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N. Hanna

Moderator of

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    ORAL 23 - Prevention and Cancer Risk (ID 121)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Prevention and Tobacco Control
    • Presentations: 8
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      ORAL23.01 - A Randomized Phase IIb Trial of Myo-Inositol in Smokers with Bronchial Dysplasia (ID 856)

      10:45 - 12:15  |  Author(s): S. Lam, S. Mandrekar, K. Allen Ziegler, D. Seisler, D. Midthun, J. Mao, M.C. Aubry, A. McWilliams, D. Sin, T. Shaipanich, A. Spira, D. Ionescu, J. Mayo, J.E. Yi, H. Tazelaar, W. Harmsen, J. Smith, P. Limburg, E. Szabo

      • Abstract
      • Presentation
      • Slides

      Background:
      Previous preclinical studies and a phase I clinical trial suggested myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled, phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia.

      Methods:
      Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once/day for two weeks, and then twice/day for 6 months. The primary endpoint was change in dysplasia rate after six months of intervention on a per participant basis. Other trial endpoints reported herein include Ki-67 labeling index and pro-inflammatory, oxidant/anti-oxidant biomarker levels in blood and bronchoalveolar lavage fluid (BAL).

      Results:
      Seventy four (n=38 myo-inositol, n=36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (p=0.76). The mean percent change in Ki67 labeling index in bronchial biopsies with dysplasia was -22.8% and -6.2%, respectively, in the myo-inositol and placebo arms (p=0.34). Compared with placebo, myo-inositol intervention significantly reduced IL-6 levels in BAL over 6 months (p=0.03) and had borderline significant effects on BAL myeloperoxidase (p= 0.06) level.

      Conclusion:
      The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent.

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      ORAL23.02 - Pioglitazone for the Chemoprevention of Lung Cancer (ID 2419)

      10:45 - 12:15  |  Author(s): R.L. Keith, P.J. Blatchford, M.K. Jackson, W.A. Franklin, P.A. Bunn, Jr, B. Bagwell, D.T. Merrick, Y.E. Miller

      • Abstract
      • Presentation
      • Slides

      Background:
      Prior clinical studies have shown that the oral prostacyclin agonist iloprost improves bronchial dysplasia in former smokers. Prostacyclin is a PPAR gamma agonist, and epidemiologic and pre-clinical studies suggest PPAR gamma agonists like pioglitazone may chemoprevent lung cancer. Based on these promising results, a double-blind, placebo controlled, phase II trial of pioglitazone in subjects at increased risk for lung cancer was sponsored by the Department of Veterans Affairs.

      Methods:
      Subjects were selected for the trial if they met one the following criteria: current or former smoker (> 10 pack years); biopsy proven endobronchial dysplasia; airflow obstruction (FEV1/FVC < 0.70); or at least mild sputum cytologic atypia. Fluorescent bronchoscopy was performed with biopsy of 6 standard endobronchial sites and all other abnormally appearing areas. Subjects also had pulmonary function testings and quantitative high resolution CT scans at the start and completion of the trial. Subjects were then randomized to oral pioglitazone or placebo for 6 months and then a second fluorescent bronchoscopy with repeat biopsy of all the central airway areas sampled on the first bronchoscopy. The endobronchial biopsies were scored on a 1-8 scale based on WHO criteria. The primary endpoint for the study is change in maximum (worst) endobronchial histology.

      Results:
      A total of 90 subjects (46 pioglitazone, 44 placebo) have been enrolled in the trial, with 76 completing both bronchoscopies. Subjects are well matched in terms of age, gender, tobacco exposure, and sputum cytology. No significant differences in lung function were observed between the treatment groups. While the investigators remain blinded in regards to treatment group, aggregate data is available. Overall, mild dysplasia or worse was seen in 26% of the initial biopsies. Similar to prior studies, current smokers exhibited more dysplasia at baseline compared to former smokers (32.4% vs. 16.6%) and also had more angiogenic squamous dysplasia (11.7% vs. 3.2%). Our primary endpoint is change in maximum histology, and histologic scores from matched biopsies in all participants showed a change of at least 1 grade in 50.2% (25.9% improved, 24.3% progressed). More histologic changes were observed in current smokers (59.2%) than former smokers (41.7%). Summary data for the non-normal biopsy pairs (ie those with a histologic score of at least 2 on baseline biopsy) showed that the majority of pairs (73.7%) changed by at least one grade. Current smokers exhibited more progression (29.3%) compared to former smokers (14.6%).

