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B. Han



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    JCHS - Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session (ID 239)

    • Event: WCLC 2015
    • Type: Joint Chinese/ English Session
    • Track: Other
    • Presentations: 2
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      JCHS.02 - Molecular Epidemiology of Lung Cancer in China (ID 3452)

      07:35 - 07:55 AM  |  Author(s): B. Han

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCHS.07 - First-Line Icotinib Versus Cisplatine/Pemetrexed plus Pemetrexed Maintenance in Advanced NSCLC Patients with EGFR Mutation (ID 3524)

      09:15 - 09:25 AM  |  Author(s): B. Han

      • Abstract
      • Presentation
      • Slides

      Background:
      Clinical studies with anti-EGFR agents demonstrate that EGFR TKIs play critical roles in the treatment of non-small cell lung cancer, especially in patients with positive EGFR mutation. Icotinib is an oral, selective EGFR TKIs. Phase 3 study showed that icotinib is non-inferior to gefitinib in treating unselected or EGFR-mutated advanced NSCLC patients as second-line therapy but better safety profile, which provide a rationale to examine icotinib in first-line setting. The objective of this study is to evaluate progression-free survival (PFS), overall survival (OS) and safety of icotinib in chemotherapy naïve NSCLC patients with EGFR mutation.

      Methods:
      In this phase 3, open-label, randomized study (CONVINCE, NCT01719536), 285 patients (pathologically confirmed NSCLC, positive 19/21 EGFR mutation, treatment naive) will be 1:1 randomized to receive oral icotinib (125 mg, three times daily) or cisplatine (intravenous [IV], 75 mg/m2, day 1) plus pemetrexed (IV, 500 mg/m2, day 1), patients achieving disease control after 4-cycle chemotherapy continue to receive single pemetrexed (IV, 500 mg/m2, day 1) as maintenance therapy until progression. Randomization will be stratified by performance status (0-1/2), smoking status (smoker/non-smoker), disease stage (IIIB/IV), and mutation type (19/21). A total of 228 events would provide 90% power to detect an HR for PFS of 1 at 2-sided significance level of 0.05. Response will be reviewed by both investigator and independent data monitoring committee. Patient enrollment was completed in June 2014, and the results are expected in June, 2015.

      Results:
      Not applicable

      Conclusion:
      Not applicable.

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    MINI 01 - Pathology (ID 93)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI01.05 - Local Diagnostic Practices for Advanced Non-Small-Cell Lung Cancer in Europe and Japan: ASSESS Study (ID 2629)

      11:10 - 11:15 AM  |  Author(s): B. Han

      • Abstract
      • Presentation
      • Slides

      Background:
      ASSESS (a large, multicentre, non-interventional, diagnostic study; NCT01785888) evaluated local diagnostic practices for patients with advanced non-small-cell lung cancer (aNSCLC) in Europe/Japan.

      Methods:
      Eligible patients: local/metastatic aNSCLC; chemotherapy-naïve, newly diagnosed/recurrent disease after resection; ineligible for curative treatment. We report diagnostic assessments and epidermal growth factor receptor (EGFR) mutation test turnaround times (secondary endpoints) associated with tissue/cytology samples from patients in Europe/Japan.

      Results:
      1311 patients enrolled (300 Japan). Immunohistochemistry (IHC) was used to confirm pathological diagnosis in 727/960 (76%) and 142/146 (97%) patients in Europe and Japan, respectively (where data were available); the following markers were assessed using IHC: TTF-1 (Europe 96% and Japan 79%); p65 (4% and 8%); and p40 (9% and 24%). EGFR mutation tests were not performed on samples from 110 patients and tested samples from 17 patients did not yield results. The most common reason for not testing was insufficient material provided (Europe 60% [47/78 responses]; Japan 56% [5/9 responses]). The percentages of neoplastic cells in samples (data available: Europe n=281; Japan n=20) were: <20% tumour cells: Europe 15% vs Japan 35%; 20–50% tumour cells: 23% vs 45%; >50% tumour cells: 61% vs 20%. Considering sampling methodologies, the most common sampling sites (data available: Europe n=996; Japan n=291) were the lung parenchyma (Europe 73%; Japan 79%) or lymph nodes (Europe 9%; Japan 9%); the most common sample collection method was bronchoscopy (Europe 39%; Japan 68%; Table 1). Median EGFR mutation test turnaround time was longer in Europe (11 days) versus Japan (8 days; Table 2). Mutation test success rates for Europe and Japan were 98.3% and 99.6%, respectively.

      Conclusion:
      Diagnostic assessments, sampling methodologies and EGFR mutation testing practices vary between and within Europe and Japan; further understanding of local practices will drive improvements and enable more patients to receive appropriate personalised treatment. Figure 1 Figure 2





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    MINI 36 - Imaging and Diagnostic Workup (ID 163)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Screening and Early Detection
    • Presentations: 1
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      MINI36.07 - Diagnostic Value of Electromagnetic Navigation Bronchoscopy for Peripheral Pulmonary Lesions : A Randomized Controlled Trial (ID 1152)

      07:05 - 07:10 PM  |  Author(s): B. Han

      • Abstract
      • Presentation
      • Slides

      Background:
      Navigational bronchoscope including conventional electromagnetic navigation bronchoscope(ENB) and endobronchial ultrasound(EBUS) with a guide sheath(GS) for transbronchial lung biopsy (TBLB) has improved the diagnostic outcome for peripheral pulmonary lesions (PPLs). However, ENB required the bronchoscope for large diameter of the working channel(>2.6mm) which could limit the deep of the insertion and EBUS-GS could be regarded as the confirmation tool other than navigation system. A new, realtime electromagnetic guidance system for bronchoscopy using a thin bronchoscope(4.0mm) with a GS(1.95mm) for TBLB is a novel method to increase diagnostic yield of PPLs.

