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F.R. Hirsch

Moderator of

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    JCES01 - Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session (ID 413)

    • Event: WCLC 2016
    • Type: Joint Chinese / English Session
    • Track:
    • Presentations: 28
    • Now Available
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      Abstract Presentations from China Related to Precision Medicine (ID 6819)

      • Abstract

      Abstract not provided

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      Discovering the East: Precision Medicine in China (ID 6811)

      • Abstract

      Abstract not provided

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      Precision Medicine – Perspectives from the West (ID 6815)

      • Abstract

      Abstract not provided

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      JCES01.01 - Breakfast and Informal Networking (ID 6809)

      • Abstract

      Abstract not provided

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      JCES01.02 - Welcome and Introduction (Now Available) (ID 6810)

      F.R. Hirsch, Y.L. Wu, C. Bai

      • Abstract
      • Presentation

      Abstract not provided

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      JCES01.03 - Perspectives on Precision Medicine for Early Stage NSCLC (Now Available) (ID 6812)

      J. Hu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCES01.04 - Liquid Biopsy in Monitoring Dynamic Changes of Driver Genes in Advanced NSCLC (Now Available) (ID 6813)

      Q. Zhou

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Epidermal growth factor receptor (EGFR) activating mutations in the tyrosine kinase domain serve as predictive biomarkers for EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment outcome for patients with advanced non-small cell lung cancer (NSCLC).[1] However, due to the invasive procedures required to obtain tumor tissues, not all patients can provide enough high-quality tissues for EGFR mutation analysis. Circulating free DNA (cfDNA) in plasma provides a noninvasive substitute for tumor tissues. Several studies have reported a concordance rate between tumor and plasma > 90%, even reaching 97%, demonstrating the feasibility of detecting EGFR mutations in cfDNA.[2-4]EGFR mutation status detection in cfDNA has been approved by the European Society for Medical Oncology and by China to be used with EGFR-TKI treatment for NSCLC.[5,6] In addition to providing pretreatment information, plasma-based EGFR mutation detection makes it possible to monitor dynamic changes in this mutation during treatment. Several studies have reported a quantitative change in EGFR mutations during EGFR-TKI treatment by comparing pre- and post-treatment plasma, in which various types of plasma EGFR mutations were found.[7,8] The quantity of the plasma EGFR mutation sometimes decreases, or sometimes decreases slowly or rapidly. Patients whose plasma EGFR mutations decrease rapidly usually exhibit a better response to EGFR-TKI treatment.[8] However, these studies were not based on prospective clinical trials, therefore the number of patients who had serial plasma specimens tested during EGFR-TKI treatments was limited, and very few plasma specimens were collected as part of a pre-planned schedule. The only recent study on plasma EGFR mutation changes based on a prospective clinical trial was reported by Mok et al.[9] In this phase III trial (FASTACT-2), patients received gemcitabine/platinum plus sequential erlotinib or placebo. EGFR mutation-specific cfDNA levels decreased at cycle 3 and increased at the time of disease progression. Positive plasma EGFR mutant DNA at cycle 3 predicted a worse clinical outcome. In this study, the treatment was chemotherapy plus EGFR-TKI or placebo, not EGFR-TKI, and there was no information on the plasma EGFR mutation at other time points except at baseline, cycle 3, and at disease progression. The dynamic changing types of plasma EGFR mutations during the whole course of EGFR-TKI treatment and its correlation with clinical outcomes were not determined. To measure changes of plasma EGFR L858R mutation during EGFR-TKI treatment, and to determine its correlation with the response and resistance to EGFR-TKI, we conducted a study. This study was a pre-planned exploratory analysis of a randomized phase III trial conducted from 2009 to 2014 comparing erlotinib with gefitinib in advanced NSCLC harboring EGFR mutations in tumor (CTONG0901). Serial plasma samples were collected as a pre-planned schedule. This trial was conducted in Guangdong Lung Cancer Institute, China. Totally, 256 patients were enrolled in CTONG0901. One hundred and eight patients harbored L858R mutation in tumors and 80 patients provided serial blood samples as pre-planned scheduled. Patients were randomized to receive erlotinib or gefitinib. Serial plasma L858R in 80 patients was detected using quantitative polymerase chain reaction. Changing types of plasma L858R were analyzed using Ward's Hierarchical Clustering Method. Progression-free survival (PFS) and overall survival (OS) were compared between different types. As a whole, the quantity of L858R decreased and reached the lowest level at the time of best response to EGFR-TKI. In 61 patients, L858R increased to its highest level when disease progressed (Ascend Type), while in 19 patients, L858R maintained a stable level when disease progressed (Stable Type). Median PFS was 11.1 (95%CI, 6.6–15.6) and 7.5 months (95%CI, 1.4–13.6) in patients with Ascend and Stable Types, respectively (P = .023). Median OS was 19.7 (95%CI, 16.5–22.9) and 16.0 months (95%CI, 13.4–18.5), respectively (P = .050). This is the first report finding two different changing types of plasma L858R mutation during EGFR-TKI treatment based on a prospective randomized study. Different changing types were correlated with benefits from EGFR-TKI. The impact of plasma L858R levels at disease progression on subsequent treatment strategy needs further exploration. This study was recently published in Journal of Hematology&Oncology.[10] In summary, liquid biopsy is very promising in monitoring dynamic changes of driver genes in advanced NSCLC, which promotes the development of precision medicine. References 1. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 2009;361(10):947-957. 2. Kimura H, Suminoe M, Kasahara K, et al. Evaluation of epidermal growth factor receptor mutation status in serum DNA as a predictor of response to gefitinib (IRESSA). Br. J. Cancer. 2007;97(6):778-784. 3. Douillard JY, Ostoros G, Cobo M, et al. Gefitinib treatment in EGFR mutated caucasian NSCLC: circulating-free tumor DNA as a surrogate for determination of EGFR status. J. Thorac. Oncol. 2014;9(9):1345-1353. 4. Couraud S, Vaca-Paniagua F, Villar S, et al. Noninvasive diagnosis of actionable mutations by deep sequencing of circulating free DNA in lung cancer from never-smokers: a proof-of-concept study from BioCAST/IFCT-1002. Clin. Cancer Res. 2014;20(17):4613-4624. 5. European Medicines Agency. Summary of Product Characteristics 2014 [EB/OL], 10/14 update. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001016/WC500036358.pdf. 6. Iressa 250mg Leaflet professional China. CN52-086A. 20150203. . 7. Sacher AG, Oxnard GR, Mach SL, et al. Prediction of lung cancer genotype noninvasively using droplet digital PCR (ddPCR) analysis of cell-free plasma DNA (cfDNA). Paper presented at: Journal Of Clinical Oncology 2014. 8. Marchetti A, Palma JF, Felicioni L, et al. Early Prediction of Response to Tyrosine Kinase Inhibitors by Quantification of EGFR Mutations in Plasma of NSCLC Patients. J. Thorac. Oncol. 2015;10(10):1437-1443. 9. Mok T, Wu YL, Lee JS, et al. Detection and Dynamic Changes of EGFR Mutations from Circulating Tumor DNA as a Predictor of Survival Outcomes in NSCLC Patients Treated with First-line Intercalated Erlotinib and Chemotherapy. Clin. Cancer Res. 2015;21(14):3196-3203. 10. Zhou Q, Yang JJ, Chen ZH, et al. Serial cfDNA assessment of response and resistance to EGFR-TKI for patients with EGFR-L858R mutant lung cancer from a prospective clinical trial. Journal of Hematology&Oncology. 2016;9:86.

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      JCES01.05 - New Clinical Trials on Gene Alteration in China (Now Available) (ID 6814)

      S. Lu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCES01.06 - European Perspective Phase I Strategy (Now Available) (ID 6816)

      C. Rolfo

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCES01.07 - North American Perspective (Now Available) (ID 6817)

      P.A. Bunn, Jr.

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCES01.08 - Break (ID 6818)

      • Abstract

      Abstract not provided

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      JCES01.09 - A Comparison of ddPCR and ARMS for Detecting EGFR T790M Status from Advanced NSCLC Patients with Acquired EGFR-TKI Resistance (Now Available) (ID 7053)

      W. Wang, Z. Song, Y. Zhang, Y. Jin

      • Abstract
      • Presentation
      • Slides

      Background:
      To assess the ability of droplet digital PCR and ARMS technology to detect epidermal growth factor receptor (EGFR) T790M mutations from circulating tumor DNA (ctDNA) in advanced non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance. A sensitive and convenient method for detecting T790M mutation would be desirable to direct patient sequential treatment strategy.

      Methods:
      To assess the ability of droplet digital PCR and ARMS technology to detect epidermal growth factor receptor (EGFR) T790M mutations from circulating tumor DNA (ctDNA) in advanced non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance. A sensitive and convenient method for detecting T790M mutation would be desirable to direct patient sequential treatment strategy.To assess the ability of droplet digital PCR and ARMS technology to detect epidermal growth factor receptor (EGFR) T790M mutations from circulating tumor DNA (ctDNA) in advanced non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance. A sensitive and convenient method for detecting T790M mutation would be desirable to direct patient sequential treatment strategy.

