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Philip Bonomi



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    OA01 - Precision Medicine and Personalized Therapy for Lung Cancer (ID 1)

    • Event: NACLC 2019
    • Type: Oral Abstract Session
    • Track:
    • Presentations: 1
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      OA01.02 - Prognostic Value of Baseline Autoantibodies in Metastatic NSCLC Patients Receiving PD-/PDL-1 Targeted Immunotherapy   (ID 105)

      14:00 - 15:40  |  Author(s): Philip Bonomi

      • Abstract
      • Slides

      Background:
      Immune checkpoint inhibitors targeting either programmed cell death protein-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) have advanced the paradigm for management of Non-small Cell Lung Cancer (NSCLC). However, only a subset of patients showed durable response leaving the majority at risk of progression especially with lack of feasible biomarkers for appropriate selection of candidates. Humoral immunity is involved in tumor-immune interaction by generation of neoantigens associated autoantibodies. These circulating autoantibodies might provide clinically important prognostic information on response to immunotherapy.


      Method:
      Pretreatment sera from metastatic stage NSCLC patients (n=81) receiving non-frontline standard PD-1/PDL-1 targeted immunotherapy as non-frontline were evaluated for autoantibodies using EMD Millipore’s MILLIPLEX® Human Cancer Autoantibody Magnetic Bead Panel. This panel includes Alpha-enolase (ENO1), Cancer/Testis Antigen 1? (CTAG1B/NY-ESO-1), Cyclin-dependent kinase 4 inhibitor A (p16-INK4a), G2/mitotic-specific cyclin-B1 (CCNB1), Galactose-specific lectin-1 (Galectin 1), Galactose-specific lectin-3 (Galectin 3), Heat shock protein 60 (HSP60), Hypoxia-inducible factor 1-alpha (HIF1?), Insulin-like growth factor 2 mRNA-binding protein 2 (IMP-2), Insulin-like growth factor 2 mRNA-binding protein 3 (IMP-3), Mucin 1 (MUC1), Receptor tyrosine-protein kinase (HER2/ErbB2), sex determining region Y (SRY)-box 2 (SOX2), Survivin (Survivin/BIRC5), Tumor protein p53 (p53). The Panel was processed according to manufacturer-defined protocols and read using a Luminex® FLEXMAP 3D®.All statistical relationships were determined using the Log-Rank test in relation to overall survival (OS) and progression-free survival (PFS). Additionally, observed adverse events were correlated to the autoantibody’s levels, excluding any autoimmune preoccupied co-morbidity, and statistically assessed using Mann-Whitney U test.


      Results:
      Baseline level of autoantibodies specific to IMP2 was significantly associated with time to progression (HR=2.28, 95%CI=1.21-4.3, p=0.01), whereas P53(HR=2.05, 95%CI=1-4.17, p=0.049), HIF1?(HR=3.02, 95%CI=1.05-8.65, p=0.04), HSP60(HR=0.39, 95%CI=0.16-0.85, p=0.02,), and CTAG1B/NY-ESO-1(HR=0.29, 95%CI=0.1-0.8, p=0.017) autoantibodies where significantly associated with overall survival. After considering comorbidity, patients who developed treatment associated pneumonitis (n=5) showed lower levels of ENO1, MUC1, and CTAG1B (all p<0.02) compared to the rest of the cohort. Skin adverse events (n=7) were also associated with significantly lower level of MUC1, CTAG1B, and GAL1 (all p<0.02) compared to the rest of the cohort.


      Conclusion:
      Baseline autoantibodies appeared to have a potential benefit in selecting candidates for PD-1/PDL-1 targeted immunotherapy in metastatic NSCLC and in this limited dataset were associated with the development of some autoimmune adverse events. Further studies are ongoing.

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    OA03 - IO Concerns and Targeted Therapies (ID 3)

    • Event: NACLC 2019
    • Type: Oral Abstract Session
    • Track:
    • Presentations: 1
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      OA03.01 - Biomarkers of Autoimmune Toxicity in Metastatic SCLC Patients Receiving PD-1/PDL-1 Targeted Therapy (ID 104)

      09:45 - 11:15  |  Author(s): Philip Bonomi

      • Abstract
      • Slides

      Background:
      Cancer immunotherapy has resulted in durable responses in patients with metastatic lung cancer. With general unleashing of the immune system to enhance antitumor responses, a consequent, organ-specific immune-related adverse events can be serious, and even life-threatening. Despite the durable benefit of immunotherapy, these adverse events can indicate the cessation of therapy or incur complex management with a multidisciplinary approach. Prognostic biomarkers for treatment toxicity are required for appropriate selection of candidates for immunotherapy.


