Author of

• 25776

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  MA04 - Novel Approaches with IO (ID 900)

  • Event: WCLC 2018
  • Type: Mini Oral Abstract Session
  • Track: Immunooncology
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/24/2018, 13:30 - 15:00, Room 107

  • 25782

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    MA04.11 - Neoantigen Targeting and T Cell Reshaping in Resectable NSCLC Patients Treated with Neoadjuvant PD-1 Blockade (ID 12605)

    14:40 - 14:45  |  Author(s): Kristen A. Marrone
    • Abstract
    • Presentation
    • Slides

    Background
    

    PD-1 blockade is now standard treatment for advanced non-small cell lung cancer (NSCLC) and has recently shown impressive efficacy in promoting major pathologic response (MPR) and delaying relapse in the neoadjuvant setting. The role of tumor mutational burden, and specifically T cells targeting neoantigens derived from these mutations, in facilitating tumor clearance has been demonstrated in advanced NSCLC. However, it is unknown how neoadjuvant PD-1 blockade impacts the frequency and function of tumor specific T cells and their ability to promote major pathologic response, or how these factors may synergize to prevent or delay relapse after surgical resection.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    Whole exome sequencing and neoantigen prediction was performed on pre-treatment tumor biopsies and matched normal tissue from 11 patients with resectable NSCLC treated with neoadjuvant nivolumab as part of a clinical trial (NCT02259621). T cell recognition of peptides representing candidate neoantigens was evaluated using the MANAFEST assay, which identifies T cell receptor clonotypes corresponding to antigen specificities. T cell receptor sequencing was additionally performed on serial peripheral blood T cells, pre-treatment tumor biopsies, and resected post-treatment tissues. A bioinformatic platform was developed to evaluate the dynamics of intratumoral T cell clonotypes, and more specifically neoantigen-specific clonotypes detected before, during, and after treatment and during long-term follow-up.

    4c3880bb027f159e801041b1021e88e8 Result
    

    High-magnitude, polyclonal neoantigen-specific T cell responses were detected in the peripheral blood and persisted for many months after surgical resection and cessation of treatment. Binding to and stability with cognate HLA I molecules was validated for reactive neoantigens. Significant treatment-induced systemic perturbations in the tumor-specific T cell repertoire and an influx of peripheral T cell clonotypes into tumor tissue and lymph nodes was observed in patients regardless of pathologic response, whereas peripheral clonotypic reshaping of the anti-tumor repertoire and intratumoral T cell clonality were associated with MPR status.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    We show significant and systemic alterations in the peripheral anti-tumor T cell repertoire in NSCLC patients treated with neoadjuvant anti-PD-1 regardless of MPR status. Notwithstanding, the impaired restructuring of the anti-tumor T cell repertoire in patients without MPR highlights a potential immunological deficiency to overcome in future therapeutic approaches aiming to increase the MPR rate in NSCLC patients treated with neoadjuvant PD-1 blockade.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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• 25955

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  P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall

  • 27426

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    P3.01-70 - Meta-Analysis of Metformin in Combination with Platinum Chemotherapy in Advanced Non-Squamous Non-Small Cell Lung Cancer (ID 12602)

    12:00 - 13:30  |  Presenting Author(s): Kristen A. Marrone
    • Abstract
    • Slides

    Background
    

    Metformin has been shown to have a variety of insulin-dependent and –independent antitumor effects, primarily through cellular growth inhibition via the AMP-activated protein kinase (AMPK) pathway and the IGF1-insulin axis. Two prospective trials evaluating metformin with platinum doublet chemotherapy +/- bevacizumab have demonstrated competitive outcomes in non-diabetic, chemotherapy-naïve advanced non-small cell lung cancer (NSCLC) patients. Outcomes in KRAS-mutated NSCLC, an area of interest due to potential co-occurring LKB1 mutations, an AMPK pathway upstream kinase, is currently unknown.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    This meta-analysis is of two phase II study treatment arms (NCT02019979, NCT01578551), evaluating the use of concurrent metformin and platinum-based doublet chemotherapy +/- bevacizumab. Patient’s demographic, molecular and adverse event (AE) profiles were summarized with descriptive statistics. Kaplan-Meier curves for progression free survival (PFS) and overall survival (OS) were generated for all patients, as well as known KRAS and EGFR mutation subsets.

