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E.E. Vokes



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    ED10 - Locally Advanced NSCLC: State-of-the-Art Treatment (ID 279)

    • Event: WCLC 2016
    • Type: Education Session
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      ED10.04 - New Developments for Systemic Therapies in Stage III NSCLC (ID 6484)

      16:00 - 17:30  |  Author(s): E.E. Vokes

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Concomitant chemoradiotherapy is currently the most widely accepted standard of care for patients with locoregionally advanced NSCLC. Induction chemotherapy represents an evidence-based alternative and is a particular attractive prior to surgery in patients with marginally resectable disease (1). Over the past two decades, the regimens of cisplatin and etoposide and carboplatin and paclitaxel with concurrent radiotherapy, respectively have been most widely used, with cisplatin and vinorelbine with radiotherapy as possible alternative. More recently interest in the cisplatin/pemetrexed/radiotherapy combination has gained interest based on the superior toxicity and efficacy profile of this regimen in the stage IV setting for patients with non-squamous cell malignancies (2). In addition, it is possible to administer this combination of drugs at systemic doses together with radiotherapy (3). In the randomized phase III PROCLAIM study, this regimen was directly compared with etoposide and cisplatin. The goal of this trial was to establish superiority of this regimen. The trial was closed prior to full enrollment with approximately 300 patients per arm evaluated, due to futility for superiority. Median survival for both study groups was very similar at 26.8 and 25.0 months, respectively and better than statistically assumed (4). Additional chemoradiotherapy regiments of current interest include the addition of the PARP inhibitor veliparib to chemoradiotherapy as recently presented (5). Over the last decade, systemic therapy for patients with metastatic lung cancer has been transformed through the use of tumor mutation analyses and targeted therapies as well as the emergence of immune-oncology. However, application of these strategies to the stage III setting has been slow and no definitive data exist currently to support these strategies in the curative intent setting. The addition of cetuximab to chemoradiotherapy did not result in a survival benefit in RTOG 0612 (6). There are, however several ongoing trials that will be described, including RTOG 1306-Alliance 31101. In this trial patients with EGFR mutation or an alk translocation are randomized to either induction chemotherapy with the appropriate targeted agent (erlotinib and crizotinib, respectively) followed by concurrent chemoradiotherapy or concurrent chemoradiotherapy alone. This trial is actively accruing patients. Regarding immune-oncology, a trial evaluating a liposome-based MUC vaccine (tecemotide) has been completed. MUC1 is a mucinous glycoprotein that is overexpressed and aberrantly glycosylated in NSCLC and a vaccination strategy was supported by preclinical studies as well as clinical data in a stage III subgroup analysis of an earlier exploratory trial. Butts et al (7) reported on a randomized trial in which patients completing locoregional sequential or concurrent therapy were randomized to placebo versus tecemotide vaccination therapy reporting a trend for improved overall survival that was statistically significant in the subset analysis of patients receiving concurrent radiotherapy as their primary therapy. Further investigations of this agent however were halted following emergence of additional negative data from a Japanese phase II trial that remains unpublished. Regarding PD-1 or PD-L1 inhibitors, trials have recently been activated investigating the addition of such agents in the consolidation setting following primary treatment of patients with unresectable SCLC. For example, in the ‘Pacific’ trial patients are randomized in a 2-1 fashion to durvalumab for up to 12 months or placebo. In the Alliance, a trial looking at induction chemotherapy with atezolizumab is currently in the process of activation. Here patients will receive induction chemotherapy with atezolizumab for up to four cycles followed by concurrent chemoradiotherapy and additional adjuvant immune therapy. These strategies are well supported by preclinical data showing irradiation upregulating PD1 expression on myeloid and tumor cells and synergistic amplification of radiation antitumor effects by PD-L1 blockade (8). Updated information on these trials and relevant preclinical data will be presented. References: 1. Schild SE, Vokes EE. Pathways to improving combined modality therapy for stage III nonsmall-cell lung cancer. Ann Oncol 2016 Apr;27(4):590-9. 2. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. 3. Govindan R, Bogart J, Stinchcombe T, Wang X, Hodgson L, Kratzke R, Garst J, Brotherton T, Vokes EE. Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407. J Clin Oncol. 2011 Aug 10;29(23):3120-5. 4. Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. 5. Cristea MC, Miao, J, Argiris A, Chen AM, Daly ME, Decker RH, Garland LL, Wang D, Koczywas M, Moon J, Kelly K, Gandara DR. SWOG S1206: A dose-finding study of veliparib added to chemoradiotherapy with carboplatin and paclitaxel for unresectable stage III non-small cell lung cancer. J Clin Oncol. 2016 34:(suppl; abstr 8537). 6. Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015 Feb;16(2):187-99. 7. Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, Nawrocki S, Ciuleanu TE, Bosquée L, Trigo JM, Spira A, Tremblay L, Nyman J, Ramlau R, Wickart-Johansson G, Ellis P, Gladkov O, Pereira JR, Eberhardt WE, Helwig C, Schröder A, Shepherd FA; START trial team. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Jan;15(1):59-68. 8. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014 Feb;124(2):687-95.