      Results:
      A total of 108 patients were enrolled in this study. 108 patient plasma samples were detected by ddPCR and 75 were detected by ARMS. And 16 patients experienced re-biopsy were detected T790M status by ARMS method. 43.7% (47/108) had acquired T790M mutation by ddPCR. In 75 patient plasma samples, comparing ddPCR with ARMS, the rates of T790M mutation were 46.7% (35/75) and 25.3% (19/75) by ddPCR and ARMS, respectively. Of all, 16 patients both had tumor and plasma samples, the T790M mutation rates were 56.3% (9/16) by ARMS in tissue and 50.5% (8/16) by ddPCR in plasma ctDNA. Among them, there were two ctDNA T790M mutations by ddPCR but T790M gene negative in tumor tissue by ARMS method. For all patients, the median PFS and OS were 12.3 months and 32.8 months, respectively. The patients with T790M-positive tumors had a longer time to disease progression after treatment with EGFR-TKIs (median, 13.1 months vs 10.8 months; P=0.010) and overall survival (median, 35.3 months vs 30.3 months; P=0.214) compared with those with T790M-negative patients.

      Conclusion:
      Our study demonstrates dPCR assay provide feasibility and sensitive method in detecting EGFR T790M status in plasma samples from NSCLC patients with acquired EGFR-TKI resistance.And T790M-positive patients have better clinical outcomes to EGFR-TKIs than patients with T790M negative.

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      JCES01.10 - Serial Quantitative Assessment of Plasma Circulating Tumor DNA by Digital NGS in Patients with Lung Cancer (Now Available) (ID 7054)

      Y. Zhao, J. Gong, W. Ma, K.C. Banks, H. Wen, E.H. Moore, R.B. Lanman, T. Li

      • Abstract
      • Presentation
      • Slides

      Background:
      Next generation sequencing (NGS) has been increasingly used in oncology practice but proven practically difficult when serial tumor specimens are needed. The objectives of this study were to determine feasibility and explore clinical utility of serial NGS analyses of circulating tumor DNA (ctDNA) in patients (pts) with advanced solid tumors undergoing treatment.

      Methods:
      ctDNA digital NGS was performed by a CLIA-certified lab (70-gene panel with mutant allele fraction (MAF) quantification). ctDNA results were retrospectively analyzed and decreases/increases/stability of molecular tumor load (MTL) defined here as MAFs of truncal driver mutations were correlated with clinical and radiographic response to treatment (response, progression, or stable disease, respectively).

      Results:
      From Jan 2015 to July 2016, 38 consecutive pts with advanced lung tumors (84% LUAD, 5% LUSC, 5% SCLC, 5% NOS) receiving treatment (Table) had serial ctDNA analyses (median 2, range 2-7). ctDNA alterations were detected at least once in 37 (97.4%) pts. Changes in MTL correlated with or predicted all (95% CI, 82.0-99.8%) radiological and/or clinical responses except for the patient with no genomic alteration detected. MTL results clarified response status when radiographic responses were difficult to assess in 9 (28%) of pts with either complex pleural disease (n=6), pneumonitis during PD-1 inhibitor therapy (2). Two MTL change patterns were observed: 1) clonal changes while receiving targeted therapy, including EGFR (12), ALK (3), MET (2), ERBB2 (2); 2) global changes to PD-1 inhibitors, chemotherapy or radiation. Representative tumor response maps will be presented. Table. Summary of tumor types and cancer treatment.

      Cancer Type Targeted Therapy Immunotherapy Chemotherapy Radiation TOTAL
      LUAD 14 8 7 3 32
      LUSC 1 1 0 0 2
      SCLC 0 0 2 0 2
      NOS 1 0 1 0 2
      All 16 9 10 3 38


      Conclusion:
      Serial liquid biopsies and ctDNA digital NGS are feasible and clinically useful in monitoring MTL and genomic alterations during cancer treatment, especially in situations when radiographic responses are equivocal. Prospective evaluation of impact on clinical decision making is warranted.

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      JCES01.11 - Altered Expression of Programmed Death-Ligand 1 after Neo-Adjuvant Chemotherapy in Patients with Lung Squamous Cell Carcinoma (Now Available) (ID 7055)

      Z. Song, Y. Zhang, X. Yu

      • Abstract
      • Presentation
      • Slides

      Background:
      Programmed death-ligand 1 (PD-L1) is known to be over-expressed in non-small cell lung cancer (NSCLC). However, the impact of chemotherapy on the altered status of PD-L1 expression has not been examined for NSCLC. The present study was intended to examine the impact of neoadjuvant chemotherapy on PD-L1 expression and its prognostic significance in lung squamous cell carcinoma (SCC).

      Methods:
      Matched tumor samples were obtained from SCC patients prior to and after neoadjuvant chemotherapy. The expression of PD-L1 was evaluated by immunohistochemistry. Survival analysis was performed by the Kaplan-Meier method.

      Results:
      A total of 76 eligible SCC patients were recruited. There were 51 males and 25 females with a median age of 60 (39-72) years. The smoking status was former (n=46) and never (n=34). Prior to neoadjuvant chemotherapy, PD-L1 expression was identified in 52.6% (40/76) of SCC patients while 61.8% (47/76) were positive for PD-L1 expression after neoadjuvant chemotherapy . Nine patients switched from negative to positive while another two patients’ samples showed the reverse of the above result. Multivariate analysis demonstrated that postoperative expression of PD-L1 was an independent prognostic factor for overall survival (HR=0.50, P=0.003), but not for PD-L1 expression prior to neoadjuvant chemotherapy.

      Conclusion:
      Neoadjuvant chemotherapy may up-regulate the expression of PD-L1. As compared with the status of PD-L1 expression prior to chemotherapy, the postoperative expression of PD-L1 is a better prognostic factor for overall survival in SCC.

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      JCES01.12 - Discussant Oral Abstracts (Now Available) (ID 6820)

      J.C. Yang

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCES01.13 - Discussant Posters (Now Available) (ID 6821)

      X. Zhang

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCES01.14 - Mutational Profiling of Non-Small-Cell Lung Cancer Patients Resistant to First-Generation EGFR Tyrosine Kinase Inhibitors Using next Generation Sequencing (ID 7056)

      Y. Jin, X. Yu, X. Shi, Y. Zhang, G. Lou

      • Abstract
      • Slides

      Background:
      Patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Although previous research have identified several mechanisms of resistance, the systematic evaluation using next generation sequencing (NGS) to establish the genomic mutation profiles at the time of acquired resistance has not been conducted.

      Methods:
      In our single center, we performed NGS of a pre-defined set of 416 cancer-related genes in a cohort of 97 patients with NSCLC harboring TKI-sensitive EGFR mutations at the time of acquired resistance to first-generation EGFR-TKIs between January 2015 to December 2015.

      Results:
      In 97 samples we found total 345 gene alterations (mean 3.6 mutations per patient, range 1-10). Fifty-six patients (57.7%) still exhibit EGFR-sensitive mutations as pretreatment, 93 patients (95.9%) exhibit at least one mutation except for previous existed EGFR-sensitive mutations. In all the 97 patients, most frequently mutated genes were TP53 (59.8%), T790M (28.9%), TET2 (11.3%), EGFR amplification (10.3%), PIK3CA (8.2%), BIM (8.2%), KRAS (7.2%), APC (7.2%), RB1 (7.2%), HER2 (6.2%), DNMT3A (6.2%) and MET (5.2%).

      Conclusion:
      NGS in this study uncovered many new genetic alterations potentially associated with EGFR TKI resistance and provided information for the further study of drug resistance and corresponding relevant tactics against the challenge of disease progression.

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      JCES01.15 - Analysis of Genomic Alterations and Heterogeneity in Pulmonary Adenoid Cystic Carcinoma by Next-Generation Sequencing (ID 7057)

      M. Li, B. Zhao, P. Deng, L. Cao, H. Yang, Q. Gu, C. Hu

      • Abstract
      • Slides

      Background:
      Pulmonary adenoid cystic carcinoma (PACC) is one of the rare malignancies, that primary from glandular tissues of lung. Currently, the treatment of PACC relies on surgery and local radiotherapy. However the therapy for advanced PACC patients is limited. A larger number of studies demonstrated that advanced PACC patients obtained little benefit from chemotherapy. Moreover, only a few case reports revealed PACC patients were appropriate for target therapy. Using high-flux and high-resolution techniques to detect the genomic alterations of PACC could provide theoretical foundation for the precision therapy of PACC.

      Methods:
      8 PACC patients who received surgical resection between January 2013 to December 2015 were enrolled. The tumor tissues from different locations and blood samples were collected. The oncoscreen[TM] panel by Illumina platform, which utilizing probe hybridization to gathering 287 exon regions and 22 intron regions, were used to detect the gene mutation status of PACC. And the embryonal system mutations were filtered by contrasting the gene mutation status of the leukocytes. The tumor heterogeneity was revealed by comparing the gene mutation status in different areas of the same PACC, and the phylogenetic relationships were analyzed to disclose the evolving and developing progression of PACC.

      Results:
      There were 69 gene mutations together among 8 patients including 29 samples. Each patient has 8.6 mutations averagely. The high-frequency mutations were PAK3-D219E, FBXW7-D112E, TET2-T418I, KAT6A-E796A, and MET-R1005Q. However, the common mutations in other NSCLC, like EGFR, KRAS, ALK, etc., weren’t happened in this group of PACC. In this study, the spatial heterogeneity was discovered in PACC, not only in the mutation site, but also in the mutant abundance. Moreover, the phylogenetic relationships revealed that the clonal evolution and development existed in PACC.

      Conclusion:
      The status of genomic alterations in PACC was different from the other non-small cell lung cancer (NSCLC). PACC showed obvious spatial heterogeneity and clonal evolution.

