant to immune checkpoint inhibitors. Two patients with PIK3CA K111N and FBXW7 R465H have started to receive mTOR inhibitor everolimus mono therapy after 6 cycle nivolumab or pembrollizumab treatments. So far both showed stable disease or minor shrinkage on tumor. More investments are under way.
    
    Conclusion:
    In our study, PI3K/mTOR pathway alterations occurred more frequently in the NSCLC patients with higher TMB values. Several PD-1/PD-L1 blockade resistance patients harbored PI3K/mTOR mutations showed responses. The activation of PI3K/mTOR pathway might mediate the acquired resistance to immune checkpoint inhibitors. This finding suggested that mTOR inhibitors might be a potential strategy for those who harbored mutations in PI3K/mTOR pathway after the resistance of PD-1/PD-L1 blockade therapies.