      Methods:
      A prospective, open label, two centers, randomized controlled pilot study involves two diagnostic arms: ENB-GS-TBLB and traditional GS-TBLB which was conducted to determine the ability and safety.ENB-GS-TBLB is performed using an electromagnetic navigation system with a GS and an internal locatable guide with diameter of 1.45 mm. Primary outcome was diagnostic yield. Secondary outcomes were yields by total procedure time, the time for finding lesions and the X-ray time using during operation. Complications were also documented.

      Results:
      Of the 86 patients recruited, 81 had a definitive histological diagnosis and were included in the final analysis. The diagnostic yield of the ENB-GS-TBLB (87%) was greater than GS-TBLB (64%; p<0.05). The time for finding lesions of the ENB-GS-TBLB(3min 43s) was significantly less than GS-TBLB(4min 44s; p<0.05). ENB-GS-TBLB was independent of lesion size or lobar distribution. No complications were found in both two groups.

      Conclusion:
      ENB-GS-TBLB seems to be an accurate and safe procedure. It allowed us to improve the diagnostic yield of flexible bronchoscopy in PPLs.

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    ORAL 01 - Chemotherapy Developments for Lung Cancer (ID 88)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL01.06 - S-1 and Cisplatin versus Docetaxel and Cisplatin in Patients with Untreated Advanced NSCLC: An Randomised, Multicenter, Phase 3 Trial (ID 2734)

      11:39 - 11:50 AM  |  Author(s): B. Han

      • Abstract
      • Presentation
      • Slides

      Background:
      Platinum-based doublet chemotherapy is the standard chemotherapeutic regimen for treatment-naïve advanced non-small cell lung cancer (NSCLC). S-1, an oral fluoropyrimidine, combined with carboplatin or cisplatin (CDDP) has demonstrated the non-inferiority to the standard platinum doublet chemotherapy in Japanese NSCLC patients. However, its effectiveness in Chinese NSCLC patients is uncertain. The purpose of this study is to compare the efficacy and safety of these chemotherapeutic regimens in Chinese NSCLC patients.

      Methods:
      We did this randomized controlled study in 21 sites in China. Eligible patients were those aged 18-70 years who was histologically or cytologically confirmed with locally advanced or metastatic NSCLC with no prior radiotherapy, molecular targeted therapy or chemotherapy. Patients were randomized to receive either S-1 orally 80 mg/m[2]/day (40 mg/m[2]2 b.i.d., 80–120 mg/day) with 60 mg/m[2] CDDP on day 8 every 5 weeks (SP) or docetaxel and CDDP (both 75 mg/m[2]) on day 1 every 3 weeks (DP) for up to 6 cycles. Randomisation was stratified by centre, pathological classification, disease stage and gender. The primary endpoint was progression free survival (PFS), analyzed in the full analysis set. The study is registered at ClinicalTrials.jp, number Japic CTI-111479.

      Results:
      Between March 2011 and November 2012, 246 patients from 21 institutions in China were randomly assigned and received SP or DP treatment (124 vs 122) with 18-month follow-up period from the last patient randomized. In the SP and DP group, median PFS was 5.9 and 5.7 months (HR=0.68; 95% CI, 0.48-0.96) respectively, median overall survival was 19.1 and 14.8 months, respectively (HR=0.84; 95% CI, 0.61-1.14). The most common grade 3 or worse adverse events in both treatment groups were neutropenia 3.3% vs 55.1%, leukopenia 1.7% vs 39.0%, and febrile neutropenia 0.8% vs 5.9%, of 121 patients in the SP group and of 118 patients in the DP group, respectively.

      Conclusion:
      The efficacy of SP was non-inferior to DP with a better safety profile. SP would be a new standard first-line chemotherapy regimen for Chinese patients with advanced NSCLC.

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    ORAL 03 - New Kinase Targets (ID 89)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL03.01 - Anlotinib as 3rd-Line Treatment for Refractory Advanced NSCLC: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial (ID 2570)

      10:45 - 10:56 AM  |  Author(s): B. Han

      • Abstract
      • Presentation
      • Slides

      Background:
      Anlotinib is a multi-target RTK inhibitor, especially on VEGFR2/3, EGFR, c-Kit, PDGF, FDFR, c-MET, with highly selective inhibition effect. This phase II study was to investigate efficacy and safety of anlotinib in refractory NSCLC patients

      Methods:
      Patients ≥18 years with metastatic or recurrent advanced NSCLC and ECOG status of 0–1 were randomized 1:1 to receive Anlotinib or placebo (Anlotinib 12mg/day, po, day 1-14 each 3-week) until progression, unacceptable toxicity, withdrawal or death. Patients had received first and second line treatment for advanced NSCLC. Patients were stratified by gender, smoking status and age. We used RECIST (version 1.1) criteria to assess response and progression. Primary endpoint was PFS in ITT population; secondary endpoints included ORR, OS, biomarkers and safety.