      Conclusion:
      The pioglitazone lung cancer chemoprevention trial is currently in progress. The treatment has been well tolerated and histologic changes were observed in many of the subjects.

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      ORAL23.03 - Role of Inflammatory Infiltrates in Promoting Persistence or Regression of Bronchial Dysplasia (ID 3026)

      10:45 - 12:15  |  Author(s): D.T. Merrick, E.J. Donald, D. Olson, M.C. Okeefe, M.G. Edwards, W.A. Franklin, L. Dwyer-Nield, D. Orlicky, R.L. Keith, Y.E. Miller, M. Tennis, A.E. Barón, X. Lu, A. Van Bokhoven, H. Malinowski, P.A. Bunn, Jr, M.W. Geraci, R. Nemenoff

      • Abstract
      • Presentation
      • Slides

      Background:
      Inflammatory infiltrates show differing capacities to eliminate malignant cells. This capacity is related to the polarization of key inflammatory cells in tumor infiltrates. A pathway analysis of genes that are differentially expressed between persistent and regressive bronchial dysplasia (BD) identified 13 pathways associated with persistence of which 8 were related to inflammation. We have hypothesized that differences in inflammatory infiltrate polarization may contribute to lung carcinogenesis and have employed gene expression and in situ analyses to characterize differences in inflammatory infiltrates related to persistence and regression of pre-malignant BD.

      Methods:
      Normalized gene expression levels (Affymetrix Hu 1.0) of selected genes related to inflammatory cell polarization features were analyzed to find differences associated with follow-up histology for BD. Validational analyses of these relationships were undertaken in studies of baseline biopsies selected to represent persistent (n=43) and regressive BD (n=39). These biopsies were analyzed by quantitative immunohistochemistry and dual immunofluorescence studies to characterize the overall proportion of subsets of T-lymphocytes and macrophages in each of the groups. Image analysis tools (Aperio) were used to characterize the density of inflammatory cell subsets in the stromal and epithelial compartments of biopsy tissue within defined areas.

      Results:
      Analysis of expression levels for a subset of inflammatory cell related genes assessed in a global gene expression analysis indicated significantly higher levels of expression of macrophage M1 markers HLA-DRA (p=0.01) and inducible nitric oxide synthetase (iNOS; p=0.02) and T-helper lymphocyte marker CD4 (p=0.04) in regressive BD compared to persistent BD. There was also a trend toward higher expression of cytotoxic T-lymphocyte marker CD8 in regressive BD (p=0.25). Expression of B-lymphocyte and neutrophil markers were not different between regressive and persistent BD. CD68 immunohistochemical stains (IHC) demonstrated a trend toward an increase in macrophages per area of combined dysplastic epithelium and underlying stroma with a mean increase in IHC positivity of 1.75-fold in regressive versus persistent BD (p=0.08). CD4 and CD8 IHC showed 1.36- and 1.19-fold increases, respectively, in regressive BD but these changes were not statistically significant (p=0.36 and p=0.43 respectively). Dual immunofluorescence was undertaken to determine if polarization specific subsets of macrophages correlated with regression or persistence of BD. Analysis of a preliminary subset of regressive (n=3) and persistent (n=3) BD demonstrates a wide range of M1 to M2 ratios (range = 0.84 – 4.82 for ratio of HLA-DRA-CD68 dual positive M1 to CD206-CD68 dual positive M2 macrophages per high power field, 400X). Additional analyses of macrophages are ongoing to determine if the polarization status is related to regression or persistence of BD, and analysis of markers of T-helper lymphocyte subsets are planned.