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    MA06 - Locally Advanced NSCLC: Risk Groups, Biological Factors and Treatment Choices (ID 379)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      MA06.10 - A Pooled Analysis Comparing the Outcomes of Elderly to Younger Patients on NCTN Trials of Concurrent CCRT for Stage 3 NSCLC  (ID 4219)

      16:00 - 17:30  |  Author(s): E.E. Vokes

      • Abstract
      • Presentation
      • Slides

      Background:
      Concurrent chemoradiotherapy (CCRT) is the standard treatment (TRT) for stage 3 NSCLC. Elderly patients (pts) are common, may have increased toxicity,& poorer results from CCRT

      Methods:
      Individual patient data (IPD) from NCTN phase 2/3 trials of CCRT for stage 3 NSCLC from 1990-2012 was collected. We compared the overall survival (OS), progression-free survival (PFS), & adverse events (AE’s) for pts age ≥70 years (yrs) (elderly) vs. <70 yrs (younger). Unadjusted & adjusted Hazard Ratios (HRs) for survival time & their confidence intervals (CIs) were estimated by single-predictor & multivariable Cox models. Unadjusted & adjusted Odds Ratio (OR) for AE’s & their CIs were obtained from single-predictor & multivariable logistic regression models

      Results:
      IPD from 16 trials were analyzed; 2,768 pts were younger & 832 were elderly. Median OS & PFS for elderly & younger pts are in the table. In the unadjusted & multivariable models elderly pts had worse OS (HR=1.23; 95%CI =1.13-1.35, and 1.20; 95%CI=1.10-1.32, respectively). In the unadjusted & multivariable models, elderly & younger pts had a similar PFS (HR=1.02; 95% CI=0.94-1.11 and 1.01, 95% CI=0.92-1.10, respectively). Elderly pts had a higher rate of grade ≥3 AE’s in the unadjusted & multivariable models (OR=1.25; 95% CI=1.00-1.57 and 1.30; 95%CI=1.03-1.62, respectively). A lower percentage of elderly pts compared to younger completed TRT (47% and 57%, respectively; P<0.0001) & higher percentage stopped due to AE’s (20% and 13%; P<0.0001). Grade ≥ 3 AE’s (occurring at a rate ≥ 2.5%) with a higher rate in the elderly: neutropenia, dyspnea, fatigue, anorexia, vomiting, dehydration, hypoxia, hypotension, & pneumonitis (P<0.05).

      Age ≥ 70yrs Age < 70 yrs P-value[a]
      Median OS (months) 17.0 20.7 < 0.01
      Median PFS (months) 8.7 9.1 0.68
      All toxicities grade ≥3 86% 84% 0.04
      Hematologic AE’s grade ≥3 65% 61% 0.04
      Non-hematologic AE’s ≥3 68% 62% <0.01
      Grade 5 AE’s 9.0% 4.4% <0.01
      TRT related deaths[b] 3.2% 2.0% 0.12
      a: Log-rank test for survival times, chi-square test for AE’s, and Fisher’s exact test for deaths. The P-values from these tests are unadjusted. b: Data available on 2,091 patients

      Conclusion:
      Elderly pts in CCRT trials had worse OS, similar PFS, & a higher rate of severe AE's.

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    MA15 - Immunotherapy Prediction (ID 400)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      MA15.07 - Molecular Determinants of Lack of Tumor Immune Infiltration in NSCLC (ID 5191)

      14:20 - 15:50  |  Author(s): E.E. Vokes

      • Abstract
      • Slides

      Background:
      Non-small cell lung cancer (NSCLC) make up the majority of all lung cancer cases and is associated with very poor prognosis. Immune checkpoint blockers have now been shown to induce unprecedented durable response in a fraction of NSCLC patients with pre-existing T cell infiltration within their tumor. However in order to improve their efficacies beyond this subset of patients, a detailed molecular characterization to identify factors associated with lack of T cell infiltration is needed. A recent analysis in metastatic melanoma identified Wnt/B-catenin pathway activation as a mechanism for lack of T cell infiltration. We pursued similar analyses of immunologic gene signatures and molecular associations in squamous cell lung cancer (SCC) and lung adenocarcinoma (LA).

