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F.R. Hirsch

Moderator of

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    PLEN 02 - Lung Cancer: IASLC Global Initiatives (ID 51)

    • Event: WCLC 2015
    • Type: Plenary
    • Track: Plenary
    • Presentations: 3
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      Introduction (ID 2098)

      • Abstract

      Abstract not provided

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      PLEN02.01 - 2015 WHO Classification of the Pathology and Genetics of Tumors of the Lung (ID 2041)

      W.D. Travis

      • Abstract
      • Presentation

      Abstract:
      The 2015 WHO Classification of Tumors of the Lung, Pleura, Thymus and Heart has just been published with numerous important changes from the 2004 WHO classification, due in part to remarkable advances in lung cancer genetics and therapy.[1] Multiple major changes for the common lung cancers mostly follow the 2011 lung adenocarcinoma classification sponsored by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS) and European Respiratory Society (ERS).[2 ] This 2015 edition follows previous WHO Classifications of Lung Tumors in 1967 and 1981, of Lung and Pleural Tumors in 1999 and Tumors of the Lung, Pleura, Thymus and Heart in 2004.[3, 4] Through support of its Pathology Committee, the IASLC has played a key role in the last three WHO Classifications.[5] With each subsequent classification, new techniques were introduced resulting in increased complexity, but greater ability to personalize therapeutic strategies that are now frequently dependent on histology and genetics. The most significant changes in the 2015 Classification involve: 1) Use of immunohistochemistry throughout the classification, when possible, not only for small biopsies/cytology, but also for resected specimens in certain settings such as solid adenocarcinoma, nonkeratinizing squamous cell carcinoma, large cell carcinoma, neuroendocrine tumors and sarcomatoid carcinomas. 2) A new emphasis on genetic studies, in particular integration of molecular testing to help personalize treatment strategies for advanced lung cancer patients. Due to the therapeutic implications, molecular testing for EGFR mutation and ALK rearrangement is today recommended in tumors classified as adenocarcinoma and in cases where an adenocarcinoma component cannot be excluded.[2, 6] 3) A new classification for small biopsies and cytology similar to that proposed in the 2011 IASLC/ATS/ERS Classification[2] proposes that tumors that have clear morphologic patterns of adenocarcinoma or squamous cell can be diagnosed as adenocarcinoma or squamous cell carcinoma, respectively, without immuhistochemistry, unless a pneumocyte marker such as TTF-1 is desired to address primary versus metastatic adenocarcinoma. However, in the setting of poorly differentiated tumors that do not show clear differentiation by routine microscopy, a limited immunohistochemical workup is recommended to allow for an accurate diagnosis and also to preserve as much tissue for molecular testing as possible. Most tumors can be classified using a single adenocarcinoma marker (e.g. TTF-1) and a single squamous marker (e.g. p40 or p63). Nonsmall cell carcinomas (NSCC) that show no clear adenocarcinoma or squamous cell carcinoma morphology or immunohistochemical markers are regarded as NSCC not otherwise specified (NOS). If a tumor with this morphology stains with pneumocyte markers (i.e. TTF-1), it is classified as NSCC, favor adenocarcinoma and if it stains only with squamous markers (i.e. p40) it is classified as NSCC, favor squamous cell carcinoma. Using this approach, a diagnosis of NSCC-NOS can be avoided in up to 90% of cases.[7, 8 ] 4) According to the 2011 IASLC/ATS/ERS Classification of lung adenocarcinoma, adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) were defined as entities to have 100% or near 100% disease free survival if completely resected, respectively. Also, invasive adenocarcinomas are classified according to the predominant pattern using comprehensive histologic subtyping (CHS). Multiple studies have shown prognostic significance to this approach with favorable outcome for lepidic adenocarcinomas and poor outcome for solid and micropapillary adenocarcinomas. CHS can be helpful in staging as well: 1) along with other morphologic features, it can be useful in comparing multiple lung adenocarcinomas in a single patient in order to distinguish multiple primary tumors from intrapulmonary metastases and 2) it can also help in measuring invasive size in lepidic adenocarcinomas. Micropapillary or solid predominant subtyping also appears to predict improved responsiveness to adjuvant chemotherapy compared to acinar or papillary predominant tumors in surgically resected lug adenocarcinoma patients when analyzed by disease free survival and specific disease free survival.[9] 5) The diagnosis of large cell carcinoma is restricted only to resected tumors that lack any clear morphologic or immunohistochemical differentiation with reclassification of the remaining former large cell carcinoma subtypes into different categories. 6) Squamous cell carcinomas are reclassified into keratinizing, nonkeratinizing and basaloid subtypes with the non-keratinizing tumors requiring immunohistochemistry proof of squamous differentiation. 7) Neuroendocrine tumors are grouped together in one category, although new genetic data supports previous clinical, epidemiologic and pathologic data showing that low and intermediate grade typical (TC) and atypical carcinoids (AC) are distinct from the high grade small cell carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC). Ki-67 is useful to distinguish carcinoids from SCLC and LCNEC especially in small crushed biopsies. However, published data do not support incorporation into the classification, particularly in separating TC from AC. Spread through air spaces (STAS) is a newly recognized pattern of invasion which consists of micropapillary clusters, solid nests or single cells beyond the edge of the tumor into air spaces in the surrounding lung parenchyma, It probably contributes to the significantly increased recurrence rate for patients with small stage 1 adenocarcinomas who undergo limited resections.[10] Future clinical trials and large scale genetic studies such as The Cancer Genome Atlas (TCGA) need to incorporate the new pathologic criteria for both small biopsies and resection specimens which now require immunohistochemistry to precisely classify poorly differentiated tumors such as solid adenocarcinoma or nonkeratinizing squamous cell carcinoma. Despite promising preliminary data, additional work is needed to develop a histological grading system for lung cancer. Acknowledgement: This abstract is presented with gratitude on behalf of the WHO Panel and the IASLC Pathology Committee. References: 1. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: International Agency for Research on Cancer; 2015. 2. Travis WD, Brambilla E, Noguchi M, et al. The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification. JThoracic Oncol 2011;6:244-85. 3. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E, in collaboration with LHS, Countries pf. Histological Typing of Lung and Pleural Tumors. Berlin: Springer; 1999. 4. Travis WD, Brambilla E, Mller-Hermelink HK, Harris CC. Pathology and Genetics: Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC; 2004. 5. Tsao MS, Travis WD, Brambilla E, Nicholson AG, Noguchi M, Hirsch FR. Forty years of the international association for study of lung cancer pathology committee. J Thorac Oncol 2014;9:1740-9. 6. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M. Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J ThoracOncol 2013. 7. Nicholson AG, Gonzalez D, Shah P, Pynegar MJ, Deshmukh M, Rice A, Popat S. Refining the Diagnosis and EGFR Status of Non-small Cell Lung Carcinoma in Biopsy and Cytologic Material, Using a Panel of Mucin Staining, TTF-1, Cytokeratin 5/6, and P63, and EGFR Mutation Analysis. JThoracOncol 2010;5:436-41. 8. Loo PS, Thomas SC, Nicolson MC, Fyfe MN, Kerr KM. Subtyping of Undifferentiated Non-small Cell Carcinomas in Bronchial Biopsy Specimens. JThoracOncol 2010;5:442-7. 9. Tsao MS, Marguet S, Le Teuff G, Lantuejoul S, Shepherd FA, Seymour L, Kratzke R, Graziano SL, Popper HH, Rosell R, Douillard JY, Le-Chevalier T, Pignon JP, Soria JC, Brambilla EM. Subtype Classification of Lung Adenocarcinoma Predicts Benefit From Adjuvant Chemotherapy in Patients Undergoing Complete Resection. J Clin Oncol 2015. 10. Kadota K, Nitadori JI, Sima CS, Ujiie H, Rizk NP, Jones DR, Adusumilli PS, Travis WD. Tumor Spread Through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences Following Limited Resection for Small Stage I Lung Adenocarcinomas. J Thorac Oncol 2015;10:806-14.