      Conclusion:
      Gene expression analyses indicate that increased expression of markers of M1 macrophages and T-helper lymphocytes are associated with regression, and in situ analyses suggest that differences in the amount of inflammatory cell subsets may be related to outcome in BD. These studies could have implications for predicting the behavior of premalignant disease and manipulating inflammatory activity in preventing progression of BD to invasive lung cancer.

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      ORAL23.04 - Discussant for ORAL23.01, ORAL23.02, ORAL23.03 (ID 3357)

      10:45 - 12:15  |  Author(s): E. Szabo

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ORAL23.05 - Increased Proportion of Female and Young Mesothelioma Cases Are Indicators of Environmental Exposure to Carcinogenic Mineral Fibers in Nevada (ID 959)

      10:45 - 12:15  |  Author(s): F. Baumann, B.J. Buck, R.V. Metcalf, B.T. McLaurin, D. Merkler, M. Carbone

      • Abstract
      • Presentation
      • Slides

      Background:
      Inhalation of asbestos and other carcinogenic mineral fibers cause malignant mesothelioma (MM) and lung cancer. Occupational exposure leads to a MM male to female (M:F) sex-ratio of 4-8:1, with a mean age of diagnosis of 74 years old because of the 30-50 years latency between initial exposure and MM development. In places where people are only environmentally exposed to carcinogenic fibers, the M:F sex-ratio is about 1:1 and the mean age of diagnosis is 50-60 years. In places where both types of exposure exist, the M:F sex ratio decreases and the proportion of young (<55 years old) cases increases, compared to places with occupational exposure only. Therefore, incidence rates cannot distinguish between occupationally- and environmentally-caused mesotheliomas.

      Methods:
      In order to detect areas with possible environmental exposure to carcinogenic fibers, we studied the geology of Nevada. We compiled and integrated known presence of fibrous minerals in Nevada from published sources. We used the CDC 2006-2010 cancer data to study MM incidence and death rates by state and by gender. We also analyzed MM mortality data from the CDC in different Nevada Counties, per sex and age group, for the 1999-2010 period.

      Results:
      Several fibrous minerals were identified in Nevada, including actinolite asbestos, other amphiboles such as magnesioriebeckite, winchite and richterite that caused an epidemic of asbestos-related disease in Libby, Montana, and the highly carcinogenic erionite. For the 2006-2010 period, Nevada has a global MM age-standardized incidence rate of 10 cases per million inhabitants-year (95% confidence interval (CI): 8-12), similar to the average MM rate in the US (10 per million; 95% CI: 10-10). We discovered that Clark and Nye counties in southern Nevada had higher proportion of young (<55 years) MM cases (11.28%) and lower M:F sex-ratio (2.69:1), compared with other Nevada counties (M:F sex-ratio=6.33:1, p=0.04; proportion of young MMs=9.09%, p=0.80) and with the US (M:F sex-ratio=4.97:1, p=0.04; proportion of young MMs=6.21%, p=0.02).

      Conclusion:
      The significant decrease of MM M:F sex-ratio and increase of young cases are indicators of possible environmental exposure to carcinogenic fibers in southern Nevada. In this arid region, naturally occurring asbestos minerals are present in urban and rural areas where people use to enjoy outdoor activities including horseback riding, running, hiking, bicycling, and off-road vehicle (ORV) recreation. Airborne dust is common due to wind erosion. Asbestos fibers have been found in air and dust samples in Clark County. Further research should be conducted in this area to help identify sources of environmental exposure to these mineral fibers, activities that lead to the release of these carcinogenic fibers into the air, and measures to reduce the consequent risk of MM and other cancers.

