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M. Edelman



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    HOD 01 - Highlights of the Previous Day: Treatment of Advanced, Localized and LocoRegional Disease and Small Cell, Thymoma, Mesothelioma (ID 240)

    • Event: WCLC 2015
    • Type: Highlights of the Day
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      HOD01.04 - Small Cell/Thymoma/Mesothelioma/Other (ID 3410)

      M. Edelman

      • Abstract
      • Presentation

      Abstract not provided

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    HOD 03 - Highlights of the Previous Day: Treatment of Advanced, Localized and LocoRegional Disease and Small Cell, Thymoma, Mesothelioma (ID 242)

    • Event: WCLC 2015
    • Type: Highlights of the Day
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      HOD03.04 - Small Cell/Thymoma/Mesothelioma/Other (ID 3414)

      M. Edelman

      • Abstract
      • Presentation

      Abstract not provided

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    MINI 02 - Immunotherapy (ID 92)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI02.04 - Sequential Assessment of DNA Damage Response and PD-L1 Expression in Circulating Tumor Cells of Lung Cancer Patients during Radiotherapy (ID 2511)

      M. Edelman

      • Abstract
      • Presentation
      • Slides

      Background:
      Recent evidence suggests that PD-L1 expression can be induced with radiotherapy and may be a mechanism for resistance to radiotherapy and immunotherapy. Sequentially assessing PD-L1 expression on cancer associated cells in circulation during treatment regimens may be a way to assess the efficacy of radiotherapy and immunotherapy in clinical trials. For this feasibility study, we evaluated the association of RAD50 induction, and PD-L1 expression, on CTCs and Cancer Associated Macrophage-Like Cells (CAMLs) in lung cancer patients (pts) before and during radiotherapy to determine expression changes of these markers.

      Methods:
      Eleven pts with stage I-IV lung cancer were included in this pilot study. Three pts received Stereotactic Body Radiation Therapy (SBRT) for stage I disease and 8 other pts received chemoradiation for stage II-IV disease. Baseline blood samples (7.5 ml) were drawn prior to the start of radiotherapy (T0) and a second blood sample was drawn at a follow up visit during radiotherapy; or for three pts, after completing SBRT (T1); for a total of 22 samples. Blood was processed using CellSieve™ microfiltration (Creatv Microtech), stained for cytokeratin 8, 18 & 19 and CD45, and imaged. Using the QUAS-R (Quench, Underivatize, Amine-Strip and Restain) technique to remove fluoresce signal, all cells were restained for RAD50-AlexaFluor550 and PD-L1-AlexaFluor 488, along with DAPI nuclear stain. The RAD50 foci numbers within nuclear regions were quantified. PD-L1 pixel intensity was measured by the ZenBlue software and grouped into 4 IHC groups: 0-negative (pixel average 0-215), 1-low (pixel average 216-300), 2-medium (pixel average 301-750), and 3-high (pixel average 751+).

      Results:
      There was at least one cytokeratin positive cell (i.e. CTC or CAMLs) found in each of the samples. Specifically CTCs were found in 82% of T0 and 64% of T1 samples, and CAMLs were found in 91% of T0 and 100% of T1 samples. RAD50 foci ranged from 0-16 per cell, with an average of 0.69 at T0 that increased to 3.46 at T1 (p=0.002) during radiotherapy. Distinctively, there were 6 pts with greater than 2 fold RAD50 foci increase at T1 and 5 pts with ≤ 2 fold induction. PD-L1 expression ranged from 34-2004 pixel intensity, with an average of 170 at T0 and 336 at T1 (p=0.08). Interestingly, 4 pts had no PD-L1 expression at T0 but an increase to 2 to 3+ at T1, 4 pts with low/no PD-L1 expression remained low at T1, and 3 pts had high PD-L1 expression that remained high or decreased at T1. There was no correlation between RAD50 induction and PD-L1 expression.

      Conclusion:
      Both RAD50 foci and PD-L1 expression were quantifiable in both CTCs and CAMLs, and had variable responses to radiotherapy +/- chemotherapy. These data suggest that sequential tracking of CTCs or immune-related cells from the primary lung tumor is feasible using microfiltration and potentially can serve as predictive biomarkers for cancer therapy.

