Scientific Program

Filter Results:

Show Only CME Accredited Sessions

  • +

    MS24 - Global Perspectives on Tobacco Control

    • Type: Mini Symposium
    • Track: Prevention and Tobacco Control
    • Moderators:
    • +

      MS24.01 - Tobacco Control Impacting the Effectiveness and Cost of Cancer Care

      10:30 - 10:45  |  Presenting Author(s): Graham Warren

      • Abstract

      Abstract not provided

    • +

      MS24.02 - Legal Action Against the Tobacco Industry in Europe

      10:45 - 11:00  |  Author(s): Wanda De Kanter

      • Abstract

      Abstract not provided

    • +

      MS24.03 - The Importance of Physician Involvement in Tobacco Control

      11:00 - 11:15  |  Presenting Author(s): Jacek Jassem

      • Abstract

      Abstract not provided

    • +

      MS24.04 - Challenges of Tobacco Control in China

      11:15 - 11:30  |  Presenting Author(s): Caicun Zhou

      • Abstract

      Abstract not provided

    • +

      MS24.05 - Q&A

      11:30 - 12:00

      • Abstract

      Abstract not provided

  • +

    MS25 - Genetic and Prognostic Markers in Mesothelioma; Going Beyond the Histology Subtypes

    • Type: Mini Symposium
    • Track: Mesothelioma
    • Moderators:
    • +

      MS25.01 - Impact of Tumor Volume on Outcome: What Are the Limitations?

      10:30 - 10:45  |  Presenting Author(s): Anna K. Nowak

      • Abstract

      Abstract

      A key goal of cancer staging is to stratify patient survival using anatomical tumour characteristics identified on imaging at presentation. The relationship between burden of cancer and patient outcomes is an established tenet of oncology, and most staging and prognostic systems incorporate surrogates or estimates of total tumour burden. Nevertheless, malignant pleural mesothelioma has long posed challenges in quantifying tumour burden for staging and prognostication. Many cancers grow outward from a nidus to form a mass of tumour cells which can be measured in three dimensions and volume of tumour quantified. However, the unique morphology of mesothelioma, growing as a sheet of tumour around the pleural cavity, adds complexity to the routine quantification of tumour burden. Furthermore, CT imaging, at least using human interpretation, may have difficulty distinguishing between pleural tumour and atelectasis, pleural fluid, and pleural scarring or plaques, confounding the accurate measurement of tumour volume.

      The relationship between tumour burden and outcomes in mesothelioma was first reported in 1997, noting that tumour size as measured using 3-D reconstructions of chest CT was prognostic in patients undergoing surgical resection, with a tumour volume <100cc predicting better survival1. These findings have been reproduced in a number of studies, both using CT imaging in the context of extrapleural pneumonectomy2 and using FDG-PET to estimate pleural tumour volume in non-surgically treated patients3. However, the technical challenges of accurately and reproducibly measuring tumour volume have remained barriers to routinely incorporating this metric into clinical practice prognostication, staging systems, and clinical trial stratification.

      In practical terms, what do we need to be able to apply an estimate of tumour volume in everyday clinical practice? Centres of excellence and radiology research laboratories may be able to use computerised estimates of volume as measured by CT scan or FDG-PET scan, however a sound prognostic indicator which can be applied to the population as a whole must also be applicable in a less resource-rich environment. Currently, there are numerous commercial and research tools for measuring tumour volume, however each requires a different level of clinician or radiographer input, and those which require manual oversight or contouring are also prone to inter-observer variability. Furthermore, it is not clear whether there is consistency between platforms.

      The most recent iteration of the IASLC staging database collected information on unidimensional measurements of pleural tumour thickness from 472 patients as a surrogate measure of tumour bulk, attempting to approach the semi-quantification of tumour bulk using a technique which could be rapidly applied in any setting, including community practice or low resource settings. In brief, measurements of pleural tumour were taken perpendicular to the chest wall or mediastinum at the point of maximum tumour thickness, one each in the upper, middle and lower thirds of the thorax4 (Figure 1a and b). As published in the recent update of the AJCC/IUCC staging system for mesothelioma, these measurements could be analysed in a number of ways, but were consistently identified as prognostic indicators and may even provide better discrimination between patient outcomes than existing T stages, which classify by the extent of anatomical organ involvement or invasion, rather than tumour bulk. Whether these measurements were summated, or dichotomised by maximal thickness, or ranked by quartile, these findings were consistent and predicted for overall survival.

      Another recent publication supports the relationship between unidimensional tumour measurements of thickness, and both tumour volume and survival5. Taking three structured measurements from the mediastinum, chest wall, and diaphragm, nine measurements were determined, which correlated significantly (p<0.0001) with total tumour volume as estimated by gross tumour volume from a radiation boost volume calculation. Diaphragmatic tumour thickness was more strongly associated with time to recurrence (p<0.0001) and survival (p=0.001) than mediastinal or chest wall tumour thickness.

      In conclusion, whilst tumour volume is clearly a prognostic indicator in mesothelioma, the question of how to best incorporate this metric into routine staging and clinical practice remains open. The IASLC Mesothelioma Staging Database will shortly open to further data collection, and will again incorporate unidimensional measurements of tumour thickness, in an effort to further define a simple and readily applied surrogate of volume. Automated measurement of volume continues to be refined by multiple investigators, and concordance between platforms will be needed to move the field forward.

      1. Pass HI, Temeck BK, Kranda K, Steinberg SM, Feuerstein IR. Preoperative tumor volume is associated with outcome in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1998;115:310-7; discussion 7-8.

      2. Gill RR, Richards WG, Yeap BY, et al. Epithelial malignant pleural mesothelioma after extrapleural pneumonectomy: stratification of survival with CT-derived tumor volume. AJR Am J Roentgenol 2012;198:359-63.

      3. Nowak AK, Francis RJ, Phillips MJ, et al. A Novel Prognostic Model for Malignant Mesothelioma Incorporating Quantitative FDG-PET Imaging with Clinical Parameters. Clin Cancer Res 2010;16:2409-17.

      4. Nowak AK, Chansky K, Rice DC, et al. The IASLC Mesothelioma Staging Project: Proposals for Revisions of the T Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Pleural Mesothelioma. J Thorac Oncol 2016;11:2089-99.

      5. de Perrot M, Dong Z, Bradbury P, et al. Impact of tumour thickness on survival after radical radiation and surgery in malignant pleural mesothelioma. The European respiratory journal 2017;49.

      Figure 1: In the IASLC T staging database, tumour bulk was estimated by measuring the thickest tumour at the upper, middle and lower hemithorax bounded by structures shown above and below lines in (a), (b). Tumour is measured perpendicular to the chest wall or mediastinum (c).


      wclc extended abstract figure 1.jpg

      e353dbe42c8654f33588d4da0b517469

    • +

      MS25.02 - How Should P16, BAP1, and NF2 Mutations Be Integrated in Therapeutic Algorithms?

      10:45 - 11:00  |  Presenting Author(s): Francoise Galateau-Salle

      • Abstract

      Abstract not provided

    • +

      MS25.03 - Impact of Innate and Adaptive Tumor Infiltrating Cells on Prognosis

      11:00 - 11:15  |  Presenting Author(s): Thomas John

      • Abstract

      Abstract not provided

    • +

      MS25.04 - Biomarkers in Clinical Practice: Is It Prime Time?

      11:15 - 11:30  |  Presenting Author(s): Harvey Pass

      • Abstract

      Abstract not provided

    • +

      MS25.05 - Targeting the Micro-RNA: A New Therapeutic Venture

      11:30 - 11:45  |  Presenting Author(s): Nick Pavlakis

      • Abstract

      Abstract not provided

    • +

      MS25.06 - Q&A

      11:45 - 12:00

      • Abstract

      Abstract not provided

  • +

    MS26 - From Textbook to Practice Around the World

    • Type: Mini Symposium
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Moderators:
    • +

      MS26.01 - Translation of Clinical Data to Real World - Asia

      10:30 - 10:45  |  Presenting Author(s): Dae Ho Lee

      • Abstract

      Abstract not provided

    • +

      MS26.02 - Translation of Clinical Data to Real World - North America

      10:45 - 11:00  |  Presenting Author(s): Cheryl Ho

      • Abstract

      Abstract not provided

    • +

      MS26.03 - Translation of Clinical Data to Real World - Europe

      11:00 - 11:15  |  Presenting Author(s): Fabrice Barlesi

      • Abstract

      Abstract not provided

    • +

      MS26.04 - Translation of Clinical Data to Real World - Latin America/Africa

      11:15 - 11:30  |  Presenting Author(s): Luis Ubillos

      • Abstract

      Abstract not provided

    • +

      MS26.05 - Panel Discussion

      11:30 - 12:00

      • Abstract

      Abstract not provided

  • +

    MS27 - Therapeutic Implications of Staging Issues

    • Type: Mini Symposium
    • Track: Treatment of Early Stage/Localized Disease
    • Moderators:
    • +

      MS27.01 - Staging of Lymph Nodes in Early Stage NSCLC: Therapeutic Implications

      10:30 - 10:45  |  Presenting Author(s): Raymond U. Osarogiagbon

      • Abstract

      Abstract not provided

    • +

      MS27.02 - Invasive Staging in Medically Inoperable Patients Treated with SBRT: Is It Necessary?

      10:45 - 11:00  |  Presenting Author(s): Anand Swaminath

      • Abstract

      Abstract not provided

    • +

      MS27.03 - Multiple Lung Nodules: M1, T4 or T3? Are They Really Different?

      11:00 - 11:15  |  Presenting Author(s): Frank Detterbeck

      • Abstract

      Abstract not provided

    • +

      MS27.04 - Therapeutic Implications of AJCC 8th Edition T1 Subsets

      11:15 - 11:30  |  Presenting Author(s): Laura Donahoe

      • Abstract

      Abstract not provided

    • +

      MS27.05 - The Future of Precision Therapy for Localized Lung Cancer

      11:30 - 11:45  |  Presenting Author(s): Takashi Seto

      • Abstract

      Abstract not provided

    • +

      MS27.06 - Q&A

      11:45 - 12:00

      • Abstract

      Abstract not provided

  • +

    OA13 - Therapeutics and Radiation for Small Cell Lung Cancer

    • Type: Oral Abstract Session
    • Track: Small Cell Lung Cancer/NET
    • Moderators:
    • +

      OA13.01 - The Impact of [<sup>18</sup>F]fludeoxyglucose PET/CT in Small-Cell Lung Cancer: Analysis of the Phase 3 CONVERT Trial 

      10:30 - 10:40  |  Presenting Author(s): Corinne Faivre-Finn  |  Author(s): Prakash Manoharan, Ahmed Salem, Hitesh Mistry, Michael Gornall, Susan V Harden, Peter Julyan, Imogen Locke, Jonathan McAleese, Rhona McMenemin, Nazia Mohammed, Michael Snee, Thomas Westwood, Sarah Woods

      • Abstract

      Background

      The role of 18fludeoxyglucose (18F-FDG) PET/CT in the management of limited stage small-cell lung cancer (LS-SCLC) is uncertain. Previous studies have shown that 18F-FDG PET/CT upstages up to 30% of LS-SCLC patients. Data from the CONVERT trial was analysed to investigate the impact of 18F-FDG PET/CT in the management of LS-SCLC. The prognostic significance of pre-treatment 18F-FDG PET parameters was also investigated in an exploratory analysis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      CONVERT is an international multi-centre phase III trial that randomly assigned fit patients to receive either twice-daily (45Gy in 30 fractions) or once-daily (66Gy in 33 fractions) radiotherapy starting on day 22 of chemotherapy cycle 1 (NCT00433563). Chemotherapy consisted of 4-6 cycles of cisplatin and etoposide. Prophylactic cranial irradiation was offered, if indicated. Contrast-enhanced thorax and abdomen CT and brain imaging (with/without bone scintigraphy according to clinical indication) were mandated for all CONVERT participants (conventional imaging). Staging with 18F-FDG PET/CT was allowed but not mandated. The primary endpoint was overall survival. Pre-treatment 18F-FDG PET metabolic parameters were investigated in a subset of patients (n=96) including standardised uptake values (max, mean and peak), volumetric and heterogeneity parameters.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 547 patients recruited to CONVERT, 540 patients with data on staging investigations and outcome were included in this analysis. The use of staging 18F-FDG PET/CT was variable in the 8 countries recruiting to CONVERT (range, 41-100%). Compared to patients who underwent conventional imaging (n=231), patients who were also staged with 18F-FDG PET/CT (n=309) had smaller gross tumour volume (p=0·003), were less likely to have elevated pre-treatment serum lactate dehydrogenase (p=0·035), and received more chemotherapy cycles (p=0·026). There were no other significant differences in baseline and treatment characteristics between the two groups. There were no significant differences in overall (hazard ratio 0·87 [95% CI 0·70-1·08]; p=0·192) and progression-free survival (hazard ratio 0·87 [95% CI 0·71-1·07]; p=0·198) between patients staged with 18F-FDG PET/CT in addition to conventional imaging or with conventional imaging alone. These results were observed irrespective of treatment group (once-daily and twice-daily radiotherapy). Pre-treatment 18F-FDG PET parameters were also not prognostic.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In CONVERT, survival outcomes were not different in LS-SCLC patients staged with or without 18F-FDG PET/CT. This was despite those patients staged with 18F-PET/CT having more favourable baseline and treatment characteristics. Our findings suggest that conventional imaging is sufficient to select LS-SCLC patients for concurrent chemoradiotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      OA13.02 - Two Novel Immunotherapy Agents Targeting DLL3 in SCLC: Trials in Progress of AMG 757 and AMG 119

      10:40 - 10:50  |  Presenting Author(s): Taofeek Owonikoko  |  Author(s): Marie-Anne Damiette Smit, Hossein Borghaei, Ravi Salgia, Michael Boyer, Erik R. Rasmussen, Lauren Byers

      • Abstract

      Background
      Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by initial response to chemotherapy and radiotherapy followed by relapse or progression with chemoresistant disease. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is specifically upregulated in SCLC. IHC profiling of tumor samples showed DLL3 expression in 86% of SCLC tumors and minimal expression in normal tissue.
      We are conducting clinical trials of two novel immunotherapy agents that target DLL3. AMG 757 is a half-life extended bispecific T cell engager (BiTE®) antibody construct that is designed to transiently crosslink DLL3-positive SCLC cells to CD3-positive T cells and induce T cell–mediated tumor cell lysis and concomitant T cell proliferation. AMG 119 is an adoptive cellular therapy that consists of a patient’s autologous T cells that have been genetically modified ex vivo to express a transmembrane chimeric antigen receptor that targets DLL3 on the surface of SCLC cells. Both AMG 119 and AMG 757 showed potent killing of SCLC cell lines with a broad range of DLL3 expression in vitro and inhibition of tumor growth in the SHP-77 human SCLC xenograft model in vivo. AMG 757 was well tolerated in a preclinical multi-dose GLP toxicology study, with no evidence of tissue damage at weekly doses as high as 4.5 mg/kg.
      a9ded1e5ce5d75814730bb4caaf49419 Method
      NCT03319940 is an open label, phase 1 study evaluating the safety, tolerability and pharmacokinetics of AMG 757 that will initially enroll adult patients with SCLC who have progressed or recurred following platinum-based chemotherapy. Key inclusion criteria: ECOG PS 0–2, life expectancy ≥12 weeks, at least 2 measurable lesions per modified RECIST 1.1 criteria, and adequate organ function. The study will later enroll patients with extended disease SCLC with ongoing clinical benefit following no more than 6 cycles of first-line platinum-based chemotherapy. AMG 757 will be administered as an intravenous infusion once every 2 weeks.
      NCT03392064 is an open-label, phase 1 study evaluating the safety, tolerability and efficacy of AMG 119 in adult patients with SCLC whose disease has progressed or recurred after at least one platinum-based regimen. Key inclusion criteria: ECOG PS 0–1, at least 2 measurable lesions per modified RECIST 1.1 criteria, no evidence of CNS metastasis, and adequate organ function. AMG 119 will be administered as a one-time intravenous infusion.
      Both of these studies are currently enrolling patients. For more information, please contact Amgen Medical Information: medinfo@amgen.com.
      4c3880bb027f159e801041b1021e88e8

    • +

      OA13.03 - Anlotinib as Third-Line or Further-Line Treatment in Relapsed SCLC: A Multicentre, Randomized, Double-Blind Phase 2 Trial

      10:50 - 11:00  |  Presenting Author(s): Ying Cheng  |  Author(s): Qiming Wang, Kai Li, Jianhua Shi, Lin Wu, Baohui Han, Gongyan Chen, Jianxing He, Jie Wang, Haifeng Qin, Xiaoling Li

      • Abstract

      Background

      Treatment for patients with relapsed small cell lung cancer (SCLC) who failed ≥ 2 lines of chemotherapy have high unmet needs. Anlotinib is a novel TKI with highly selective inhibition effects on multi-targets, especially on VEGFR, c-Kit, PDGFR, FGFR. Here we report results of a phase 2 study of anlotinib for the third-line and further-line treatment of SCLC. (ALTER1202, NCT03059797).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible either limited- or extensive-stage SCLC patients with disease progression after ≥ 2 lines of chemotherapy were randomized 2:1 to anlotinib or placebo (12 mg PO QD from day 1 to 14, every 3 weeks). The primary endpoint was PFS and secondary endpoints was OS, ORR, DCR, quality of life and safety.

      4c3880bb027f159e801041b1021e88e8 Result

      Between March 2017 and May 2018, 120 patients from 11 centers were randomized to either anlotinib arm (n=82) or placebo arm (n=38). Until the data cutoff date (30 Jun 2018), median PFS was 4.1 months (95%CI, 2.8 to 4.2 months) in anlotinib arm and 0.7 months (95% CI, 0.7 to 0.8 months) in placebo arm (HR, 0.19; 95% CI, 0.12 to 0.32, p<0.0001). OS data were not sufficiently mature for analysis. Although ORR was similar, considerable improvement in DCR was observed in anlotinib arm (71.6% vs 13.2%, p<0.0001). Treatment-related adverse events (TRAEs) occurred more frequently in anlotinib arm than that in placebo (87.7% and 74.4%). The most common TRAEs were hypertension, anorexia, fatigue, and hand-foot syndrome. Grade ≥3 TRAEs occurred in 29 (35.8%) of patients in anlotinib arm and 6 (15.4%) in placebo arm, respectively.

      figure 1 kaplan-meier estimates of progression-free survival.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      ALTER 1202 study demonstrates anlotinib should be considered a treatment option for patients with relapsed SCLC who have experienced treatment failure with two lines of chemotherapy. The safety profile was consistent with the previous report and no newly adverse events were identified.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      OA13.04 - Discussant - OA 13.01, OA 13.02, OA 13.03

      11:00 - 11:15  |  Presenting Author(s): Normand Blais

      • Abstract

      Abstract not provided

    • +

      OA13.05 - Prophylactic Cranial Irradiation (PCI) for Limited-Stage Small-Cell Lung Cancer: Results from the Phase 3 CONVERT Trial

      11:15 - 11:25  |  Presenting Author(s): Cecile Le Pechoux  |  Author(s): Antonin Levy, Hitesh Mistry, Isabelle Martel-Lafay, Andrea Bezjak, Delphine Lerouge, Laetitia Padovani, Paul Taylor, Corinne Faivre-Finn

      • Abstract

      Background

      PCI is considered standard of care in limited-stage small-cell lung cancer (LS-SCLC) patients. However the impact of the dose and fractionation of thoracic radiotherapy (RT) on the risk of developing brain metastasis (BM) has not been evaluated prospectively.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      CONVERT is an international, phase 3 trial that randomly assigned patients to receive twice-daily (BD 45Gy in 30 fractions) or once-daily (OD 66Gy in 33 fractions) RT starting on day 22 of chemotherapy (CT) cycle 1 (NCT00433563). PCI was offered, if indicated. Data on thoracic and brain RT delivery and timing, rate of BM and overall survival (OS) in patients treated with PCI was analysed. The association of the risk of developing BM/OS and predictor variables, using a competing risk regression model developed by Fine and Gray for BM or the standard Cox proportional hazards model for OS, was investigated.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 547 patients recruited to the study, 449 (82%) received PCI after completion of CTRT. PCI was delivered to 220/273 participants (81%) in the BD group and 229/270 in the OD group (85%; p=0.49). Pre-CTRT brain imaging consisted of CT-scan in 356/449 patients (79%) and MRI in 83/449 (18%) patients. Total median PCI dose was 25 Gy in both BD and OD groups (p=0.74). PCI was delivered later after CT in the OD group compared to the BD group (median days post CT 37 vs. 35 days, respectively; p=0.04). In patients who received PCI, 75 (17%) developed BM (35 [8%] in OD and 40 [9%] in BD) and 173 (39%) other extracranial progression. In the univariate analysis, GTV was associated with an increased risk of BM (HR: 1.37 [95%CI 1.09-1.73]; p=0.007) or other radiological progression events (HR: 1.43 [95%CI 1.11-1.85]; p=0.006), whereas in a multivariate analysis both GTV and PS were associated with either progression type. The median OS of patients treated with PCI was 29 months (95%CI 25.8-35.7). Median OS was 28 months in BD (95%CI 22-35) and 31 months in OD (95%CI 27-52; p=0.1). In the univariate analysis of OS, PCI timing from end of CT, weight loss >10%, and thoracic GTV were prognostic factors associated with OS. In the multivariate analysis, only thoracic GTV was associated with OS. Delay between end of CT and PCI was not associated with OS (p=0.2).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients receiving OD or BD thoracic RT have the same risk of developing BM. Larger tumours are associated with a higher risk of BM.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      OA13.06 - Final Report of a Prospective Randomized Study on Thoracic Radiotherapy Target Volumes in Limited-stage Small Cell Lung Cancer with Radiation Dosimetric and Pathologic Analyses

      11:25 - 11:35  |  Presenting Author(s): Xiao Hu  |  Author(s): Yong Bao, Yu Jin Xu, Hui Neng Zhu, Jin Shi Liu, Li Zhang, Xinmin Yu, Yun Fan, Yi Ping Zhang, Wen Yong Sun, Weimin Mao, Ming Chen

      • Abstract

      Background

      The interim analysis of our prospective trial, which compared irradiation to pre-chemotherapy or post-chemotherapy tumour extent while application of involved field radiotherapy (IFRT) for limited-stage small cell lung cancer (SCLC), showed that reduced field did not result in increased local/regional out-field recurrence. This report presents the final results of the clinical study with radiation dosimetric and pathologic analysis as interpretations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Chemotherapy consisted of 4 to 6 cycles of etoposide and cisplatin (EP). After 2 cycles of EP, patients were randomly assigned to receive thoracic radiotherapy (TRT) to either the post- or pre-chemotherapy tumour extent as study arm or control. TRT was administered concurrently with cycle 3 chemotherapy. IFRT was applied for both arms. The lymph node regions (groups 1 to 10) were contoured in treatment planning system. The intentional or incidental radiation doses to each lymph node regions were recorded. Patients with stage T1-2N0-1M0 SCLC received radical lobectomy. The minimal distances between microscopic nidus and the edge of gross tumor were measured. The clinical target volume of the primary tumor (CTV-T) was defined as the margins covering 95% of microscopic disease extension.

      4c3880bb027f159e801041b1021e88e8 Result

      Between June, 2002 and January, 2017, 159 and 150 patients were randomly assigned to study arm or control. The 1-, 3-, and 5-year local/regional progression free probability were 79.4%, 60.1% and 60.1% respectively in the study arm versus 79.8%, 64.5%, and 57.3% in the control (p=0.73). The median overall survival (OS) time was 22.1 months in the study arm (95% CI, 18.2-26.0) and 26.9 months (95% CI, 23.5-30.3) in the control, the 1-, 3-, 5-, and 7-year OS rates were 81.1%, 31.6%, 23.9% and 22.2% respectively in the study arm versus 85.3%, 36.6%, 26.1% and 20.0% in the control arm (p=0.51). A total of 1680 lymph node regions in 105 patients were contoured. The lymph node regions that received incidental radiation doses over 30Gy were: 7, 3P, 4L, 6, 4R, 5 and 2L. Eight patients were enrolled in the pathologic evaluation of CTV-T. The median range of CTV-T in patients received or did not receive neoadjuvant chemotherapy were 0.4mm and 1.7mm respectively, a margin of 1.4mm and 10.2mm could cover 95% of microscopic nidus extension respectively (p=0.00).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Irradiating post-chemotherapy tumour extent and applicant of IFRT didn't increase local/regional failure, and the OS difference wasn't statistically significant between the two arms. TRT could be limited to post-chemotherapy tumour extent, while IFRT could be routinely applied for limited-stage SCLC patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      OA13.07 - Survival Outcomes After Whole Brain Radiotherapy for Brain Metastases in Elderly Patients with Newly Diagnosed Metastatic Small Cell Carcinoma.

      11:35 - 11:45  |  Presenting Author(s): Paul Renz  |  Author(s): Shaakir Hasan, Andrew Turrisi Iii, Athanasios Colonias, Rodney Wegner

      • Abstract

      Background

      Small cell lung cancer (SCLC) is an aggressive malignancy with a tendency to affect the elderly and to metastasize to the brain. However, elderly patients tolerate whole brain radiotherapy (WBRT) poorly with potentially detrimental effects on quality of life. Accordingly, the survival benefit of WBRT in this population is unclear. We utilized the national cancer database (NCDB) to evaluate the survival outcomes following WBRT in elderly patients with SCLC and brain metastases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We analyzed 1615 patients >75 years old diagnosed with SCLC and brain metastases at diagnosis. Patients were categorized by type of therapy: chemotherapy + WBRT (n=576), chemotherapy alone (n=238), WBRT alone (n=360) and no chemotherapy or WBRT (n=441). Clinical and demographic characteristics were reported for each treatment cohort with a subsequent multivariable regression analysis for survival. Propensity score-matching analysis was used for balance between comparison groups.

      4c3880bb027f159e801041b1021e88e8 Result

      Median patient age was 79 years. 51% had brain-only metastatic disease. Whole brain radiation median dose delivered was 30 Gy (1.8-40 Gy). Median follow up was 2.8 months (0.03-68.01) for all patients. Of the patients included in this study, 1530 had died at time of analysis yielding a median OS of 2.9 months with 6 month and 1 year survivals of 31% and 12%, respectively.

      For patients without chemotherapy, median OS with WBRT was 1.9 months compared to 1.2 months without WBRT (p<0.0001). For patients receiving chemotherapy with, and without WBRT, median OS was 5.6 months and 6.4 months, respectively (p=0.43). Multivariable cox regression revealed age >80, extracranial disease, male sex, and rural location as predictors of increased risk of death.

      figure 1.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      In elderly patients 75 years old or greater with SCLC brain metastasis, WBRT was associated with a modest increase in survival in patients not fit for chemotherapy, and there was no association with increased survival over chemotherapy alone.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      OA13.08 - Discussant - OA 13.05, OA 13.06, OA 13.07

      11:45 - 12:00  |  Presenting Author(s): Inga Grills

      • Abstract

      Abstract not provided

  • +

    PC09 - Approaches to Management of Advanced NSCLC

    • Type: Pro-Con Session
    • Track: Advanced NSCLC
    • Moderators:
    • +

      PC09.01 - Debate 1: Early vs Delayed Treatment of Asymptomatic Brain Metastases in Wild-Type NSCLC - Early

      10:30 - 10:45  |  Presenting Author(s): Qing Zhou

      • Abstract

      Abstract not provided

    • +

      PC09.02 - Debate 1: Early vs Delayed Treatment of Asymptomatic Brain Metastases in Wild-Type NSCLC - Delayed

      10:45 - 11:00  |  Presenting Author(s): Walter John Curran, Jr.

      • Abstract

      Abstract not provided

    • +

      PC09.03 - Discussion

      11:00 - 11:15

      • Abstract

      Abstract not provided

    • +

      PC09.04 - Debate 2: Large Cell Neuroendocrine Carcinoma Should Be Treated like NSCLC or SCLC? - NSCLC

      11:15 - 11:30  |  Presenting Author(s): Noemi Reguart

      • Abstract

      Abstract not provided

    • +

      PC09.05 - Debate 2: Large Cell Neuroendocrine Carcinoma Should Be Treated like NSCLC or SCLC? - SCLC

      11:30 - 11:45  |  Presenting Author(s): Scott A. Laurie

      • Abstract

      Abstract not provided

    • +

      PC09.06 - Discussion

      11:45 - 12:00

      • Abstract

      Abstract not provided

  • +

    ISS16 - Symposium Supported by AbbVie: Biomarker Driven SCLC Treatment: Fact or Fiction? (Not IASLC CME Accredited)

    • Moderators:
    • +

      Introductions

      12:00 - 12:05  |  Presenting Author(s): Peter Michael Ellis

      • Abstract

      Abstract not provided

    • +

      Expanding options in treatment of SCLC: Unmet needs and new targets

      12:05 - 12:25  |  Presenting Author(s): Peter Michael Ellis

      • Abstract

      Abstract not provided

    • +

      Incorporating biomarker testing in SCLC patient evaluation: Current challenges and lessons learned from NSCLC

      12:25 - 12:50  |  Presenting Author(s): Philippe Joubert

      • Abstract

      Abstract not provided

    • +

      Changing treatment paradigm in SCLC: Emerging data on use of biomarkers in SCLC treatment

      12:50 - 13:20  |  Presenting Author(s): David P Carbone

      • Abstract

      Abstract not provided

    • +

      Panel discussion and Closing remarks

      13:20 - 13:30  |  Presenting Author(s): Peter Michael Ellis, Philippe Joubert, David P Carbone

      • Abstract

      Abstract not provided

  • +

    P3.01 - Advanced NSCLC (Not CME Accredited Session)

    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Moderators:
    • +

      P3.01-02 - Patients with a Smaller Primary Tumor and Fewer Metastases Could be Cured Even in Advanced Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Takuya Aoki  |  Author(s): Naoki Okada, Keito Enokida, Shigeaki Hattori, Tomoe Takeuchi, Fuminari Takahashi, Genki Takahashi, Kazuki Harada, Jun Tanaka, Masako Sato, Yukihiro Horio, Hiroto Takiguchi, Hiromi Tomomatsu, Katsuyoshi Tomomatsu, Takahisa Takihara, Kyoko Niimi, Naoki Hayama, Tsuyoshi Oguma, Tetsuya Urano, Koichiro Asano

      • Abstract

      Background

      Various types of immunothrapies have been extensively developed in advanced non-small cell lung cancer (NSCLC). Although median survival times have been getting very long in a certain population, complete remission (CR) is still uncommon. This study aimed to elucidate features of CR cases with advanced NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From our hospital database, 1,699 patients, registered as having lung cancer between August 2004 and April 2011, were examined. Those with stage III or IV histologically or cytologically confirmed NSCLC, whose treatment included chemotherapy, were retrospectively evaluated on Feb 13, 2017. CR, for the purposes of this study, was defined as a sustained CR at the five-year follow-up without treatment for one year, and features of CR patients were compared with those of long-surviving patients whose overall survival time (OS) exceeded 3 years.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 279 stage IV and 164 stage III patients. OS of 51 (18.3%) and 37 (22.6%) patients with stage IV and III were over 3 years, respectively. Five and 12 patients with stage IV and III, respectively, showed CR. The tale effects were observed in Stage III and IV advanced NSCLC mainly by chemotherapies without immunocheckpoint inhibitors. In stage IV, primary tumor diameters in the CR patients were shorter than those in the 3 OS < 5 patients, and metastatic numbers in the CR patients were fewer than those in the 3 OS < 5 patients. In stage III, there were no differences in primary tumor diameters and metastatic numbers among the 3 OS < 5, the 5 ≤ OS with existence of tumor, and the CR (5 ≤ OS without tumor) groups.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study demonstrated that CR might be possible in certain patients with small primary tumors and fewer metastases even in advanced NSCLC by employing combinations of various treatment modalities.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-03 - The Cost Benefit from Second Line Immunotherapy in Metastatic NSCLC: ASCO Value Framework Prospective

      12:00 - 13:30  |  Presenting Author(s): Ahmed Ashour Badawy  |  Author(s): Gehan Khedr, Waleed Arafat

      • Abstract

      Background

      In recent years there has been a major paradigm shift in the management of advanced stage NSCLC with uses of novel immunotherapy. Three immune check point inhibitors were approved as second line in advanced stage NSCLC namely nivolumab, pembrolizumab and atezolizumab. The high cost of these drug making decision for both physicians and patients challenging. ASCO developed a tool for help in decision making based on data obtained from clinical trial

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this study we used ASCO Value Framework to compare the net health benefit (NHB) of second line immune check point inhibitors approved in metastatic NSCLC

      4c3880bb027f159e801041b1021e88e8 Result

      Nivolumab was approved based on Check mate 17 and check mate 057 which compare nivolumab vs docetaxel in both squamous cell carcinoma and non-squamous NSCLC respectively with statistically significant improvement in overall survival with hazard ratio(0.59; 95% CI, 0.44 to 0.79; P<0.00) and ( 0.73; 96% CI, 0.59 to 0.89; P = 0.002) for both squamous cell carcinoma and non-squamous respectively. The calculated NHB for nivolumab vs docetaxel were 62.8 and 49.8 in both squamous cell carcinoma and non-squamous NSCLC respectively.

      Pembrolizumab was approved based on Keynote 010 which compare pembrolizumab vs docetaxel in metastatic NSCLC with statistically significant improvement in overall survival with hazard ratio 0·71, 95% CI 0·58–0·88; p=0·0008.The calculated NHB for pembrolizumab vs docetaxel was 46.1

      Atezolizumab was approved based on OAK trial which compare atezolizumab vs docetaxel for metastatic NSCLC with statistically significant improvement in overall survival with hazard ratio 0·73, 95% CI 0·62–0·87, p=0·0003. The calculated NHB for atezolizumab vs docetaxel was 49.8

      CheckMate 017

      CheckMate 057

      KEYNOTE-010

      OAK

      Clinical Benefit

      HR 0.59, P<0.001

      HR 0.73; P = 0.002

      HR 0·71; p=0·0008

      HR 0·73 ; P = 0·0003

      (HR death)

      9.2 vs. 6.0 months

      12.2 vs. 9.4 months

      12.7 vs. 8.5 months

      13.8 vs. 9.6 months

      +41 points

      +27 points

      +29 points

      +27 points

      Toxicity

      7% versus 55%, -87%

      10% vs. 54%, -79%,

      13% vs. 35%, -60%,

      15% vs. 43%, -63%,

      +7.2 Ponts

      +6.8 Points

      -2.9 Points

      +6.8 Points

      Bonus Points

      20 Points

      16 Points

      20 Points

      16 Points

      NHB

      68.2

      49.8

      46.1

      49.8

      Cost

      $39,300

      $39,300

      $39,000

      $37,500

      8eea62084ca7e541d918e823422bd82e Conclusion

      For second line immunotherapy for metastatic NSCLC calculated NHB is comparable for both three Immune check points inhibitors with nivolumab has best calculated NBH for metastatic squamous cell carcinoma NSCLC patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-04 - Immune Checkpoint Inhibitors (ICIs) in NSCLC: Immune Related Adverse Events (irAEs) and Outcomes. A Canadian Single Institution Experience.

      12:00 - 13:30  |  Presenting Author(s): Kiran Virik  |  Author(s): Bassam Basulaiman, Andrew G Robinson, Wilma Hopman, Kiran Virik

      • Abstract

      Background

      The ICIs are a major therapeutic advance in NSCLC with recognized toxicity in the form of irAEs. The association between irAEs and clinical benefit remains unclear but promising. The aim of this study was to examine the incidence and nature of of irAEs and correlative outcomes in patients treated with ICIs for advanced/recurrent NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective chart review of all advanced NSCLC patients treated with immunotherapy between January 2015 to December 2016 was undertaken. Treatment was either on a clinical trial or as a standard of care. Patient demographics, clinical, pathological, and radiological parameters were assessed and an exploratory analysis was conducted to review these factors and outcomes in patients with and without irAEs. The nature and timing of the irAES was also evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      47 patients had ICIs: 24 (51%) received either Nivolumab, Pembrolizumab or Durvalumab alone (SAIO), 15 (32%) had dual agent immunotherapy (DAIO), 8 (17%) had chemotherapy plus ICI. 26 pts (55.3%) were female; median age was 65 years (range 50-90), 15 (31%) had squamous NSCLC. Median months (m) of ICI treatment were 5 (1 – 32). 21/47 (45%) were alive at 1 year. IrAEs occurred in 29 patients (61.7%), 13% SAIO, 23% DAIOs and 15% chemotherapy plus ICI. IrAEs were: dermatological (n=13), diarrhea/colitis (n=10/1), thyroid dysfunction (n=9), and pneumonitis (n=8), hypophysitis (n=1) and nephritis (n=1). The earliest irAE was dermatological with a median onset of 6 weeks. In those with irAEs versus (v) no irAEs: RR = 55% v 11%, disease control rate (DCR) 76% v 33%. 13/29 (45%) had an irAE in ≤ 6 weeks: RR = 38%, DCR = 53% and 6 of these (46%) were alive at 1 year. 21 patients were alive at 1 year: 16/21 (76%) had an irAE and of these, 13/16 (81%) had 2 irAES or irAEs ≥ grade (G) 2. Median overall survival (OS) for all patients was 9m (6.3-11.7). Landmark analysis at 3m: median OS for no irAES v irAEs was 15m v 18 m, log rank p=0.76. Median survival of those with no irAE v G1 v ≥ G2 was 2m v 8m v 23m, log rank p= 0.014. Further correlative outcome data will be presented.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A landmark analysis at 3m did not show a statistically significant correlation between irAEs and survival. This merits further study as does the suggestion of a correlation between number of irAEs and grade with regards to outcome.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-05 - Mature Progression-Free Survival in Stage IV Non-Small Cell Lung Cancer Patients Treated With Pemetrexed Maintenance Therapy

      12:00 - 13:30  |  Presenting Author(s): Marta Batus  |  Author(s): Parva Kiran Bhatt, Philip Bonomi, Sanjib Basu

      • Abstract

      Background

      Pemetrexed maintenance therapy is associated with superior survival in stage IV Non-Squamous, Non-small Cell Lung Cancer patients. We have observed long term disease control in real world patients treated with Pemetrexed(Pem)/Platinum(Plat) +/- Bevacizumab(Bev) followed by Pem +/- Bev maintenance therapy. To our knowledge, there is no mature data regarding the tail of the Progression Free Survival (PFS) curve in these patients. The objectives of this retrospective analysis are to determine the frequency of long term disease control on Pem+/- Bev maintenance and to identify parameters associated with absence of disease progression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Our study looked at patients with Stage IV nsqNSCLC who received first line Pem/Plat followed by Pem maintenance between May 2010 and December 2017. We identified 241 patients from our database and analyzed their demographics, lab values, dates of therapy, and dates of progression. PFS was estimated by the Kaplan-Meier method and associations with patient characteristics were assessed by log-rank tests and Cox proportional hazards analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      Median age was 66 years, 60% female, and 72% Caucasian. Baseline ECOG performance status (PS) was 0(22%), 1(50%) and ≥ 2(22%). Disease progression was observed in 233 of 241 pts. with median PFS of 6.2 months. Absence of disease progression was observed in 34 pts. (14.2%) at 2 years, 19 pts. (7.9%) at 3 years, and 3 pts. (1.2%) at 5 years. Improved PFS was strongly associated with lower baseline neutrophil: lymphocyte ratio (NLR) when using NLR≤3.5 vs >3.5 (median PFS 9.7 mo vs 5.2 mo, p =0.004) as well as in a continuous scale (HR=1.04, p < 0.001). ECOG PS of 0/1 was also associated with superior PFS (p<.001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The similarity in median PFS in our patients (6.2 mo) and clinical trial data suggests that our group of real world patients did not have uniquely favorable baseline characteristics. Although long term absence of progression may have been solely due to favorable natural history of disease, we believe that it was also due to Pem maintenance. As a result, continued development of Pem plus immunotherapy regimens in nsqNSCLC may result in a higher rate of long term disease control.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-06 - Concomitant Plasma-Genotyped T790M Positivity and Small Cell Carcinoma Transformation in EGFR-Mutated NSCLC

      12:00 - 13:30  |  Presenting Author(s): Sourin Bhuniya  |  Author(s): Prasanta Raghab Mohapatra, Pritinanda Mishra, Susama Patra, Manoj Kumar Panigrahi, Gourahari Pradhan, Satyajeet Sahoo, Swagatika Samal

      • Abstract

      Background

      Patients of non-small cell lung cancer (NSCLC) having epidermal growth factor receptor (EGFR) gene mutation, initially show clinical response to EGFR Tyrosine-Kinase Inhibitors (TKI), but develop resistance after some months. However, the type and timing of TKI-resistance cannot be predicted as it is highly variable. Transformation to small cell lung cancer (SCLC) at progression during TKI-therapy and simultaneous acquisition of T790M EGFR-mutation is uncommonly reported.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Case report: Our patient is a 51 year-male, with stage IV NSCLC of adenocarcinoma subtype (TTF1 positive by IHC). He was initially treated with six cycles of pemetrexed and carboplatin to which he showed good response and was on regular follow up since September 2015. In the meantime, he was detected to have EGFR exon 21-mutation and was treated with Gefitinib for over two years. Patient was doing well and had complete disappearance of the tumour radiologically. After about 26 months of treatment he again became symptomatic. Repeat Computed tomography showed a lobulated mildly enhancing lesion 4.4 × 3 cm in right upper lobe. There were small nodules over bilateral lung fields and subpleural areas in right lower lobe, likely to be metastatic. Lytic lesions were also detected in dorsal (D2) and cervical (C5) vertebral bodies. Liquid biopsy showed T790M EGFR-mutation. Re-biopsy from right upper lobe showed transformation to neuroendocrine carcinoma (SCLC). Gefitinib was stopped and the patient was started on standard platin based doublet regimen for SCLC for the transformation. Patient has received four cycles of platin based chemotherapy and is doing well.

      4c3880bb027f159e801041b1021e88e8 Result

      "Section not applicable"

      8eea62084ca7e541d918e823422bd82e Conclusion

      This case report shows the possible underlying relationship between SCLC transformation and the T790M mutation, and that liquid biopsy approach may help overcome the problem of heterogeneity in acquired resistance to EGFR-tyrosine kinase inhibitors. In advanced NSCLC with EGFR-mutation, delayed onset of TKI-resistance can occur during TKI-treatment. Re-biopsies have increased the chance of detecting a T790M mutation and transformation. “Liquid biopsies” may potentially help identify heterogeneous genetic resistance-mechanisms; however, assessment of mechanisms such as SCLC-transformation needs tissue biopsies.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-07 - Outcome and Prognostic Factors in ALK+ve Metastatic Adenocarcinoma of Lung: Single Center Experience From Eastern India

      12:00 - 13:30  |  Presenting Author(s): Bivas Biswas  |  Author(s): Deepak Dabkara, Sandip Ganguly, Raj kumar Shrimali, Joydeep Ghosh, Prasad E, Divya Midha, Geetashree Mukherjee, Mayur Parihar, Deeapk Kumar Mishra, Neeraj Arora

      • Abstract

      Background

      Anaplastic lymphoma kinase (ALK) positive metastatic adenocarcinoma of lung constitutes 3-5% of all lung cancers. Outcome of this small sub-group improved substantially over last few years with discovery of many ALK-inhibitors. Indian patients scarcely represented in the registration trials of ALK-inhibitors. Here, we report our experience of clinic-pathological characteristics, treatment outcome & prognostic factors in ALK-positive metastatic adenocarcinoma of lung

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a single institutional review of patients treated between Oct’13 and Feb’18. ALK was assessed by Ventana immunohistochemistry and/or fluorescent-in-situ hybridization analysis. Response assessment was done by RECIST v1.1. Patient who received at least one cycle of chemotherapy or one month of ALK-inhibitor was assessed for survival analysis in a modified intent-to-treat analysis

      4c3880bb027f159e801041b1021e88e8 Result

      Seventy-eight patients were registered with median age of 53 years (range: 24-82). Baseline features and treatment details are mentioned in Table 1. After median follow-up of 15 months (range: 1-53), median overall survival (OS) was 52.2 months (95 CI: 37.2 – not reached) and median progression-free survival (PFS) was 17.8 months (95 CI: 13.1-24.2). Median OS was 37.2 months & not reached whereas median PFS was 14.2 months & 22 months in patients treated with upfront chemotherapy (n=24) and with upfront ALK-inhibitor (n=32), respectively. 2ndline PFS was 22.6 months among patients (n=13) treated with 2nd line treatment. On multivariate analysis, gender (p=0.007) and upfront treatment regimen (p=0.001) emerged as independent prognostic factors for PFS whereas performance status (p=0.02) and upfront treatment regimen (p=0.01) showed significance for OS.

