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D.P. Carbone



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    MINI 02 - Immunotherapy (ID 92)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 2
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      MINI02.05 - Discussant for MINI02.01, MINI02.02, MINI02.03, MINI02.04 (ID 3299)

      11:05 - 11:15 AM  |  Author(s): D.P. Carbone

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI02.09 - ERK Activation Mediates Increased PD-L1 Expression in KRAS Mutated Premalignant Human Bronchial Epithelial Cells (ID 1620)

      11:30 - 11:35 AM  |  Author(s): D.P. Carbone

      • Abstract
      • Presentation
      • Slides

      Background:
      Immune checkpoint pathways including the PD-1/PD-L1 pathway are involved in tumor evasion from the immune system. Elevated PD-L1 expression in tumor cells inhibits tumor-infiltrating T cell function and may be associated with poor prognosis in lung cancer patients. There is increasing interest in developing immunotherapies that block the immunosuppressive effects of checkpoint pathways such as PD-L1, and identifying patients who may benefit from PD-L1 blockade. Activating KRAS mutations are common driver mutations in non-small cell lung carcinoma. Patients with mutated KRAS demonstrate less benefit from adjuvant chemotherapy and resistance to tyrosine kinase inhibitors. The effect of cancer cell driver mutations on immune checkpoint immune regulation is poorly understood. While recent clinical trials have suggested better response to PD-1 blockade in KRAS mutation subjects, it is unclear if this clinical finding is directly driven by KRAS regulating the PD-1/PD-L1 pathway with resultant improved efficacy to anti-PD-L1 immunotherapy or if the presence of a KRAS mutation is merely a surrogate marker of the overall mutational load and tumor immunogenicity. KRAS mutations are known to activate the RAF-MEK-ERK pathway. We hypothesize that KRAS mutation directly regulates the PD-1/PD-L1 pathway through ERK activation.

      Methods:
      Immortalized human bronchial epithelial cells (HBEC-vector control), KRAS–mutated (KRAS[v12]) HBEC cells (HBEC-KRAS), p53 knockdown HBEC cells (HBEC-p53), and p53 knockdown/KRAS mutated cells (HBEC-p53/KRAS) were used to assess mRNA and/or surface protein expression levels of immune checkpoints including Lag-3, Tim-3, PD-L1 and PD-L2 by real time-qPCR (RT-qPCR) and flow cytometry, respectively. HBEC-vector and HBEC-KRAS cells were treated with MEK (ERK kinase) inhibitor (PD0325901) at 1µM for 24hrs and evaluated for mRNA and surface protein expression of PD-L1. The premalignant HBEC cell lines were used instead of human lung cancer cell lines in order to assess the role of KRAS mutation in isolation without other mutations.

      Results:
      PD-L1 and PD-L2 mRNA levels increased 2.4 fold (p<0.001) and 3.6 (p<0.001) fold in comparing HBEC-KRAS to HBEC-vector (wild-type) cells, while Lag-3 and Tim-3 mRNA expression levels were unchanged. Based on mean fluorescence intensity on flow cytometry, cell surface PD-L1 protein expression level was 2.2 and 1.6 fold higher in HBEC-KRAS and HBEC-p53/KRAS, respectively, compared to HBEC-vector cells. There was no increase in surface PD-L1 expression in HBEC-p53 cells compared to HBEC-vector control, suggesting that p53 mutation did not alter PD-L1 expression in HBEC-p53/KRAS cells. With MEK inhibition, PD-L1 mRNA levels decreased 10 and 11 fold in HBEC-vector and HBEC-KRAS cells, respectively. Analogously, PD-L1 surface protein levels were reduced 2.7 fold in HBEC-vector and HBEC-KRAS cells, respectively. These findings suggest that ERK activation mediates intrinsic expression and KRAS mutation mediates over-expression of PD-L1 mRNA and protein.

      Conclusion:
      Here, we demonstrate that PD-L1 expression is elevated in premalignant KRAS mutated human bronchial epithelial cells, and ERK activation mediates constitutive and KRAS mutation driven up-regulation of PD-L1 in these cells. Our findings suggest that KRAS mutation may directly regulate the PD-1/PD-L1 immune checkpoint pathway. Further understanding of KRAS driven molecular pathways that modulate immune checkpoints may elucidate therapeutic targets for potential combinational drugs to PD-L1 inhibition.

