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  P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)

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

  • 26454

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    P1.04-20 - Computational Biological Model Prediction of PD-L1 Expression and Immunotherapy Response for KRAS Mutated Lung Cancer Based on Co-Mutations (ID 13049)

    16:45 - 18:00  |  Author(s): Upasana Mitra
    • Abstract
    • Slides

    Background
    

    Emerging data suggest that KRAS mutated non-small cell lung cancer (NSCLC) is a heterogeneous disease based on the presence of co-mutations. These co-mutations may impact PD-L1 expression, a predictive biomarker for PD-1/PD-L1 immunotherapy, and may result in differential responses to immunotherapy.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    Genomic information of NSCLC patients, including 2888 from publically available datasets and 86 from Stanford University, was input into computational biological model (CBM) software (Cellworks Group, San Jose, CA). Customized computational protein network maps of disease characteristics were generated for each patient. CBM was used to predict PD-L1 protein expression and also response to PD-1/PD-L1 immunotherapy in KRAS co-mutation subsets using 3 key metrics: PD-L1 expression; Dendritic Cell Infiltration Index (9 chemokine markers); and Immunosuppressive Biomarker Expression (14 markers).

    4c3880bb027f159e801041b1021e88e8 Result
    

    The major co-mutations observed with the KRAS mutation were in tumor suppressor genes (TP53, STK11, CDKN2A, KEAP1) and a downstream effector (PIK3CA). Using the CBM approach, KRAS mutated NSCLC tumors with TP53 co-mutations had the highest prevalence of PD-L1 protein expression whereas tumors with KRAS/KEAP1 and KRAS/STK11/KEAP1 co-mutations were associated with the lowest expression. Expression of PD-L1 in tumors with KRAS/STK11, KRAS/CDKN2A, KRAS/PIK3CA co-mutations, and KRAS without co-mutations was higher than in tumors with KRAS/STK11/KEAP1 and KRAS/KEAP1 co-mutations. Of the 30 NSCLC tumors in the Stanford dataset with available PD-L1 immunohistochemistry results, including 19 with KRAS/TP53 and 11 with KRAS/KEAP1 or KRAS/STK11/KEAP1, CBM accurately predicted PD-L1 expression in these two groups at rates of 79% and 72%, respectively. In regards to prediction of response to PD-1/PD-L1 immunotherapy, CBM predicted the majority of patients with KRAS/KEAP1 and KRAS/STK11/KEAP1 to be non-responders, whereas CBM predicted the majority of patients with KRAS/TP53, KRAS/PI3KCA, and KRAS without co-mutations to be responders. The proposed mechanism for KRAS co-mutations’ impact on PD-L1 expression from the CBM model integrates differential activation of (i) downstream pathways of KRAS (PI3K/AKT, RAF/ERK, and RAL) and (ii) transcription factors involved in PD-L1 expression (i.e., MYC, HIF1α, NFKβ, AP1, and STAT1/3).

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    KRAS mutated NSCLC is emerging as a diverse disease based on co-mutations. The CBM approach demonstrates that PD-L1 expression varies among KRAS co-mutation subtypes along with likelihood of response to PD-1/PD-L1 immunotherapy. CBM provides proposed mechanisms underlying these differences and therefore, provides further rationale to examine more precise delivery of immunotherapy.

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