Author of

• 31446

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  P1.14 - Targeted Therapy (ID 182)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Targeted Therapy
  • Presentations: 1
  • Now Available
  • Moderators:
  • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall

  • 31473

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    P1.14-23 - Resistance Mechanisms to Osimertinib Treatment in EGFR-Mutated Lung Cancer in a Real Life Cohort (Now Available) (ID 1657)

    09:45 - 18:00  |  Author(s): Jan H. Von Der Thüsen
    • Abstract
    • Slides

    Background
    

    Targeted therapies in Epidermal Growth Factor Receptor (EGFR)-mutated advanced lung cancer are developing rapidly, with registration for third generation EGFR-tyrosine kinase inhibitor (TKI) osimertinib for first line treatment recently. The resistance mechanisms that develop during first line treatment with osimertinib seem to differ from resistance developing during treatment for p.T790M mutation after first- or second generation EGFR-TKI based on current limited knowledge. We investigated the resistance mechanisms at progression on osimertinib treatment in a real life cohort.

    Method
    

    In the START-TKI study, patients with EGFR-mutated lung cancer were pospectively sampled for plasma analysis during TKI treatment. We analysed the included osimertinib cohort until March 1, 2019, which included both first line and second line (based on p.T790M positivity) treated patients. Exclusion criteria were lack of subsequent samples until progression, double gene/TKI treatment or switch to other treatment because of toxicity. Next-generation sequencing (NGS) analysis was performed at progression on plasma and tissue specimens (when available).

    Result
    

    A total of 42 patients was included, which consisted of N=27 in the p.T790M positive (second line treatment) and N=15 in the p.T790M negative (first line treatment) subgroup. We excluded 4 patients in the first, and 5 patients in the second line treatment group. Evaluable progression was reached by N=11 and N=3 patients respectively.

    In the second line (p.T790M positive) subgroup, resistance mechanisms were identified in 7 patients, and comprised MET amplification (N=2), small-cell transformation (N=2), EGFR p.C797S mutation (N=2) and BRAF mutation (N=1). In the p.T790M negative (first line) subgroup, resistance mechanisms were not identified.

    Conclusion
    

    Tissue specimen can provide important additional information on resistance mechanisms to EGFR-TKI treatment next to plasma analysis due to morphological information and in situ analyses (immunohistochemistry and in situ hybridization).

    Resistance mechanisms to osimertinib in EGFR-mutated lung cancer are still under investigation, and may differ in a p.T790M positive and p.T790M negative setting.

    This study was partly funded by a grant from AstraZeneca.

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• 30943

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  P2.04 - Immuno-oncology (ID 167)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Immuno-oncology
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall

  • 30996

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    P2.04-47 - Tumor Mutational Load, CD8+ T Cells, Expression of PD-L1 and HLA Class I to Guide Immunotherapy Decisions (ID 1259)

    10:15 - 18:15  |  Author(s): Jan H. Von Der Thüsen
    • Abstract

    Background
    

    A minority of NSCLC patients benefit from anti-PD1 immune checkpoint inhibitor therapy. A rational combination of biomarkers is needed. The value of using a series of mechanism-of-action based parameters was studied for response prediction of immunotherapy: tumor mutational load (TML), CD8⁺ T cell infiltration, HLA class I expression and the currently used PD-L1 tumor proportion score.

    Method
    

    Patients were prospectively included between April 2016 and August 2017, and retrospectively analyzed. Metastatic NSCLC patients (n=30) with sufficient archival tissue, obtained prior to the first nivolumab administration, were selected. Response was assessed by RECIST v1.1. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier methodology. TML was determined using a next-genome sequencing panel (409 cancer-related genes). Immunohistochemistry was performed to score PD-L1, total CD8⁺ T cell infiltration and HLA class I.

    Result
    

    In 30 patients with adenocarcinoma (67%) or squamous cell carcinoma (33%), high TML was significantly associated with better PFS (p=0.004) and OS (p=0.025). Interaction analyses revealed that patients with both high TML and high total CD8⁺ T cell infiltrate (p=0.023) or no loss of HLA class I (p=0.026), patients with high total CD8⁺ T cell infiltrate and no loss of HLA class I (p=0.041) or patients with both high PD-L1 and high TML (p=0.003) or no loss of HLA class I (p=0.032) were significantly associated with better PFS. Unsupervised cluster analysis based on the four markers revealed three sub-clusters, of which cluster 1A was overrepresented by patients with progressive disease (15 out of 16), with significant effect on PFS (p=0.007).

    Conclusion
    

    This proof-of-concept study suggests that a combination of PD-L1 expression, TML, CD8⁺ T cell infiltration and HLA class I expression function as a better predictive biomarker for the response to anti-PD-1 immunotherapy and PFS. Consequently, refinement of this proposed set of biomarkers and validation in a larger set of patients is warranted.