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H. Roder



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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02b-009 - Plasma and Tissue Inflammatory and Angiogenic Biomarkers to Explore Resistance to EGFR-TKIs and Association with VeriStrat Status (ID 5750)

      14:30 - 14:30  |  Author(s): H. Roder

      • Abstract

      Background:
      VeriStrat is a proteomic test validated to be prognostic and predictive of overall survival (OS) to EGFR Tyrosine Kinase Inhibitors (TKIs) in EGFR wild type patients[1]. Serum Amyloid A1 (SAA1) and its two truncated forms are responsible for 4 of the 8 peaks overexpressed in Veristrat (VS) Poor classified patients. The aim of the study was to explore if the microenvironment, with its complex network mediated by inflammation and angiogenesis could represent the base of the aggressive disease behavior of VS Poor subjects. Moreover, the activity of the immune escape axis PD-1/PD-L1 was explored.

      Methods:
      Plasma biomarkers analyses were retrospectively performed on plasma baseline samples of 244 patients enrolled in the PROSE trial[1], while exploratory tissue analysis was performed on 37 available histological specimens. Circulating levels of HGF, VEGF, FGF, Cromogranin A (CgA) and its pro- and anti-angiogenic fragments (fragment 1-373 and 1-76, respectively) were determined by an ELISA assay. PD-L1 expression both on tumor cells and inflammatory elements of the tumor microenvironment, and the tissue expression (T) of HGF and its receptor c-MET were measured by immunohistochemistry.

      Results:
      CgA, HGF, VEGF, and FGF plasma levels were statistically significantly higher in VS Poor subjects. High plasma HGF levels were associated with lower PFS (3.4 versus 2.0 months, HR 1.67; 95% CI 1.25-2.23; p<0.001) and OS (11.2 versus 6.4 months, HR 1.64; 95% CI 1.12-2.23 p=0.002). High PD-L1- tumor expression was associated with worse PFS (5.9 versus 1.9 months, HR 2.28; 95% C.I. 1.14-4.57; p<0.020) and a trend for lower OS (14.6 versus 6.7 months, HR 1.47; 95% CI 0.85-2.53; p=0.165), but not significantly associated with VS status (p=0.656). At the multivariate analysis, CgA, HGF and VEGF were independently associated with VS Poor status. When clinical variables were also included (histology and PS), multivariate analysis evidenced VEGF as the only independent biomarker associated with the VS Poor classification (p=0.0013). Plasma HGF levels (HR 2.083; 95% C.I. 1.306-3.321; p=0.0021) and tumor PD-L1 expression (HR 2.579; 95% CI 1.036-6.421; p=0.0417) remained independent prognostic biomarkers for shorter PFS.

      Conclusion:
      Inflammation and angiogenesis appear to be associated with the complex processes at the base of the Veristrat signature. Plasma HGF levels and tumor tissue PD-L1 are prognostic in terms of a worse PFS, but VeriStrat remains the only highly reproducible clinically relevant biomarker associated with OS. [1]V Gregorc et al, The Lancet Oncology, p713, 15(7),2014.

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

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 2
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      P3.02c-051 - A Pre-Treatment Serum Test Based on Complement and IL-10 Pathways Identifies Patients Benefiting from the Addition of Bavituximab to Docetaxel (ID 7068)

      14:30 - 14:30  |  Author(s): H. Roder

      • Abstract

      Background:
      SUNRISE, a global, double-bind, Phase III trial of docetaxel (D) plus bavituximab (B) or D plus placebo (P) in previously treated non-squamous non-small cell lung cancer, demonstrated similar overall survival (OS) in both treatment arms. Mass spectrometry and correlative analysis were used to create a test able to identify a subgroup of patients benefitting from the addition of B to D.