      Results:
      From Aug. 2013 to May 2014, we enrolled 117 patients from 13 centers, including 60 patients to anlotinib arm and 57 patients to placebo. Baseline characteristics were similar in both treatment groups. PFS was prolonged with anlotinib 4.83 month vs placebo 1.23 months (HR 0.32, 95% CI 0.20–0.51, p<0.0001). ORR was improved with addition of anlotinib: 10% vs 0% with placebo (p<0.027).DCR was 83.3% with anlotinib vs 31.5% with placebo (p<0.0001). mOS was prolonged with Anlotinib 10.33 months vs placebo 6.3 months. (HR, 0.656; 95% CI, 0.411 to 1.048; P = 0.0776; Cutoff date: April 12, 2015. This mOS is an estimated data, OS events for both arms still not reach 75%). OS rate of >12 months is 22.8% in placebo arm and 38.3% in anlotinib arm. AEs occurred more frequently with anlotinib than placebo; the most common AEs of any grade were hypertension (53.33%), increased TSH (36.67%), hand foot syndrome (28.33%), increased TG (26.67%), increased TC (25%), cough (21.67%), diarrhea (21.67%), increased LDL (16.67%), hemoptysis (16.67%) oral mucositis (13.33%), and sore throat (13.33%). Grade III/IV treatment-related AEs increased 16.4% in anlotinib group (anlotinib: 21.6% , placebo: 5.3%, p=0.0140).

      Conclusion:
      This study confirms that anlotinib to third-line platinum-based chemotherapy appears to provide significant PFS benefits in Chinese patients with refractory advanced NSCLC compared with placebo. No serious safety concerns were reported in the study.

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    ORAL 17 - EGFR Mutant Lung Cancer (ID 116)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL17.01 - First-Line Icotinib Versus Cisplatine/Pemetrexed Plus Pemetrexed Maintenance in Advanced NSCLC Patients with EGFR Mutation (ID 742)

      10:45 - 10:56 AM  |  Author(s): B. Han

      • Abstract
      • Presentation
      • Slides

      Background:
      Clinical studies with anti-EGFR agents demonstrate that EGFR TKIs play critical roles in the treatment of non-small cell lung cancer, especially in patients with positive EGFR mutation. Icotinib is an oral, selective EGFR TKIs. Phase 3 study showed that icotinib is non-inferior to gefitinib in treating unselected or EGFR-mutated advanced NSCLC patients as second-line therapy but better safety profile, which provide a rationale to examine icotinib in first-line setting. The objective of this study is to evaluate progression-free survival (PFS), overall survival (OS) and safety of icotinib in chemotherapy naïve NSCLC patients with EGFR mutation.

      Methods:
      In this phase 3, open-label, randomized study (CONVINCE, NCT01719536), 285 patients (pathologically confirmed NSCLC, positive 19/21 EGFR mutation, treatment naive) will be 1:1 randomized to receive oral icotinib (125 mg, three times daily) or cisplatine (intravenous [IV], 75 mg/m2, day 1) plus pemetrexed (IV, 500 mg/m2, day 1), patients achieving disease control after 4-cycle chemotherapy continue to receive single pemetrexed (IV, 500 mg/m2, day 1) as maintenance therapy until progression. Randomization will be stratified by performance status (0-1/2), smoking status (smoker/non-smoker), disease stage (IIIB/IV), and mutation type (19/21). A total of 228 events would provide 90% power to detect an HR for PFS of 1 at 2-sided significance level of 0.05. Response will be reviewed by both investigator and independent data monitoring committee using Response Evaluation Criteria In Solid Tumors (RECIST version 1.1). Progression Between January, 2013 and August, 2014, 285 patients were randomized and treated at 18 centers from 13 cities in China. The data cut-off was planned at October, 2015 when 228 PFS events were observed in full analysis set (80% maturity). Final results were expected on December, 2015.

      Results:
      Not applicable

      Conclusion:
      Not applicable.

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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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      P1.01-021 - Crizotinib Efficacy in ALK-Positive Advanced NSCLC Chinese Patients (ID 261)

      09:30 - 09:30 AM  |  Author(s): B. Han

      • Abstract
      • Slides

      Background:
      Anaplastic lymphoma kinase (ALK) is a new tyrosine kinase target that has been validated recently in NSCLC. Crizotinib, an oral, small-molecule, tyrosine kinase inhibitor that targets ALK, MET and ROS-1, has been reported to be particularly effective and to have acceptable toxicity in advanced anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC). In a phase 1, open-label, multicenter trial evaluating the efficacy and adverse event profile of crizotinib in a cohort of 82 ALK-positive lung cancer patients, treatment for a mean duration of 6.4 months achieved an overall response rate (ORR) of 57%, and the estimated probability of 6-months’ progression-free survival (PFS) was 72%. Mild gastrointestinal disturbances were the main adverse effects observed in this study. Subsequently, updated data from a study involving 143 patients confirmed the durable response and tolerable adverse effect profile of crizotinib in patients with ALK-positive NSCLC.

      Methods:
      A total of 72 patients with ALK-positive NSCLC who received crizotinib between June 1, 2013 and October 15, 2014 at Shanghai Chest Hospital, Shanghai JiaoTong University, were prospectively enrolled in the study. All were histologically diagnosed and staged as clinically advanced (stage IV, or stage IIIB with pleural effusion) NSCLC. All patients received oral crizotinib 250 mg twice daily in 28-day cycles. The tumor response was assessed after the first cycle of crizotinib therapy and subsequently after every 2 cycles using the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. Tolerability was assessed at least twice per cycle until crizotinib was discontinued.