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    MINI 30 - New Kinase Targets (ID 157)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI30.04 - A Randomized Phase 2 Trial of Cabozantinib, Erlotinib or the Combination as 2nd or 3rd Line Therapy in EGFR Wild-Type NSCLC: ECOG-ACRIN E1512 (ID 404)

      06:45 - 06:50 PM  |  Author(s): D.P. Carbone

      • Abstract
      • Slides

      Background:
      Cabozantinib (C) is a small molecule inhibitor of multiple receptor tyrosine kinases, including MET, VEGFR2 & RET. MET is involved in tumor differentiation & VEGFR2 is a mediator of angiogenesis. Erlotinib (E) is FDA approved for the treatment of NSCLC.

      Methods:
      The primary objective of this randomized phase 2 study was to compare progression-free survival (PFS) of pts treated with E vs. C, & E vs E+C; each comparison had 91% power to detect a PFS hazard ratio (HR) of 0.5 with a 1-sided 0.10-level test stratified on prior number of therapies & ECOG PS. Secondary objectives included overall survival (OS), RECIST 1.1 response & CTCAE v4 toxicity. Pts were selected with previously treated (1-2 regimens) metastatic non-squamous EGFR wt NSCLC. Submission of archival tissue for central MET IHC testing was required. Oral daily dosing was: E-150 mg; C-60 mg; E+C-150 mg E, 40 mg C. Imaging was performed every 8 weeks. Pts optionally crossed over to E+C following progression on E or C.

      Results:
      125 pts were enrolled, of which 115 were eligible & treated (E, n=39; C, n=39; E+C, n=37). Pt characteristics were balanced between arms except for lower rate of brain mets history on E (p=0.02). Median follow up is 8.5 m. Compared with E (median 1.9 m), PFS was significantly improved on C (3.9 m, HR 0.33, p=0.0002, 80% CI 0.22-0.49) & E+C (4.1 m, HR 0.31, p=0.0002, 80% CI 0.21-0.46). Similarly, compared with E (median 4.0 m), OS was significantly improved on C (HR 0.52, p=0.02) & E+C arm HR 0.50, p=0.02). Grade 3-4 treatment-related hypertension & mucositis were higher on C and grade 3-4 diarrhea was higher on E+C. Overall worst grade toxicities were also significantly higher on C and E+C. MET IHC results were available on 88 patients from the primary analysis & 85% were positive (1-3+ membrane or cytoplasm staining with MET4 antibody). There was no correlation between MET status and PFS.

      Conclusion:
      C & C+E significantly improved PFS over E alone in pts with EGFR wt NSCLC. Cabozantinib-based regimens are promising for further investigation in this patient population. Funded by ECOG-ACRIN and NCI Contract No. HHSN261200800001E.

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    MINI 35 - Biology (ID 161)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI35.11 - Mutant ARAF Drives Lung Carcinogenesis Through a Distinct Oncogenic Mechanism (ID 1016)

      07:25 - 07:30 PM  |  Author(s): D.P. Carbone

      • Abstract
      • Presentation
      • Slides

      Background:
      We recently identified a novel somatic mutation in ARAF in a lung adenocarcinoma from a patient that demonstrated a remarkable response to sorafenib. The S214C lies in a negative regulatory domain of ARAF, distinct from the catalytic domain mutations commonly found in BRAF. The aim herein was to characterize the biochemical and functional aspects of ARAF S214C.

      Methods:
      ARAF constructs were generated and ectopically expressed in an immortalized bronchial epithelial cell line (BEAS-2B). We evaluated the acquisition of anchorage independence, MEK activation, and cell morphology. COS7 cells were used for co-immunoprecipitation (IP) and kinase assays.