      WHO CLASSIFICATION
      Adenocarcinoma
      Lepidic adenocarcinoma
      Acinar adenocarcinoma
      Papillary adenocarcinoma
      Micropapillary adenocarcinoma
      Solid adenocarcinoma
      Invasive mucinous adenocarcinoma Mixed invasive mucinous and non-mucinous adenocarcinoma
      Colloid adenocarcinoma
      Fetal adenocarcinoma
      Enteric adenocarcinoma
      Minimally invasive adenocarcinoma Non-mucinous Mucinous
      Preinvasive lesions Atypical adenomatous hyperplasia Adenocarcinoma in situ Nonmucinous Mucinous
      Squamous cell carcinoma
      Keratinizing squamous cell carcinoma
      Non-keratinizing squamous cell carcinoma
      Basaloid squamous cell carcinoma
      Preinvasive lesion Squamous cell carcinoma in situ
      Neuroendocrine tumors
      Small cell carcinoma Combined small cell carcinoma
      Large cell neuroendocrine carcinoma Combined large cell neuroendocrine carcinoma
      Carcinoid tumors Typical carcinoid Atypical carcinoid
      Preinvasive lesion Diffuse idiopathic pulmpnary neuroendocrine cell hyperplasia
      Large cell carcinoma


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      PLEN02.02 - Revised (8th) Edition of TNM Staging System for Lung Cancer (ID 2042)

      R. Rami-Porta

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The changes introduced in the 7[th] edition of the tumour, node and metastasis (TNM) classification for lung cancer derived from the analyses of the International Association for the Study of Lung Cancer (IASLC) database. These analyses were conducted by the members of the IASLC Staging and Prognostic Factors Committee (SPFC) and the biostatisticians of Cancer Research And Biostatistics (CRAB). For the first time in the history of the TNM classification for lung cancer, the 7[th] edition was based on a truly international database of more than 80,000 evaluable patients collected in 45 different sources in 20 countries and treated with all treatment modalities from 1990 to 2000. (1) The changes recommended by the IASLC were accepted by the Union for International Cancer Control (UICC) and by the American Joint Committee on Cancer (AJCC) and were eventually published in their staging manuals. With this involvement of the IASLC in the revision of the TNM classification for lung cancer, the IASLC became the most important provider of data to the UICC and the AJCC for future editions of the classification. A similar process was used for the revision of the 7[th] edition into the 8[th] edition. The IASLC made an international call for submission of more data to the IASLC database. (2) The resulting international contribution amounted to more than 77,000 evaluable patients diagnosed with either non-small cell lung cancer (70,967 patients) or small cell lung cancer (6,189 patients) from 1990 to 2010. They were submitted from 35 different databases located in 16 countries in Europe, Asia, North and South America, and Australia. (3) The different subcommittees of the Lung Cancer Domain of the IASLC SPFC were in charge of analysing the data pertaining to the T, the N and the M component of the classification, as well as the stages and the small cell lung cancer. For the T component, the prognostic impact of the T descriptors was analysed in five different populations: pT1-4N0M0R0, pT1-4anyNM0R0, pT1-4anyNM0anyR, i.e., including incomplete resections, either microscopically incomplete, R1, or macroscopically incomplete, R2; and cT1-4N0M0 and cT1-4anyNM0. Survival analyses were completed with univariate and multivariate analyses adjusted by histological type, gender, region and age. The main results showed that the capacity of tumour size to separate tumours of different prognosis was greater than that shown in previous analyses, and that its influence could be spread to all T categories; the role of visceral pleura invasion as a T2 descriptor was confirmed; the prognostic impact of endobronchial location less than 2 cm from the carina (T3 in 7[th] edition) and of total atelectasis/pneumonitis (T3 in 7[th] edition) was found to be similar to that of their T2 counterparts; diaphragm invasion was found to have worse prognosis than that of other T3 descriptors; and mediastinal pleura invasion was found to be scarcely used as a T descriptor. (4) For the N component, the present N descriptors (N0, N1, N2 and N3) were found to separate tumours of different prognosis in clinically and pathologically (both in the R0 and any R populations) staged tumours. The impact of tumour burden in the lymph nodes could also be assessed when survival was analysed according to the number of nodal stations, but this could only be analysed in the population of patients who had undergone tumour resection and systematic nodal dissection, and could not be validated at clinical staging. (5) For the M component, the 7[th] edition M1a descriptors were validated, as all showed similar survival. However, when the M1b descriptors were analysed in detail, single metastasis (one metastasis in one organ) had better prognosis than multiple metastases in one or several organs. (6) Table 1 shows the changes recommended by the IASLC SPFC based on the analyses of the new IASLC database. The described changes implied some modifications in the stage grouping, creating more stages for early and advanced disease, (7) and were also applicable to small-cell lung cancer. (8) The IASLC recommendations emphasize the prognostic impact of tumour size; simplify the T descriptors by combining some of them; maintain the current N descriptors; separate tumours with single metastasis in a distinct group; and establish more stage groupings to refine prognosis based on anatomic extent of disease. They improve our capacity to indicate prognosis, which is one of the objectives of the TNM classification, and, therefore, they should be implemented in the 8[th] edition of the TNM classification. Table 1

      Descriptor 7th edition 8th edition (recommended classification)
      T component
      T1a T1a
      >1-2cm T1a T1b
      >2-3cm T1b T1c
      >3-4cm T2a T2a
      >4-5cm T2a T2b
      >5-7cm T2b T3
      >7cm T3 T4
      Bronchus <2cm from carina T3 T2
      Total atelectasis/pneumonitis T3 T2
      Invasion of diaphragm T3 T4
      Invasion of mediastinal pleura T3 -
      N component
      No involvement or involvement of regional lymph nodes N0, N1, N2, N3 N0, N1, N2, N3
      M component
      Metastases within the thoracic cavity M1a M1a
      Single extrathoracic metastasis M1b M1b
      Multiple extrathoracic metastases M1b M1c
      References 1. Goldstraw P, Crowley JJ. The International Association for the Study of Lung Cancer international staging project on lung cancer. J Thorac Oncol 2006; 1: 281-286. 2. Giroux DJ, Rami-Porta R, Chansky K et al. The IASLC Lung Cancer Staging Project: data elements for the prospective project. J Thorac Oncol 2009; 4: 679-683. 3. Rami-Porta R, Bolejack V, Giroux DJ et al. The IASLC Lung Cancer Staging Project: the new database to inform the 8[th] edition of the TNM classification of lung cancer. J Thorac Oncol 2014; 9: 1618-1624. 4. Rami-Porta R, Bolejack V, Crowley J et al. The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol 2015;10:990-1003. 5. Asamura H et al. J Thorac Oncol 2015; in preparation. 6. Eberhardt WEE et al. J Thorac Oncol 2015; in preparation. 7. Golstraw P et al. J Thorac Oncol 2015; in preparation. 8. Nicholson AG et al. J Thorac Oncol 2015; in preparation.

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    PLEN 04 - Presidential Symposium Including Top 4 Abstracts (ID 86)

    • Event: WCLC 2015
    • Type: Plenary
    • Track: Plenary
    • Presentations: 12
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      Q&A (ID 3537)

      • Abstract

      Abstract not provided

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      Q&A (ID 3538)

      • Abstract

      Abstract not provided

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      Q&A (ID 3541)

      • Abstract

      Abstract not provided

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      Q&A (ID 3540)

      • Abstract

      Abstract not provided

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      PLEN04.01 - A Randomized, Phase III Study Comparing Carboplatin/Paclitaxel or Carboplatin/Paclitaxel/Bevacizumab with or without Concurrent Cetuximab in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC): SWOG S0819 (ID 3612)

      R. Herbst, M. Redman, E.S. Kim, T.J. Semrad, L. Bazhenova, G. Masters, K. Oettel, P. Guaglianone, C. Reynolds, A. Karnad, S.M. Arnold, M. Varella-Garcia, J. Moon, P.C. Mack, C.D. Blanke, F.R. Hirsch, D.R. Gandara

      • Abstract
      • Presentation
      • Slides

      Background:
      This abstract is under embargo until September 9, 2015 and will be distributed onsite on September 9 in a Late Breaking Abstract Supplement.

      Methods:


      Results:


      Conclusion:


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      PLEN04.02 - Discussant for PLEN04.01 (ID 3613)

      R. Pirker

      • Abstract
      • Presentation

      Abstract not provided

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      PLEN04.03 - Randomized Phase III Trial of Adjuvant Chemotherapy with or without Bevacizumab in Resected Non-Small Cell Lung Cancer (NSCLC): Results of E1505 (ID 1608)

      H.A. Wakelee, S.E. Dahlberg, S.M. Keller, W.J. Tester, D.R. Gandara, S.L. Graziano, A. Adjei, N. Leighl, S.C. Aisner, J.M. Rothman, J. Patel, M.D. Sborov, S.R. McDermott, R. Perez-Soler, A.M. Traynor, C. Butts, T. Evans, L. Horn, S.S. Ramalingam, J. Schiller

      • Abstract
      • Presentation
      • Slides

      Background:
      Adjuvant chemotherapy for resected early stage NSCLC provides modest survival benefit. Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor, improves outcomes when added to platinum-based chemotherapy in advanced stage non-squamous NSCLC. We conducted a phase 3 study to evaluate the addition of bevacizumab to adjuvant chemotherapy in early stage resected NSCLC. The primary endpoint was overall survival and secondary endpoints included disease-free survival and toxicity assessment.

      Methods:
      Patients with resected stage IB (>4 centimeters) to IIIA (AJCC 6th edition) NSCLC were enrolled within 6-12 weeks of surgery and stratified by chemotherapy regimen, stage, histology and sex. All patients were to receive adjuvant chemotherapy consisting of a planned 4 cycles of every 3 week cisplatin at 75 mg/m[2] with either vinorelbine, docetaxel, gemcitabine or pemetrexed. Patients were randomized 1:1 to arm A (chemotherapy alone) or arm B, adding bevacizumab at 15 mg/kg every 3 weeks starting with cycle 1 of chemotherapy and continuing for 1 year. Post-operative radiation therapy was not allowed. The study had 85% power to detect a 21% reduction in the overall survival (OS) hazard rate with a one-sided 0.025-level test.