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    MTE 02 - Patients, Investigators and Pharmaceuticals Working Together to Accelerate Research and Access: The Lung Cancer Master Protocol (Lung-MAP) Clinical Trial (Ticketed Session) (ID 54)

    • Event: WCLC 2015
    • Type: Meet the Expert (Ticketed Session)
    • Track: Advocacy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/07/2015, 07:00 AM - 08:00 AM, 105
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      MTE02.01 - Patients, Investigators and Pharmaceuticals Working Together to Accelerate Research and Access: The Lung Cancer Master Protocol (Lung-MAP) Clinical Trial (ID 1979)

      M. Edelman

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The traditional obstacles to approval of oncologic therapeutic agents, especially targeted therapies that address a rare-biomarker defined group of patients are the long processes from initial drug discovery to clinical implementation, the difficulties in recruitment for these clinical trials and high number of screen failures and the overall low rate of enrollment in clinical trials. The Lung Master Protocol (Lung-MAP, S1400) is a precedent-setting clinical trial designed to advance the efficient development of targeted therapies for squamous cell cancer of the lung (SCCA). There are few new effective therapeutic options for patients with advanced lung SCCA. Immunotherapies, including nivolumab, have already shown clear benefit for patients with SCCA in 2015 leading to approval by the FDA which has been an unprecedented step forward for the treatment of patients, however we are still lacking predictive markers for these therapies that are reliably selecting patients more likely to benefit. Lung-MAP (S1400) is aiming to identify biomarker-drug pairs that will lead to successful therapeutic outcomes and registration of new agents. It is a registration-intent master protocol that includes a screening component and clinical trial component; the clinical trial component includes multiple sub-studies which independently evaluate investigational therapies. The clinical trial component is designed to be modular such that new sub-studies can be added either as other sub-studies close or as new biomarker-drug pairs are identified for testing in this patient population. Lung-MAP is utlilizing a broad NGS screening platform capitalizing on the expanding application of genomic sequencing in oncology that has through the Cancer Genome Atlas and other sequencing initiatives revealed targetable genetic aberrations including gene mutations, rearrangements, amplifications, and deletions, and creating an immense opportunity to implement personalized therapy with a high potential to improve patients outcomes. Immunotherapy has been integrated in the design of Lung-MAP from its launch in June of 2014. The original study design and structure is shown in the figure. Figure 1 The modular design of the study has allowed for the flexibility to adapt to the approval of nivolumab and the hault in further development of AMG102 (rilotumumab) with discontinuation of the corresponding sub-study by implementing timely modifications which include the following:1)Eligibility has changed from exclusively second line therapy to second-or more line therapy 2)Pre-screening, while patient receive first line therapy has been added to boost accrual 3)the unmatched arm has been changed to a single (not randomized) arm study with the anti-PD-L1 agent MEDI-4736. Theses changes are reflected in the figure. Each independently conducted and analyzed sub-study specifies investigator-assessed progression-free survival (IA-PFS) and overall survival (OS) as the co-primary endpoints for the phase 3 primary objectives. The primary objectives for the phase 3 are to determine if there is a statistically significant difference in OS and to determine if there is both a clinically meaningful and statistically significant difference in IA-PFS. The conduct of Lung-MAP relies on close collaboration (a public-private partnership) among the NCI and NCTN (spearheaded by SWOG), the pharmaceutical industry, the Foundation for the NIH (FNIH), Friends of Cancer Research, advocates, and FDA. This Master Protocol will improve genomic screening of SCC patients for clinical trial entry, and improve time lines for drug-biomarker testing, allowing for inclusion of the maximum numbers of otherwise eligible patients. The clinical trial continues to be updated following science and alterations in the therapeutic landscape, with adaptations in design and incorporation of new agents against matched targets and the implementation of novel immunotherapy approaches for the unmatched arm. Figure 2





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    P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P1.01-075 - Phase III, Randomized, Double-Blind Trial of Bavituximab Plus Docetaxel in Previously Treated Stage IIIb/IV Non-Squamous NSCLC (SUNRISE) (ID 1581)