      Table 1: Baseline clinical characteristics & treatment details (n=78)

      Characteristics

      Number

      Percentage (%)

      Median (range)

      Age (years)

      53 (24 – 82)

      Sex

      Male

      Female

      47

      31

      60

      40

      Smoking status (n=74)

      Never smoker

      Current smoker

      Former smoker

      45

      26

      03

      61

      35

      04

      Symptom duration (months)

      1.5 (0.2 – 12)

      Eastern Cooperative Oncology Group performance status

      PS 1

      PS 2

      PS 3

      PS 4

      36

      29

      11

      02

      46

      37

      14

      03

      Tumor size (cm) n=44

      4.1 (0.9 – 12.2)

      Nodal status (n=63)

      N1

      N2

      N3

      03

      32

      28

      05

      51

      44

      No of involved organ metastasis

      Single

      Two

      Three

      Four

      Five

      19

      24

      20

      11

      04

      24

      31

      26

      14

      05

      Brain metastasis

      Yes

      No

      20

      58

      26

      74

      Treatment taken

      Yes

      No

      56

      22

      72

      28

      Upfront treatment type (n=56)

      Chemotherapy

      Chemotherapy f/b crizotinib

      Crizotinib

      Ceritinib

      24

      11

      18

      03

      43

      20

      32

      05

      Treatment response (n=44)

      Ccomplete response

      Partial response

      Stable disease

      Progressive disease

      02

      23

      17

      02

      4.5

      52

      39

      4.5

      Site of progression (n=21)

      Brain

      Lung/pleura

      Others

      10

      08

      03

      48

      38

      14

      2nd line treatment (n=13)

      Chemotherapy

      Crizotinib

      Ceritinib

      02

      03

      08

      15

      23

      62

      8eea62084ca7e541d918e823422bd82e Conclusion

      Primary tumor size was small with higher nodal burden and brain metastases in our cohort. Outcome was excellent with use of ALK-inhibitors in our series. Female sex and upfront use of ALK-inhibitors showed superior PFS whereas as good performance status and upfront use of ALK-inhibitors showed superior OS.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-08 - Gender Differences in Lung Cancer Survival

      12:00 - 13:30  |  Presenting Author(s): Marko Jakopovic  |  Author(s): Lela Bitar, Fran Seiwerth, Dražena Srdić, Ana Bačelić-Gabelica, Sanja Pleština, Miroslav Samaržija

      • Abstract

      Background

      Lung cancer death rate in women rose in the past years surpassing breast cancer as the main cause of cancer mortality. The rise in lung cancer mortality in women appears to corelate with the increased prevalence of smoking. Adenocarcinoma has become the most frequent histologic subtype in both genders, and women present with adenocarcinoma in a higher proportion than men do.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Medical records of the patients diagnosed with lung cancer in Clinical hospital center Zagreb, Department for respiratory diseases Jordanovac during the year 2012 were retrospectively collected and reviewed. Baseline data were reported using descriptive statistics. Survival analysis was measured and analyzed using the Kaplan-Meier and log-rank test.

      4c3880bb027f159e801041b1021e88e8 Result

      During the year 2012 there were 661 patients diagnosed with lung cancer in our Department. 482 (73%) were men and 179 (27%) were women. Median age at diagnosis was 64 (37-90). Total lifetime amount smoked varied from 2 to 200 pack/years in the smokers, with median 41 pack/years. The most predominant histological type was adenocarcinoma (287 patients, 43%), followed by squamous cell carcinoma (185; 28%) and microcellular carcinoma (79; 12%). Women had proportionally more adenocarcinoma and less squamous cell carcinoma than men. Cumulative exposure of smoking (as measured by pack-years of cigarettes) is significantly different with 33,6% of men smoking more than 50 pack years compared to 11,7% of women (p < 0.01). No significant difference in stage was observed across genders (p = 0.40). There were no significant differences in treatment between genders. Median overall survival (mOS) for all diagnosed lung cancer patients was 9 months. 1-year survival for all lung cancer patients is 39%, and 5-year survival is 8.1%. Female patients had significantly better survival rates. 1-year survival for female patients is 46% versus male patients 37%. 5-year survival rate for female patients is 11% versus male patients 7%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Male gender has been reported as a significant independent negative prognostic factor for patients with lung cancer in previous studies. Our results are similar to these findings. Over the last 20 years there were changes in the epidemiology of lung cancer between men and women. Characteristics of our patient population reflect the current trends of lung cancer epidemiology. Female patients smoke less but seem more susceptible to develop lung cancer. Although adenocarcinoma is the most common subtype in both genders, women have proportionally more adenocarcinomas than men do. Women have better survival than men.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-09 - Impact of Urban or Rural Residence on Overall Survival for Patients with Metastatic Non-Squamous NSCLC

      12:00 - 13:30  |  Presenting Author(s): Jacqueline Theresa Brown  |  Author(s): Lisa Xiang Li, Margaret Moore, Andrew Reese Moore, Rajesh Piyush Desai, Ryan Gentzler, Rajesh Balkrishnan, Richard Hall

      • Abstract

      Background

      Although data suggests that disparities in ethnicity impact survival outcomes in lung cancer, little is known about whether disparities according to primary residence (rural vs urban) impact survival outcomes in metastatic non-squamous, non-small cell lung cancer (ns-NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a retrospective study of 176 patients with stage IV ns-NSCLC treated at our institution from 2014-2016. Patients were classified as urban or rural residents based on zip codes using the RUCA and SAS zip code databases. Socioeconomic factors were derived from the AHRF database. Risk of death and overall survival (OS) were calculated using COX proportional hazards regression.

      4c3880bb027f159e801041b1021e88e8 Result

      Baseline characteristics are in Table 1. Patients from rural zip codes had worse median OS (12.2 mo, 95% CI 5.1-16.0) compared to patients from urban zip codes (15.7 mo, 95% CI 9.6-27.9), with a hazard ratio (HR) of 1.589 (95% CI 1.052-2.401, p=0.0278). When adjusted for age, gender, smoking status, median income, percent in poverty per county, and EGFR mutational status, these results remained significant (HR 1.670, 95% CI 1.016-2.743, p=0.0376). A secondary analysis based on median household income (MHI) showed that those from regions with MHI less than the median of the cohort were 1.931 times more likely to die than those from regions with greater MHI (95% CI 1.038-3.595, p=0.0378).

      Table 1. Baseline patient characteristics
      Characteristic Rural Urban
      Total (%) 76 (43.2) 100 (56.8)
      Median age in years 65 64
      Male gender (%) 36 (47.4) 50 (50)
      Race/ethnicity
      White 66 (86.8) 75 (75.0)
      Black 9 (11.8) 16 (16.0)
      Hispanic 1 (1.3) 2 (2.0)
      Other 0 7 (7.0)
      Ever-smokers (%) 65 (85.5) 80 (80.0)
      Median household income in dollars 52818 63343
      Percent persons in poverty 14.4 14.3
      EGFR mutation present (%) 14 (18.4) 19 (19.0)

      8eea62084ca7e541d918e823422bd82e Conclusion

      Overall survival for rural patients with metastatic ns-NSCLC was inferior to those living in urban areas. This risk was more pronounced after adjusting for potential confounders. Those from regions with MHI below the median also had increased risk of death compared to those from areas above the median, suggesting that rural financial toxicity may influence lung cancer survival in our area. Further efforts to characterize the socioeconomic determinants of poorer outcomes in rural areas are needed and could support the formation of programs aimed at improving access to care.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-10 - Dyspnea as a Prognostic Factor in Hispanic Patients with Non-Small Cell Lung Cancer Cohort

      12:00 - 13:30  |  Presenting Author(s): Saul Campos-Gomez  |  Author(s): Karen A Campos-Gomez, Juan J Valdés-Andrade

      • Abstract

      Background

      Lung cancer is a commonly diagnosed cancer, and the leading cause of cancer death around the world. Over 80% of lung cancer patients in México are diagnosed in advanced stage. Common symptoms include cough, dyspnea, weight loss, and chest pain. Dyspnea is one of the most common symptoms in patients with lung cancer at initial presentation with a prevalence of 55–90%. The intensity of dyspnea is an important and validated factor for assessment of quality of life (QOL) in cancer patients. In addition, improvement of health-related QOL and symptoms, such as dyspnea, are related with the efficacy of chemotherapeutic regimens and favorable outcome in lung cancer. In this study, we investigated the association between the degree of dyspnea and clinical outcomes to identify the prognostic role of dyspnea in hispanic patients with non-small cell lung cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed lung cancer database of Centro Oncologico Estatal ISSEMYM. From 2013 to 2016 we enrolled patients with diagnosis of advanced NSCLC. Clinicopathological information on age, sex, smoking history, histologic type, stage, Eastern Cooperative Oncology Group (ECOG) performance status, clinical outcomes and evaluation of symptoms of dyspnea at diagnosis using modified Medical Research Council (mMRC) scores from each patient were recorded.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 120 patients with diagnosis of NSCLC were identified, of these only in 65 patients (54%) the symptom of dyspnea were detected and evaluate using modified Medical Research Council (mMRC) scores at initial diagnosis. The median age was 58 years. Among those patient with dyspnea and mMRC scores available at diagnosis, 29 (45%) patients had an mMRC score ≥ 2, while 36 (55 %) had an mMRC score < 2. In multivariate analysis, poor performance status and an mMRC score ≥2 were found to be significant prognostic factors for patient survival. The overall median survival for all patients was 18 months. The overall survival of patients with dyspnea (mMRC grade 2 or higher) was significantly lower than that for patients without or low grade dyspnea (median survival, 17 months vs. 35 months, p<0.036).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In conclusion, this study showed that the dyspnea mMRC mMRC grade 2 or higher in Hispanic patient with NSCLC were significantly associated with poor prognosis. Therefore, clinicians should pay more attention to evaluation and management of dyspnea.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-11 - Depression and Inflammation in Patients with EGFR-Mutated Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Andrés F. Cardona  |  Author(s): Oscar Arrieta, Leonardo Rojas, Zyanya Lucia Zatarain-Barrón, Luisa Ricaurte, Alejandro Ruiz-Patiño, Claudio Martin, Hernan Carranza, Carlos Vargas, Jorge Otero, Luis Corrales

      • Abstract

      Background

      Although depression appears to be associated with worse survival outcomes in cancer patients, the underlying mechanisms and basis of this association remain unknown. EGFR mutations have been associated with improved treatment response and prognosis in advanced non-small lung cancer (NSCLC). However, previous reports have described a positive association between this genotype and depression. This relationship could be at least partially explained by TNFa-mediated inflammation, which activates the hypothalamus-pituitary-adrenocortical (HPA) axis, leading to tryptophan depletion through the stimulation of indoleamine 2,3 dioxygenase.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      32 patients diagnosed with metastatic NSCLC with an EGFR mutation were enrolled and followed monthly. In all cases patients were evaluated using the Self-rating depression scale (SDS) and the Numeric Rating Scale (NRS) in order to obtain a detailed evaluation of the initial symptoms and a qualitative assessment of the state of depression. In parallel we measured TNFa levels in serum/plasma (MaxDiscovery™ Human TNF-α ELISA Test Kit) upon receipt of genotype report, 4 and 12 weeks after initiating the targeted therapy, and at the time of progression. We examined differences between patients with and without depression with respect to the TNFa, as well as impact on various outcomes.

      4c3880bb027f159e801041b1021e88e8 Result

      Mean age was 58.9 years (+/- 12.4), 22 (68.8%) were women and 94% had an ECOG <2. Nineteen patients (59.4%) carried a del19, 8 (25%) had L858R, 2 (6.3%) L858R+T790M, 2 (6.3%) G719S and one patient had a del19+S768I (3.1%). Median follow-up was 15.4 months (95%CI 2.8-32.0), overall survival (OS) was 28.1 months (95%CI 25.5-30.6) and median progression-free survival (PFS) to first-line TKI was 13.1 months (95%CI 9.6-16.6).37.5% (n=12) of patients self-reported depression; in 25, 9.4 and 3.1% the clinical manifestations were mild (SDS 50-59; supportive psychotherapy), moderate (SDS 60-69; requirement of antidepressants) and severe (SDS 70 and above; required hospitalization). Depression was significantly associated with moderate-to-severe basal dyspnea (p=0.043), with brain metastases (p=0.003), and poor performance status (p=0.021). The average TNF at the time of genotype report was 12.2 pg/mL (SD±4.1), and was significantly higher in those who manifested depression (p=0.03). TNF levels increased 11% at 4 weeks and 75% at 12 weeks. Depression did not influence OS or first-line PFS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Mild to moderate depression is prevalent in patients with lung cancer harboring EGFR mutations. As previously reported, TNFa levels are elevated in patients with lung cancer and depression, particularly in the first 12 weeks post-treatment, a finding attributable to inflammation.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-12 - EGFR Mutation and Targeted Therapies: Difficulties and Disparities in Access to NSCLC Treatment in Brazil.

      12:00 - 13:30  |  Presenting Author(s): Gilberto Castro Jr  |  Author(s): Eduardo Cronemberger, Clarissa Baldotto, Felipe Marinho, Pedro De Marchi, Luiz H. Araujo, Fabio Andre Franke, Paulo Salles, Aknar Calabrich, Thais Almeida, Marcelo Graziano Custodio, Cleomines Araujo, Marcelo Horacio

      • Abstract

      Background

      Non-small cell lung cancer (NSCLC) is the most prevalent lung cancer subtype, commonly presenting as advanced disease at diagnosis. Epidermal growth factor mutation (EGFRm) occurs in 10-15% of Western population with advanced NSCLC and its management includes the use of mutation-driver EGFR tyrosine kinase inhibitors (EGFR-TKIs). In Brazil, patients with EGFRm NSCLC may face barriers to access EGFR test and directed-therapy; otherwise, there is a lack of national clinical data addressing this issue. This study intended to evaluate the access to molecular EGFR testing, initial treatment, and its respective response in this patients setting in public and private institutions in Brazil.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this retrospective cohort, patients with newly diagnosed advanced NSCLC between January and December 2014 were consecutively included. Data were collected from medical records of 10 Brazilian cancer institutions, and recorded in electronic clinical report form. Demographic data, medical history, tumor staging, pathological characteristics, treatments and outcomes were collected and analyzed. For each patient, maximum follow-up was 36 months.

      4c3880bb027f159e801041b1021e88e8 Result

      402 patients from 8 different Brazilian states were enrolled, and 391 were included in the analysis, being 236 men (60.4%). Median age was 64 years, 80% have been treated in the public and 20% in private health system; 74.9% (n = 293) were former or current smokers. The most frequent histological subtypes of NSCLC were adenocarcinoma (ADC) with 267 cases (68.3%) and squamous cell carcinoma (SqCC) with 87 cases (22.3%). Among smokers, 66.6% were diagnosed with ADC and 24.6% with SqCC; among never smokers (n = 63), 84.1% had ADC and 9.5% SqCC. Clinical staging (CS) at diagnosis was IV in 251 cases (81.6%) and locally advanced (stage IIIB) in 62 cases (18.4%). From patients diagnosed with ADC, only 52.1% (n = 139) have been tested for EGFR mutation and, of these, 21.6% (n = 30) had an EGFR activating mutation. Only 43.3% (n = 13) of those with EGFRm (n=30) received an EGFR-TKI as initial therapy, while the remaining were treated with cytotoxic chemotherapy. Based on the number of patients with EGFRm, the rate of access of EGFR-TKIs in first-line treatment was 75% in private care, compared to 31.8% in public care. Only 8 of 13 mutated patients (61.5%) treated with EGFR-TKI were evaluable for response, and the disease control rate was 62.5%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The frequency of EGFRm in locally advanced or metastatic ADC in Brazil was comparable to previous studies. Access to EGFR test and EGFR-targeted therapies are restricted specially in public health system. In Brazil, public policies to assure a broader access to these technologies must be implemented.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-13 - Prognosis of Non-driver, Never Smoker Metastatic Non-Small Lung Cancer (NSCLC)

      12:00 - 13:30  |  Presenting Author(s): Anna Chalmers  |  Author(s): Ben Haaland, Shiven Patel, Kelly Moynahan, Laura Cannon, Wallace Akerley

      • Abstract

      Background

      The overwhelming majority of NSCLC does not have an actionable driver mutation, termed wild type (WT). Never smoking (NS) lung cancer has a high frequency of actionable driver mutations relative to smoking (S) related lung cancer. Those with EGFR or ALK mutations who receive appropriate targeted therapy, regardless of smoking status, demonstrate twice the survival of WT NSCLC in the metastatic setting. It is unclear if WT NS behaves more like WT S or EGFR/ALK.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Electronic medical record data from lung cancer patients treated at Huntsman Cancer Institute was processed by Flatiron Health using technology-enabled abstraction and supplemented with third-party death information. Patients with metastatic NSCLC were categorized according to smoking status (never [NS] or history of smoking[S]) and molecular profile (EGFR, ALK or WT). Kaplan-Meier estimates of survival from advanced/metastatic diagnosis were plotted by category, and survival times compared between groups in the context of Cox proportional hazards models.

      4c3880bb027f159e801041b1021e88e8 Result

      From 2016, 202 patients were identified with smoking data and EGFR/ALK testing in the data set. The respective median ages and median survival in the NS WT, ALK/EGFR, and S WT groups were 68 (N=31), 63 (N=71), and 68 (N=100) years and 1.8, 1.8, and 0.7 years, respectively. Estimated survival curves are shown below. NS WT was the reference population with hazard ratio=1. Hazard ratios for the remaining categories were ALK/EGFR 1.09 (p=0.823) and S WT 2.64 (p=0.005).

      slide1.jpeg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Survival times for NS WT are significantly greater than S WT NSCLC and behave more like EGFR/ALK. Clinical history may be more important than molecular biomarkers, but further study is needed.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-14 - mTORC1 Regulates the Radiosensitivity of NSCLC Cells with Wildtype PI3KCA and KRAS Genes by Affecting EMT

      12:00 - 13:30  |  Presenting Author(s): Yuan Chen  |  Author(s): Yu Chen, Ping Peng, Shu Xia

      • Abstract

      Background

      Resistance to radiotherapy has been shown to be a key cause of treatment failure in NSCLC and associates with local recurrence and metastasis. Understanding how NSCLC cells sensitize to radiation is therefore important for developing new treatments and prognostics. It has been shown that mTORC1 can regulate tumor cell radiosensitivity, although the mechanisms that underlie this phenomenon are unclear. It have found that mTORC1 also regulates EMT, important to metastasis and recurrence. We therefore hypothesized that mTORC1 might affect NSCLC cell radiosensitivity by suppressing EMT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We analyzed the expression of mTOR protein in NSCLC tissues from patients, in addition to adjacent and normal tissue.These data showed that mTOR protein was elevated in NSCLC tissue. We then evaluated the effect of the mTORC1 inhibitor RAD001 (everolimus) on in vitro radiosensitivity, protein levels, and dose-survival curves using NCI-H460 and NCI-H661 NSCLC cell lines. RAD001 inhibited the mTORC1 pathway in both lines and enhanced the radiosensitivity of NCI-H661 cells with wildtype PIK3CA and KRASgenes. However, there was no evidence of a similar effect in NCI-H460 cells with mutant PIK3CA and KRAS genes. We also analyzed the expression of various EMT-associated proteins after irradiation in RAD001-treated and control cells. This showed that mTORC1 inhibition led to changes in the expression of several EMT-associated proteins in NCI-H661 cells after irradiation. Finally, we used publicly available expression data to confirm that mTOR and EMT-associated genes were affected by irradiation at the transcript level in NSCLC cells.

      4c3880bb027f159e801041b1021e88e8 Result

      In conclusion, our study has revealed that the mTORC1 signaling pathway is involved in regulating the radiosensitivity of some non-small cell lung cancer (NSCLC) cells. Our data showed that there was increased expression of mTOR in primary tumors and matched adjacent tissues in patients with NSCLC. We also confirmed that the mTORC1 inhibitor RAD001 had a cytostatic effect on NCI-H661 and NCI-H460 NSCLC cells lines. However, mTORC1 inhibition only increased radiosensitivity and affected mTOR signaling downstream targets in NCI-H661 cells with wildtype PIK3CA and KRAS genes. RAD001 had only a marginal effect on NCI-H460 cells with mutant PIK3CA and KRASgenes. Finally, the effect of radiation on EMT-associated markers was also assessed, revealing that mTORC1 inhibition couldalleviate irradiation-specific EMT changesin NCI-H661 cells.

      8eea62084ca7e541d918e823422bd82e Conclusion

      these data suggest that mTORC1 inhibition in NSCLC may enhance radiosensitivity by affecting the expression of EMT-associated proteins.This suggests targeting mTORC1 may provide a potential new strategy for the treatment of NSCLC with wildtype PIK3CA and KRAS genes.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-15 - Efficacy of Paclitaxel Plus TS1 Against Non-Small Cell Lung Cancer Previously Treated

      12:00 - 13:30  |  Presenting Author(s): Yuh-Min Chen  |  Author(s): Yen-Han Tseng, Jen-Fu Shih, Heng-Sheng Chao

      • Abstract

      Background

      Salvage chemotherapy is frequently used. However, the efficacy of salvage chemotherapy of paclitaxel plus TS1 (TTS1) is still unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed the chart records of our non-small cell lung cancer patients who were treated between 2010 and 2013. Clinical characteristics, type of tumor EGFR mutation, response to first-line EGFR-TKI treatment or not, and efficacies of TTS1, were collected.

      4c3880bb027f159e801041b1021e88e8 Result

      Total 25 patients were enrolled in this study. No patients archived complete response and six patients had partial response (ORR: 24%). The disease control rate was 60% (15/25). The progression free survival (PFS) was 4.8 months and overall survival (OS) was 12.4 months. Among these 25 patients that received TTS1, 17 of them had driver mutations. Patients with driver mutations had better PFS (4.9 months vs 1.8 months) and OS (15.5 months vs 7.2 months) compared with those without driver mutations.

      8eea62084ca7e541d918e823422bd82e Conclusion

      TTS1 are effective salvage chemotherapeutic agents, especially in tumor EGFR mutated patients. Paclitaxel plus TS1 is another treatment of choice for NSCLC patients before a more efficient salvage treatment strategy is found.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-16 - Low Dose Apatinib Combined with EGFR-TKI in Treating Advanced NSCLC After First-Generation EGFR-TKIs Treatment Failure

      12:00 - 13:30  |  Presenting Author(s): mingda Chen  |  Author(s): Junli Song, Weidong Liu

      • Abstract

      Background

      EGFR TKIs have been approved as the first-line therapy for treating advanced non-small-cell lung cancer (NSCLC). However, treatment failures frequently occurred in NSCLC patients with EGFR-sensitizing mutations. Apatinib, a novel small molecule TKI targeted VEGFR2, recommended as third-line treatment for metastatic gastric cancer patients. This retrospective study tried to investigate the efficacy and safety of low dose Apatinib combined with original targeted drugs in treating advanced NSCLC after first-generation EGFR-TKIs treatment failure and trying to explore the underlying mechanisms.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From March 2016 to November 2016, 11 patients of advanced NSCLC acquired resistance for Erlotinib, gefitinib and Icotinib treated with original targeted drugs plus Apatinib(250 mg, once daily), and CT scan every 4 weeks. Meanwhile observe drug-related adverse events.

      4c3880bb027f159e801041b1021e88e8 Result

      In 11 patients, there were 10 patients available for efficacy and safety evaluation. 2 of 10 patients were progress disease in 12 weeks, 8 of 10 patients were stable disease and still in treatment. The disease control rate (DCR) was 80%. The rate of PFS at 12 weeks was 72.73%. The most frequent treatment-related adverse events were fatigue (20%, 2/10), rash (20%, 2/10), poor appetite (20%, 2/10), respectively. Severe AEs included grade 3 proteinuria (10%, 1/10).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Low dose Apatinib combined with original targeted drugs is efficacious in treating patients with advanced NSCLC who failed to first-generation EGFR-TKIs treatment, with acceptable toxic effects. The mechanism may be related to Apatinib regulate tumor microenvironment and reverses multidrug resistance.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-17 - Long Survivors with Advanced Lung Cancer -  Efficacy and Tolerability of Nivolumab

      12:00 - 13:30  |  Presenting Author(s): Ewa Chmielowska  |  Author(s): Anna Krause, Monika Olejniczak, Marcin Swiezynski, Jan Kopec

      • Abstract

      Background

      The group of the patients with advanced lung cancer surviving more than two years was limitated, particullary at era of the classic chemotherapy.In our material presented in 2013 on WCLC it made up 11%.The differences in efficacy betweeen Nivolumab and conventional treatment in pretreated patients remains unclear, particullary in the group with good response on chemotherapy with long interval between lines. We analyzed the efficacy and tolerance of Nivolumab in the long surviving group.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      7 patients characterized by long earlier history of lung cancer were found. Baseline characteristic and historical treatment data are presented in table 1.

      methods.jpg

      4c3880bb027f159e801041b1021e88e8 Result

      Table nr 2 presents the efficacy and tolerability of Nivolumab.

      The patients obtained 190 injections of drug and only one patient requires 2,5 months break beacuse of typical AE-tyreoiditis G3. Other short breaks were dependent on personal requests ,not from AE. Treatment time is 12-17 months and is plannig to continue .No progression has been noticed. Follow-up is planned.

      results.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Long surviving patients with significant interval between chemotherapy lines show excellent tolerability and good efficacy of Nivolumab regardless of the type of previous chemotherapy.Efficacy and tolerance of these patients are comparable to described group with better prognosis from trials Checkmate 003 and 153

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-18 - Comparison of PD-L1 Immunohistochemical Assays and Clinical Response to Anti PD-1 Checkpoint Inhibitors in Patients with Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Jang Ho Cho  |  Author(s): Jiyeon Hyeon, Yoon-La Choi, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn

      • Abstract

      Background

      The anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors, nivolumab and pembrolizumab, are currently approved for the treatment of patients with NSCLC. The PD-L1 expression represents the most validated predictive marker of response to PD-1 inhibitors. However, there are several different immunohistochemical assays to assess the PD-L1 expression using different antibodies, platforms, and cutoff values. We compared the PD-L1 expression evaluated by IHC 22C3 PharmDx with that observed by Ventana SP263 and analyzed correlation with response to anti PD-1 inhibitors.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively analyzed 109 patients with lung cancer to be treated with anti PD-1 inhibitors who have PD-L1 expression levels obtained with both the 22C3 and SP263 assays. We reviewed medical records to obtain information about the patient’s clinical characteristics, response evaluation and survival data. The relationship between PD-L1 expression levels evaluated by the 22C3 and SP263 assays was calculated using the concordance correlation coefficient, Pearson’s precision analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      Most patients were male (70%), smoker (65%), ECOG PS 1 (73%), and histologically adenocarcinoma (55%) or squamous cell carcinoma (29%). 30% of patients had EGFR mutations. Patients were treated with pembrolizumab (n=41, 38%), or nivolumab (n=67, 61%). The median cycle of anti PD-1 checkpoint inhibitor was three (range, 1-25). There was moderate analytical correlation between 22C3 and SP263 PD-L1 levels. At the clinically relevant cutoffs ( < 10% vs. 10%; and <1% vs. 1-49% vs. 50%), the concordance correlation coefficient between 22C3 and SP263 were 0.68 (95%CI: 0.59-0.77) and 0.66 (95%CI: 0.51-0.81), respectively. The overall response rate (ORR) was 25.0% for all patients. The ORR was comparable regardless of the cutoff levels of PD-L1 expression by SP263 assays (ORR 39.6%, 41.7%, and 47.4% respectively for PD-L1 expression by 1%, 10%, 50% cutoff levels). But, the correlation between ORR and PD-L1 expression by 22C3 assays was not statistically significant. At 1% cutoff value, progression free survival was longer in patients with high vs. low tumor PD-L1 expression (2.8 months vs. 1.2 months, HR 0.63, 95%CI: 0.41-0.97, p=0.03) by the 22C3 and (3.1 months vs. 1.3 months, HR 0.61, 95% CI:0.40-0.93, p=0.02) by the SP263, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We showed a moderate correlation between PD-L1 expression data obtained with the 22C3 and SP263 assays. These two assays could be used interchangeably and might be helpful for decision with anti PD-1 checkpoint inhibitors. Further analysis will be updated.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-19 - Sequencing of Ramucirumab+Docetaxel Post-Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer Patients

      12:00 - 13:30  |  Presenting Author(s): Cliff Molife  |  Author(s): Jeffrey Melson Clarke, Victoria Jennifer Stefaniak, Marta Batus, Katherine B Winfree, Zhanglin L Cui, Yimei Han, Mahesh K Tawney, Philip Bonomi

      • Abstract

      Background

      The Phase III REVEL study demonstrated the efficacy and safety of ramucirumab+docetaxel (ram+doc) in advanced non-small cell lung cancer (aNSCLC) patients who had disease progression on prior platinum-based chemotherapy (chemo). Given recent positive data disclosures supporting the use of chemo+immune checkpoint inhibitor (ICI) combinations in frontline, there is a need for additional data on the sequencing of ram+doc post-ICIs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Baseline characteristics and outcomes were assessed for aNSCLC patients identified in the Flatiron Health EHR-derived database, who received ram+doc as 3rd line therapy (3L) between March 2015 - May 2017 in the United States after 1st or 2nd line platinum-based chemotherapy, with ≥ 3 months of potential follow-up. Analyses were conducted for the overall cohort and among the subset of patients who received 3L ram+doc post-ICI. Overall survival (OS) was calculated from start of 1st line therapy. Real-world progression-free survival (rwPFS) and time-to-progression (rwTTP) were measured from start of 3L ram+doc. OS, rwPFS, and rwTTP were estimated using Kaplan-Meier method.

      4c3880bb027f159e801041b1021e88e8 Result

      Among platinum-treated patients who subsequently received ram+doc in 3L overall (N=98), of whom the majority (n=65, 66.3%) received ram+doc post-ICI, the median age was 66 years and the majority were male (54.1%), Caucasian (67.4%), and had nonsquamous histology (81.6%). Of the 61 (62.2%) with available ECOG performance status (PS) data, 72.1% had ECOG PS of 0 or 1. Baseline characteristics were similar between the overall cohort and ram+doc post-ICI patients, as were clinical outcomes between the two groups (Table 1).

      Table 1. Clinical Outcomes for 3L Ram+Doc Treated Patients

      3L Ram+Doc (Overall)

      n=98

      3L Ram+Doc (Post-ICI)

      n= 65

      Median OS (95% CI), month

      19.1 (16.3 - 23.7)

      19.0 (15.7 - 23.7)

      Median PFS (95% CI), month

      3.6 (3.0 - 4.2)

      3.6 (3.0 - 4.6)

      Median TTP (95% CI), month

      5.5 (4.0 - 7.9)

      5.5 (3.6 - 7.9)

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this real-world platinum-treated cohort, most 3L ram+doc usage was post-ICI. Clinical outcomes for ram+doc post-ICI patients were consistent with those for the overall 3L ram+doc cohort. These data may support the use of ram+doc post-ICI among platinum-treated patients with aNSCLC. Further research is needed to evaluate the efficacy and safety of ram+doc following chemo+ICI combinations.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-20 - Advanced NSCLC Treatment and Outcomes After Nivolumab

      12:00 - 13:30  |  Presenting Author(s): Girish Mallesara  |  Author(s): Elizabeth Anne Connolly, Ina Nordman

      • Abstract

      Background

      Nivolumab is now often used in the second line in non-small cell lung cancer (NSCLC). Fitness for further treatment and outcomes in clinical practice, after discontinuation of nivolumab, are not well documented.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A single centre retrospective analysis was conducted on all patients who had received and ceased nivolumab between July 2015 and February 2018. 61 patients were identified. Management after nivolumab and survival outcomes were reviewed.

      4c3880bb027f159e801041b1021e88e8 Result

      The median age of patients was 66 years (range 28-82). 31 patients were male (51%). 71% had adenocarcinoma (n=43), 21% had squamous carcinoma (n=13), and 8% other NSCLC (n=5).

      33 received nivolumab as second line therapy, 18 as third line, 9 as fourth line, and 1 as fifth line. 79% of patients ceased nivolumab due to progressive disease (n=48) and 16% due to toxicity (n=10). 3 patients discontinued treatment after developing unrelated medical issues.

      36% of patients (n=22) underwent further treatment. Next line treatments included pemetrexed (n=10), platinum doublet rechallenge (n=4), docetaxel (n=4), vinorelbine (n=2), weekly gemcitabine (n=1), and crizotinib (n=1). Of those who received further treatment, 9 were alive at censoring and 13 were deceased.

      In Australia, carboplatin/gemcitabine is more likely to be used in first line treatment of metastatic adenocarcinomas because of Medicare restriction on reimbursement. Nivolumab and pemetrexed are used subsequently after progression. The efficacy of pemetrexed when used after nivolumab is not well documented. In our cohort, 10 patients received pemetrexed after nivolumab, and showed a median survival of 10.6 months after discontinuation of nivolumab. The median duration of pemetrexed therapy was 5.4 months.

      Median overall survival, from last nivolumab dose, of all patients was 4.4 months (n=61). The median survival in patients who received any treatment after nivolumab was 10.5 months (n=22). Those who received nivolumab as a 2nd line treatment after platinum doublet therapy (n=33) had a median overall survival of 8.0 months.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In a heavily pre treated heterogeneous population, median survival after nivolumab was 4.4 months. 36% commenced further treatment and this population had an increased median survival of 10.5 months. Pemetrexed has efficacy in the 3rd line setting after platinum doublet and nivolumab therapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-21 - Metastatic Lung Carcinoma —An Institutional Experience from Eastern India

      12:00 - 13:30  |  Presenting Author(s): Saroj Kumar Das Majumdar  |  Author(s): Subhasis Mishra, Deepak Kumar Das, Sovan Sarang Dhar, Nabiza Begum, Saroj Kumar Das, Susama Patra, Sudipta Mohakud, Prasanta Raghab Mohapatra, Dillip Kumar Parida

      • Abstract

      Background

      Carcinoma lung carries poor prognosis and is the leading cause of death among all malignancies.In developing countries like India,two-third of patients present with advanced stage of disease,where survival is dismal.Hence a retrospective study was planned to be conducted to observe the clinicopathological profile of patients presenting with metastatic lung carcinoma and to analyse the treatment response and survival in these cases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective analysis was done from hospital files of patients with metastatic carcinoma lung presenting to our hospital from January 2015 to April 2018.

      4c3880bb027f159e801041b1021e88e8 Result

      Out of 55 patients of metastatic lung carcinoma ,36(65%) were male and 19(35%) were female.Majority of the patients were of elderly age group >60yrs i.e 47%(36patients),followed by 40-60yrs age group i.e 31%(17 patients).Considering laterality of primary malignancy,right lung was more commonly affected than left lung(60% vs 40%).Histopathologically adenocarcinoma was the most common variety encountered(85.45%,47 patients) followed by squamous cell variety(0.9%,5 patients).Among 47 patients of adenocarcinoma variety,20 patients(42.5%)have EGFR mutations,whereas 27 patients(57.5%) were EGFR nonmutated.The pattern of metastases shows single organ metastasis in 19 patients(34.5%) and multiple organ metastases in 36 patients(65.5%). Overall bone was the most common site(25 patients) of metastases whereas brain was the most common single organ metastasis site.The followup period ranged from 2months to 40 months(median followup period-7mnths).One year and two year overall survival was 30% and 10.9% respectively.Subgroup analysis between patients who have received Tyrosine Kinase Inhibitors(TKI)±chemotherapy group and those who have received chemotherapy only group showed median overall survival of 19 months vs 6mnths respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Inspite of increased awareness,incidence of metastatic lung carcinoma is still high.Adenocarcinoma is the most common histopathological variety.Bone,contralateral lung and brain were the common organs involved by metastases.EGFR mutation status should be assessed in all cases of adenocarcinoma lung.Adding TKI in EGFR mutated cases has shown increased survival in our study.Larger sample size and longer followup period can further validify the results.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-22 - An Exploratory Analysis of PD-L1 Expression and Smoking History in a Cohort of Advanced Non-Small Cell Lung Cancer Patients

      12:00 - 13:30  |  Presenting Author(s): Marios P Decatris  |  Author(s): Philippe Taniere, Mark Hayes, Joy Thomas, Ketan Gaikwad, Maninder Kalkat, Kate Birchall, Jan Osbaldiston, Aled Phillips, Phil Ryan, Nick Reed, Ingrid Du Rand

      • Abstract

      Background

      Response to PD-1 checkpoint inhibitors in NSCLC is associated with PD-L1 expression. One hypothesis is that high PD-L1 expression may correlate with tumour mutational load, the latter reflecting past tobacco exposure.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We examined PD-L1 expression by tumour proportion score (TPS) in patients with advanced NSCLC and correlated this with the subjects’ smoking history. Number of pack-years was estimated by the same individual during the initial consultation. Demographic characteristics, performance status(PS), stage, histology were obtained from the electronic patient records. PD-L1 testing was performed using the Dako PD-L1 IHC 22C3 pharmDx test in all but 3 cases where the SP263 Roche antibody was used. We compared pack-years and smoking status of subjects with PD-L1 negative(TPS<1%), weakly-positive (TPS1-49%) and strongly positive (TPS≥50%) NSCLC.

      4c3880bb027f159e801041b1021e88e8 Result

      wclc 2018-table.tiffBetween 12/2016-3/2018, 54 biopsy specimens from 52 patients with advanced NSCLC were tested for PD-L1 expression at UHB. In 5 biopsies, material was not tested, as unsuitable in 4(<100 tumour cells present) and testing was cancelled in 1 patient who declined treatment. For the remaining 47 biopsies patient characteristics were: Median age 70 (43-82), male/female 26/21, PS 0/1/2/3-4 was 10/26/8/3, stage IIIA/IIIB/IV 3/18/26, histology adenoca/squamous/mixed 33/11/3. Median pack-years in PD-L1 negative 30(0-60), PD-L1 weakly positive 35(0-80), PD-L1 strongly positive 33(0-100); current+former smoker/never smoker numbers: PD-L1 negative 14/3(82.4%/17.6%), PD-L1 weakly positive 11/1(91.7%/8.3%), PD-L1 strongly positive 15/3(83.3%/16.7%). Strong/weak PD-L1 expression was seen in 3/1 never smokers; of these 2 had EGFR mutation. Weak expression was also seen in 1 ALK-positive NSCLC patient, former light smoker (5pack-years).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this small retrospective cohort there were no differences in median pack-years of smoking or proportions of current+former/never smokers between PD-L1 negative and positive tumours. Smoking history alone may not be the only factor influencing PD-L1 expression. Never smoking status and EGFR-mutated/ALK-positive NSCLC should not be excluded from PD-L1 testing.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-23 - Imaging Modalities for Surveillance and Follow-Up of Patient with Lung Cancer After Adjuvant Chemotherapy

      12:00 - 13:30  |  Presenting Author(s): Aya El Helali  |  Author(s): Laura Feeney, Catherine Joan Davidson, Kirsty Taylor, Michael John Devlin, Paula Scullin, Lynn Campbell

      • Abstract

      Background

      Non-small cell lung cancer (NSCLC) represents over 80% of lung tumours. If diagnosed early, treatment is surgical with curative intent. The addition of postoperative cisplatin-based chemotherapy has demonstrated a significant survival advantageand is generally accepted as a standard treatment in patients of good performance status.

      Despite this, risk of relapse remains high and current ESMO (2017) guidance suggests ‘NSCLC patients treated with radical intent should be followed for treatment-related complications, detection of treatable relapse or occurrence of second primary lung cancer. Recommendations for surveillance, include regular review, physical exam and imaging. This should be tailored to suitability of individual patients for further intervention. Local practice mandates a chest x-ray (CXR) with CT and/or PET follow-up of anomalies.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between January 2004 and May 2017 165 patients underwent surgical resection for Stage 1B-IIIA NSCLC. We identified all patients within this cohort with radiological evidence of thoracic recurrence who had relapsed following postoperative chemotherapy. Electronic patient care records were used for data collection. Patient characteristics, surveillance modalities and overall survival (OS) from date of diagnosis to first relapse were analysed. Imaging modalities detecting recurrence and OS were determined using Kaplan-Meier methodology (SPSS).

      4c3880bb027f159e801041b1021e88e8 Result

      89 patients were identified, the median age was 62 years (range 42-77 years). Patients underwent surveillance initially every 3 months following completion of postoperative chemotherapy. Median time to relapse was 25.6 months (range 0.53 to 50.9 months). 62 patients (69.7%) had radiological confirmed evidence of disease recurrence. 4 (6.5%) had relapsed with extra-thoracic recurrence. 28 patients (45.2%) had confirmed intra thoracic disease recurrence on CXR despite chest CT imaging performed at designated time intervals. However, 27 patients (43.5%) that underwent surveillance with CXR had confirmed intra thoracic disease recurrence with chest CT imaging. Median OS for CXR detected recurrence was 27.5 months (range 6.5 – 99.1 months) and 27.45 months (range 5.9 to 104.2 months) for chest CT detected recurrence (p-value 0.46).

      8eea62084ca7e541d918e823422bd82e Conclusion

      There is a paucity evidence specifically around the follow-up and surveillance modalities aimed at detecting relapse to improve survival after curative intent therapy in NSCLC.Our data demonstrate that 3 monthly CXR is an appropriate surveillance modality for initial detection of intra-thoracic disease recurrence.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-24 - The Importance to Switch from EGFR-TKI to Cytotoxic Chemotherapy for EGFR Mutation-Positive Adenocarcinoma

      12:00 - 13:30  |  Presenting Author(s): Daisuke Eriguchi  |  Author(s): Tetsuya Okano, Yohei Kawaguchi, Junichi Maeda, Masaru Hagiwara, Masatoshi Kakihana, Naohiro Kajiwara, Tatsuo Ohira, Norihiko Ikeda

      • Abstract

      Background

      Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become the first-line treatment for EGFR-positive non-small cell lung cancer (NSCLC) patients all over the world. Furthermore, EGFR-positive patients who received not only EGFR-TKI but also chemotherapy have good prognosis. However, transition rate from first-line EGFR-TKI to chemotherapy is low.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 229 consecutive patients with adenocarcinoma were treated with EGFR-TKI from January 2010 to December 2016 at Tokyo Medical University Hospital. Among these, 159 patients were analyzed in the present study. After excluding 70 patients (45 patients undergone first-line treatment, 7 received chemoradiotherapy,and 18 received osimertinib). The prognosis according to treatment sequence and the reasons patients could not switch from first-line EGFR-TKIs to chemotherapy were analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      The median follow-up period was 22.5 months. Of the total 159 patients, 113 (71%) were female, 114 (72%) were <75 years old, and 86 (54%) showed postoperative recurrence. The most frequent subtypes of EGFR were exon 19 deletion in 84 patients (53%) followed by exon 21 L858R in 54 patients (34%). EGFR-TKIs were administered as a first-line therapy in 93 (58%) patients, and chemotherapy was administered in 66 (42%) patients. The most common first administered EGFR-TKI as a first-line was gefitinib in 133 (84%) of 159 patients. Among the 93 patients who were administered EGFR-TKIs as a first-line treatment, 32 (34%) patients transitioned to chemotherapy. The median survival times (MST) of EGFR-TKIs combined with chemotherapy group and EGFR-TKIs alone group were 59.8 months and 22.5 months, respectively (p < 0.001), and MST of patients who received EGFR-TKIs first and chemotherapy first were 38.8 months and 66.4 months, respectively (p = 0.016). The main reasons patients could not transition to chemotherapy was worsening of performance status followed by the patient’s preference.

      8eea62084ca7e541d918e823422bd82e Conclusion

      EGFR-TKIs and chemotherapy led to good prognosis in EGFR mutation-positive adenocarcinoma patients. It is necessary to consider the timing to switch the treatment strategy before PS becomes worse.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-25 - Feasibility of Moderate Hypofractionated Thoracic Irradiation for Non-Small Cell Lung Cancer Patients with Very Limited Lung Function

      12:00 - 13:30  |  Presenting Author(s): Maurice Dantes  |  Author(s): Farkhad Manapov, Olarn Roengvoraphoj, Julian Taugner, Lukas Käsmann, Cherylina Wijaya, Nina-Sophie Schmidt-Hegemann, Claus Belka, Chukwuka Eze

      • Abstract

      Background

      To determine the feasibility of moderate hypofractionated image-guided thoracic irradiation (modHypo-IGRT) in locally advanced node-positive non-small cell lung cancer patients with very limited pulmonary function.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eight selected patients with highly diminished pulmonary function (FEV1 ≤ 1.0L and/or DLCO ≤ 40% and/or long-term oxygen therapy) were treated with modHypo-IGRT. Planning was based on 18F-FDG-PET/CT and 4D-CT. Gross tumor volume (GTV) included primary tumor and involved lymph nodes. Internal target volume (ITV) was defined through the overlap of GTVs on 10 phases of 4D-CT. An isotropic margin of 5 mm was added to ITV to generate the planning target volume (PTV). modHypo-IGRT was delivered to a total dose of 45 Gy (ICRU) in 15 daily fractions under strict image-guidance. Vital capacity (VC), forced expiratory volume in 1s (FEV1), and single-breath diffusing capacity of the lung for CO (DLCO-SB) were analyzed prior to, 3 and 6 months after modHypo-IGRT.