      Methods:
      We analyzed RNAseq data from two lung cancer datasets of The Cancer Genome Atlas (TCGA) (N = 499 for SCC and N = 514 for LA). Samples were categorized into non-T cell inflamed and T cell-inflamed groups using unsupervised consensus clustering based on the expression of 160 immune-related genes. Ingenuity pathway analysis was utilized to identify molecular pathways activated in non-T cell-inflamed tumors.

      Results:
      A similar proportion of non-T cell-inflamed tumors were identified in the two cohorts (SCC: 34%; LA: 31%). 47% of the SCC tumors were identified as T cell-inflamed, as compared to 37% in LA. A positive correlation was observed between CD8A and PD-L1, IDO1, LAG3 and TIM3 (p<0.00001). Total of 1,216 genes are significantly up-regulated in non-T cell-inflamed SCC tumors and 596 in LA with at least 1.5-fold change and FDR-adjusted p<0.05. Among these, a total of 194 genes are up-regulated in both SCC and LA, with the rest being specific for each subtype (SCC: 84%; LA: 67%). Pathway analysis suggested 35 upstream regulators were activated in SCC and 32 in LA (activation z-score≥2.0). Among these, 10 upstream regulators are activated in both datasets (ATF4, CTNNB1, KAT6A, KLF4, MYC, NFE2L2, PI3K, SCAP, SP1, SREBF2). Finally, we performed the same gene expression analysis on RNAseq data from matched normal tissues (N = 51 for SCC and N = 59 for LA) and confirmed that the T-cell inflamed gene signature is a property of the tumor rather than normal lung tissue.

      Conclusion:
      Our analyses successfully identified genes and associated pathways that are enriched in NSCLC subtypes with no immune infiltration. Rational strategies to improve the efficacy of immune checkpoint blockers beyond the current subset of responders should be based on targeting these pathways.

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    P2.03a - Poster Session with Presenters Present (ID 464)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P2.03a-055 - Predicting Risk of Chemotherapy-Induced Severe Neutropenia in Lung Patients: A Pooled Analysis of US Cooperative Group Trials (ID 3975)

      14:30 - 15:45  |  Author(s): E.E. Vokes

      • Abstract

      Background:
      Neutropenia is the most serious hematologic toxicity associated with the use of chemotherapy. Severe neutropenia (SN) may result in dose delays and/or reductions, and the use of growth colony stimulating factors (CSFs) increases the cost of therapy. Lyman et al. (2011) published a risk model to predict individual risk of neutropenia in patients receiving chemotherapy for multiple types of cancer. The Lyman model (LM) has not been validated by external datasets. We investigated the LM with a large external lung cancer dataset based on clinical criteria of SN and investigated new risk prediction models for SN.

      Methods:
      Stage IIIA/IIIB/IV non-small cell lung cancer (NSCLC) and extensive small cell lung cancer (SCLC) chemotherapy phase II/III trials completed in 1990-2012 were assembled from U.S. cancer cooperative groups. SN was defined as any neutropenic complications grade ≥ 3 according to CTCAE. A risk score was calculated as a weighted sum of regression coefficients of the LM for all patients in the database. The performance of risk models was evaluated by the area under the ROC curve (AUC) with a good model defined as AUC ≥ 0.7. To develop new risk models, a random split was used to divide the database into training cohort (2/3) and testing cohort (1/3). Multivariable logistic regression models with stepwise selection and lasso selection (Tibshirani, 1996) were built in training cohort and validated in testing cohort. Candidate predictors included patient-level and treatment-level variables. The patients with complete data were used for validation and all patients, including those with imputed predictors, were used to develop new risk models.

      Results:
      Eighty seven trials with 14,829 patients were included. The LM had a good performance in SCLC patients (AUC=0.86), but it had poor performance in NSCLC patients (AUC=0.47), and an overall unsatisfactory performance in all patients (AUC=0.56). The stepwise model had superior performance than the lasso model (AUC: 0.84 vs. 0.76) in training, while the lasso model had smaller shrinkage in testing. A parsimonious model, based on histology, prior chemo, platinum-based, taxanes, gemcitabine, CSFs, age as continuous variable, relative dose intensity, and white blood cell (WBC), performed slightly worse (AUC=0.71) in testing than the stepwise model and the lasso model.

      Conclusion:
      The U.S. cooperative group data failed to validate the LM in predicting the risk for severe neutropenia in lung cancer patients receiving chemotherapy. The parsimonious model involving nine predictors showed good performance in predicting severe neutropenia. Prospective validation is warranted.

