Author of

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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

  • 26442

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    P1.04-09 - Immunomodulatory Effects of Afatinib and Pembrolizumab in EGFR-Mutant NSCLC with Progression on Prior EGFR-TKI (ID 12185)

    16:45 - 18:00  |  Author(s): Arta M Monjazeb
    • Abstract

    Background
    

    EGFR-mutant NSCLC is less responsive to single agent PD-1 blockade than smoking associated NSCLC. Preclinical models suggest EGFR-TKI can render a more immunocompetent tumor microenvironment. This study examined the immunomodulatory effects of combination second generation EGFR-TKI and PD-1 antibody.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    In this phase 1 dose de-escalation study, patients were treated with afatinib 40 mg oral daily and pembrolizumab 200 mg IV q21day. Key Eligibility: advanced EGFR-mutant NSCLC with progression (PD) on prior EGFR-TKI, age≥18, ECOG PS≤1, acceptable organ function, no significant autoimmune diseases, measurable disease and controlled brain metastases. Tissue biopsy performed baseline and week 5-6 on treatment for PD-L1 IHC (22C3) and quantitative immunofluorescence for immune cell subsets and next-generation sequencing. Blood at baseline and at serial on-treatment timepoints were collected for ctRNA of PD-L1, EGFR, HER2 and MET; changes in circulating immune cell subsets, T-Cell repertoire and cytokine levels were evaluated by flow cytometry and Luminex.

    4c3880bb027f159e801041b1021e88e8 Result
    

    No DLTs were observed in the first 6 patients and the 10 patient expansion cohort proceeded at afatinib 40 mg daily and pembrolizumab 200 mg IV q21day. Eleven patients enrolled to date. Key molecular and pathologic characteristics: adenocarcinoma 9, neuroendocrine 1, squamous 1. EGFR-TKI resistance mechanism: EGFR-T790M 4, EGFR-T790M/C797S 1, HER2 amp 1, MET 2, Her2 amp+neuroendocrine differentiation 1, unknown 2. Five patients had prior second line osimertinib. Three (27%) patients had immune related AEs (G2 adrenal insufficiency, G2 nephritis, G3 colitis). Nine patients were evaluable for response: (1 PR, 7 SD ((6/7) with tumor reduction <30%)). The responding patient had squamous histology tumor, prior PD on erlotinib, and PFS of 11 months with PD-L1 (22C3) TPS 40% and PD-L1 and PD-L2 amplification. Treatment with afatinib and pembrolizumab induced systemic immune changes including trend for increased soluble IDO, MIG, TIM3, IP-10, LAG3, PD-L1 and PD-L2 and decreased IFN-gamma. ctRNA for EGFR and PD-L1 were detected in 7/7 and 6/7 patients, respectively, with dynamic changes in allele frequency of EGFR and PD-L1 observed. Baseline PD-L1 (22C3) TPS ranged from 0% to 75% expression. Four patients had repeat biopsy and in paired samples analyzed PD-L1 (22C3) expression decreased in the stroma.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Immunomodulatory effects of afatinib with pembrolizumab were noted in the tumor microenvironment and peripheral blood. Only modest clinical activity has been observed thus far in patients with PD on prior EGFR-TKI. Genomic and immune-profiling is feasible in EGFR-mutant NSCLC and may identify EGFR-mutant NSCLC patients who may respond or lack benefit to PD-1 blockade.

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