    4c3880bb027f159e801041b1021e88e8 Result
    

    33 non-squamous NSCLC patients were treated; 60% were female and the median age was 64 (Range: 37-77). The most common AE was neutropenia (Grade 3-4: 30%). No patients required study treatment cessation due to metformin-related toxicity. Across all patients, mPFS was 6 months (95% CI: 1.36-7.96); mOS was 14.83 months (95% CI: 8.25-19.99). In KRAS-mutated patients (n=13), mPFS was 7.21 months; mOS was 17.46 months. In EGFR-mutated patients (n=7), mPFS was 6.57 months; mOS was 13.25 months.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Combination metformin and chemotherapy +/- bevacizumab was safe and well-tolerated in advanced, chemotherapy-naïve non-squamous NSCLC across two phase II clinical trials. Metformin appeared particularly effective in KRAS-mutated NSCLC. Data for LKB1 status was unknown for a majority of patients, but may be an important co-mechanism for benefit. Metformin appeared to underperform in the EGFR subset, perhaps due to lack of TKI use. Given the tolerability, low cost and activity observed in NSCLC, further investigation into metformin’s antitumor effects in molecularly defined subsets is needed.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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• 25958

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  P3.04 - Immunooncology (Not CME Accredited Session) (ID 970)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall

  • 27534

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    P3.04-23 - Phase 1b/2 Study to Evaluate Novel Combinations With Oleclumab (MEDI9447) in Previously Treated Advanced EGFRm NSCLC (ID 12300)

    12:00 - 13:30  |  Author(s): Kristen A. Marrone
    • Abstract
    • Slides

    Background
    

    Patients with mutant EGFR (EGFRm) non–small cell lung cancer (NSCLC) have a limited chance of benefiting from treatment with programmed death-1 inhibitors. EGFR activation leads to overexpression of CD73 and may provide a mechanism of immune evasion. CD73 overexpression has also led to worse outcomes in multiple tumor types, including NSCLC. Recent studies demonstrated that an orthogonal therapeutic approach to cancer, such as combining tyrosine kinase inhibitors (TKIs) with immunotherapy, may result in synergistic clinical activity. Oleclumab is a human monoclonal antibody (mAb) that selectively binds to CD73 and inhibits the enzymatic production of adenosine. Adenosine exerts its immunosuppressive effects on various immune cells via the adenosine 2A receptor (A₂AR). AZD4635 is a potent, selective A₂AR antagonist that inhibits this signaling pathway. Osimertinib is a potent and selective inhibitor of EGFRm, including the T790M resistance mutation. We hypothesize that novel combinations of targeted and immunotherapeutic agents targeting the adenosine pathway will be well tolerated and lead to increased antitumor activity in subjects with EGFRm NSCLC.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    This is a multi-arm, open-label, multicenter, phase 1b/2 study (NCT03381274) consisting of 2 parts. In Part 1, the safety and tolerability of oleclumab in combination with either osimertinib (Arm A) or AZD4635 (Arm B) will be evaluated, and a recommended phase 2 dose for each combination will be identified. In Part 2, the safety, tolerability, and preliminary antitumor activity will be evaluated. In both parts, patients will be allocated to treatment arms based upon their EGFRm status and their prior therapy. For Part 2, the primary objective of antitumor activity will be assessed by objective response according to RECIST v1.1. Key secondary objectives include additional evaluation of clinical activity, the pharmacokinetic profiles of oleclumab, osimertinib, and AZD4635, and the evaluation of oleclumab immunogenicity. Additional treatment arms may be added as the study progresses. The study is open for enrollment and recruitment is ongoing, with a planned enrollment of up to approximately 98 patients.

    4c3880bb027f159e801041b1021e88e8 Result
    

    Section not applicable

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Section not applicable

    6f8b794f3246b0c1e1780bb4d4d5dc53

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