      Results:
      The patients tended to be young (mean age 55 years, range 31-83 years), never or light smokers (smoking index <400), and to have an adenocarcinoma histology. Most (49/72; 68.1%) had received previous anticancer treatment before crizotinib therapy. Sixty-seven patients (93%) were able to be assessed for efficacy. The objective response rate (ORR) and disease control rate (DCR) were 52.2% (95% CI 40.5%-63.9%) and 64.2% (95% CI 52.75%-75.7%), respectively. The estimated median progression-free survival (PFS) for all 67 patients was 10.3 months (95% CI 8.6-12.0 months). Mild visual disturbances, nausea, vomiting, diarrhea and constipation were the most commonly reported adverse effects.Figure 1



      Conclusion:
      crizotinib was well tolerated and showed promising efficacy in Chinese patients with ALK-positive, advanced NSCLC. Further prospective, multicenter studies with a larger sample size are needed to confirm these findings.

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    P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 5
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      P1.04-044 - Local Diagnostic Practices for Advanced Non-Small-Cell Lung Cancer in Asia-Pacific and Russia: IGNITE Study (ID 2650)

      09:30 - 09:30 AM  |  Author(s): B. Han

      • Abstract
      • Slides

      Background:
      IGNITE (a large, multicentre, interventional, non-comparative diagnostic study; NCT01788163) evaluated local diagnostic practices for patients with advanced non-small-cell lung cancer (aNSCLC) in Asia-Pacific/Russia.

      Methods:
      Eligible patients: local/metastatic aNSCLC; chemotherapy-naïve, newly diagnosed/recurrent disease after resection; ineligible for curative treatment. We report diagnostic assessments and epidermal growth factor receptor (EGFR) mutation test turnaround times (secondary endpoints) associated with tissue/cytology samples from patients in Asia-Pacific/Russia.

      Results:
      3382 patients enrolled (972 Russia). Immunohistochemistry (IHC) analysis was used to confirm diagnosis in 989/2093 (47%) and 165/949 (17%) patients in Asia-Pacific and Russia, respectively (where data were available). Where IHC was used, the markers assessed were: TTF-1 (Asia-Pacific 95% and Russia 90%); p65 (3% and 5%); and p40 (17% and 4%). EGFR mutation tests were not performed on samples from 262 patients and tested samples from 23 patients did not yield results. The most common reason for not testing was insufficient material provided to test (Asia-Pacific 93% [100/108 responses], Russia 67% [24/36]). The percentages of neoplastic cells in samples (data available: Asia-Pacific n=1042; Russia n=187) were: <20% tumour cells: Asia-Pacific 33% vs Russia 6%; 20–50% tumour cells: 28% vs 33%; and >50% tumour cells: 40% vs 61%. Considering sampling methodologies (data available: Asia-Pacific n=2410; Russia n=972), the most common sampling sites were the lungs (Asia-Pacific 68%; Russia 80%) or lymph nodes (Asia-Pacific 14%; Russia 10%); the most common sample collection method was bronchoscopy (Asia-Pacific 22%; Russia 45%; Table 1). Median EGFR mutation test turnaround time was within 2 weeks for all countries except Thailand (70 days; Table 2). Mutation test success rates were high for Asia-Pacific (99.5%) and Russia (98.7%).

      Conclusion:
      Diagnostic assessments, sampling methodologies and EGFR mutation testing practices vary between and within Asia-Pacific and Russia; further understanding of local practices will drive improvements and enable more patients to receive appropriate personalised treatment. Figure 1 Figure 2





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      P1.04-046 - MFN2 Regulates Lung Adenocarcinoma Cell Proliferation and Invasion (ID 2231)

      09:30 - 09:30 AM  |  Author(s): B. Han

      • Abstract

      Background:
      Mitofusin-2 gene (MFN2) encodes a mitochondrial protein which is critical for mitochondrial fusion process. MFN2 was initially identified as a hypertension-associated gene and implicated in the pathogenesis of multiple cancer types. However, roles and underlying mechanisms of MFN2 in lung adenocarcinoma development remain to be determined.

      Methods:
      MFN2 expression at protein level was examined in 30 pair lung adenocarcinoma/adjacent normal lung samples with immunohistochemistry staining. Then MFN2 knockdown was performed in human lung adenocarcinoma cells A549 with lentiviral-mediated shRNA strategy. The effects of MFN2 knockdown on cell proliferation, cell cycle process, cell migration and invasion was investigated in A549 cells. Then MFN2-knockdown induced gene expression changes in A549 cells was analyzed by microarray assay and then functional pathway enrichment analysis was performed to identify critical pathways involved in MFN2-mediated lung adenocarcinoma development. The expression changes of downstream factors were further determined in A549 cells by western blot.

      Results:
      As compared to adjacent normal lung tissues, MFN2 expression was significantly higher in lung adenocarcinoma tissues with positive MFN2 signals in 90% (27/30) lung adenocarcinoma tissues and only in 26.7% (8/30) adjacent normal tissues (Fig. 1A, B). Furthermore, MFN2 knockdown inhibited cell proliferation (Fig. 1C), induced cell cycle arrest (Fig. 1E) and blocked invasion behavior (Fig. 1D) in A549 lung adenocarcinoma cells. Microarray analysis revealed that a lot of genes were deregulated in A549 cells with MFN2 knockdown (Fig. 1F). Then functional pathway enrichment revealed six pathways were enriched in deregulated genes including Cell cycle, DNA replication, ECM-receptor interaction, Focal adhesion, MAPK signaling pathway and Chemokine signaling pathway (Fig. 1G). Furthermore, the downregulation of RAP1A and upregulation of RALB and ITGA2 identified in MFN2-knockdown cells by microarray analysis were confirmed by western blot (Fig. 1H).Figure 1



      Conclusion:
      Our results confirmed the involvement of MFN2 in the pathogenesis of lung adenocarcinoma and revealed that MFN2 was critical for cell proliferation and invasion in lung adenocarcinoma cell line A549. Furthermore, microarray analysis identified multiple pathways deregulated in MFN2-knockdown cells, providing valuable insights about the mechanisms underlying MFN2-associated lung adenocarcinoma development.