      Method:
      Serum specimens from previously treated advanced stage SCLC (n=32) were evaluated with 16 soluble checkpoint molecules and immune regulators using the Human Immuno-Oncology Checkpoint Protein Panel (MilliporeSigma). This panel consists of the following targets: B and T Lymphocyte Associated protein BTLA, CD27, CD28, T-cell immunoglobulin and mucin-domain containing-3 TIM-3, HVEM, CD40, GITR, GITRL, LAG-3, TLR-2, PD-1, PD-L1, CTLA-4, CD80/B7-1, CD86/B7-2, and ICOS. All primary data points were collected on a Luminex FLEXMAP 3D® system. Analyte concentrations were calculated from a 7-point curve using a five-parametric fit algorithm (xPONENT® v4.0.3 Luminex Corp., Austin, TX). The Panel was processed according to manufacturer-defined protocols and read using a Luminex® FLEXMAP 3D®. minimum follow up was three months, and the cohort was grouped into two groups; first group who developed ?grade III adverse events (n=10), and a second group who did not develop ?grade III adverse events(n=22). All statistical comparisons were determined using Mann-Whitney U and one way ANOVA test.


      Results:
      Serum level of six soluble immune checkpoints were significantly associated with the development of grade III immune-related adverse events. Development of grade III immune-related adverse events was associated with higher pretreatment serum level of GIRTL, CD80, CD86, and ICOS( p=0.001,0.019,0.04, and 0.035, respectively), and lower pretreatment serum level of CD27 and CD40 in this cohort( p=0.037, and 0.018, respectively).


      Conclusion:
      In this exploratory analysis circulating biomarkers were associated with the development of autoimmune toxicity in small cell lung cancer patients. larger sample series, further development is required.

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    P1 - Poster Viewing (ID 5)

    • Event: NACLC 2019
    • Type: Poster Session
    • Track:
    • Presentations: 3
    • Moderators:
    • Coordinates: 10/11/2019, 16:45 - 18:00, Exhibit Hall
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      P1.02 - Chemotherapy with VMAT (Volumetric Modulated Arc Therapy) Radiation Therapy for Poor Risk Stage IIIA-C NSCLC Patients (ID 40)

      16:45 - 18:00  |  Author(s): Philip Bonomi

      • Abstract

      Background:
      Concurrent chemoradiation (CRT) for treatment of locally advanced lung cancer often leads to adverse events and discontinuation of therapy, even in healthy patients. Poor risk and/or elderly patients are often offered palliative doses of radiation and/or chemotherapy, with little chance for cure. In this single institution retrospective analysis, we examine a unique approach of curative, concurrent chemoradiation for these poor risk (defined as ECOG performance status of 2) and/or elderly patients (?80yo). Specifically, we examine the tolerability, compliance and efficacy of the regimen in a modernly treated patient population.


      Method:
      Consecutive patients treated at a single institution with the diagnosis of locally advanced (i.e. stage IIIA-C) non-small cell lung cancer (NSCLC) who were treated with four-phase concurrent chemoradiotherapy (CRT) from January 2016 to May of 2018 were included in this IRB-approved retrospective analysis. Chemoradiation was administered in four phases of 1.5 weeks each, with 1.5 week breaks in between each phase (total treatment duration of 12 weeks). All patients were treated with modern IMRT (intensity modulated radiation therapy), specifically VMAT. The primary end points were compliance (defined as completion of curative dosing of both radiation and chemotherapy), one-year overall survival, and one-year progression free survival. Survivals calculated with Kaplan Meier analyses). Analyses of adverse toxicities (CTCAE v.4) were also included in the study.


      Results:
      Twenty-seven (27) consecutive patients with median age of 74 (range: 48-84) were analyzed for this study. 36% of the patients had an ECOG score of 2. There were no ECOG 3 or 4 patients who underwent treatment. There was a 100% completion rate for patients treated with split-course CRT. The overall median survival for all patients was 13.7 months. Progression free survival was 10.7 months; and metastasis-free survival was 14.8 months. 18.5% of patient experienced grade 2 toxicities (pneumonitis, dyspnea, dermatitis, dysphagia) during treatment and there was no grade three or higher toxicities observed.


      Conclusion:
      Initial findings suggest that this unique 4-phase CRT regimen employing VMAT and interdigitated treatment breaks has an inordinately low toxicity profile (zero grade 3+ toxicities), a 100% completion rate, and favorable outcomes in a patient population who otherwise would not necessarily have curative therapy options. Prospective study of this treatment course is warranted, in addition to investigation of the adjuvant utilization of immunotherapy to maximize long-term cure rate in this patient population.