      Results:
      From July 2007 to September 2013, 1501 patients were enrolled. Patients were 49.8% male, predominantly white (87.9%) with a median age of 61 years. Patients enrolled had tumors that were 26.2% stage IB, 43.8% stage II and 30.0% stage IIIA and 28.2% of patients had squamous cell histology. Chemotherapy options were utilized with the following distribution: vinorelbine 25.0%, docetaxel 22.9%, gemcitabine 18.9% and pemetrexed 33.2%. At a planned interim analysis, with 412 of 676 overall survival events needed for full information (60.9%), though the pre-planned futility boundary was not crossed, the Data Safety Monitoring Committee recommended releasing the trial results based on the conditional power of the logrank test. At the time of interim analysis, with a median follow-up time of 41 months, the OS hazard ratio comparing the bevacizumab containing arm (Arm B) to chemotherapy alone (Arm A) was 0.99 (95% CI: 0.81-1.21, p=0.93). The DFS hazard ratio was 0.98 (95% CI: 0.84-1.14, p=0.75). Completion of treatment per protocol was 80% on Arm A and 36% on Arm B. Statistically significantly increased grade 3-5 toxicities of note (all attributions) included: overall worst grade (67% versus 84%); hypertension (8% versus 30%), and neutropenia (33% versus 38%) on Arms A and B, respectively. There was no significant difference in grade 5 adverse events per arm with 16 (2%) on arm A and 19 (3%) on arm B.

      Conclusion:
      The addition of bevacizumab to adjuvant chemotherapy failed to improve survival for patients with surgically resected early stage NSCLC.

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      PLEN04.04 - Discussant for PLEN04.03 (ID 3450)

      P.A. Bunn, Jr

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      PLEN04.05 - Multiregion Whole Exome and Transcriptome Sequencing Defines the Genomic Spectrum of EGFR+ NSCLC and Reveals Novel Mechanisms of TKI Resistance (ID 3118)

      D.S. Tan, R. Nahar, A. Takano, A. Khng, T. Zhang, T.P. Koh, A. Gogna, T.K. Lim, W.A. Zaw, X. Liu, A. Teo, C. Chan, Y.Y. Lee, G. Iyer, L.H. Chen, M. Ang, Q. Ng, C. Toh, R. Kanesvaran, A. Jain, A. Devanand, V. Krishnan, P. Ng, B.S. Tan, C.H. Lim, B. Chowbay, W. Lim, W.L. Tam, B. Lim, E.H. Tan, W.W. Zhai, A. Hillmer

      • Abstract
      • Presentation

      Background:
      EGFR mutant (M+) NSCLC is an archetypical oncogene-driven solid tumor, typified by high response rates when treated with a tyrosine kinase inhibitor (TKI), and median progression free survival of 10 months, commonly due to emergence of T790M. The genomic architecture and spectra of EGFR M+ tumours may provide insights to mechanisms of treatment failure and has not been well described to date.

      Methods:
      Paired tumor-normal exome/ transcriptome sequencing and SNP array was performed on 30 tbiopsies from 25 patients with TKI resistance (TKI-R) as well as multiple regions (n=46) of 8 treatment naïve (TKI-N), never smoker East Asian EGFR M+ NSCLC (L858R, n=5; exon 19 del, n=2; exon 20 ins, n=1). Genomic alterations were validated with targeted re-sequencing at a mean depth of 2000x. Alterations were identified and annotated using established pipelines.

      Results:
      Exome sequencing of 46 sectors (4-11 sectors/tumor) from 8 resected NSCLC (Stage IA, n=5; Stage IB, n=3), revealed a median of 52.5 validated mutations (Range: 15-112) per tumor. Primary EGFR mutations (including exon 20 ins) were identified as truncal events in all cases, with the notable absence of T790M even at sequencing depths of 2000x. Private mutations comprised 10-33% of all mutations per tumor, and in some cases harbored potential drivers of subclonal diversity including p53, AKT1 and ATXN1. For the 30 TKI-R tumors (T790M+, n=16; T790M-, n=14), exome sequencing revealed a higher mutation burden (median 80 vs 49 in TKI-N), while SNP array and expression data confirmed ERBB2 and MET as common co-existing resistance mechanisms. We next inferred the relevance of alterations and their hierarchical order (trunk, T; branch, B; private, P). In a TKI-N tumor where 11 sectors were subject to exome-sequencing, 39 of 112 mutations were truncal events – with MAP3K19 and PTEN splice site mutations co-existing with EGFR L858R mutation. Strikingly, when comparing the transcriptomic profiles of TKI-N and TKI-R tumors, all 8 evaluated sectors in this tumor clustered together with the TKI-R signature, suggesting that truncal co-mutations can contribute to primary TKI resistance. Finally, we attempted to curate novel genes in the 46 TKI-N sectors that may be implicated in TKI resistance by identifying genes in common with those altered in TKI-R samples with allele frequency > 0.25. We shortlisted approximately 150 recurrent genes or putative drivers – 85% of which were either trunk or branch mutations including TP53 (T,P), PTEN (B), LRP1B (B), GPRIN3 (B), MAP3K19 (T), ARID3A (P) and MED12 (P).

      Conclusion:
      Multi-region sequencing of 8 never smoker EGFR M+ NSCLC revealed a low mutation burden, with a significant proportion of alterations occurring as trunk or branch events. The different activating EGFR mutations were ubiquitous truncal events and T790M was not found in ultra-deep sequencing across 46 sectors. Mutation hierarchy provides a basis for patterns of TKI treatment failure: with co-occurring truncal events (e.g. MAP3K19, PTEN) potentially contributing to primary resistance, and the low incidence of private subclonal drivers consistent with the relatively high prevalence of T790M mutation in the setting of secondary resistance.

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      PLEN04.06 - Discussant for PLEN04.05 (ID 3569)

      R.K. Thomas

      • Abstract
      • Presentation

      Abstract not provided

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      PLEN04.07 - Stopping Smoking Reduces Mortality in Low-Dose Computed Tomography (LDCT) Screening Volunteers (ID 2458)

      U. Pastorino, R. Boffi, A. Marchianò, S. Sestini, E. Munarini, G. Calareso, M. Boeri, G. Pelosi, G. Sozzi, M. Silva, N. Sverzellati, C. Galeone, A. Ghirardi, G. Corrao, C. La Vecchia

      • Abstract
      • Presentation
      • Slides

      Background:
      The National Lung Screening Trial (NLST) has achieved a 7% reduction in mortality from any cause with low-dose computed tomography (LDCT) screening, as compared with the chest radiography arm. Other randomized trials are under way, comparing LDCT screening with no intervention in heavy smokers populations. None of these studies is designed to investigate the impact of smoking habits on screening outcome. In the present study, we have tested the effect of stopping smoking on the overall mortality of volunteers undergoing LDCT screening.

      Methods:
      Between 2000 and 2010, 3381 heavy smokers aged more than 50 years were enrolled in two LDCT screening programmes. Sixty-nine percent were males with median age of 58 years and median smoking exposure of 40 pack-years. Based on the last follow-up information, subjects were divided in two groups: current smokers throughout the screening period, and former smokers. The latter group included ex-smokers at the time of baseline screening (early quitters), and those who stopped smoking during the screening period (late quitters).The effect of smoking on mortality was adjusted according to the following covariates: gender, age, body-mass index (BMI), lung function (FEV1 %) and pack years at baseline.

      Results:
      With a median follow-up time of 9.7 years, and a total of 32,857 person/years (P/Y) follow-up, a total of 151 deaths were observed in the group of 1797 current smokers (17,846 P/Y) and 109 in 1584 former smokers (15,011 P/Y). As compared to current smokers, the Relative Risk (RR) of death of former smokers was 0.77 (95% CI, 0.60 to 0.99, p = 0.0416), corresponding to a 23% reduction of total mortality. Excluding 239 subjects who had stopped smoking from less than 2 years from the end-point of follow-up, RR was 0.64 (95% CI, 0.48 to 0.84, p = 0.0016), with a 36% mortality reduction. A similar risk reduction was observed in the subset of 476 late quitters (27 deaths, 4,777 P/Y), with a RR of 0.60 (95% CI, 0.40 to 0.91, p = 0.0158).

      Conclusion:
      Stopping smoking is associated with a significant reduction of the overall mortality of heavy smokers enrolled in LDCT screening programs. The benefit of stopping smoking appears to be 3 to 5-fold greater than the one achieved by earlier detection in the NLST trial.

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      PLEN04.08 - Discussant for PLEN04.07 (ID 3483)

      N. Yamaguchi

      • Abstract
      • Presentation

      Abstract not provided

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Author of

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    ED 07 - How to Treat Advanced Squamous Carcinoma of the Lung (ID 7)

    • Event: WCLC 2015
    • Type: Education Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ED07.03 - Lung Master Protocol in Squamous Cell Lung Cancer (Lung-MAP, S1400) (ID 1800)

      F.R. Hirsch

      • Abstract
      • Presentation

      Abstract:
      In recent years, our understanding of non-small cell lung cancer (NSCLC) has evolved from thinking of this malignancy as a single disease, or a small number of histologic subtypes, to now a multitude of genomically-defined subsets, both in adenocarcinoma and squamous lung cancer. In development of new targeted therapies against these abnormalities, so-called Master Protocols offer a number of advantages over traditional single study designs for drug-biomarker approval, including a common infrastructure, homogeneous patient populations with consistent eligibility across multiple independent sub-studies, and the ability to screen large numbers of patients in rapid fashion. Thus, the Lung-MAP project was designed to facilitate approval of targeted therapy-predictive biomarker combinations in squamous lung cancer, a recognized area of unmet need. Lung-MAP is constructed as a unique public-private partnership engaging the National Cancer Institute (NCI) and its Thoracic Malignancies Steering Committee (TMSC), the Foundation of the NIH (FNIH), the pharmaceutical industry and advocacy groups such as Friends of Cancer Research (FOCR), along with an advisory role by the Federal Drug Administration (FDA). The design is multiple simultaneously running Phase II/III trials, each capable of independently opening and/or closing without affecting the other sub-studies, in which patients eligible for 2[nd] line therapy for lung SCC have their cancers genomically screened through a next generation sequencing (NGS) platform (Foundation Medicine). Patients are then randomized into one of several sub-studies, each comparing an experimental targeted therapy with standard of care therapy, based on identification of candidate predictive biomarkers associated with each sub-study. At launch, drug targets under study consisted of “match sub-studies” for PI3K, FGFR, CDK 4/6 and HGF, and a non-match sub-study testing PD-L1-directed therapy, as described below. Rapid turn-around time of NGS screening results, within 2 weeks, allows real time assignment into the appropriate sub-study. For those patients with cancers that do not “match” into a biomarker-driven sub-study, there is a ‘non-match” sub-study, in which a predictive biomarker is not yet of sufficient validation to utilize it in a drug-biomarker registration strategy. Due to changes in the therapeutic landscape since the launch of Lung-MAP, a number of amendments and modifications have been implemented, which will be discussed during this presentation.