      M. Edelman

      • Abstract
      • Slides

      Background:
      Exposed phosphatidylserine (PS) in the tumor microenvironment is highly immunosuppressive. PS binding to PS receptors on myeloid derived suppressor cells (MDSC) and M2 macrophages leads to production of anti-inflammatory cytokines such as TGF-β and IL-10. Bavituximab, a first-in-class PS-targeting monoclonal antibody, counters these effects, resulting in production of pro-inflammatory cytokines such as TNF-α and IL-12, maturation of dendritic cells and induction of tumor specific cytotoxic T lymphocyte (CTL) immunity. Docetaxel has also been shown to suppress MDSCs while increasing tumor antigens and T-cell mediated cytotoxicity, thereby enhancing bavituximab’s immunomodulatory effects. In a prior double-blind Phase II trial in 2nd line non-squamous non-small cell lung cancer, bavituximab 3 mg/kg plus docetaxel was well-tolerated and demonstrated 60% improvement (11.7 vs 7.3 month) in median overall survival (OS) compared to control.

      Methods:
      SUNRISE is a Phase III, double-blind trial where patients with previously treated Stage IIIb/IV non-squamous, non-small cell lung cancer are randomized in a 1:1 ratio to receive up to six 21-day cycles of docetaxel in combination with either weekly 3 mg/kg bavituximab or placebo, followed by maintenance with weekly bavituximab or placebo until progression or toxicity. Patients will be stratified by region (North America, Europe, or Rest of World), disease stage (IIIb or IV), and previous maintenance/targeted therapy (yes or no). This trial was initiated in December 2013 and accrual of 582 patients across 160+ sites in 14 countries is planned over 24 months. The primary endpoint is OS and two interim analyses are planned. Secondary endpoints include progression-free survival (PFS), overall response rate (ORR) and safety. Radiographic tumor response is centrally assessed every two cycles during combination therapy and every nine weeks during maintenance. Exploratory analysis will include the assessment of changes in circulating immune cells and cytokines to better understand the immunotherapeutic mechanism.

      Results:
      Trial in progress

      Conclusion:
      Trial in progress

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    P1.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 212)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 2
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      P1.03-029 - Obesity Is Associated with Long-Term Improved Survival in Definitively Treated Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC) (ID 2958)

      M. Edelman

      • Abstract
      • Slides

      Background:
      Limited studies suggest that obese patients (pts) with NSCLC paradoxically have improved survival. However, characterization of factors influencing Body Mass Index (BMI) at disease presentation and the impact that it may have on outcomes in NSCLC patients remains incomplete. We evaluated the prognostic effect of BMI in a retrospective cohort treated for LA-NSCLC (AJCC 7[th] edition stage III).

      Methods:
      From January 2000 to December 2010, 311 consecutive LA-NSCLC pts were definitively treated at our institution with chemotherapy and radiotherapy ± surgery. Radiation was most commonly administered with concurrent chemotherapy. After excluding pts for whom pre-treatment BMI was not available, we evaluated 291 pts who were stratified into four BMI groups based on World Health Organization criteria: underweight (< 18.5 kg/m2), normal weight (18.5 to < 25 kg/m2), overweight (25 to < 30 kg/m2), and obese (>= 30 kg/m2). Kaplan-Meier survival analysis was performed with log-rank test-for-trend. Cox proportional hazards modeling was used for univariate and multivariate analyses.

      Results:
      Baseline characteristics were similar between obese and normal weight pts (Table 1). Median survival was 17 months (mo), 19 mo, 23 mo, and 29 mo for each BMI group respectively. A trend for improved survival with increasing BMI was highly significant (P=0.009) and persisted even when underweight cases were excluded, suggesting that the survival benefit is not driven by unfavorable prognostic factors in the underweight cases. There was a sustained 31% to 58% reduction in mortality of obese relative to normal weight pts (HR 0.68±0.21, 0.61±0.19, and 0.42±0.19, for each year post-treatment respectively). Additionally, there was no correlation between BMI and smoking pack-years, even when underweight pts were excluded. (correlation coefficient 0.033 [95% CI 0.09 – 0.15, P=0.59]). Table 1: Baseline Characteristics of Study Cohort Figure 1



      Conclusion:
      In this retrospective study of definitively treated LA-NSCLC patients, obese pts had significantly improved survival relative to normal weight pts. This favorable prognostic effect was independent of stage and was significantly more durable than previously reported in advanced NSCLC patients. Additionally, the putative relationship between BMI and smoking history was not observed in this cohort. These new findings suggest that the protective effect of obesity in NSCLC is not solely due to short-term treatment effects or decreased smoking exposure. We plan to investigate additional parameters such as histology, chemoradiation course, subsequent surgery, and metformin use to further clarify the role of obesity in survival of NSCLC pts.