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      P1.05 - Clinical Factors Associated with Progression in Previously Treated Patients with Metastatic NSCLC on Anti-PD-1 Therapy (ID 106)

      16:45 - 18:00  |  Author(s): Philip Bonomi

      • Abstract

      Background:
      Known prognostic indicators for treatment outcomes in patients with metastatic NSCLC include tumor PD-L1 expression, tumor mutational burden (TBM), and neutrophil to lymphocyte ratio (NLR). This study reports patient characteristics associated with rapid progression (defined as progression within 30 days) in 141 patients with metastatic NSCLC who were treated with single-agent immune checkpoint inhibitors (ICI) at a tertiary care center.


      Method:
      A retrospective chart review and analysis of patients with previously treated stage IV NSCLC who received second or third line, single agent ICI was conducted. Pre-treatment (? 6 weeks prior to receiving ICI) values for weight, BMI, and NLR were compared to baseline values at initiation of treatment with ICI and correlated with rapid progression (progression at 1 month) and progression free survival (PFS).


      Results:
      141 patients were included in analysis. Of these, 59% were female, 70% were Caucasian, and 75% were current or former smokers. 85 patients had pre-treatment NLR values and 41% and 28% had NLR >3.5 and >5, respectively. 106 patients had pre-treatment weight and BMI available. Of these, 14% had pre-treatment BMI < 20, and 63% had a negative change in BMI prior to initiation of ICI with 26% of patients having had a >5% weight loss. Weight loss (p = <0.01) on a continuous scale and weight loss >5% (p = <0.01) were significantly associated with shorter PFS. Rapid progression (PFS *<* 30 days) was associated with pre-treatment NLR >3.5 (p = 0.02), increase in NLR from 6 weeks pre-treatment to baseline at initiation of therapy (p = <0.01), BMI decrease >5% (p = <0.01) and weight loss >5% (p = <0.01) prior to initiation of ICI. Rapid progression was additionally associated with pre-ICI changes in NLR, weight, and BMI analyzed as continuous variables (p = <0.01).


      Conclusion:
      This retrospective study identified clinical features of weight change and NLR in the pre-ICI treatment period that were associated with rapid progression on ICI therapy. These parameters should be investigated in the front line population and may have utility in identifying patients that would benefit from intensification of therapy beyond single agent ICI.

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      P1.21 - RNA Pathway Enrichment in Serum Based Mass Spectroscopy Prognostic Analyses. (ID 98)

      16:45 - 18:00  |  Author(s): Philip Bonomi

      • Abstract

      Background:
      Veristrat(VS) good and poor labels were found to be prognostic in the front-line NSCLC setting with or without immune checkpoint inhibitors. Little is known about RNA expression data corresponding to these good and poor prognostic labels.


      Method:
      Raw RNA seq expression data was obtained from TEMPUS XP RNA analysis. Sequences were filtered for allowing only genes that had an overall count of atleast 20 across all samples. Samples were then processed through the EdgeR analysis in the R programming environment. Along with a Z-scored heatmap, PCA plot was also generated. Differential abundance analysis was done further filter out the genes. Benjamini-Hochberg correction was done and only genes with corrected p-value of <0.05 were selected for further pathway analysis. 242 genes with corrected p-value < 0.05 were used. Pathway analysis was performed using the Broad Institute GSEA (Gene Set Enrichment Analysis) and DAVID (Database for Annotation, Visualization and Integrated Discovery). The gene list was ran using KEGG database in GSEA and using KEGG, BioCarta and Reactome pathway databases. Functional analyses against the KEGG and REACTOME database were reported out to determine the enriched pathways in the VS poor and VS good groups.


      Results:
      26 patients had VS label and RNA expression data available. Nine patients had VS poor label and 17 patients had VS good label. 242 genes had significantly different abundance in the VS poor vs good patients with the majority (211) over expressed in the poor label patients. VS poor label patients had differential expression of acute phase reactants reflective of the major constituents of the VS panel. Significant pathways enriched in the VS Poor group included the Intrinsic pathway of fibrin clot formation, platelet degranulation (DAVID), steroid hormone biosynthesis and dilated cardiomyopathy (KEGG) with systemic lupus erythematous enriched in the VS good group (KEGG).


      Conclusion:
      In this small set of front-line patients with RNA pathway analysis and known VS poor or good labels, differential expression of acute phase reactants were found in VS poor patients. DAVID and KEGG pathways were differentially enriched and may reveal potential targets to mitigate prognosis in poor risk NSCLC.

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    D01 - What do you give to patients with EGFR Mutation in the first line? (ID D01)

    • Event: TTLC 2020
    • Type: General Session
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 2/20/2020, 09:45 - 10:00,
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      Chemo plus TKI (ID D01.02)

      09:45 - 10:00  |  Presenting Author(s): Philip Bonomi

      • Abstract
      • Slides

      Abstract not provided

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