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      ORAL23.06 - Radon Gas Exposure and Lung Cancer in a Cohort of Lung Cancer Patients Who Never Smoked (ID 2859)

      10:45 - 12:15  |  Author(s): C. Egan, A. D'Silva, J. Macklow, G. Bebb, D. Morris

      • Abstract
      • Presentation
      • Slides

      Background:
      Radon is a naturally occurring radioactive gas produced by the breakdown of uranium and uranium progeny in soil and rocks. This colourless and odourless gas moves easily through bedrock and foundations to accumulate within homes (basements) and buildings. Once inhaled, radon gas can decay to solid radionucleotides that deposit within tissue of the airways and lungs and continue to emit alpha particle radiation over the course of >25 years. Exposure to radon gas is thought to be a major epidemiological risk for the development of lung cancer in people who have never smoked, but the precise relationship between exposure and molecular alterations associated with lung cancer are poorly described. In order to explore the relationship between domestic radon gas levels and lung cancer incidence in never-smokers, we set out to identify a cohort of Alberta lung cancer patients who have never smoked and measure radon gas levels of in their homes.

      Methods:
      The Glans-Look Database, comprised of clinicopathological and outcome data for over 5000 patients with non-small cell lung cancer (NSCLC) consulted at the Tom Baker Cancer Centre between 1999 and 2010, was searched for patients who had developed NSCLC but never smoked. Follow-up information was obtained to determine if the patients or their family members still lived at the address provided at diagnosis. Initial letters of contact were sent explaining the study. Patients and their family members will be notified by mail of the levels of radon gas in their homes, and how best to mitigate levels if high. Radon concentration was examined as a continuous variable and as a dichotomous variable, using the cut point value of 200 Bq/m[3] suggested by Health Canada guidelines. Statistical analysis of data utilizes Cox proportional hazard regression models to examine the independent effects of radon exposure on patient outcome, utilizing IBM SPSS Statistical Package version 19. The model addresses the possible confounding variables of exposure to second hand smoke, type and age of dwelling, family history of lung cancer, profession and hours spent within the home.

      Results:
      A cohort of 317 patients was identified, 189 of whom met study criteria requirement. As of March 2015, 42 patients or their family members agreed to participate in this study. 30 long term testing radon monitors have been placed in the homes where patients lived for at least five years before developing NSCLC. These monitors are being collected by the study team by: all will be retrieved by June 30, 2015, three months after initial placement.

      Conclusion:
      This study will contribute significantly to our understanding of residential radon gas exposure in NSCLC, and in the short term, alert patients and their families to potential risk of high level radon gas exposure. In the longer term, as this will be the first study of its type in Alberta, the findings may be seminal in forming the basis of a health program for improved testing for radon gas in the home and educating the public with respect to the dangers of radon gas exposure.

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      ORAL23.07 - Interactions Between Smoking and the Dietary Inflammatory Index in Relation to Lung Cancer in the Prostate Lung Colorectal and Ovarian Trial (ID 1220)

      10:45 - 12:15  |  Author(s): A. Shoaibi, N. Shivappa, M. Wirth, S. Vyas, J. Houston, J. Hebert

      • Abstract
      • Presentation
      • Slides

      Background:
      Chronic inflammation can influence the process of lung carcinogenesis. Dietary factors can modulate inflammation and may modify the effect of tobacco smoke. In this study, we aim to investigate the association between the inflammatory potential of usual diet, as assessed by the novel Dietary Inflammatory Index (DII), and lung cancer and to assess the interactions between the DII and tobacco use.

      Methods:
      Existing data from the Prostate Lung Colorectal and Ovarian Cancer (PLCO) screening trial was used to test the hypothesis that DII influences lung cancer and modifies the effect of tobacco smoke. PLCO participants were enrolled between 1993 and 2001 and randomized to a control arm or screening arm for four target cancers. Data were collected on cancer diagnoses and deaths from all causes that occurred through December 31, 2009. The baseline DII score for each subject was calculated from self-reports via food frequency questionnaires. A proportional hazards model was used to assess the association between the DII and DII-smoking interaction in relation to the probability of developing lung cancer. To investigate the association between DII and lung cancer prognosis, we explored the distribution of the lung cancer stage by the DII quintiles