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    MINI 04 - Clinical Care of Lung Cancer (ID 102)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI04.03 - Real-World Patterns of Access to Cancer Specialist Care Among Patients With Lung Cancer in the United States: A Claims Database Analysis (ID 1592)

      F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background:
      Timely access to specialist care is an important first step in the care of patients with lung cancer (LC). This study describes real-world patterns of access to cancer specialist (CS) care in all LC patients and those with metastatic LC (mLC).

      Methods:
      Adult patients diagnosed with primary LC or mLC were identified in a US commercial claims database (01/01/2008 - 03/31/2014). Patients’ specialist visits were assessed before and after their first biopsy (index date). All patients had ≥3 months follow-up after index date. CS was defined as oncologists or hematologists. Patients were divided in four mutually exclusive groups based on the specialists seen in the 6 weeks pre-index period: patients seen by CS (± other specialists), pulmonologists (no CS, ± other specialists), internists or family physicians (no CS/pulmonologist, ± other specialists), and other. CS visits in the 8-weeks post-index were assessed for each group. Reversed Kaplan-Meier plots were used to describe time from index date to first CS visit.

      Results:
      The analysis included 75,163 LC and 25,191 mLC patients, with a median age of 67 [interquartile range (IQR): 59-76)] and 63 (IQR: 57-73) years and a median follow-up of 11 and 9 months, respectively. In the 8-week post-index period, over half of LC patients (54%) and nearly two-thirds of mLC patients (66%) had their first CS visit (Figure 1), while 38% of LC patients and 28% of mLC patients never saw a CS within 1-year of biopsy (Figure 1). In both samples, patients in the CS and pulmonologist pre-index groups were more likely to see a CS in follow-up (Figure 2; p<0.001 for all groups). Figure 1 Figure 1 Figure 2 Figure 2





      Conclusion:
      A substantial proportion of patients diagnosed with LC and mLC did not see any CS after biopsy, which may negatively affect access to optimal and timely treatment.

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    MINI 10 - ALK and EGFR (ID 105)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI10.02 - Intratumoral Heterogeneity of ALK-Rearranged and ALK/EGFR Co-Altered Lung Adenocarcinoma (ID 685)

      F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background:
      Genetic intratumoral heterogeneity has a profound influence on the selection of clinical treatment strategies and addressing resistance to targeted therapy. The purpose of our study is to explore the potential effect of intratumoral heterogeneity on both the genetic and pathologic characteristics of ALK-rearranged lung adenocarcinoma (LADC).

      Methods:
      We tested ALK fusions and EGFR mutations in 629 LADC patients by using laser capture microdissection (LCM) to capture spatially separated tumor cell subpopulations in various adenocarcinoma subtypes and test for ALK fusions and EGFR mutations in ALK-rearranged, EGFR-mutated, and ALK/EGFR co-altered LADCs in order to compare the oncogenic driver status between different tumor cell subpopulations in the same primary tumor.

      Results:
      Among the 629 patients, 30 (4.8%) had ALK fusions, 364 (57.9%) had EGFR mutations, and 2 had ALK fusions coexisting with EGFR mutations. Intratumoral heterogeneity of ALK fusions was identified in 9 patients by RT-PCR. In the 2 ALK/EGFR co-altered patients, intratumoral genetic heterogeneity was observed both between different growth patterns and within the same growth pattern. Genetic intratumoral heterogeneity of EGFR mutations was also identified in EGFR-mutated NSCLC. ALK fusions were positively associated with a micropapillary pattern (P=0.002) and negatively associated with a lepidic pattern (P=0.008) in a statistically-expanded analysis of 900 individual adenocarcinoma components, although they appeared to be more common in acinar-predominant LADCs in the analysis of 629 patients.

      Conclusion:
      Intratumoral genetic heterogeneity was demonstrated to co-exist with histologic heterogeneity in both single-driver and EGFR/ALK co-altered LADCs. As for the latter, one of the dual altered drivers may be the trunk-driver for the tumor.

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    MINI 13 - Genetic Alterations and Testing (ID 120)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 2
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      MINI13.03 - Characterization of MET Gene and MET Protein Expression in Lung Cancer (ID 2155)

      F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background:
      Activation of the MET signaling pathway can propel the growth of cancer cells in non-small cell lung cancer (NSCLC). Increased MET gene by amplification and/or polysomy can cause MET protein overexpression; less common causes include mutations, translocations, and alternative RNA splicing. Clinical trials using MET as a biomarker for selection of lung cancer patients who might most benefit from targeted therapy have experienced variable outcomes. We aimed to characterize the relationship between MET protein overexpression and MET amplification or mean copy number alterations in patients with NSCLC.

      Methods:
      The Lung Cancer Mutation Consortium (LCMC) is performing an ongoing study of biomarkers with patients with NSCLC from 16 cancer center sites across the United States. For this analysis, 403 cases had complete data for MET protein expression by immunohistochemistry (IHC, monoclonal antibody SP44, Ventana) and MET gene amplification by fluorescence in-situ hybridization (FISH, MET/CEP7 ratio). Pathologists evaluated MET expression using the H-score, a semi-quantitative assessment of the percentage of tumor cells with no, faint, moderate, and/or strong staining, ranging from 0-300. Spearman's correlation was used to analyze the correlation between MET protein expression (H-scores) and FISH results (MET/CEP7 ratio (N=403) and MET copy number (N=341). Protein overexpression using 5 different cut-offs was compared with amplification defined as MET/CEP7 ≥ 2.2 and high mean copy number defined as ≥ 5 MET gene copies per cell using the Fisher’s exact test. Cox Proportional Hazards models were built to examine the associations of these different definitions of positivity with prognosis, adjusting for stage of disease.

      Results:
      MET protein expression was significantly correlated with MET copy numbers (r=0.17, p=0.0025), but not MET/CEP7 ratio (r=-0.013, p=0.80). No significant association was observed between protein overexpression using a commonly used definition for MET positivity (“at least moderate staining in ≥ 50% tumor cells”) and MET amplification (p=0.47) or high mean copy number (p=0.09). A definition for MET protein overexpression as “≥ 30% tumor cells with strong staining” was significantly associated with both MET amplification (p=0.03) and high mean copy number (p=0.007), but a definition of “≥ 10% tumor cells with strong staining” was not significantly associated with either. Definitions of protein overexpression based on high H-scores (≥200 or ≥250) were associated with high MET mean copy numbers (p=0.03 and 0.0008, respectively), but not amplification (p=0.46 and 0.12, respectively). All 5 definitions of MET protein overexpression demonstrated a significant association with worse prognosis by survival analyses (p-values ranged from 0.001 to 0.03). High MET copy number (p=0.045) was associated with worse prognosis, but MET amplification was not (p=0.07).

      Conclusion:
      Evaluation of NSCLC specimens from LCMC sites confirms that MET protein expression is correlated with high MET copy number and protein overexpression is associated with worse prognosis. Definitions of MET protein overexpression as “an H-score ≥250” and “≥30% tumor cells with strong staining” were significantly associated with high mean MET copy number. It may be worth reevaluating the performance of MET as a biomarker by different definitions of positivity to predict response to MET-targeted therapies.

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      MINI13.06 - Mutation Prevalence for Oncogenic Drivers in Lung Adenocarcinoma (ID 3279)

      F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background:
      Identification of mutations which drive pulmonary adenocarcinomas (ADC) has rapidly moved from the research arena to clinical practice. The prevalence of these mutations has been suggested by a multitude of studies but here we describe the prevalence of mutations from a large study of patients with advanced ADC treated in the international phase III study INSPIRE (Lancet Oncology 2015) with all testing performed in one CLIA-certified laboratory under standardized conditions.

      Methods:
      Mutation testing was performed on 412 adenocarcinoma specimens using SNaPshot® methodology. Mutations were examined in the AKT, EGFR, KRAS, BRAF, NRAS, PIK3CA, TP53, PTEN, CTNNB1, and MEK1 genes. The relative frequencies of genetic alterations were calculated based on the total number of adequate specimens and specific consent for testing.