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      JCES01.16 - A MET Inhibitor in the Treatment of Metastatic Non Small Cell Lung Cancer with MET Amplification (ID 7058)

      T. Zhang, J. Li

      • Abstract
      • Slides

      Background:
      Amplification of the mesenchymal-epithelial transition factor (MET) gene plays a vital role in non-small cell lung cancer (NSCLC). The anti-MET therapeutic strategies are still unclear in epidermal growth factor receptor (EGFR) mutant patients and EGFR-naive patients. Aims of our study are to discuss role of MET amplification in Chinese NSCLC patients, and evaluate the antitumor activity of crizotinib (MET inhibitor) in Chinese NSCLC patients with MET gene amplification.

      Methods:
      From Jun 2015 to Jan 2016, we detected 11 metastatic NSCLC patients with MET amplification by fluorescence in situ hybridization (FISH). MET amplification was defined as gene focal amplification or high polysomy (at least 15% cells with ≥5 copy numbers). Patients with MET de novo amplification received crizotinib, patients with concomitant MET acquired amplification and EGFR mutation received combined therapy of EGFR-tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib, icotinib)and crizotinib. All enrolled subjects received tumor measurement according to RECIST1.1

      Results:
      The frequency of MET de novo amplification was 54.5%(6/11), and that of concomitant MET acquired amplification and EGFR mutation was 45.5%(5/11) respectively. 4 of 6 patients with MET de novo amplification received crizotinib, 2 patients had partial response (PR), 1 patient had stable disease (SD), 1 patient died due to heart disease. Response rate (RR) of crizotinib was 50%(2/4). Encouraging response was observed in one case, a CT scan performed 31 days after starting crizotinib revealed 42.2% decrease in tumor measurement, until now, a 7-month CT revealed 60.0% decrease. 3 of 5 patients with concomitant MET acquired amplification and EGFR mutation received the combined therapy of EGFR-TKIs and crizotinib. 1 patient achieved PR, 2 patients had SD. RR of combined therapy was 33.3%(1/3). Dramatic response was observed in one case with combined therapy, a 2-month CT revealed 31.0% decrease in tumor measurement.

      Conclusion:
      According to our study, patients with MET amplification benefited from crizotinib, and RR was inspiring. Patients with concomitant MET acquired amplification and EGFR mutation need combined targeted therapy.

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      JCES01.17 - A Phase I Dose Expansion Study of Epitinib to Evaluate Efficacy and Safety in EGFR Mutation Positive (EGFRm+) NSCLC Patients with Brain Metastasis (ID 7059)

      Q. Zhou, B. Gan, Q. Hong, M. Wang, X. Liu, L. Yuan, Y. Hua, H. Ren, W. Su, Y.L. Wu

      • Abstract
      • Slides

      Background:
      A significant portion of patients with non-small cell lung cancer (NSCLC) develop brain metastasis. Patients with brain metastasis suffer from poor prognosis with a median survival of less than 6 months and low quality of life with limited treatment options. First generation EGFR tyrosine kinase inhibitors (EGFR TKIs) have demonstrated significant clinical benefit for patients with EGFR-mutant NSCLC. However, their effect on brain metastasis is limited due to poor drug penetration into the brain. Epitinib is an EGFR TKI designed to improve brain penetration. A Phase I dose escalation study on epitinib has been completed and the recommended Phase 2 dose (RP2D) determined (Y-L Wu, 2016 ASCO). This Phase I dose expansion study was designed to evaluate the efficacy and safety of epitinib in EGFR-mutant NSCLC patients with brain metastasis.

      Methods:
      This is an ongoing open label, multi-center Phase I dose expansion study. EGFR-mutant NSCLC patients with confirmed brain metastasis, either prior EGFR TKI treated or EGFR TKI treatment naïve, were enrolled to receive oral epitinib 160 mg per day. Patients with extra-cranial disease progression while on treatment with an EGFR TKI were excluded. Tumor response was assessed per RECIST 1.1.

      Results:
      As of 31 May, 2016, 27 patients (13 EGFR TKI pretreated, 14 EGFR TKI treatment naïve) have been enrolled and treated with epitinib. The most frequent adverse events (AEs) were skin rash (89%), elevated ALT (41%)/AST (37%), hyper-pigmentation (41%) and diarrhea (30%). The most frequent Grade 3/4 AEs were elevations in ALT (19%), gamma-GGT (11%), AST (7%), hyperbilirubinemia (7%) and skin rash (4%). There have been no Grade 5 AEs to date. Among the 24 efficacy evaluable patients (11 TKI pretreated, 13 TKI naïve), 7 (7/24, 29%) achieved a partial response (PR), including 1 unconfirmed PR. All PRs occurred in EGFR TKI treatment naïve patients (7/13, 53.8%). Of the 24 evaluable patients, 8 (5 EGFR TKI treatment naïve, 3 EGFR TKI pretreated) had measurable brain metastasis (lesion diameter>10 mm per RECIST 1.1) with 2 PRs (both EGFR TKI treatment naïve patients, 2/5, 40%).

      Conclusion:
      Epitinib 160mg per day treatment in EGFR-mutant NSCLC patients with brain metastasis demonstrated clinical activity both extra- and intra-cranial. Epitinib was well tolerated. The data to date appears encouraging and warrants further development of epitinib.

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      JCES01.18 - Dual Positive PD-L1 and CD8+ TIL Represents a Predominant Subtype in NSCLC and Correlates with Augmented Immunogenicity (ID 7060)

      S. Liu, Z. Dong, W. Zhong, S. Wu, Z. Xie, H. Tu, Y.L. Wu

      • Abstract
      • Slides

      Background:
      Recent studies have identified that the degree of tumor infiltrating lymphocyte (TIL) infiltration and PD-L1 expression in the tumor microenvironment (TME) are significantly correlated with the clinical outcomes of anti-PD-1/PD-L1 therapies. Here we conducted this study to verify the distribution of PD-L1/CD8[+] TIL expression and its clinical significance in non-small cell carcinoma (NSCLC). Potential mechanism predicted for PD-1 blockade was explored in depth as well.

      Methods:
      Immunohistochemistry was performed to detect PD-L1 and CD8 expression in NSCLC. The Kaplan–Meier (KM) survival curve was used to estimate disease free survival (DFS) and overall survival (OS). Gene Set Enrichment Analysis (GSEA) was used to determine potentially relevant gene expression signatures.

      Results:
      288 cases with stage I-IIIA NSCLC were evaluated for PD-L1 and CD8+ TIL staining. Dual positive PD-L1 and CD8 (PD-L1+/CD8+) represents a predominant subtype in NSCLC, accounting for 36.5% (105/288), followed by PD-L1-/CD8- (24.3%, 70/288), PD-L1-/CD8+ (26.0%, 75/288) and PD-L1+/CD8- (13.2%, 38/288). Survival analysis of DFS (p=0.031) and OS (p=0.002) showed a significant difference between four subgroups. Furthermore, we analyzed the correlation between expression types of PDL1/CD8 and mutation burden and angtigen presentation. We can identified dual positive PD-L1 and CD8 was significant with increased mutation burden (p<0.001), high frequency of mismatch repair (MMR) related gene mutation. More interestingly, tumor with dual positive PD-L1 and CD8 manifested a remarkable activated angtigen presentation and T cell receptor signature compared with other subgroups.

      Conclusion:
      Dual positive PD-L1 and CD8 was identified as a predominant subtype in NSCLC and correlates with increased immunogenicity. These findings provide the evidence that combined analysis of PD-L1 and CD8 in NSCLC may be a promising way to predict PD-1 blockade immunotherapy.

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      JCES01.19 - Clinicopathologic Characteristics, Genetic Variability and Therapeutic Options of RET Rearrangement Patients in Lung Adenocarcinoma (ID 7061)

      Z. Song, X. Yu, Y. Zhang

      • Abstract
      • Slides

      Background:
      RET fusion gene is identified as a novel oncogene in a subset of non-small cell lung cancer (NSCLC). However, few data are available about the prevalence, clinicopathologic characteristics, genetic variability and therapeutic options in RET-positive lung adenocarcinoma patients.

      Methods:
      For 615 patients with lung adenocarcinoma, RET status was detected by reverse transcription-polymerase chain reaction (RT-PCR). Next-generation sequencing (NGS) and FISH were performed in positive cases. Thymidylate synthetase (TS) mRNA level was assayed by RT-PCR. Overall survival (OS) was evaluated by Kaplan-Meier method and compared with log-rank test.

      Results:
      Twelve RET-positive patients were identified by RT-PCR. However, one patient failed the detection of RET arrangement by FISH and NGS. Totally, 11 patients (1.8%) confirmed with RET rearrangements by three methods , including six females and five males with a median age of 54 years. The presence of RET rearrangement was associated with lepidic predominant lung adenocarcinoma subtype in five of 11 patients. RET rearrangements comprised of nine KIF5B–RET and two CCDC6–RET fusions. Four patients had concurrent gene variability by NGS detection,including EGFR(n=1),MAP2K1 (n=1), CTNNB1 (n=1) and AKT1 (n=1) . No survival difference existed between RET-positive and negative patients (58.1 vs. 52.0 months, P=0.504) . The median progression-free survival of first-line pemetrexed/platinum regimen was 7.5 months for four recurrent cases,and longer than RET-negative patients(7.5 vs.5.0 months, P=0.026). . The level of TS mRNA was lower in RET-positive patients than that in those RET-negative counterparts (239±188×10[-4] vs. 394±457×10[-4],P=0.019) .

      Conclusion:
      The prevalence of RET fusion is approximately 1.8% in Chinese patients with lung adenocarcinoma. RET arrangement is characterized by lepidic predominance and a lower TS level. RET-rearranged patients may benefit more from pemetrexed-based regimen.