      Results:
      Of 110,317 participants who met our eligibility criteria, 1850 (1.68%) developed lung cancer. The median follow-up time was 8.38 years. The association between DII and C-reactive protein was significant (beta coefficient of Quintile5 vs. Quntile1 =0.45, p-value<0.01). Results from the proportional hazards model show that those at the higher DII quintiles were at higher risk of lung cancer. The risk of lung cancer among Participants at the 5[th] quintile was 1.28 times higher the risk among these at 1[st] quintile (HR~Q5vsQ1~ = 1.28, 95 % CI 1.09–1.51, and P~trend~ <0.03, after controlling for possible confounders (demographics, smoking, family history, intervention and others) . An interaction was observed between DII score and tobacco smoke in relation to lung cancer (p-value for the interaction =0.01). Among current and former smokers combined HR~Q5vs.Q1~ was 2.00, 95 % CI 1.6-2.36 ( P~trend~ <0.001) compared to 0.82, 95 % CI 0.48-1.41 among never smokers. Table 1 shows the distribution of the lung cancer stage. Cases with worse prognosis were more likely to be in the higher DII quintile. Figure 1



      Conclusion:
      Overall, more pro-inflammatory diets are associated with increased risk of lung cancer, particularly for former and current smokers, suggesting that dietary-mediated inflammation plays an important role in lung carcinogenesis

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      ORAL23.08 - Discussant for ORAL23.05, ORAL23.06, ORAL23.07 (ID 3563)

      10:45 - 12:15  |  Author(s): M. Carbone

      • Abstract
      • Presentation

      Abstract not provided

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Author of

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    ORAL 01 - Chemotherapy Developments for Lung Cancer (ID 88)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL01.03 - A Randomized Phase 2 Trial of Vintafolide and Docetaxel in Folate-Receptor Positive (FR+) Advanced NSCLC Patients: Final Efficacy Results (ID 1600)

      10:45 - 12:15  |  Author(s): N. Hanna

      • Abstract
      • Presentation
      • Slides

      Background:
      Vintafolide (folic acid-vinca alkaloid conjugate) binds to the folate receptor (FR), which is overexpressed in approximately 80% of patients with NSCLC, including patients with squamous cell and adenocarcinoma. Using the molecular imaging agent 99mTc-etarfolatide for SPECT imaging, the FR status of malignant lesions can be determined. Vintafolide has demonstrated single agent activity in patients with advanced NSCLC whose tumors all expressed FR [FR(100%)] compared to patients not FR(100%) (Edelman et al, 2012).

      Methods:
      This study randomized patients with advanced NSCLC whose tumors were FR(100%) to vintafolide, vintafolide + docetaxel, or docetaxel. Key eligibility criteria: age ≥18 years; 1 prior systemic therapy for advanced disease; ECOG PS 0-1. Patients underwent [99m]Tc-etarfolatide SPECT screening for FR assessment. Vintafolide (2.5 mg) was administered on days 1, 4, 8, 11 every 21 days and docetaxel (75 mg/m[2]) on day 1 every 21 days. The primary endpoint was progression-free survival (PFS). Pre-specified PFS comparisons were performed for vintafolide vs docetaxel and vintafolide+docetaxel vs docetaxel in all patients as well as those with adenocarcinoma. Significance testing for each PFS analysis was one-sided without adjustment for multiplicity (alpha=0.10). Overall survival (OS) was a secondary endpoint.

      Results:
      Over 14 months, 199 FR(100%) patients were randomized and treated (vintafolide: 63; vintafolide+docetaxel: 68; docetaxel: 68). Patient and disease characteristics were well-balanced between arms. The vintafolide+docetaxel arm met the primary endpoint of superior PFS over the docetaxel arm in all patients regardless of histology (17.0% censored; unstratified Cox model hazard ratio [HR] =0.75; unstratified one-sided p-value=0.0696) as well as in the prespecified 133 patient adenocarcinoma subgroup (18.8% censored; HR=0.73; p-value=0.0899). Trends in OS favored the vintafolide+docetaxel arm over the docetaxel arm in all patients (37.7% censored; HR=0.88; p-value=0.2874) and showed the greatest benefit in the adenocarcinoma subgroup (42.8% censored; HR=0.70; p-value=0.1018). The single-agent vintafolide arm was not superior to docetaxel. Vintafolide+docetaxel treatment was associated with more neutropenia (all grades: 77% versus 62%), febrile neutropenia (13% versus 6%), and peripheral neuropathy (34% versus 21%) compared to docetaxel alone.