      4c3880bb027f159e801041b1021e88e8 Result

      Eight patients completed modHypo-IGRT. The median follow-up was 20 months. The median age was 64 years. Two, 4 and 2 patients presented with stage IIIA, IIIB, and IIIC. Seven patients were with performance status ECOG 2 and 1 with ECOG 3. Five patients (63%) were on long-term oxygen. Three patients received chemotherapy prior to modHypo-IGRT. The median PTV was 226.9 cm³ (range: 100.17 - 379.80). The median overall (OS) and progression-free survival (PFS) for the entire cohort were not reached. The 1- and 2-year OS rates were 100% and 87.5%. The 6- and 12- months PFS rates were 100% and 63%. Three patients developed local failure. Median mean lung dose was 9.4 Gy (range: 5.3 -11.6). V15 and V20 for both lungs were 22% (range: 10-25) and 15% (range: 6-19). Median mean esophageal dose was 12.76 Gy (range: 2.1-26.7). There was no case of radiation pneumonitis. Four patients developed grade 2 radiation esophagitis. Median initial VC, FEV1 and DLCO-SB was 1.69L/64.8% predicted (range: 1.36-2.66/33-80%), 1L/39.4% predicted (range:0.78-1.26/28-60%) and 33.3% (range: 13.3-54), respectively. Median value for VC, FEV1 and DLCO-SB 3 months after modHypo-IGRT was 2.05L/56.35% predicted (range: 1.34-2.33/47-81.5%), 1.08L/47.5% predicted (range: 0.74-1.60/30.8-59.59%) and 38.55% (range: 24-68). At 6 months post-treatment, the median value for VC, FEV1 and DLCO-SB was 1.64L/66% predicted (range: 1.41-2.79/35.5-75.5%), 1.0L/47% predicted (range: 0.65-1.28/24.5-54.10%) and 31% (range: 27-43%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      modHypo-IGRT can be considered for individual patients with locally advanced node-positive NSCLC patients with very limited pulmonary function hence inadequate for conventional treatment. This protocol is being assessed in an ongoing single-center prospective study.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-26 - A Framework for Systematic Clinical Evaluation of Technical Innovations in Lung Cancer Patients Treated on the MR-Linac (MRL)

      12:00 - 13:30  |  Presenting Author(s): Corinne Faivre-Finn  |  Author(s): David Catharina Petrus Cobben, Hannah Bainbridge, Jose Belderbos, Patrick Cheung, Michael Dubec, Daniel Gomez, Elizabeth Gore, Elizabeth Knowles, Ferry Lalezari, Uwe Oelfke, Jan-Jakob Sonke, Rob H.N. Tijssen, Corine Van Es, Marcel Van Herk, Andreas Wetscherek, Fiona McDonald

      • Abstract

      Background

      A recent innovation in radiotherapy is the MRL developed by Elekta and Philips. The MRL combines a 1.5 T MRI with a 7 MV linac. It allows the acquisition of high resolution MR images for on treatment verification, adaption and response monitoring.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Seven cancer institutions from Europe and North America, are working within the Elekta MR-Linac Consortium to evaluate the MRL within a framework called ‘R-IDEAL’ (Radiotherapy Idea Development Exploration Assessment Long-term Evaluation) 1.

      4c3880bb027f159e801041b1021e88e8 Result

      The table below summarizes the ongoing and planned work within the Elekta MR-Linac Consortium.

      table for wlcc 3-5-2018.jpg

      Progress to date:
      Stage 0:
      We defined in 80 patients the optimal MRI sequences suitable for GTV and organ at risk (OAR) contouring: T2 Turbo Spin Echo (TSE), T2 TSE with fat sat, T1 radial gradient echo, and DIXON TSE. Two radiology-led workshops were organized and inter-observer agreement was assessed for OARs. These led to a consensus-based OAR atlas. A study is being prepared to compare the image quality of the current standard CBCT and MR images at baseline and mid-treatment for treatment verification and set-up correction.
      Stage 1: we will investigate the clinical feasibility of the MRL for standard of care radiotherapy and the scope for adaptive radiotherapy (margin reductions) and detecting changes in oxygenation during treatment on the MRL in patients with locally advanced (LA) NSCLC .
      Stage 2a/b : Based on the results from stage 1 we will design a study aiming to reduce margins around the tumour and dose escalate in patients with LA NSCLC.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The aim of this programme of work is to generate robust evidence to support the introduction of the MRL and to improve outcomes of patients with LA NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-27 - Characterization and Sensitization of Non-Small Cell Lung Cancer Cell Line Variants Selected for Resistance to Osimertinib

      12:00 - 13:30  |  Presenting Author(s): Peter John Ferguson  |  Author(s): Mark David Vincent, James Koropatnick

      • Abstract

      Background

      Many non-small cell lung cancers (NSCLC) are oncogenically driven by mutant epidermal growth factor receptor (EGFR). EGFR tyrosine kinase inhibitors (TKIs) are commonly used as first-line treatments against such tumours, but NSCLC tumours recur with novel EGFR mutation(s) (often a T790M mutation in exon 20) that confers resistance to these drugs [Ther Adv Respir Dis 10(6): 549-565, 2016]. Third generation EGFR TKIs (e.g., osimertinib) have been designed that are highly active against both T790M EGFR and the original oncogenic EGFR lacking the T790M mutation. Clinical resistance to third generation TKIs has been observed, but model systems in which to study the mechanisms of resistance are few. The human NSCLC cell line H1650 has the EGFR-activating mutation del E746-A750. The human NSCLC line H1975, derived from an EGFR-TKI-resistant tumor, contains EGFR-activating mutation L858R as well as resistance-conferring T790M. To explore mechanisms mediating resistance to third generation TKIs, we selected variants of the H1650 and H1975 cell lines for resistance to osimertinib to create models in which mechanisms of resistance can be characterized and tested for potential methods to overcome that resistance.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Cells were exposed continuously to a single concentration of osimertinib, in some cases with the inclusion of verapamil to avoid possible selection of multidrug-resistant cells. After 4 weeks, with weekly changes of drug-medium, clonal cell lines were selected from H1650 cultured in the presence of 25 or 50 µM osimertinib plus 10 µM verapamil, and selected from H1975 cultured in 6 or 10 µM osimertinib alone or 5 µM osimertinib plus 10 µM verapamil.

      4c3880bb027f159e801041b1021e88e8 Result

      The H1650 osimertinib-resistant cell lines (H1650/osi-25a/VPL and H1650/osi-50a/VPL) are 1.6- to 1.8-fold resistant to osimertinib. The H1975 osimertinib-resistant cell lines (H1975/osi-6b, osi-10c, and osi-5b/VPL) were, respectively, 90-, 95-, and 38-fold resistant to osimertinib. None of the cell lines was cross-resistant to imatinib. The compound 2-(benzylsulfonyl)-1-(1H-indol-3-yl)-1,2-dihydroisoquinoline (IBR2) is an inhibitor of the DNA repair protein RAD51 and enhances cytotoxicity of EGFR inhibitors against numerous cell lines (Ferguson et al., JPET 2018, doi.org/10.1124/jpet.117.241661). IBR2 decreased osimertinib-resistance by up to 80% in the H1650- and H1975-derived osimertinib-resistant cell lines. Further analyses of the resistant cell lines are being undertaken.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The H1650 and H1975 osimertinib-resistant cell lines are a valuable resource in which to test methods to circumvent resistance to third generation EGFR TKIs.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-28 - The Clinical Impact of Comprehensive cfDNA Genomic Testing in Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Laila C Roisman  |  Author(s): Smadar Geva, Anna Belilovski Rozenblum, Tal Twito, Roxana Denisa Grinberg, Addie Dvir, Lior Soussan Gutman, Maya Ilouze, Elizabeth Dudnik, Alona Zer, Ofer Rotem, Richard B Lanman, Nir Peled

      • Abstract

      Background

      Next-generation sequencing (NGS) of cell-free circulating tumor DNA (cfDNA) enables a non-invasive option for comprehensive genomic analysis of non-small cell lung cancer (NSCLC) patients. Although plasma-detected genomic alterations have been shown to predict targeted therapy response, evidence of durability of response is lacking or limited to small cohorts as is the impact of cfDNA NGS results on clinical decision making.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this retrospective study, data was collected on stage IIIB/IV NSCLC patients between the years 2014-2017 in Israel. We utilized cfDNA NGS (Guardant360) which covers the seven genes targetable with FDA-approved therapies in NSCLC.

      4c3880bb027f159e801041b1021e88e8 Result

      116 consecutively NSCLC patients were tested, 41.4% (48/116) before 1st line therapy (Group A), 34.5% (40/116) upon progression on chemotherapy or immunotherapy (Group B1) and 24.1% (28/116) upon progression on EGFR TKIs (Group B2). Targetable genomic alterations were found in 65% of group A (15/48), 53% in group B1 (21/40) and 71% in group B2 (20/28). Treatment decision was changed to targeted therapy based on cfDNA NGS analysis in 23% (11/48), 25% (10/40) and 32% (9/28), respectively (total cohort 26%; 30/116). Response assessment (RECIST) showed complete response in 4% (1/28), partial response in 39% (11/28), stable disease in 32% (9/28) and progressive disease in 25% (7/28). Total objective response rate (ORR) was 43% and disease control rate was 75% for 5 months treatment duration.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Comprehensive cfDNA testing impacted clinical decisions in 23% of naïve patients, 25% in patients who progressed on chemotherapy and 32% in EGFR TKI progressors. Median treatment duration was 5 months. This retrospective study extends previous reports by showing that responses based on cfDNA are durable and change treatment decisions at initial presentation and at progression.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-29 - St.Iv Lung Adenocarcinoma Treated by First-Line EGFR–Tyrosine Kinase Inhibitors-Survival, EGFR Mutation, Histologic Subtype

      12:00 - 13:30  |  Presenting Author(s): Tomasz Gil  |  Author(s): Grzegorz Czyżewicz, Marta Skoczek, Piotr Wójcik, Piotr Hajder, Batrosz Kołodziejczyk, Wiktor Cieślak, Jarosław Kużdżał

      • Abstract

      Background

      The aim of the study is to evaluate the correlation of survival, EGFR mutation and histologic subtype of stage IV lung sensitive mutant adenocarcinoma treated with first-line EGFR–tyrosine kinase inhibitors (EGFR-TKI).

      o:p>

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively analyzed the clinical outcomes of 60 consecutive patients with EGFR-TKI sensitive mutations (exon 19 deletion or exon 21 L858R ) who received first-line erlotinib, gefitinib or afatinib therapy between October 2011 and September 2017. Histologic subtype was classified according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society pulmonary adenocarcinoma classification.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 60 patient enrolled, including 26 men, mean age 68.88 years (range: 49-89 ) and 34 women, mean age 65.68 years (range: 44-82).

      The average survival in women was 14.1 months and in men it was 13.3 months.

      Average survival in 28 patients were treated with Erlotinib was 14.51 months, in 18 patients treated with Gefitinib it was 12.79 months and in 14 patients treated with Afatinib it was 13.55 months.

      In 30 patients with the mutations (exon 19 deletion), the mean survival was 14.56 months.

      In the group of 26 patients with mutations (exon 21 L858R ), the mean survival was 12.68 months.

      The mean survival in the group of patients with acinar adenocarcinoma was 15.49 months, and in solid adenocarcinoma - 4.8 months.

      Currently, 21 patients are alive and remain in observation, 12 of them are treated and 39 patients died.

      In the multidimensional linear regression analysis, smoking was a factor decreasing the survival at p = 0.12, male gender decreased the survival rate p = 0.04, and the type of cancer subtype increased the survival rate p = 0.04. Erlotinib influenced the increase in survival at p = 0.15

      8eea62084ca7e541d918e823422bd82e Conclusion

      Mutation in (exon 19 deletion), histological subtype of tumor and Erlotinib treatment are factors significantly affecting the survival of patients with stage IV adenocarcinoma of the lung.The EGFR mutation frequency is higher in the acinar subtype than in other subtypes.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-30 - Treatment Sequencing in Patients With Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer (NSCLC) in Japan

      12:00 - 13:30  |  Presenting Author(s): Yasushi Goto  |  Author(s): Nobuyuki Yamamoto, Elizabeth T. Masters, Hironori Kikkawa, Jack Mardekian, Robin Wiltshire, Kanae Togo, Heyun Ma, Yuichiro Ohe

      • Abstract

      Background

      Limited data are available on real-world treatment patterns and outcomes of ALK inhibitors used sequentially. Access to a large medical records database and availability of multiple ALK inhibitors in Japan, the first country to approve alectinib in 2014, presents a unique opportunity to evaluate real-world treatment sequencing and outcomes in ALK-positive NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This descriptive, retrospective observational study used inpatient/outpatient medical and prescription records, claims and diagnoses from the Japan Medical Data Vision (MDV) Database. Included patients had confirmed diagnosis of lung cancer, an ALK test and first prescription order for an ALK inhibitor (prescription date = index date) on or before March 31, 2017. Descriptive analyses included demographics, baseline characteristics, treatment patterns including ALK inhibitor sequences, non-ALK inhibitor treatments received, and treatment duration.

      4c3880bb027f159e801041b1021e88e8 Result

      Overall, 378 patients (mean age 61 years; 53% female; 48% no history of smoking) met inclusion criteria. Baseline characteristics were similar among mutually exclusive groups of patients receiving 1, 2, or 3 ALK inhibitors. Similar proportions of patients received crizotinib (52%) and alectinib (48%) as index ALK inhibitor. Prior to the index date, 40% of patients received chemotherapy. ALK inhibitor sequences are shown (Table). In patients who had discontinued all ALK inhibitors, the next treatments were chemotherapy (46%) and immunotherapy (6%). The most common sequence was a crizotinib-led sequence of 2 ALK inhibitors; median duration of treatment was 53 months. Changes in treatment patterns over time and further duration of treatment data will be presented.

      Sequence

      Overall Population

      N = 378

      n (%)
      1 ALK inhibitor (n=261)
      Crizotinib 91 (24.07)
      Alectinib 170 (44.97)
      2 ALK inhibitors (n=98)
      Crizotinib -> Alectinib 89 (23.54)
      Crizotinib -> Ceritinib 1 (0.26)
      Alectinib -> Crizotinib 7 (1.85)
      Alectinib -> Ceritinib 1 (0.26)
      3 ALK inhibitors (n=19)
      Crizotinib -> Alectinib -> Ceritinib 16 (4.23)
      Alectinib -> Crizotinib -> Ceritinib 3 (0.79)
      8eea62084ca7e541d918e823422bd82e Conclusion

      Treatment patterns in ALK-positive NSCLC patients have evolved over time. The most common sequence for patients receiving > 1 ALK inhibitor was crizotinib-led. Median duration of treatment with crizotinib-led sequences is consistent with what has been reported previously. Additional research is warranted to evaluate non-crizotinib-led sequences as data mature.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-31 - Prognostic Factors in Patients with Resected Pathological N2 Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Tatsuya Goto  |  Author(s): Masaya Nakamura, Yuki Shimizu, Seijiro Sato, Terumoto Koike, Masanori Tsuchida

      • Abstract

      Background

      Postoperative outcome for non-small cell lung cancer (NSCLC) patients with mediastinal lymph node metastasis is unfavorable even after complete resection. To identify the subgroup of NSCLC patients with mediastinal lymph node metastasis whom we recommend surgical treatment, we sought to investigate prognostic factors in these patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed NSCLC patients with pathologically identified mediastinal lymph node metastasis who underwent complete resection with systematic nodal dissection between 2000 and 2016. Demographic, clinical, and pathologic factors (sex, age, Brinkman index, performance status [PS], % vital capacity, forced expiratory volume % in 1 second, preoperative carcinoembryonic antigen [CEA], histological subtype, pathological tumor size, p-T factor [7th edition], pleural invasion, pulmonary metastasis, histological grade, number of positive mediastinal nodal stations [single station vs multiple stations], number of positive mediastinal lymph nodes [1-2 vs ≥3], epidermal growth factor receptor [EGFR] mutation status, and adjuvant chemotherapy) were analyzed using the log-rank test as univariate analyses and a Cox proportional hazards regression model for multivariate analyses to identify independent predictors of favorable overall survival (OS).

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 54 eligible patients, 38 were male and 16 were female. The median age and CEA were 65 years and 5.3 ng/mL, respectively. Lobectomy, bilobectomy, and pneumonectomy were performed in 49/3/2 patients. Histological subtypes were adenocarcinoma in 29 patients, squamous cell carcinoma in 17, and others in 8. EGFR was inspected in 33 patients, and 10 patients were EGFR mutated. Adjuvant chemotherapy was performed in 26 patients. The details of adjuvant chemotherapy were cisplatin-based combination chemotherapy in 18 patients, and carboplatin-based combination chemotherapy in 8.

      The 3-year and 5-year OS were 64.9% and 44.7%, respectively, with a median follow-up period of 41 months. The preoperative CEA <5.3 ng/mL (HR: 0.2151) and undergoing adjuvant chemotherapy (HR: 0.3580) were identified as significant predictors of favorable OS. The 3-year and 5-year OS in patients with CEA <5.3 and ≥5.3 ng/mL were 88.3/70.8% vs 41.0/17.9%, respectively (p<0.001). The 3-year and 5-year OS in patients who underwent adjuvant chemotherapy or none were 75.3/70.3% vs 55.3/23.1%, respectively (p = 0.009).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Even if NSCLC patients have mediastinal lymph node metastasis, favorable postoperative prognosis may be expected in patients with low preoperative serum CEA. Adjuvant chemotherapy should be considered in patients with mediastinal lymph node metastasis on pathological examination.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-33 - EGFR Mutation in Patients with NSCLC and Its Relationship Between Survival and Clinicopathological Features: An Update Analysis

      12:00 - 13:30  |  Presenting Author(s): Mahmut Gumus  |  Author(s): Akın Ozturk, Sinemis Celik, Hilmi Kodaz, Ibrahim Yildiz, Ayse Ocak, Ilhan Hacibekiroglu, Ibrahim Vedat Bayoglu, Ozlem Ercelep, Ahmet Siyar Ekinci, Serkan Menekse, Ozge Gumusay, Basak Oven, Mehmet Naci Aldemir, Caglayan Geredeli, Meltem Baykara, Mukremin Uysal, Alper Sevinc, Asude Aksoy, Arife Ulas, Mevlude Inanc, Ozgur Tanriverdi, Nilufer Avci, Nedim Turan

      • Abstract

      Background

      There has been important developments in NSCLC since the understanding of molecular pathways. The aim of the study is to find the EGFR mutation frequency and its correlation to survival and clinicopathological features. We reported our data in this subject three years ago. We aim to resubmit our updated data.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this multicenter study, 1352 NSCLC (adenocarcinoma) patients were included retrospectively to find out the EGFR mutation status with age, sex, performance status, histopathological diagnosis, smoking status and stage. Survival correlates were determined. The aim of the study was to find out the EGFR mutation status with all of the features in the database.

      4c3880bb027f159e801041b1021e88e8 Result

      The median age was 59 (24-87) years. Median follow-up time was 14 (2-117) months. 26,2 % were female. 85,2% were stage IIIB-IV and 86 % was adenocarcinoma. EGFR mutation frequency was 22,3 % including exon 19 (63,0%). There was no correlation between mutational status and age, performance status, and stage at diagnosis (p>0,05). However, there was a correlation between gender and, smoking.. (p= 0.000 and 0,000. respectively). The frequency of mutation in female patients was more pronounced in non-smokers/ex-smokers. In the group that can perform survival analysis (827 pts), median progression-free survival was 9 months and overall survival was 20 months. The overall survival was 27 (SE:5; 95% CI 17-36) months in EGFR positive cases whereas 19 (SE:1; 95% CI 16-21) months in EGFR negative cases (p=0,008). The multivariate analysis showed good performance status, early stage disease and presence of EGFR mutation as a prognostic factor (p<0,05).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our investigation shows that the EGFR mutation rate in our patient population with adenocarcinoma of the lung was higher than in Western countries population and was lower than the East Asian population. The determination of EGFR mutation will lead the pathway for a better treatment outcome and individualized therapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-34 - Short Hydration Regimen with a Modified Dose of Magnesium Supplementation for Lung Cancer Patients Receiving Cisplatin-Based Chemotherapy

      12:00 - 13:30  |  Presenting Author(s): Tetsunari Hase  |  Author(s): Masayuki Miyazaki, Kazuya Ichikawa, Naoyuki Yogo, Naoya Ozawa, Masahiko Ando, Masahiro Morise, Mitsuo Sato, Masashi Kondo, Kiyofumi Yamada, Yoshinori Hasegawa

      • Abstract

      Background

      Intravenous administration of magnesium is recommended for patients receiving high-dose cisplatin with a short hydration regimen in terms of protection against cisplatin-induced nephrotoxicity. However, the optimal dose of the magnesium supplementation has not been clarified. The aim of this trial was to investigate the safety and efficacy of short hydration regimen with 20mEq of magnesium supplementation for lung cancer patients receiving cisplatin-based chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The key eligibility criteria included cytologically or histologically proven lung cancer, candidates for cisplatin (≥60 mg/m2) based chemotherapy or chemoradiotherapy, no prior chemotherapy, age ranged 20 and 75 years old and adequate renal function. Cisplatin was administered with pre-hydration containing 20 mEq of magnesium sulfate. Mannitol was administered just before the cisplatin infusion as an enforced diuresis. The primary endpoint was the proportion of patients without a Grade 2 or higher elevation in creatinine. The study was registered at UMIN-CTR as UMIN000011687.

      4c3880bb027f159e801041b1021e88e8 Result

      Forty patients with a median age of 66 years (range, 35-74) were enrolled in the study. Of these, 16 had adenocarcinoma, 12 had squamous cell carcinoma, 5 had small cell carcinoma, 2 had large cell carcinoma and 5 had other histology. The median baseline creatinine value was 0.71 mg/dl. The median dose of cisplatin at the first cycle was 80 mg/m2. Twenty-nine patients received cisplatin and vinorelbine as their most frequent regimen and 24 patients received 4 cycles of chemotherapy. In the first cycle, no patients developed Grade 2 creatinine toxicity. During the whole treatment period, one patient developed Grade 2 creatinine elevation, and thus, the proportion of patients without a Grade 2 or higher elevation in creatinine was 97.5% (95%CI 86.8‐99.9). Grade 1 hypermagnesemia was observed in 3 patients.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study indicates short hydration regimen with 20mEq of magnesium supplementation was safe and feasible for lung cancer patients receiving cisplatin-based chemotherapy without risk of severe nephrotoxicity.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-35 - Outcomes in Advanced Non-Small Cell Lung Cancer After Discontinuation of PD-1 Checkpoint Inhibitor Due to Toxicity. A Retrospective Study

      12:00 - 13:30  |  Presenting Author(s): Jonathon Hill  |  Author(s): Adnan Nagrial, Rina Hui

      • Abstract

      Background

      Programmed cell death ligand (PD-1) checkpoint inhibitors have been shown to improve survival in advanced non-small cell lung cancer. Although immune-related adverse events from single agent anti PD-1 or PDL-1 are manageable, severe toxicities require treatment discontinuation. There are limited data on patient outcomes after treatment discontinuation and the necessary cessation of treatment can cause concern of disease control for the patient and clinician. This retrospective study examined disease outcomes in patients after discontinuation of PD-1 checkpoint inhibitor due to toxicity.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients treated with pembrolizumab or nivolumab monotherapy for advanced non-small cell lung cancer at our cancer centre were identified. A retrospective review of electronic and paper records was performed. Information including patient baseline characteristics, progression- free survival, overall survival, toxicity leading to treatment discontinuation and time to progression after treatment cessation were obtained. Imaging was reviewed to confirm events of disease progression.

      4c3880bb027f159e801041b1021e88e8 Result

      54 advanced non-small cell lung cancer patients treated between 2012 and 2017 with single agent pembrolizumab or nivolumab were included in the analysis. 8 (14.8%) patients experienced toxicity necessitating treatment discontinuation. Baseline characteristics including age, ECOG performance status, prior lines of therapy and smoking status were similar in patients with or without severe immune-related toxicities. Pneumonitis was the most common toxicity requiring treatment cessation (n=4). Other toxicities included colitis (n=1), vasculitis (n=1), myositis (n=1) and bullous pemphigoid (n=1). The overall survival at 1 year was 42.6% for all patients versus 37.5% for patients with toxicities requiring treatment cessation. 2 of the patients with pneumonitis died as a result of this toxicity prior to achieving disease control. The patient with bullous pemphigoid and those survived pneumonitis had not experienced disease progression at time of analysis (all censored, alive and progression free for minimum of 6 months after treatment discontinuation). Time to progression was <5 months in the patients with colitis, myositis and vasculitis.

      8eea62084ca7e541d918e823422bd82e Conclusion

      With the limitations of this small study at a single site, patients requiring treatment cessation from toxicity had comparable progression-free and overall survival to those without severe toxicities. The risk of Grade 5 immune- related pneumonitis might have contributed to the numerically lower survival rates in the group that experienced toxicity. Prolonged disease control was observed in patients who survived pneumonitis despite treatment discontinuation.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-36 - Prognostic Factors in Elderly Patients with Advanced Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Marta Honorio  |  Author(s): Nuno Guerra Pereira, Andreia Tereso, Maria Amélia Almeida

      • Abstract

      Background

      There is no consensus method for identifying frail older patients. A number of clinical screening tests are now available but the prediction of outcome of treatment is difficult. Sarcopenia, as simply determined by a baseline Computed Tomography (CT) image, has been shown to be predictive of prognosis in Lung Cancer (LC). The purpose of this analysis was to determine the prognostic significance of CT determined sarcopenia, and other clinical parameters, on overall survival (OS) among elderly patients with advanced-stage Non-Small Cell Lung Cancer (NSCLC) and on active treatment. We also sought to determine the OS of this population, according to the different clinical parameters evaluated.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective analysis of 77 patients older than 65 years old with advanced NSCLC and ECOG PS 0-2 treated between 2014 and 2017 was performed. The variables tested were age, gender, ECOG PS, polypharmacy (the use of 5 or more medications), The Charlson Comorbidity Index (CCI), Body Mass Index (BMI), Lactate dehydrogenase value and sarcopenia. For the quantification of Sarcopenia two methods were used: Total Psoas Index (TPI) and the Hounsfield Unit Calculation (HUAC). Both obtained from a single axial Computed Tomography (CT) image at L3 level. Median OS was assessed by Kaplan-Meier method. Cox survival analysis was performed for a 95% CI for the hazard ratios, considering a p value of 0.05 as an indicator of statistical significance. Analyses were performed with use of SPSS v.18 software.

      4c3880bb027f159e801041b1021e88e8 Result

      On our population we found sex, CCI and polypharmacy as independent risk factors associated with mortality. Median OS of the population was 14 months. Men and patients who presented with ECOG PS 2, BMI below 22 Kg/m2 and sarcopenia had worse outcome, but without statistical significance.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Clinical variables may help to discuss prognosis with elderly LC patients. The identification of these factors can be used to improve patient selection for the different treatment options.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-37 - Phase II Study of Amrubicin Plus Erlotinib in Previously Treated, Advanced Non-Small Cell Lung Cancer Patients with Wild-Type EGFR: TORG 1320

      12:00 - 13:30  |  Presenting Author(s): Shinobu Hosokawa  |  Author(s): Sakiko Otani, Jiichiro Sasaki, Tomoya Fukui, Yoshiro Nakahara, Akihiro Bessho, Nobuaki Fukamatsu, Yukiko Nakamura, Takashi Kasai, Tomohide Sugiyama, Takaaki Tokitho, Nobuhiko Seki, Akinobu Hamada, Noriyuki Masuda, Hiroaki Okamoto

      • Abstract

      Background

      The combination of amrubicin (AMR) and erlotinib (ERL) was reported to have synergistic effect on non-small cell lung cancer (NSCLC) cell line with wild-type EGFR in vitro. We accomplished a phase I study of AMR plus ERL in previously treated advanced NSCLC patients, and determined the maximum tolerated dose (MTD). Furthermore, we observed a high response rate of 33% (Am J Clin Oncol 2015).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We conducted a multi-center, single-arm phase II trial to evaluate the efficacy of AMR and ERL combination therapy in patients with previously treated, advanced NSCLC with wild-type EGFR. Patients were treated at 3weeks intervals with AMR (35mg/m2 on days 1-3) plus ERL (100mg/day on days 1-21). The patients without disease progression after 4 cycles continued ERL until disease progression or unacceptable toxicity. The primary endpoint is progression free survival (PFS). Secondary endpoints are response rate (RR), disease control rate (DCR), time to treatment failure (TTF), overall survival (OS), and toxicity. The concentration of trough ERL was measured after first cycle of treatment and in maintenance phase as an exploratory research to analyze relation between effectivity/safety and pharmacokinetics.

      4c3880bb027f159e801041b1021e88e8 Result

      From June 2013 to July 2016, 25 patients were enrolled. With a median follow-up of 14.3 months (95%CI: 10.9 – 17.6), median PFS was 3.6 months (95%CI: 2.1 - 5.1). The RR and the DCR were 24.0% and 64.0%, respectively. Median OS was 15.4 months (95%CI: 13.4 – 17.4). We observed grade 3 or 4 toxicities such as leukopenia (68%), neutropenia (72%), anemia (8%), febrile neutropenia (12%), anorexia (12%), oral mucositis (12%) and rash (8%). We had no treatment related death. In pharmacokinetic analysis, the mean (±SD) trough concentrations (C trough) of ERL in induction and maintenance phase were 1.070±0.463µg/mL and 0.879±0.427µg/mL, respectively. The C trough of ERL in induction phase was higher than that in maintenance phase (p=0.0371). There was no relation between C trough of ERL and any toxicity/response.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although the primary endpoint was not met in this trial, the PFS of AMR and ERL combination therapy was superior to that of AMR monotherapy which was previously reported. In this study, pharmacokinetic analysis showed that C trough of ERL were elevated in combination therapy. This combination therapy might be an optional treatment as cytotoxic chemotherapy for NSCLC patients after platinum-doublet failure. Clinical trial information: UMIN 000010582.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-38 - Therapeutic Effects of FMNP-MSC for Hyperthermia on Lung Cancer A549 in Nude Mice

      12:00 - 13:30  |  Presenting Author(s): Runlei Hu

      • Abstract

      Background

      To study therapeutic effects of fluorescent magnetic nanoparticles labeled mesenchymal stem cells (FMNP-MSC) for hyperthermia induced by an alternating magnetic field on lung cancer A549 in nude mice.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The fluorescent magnetic nanoparticles (FMNP) was prepared and characterized, and then were used to label mouse mesenchymal stem cells(MSCs) in vitro. The FMNPs-labeled MSCs were injected via tail vein into nude mice bearing non-small cell lung cancer A549 cells. The subcutaneous lung cancer tissues in the nude mice models were subsequently treated in external alternating magnetic field once a week for four weeks, temperature of tumor was detected by optical fiber. Four weeks after treatment, the tumor were collected after euthanizing the animals. Pathology change of tumor tissue was detected by light microscope, cell apoptosis proteins (Bax, Caspase-3) and anti-apoptotic protein (Bcl-2) were detected by Western blot

      4c3880bb027f159e801041b1021e88e8 Result

      In vivo experiments confirmed that MSC FMNP can be carried to the tumor area. Temperature of tumor can heat up to 53 ℃ under alternating magnetic field. FNMP - MSC thermal therapy group mice tumor volume and weight growth was significantly inhibited, FMNP-MSC group of mice with tumor volume growth is restrained, the weight was not significantly inhibited. Apoptosis and necrosis change of tumor tissue could be detected by light microscope. Western blot confirmed, Bax protein expression in two treatment group obviously, and Caspase 3, the Bcl-2 in the two treatment groups have no significant expression

      8eea62084ca7e541d918e823422bd82e Conclusion

      FMNP-MSC can accurately targeting to the tumor area, which heat up to the effective temperature under alternating magnetic field, the growth of tumor in mice was significantly inhibited; apoptosis and necrosis could be seen in tumor, may be achieved by increasing the expression of Bax

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-39 - Analysis of Acquired EGFR T790M Mutation in Patients with Non-Small Cell Lung Cancer Who Received Icotinib Progress

      12:00 - 13:30  |  Presenting Author(s): Chunwei Xu  |  Author(s): Rongfang Huang, Wenxian Wang, Jianying Li, Cheng He, Youcai Zhu, Wu Zhuang, Zhangzhou Huang, Yanping Chen, Gang Chen, Meiyu Fang, Tang Feng Lv, Yong Song

      • Abstract

      Background

      As the first epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in China, icotinib shows promising anticancer activity in vitro and vivo. The phase III clinical study (ICOGEN) showed that icotinib has a good efficacy and tolerability in Chinese patients with advanced non-small cell lung cancer (NSCLC) compared with gefitinib. The aim of this study is to investigate the acquired EGFR T790M situation of the non-small cell lung cancer patients who received icotinib treatment progress.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The ARMS method was used to detect the samples in 209 cases of EGFR 19del or L858R mutation non-small cell lung cancer.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 123 cases accompanied 19del and 86 cases accompanied L858R in 209 cases non-small cell lung cancer samples who received icotinib treatment progress, the acquired T790M mutation type patients was 45.93% (96/209), icotinib treatment. resistance after the acquired T790M mutation with 19 del/L858R group had statistical difference (P<0.034).

      8eea62084ca7e541d918e823422bd82e Conclusion

      19 del patients who received treatment for icotinib are more likely to appear acquired T790M mutation than L858R patients from NSCLC, and we should attach importance to it.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-40 - Treatment of Super Elderly Patients for Non-Small Cell Lung Cancer in Japan

      12:00 - 13:30  |  Presenting Author(s): Tatsuya Ibe  |  Author(s): Hiroaki Kodama, Yoichiro Hamamoto

      • Abstract

      Background

      Japan is the one of the country with the longest life expectancy in the world; many elderly Japanese are treated for lung cancer. The number of people dying from lung cancer is consistently increasing, and nearly half of lung cancer patients are older than 75 years of age. It is said that 60% patients died of the lung cancer are patients over 75 years. Approximately half of lung cancers are found in advanced stage, and are treated by chemotherapy. However, many clinical trials of lung cancer treatment using conventional anticancer drugs are targeted toward patients younger than 70years old. No clear evidence on treatment for elderly patients over 80 years has been established.

      We conducted a retrospective analysis of patients over 80 years old who were diagnosed with advanced non small cell lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed the outcome of patients over 80 years old who were diagnosed with advanced non small cell lung cancer between 2012 to 2016.

      4c3880bb027f159e801041b1021e88e8 Result

      48 patients were incorporated in the study; 26 were treated by chemotherapy (Median age 84years (80-89), 16 males), 22 were in BSC (Median age 84 years (80-96years), 13 males). 69%(18/26) of the treatment group were in Performance Status 0-1, compared to 18%(4/22) in the BSC group.(p=0.0005)

      Adenocarcinoma was the most common type in the treatment group(16/28), followed by Squamous cell carcinoma (7/28). Half of the treated patients were in stage Ⅳ, 6 cases were stageⅢb, and 6 cases stageⅢa.

      The median overall survival in treatment group was 378 days, median number of regimen conduced was 1 (average 1.37). In BSC group, it was difficult to follow until death, therefore comparison with the treatment group is not analyzed.

      8eea62084ca7e541d918e823422bd82e Conclusion

      It was suggested that the prognosis was prolonged by chemotherapy in the treatment group, compared to the previous chemotherapy trials for elderly patients. Chemotherapy should also be considered in super elderly patients over 80 years old, when he/she has good PS. However, regarding chemotherapy for the elderly patients with non small cell lung cancer, it is important to carefully consider adverse events.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-41 - Anatomical and Clinical Basis of #11 LN by Systematic Bilateral Mediastinal Nodal Dissection for Left Lung Cancer through Median Sternotomy

      12:00 - 13:30  |  Presenting Author(s): Shingo Ikeda  |  Author(s): Toshiya Yokota, Kurumi Fukui, Tatsuhiro Hoshino

      • Abstract

      Background

      Patients with mediastinal lymph node metastasis have a poor prognosis, and lung operation is not typically indicated. We performed bilateral mediastinal lymph node dissection by median sternotomy to resect lung cancer and dissect the bilateral mediastinal lymph nodes. Although some studies have examined the communications between the left and right lymphatic pathways in lung cancer cases, we anatomically analyzed this technique of bilateral lymph node dissection, and confirmed its usefulness. There are some reports on #11LN positive cases and other lymph node metastasis cases. We investigated metastatic status between #11 lymph node positive cases and other lymph nodes by systematic bilateral mediastinal nodal dissection for left lung cancer through median sternotomy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed this operation in 314 patients with primary left lung cancer excluding small cell carcinoma and stage IV since 1987. From among the 314 patients, 25 had in p-N1, 50 in p-N2, 24 in p-N3 lymph node metastases. Based on macroscopic dissection procedures, dissection of the lymphatics from the lungs to the supraclavicular lymph nodes was performed by sequential removal of the related organs. In particular we examined the metastatic status and clinical significance of #11 lymph node in N1-3 52cases. We systematically compared and analyzed the route of lymphatic communications to the contralateral side with emphasis on the anatomical significance of the left-to-right lymphatic communications of the bilateral mediastinal lymph nodes.

      4c3880bb027f159e801041b1021e88e8 Result

      The overall 5-year survival rate (Kaplan-Meier method), including operative deaths and deaths due to unrelated diseases, was 65.5%(MST11.3yrs) in the patients with left lung cancer. With respect to the p-N factor, the 5-year survival rate were 40% in p-N1, 48.7% in p-N2, 53.6% in p-N3, 38.3% in #11LN positive in left lung cancer patients.

      We will report the investigation of the prognosis of left non small cell lung cancer patients who underwent initially our extended bilateral mediastinal dissection, focused on the patients with #11LN positive cases.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We identified the route of lymphatic communications to the contralateral side, and systematically analyzed the anatomical significance of the left-to-right lymphatic communications in #11 LN positive cases. The overall 5-year survival rate (Kaplan-Meier method), including operative deaths and deaths due to unrelated diseases, was 65.5%(MST11.3yrs) in the patients with left lung cancer. With respect to the p-N1-3 factor, the 5-year survival rate were 40% in p-N1, 48.7% in p-N2, 53.6% in p-N3, 38.3% in #11LN positive in left lung cancer patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-42 - Phase II Trial Allowed Surgery After Induction Chemotherapy of CBDCA+PTX, Bevacizumab in Patients with Stages IIIA-IV Nonsquamous NSCLC

      12:00 - 13:30  |  Presenting Author(s): Kazuhiro Imai  |  Author(s): Taku Nakagawa, Ikuo Matsuzaki, Kimito Orino, Hajime Saito, Kazuhiro Sato, Masaaki Sano, Yusuke Sato, Satoru Motoyama, Hiroyuki Shibata, Yoshihiro Minamiya

      • Abstract

      Background

      Surgery remains the best therapy for cure in non-small cell lung cancer (NSCLC). However, the treatment strategy for advanced NSCLC patient including Stage III with N2 remains controversial. Bevacizumab (Bv), a humanized monoclonal antibody targeting VEGF, combined with the standard platinum doublet-based chemotherapy is approved for the first-line treatment of NSCLC. This study aimed to determine whether the treatment allowed surgery after induction chemotherapy of carboplatin (CBDCA) and paclitaxel (PTX) with Bv provides a reduction in the risk of progression in patients with stages IIIA to IV non-squamous NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This clinical trial was an open-label, multicenter, single-arm study involving 10 institutions in Akita, Japan (UMIN000007916). Chemotherapy/radiation-naive patients > 20 years of age, ECOG performance status of 0 to 1, and adequate hematologic, hepatic, and renal function with cytologically or histologically confirmed stages IIIA to IV nonsquamous NSCLC not amenable to surgical resection or radiation with curative intent, were eligible. Treatment plan is showed in Figure 1.

      fig.1 cbdca+ptx, bv schema.jpg

      4c3880bb027f159e801041b1021e88e8 Result

      Between April 2012 and October 2017, a total 29 patients were enrolled. The overall response rate was 72.4%, 10 of 29 patients underwent radical surgery included lymph node dissection 2a-2 basically after the chemotherapy. Complete resection was achieved in 7 patients of them (70%) in the induction chemotherapy group. Bronchial stump and anastomoses were buttressed with a pericardial flap or intercostal muscle flap in some cases. The 30-day hospital mortality was 0% in the all patients who underwent operation. Grade 3 or 4 adverse events occurred in 72.4% such as neutropenia, just one case has pulmonary hemorrhage and GI bleeding.

      8eea62084ca7e541d918e823422bd82e Conclusion

      These results suggest that CBDCA+PTX, Bv which has higher response rate will introduce the better potential to reduce tumor size, increase operability, and eradicate micro-metastases. However, a survival benefit might be limited even though surgery was added after induction chemotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-43 - Predictive Value of Computed Tomography Characteristics for Nivolumab Response in Pretreated Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Hisao Imai  |  Author(s): Hiroyuki Minemura, Hiroshi Moriya, Tomohide Sugiyama, Yutaka Yamada, Mitsunori Higuchi, Kyoichi Kaira, Yuki Ozaki, Kenya Kanazawa, Hiroshi Yokouchi, Takashi Kasai, Takayuki Kaburagi, Hiroyuki Suzuki, Koichi Minato, Yoko Shibata

      • Abstract

      Background

      The efficacy and safety of nivolumab for the treatment of pretreated non-small cell lung cancer (NSCLC) have been established. We conducted a retrospective multicenter trial to determine the significance of computed tomography (CT) morphologic characteristics as a predictor of nivolumab efficacy for advanced NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From April 2013 to March 2017, 78 pretreated NSCLC patients were enrolled. Our radiologist assessed the following tumor characteristics on CT before nivolumab treatment; interstitial septal thickening, peritumoral ground-glass opacity, spiculated margin, air bronchogram, cavity or necrosis, adjacent organ invasion, bulky lymph node (≥ 2.5 cm), and accumulation of small lymph nodes. After nivolumab treatment, objective response rate (ORR), disease control rate (DCR) and progression free survival (PFS) were analyzed with logistic regression and Cox proportional hazards regression models. Patient and CT morphologic characteristics were retrospectively analyzed. Significant parameters identified by univariate analysis were included in a multiple analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 78 patients, 60 (77%) were male, and 72 (92%) patients were of performance status 0 to 1. Heavy smoking was related to higher ORR than light or never smoking (28% vs 0%, p=0.01).No morphologic characteristics were related to ORR or DCR. Interstitial septal thickening was significantly associated with shorter PFS (p=0.015, 77 vs 126 days). Adjacent organ invasion was also significantly associated with shorter PFS (p=0.047, 72 vs 118 days). However, they were not found to be significant on multivariate analysis.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Interstitial septal thickening and adjacent organ invasion may be negative prognostic factors of nivolumab treatment for NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-44 - CYFRA 21-1 As a Predictor to Response to Chemotherapy and Overall Survival in Patients with Advanced NSCLC

      12:00 - 13:30  |  Presenting Author(s): Kashif Iqbal

      • Abstract

      Background

      In era of ever evolving, promising new therapies for advanced NSCLC, early predictors of response are needed. We evaluated early variations in serum CYFRA 21-1 of patients with advanced NSCLC receiving first line chemotherapy and correlated the results with objective tumor response and overall survival.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      29 consecutive untreated patients of advanced NSCLC with measurable disease on CTscan were evaluated. All patients were treated with conventional systemic chemotherapy. Serum samples were obtained before start of 1st and 2nd cycles. CYFRA 21-1 was measured with an electrochemiluminescense immunoassay. All patients were followed for a period of five years. Response was evaluated using RECIST.