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      P1.03-030 - Marital Status Is Strongly Prognostic and Associated with More Favorable Nutritional Status in Locally Advanced Non-Small Cell Lung Cancer (ID 2390)

      M. Edelman

      • Abstract

      Background:
      We updated our previous analysis demonstrating marital status is prognostic in stage III NSCLC. We hypothesized that married patients have more favorable nutritional or immunologic status than unmarried patients as a potential mechanism for this survival advantage.

      Methods:
      Between January 2000 and December 2010, 268 patients with stage III NSCLC received definitive chemotherapy and radiation therapy, with or without surgery at our institution. All had complete demographic, diagnosis, treatment, lab, and survival data. A Kaplan-Meier method estimated overall survival and we applied the log-rank test to compare mortality between groups. Multivariable analysis of prognostic factors was conducted using the Cox proportional hazards model. We tested the interaction between marital status and pre-treatment body mass index (BMI), albumin, white blood count, absolute neutrophil count, absolute lymphocyte count and calculated neutrophil-lymphocyte ratio (NLR).

      Results:
      More married patients presented with stage IIIA (rather than IIIB) disease (58% vs. 46%, P=0.03), had a PS 0 (57% vs. 36%, P<0.001), were white (69% vs. 43% (P<0.001) and lived in higher median income areas ($45,646 vs. $38,331, P<0.001) than non-married patients. There was no difference in tobacco history or diagnosis age between married and unmarried patients. After adjusting for stage, PS, race, and median household income, the hazard ratio for any-cause mortality in married patients was 0.59, 95% CI (0.45, 0.78), P<0.001. Median OS for married vs. unmarried patients was 28 (23, 34) vs. 16 (13, 19) months (P<0.001). Contrary to other reports, the reduction in mortality associated with being married was similar in males, 45%,and females 43%, with the test for interaction in a multivariable Cox model being non-significant (P=0.38). Figure 1 We also found married status was associated with higher median, 25[th], and 75[th] percentile BMI (26.3 vs. 23.8; 23.3 vs. 20.6, and 30.8 vs. 28.4, respectively; P=0.014) and albumin (3.7 vs. 3.6; 3.4 vs. 3.1; and 4.0 vs. 3.8, respectively; P=0.001).



      Conclusion:
      Marital status is an important predictor of survival in stage III NSCLC and appears to offset the disadvantage of higher stage disease. Our results suggest one mechanism for this may be married patients have more favorable nutritional status evidenced by higher BMI and albumin. We did not find an association between marital status and immunologic status in our analysis. Future studies that evaluate how social support impacts nutritional status prior to therapy may lead to interventions to target vulnerable populations. Marital status may be an important stratification factor in clinical trials.

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    P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P2.01-082 - Pathological Response with Angiotensin Converting Enzyme Inhibitor/Angiotensin Receptor Blocker Use in Advanced Non-Small Cell Lung Cancer (ID 2156)

      M. Edelman

      • Abstract
      • Slides

      Background:
      Angiotensin converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) are among the most common medications in the treatment of hypertension and diabetes. These drugs are under evaluation as a means to mitigate radiation pneumonitis/fibrosis likely mediated by anti-inflammatory and endothelial effects. Their collateral impact on oncological outcomes is unknown. We retrospectively evaluate the effect of ACEi and ARB usage on pathological response during preoperative platinum-based concurrent chemoradiotherapy (CCRT) with high-dose radiotherapy (≥59.4 Gy) in a cohort of patients with stage III non-small cell lung cancer (NSCLC).

      Methods:
      Between June 2000 and December 2009, 79 patients with stage III NSCLC (AJCC 7[th] ed.) were treated with preoperative CCRT at our institution. Data on ACEi/ARB usage during CCRT and pathological response was available for 72 patients. The primary end-point was pathological complete response (pCR), in both the primary site and involved lymph nodes. X[2] analysis was to assess distribution of categorical variables, Kaplan-Meier survival analysis with log rank test for univariate and Cox regression multivariate (age, gender, race, stage, RT dose and chemotherapy regimen) analysis of overall survival (OS) and freedom-from recurrence (FFR) was performed.