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      JCES01.20 - Patients with ROS1 Rearrangement Positive Non-Small Cell Lung Cancer Benefit from Pemetrexed-Based Chemotherapy (ID 7062)

      Z. Song, Y. Zhang, X. Yu

      • Abstract
      • Slides

      Background:
      ROS1 gene-rearrangement in non-small cell lung cancer (NSCLC) patients has recently been identified as a driver gene and benefited from crizotinib treatment. However, no data is available for ROS1-positivity NSCLC about chemotherapeutic options and prognostic data. We investigated pemetrexed-based treatment efficacy in ROS1 translocation NSCLC patients and determined the expression of thymidylate synthetase (TS) to provide a rationale for the efficacy results.

      Methods:
      We determined the ROS1 status of 1750 patients with lung adenocarcinoma. Patients’ clinical and therapeutic profile were assessed. In positive cases, thymidylate synthetase (TS) mRNA level was performed by RT-PCR. For comparison, we evaluated the TS mRNA status and pemetrexed-based treatment efficacy from 170 NSCLC patients with anaplastic lymphoma kinase (ALK) translocation(n=46), EGFR mutation (n=50), KRAS mutation (n=32) and wild-type of EGFR/ALK/ROS1/KRAS (n = 42).

      Results:
      Thirty-four ROS1 translocation patients were identified at two institutions. Among the 34 patients, twelve with advanced stage or recurrence were treated with pemetrexed-based first-line chemotherapy. The median progression-free survivals of pemetrexed-based first-line chemotherapy in ROS1 translocation, ALK translocation, EGFR mutation, KRAS mutation and EGFR/ALK/ROS1/KRAS wild-type patients were 6.8, 6.7, 5.2, 4.2 and 4.5 months, respectively (P=0.003). The TS mRNA level was lower in patients with ROS1-positive than ROS1-negative patients (264±469×10[-4] vs. 469 ± 615×10[-4] , P=0.03), but similar with ALK-positive patients (264±469×10-4 vs. 317±524×10[-4], P=0.64).

      Conclusion:
      Patients diagnosed with ROS1 translocation lung adenocarcinoma may benefit from pemetrexed-based chemotherapy. TS mRNA level enables the selection of therapeutic options for ROS1translocation patients.

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      JCES01.21 - Molecular Profiling and Survival of Primary Pulmonary Neuroendocrine Carcinoma with Completely Resection (ID 7063)

      G. Lou, Z. Song, Y. Zhang

      • Abstract
      • Slides

      Background:
      According to the 2015 World Health Organization classification of lung tumors, pulmonary Large cell neuroendocrine carcinoma (PLCNC) is grouped with the small cell lung cancer (SCLC) and carcinoid as pulmonary neuroendocrine carcinoma(PNC) for the common features of neuroendocrine characteristics . Molecular profiles and prognosis of primary pulmonary neuroendocrine carcinoma(PNC) are not well investigated currently. We conducted present study to evaluate genomic abnormality and survivals in patients with primary PNC.

      Methods:
      Tumor samples of PNC after completely resection from Zhejiang Cancer Hospital were collected from 2008 to 2015. Nine driver genes including six mutation (EGFR, KRAS, NRAS, PIK3CA, BRAF, HER2) and three fusions (ALK, ROS1, RET) were evaluated by RT-PCR. Survival analysis was evaluated using the Kaplan-Meier method.

      Results:
      Totally, 108 patients with pathologic confirmed PNC were enrolled. Samples included 52 PLCNC, 44 small cell lung cancer (SCLC) and 12 carcinoid. Twelve patients were found to harbor genomic aberrations (11.1%). The most frequent gene abnormality was PIK3CA (n=5,4.6%),followed with EGFR (n=3,2.8%), KRAS (n=2,n=1.9%), ALK (n=1,0.9%), RET (n=1,0.9%). No ROS1,BRAF,NRAS and HER2 mutations were observed. The frequencies of gene aberrations in PLCNC, SCLC and carcinoid were 15.4%,6.8% and 8.3%,respectively. Sixty-seven patients were with recurrence or metastasis after surgery, including 32 PLCNC, 33 of SCLC, and two of carcinoid (both were atypical carcinoid). Among the 32 patients with PLCNC,none received molecular targeted treatment,28 received first-line chemotherapy,including 18 of etoposide/platinum regimen and 10 of other platinum-based treatment. The progression free survival in patients with etoposide/platinum regimen was longer than patients with non-etoposide/platinum treatment (4.8 vs.3.4 months,P=0.019) . Survival difference was observed among the PLCNC,SCLC and carcinoid group (37.0 vs. 34.0 vs.not reached, P=0.035), but no difference existed between the PLCNC and SCLC group (P=0.606).

      Conclusion:
      Common genomic abnormality is rare in PNC patients and most frequently observed in PLCNC. Patients with carcinoid had a superior survival than PLCNC and SCLC.

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      JCES01.22 - Comparison of Four Leading Technologies for Detecting EGFR Mutations in Circulating Tumor DNA from Patients with Non-Small Cell Lung Carcinoma (ID 7064)

      X. Kang, T. Xu, G. Xu, K. Chen

      • Abstract
      • Slides

      Background:
      This study aimed to assess the ability of different technology platforms to detect epidermal growth factor receptor (EGFR) mutations including L858R, E19-dels, T790M, and G719X from circulating tumor DNA (ctDNA) in patients with non-small cell lung cancer (NSCLC).

      Methods:
      Plasma samples were collected from 20 patients with NSCLC including detailed clinical information along with data regarding treatment response. ctDNA was extracted from 10 mL plasma using the QIAamp Circulating Nucleic Acid Kit (Qiagen). Extracted ctDNA was analyzed using two real time-amplification refractory mutation system-quantitative PCR platforms (cobas® EGFR Mutation Test: cobas; and AmoyDx® EGFR 29 Mutations Detection Kit: ADx), one digital platform (Droplet Digital[TM] PCR, ddPCR: Bio-rad), and one next-generation sequencing platform (firefly NGS: Accuragen).

      Results:
      If a positive result was obtained from any one of the four platforms, the sample was categorized as positive. We identified 15 EGFR mutations in 20 patients with NSCLC using the four platforms, for which 7, 11, 10, and 12 mutations were detected by ADx, cobas, ddPCR, and firefly NGS, respectively. Among the 15 EGFR mutations, six and seven EGFRalterations demonstrated an allele frequency of more or less than 1% (group A or B, respectively), and two exhibited unknown allele frequency. In group A, 5, 5, 5, and 6 EGFR mutations were detected by ADx ,cobas, ddPCR, and firefly NGS, respectively. The positive coincidence rate of any two platforms ranged from 66.7% to 100% and the kappa value varied from 0.787 to 1.000 in group A. In group B, 1, 5, 5, and 6 EGFR mutations were detected and the positive coincidence rate of any two platforms ranged from 16.7% to 100% and the kappa value varied from 0.270 to 1.000. The output of cobas, ddPCR, and firefly NGS were highly correlated, whereas ADx displayed weak concordance with these three platforms in group B. In addition, we identified 75 wild-type loci when EGFR alleles identified as negative by one or more platforms were considered as negative. ADx, cobas, ddPCR, and firefly NGS uncovered 73, 69, 70, and 68 EGFR wild-type loci, respectively. The concordance and negative coincidence rates between any two platforms were over 90%.

      Conclusion:
      The detection rate and concordance were probably affected by the abundance of EGFR mutations and the sensitivity of different platforms. Three platforms, including cobas, ddPCR, and firefly NGS, exhibited higher positive coincidence and detection rates when the allele frequency was lower than 1%.

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      JCES01.23 - EGFR Mutation Status Analysis in Cerebrospinal Fluid and Plasma of Advanced Lung Adenocarcinoma with Brain Metastases (ID 7065)

      L. Shi, Z. Liu, J. Tang, H. Wu, L. Guo, M. Li, L. Tong, W. Wu, H. Tao, W. Wu, H. Li, Q. Meng, L. Xu, Y. Zhu

      • Abstract
      • Slides

      Background:
      We aimed to investigate the feasibility of droplet digital PCR (ddPCR) for the detection of epidermal growth factor receptor (EGFR) mutations in circulating free DNA (cfDNA) from cerebrospinal fluid (CSF) and plasma of advanced Lung Adenocarcinoma (ADC) with brain metastases (BM).

      Methods:
      Fourteen advanced ADC patients with BM carrying activating EGFR mutations in tumour tissues were enrolled in this study, and their matched CSF and plasma samples were collected. EGFR mutations were detected by the Amplification Refractory Mutation System (ARMS) in tumour tissues. EGFR mutations, including 19del, L858R, and T790M were examined in cfDNA isolated from 2milliliter CSF or plasma by ddPCR assay. The clinical response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. Overall survival (OS) and progression free survival (PFS) after the diagnosis of BM were also evaluated.

      Results:
      Out of 14 patients, eleven were females and three males aged from 34 to 74 years old (median age of 55 years old). In all of cases, CSF cytology were negative. In ddPCR assays, EGFR mutations were detected in CSF of three patients (21.4%; one of 19del and two of L858R), and in plasma of six patients (42.9%; one of 19del, one of L858R, one of T790M, two of L858R&T790M, and one of 19del&T790M). All EGFR T790M mutations were found during or after EGFR-TKIs treatments. The three patients with activating EGFR mutations in CSF achieved partial response (PR) of BM after treated with combination of WBRT and EGFR-TKIs. The median OS and PFS after the diagnosis of BM were 18.0 months and 9.0 months, respectively.