      4c3880bb027f159e801041b1021e88e8 Result

      10 patients had partial response, 9 had stable disease and 9 had progression. None had complete response. 21/29 patients had elevated baseline value of CYFRA. 18/29 patients had decrease in CYFRA 21-1 after 1 cycle of chemotherapy. The average reduction in 2nd reading was irrespective of baseline value being normal or not. The average reduction was statistically significant (P = 0.002). 8/10 patients with partial response had reduction in their 2nd reading which was significant. We observed that 6/9 patients whose disease remained stable had a decrease in their subsequent reading (P=0.0106), though was not significant statistically. 5/9 patients who had an increase in their 2nd reading had progression, it was not statistically significant (P= 0.537). 14/19 who had partial response or stable disease, had a reduction in their 2nd value of CYFRA 21-1 and was significant statistically (P 0.004). We observed that except for 1, all patients who had decrease of 42% or more were responders (P 0.001), which was statistically significant.We followed all patients for five years. None was alive at 5 years. 10 patients were alive at 3 years and 6 were alive at 4 years. All patients who progressed after chemotherapy died within 1 year. 7/10 and 4/6 patients had reduction in their CYFRA 21-1 but was not statistically significant (P 0.24 95%CI -9.7-15.7). We observed that 3/4 patients who were alive at 4 years had a decrease of 30% or more in their subsequent CYFRA 21-1 level.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We conclude that monitoring CYFRA 21-1 early during first-line chemotherapy may be useful prognostic tool for evaluation of early tumor response in patients with advanced NSCLC. Although decrease in CYFRA 21-1 was non statistically significant for monitoring overall survival, it can be used as surrogate marker in identifying patients for aggressive treatment but it needs validateion by large RCT

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-45 - Multifactorial Gene Alterations in EGFR Bypass Pathway are Induced by Afatinib in T790M-Mutant NSCLC Resistant to Osmertinib

      12:00 - 13:30  |  Presenting Author(s): Hidenobu Ishii  |  Author(s): Koichi Azuma, Kazuko Sakai, Yoshiko Naito, Norikazu Matsuo, Takaaki Tokito, Kazuhiko Yamada, Tomoaki Hoshino, Kazuto Nishio

      • Abstract

      Background

      The 3rd generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) was developed to target the EGFR T790M resistance mutation in non-small cell lung cancer patients resistant to 1st or 2nd generation EGFR-TKIs. Although some mechanisms of acquired resistance to 3rd generation EGFR-TKI such as EGFR C797S mutation have been reported, the effect and resistant mechanisms to afatinib followed by osmertinib has not been well-known.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Nine patients with EGFR T790M-mutant NSCLC resistance to 3rd generation EGFR-TKI were enrolled in this study and treated with afatinib. Plasma samples were collected before treatment, 4 weeks after treatment, and at disease progression. Mutation profile and tumor mutation burden (TMB) in plasma cell free DNA (cfDNA) were analyzed by CAPP-seq.

      4c3880bb027f159e801041b1021e88e8 Result

      The objective response rate and median progression-free survival of afatinib were 0% and 2.0 months, respectively. At the time of 4 weeks after treatment, four patients developed disease progression and five patients showed stable disease. A total of 36 somatic mutations or amplification were detected in plasma cfDNA before afatinib treatment; EGFR activating mutations in 8 patients, T790M mutation in 4, TP53 mutations in 6, PIK3CA mutations in 3, BRAF mutations in 3, MET amplification in 3, CTNNB1 mutations in 2, ERBB2 mutations in 2, C797S mutation in 1, SMAD4 mutation in 1, EGFR minor mutation in 1, KRAS mutation in 1, and APC mutation in one patient. EGFR C797S mutation in cfDNA was detected during afatinib treatment in two cases. In the patients having stable disease at 4 weeks after treatment, mutant allele frequency and TMB tended to decline once, and then increased in association with disease progression.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Detection of mutant allele frequency and TMB of ctDNA by CAPP-seq could monitor the effectiveness and resistance to afatinib. Resistant mechanisms to afatinib might be characterized by multifactorial bypass pathway activation.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-46 - Prognostic Utility of Advanced Lung Cancer Inflammation Index (ALI) in Thoracic Malignancies: A Meta-Analysis

      12:00 - 13:30  |  Presenting Author(s): Syed Hasan Raza Jafri  |  Author(s): Hazem Elosta

      • Abstract

      Background

      Introduction: We developed ALI as a prognostic marker in metastatic non-small cell lung cancer. ALI has now been validated in a variety of cancers. Here we report a meta-analysis of ALI as a prognostic marker in thoracic malignancies

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Methods: ALI is calculated as follows: ALI= BMI x ALB/NLR, where BMI= body mass index, ALB=serum albumin, NLR=Neutrophil/lymphocyte ratio. ALI <18 is a marker of shorter progression free and overall survival. We searched database in PubMed up until January 31, 2018. We selected all the studies that compared the survival of patients with thoracic malignancies according to their ALI. We used the random effect model to calculate the pooled hazard ratio of overall survival. Meta-regression analyses, heterogeneity of data and publication bias were also appreciated.

      4c3880bb027f159e801041b1021e88e8 Result

      ali metanalysis figure.jpgResults: a total of 6 studies, all retrospective in design, were included in the meta-analysis. Among these, 3 evaluated the prognostic value of ALI score in non-small-cell lung cancer, 2 in small cell lung cancer and 1 in esophageal cancer. By random effect model, we detected a statistically significant higher overall survival for patients with high ALI score (AL≥18). This corresponded to a pooled of hazard ratio of death of 0.619 (95% confidence interval: 0.531-0.721, p-value <0.001), with the subgroups of patients with low ALI score used as reference. Interestingly, no heterogeneity of data was found (Q-value=3.598, I-square = 0.000, p=value=0.609). By meta-regression analysis, the covariate “type of tumor” (non-small cell lung cancer vs. others) did not influence the predictive value of ALI score (test of model Q-value=0.34, p-value=0.55). No publication bias was detected by Egger test (p-value=0.24).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Conclusion: ALI significantly correlate with prognosis in thoracic malignancies regardless of tumor type and should be used in clinical practice and research to identify high-risk patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-47 - Clinical Characteristics and Outcome for Patients with Advanced Lung Adenocarcinoma Treated with First-Line Pemetrexed Plus Platinum

      12:00 - 13:30  |  Presenting Author(s): Xue Ji  |  Author(s): Xingsheng Hu, Yixiang Zhu, Yutao Liu, Lin Lin, Puyuan Xing, Xuezhi Hao, Yan Wang, Junling Li

      • Abstract

      Background

      To evaluate the efficacy and safety of pemetrexed combined with platinum first-line therapy for advanced lung adenocarcinoma, as well as the clinical factors influencing outcomes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively evaluated the data from 450 pemetrexed-treated patients with stage IIIb/IV lung adenocarcinoma that confirmed by cytology or histology from February 2011 to August 2017. Patients were divided into 2 groups according to the presence of maintenance therapy (yes or no) after the first-line chemotherapy. The primary endpoint was progression-free survival (PFS), secondary endpoints included objective response rate (ORR), disease control rates (DCR), and safety.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 292 received only first-line pemetrexed-based therapy, while 158 patients received maintenance pemetrexed after induction. The overall median PFS was 5.83 months (95% CI was 0.33 to 55.72 months). The maintenance treatment group had longer PFS (9.92 months, 95%CI: 3.98 to 5.21 months) than (P < 0.001) the non-maintenance treatment group (4.60 months, 95%CI: 8.70 to 11.14 months) after the first line chemotherapy (P < 0.001). The ORR and DCR of 450 patients with lung adenocarcinoma was 33.6% and 87.6%, respectively. Single-factor and multiple-factor analysis showed that positive mutation of epidermal growth factor receptor (EGFR), PS 0, exposure more than 4 cycles, and the addition of maintenance treatment were the positive prognostic factors for survival. The main adverse reactions of the patients were hematological toxicity, gastrointestinal reaction, abnormal and asthenia of liver function. However, low incidence of grade 3 or higher toxicity was seen in this study.

      8eea62084ca7e541d918e823422bd82e Conclusion

      First-line therapy with pemetrexed combined with platinum is safe and effective for advanced lung adenocarcinoma, and pemetrexed maintenance therapy has a better survival benefit.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-48 - The Efficiency of Low-Dose Apatinib in Treatment of Advanced Lung Squamous Cell Carcinoma

      12:00 - 13:30  |  Presenting Author(s): Yu-Ming jia  |  Author(s): Ting Li, Shan-Bin Wang, Kai-Jian Lei, Bang-Xian Tan, Li-Hua Qiu, Mao-Qiong Jiang, Jian Jiang, Lei-Ya Du, Ye Qiu, Xia Zhang, Ming-Zong Hu, Wen-Jing Ye, Yu-Lan Jiang

      • Abstract

      Background

      Chemotherapy is the main treatment for advanced lung squamous cell carcinoma(LSCC) patients due to lack of effective targeted agents. Previous studies proved that apatinib, which is an antiangiogenic and small-molecule targeted drug, showed clinical benefit in patients with advanced non-squamous non-small cell lung cancer. In this study, we assessed the efficacy and safety of low-dose (125mg or 250mg, QD, oral) apatinib in the treatment of advanced LSCC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 8 advanced LSCC patients clinical data were reviewed retrospectively including 1 patient treated only by apatinib and 7 patients combined with other anti-tumor therapies (i.e., bronchial artery embolization (BAE), chemotherapy, radiotherapy or surgery) between May 2016 to July 2017. Efficacy was evaluated with the RECIST version 1.1 and adverse effects (AEs) were graded using the NCI CTC version 4.0.

      4c3880bb027f159e801041b1021e88e8 Result

      One SD and 7 PR were confirmed, resulting in an objective response rate of 87.5% (7/8) and a disease control rate of 100% (8/8), respectively. The median progression-free survival (PFS) was 197 days (95% CI, 122-272 days), and the median overall survival (OS) was 252 days (95% CI,161-342 days). Both PFS and OS were 93 days for the patient with monotherapy, while the median PFS and median OS were 212 days (95% CI, 132-292 days) and 274 days (95% CI,182-366 days), respectively for the 7 patients with combined treatment. Patients with grade 3 or 4 AEs included 2 hemoptysis, 1 leukopenia and 1 fatigue. Patients characteristics are shown in the table below.table.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Low-dose apatinib combined with BAE, chemotherapy, radiotherapy or surgery is effective and well tolerated in advanced LSCC patients. Risk of massive hemoptysis should be considered in LSCC patients treated with apatinib alone. BAE or radiotherapy may play a role in the prevention and treatment of severe hemoptysis associated with apatinib.Further prospective studies with larger numbers of patients are required.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-49 - Effciency of Low-Dosage Apatinib Monotherapy in Treatment of Advanced Lung Squamous Cell Carcinoma

      12:00 - 13:30  |  Presenting Author(s): Hua Jiang  |  Author(s): Qian Geng, Mengjie Wang, Yingzhi Lu, Wenyu Zhu, Zhiqiang Sun

      • Abstract

      Background

      Lung squamous cell carcinoma (SqCC) is the second most common histology in non-small-cell lung carcinomas (NSCLCs). Chemotherapy of two drugs based on platinum is the standard treatment of advanced lung SqCC. However, few drugs could be selected when the disease progressed after second-line treatment. Apatinib, a small molecule inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), have shown benefit in advanced NSCLC patients. This study aimed to preliminarily assess the efficacy and safety of apatinib at a lower dosage (125-500mg/d) in patients with advanced lung squamous cell carcinoma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible patients should be definitive diagnosed SqCC, who refused chemotherapy or failed first line, second line or even later lines of chemotherapy. Key exclusion criteria included major blood vessel involvement and massive haemoptysis with the amount more than 20ml. Apatinib was given every day, and treatment was continued until disease progression or unacceptable toxic effects. Progression free survival (PFS) was assessed by Kaplan–Meier test. Tumor responses were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

      4c3880bb027f159e801041b1021e88e8 Result

      Total 19 patients were enrolled from June 2015 to August 2017. Among them, 12 patients suffered from distant metastases before apatinib administration; 11 patients were with ECOG 2-3. Ten patients (52.6%) received 250mg daily of apatinib, 4 received 125mg, 1 received 375mg, 2 received 425mg and 2 received 500mg daily. Two patients failed to evaluate efficacy for personal reason so that 17 patients were eligible for tumor response to apatinib evaluation. Followed up to April 2018, 14 of 19 patients were dead, and 1 year survival rate was 21.1% (4/19). The median PFS was 5.3 months (95% CI: 2.7–7.9 months). Three patients achieved partial response (PR) and the objective response rate (ORR) was 17.6% (3/17) and the total disease control rate (DCR) was 76.5% (13/17). There was no significant associations between the dose of apatinib and efficacy (p=0.648). The main adverse events were fatigue (47.4%), hypertension (36.8%), hemoptysis (26.3%), loss of appetite (26.3%), proteinuria (21.1%) and hand-foot reaction (15.8%). No grade 4 adverse event was reported. All the dead events were not drug-related by physician’s judgment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Apatinib monotherapy at a lower dosage might be an optional choice for patients with advanced lung squamous cell carcinoma. Perspective clinical studies with large sample size are needed to validate our results.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-50 - Identification of EGFR Mutational Profile in Lung Cancer Moroccan Cohort

      12:00 - 13:30  |  Presenting Author(s): Houda Kaanane  |  Author(s): Hicham El Atar, Latifa Badre, Amal Louahabi, Hind Berradi, Meriem Khyatti, Sellama Nadifi

      • Abstract

      Background

      Despite recent progress in diagnostic and oncology therapy, lung cancer constitutes the leading cause of cancer-associated mortality worldwide, with approximately 85% of lung cancer cases being non-small cell lung cancer (NSCLC) histological type. The study of epidermal growth factor receptor (EGFR) gene mutational profile in non-small cell lung cancer patients has a special clinical significance in the selection of patients for tyrosine-kinase inhibitor therapy. The aim of this study was to identify the frequency and spectrum of EGFR mutations in a cohort of Moroccan patients with lung cancer using the ADx-ARMS technology.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed a retrospective study by processing 125 cases of NSCLC patients recruited between March 2015 and December 2017. Using the DNA extracted from the FFPE tissue, we attempted to identify somatic mutations in exons 18 to 21 of the tyrosine-kinase “TK” domain of EGFR gene. We evaluated EGFR mutations using HRM polymerase chain reaction (PCR) and real time PCR “ADx-ARMS technology” for results confirmation.

      4c3880bb027f159e801041b1021e88e8 Result

      Most of our patients were males (69.6%) in the age range of 32-82 years old, with an average age of 61,5 ± 8.62. The most represented histological type in the studied sample was adenocarcinoma (ADK: 88%) and only 12% of squamous cell carcinoma (SCC) subtype. In regards to the smoking status 57.6% of the analyzed patients were smokers and 42.4% were nonsmokers. Six different point mutations were detected in 25 patients, representing 20% of our study population. Among the mutant positive cases, the resulting mutations were as follows : 60% of patients have a deletion in exon 19, 16% in exon 20 (12% T790M and 4% S768L), 12% in exon 18 (G719A/C) and 12% in exon 21(L858R). The EGFR mutations were more frequent among males compared to females (64,0% and 36,0% respectively), all of the positive patients with EGFR mutations were ADK and 40,0% of them were smokers.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The presented method can be implemented at the laboratories to identify the most frequent EGFR mutations that are important for targeted therapy of advanced lung cancer patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-51 - Outcomes with Systemic Chemotherapy in Advanced  NSCLC Patients with Performance Status 2 and Above and without Driver Mutation

      12:00 - 13:30  |  Presenting Author(s): Harish Kancharla  |  Author(s): Prabhat S. Malik, Sachin Khurana, Naresh Gundu, Ajay Yadav, Deepali Jain, Sushmita Pathy, Sunil Kumar

      • Abstract

      Background

      Platinum-based combination chemotherapy is recommended as the standard treatment for patients with advanced NSCLC, but its benefit is limited to patients with performance status (PS) of 0 or 1. However, it is not clear whether these benefits apply to patients with poor performance status ((PS 2 and above)). These patients have inferior outcomes and have been excluded from clinical trials. This population accounts for a significant portion (up to 30%) of patients of our practice and some of them have been treated with systemic chemotherapy based on clinician’s discretion. We have analyzed the outcome of these patients who have been treated with chemotherapy despite poor performance status.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed a retrospective analysis of patients of advanced NSCLC with poor PS (ECOG PS 2 or more) registered at our lung cancer clinic between January 2016 and September 2017 and treated with systemic chemotherapy. Patients with driver mutations who were treated with first line TKIs were excluded. Hospital case records were reviewed for baseline characteristics, treatment details and outcome data.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 78 patients were found to be eligible for this analysis. Median age was 60 years (33-77 years) including 15% patients 70 years or above. At presentation out of these 78 patients, 48 (62.5%) were smokers, 24 patients (30 %) had pleural effusion, 8 patients (10%) had brain metastasis and 30 patients (38%) had bone metastasis. Majority patients had ECOG PS 2 but 35 % had PS 3 or 4 also and 38(48 %) had one or more associated comorbidities. The most common chemotherapy regimen used was weekly paclitaxel and carboplatin (50 %) followed by pemetrexed and carboplatin (23 %). Majority (61.5 %) patients could complete 4 or more cycles of chemotherapy however 10 patients (13%) could receive only one cycle and 21 (27%) patients even received maintenance chemotherapy. Chemotherapy was interrupted or stopped due to toxicity in 33% patients. At least one point improvement in ECOG PS from baseline was observed in 44 patients (56%) after 2 cycles of chemotherapy. Objective response and disease control rates were 21 % and 48.6 % respectively. After a median follows up of 8.6 months, median progression free survival was 5.8 months.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Systemic chemotherapy in modified doses and schedules in advanced NSCLC patients with PS 2 and above is feasible and may be associated with better symptom palliation with clinical benefit and improvement in survival. Further studies addressing this neglected subgroup are indicated.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-52 - The Role of Serum Carcinoembryonic Antigen to Predict  the Response of Treatment in  Non‑Small Cell Lung Cancer Patients

      12:00 - 13:30  |  Presenting Author(s): Muhammet Ali Kaplan  |  Author(s): Nadiye Akdeniz, Mehmet Kucukoner, Zuhat Urakci, Ogur Karhan, Abdurrahman İsikdogan

      • Abstract

      Background

      Imaging techniques are routinely used in non-small cell lung cancer (NSCLC) to monitor response to chemotherapy. Biomarkers have been investigated in NSCLC for monitoring treatment response. We have measured tumor marker levels at the time of diagnosis and response assessment. In this study, the change in serum carcinoembryonic antigen (CEA) levels and the association with treatment response was evaluated.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      One hundred patients with NSCLC diagnosed in our institution between 2013-2017 has been included retrospectively in this study. One hundred and thirty-five treatment responses were evaluated from 100 patients. Age, sex, stage, histologic subtype, tumor marker levels in the diagnosis, the change in serum CEA levels and the association with treatment response were analyzed. The treatment responses of the patients were evaluated as those with clinical response [stable response (SD) + complete response (CR) + partial response (PR)] versus progression disease (PD)] and relations with CEA level were assessed.

      4c3880bb027f159e801041b1021e88e8 Result

      Seventy-four (74%) patients were male, and the median age was 57.5 (23-83) years. Thirty-one (31%) were locally advanced and inoperable, and 68 patients (68%) were metastatic. Histologic subtype was adenocarcinoma in 73 patients (73%). At the time of diagnosis, median CEA level was 16.2 ng/ml (1.53-1.000), CA19-9 level was 16 U/ml (0.6-1611), CA 15-3 level was 42 U/ml (8.4-895) and CA 125 level was 70 U/ml (7-1111). There was a high baseline level of serum; CEA in 54 of 88 patients (61.4%), CA19-9 in 20 of 70 patients (28.6%), CA 15-3 in 29 of 39 patients (74.4%) and CA125 in 34 of 43 patients (79.1%) at the time of diagnosis. İn 135 evaluated responses; clinical response and progression were observed in 100 (74.1%) and 35 (25.9%) patient, respectively. CEA level was stable or decreased in 86/100 (86%) clinical responsive patients, while it was elevated in 26/35 (74.3%) progressive patients. The change in CEA level, predict response to therapy with 86% sensitivity and 74.2% specificity. The positive predictive and negative predictive value were calculated as 90.5% and 65%, respectively. The baseline level of CEA was not a prognostic factor.

      8eea62084ca7e541d918e823422bd82e Conclusion

      CEA levels were associated with treatment response in the previous studies and similar results were obtained in our study. CEA is readily detected in serum samples making it a valuable tool for the follow-up of patients and may better predict response to treatment.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-53 - Comparison of the Treatment Efficacy of Osimertinib in Young and Elderly Patients with T790M-Positive NSCLC

      12:00 - 13:30  |  Presenting Author(s): Yasuhiro Kato  |  Author(s): Yukio Hosomi

      • Abstract

      Background

      Osimertinib is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The AURA3 trial showed that osimertinib is superior to platinum doublet chemotherapy in T790M-positive non-small cell lung cancer (NSCLC) with acquired resistance to first or second generation EGFR-TKIs in patients, irrespective of age. In contrast, another study showed that first or second generation EGFR-TKIs may have poorer efficacy and prognosis in young subjects than in elderly patients with EGFR mutation-positive NSCLC. Thus, we aimed to determine whether osimertinib exerted similar effects on young and old patients with T790M-positive NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively investigated T790M-positive NSCLC patients with acquired resistance to first or second generation EGFR-TKIs who were administered osimertinib therapy from May 2015 to January 2018 by referring to their charts in the Tokyo Metropolitan Cancer and Infectious disease Center, Komagome Hospital, Japan. We defined patients > 65 years old as elderly and those < 65 years old as young. We compared the clinical characters, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the two age groups.

      4c3880bb027f159e801041b1021e88e8 Result

      Total 31 patients with acquired resistance to first or second generation EGFR-TKIs were administered osimertinib. Twenty-three subjects belonged to the older age group, while 8 belonged to the younger age group. The median ages of the elderly and young patients were 75 years (range: 65–88 years) and 54 years (34–64) years, respectively. There were no significant differences in their clinical characteristics (sex, Eastern Cooperative Oncology Group Performance Status, smoking history, histology, type of de novo EGFR mutation, initial EGFR-TKI therapy, re-biopsy sample, central nervous system metastasis, and osimertinib line). The median PFS duration after initial EGFR-TKI treatment was greater in the elderly patients (17.2 vs. 10.5 months; hazard ratio; 2.86; 95% confidence interval [CI] , 1.03–7.97; P = 0.0022); the ORR of osimertinib in the elderly and young patients was 53.3% and 37.5%, respectively. The median follow up interval after osimertinib initiation was 10.1 months. The total median PFS duration was 5.6 months. The median PFS duration tended to be greater in elderly patients (3.5 vs. 9.1 months; hazard ratio; 1.90; 95% CI, 0.75–4.78; P = 0.17). The median OS duration after osimertinib initiation was significantly greater in elderly patients (5.3 months vs. NA; hazard ratio; 3.36; 95% CI, 1.11–10.1; P = 0.027).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Osimertinib showed poorer efficacy in younger patients than in elderly patients with T790M positive NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-54 - A Historical Comparison of Patients with Advanced NSCLC Harboring Uncommon EGFR Mutations Before and After the Approval of Afatinib in Japan

      12:00 - 13:30  |  Presenting Author(s): Takahisa Kawamura  |  Author(s): Haruyasu Murakami, Haruki Kobayashi, Kazuhisa Nakashima, Shota Omori, Kazushige Wakuda, Akira Ono, Hirotsugu Kenmotsu, Tateaki Naito, Masahiro Endo, Toshiaki Takahashi

      • Abstract

      Background

      Afatinib demonstrated durable responses in patients with metastatic non-small cell lung cancer (NSCLC) harboring uncommon non-resistant epidermal growth factor receptor (EGFR) mutations (G719X, L861Q, and/or S768I) in a pooled analysis of three clinical trials. However, the clinical impact of afatinib therapy in patients with these uncommon EGFR mutations remains unclear.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively evaluated patients with advanced NSCLC whose tumors have uncommon EGFR mutations, and who had received first-line systemic therapy at the Shizuoka Cancer Center between January 2010 and December 2017. Patients with resistant EGFR mutations (T790M, exon 20 insertions) and patients who had received investigational EGFR-TKIs were excluded from this study. Characteristics, therapy regimens and survival outcomes were compared between patients who had received a systemic therapy before (Group A) and after (Group B) the approval of afatinib in Japan. Overall survival (OS) was measured from the first day of first-line systemic therapy until death or the final day of the follow-up period.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 23 patients (11 in Group A, and 12 in Group B) were included in this study. The characteristics of the 23 patients were: median age 69 years (range: 41 to 82); 39% male; 26% performance status (PS) 0, 57% PS 1, 13% PS 2 and 4% PS3; 48% with brain metastasis; and 57% current or former smokers. With regard to EGFR mutation type, 30% had G719X, 30% had L861Q, 5% had S768I, 22% had a complex of uncommon mutations, and 13% had both uncommon and common mutations. Patient characteristics were similar in the two groups except for PS. First-line systemic therapy regimens were: gefitinib 73%, erlotinib 9% and platinum-doublet chemotherapy 18% in Group A; gefitinib 8%, erlotinib 25% and afatinib 67% in Group B. Median OS was 10 months for Group A and 25 months for Group B. A significant difference in OS was observed between the two groups (P = 0.018). In a subgroup analysis of patients with PS 0 or 1, there was also a significant difference in OS between the two groups (median, 10 months for Group A vs. 25 months for Group B; P = 0.033).

      8eea62084ca7e541d918e823422bd82e Conclusion

      After the approval of afatinib in Japan, a majority of patients with advanced NSCLC harboring uncommon EGFR mutations received afatinib therapy as first-line systemic therapy, and it may be related to OS improvement.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-55 - SF2: A PCYT-2 Inhibitor Prototype is Capable of Inducing Citotoxicity in NSCLC

      12:00 - 13:30  |  Presenting Author(s): Bárbara Kawamura  |  Author(s): Sarah Fernandes Teixeira, Lisley Inata Mambelli, Salomão Doria Jorge, Marcio Henrique Zaim, Kerly Fernanda Mesquita Pasqualoto, Debora Levy, Jose Alexandre Marzagão Barbuto, Adilson Kleber Ferreira

      • Abstract

      Background

      Lung cancer is one of the most common malignant tumors in the world and in most cases this disease has an unfavorable prognosis. Due to the relative failure of current therapeutic protocols, there is an urgent need for the development of new treatments. Then, new classes of drugs may be considered. The development of new drugs could benefit a large portion of the population affected by lung cancer. The enzyme CTP: phosphoethanolamine cytidylstransferase (Pcyt-2), which has phosphoethanolamine as the substrate, is a key regulator in the Kennedy pathway for the production of membrane phospholipids. Phosphoethanolamine is one of the most abundant phospholipids in eukaryotic cells and, therefore, the reduction of its production could directly affect cell division and apoptosis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In the present study it was evaluated the cytotoxic effects of a new prototype, named as SF2, in NSCLC. In order to evaluate the effect of SF2 on Pcyt-2; the radiolabeling assay of the intermediates of the Kennedy pathway was performed. The cytotoxic activity was investigated in A549 and NCI-H460 cell lines by the MTT colorimetric assay. Mitochondrial membrane depolarization and apoptosis analysis were performed by High Content Screening (HCS) using TMRE probe and double annexin V / PI labeling, respectively.

      4c3880bb027f159e801041b1021e88e8 Result

      SF2 was able to reduce the activity of Pcyt-2 enzyme (65% related to control group, p<0.01). This reduction also lead to the decrease of the CDP-ethanolamine (CDP-Etn) production (29%, p<0.001) and the transport of ethanolamine (Etn) (69% related to control, p<0.0001). SF2 presented IC50 values of 40 and 90 μM for A549 and NCI-H460 cell lines, respectively. In addition, SF2 was able to induce cell death by apoptosis in A549 (35% p<0.01) and in NCI-H460 (33%, p<0.03) and to reduce mitochondrial membrane potential of NCI-H460 cell line (27% related to control, p<0.05).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Therefore, SF2 is a potential candidate of antitumor drug by the inhibition of Pcyt-2 enzyme in NSCLC models.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-56 - Hyperprogression and Pseudoprogression in Patients with Non-Small Cell Lung Cancer on Checkpoint Blocking Immunotherapy

      12:00 - 13:30  |  Presenting Author(s): Seoree Kim  |  Author(s): Joori Kim, Sook-Hee Hong, Jin-Hyoung Kang, Sang Hoon Chun

      • Abstract

      Background

      Immune checkpoint inhibitors in metastatic non-small cell lung cancer (NSCLC) can result in improved quality of life and survival when compared with cytotoxic chemotherapy. While immune checkpoint inhibitors are disrupting the management of patients with cancer, some patients experienced pseudoprogression,On the other hand there is another special response pattern of occurrences of rapid progression (i.e., hyperprogressive disease or HPD), suggesting potentially effects of these drugs. Due to HPD is not only different from the pseudoprogression, but also tremendous progression, clinicians must evaluate the efficacy of these novel drugs and avoid either premature withdrawal of the treatment or prolonging ineffective treatment

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We idendified the medical records of all consecutive in non-small cell lung cancer patients (n=118) analyzed retrospectively who treated with monotherapy by anti-PD-1 or an anti-PD-L1 at Seoul & Bucheon St. Mary's Hospital between December 2015 and April 2018.

      Tumor size (D) was defined as the sum of the longest diameters of the target lesions as per the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria. We calculated the TGK across clinically relevant treatment periods. As per the RECIST system, patients with nonmeasurable disease only at baseline could not be assessed by TGK. For patients who had disease progression with new lesions, the TGK was computed on the target lesions only (new lesions were not included in the RECIST sum).

      4c3880bb027f159e801041b1021e88e8 Result

      Median age was 65.4 years with a majority being Male(94.4%) and non current smoker (66.6%, consists in never smoker 11.1% and Ex smoker 55.5%). Their average smoking history was 38.6 pack years

      The rate of over-growth was 15.2%(n=18), among them, the rate of hyperprogression was 72.2%(n=13).

      The probability of expression of the EGFR gene mutation on the over-growth group was 16.6%.

      We found increasing the probability of hyperprogression was seen at the EGFR expression group compared to non-hyperproliferation group(p=0.440)

      8eea62084ca7e541d918e823422bd82e Conclusion

      While immunotherapy can produce a significant and durable response in patients with NSCLC, physicians must be recognized of the potential for an aggressive pattern of accelerated progression in a subset of patients. Even though the improved recognition of hyperprogression and pseudoprogression, the etiology of HPD remains unclear, apart from the pseudoprogression. However we found that patients with EGFR genetic mutations may show the hyperprogression-excess growth when they used immune checkpoint inhibitors.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-57 - Real-World (RW) Predictors of Immuno-Oncology (IO) vs Chemotherapy (C) Use in Advanced Non-Small Cell Lung Cancer (aNSCLC)

      12:00 - 13:30  |  Presenting Author(s): Bruce Feinberg  |  Author(s): Janna Radtchenko, Beata Korytowsky, Esmond Nwokeji, Ken Tuell

      • Abstract

      Background

      For patients with aNSCLC without known mutations, demographic and clinical characteristics may impact second-line (2L) treatment decisions. Describing predictors of 2L RW drug utilization may help optimize outcomes of patients with aNSCLC who eventually progress. This study evaluated predictors for 2L IO vs. C use in patients with aNSCLC treated with 1L C (proxy for patients without treatment-altering mutations).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective cohort of continuously enrolled adult patients with lung cancer initiating 1L C ≤6 months of diagnosis was identified from Inovalon’s MORE2 Registry® claims post IO approval in lung cancer (Mar 2015 - Dec 2016). Patients receiving 2L systemic therapy following 1L C were selected, excluding patients with SCLC, treated for secondary malignancies, with <1 month follow-up, or on clinical trials. The influence of baseline characteristics on choice of 2L IO vs C was evaluated using binary multiple logistic regression (LR), excluding targeted therapy (TT) due to small sample. Odds ratio (OR) >1 indicated greater chance of IO use. P-value <0.05 was considered significant.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 2,700 patients initiating 1L C, 829 (31%) received 2L: 539 (65%) received C, 262 (32%) IO, 28 (3%) TT. By subgroup (C, IO, TT), 46%, 54%, 57% (p=0.055) were female; mean age at 2L start was 65.3, 66.0, 61.0 years (p=0.045); Charlson comorbidity index: 2.8, 2.0, 1.5 (p=0.001); lines of therapy per patient: 2.4, 2.3, 2.5 (p=0.012); comorbidity count: 1.5, 1.1, 0.7 (p<0.001); follow-up from 1L start: 11.3, 10.9, 11.6 months (p=0.499); 18%, 26%, 21% (p=0.028) commercially insured; 70%, 68%, 39% (p=0.003) had evidence of smoking cessation/ counselling; 30%, 13%, 11% (p<0.001) had evidence of another malignancy at diagnosis; and 7%, 3%, 0% (p=0.032) had evidence of diabetes with chronic complications at diagnosis.

      LR model showed factors increasing likelihood of 2L IO use included evidence of chronic obstructive pulmonary disease (COPD) at diagnosis (OR=1.54, p=0.025), longer time to 1L discontinuation (1.27, p<0.001), and commercial insurance (2.29, p=0.001). Factors negatively impacting IO choice were: 1L combination therapy use (0.48, p<0.001), evidence of secondary malignancy at diagnosis (0.21, p=0.001), and evidence of diabetes with chronic complications at diagnosis (0.33, p=0.031).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This retrospective RW study showed that aNSCLC patients with COPD, longer 1L treatment, on 1L monotherapy, and private insurance are more likely to receive 2L IO vs C. As such, early consideration needs to be given in order to monitor these patients more closely.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-58 - Relative Abundance Of EGFR Mutations in Plasma Predicts Tumor Response to EGFR-TKI in Advanced Lung Adenocacarcinoma

      12:00 - 13:30  |  Presenting Author(s): Yuping Li  |  Author(s): Hanyan Xu, Sansan Su, Junru Ye, Chengshui Chen

      • Abstract

      Background

      It is unclear whether relative abundance of EGFR mutations in plasma predicts tumor response treatment with EGFR–TKIs in advanced lung adenocarcinoma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The present prospective study enrolled patients with advanced lung adenocarcinoma in the first affiliated hospital of Wenzhou Medical University from 1 April 2016 to 1 January 2017. EGFR mutations detection in tumor tissues by ADx-ARMS and in plasma cfDNA by ADx-ARMS and ADx-SuperARMS were all tested. We enrolled patients with EGFR-mutant in tumor tissue and receiving EGFR-TKIs. Mutation-positive plasma by both methods carried high abundance of EGFR mutations. Plasma that was mutation positive by ADx-SuperARMS but the result by ADx-ARMS was negative harbored medium abundance. Mutation-negative plasma by both methods was recognized as low abundance group. The correlation between EGFR mutation abundance and clinical benefit from EGFR-TKIs treatment was analyzed using Kaplan-Meier curve, Chi-square test and Cox proportional hazards model.The study protocol was approved by the Institutional Review Board of the first affiliated hospital of Wenzhou Medical University(2016-017).

      4c3880bb027f159e801041b1021e88e8 Result

      71 patients were enrolled, 42 harbored EGFR mutations in plasma detected by ADx-ARMS, while 53 were found positive result in plasma by ADx-SuperARMS. Median PFS was 10.0m and ORR was 64.8% in the patients with EGFR-mutant in tumor tissue. According to the results of the plasma detected by ADx-ARMS and ADx-SuperARMS, 42 were found high abundances of EGFR mutations, 11 were recognized as medium abundances group while the other 18 as low abundances. The ORRs were 69.0%,63.6% and 55.6% for patients with high、medium and low abundance of EGFR mutations, respectively. Pwith high abundances of EGFR mutations were seemed to acquire high ORRs, the difference was significant between high and low abundances group(P=0.006) but the differences were not significant when compared high abundances group with medium abundances group (P=0.732) and medium abundances group with low abundances group (P=0.114). Medium PFS for high,medium and low abundances groups were 11.0m, 8.5m and 9.0m, respectively(P<0.001). For the patients with 19-Del in tumor tissues, the ORRs were 70.4%,57.1% and 54.5% in high、medium and low abundance of EGFR mutations groups, respectively. Medium PFS of high abundance group was longer than medium and low abundance groups (12.0m vs 9.0m vs 9.0m). As for L858R, the ORRs were 66.7%,50.0% and 50.0%,respectively, Medium PFS were 9.6m, 5.5m and 9.5m.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The relative EGFR mutation abundance in plasma could predict tumor response to EGFR-TKI treatment for advanced adenocarcinoma. The higher the EGFR mutation abundance is, the better efficacy of EGFR-TKI is.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-59 - Comparison of Lobectomy, Segmentectomy and Wedge Resection for Early Stage NSCLC: A Direct and Network Meta-Analysis

      12:00 - 13:30  |  Presenting Author(s): Wang Liang

      • Abstract

      Background

      Aim: The purpose of this study was to compare the effect of lobectomy, segmentectomy and wedge resection for early stage non-small cell lung cancer (NSCLC) treatment.

      surgical section is a first choice for surgical treatment of early stage NSCLC (5). However, it is not applied for most NSCLC with advanced stages owing to its high metastasis and recurrence rates . In addition, video-assisted thoracoscopic surgery (VATS) as a less invasive surgical method is widely used for clinical stage I NSCLC during lobectomy, segmentectomy, and wedge resection .

      Lobectomy is a traditionally gold standard for early stage NSCLC treatment . In recent years, segmentectomy and wedge resection as alternative sublobar resection to lobectomy are recommended. Many studies have indicated that sublobar resection results in equivalent outcomes in patients with stage I NSCLC in comparison with lobectomy, and it is gradually considered that pneumonectomy is unnecessary . However, sublobar resection for NSCLC treatment remains controversial due to an increased risk in local recurrence and poorer long-term survival compared to lobectomy, thus additional local therapy is recommended to patients undergoing sublobar resection .

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible studies were retrieved from PubMed, Embase, and Cochrane Library. The 1, 2 or 5-year overall survival (OS) and disease-free survival (DFS), and complications rates were used as outcomes indictors. The pooled results for comparison indicators were measured by odds ratios (ORs) with 95% confidence interval (CI) as dichotomous variables. The random effects model was used for all test models in the present study. The consistency assessment in this network meta-analysis was conducted by Node-splitting analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 23 studies encompassing 13406 early stage NSCLC patients were included into this network meta-analysis. The results revealed that although 1, 2 and 5-year OS and DFS of lobetomy was superior to segmentectomy and wedge resection, and segmentectomy was better than wedge resection, except for 2-year OS, only result of 5-years OS between groups (wedge resection vs. segmentectomy, OR= 0.56, 95%CI: 0.36-0.87; wedge resection vs. lobetomy, OR= 0.51, 95%CI: 0.33-0.79) were significant difference. On the contrary, the complications rate in wedge resection was significant lower than that of lobetomy (lobetomy vs. wedge resection, OR= 1.73, 95%CI: 1.05-2.72) and segmentectomy (segmentectomy vs. wedge resection, OR= 1.66, 95%CI: 1.02-2.74), and it was highest in lobetomy.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Segmentectomy might be recommended as a reasonable alternative to lobectomy with lower complications rate for early stage NSCLC treatment.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-60 - A Novel MET D1246H Mutation After Progression of EGFR-TKI/MET Inhibitor Combined Therapy in a NSCLC Patient with Acquired MET Amplification

      12:00 - 13:30  |  Presenting Author(s): Ying Liang  |  Author(s): Qinchang Chen, Yongbin Lin, Hui Liu, Bo Qiu

      • Abstract

      Background

      MET amplification was the second common acquired resistance mechanism to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC). It may be benefited by combinations of EGFR TKIs and the MET inhibitor. However, the acquired resistance mechanism to this combination therapy remains to be identified.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A patient with advanced lung adenocarcinoma harboring both EGFR L858R mutation and acquired MET amplification, progressed after the combination of MET inhibitor gefitinib and EGFR-TKI crizotinib. The next generation sequencing (NGS) based circulating tumor DNA (ctDNA) assay was performed. Results were applied to discover a novel mutation after resistance to target therapy.

      4c3880bb027f159e801041b1021e88e8 Result

      A 52-year-old Chinese never-smoking woman with EGFR L858R mutant adenocarcinoma had systemic progression after gefitinib, pemetrexed/platinum-pemetrexed maintenance, and SBRT local progressed lung metastasis. The NGS-based ctDNA analysis revealed that the MET amplification was found besides continually present EGFR L858R mutation. The patient started treatment with crizotinib (250mg Bid) and gefitinib (250mg/d). The NGS was performed after progression of this combined therapy. It revealed two novel mutations of MET D1246H (MAF 0.9%) and EGFR T790M mutation (MAF 0.2%), in addition to the initial presence of EGFR L858R mutation (MAF 9.8%) and MET amplification (LR 6.7). The patient started to receive osimertinib (80mg/d) and cabozantinib (20mg/d and later increased to 40mg/d). The patient tolerated this combination well while the symptoms did not relief. After 8 weeks, the re-scan CT showed pulmonary lesions progressed. The NGS-based ctDNA assay performed again and it showed that L858R mutation (MAF 11.4%) and MET amplification (LR 4.9) presented while the EGFR T790 mutation and MET D1246H disappeared. Then the patient received osimertinib (80mg/d) and crizotinib (250mg Bid). The patient felt symptoms improved greatly after 1 week’s administration and CT scan after 2 months showed good response. However,one more month later, the patient felt deteriorative symptoms of dyspnea and chest X-ray showed increasing pleural effusion , progressing pulmonary lesions. The NGS-based ctDNA assay at that time revealed that MET D1246H (MAF 14.4%) appeared again, in addition to the initial presence of EGFR L858R mutation (MAF 22.4%) and MET amplification (LR 8.2) while the EGFR T790 mutation was not existed. However, the patient died because of respiratory failure.

      8eea62084ca7e541d918e823422bd82e Conclusion

      MET mutations might be a potential acquired resistance mechanism after progression during EGFR-TKI /MET inhibitor combined therapy in advanced NSCLC patient with primary EGFR mutation and secondary acquired MET amplification.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      • Abstract

      Background

      KRAS mutations are reported in 20-25% of non-small cell lung cancer (NSCLC); their prognostic role in advanced NSCLC is still under dispute. Given that ethnicity may play a role on mutational profiles of NSCLC, we report here on KRAS mutations in Greek NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      KRAS and EGFR genotypes were evaluated in 424 NSCLC patients diagnosed from March 2000 to December 2012 and associated with clinicopathological parameters. Outcome comparisons were performed in 234 metastatic patients with available treatment data, following 1st line chemotherapy without tyrosine kinase inhibitors.

      4c3880bb027f159e801041b1021e88e8 Result

      KRAS mutations were found in 71 tumors of all histologies (22.2% in adenocarcinomas); most common types were p.G12C (39.5%), p.G12D (32%) and p.G12V (14%). EGFR mutations were found in 45 tumors (14.8% in adenocarcinomas; 72.6% of the classical type) and were mutually exclusive with KRAS mutations except for one case. At a median 3-year follow-up for all patients, KRAS status was a strong negative prognostic factor for overall survival (OS, p=0.0213) but not for progression-free survival (PFS), irrespective of mutation type. KRAS mutations conferred 64% increased risk of death in all 1st line treated patients and the worst OS compared to EGFR and any wild-type status in 1st line platinum-treated patients (p=0.0547). Rare EGFR mutations conferred significantly better outcome to platinum-treated patients (OS, p=0.0074; PFS, p=0.0338).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The presence of KRAS mutations seemed of adverse prognostic significance for survival, also in the presence of platinum-based 1st line treatment, while no prognostic differences were seen among different types of mutations.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-62 - A New Method for Non-Invasive Prediction of Radiotherapy: SDH5 Depletion Enhances Radiosensitivity by Regulating P53

      12:00 - 13:30  |  Presenting Author(s): Jun Liu  |  Author(s): Yan Zong, Gang Wu

      • Abstract

      Background

      Radiotherapy is an important and effective treatment for lung cancer. Some molecules can predict the effect of radiotherapy, but it is an invasive test that will cause trauma to patient. So the development of reliable non-invasive methods for predication of radiotherapy has become essential to guide therapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We initiated an analytical, observational, open, and retrospective study (ChiCTR1800014878) of 53 patients with stage III lung adenocarcinoma who were ready for radiotherapy. The performance status (PS) scores of the patients are all over 2. Blood and tumor tissue before treatment were collected to detect SDH5 concentration. We then evaluated the prognostic role of SDH5 expression in these patients. To further verify the effect of SDH5 on radiosensitivity, two mice models (orthotopic mice bearing lung cancer and SDH5 gene knock-out mice) were established and the internal mechanism between SDH5 and radiotherapy was explored.