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      P1.04-057 - Wnt Signaling Regulates Cancer Stem Cell in Lung Cancer SPC-A1 Cells (ID 633)

      09:30 - 09:30 AM  |  Author(s): B. Han

      • Abstract

      Background:
      Wnt signaling is invovled in driving cancer stem cells (CSCs) activity in a variety of cancers. The aim of this study was to explore the role of Wnt signaling in the lung cancer stem cells (LCSCs).

      Methods:
      Sphere culture was processed by treating human lung adenocarcinoma cell line SPC-A1 with IGF, EGF and FGF-10 to obtain the LCSCs. After confirming the stemness by immunoflurescence, functional genome screening and RT-PCR were employed to perform pathway analysis. The relationship between the identified signaling pathway and stemness gene expression was explored by agnoist/antagonist assay. Moreover, the effects on sphere formation, cell viability and colony formation by different signaling molecule inhibitors were also analyzed.

      Results:
      The results showed that LCSCs were successfully generated and the phenotype characterization was confirmed by expressing pluripotent stem cell markers Nanog and Oct 4, and lung distal epithelial markers CCSP and SP-C. The involvement of Wnt pathway in LCSCs was confirmed by functional genome screening and verified by RT-PCR. The expression of Wnt signaling components were related with the expression of the Nanog and Oct 4. Anti-cancer effects could be exerted by using different signaling molecule inhibitors targeting Wnt signaling pathway.

      Conclusion:
      In conclusion, Wnt signaling pathway is involved in the stemness regulation of LCSCs and could be considered as a potential therapeutic target in the lung adenocarcinoma.

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      P1.04-090 - Roles of MLF1IP in the Proliferation of Lung Adenocarcinoma Cells (ID 2234)

      09:30 - 09:30 AM  |  Author(s): B. Han

      • Abstract

      Background:
      MLF1IP was initially identified as a MLF1 interacting protein, which encodes a centromere protein essential for cell cycle and mitosis. It has been reported that MLF1IP depletion impaired the interaction between centromere and microtubules, finally inducing defects in cell mitosis. However, the involvement of MLF1IP in lung adenocarcinoma development and related mechanisms remain to be elucidated.

      Methods:
      MLF1IP expression at mRNA level in 15 pair lung adenocarcinoma/adjacent normal lung samples was examined with real-time PCR assay. Then the expression of MLF1IP in human lung adenocarcinoma cells A549 was inhibited with lentiviral-mediated shRNA strategy. Effects of MLF1IP knockdown on cell proliferation was analyzed by Cellomics cell counting method and MTT assay. Then the impact of MLF1IP knockdown on colony formation, cell cycle process and cell survival was determined in A549 cells by colonogenesis assay, PI staining and Annexin V-APC staining respectively.

      Results:
      MLF1IP expression was significantly increased in lung adenocarcinomas as compared to adjacent normal lung tissues (fold change=2.50, P<0.05), with higher MLF1IP expression observed in 66.7% (10/15) samples while lower expression observed in only 20% (3/15) samples (Fig. 1A). Furthermore, MLF1IP knockdown impaired cell proliferation (Fig. 1B, C), inhibited colony formation ability (Fig. 1D), induced cell cycle arrest (Fig. 1E) and promoted cell apoptosis (Fig. 1F) in A549 lung adenocarcinoma cells.Figure 1



      Conclusion:
      Our study showed that MLF1IP expression is correlated with lung adenocarcinoma development and MLF1IP expression is critical for cell proliferation and survival in lung adenocarcinoma cell line A549. MLF1IP represents a novel potential target for lung adenocarcinoma therapy.

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      P1.04-099 - Wnt Blockers Inhibit the Proliferation of Lung Cancer Stem Cells (ID 632)

      09:30 - 09:30 AM  |  Author(s): B. Han

      • Abstract

      Background:
      Previous study has confirmed that the occurrence of Wnt pathway activation is associated with risk of non-small-cell lung cancer recurrence. However, whether the pharmacologic blocking of the Wnt signaling pathway could provide therapeutic possibility remains unknown. The aim of the present study was to evaluate the therapeutic functions of the Wnt signaling pathway inhibitor pyrvinium pamoate (PP) on lung cancer stem cells (LCSCs) in vitro.

      Methods:
      Colony formation and sphere culture were performed to enrich LCSCs from three lung cancer cell lines: PC9, SPC-A1, and A549. After confirming stemness by immunofluo­rescence, PP was employed for cell viability assay by comparison with three other kinds of Wnt signaling inhibitor: salinomycin, ICG-001, and silibinin. The effect of PP on LCSCs was further verified by colony formation assay and gene expression analysis.

      Results:
      LCSCs were successfully generated by sphere culture from SPC-A1 and PC9 cells, but not A549 cells. Immunofluorescence assay showed that LCSCs could express pluripotent stem cell markers, including NANOG, Oct4, KLF5, and SOX2, and Wnt signaling pathway molecules β-catenin and MYC. Half-maximal inhibitory concentrations of PP on SPC-A1, PC9, and A549 were 10 nM, 0.44 nM, and 0.21 nM, respectively, which are much lower than those of salinomycin, ICG-001, and silibinin. Moreover, significantly decreased colony formation and downregulation of pluripotent stem cell signaling pathway were observed in lung cancer cells after treatment with PP.