      Conclusion:
      The addition of vintafolide to docetaxel resulted in a statistically significant improvement in PFS in FR(100%) NSCLC patients regardless of histology (PFS HR= 0.75) and in the adenocarcinoma subset (PFS HR= 0.73). Additionally, there was a trend towards improvement in OS in all patients regardless of histology (OS HR= 0.88) and in the adenocarcinoma subset (OS HR= 0.70). Vintafolide +docetaxel was generally well tolerated, although rates of neutropenia, neutropenic fever, and neuropathy were higher than with docetaxel alone. Final survival results will be presented at the conference.

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    P2.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 213)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 1
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      P2.03-011 - A Phase II Trial of Concurrent Chemoradiation with Consolidation Pembrolizumab in Unresectable Stage III Non-Small Cell Lung Cancer (ID 2487)

      09:30 - 17:00  |  Author(s): N. Hanna

      • Abstract
      • Slides

      Background:
      Outcomes for patients with locally advanced non-small cell lung cancer (NSCLC) are poor, and the landscape of treatment in this disease has not changed considerably over the last several years. In those patients with unresectable stage IIIA/IIIB tumors, concurrent chemoradiation has become the standard of care in fit patients, and no alternative approach including induction, consolidation, or maintenance chemotherapy, has been shown to improve overall survival (OS). New treatment paradigms are desperately needed in this setting. Pembrolizumab is a humanized monoclonal antibody that binds to the programmed death-1 (PD-1) receptor on regulatory T-cells (T-reg) and inhibits its interaction with its ligands, PD-L1 and PD-L2. PD-1 exerts an inhibitory effect on T-regs, and blocking this pathway allows for enhanced T-reg activity and an improved anti-tumor immune response. In a phase I trial of previously treated NSCLC patients, Pembrolizumab was well tolerated and demonstrated a 21% response rate by RECIST criteria. Furthermore, preclinical data suggests that the combination of radiation therapy and immunotherapy may have additive or even synergistic effects. Based on these findings, we proposed a phase II trial of consolidation Pembrolizumab following concurrent chemoradiation for patients with inoperable or unresectable stage IIIA or IIIB NSCLC.

      Methods:
      This study is a multi-institutional phase II trial investigating the PD-1 inhibitor Pembrolizumab as consolidation therapy following initial concurrent chemoradiation in patients with unresectable or inoperable stage IIIA/IIIB NSCLC. Concurrent chemoradiation is defined as platinum-based chemotherapy (Cisplatin/Etoposide or Carboplatin/Paclitaxel) that overlaps with radiotherapy (total dose of 59.4-66Gy). Patients must demonstrate stable disease or disease response following chemoradiation and must have no evidence of metastatic disease. Patients who qualify will receive Pembrolizumab at a dose of 200mg IV every 3 weeks starting a minimum of 4 weeks and a maximum of 8 weeks after completion of chemoradiation. The primary endpoint will be time to distant metastatic disease, defined as disease recurrence outside of the radiated field. Secondary endpoints will include progression free survival (PFS), OS, and toxicity. An exploratory objective will involve assessing PD-L1 expression levels in the tumor samples of participating subjects and correlating that with time to metastatic disease, PFS, OS, and treatment toxicity. Approximately 93 patients will be enrolled. The sample size was calculated based on the hypothesis that consolidation Pembrolizumab will improve time to metastatic disease to 18 months from a historical control of approximately 12 months with a power of 0.80 and a type I error of 0.05.

      Results:
      Accrual for this trial has begun, and the first patient was enrolled in March 2015.

      Conclusion:
      This study will determine whether immunotherapeutic consolidation with Pembrolizumab will increase the time to metastatic disease in patients with stage IIIA/IIIB NSCLC following concurrent chemoradiation. It will also answer questions about the safety and tolerability of this combination of therapies in this patient population.

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