      4c3880bb027f159e801041b1021e88e8 Result

      The patients whose tumor shrink significantly one month after radiotherapy had lower expression of SDH5 in tumor, and loss of SDH5 expression correlated with down regulation of DNA-PKcsThr2609 and ku86. More importantly, SDH5 can be directly detected in blood by qRT-PCR, and the result is consistent with that in tissue. And more exciting, patients with deficiency of SDH5 had longer PFS and OS after radiotherapy, and the results in blood and in tumor are consistent. To further verify the effect of SDH5 on radiosensitivity, in vivo experiments were carried out. In the orthotopic model, SDH5 knock down tumors showed higher radiation sensitivity with smaller volume. In SDH5 knock-out mice, lung epithelial cells exhibited elevated DNA damage after radiation. Moreover, our data indicated that SDH5 depletion causes P53 translocated from cytoplasm to nucleus, which enhances radiosensitivity of non-small cell lung cancer. Furthermore, consistent with in vivo data, the tumor growth was partially reversed when p53 was co-depleted with SDH5.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this experiment we found that SDH5 regulated radiosensitivity by P53 and it can be detected in tumor tissue. It is a suitable marker for predicting radiosensitivity. More than this, the expression of SDH5 can be directly measured by qRT-PCR in the blood, and it is consistent with that in the tumor tissue. This provides a novel non-invasive method for predicting the radiosensitivity of the patients unable to tolerant the biopsy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-63 - Baseline Biomarkers for Outcome of Advanced NSCLC Patients Receiving Anti-PD1/PD-L1 Treatment—Data from a Chinese Population

      12:00 - 13:30  |  Presenting Author(s): Shun Lu  |  Author(s): Yang Yi

      • Abstract

      Background

      Immune checkpoint inhibitor therapy has shown optimal efficacy in advanced non-small-cell lung cancer (NSCLC). However, the biomarkers of immunotherapy response are not well established. In the present study, we aimed to determine baseline prognostic factors associated with progression-free survival (PFS) in anti-PD1/PD-L1 treatment and to identify a predictive biomarker for immunotherapy response.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Data of 54 advanced NSCLC patients receiving anti-PD1/PD-L1 treatment were prospectively collected in Shanghai Chest Hospital from Dec. 2015 to May 2017. Clinical data included baseline routine blood examination and demographic characteristics of patients prior to immunotherapy. Systemic inflammatory biomarkers were obtained from routine blood tests to calculate leukocyte-to-lymphocyte ratio (LLR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR) and systemic immune-inflammation index (SII, neutrophil × platelet/lymphocyte). Receiver operating characteristic (ROC) and area under the curve (AUC) were used to identify the optimal cut-off value of LLR, NLR, PLR, LMR and SII for survival analysis. Endpoints were PFS and objective response rate (ORR) following anti-PD1/PD-L1 treatment. Univariate survival analysis for PFS was used by Kaplan-Meier method and statistical differences were determined by Log rank test. The Cox proportional hazards model was used for multivariable analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 54 cases were analyzed, with 38 treated with Atezolizumab and 16 treated with Nivolumab. Median PFS was 2.8±0.18 and 1.8±1.2 months, respectively (P = 0.988). 44 patients received second-line anti-PD1/PD-L1 treatment and 10 patients underwent three-line or above. The median PFS of the two groups were 2.8±0.88 and 2.8±0.23 months, respectively, (P=0.851). ROC and AUC identified LLR=6.3, NLR=4.5, PLR=124.45, LMR=3.4 and SII=1066 as the best cut-off values. Univariate survival analysis showed that LLR, age, pathological type, neutrophil percentage, hemoglobin, platelet count, albumin, serum lactate dehydrogenase (LDH), NLR and SII were associated with PFS (P<0.05). Cox multivariate analysis showed that LLR (P=0.003;HR 2.99;95%CI:1.45-6.17), albumin (P=0.000;HR 8.11; 95%CI:2.63-25.06) and LDH (P=0.000;HR 4.55;95%CI:2.13-9.73) were independent prognostic factors for PFS . For patients with favorable (1 IN 3 factors), (2 IN 3 factors) and (3 IN 3 factors) biomarker profile median PFS were 0.94, 1.63 and 8.17 months, respectively (P =0.000) .

      8eea62084ca7e541d918e823422bd82e Conclusion

      Blood markers predict survival in advanced NSCLC treated with immune checkpoint blockade. Our findings show that baseline LLR≤6.3, normal serum levels of albumin and LDH were independently and advantageously associated with the PFS of patients receiving anti-PD1/PD-L1 treatment , and they may help identify patients with benefit from immune therapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-64 - Preliminary Data of Diverse Therapies in Patients with Advanced Non–Small-Cell Lung Cancer Harbouring RET-Rearrangement

      12:00 - 13:30  |  Presenting Author(s): Chang Lu  |  Author(s): Hai-Yan Tu, Hong-Hong Yan, Xu-Chao Zhang, Bin-Chao Wang, Zhen Wang, Anna Li, Jia-xin Lin, Yang-Si Li, E-E Ke, Jin Song, Si Chen, Yuqi Wang, Yanfang Guan, Xuefeng Xia, Xin Yi, Yi-Long Wu, Jin -Ji Yang

      • Abstract

      Background

      Activating RET-rearrangement has been discovered to play a crucial role in NSCLC tumorigenesis. However, the lack of specificity narrowed efficacy of multi-kinase inhibitors (MKIs) and the optimal treatment remains unknown. In this study, we compared chemotherapy, immunotherapy and MKIs in this group of patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively evaluated the efficacy of these three treatments in advanced, RET-rearranged NSCLC patients between January 2013 and April 2018 at our institution. RET-rearrangements were assessed by Next-generation sequencing (NGS) or any of FISH, IHC, RT-PCR. Treatment data were collected after the patients had been diagnosed with RET-rearranged advanced NSCLC. Progression-free survival (PFS) was measured from treatment start to disease progression, all-cause mortality or last follow up. Median follow-up time was 5.1months. NGS was performed to assess somatic mutation of available samples.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 30 patients with RET-rearrangement were investigated in this study. After the diagnosis, 15 patients, genetic profiles confirmed by NGS, received chemotherapy (n=10), checkpoint-inhibitors (n=7) and RET targeted MKI (n=6) with evaluable response. Several patients take any two of these three treatments as different line therapies. The disease control rate of chemotherapy, immunotherapy, MKI group was 70.0%, 71.43% and 50%, respectively. While the median PFS of three groups was 2.50 months, 2.70 months, 0.30 months, respectively, which of no significance. The NGS data of 10 patients showed that RET-rearrangement co-occurred with several other genes, including TP53, NTRK, CDK4, ERBB4. A low mutation burden (mean 4.5 mutations) was observed (Figure 1).

      figure of abstract 13677.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      We confirmed relatively low PFS in advanced RET-rearranged NSCLC with MKIs reported in previous studies. But further investigation is warranted. Treatment with checkpoint-inhibitors seemed to encouragingly prolong PFS but a larger group of patients is needed to draw a definite conclusion.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-65 - First-Line Radical Local Therapy May Provide Additional Survival Gain for Patients with EGFR-Mutant Metastatic NSCLC Receiving TKIs

      12:00 - 13:30  |  Presenting Author(s): Jingbo Wang  |  Author(s): Xiaotong Lu, Chunyu Wang, Nan Bi, Zongmei Zhou, Yan Wang, Luhua Wang

      • Abstract

      Background

      Tyrosine kinase inhibitors (TKIs) have been widely accepted as first-line therapy for patients with EGFR-mutant metastatic non-small cell lung cancer (NSCLC), achieving a median progression free survival (PFS) and overall survival (OS) of 8.0 to 13.1 months and 19.3 to 30.9 months respectively. Patterns-of-failure studies suggest that the first progression after first-line TKIs occurs most often at sites of disease known to exist at the baseline. In this retrospective study, we aimed to investigate whether the radical local therapy could offer survival benefit in addition to st

      a9ded1e5ce5d75814730bb4caaf49419 Method

      NSCLC patients with activating EGFR mutations and treated with TKIs as first-line management after the diagnosis of stage IV disease (either synchronous or metachronous) between 2010 and 2017 at our institution were reviewed. All enrolled patients should receive radical local therapy (either surgery or radiotherapy with curative intent) at least to the main site of disease. We defined the main site as the primary site for synchronous IV-stage patients and at least 1 progression site for metachronous IV-stage patients. OS and PFS were calculated from the first day of IV-stage treatment. Kaplan-Meier method was used for survival estimation and Log-rank test was rendered for survival comparison between groups.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 45 patients entered into the final analysis, including 18with synchronous stage IV diseases and 27patients with metachronous diseases. A total of 208 gross tumor sites were identified and 130 of them received local treatment, including 90 sites treated with radical approaches and another 30 sites with palliative therapy. At a median follow-up period of 37.8months, the median OS was 51.4 months, with 1-, 3- and 5-year rate of 97.7%, 58.7% and 25.2%, respectively. The median PFS was 16.4months, with 1-, 2- and 3-year rate of 64.7%, 29.1% and 6.8%, respectively. There was no difference between synchronous and metachronous groups. In 38patients who progressed, 19 (42.2%) involved new metastatic sites only, 12(26.6%) involved initial sites only, and 3 (6.7%) involved both.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Metastatic EGFR-mutant NSCLC patients who received TKIs and radical local therapy in our study obviously provided longer OS and PFS compared with historical results using TKIs alone. Prospective randomized evidences are warranted to clarify the clinical efficacy of additional local therapy to first-line TKIs for this highly selective subgroup of patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-66 - Clinicopathological Characteristics and Mutation Status of Pulmonary Invasive Mucinous Adenocarcinoma

      12:00 - 13:30  |  Presenting Author(s): Fangliang Lu

      • Abstract

      Background

      In the 2015 classification, invasive mucinous adenocarcinoma(IMA)is categorized as one but an uncommon subtype of lung adenocarcinoma. This study attempted to clarify the clinicopathological characteristics and mutation status of IMA.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 37 patients with IMA from among 1376 surgically resected patients with lung adenocarcinoma were enrolled. We analyzed them from the standpoints of clinicopathological characteristics, mutation status and the prognosis.

      4c3880bb027f159e801041b1021e88e8 Result

      KRAS mutations were observed in 9 patients and all of them were Codon 12 mutations. A total of 10 cases exhibited EGFR mutations. ALK rearrangement was detected in only 1 case. The DFS at 5 years were 68.0%. On univariate analysis for DFS, high CEA level (p =0.024), lymphatic permeation and vascular invasion (p =0.015), pleural invasion (p =0.031), tumor size (p=0.023) and N staging(p=0.027) were poor prognostic predictors for DFS.

      Characteristic

      n(%)

      Age(years)

      <65

      23(62.2)

      ≥65

      14(37.8)

      Sex

      Male

      15(40.5)

      Female

      22(59.5)

      Smoking

      Positive

      13(35.1)

      Negative

      24(64.9)

      Tumor size(cm)

      <3

      18(48.6)

      ≥3

      19(51.4)

      CEA level(ng/ml)

      <5

      25(67.6)

      ≥5

      12(32.4)

      SUVmax

      <5

      9(40.9)

      ≥5

      13(59.1)

      Pleural invasion

      Positive

      13(35.1)

      Negative

      24(64.9)

      Lymphatic permeation and

      Vascular invasion

      Positive

      4(10.8)

      Negative

      33(89.2)

      N stage

      N0

      24(64.9)

      N1 and N2

      13(35.1)

      Mutation

      n(%)

      EGFR

      Exon 18

      1(3.0)

      Exon 19

      4(12.1)

      Exon 20 and 21

      1(3.0)

      Exon 21

      4(12.1)

      None

      23(69.7)

      KRAS

      Codon 12

      9(29.0)

      Codon 13

      0

      None

      22(71.0)

      EGFR, epithelial growth factor receptor; KRAS, Kirsten rat sarcoma viral oncogene.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The results revealed that different mutation statuses were observed in IMA. So, we believe that IMA would be subclassified into distinct subtypes with mutation status. And CEA level, lymphatic permeation and vascular invasion, pleural invasion, tumor size and N staging may be the factors related to mitigating DFS in IMA.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-67 - Integrated Network Analysis to Understand the Potential Mechanisms of Hydroxychlrorquine in Non-Small Cell Lung Cancer Treatment

      12:00 - 13:30  |  Presenting Author(s): Jingyun Chen  |  Author(s): Xin Lyu, Lizhong Zeng, Jingyan Yuan, Xia Meng, Ruiying Sun, Boxuan Liu, Ying Bai, Xuan Liu, Zongfang Li, Shuanying Yang

      • Abstract

      Background

      The aim of this study is to investigate the novel mechanisms of hydroxychloroquine in non-small cell lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The primary targets and their related genes of hydroxychloroquine were compiled from open portals (DrugBank and STRING). Functional enrichments and pathway network were mined in DAVID and GlueGO databases. The cBioportal, Oncomine and Kaplan Meier Plotter were used to analyze the genetic alterations, mRNA expression as well as prognosis of target genes enriched in non-small cell lung cancer pathway.

      4c3880bb027f159e801041b1021e88e8 Result

      The biological effects of hydroxychloroquine depended on 3 primary targets (DNA, TLR7 and TLR9), and there was no common gene in all 3 primary directed protein targets. Functional enrichments indicated that hydroxychloroquine exerted beneficial effects on anticancer and anti-infectious disease, especially on non-small cell lung cancer. Pathway network and genetic alternatives of 5 enriched genes (CDKN2A, EGFR, KRAS, AKT1 and TP53)implied TP53 was the axis of pathway interactions in non-small cell lung cancer . Statistically significant prognoses of the 5 genes were also exhibited in lung adenocarcinoma, but not in squamous cell lung carcinoma.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study indicates that hydroxychloroquine may exert anti-tumor effect in non-small cell lung cancer via TP53 signaling axis.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-68 - Early SBRT to the Primary Tumor May Overcome the Icotinib Resistance in Patients with Advanced NSCLC Harboring EGFR Mutations

      12:00 - 13:30  |  Presenting Author(s): Dongqing Lv  |  Author(s): Wei Wang, Jiapei Ding, Xiaomai Wu, Chao Zhou, Biyun Wang, Feng-Ming Spring Kong, Haihua Yang

      • Abstract

      Background

      Icotinib resistance is common in first-line setting for non-small-cell lung cancer (NSCLC) harboring EGFR mutations in China. It has been reported that 47% of EGFR-TKI drug resistance was from the primary tumor, 32.6% the primary and distant, and only 20.4% was distant alone (JTO, 2015). We hypothesized that effective local radiation to the primary tumor will delay Icotinib resistance. This study aimed to investigate the safety and efficacy of primary tumor stereotactic body radiotherapy (SBRT) in combination with the first-line Icotinib therapy in advanced NSCLC patients harbouring EGFR mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a prospective pilot study (ChiCTR-OIN-17013920) from a single institution. Eligible patients included pathologically confirmed primary NSCLC with 19/21 EGFR mutation. Patients have to have no disease progression, i.e. stable disease or partial response after one month of Icotinib treatment (125 mg, three times daily). Stereotactic body radiotherapy (SBRT) was given to the primary tumor, using 50Gy/5F or 60Gy/8F for peripheral and central primary, respectively. The primary endpoint was progression free survival (PFS). The adverse events (AEs) were assessed.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 20 patients were enrolled between September 2016 and March 2018. Median age was 69 years (range 62-80). There were 9 males and 11 females. The baseline KPS was scored above 70 in 18 patients, 60 in 2 patients. Sixteen patients had stage IV disease and 4 had IIIb. There were 11 patients with 19Del and 9 patients with L858R mutations. After a median follow-up time of 10.4 months (range 3-19.3),only one patient had disease progression around the treated primary tumor. Nine patients had disease progression distantly outside of radiated region. Median PFS was 15.2 (95% CI 8.5-21.9) months for the whole cohort. At 10 months of follow-up, the rates of OS, PFS, local and distant PFS were 100%, 67.2%, 100% and 67.2% respectively. There were no acute or late grade 3+ treatment related toxicities.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Early primary tumor SBRT improved primary tumor control without causing serious side effects. SBRT may delay the development of icotinib resistance in patients with advanced NSCLC harboring EGFR mutations. Randomized study is needed to determine whether early SBRT can improve PFS and over survival.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-69 - Stereotactic Ablative Radiotherapy Improves Progression-Free Survival &amp; Local Control in Oligometastatic Lung Cancer Patients

      12:00 - 13:30  |  Presenting Author(s): Federico Maldonado

      • Abstract

      Background

      Non-small cell lung cancer (NSCLC) represents approximately 75% of the histological types of lung cancer. In patients with oligometastatic NSCLC, definitive treatment to primary tumor and low thoracic tumor burden are associated with better outcomes. The use of stereotactic ablative radiotherapy (SABR) has demonstrated high rates of local control for lung metastases and long-term survival improvement. The aim of this study is to evaluate Local Control (LC), Progression Free Survival (PFS) and toxicity of patients with oligometastatic NSCLC treated with SABR.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A prospective study was conducted with oligometastatic NSCLC patients. From July 2016 to December 2017, with a median follow up of 21.7 months, eighteen patients were enrolled. All patients received systemic therapy, those with partial response (PR), assessed by PET CT, were referred for SABR treatment (45-60 Gy in 3-7 fractions) to the thoracic lesion (primary or metastatic) depending on location, size and number of lesions, always keeping BED (Biologically Effective Dose) >100 Gy for tumor.

      4c3880bb027f159e801041b1021e88e8 Result

      Eighteen patients were treated with SABR, response to treatment was as follows: global response was 94%, partial response 22% and complete response 72.2%. Mean time to progression after SABR treatment was 7.04 months (CI 95% 0.27-17.84 months). Progression free survival since beginning of any treatment was 20.14 months (CI 95% 12.92 - 27.35 months). The pattern of recurrence/progression was as follows: local (in field) 1/18, regional (mediastinal lymph node) 1/18 and systemic 4/18, 12/18 did not show any recurrence. Sixteen patients developed grade 1 pneumonitis; one patient developed grade 2 pneumonitis and grade 3 pneumonitis was reported in one patient. Only three patients required treatment with steroids (16.7%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      SABR is a suitable and well-tolerated therapeutic option for patients with oligometastatic NSCLC. SABR have shown to improve local control and increase progression-free survival. Future clinical trials are required to fully evaluate the effects of this treatment.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-70 - Meta-Analysis of Metformin in Combination with Platinum Chemotherapy in Advanced Non-Squamous Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Kristen A. Marrone  |  Author(s): Anish Parikh, Daniel Becker, Julie R. Brahmer, David S Ettinger, Benjamin P Levy

      • Abstract

      Background

      Metformin has been shown to have a variety of insulin-dependent and –independent antitumor effects, primarily through cellular growth inhibition via the AMP-activated protein kinase (AMPK) pathway and the IGF1-insulin axis. Two prospective trials evaluating metformin with platinum doublet chemotherapy +/- bevacizumab have demonstrated competitive outcomes in non-diabetic, chemotherapy-naïve advanced non-small cell lung cancer (NSCLC) patients. Outcomes in KRAS-mutated NSCLC, an area of interest due to potential co-occurring LKB1 mutations, an AMPK pathway upstream kinase, is currently unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This meta-analysis is of two phase II study treatment arms (NCT02019979, NCT01578551), evaluating the use of concurrent metformin and platinum-based doublet chemotherapy +/- bevacizumab. Patient’s demographic, molecular and adverse event (AE) profiles were summarized with descriptive statistics. Kaplan-Meier curves for progression free survival (PFS) and overall survival (OS) were generated for all patients, as well as known KRAS and EGFR mutation subsets.

      4c3880bb027f159e801041b1021e88e8 Result

      33 non-squamous NSCLC patients were treated; 60% were female and the median age was 64 (Range: 37-77). The most common AE was neutropenia (Grade 3-4: 30%). No patients required study treatment cessation due to metformin-related toxicity. Across all patients, mPFS was 6 months (95% CI: 1.36-7.96); mOS was 14.83 months (95% CI: 8.25-19.99). In KRAS-mutated patients (n=13), mPFS was 7.21 months; mOS was 17.46 months. In EGFR-mutated patients (n=7), mPFS was 6.57 months; mOS was 13.25 months.overall survival.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Combination metformin and chemotherapy +/- bevacizumab was safe and well-tolerated in advanced, chemotherapy-naïve non-squamous NSCLC across two phase II clinical trials. Metformin appeared particularly effective in KRAS-mutated NSCLC. Data for LKB1 status was unknown for a majority of patients, but may be an important co-mechanism for benefit. Metformin appeared to underperform in the EGFR subset, perhaps due to lack of TKI use. Given the tolerability, low cost and activity observed in NSCLC, further investigation into metformin’s antitumor effects in molecularly defined subsets is needed.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-71 - Results of Extended Resection in T4 Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Takeshi Matsunaga  |  Author(s): Kenji Suzuki, Kazuya Takamochi, Shiaki Oh

      • Abstract

      Background

      The strategy for T4 non-small cell lung cancer remains controversies. Extended resection carried a high mortality rate and high advances in surgical technique was needed. However, extended resection may improve survival in selected patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between 2000 and 2015, 41 patients with pT4 non-small cell lung cancer, undergoing extended mediastinal resection, were selected. Patients with pulmonary metastasis were excluded. The type of extended resection was carina in 11 (27%), superior vena cava in 9 (22%), the aorta in 6 (15%), esophagus in 2 (5%), left atrium in 7 (17%) and mediastinal tissue in 4 (10%). We investigated the results of surgical resection and over-all survival.

      4c3880bb027f159e801041b1021e88e8 Result

      There were p-stage IIIA in 26 and p-stage IIIB in 15. In histology, squamous cell carcinoma was observed in 22, adenocarcinoma in nine, pleomorphic carcinoma in four and others in six. The median of in-hospital days was 17d, that of operative time was 302m, and that of operative bleeding was 470cc. The rate of induction therapy was 10%. Pneumonectomy was performed in 22 (54%) and bronchoplasty was did in 18 (44%). The rate of morbidity was 66% and that of reoperation was 17%. 30-day mortality was 5%, 90-day mortality was 7% and in-hospital death was 2%. The median follow-up time was 34 months and overall 3- and 5-year survival was 57% and 39%. Significant prognostic factors were complete resection (p-value=0.0485) and smoking status (p-value=0.0498) in univariate analysis. Multivariate analysis did not reveal significant prognostic factors.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Surgical resection for T4 lung cancer was feasible in this study. But, the frequency of morbidity and reoperation was high because of high ratio of pneumonectomy and mediastinal extended resection. So, we need to care for patients after operation, intensively.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-72 - Pulmonary Resection in a Prone Position for Lung Cancer Invading the Spine: Two Cases Report

      12:00 - 13:30  |  Presenting Author(s): Shunsaku Miyauchi  |  Author(s): Junichi Soh, Kota Araki, Akihiro Miura, Yuta Takahashi, Eisuke Kurihara, Yusuke Ogoshi, Kazuhiko Shien, Hiromasa Yamamoto, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

      • Abstract

      Background

      The prone position is usually not selected for pulmonary resection. The intraoperative body position is an important issue in surgery for non-small cell lung cancer (NSCLC) invading the spine because the standard intraoperative body position for vertebrectomy is a prone position, while that for pulmonary resection is a lateral decubitus position. Intraoperative changes in body position are correlated with disadvantages such as the risks of infection and nerve injury.

      We have previously reported significantly favorable clinical outcome of induction chemoradiotherapy (iCRT) followed by surgery among patients with clinical T3 or T4 locally advanced NSCLC, compared with initial surgery. iCRT can prevent cancer cell microresidues at local sites and to eradicate micrometastatic disease at distant sites.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Case 1: A 60-year-old man was found to have squamous cell carcinoma of the left lung with invasion of the adjacent chest wall and vertebral bodies from Th3 to Th5 and his clinical stage (UICC 7th edition) was diagnosed as c-stage IIIA (cT4N0M0).

      Case 2: A 63-year-old man was found to have adenocarcinoma of the right lung with invasion of the adjacent chest wall and Th3 and Th4 vertebral bodies and was diagnosed as c-stage IIIA (cT4N1M0).

      They were treated with iCRT consisting of two cycles of cisplatin plus docetaxel with concurrent radiotherapy of total 46 Gy.

      4c3880bb027f159e801041b1021e88e8 Result

      They obtained a moderate decrease in tumor size after iCRT (restaging ycT4N0M0: Case 1, ycT4N0M0: Case 2).

      The surgery was started in the prone position. After partial vertebrectomy and chest wall resection were performed using an O-arm with a navigation system, upper lobectomy with systemic lymph node dissection (sLND) was performed through the chest wall defect via the posterior approach. Firstly, all pulmonary arterial branches to upper lobe were divided. Next, after division of the posterior and anterior interlobar fissure, the upper lobe bronchus was transected. Finally, the upper pulmonary vein was divided, and sLND was performed under an excellent view.

      Pathologic examination confirmed complete resection of squamous cell carcinoma invading the vertebral bodies and a diagnosis of Ef3 and ypN0 in Case 1, and complete resection of adenocarcinoma adjacent to the vertebral bodies, which had not been infiltrated, and a diagnosis of Ef2 and ypN0 in Case 2.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lobectomy with systemic LND in the prone position, especially after wide resection of the bony thorax, can be performed via the posterior approach without any significant difficulties in the patients with NSCLC invading the spine.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-73 - Talc Versus Minocycline and OK-432 Pleurodesis for Malignant Pleural Effusion.

      12:00 - 13:30  |  Presenting Author(s): EISUKE Mochizuki  |  Author(s): Yasutaka Mochizuka, Kyohei Oishi, Hyogo Naoi, Shun Matsuura, Shinichiro Mikura, Miyuki Nagaoka, Masaru Tsukui, Naoki Koshimizu

      • Abstract

      Background

      Globally, talc pleurodesis is the standard treatment for malignant pleural effusion. In Japan, a combination of minocycline (MINO) and OK-432 has been commonly used for treating pleurodesis of malignant pleural effusion; however, data comparing talc and MINO + OK-432 are insuffient.

      To compare the success rates and adverse events of talc and MINO + OK-432.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively assessed 73 patients receiving pleurodesis for malignant pleural effusion (lung cancer, 60; malignant mesothelioma, 3; others, 10) for the first time between January 2010 and January 2017 at our hospital. We assessed the rates of fever, pain, after drug administration and success of pleurodesis. Moreover, we assessed the difference in success rates according to the pathology of the disease or chemotherapy.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 73 patients, 51 were men and 22 were women, the median age was 75 years (range 47-98). The rate of fever was significantly low in the talc group, although no statistical difference was observed in the success rate (talc, 75.9%, MINO + OK-432, 85.1%), period of drainage tube insertion (3.2 and 3.6 days) and the rate of pain (30% and 50%). No statistical difference according to the pathology of the disease or chemotherapy was observed.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Thus, we can perform pleurodesis in patients with talc less invasively than with MINO + OK-432.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-74 - Clinical and Radiological Predictors of Efficacy to Nivolumab in NSCLC: A Multi-Institutional, Retrospective Cohort Study. 

      12:00 - 13:30  |  Presenting Author(s): Rebecca Jane Moor  |  Author(s): Kate E Roberts, Rahul Ladwa, Kenneth Miles, Kenneth O’byrne

      • Abstract

      Background

      Identification of sub-populations of patients with a greater likelihood of response to anti-programmed death-1 (PD1) inhibitors in non-small cell lung cancer (NSCLC) would enable treatment to be directed to those most likely to benefit, thereby increasing efficacy and cost effectiveness. The relationship, however, between clinical and radiological parameters with efficacy of single agent Nivolumab remains unclear in advanced NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective analysis was conducted for patients who received second-line Nivolumab following progression after platinum based chemotherapy for advanced NSCLC on a Compassionate Access Program across seven oncology institutions in Queensland, Australia.

      ECOG Performance status (PS), immune related adverse events (IrAEs), and baseline CT texture analysis (as a surrogate for tumour heterogeneity) was assessed. The endpoints were overall survival (OS), progression free survival (PFS) and objective response rate (ORR). An institutional ethical approval was obtained.

      4c3880bb027f159e801041b1021e88e8 Result

      Two hundred and fourteen patients were enrolled over two years, median age 67 (range 42 to 84 years). PS 0-1 (64 %); PS 2-3 (36%).

      The median OS was 8.9 months (95% CI, 6.6 to 11.67); 13.3 months in PS 0-1 patients and 4.9 months in PS 2-3 patients. At 1 year, the OS rate was 41%; 55% in patients with PS 0-1 and 19% in PS 2-3 patients. ORR was recorded in 23% of patients (50/214), an additional 27% (58/214) had stable disease.

      Toxicity data was available for 90% of patients (N=194). The presence of IrAEs of any grade occurred in 36% of patients and was associated with a longer median PFS of 5.9 months versus 2.3 months in patients with no immune toxicity (P value <0.01, 95% CI). In patients with IrAE the ORR was 32% versus 18%, 1 year OS 59% versus 29% in those without any immune mediated toxicity.

      CT texture analysis findings (N=47) consistent with increased tumour heterogeneity showed significantly longer PFS (median NR versus 1.5 months, Hazard Ratio: 2.05, p=0.018).

      8eea62084ca7e541d918e823422bd82e Conclusion

      We found Nivolumab had clinically significant long-term benefits in the treatment of locally advanced and metastatic NSCLC with 12 month survival rates in keeping with clinical trials in PS 0-1 patients. An ECOG PS 0/1, the development of IrAEs and increased tumour heterogeneity by CT texture analysis was associated with a significantly longer PFS and increased clinical benefit in this cohort. The combination of these clinical and radiological parameters may identify subgroups of patients benefitting from this therapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-75 - RELAY+, an Exploratory Study of Gefitinib with Ramucirumab in Untreated Patients with EGFR Mutation-Positive Metastatic NSCLC

      12:00 - 13:30  |  Presenting Author(s): Makoto Nishio  |  Author(s): Kazuto Nishio, Kazumi Suzukawa, Yukie Omori, Sotaro Enatsu, Carla Visseren-Grul, Kazuhiko Nakagawa

      • Abstract

      Background

      RELAY is a randomized, double-blind phase 1b/3 study investigating the efficacy and safety of the addition of ramucirumab (a human IgG1 monoclonal antibody that binds to Vascular Endothelial Growth Factor (VEGF) Receptor 2) to erlotinib (an EGFR TKI) in treatment-naïve EGFR-mutant metastatic NSCLC. Results from the Phase 1b cohort showed that combining ramucirumab with erlotinib was safe with encouraging clinical activity and a median PFS of 17.1mo (Reck et al., Clinical Lung Cancer 2017). While enrolment for the RELAY Phase 3 cohort has been completed, the RELAY+ cohort was recently added to explore the safety and efficacy of the combination of ramucirumab with gefitinib, a frequently used EGFR TKI in East Asia.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      RELAY+ is an open-label, 2-period, single-arm exploration of the efficacy and safety of the addition of ramucirumab to gefitinib in previously untreated East-Asian patients with EGFR mutation-positive metastatic NSCLC (Period 1) and of ramucirumab to osimertinib in patients whose disease progressed in Period 1 and harbors the T790M mutation (Period 2). The trial is planned to be conducted in Japan, Taiwan and South-Korea and is currently open for enrollment. Approximately 80 patients will be enrolled.

      In Period 1 patients will receive ramucirumab (10mg/kg) every two weeks and gefitinib (250mg/day) until disease progression, unacceptable toxicity or other withdrawal criteria are met. The study objectives are to determine the 1-yr PFS rate, safety and patient reported outcomes (Lung Cancer Symptom Scale and EQ-5D-5L]). In Period 2 the efficacy and safety of ramucirumab (10mg/kg) every two weeks with osimertinib (80mg/day) will be explored.

      Both RELAY+ and RELAY participants will be enrolled in a liquid biopsy exploratory substudy. ctDNA (circulating tumor DNA) from plasma samples will be used for ddPCR (droplet digital PCR) and NGS (Next Generation Sequencing) to characterize mechanisms of acquired resistance and to test the hypothesis if the addition of ramucirumab to an EGFR TKI delays or modifies the emergence of EGFR TKI resistance.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-76 - Clinical Background and Response to Chemotherapy in NSCLC Patients with MET Exon14 Skipping Mutation or High MET Gene Copy Number

      12:00 - 13:30  |  Presenting Author(s): Kaname Nosaki  |  Author(s): Yasuhiro Umeyama, Ryo Toyozawa, Shinkichi Takamori, Naoki Haratake, Naoko Miura, Taro Oba, Masafumi Yamaguchi, Takashi Seto, Mitsuhiro Takenoyama, Yukito Ichinose

      • Abstract

      Background

      MET exon14 skipping mutation (SM) and high gene copy number (HGCN) are present in 3-4% and <1% of NSCLCs. The response to MET inhibitor treatment has been reported in ongoing clinical trials; however, the response to chemotherapy, including immunotherapy, is currently unknown. We conducted a retrospective analysis of patients with MET gene alteration.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We collected the clinicopathological data of NSCLC patients with MET gene alteration. The response to chemotherapy was evaluated according to RECIST v1.1.

      4c3880bb027f159e801041b1021e88e8 Result

      Systemic chemotherapy was given to 10 patients: SM (n=5) and HGCN (n=5). The median age was 67.5 (range 41- 77) years. Thirty percent of the patients were female and 40% were never smokers. The most common histology was adenocarcinoma (40%), followed by pulmonary sarcomatoid carcinoma (20 %). The tumor PD-L1 expression was >50% in 57% (4/7) of the cases and 1-49% in 43% (3/7) of the cases. Platinum doublet, MET inhibitor, immunotherapy (I-O), and I-O+chemotherapy were given to 6, 8, 2 and 1 patients. The overall response rate was 50%, 83%, 0% and 100%, respectively. Hyper-progressive disease after immunotherapy was observed in one patient with SM.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The responses to platinum doublet and MET inhibitor treatment were good, while the response to immunotherapy was poor in NSCLC patients with MET gene alteration. MET gene alterations should be identified before the administration of immunotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-77 - Clinical Characteristics of Korean Lung Cancer Patients with Programmed Death-Ligand 1 Expression

      12:00 - 13:30  |  Presenting Author(s): In-Jae Oh  |  Author(s): Ha-Young Park, Cheol-Kyu Park, Young-Chul Kim, Sang-Yun Song, Seok Kim, Yoo Duk Choi

      • Abstract

      Background

      Programmed death-ligand 1 (PD-L1) is a transmembrane protein that binds to the programmed death-1 (PD-1) receptor and anti-PD-1 therapy enables the immune response against tumors. The aim of this study was to assess the clinical and pathologic characteristics of PD-L1 positive lung cancer patients in Korea. And we examined correlation between immunohistochemical assays.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed the clinical and pathologic data of pathologically proven lung cancer patients, and collected 267 cases of formalin-fixed, paraffin-embedded tissue sample from single institution. PD-L1 expression was detected by qualitative immunohistochemical assay using Monoclonal Mouse Anti-PD-L1, Clone 22C3. PD-L1 protein expression is determined by using Tumor Proportion Score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining. We categorized according to the percentage of TPS; more than 1% or more than 50%. Among 267 patients, 34 were analyzed by both 22C3 and SP263 assays. We examined the concordance correlation between IHC assays.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 267 patients were enrolled and major histologic types were adenocarcinoma (69.3%). The majority was smoker (67.4%) and clinical stage IV (60.7%). Thirty one (11.6%) cases of EGFR mutation and 17 (6.4%) cases of ALK FISH positive were included. The patients who showed TPS ≥ 1% and 50% were 116 (42%) and 58 (21%), respectively. More than 1% of TPS group was consisted of adenocarcinoma (67.8%), squamous cell carcinoma (29.6%), and small cell carcinoma (1.9%) histology. And more than 50% of TPS group was composed of adenocarcinoma (72.4%), squamous cell carcinoma (22.4%). More than 1% of TPS group was significantly older than less than 1% of TPS group (64.83 ± 9.38 vs. 61.73 ± 10.78 years, p=0.014). The rate of poorly differentiated pathology was significantly higher in TPS ≥ 1% group (40.8% vs. 25.8%) and TPS ≥ 50% group (53.2% vs. 27.2%). There was no difference in smoking, EGFR mutation, ALK rearrangement status or biopsy site. Among 34 patients analyzed by both 22C3 and SP 263, 27 patients showed positive by both 22C3 and SP263, at the cut-off of 1% or higher. The concordance correlation coefficient was 0.826 (95% confidence interval: 0.736-0.916).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In Korean lung cancer patients, PD-L1 positive group defined as TPS ≥ 1% was older than negative group. And major histology was poorly differentiated non-small cell lung cancer in both TPS ≥ 1% and 50% groups. And our results showed a high correlation between PD-L1 IHC expression data analyzed by 22C3 and SP263 assays.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-78 - The Cytology Samples and Plasma Specimens were Feasible for the EGFR Molecular Testing.

      12:00 - 13:30  |  Presenting Author(s): Tatsuo Ohira  |  Author(s): Wakako Hamanaka, Yoshihisa Shimada, Sachio Maehara, Junichi Maeda, Masaru Hagiwara, Masatoshi Kakihana, Tetsuya Okano, Naohiro Kajiwara, Norihiko Ikeda

      • Abstract

      Background

      EGFR mutation detection with real-time PCR is standard method to identify eligible patients for EGFR-TKI treatments in daily routine practice. Surgically resected tissues or biopsy specimens are mainly used as the sample materials for testing. However, the biopsy samples sometimes have a certain limitation in their volume and so the cytology specimens are chosen for EGFR testing instead. Plasma has also become an option especially in EGFR-TKI resistant cases in which often have difficulties to obtain the adequate tumor yield. In this study, we evaluated the feasibilities of using cytology samples and plasma specimens for the EGFR molecular testing.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      atients provided written informed consent for use of the samples were participated in this prospective research. Cytology samples were obtained from biopsy and cells were suspended into liquid-based cytology (LBC) media. Tumor contents in the samples were confirmed with Papanicolaou stained slides. Plasma samples were also collected from patients shortly before the tissue biopsy. EGFR mutations in these samples were analyzed by cobas EGFR Mutation Test v2. Also, EGFR testing result of tissue specimens of the patients corresponded were collected from the medical records measured by cobas EGFR Mutation Test v2 as reference.
      The feasibilities of both cytology and plasma specimen were evaluated comparing with the tissue samples.

      4c3880bb027f159e801041b1021e88e8 Result

      One-hundred fifty-eight patients were registered to this study. Among those patients, 77 patients with matched set of samples were enrolled to this study. EGFR mutation rates in tissue, cytology, and plasma were 37.7, 29.9 and 16.9 %, respectively. Overall agreement rate of the cytology specimens and the plasma specimens against the tissue samples were 87.0 and 75.3%, respectively. All eightT790M mutation positive cases were perfectly matched between tissue and cytology specimens.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The results suggested that tissue specimen is the most suitable sample for detecting mutations. Since high specificities were confirmed in both cytology and plasma specimens, the results are reliable as long as the call is positive. Choosing cytology or plasma specimens for EGFR testing can be the considerations for the patients who have difficulties in collecting tissue samples in the real world setting.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-79 - Intracerebral Efficacy of Immune Check-Point Inhibitors in NSCLC Patients with Brain Metastases

      12:00 - 13:30  |  Presenting Author(s): Fumiyoshi Ohyanagi  |  Author(s): Jun Shiihara, Fumiaki Kudo, Yoshiko Mizushina, Hiromitsu Ota, Shinichiro Koyama

      • Abstract

      Background

      The brain is a common site of metastatic disease in patients with non-small cell lung cancer (NSCLC). Approximately 30–50% of patients will develop brain metastases during the course of treatment. Several immune check-point inhibitors (ICIs) have shown efficacy against non–small-cell lung cancers (NSCLCs) and approved in second line setting. However, regarding ICIs intracerebral efficacy and tolerability in NSCLC patients with active brain metastases (BMs) remains unkown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed the medical charts of 49 patients with advanced NSCLC treated with ICIs between January 2016 and March 2018. The intracranial activity of ICIs in patients with brain metastases was assessed by brain magnetic resonance imaging (MRI) using RECIST v. 1.1 criteria. The primary endpoint was intracerebral objective response rate (IORR). Secondary endpoints included intracerebral control rate, intracerebral and general progression-free survival (PFS), overall survival (OS) and tolerance.

      4c3880bb027f159e801041b1021e88e8 Result

      Ten NSCLC patients with BMs were identified. The median age of patients was 61 years (range 44–80 years) and the majority of patients were male (n = 9; 90%). All patients were pretreated with stereotaxic radiosurgery (n = 7) or whole brain radiation therapy (n = 3). All but one patients received prior systemic treatment for NSCLC. Three patients received two prior lines of systemic therapy. Two patients were treated with pembrolizumab. Median follow-up was 5.7 (95% CI: 2.7–8.4) months. IORR and extracerebral response rate were, respectively, 0% (95% CI: 0–25.9%) and 20% (95% CI: 2.5–55.6%). Intracerebral control rate was 60% (95% CI: 26.2–87.8%). Median intracerebral and general PFS lasted 1.8 (95% CI: 0.9–7.1) and 2.8 (95% CI: 1.8–4.6) months, respectively. Median OS was 8.9 (95% CI: 4.9–not reached) months. No neurological adverse events occurred.

      8eea62084ca7e541d918e823422bd82e Conclusion

      ICIs might have the efficacy and favorable safety profile in NSCLC patients with BMs.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-80 - Retrospective Analysis of the Impact of EGFR T790M Mutation Detection by Re-Biopsy in Patients with NSCLC Harboring EGFR Mutations.

      12:00 - 13:30  |  Presenting Author(s): Naoko Okura  |  Author(s): Tadaaki Yamada, Akihiro Yoshimura, Takayuki Takeda, Yutaka Kubota, Shinsuke Shiotsu, Osamu Hiranuma, Junji Uchino, Koichi Takayama

      • Abstract

      Background

      EGFR-TKIs show a good response to most of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. However, it ultimately becomes the acquired resistance to EGFR-TKIs after various periods. We currently attempt to detect EGFR-T790M mutation by re-biopsy that induced a half of acquired resistances to them, because the third generation EGFR-TKI osimertinib had an effective response against the refractory tumors with EGFR-T790M mutations. However, the re-biopsy from tumors is relatively invasive and some cases are impossible to perform them. Therefore, it is a critical issue to select the population with EGFR-T790M mutations. In this study, we analyzed the refractory cases to initial EGFR-TKIs with successful re-biopsy samples to disclose these clinical questions.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      78 advanced NSCLC patients with EGFR mutations who had successful re-biopsy samples after the resistance to initial EGFR-TKI treatment are enrolled at five institutions in Japan. We validated for the association between the emergence of EGFR-T790M mutation and their profiles, such as clinical outcomes with EGFR-TKI treatment and EGFR activating mutation status.

      4c3880bb027f159e801041b1021e88e8 Result

      Results

      Of 78 advanced NSCLC patients with EGFR mutations, 39 cases were EGFR-T790M positive and 39 were negative in the re-biopsy samples. Of EGFR-T790M positive patients, 2 cases achieved a complete response (CR), 33 a partial response (PR), and 4 stable desease (SD). In contrast, 1 patients experienced a CR, 19 a PR, 18 SD, and 1 progressive disease (PD) in T790M negative patients. The objective response rate was higher in patients with T790M positive mutations than in those with T790M negative mutations (89.7% versus 51.2%, p< 0.01). There were no difference between each patients in progression free survival and time to failure treated with initial EGFR-TKIs.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Conclusions

      The response to initial EGFR TKI treatment might be one of good predictors for emerging of refractory tumors with EGFR-T790M mutations. Further experiments are needed to identify them.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-81 - Long-Term Outcome of Surgically Resected Unsuspected N2 Lung Adenocarcinoma

      12:00 - 13:30  |  Presenting Author(s): Byung Jo Park  |  Author(s): Tae Ho Kim, Junghee Lee, Sumin Shin, Jong Ho Cho, Hong Kwan Kim, Yong Soo Choi, Jae Ill Zo, Young Mog Shim, Jhingook Kim

      • Abstract

      Background

      This study was performed to assess the long-term outcome of lung adenocarcinoma in patients without clinical suspicion of mediastinal lymph node involvement and whose tumors were finally proven to be pathologic N2.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a retrospective study of a prospective lung cancer database at our institution from January 2004 to December 2014. We retrospectively reviewed the medical records of 299 patients with unsuspected pathologic N2 disease.