      Conclusion:
      Wnt signaling inhibitor PP can inhibit proliferation of LCSCs, and the Wnt signaling pathway could be considered a promising therapeutic or interventional target in lung adenocarcinoma.

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    P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P2.01-024 - An ENSURE Extension Study to Evaluate 2<sup>nd</sup> Line Erlotinib and Gemcitabine/Cisplatin Cross-Over Treatment for EGFR-Mutant Chinese NSCLC Patients (ID 1747)

      09:30 - 09:30 AM  |  Author(s): B. Han

      • Abstract
      • Slides

      Background:
      ENSURE study shows that 1[st] line treatment with erlotinib provides longer PFS over gemcitabine/cisplatin (GP) for stage IIIB/IV NSCLC patients with EGFR mutations. Cross-over treatments after progression of disease (PD) was allowed in ENSURE study. However, post-study treatments might have significant impact on patient survival or other clinical benefits, which is insufficiently investigated. This trial in an extension of the ENSURE study, intended to evaluate PFS in 2[nd] line progression after cross-over treatments in ENSURE.

      Methods:
      Chinese patients who had PD after 1[st] line treatment in ENSURE were enrolled. Enrolled patients received cross-over treatment as 2[nd] line treatment after 1[st] line PD. The primary endpoint was PFS, defined as the time of randomization in ENSURE to disease progression or death while on 2[nd] line treatment. For patients who had already progressed after 2[nd] line therapy prior to entering this extension study, relevant information would be collected retrospectively. PFS from 1[st] line PD to 2[nd] line PD was also calculated. The study was approved by IRB and all patients signed informed consent. This study was registered in clinicalgrials.gov (NCT02000531). We also retrospectively analyzed the time to 2[nd] line treatment failure (TTF) defined as the time from randomization to discontinuation of 2[nd] line treatment for any reason.

      Results:
      Forty-five patients (21 from erlotinib arm and 24 from GP arm) were enrolled in the final analysis in this ENSURE extension study. Limited recruitment was mainly due to later initiation of this study (from January to December of 2014), many deaths at the beginning of this study, or unwillingness to sign informed consent by some patients. Age, sex, and ECOG at baseline in erlotinib group and GP group were balanced. Among 45 enrolled subjects, 33 (73.3%) subjects completed the study. There was no significant difference in median PFS from the date of randomization in ENSURE study to 2[nd] line PD for both arms 26.3 (95%CI: 19.8 , 34.0 ) months vs 23.4 (95%CI: 17.8, 39.0 ) months, HR=1.26 (95%CI: 0.61, 2.62), p=0.529). For 2[nd] line cross-over treatment, ORR in erlotinib and GP arms was 33.3% (7PR/21) and 66.7% (16PR/24) respectively (p=0.0377). In a retrospective analysis of 175 patients from the whole ENSURE study, 63.2% patients in erlotinib arm (n=87) received 2[nd] line chemotherapy and 86.4% patients in GP arm (n=88) received 2[nd] line targeted therapy. The median TTF in erlotinib and GP arm were 29.4 (95%CI: 24.7, 34.2) and 24.7 (95%CI: 21.9, 28.4) months respectively (HR=0.74(95%CI: 0.47, 1.17), p=0.192).The subgroup analysis (mutation type, ECOG performance status, gender) for TTF between erlotinib and GP arm showed similar trend to the primary analysis.

      Conclusion:
      Despite limitations, both median PFS (in prospective analysis) and TTF (in retrospective analysis) for erlotinib patients were numerically larger than that in GP arm. This first cross-over treatment ENSURE extension study further confirms benefits of erlotinib as standard 1[st] line treatment for EGFR mutant NSCLC. It also supports the importance of 1[st] and 2[nd] line treatment sequence of erlotinib and platinum-based chemotherapy for the treatment of EGFR mutant NSCLC.

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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: 2
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      P2.06-002 - Preliminary Results of Early Stage Lung Cancer Detection Using Low-Dose Computed Tomographic Screening (ID 609)

      09:30 - 09:30 AM  |  Author(s): B. Han

      • Abstract

      Background:
      The overall 5 years survival for lung cancer patients is approximately 16%, a survival advantage is noted for early stage lung cancer, with 5-year survivals up to 65%. However, only 10% patients are diagnosed when the primary tumor is resectable. Our trial was conducted to improving the early stage lung cancer detection rate using low-dose CT.

      Methods:
      Eligible participants enrolled in our trial were local residents in 6 communities located in Xuhui District, Shanghai, China, aged from 45 to 70 years and with either of the following risk factors: 1) history of cigarette smoking ≥ 20 pack-years, and, if former smokers, had quit within the previous 15 years; 2) malignant tumors history in immediate family members; 3) personal cancer history; 4) professional exposure to carcinogens; 5) long term exposure to second-hand smoke; 6) long term exposure to cooking oil fumes. From November 2013 to November 2014, the high risk residents received free chest low-dose CT (LDCT) scans at Shanghai Jiao Tong University Affiliated Shanghai Chest Hospital. The findings of CT scan were identified by three experts. The shadows on the lungs were grouped accordingly. If imaging was highly suggestive of malignancy, the expert group would have further discussion. The residents would be assigned to undergo biopsy or surgical resection directly.