      Methods:
      Pre-treatment serum samples were available for 197 of the first 200 subjects enrolled in the trial. Mass spectra could be generated for 193 samples using the Deep MALDI method (Duncan et al, ASMS 2013), processed and features (peaks) identified. Mass spectral (MS) features associated with various biological functions were identified using a gene set enrichment analysis approach. Analysis of scores based on these MS feature, subsets indicated that in patients with high complement activation outcome depended on IL-10 activation in D+B but not in D+P. A test using the MS features associated with these functions was created to reliably identify a patient subgroup associated with clinical benefit using modern machine learning methods.

      Results:
      Complement activation, as assessed by a classifier trained using related MS features, was a prognostic factor in both treatment arms, with high activation associated with poorer clinical outcome (OS HR = 0.54, log-rank p = 0.013 for D+B; OS HR = 0.60, log-rank p = 0.040 for D+P). Within the subgroup with high complement activation [N=50 (D+B); N=54 (D+P)], a second classifier using features related to IL-10 activation was able to isolate a subgroup of patients showing numerical benefit from the addition of B [median OS 5.9 months (D+P), 12.5 months (D+B)]. The remaining subgroup showed no benefit from addition of B [median OS 10.4 months (D+P), 5.6 months (D+B)]. Blinded validation of the test in the remainder 397 patients randomized in SUNRISE is will be presented.

      Conclusion:
      Proteomic and correlative approaches identified complement activation and low IL-10 levels as important pathways for predicting improved outcomes of patient treatment with D+B, in line with preclinical work on B’s mechanism of action. The test resulting from this work will undergo blinded independent validation.

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      P3.02c-074 - Evaluation of a Pretreatment Serum Tests for Nivolumab Benefit in Patients with Non-Small Cell Lung Cancer (ID 5505)

      14:30 - 14:30  |  Author(s): H. Roder

      • Abstract

      Background:
      Anti-PD1 inhibitors are becoming the treatment of choice for 2[nd] line non-small cell lung cancer (NSCLC). While existing testing for PDL-1 expression may correlate with anti-PD1 benefit, current data do not support these tests to be sufficient to guide therapy. We evaluated the utility of a serum-based pre-treatment test first developed to identify patients benefitting from anti-PD1 therapy in metastatic melanoma[1] in patients with NSCLC. These results were compared to the data obtained from application of the established VeriStrat[2] test to the same samples.

      Methods:
      60 advanced NSCLC patients treated with nivolumab in an observational study were included. Pretreatment serum samples were classified using the fully locked mass spectrometry-based multivariate tests BDX008 and VeriStrat. BDX008 generates a classification of positive (BDX008+, good outcomes) or negative (BDX008-, poor outcomes); VeriStrat classifies samples as Good and Poor. The association of test classifications with overall survival (OS), progression-free survival (PFS), and time-to-failure (TTF) were assessed using Kaplan-Meier method and Cox proportional hazards model.

      Results:
      37% of patients were classified as BDX008+ and 63% as BDX008-; 62% were classified as VeriStrat Good and 38% as Poor. Both tests significantly stratified OS (Table), but not PFS or TTF, and remained significant for OS in multivariate analyses (p=0.0167 and 0.0184, for BDX008 and VeriStrat, respectively). Out of 11 patients who died before the first radiological evaluation, 10 were classified as BDX008-, 9 as VeriStrat Poor.

      Test Log-rank p value CPH HR [95% CI] Median Survival (months) [95% CI]
      BDX0008 (+ vs -) 0.0026 0.189 [0.056-0.637] BDX0008+: Not reached BDX0008-: 5.5 [2.6-11.9]
      VeriStrat (Good vs Poor) 0.0186 0.390 [0.173-0.880] VS Good: Not reached VS Poor: 4.1 [1.0-Undef.]


      Conclusion:
      BDX008 developed for immunotherapy of patients with melanoma can be applied to NSCLC patients, and shows a significant separation for OS. Clinical utility of BDX008 will need to be further evaluated. VeriStrat is also prognostic for the same patients. 1. J. Weber et al, “Pre-treatment patient selection for nivolumab benefit based on serum mass spectra”, SITC 2015. 2. V. Gregorc et al, The Lancet Oncology, p713, 15(7), 2014.