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E.B. Haura



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    MO15 - Novel Genes and Pathways (ID 89)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO15.01 - Pathway activation mapping of KRAS wild type and mutated adenocarcinomas of the lung: new implications for patient stratification for MAP kinase pathway inhibition (ID 2705)

      16:15 - 17:45  |  Author(s): E.B. Haura

      • Abstract
      • Presentation
      • Slides

      Background
      KRAS proto-oncogene is one of the most frequent mutated genes in Non-Small Cell Lung Cancer (NSCLC) with greater incidence among adenocarcinomas (AD). While the clinical importance of KRAS mutation as a negative predictor for anti-EGFR therapy is not clearly understood in NSCLCs, selection of targeted therapies for KRAS mutated (MUT) patients has often focused on the inhibition of its direct downstream effectors. The aim of this study was to explore the impact of the KRAS status on the cellular signaling network of ADs of the lung harboring different KRAS mutations with a focus on ERK signaling architecture.

      Methods
      A total of 58 AD samples were collected from chemo-naïve patients at the H. Lee Moffitt Cancer Center & Research Institute (Tampa, FL) and at S. Maria della Misericordia Hospital (Perugia, Italy). Twenty-four tumors were KRAS wild type (WT) and 34 were KRAS MUT (G12C n=18, G12V n=9, G13D n=3 and G12D n=4, respectively). All samples were subjected to laser capture microdissection and reverse phase protein microarray to quantitatively evaluate the activation status of the MAP Kinase signaling network.

      Results
      Statistical analysis of signaling protein activation based on KRAS status revealed an overall increase in activation level of the MAPK signaling network in the KRAS MUT tumors compared to tumors expressing KRAS WT: ERK 1/2 (T202/Y204), Elk-1 (S383), p90RSK (S380), Smad2 (S245/250/255) and p70S6K (p<0.01; p<0.01; p<0.01, p=0.04 and p<0.01 respectively). Nevertheless, 6 KRAS WT patients (25%) showed activation of ERK greater than the median of the entire population and an overall MAPK signaling activation comparable to tumors harboring KRAS MUT. Eleven of the KRAS MUT tumors (32%) had ERK activation lower than the median of the population as a whole. Interestingly a high activation level of Estrogen Receptor alpha (ERα) (S118) was detected in the KRAS MUT tumors compared to the KRAS WT one (p=0.02). Moreover the nonparametric test performed to establish the correlation of activated ERK 1/2, Raf, B-Raf, C-Raf and Mek 1/2 with the expression/activation levels of the 152 endpoints analyzed in this study, revealed the activation of distinct pathways in the KRAS MUT tumors when compared to KRAS WT tumors. Significant correlations were detected with Akt, KRAS, their downstream substrates and with several receptor tyrosine kinases (p<0.0003).

      Conclusion
      Our results suggest that MAPK signaling activation was clearly observed in KRAS MUT tumors. However, the heterogeneity in the activation level of MAPK downstream substrates within KRAS MUT and WT tumors suggests that selection of patients for MAPK targeting might benefit from the evaluation not only of the mutation itself, but also from a direct analysis of the MAPK protein network architecture. In particular the role played by ERα in KRAS MUT tumors deserves further investigations as a possible novel therapeutic target in KRAS MUT adenocarcinomas of the lung.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-024 - A phase I/II randomized trial using GM-CSF-producing and CD40L-expressing bystander cell line (GM.CD40L) vaccine plus or minus CCL21 in stage IV lung adenocarcinoma: Updated results (ID 1878)

      09:30 - 16:30  |  Author(s): E.B. Haura

      • Abstract

      Background
      Background: The GM.CD40L vaccine, an allogeneic tumor cell-based vaccine generated from a human bystander cell line which secretes GM-CSF and expresses CD40L on the surface (GM.CD40L), was developed by our team. It serves to recruit and activate dendritic cells. The mature dendritic cells in turn travel to regional lymph nodes and help to activate T cells which result in systemic tumor cell killing. CCL21 is a chemokine which serves to enhance recruitment of T cells and enrich T cell responses. In NSCLC mouse model, the vaccine combination of GM.CD40L plus CCL21 demonstrated additive effects.

      Methods
      Methods: We conducted a phase I/II randomized study to evaluate the GM.CD40L (Arm A) vs. GM.CD40L.CCL21 (Arm B) vaccine in patients with lung adenocarcinoma who had failed first-line therapy. Primary endpoints were safety and tolerability of Arm B in phase I and 6 month progression-free survival (PFS) in phase II; secondary endpoints included anti-tumor immune responses and T-cell responses by ELISpot assay on PBMC. Immune-related response criteria (irRC) determined discontinuation from study treatment at the discretion of the PI/treating physician. Intradermal vaccines were administered in the bilateral axilla and groin every 14 days for 3 doses and then monthly for 3 doses. A two-stage minimax design was used. Survival probabilities over time in each treatment group were estimated using the method of Kaplan and Meier.