      Results:
      Up to January 2015, 2933 participants were received LDCT screening. According to the inclusion criteria, 2892 persons at high risk for lung cancer were included in our trail, and 41cases were finally excluded. Of the 2892 aged 45 -70 years old cases, the median age was 61years old. Of the included participants, 1151 cases were male, and 1741 cases were female. Pulmonary small nodules were found in 742 cases; small nodules detection rate was 25.66% (742/2892). 69 cases were suspected of lung cancer. Accounting for pulmonary small nodules was 9.30% (69/742), and was 2.39% (69/2892) of the total number of screening high risk population. 23 cases underwent surgery, with 22 lung cancer (10 males and 12 females) and 1 hamartoma, representing a positive lung cancer detection rate with low-dose CT screening of 0.76% (22/2892). 21 of the 22 cases resected lung cancers were stage I (95.45%) and 1 was stage II (4.55%), with 21 adenocarcinomas (95.45%) and 1 squamous lung cancer (4.55%).

      Conclusion:
      The application of low-dose CT screening prompted an increase detection rate of early stage lung cancers (stage I and II) in the high risk population.

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      P2.06-021 - Analysis of Autofluorescence Bronchoscopy Used for Characterisation and Identification of Bronchopulmonary Cancer (ID 1169)

      09:30 - 09:30 AM  |  Author(s): B. Han

      • Abstract

      Background:
      The aim of the study is to introduce a more effective quantitative method(optimal identification index and reference value) for characterizing the AFB images within the region of interest and to explore the value of AFB in diagnosis of different types of lung cancer.

      Methods:
      Patients with one or more preinvasive bronchial lesions were entolled, followed-up by white light bronchoscope(WLB) and AFB. A quantitative analysis based on color space(red-to-green value, R/G value) was conducted and the result was compared with the final diagnosis obtained by the pathology of biopsy and/or by surgical pathology.

      Results:
      A retrospective analysis was conducted on 218 cases with 1,208 biopsies. 173 cases were diagnosed as positive by WLB associated with AFB, which included 151 true positive cases and 22 false positive cases. There were 45 cases in 151 true postive cases which included 13 false negative cases and 32 true negative cases. WLB associated with AFB was able to differentiate between benign and malignant lesion lymph nodes with a high sensitivity, specificity, positive predictive value and negative predictive value(92.1%, 59.3%, 87.3% and 71.1%, respectively). The quantitative method of R/G value allowed an more excellent discrimination and yielded a high sensitivity and specificity(82.3% and 80.5%), based on a cut-off level of 1.485.

      Conclusion:
      AFB associated with WLB is a promising method which allows characterisation and differentiation of benign and malignant lesions with a high sensitivity, specificity based on R/G value.

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    P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 2
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      P3.01-010 - Multivariate Survival Analysis of China IRESSA Charitable Aid Project in Shanghai (ID 2671)

      09:30 - 09:30 AM  |  Author(s): B. Han

      • Abstract
      • Slides

      Background:
      Since Jan 2007, China Charity Federation launched IRESSA Charitable Aid Project for advanced non small cell lung cancer which oral IRESSA was effective for 6 months and have failed previous chemotherapy or received first line IRESSA for EGFR mutation positive. This study investigated the survival and correlation influencing factor of China Charitable Aid Project in shanghai by COX multivariate analysis .

      Methods:
      A retrospective investigation enrolled advanced non small cell lung cancer patient of IRESSA Charitable Aid Project from Jan 2007 to 30 Jun 2013 at 7 centre in Shanghai . The patients oral IRESSA was effective for 6 months who have failed previous chemotherapy or received first line IRESSA for EGFR mutation positive. IRESSA 250mg QD was taken and prescribed monthly. Tumor assessment was performed every 8 weeks, patients continued to receive IRESSA until disease progression (timely withdraw) or unacceptable toxicity or no benefit from this project which was considered as slower progression(late withdraw). The patient were Followed up until 30 Aug 2014. The primary end point was OS and correlation influencing factor. Using the Kaplan-Meier and COX proportional hazards model analyze the correlation between survival and age, gender, smoking status, pathology, indications and timely withdraw of IRESSA.

      Results:
      A total of 1066 patients were enrolled, the median age was 64, including 339 cases of greater than or equal to 70. Most patients were female (845,79.3%) and no-smokers (992,93.1%), and 94.1% was adenocarcinoma. Indication for second and multiple line patients were 96.1%(1024). The midian PFS was 33 months (95%CI:29.8-36.2),and the MST was 37 months (95%CI:32.5-41.5). COX multivariate analysis revealed timely withdraw group was significantly longer OS ( hazard ration 1.627; 95%CI:1.378-1.922, p=0.000) , more than 70 years old, smoking and indication for second line patient was significantly worse OS (hazard ration 0.692; 95%CI:0.587-0.816, p=0.000; 0.714; 95%CI: 0.531-0.960, p=0.026; 0.498 ;95%CI: 0.265-0.935,p=0.03 respectively.

      Conclusion:
      96.1% of the patient in Iressa charitable aid projects were second or multiple line treatment due to chemotherapy failure, PFS and OS still reached 33 and 37 months, significantly better than the historical reports. The possible reason was enrolled patients with IRESSA effective for 6 months , It could be EGFR mutation positive, of which no-smoking patients ratio were as high as 93.1%, they maybe have a better prognosis. Multivariate analysis showed OS was significantly prolonged in timely withdraw group after disease deteriorate.

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      P3.01-013 - Combination of Chemotherapy and Gefitinib as First-Line Treatment of Patients with Advanced Lung Adenocarcinoma and Sensitive EGFR Mutations (ID 634)

      09:30 - 09:30 AM  |  Author(s): B. Han

      • Abstract

      Background:
      The results of fastact2 show that chemotherapy plus erlotinib significantly prolonged PFS and OS of patients with NSCLC. However, outcome of the combination therapy are similar to those reported in several trials of single-agent EGFR TKIs. So which is the optimal first-line treatment for patients who harbored a sensitive EGFR mutation? We need a head-to-head study to reply.