      Results:
      Cells expressing ARAF S214C substantially increased soft agar colony formation relative to vector, wild-type, kinase-dead (D429A), and double-mutant (S214C+D429A) variants. Accordingly, ARAF S214C cells exhibited increased phospho-MEK levels, suggesting that the transforming potential is dependent on its kinase activity. Interestingly, ARAF S214C cells acquired an elongated, fibroblast-like shape, characteristic of MEK-active cells, whereas none of other variants presented this morphology. We also demonstrated that cells expressing ARAF S214C with an additional RAS-binding domain mutation (R52L) or dimerization interface mutation (R362H) lacked MEK activation, showing that RAS binding and RAF-RAF dimerization are essential for activity. To elucidate the role of BRAF and RAF1 as dimerization partners of ARAF S214C, we performed knockdowns of BRAF, RAF1, or both. ARAF S214C-induced MEK activation was not reversed by the BRAF knockdown, however both RAF1 and double knockdowns (BRAF and RAF1) led to loss of MEK activation, suggesting that RAF1 is required. Subsequently, COS7 cells were co-transfected with tagged constructs of ARAF and either BRAF or RAF1, followed by co-IP. We showed that mutant ARAF presents a higher rate of dimerization than wild-type ARAF in the presence of sorafenib. Importantly, sorafenib-induced heterodimers lacked kinase activity, compatible with the clinical response reported.

      Conclusion:
      ARAF S214C demonstrates the in vitro features of a driver oncogene, and also a distinct mechanism of action. This oncogenic process can be successfully suppressed by RAF inhibitors like sorafenib, and could represent a new target for personalized therapy in advanced lung adenocarcinoma. Figure 1 Figure: Summary of the ARAF S214C oncogenic mechanism.



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    MS 16 - Novel SCLC Therapies (ID 34)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      MS16.02 - Stem Cell/Notch/Hedgehog (ID 1917)

      02:33 - 02:46 PM  |  Author(s): D.P. Carbone

      • Abstract
      • Presentation

      Abstract not provided

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    ORAL 22 - Moving Beyond a Smoking Related-Cancer to the Young, Never-smokers and Inherited Disease (ID 117)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL22.02 - Spectrum of Cancer Types in Kindreds with NSCLC and EGFR T790M Mutations: Results from INHERIT EGFR (ID 3180)

      10:56 - 11:07 AM  |  Author(s): D.P. Carbone

      • Abstract
      • Slides

      Background:
      EGFR T790M is most commonly seen as a somatic mutation in non-small cell lung cancer (NSCLC) following resistance to EGFR targeted therapies. Rarely EGFR T790M can be seen as a germline mutation where, in case reports, it has been associated with inherited lung cancer risk. However, the penetrance of the T790M germline mutation for NSCLC is not known, nor is it known whether germline carriers are also at risk for other cancers. The INHERIT study (INvestigating HEreditary RIsk from T790M, NCT01754025) is designed to prospectively identify and study individuals and family members with this rare germline mutation.

      Methods:
      Eligible subjects had EGFR T790M identified on routine cancer genotyping (excluding acquired T790M after therapy), or if they or a relative had already been found to carry a germline EGFR mutation. Confirmatory testing of saliva or blood was done to identify germline T790M carriers. Detailed 3-4 generation pedigrees of probands were constructed and analyzed for type of cancer, age at diagnosis, and relationship to proband with T790M mutation.

      Results:
      23 eligible kindreds were enrolled between 12/12 and 4/15, with 17 probands identified to have germline T790M and 6 probands shown to have acquired T790M. Average age at diagnosis for probands with germline T790M mutation was 55.8 (range 29 to 76) compared to 62 years (range 47 to 74) for non-germline probands. Pedigrees from confirmed T790M probands had an average kindred size of 28 members (range 3 to 40). Among the 325 1[st] and 2[nd] relatives, there were a total of 61 (18.7%) cancer diagnoses; 25 (39.7%) in lung, 4 (6.3 %) breast, 3 (4.8 %) colon, 4 (6.3) esophagus, 4 (6.3 %) leukemia/lymphoma, 3 (4.8 %) prostate, 3 (6.8%) bladder, 2 (3.2%) testes with about 1% or less with pancreatic, renal, brain, cervical cancer. Further, 7 of these 17 kindreds (41%) had multi-generational lung cancers consistent with autosomal dominant inheritance. In contrast, the cancer profile from the non-germline T790M kindreds showed high prevelance of breast cancer (61%; 13 of 21 relatives with cancer) and low prevalence of lung cancer (9%; 2 of 21). None of these 6 kindreds showed an autosomal dominant pattern of inheritance.

      Conclusion:
      A wide variety of tumor types were reported in this unique set of kindreds identified by tumor typing of probands for EGFR T790M mutations, with lung cancer as the most frequently reported cancer in close relatives. A high proportion of germline T790M kindreds also had a strong family history consistent with dominant inheritance. Future research will be needed to clarify the cancer risks in relatives of patients with EGFR T790M germline mutations and to develop guidelines and standards for prevention and early detection.