      Results:
      Of the 412 adenocarcinoma specimens tested, 372 (90.3%) had evaluable results from mutation testing. A single mutation was detected in 157 (42.2%) specimens, whereas mutations in two genes were detected in an additional 20 (5.4%). The overall prevalence of mutations for each specific gene was as follows: KRAS (34.2%), EGFR (12.2%), TP53 (4.9%), PTEN (2.8%), PIK3CA (2.2%), CTNNB1 (2.2%), NRAS (1.8%), BRAF (1.2%), MEK1 (0.3%), and AKT (0%). Figure 1 Evaluation of smoking status identified a substantially higher percentage of KRAS mutations in ex-light smokers and current smokers (38.2% and 40.5%) combined compared to never smokers (7.6%, p<0.0001) , and a lower proportion of EGFR mutations in ex-light and current smokers (10.9% and 4.9%) combined compared to never smokers (39.7%, p<0.0001). Patients ≥70 years old had a higher proportion of both NRAS (7.1% vs. 0.7%, p=0.009) and TP53 mutations (12.5% vs. 3.3%, p=0.010). In addition, males had a lower incidence of EGFR mutation (8.6% vs. 19.0%, p=0.007) as compared to females. Patients from North America, Europe, and Australia/New Zealand demonstrated lower rates of mutation in CTNNB1 (1.4% vs. 8.6%, p=0.030) and PIK3CA (1.4% vs. 8.3%, p=0.032) compared to patients from Central/South America, South Africa and India. Finally, among specimens with two mutations, combinations involving KRAS were the most prevalent (70%, 14/20) followed by TP53 (50%, 10/20).



      Conclusion:
      These results demonstrate the wide spectrum of mutations that can be detected in adenocarcinoma specimens, with high prevalence rates in the EGFR and KRAS genes. Most patients had only one identified driver mutation. The study revealed age and geographical associations in some mutations. The clinical relevance of the studied mutations in relation to chemotherapy and the human EGFR antibody, Necitumumab, will be studied.

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    MINI 17 - WT EGFR, Angiogenesis and OMD (ID 131)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI17.02 - SWOG 0709: Randomized Phase II Trial of Erlotinib vs. Erlotinib plus Carboplatin/Paclitaxel in Patients (Pts) with Advanced Non-Small Cell Lung Cancer (NSCLC) and Impaired Performance Status (PS2) as Selected by Serum Proteomics (ID 658)

      F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background:
      Advanced NSCLC pts with Zubrod PS2 are often excluded from clinical trials and platinum-based therapy. In SWOG 0341, erlotinib in PS 2 pts yielded progression-free (PFS) and overall survival (OS) of 2.1 and 5 months respectively. In a trial of erlotinib versus carboplatin/paclitaxel in PS2 pts (Lilenbaum, JCO 2008), PFS for erlotinib and chemotherapy were 1.9 and 3.5 months, respectively. Early reports suggested a potential role for serum proteomics in predicting erlotinib benefit beyond that of EGFR mutational status. We therefore conducted a prospective trial of erlotinib +/- chemotherapy in NSCLC pts with PS2 enriched by serum proteomics (Veristrat assay).

      Methods:
      Metastatic NSCLC pts with PS2, acceptable end-organ function, and “good” classification by serum proteomics were randomized to either Arm A (erlotinib 150 mg orally QD) or Arm B (erlotinib 150 mg orally QD on days 2-16 plus carboplatin AUC 5 IV day 1 and paclitaxel 200 mg/m2 IV day 1 x 4 cycles, followed by erlotinib 150 mg orally QD). Cycle length was 3 weeks. Arm B agents were “pharmacodynamically separated” to mitigate potential antagonism. The arm with superior observed median PFS would be selected for further evaluation, but only if ≥ 3 months. A sample size of 98 pts was based on a variety of assumed PFS probabilities for each arm. The trial was prematurely closed after the FDA determined midway through accrual that an IDE application was required for the proteomics assay; however SWOG had limited resources available for such filing.

      Results:
      Of 156 pts screened, 83 (59%) were classified as “good” by serum proteomics. 59 of 83 pts (60%) met trial eligibility and were randomized. Treatment-related grade 4 adverse events were seen in 2 pts in Arm A (thrombosis, hypomagnesemia) and 5 pts in Arm B (neutropenia -5, febrile neutropenia-1, leukopenia -1), with no treatment related deaths. Figure 1



      Conclusion:
      In Zubrod PS2 pts with advanced NSCLC and “good” classification by serum preoteomics, pharmacodynamically-separated erlotinib plus chemotherapy had better observed median PFS/OS versus erlotinib alone and surpassed the protocol-specified benchmark of PFS >= 3 months required for further study. Updated data will be presented.

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    MINI 21 - Novel Targets (ID 133)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI21.10 - The TORK/DNA-PK Inhibitor CC-115 Shows Combination Anti-Proliferative Effects with Erlotinib in NSCLC Cells Resistant to EGFR Inhibition (ID 641)

      F.R. Hirsch

      • Abstract
      • Slides

      Background:
      In non-small cell lung cancer (NSCLC), activation of the phosphoinositide-3-kinase (PI3K)/mTOR pathway is common in tumors resistant to Epidermal Growth Factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). CC-115 (Celgene Corporation), an mTOR kinase inhibitor that targets both mTORC1 and mTORC2 as well as DNA-dependent protein kinase (DNA-PK), is currently under early clinical development. We evaluated CC-115 in combination with Erlotinib to overcome resistance to EGFR tyrosine kinase inhibition in non-small cell lung cancer (NSCLC) cell lines and xenografts in nude mice.

      Methods:
      In the present study we investigated whether CC-115 is able to increase the therapeutic effect of the EGFR TKI Erlotinib in several different NSCLC cell lines which exhibit intermediate or high resistance to EGFR TKIs: A549, H1975, H1650, HCC95, H2122 and H23. Mechanisms of inhibition were analyzed with assays for proliferation, apoptosis, and cell cycle progression. Cell signaling activity was analyzed using phospho-specific antibodies in Western blotting. Xenograft mice studies were performed to confirm the results in vivo.

      Results:
      CC-115 demonstrated anti-proliferative activity in NSCLC cell lines with various degrees of sensitivity as reflected in different IC50 values, ranging from 0.07 up to 6.9 mM. The anti-proliferative efficacy of Erlotinib was increased in the NSCLC cells synergistically by combination treatment with CC-115 with combination indices down to 0.04-0.2, indicating strong synergy. The synergistic, anti-proliferative effect of the combination treatment could be explained by increased cell cycle arrest and inhibition of signaling components in the mTOR pathway, especially 4E-BP1. In vivo studies in mice xenografts demonstrated a strong synergistic effect of the combination treatment of Erlotinib and CC-115.

      Conclusion:
      We demonstrate that the therapeutic effect of the EGFR tyrosine kinase inhibitor Erlotinib can be increased by simultaneous treatment with the mTOR kinase/DNA-PK inhibitor CC-115, justifying further clinical studies in lung cancer patients with primary or acquired resistance to EGFR TKIs.

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    MS 28 - Future Clinical Trials (ID 46)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Other
    • Presentations: 1
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      MS28.03 - Biomarkers (ID 1975)

      F.R. Hirsch

      • Abstract
      • Presentation

      Abstract not provided

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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)

      F.R. Hirsch

      • 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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    ORAL 25 - Biology and Other Issues in SCLC (ID 125)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      ORAL25.06 - Association of Expression of PD-L1 with the Tumor Immune Microenvironment in Small Cell Lung Cancer (ID 859)

      F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background:
      Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and has been under-studied relative to novel therapies. Therapeutic antibodies to immune checkpoints are showing promising clinical results. Programmed death-ligand 1 (PD-L1), which can be expressed on many cancer and immune cells, plays an important role in blocking the cancer immunity cycle by binding programmed death-ligand 1 receptor (PD-1), which is a negative regulator of T-lymphocyte activation. Since knowledge about PD-L1 expression in SCLC is limited, we aimed to characterize PD-L1 expression in a cohort of 98 SCLC patients.

      Methods:
      PD-L1 protein expression and mRNA levels were determined by immunohistochemistry (IHC, SP142, Spring Bioscience) and mRNA in situ hybridization (ISH) in primary tumor tissue microarrays obtained from 98 SCLC patients. Membranous staining of PD-L1 protein and mRNA expression on tumor cells and protein expression on tumor-infiltrating immune cells (TIICs) were scored separately using semi-quantitative scores (H-score 0-300 and RNA score 0-4). An H-score ≥ 5 and an RNA score > 2 were defined as the cutoffs for PD-L1 protein and RNA expression positivity. The degree of TIICs was semi-quantitatively scored on hematoxylin and eosin-stained TMA slides as having “0” (no), “1” (mild), “2” (moderate), or “3” (marked) infiltration. The data was analyzed using the Fisher’s exact test, Spearman correlation, two-sample t-test, log-rank test and Kaplan- Meier survival analysis with significance level assumed to be 0.05.

      Results:
      3.16% of cases (3/95) were positive for PD-L1 protein expression in tumor cells, and 30.21% were positive for PD-L1 in TIICs (29/96, p<0.0001). PD-L1 mRNA expression was positive in 15.46% of the tumor cells (15/97). PD-L1 protein and mRNA expression on tumor cells demonstrated a positive correlation (p<0.0001, r=0.431). PD-L1 mRNA expression on tumor cells positively correlated with PD-L1 protein expression on TIICs (p<0.0001, r=0.354). The degree of TIICs positively correlated with both PD-L1 protein expression in tumor cells (p=0.011, r=0.264) and PD-L1 mRNA expression in tumor cells (p<0.0001, r=0.405). The degree of TIICs positively correlated with PD-L1 protein expression in TIICs (p<0.0001, r=0.625). The only significant association observed between PD-L1 expression with clinical characteristics or prognosis of the 78 SCLC patients with clinical data, was between age of patients and PD-L1 protein (p<0.0001) and mRNA expression (p=0.0006) on tumor cells.