      Methods:
      77 untreated patients with advanced lung adenocarcinoma who harbored sensitive EGFR mutations, and with ECOG PS 0-1, were randomly assigned to 3 groups. 25 patients were allocated to the combination therapy group (group A), received pemetrexed (500 mg/m(2) on day 1) plus carboplatin (AUC 5 on day 1) combined with gefitinib (250 mg/day on days 5-21) and repeated every 4 weeks for up to six cycles, then continued to receive pemetrexed combined with gefitinib every 4 weeks. 26 patients allocated to the chemotherapy group (group B), received the same chemotherapy regimen alone every 4 weeks for up to six cycles, then continued to receive pemetrexed alone every 4 weeks. 26 patients allocated to the gefitinib group (group C), and received gefitinib alone. All therapies of 3 groups were continued until progression or unacceptable toxicity or death. The primary endpoint was Median PFS. Analyses were done on an ITT basis.

      Results:
      Median PFS for patients in group A was 19.1months, 95% CI (17.1, 21.1), Median PFS for patients in group B was 5.5months, 95% CI (4.4, 6.8), Median PFS for patients in group C was 9.9months, 95% CI (7.0, 12.7). 6-month PFS was96.0% (24 of 25) in the group A, 38.5% (10 of 26) in the group B, and 73.1% (19 of 26) in the group C. ORR was 80.0% in the group A, 34.6% in the group B, and 61.5% in the group C. The most common grade 3-4 adverse events were neutropenia (3 [12.0%] of patients in the group A vs 4 [15.4%] in the group B vs 0 [0.0%] in the group C ), fatigue (2 [8.0%] of patients in the group A vs 2 [7.7%] in the group B vs 0 [0.0%] in the group C ), and liver dysfunction (3 [12.0%] of patients in the group A vs 0 [0.0%] in the group B vs 1 [3.8%] in the group C ), skin allergy (0 [0.0%] of patients in the group A vs 1 [3.8%] in the group B vs 0 [0.0%] in the group C )

      Conclusion:
      Patients with lung adenocarcinoma who harbored a sensitive EGFR mutation have longer PFS if they are treated with pemetrexed plus carboplatin combined with gefitinib.

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    P3.02 - Poster Session/ Treatment of Localized Disease – NSCLC (ID 211)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      P3.02-004 - PD-L1 Overexpression in NSCLC Inversely Correlated with Survival of NSCLC Patients (ID 1100)

      09:30 - 09:30 AM  |  Author(s): B. Han

      • Abstract
      • Slides

      Background:
      Programmed cell death protein 1, also known as PD1, is a 288 amino acids cell surface protein in the immunoglobulin superfamily. [[1]] PD-1 is expressed on T-cells and pro-B cells, plays a pivotal role in their differentiation. [[2]] PD-1 has two ligands, PD-L1 and PD-L2, which are the members of a peripheral membrane protein family called B7. [[3][4]] PD-L1 can suppress immune system in some special events such as pregnancy and auto immune disease. Binding of PD-L1 with its receptor PD-1 on T cells delivers a signal that inhibits TCR-mediated activation of IL-2 production and T cell proliferation. [[5]] PD-L2’s expression is more restricted compare to PD-L1 and mainly in antigen-presenting cells like Dendritic Cells and microphages. [[4]] Here we report a study of 139 NSCLC patients diagnosed and undergone primary surgery in Shanghai Chest Hospital. The expression of PD-L1 was exanimated by immunohistochemistry, and has a positive correlation with the stage of NSCLC. We also observed a significant correlation between PD-L1 over expression and EGFR mutation, which has the potential to be an favorable prognostic factor. High PD-L1 expression and EGFR mutation also correlated with a significant longer survival time of patients

      Methods:
      One pathologist examined the H&E- and IHC-stained slides and evaluated the results. The evaluation were done blinded as to the clinical pathologic characteristics and patient outcome. A series of 139 patients diagnosed with NSCLC and undergone primary surgery at Shanghai Chest Hospital (Shanghai, China) from January to December of 2008 were selected in this study. All the patients received lobectomy standard with systematic lymph node dissection. Immunohistochemistry staining for PD-L1 were performed both for tumor and tissue surrounding the tumor.PD-L1 positivity (PDL1+) was defined as 5% tumor cell membrane staining at any intensity.One pathologist examined the H&E- and IHC-stained slides and evaluated the results. The evaluation were done blinded as to the clinical pathologic characteristics and patient outcome. Overall survival data were obtained for each patient by following up visit performed on 2014.

      Results:
      A total of 139 tumors were examined after exclusion of uninformative slides. There were 72 patients (54.1 %) with stage II, and 61 (45.9 %) with stage III disease. For histological sub­types, there were 90 with adenocarcinoma, 43 with square carcinoma, and 6 with others. Of these, positive evaluation of PD-L1 staining was present in 81 (61.8 %) specimens, while 50 ( 38.2 %) specimens showed negtive/low PD-L1 staining, while the tumor adjacent tissue showed also negtive/low PD-L1 expression .We also did genotyping for the specimens and found about one third of them (50 in a total 133 specimens, 33.3%) carry EGFR mutation. Among the mutations,15 are happened on exome 19 and 33 are on exome 21. PD-L1 positively expression imply a longer survival time compared with PD-L1negatively expression.

      Conclusion:
      Our results suggest a prognostic value of PD-L1 expression evaluation, which can also be a potentiall immuno-target therapy for lung cancer

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