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    ORAL 42 - Drug Resistance (ID 160)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL42.05 - <em>SMARCA4</em>/BRG1 Is a Biomarker for Predicting Efficacy of Cisplatin-Based Chemotherapy in Non-Small Cell Lung Cancer (NSCLC) (ID 849)

      07:13 - 07:24 PM  |  Author(s): D.P. Carbone

      • Abstract
      • Slides

      Background:
      Adjuvant platinum-based chemotherapy remains a primary treatment of non-small-cell lung cancer (NSCLC); however, identification of predictive biomarkers is critically needed to improve the selection of patients who derive the most benefit. In this study, we hypothesized that decreased expression of SMARCA4/BRG1, a known regulator of transcription and DNA repair, is a predictive biomarker of increased sensitivity to platinum-based therapies in NSCLC. Moreover, this study also sought to confirm the prognostic role of SMARCA4/BRG1 in NSCLC.

      Methods:
      The prognostic value of SMARCA4 expression levels was tested using a microarray dataset from the Director’s Challenge Lung Study (n=440). Its predictive significance was determined using a gene expression microarray dataset (n=133) from the JBR.10 trial, and RT-PCR data from 69 patients enrolled on the MADe-IT trial and 33 platinum-treated patients from an institutional cohort.

      Results:
      In the Director's challenge study, low expression of SMARCA4 was found to be associated with poor overall survival compared to high and intermediate expression (P = 0.006). Upon multivariate analysis, compared to high, low SMARCA4 expression predicted an increased risk of death and confirmed its prognostic significance (HR=1.75; P=0.002). In the JBR.10 trial, improved five-year disease-specific survival was noted only in patients with low SMARCA4 expression when treated with adjuvant cisplatin/vinorelbine (HR 0.1, P= 0.001 (low); HR 1.1 , P= 0.762 (high)). An interaction test showed significance (P=0.007). In addition, a trend toward improved progression-free survival was noted only in patients with low SMARCA4 receiving a carboplatin- versus a non-carboplatin-based regimen in the MADe-IT trial. Figure 1 Fig1. Low SMARCA4 correlates with improved disease-specific survival with adjuvant cisplatin-based chemotherapy in the JBR.10 trial.



      Conclusion:
      Although decreased expression of SMARCA4/BRG1 is significantly associated with worse prognosis, it is a novel significant predictive biomarker for increased sensitivity to platinum-based chemotherapy in NSCLC patients.

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    P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      P1.08-004 - Aki1 as a Potential Therapeutics Target in CREB1 Signaling in Malignant Mesothelioma (ID 234)

      09:30 - 09:30 AM  |  Author(s): D.P. Carbone

      • Abstract

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive tumor arising from the mesothelial cells of serosal membranes. Since current treatment options are largely ineffective, novel therapeutic strategies based on molecular mechanisms and the disease characteristics are needed to improve its prognosis. Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A known as a scaffold protein of PI3K/PDK1/Akt that determines receptor signal selectivity for EGFR has been suggested as a therapeutic target in lung cancer. The aim of this study was to elucidate the role of Aki1 and its potential for treatment of MPM.

      Methods:
      We tested the effects of the treatment with Aki1 or CREB1 siRNAs on cell viability by MTT assay, cell cycle by FACS analysis, cell signaling by WB, and CREB transcriptional activity in 7 MPM cells and 1 mesothelial cells using in vitro experiments. We investigated the efficacy of Aki1 siRNA against growth of 211H cells in an orthotropic implantation model using SCID mice. We further examined Aki1 and p-CREB1 expressions in MPM tumors from 35 patients by TMA specimens and from 33 patients by the tissues.

      Results:
      Cell based assay showed that silencing of Aki1 inhibited cell viability and caused cell arrest of some of MPM cells but not mesothelial cells. Importantly, we identified that the efficacy of Aki1 is regulated by CREB1 signaling which is involved in cell viability, cell cycle, and transcriptional activity. Aki1 and phosphorylated CREB1 were frequently expressed in MPM patients (65/68 cases) (30/35 cases), respectively. Furthermore, the expression of Aki1 correlated with phosphorylation of CREB1 (Spearman rank correlations = 0.521; p = 0.002). Furthermore, direct application of Aki1 siRNA into the pleural cavity significantly inhibited growth of 211H cells compared with that of control siRNA in an orthotropic implantation model using SCID mice.

