Author of

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  MA15 - Immunotherapy Prediction (ID 400)

  • Event: WCLC 2016
  • Type: Mini Oral Session
  • Track: Chemotherapy/Targeted Therapy/Immunotherapy
  • Presentations: 1
  • Moderators:O. Arrieta
  • Coordinates: 12/07/2016, 14:20 - 15:50, Schubert 1

  • 18192

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    MA15.02 - Non-Synonymous Mutation Burden in Lung Carcinoma is Associated with Durable Clinical Response to Immune Checkpoint Blockade (ID 5780)

    14:20 - 15:50  |  Author(s): A. Adeni
    • Abstract
    • Slides

    Background:
    Recent evidence indicates that efficacy and durability of responses to immune checkpoint inhibitors in lung carcinomas correlate with increased nonsynonymous mutation (NSM) burden, putative neoantigen number, and in some tumor types, PD-L1 protein expression. In this study, we retrospectively analyzed the relationship of lung carcinoma mutation burden, PD-L1 expression and immune infiltrates with clinical response in patients receiving immune checkpoint blockade.
    
    Methods:
    Tumor nonsynonymous mutation data derived from clinical targeted next generation sequencing (309 genes) of lung carcinomas from 94 patients treated with immune checkpoint inhibitors was correlated with clinical outcomes, including durable clinical benefit (DCB; >6 months partial or stable response) and progression-free survival (PFS). PD-L1 immunohistochemistry (clone E1L3N, Cell Signaling Technology, Envision+ detection, Dako) was considered positive if ≥1% of tumor cells and/or tumor-infiltrating immune cells (IC) stained. PU.1, CD3, and FOXP3 immunohistochemistry was used to highlight tumor-associated macrophages and non-regulatory and regulatory T cell populations, which were manually quantified per mm[2].
    
    Results:
    The mean patient age was 62 years (range: 32-91 years). Lung tumor types included 69 adenocarcinomas, 11 squamous cell carcinomas, 5 small cell carcinomas, and 9 of other/combined histology. Therapies included PD1 inhibitors (82), a PD-L1 inhibitor (5) and multiple agents (7). Across all tumor types, patients with DCB had a significantly higher number of NSM (range: 1-42) than patients who showed no durable benefit (NDB) [DCB: 12; NDB: 8, p = 0.0027]. Patients with greater than the median number of NSM (9) had significantly longer PFS than those with ≤9 (p = 0.015). Increasing smoking history correlated with higher mutation load (p = 0.047) and patients with a longer smoking history tended to have longer PFS although this trend did not reach statistical significance (p = 0.07). Expression of PD-L1 in either tumor cells or ICs was not associated with NSM burden (p = 0.47) or PFS (p = 0.92). PD-L1 expression in the tumor microenvironment was associated with increased numbers of tumor-associated macrophages (p = 0.0002), and non-regulatory and regulatory T cells (p = 0.0038 and 0.01 respectively).
    
    Conclusion:
    The non-synonymous mutation burden in lung carcinoma as assessed by targeted next generation sequencing is associated with increased PFS and durable clinical benefit to immune checkpoint inhibitors. In this limited cohort, PD-L1 expression using clone E1L3N does not predict response to these therapies. We add to growing evidence that increased somatic mutations in carcinomas influence response to immune checkpoint blockade.
    
    

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