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P. Kavathas



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    P3.02c - Poster Session with Presenters Present (ID 472)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02c-088 - Acquired Resistance to Programmed Death-1 Axis Inhibitors in Non-Small Cell Lung Cancer (NSCLC) (ID 5625)

      14:30 - 14:30  |  Author(s): P. Kavathas

      • Abstract

      Background:
      Programmed death-1 (PD-1) axis inhibitors are increasingly being used to treat patients with advanced NSCLC. Despite durable responses relative to chemotherapy, resistance to such therapy develops in the majority of responders, with median duration of response from 12-17 months. Mechanisms of acquired resistance (AR) to PD-1 axis inhibitors are poorly understood.

      Methods:
      Patients with advanced NSCLC and acquired resistance (AR) to PD-1 axis inhibitor therapy were enrolled to an IRB approved repeat biopsy protocol allowing collection of clinical data, archived and fresh tumor tissue, and blood for analysis. Molecular analyses including whole exome sequencing of pre- and post-treatment tumor specimens were performed.

      Results:
      Twelve cases were available for analysis (table 1). Eight and two patients developed resistance limited to lymph nodes (LNs) and adrenal gland respectively. The two remaining patients experienced tumor progression in LNs with other sites of tumor growth (one in liver, one in lung). Nine patients had sufficient archived pre- PD-1 axis inhibitor tumor tissue for analysis/ comparison, leaving three unpaired cases. Genomic analysis of tumor specimens identified two patients with acquired tumor beta-2-microglobulin (B2M) defects at resistance. A patient derived xenograft generated from one of the resistance samples (patient #6) lacked production of B2M protein and did not express surface MHC-1. Additional analyses including immunophenotyping with multiplexed quantitative immunofluorescence on these and other patient samples are ongoing. Figure 1



      Conclusion:
      Lymph nodes may be a particularly susceptible area to AR to PD-1 axis inhibitors. Defects in B2M leading to loss of tumor MHC-1 presentation may represent a unique mechanism of AR to immune checkpoint inhibitors. Further studies to determine the frequency of defects in antigen presentation machinery in tumors with resistance to PD1 axis inhibitors are warranted.