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J.E. Gray



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    ISS03 - Industry Supported Symposium: Non-Small Cell Lung Cancer: The Programmed Death-Ligand 1 (PD-L1) Receptor as a Target for Monotherapy and in Combination – Merck-Pfizer Alliance (ID 437)

    • Event: WCLC 2016
    • Type: Industry Supported Symposium
    • Track:
    • Presentations: 1
    • Moderators:S. Popat
    • Coordinates: 12/04/2016, 03:30 PM - 05:00 PM, Hall C2
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      ISS03.03 - Anti-PD-L1 Combined with Other Agents in NSCLC: Combinations with non-Immunooncology Agents (ID 7039)

      J.E. Gray

      • Abstract

      Abstract not provided

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    P1.01 - Poster Session with Presenters Present (ID 453)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Epidemiology/Tobacco Control and Cessation/Prevention
    • Presentations: 1
    • Now Available
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      P1.01-041 - Quantitative Imaging Features Predict Response of Immunotherapy in Non-Small Cell Lung Cancer Patients (Now Available) (ID 5729)

      J.E. Gray

      • Abstract
      • Slides

      Background:
      Although immunotherapy has revolutionized the field of cancer treatment, response rates are only ~20% in non-small cell lung cancer (NSCLC) patients and cost of this therapy is high. Predictive biomarkers are needed to identify patients likely to benefit. Converting digital medical images into high-dimensional data (‘Radiomics’) contains information that reflects underlying pathophysiology and that can be revealed via quantitative analyses. We extracted radiomic imaging features from baseline CT scans (prior to initiation of immunotherapy) and identified features that predict response to immunotherapy in NSCLC patients. This work is an initial test of the hypothesis that radiomic data may predict who will respond favorably and who will not.

      Methods:
      We curated a subset of data and images from 13 different institutional immunotherapy clinical trials. Patients were stage III/IV NSCLC and received PD-1, PD-L1, or doublet checkpoint inhibitors. All target nodules were identified on the CT prior scan prior to initiation of immunotherapy. RECIST guidelines 1.1 were used to measure patient response from baseline to last follow-up scan. Based on last follow-up, 43 patients had progressive disease (PD) and 28 patients with partial response (PR) or complete response (CR). Since we focused on extreme responses, stable disease (SD) patients were not included in the current analyses. We extracted 219 radiomic features including size, shape, location, and texture information from a total of 210 target nodules (lung, lymph nodes, or other). Backward-elimination analyses were utilized to generate parsimonious radiomic models associated with objective responses (PD vs. PR/CR) and post estimation computed performance statistics.

      Results:
      There were no significant differences for the patient characteristics between patients with PD vs. CR/PR. Analysis of the radiomic features for all target nodules to differentiate PD patients vs. PR/CR patients resulted in a final model containing 2 features that provided an AUROC of 0.64 (95% CI 0.56–0.72). When we analyzed features for only lung target nodules, we identified a final model with 4 features that produced an AUROC of 0.79 (95% CI 0.68–0.89). When we analyzed the imaging features for lymph node target nodules, we found that a final model with 1 feature yielded an AUROC of 0.67 (95% CI 0.51–0.82).

      Conclusion:
      Radiomic features of lung target nodules have better performance statistics for predicting response to immune therapies compared to target nodules from other organ sites. With this model, cutoffs can be chosen to reduce non-responders with high confidence. Change feature analyses following therapy are underway.

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    P2.01 - Poster Session with Presenters Present (ID 461)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
    • Now Available
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      P2.01-072 - Clinical Associations of MUC1 Expression in Human Lung Cancer and Precancerous Lesions (Now Available) (ID 4473)

      J.E. Gray

      • Abstract
      • Slides

      Background:
      Mucin 1 (MUC1) is a cell membrane glycoprotein overexpressed in many human cancers, including non­small cell lung cancer (NSCLC). Its role has been implicated in carcinogenesis of premalignant lung lesions in animal models and in clinical association with prognosis in NSCLC. Thus, MUC1 has been a target of interest for vaccine strategies as an mmunomodulatory approach to lung cancer treatment and prevention.

      Methods:
      Tumor samples from 38 patients with biopsy­-proven NSCLC were assessed for MUC1 expression as determined by immunohistochemistry, expressed on a 0 to 3 scale. Levels of MUC1 expression in areas of dysplasia, metaplasia, bronchoalveolar carcinoma (BAC) and carcinoma present within the same tissue sample were characterized independently and compared using the paired t­test. Clinical data including patient characteristics, staging, treatment and survival were also assessed for correlation with MUC1 expression.

      Results:
      16 patients with squamous and 19 patients with glandular lesions had tumor samples that were satisfactory for analyses. Among squamous lesions, there was a significant increase in MUC1 expression score in dysplastic compared with metaplastic areas (mean difference = 0.83, 95% CI, 0.21 to infinity; p = 0.021). We also observed an increase in squamous cell carcinoma compared with dysplastic areas (mean difference = 0.44, 95% CI, ­0.006 to infinity; p = 0.052). Among glandular lesions, there was a non­significant increase in MUC1 expression in adenocarcinoma compared with BAC (mean difference = 0.20, 95% CI, ­0.055 to infinity; p = 0.094). According to the Spearman correlation test (p = 0.020 for carcinoma score; p = 0.008 for dysplasia score), a significant positive correlation was observed between MUC1 expression and survival in patients with squamous lesions; however, no significant correlation was observed between MUC1 expression and survival in patients with adenocarcinoma.