      Patient Tissue EGFR CSF EGFR Plasma EGFR Systematic Treatment BM Treatment
      1 19del WT T790M Erotinib+Chemotherapy WBRT+Gamma knife
      2 19del WT 19del Erotinib+Chemotherapy WBRT
      3 L858R L858R L858R Gefitinib+Chemotherapy WBRT
      4 L858R WT WT Gefitinib+Chemotherapy WBRT
      5 19del WT WT Gefitinib+Chemotherapy WBRT
      6 L858R WT L858R/T790M Erotinib+Chemotherapy WBRT
      7 L858R WT WT Gefitinib WBRT
      8 19del 19Del 19Del/T790M Gefitinib WBRT
      9 L858R WT WT Erotinib+Chemotherapy NONE
      10 19del WT WT Erotinib+Chemotherapy WBRT
      11 19del WT WT Icotinib+Chemotherapy WBRT
      12 L858R WT L858R/T790M Chemotherapy WBRT
      13 L858R L858R WT Icotinib WBRT
      14 19del WT WT Gefitinib+Chemotherapy WBRT


      Conclusion:
      It was feasible to test EGFR mutation in CSF. CSF may serve as liquid biopsy of advanced ADC with BM by enabling measurement of cfDNA within CSF to characterize EGFR mutations.

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      JCES01.24 - Molecular Mechanism of Transformation from Adenocarcinoma to Small-Cell Lung Cancer after EGFR-TKI (ID 7066)

      J. Han, Q. Zhang, B. Wang, Q. Zhou, L. Yan, Z. Zhang, H. Chen, J. Su, Z. Xie, F. Niu, Y.L. Wu, S. Chuai, J. Yang, Z. Dong

      • Abstract
      • Slides

      Background:
      In patients with advanced non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations, EGFR-tyrosine kinase inhibitors (TKIs) are recommended as first-line treatment due to favorable clinical efficacy. However, acquired resistance inevitably develops after median progression-free survival (PFS) of 9-14 months. Among the mechanisms of acquired resistance, small-cell lung cancer (SCLC) transformation was reported to account for nearly 5%. However, the molecular details underlying this histological change and resistance to EGFR-TKI therapy remain unclear.

      Methods:
      15 out of 233 (6.4%) patients were confirmed to develop SCLC transformation after failure to EGFR-TKI. We analyzed the clinical parameters of these patients by using chi-square test and Kaplan-Meier analysis. To explore gene alterations that might contribute to SCLC transformation, next generation sequencing (NGS) was performed on four pairs of matched pre- and post-transformation tumor tissue samples. We further performed NGS on 11 matched circulating tumor DNA (ctDNA) to explore the potential mechanism of resistance to EGFR-TKI.

      Results:
      The median age of SCLC transformed patients was 53 years. 93.3% (14/15) patients harbored EGFR exon19 deletion. The median PFS and overall survival (OS) of SCLC-transformed patients treated with EGFR-TKI compared to those without transformation were 11.7 versus 11.9 months (P=0.473) and 29.4 versus 24.3 months (P=0.664), respectively. All 4 patients developed loss of heterozygosity of TP53/RB1 after transformation. Besides, increased copy number of five proto-oncogenes were identified in post-transformation tissue samples. Three patients developed EGFR T790M mutation in the post-transformation ctDNA rather than their tissue samples.

      Conclusion:
      SCLC transformation was commonly seen in patients harboring EGFR exon 19 deletion. The clinical outcomes of TKI and OS in SCLC transformed patients were similar to non-transformed patients. The loss of heterozygosity of TP53 and RB1along with increased copy number of proto-oncogenes may lead to the SCLC transformation. The mechanisms of acquired resistance to TKI during SCLC transformation might be the emergence of classic drug resistance mutations, which was undetectable due to the intra-tumor heterogeneity.

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      JCES01.25 - Closing Remarks (Now Available) (ID 6822)

      • Abstract
      • Presentation

      Abstract not provided

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    PL02a - Distinguished Lecture (ID 480)

    • Event: WCLC 2016
    • Type: Plenary
    • Track:
    • Presentations: 1
    • Now Available
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      Welcome Address (Now Available) (ID 7160)

      H. Fischer

      • Abstract
      • Presentation

      Abstract not provided

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    PL04b - Plenary Keynote Lecture (ID 489)

    • Event: WCLC 2016
    • Type: Plenary
    • Track:
    • Presentations: 1
    • Now Available
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      PL04b.01 - The Role of Doctors in a Globalized World (Now Available) (ID 6896)

      • Abstract
      • Presentation

      Abstract not provided

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Author of

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    IASLC Business Meeting (ID 450)

    • Event: WCLC 2016
    • Type: Networking Opportunity
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 12/06/2016, 02:30 PM - 03:00 PM, Schubert 2
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      Travel Award Winners (ID 7286)

      F.R. Hirsch

      • Abstract
      • Slides

      Abstract not provided

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      WCLC 2016 Business Meeting Awards (ID 7287)

      F.R. Hirsch

      • Abstract
      • Slides

      Abstract not provided

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    JCES01 - Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session (ID 413)

    • Event: WCLC 2016
    • Type: Joint Chinese / English Session
    • Track:
    • Presentations: 1
    • Now Available
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      JCES01.02 - Welcome and Introduction (Now Available) (ID 6810)

      F.R. Hirsch

      • Abstract
      • Presentation

      Abstract not provided

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    MA15 - Immunotherapy Prediction (ID 400)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 2
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      MA15.03 - The Predictive Value of Mutation/Neoantigen Burden from ctDNA on the Efficacy of PD-1 Blockade in Advanced NSCLC (ID 5884)

      F.R. Hirsch

      • Abstract
      • Slides

      Background:
      Immune checkpoint, PD-1, inhibitors, have been approved to treat advanced NSCLC patients without oncogenic driver in the second-line setting based on durable clinical benefit. It has been demonstrated that the overall mutational burden in tumor tissue was significantly associated with progression free survival (PFS) of advanced NSCLC patients treated with PD-1 inhibitor. However, tumor tissue may not be available from all patients at any time during PD-1 blockade therapy. Therefore, the purpose of this study was to explore the predictive value of mutation/neoantigen burden from ctDNA on efficacy of PD-1 inhibitors.

      Methods:
      We treated advanced NSCLC patients without oncogenic drivers with PD-1 inhibitor in the second or more line setting. The whole-exome of tumor tissues and ctDNA at baseline and ctDNA at every time of efficacy evaluation from these patients were sequenced by NGS. The hybrid-capture-enriched libraries were sequenced on the Illumina HiSeq 4000 platform with 75-base paired-end reads, sequencing depth was 300 for ctDNA whole-exome sequencing. We compared the results of whole-exome sequencing between patients who achieved objective response to PD-1 inhibitor and patients who experienced disease progression. Besides, we also compared the results of whole-exome sequencing between baseline ctDNA and ctDNA extracted at efficacy evaluation.

      Results:
      Up to now, a total of 23 patients treated with PD-1 inhibitor received efficacy evaluation at least once in this study. Of them, 4 patients achieved partial response (PR), 3 patients achieved stable disease (SD). Of 4 patients with PR, 3 patients were found to harbor high mutation burden (more than 400 nonsynonymous mutations) from ctDNA and only 1 patient harbored mutation burden of less than 100 from ctDNA at baseline. We found the mutation or neoantigen burden from ctDNA changed during PD-1 blockade therapy. The efficacy of PD-1 inhibitor appeared to be more significantly associated with neoantigen burden rather than mutation burden. Only one ctDNA sample was found positive for MSH6 mutation (C1337X) and all baseline ctDNA samples were negative for microsatellite instability (MSI) status.

      Conclusion:
      Evaluating nonsynonymous mutation burden/neoantigen burden from ctDNA was feasible in advanced NSCLC patients treated with PD-1 inhibitors. The predictive value of neoantigen burden from ctDNA on the efficacy of PD-1 inhibitor may be better than that of mutation burden in advanced NSCLC. It may not be feasible to determine the status of mismatch-repair deficiency and MSI using ctDNA samples in advanced NSCLC. An expanded study is ongoing. More details will be presented in the conference.

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      MA15.11 - Acquired Resistance Mechanisms to EGFR Kinase Inhibitors Alter PD-L1 Expression Status in Lung Cancer (ID 4652)

      F.R. Hirsch

      • Abstract
      • Slides

      Background:
      Immunotherapies that target PD-1/PD-L1 exploit the primary roles of cytotoxic agents in lung cancers. However, tyrosine kinase inhibitors (TKIs) are still considered to be the first choice in lung cancer patients with EGFR mutations. Although immunotherapies may be applied as second line or later therapeutic approaches in these patients, after acquisition of resistance to EGFR-TKIs, it is unclear if acquired resistance mechanisms alter PD-L1 expression status that is employed as an important predictive biomarker for PD-1/PD-L1 targeting agents.

      Methods:
      Lung cancer cell lines with EGFR mutations (HCC827, HCC4006, PC9, and H1975) and their isogenic descendants with acquired resistance to various EGFR-TKIs were examined in this study. The resistance mechanisms of descendants include T790M secondary mutation, MET gene amplification, epithelial to mesenchymal transition (EMT), and loss of amplified EGFR mutant allele. PD-L1 expression status was analyzed by immunohistochemistry (IHC) and immunoblotting. Effects of acquired resistance mechanisms on PD-L1 expression were also evaluated by shRNA mediated knockdown of candidate molecules, and co-localization analysis using fluorescent imaging. IFN-gamma was used to mimic immune cell attack. Published microarray data of cells with acquired resistance to EGFR-TKIs were also employed to evaluate our findings.