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

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02c-058 - In-Depth Molecular Characterization of T Cell Clonal Expansion Induced by Anti-PD1 Therapy in NSCLC (ID 5183)

      14:30 - 15:45  |  Author(s): E.E. Vokes

      • Abstract

      Background:
      Inhibitors of PD1/PD-L1 checkpoint have been shown to be active among a broad range of cancers including NSCLC. They induce proliferation of T cells within the tumor microenvironment (as revealed by IHC) leading to tumor eradication. There is however lack of detailed molecular characterization of these proliferating T cells including the dynamics of their clonalilty during treatment and its correlation with response, their antigen specificity and the molecular changes induced in the expanded clones at single cell level. Such understanding will serve as a biomarker to detect early response after one dose of therapy, ascertain efficacy (especially when radiological assessments are equivocal) and guide determination of optimal duration of therapy. Furthermore, insight into molecular changes in the proliferating T cell clones induced by these agents at single-cell level will identify the baseline unique characteristics of T cells clones that undergo rapid expansion upon exposure to anti-PD1 therapy, define the molecular mediators of tumor eradication in responders and serve as a foundation for the development of novel treatment strategies for non-responders.

      Methods:
      We performed next-generation T cell receptor alpha/beta chain sequencing on serially obtained tumor and PBMC samples from 54 NSCLC patients undergoing anti-PD1 therapy. We compared the dynamics of the T cell repertoire in responders versus non-responders within unsorted PBMC and in CD8 positive/negative T cells. We also assessed the expression of key mediators of cytotoxicity and T cell activation/dysfunction in these expanded CD8 T cell clones at single cell level among responders and non-responders.

      Results:
      We identified concordant early clonal T cell expansion after 1-4 doses of anti-PD1 therapy within the tumor and PBMC of responders. We confirmed these expanded T cell clones to be CD8 positive subgroup of CD3+ T cells in responders and CD8 negative subgroup of CD3+ T cells in non-responders. Furthermore, among responders we found that persistence of the expanded T cell clones for several months while on treatment is associated with durable response. Additional results on antigen specificity and gene expression of the expanded T cell clones in responders versus non-responders will be presented.

      Conclusion:
      Our results showed that early concordant clonal expansion of a defined population of CD8+ T cells detected both within the tumor and PBMC correlate with response to therapy. We also confirmed that the persistence of these unique T cell clones several months after their initial expansion correlates with durable response.

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    P3.03 - Poster Session with Presenters Present (ID 473)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      P3.03-036 - Prognostic Model for Mesothelioma Based on Cancer and Leukemia Group B (CALGB) Trials (Alliance) (ID 3976)

      14:30 - 15:45  |  Author(s): E.E. Vokes

      • Abstract

      Background:
      Prognostic models play an important role in the design and analysis of mesothelioma treatment trials. The European Organisation for Research and Treatment of Cancer (EORTC) developed a well-known tool in 1998 to predict overall survival (OS) in patients with malignant mesothelioma. In this study, we built and assessed the performance of a new mesothelioma prognostic model OS using data from multiple CALGB clinical trials data.

      Methods:
      This study included 595 mesothelioma patients from fifteen completed CALGB treatment trials accrued between June 1984 and August 2009. We split the cohort of patients into two parts - 67% of patients as training and 33% as testing. We developed a Cox model using the training set with PS, age, WBC count, and platelet count as prognostic variables. To compare the EORTC and our new models, the concordance of predicted survival times and risk scores were estimated by concordance C (c-index) (Harrell et al. 1996) and AUC score at 6-months (Patrick et al. 2000). 95% confidence intervals were calculated for the c-index. Based on the prediction model fit from training set, we partitioned testing set patients into high-risk and low-risk groups using the median for their risk score values for the new model. For the EORTC model, the cut off of 1.27 from the original paper was used to assign the high-risk and low-risk groups. A Log-rank test was used to compare the survival curves of these two groups. We also compared our results with a model using PS alone.

      Results:
      For OS, the EORTC model c-index was 0.55 (0.52, 0.58) and P = 0.0007 comparing high- and low- risk patients for testing set. The new model c-index was 0.60 (0.56, 0.64), with P < 0.000001 for testing set. Using the new model, the median OS in the high-risk and low-risk groups in the testing set were 5.16 (4.70, 6.37) and 10.41 (7.95, 14.32) months, respectively. PS alone produced c-index of 0.55 (0.53, 0.57) and P = 0.0002 for testing set. The AUC scores at 6-months for testing set generated by EORTC and PS alone models are 0.62 and 0.66. The new model generated AUC scores at 6-months of 0.70.

      Conclusion:
      Our new model performs better than the EORTC model or PS alone for survival prognostication in patients with mesothelioma.