      Conclusion:
      Our data suggest an important role of Aki1/CREB axis in pathogenesis of MPM and provide a rationale for targeting Aki1 by intrathoracic therapy in locally advanced tumors.

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    P1.12 - Poster Session/ Community Practice (ID 232)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Community Practice
    • Presentations: 1
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      P1.12-011 - Treatment Patterns and Overall Survival for Advanced NSCLC Following Platinum-Based Chemotherapy in US Community Oncology Clinical Practice (ID 3284)

      09:30 - 09:30 AM  |  Author(s): D.P. Carbone

      • Abstract
      • Slides

      Background:
      While clinical guidelines provide clinical decision support for selection of agent, combination, and order of administration, there are few studies that provide a comprehensive description of contemporary advanced NSCLC treatment patterns in patients following platinum therapy over time; there are limited recent US data on practice patterns and outcomes for advanced NSCLC patients following chemotherapy. The purpose of this study is (1) to describe patient flow from advanced NSCLC diagnosis to anti-cancer treatment following completion of a platinum regimen, and if EGFR mutation or ALK translocation positive, an appropriate TKI; (2) to describe the characteristics of advanced NSCLC patients treated with anti-cancer therapy following platinum therapy and, if EGFR mutation or ALK translocation positive, an appropriate TKI; to describe anti-cancer treatment patterns following completion of platinum therapy and, if EGFR mutation or ALK translocation positive, an appropriate TKI.

      Methods:
      Retrospective EMR database cohort study using data from a cloud-based Oncology Electronic Medical Record (EMR) system with 220 cancer clinics, 700 community-based cancer treatment clinics, 1750 clinicians, and 725,000 active cancer patients, representing 17% of incident cases in the United States. The data represents lab values and physician notes from both structured and unstructured data. Variables of interest include demographic, disease-related, biomarker testing-related, anti-cancer treatment. Treatment patterns include regimens by line of therapy, agents and number of doses administered or prescribed, and distribution of dosage strengths. Analyses will be conducted by histology and EGFR/ALK status (among non-squamous cell carcinoma patients). Data will be analyzed descriptively. Overall survival, if data are available, will be estimated using a series of Kaplan Meier curves, with median OS (95% confidence interval) reported.

      Results:
      Approximately 1598 patients with advanced NSCLC initiating a line of therapy after completing a platinum regimen and, if EGFR mutation or ALK translocation positive, an appropriate TKI between January 1, 2013 and October 31, 2014 will be followed until April 30, 2015. Preliminary results identified 6536 patients with advanced NSCLC; of these, 5048 (77.2%) received any 1L treatment after advanced NSCLC diagnosis with 3786 (57.9%) receiving platinum-based chemotherapy as 1L treatment. Among the final cohort of patients (n=1598), the majority were men (54.0%) initially diagnosed with stage IV disease (68.5%) at age 66. The distribution of histological subtypes in the sample included non-squamous (74.4%), squamous (21.0%), and NOS (4.6%). Treatment patterns will be described according to histology and biomarker status at index date. Patient characteristics and overall survival will be reported by histology, biomarker status at index date, and regimen type.

      Conclusion:
      Results from this study will describe treatment patterns in the second-line setting, prior to the introduction of newer therapies, such as anti-PD1/PD-L1 inhibitors and angiogenesis inhibitors. Additionally, it will advance current understanding of the specific patterns of 2L care for patients being treated with anti-cancer therapy in the real world of community settings.

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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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      P2.04-018 - Whole Transcriptome Analysis of EGFR Wildtype Non-Small Cell Lung Cancer Patients with Clinical Benefit from Erlotinib (ID 2357)

      09:30 - 09:30 AM  |  Author(s): D.P. Carbone

      • Abstract
      • Slides

      Background:
      Despite the success of targeted assays of EGFR mutations in defining the non-small cell lung cancer patients who benefit from EGFR-tyrosine kinase inhibition, there still remains a significant portion of patients whose tumors do not harbor EGFR mutations, yet achieve clinical benefit (progression-free survival > 6 months) from erlotinib treatment. We apply whole transcriptome sequencing (RNAseq) to discover expression and mutation changes associated with erlotinib response.