      4c3880bb027f159e801041b1021e88e8 Result

      The median follow-up time was 51.5 months (range, 1.1 to 172.3 months). The median recurrence-free survival (RFS) was 25.3 months and the 1-year, 3-year, and 5-year RFS rates were 78.2%, 41.0%, and 29.5%. The median overall survival (OS) was 75.2 months and the 1-year, 3-year, and 5-year OS rates were 92.6%, 85.9%, and 62.7%, respectively. The most common type of resection was lobectomy (88.6%). Adjuvant therapy was administered in 255 patients (85.3%). N2 involvement was single station without N1 involvement (“skip” metastasis, N2a1) in 73 (24.4%), single station with N1 involvement (N2a2) in 148 (49.5%), and N2 at multiple stations (N2b) in 78 (26.1%). The median RFS and 5-year RFS rate of N2a1 were 42.9 months and 44.8%. The median and 5-year OS and OS rate of N2a1 were 86.2 months and 69.0%. In multivariate analysis, N2a1, low T-stage, and adjuvant therapy were significantly associated with a longer RFS, whereas pneumonectomy was significantly associated with a worse RFS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The long-term outcome of unsuspected pN2 group of patients with lung adenocarcinoma was better than expected. Especially the RFS and OS of pN2a1 group of patients were similar to the those of N1 group of patients reported for survival in our group. Therefore, resection of properly staged unsuspected pathologic N2 lung adenocarcinoma is reasonable and should not be avoided if a complete resection without pneumonectomy can be done.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-82 - Survival Impact of Surgery in the Treatment of Stage IIIB-IVA Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Ji Young Park  |  Author(s): Seung Hun Jang, Hwan Il Kim, Joo-Hee Kim, Sunghoon Park, Yong Il Hwang, Ki-Suck Jung

      • Abstract

      Background

      Surgery is usually not indicated in far advanced stage non-small cell lung cancer (NSCLC), but a few recent clinical trials demonstrated aggressive local therapy such as (chemo) radiotherapy or surgical resection improved survival outcomes in oligometastatic NSCLC. This study aimed to evaluate survival impact of cytoreductive surgery in stage IIIB-IVA (based on the 8th TNM classification) NSCLC in the era of effective anticancer drugs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with stage IIIB, IIIC or IVA NSCLC was recruited from the Hallym Lung Cancer Registry for this retrospective analysis. Other eligibility criteria were ECOG performance 0-1, age under 85 years old and good adherence to lung cancer treatment.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 203 patients were analyzed. All the patients received adequate anticancer drugs during their disease courses. Twenty-two patients (10.8%) received cytoreductive surgery. Significantly better overall survival (OS) was observed in surgery group compared with non-surgery group; Kaplan-Meier estimation for OS was 33.1 months [95% CI, 15.6-50.6] vs. 16.6 months [14.0-19.2] (p=0.007). The Cox proportional hazard ratio (HR) for death was 0.528 [0.290-0.961] (p=0.037) in surgery group when it was analyzed with covariates such as age, sex, performance, histology, stage, and smoking status. ECOG performance 0 and adenocarcinoma histology were also revealed as independent favorable prognostic factors for OS (HR .0.660 [0.474-0.919], p=0.014 and HR 0.481 [0.328-0.707], p<0.001, respectively).

      Table. Cox proportional hazard ratio for death

      Variable HR [95% CI] p-value
      AGE < 65 y.o. vs. ≥ 65 y.o. 0.722 0.520-1.002 0.052
      Sex Female vs. Male 1.950 0.955-3.984 0.067
      ECOG performance 0 vs. 1 0.660 0.474-0.919 0.014
      Histology ADC vs. non-ADC 0.481 0.328-0.707 <0.001
      Stage IIIB/C vs, IVA 0.761 0.520-1.114 0.160
      Smoking ≤ 10 p.y. vs. > 10 p.y. 0.488 0.145-1.639 0.246
      Surgery (+) vs. (-) 0.528 0.290-0.961 0.037

      8eea62084ca7e541d918e823422bd82e Conclusion

      Surgery backed up with adequate anticancer treatments may be a treatment option in far advanced stage NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-83 - Use of Blood Outgrowth Endothelial Cells as a Cellular Carrier for Oncolytic Vesicular Stomatitis Virus in Preclinical Models of NSCLC

      12:00 - 13:30  |  Presenting Author(s): Manish Patel  |  Author(s): Blake A. Jacobson, Yan Ji, Robert A. Kratzke

      • Abstract

      Background

      Oncolytic virus therapy has demonstrated efficacy in numerous tumor models including non-small cell lung cancer. One of the limitations of viral therapy for metastatic lung cancer is that systemic administration can be hindered by complement and antiviral immunity. Thus, we investigated the possibility of using ex-vivo infected blood outgrowth endothelial cells with tumor-homing properties to deliver oncolytic VSV-IFNβ in preclinical models of NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      BOECs were obtained from either human donors or C57/Bl6 mice. Cells were confirmed to maintain the BOEC phenotype and growth characteristics. Indiana strains of VSV were engineered to produce GFP or IFNβ and were titered on Vero cells using either plaque assay or limiting dilution assay. Human NSCLC cell lines, H2009 and H2030 were used for in vitro assays. A549 expressing firefly luciferase cells were used to induce lung metastasis in NOD/SCID mice and treated with BOECs, VSV-IFNβ, or BOECs-infected with VSV-IFNβ. Additionally, syngeneic murine adenocarcinoma cell line, LM2 was used in vivo in A/J mice (n=5).

      4c3880bb027f159e801041b1021e88e8 Result

      BOEC cells were able to home to metastatic LM2 lung tumors and were retained there for up to 72 hours post-infusion. BOEC cells were retained within lung tumors of mice bearing tumors, but there were none detected in lungs of mice without lung tumors. Both human and murine BOECs could be infected and lysed by VSV-GFP and VSV-IFNβ, however, VSV-IFNβ was attenuated compared to VSV-GFP. Maximal viral titer was obtained at 24 or 48 hours for VSV-GFP and VSV-IFNβ, respectively. Co-culture experiments showed near complete lysis of H2009 cells using infected BOECs. Both H2009 and H2030 cells were lysed efficiently by infected BOECs while naked VSV was completely inhibited in the presence anti-VSV neutralizing antibodies. Using Firefly luciferase-expressing A549 cells, metastatic lung tumors were induced in NOD/SCID mice. Compared to BOEC alone and PBS-treated mice, VSV-IFNβ-infected BOECs resulted in superior antitumor efficacy as measured by luciferase activity (p<0.02). Infected BOECs resulted in superior survival of mice compared to VSV-IFNβ alone (n=10, p<0.05). Using immune competent A/J mice, infected BOECs trended toward improved antitumor efficacy to BOEC alone and intravenous VSV-IFNβ treatment (n=5, p=0.09). Replicating virus was recovered only from lungs of infected BOEC treated mice.

      8eea62084ca7e541d918e823422bd82e Conclusion

      BOECs can be used as cellular carrier for systemic delivery of oncolytic VSV-IFNβ. For clinical translation, the use of cellular carriers might be an effective method of virotherapy for metastatic NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-84 - The Association of CDKN2A Gene Mutation with Clinicopathological Features and Prognosis in Advanced Lung Cancer Patients

      12:00 - 13:30  |  Presenting Author(s): Xiujuan Qu  |  Author(s): Ling Xu, Xiaowei He, Huiming Zhou, Yunpeng Liu

      • Abstract

      Background

      The cell cycle-dependent kinase inhibitor gene (CDKN2A) is a tumor suppressor gene, and encodes two kind of cell cycle inhibitor proteins p16INK4a and p14ARF to regulate cell cycle. The aim of this study was to evaluate the association of CDKN2A gene mutation with clinicopathological features and prognosis in Chinese advanced lung cancer patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      CDKN2A gene mutation was screened in tumor specimens using second generation sequencing technology. The correlation between CDKN2A gene mutation and clinicopathological characteristics was analyzed by Spearman’s correlation. The overall survival (OS) and progression free survival (PFS) were analyzed by using the Kaplan–Meier method and compared by the log-rank test. The COX model was used to study the single factors and multiple factors. Statistical data was obtained by using SPSS for Windows version 20.0. P values < 0.05 were considered to indicate statistically significant results.

      4c3880bb027f159e801041b1021e88e8 Result

      CDKN2A gene mutation was 4.57 % (10/219) in lung cancer patients. Patients harboring CDKN2A mutation were more commonly observed in squamous carcinoma patients (P = 0.002). Most of patients with CDKN2A gene mutation were progression disease (PD) in the assessment of first-line treatment efficacy, while the patients without CDKN2A mutation were disease control rate (DCR) (P = 0.011). The OS in patients with CDKN2A gene mutation was 19.1 months compared to 42.8 months in patients without mutation (P = 0.010). The PFS in patients with CDKN2A mutation was 3.5 months compared to 9.7 months in patients without mutation (P = 0.000). In addition, multi-factor analysis showed that CDKN2A gene mutation (HR=2.385, P = 0.025), age 60 years or older (HR=1.588, P = 0.027), T4 stage (HR=1.533, P = 0.019) and high ECOG score (HR=1.694, P = 0.009) were independent risk factor for the survival of lung cancer patients.

      8eea62084ca7e541d918e823422bd82e Conclusion

      CDKN2A gene mutation had an important influence on the clinicopathological features and prognosis of Chinese advanced lung cancer patients. The patients with CDKN2A gene mutation had more poor survival.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-85 - Real-World Gefitinib 1st Line Treatment of Patients with Advanced NSCLC and EGFR Mutations - Serbian Single Center Experience

      12:00 - 13:30  |  Presenting Author(s): Davorin Radosavljevic  |  Author(s): Jelena Spasic, Marija Ristic, Vladimir Nikolic, Neda Nikolic, Nemanja Stanic, Fedja Djordjevic, Dusica Gavrilovic

      • Abstract

      Background

      Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) revealed their efficacy in advanced non-small cell lung cancer (NSCLC), in patients with EGFR mutated tumors, in large scale of clinical trials. Here we present data from clinical practice, patient characteristics and clinical outcome of consecutive patients treated with gefitinib in first-line setting at the Institute for Oncology and Radiology of Serbia between 2011-2016.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Previously untreated patients with lung adenocarcinoma in stages IIIB and IV and PS 0 or 1 have been reviewed by institutional multidisciplinary tumor board and selected for molecular EGFR testing since 2011. Patients with activating EGFR mutations (9.5%) received gefitinib, at that time the only approved EGFR TKI for the first line treatment

      4c3880bb027f159e801041b1021e88e8 Result

      Sixty consecutive patients were included in this analysis. M/F ratio was 21/39, median age 60 years, non-smokers 48%, PS 0/1 85%, metastatic sites (more than 5% of patients) were lungs and pleura in 40%, bones in 27%, liver in 15%, pericardium in 10%, brain in 7% of patients. Only one metastatic site was present in 56% of patients, two sites in 35% and three sites in 6%. Del19 and L858R were detected in 82% of patients (del19 55% and L858R 27%) and umcommon mutations in 18%. Median duration of gefitinib treatment was 8 months, median follow-up 12.5 months. Partial response (PR) was achieved in 33% of patients, stable disease (SD) in 47%, progressive disease (PD) in 18%. Type of progression was a new lesson(s) in 20% of patients, progression of existing lesion(s) in 42% and both in 10%. Second-line treatment was administered to 38% of patients, and 63% were dead at the time of analysis. Median overall survival was 19 months, median progression-free survival 12 months. In patients with PR median OS was 26 months, in SD patients 22 months and in PD patients only 5 months. No statistically significant differences were shown in OS with regards to age, gender, M1a/M1b stage, exon19/21 mutations, common/uncommon mutations or different sites of metastatic disease.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Serbian patients with EGFR mutated lung adenocarcinoma treated with gefitinib in first-line have similar characteristics and outcome compared with published data, particularly when compared with similar analysis on Caucasian population. Probably due to small number of patients, we were not able to select subpopulations of patients with greater benefit from receiving gefitinib

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-86 - Treatment Outcomes with Reduced Frequency of Nivolumab Dosing as Second-Line Therapy in Patients with Advanced NSCLC

      12:00 - 13:30  |  Presenting Author(s): Shabnam Rehman  |  Author(s): Austin Miller, Allison Meagher, Hongbin Chen, Grace K Dy

      • Abstract

      Background

      Nivolumab (Nivo) was approved as second-line therapy in 2015 for patients (pts) with advanced NSCLC. The optimal effective interval between doses is not well-established. We want to evaluate the effect of reduced dose density on the efficacy and safety of Nivolumab.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a single-institution, IRB approved retrospective review of stage IIIB/IV NSCLC who received Nivo after prior platinum-based chemotherapy in the second line setting or beyond between April 2015-January 2018. Characteristics of pts who received Nivo 240mg every(q) 4 weeks or longer, reasons for alternate dosing and their treatment outcomes are described.

      4c3880bb027f159e801041b1021e88e8 Result

      Out of 181 pts with NSCLC who received Nivo during this time frame, 32 pts (18Male:14 Female) received an alternate dosing schedule (median q 4 weeks, range q 3-12 weeks). Median age was 65 years. Majority were former smokers (62%) and had adenocarcinoma (81%). 17 pts started on a regular schedule q 2 weeks and then switched to an alternate schedule, the remaining 15 pts started on an alternate schedule. 28% (9/32) patients were on an alternate schedule due to adverse event. Median expected total cumulative dose (240mg*no. of expected doses until disease progression or death) per pt is 4032mg (range 480 -15840). Median actual cumulative dose (240mg*actual no. of doses) received per pt is 1920mg (range 480 - 10560). This represents a median of 52% of the expected total cumulative dose received. Objective response rate (CR+PR) in the entire cohort was 66%. Median progression-free survival(PFS) from start of alternate schedule is 17.1 months (95% CI 5.2- not reached). 6-month PFS is 65% (95% CI 46%-79%) starting from when alternate schedule of Nivo was begun. We will present updated toxicity and treatment outcomes in the meeting.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Nivolumab 240mg administered at q 4 weeks or longer is feasible. Further investigation is needed to optimize patient selection for alternate dosing schedule.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-88 - Clinical and Molecular Analysis of Long-Term Survivors with Advanced Non-Small Cell Lung Cancer: A Multicenter Experience in Madrid

      12:00 - 13:30  |  Presenting Author(s): María Sereno Moyano  |  Author(s): Sandra Falagan, Juan Moreno Rubio, Rosa Álvarez Álvarez, Maria Eugenia Olmedo, Xabier Mielgo, Fátima Navarro, Ricardo Ramos, Ana Belen Enguita, Amparo Benito, María Cebollero, Isabel Alemany, Carolina Castillo, Enrique Casado, Santiago Ponce Aix

      • Abstract

      Background

      Long survivors (LS) in non-small-cell lung cancer (NSCLC), defined as an overall survival (OS) greater than 2 years, are less than 10% in most series. Classical prognosis factors include stage, weight loss and ECOG, but there are other factors whose influence on the evolution of these patients is uncertain. Recently, different drugs targeted against EGFR, ALK and ROS 1 reach OS longer than 2 years in a limited number of patients (less than 20%). Immunotherapy in NSCLC has demonstrated very promising results with more LS compared to chemotherapy in first and second line setting. In this study, we have focused in the analysis of LS patients with advanced NSCLC EGFR wt (wild type) and ALK nt (non-translocated), defined as those with OS greater than 36 months, in 8 hospitals in Madrid.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this serie, first of all, we will try to make a clinical, histopathological and immunological characterization collecting data from clinical reports according to a previously defined information. In a second step, we will carry out a genetic analysis of these patient samples comparing to an opposite extreme short survivors (SS) samples (OS less than 9 months) from same centers. We used a NGS method of RNA-seq technology with the idea of identify differentiating profiles of gene expression between the two opposite populations with a later confirmation by RT-PCR in the rest of the tissue samples and liquid biopsy.

      4c3880bb027f159e801041b1021e88e8 Result

      We have obtained a differential transcriptome expression between samples from 6 LS and 6 SS, resulting 13 overexpressed and 42 under-expressed genes in LS comparing to SS transcriptome expression. Some of the genes involved in this profile belong to different families and cellular pathways: Secretin receptor, Surfactant Protein, Trefoil Factor 1, Serpin Family, Ca bindings protein channel and Toll like Receptor family. A further confirmation of this profile is carrying on by RT-PCR in the rest of the samples and liquid biopsy from the rest of the patients included in the study.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We present the first data from a genetic analysis of a LS population with NSCLC EGFR wt (wild type) and ALK nt (non-translocated), obtaining a differential RNA profile

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-89 - Upfront Surgery Versus Neoadjuvant Treatment Followed by Surgery in Pathologic N2 Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Byoung Yong Shim  |  Author(s): Sung Kyoung Kim, Hyung Soon Park, Kyu Do Cho, Deog Gon Cho, Young Ha Park, Jinyoung Yoo, Sung Hwan Kim, Jeong Min Ko, Eun Jung Park, Gyu Rim Heo, Chi Hong Kim

      • Abstract

      Background

      Non-small cell lung cancer (NSCLC) patients with ipsilateral mediastinal nodal metastases (N2) had poor prognosis. Although definitive chemoradiation was frequently used as a standard of care for clinical N2 NSCLC, surgery can be a preferred treatment option in selected patients with upfront surgery plus adjuvant treatment or neoadjuvant treatment followed by surgery. Before starting a prospective study in our institution, we checked a treatment outcome of pathologic N2 NSCLC patients treated by upfront surgery or neoadjuvant treatment approach.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The present study evaluated 21 patients with pathologic N2 NSCLC at St. Vincent hospital from February 2007 to September 2017. Patient with upfront surgery or neoadjuvant treatment followed by surgery was included, and pathologic N2 was confirmed before surgery in neoadjuvant group. Taxane and platinum was used as a neoadjuvant treatment or post-operative therapy in both group. Chemotherapy alone or combined with radiotherapy was conducted. Disease free survival (DFS) and overall survival (OS) was evaluated and Kaplan-Meier survival analysis was used for these analyses.

      4c3880bb027f159e801041b1021e88e8 Result

      Eleven (52%) underwent upfront surgery, and 10 patients (48%) underwent neoadjuvant treatment followed by surgery. Clinical T1N2, T2N2 and T3N2 were 4 (19%), 11 (52%) and 6 (29%), respectively. Baseline characteristics did not show significant difference in these two groups. Upfront surgery group received post-operative treatment including chemotherapy alone (n=7), radiotherapy alone (n=2) or chemoradiotherapy (n=1). Neoadjuvant group received chemoradiotherapy (n=3) or chemotherapy alone (n=10). Regarding DFS, there are no significant differences between upfront surgery group and neoadjuvant group (median DFS, 10.0 months vs. 15.1 months, P=0.925). Five year disease free survival rate was 40% and 30%, respectively. In addition, OS did not show significant differences between two groups (medians OS, 79.5 months vs. 47.7 months, P=0.295). Fiver year overall survival rate were 90% and 50%, respectively. In upfront surgery group, 4 of 7 patients did not complete chemotherapy schedule due to adverse event. But, 9 of 10 patients had a completion of chemotherapy in neoadjuvant group.

      8eea62084ca7e541d918e823422bd82e Conclusion

      There are no significant survival differences between upfront surgery group and neoadjuvant treatment group, but both strategies can be effective treatment option for selected pathologic N2 NSCLC. Further studied need to be done for these patients, and currently our institution are preparing clinical trials in a prospective manner.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-90 - A Phase II Study Evaluating Continuation of EGFR-TKIs Beyond Progressive Disease Followed by the Addition of CDDP+PEM+Bev

      12:00 - 13:30  |  Presenting Author(s): Satoshi Shoji  |  Author(s): Satoshi Watanabe, Koichiro Nozaki, Kosuke Ichikawa, Rie Kondo, Satoru Miura, Masaaki Okajima, Tetsuya Abe, Hiroshi Tanaka, Junta Tanaka, Hirohisa Yoshizawa, Hiroshi Kagamu, Toshiaki Kikuchi

      • Abstract

      Background

      Previous studies demonstrated that EGFR- tyrosine-kinase inhibitors (EGFR-TKIs) have antitumor effects even after disease progression during EGFR-TKI treatment. In this phase II study (NLCTG1301), we assessed the safety and efficacy of continuing EGFR-TKIs beyond progressive disease followed by the addition of cisplatin (CDDP), pemetrexed (PEM) and bevacizumab (Bev) in patients with EGFR mutation-positive advanced NSCLC with acquired resistance to first-line EGFR-TKIs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible patients were aged at least 20 years with histologically confirmed, cytotoxic chemotherapy-naive, stage IIIB–IV EGFR mutation-positive NSCLC with previous disease control for at least 6 months with first-line EGFR-TKIs. Patients received CDDP 75 mg/m2, PEM 500 mg/m2 and Bev 15 mg/kg on the first day of each cycle with the continuation of EGFR-TKIs. After completion of a maximum of four chemotherapy cycles, patients continued EGFR-TKIs along with maintenance Bev and PEM until disease progression. The primary endpoint was response rate according to RECIST version 1.1.

      4c3880bb027f159e801041b1021e88e8 Result

      The study was terminated because of slow accrual. Between March 2013 and January 2018, 10 patients were enrolled in this trial and were evaluable for safety and efficacy. Their subtypes of EGFR mutation were exon 19 deletions (7 cases), L858R (2 cases), and L858R+790M (1 case). EGFR-TKIs used in initial treatment were gefitinib (7 cases), erlotinib (3 cases), and the efficiency was PR (9 cases) and SD (1 cases). The objective response rate was 70%, median progression-free survival was 11.4 months, and median overall survival was not reached. The reasons for discontinuation were 6 cases with disease progression, 3 cases with toxicity (Gr3 infection, Gr3 g-GTP increased, Gr2 creatinine increased), and one case with bone fracture caused by accidental falling. Although there were 3 cases of treatment discontinuation due to toxicities, no serious adverse events were observed in the current study. After acquisition of resistance to EGFR-TKIs, tumor re-biopsy was performed in 4 cases, of which T790M was confirmed in 2 cases.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study showed the possibility of benefit of the addition of CDDP+PEM+Bev to EGFR-TKIs in patients with acquired resistance. However, further investigation of this strategy seems to be difficult because of the approval of osimertinib and the results of the IMPRESS study.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-91 - Computing the Impact of Immunotherapy on the Non-Small Cell Lung Cancer (NSCLC) Therapeutic Landscape

      12:00 - 13:30  |  Presenting Author(s): George R. Simon  |  Author(s): Viralkumar Bharatbhai Vaghani, Sheenu Chandwani, Meita Hirschmann, Seydeh Dibaj, Lara Lacerda Landry, Emily Roarty, Jianjun Zhang, Waree Rinsurnogkawong, Jeff Lewis, Jack Lee, Jack A Jack A. Roth, Stephen Swisher, John V Heymach, Thomas Burke

      • Abstract

      Background

      The Advanced Non-Small Lung Holistic Registry (ANCHoR) is established to examine the real-world impact of immunotherapy on choice of treatment, clinical outcomes, and patient reported outcomes of patients with Stage IV NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Stage IV NSCLC patients diagnosed or initiating treatment at MD Anderson from January 1, 2017 are enrolled in the ongoing ANCHoR study. Their demographic, clinicopathological, molecular, and treatment data were populated in a prospective database. Treatment patterns by line and PD-L1 status were summarized in this interim analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      At the time of data cut off (Dec 31, 2017) 182 patients were enrolled in the registry, of which 150 were tested for PD-L1. Number of patients initiating first-, second-, and third-line treatment were 163, 42 and 7, respectively. Of the 30 patients not tested for PD-L1, 10 did not have enough tissue and 8 had actionable mutations.

      table 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The emergence of immunotherapy has had a dramatic impact on the first-line treatment of patient with advanced NSCLC. As of December, 2017 up to 41% of patient received immunotherapy either singly (23%) or in combination with chemotherapy. Only 40% of the patients now receive chemotherapy alone. There has been dramatic decrease in the use of chemotherapy with an anti-angiogenesis agent (1.23%). In our dataset 16% of the patients were eligible for targeted therapy as initial treatment.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-92 - Blood Test Parameters as Prognostic Factors In EGFR-Mutated Non-Small Cell Lung Cancer Treated With TKIs

      12:00 - 13:30  |  Presenting Author(s): Jelena Spasic  |  Author(s): Nemanja Stanic, Fedja Djordjevic, Vera Jokic, Davorin Radosavljevic

      • Abstract

      Background

      Systemic inflammation is an important factor contributing to tumor progression. High neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are markers of host inflammation whose association with worse overall survival (OS) in non-small cell lung cancer (NSCLC) has been shown in various studies. However, there are few studies investigating the association of these, and other haematological parameters of inflammation with prognosis of EGFR mutated NSCLC treated with tyrosine-kinase inhibitors (TKIs). We therefore examined the association between various blood test parameters and prognosis in this group of patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This retrospective analysis included 74 consecutive advanced lung adenocarcinoma patients of caucasian descent, stage IIIB or IV, treated with EGFR TKIs in the first line at the Institute for oncology and radiology of Serbia within a five year period. The analysed haematological parameters were derived from the absolute differential counts of a complete blood count (CBC) taken within one week of TKI treatment initiation. Parameters included in this analysis were NLR, PLR, lymphocyte-to-monocyte ratio (LMR), mean platelet volume (MPV), lymphocyte-to-white blood cell ratio (LWR) and neutrophil-to-white blood cell ratio (NWR). Cut-off values were determined using ROC curves. Correlation between each haematological parameter and progression-free survival (PFS) and OS was examined by Kaplan-Meier method and Cox regression

      4c3880bb027f159e801041b1021e88e8 Result

      Median PFS in the whole group was 13.6 months (10.25-16.95, CI 95%) and median OS was 19.48 months (15.91-23.05, CI 95%). Low LWR (< 0.14) was associated with a shorter PFS in this group of patients (9.2 vs 14.29 months, p=0.008). High NLR (≥ 2.63), high MPV (≥ 8.1) and low LWR (< 0.14) were associated with shorter OS (18.0 vs 27.6 months, p=0.05; 15.57 vs 22.18 months, p=0.04 and 16.13 vs 22.19, p=0.038 respectively). No other analysed parameters showed an association with either PFS or OS

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pre-treatment NLR, LWR and MPV could be reliable, simple and easy to reproduce parameters for prediction of survival and outcome of targeted therapies in caucasian EGFR-mutated NSCLC patients. Further prospective trials are needed to definitively confirm this possible prognostic and predictive role

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-93 - Osimertinib-Related Hematological and Pulmonary Toxicities in Advanced NSCLC Patients: Combined Analysis of Phase III Trials

      12:00 - 13:30  |  Presenting Author(s): Sriman Swarup  |  Author(s): Kyaw Zin Thein, Somedeb Ball, Miguel Quirch, Yuttiwat Vorakunthada, Anita Sultan, Fred Hardwicke, Lukman Tijani, Sanjay Awasthi

      • Abstract

      Background

      In both epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) sensitizing and EGFR T790M resistance mutations in patients with advanced non-small-cell lung cancer (NSCLC), osimertinib, a third-generation and irreversible oral EGFR-TKI, has been shown to improve survival in studies. We performed a systematic review and meta-analysis of phase III randomized controlled trials (RCT) to determine the risk of hematological and pulmonary toxicities among patients with advanced NSCLC treated with osimertinib.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We undertook a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through March 2018. Phase III RCTs that mention hematological and pulmonary toxicities as adverse effects were incorporated in the analysis. The primary meta- analytic approach was a fixed effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI).

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 971 patients with advanced NSCLC from two phase III studies were eligible for analysis. The study arm used osimertinib while the control arm utilized either chemotherapy (carboplatin/cisplatin+ pemetrexed) or standard EGFR-TKIs (gefitinib or erlotinib). The randomization ratio was 1:1 in the FLAURA study and 2:1 in the AURA3 study. Osimertinib was utilized in T790M-positive advanced NSCLC after prior first-line EGFR-TKIs in the AURA3 study (n= 556) and as first-line treatment in the FLAURA study (n= 415). The RR of all-grade side effects were as follows: anemia, 0.594 (95% CI: 0.433 – 0.814, p = 0.001); cough, 1.122 (95% CI: 0.829 – 1.520, p = 0.455); dyspnea, 1.143 (95% CI: 0.784 – 1.666; p = 0.487); and ILD, 2.378 (95% CI: 0.984 – 5.744; p = 0.054). The RR of high-grade adverse effects were as follows: anemia, 0.175 (95% CI: 0.072 – 0.425, p < 0.001); neutropenia, 0.293 (95% CI: 0.138 – 0.623; p = 0.001); thrombocytopenia, 0.183 (95% CI: 0.060 – 0.564, p = 0.003); pneumonia, 1.237 (95% CI: 0.442 – 3.459; p = 0.685); dyspnea, 0.895 (95% CI: 1.192 – 4.175; p = 0.888); and ILD, 1.238 (95% CI: 0.404 – 3.789; p = 0.708).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our meta-analysis demonstrated that patients on osimertinib experienced a significant decrease in the risk of hematological toxicities, compared to control arm. Moreover, no increase in the risk of pulmonary toxicities was noted in the osimertinib group.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-94 - Safety and Efficacy of First-Line Pemetrexed Versus Bevacizumab-Containing Regimens in Advanced Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Konstantinos Syrigos  |  Author(s): Andriani Charpidou, Dimitra Grapsa, Dimitrios Vassos, Sotirios Tsimpoukis, Sofia Tsagouli, Ioannis Gkiozos

      • Abstract

      Background

      Previous trial data have documented the efficacy of first-line bevacizumab-based regimens, including bevacizumab-pemetrexed combinations in advanced non-small cell lung cancer (NSCLC). We herein aimed to further assess the safety and efficacy of pemetrexed monotherapy versus bevacizumab-containing or other chemotherapy regimens in a real-world NSCLC population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The medical records of 753 patients with advanced-stage non-squamous NSCLC, treated with bevacizumab-based regimens, pemetrexed monotherapy, or other treatments, as first-line therapy, were retrospectively reviewed and analyzed for efficacy and safety endpoints.

      4c3880bb027f159e801041b1021e88e8 Result

      The bevacizumab-based group had the highest percentage of partial response/PR (32.3% vs 22.8% for pemetrexed and 20.0% for other treatments) and a significantly lower incidence of progressive disease/PD (35.92%, 30.17%, and 50.48%, for pemetrexed, bevacizumab-based, and other, respectively; p < 0.0001). Bevacizumab-based regimens achieved a better overall survival (OS) rate (measured at the end of treatment) (pemetrexed 29.6%, bevacizumab-based 35.7%, and other treatments 8.9%; p < 0.0001). However, median OS was not improved (10 months, 12 months, and 13 months for pemetrexed, bevacizumab-based, and other treatments, respectively; p=0.007). A significantly higher incidence of cough (p = 0.001) and hemoptysis (p < 0.0001) in the bevacizumab-based arm, pain in the pemetrexed arm (p = 0.007), and alopecia in the other treatments arm (p < 0.0001) was observed during treatment. A significantly higher incidence of hemoptysis in the bevacizumab-based arm (p < 0.0001) and alopecia in the other treatments arm (p < 0.0001) was seen at the end of first-line treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Bevacizumab-based regimens resulted in improved treatment response and short-term survival rate, but not in improved OS. An increased, albeit acceptable, toxicity was also observed among bevacizumab-treated patients as compared to those treated with pemetrexed monotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-95 - EGFR Genotype as a Predictor of Survival in EGFR Mutant Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Konstantinos Syrigos  |  Author(s): Sofia Tsagouli, Ioannis Gkiozos, Maria Paraskeva, Ilias Kotteas, Sotirios Tsimpoukis, Marios Zontanos, Dimitra Grapsa

      • Abstract

      Background

      Patients with epidermal growth factor (EGFR)-mutant non-small cell lung cancer (NSCLC) represent a distinct treatment and prognostic subgroup, typically responding to treatment with tyrosine-kinase inhibitors (TKIs) but also displaying a highly variable prognosis. We herein aimed to further investigate the potential value of EGFR genotype as a predictor of survival in EGFR-mutant NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The medical records of 68 patients with NSCLC and positive EGFR mutation status, who had been treated with EGFR-TKIs, were retrospectively reviewed. Demographic, clinicopathological features and EGFR mutation testing results of patients were correlated with survival.

      4c3880bb027f159e801041b1021e88e8 Result

      (EGFR) exon 19 E746-A750 deletion and (EGFR) exon 21 L858R point mutation were the commonest EGFR mutations, observed in 58% and 24% of patients, respectively. Median progression-free survival (PFS) among patients with (EGFR) exon 21, 19 and 18/20 was 22.9, 13.9 and 4.7 months, respectively. Median overall survival (mOS) for the above subgroups was 25.1, 35.8 and 13.8 months, respectively. The presence of (EGFR) exon 21 L858R point mutation was correlated with reduced risk of disease recurrence as compared to (EGFR) 18/20 mutations (HR=0,25, p=0,018); patients with (EGFR) exon 19 mutations had reduced risk of death as compared to those with (EGFR) exon 18/20 mutations (HR=0,29, p=0,007).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The presence of (EGFR) exon 19 mutations may be associated with increased OS among patients with EGFR-mutant NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-96 - Clinical Characteristics of Non–Small Cell Lung Cancer Harboring Mutations in Exon 20 Of EGFR or HER2

      12:00 - 13:30  |  Presenting Author(s): Masayuki Takeda  |  Author(s): Kazuko Sakai, Hidetoshi Hayashi, Kaoru Tanaka, Junko Tanizaki, Takayuki Takahama, Koji Haratani, Kazuto Nishio, Kazuhiko Nakagawa

      • Abstract

      Background

      Unlike common epidermal growth factor receptor gene (EGFR) mutations that confer sensitivity to tyrosine kinase inhibitors (TKIs) in non–small cell lung cancer (NSCLC), mutations in exon 20 of either EGFR or the human EGFR2 gene (HER2) are associated with insensitivity to EGFR-TKIs, with treatment options for patients with such mutations being limited.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Clinical characteristics, outcome of EGFR-TKI or nivolumab treatment, and the presence of coexisting mutations were reviewed for NSCLC patients with exon-20 mutations of EGFR or HER2 as detected by routine application of an amplicon-based next-generation sequencing panel.

      4c3880bb027f159e801041b1021e88e8 Result

      Between July 2013 and June 2017, 206 patients with pathologically confirmed lung cancer were screened for genetic alterations including HER2 and EGFR mutations. Ten patients harbored HER2 exon-20 insertions (one of whom also carried an exon-19 deletion of EGFR), and 12 patients harbored EGFR exon-20 mutations. Five of the 13 patients with EGFR mutations were treated with EGFR-TKIs, two of whom manifested a partial response, two stable disease, and one progressive disease. Among the seven patients treated with nivolumab, one patient manifested a partial response, three stable disease, and three progressive disease, with most (86%) of these patients discontinuing treatment as a result of disease progression within 4 months. The H1047R mutation of PIK3CA detected in one patient was the only actionable mutation coexisting with the exon-20 mutations of EGFR or HER2.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Potentially actionable mutations thus rarely coexist with exon-20 mutations of EGFR or HER2, and EGFR-TKIs and nivolumab show limited efficacy in patients with such exon-20 mutations.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-97 - Which is Better Prognostic Factor, PS, Inflammatory Marker, or PD-L1 Expression in Treating NSCLC with Nivolmab; A Retrospective Analysis

      12:00 - 13:30  |  Presenting Author(s): Akihiro Tamiya  |  Author(s): Yoshihiko Taniguchi, Yuji Inagaki, Nobuhiko Saijo, Yoko Naoki, Kenji Otsuka, Kyoichi Okishio, Takahiko Kasai, Shinji Atagi

      • Abstract

      Background

      Although nivolumab showed the significantly longer overall survival (OS) compared with standard second-line therapy using docetaxel for both squamous and non-squamous non-small cell lung cancer (NSCLC) based on two phase III randomized controlled trials, PD-L1 expression alone is not yet an adequate biomarker in treating NSCLC patients with nivolmab. This single institute retrospective study aimed to analyze which biomarker or pretreatment patients’ status were more associated with outcomes in NSCLC patients treated with nivolumab.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed the medical records of all patients with previously treated advanced NSCLC who received nivolumab between December 2015 and May 2016 in our institute. And we confirmed PD-L1 expression in the patients who were able to examine PD-L1 status. Multivariable logistic regression and Cox proportional hazards models were used to assess the impact of pretreatment PD-L1 expression, performance status (PS), and inflammation parameter (neutrophil-to-lymphocyte ratio (NLR)) on progression-free survival (PFS) and OS. The data cut off was on 31th October 2017.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 66 patients were included in this analysis. Median age was 66 (range, 46–85) years old, 48 patients were men, 54 patients were non-squamous cell carcinoma, 57 patients had a smoking history, 15 patients had a PS of 2 or higher, 23 patients were NLR ≥4, and 10 patients were PD-L1 expression ≥50 and 19 patients were PD-L1 expression 1-49. As for pretreatment prognostic factors, multivariate analyses revealed that never smoker (hazard ratio (HR): 4.22, 95% confidence interval (CI): 1.23 - 15.90), PS ≥2 (HR: 3.72, 95% CI: 1.80 - 7.52), and no PD-L1 expression (HR: 2.03, 95% CI: 1.10 – 3.84) were significantly associated with poor PFS, and furthermore PS ≥2 (HR: 6.27, 95% CI: 2.72 - 14.65) was independently associated with poor OS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      PS is the better prognostic factor than NLR and PD-L1 expression in NSCLC patients treated with nivolumab.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-99 - Effect of Pembrolizumab on Patients Harboring Uncommon Epidermal Growth Factor Receptor Mutations

      12:00 - 13:30  |  Presenting Author(s): Yoshihiko Taniguchi  |  Author(s): Akihiro Tamiya, Yuji Inagaki, Nobuhiko Saijo, Yoko Naoki, Kenji Otsuka, Keiko Nakao, Kyoichi Okishio, Shinji Atagi

      • Abstract

      Background

      The characteristics of non-small cell lung carcinoma (NSCLC) patients harboring uncommon epidermal growth factor receptor (EGFR) mutations differ from those of patients with common EGFR mutations. For example, male smokers were more common among patients with uncommon mutations. The efficacies of non-afatinib treatment strategies for patients harboring uncommon EGFR mutations are uncertain. The efficacy of immune checkpoint inhibitors (ICIs) in advanced NSCLC patients with EGFR mutations is limited. Furthermore, the efficacy of ICIs in patients harboring uncommon EGFR mutations is unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed five NSCLC cases with uncommon EGFR mutations and high program death (PD)-ligand (L)1 expression (> 50%) on tumor cells that were treated with the ICI pembrolizumab in our institute from April 2017 to April 2018. We collected data include sex, age, performance status, smoking history, PD-L1 expression, EGFR mutations status and clinical outcome.

      4c3880bb027f159e801041b1021e88e8 Result

      Four cases were male, median age was 68 (45-78), 4 cases were former/current smokers, 1 case was stage IIIC, 2 cases were stage IVA and 2 cases were stage IVB, 4 cases had G719X and 1 case had both exon 19 deletion and T790M. Four cases were treated with pembrolizumab as first line treatment and 1 case were treated as second line treatment after afatinib. Median number of pembrolizumab doses were 4 (1-7) and best responses were 2 partial response (PR), 2 stable disease (SD) and 1 progressive disease (PD). As adverse events, 1 case had grade 3 colitis and 1 case had grade 1 pneumonitis.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Four patients with the G719X mutation were male former/current smokers and were effectively treated (PR of SD) with pembrolizumab. However, one patient with both common mutation and de novo T790M did not respond to pembrolizumab (PD). ICI-based treatment for patients harboring uncommon EGFR mutations may be one of the treatment option.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-100 - Risk of Gastrointestinal and Hepatic Toxicities in Patients with Advanced Non-Small-Cell Lung Cancer Treated with Osimertinib

      12:00 - 13:30  |  Presenting Author(s): Kyaw Zin Thein  |  Author(s): Sriman Swarup, Somedeb Ball, Miguel Quirch, Yuttiwat Vorakunthada, Saad Khan, Fred Hardwicke, Sanjay Awasthi, Lukman Tijani

      • Abstract

      Background

      Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard first-line therapy in patients with advanced non-small-cell lung cancer (NSCLC) who harbors EGFR mutation. The presence of T790M point mutation, later, mediates the resistance to first-generation and second-generation EGFR-TKIs. Osimertinib, an oral third-generation EGFR-TKI, targets both EGFR-TKI sensitizing and EGFR T790M resistance mutations. We undertook a systematic review and combined analysis of two phase III randomized controlled trials (RCT) to determine the risk of gastrointestinal and hepatic toxicities among patients with advanced NSCLC treated with osimertinib.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through March 2018. Phase III RCTs that mention diarrhea, nausea, vomiting, stomatitis and elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Fixed effects model was applied.

      4c3880bb027f159e801041b1021e88e8 Result

      Two phase III RCTs with a total of 971 patients with advanced NSCLC were included in the analysis. Studies compared osimertinib vs carboplatin/cisplatin + pemetrexed and osimertinib vs gefitinib/erlotinib. The randomization ratio was 1:1 in the FLAURA study and 2:1 in the AURA3 study. Osimertinib was utilized in T790M-positive advanced NSCLC after prior first-line EGFR-TKIs in the AURA3 study (n= 556) and as first-line treatment in the FLAURA study (n= 415). The RR of all-grade side effects were as follows: diarrhea, 1.305 (95% CI: 1.128 – 1.509, p < 0.0001); nausea, 0.480 (95% CI: 0.378–0.611; p < 0.0001); vomiting, 0.783 (95% CI: 0.561–1.092; p = 0.149); stomatitis, 1.262 (95% CI: 0.980 – 1.626, p = 0.071); elevated AST, 0.397 (95% CI: 0.277–0.569; p < 0.0001); and elevated ALT, 0.312 (95% CI: 0.212–0.458; p < 0.0001). The RR of high-grade side effects were as follows: diarrhea, 0.912 (95% CI: 0.354 – 2.347, p = 0.849); vomiting, 0.135 (95% CI: 0.022 – 0.831; p = 0.031); stomatitis, 0.532 (95% CI: 0.124 – 2.293, p = 0.397); elevated AST, 0.296 (95% CI: 0.096 – 0.907; p = 0.033); and elevated ALT, 0.112 (95% CI: 0.034 – 0.372; p < 0.0001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients on osimertinib noted a significant increase in the risk of all-grade diarrhea. Nevertheless, the risk of developing any-grade nausea, all grades of elevated AST/ALT and high-grade vomiting, was significantly reduced in osimertinib arm, favoring osimertinib.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-101 - A Retrospective Study of Lung Cancer that has Progressed to Brain Metastasis Alone

      12:00 - 13:30  |  Presenting Author(s): Kenjiro Tsuruoka  |  Author(s): Hiroyuki Tsuji, Keiji Miyoshi, Ninso Matsunaga, Takahiko Nakamura, Yosuke Tamura, Masafumi Imanishi, Soichiro Ikeda, Yasuhito Fujisaka, Isao Goto

      • Abstract

      Background

      There is no consensus whether systemic therapy is needed after local treatment of lung cancer that has progressed to brain metastasis alone. To clarify the effect of treatment differences on patient survival, we conducted a retrospective study of treatment outcomes in patients with lung cancer that progressed to brain metastasis alone.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The study included patients diagnosed with lung cancer at our hospital between January 2011 and December 2016 and those with disease progression to brain metastasis alone by December 2017. We divided the patients according to the treatment administered and compared their characteristics and survival.

      4c3880bb027f159e801041b1021e88e8 Result

      This study included 26 patients. Among them, 7 patients were followed up after local treatment (FU) and 19 patients received systemic therapy after local treatment (ST). The patient characteristics were as follows: median age (years): FU, 71 and ST, 68; sex (male/female): FU, 5/2 and ST, 8/11; disease stage at diagnosis (I/II/III/IV/postoperative recurrence): FU, 3/0/3/1/0 and ST, 0/1/7/9/2; and histology (small cell lung cancer/non-small cell lung cancer): FU, 1/6 and ST, 6/13. There were no significant differences in survival between the two groups (median progression-free survival [PFS; months], FU vs. ST=9 vs. 5, P=0.581; median overall survival [months], FU vs. ST=26 vs. 13, P=0.656). Analysis of prognosis showed significant differences only in disease stage at diagnosis based on univariate Cox analysis of PFS (I–III vs. IV or postoperative recurrence; hazard ratio, 3.440; 95% confidence interval, 1.16-10.22; P=0.026).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In patients with lung cancer that has progressed to brain metastasis alone, administration of systemic therapy may not be necessary until further disease progression after local treatment.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-102 - Potential Predictors of Unexpected Readmission After Lung Resection

      12:00 - 13:30  |  Presenting Author(s): Shinsuke Uchida  |  Author(s): Yukihiro Yoshida, Keisuke Asakura, Kazuo Nakagawa, Shun-ichi Watanabe

      • Abstract

      Background

      Postoperative unexpected readmissions are sentinel events that negatively impact patients. Previous analyses of risk factors of unexpected readmission after lung resection have identified several predictive factors. However, both the operative procedures and perioperative care can vary between institutions. The current study aimed to investigate the incidence levels and potential predictors of unexpected readmission after lung cancer surgery at our institution.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients who underwent lung resection for primary lung cancers between January 2016 and December 2017 at our institution were enrolled in this study. Operative procedures included pneumonectomy, lobectomy, segmentectomy, and wedge resection. Pleural biopsy and unresectable cases were excluded from this study. Unexpected readmissions were defined as an unscheduled readmission after surgery to our hospital. All patients were examined at our outpatient clinic within 14 days after initial discharge. Thirty-day readmission rates and diagnoses were edaluated. Univariate analysis was performed to identify perioperative factors associated readmission.