      Conclusion:
      A subset of SCLCs is characterized by positive PD-L1 protein and/or mRNA expression in tumor cells and TIICs. PD-L1 mRNA expression was more frequently positive than PD-L1 protein expression in the tumor cells. PD-L1 protein expression was expressed more in TIICs than tumor cells. Higher PD-L1 protein and mRNA expression correlated with more infiltration of TIICs. PD-L1 expression represents the immune response in SCLC. The microenvironment may play a major role on the PD-1/PD-L1 pathway of SCLC. SCLC Patients with PD-L1 expression may respond to anti-PD-L1 treatment.

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    ORAL 30 - Community Practice (ID 141)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Community Practice
    • Presentations: 1
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      ORAL30.03 - Access to Cancer Directed Therapies and Cancer Specialists in Patients with Metastatic Lung Cancer (ID 2899)

      F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background:
      Access to cancer specialists and directed therapies is critical in the management of patients with metastatic lung cancer (mLC). This study aims to assess treatment patterns overall and stratified based on whether patients were seen or not by a cancer specialist in patients with de novo mLC.

      Methods:
      Adult patients diagnosed with de novo mLC between January 1, 2008 and March 31, 2014 were selected from a US commercial health claims database. All patients were followed for a minimum 3 months after the index date, defined as their first biopsy date. Patients who saw an oncologist/hematologist from 6 weeks before index date until the end of follow-up (end of data availability or health plan eligibility) were included in the cohort of patients who saw a cancer specialist. The remaining patients were included in the cohort of patients who did not see a cancer specialist. In both cohorts, the use of systemic antineoplastic therapy (Table 1) and radiation therapy was assessed following the index date.

      Results:
      The study sample consisted of 25,191 mLC patients, followed for a median of 9 months. Median age was 63 years (interquartile range: 57-73). 28.4% of the patients did not see a cancer specialist. Overall, 89.9% of the mLC patients received a cancer directed therapy during the follow-up (Table 1). The proportion of patients who received a cancer directed therapy during the follow-up was larger among patients seen by a cancer specialist (91.2% vs. 86.7%, p < .0001) (Table 1). Among patients who did not see a cancer specialist, 86.7% received antineoplastic therapy and/or radiotherapy during the follow-up, 2.6% were untreated and admitted to hospice, and 10.6% were untreated and were not admitted to hospice. The majority of patients who were not seen by a cancer specialist and received treatment were seen prior to the initiation of therapy by pulmonologists, internists, family physicians, and/or radiologists. Figure 1



      Conclusion:
      Approximately one in ten patients with de novo mLC did not receive any cancer directed therapy and a little more than one in four patients were not seen directly by a cancer specialist. Among patients not seen by a cancer specialist many received some form of cancer directed therapy. However, the access to cancer directed therapy of these patients remained significantly lower than that of mLC patients seen by a cancer specialist. Further research should be directed towards understanding and addressing disparities in access to appropriate cancer care.

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    ORAL 32 - EGFR WT and MT Targeting (ID 144)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL32.05 - EGFR IHC and FISH Correlative Analyses (SQUIRE Trial): Necitumumab + Gemcitabine-Cisplatin vs Gemcitabine-Cisplatin in 1st-Line Squamous NSCLC (ID 2651)

      F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background:
      SQUIRE, a randomized phase III study, demonstrated that the addition of necitumumab (N) (a second-generation, recombinant, human immunoglobulin G1 EGFR antibody) to gemcitabine-cisplatin (GC) improved overall survival (OS) in patients with stage IV squamous non-small cell lung cancer (NSCLC). Analyses of the relationship between efficacy and epidermal growth factor receptor (EGFR) protein expression using the immunohistochemistry (IHC) H-score=200 cut-point were previously reported (Thatcher et al. Lancet Onc, 2015; doi: 10.1016/S1470-2045(15)00021-2). Here we report additional exploratory analyses of the relationship with EGFR protein, as well as analyses of EGFR gene copy number.

      Methods:
      SQUIRE included mandatory tissue collection from archived tumor. EGFR protein expression was assessed by IHC in a central lab, using the Dako EGFR PharmDx kit. Analyses of the relationships between efficacy outcomes with EGFR across the range of protein levels were performed, using methodologies including subpopulation treatment effect pattern plot (STEPP) with a sliding window target size of 200 patients. An exploratory assessment of EGFR gene copy number gain was performed in tissue sections using fluorescence in situ hybridization (FISH) (J Clin Pathol; 2009;62(11):970-7). Efficacy outcomes were estimated using the Kaplan-Meier method and hazard ratios estimated using an un-stratified Cox model. .

      Results:
      A total of 982 patients (89.8% of the ITT) had evaluable IHC assay results. The large majority of these patients (95.2%) had tumor samples expressing EGFR protein; only 4.8% had tumors without detectable EGFR protein (H-score=0). The STEPP analyses showed no consistent trend or obvious cut-point for the relationship between either OS or PFS with EGFR protein across the range of IHC values when comparing treatment arms. Archived tumor tissue with evaluable results for exploratory EGFR FISH analysis was available for 51.0% of patients (557 of 1093 ITT patients). Of these patients, 208 patients (37.3%) had increased EGFR gene copy number (FISH positive). A trend for greater necitumumab benefit was observed in EGFR FISH positive patients. Treatment HR (95% CI) for FISH positive and negative patients were 0.70 (0.52, 0.96) and 1.02 (0.80, 1.29) for OS, and 0.71 (0.52, 0.97) and 1.04 (0.82, 1.33) for PFS. However, the interaction of EGFR gene copy number gain with treatment was not statistically significant for either OS or PFS (p=0.066 and 0.057, respectively).

      Conclusion:
      The analysis of EGFR protein expression did not identify consistent trends related to efficacy outcomes across the range of IHC values. EGFR gene copy number gain showed a trend for a more favorable HR, but did not appear to be strongly predictive. However, both markers showed some evidence of potential trends that will be investigated further in future trials.

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    ORAL 37 - Novel Targets (ID 146)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL37.07 - Lung Cancer Mutation Consortium Pathologist Panel Evaluation of MET Protein (ID 2129)

      F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background:
      MET is a receptor tyrosine kinase with frequently activated signaling in lung cancers. Multiple studies indicate that MET overexpression correlates with poor clinical prognosis. Tumors with MET amplification and overexpression may respond better to MET inhibitors than tumors with low expression. The prevalence of MET overexpression in lung cancer cohorts has varied from 20%-80%, as has the proportion of patient’s testing positive for prospective clinical trials with entry based on MET overexpression. The Lung Cancer Mutation Consortium (LCMC) Pathologist Panel endeavored to standardize evaluation of MET protein expression with “Round Robin” conferences.

      Methods:
      508 FFPE non-small cell lung cancer specimens were stained by immunohistochemistry for MET protein expression (SP44 antibody, Ventana). Seven pathologists from LCMC sites with specialized training in MET scoring evaluated 78 Aperio-scanned images of MET-stained slides in two successive rounds of 39 different cases per round. The percentage of tumor cells with membranous and/or cytoplasmic staining at different intensities were evaluated with H-scores ranging from 0 to 300. Overall group and individual pathologist’s scores were compared with intraclass correlation coefficients (ICCs). Between rounds, a “Round Robin” teleconference was conducted to review discordant cases and improve consistency of scoring. Steps to improve scoring included: review of a Roche MET training document, sharing pictures of cases with concordant scores (Figure 1), and provision of H&E images for the second round to facilitate identification of tumor areas. Figure 1



      Results:
      The overall average MET H-score for the 78 cases was 165.3 (H-score range: 42.5-279.7). The average H-score was <125 for 14 specimens, 125-175 for 35 specimens, and >175 for 29 specimens. The overall group ICC comparing the consistency of H-scores from all 7 pathologists improved from 0.50 (95% confidence interval: 0.37-0.64, “fair” correlation) for the first scoring round to 0.74 (95% confidence interval: 0.64-0.83, “good” correlation) for the second round. A comparison of the individual pathologist’s ICCs demonstrated improved individual scoring consistency for all seven pathologists between rounds with an average of 0.64 (“moderate” correlation, range 0.43-0.76) for the first round and 0.82 (“almost perfect” correlation, range 0.75-0.93) for the second round.

      Conclusion:
      Development of standardized, reproducible strategies for evaluation of complex biomarkers, such as MET, are critical to clinical trial design. The consistency of scoring for MET protein expression and other biomarkers may be improved by continuous training and communication between pathologists with easy access to H&E images and other visual aids.