      Results:
      PD-L1 expression was upregulated in several resistant cells and correlated with EGFR activation. In addition, we found that the phosphorylation of EGFR tyrosine (Y) 992 site, but not Y845, Y1068, or Y1173, was correlated with increased expression of PD-L1. We also observed that TKI-resistant cells with marked E-cadherin downregulation (HCC4006 erlotinib resistant cells and H1975 osimertinib resistant cells), one of hallmarks of EMT, showed decreased expression of PD-L1. However, one cell line (853#10), displaying EMT-like phenotype but only slight E-cadherin downregulation, showed PD-L1 upregulation. Published microarray data from three TKI-resistant lines with EMT-like features also support the correlation of low E-cadherin and reduced PD-L1 expression. ShRNA mediated knockdown of E-cadherin decreased the expression of PD-L1 in parental cell lines. IFN-gamma treatment upregulated PD-L1 expression in both parental and in resistant cells with E-cadherin downregulation, however PD-L1 expression in resistant cells was still lower and localized mainly in the cytoplasm rather than the cell membrane.

      Conclusion:
      We observed a dramatic change of PD-L1 expression status in lung cancers with EGFR mutation after acquisition of resistance to EGFR-TKIs, depending on the resistance mechanisms. These results support the importance of re-biopsy after acquisition of resistance to EGFR-TKIs, not only for the resistance mechanisms but also for the evaluation of PD-L1 expression status.

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    MA16 - Novel Strategies in Targeted Therapy (ID 407)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
    • Now Available
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      MA16.10 - Lung-MAP (S1400) Lung Master Protocol: Accrual and Genomic Screening Updates (Now Available) (ID 3995)

      F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung-MAP (S1400), is a master protocol that incorporates genomic testing of tumors through a next generation sequencing (NGS) platform (Foundation Medicine) and biomarker-driven (matched) therapies for patients with squamous cell lung cancer (SCCA) after progression on first-line chemotherapy.

      Methods:
      The Lung-MAP trial, activated June 16, 2014, includes 3 matched- and 1 non-match study. Matched studies include: S1400B evaluating taselisib, a PI3K inhibitor, S1400C evaluating palbociclib, a CDK 4/6 inhibitor and, S1400D evaluating AZD4547, an FGFR inhibitor. The non-match study S1400I tests nivolumab + ipilimumab vs. nivolumab. Two studies have closed: S1400E evaluating rilotumumab an HGF monoclonal antibody + erlotinib closed 11/26/2014 and S1400A evaluating MEDI4736 in non-match pts, closed 12/18/2015.

      Results:
      From June 16, 2014 to June 15, 2016, 812 pts were screened and 292 pts registered to a study: 116 to S1400A, 27 to S1400B, 53 to S1400C, 32 to S1400D, 9 to S1400E and 55 to S1400I. Demographics: Screening was successful for 705 (87%) of screened eligible pts. Median age 67 (range 35-92); male 68%; ECOG PS 0-1 88%, PS 2 10%; Caucasian 85%, Black 9%, other 5%; never/former/current smokers 4%/58%/36%. Table 1 displays biomarker prevalence; 39% of pts matched; 33.9%, 4.8%, and 0.3% with 1, 2, and all 3 biomarkers, respectively. Tumor mutation burden (TMB) was available for 636 (90.4%) of eligible pts. The distribution of TMB is: 126 (19.8%) low (≤5 mutations Mb), 415 (65.1%) intermediate (6-19 mutations/Mb), and 96 (15.1%) high (≥20 mutations/Mb). The median TMB was 10.1.

      Conclusion:
      Genomic screening is feasible as part of this master protocol designed to expedite drug registration, confirm anticipated prevalence of targeted alterations in SCCA and reveal intermediate or high TMB in most (80.2%) pts. Treatment results are not yet available as patients continue to accrue. Clinical trial information: NCT02154490

      Total FGFR CDK PIK3CA
      FGFR (15.9%) 12.9% 2.4% 0.6%
      CDK (18.8%) 14.6% 1.8%
      PIK3CA (8.8%) 6.4%
      Biomarker prevalence and overlap.


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    OA19 - Translational Research in Early Stage NSCLC (ID 402)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Early Stage NSCLC
    • Presentations: 1
    • Now Available
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      OA19.01 - A Standardized and Validation of Prognostic Gene Expression Signatures for Squamous Cell Lung Carcinoma by the SPECS Lung Consortium (Now Available) (ID 4329)

      F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background:
      High-throughput gene expression profiling led to proposal of multiple expression-based prognostic signatures for squamous cell lung carcinoma (SCC), but none has been validated. A multi-institutional squamous lung cancer consortium of investigators is developing prognostic signatures through the US NCI Lung SPECS (Strategic Partnership for Evaluation of Cancer Signatures) program. Six institutions contributed tumor specimens and published/unpublished expression-based prognostic signatures for validation using standardized sample cohorts (a primary validation cohort comprising institutional cases, and additional validation cohorts from two prospective cooperative group studies) and quality controlled assessment in independent laboratory and statistical cores. Here, we report the results of the primary validation.

      Methods:
      Cases of primary SCC (by central pathology review) meeting clinical (Stage I-II; surgical treatment only; 3-year followup) and specimen quality criteria (Tumor cellularity >= 50%; necrosis <= 20%) were submitted. Clinical, pathological and outcome data were uploaded to a central database. Frozen tumor samples underwent centralized mRNA extraction (Qiagen Symphony), quality control (RIN >= 6.0) and microarray profiling (Affymetrix U133) in core labs. An independent statistical core assessed validation of 7 pre-existing mRNA signatures and generated new models using MCP clustering.

      Results:
      Among 250 cases meeting entry criteria, median age was 70 (43-92), 161 (65%) were male, and most were former (70%) or current (28%) smokers. Surgery was pneumonectomy: 5%; bilobectomy: 2%; lobectomy: 74%; sublobar: 18%. Pathologic staging was T1: 49%; T2: 50%; T3: 1%; N0: 88%; N1: 12%, and grade was G1: 4%; G2: 50%; G3: 44%. At followup, 148 (59%) were deceased. Three mRNA signatures demonstrated significant univariable association with OS and added independent prognostic value (see Figure) to a multivariable model accounting for age, sex and stage (c-index = 0.641).

      Conclusion:
      The validated signatures, along with two novel signatures generated from the current dataset, are currently undergoing further validation studies using two prospective co-operative group cohorts. Figure 1



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    OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      OA23.07 - Analysis of Outcomes in US IRESSA Clinical Access Program (ICAP) Patients on Gefitinib for More Than 10 Years (Now Available) (ID 3731)

      F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background:
      In 2011, following gefitinib (IRESSA[®]) NDA voluntary withdrawal, US patients benefiting from gefitinib were eligible to continue gefitinib through the IRESSA Clinical Access Program (ICAP), an IRB-approved protocol. A subset of ICAP investigators subsequently collected additional retrospective data on their ICAP patients through another IRB-approved project (“chart-review subset”).

      Methods:
      For all enrolled ICAP patients, demographic and serious adverse event (SAE) reports were reviewed. All ICAP investigators were invited to participate in chart review; 47 accepted and collected data on patient/tumor characteristics and safety/tolerability of prolonged gefitinib therapy among their 79 ICAP patients.

      Results:
      Across 137 US sites, 191 patients enrolled in ICAP. As of September 2016, 75 (39%) remain on gefitinib; discontinuations were due to progression (36%), death (34%), AEs (13%), or other (17%). Sixty-four (34%) patients reported 162 SAEs; 5 (2.6%) patients had 12 SAEs considered to be gefitinib-related by investigators. The chart-review subset included 79 (41%) patients with median age of 69 years at ICAP enrollment, who were predominantly female (70%) and white (84%); 95% had a confirmed NSCLC diagnosis. Due to the evolving understanding of genetic mutations in NSCLC at the time of gefitinib initiation, the majority of patients (79%) never had EGFR sequencing performed. Although tissue is not available for EGFR status confirmation, we assume these patients are nearly exclusively EGFR mutation-positive. Median total length of gefitinib was 11.1 years (6.5-15.1; Table). Long-term gefitinib was well-tolerated; 5% discontinued due to a gefitinib-related AE. Ten-year survival rate from first-ever initiation of gefitinib was 86% and 15-year was 59%. Table. Gefitinib treatment patterns and tolerability among ICAP chart-review patients.

      Parameter n, % Observed Population (N=79)
      Total time on gefitinib, prior to and during ICAP
      Median duration, y, range 11.1 (6.5-15.1)
      Prior to ICAP
      Median duration, y, range 7.8 (5.4-10.9)
      Starting dose 250 mg/day 67 (84.8)
      No dose changes due to AEs 75 (94.9)
      During ICAP
      Median duration, y, range 3.5 (0.04-4.7)
      Dose: 250 mg/day 76 (96.2)
      Treatment-related AEs Grade 1-2 Grade ≥3 Grade unknown 13 (16.5) 1 (1.3) 2 (2.5)
      Dose reductions due to treatment-related AEs 1 (1.3)
      Discontinuations due to treatment-related AEs 4 (5.1)
      Discontinuations due to progressive disease 11 (28.9)


      Conclusion:
      The majority of this subset of patients who participated in ICAP based on long-term clinical benefit from gefitinib continue to do well with gefitinib, demonstrating good tolerance of therapy and survival for a median duration of more than 10 years.

