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  P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11583

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    P2.06-040 - Circulating cytokines and angiogenic factors (CAFs) as markers of clinical response in a randomized phase II study of trametinib vs docetaxel for patients with KRAS-mutant non-small cell lung cancer (NSCLC) (MEK114653, NCT01362296) (ID 2880)

    09:30 - 09:30  |  Author(s): R.C. Gagnon
    • Abstract

    Background
    Trametinib is a reversible and highly selective allosteric inhibitor of MEK1/MEK2. In a 2:1 randomized, open-label phase 2 study, trametinib showed an overall response rate of 12% but did not show improvement in progression-free survival (PFS) over docetaxel as second-line treatment in patients with KRAS-mutant NSCLC. Median overall survival (OS) was 8 months in the trametinib arm and has not been reached in the docetaxel arm (ASCO 2013 abstract #8029). Several CAF markers were identified as prognostic and predictive of clinical benefit in patients with renal cell carcinoma (Tran, Lancet 2012), and of tumor shrinkage in patients with NSCLC (Nikolinakos, Cancer Research 2010), after receiving targeted therapy.

    Methods
    Of 134 patients randomized, plasma samples (n = 116 baseline [113 KRAS-mutant], n = 89 day 22) from patients who consented for this optional study were analyzed for 38 CAFs using SearchLight multiplex assays in a CLIA-certified laboratory. Baseline CAF levels were tested for association with PFS using proportional hazards regression within and between arms. Correlation between baseline CAFs and baseline tumor burden was assessed using the Spearman rank correlation test. Change from baseline was assessed using Wilcoxon signed rank tests. P < .01 was considered significant; for treatment arm by CAF-level interaction, P < 0.05 was considered significant.

    Results
    Lower baseline levels of IL-6 and OPN and higher baseline levels of TRAIL were associated with longer PFS in patients treated with trametinib but not those treated with docetaxel. Interaction between CAFs and trametinib or docetaxel treatment was significant for IGFBP-1, MMP-9, E-selectin, and VEGF. There was a positive correlation between IL-6 levels and baseline tumor burden. At day 22, decreases (trametinib: ANG-2, IGF-1, IGFBP-3, IL-10, IL-2R, TIMP-1; docetaxel: IL-6, MIP-1A, MIP-1B, SDF-1) and increases (trametinib: IGFBP-1, IL-6, MMP-2, PIGF, VEGF) in CAF levels were observed. Additional results (pairwise correlation, CAF levels and OS, change from baseline CAF levels and PFS and OS) will be reported.

    Conclusion
    Circulating baseline CAF levels may be predictive of PFS for patients treated with trametinib or docetaxel. CAF levels are modulated by each treatment. The impact of circulating baseline CAFs on PFS warrants additional investigation in well-designed clinical trials. Plasma CAF profiling may aid in the prognostic evaluation of patients and determine potential therapeutic response to trametinib treatment in patients with NSCLC.