      4c3880bb027f159e801041b1021e88e8 Result

      During the 24-month study period, 1,000 patients underwent lung resection for primary cancer. The median age was 69 years (32–90 years). Fourteen pneumonectomies, 687 lobectomies, 193 segmentectomies, and 106 wedge resections were performed. The median length of postoperative hospital stay was 4 days (2–117 days). The 30-day mortality rate was 0.3% (3 of 1,000 patients). Forty-three patients (4.3%) experienced an unexpected readmission within 30 days after discharge. The median interval to readmission from the day of discharge was 10 days (1-29 days). The most common diagnoses for readmission were empyema (n=11; 26%), exacerbation of interstitial pneumonia (n=7; 16%), pneumothorax (n=7; 16%), and pneumonia (n=5; 12%). The median length of readmission hospital stay was 10 days (2–90 days). Among readmitted patients, 9.3% (4 of 43) had died in the hospital due to exacerbation of interstitial pneumonia. In a univariate analysis, significant factors (p<0.05) associated with increased risk of unexpected readmission were man, smoking history, diabetes mellitus, larger tumor size, positive lymph node, either lobectomy or pneumonectomy, longer operative time, either prolonged air leakage (i.e., more than 5 days) or reoperation for air leakage, longer hospital stay after initial surgery.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The unexpected readmission rate after lung resection was 4.3% (n=43), with respiratory complications (n=30; 70%) being the most common cause. Four patients (9.3%) died in the hospital due to exacerbation of interstitial pneumonia. Several perioperative factors were identified as risk factors for readmission in this study.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-103 - Efficacy of Crizotinib in Chinese Non-Small Cell Lung Cancer Patients with Brain Metastasis: A Multicenter Retrospective Study

      12:00 - 13:30  |  Presenting Author(s): Shouzheng Wang  |  Author(s): Puyuan Xing, Di Ma, Qiang Wang, Xuezhi Hao, Mengzhao Wang, Yan Wang, Li Shan, Tao Xin, Li Liang, Hongge Liang, Yang Du, Zhaohui Zhang, Junling Li

      • Abstract

      Background

      Brain metastasis in advanced non-small cell lung cancer (NSCLC) patients is often considered as a terminal stage. Crizotinib is a small-molecule tyrosine kinase inhibitor (TKI) for ALK-rearranged NSCLC patients. Herein we conducted a multi-center retrospective study to explore how crizotinib affects the control of brain metastasis and survival outcomes among advanced ALK-rearranged NSCLC patients with brain metastasis in Chinese population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed medical records of 484 unselected ALK-positive NSCLC patients treated with crizotinib at five cancer centers in China from January 2013 to November 2017. Patients developing brain metastasis either before or during the crizotinib treatment were enrolled. Survival outcomes were analyzed with Kaplan-Meier method and prognostic factors were analyzed with multivariate COX analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 174 patients were enrolled into this study, of whom 95 patients had baseline brain metastasis and 79 patients developed brain metastasis during crizotinib treatment. Among patients with baseline brain metastasis, the median intracranial progression-free survival (PFS) was 15.34 months [95% confidence interval (CI): 10.62-20.07] and median overall survival (OS) was 53.38 months (95%CI: 30.58-76.17). The intracranial objective response rate (ORR) was 17.1%, and the intracranial disease control rate (DCR) was 88.6%. Multivariate COX analysis revealed that patients receiving first-line crizotinib [>first-line vs. first-line, hazard ratio (HR): 2.44, 95%CI: 1.05-5.68, p=0.038], withtout intracranial progression during crizotinib treatment (with vs. without intracranial progression, HR: 18.68, 95%CI: 2.43-143.31, p=0.005) were associated with better OS, while age, sex, number of brain lesions, and operation/radiation therapy for brain metastasis were not significantly associated with OS. Among patients developing brain metastasis during crizotinib treatment, the median OS was 35.64 months (95%CI: not reached). Multivariate COX analysis revealed that brain progression only (brain progression only vs. both brain and extracranial progression, HR: 0.23, 95%CI: 0.08-0.71, p=0.011) was associated with better OS, while age, sex, line of crizotinib treatment, treatment after progression and operation/radiation therapy for brain metastasis were not significantly associated with OS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Advanced ALK-rearranged NSCLC patients with baseline brain metastasis could still benefit from crizotinib treatment. However, brain progression during crizotinib treatment may be associated with worse survival outcomes.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-104 - EGFR-RAD51 Fusion Variant in Lung Adenocarcinoma and Response to Erlotinib: A Case Report

      12:00 - 13:30  |  Presenting Author(s): Chunwei Xu  |  Author(s): Wenxian Wang, Wu Zhuang, Zhengbo Song, Yunjian Huang, Yanping Chen, Gang Chen, Meiyu Fang, Tang Feng Lv, Yong Song

      • Abstract

      Background

      The most frequent epidermal growth factor receptor (EGFR) mutations of lung cancer include exon 19 in deletion and the exon 21 L858R mutation. And EGFR-tyrosine kinase inhibitor (TKI) as the standard first line treatment show good response to classical/sensitizing EGFR mutations. With the development of detection methods, some uncommon genomic mutation events such as exon 18-25 kinase domain duplications (KDD) and EGFR rearrangements (EGFR-RAD51 or EGFR-PURB) are found. We reported a case of EGFR-RAD51 fusion in non-small-cell lung cancer(NSCLC) and the efficacy of erlotinib to this type fusion of NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A 48-year-old male diagnosed with adenocarcinoma (IV, T1N2M1), who was shown to have EGFR fusion by next generation sequencing.

      4c3880bb027f159e801041b1021e88e8 Result

      The patient with right lung tumor and multiple brain metastases NSCLC. Histological examination of surgical specimens from the brain tumor showed lung adenocarcinoma metastasis. By using next generation sequencing assay, we found that tumor had EGFR-RAD51 fusion rather than the most common kind of EGFR mutations. Then the patient experienced a remarkable tumor response to erlotinib. Considering this rare EGFR fusion and remarkable response to TKI treatment, we conclude that the incidence of EGFR fusions in NSCLC patients should be attentive. NSCLC patients with EGFR-RAD51 fusion gene response to treatment with EGFR inhibitor.

      8eea62084ca7e541d918e823422bd82e Conclusion

      With the guidance of precise diagnosis, it is important that we should realize other rare EGFR gene mutations and novel diagnostic method.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-105 - Retrospective Analysis of Efficacy and Safety in Chinese Elderly Patients Treated with Nab-Paclitaxel

      12:00 - 13:30  |  Presenting Author(s): Shuhang Wang  |  Author(s): Qiu Ping, Jun Zhao

      • Abstract

      Background

      Albumin-bound paclitaxel (nab-PC) could benefit advanced non-small cell lung cancer (NSCLC) either in first line or second line. However, the safety and efficacy in Chinese elderly population remains unclear. In this study, we retrospectively analyzed the efficacy and safety of nab-pc in Chinese elderly patients (≥65 year old) from a single cancer center.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively collected data from 75 patients who were treated with weekly nab-paclitaxel (125 or 130 mg/m2d1, d8) from Janurary 2010 to December 31, 2017 in Peking University Cancer Hospital. Among which, 33 patients were non-squamous NSCLC, and 42 patients were squamous NSCLC. Twelve of these patients received nab-paclitaxelas first line treatment (7 of which were combined with carboplatin) and 63 patients received single nab-paclitaxel as latter line treatment.

      4c3880bb027f159e801041b1021e88e8 Result

      Results: Sixty-eight out of 75 patients were available for efficacy evaluation, the overall objective response rate (ORR) was 13.1 (10/68), disease control rate (DCR) was 69.3%(52/68), median progression free survival (PFS) was 5.2 months and overall survival was 12.2 months in the entire population. For fist-line and latter line setting subgroup, the ORR, DCR, PFS and OS were 18.2% and 14.0%; 90.9% and 73.7%; 6.7 months and 5.0 months; 17.7 months and 12.2 months, respectively. For the patients ≥70 years old, the PFS significantly longer compared with patient <70 years old (6.3 months vs. 3.7 months p=0.021; the same trend was observed in OS, however the difference was not significant (13.3 months vs. 10.0 months, p=0.089). For all grade of adverse events (AEs), the most common AEs were leukopenia (37.3%, n=28), anemia (40%, n=30) fatigue (18.7%, n=14) and Peripheral neuritis (17.3%, n=13) which were all manageable, and the incidence of grade 3 were 13.3% (10/75), no grade 4 AEs were found and no AEs related death. Totally 7 patients discontinued treatment because of AEs. And the incidence of AEs was not different among subgroups of patients defined with age (65≤age<70, 70≤age<75 and age≥75).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The efficacy of nab-paclitaxel in Chinese elderly patients was desirable. The toxicity was tolerable and manageable. Patients over 70 may benefit more from nab-paclitaxel. Prospective clinical trials are expected to further confirm the results.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-106 - Real-World Data to Evaluate the Clinical Benefit of NGS for Directing Lung Adenocarcinoma Treatment

      12:00 - 13:30  |  Presenting Author(s): Zhaoxia Wang  |  Author(s): Binbin Lu, Guojian Liu, Tianwei Xu, Mingming Yuan, Rongrong Chen, Xuefeng Xia

      • Abstract

      Background

      Since mid-2017, multiple NGS-based companion diagnostic tests have been approved in NSCLC to select patients eligible for targeted therapy and immunotherapy. Here, we retrospectively analyzed the benefit of NGS for advanced lung adenocarcinoma in routine clinical practice.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From 2016 to 2018, the samples taken from 9 lung adenocarcinoma patients were sent to Geneplus-Beijing Institute for genetic testing. Mutation profiles were analyzed using hybridization capture based NGS, which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of at least 59 genes (range 59 – 1021 genes). The tumor response was evaluated using RECIST v1.1.

      4c3880bb027f159e801041b1021e88e8 Result

      Six tumor tissue samples, two blood samples and one pleural effusion sample were analyzed (Table 1). No actionable mutation was detected in patient 1 and then he left hospital without additional treatment. The KRAS mutation present in patient 2 suggested that he might be resistant to EGFR-TKIs. Therefore, he received chemotherapy. According to the genetic testing results, all the other patients received EGFR-TKIs and the disease control rate was 100% at the 2nd month. Apart from EGFR T790M mutation, EGFR amplification was present in patient 8 with disease progression following gefitinib therapy. She received osimertinib and achieved PR at the 2nd month. The response has maintained for over 7 months up to now, which made us reconsidering the controversial correlation between EGFR amplification and EGFR-TKI effectiveness. Rare EGFR mutation and MET amplification were detected in patient 9, and then he was treated with icotinib.The best response was SD at the 4th month. However, he died of pulmonary embolism or cerebral infarction, making the duration of response 4 months.

      Table 1. Clinical and genetic characteristics of 9 patients   
      Patient No Age/Gender Sample Previous Targeted Therapy Actionable Mutations Following Treatment Response Evaluation (2nd month) Duration of response (months)
      1 72/Male Blood No No No treatment Not applicable Not applicable
      2 62/Male Tissue No KRAS p.G12A, STK11 p.D53Gfs*110 Chemotherapy Not available Not available
      3 62/Male Tissue No EGFR p.L747_T751del (EX19del) Gefitinib PR 20+
      4 63/Female Tissue No EGFR p.L858R (EX21) Gefitinib PR 5+
      5 75/Female Tissue No EGFR p.L858R (EX21) Icotinib SD 11+
      6 63/Male Blood Icotinib EGFR p.L858R (EX21),CHEK2 c.445-1G>A Combined gefitinib and bevacizumab SD 6+
      7 79/Male Tissue No EGFR p.L747_T751del (EX19), NF1 c.587-1G>C, ATM c.2124+1G>T Gefitinib PR 2+
      8 80/Female Pleural effusion Gefitinib EGFR p.L858R (EX21), EGFR p.T790M (EX20), EGFR amplification Osimertinib PR 7+
      9 81/Male Tissue No EGFR p.G719A (EX18), MET amplification, CDK4 amplification Icotinib SD 4
      8eea62084ca7e541d918e823422bd82e Conclusion

      NGS-based genetic testing comprehensively predicts the effectiveness of targeted therapy. It can be widely used in routine clinical practice.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-107 - Correlation Study of Bone Metastasis and Cholesterol Level in Patients with Lung Adenocarcinoma

      12:00 - 13:30  |  Presenting Author(s): Yan Wang

      • Abstract

      Background

      To explore the correlation between bone metastasis and laboratory examination such as cholesterol level in patients with lung adenocarcinoma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Medical records were studied for patients who were admitted into this high-volume institution from Jan 1, 2017 to the present. 114 patients diagnosed and treated as esophageal squamous cell carcinoma with bone metastasis were retrospectively analyzed for the present study. Along with them were 114 patients without bone metastasis in the control group.

      4c3880bb027f159e801041b1021e88e8 Result

      There was no significant statistical difference between groups with respect to neutrophils count, lymphocyte count, monocyte count, bilirubin, calcium ion, phosphorus, or blood sugar. Univariable analysis found that total cholesterol levels (OR: 0.230; 95% CI: 0.064–0.822; P=0.024) and triglyceride levels (OR: 0.001; 95% CI: 0.000–0.201; P=0.012) , and Multivariate analysis indicated that triglyceride levels (OR: 0.001; 95% CI: 0.000–0.327; P=0.020) were independently associated with development of bone metastasis in patients with lung adenocarcinoma.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Triglyceride levels were independently associated with the development of bone metastasis in patients with lung adenocarcinoma.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-108 - Oncologist Treatment Considerations and Selection in EGFR M+ NSCLC

      12:00 - 13:30  |  Presenting Author(s): Vera Hirsh  |  Author(s): Thomas Wehler, Bernd Tischer, Steffen Reisgys

      • Abstract

      Background

      The treatment landscape for EGFR M+ stage IIIb/IV NSCLC has significantly changed in the past few years: at the end of 2015, 3rd generation TKI osimertinib was approved for the treatment of EGFR T790M+ NSCLC, and in 2018, osimertinib was approved for the first-line treatment of EGFR M+ patients. As such, there is much debate amongst oncologists around which TKI to prescribe to patients first, now that more targeted treatments are available. The aim of this study was to assess current attitudes towards decision making for TKI sequencing to determine what matters most when selecting a treatment and what challenges oncologists face.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A representative online survey was conducted with 310 HCPs (Oncologists, Pulmonologists, Respiratory Surgeons and Internal Respiratory Specialists) across four countries (China, Germany, Japan and USA) between April 2018 and May 2018.

      4c3880bb027f159e801041b1021e88e8 Result

      For all four countries and irrespective of treatment line, increasing overall survival (OS), followed by increasing quality of life (QoL) emerged as the most important treatment ambitions when prescribing TKIs. However, examination of treatment goals in the first-line setting revealed that clinically meaningful OS stands out for the US, Germany and Japan. In contrast for China, offering a clinically meaningful progression-free survival (PFS), OS, and improved health related QoL appear to be of equal importance.

      Predictability of treatment outcome in first-line therapy was also a relevant influence on treatment choice. This included a predictable pattern of resistance to TKIs for the majority of patients, efficacy in specific EGFR M+ subtypes, availability in flexible dose adjustment and if a compound was part of a sequence of targeted treatments which may delay time to chemotherapy.

      In terms of the sequencing of TKIs, 55% strongly prefer a treatment sequence offering maximum time on targeted therapies. Furthermore, there is a strong need across all countries for information on potential resistance mutations before changing current treatment practice – and over a third (36%) of all HCPs agreed that they do not feel they have all the data required to make informed decisions on how to sequence EGFR M+ NSCLC treatments.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The study confirms that increasing survival time across treatment lines is the overarching ambition when using TKIs in EGFR M+ NSCLC together with increasing QoL. In order to overcome uncertainties regarding the appropriate treatment decisions for patients EGFR M+ NSCLC, HCPs require more information about the possible impact of treatment sequencing on extending survival.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-109 - Real-World Patient-Reported Outcome Assessment of Patients with Metastatic Non-Small Cell Lung Cancer 

      12:00 - 13:30  |  Presenting Author(s): Loretta A Williams  |  Author(s): Seydeh Dibaj, Sheenu Chandwani, Viralkumar Bharatbhai Vaghani, Qiuling Shi, Meita Hirschmann, Lara Lacerda Landry, Emily Roarty, Jianjun Zhang, Waree Rinsurnogkawong, Jeff Lewis, Thomas Burke, Charles Cleeland, Jack Lee, Jack A Jack A. Roth, Stephen Swisher, John V Heymach, George R. Simon

      • Abstract

      Background

      Patient-Reported Outcomes (PROs) provide information on patient treatment experience. We have established a real-world Advanced Non-Small Cell Lung Holistic Registry (ANCHoR) to understand how the advent of immunotherapy impacts treatment choice, clinical outcomes, and PROs of metastatic non-small cell lung cancer (mNSCLC). The aim of this analysis is to report early results of baseline symptom status and quality of life among mNSCLC patients using the MD Anderson Symptom Inventory lung cancer module (MDASI-LC) and EuroQol-5D 5-level version (EQ-5D-5L).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      During 2017, patients with mNSCLC at a single institution were enrolled in ANCHoR and completed the PRO questionnaires at clinic visits. MDASI-LC consists of thirteen core and three lung cancer-specific symptom severity questions, and six interference items rated on 0-10 scales (0 = no symptom or interference, 10 = worst imaginable symptom or complete interference). EQ-5D-5L captures five health state dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression rated on a five-level scale (1= no problems, 5= extreme problems). A single visual analogue scale (VAS) on EQ-5D-5L records patient self-rated health between ”best imaginable” (100) and “worst imaginable” (0) health state. Descriptive statistics for PRO scores at baseline are summarized.

      4c3880bb027f159e801041b1021e88e8 Result

      Forty-two patients completed baseline PROs before the start of therapy. Mean patient age was 63 years and 45% were males. For MDASI-LC, the mean scores for the core symptom, lung cancer-specific symptom, and interference subscales at baseline were 2.2 (standard deviation [SD] = 2.80), 2.1 (SD = 2.80), and 2.8 (SD = 3.10), respectively. Fatigue was the most severe symptom reported at baseline (mean = 4.1, SD = 3.01), followed by shortness of breath (mean = 3.2, SD = 2.81) and pain (mean = 3.19, SD = 3.00). The highest percentages of patients reporting moderate to severe symptom levels (score of ≥5) were 38% for fatigue, 33% for pain, 31% for drowsiness, 29% for shortness of breath and disturbed sleep, and 26% coughing. For EQ-5D-5L, 91% of patient reported problems with self-care, 81% with mobility, 48% with usual activity and anxiety, and 33% with pain. Mean EQ-5D VAS was 73.9 (SD = 18.2).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Prior to the start of treatment, fatigue, pain, drowsiness, disturbed sleep, and coughing were the most common symptoms with fatigue, shortness of breath, and pain being the most severe. Additional follow up will confirm and expand these findings and will also allow us to examine change in PROs after first-line treatment is administered.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-110 - Defining Aggressive Disease in Patients With Advanced NSCLC Receiving Second-Line Treatment: A Systematic Review

      12:00 - 13:30  |  Presenting Author(s): Cliff Molife  |  Author(s): Katherine B Winfree, Claire Ainsworth, Annete Njue, Matthew Lyall, Min-Hua Jen, Marisa Bittoni, Anne Heyes, David P Carbone

      • Abstract

      Background

      Recent randomized clinical trials (RCTs) have explored survival benefits of second-line treatments (2LTs) in patients who have rapidly progressed and/or are refractory to first-line treatment, and these trials have determined an existing unmet need for these patients with aggressive non-small cell lung cancer (NSCLC). However, specific characterization of aggressive NSCLC is lacking, thus a systematic literature review was conducted to explore the definitions of aggressive NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We systematically searched Medline, Embase, BioSciences Information Service, the Cochrane Library, and abstracts from scientific meetings (through October 2017) to identify RCTs reporting the efficacy and/or safety of select 2LTs in patients with advanced NSCLC who have characteristics associated with aggressive disease (AD). Six potential overarching categorizations of these characteristics (based on expert clinical opinion) were explored: (1) refractory and/or progressive disease as best response to prior treatment, (2) rapid progression, (3) short duration on previous treatment, (4) high tumor burden or size, (5) short duration since start of last treatment, and (6) high symptom burden.

      4c3880bb027f159e801041b1021e88e8 Result

      The 14 identified studies had one or more subgroups within five of the six categorizations (11, 2, 1, 2, and 4 studies presented subgroups within categories 1-5, respectively). No RCTs presenting a subgroup of patients for category 6 were identified. Within each category, the identified subgroup definitions varied (15, 4, 3, 2, and 7 different definitions within categories 1-5, respectively). Reporting of whether a subgroup was prespecified or not was limited and often unclear; 6 studies indicated that subgroup analyses of patients with AD characteristics were preplanned. Moreover, baseline characteristics for the subgroup of patients with AD were often not reported.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Definitions of AD varied, both across the identified studies of 2LTs and within the predetermined categorizations, with refractory being the most frequent followed by short duration since start of last treatment. With the emerging clinical importance of AD, more standard use of these definitions within RCTs may allow for greater comparison across 2LTs and will enable indirect treatment comparisons of the results. As with any subgroup, clarity on preplanned versus post hoc analysis is important for interpretation and should be specified. Additional studies powered to assess treatment benefits in advanced NSCLC patients with AD are needed.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-111 - Efficacy and Safety of Cytotoxic Drug Chemotherapy After First-Line EGFR-TKI in Elderly Patients with NSCLC Harboring Sensitive EGFR Mutations

      12:00 - 13:30  |  Presenting Author(s): Yutaka Yamada  |  Author(s): Hisao Imai, Tomohide Sugiyama, Hiroyuki Minemura, Kyoichi Kaira, Kenya Kanazawa, Takashi Kasai, Takayuki Kaburagi, Koichi Minato

      • Abstract

      Background

      Subsequent therapies confound the ability to discern the effect of first‑line chemotherapy on overall survival (OS). Therefore, the objective of our study was to determine the relationships between progression-free survival (PFS) or post-progression survival (PPS) and OS after first-line EGFR-TKI treatment in , using individual level data.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between April 2008 and December 2015, we analyzed 68 cases of elderly patients with NSCLC harboring sensitive EGFR mutations treated with first-line EGFR-TKI. The relationships between PFS and PPS with OS were analyzed at an individual level.

      4c3880bb027f159e801041b1021e88e8 Result

      PPS was more closely associated with OS (R2 = 0.54) compared to PFS (R2 = 0.48), based on linear regression. Best response at first-line treatment, PS at the end of first-line treatment and administration of EGFR-TKI rechallenge were significantly linked to the PPS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      PPS has a stronger impact on OS than PFS in elderly patients with NSCLC harboring sensitive EGFR mutations treated with first-line EGFR-TKI. fluenced by treatments subsequent to first-line chemotherapy; however, this remains to be verified with prospective studies.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-112 - The Prognosis of Lung Cancer Patients with Unexpected Malignant Pleural Effusion and Without Pleural Dissemination Detected at Thoracotomy

      12:00 - 13:30  |  Presenting Author(s): Takashi Yamamichi  |  Author(s): Masahiko Harada, Ayaka Asakawa, Masayuki Okui, Hirotoshi Horio

      • Abstract

      Background

      Generally, primary lung cancer patients with malignant pleural effusion are not candidate for surgery. But in cases, we have no choice but to perform the surgery for biopsy, prevention for obstructive pneumonitis. We analyzed the surgery for lung cancer patients with unexpected malignant pleural effusion retrospectively.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed the patients with unexpected malignant pleural effusion and without pleural dissemination detected at thoracotomy underwent surgery in our hospital from 2003 to 2017. Pleural effusion was almost small amount (<50ml), and we included the cases that pleural effusion was malignant in the final report however it was suspicious in intraoperative report. Patient demographics, comorbidity, pathological findings, surgical approach, number of lymph nodes harvested, overall survival were evaluated retrospectively. Overall survivals were analyzed with the Kaplan–Meier method and prognostic factors were analyzed with the Cox proportional hazards model.

      4c3880bb027f159e801041b1021e88e8 Result

      24 patients underwent resection for NSCLC. The median age was 71 years old (56-79 years old) and 7 cases were male. Pleural effusions of all patients were taken before resection and submitted for rapid diagnosis. The reason we performed surgery was because we judged that we could perform surgery because of pulmonary nodule diagnosis and prevention of obstructive pneumonitis and so on. Surgical procedures were lobectomy in 15 cases, segmentectomy in 1, wedge resection in 8. The median size of resected nodule was 2.7cm (1.1cm-10.0cm). Histological types of lung cancer were adenocarcinoma in 21 cases, squamous cell carcinoma, adenosquamous carcinoma and small cell carcinoma each in 1. There was no surgical-related death or severe complications. The median follow-up time was 40 months and median survival was 66 months. At 5 years after pulmonary resection, 9 patients (38%) were dead. 5-year survival was 59.7% and 70.0% at cT1-2N0 patients, respectively. In a previous report, 5-year survival on resected stage I patients was almost 75%, and it is almost as good prognosis as our cT1-2N0 patients. Univariate analysis of gender, age, lymph node dissection, pathological findings (PL, ly, v, histology), surgical procedure and Brinkman Index were performed. Only PL0 or 1 was revealed as a prognostic factor (HR=0.12, p=0.049).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The prognosis after surgery of lung cancer patients with unexpected malignant pleural effusion and without pleural dissemination may be better than expected and PL0 or 1 was thought as a prognostic factor. Thus, subsequent analysis should be performed to identify patients who could benefit from surgery.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-113 - A Multicenter Survey of One Year Survival Among Chinese Patients with Advanced Nonsquamous Non-Small Cell Lung Cancer (CTONG1506)

      12:00 - 13:30  |  Presenting Author(s): Qing Zhou  |  Author(s): Ping Yu, Yong Song, Xin Zhang, Gongyan Chen, Yi Ping Zhang, Jianhua Chen, Zhuang Yu, Yi Hu, Xia Song, Diansheng Zhong, Guosheng Feng, Lulu Yang, Lujing Zhan, Luan Di Yao, Yun Chen, Yue Gao, Yi-Long Wu

      • Abstract

      Background

      Previous results of CTONG1506 study showed that gene aberration test rate was increasing in Chinese NSCLC patients and first-line treatment was standardized accordingly. This survey further described one year survival of patients with different gene aberration status and under different first-line treatments.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      CTONG1506 was a two-year series cross-sectional study. Patients with advanced nonsquamous NSCLC who were admitted from August 2015 to March 2016 and who received first-line anti-cancer treatment at one of 12 tertiary hospitals across China were included. Data extracted from medical charts were entered into medical record abstraction forms, which were collated for analysis. Survival information was collected one year after patients were admitted to hospital. One year survival rate and its 95% confidence interval were analysed by Kaplan-Meier method.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 707 patients were analysed, with mean age of 57 years and 56.7% were male. Among the 487 patients who had survival data, 192 were EGFR- mutation positive (86 mutated in exon 19 [one year survival rate 0.90, 95% CI: 0.81-0.94] and 88 mutated in exon 21 [one year survival rate 0.84, 95% CI: 0.75-0.90]), 27 patients were ALK positive and 164 patients were EGFR and ALK wild type. Most EGFR mutation positive patients (128/192) received tyrosine kinase inhibitors (TKIs) as first-line treatment and most EGFR wild type patients (155/175) received first-line chemotherapy (Chemo). Pemetrexed was the most common non-platinum chemotherapy-backbone agent (120/155) in platinum doublet regimens. One year survival rates are shown in the table.

      abstract 12337 ctogn1506 one-year survival.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      This national-wide real world study of tertiary hospitals in China revealed that a majority of (>75%) advanced nonsquamous NSCLC patients survived more than one year and was comparable to well-controlled clinical trial results, indicating survival benefits by gene aberration status guided standard of care. This result may be further validated by our on-going two-year survey.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-114 - Dissociation of Heart and Great Vessels for Long Tracheal Tumors and Lung Cancer Invaded Trachea: The Chinese Experience.

      12:00 - 13:30  |  Presenting Author(s): Qinghua Zhou

      • Abstract

      Background

      The length limit of tracheal resection is less than five centimeters. Up to know, there is no any report about resection of more than five centimeters for tracheal tumors. We created a new technique and successfully remove 124 tracheal tumors more than 5 cm in length and 52 lung cancer invaded trachea through dissociation heart and great vessels. Here, we report the results of 176 patients surgically treated in series.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All patients were given general anesthesia and single cavity endotracheal intubation. After thoracotomy, the right pericardium was totally excised, the heart, inferior vena cava, superior vena cava, ascending aorta and innominate artery were dissociated. Then, thoracic trachea, left and right main bronchus were dissociated; the proximal and distal end of trachea, or left and right main bronchus, or left main bronchus and right middle trunk bronchus were cut off. Fallowing, the distal end of trachea was anastomosed to the proximal end of trachea, or anastomosed to the left and right main bronchus, or anastomosed to the left main bronchus and right middle trunk bronchus with 3-0 micro Joe lines. Finally, the pulmonary artery sleeve reconstruction was performed, and resection and reconstruction of SVC was performed.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 124 patients with tracheal tumor over than 5cm in length and 52 patients with lung cancer invaded trachea. The length of trachea tumor was 5.5 cm to 10.9 cm. 5 tracheal tumor involved SVC and combined with SVCS. The trachea length invaded by the cancer was 4.5cm-7.0cm in the 52 patients with lung cancer. Of the 52 cases, 10 cancer invaded right main pulmonary artery, 22 cancer involved right main pulmonary artery and SVC. The operative procedures included: (1) resection and reconstruction of trachea, or combined with carina in 124 cases, and combined with resection and reconstruction of SVC in 5 cases in the tracheal tumor group; (2) Sleeve right upper lobectomy combined with resection and reconstruction of trachea and carina in 52 cases, combined with sleeve pulmonary artery in 10 cases, combined with sleeve pulmonary artery, and resection and reconstruction of SVC in 32 cases of lung cancer group. There were 5 operative death in this series. The 1-, 3-, 5- and 10-year survival were 71.2%, 54.3%, 33.1% and 22.5%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We pioneered a new technique and treated 124 tracheal tumor more than 5 cm in length and 52 lung cancer invaded trachea in the world.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-115 - Liposomal Paclitaxel Versus Gemcitabine: Which is Better?

      12:00 - 13:30  |  Presenting Author(s): Xiangdong Zhou  |  Author(s): Liu Pan, Liang Lan

      • Abstract

      Background

      Lung cancer tends to metastasize to lymph nodes in the early stage.The liposomal Paclitaxel(LP) injection has less side effects and higher uptake.It is also characterized as being able to target to organs with rich reticuloendothelial system and keeping a high concentration for a long time. We assume that LP injection has a better curative effect against NSCLC with regional lymph node metastasis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients divide to 58 for LP and 56 for Gemcitabine plus cisplatin (GP).Those patients have good comparability in gender,age,ECOG points,pathological pattern,TNM staging and chemotherapy cycles.21 days as a single cycle, each patient finished at least 2 cycles. Estimation was carried on within one week when they have finished the chemotherapy. Chemotherapy Continues if the result turns out CR+PR+SD. surgical treatment would be suggested if the stage of cancer decreases and the lesions of NSCLC turn technically removable. Then continue chemotherapy after surgery, 4 to 6 cycles in total.

      4c3880bb027f159e801041b1021e88e8 Result

      The alleviation rate of lymph nodes metastasis in LP group is significantly higher.The disease control rate of lymph nodes metastasis is 96.551% vs. 92.857%, p=0.38.The alleviation rate of squamous cell carcinoma and the disease control rate is not statistically significant. The alleviation and disease control rate of primary tumor in LP and GP group does not have statistical significance.And among LA patients,it the same trend.
      The LP group has a longer period without disease progression and a higher survival rate in 1 year than the GPgroup.The medium PFS of squamous cell carcinoma in 5 LP group is 8 months which is higher than that in GP group (5.5 months) but does not have statistical significance. The survival rate in 1 year of squamous cell is 50% (16/32).

      The PFS of IIIB stage in LP group is 10 months, significantly higher than GP group(4 months),survival rate in 1 year in LP group is also higher but is not statistically significant.

      As to side effect, the LP group is significantly lower in the incidence of thrombocytopenia, granulocytopenia, anemia and white blood cell reduction.However, the LP group is higher incidence of alopecia.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Chemotherapy with LP has higher alleviation rate than chemotherapy with GP in treating advanced NSCLC with regional lymph node metastasis, especially for squamous cell carcinoma. The survival rate and PFS in stage IIIB/IV of LP is also higher than that of GP. Meanwhile, LP is able to reduce the incidence rate of side effects such as hrombocytopenia, granulocytopenia,anemia, white blood cell reduction, nausea and vomiting.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.01-116 - Randomized Clinical Trial on Three Different Platinum Based Chemotherapy in Advanced NSCLC in Bangladeshi Population

      12:00 - 13:30  |  Presenting Author(s): Ferdous ARA Begum  |  Author(s): Nazrina Khatun, Parveen Shahida Akhtar, A S M Fazlul Karim Chowdhury, Md. Arifur Rahman, Qamruzzaman Chowdhury

      • Abstract

      Background

      Lung cancer constitutes the major mortality in the world and incidence of the disease varies considerably among different ethnic population throughout the world. Palliative chemotherapy has been a choice in advance Non-Small Cell Lung Cancer (NSCLC) due to better result. The primary objective of the study was to evaluate the response and toxicity of three different platinum based regimens in Bangladeshi people.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This Randomized Clinical Trial (RCT) was carried out in the Department of Medical Oncology at National Institute of Cancer Research & Hospital (NICRH), Mohakhali, Dhaka. Patients were enrolled from January 2012 for one year. Total 90 patients with above 18 years of age, both sexes presented with histologically confirmed stage IIIA, IIIB & IV NSCLC were enrolled and randomized (1:1:1) in to three arms. Cumulatively 26 patients were lost to follow up.

      Chemotherapy was given in 21 days interval (4-6 cycles). Toxicities were measured on Day 1, 7, 21, 28, 42, 3 months and on 6 months. Median follow up period was 6 months. Survival data was estimated by Kaplan-Meier method.

      4c3880bb027f159e801041b1021e88e8 Result

      Significant G-1/2 Hb% was found in Day7 in TP (16.67%) and EP (10.52%) arm and in 6 months EP (31.58%) & TP (29.17%). WBC G-1/2 toxicity was found in EP (31.58%) & TP (20.83%) arm at 6 months. Similarly, in case of neutropenia and thrombocytopenia, GP arm was found to be significantly less toxic than TP and EP arm at 6 months. Response rate and survival data are provided in table 1.

      response rate and survival table wclc.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      In locally advanced or metastatic NSCLC response rate of platinum based combination therapy was satisfactory with increased survival than other reference trials along with lower G1/2 toxicity in GP arm followed by TP and EP in Bangladeshi Ethnic population.

      6f8b794f3246b0c1e1780bb4d4d5dc53

  • +

    P3.03 - Biology (Not CME Accredited Session)

    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Moderators:
    • +

      P3.03-01 - BRAF V600 and Non-V600 Mutations in Chinese Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Yang Gao  |  Author(s): Ruimin Chang, Jiaojiao Huan, Xiaoxiong Xiao, Yongchang Liu, Yanwu Zhou, Linfeng Li, Yuanda Cheng, Chunfang Zhang, Pingping Dai, Yanfang Guan, Xin Yi, Xuefeng Xia, Ling Yang

      • Abstract

      Background

      BRAF gene mutation, especially V600E, was frequently mutated in cancer. Vemurafenib and dabrafenib has already been approved in melanoma as well as NSCLC and preclinical studies have demonstrated promising results in non-V600 NSCLC. But the landscape of BRAF non-V600 mutation in Chinsese lung cancer was rarely descripted.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      7,417 normal-paired samples from lung cancer patients were analyzed using hybridization capture-based next generation sequencing and alterations including single nucleotide variants (SNVs), short insertions/deletions (indels), copy number variations (CNVs) and structural variations (SV) were analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      BRAF was altered in 1.8% (133 of 7,417) of all tumors. BRAF V600 (gain of function, GOF) and non-V600 mutations (GOF: G469V/R/E/A, K601N/E, L597V/R, T599dup/T599R, N486_P490del, L525R, and loss of function/LOF: D594N/G, N581S/I, G466V/A, K483E, G596R), has previously been reported to increase MEK/ERK activation, were detected in 52.3% (58/111) and 47.7% (53/111) of BRAF functional mutation patients. CNVs and SVs were both observed at a frequency of 0.9% (1/111). Two patients have two GOF mutations (V600E/T599R). We also found that 82.0% (91/111) of the BRAF functional mutation carriers also owned the other actionable or driver mutation, the most frequent one was TP53 (68.1%), then was EGFR (18.7%), KRAS/NRAS (14.3%), PIK3CA (11.0%) as well as CDKN2A/B (9.9%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      BRAF gene mutations, non-V600 especially, was extensively mutated in Chinese lung cancer. This work supports a broad profiling approach in lung cancers and suggests that non-V600E BRAF alterations represent a subgroup of lung cancers in which targeted therapy should be considered.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-02 - Single-Cell RNA-Seq in Human Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Jinhong Kim  |  Author(s): Zhaolin Xu, Paola A Marignani

      • Abstract

      Background

      Lung cancer has the highest mortality rate amongst cancers primarily due to delay of diagnosis. Until recently, the focus on genomic and transcriptomic characterization of lung cancers has guided to the diagnosis and treatments of the cancers. Although RNA sequencing (RNA-seq) has been used for transcriptome profiling in cancer research, few studies have employed single cell (sc) RNA-seq approaches to investigation of the heterogeneity among individual cells directly isolated from resected surgical human lung cancer tissues. The aim of our work is to identify new biomarkers indicating early stage versus late stage of lung cancers. As an initiative step, the current study presents a profile of differentially expressed genes (DEG) of single cells of lung cancer tissues collected from diverse lung cancer patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tumours resected from lung cancer patients were prepared for scRNA-seq. Microfluidic system, C1 (Fluidigm), was used to capture individual cells, and full-length cDNAs (FL-cDNA) were synthesized in the system. Next-generation sequencing (Illumina) of FL-cDNA libraries generated sequence reads from transcriptomes of single and bulk cells, respectively. Following read mapping, DEGs were selected by >2x fold-change difference in normalized expression values. qPCR was employed to validate transcriptional changes in selected DEGs comparing expression values resulted from scRNA-seq and bulk RNA-seq. Both gene set enrichment and signaling pathway analyses were used to identify mechanism of action for validated DEG-encoding molecules.

      4c3880bb027f159e801041b1021e88e8 Result

      Raw scRNA-seq datasets were processed for read mapping. More than 1 million processed reads per single-cell FL-cDNA library were used for DEG selection. We examined standard deviation of normalized expression value per selected DEG to characterize transcriptomic features of individual tumour cells. We identified a minimum of a dozen DEGs showing certain fold-change differences in each stage of lung cancers. Selected DEGs were validated by qPCR whereby unique patterns of gene expression at specific stages were confirmed.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The heterogeneity of lung cancers coupled with late stage diagnosis contributes to poor outcomes. The advent of scRNA-seq allows for the identification of differential gene expression and stage-specific markers that can be used to improve our understanding of highly complex intratumour heterogeneity in lung cancers. In the future, our discoveries will lead to the development of targeted therapies based on validated DEGs, ultimately allowing for early diagnosis, treatment and improved lung cancer survivorship.

      PAM is supported by CCSRI-i2I and DMRF.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-03 - Differential Microbiota Features in Lung Tumor and Adjacent Normal Tissues in Lung Cancer Patients

      12:00 - 13:30  |  Presenting Author(s): Qixing Mao  |  Author(s): Jianzhong Hu

      • Abstract

      Background

      Emerging evidence has demonstrated the link between the host microbiota and varied malignancies, including colorectal, gastric, hepatocellular, and pancreatic cancers. However, for lung cancer, one of the leading cause of the cancer-related morbidity and mortality worldwide, the interplay between the lung cancer and the lung microbiome has yet not been well investigated. In this study, we surveyed and compared the microbiota composition and diversity in paired tumor and adjacent normal tissues to test whether any tumor specific microbial features can be identified in tumor tissues.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We surveyed the microbiota composition of 55 lung tumor and 55 paired adjacent normal tissue samples using bacterial 16S sequencing protocol. The microbial diversity was further analyzed using QIIME pipeline. The differential taxa feature by tumor status was selected using LefSe method.

      4c3880bb027f159e801041b1021e88e8 Result

      We observed diversified microbiota in lung tissue samples. The dominant phyla include Proteobacteria, Firmicutes, Bacteroidetes and Actinobacteria. The overall microbiota similarity in paired tumor and adjacent tissues was significantly higher than unpaired (p<0.01). Compared to adjacent normal tissues, the lung tumors showed significantly lower alpha diversity (p=0.05) but no difference in beta diversity (PERMANOVA test, p-value=0.27). At taxa level, tumor samples showed increased Modestobacter and decreased Propionibacterium, and Enterobacteriaceae.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In conclusion, our study demonstrated and compared the lung microbiota diversity and composition in paired tumor and adjacent normal tissues. Compared to non-tumor tissues, the reduction of potential pro-inflammatory microbial families/genera in tumor tissues suggest the possible link between the tumor microbiota to the immunosuppression tumor microenvironment.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-04 - Is the Ciliary Function of the Lesion Bronchus Maintained in Patients with Lung Cancer?

      12:00 - 13:30  |  Presenting Author(s): Toshiyuki Sawa  |  Author(s): Tsutomu Yoshida, Takashi Ishiguro, Akane Horiba, Yohei Futamura, Shigekuni Hosogi, Takashi Nakahari

      • Abstract

      Background

      In patients with lung cancer, infections of the lower respiratory tract are often complicated, while It is not known whether ciliary function will be maintained in lung cancer lesion bronchus.

      We reported the newly developed simple method to evaluate patients bronchial mucoculliary movement using bronchoscopic sample. To evaluate human bronchial ciliary movement in the patients with lung cancer, the ciliary beat frequency (CBF) and amplitude (CBA) and drug reaction of bronchodilator were examined by our method using bronchoscope sample which collected in the transbronchial biopsy for the diagnosis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Objective: Fifty eight patients with lung cancer were enrolled who had met the following eligibility criteria. 1) necessity of bronchoscopic biopy by the medical reason, 2) Adult and written informed consent, 3) tolerable organ function to perfume bronchoscopy.

      Method: When the bronchoscopy was performed in the patients with respiratory disease, bronchial lavage to the transbronchial biopsy site was examined to collect peripheral bronchial epithelial cells.

      After ciliary motion were observed to identify with microscopy, the cilliary beat were captured at 240 frames per second using a high-speed photographing function of the general-purpose digital video camera on the market. After inhalation of clinical dose of bronchodilator (tiotropium + Olodaterol or Fluticasone / Formoterol) the cilliary beat were captured again. By software analysis, frequency and amplitude of the ciliary movement was measured.

      4c3880bb027f159e801041b1021e88e8 Result

      There were cases in which epithelial cells could not be collected, 50 of 58 cases were able to analyze ciliary function. Ciliary epithelium in the patients with lung cancer was confirmed in the amplitude of 4 ~ 8μm and frequency of 5 ~ 20bps.