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    P1.05 - Poster Session with Presenters Present (ID 457)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Early Stage NSCLC
    • Presentations: 2
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      P1.05-001 - Creation and Early Validation of Prognostic miRNA Signatures for Squamous Cell Lung Carcinoma by the SPECS Lung Consortium (ID 6088)

      F.R. Hirsch

      • Abstract

      Background:
      Despite overall favorable prognosis for operable early stage non-small cell lung cancer, predicting outcome for individual patients has remained challenging. Small retrospective studies have reported potential non-coding micro(mi)RNAs that might have prognostic significance; however, these studies lacked statistical power and validation. To refine these initial findings to clinical application, the investigators have undertaken a collaborative, structured evaluation of multiple signatures putatively prognostic for lung squamous cell carcinoma (SCC) under a NCI/SPECS (Strategic Partnerships fo Evaluating Cancer Signatures) award. The study design specifies a primary validation cohort comprising institutional cases, and additional validation cohorts of Cooperative Group cases, all profiled via a common pipeline.

      Methods:
      Completely resected SCC (confirmed by central pathology review) meeting clinical (Stage I-II; complete 3-year follow-up) and specimen quality criteria (Tumor cellularity ≥ 50%;necrosis ≤ 20%) were submitted by 6 institutions. Clinical, pathological and outcome data were uploaded to a central database. Lysates from 5 um sections of FFPE SSC tumor samples were run on the HTG EdgeSeq Processor (HTG Molecular Diagnostics, Tucson, AZ) using the miRNA whole transcriptome assay in which an excess of nuclease protection probes (NPPs) complimentary to each miRNA hybridize to their target. S1 nuclease then removes un-hybridized probes and RNA leaving behind only NPPs hybridized to their targets in a 1-to-1 ratio. Samples were individually barcoded (using a 16-cycle PCR reaction to add adapters and molecular barcodes), individually purified using AMPure XP beads (Beckman Coulter, Brea, CA) and quantitated using a KAPA Library Quantification kit (KAPA Biosystems, Wilmington, MA). Libraries were sequenced on the Illumina HiSeq platform (Illumina, San Diego, CA) for quantification. Standardization and normalization was provided to the project statistical core for validation of two pre-existing signatures and generation of new models (MCP clustering).

      Results:
      Among 224 cases with miRNA data, median age was 70 (43-92), 143 (64%) male, with 67% former (67%) and current (26%) smokers. All patients were completely resected stage I or II. . At follow-up, 59 (26%) had documented recurrence and 129 (58%) were deceased. To date, we have been unable to validate the previous models, but have created a novel signature of three miRNAs (see Figure) that is being validated in the second phase of the project using an independent, blinded multi-institutional cohort.

      Conclusion:
      The Squamous Lung Cancer SPECS Consortium has established well-annotated and quality-controlled resources for validation of prognostic miRNA signatures. A new candidate 3-miRNA signature has been identified for further development as a clinically useful biomarker.

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      P1.05-027 - Novel Prognostic Gene Expression Signatures for Squamous Cell Lung Carcinoma: A Study by the SPECS Lung Consortium (ID 4490)

      F.R. Hirsch

      • Abstract

      Background:
      A multi-institutional squamous lung cancer consortium of investigators is developing prognostic signatures through the US NCI Lung SPECS (Strategic Partnership for Evaluation of Cancer Signatures) program. Six institutions contributed tumor specimens and published/unpublished expression-based prognostic signatures for validation using standardized sample cohorts (a primary validation cohort comprising institutional cases, and additional validation cohorts from two prospective cooperative group studies) and quality controlled assessment in independent laboratory and statistical cores. Here, we report on de novo prognostic signatures derived using the pooled institutional dataset.

      Methods:
      Highly quality-controlled cases of primary SCC from the pooled cohort (N=249) were analyzed to generate de novo prognostic signatures from among the 147 genes comprising pre-existing signatures, and from among all profiled genes. Minimax Concave Penalty (MCP) selection and Ward’s minimum variance clustering yielded survival analyses with 2 clusters that were evaluated using Cox regression and bootstrap cross validation (bCV; 500 iterations).

      Results:
      Two significantly prognostic models were generated (see Figure): Pooled Model A (PMA) was the optimal 2-cluster model using probesets representing 6 genes selected from components of pre-existing signatures: CASP8, MDM2, SEL1L3, RILPL1, LRR1, COPZ2. Pooled Model B (PMB) was the optimal 2-cluster model using probesets representing 6 genes selected from among all those profiled: SSX1, DIAPH3, LOC619427, CASP8, EIF2S1, HSPA13. PMA and PMB each remained independently prognostic in multivariable analyses incorporating an a priori baseline model (age, sex, stage; c-index = 0.641).

      Conclusion:
      Two de novo prognostic signatures were derived using a pooled multi-institutional cohort of SCC assembled for validation of pre-existing signatures. PMA and PMB were each found to be independently prognostic, accounting for established clinical predictors. Both now move forward, along with validated pre-existing signatures, to additional assessment of discrimination, calibration and clinical usefulness using additional independent prospective US co-operative group cohorts of cases. Figure 1



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    P2.03b - Poster Session with Presenters Present (ID 465)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 3
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      P2.03b-035 - EGFR FISH as Potential Predictor of Necitumumab Benefit with Chemotherapy in Squamous NSCLC: Subgroup Analyses from SQUIRE (ID 5708)

      F.R. Hirsch

      • Abstract

      Background:
      Necitumumab (Neci) is a monoclonal antibody directed against the human epidermal growth factor receptor (EGFR). In the SQUIRE trial (NCT00981058), the addition of Neci to gemcitabine plus cisplatin (Gem-Cis) in squamous cell lung cancer resulted in a significant advantage in terms of overall survival (OS), but the expression of EGFR assessed by immunohistochemistry was not able to robustly predict the benefit from Neci. In a post-hoc analysis of SQUIRE, EGFR gene copy number gain determined by fluorescence in situ hybridization (FISH) showed a trend towards improved OS (HR=0.70) and progression-free survival (PFS) (HR=0.71) with the addition of Neci. We present the analysis of granular EGFR-FISH data from SQUIRE to examine the potential predictive role of high polysomy (HP) vs gene amplification (GA) as both were included in the “FISH-positive” category.

      Methods:
      Suitable specimens from SQUIRE patients underwent FISH analysis. Probe hybridization was performed in a central laboratory and each sample was analyzed using the Colorado EGFR scoring criteria. FISH was considered positive in cases of HP (≥40% cells with ≥4 EGFR copies) or GA (EGFR/CEP7 ≥2 or ≥10% cells with ≥15 EGFR copies). The correlation of granular FISH parameters with clinical outcomes was assessed.

      Results:
      FISH analysis was available for 557 patients (out of 1093); 208 patients (37.3%) were FISH+, including 167 (30.0%) with HP and 41 (7.4%) with GA. The outcome data for HP and GA are reported below:

      HIGH POLYSOMY GENE AMPLIFICATION
      Neci+Gem-Cis (N=89) Gem-Cis (N=78) Neci+Gem-Cis (N=22) Gem-Cis (N=19)
      Median OS in months (95% CI) 12.58 (11.04-16.00) 9.53 (7.16-12.48) 14.78 (10.02-31.51) 7.62 (4.99-16.10)
      Hazard ratio within subgroup (interaction model) 0.77 (0.55-1.08) p = 0.133 0.45 (0.21-0.93) p = 0.033
      Interaction p value 0.189
      Median PFS in months(95% CI) 6.08 (5.59-7.59) 5.13 (4.24-5.72) 7.36 (4.27-11.40) 5.55 (2.79-8.34)
      Hazard ratio within subgroup (interaction model) 0.70 (0.50-0.99) p = 0.044 0.69 (0.33-1.45) p = 0.334
      Interaction p value 0.980


      Conclusion:
      The OS benefit from the addition of Neci to Gem-Cis appeared to be more pronounced in the small subset of patients with GA when compared to HP, but the same trend was not observed for PFS. The potential predictive value of different EGFR FISH parameters should be evaluated in future studies.

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      P2.03b-048 - Access to Biomarker Testing in Patients with Advanced Non-Small Cell Lung Cancer (ID 4461)

      F.R. Hirsch

      • Abstract

      Background:
      Access to biomarker testing is critical for selecting appropriate treatment for patients with advanced non-small cell lung cancer (aNSCLC). This study assessed rates and patterns of biomarker testing among patients with aNSCLC.

      Methods:
      Patients aged ≥65 years diagnosed with aNSCLC between 2007-2011 were identified in the SEER-Medicare database and were followed for ≥4 months post-diagnosis (n = 9,651). Patients’ first biopsy within ±8 weeks of diagnosis was defined as the index date. Biomarker tests included procedure codes for gene analyses to test for EGFR, ALK, and other mutations. IHC tests, which are mostly used for diagnosis, were excluded. The use of biomarker tests was assessed from the index date until the end of data availability (12/31/2013) or end of Medicare Parts A, B and D eligibility. Analyses were replicated in the subgroup with cancer stages IIIB-T4 or IV and adenocarcinoma, adenosquamous or unknown type of NSCLC histology (n = 6,193).