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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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      P1.01-071 - Long-Term Tolerability Among IRESSA Clinical Access Program (ICAP) Participants in the United States (US) (ID 780)

      F.R. Hirsch

      • Abstract
      • Slides

      Background:
      Following the gefitinib (IRESSA[®]) NDA voluntary withdrawal, which previously had allowed for limited commercial distribution of IRESSA, gefitinib became available under the IRESSA Clinical Access Program (ICAP) in June 2011. The ICAP continued to provide drug access to patients who were benefiting or had benefited from treatment with gefitinib through restricted distribution (2005-2011) or through a clinical trial that was IRB approved prior to June 2005. ICAP participants constitute a unique subset of cancer patients in whom long-term use of gefitinib can be studied. Consequently, this is the first study to describe long-term safety and tolerability data for an EGFR TKI in cancer patients outside of the clinical trial setting.

      Methods:
      This study utilizes 2 data sources: (1) retrospective patient medical chart review of demographics, including safety and tolerability of prolonged treatment with gefitinib as part of the ICAP; and (2) retrospective review of serious adverse event (SAE) reports in the AstraZeneca safety database, as all ICAP investigators are responsible, per protocol, for reporting all SAEs observed for ICAP participants.

      Results:
      A total of 188 patients were enrolled in the ICAP from 134 sites across the US; 94 patients (50.0%) remain on active treatment. This study aims to include as many sites and patients as feasible. Currently, 46 sites representing 77 patients have agreed to participate; site enrollment and data collection are ongoing. As of July 16, 2015, chart abstractions of 16 patients were completed. These patients have a median age of 68.0 years, are predominantly female (75.0%), non-Hispanic white (87.5%), with a confirmed NSCLC diagnosis (93.8%). More patients received gefitinib in second line (43.8%) followed by first line (37.5%) and third line (18.8%). Median gefitinib duration prior to ICAP initiation was 11.3 years (range 9.1-13.9 years), with median gefitinib duration as part of the ICAP being an additional 3.5 years (range: 0.3-3.8 years). During the ICAP, 93.8% of patients (95% CI: 87.9-99.6) did not experience any dose reductions, interruptions, or discontinuation due to gefitinib-related adverse events. The AstraZeneca Safety Database showed 123 SAEs reported from 54 ICAP patients as of February 26, 2015. The majority of SAEs were consistent with underlying disease conditions and were considered unrelated to gefitinib therapy by investigators. 5.6% of patients (3/54) had potentially causally related SAEs as determined by investigators: one patient had procedure-related bronchitis, lung infection, and exacerbation of preexisting COPD with a fatal outcome; one patient experienced interstitial lung disease, pulmonary alveolar hemorrhage, and acute respiratory and renal failure (patient recovered with sequelae); and one patient developed dermatitis acneiform and pruritus. Of the remaining 51 patients, 20 had fatal outcomes (39.2%). The majority of fatalities (12) had insufficient information to assess cause of death and may have had other alternative causes, including underlying or concurrent diseases (6) and possible disease progression (2).

      Conclusion:
      : Characterization of long-term gefitinib use among this subset of NSCLC patients indicates acceptable long-term tolerability and indicates that some patients have long-term (>10 year) benefit. Clinical and genetic features associated with long-term benefit need further study.

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    P1.06 - Poster Session/ Screening and Early Detection (ID 218)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Screening and Early Detection
    • Presentations: 1
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      P1.06-009 - Volatolomic Signatures to Assess Sensitivity to FGFR Tyrosine Kinase Inhibitors (ID 1711)

      F.R. Hirsch

      • Abstract
      • Slides

      Background:
      Targeted therapy is transforming the treatment of lung cancer. Such therapies are critically dependent on companion diagnostics that can predict the response to therapy. An ideal test is one that is quick, inexpensive, and non-invasive. In this regard, artificial intelligence nanosensor-based devices that profile volatolomic signatures (through volatile organic compounds (VOCs) analysis) have shown exciting potential. Numerous studies have shown cancer cells produce characteristic patterns of VOCs as a byproduct of their metabolism. These patterns can be used to diagnose patients with cancer using exhaled-breath samples. Here we asked whether the VOC patterns emanating from cancer cells could also be used to guide targeted therapy. In particular, we investigated whether lung cancer cell lines known to be sensitive to FGFR tyrosine kinase inhibitors (TKIs) can be distinguished from cell lines known to be resistant using an array of cross reactive, highly sensitive chemiresistors composed of gold nanoparticles (GNP) and carbon nanotubes (CNTs) coated with various recognition layers previously shown to be highly effective at profiling VOCs.

      Methods:
      Fourteen sensitive cell lines having an IC~50~ ≤ 50 nM for Ponatinib and AZD4547 (nonspecific and specific FGFR TKIs, respectively) and 21 resistant cell lines representing small cell and non-small cell lung cancers were cultured in complete media (RPMI 1640, 10% fetal bovine serum, and penicillin/streptomycin) under standard conditions to 50% to 75% confluency. SKC Tenax® TA Adsorbent resin was used to collect the VOCs from the head space of each cell line over a period of 60 to 72 hours. Triplicate measures were collected on each sample along with biological replicates. VOCs were also collected at the same time from control plates containing media only. After thermal desorption, the VOC pattern of each sample was characterized using a chemiresistor array of 36 sensors and 4 features per sensor. A statistical pattern recognition analysis was then conducted using a discriminant function analysis (DFA) algorithm to identify the most informative sensors and features.

      Results:
      We found that sensitive cell lines could be distinguished from resistant cell lines using only 4 sensors and one feature from each (GNP+dodecanethiol, CNT+PAH, GNP+thiol and CNT+β dextrin). Leave-one-out cross validation indicated a sensitivity of 88% for the FGFR TKI-sensitive cell lines with 100% specificity and 92% accuracy. The area under the receiver-operating characteristic curve was 70% and Wilcoxon p-value of 0.06.

      Conclusion:
      Profiling the VOCs emanating from lung cancer cells shows excellent diagnostic potential as a means of gauging initial sensitivity to FGFR1 TKIs. Consequently, this study suggests that the electronic nose devices currently being developed to profile exhaled breath for cancer detection could also play an important role in predicting responses to targeted therapies. Although cell lines are useful for identifying the VOC pattern that predicts the cancer cell response to therapy, they do not necessarily reflect the complexity that occurs in vivo due to interactions with the microenvironment. Therefore, future studies are needed to confirm if these results can be extended to project efficacy in patients assigned to FGFR TKI therapy.

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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: 2
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      P2.04-006 - MiRNA Signature to Assess Sensitivity to FGFR Tyrosine Kinase Inhibitors (ID 1717)

      F.R. Hirsch

      • Abstract
      • Slides

      Background:
      Increased signaling through the FGF/FGFR signaling pathway has been implicated as a driver in a number of different malignancies including lymphomas, prostate cancer, breast cancer, and lung cancer. This pathway also appears to play a role in conferring de novo and acquired resistance to cancers driven by EGFR mutations. Consequently, drugs that inhibit FGFRs are being investigated as potential therapeutics for cancer. Here we screened a large panel of miRNAs as potential predictors of sensitivity to FGFR tyrosine kinase inhibitors (TKIs).

      Methods:
      A panel of 377 miRNAs (Megaplex Card A, Life Technologies) was screened for expression level differences between four lung cancer cell lines that are sensitive (IC~50~< 50 nM) and four lines that are resistant (IC~50~ > 100 nM) to ponatinib (non-specific FGFR TKI) and AZD4547 (FGFR-specific TKI). Expression levels were assayed by RT-qPCR and analyzed using the Statistical Analysis of Microarrays (SAM) method. Thirty-nine miRNAs having an estimated false discover rate (FDR) of zero and large median fold differences (> 8) between the sensitive and resistant lines were selected for signature development. RT-qPCR assays were incorporated into a custom microfluidics card (Life Technologies), which was used to profile the original 8 cell lines and 10 additional sensitive lines and 16 additional resistant lines (34 lines total). Logistic regression was then used to identify the best signature panel for distinguishing sensitive cell lines from resistant.

      Results:
      Univariate analysis indicated three miRNAs (let-7c, miR-338, and miR-218) that differed between the sensitive and resistant lines at p < .05. The best signature panel consisted of let-7c, miR-200a and miR-200b, which gave an area under the receiver operator characteristic (AUROC) curve of 0.90 (95% CI = 0.8 to 1). This performance was nearly as good as using FGFR1 mRNA alone (AUROC = 0.94). The predominant miRNA in our 3-miRNA signature was let-7c, which also exhibited a suggestive additive effect to using FGFR1 as a biomarker (p = 0.09). We also tested whether cell lines with high sensitivity to ponatinib can be made resistant by reducing the high level of let-7c in these lines. We have found that transient transfection of let-7c silencing RNA (Life Technologies) produces a decrease in FGFR1 mRNA levels for some cell lines but not others.

      Conclusion:
      It appears possible to predict sensitivity to an FGFR1 inhibitor using miRNA expression signatures. More studies, however, are needed to confirm the 3-marker signature developed in this study. Modulating let-7c, the predominant predictor within the signature, appears to modulate FGFR1 levels in a manner consistent with altering ponatinib sensitivity. This effect is most likely indirect as the mRNA of FGFR1 does not contain predicted binding sites for let-7c.

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      P2.04-016 - Minority Exon 19 Deletions Also Have Major Response of EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer (ID 2658)

      F.R. Hirsch

      • Abstract
      • Slides

      Background:
      This study points out an issue of PCR methods to detect exon 19 deletions. Exon 19 deletions are most important among exon 18 to 21 EGFR mutations to dictate EGFR tyrosine kinase inhibitors (EGFR-TKIs) therapy in non-small cell lung cancer (NSCLC), and exon 19 deletions and insertions have over 170 species by catalog of somatic mutation in cancer (COSMIC). PCR methods are used for clinical examination, because they are useful, rapid and cost-effective to detect EGFR mutations. Some PCR methods could detect all of exon 19 deletions and insertions, while others could not. We investigated the clinical significance of minority exon 19 deletions, which could not be detected according to the PCR methods, selected majority deletions.