      Conclusion:
      MUC1 overexpression appears to be increased with the progression of premalignant lung lesions to invasive carcinoma in patients with NSCLC. This supports the rationale for MUC1 as a therapeutic target in tumor vaccines that could be ultimately used to prevent or reverse precancerous lesions and treat lung cancer.

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    P2.06 - Poster Session with Presenters Present (ID 467)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
    • Presentations: 1
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      P2.06-011 - Phase 2 Study of MM-121 plus Chemotherapy vs. Chemotherapy Alone in Heregulin-Positive, Locally Advanced or Metastatic NSCLC (ID 4158)

      J.E. Gray

      • Abstract

      Background:
      The role of the HER3 receptor and its ligand heregulin (HRG) in the progression of multiple cancers has been well established. Seribantumab (MM-121) is a fully human, monoclonal IgG2 antibody that binds to the HRG domain of HER3, blocking HER3 activity. The correlation between the level of HRG mRNA in tumor tissue and progression free survival (PFS) were retrospectively analyzed in three completed randomized Phase 2 studies of seribantumab plus standard of care (SOC) versus SOC alone (NSCLC, breast cancer and ovarian cancer). In each of these studies, high levels of HRG mRNA predicted shortened PFS for patients who received SOC treatment, while the addition of seribantumab to SOC improved PFS for patients with HRG-positive (HRG+) tumors. This is consistent with the hypothesis that HRG expression defines a drug tolerant cancer cell phenotype shielded from the effects of cytotoxic or targeted therapies and that blockade of HRG-induced HER3 signaling by seribantumab counters the effects of HRG on cancer cells, with the potential to improve outcomes for HRG+ patients. It is estimated that up to approximately 50% of cases of all solid tumor indications are HRG+. This HRG expression may contribute to rapid clinical progression in a subset of patients with poor prognosis.

      Methods:
      In the ongoing randomized, open-label, international, Phase 2 study, NSCLC patients with HRG+ tumors are being prospectively selected using a HRG RNA in situ hybridization assay performed on a recent tumor tissue sample collected via fine needle aspiration, core needle biopsy or excision. Approximately 560 patients will be screened to support enrollment of 280 HRG+ patients, who will be randomized in a 2:1 ratio to receive seribantumab plus investigator’s choice of docetaxel or pemetrexed, or docetaxel or pemetrexed alone. Patients will be wild-type for EGFR and ALK and will have progressed following one to three systemic therapies, one of which must be an anti-PD-1 or anti-PD-L1 therapy, for locally advanced and/or metastatic disease. Overall survival (OS) is the primary endpoint of the study and secondary endpoints include PFS, objective response rate and time to progression. Safety and health-related quality of life will also be assessed. An interim analysis is planned when 50% of final OS events have been reported. Enrollment has been initiated with approximately 80 sites expected to participate worldwide. Clinical Trials Registry number: NCT02387216

      Results:
      Section not applicable

      Conclusion:
      Section not applicable

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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-024 - Dynamics of EGFR Mutational Load in Urine and Plasma Correlates with Treatment Response in Advanced NSCLC (ID 5529)

      J.E. Gray

      • Abstract

      Background:
      NSCLC is a heterogeneous and dynamic disease where testing for key mutations is essential. With the emergence of clonal resistance, obtaining serial biopsies to assist in the real-time treatment decision-making has proven challenging. Molecular assessments of circulating tumor (ct)DNA has been previously shown feasible utilizing blood specimens. Here we additionally investigated the utility of serial urine ctDNA analysis in NSCLC.

      Methods:
      This is a prospective observational study of patients with non-squamous, tissue-confirmed EGFR, KRAS or ALK mutant NSCLC preparing to receive a systemic treatment regimen. Urine and blood specimens were collected at baseline, on treatment and at progression for ctDNA analyses. The primary endpoints were correlation between ctDNA and tumor-based molecular results, and measurable change in ctDNA with response by RECIST v1.1. Blood and urine samples were sent to Trovagene for DNA extraction and mutation enrichment NGS.

      Results:
      Of the 34 patients enrolled thus far, interim blinded analysis of EGFR activating mutations (L858R, exon 19 deletions) was conducted in 20 patients with EGFR-positive tumors. Of 20 patients, 17 (85%) had detectable concordant EGFR mutation in pre-treatment urine and/or plasma. Of 11 patients with matched serial ctDNA samples, detectable EGFR mutation signal was observed in pre-treatment urine and/or plasma of 9 patients. These 9 patients received first to sixth line treatment with single EGFR TKI (n=3), combination TKIs (n=3), chemotherapy (n=1), immune checkpoint inhibitors alone (n=1) or in combination with TKI (n=1). In 9 of 9 patients, changes in ctDNA levels from baseline to cycle 2 day 1 on therapy correlated with best response to treatment: a 100% decrease in urine and plasma EGFR mutation levels was observed in 6 of 6 patients with partial response (PR, n=3) or stable disease (SD, n=3), while less than a 90% decrease or an increase in urine and plasma EGFR levels was observed in patients with progressive disease (PD, n=3).

      Conclusion:
      Mutation enrichment NGS testing by urine and plasma ctDNA correctly identified EGFR activating mutations in 85% of patients. Monitoring EGFR levels in urine/plasma enabled accurate assessment of response in advance of radiographic evaluation and regardless of therapy type in 100% of patients, with cut-point of a 90% decrease in EGFR load discriminating between patients with disease control (PR or SD) and patients with progressive disease. With continued enrollment, our study aims to further investigate clinical utility of urine and plasma ctDNA for early detection of resistance and discontinuation of inefficient therapy.