      Results
      Results: Between 4/2012 and 4/2013, phase 1 enrolled 3 patients on GM.GD40L.CCL21, while Arm A enrolled 17 and Arm B enrolled 14 patients. The baseline characteristics, including those in phase I are as follows: median age: 66/68 years, females: 50%/50%, PS1: 64.7%/76.5%, median prior regimens: 2.5/3 for Arm A vs. Arm B, respectively. No DLT’s were observed during phase 1. The most common toxicities for Arm A vs. Arm B were injection site reaction (70.6%/70.6%), fatigue (29.4%/41.2%), anorexia (23.5%/29.4%), and pain in extremity (5.9%/5.9%). Median PFS for Arm A vs. B was 1.9 vs. 4.4 months (p=0.10). All patients who remained on study per MD discretion/irRC, did ultimately demonstrate further progression on subsequent imaging. Treatment was discontinued in all of those patients. In Arm A versus Arm B, stable disease was 4/8 and progressive disease was 8/8, respectively. The disease control rate (DCR) for Arm B compared with Arm A was 50% versus 33%, respectively. ELISpot assay for immune responses and flow cytometry studies on PBMCs are underway.

      Conclusion
      Conclusion: GM.CD40L plus CCL21 chemokine is well tolerated. The phase II trial including further immune response assays collected pre and post vaccine are underway and updated results will be presented.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-046 - A Novel Approach to Increase the Efficiency of Survival-Endpoint<br /> Phase II Trials. (ID 3153)

      09:30 - 16:30  |  Author(s): E.B. Haura

      • Abstract

      Background
      Lung cancer is the second most common cancer in United States. However, new molecular information whether arising from identification of key mutations, or Next Gen Sequencing (NGS) has lead to the fragmentation of this common disease into multiple and often very rare molecular subtypes. Even though this has enabled us to substantially improve survival in specific molecular subtypes with targeted agents, having sufficient numbers of patients to demonstrate the effectiveness of novel targeted therapies for each subtype has therefore become challenging, essentially impeding progress.

      Methods
      Use of sample size determination software allows for comparison of phase II trials with a target survival proportion at a given time T based upon Kaplan-Meier (KM) versus exponential (E) survival methods. This comparison was made in instances where the exponential distribution assumption is valid.

      Results
      The use of exponential survival fitting methods, in lieu of the currently implemented KM trial designs, to single arm phase II studies can routinely reduce patient numbers by 25-40% (Table) without compromising the statistical power. Another substantial advantage is that the variability in the survival information for the exponential fit estimate both before and after the median survival points is reduced. Since patient accrual is staggered ,this reduced variability allows for obtaining robust survival information with shorter follow up times T. Any additional follow-up beyond T only further improves the E estimate, but not the KM estimate. Thus, compared to the KM approach, the E approach will allow us to do single arm phase II trials with smaller numbers of patients without compromising statistical power. Robust survival estimates can also be achieved with shorter follow up periods. Figure 1

      Conclusion
      When conducting single arm phase II clinical trials with rare molecular entities of lung cancer, the exponential survival fitting method could replace the current standard approach. Robust survival information can be obtained with smaller numbers of patients and with shorter survival times. Detailed examples and analysis will be presented.

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    PL03 - Presidential Symposium Including Top Rated Abstracts (ID 85)

    • Event: WCLC 2013
    • Type: Plenary Session
    • Track:
    • Presentations: 1
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      PL03.07 - Treatment with Therapies Matched to Oncogenic Drivers Improves Survival in Patients with Lung Cancers: Results from The Lung Cancer Mutation Consortium (LCMC) (ID 2444)

      08:15 - 09:45  |  Author(s): E.B. Haura

      • Abstract
      • Slides

      Background
      Detecting and targeting the oncogenic drivers EGFR and ALK have transformed the care of patients with lung adenocarcinomas. The LCMC was established to use multiplexed assays to test tumors for alterations in 10 genes and provide the results to clinicians to select treatments and clinical trials matched to the driver detected.

      Methods
      Fourteen LCMC sites enrolled patients with metastatic lung adenocarcinomas and tested their tumors in CLIA laboratories for activating mutations in 10 oncogenic driver genes.

      Results
      Tumors were tested from 1,007 patients for at least one gene and 733 for all 10 genes. An oncogenic driver was found in 466 (64%) of fully-genotyped cases. Among these 733 tumors, drivers found were: KRAS 182 (25%), sensitizing EGFR 122 (17%), ALK rearrangements 57 (8%), “other” EGFR 29 (4%), two genes 24 (3%), HER2 19 (3%), BRAF 16 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (<1%), AKT1 0. For cases with any genotyping, we used results to select a targeted therapy or trial in 275 (28%). Among 938 patients with follow-up, the median survivals were 3.5 years for the 264 with an oncogenic driver treated with genotype-directed therapy, 2.4 years for the 318 with an oncogenic driver with no genotype-directed therapy, and 2.1 years for the 360 with no driver identified (p<0.0001).

      Conclusion
      Individuals with lung cancers with oncogenic drivers receiving a corresponding targeted agent lived longer than similar patients who did not. An actionable driver was detected in 64% of tumors from patients with lung adenocarcinomas; more than one was present in 3%. Multiplexed testing aided physicians in choosing therapies and targeted trials in 28% of patients. This paradigm for care and research will expand as genotyping becomes more efficient with Next-Gen platforms, additional drivers are identified (i.e.ROS1 and RET), and more targeted drugs become available in the pharmacy and through clinical trials. Supported by HSS NIH NCI 1RC2CA148394-01. Trial Registered with Clinicaltrials.gov: NCT01014286.

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