      Results:
      Of 9,651 patients observed for a median of 11 months, 18% had a biomarker test during the follow-up. The use of biomarker testing increased from 5% in 2007 to 35% in 2011, and was higher among patients who saw a cancer specialist as compared to those who did not see a cancer specialist. When comparing the patients with and without a biomarker test diagnosed in 2011 (i.e., the most recent year in the data) in the full study sample, a higher proportion of patients without a biomarker test were males (51 vs 43%), non-Hispanic Blacks (13 vs 5%), resided in areas with higher poverty (27 vs 15%) and lower education levels (26 vs 17%), and had larger tumors at diagnosis (median 41 vs 38 mm; p <.05 for all). In addition, a lower proportion of them were married (44 vs. 52%), resided in big metropolitan areas (51 vs 57%), had stage IV cancer (64 vs 69%), and adenocarcinoma histology at diagnosis (43 vs. 77%; p <.05 for all). Among tested, >40% of the patients had their first biomarker test >8 weeks after biopsy. Results were similar in the subgroup, but the rate of biomarker testing was slightly higher and with slightly shorter delays.

      Conclusion:
      Among patients with aNSCLC diagnosed in 2007-2011 a substantial proportion did not undergo biomarker testing or had their biomarker test delayed by >8 weeks post-biopsy. Significant differences exist in demographic and cancer characteristics between patients with and without a biomarker test.

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      P2.03b-053 - Role of KRAS Mutation Status in NSCLC Patients Treated on SWOG S0819, a Phase III Trial of Chemotherapy with or without Cetuximab (ID 6113)

      F.R. Hirsch

      • Abstract

      Background:
      The S0819 phase III study of chemotherapy and bevacizumab (by patient/physician choice) with or without cetuximab in NSCLC showed no benefit from the addition of cetuximab, either overall or within the EGFR FISH-positive subset. Secondary analysis suggested an overall survival benefit in EGFR FISH-positive squamous cell carcinoma (SCC) (Herbst WCLC 2015, Hirsch ASCO 2016). In colorectal cancer (CRC), benefit from EGFR monoclonal antibodies such as cetuximab is limited to patients with RAS wild type (WT) tumors; however, in NSCLC, previous studies have not been sufficiently powered to make this determination. We prospectively incorporated KRAS mutation testing in S0819 to determine whether it predicts cetuximab efficacy. Since KRAS mutations are rare in SCC, we focused this analysis on nonSCC.

      Methods:
      KRAS mutation status was determined using the Therascreen KRAS test (Qiagen), conducted in a CLIA-certified diagnostic laboratory at the UC Davis Comprehensive Cancer Center. This test is FDA-approved for KRAS diagnostics in metastatic CRC, and identifies 6 mutations at codon 12 (G12A,D,R,C,S,V) plus G13D.

      Results:
      KRAS mutation status was available for 448 nonSCC patients, and mutations were identified in 150 cases (33%). Amino acid substitutions matched the expected distribution for a NSCLC population, with 52% harboring G12C and 17% with G12V. No significant differences were observed between KRAS-mut and WT populations for PFS (HR=1.15 (0.94-1.42); p=0.18) or OS HR=1.10 (0.89-1.37); p=0.39). Furthermore, no differences in outcomes between arms were observed based on KRAS mutation status (Table). The KRAS WT, EGFR FISH+ molecular subset (hypothetically the most likely subgroup to benefit from cetuximab) showed no statistical differences in outcomes between arms. Figure 1



      Conclusion:
      Determination of KRAS mutation status did not identify a subgroup of nonSCC patients with differential outcome from addition of cetuximab to front-line chemotherapy. In contrast to CRC, cetuximab does not appear to confer benefit to patients with KRAS-WT nonSCC NSCLC.

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    P3.01 - Poster Session with Presenters Present (ID 469)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
    • Now Available
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      P3.01-021 - Reproducibility of Comprehensive Histologic Assessment and Refining Histologic Criteria in P Staging of Multiple Tumour Nodules (Now Available) (ID 5365)

      F.R. Hirsch

      • Abstract
      • Slides

      Background:
      Multiple tumor nodules (MTNs) are being encountered, with increasing frequency with the 8[th] TNM staging system recommending classification as separate primary lung cancers (SPLC) or intrapulmonary metastases (IM). Pathological staging requires assessment of morphological features, with criteria of Martini and Melamed supplanted by comprehensive histologic assessment of tumour type, predominant pattern, other histologic patterns and cytologic features. With publication of the 2015 WHO classification of lung tumours, we assessed the reproducibility of comprehensive histologic assessment and also sought to identify the most useful histological features.

      Methods:
      We conducted an online survey in which pathologists reviewed a sequential cohort of resected multifocal tumours to determine whether they were SPLC, IM, or a combination. Specific histological features for each nodule were entered into the database by the observing pathologist (tumour type, predominant adenocarcinoma pattern, and histological features including presence of lepidic growth, intra-alveolar cell clusters, cell size, mitotic rate, nuclear pleomorphism, nucleolar size and pleomorphism, nuclear inclusions, necrosis pattern, vascular invasion, mucin content, keratinization, clear cell change, cytoplasmic granules¸ lymphocytosis, macrophage response, acute inflammation and emperipolesis). Results were statistically analyzed for concordance with submitting diagnosis (gold standard) and among pathologists. Consistency of each feature was correlated with final determination of SPLC vs. IM status (p staging) by chi square analysis and Fisher exact test.

      Results:
      Seventeen pathologists evaluated 126 tumors from 48 patients. Kappa score on overall assessment of primary v. metastatic status was 0.60. There was good agreement as measured by Cohen’s Kappa (0.64, p<0.0001) between WHO histological patterns in individual cases with SPLC or IM status but proportions for histology and SPT or IM status were not identical (McNemar's test, p<0.0001) and additional histological features were assessed. There was marked variation in p values among the specific histological features. The strongest correlations (<0.05) between p staging status and histological features were with nuclear pleomorphism, cell size, acinus formation, nucleolar size, mitotic rate, nuclear inclusions, intra-alveolar clusters and necrosis pattern. Correlation between lymphocytosis, mucin content, lepidic growth, vascular invasion, macrophage response, clear cell change, acute inflammation keratinization and emperipolesis did not reach a p value of 0.05.

      Conclusion:
      Comprehensive histologic assessment shows good reproducibility between practicing lung pathologists. In addition to main tumour type and predominant patterns, nuclear pleomorphism, cell size, acinus formation, nucleolar size, and mitotic rate appear to be useful in distinguishing between SPLC and IM.

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02b-009 - Plasma and Tissue Inflammatory and Angiogenic Biomarkers to Explore Resistance to EGFR-TKIs and Association with VeriStrat Status (ID 5750)

      F.R. Hirsch

      • Abstract

      Background:
      VeriStrat is a proteomic test validated to be prognostic and predictive of overall survival (OS) to EGFR Tyrosine Kinase Inhibitors (TKIs) in EGFR wild type patients[1]. Serum Amyloid A1 (SAA1) and its two truncated forms are responsible for 4 of the 8 peaks overexpressed in Veristrat (VS) Poor classified patients. The aim of the study was to explore if the microenvironment, with its complex network mediated by inflammation and angiogenesis could represent the base of the aggressive disease behavior of VS Poor subjects. Moreover, the activity of the immune escape axis PD-1/PD-L1 was explored.

      Methods:
      Plasma biomarkers analyses were retrospectively performed on plasma baseline samples of 244 patients enrolled in the PROSE trial[1], while exploratory tissue analysis was performed on 37 available histological specimens. Circulating levels of HGF, VEGF, FGF, Cromogranin A (CgA) and its pro- and anti-angiogenic fragments (fragment 1-373 and 1-76, respectively) were determined by an ELISA assay. PD-L1 expression both on tumor cells and inflammatory elements of the tumor microenvironment, and the tissue expression (T) of HGF and its receptor c-MET were measured by immunohistochemistry.

      Results:
      CgA, HGF, VEGF, and FGF plasma levels were statistically significantly higher in VS Poor subjects. High plasma HGF levels were associated with lower PFS (3.4 versus 2.0 months, HR 1.67; 95% CI 1.25-2.23; p<0.001) and OS (11.2 versus 6.4 months, HR 1.64; 95% CI 1.12-2.23 p=0.002). High PD-L1- tumor expression was associated with worse PFS (5.9 versus 1.9 months, HR 2.28; 95% C.I. 1.14-4.57; p<0.020) and a trend for lower OS (14.6 versus 6.7 months, HR 1.47; 95% CI 0.85-2.53; p=0.165), but not significantly associated with VS status (p=0.656). At the multivariate analysis, CgA, HGF and VEGF were independently associated with VS Poor status. When clinical variables were also included (histology and PS), multivariate analysis evidenced VEGF as the only independent biomarker associated with the VS Poor classification (p=0.0013). Plasma HGF levels (HR 2.083; 95% C.I. 1.306-3.321; p=0.0021) and tumor PD-L1 expression (HR 2.579; 95% CI 1.036-6.421; p=0.0417) remained independent prognostic biomarkers for shorter PFS.

      Conclusion:
      Inflammation and angiogenesis appear to be associated with the complex processes at the base of the Veristrat signature. Plasma HGF levels and tumor tissue PD-L1 are prognostic in terms of a worse PFS, but VeriStrat remains the only highly reproducible clinically relevant biomarker associated with OS. [1]V Gregorc et al, The Lancet Oncology, p713, 15(7),2014.

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    SC21 - Predictive Biomarkers for Outcome of Systemic Therapy in NSCLC (ID 345)

    • Event: WCLC 2016
    • Type: Science Session
    • Track: Biology/Pathology
    • Presentations: 1
    • Now Available
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      SC21.03 - Predictive Biomarkers for Immune Checkpoint Inhibitors in Lung Cancer (Now Available) (ID 6687)

      F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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