      Methods:
      The study included a series of 73 NSCLC patients, which were treated with EGFR-TKI for recurrent disease after they had undergone surgery from 1992 to 2004. EGFR mutations were detected in 34 (47%) in 73 patients. Sixty patients were evaluable for response, and remaining 13 patients who had taken EGFR-TKI for less than one month. In 60 assessable patients, exon 19 deletions and exon 21 point mutation were detected from 19 patients and 10 patients, respectively. Patients with EGFR mutations had significantly higher response rates to EGFR-TKI than those with wild-type (p=.047), and exon 19 deletions had still rates (p=.024). In 51 samples, including 17 exon 19 deletions and 6 exon 21 mutations, four PCR methods are commonly used in Japan, were performed and compared. PCR-based methods were (1) PCR-Invader for the selected common mutations of exons 18, 19, 20 and 21, and micro capillary electrophoresis for the exhaustive detection of exon 19 deletions and insertions, (2) Peptide nucleic acid-locked nucleic acid (PNA-LNA) PCR clamp for the selected common mutations of exons 18, 19, 20 and 21, and direct sequence for the other mutations, (3) Cycleave PCR for the selected common mutations of exons 18, 20 and 21, and fragment analysis with micro capillary electrophoresis for the exhaustive detection of exon 19 deletions and insertions, (4) Scorpion Amplification Refractory Mutation System (ARMS) for the selected 29 mutations including 19 species of exons 19 deletions and insertions.

      Results:
      All four methods detected 6 exon 21 mutations as L858R point mutation. However, in exon 19 deletions and insertions including over 170 species, only micro capillary electrophoresis detected all 17 exon 19 deletions. PNA-LNA PCR clamp and direct sequence missed one 9 bp short deletion “L747-E749 del”, which had complete response on EGFR-TKI therapy. Scorpion ARMS missed one 24 bp deletion and insertion “T751-I759 del ins S”, which had stable disease for over 3 years on EGFR-TKI therapy.

      Conclusion:
      This study suggests micro capillary electrophoresis is necessary for the exhaustive detection of exon 19 deletions and insertions, and may identify tumors responsive to EGFR-TKIs therapy, especially those with small or unusual deletions.

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    P2.06 - Poster Session/ Screening and Early Detection (ID 219)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Screening and Early Detection
    • Presentations: 1
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      P2.06-007 - A miRNA Signature Derived From Independently Replicated Biomarkers of Non-Small Cell Lung Cancer (ID 1728)

      F.R. Hirsch

      • Abstract
      • Slides

      Background:
      miRNAs have shown exceptional promise as biomarkers of lung cancer; however, no miRNA signatures have yet reached the clinic. Towards developing a signature with a high likelihood of being validated externally for clinical use, we screened a panel of 50 miRNAs shown to be effective biomarkers in at least two previous studies for distinguishing human lung cancer samples from non-cancer samples.

      Methods:
      Sixty tumor-normal pairs (33 adenocarcinoma, 27 squamous cell carcinoma) were used to identify the best-performing combination of 4 miRNAs for distinguishing tumor samples from normal. The miRNA levels were measured by RT-qPCR using Taqman custom-made microfluidics cards and primer pools purchased from Life Technologies. All possible combinations of 4 miRNAs were tested, and best performance was defined as the highest median area-under the receiver operating curve (AUC) obtained from 1000 bootstrap replicates. A second, independent set of 68 tumor-normal samples (half adenocarcinoma, half squamous) was used as a test set, and bootstrapping was used to determine the 95% confidence interval for the AUC.

      Results:
      The median AUC for the top-performing panel of 4 miRNAs in our training set was 0.96. Several other miRNA combinations exhibited AUCs > 0.95 as well. In our test set, the top-performing panel (and only panel tested) exhibited an AUC of 0.97 (0.93, 0.99). This panel consisted of miRs 26a, 145, 183 and 486. miRs 145 and183 have previously been shown, when used individually, to be significant lung tumor biomarkers in at least 4 previous studies; miR-486 has been replicated 8 times.Figure 1



      Conclusion:
      Consistent with previous studies, we’ve identified a panel of 4 miRNAs that shows excellent potential for diagnosing lung tumors. Each of these miRNAs has been replicated as a biomarker of lung cancer in at least two previous studies, suggesting a high likelihood of achieving clinical validation. Several previous studies have also shown that these four miRNAs are potentially useful as biomarkers for diagnosing lung cancer using blood samples, and we are currently pursuing such validation studies.

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    P3.06 - Poster Session/ Screening and Early Detection (ID 220)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Screening and Early Detection
    • Presentations: 1
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      P3.06-008 - Meta-Analysis Criteria Used to Rank Biomarkers for Validation Testing: What Works? (ID 81)

      F.R. Hirsch

      • Abstract
      • Slides

      Background:
      Hundreds of biomarkers are being developed for the screening and early detection of lung cancer. The vast majority, however, even after extensive internal validation, will likely fail during external validation. For biomarkers to reach the clinic, therefore, it’s imperative that external validation studies focus on the most promising candidates. Towards this end, various strategies have been proposed to rank order and prioritize biomarker candidates. These strategies range from simple, highly intuitive ideas to highly sophisticated statistical analyses. To our knowledge, however, none of these strategies has itself been validated externally, which is an important consideration given that each strategy involves making subjective decisions. Here we conducted an independent validation test to assess the performance of the “vote-counting strategy”, a straightforward, commonly used strategy that ranks biomarkers on the basis of three highly intuitive criteria: the number of supporting studies in the literature, the combined sample size in the supporting studies, and the average fold change difference associated with the biomarker.

      Methods:
      We obtained vote-counting biomarker rankings from two recent meta-analyses that together surveyed over 180 miRNAs reported to distinguish lung tumor tissue from normal. We compared the rankings of 50 top candidates and 22 unranked miRNAs to our RT-qPCR results obtained from 45 tumor-normal pairs. We tested for a statistically significant Pearson correlation (r) between biomarker performance and the rankings according to each of the three ranking criteria.

      Results:
      We found that the number of supporting studies in the literature was indeed a statistically significant predictor of biomarker performance (r = 0.44, n = 50, p = .0006). Our results also suggested that markers supported by two studies in the literature had approximately a 50% chance of being confirmed, markers supported by 3 studies about a 67% chance, and markers supported by 6 studies about a 90% chance. Our unranked markers showed only a 5% chance of being confirmed. At the same time, we found that the combined sample size in the supporting studies was not a predictor of biomarker performance (r = 0.11, n = 50, p = 0.29). We also found that the mean fold change associated with each biomarker was not a predictor (r = 0.12, n = 47, p = 0.22) because large fold-change differences were also associated with large amounts of variability between studies.

      Conclusion:
      Considering that vote counting has obvious limitations (such as selection bias, not counting negative votes, and the variation in how different studies define significance) counting the number of supporting studies in the literature appears to work remarkably well for ranking biomarker candidates. On the other hand, using total sample size or mean fold change in the supporting studies to rank biomarker candidates appears to provide little, if any, added value. Our results also indicate a need for external validation testing of the current strategies being used to rank biomarkers across studies.

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    PLEN 04 - Presidential Symposium Including Top 4 Abstracts (ID 86)

    • Event: WCLC 2015
    • Type: Plenary
    • Track: Plenary
    • Presentations: 1
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      PLEN04.01 - A Randomized, Phase III Study Comparing Carboplatin/Paclitaxel or Carboplatin/Paclitaxel/Bevacizumab with or without Concurrent Cetuximab in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC): SWOG S0819 (ID 3612)

      F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background:
      This abstract is under embargo until September 9, 2015 and will be distributed onsite on September 9 in a Late Breaking Abstract Supplement.

      Methods:


      Results:


      Conclusion:


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    PLEN 05 - Opening Ceremony (ID 195)

    • Event: WCLC 2015
    • Type: Plenary
    • Track: Plenary
    • Presentations: 1
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      Welcome to Denver (ID 3647)

      F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    PRC 01 - Press Conference 1 (ID 196)

    • Event: WCLC 2015
    • Type: Press Conference
    • Track: Other
    • Presentations: 1
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      PRC01.01 - Introduction to WCLC, preview of Opening Ceremonies & Daily Theme - Dr. Fred R. Hirsch, IASLC CEO, Congress President, Professor of Medicine and Pathology, University of Colorado (ID 3614)

      F.R. Hirsch

      • Abstract
      • Slides

      Abstract not provided

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    PRC 04 - Press Conference 4 (ID 199)

    • Event: WCLC 2015
    • Type: Press Conference
    • Track: Other
    • Presentations: 1
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      Abstract – EGFR IHC and FISH Correlative Analyses (SQUIRE Trial): Necitumumab + Gemcitabine-Cisplatin vs Gemcitabine-Cisplatin in 1st-Line Squamous NSCLC - Dr. Fred R. Hirsch, IASLC CEO, Congress President, Professor of Medicine and Pathology, University of Colorado (ID 3639)

      F.R. Hirsch

      • Abstract
      • Presentation

      Abstract not provided

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