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N. Gibson



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    Poster Display session (Friday) (ID 65)

    • Event: ELCC 2018
    • Type: Poster Display session
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 4/13/2018, 12:30 - 13:00, Hall 1
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      59P - Circulating microRNAs as novel predictive markers of afatinib efficacy in squamous cell lung cancer (SCC): An exploratory sub-analysis of the LUX-Lung 8 trial (ID 593)

      12:30 - 13:00  |  Author(s): N. Gibson

      • Abstract
      • Slides

      Background:
      Screening of circulating microRNAs is a promising avenue for the discovery of novel biomarkers in cancer therapy. In the LUX-Lung 8 trial, the ErbB family inhibitor Afatinib (A) provided a significant progression free survival (PFS) and overall survival (OS) benefit compared to the EGFR TKI Erlotinib (E) in 2nd line treatment of advanced SCC. To detect new markers associated with clinical outcomes, we performed a post hoc extensive screening of miRNAs in serum samples from a subset of LUX-Lung 8 trial patient population.

      Methods:
      1787 miRNA expression levels were measured by miRNA-seq using the Illumina HiSeq4000 platform in baseline (BL) (n = 133) and cycle 2 (C2) (n = 109) serum samples from 133 LUX-Lung 8 patients randomly selected with stratification on smoking, treatment, and interval from last dose of chemotherapy. All variables were tested for their BL prognostic and predictive value on OS in a Cox model adjusted for prognostic factors. For miRNAs with FDR adjusted p-value <0.05, a data-driven cut-off was determined and Kaplan Meier estimates were performed comparing low- and high-expressers. Analysis of C2 values was conducted.

      Results:
      29 miRNAs were found to be prognostic of OS and 8 to be predictive of treatment effect on OS with FDR p-value p < 0.05. MiR-3150b-3p was the most significant predictive variable (FDR p < 0.001). In the A arm, median OS was 2.7 m in miR-3150b-3p high- vs 8.5 m in low-expressers (HR = 3.4, p = 0.0001) and 5.7 m in high-expressers treated with E (HR = 2.7, p = 0.01). Furthermore, in the A arm, but not in the E arm, high miR-3150b-3p expression at C2 in patients with low BL values was associated with a shorter OS compared to patients remaining low (7.4 m vs 10.4 m, HR = 2; p = 0.08).

      Conclusions:
      Using a rigorous methodology, we found new highly prognostic markers and several novel markers with high predictive value of a differential treatment benefit between A and E. This suggests the two drugs have different mechanism of action. Because this was an exploratory analysis and the effect size could be over-estimated, those results should be replicated in a larger study.

      Clinical trial identification:
      NCT01523587

      Legal entity responsible for the study:
      IntegraGen

      Funding:
      IntegraGen

      Disclosure:
      Y. Gaston Mathé, S. Martin-Lannerée, C. Marcaillou, E. Lallet: Employee of the study sponsor. P. Fogel: Subcontractor of the study sponsor. N. Krämer: Subcontractor of the clinical trial sponsor and owner of the rights on afatinib, Boehringer-Ingelheim. N. Gibson, F. Solca, E. Ehrnrooth: Employee of the clinical trial sponsor and owner of the rights on afatinib, Boehringer-Ingelheim. All other authors have declared no conflicts of interest.

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      60P - Circulating miR-31 as a predictive marker of EGFR TKI treatment efficacy in squamous cell lung cancer (SCC): A sub-analysis of the LUX-Lung 8 trial (ID 205)

      12:30 - 13:00  |  Author(s): N. Gibson

      • Abstract
      • Slides

      Background:
      MicroRNA miR-31-3p and 5p have been reported to predict anti-EGFR cetuximab efficacy in metastatic colorectal cancer but have not been studied in other indications. In the LUX-Lung 8 trial, ErbB family blocker Afatinib (A) provided a significant PFS and OS benefit compared to EGFR TKI Erlotinib (E) in 2nd line treatment of advanced SCC. We retrospectively analyzed the association of miR-31-3p and miR-31-5p serum levels with treatment benefit in a sub-population of this study.

      Methods:
      MiRNA expression levels from baseline (BL) (n = 133) and cycle 2 (C2) (n = 109) serum samples from 133 LUX-Lung 8 trial patients selected randomly with stratification on smoking status, treatment and interval from last dose of chemotherapy were measured by miRNA-Seq using Illumina HiSeq4000 platform. MiR-31-3p, miR-31-5p or combined miR-31 were tested for their prognostic and predictive value of treatment effect on OS using Cox models adjusted for prognostic factors and Kaplan Meier estimates after determination of a data-driven cut-off defining low or high expressers.

      Results:
      Mir-31-3p was detected in 19/133 BL samples and was predictive of E efficacy (p < 0.01). MiR-31-5p was prognostic of OS in the E (p = 0.03) but not in the A arm. Patients with measurable miR-31-3p or high miR-31-5p had a better OS when treated with A compared to E (miR-31-3p: 15 m [6.3;70] vs 4 m [2.7;7.8], HR = 0.3, p < 0.05; miR-31-5p: 7.3 m [4.7;16.5] vs 3.3 m [2.4;6.5], HR = 0.5, p = 0.07). No difference between treatment arms was seen in patients with no measurable miR-31-3p or low miR-31-5p expression. In the E arm only, high miR-31 expression at C2 in patients with low BL miR-31 was associated with a shorter OS compared to patients remaining low (4.2 m [2.8;9.2] vs 10.3 m [7.8;13.0], HR = 0.5, p = 0.05).

      Conclusions:
      MiR-31-3p/5p serum levels were predictive of E treatment efficacy. Patients with high BL miR-31 levels had lower benefit of E and higher benefit of A, suggesting different mechanisms of action for the drugs. Increase of miR-31 levels during treatment with E was associated with poor outcomes. Measurement of circulating mir-31 has potential to help optimizing treatment choice between E and A for SCC patients. Those results should be replicated in a larger study.

      Clinical trial identification:
      NCT01523587

      Legal entity responsible for the study:
      IntegraGen

      Funding:
      IntegraGen

      Disclosure:
      Y. Gaston Mathé: Employee of IntegraGen, the sponsor of the study and owner of IP rights on the disclosed results. P. Fogel: Fees from the study sponsor for the performance of the statistical analysis. S. Martin-Lannerée, C. Marcaillou, E. Lallet: Employee of the study sponsor. N. Krämer: Subcontracter for the clinical trial sponsor and afatinib product owner, Boehringer-Ingelheim. N. Gibson: Employee of the clinical trial sponsor and afatinib product rights owner Boehringer-Ingelheim. F. Solca, E. Ehrnrooth: Employee of the clinical trial sponsor and owner of the rights on afatinib, Boehringer-Ingelheim. All other authors have declared no conflicts of interest.

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