      Methods:
      We report the results of 108 stage IV non-small cell lung cancer patients treated with first line erlotinib. The primary endpoint assessed was progression-free survival (PFS), to which erlotinib has already shown to be beneficial when compared to placebo. Furthermore, RNAseq was performed on 73 tumors from 29 (40%) males and 44 (60%) females. The RNAseq samples were processed to obtain mutation and expression data.

      Results:
      108 patients were followed for PFS, 7 of which declined to be followed, 2 came off erlotinib due to toxicity, 3 died before completion of the first cycle of erlotinib, 5 were ineligible, and 2 have not had tumor recurrence to date. The remaining 92 patients had a mean PFS of 4.71 months (±1.03 months, 95% CI). No patients experienced a complete response, and 14 of 92 (15%) patients had a partial response. Of the tumors analyzed via RNAseq, 7 harbored EGFR mutations, including a complex exon 18 deletion in a patient with a partial response to erlotinib. 14 of 64 (22%) patients without EGFR mutations showed clinical benefit from erlotinib, none of which harbored other known actionable mutations. These EGFR wildtype tumors did not exhibit mutations in other known oncogenes in lung cancer. We hypothesize that they are addicted to EGFR signaling through other means than overactive kinase activity caused by activating mutations. Figure 1



      Conclusion:
      We present results from a clinical trial of first line erlotinib in stage IV non-small cell lung cancer. We show that there is a significant cohort of EGFR wildtype patients who receive clinical benefit from erlotinib and present preliminary data of their mutation status.

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    P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P3.04-001 - Exosomal RNA Based Liquid Biopsy Detection of EML4-ALK in Plasma from NSCLC Patients (ID 2591)

      09:30 - 09:30 AM  |  Author(s): D.P. Carbone

      • Abstract
      • Slides

      Background:
      Molecular profiling to direct targeted therapy has revolutionized cancer treatment. For instance, the tailored therapy of NSCLC patients carrying somatic EML4-ALK rearrangements with ALK inhibitors has shown to be associated with substantial clinical response. A prerequisite of this approach is highly sensitive and specific diagnostics to detect and monitor the prognostic biomarker. Today’s tissue-based diagnostics like FISH are limited by complications of biopsy and technical challenges. Therefore, biomarker assessment in plasma circulation would be a valuable alternative to tissue based testing and provide a simple new option for identifying and monitoring EML4-ALK positive NSCLC patients. We previously demonstrated the feasibility of detecting EML4-ALK fusion transcripts in 6 plasma samples from patients known to be positive by tissue FISH testing (the gold standard). Here we present more comprehensive performance characteristics of this diagnostic test analyzing the exosomal expression of EML4-ALK in plasma of NSCLC patients.

      Methods:
      We developed a diagnostic test to monitor the expression of EML4-ALK fusion transcripts in low-volume plasma samples of lung cancer patients. The Exosome Diagnostics ALK assay comprises column-based isolation of total vesicular RNA from 0.5 – 2.0 ml patient plasma, followed by discrete detection of EML4-ALK variants v1, v2 and v3 via qPCR. Assay quality is confirmed by inclusion of internal and external controls. Following validation on both synthetic and human samples, we monitored variant-specific expression of EML4-ALK in a cohort of more than 20 plasma samples from NSCLC patients. The data was analyzed for concordance with time-matched tissue and aligned with patient’s response data.

      Results:
      Applying our diagnostic test for EML4-ALK fusion variants, we were able to identify the predictive biomarker in exosomal RNA transcripts isolated from patient plasma. We determined the variant-specific expression profile of EML4-ALK fusion transcripts in a cohort of NSCLC patients with high sensitivity and specificity. We observed high concordance of the qPCR-based plasma results with FISH-based tissue information.

      Conclusion:
      Liquid biopsies represent a low-risk and viable approach to testing for predictive cancer markers in NSCLC patients. Here, we demonstrate the capability of our validated diagnostic test to determine expression of rare EML4-ALK fusion transcripts in plasma as a sensitive alternative to repeat biopsy. Monitoring discrete EML4-ALK fusion variants would enable effective personalized treatment and has clear clinical application.

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    YIS - Young Investigator Session incl. Q & A with Longstanding IASLC Members (ID 238)

    • Event: WCLC 2015
    • Type: Young Investigator Session
    • Track: Other
    • Presentations: 1
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      YIS.01 - Introduction to IALSC: What It Can Do For You (ID 3511)

      07:30 - 08:00 AM  |  Author(s): D.P. Carbone

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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