      Results:
      The median age at diagnosis was 56 years (range, 38-78) with 56% males, 74% Caucasians and 96% smokers. Stage distribution was IIIA (72%), IIIB (28%), T1/2 (54%), T3/4 (46%), N0/1 (14%) and N2/3 (86%). The median radiation dose was 66.6 Gy (range 59.4-69.6 Gy) with the most common CCRT regimen being carboplatin-paclitaxel (54%). At a median follow up of 3.8 years for all patients and 6.8 years for surviving patients, the median OS and FFR of the entire cohort were 4.9 years (95% Confidence Interval (CI): 3.5-6.5) and 3.1 years (95% CI: 1.3-4.9), respectively with overall pCR rate of 44%. During CCRT, 11 patients (15%) were taking ACEi/ARB and 61 patients (85%) were not taking ACEi/ARB. No statistical differences were seen in the distribution of baseline variables between the two cohorts. None of the patients developed acute radiation pneumonitis in the time interval between radiotherapy completion and surgery (median 55 days; range, 33-105 days). The pCR rate without and with ACEi/ARB was 46% vs 36% (p=0.56). The median FFR without and with concurrent ACEi/ARB use was 3.1 years vs. not reached, p = 0.35, while the corresponding median OS values were 4.8 years and 5.5 years, p = 0.59, respectively. On multivariate analysis, an improved OS was associated with younger age (HR: 0.39, 95%CI: 0.2-0.8, p<0.01), an improved FFR was associated with lower stage (HR: 0.3, 95%CI: 0.15-0.76, p<0.01) and Caucasian race (HR=0.37, 95% CI: 0.15-0.88, p=0.02), with no impact of ACEi/ARB use on either outcome.

      Conclusion:
      The use of ACEi/ARB did not have any apparent influence the rates of pCR in this small cohort of advanced stage NSCLC patients treated with trimodality therapy following preoperative platinum-based CCRT with high-dose radiotherapy. As the role of these drugs in mitigating radiation pneumonitis continues to be evaluated, simultaneous assessment of lack of a negative impact on disease outcomes needs to be validated in larger, prospective analyses.

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    P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P2.04-058 - Neutrophil-Lymphocyte Ratio (NLR) as a Prognostic Marker in Locally Advanced Non-Small Cell Lung Cancer (LANSCLC) (ID 2404)

      M. Edelman

      • Abstract
      • Slides

      Background:
      NLR is a measure of systemic inflammation which appears prognostic in localized and advanced NSCLC. Increased systemic inflammation portends a poorer prognosis in cancer patients. We hypothesize that low NLR measured at diagnosis is associated with improved overall survival (OS) in patients with LANSCLC.

      Methods:
      Records from 276 patients with stage IIIA and IIIB NSCLC treated with definitive chemoradiation with or without surgery at our institution between 2000 and 2010 with adequate data were retrospectively reviewed. Baseline patient demographic data and pre-treatment absolute neutrophil and lymphocyte counts were collected. Patients were grouped into quartiles based on NLR. OS was estimated using the Kaplan-Meier method and the logrank test was used to compare mortality between groups. A linear test-for-trend was used for the NLR quartile groups. The Cox proportional hazards model was used to adjust for other prognostic factors in a multivariable analysis. Distributions of NLR in subgroups were compared using the Mann-Whitney U test. All P-values are 2-tailed.

      Results:
      NLR was a highly prognostic factor for overall survival (p<0.0001). Median survival [95% CI] for the first, second, third and fourth quartile groups of the population distribution of NLR were 27 months [19-36], 28 months [22-34], 22 months [12-31] and 10 months [8-12], respectively. NLR correlated with race, gender, stage and performance status. Even after adjusting for stage (IIIA vs. IIIB), NLR remained predictive of overall survival (p=0.001). Figure 1 Figure 2





      Conclusion:
      To our knowledge, this is the first large series evaluating NLR as a prognostic indicator in LANSCLC. Pre-treatment NLR is strongly associated with OS in LANSCLC. NLR is an inexpensive biomarker which is significantly prognostic even after adjusting for race, gender and stage. It can be easily utilized at the time of LANSCLC diagnosis to help predict life expectancy. As an indicator of inflammatory response, it should be explored in the context of immunomodulatory therapy.

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