      It was observed that ciliary movement is significantly. activated by inhale bronchodilater, from 6.6 to 8.4 beat per second as frequency, and from 6.0 to 6.5 micrometer as amplitude.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Even in lung cancer lesion bronchus of the patients, ciliary function was maintained and it was shown that ciliary function will be activated by drug stimulation.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-05 - Comparative Transcriptomic Analysis of Lung-iPSC, NSCLC, and SCLC: Potential Implications for iPSC Modeling of Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Vivek Shukla  |  Author(s): Kaitlin C McLoughlin, James Gao, Yonghong Wang, Julie Hong, Mary Zhang, Lisa Gesumaria, Haobin Chen, David S Schrump

      • Abstract

      Background

      In addition to having broad applicability as cellular therapies in regenerative medicine, transplantation and oncology, induced pluripotent stem cells (iPSC) may be useful models for studying a variety of benign and malignant diseases. Presently, limited information is available pertaining to the potential utility of iPSC for investigating epigenetic mechanisms of pulmonary carcinogenesis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In the present study, RNA- seq techniques were used to examine gene expression profiles in 2 lung-iPSC (Lu-iPSC) clonesderived from normal human small airway epithelial cells (SAEC), 10 SCLC lines, and 10 NSCLC lines relative to SAEC.

      4c3880bb027f159e801041b1021e88e8 Result

      Using criteria of 2 fold change and FDR< 0.05, 6318, 12051, and 6504 genes were differentially expressed in Lu-iPSC, SCLC, and NSCLC lines, respectively. A substantial number of differentially expressed genes (44% total) in Lu-iPSC were unique to these cells. Approximately 1/3rdof genes differentially regulated in Lu-iPSC were modulated in a histology specific manner. 1515 genes representing 24%, 12%, and 23% of differentially expressed genes in Lu-iPSC, SCLC, and NSCLC lines, respectively, were commonly regulated across Lu-iPSC, SCLC and NSCLC. Top canonical pathways included cell cycle control of chromosomal replication and mitotic roles of Polo-like kinases (up-regulated), and granulocyte adhesion and role of cytokines in mediating communication between immune cells (down-regulated). 3499 genes were uniquely regulated in SCLC and NSCLC. 1937 genes were uniquely modulated in SCLC and Lu-iPSC; top canonical pathways included GABA receptor signaling and CREB signaling in neurons (up-regulated), and TREM1 signaling and IL-15 production (down-regulated). Only 102 genes were uniquely modulated in Lu-iPSC and NSCLC; top canonical pathways included tight junction signaling and hepatic fibrosis/hepatic stellate cell activation (up-regulated) and neurotrophin/TRK signaling and PTEN signaling (down-regulated). Differential gene expression signatures and associated pathways suggested that Lu-iPSC more closely reflect SCLC rather than NSCLC. To further examine similarities in epigenetic regulation of gene expression in Lu-iPSC and lung cancers, RNA-seq was performed on Lu-iPSC grown in the presence or absence of Decitabine (0.1µM x 72h). Expression levels of 885 genes were significantly altered by DAC; inflammatory cascades predominated the top canonical pathways. Additional pathways included nuclear excision repair, cell cycle control, DNA methylation and transcriptional repression, and transcriptional regulation of stem cells.DAC-mediated gene signatures in Lu-iPSC did not appear to overlap with SCLC or NSCLC signatures.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Collectively, these findings have potential implications regarding the use of Lu-iPSC models for examining lung cancer associated epigenetic events, and the development of epigenetic regimens for lung cancer therapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-06 - Differentially Expressed microRNAs in Lung Adenocarcinoma Invert Effects of Copy Number Aberrations of Prognostic Genes

      12:00 - 13:30  |  Presenting Author(s): Tomas Tokar  |  Author(s): Chiara Pastrello, Varune R. Ramnarine, Chang-Qi Zhu, Kenneth J. Craddock, Larrisa A. Pikor, Emily A. Vucic, Simon Vary, Frances A Shepherd, Ming Sound Tsao, Wan Lam, Igor Jurisica

      • Abstract

      Background

      Significant associations between chromosomal copy number aberrations (CNAs) and differential gene expression have been found across many cancers. However, significantly downregulated genes have been often found to reside within chromosomal regions with increased number of copies and vice versa, creating a paradoxical signal. This phenomenon was usually ignored as a noise, but can potentially be a consequence of interference of other regulatory mechanisms controlling mRNA transcription.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To explore existence of such paradoxes in lung adenocarcinoma (LUAD), we performed integrative analysis of 1,937 tumour and normal tissue samples, comprising copy number aberrations, gene expression and microRNA expressions data and conducted meta-analysis of 9 microRNA expression studies.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified and validated 75 “paradoxical” genes whose differential expression consistently contrasted with aberrations of their copy numbers. Of these, 41 genes (p < 0.001) are prognostic and form a clinically relevant signature. Interestingly, differential expression of 19 microRNAs that are frequently deregulated in LUAD, explains observed paradoxes.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results show that deregulation of paradoxical genes is crucial in LUAD and their expression pattern is maintained epigenetically, defying gene copy number status. Our work highlights importance of large integrative analysis of diverse biological data and the need to examine phenomena that contrast the established knowledge.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-07 - Co-Occurring Genomic Alterations in EGFR Altered Chinese Lung Adenocarcinoma Patients

      12:00 - 13:30  |  Presenting Author(s): Minghui Wang  |  Author(s): Hong Zhong, Lei Dai, Lei Wang, Peng Shen, Yu Wang, Da Jiang, Min Zheng, Duoguang Wu, Fang Shi, Kefeng Wang, Chunjie Li, Hui Chen, Yu-An Dong, Weiwei Shi, Kai Wang, Ming Yao

      • Abstract

      Background

      EGFR mutation is one of the most common driver gene mutations in non-small cell lung cancer (NSCLC) patients, especially in adenocarcinoma. Increasing numbers of rare alterations of EGFR such as kinase domain duplication and fusion have been identified with the clinical applications of next generation sequencing (NGS). However, co-occurring genomic alterations of EGFR have not been fully understood in Chinese lung adenocarcinoma patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      FFPE tumor and matched blood samples of 989 Chinese patients with confirmed histology subtype of adenocarcinoma, consisting of 503 males and 486 females with a median age of 60 years, were collected for NGS-based 450 cancer genes panel assay. Genomic alterations including single nucleotide variations (SNV), short and long insertions/deletions (Indel), copy number variations (CNV) and gene rearrangements in selected genes were assessed.

      4c3880bb027f159e801041b1021e88e8 Result

      About 57% of Chinese lung adenocarcinoma patients harbored at least one EGFR genomic alteration, which was mainly composed of patient with SNVs and Indels (74%), both gene amplifications and SNVs/Indels (23%), gene amplifications only (2.7%) and gene rearrangements (0.5%). 20% of the patients with SNVs and Indels in EGFR carried more than one EGFR mutations. Moreover, EGFR gene rearrangement was mutually exclusive with other types of genomic alterations.

      Exon 19 deletions and L858R substitution were the most common EGFR mutations, which accounted for 37.9% and 33.7% of all EGFR alterations, respectively. Exon 20 insertions, the mostly insensitive variant to EGFR-TKIs, amounted to 3.7%, and the most common resistant alteration T790M accounted for 5.9%. Uncommon EGFR mutations including L861Q, G719X, S768I and others were identified in 18.9% of patients with EGFR mutations.

      Further analysis of co-occurring EGFR mutations and kinase receptor fusions revealed that 1.1% (6 of 559) of EGFR mutated Chinese NSCLC patients harbored both EGFR mutations and known druggable kinase receptor fusions including ROS1, RET and NTRK. Three of the six patients received EGFR-TKI as the standard treatment. One patient achieved partial response for 10 months and two achieved stable disease for 5 and 4 months, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      About 38% of Chinese lung adenocarcinoma patients harbored more than one EGFR genomic alterations, and 19% of EGFR mutations identified in Chinese lung adenocarcinoma patients were uncommon mutations. In addition, 1.1% of EGFR mutated patients also harbored known druggable kinase receptor fusions. Though our preliminary data showed that the co-existence of EGFR mutations and kinase receptor fusions might be associated with shorter response time to EGFR-TKIs, further large cohort study is needed to validate this finding.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-08 - Analysis of ESR1 Mutation Spectrum from Non-Small-Cell Lung Cancer in Chinese Patients

      12:00 - 13:30  |  Presenting Author(s): Chunwei Xu  |  Author(s): Wenxian Wang, Quxia Zhang, Wu Zhuang, Youcai Zhu, Yunjian Huang, Yanping Chen, Gang Chen, Meiyu Fang, Tang Feng Lv, Yong Song

      • Abstract

      Background

      A number of studies have documented that estrogen receptor alpha (ESR1) may play an important role in the development and progression of breast cancer. While the genetic variability of ESR1 mutation NSCLC patients is unclear. The aim of this study is to investigate mutations and prognosis of NSCLC harboring ESR1 mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 501 patients with non-small-cell lung cancer were recruited between July 2012 and December 2015. The status of ESR1 mutation and other genes were detected by next generation sequencing.

      4c3880bb027f159e801041b1021e88e8 Result

      ESR1 gene mutation rate was 1.60% (8/501) in non-small cell lung cancer, including V392I (1 patient), H373Y (1 patient), E22K (1 patient), E589Q (1 patient), Q375R (1 patient), N304S (1 patient), G457V (1 patient) and M437I plus M421I (1 patient), and median overall survival (OS) for these patients was 14.0 months. Among them, all patients were ESR1 gene with co-occurring mutation. Briefly, patients with (n=3) or without (n=5) co-occurring EGFR mutations had a median OS of 19.0 months and 6.0 months respectively (P=0.36); patients with (n=4) or without (n=4) co-occurring TP53 mutations had a median OS of 11.0 months and 14.0 months respectively (P=0.45); patients with (n=2) or without (n=6) co-occurring BCRA2 mutations had a median OS of 4.0 months and 19.0 months respectively (P=0.03); patients with (n=3) or without (n=5) co-occurring RB1 mutations had a median OS of 19.0 months and 9.0 months respectively (P=0.47).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results demonstrated that decreased ESR1 gene mutation correlated with poor overall survival in non-small-cell lung cancer patients. ESR1 gene mutation may define a subset of patients with lung cancer appropriate for investigational therapeutic strategies.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-09 - Molecular Spectrum of KIT Mutations Detection in Chinese Non-Small Cell Lung Cancer Patients

      12:00 - 13:30  |  Presenting Author(s): Chunwei Xu  |  Author(s): Wenxian Wang, Quxia Zhang, Wu Zhuang, Youcai Zhu, Yanping Chen, Meiyu Fang, Gang Chen, Tang Feng Lv, Yong Song

      • Abstract

      Background

      The KIT gene activation of the gene depends on ligand binding with stem cell factor, which enables the phosphorylation of substrate proteins. Subsequently, certain signal transduction pathways are activated, which stimulate important cellular functions, such as proliferation and apoptosis. Mutations in KIT that cause autophosphoryla­tion without the presence of the ligand lead to uncontrolled cell proliferation, which eventually induces tumor develop­ment. The aim of this study is to investigate mutations and prognosis of NSCLC harboring KIT mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 402 patients with non-small-cell lung cancer were recruited between July 2012 and December 2015. The status of KIT mutation and other genes were detected by next generation sequencing.

      4c3880bb027f159e801041b1021e88e8 Result

      KIT gene mutation rate was 3.48% (14/402) in non-small cell lung cancer, including T84M (3 patients), K918Nfs*6 (1 patient), E849Q (1 patient), G961S (1 patient), I748T (1 patient), S741Y (1 patient), S712F (1 patient), D816Y (1 patient), T304A (1 patient), H180N (1 patient), R19C (1 patient) and A736D plus T734N (1 patient), and median overall survival (OS) for these patients was 23.0 months. Among them, all patients were KIT gene with co-occurring mutation. Briefly, patients with (n=4) or without (n=10) co-occurring EGFR mutations had a median OS of 23.5 months and 23.0 months respectively (P=0.63); patients with (n=6) or without (n=8) co-occurring TP53 mutations had a median OS of 15.0 months and 23.0 months respectively (P=0.47); patients with (n=2) or without (n=12) co-occurring HER2 mutations had a median OS of 4.5 months and 23.0 months respectively (P=0.01); patients with (n=2) or without (n=12) co-occurring RB1 mutations had a median OS of 14.5 months and 23.0 months respectively (P=0.26).

      8eea62084ca7e541d918e823422bd82e Conclusion

      HER2 accompanied mutations might play a worse prognosis in KIT gene mutation NSCLC. We report different mutations than those previously reported, which emphasizes the importance of personalized medicine that could be empowered by the use of bioinformatics tools in the diagnostic process and therapeutic approaches.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-10 - Transcriptomic Differences Between Early and Late Stage Lung Adenocarcinoma

      12:00 - 13:30  |  Presenting Author(s): Dongsheng Yue  |  Author(s): Bin Zhang, Rui Lin, Nan Li, Tao Wang, Liuwei Gao, Chen Chen, Changli Wang

      • Abstract

      Background

      Early and late stage lung adenocarcinoma patients differ significantly in overall survival. The tumor progression to advanced stage is driven by tumor genomic variation and the resulted abnormal gene expression profiles. A thorough study of molecular expression profiles between early and late stage lung adenocarcinoma will greatly contribute to the understanding of progression mechanism and biomarker discovery.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We used RNA-seq to investigate the gene expression differences of 17 fresh frozen tissue samples, which were collected from 7 early (IA) and 10 late stage (IIIA, 3; IIIB, 2; IV, 5) lung adenocarcinoma patients.

      4c3880bb027f159e801041b1021e88e8 Result

      In total, 232 protein coding genes show differential expression levels between early and late stage subgroups. Gene functional annotations show that the differentially expressed (DE) protein coding genes are enriched in multiple KEGG pathways: pancreatic secretion, nicotine addiction, neuroactive ligand-receptor interaction, circadian entrainment, amphetamine addiction, and serotonergic synapse. The majority of pathway enriched DE genes (16 of 24) are translated into transmembrane proteins, such as ADCY2 (high in early) and GRIN2B (high in late) etc., with no correlation between expression level and certain stage. For cancer driver genes, ALK and NTRK2 show higher expression levels in late stage than in early stage. ERBB4 shows lower expression level in the late stage We also identified a group of keratin family genes (KRT2, KRT6A, KRT6B, KRT14, and KRT16) with higher expression levels in the late stage lung adenocarcinomas; Interestingly, keratin expression level distinguishes the subgroups of solid tumors in other cancer types. Though ERBB2, PIK3CA, and TP53 were not identified as differentially expressed genes, their expression variations in the late-stage samples are significantly larger than those in the early stagewhich could be a result of regulatory network change along the progression of tumor. Furthermore, 79 non-coding RNA were identified as DE “genes”. Among them, four previously studied ncRNA prognostic markers: MIR31HG, DRAIC, LUCAT1, and LINC00261 were also identified as DE “genes” with consistent expression-stage relationship comparing with the previous report. Two other ncRNA, VLDLR-AS1 and LINC01919, are highly expressed in early stage samples and may serve as potential prognostic markers for lung adenocarcinoma.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study investigated the gene expression differences between early and late stage lung adenocarcinomas and identified differential expressed coding genes and non-coding genes, which will provide potential target information for the diagnosis and clinical intervention of lung adenocarcinoma patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-11 - Lung Cancer Stem Cells on Immune Modulation in Tumorous Microenvironment

      12:00 - 13:30  |  Presenting Author(s): Huei-Wen Chen  |  Author(s): Sheng-Fang Su, Jeremy JW Chen, Hsuan-Yu Chen, Ming-Fang Wu, Chao-Chi Ho

      • Abstract

      Background

      Cancer immunotherapy has made a big advance on benefit for cure the patients from malignancy. Recent hypothesis indicates that the crosstalk between cancer cells and tumor microenvironment can regulate the innate and adaptive immune system drives immunosuppressive condition for the immune escape of cancer cells.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Using genome-wide microarray and RNA-sequencing analysis, the immune-related gene profiling has been identified in the lung cancer stem cells (CSCs). The CSCs-condition medium was collected from the CSCs or CSCs/CAFs co-culture system to treat and analyze the functional responses of the tumor-associated macrophage (TAMs)/M2 macrophage and T cells populations. The flow cytometry and Q-PCR were used to validate the markers and related gene expression.

      4c3880bb027f159e801041b1021e88e8 Result

      We found that the tumor microenvironment is crucial to support the tumor malignancy and cancer stemness through paracrine networks (e.g., IGFII, HGF, LIF, IL-4/6/17, BMP-1/2, and CXCL6); as well as, the niche showed the impacts on the immune regulation. According to the genome-wide microarray and RNA-sequencing transcriptomic analysis of the lung cancer stem cells (CSCs), we have identified a cluster of genes and signaling involved in the immune modulation under the tumor microenvironment. Such CSCs-condition medium could significantly induce the interferon signaling, and immune checkpoints, CD274 and CD273 (PDL1 and PDL2), expression in CSCs. The population of tumor-associated macrophage (M2 population) from the malignant pleural effusion could be maintained via the CSCs-condition medium concentration-dependently. Most importantly, the population of the regulatory T cells (Treg) and the TAMs could be increased via the condition medium from CSCs; whereas, the CD8+ T-cells was significantly reduced. According to the transcriptomic/proteomic analysis of the CSCs and the niche, we have identified several important immune modulating signaling; affecting the paracrine and cytosine networks, which modulate the T cells population and may correlate with the immune escape of lung CSCs.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results have identified the roles of CSCs on the immune modulation in the tumorous microenvironment, targeting on CSCs and related immune modulating signaling could be benefit for improving the antigen presentation and inhibit the immune checkpoints PDL1 and PDL2 expression in the combinatory anti-cancer immunotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-12 - Cyclic Mechanical Strain and Myoferlin Modulates Lung Adenocarcinoma Cell Proliferation and Erlotinib Resistance

      12:00 - 13:30  |  Presenting Author(s): YouJin Cho  |  Author(s): Chris Bobba, Vasudha Shukla, Joshua Englert, Samir N Ghadiali

      • Abstract

      Background

      Lung cancer patients with mutations in the epithelial growth factor receptor (EGFR) are treated with tyrosine kinase inhibitors (TKI) such as Erlotinib. Although resistance to EGFR-TKI is common, it is not known how biomechanical factors in the lung tumor microenvironment alters resistance. Alveolar epithelial cells experience 15% cyclic strain while increased tumor stiffness result in 40-fold decrease in cyclic strain. However, it is not known if cyclic mechanical strain alters the sensitivity of lung adenocarcinoma cells to EGFR-TKI. Mechanical stretch and silencing a membrane repair protein, myoferlin (MYOF), results in fluidization of the actin cytoskeleton. In this study we investigated how cyclic strain and silencing MYOF modulates EGFR expression and Erlotinib sensitivity in lung adenocarcinoma cells.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A Flexcell system was used expose human lung adenocarcinoma cells (A549 and H1299) to 0.2Hz cyclic strain (0-15%) for 72h. To knockdown MYOF expression, cells were treated with 30uM siRNA for 24h. Cells were expose to a range of Eroltinib concentrations and a MTT cell proliferation assay was used to determine the concentration require to reduce proliferation by 50% (i.e. IC50). Western blots and immunohistochemistry were used to quantify EGFR expression and localization.

      4c3880bb027f159e801041b1021e88e8 Result

      Increasing the magnitude of cyclic strain caused a dramatic decrease in IC50 for A549 and H1299 cells. Similarly, silencing MYOF lead to a dramatic decrease in IC50 in A549 and H1299 cells. Cyclic strain and MYOF knockdown resulted in both increased EGFR expression and internalization.wclc figure.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Low levels of cyclic strain in the lung tumor microenvironment lead to increased Erlotinib resistance and exposure to physiologic levels of cyclic strain initiates EGFR signaling and increases Erlotinib sensitivity. This highlights the need for modeling and characterizing the mechanics of the lung tumor microenvironment to investigate how cyclic strain and MYOF expression influence chemosensitivity to other cancer therapeutics.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-13 - Downregulation of miRNA-506 Mediates EGFR-TKI Resistance Through Inducing Sonic Hedgehog Signaling in Non-Small-Cell Lung Cancer Cell Lines

      12:00 - 13:30  |  Presenting Author(s): Inamul Haque  |  Author(s): Mukut Sharma, Andrew Godwin, Chao H Huang

      • Abstract

      Background

      Lung cancer is the leading cause of cancer related mortality among both women and men in the United States and worldwide. Epidermal Growth Factor Receptor (EGFR) mutation predicts response to a tyrosine kinase inhibitor (TKI) of EGFR in approximately 25% of patients. All ANSCLC patients with EGFR mutation eventually develop resistance to EGFR-TKI. The mechanism of resistance is not fully elucidated but majority of the cases is related to emergence of clones with T790M mutation in EGFR, and amplification of MET. Recently, increasing numbers of miRNAs, non-coding RNAs are correlated with the drug resistance indicating that miRNAs may serve as novel targets and/or promising predictive biomarkers for anti-EGFR therapy. In this study, we investigated the role of miRNA-506 in the regulation of Sonic Hedgehog (SHh) in TKI-resistant lung cancer cell lines.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To generate cell lines resistant to EGFR TKI, HCC4006 cells were exposed to increasing concentrations of erlotinib over 6 months with increasing concentration upto 20 μM. The resultant clones (designated HCC4006 ER1 to HCC4006 ER4), following expansion from single cell. Cell viability was measured by crystal violet staining assay. The expression of miRNA in parental and resistant clones was checked by real-time qRT-PCR. The mRNA and protein expression level of SHh was determined by real-time qRT-PCR and Western blot. Invasive/migratory ability of parental and resistant clones was measured by Boyden chamber assays. EMT and stemness markers were evaluated by Western blot. Single-cell suspensions from pre-treated cells were re-suspended at a density of 500 cells/ml mammocult media in ultralow attachment dishes. Number as well as the size of the tumorosphere/spheroids in specified experimental set-up was monitored and recorded alternate day for 8-10 days.

      4c3880bb027f159e801041b1021e88e8 Result

      The studies demonstrated that miR-506 was downregulated in resistant clone as compared to parental cell lines which promotes significantly the invasive/migratory ability and EMT phenotypes of lung cancer cells through induction of SHh. Interestingly, ectopic expression of miRNA-506 in these resistant cells inhibits SHh signaling and thus reprograms EMT, EGFR-TKI resistance and stemness.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our data suggest that miR-506 downregulation and induction of SHh are associated with resistance to EGFR-TKI. miR-506 interference and inhibition of SHh pathway are potential therapeutic strategy to reverse resistance to EGFR-TKI in NSCLC with EGFR mutation.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-14 - Downregulation of FOXM1 Inhibits Tumor Proliferation, Colony Formation and Spheroid Formation of Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Yoichi Otaki  |  Author(s): Paul Yenerall, Boning Gao, Michael Peyton, Kimberley Avila, Luc Girard, Long Shan Li, Amit Das, Kenneth Huffman, Brenda Timmons, Hyunsil Park, Dhruba Deb, John D Minna

      • Abstract

      Background

      Forkhead box protein M1 (FOXM1) is a member of the forkhead superfamily of transcription factors. It plays numerous critical roles in cancer development and progression, such as the regulation of G2/M transitions of cell cycle, anti-apoptosis, DNA damage repair, invasion, and drug resistance. In a pan-cancer meta-analysis of mRNA expression signatures from ~18,000 human tumors with overall survival outcomes across 39 malignancies, over expression of the FOXM1 was a major predictor of adverse outcomes and appeared anti-correlated with tumor immune cell populations (Nat Med. 2015;21(8):938-945). Thus, we examined the prognostic and biological role of FOXM1 in non-small cell lung cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We examined the prognostic impact of FOXM1 expression in lung cancer patients using a genomic database (UTSW – “Lung Cancer Explorer” and KM-Plotter). We also assessed the expression of FOXM1 in NSCLC lines, and human bronchial epithelial cells (HBECs), and assessed the association between FOXM1 and cell cycle related genes in RNA-seq data. We examined the effect of the downregulation of FOXM1 on tumor proliferation and colony formation of lung adenocarcinoma cell lines by short hairpin RNA (Tet-pLKO-FOXM1-shRNA), and the effect of the downregulation of FOXM1 on tumor 3D spheroid formation in spheroid-forming cell lines using Nunclon Sphera.

      4c3880bb027f159e801041b1021e88e8 Result

      High FOXM1 expression correlated with poor prognosis in NSCLC patients who underwent surgical resection, especially adenocarcinoma. FOXM1 expression in lung cancer cell lines was also much higher than in HBECs. The expression level of FOXM1 was significantly correlated with cell cycle regulator genes such as CCNB1, CCNA2, and PLK1 in both tissue samples (Lung cancer explorer) and cell lines (our data). shRNA mediated reduction of FOXM1 expression significantly inhibited tumor cell proliferation and colony formation of NSCLC cells. Additionally, in the 3D spheroid formation assay, FOXM1 knockdown altered spheroid morphology.

      8eea62084ca7e541d918e823422bd82e Conclusion

      FOXM1 was over expressed in NSCLC compared to normal lung epithelial cells, and high tumor FOXM1 expression was prognostic of poor survival in patients with NSCLC who underwent surgical resection, especially in patients with adenocarcinoma. FOXM1 expression correlated with the expression of regulators of the G2/M transition, and functional knockdown studies demonstrate an important role in tumor proliferation, colony formation, and 3D spheroid formation. Overall, our results suggest that FOXM1 has important roles in NSCLC growth, while data from other groups using “CIBERSORT” analyses suggest a possible role for FOXM1 in tumor immune cells infiltration, collectively indicating that FOXM1 is a potential target for the treatment of lung cancer adenocarcinoma.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-15 - Lung Cancer Regulation of Glucose Metabolic Stress Response

      12:00 - 13:30  |  Presenting Author(s): Laila C Roisman  |  Author(s): Tali Feinberg, Maya Ilouze, Nir Peled

      • Abstract

      Background

      Cancer cells have altered metabolism in order to accommodate for the increased metabolic needs required for oncogenic transformation, proliferation, development and survival. The metabolic profile observed in cancer cells often includes increased consumption of glucose and glutamine, increased glycolysis, changes in the use of metabolic enzyme isoforms, and increased secretion of lactate. In order to better understand this hallmark of cancer, we studied the regulation of pathways by microRNAs (miRNA) expression profile under normal or deprived glucose condition in different lung cancer cell lines.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Two different NSCLC adenocarcinoma cell lines were tested in the study, A549, which is highly glycolytic (HG) and H358, which is low glycolytic (LG). Sequencing was performed using Illumina TruSeq RNA library preparation kit v2 with Illumina HiSeq 2500 sequencer using single-end 50bp protocol. Cell were analysed in two different conditions, under 24h of normal glucose concentration and under 24h glucose starvation. Samples were prepared in duplicates from the initial step of cell culturing summarizing to a total of eight samples. Differential expression analysis was performed using EdgeR algorithm with an adjusted p-value >0.05 and a log2 fold > 1.5.

      4c3880bb027f159e801041b1021e88e8 Result

      An opposite regulation profile was observed for miRNA of cells that are highly glycolytic (HG), A549, in comparison with low glycolytic, H358 cells. The formers presented 42 downregulated miRNAs from which 39 miRNAs were unique. Only 2 upregulated miRNAs, miR324 and miR616, were found significant in this cohort but they are also upregulated in the latter group. In comparison, from the 20 upregulated miRNAs found in high-glycolygic group from which 18 were unique to lower glycolytic cell line. Lower glycolytic cell lines show 4 downregulated miRNAs from which only one miRNA, miR205 was significantly uniquely downregulated, moreover, MIR205HG, which is miR205 host gene, is also found significantly downregulated, suggesting the strong involvement of miR205 in glucose metabolic stress response.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Under glucose metabolic stress, miR205 and MIR205HG are uniquely downregulated in low glycolytic NSCLC adenocarcinoma cell line.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-16 - 3D Morphometric Detection of Mismatch Repair Deficiency in Human Lung Adenocarcinoma Cell Lines using the Cell-CT® Platform

      12:00 - 13:30  |  Presenting Author(s): Daniel J Sussman  |  Author(s): Laimonas Kelbauskas, Michael Meyer, Rahul Katdare, Alan Nelson

      • Abstract

      Background

      Mismatch repair protein deficiency (MMR-D) is proving to be a predictive biomarker for the efficacy of immune checkpoint inhibitor therapy for many malignant neoplasms. MMR-D leads to microsatellite instability and high tumor mutational burden (TMB) and ultimately results in the generation of neoantigens. While multiple molecular tests are available today for the detection of MMR-D, including immunohistochemistry staining for mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2), PCR to evaluate MSI, MLH1 promoter methylation analysis, and targeted next-generation sequencing, they require invasive biopsy and are often not applicable for early stage disease.

      Studies have demonstrated that MMR-D results in histological and morphological changes. The automated Cell-CT® platform produces isometric, high-resolution 3D images of cells in liquid biopsies, such as sputum, where published studies have demonstrated 92% sensitivity to biopsy-confirmed lung cancer with 95% specificity. This new study reports the development of morphology-based classifiers for lung cancer cells that have been engineered to exhibit MMR-D.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Two human lung cancer adenocarcinoma cell lines, NCI-H23 and NCI-H1650, were transduced with lentiviral particles expressing either scrambled or MLH1 shRNAs and selected for puromycin resistance. Individual clones were isolated and screened for MLH1 expression. Several scrambled shRNA clones, with parental levels of MLH1, and several shMLH1 clones, with a range of 86 to 97% suppression of MLH1, were expanded, fixed, and analyzed using the Cell-CT® platform. Over 1,000 cells from several harvests of each cell line were used to measure 845 different 3D structural biomarkers for each cell.

      4c3880bb027f159e801041b1021e88e8 Result

      A classifier to test the degree to which the features discriminate between control scrambled shRNA and shMLH1 cell lines was developed and its performance was characterized by the area under the ROC curve (aROC). MLH1-knockdown specific differences for both the H23 and H1650 line clones as compared to pooled shRNA clone data were observed. The aROC’s for 4 different H23 shMLH1 clones were 0.86, 0.81, 0.81, and 0.84, while those for 3 H1650 shMLH1 clones were 0.83, 0.80, and 0.90.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study demonstrates the feasibility of using the Cell-CT® platform for morphometric detection of MMR-D. Discriminatory features assessed from both cell lines will be presented as well as possible correlation to TMB level.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-17 - Roles of α7nAchR Signaling in Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Yu-Feng Wei

      • Abstract

      Background

      Lung cancer is the leading cause of cancer-related mortality worldwide. Cigarette smoking is the leading risk factor driving lung cancer. Nicotine, as the major addictive component in cigarettes, can stimulate the progression of lung cancer cells through nicotinic acetylcholine receptors (nAChRs). The nAChR α7 subunit has been found to be pivotal in growth signal transduction induced by nicotine binding to nAChRs in lung cancer cells. Nevertheless, its clinical roles remain unclear.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We firstly used the bioinformatics platform to analyze whether the messenger RNA (mRNA) expression of various nAChRs might contribute to patient survival. The immunohistochemistry was additionally applied to analyze the distribution patterns of α7nAchR protein in lung cancer. Complementary DNA (cDNA) microarray, immunoblotting analysis, and Cell Proliferation Kit II (XTT) assay were used to explore the potential effects and mechanisms.

      4c3880bb027f159e801041b1021e88e8 Result

      We found that patient groups with high CHRNA7 mRNA levels had an improved overall survival rate in 1926 lung cancer cases (p<0.001). Furthermore, increased CHRNA7 mRNA expression improved overall survival of squamous cell, but not adenocarcinoma, lung cancer patients (p=0.043). In addition, high CHRNA7 mRNA expression predicted better overall survival only in female patient group (P=0.001). Nuclear and cytoplasmic α7nAChR staining were significantly increased in cancerous and metastatic lesions as compared with adjacent non-cancerous tissues. Membranous α7nAChR staining was present only in cancerous lesions and was low in metastatic lesions. Notably, H157N cells have been harvested with nicotine for 2 years and had an increased α7nAChR expression. In addition, nicotine was able to increase α7nAChR expression in both H157 and H157N cells. Anti-α7nAChR antibody suppressed cell grow in only H157N cells despite of nicotine treatment with or without. Long term nicotine exposure might change the dependence of α7nAChR signaling in squamous lung cancer cells.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results suggested that α7nAChR might play roles in squamous lung cancer and in female lung cancer. mRNA and protein levels of α7nAChR appear to represent a tumor suppressive or an oncogenic role, respectively. The exact roles and underlying mechanisms of the α7nAChR related signaling demand further investigations in particular squamous lung cancer patients with smoking history.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-18 - Collagen Type XI Promotes Lung Adenocarcinoma Dissemination Via Integrin α2 and DDR1

      12:00 - 13:30  |  Presenting Author(s): Cédric Zeltz  |  Author(s): Roya Navab, Melania Pintilie, Ming Sound Tsao

      • Abstract

      Background

      Our previous studies showed that non-small cell lung cancer (NSCLC) stroma is an important actor of lung tumorigenesis. We found integrin α11, a fibrillar collagen receptor expressed on cancer-associated fibroblasts (CAF), to be strongly up-regulated in NSCLC stroma and to promote NSCLC growth in vivo. Collagen XI is a fibrillar collagen that expression is increased in NSCLC and is correlated with integrin α11 expression. The purpose of the present study is to determine whether integrin α11-mediated lung tumorigenesis is induced via collagen XI and how that collagen may affect lung carcinoma cell invasion.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To study the effects of collagen XI, collagen XI has been incorporated in a matrix of collagen I at a ratio 1:3 (collagen I/XI). For tumor cell invasion, lung adenocarcinoma H1975 cells were allowed to form spheroids before being embedded in a collagen I or a mix of collagen I/XI matrix. Area of dissemination and migration pattern has been analyzed 48 hours later. In order to identify the collagen receptor interacting with collagen XI, we used cell attachment and ELISA assay. Knockout of integrin α2 and DDR1 has been performed using the CRISPR-Cas9 strategy in H1975 cell line.

      4c3880bb027f159e801041b1021e88e8 Result

      We showed that high collagen XI expression is associated with high risk of recurrence in the UHN cohort of 165 NSCLC patients (hazard ratio= 1.97, 95% confidence interval 1.09-3.56, P<0.026). Surprisingly, CAF embedded in a mix of collagen I/XI matrix failed to reorganize the collagen matrix as efficient as embedded CAFs in only collagen I matrix and displayed inhibition of migration in presence of collagen XI. In contrast, collagen XI greatly enhanced invasion of lung adenocarcinoma H1975 cells in a mix collagen matrix with a different invasion pattern compared to H1975 cell invasion in collagen I. Although integrin α11 expression correlates with collagen XI expression in NSCLC, this integrin bound poorly to collagen XI. Instead we found integrin α2 and DDR1 to interact with collagen type XI (Kd=5nM and Kd=24nM, respectively). Knockout of integrin α2 or DDR1 in H1975 cells suppressed collagen XI-increased invasion in a collagen I/XI matrix, indicating that both collagen receptors are required to mediate collagen XI effect on lung adenocarcinoma dissemination.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We showed that the presence of collagen XI in NSCLC stroma could enhance lung adenocarcinoma dissemination via integrin α2 and DDR1. Thus, targeting these two collagen receptors may be a new strategy to improve the outcome of lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-19 - The Lysyl Oxidase like-1 Promotes NSCLC Tumorigenecity Through Increased Matrix Reorganization and Stiffness

      12:00 - 13:30  |  Presenting Author(s): Cédric Zeltz  |  Author(s): Elena Pasko, Roya Navab, Ming Sound Tsao

      • Abstract

      Background

      The importance of the stroma in tumorigenicity has been increasingly recognized in the past few years and targeting tumor stroma has become a new strategy for the development of new therapies. The lysyl oxidase like-1 (LOXL1) is a matrix cross-linking enzyme, essentially secreted by cancer-associated fibroblasts (CAFs) in the stroma. We previously showed that LOXL1 expression strongly correlated with integrin α11 expression, a collagen receptor that promotes NSCLC tumorigenecity, suggesting that LOXL1 may also contribute to lung tumor growth and metastasis by modifying the stromal collagen matrix.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Primary CAFs (CAF094) isolated from a NSCLC resection specimen and immortalized with hTERT were infected with full length LOXL1 (LOXL1 overexpression), LOXL1 shRNA (LOXL1 knockdown) or with their respective controls, using a lentiviral system. To investigate the impact of LOXL1 on collagen matrix reorganization, we allowed CAFs expressing different levels of LOXL1 to contract collagen matrices. Contracted collagen matrices have then been submitted to second harmonic generation to analyze collagen fibers. We established the role of LOXL1 in lung carcinoma invasion and growth using an in vitro organotypic model and an in vivo xenograft model, respectively.

      4c3880bb027f159e801041b1021e88e8 Result

      LOXL1-overexpressing CAFs embedded in collagen lattices displayed greater ability to reorganize the collagen matrix than those with lower LOXL1 expression. Furthermore, analysis of the collagen matrix demonstrated that LOXL1 contributed to more linear and dense collagen fibers organization. As a consequence of collagen matrix reorganization, invasion of the lung carcinoma H661 cell line significantly increased in an organotypic model in presence of LOXL1-overexpressing CAFs. Moreover, we showed that loss of Loxl1 in mice inhibited subcutaneous growth of the lung adenocarcinoma H4006 cell line compared to the mouse wild-type counterparts.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We demonstrated that overexpression of LOXL1 in NSCLC tumor stroma results in an increased of tumor growth and invasion, due to a change in the matrix reorganization. Thus, LOXL1 appears as an interesting target to improve the outcome of lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-20 - Circulating Tumor Cell Clustering in Vitro Short-Term Culture Correlates with Poor Survival and Allows Monitoring Response to Treatment

      12:00 - 13:30  |  Presenting Author(s): Govind Babu K  |  Author(s): Deepak Koppaka, Ajay Balakrishnan, Prashant Kumar

      • Abstract

      Background

      Circulating tumor cells (CTCs) are putative markers for tumor prognosis and may serve to evaluate patient’s response to chemotherapy. CTCs are often detected as single cells but infrequently as clusters indicative of worse prognosis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Blood samples were obtained from the 86 breast cancer patients, 52 lung cancer patients.

      The nucleated cells were cultured in ellipsoidal microwells

      The microwells were prepared by placing a cover slip (22mm X 22mm) on a 35mm culture dish. Molten agar (3%) was poured on the top of the cover slip enough to cover it (500µl approx). The ellipsoidal microwell in PDMS (polydimethylsiloxane) was then placed on the top of the cover slip containing the molten agar and allowed it to solidify. The culture conditions were carried at 37°C, 5% CO2 and humidified hypoxic conditions (1% O2). The culture medium was replaced every 48-72 hrs with nominal disturbances to the microwells. Cultures were maintained for 3 weeks and imaged on day 7, 14, 21 with bright field microscope and analyzed the images using (Olympus IX71).

      4c3880bb027f159e801041b1021e88e8 Result

      To correlate cluster formation with survival, samples were obtained from 31 patients with lung cancer. These patients were enrolled, when they were presented with progressive disease since their last treatment regimen but before commencing a new treatment regimen. Blood was collected before and on 9th, 12th week after the treatment. It is interesting to note that tight cluster formation correlated with patient survival. The Kaplan-Meier survival analysis showed that cluster formation in patients who have undergone neoadjuvant therapy correlated with shorter overall survival Our culture system enabled us to successfully expand the CTCs without any prior enrichment. The method requires 2.5 ml of blood per 35-mm dish to expand CTCs. Microwells were easy to establish and replicate with minimal set-up in a laboratory.

      8eea62084ca7e541d918e823422bd82e Conclusion

      To the best of our knowledge, this study is one of the few, which suggest the possible role of cluster formation in patient survival in Lung cancer patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-21 - CXCR4 Overexpression is Associated with Poor Survival Outcome After Recurrence in Early Stage Non-Small Cell Lung Cancer Patients

      12:00 - 13:30  |  Presenting Author(s): Andrea Fung  |  Author(s): Karen Kopciuk, Michelle Dean, Adrijana D'Silva, Shannon Mary Otsuka, Alexander Klimowicz, Desiree Hao, Donald Morris, Gwyn Bebb

      • Abstract

      Background

      Overexpression of CXCR4 is associated with poor outcomes for patients with advanced non-small cell lung cancer (NSCLC). Studies suggest a gender specific difference in outcomes of stage IV NSCLC patients, with shorter survival in females with high expression of CXCR4. The current study evaluates the association between CXCR4 expression and gender, time to recurrence, and survival in early stage NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patient characteristics, clinical variables and outcome data were obtained from the Glans-Look Lung Cancer database for stage I-III NSCLC patients diagnosed between 2003-2006 at the Tom Baker Cancer Centre. Tissue microarrays were created from surgical or biopsy specimens, and CXCR4 expression was evaluated using quantitative fluorescent immunohistochemistry. CXCR4 expression and outcome data were analyzed using a Cox proportional hazards and multi-state model.

      4c3880bb027f159e801041b1021e88e8 Result

      230 patients with stage I-III NSCLC were identified, and 181 patients had corresponding tissue for CXCR4 analysis. Early stage NSCLC patients with CXCR4 overexpression had worse overall survival compared to those with low CXCR4 expression (p<0.05). No gender specific difference was observed. Time to recurrence did not correlate with CXCR4 expression, and there was no association with the site of recurrence (local versus distant). However, high CXCR4 expression was associated with increased risk of death after recurrence (p<0.05).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Early stage lung cancer patients with high CXCR4 expression have worse survival outcomes, particularly after recurrence of disease. The role of CXCR4 as a prognostic marker in NSCLC patients who have recurred should be further elucidated.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-22 - IL-1β as a New Early Predictive Biomarker for Non-Small Cell Lung Cancers Outcome

      12:00 - 13:30  |  Presenting Author(s): Carlotta Giorgi  |  Author(s): Sonia Missiroli, Nicola Tamburini, Mariasole Perrone, Pio Maniscalco, Roberta Gafà, Giovanni Lanza, Paolo Pinton, Giorgio Cavallesco

      • Abstract

      Background

      Lung cancer is the first cause of cancer mortality worldwide. Patients diagnosed with early stage disease (stage I) have been considered to have a reasonably favourable prognosis. Unfortunately, up to 40% early stage cases of all non-small cell lung cancers (NSCLCs) have a poor prognosis.

      Recent studies have suggested that combined modality treatment of NSCLC may improve survival in selected patients. One of the most critical questions in choosing the appropriate use of combined therapy is determining which patients might benefit from the more aggressive treatment.

      Recent data have enhanced the idea that inflammation is a critical component of tumour progression. It is now becoming clear that the tumour microenvironment is largely orchestrated by inflammatory cells and it is an indispensable participant in the carcinogenesis.

      In particular, IL-1b is a pleiotropic pro-inflammatory cytokine and its up-regulation is closely associated with various cancers. Chronic inflammation (sustained by overactivation of IL-1b system) is a crucial event in carcinogenesis and tumor progression and there is evidence that plasma IL-1b level is higher in patients with advanced cancers.

      Our goal is to determine whether IL-1b expression might be associated with NSCLCs patients’ clinical outcome.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients diagnosed with lung cancer stage I and treated with potentially curative resection during 2012 were recruited for this study.

      Tissue samples (tumor masses including peri-tumoral stroma and lungs) were collected during surgery, embedded in paraffin and processed for immunohistochemistry (IHC). IHC was performed by ABC-peroxidase. Adjacent sections were incubated for 1 h at room temperature with monoclonal antibody against human IL-1b.

      4c3880bb027f159e801041b1021e88e8 Result

      In our randomized experiment 35 patients with NSCLC whose tumor was resected or biopsied were enrolled during 2012 and followed up for 5 years through 2017.

      Our preliminary results showed that patients with high levels of IL-1b in the peritumoral area, revealed by IHC, present a poor prognosis and a reduced overall survival.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This retrospective analysis of patients with stage I NSCLCs who had received standard surgery resulted in statistically significant improvement in overall survival in patients with a low release of IL-1b in the tumor microenvironment.

      This data define a new role for IL-1β as a predictive biomarker of NSCLCs tumor behavior that can be used to better profile the use of treatments and improve patients’ outcome.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-23 - A Propensity Score Matching Cohort Study on Prognosis of the Diversity of MUC1 Expression in Patients with Lung Adenocarcinoma

      12:00 - 13:30  |  Presenting Author(s): Chundong Gu  |  Author(s): Zhao Shilei, Lei Zhao, Tao Guo, Peng Wang

      • Abstract

      Background

      To probe the expression of MUC1 (Mucin-1) in lung adenocarcinoma tissues, and estimate the relationship between the expression level of MUC1 and prognosis or clinical pathological factors in patients with lung adenocarcinoma simultaneously, so as to establish personal therapeutic strategies and forecast prognosis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective analysis was originally conducted on 182 lung adenocarcinoma patients who underwent surgical resection collected from July 2007 and September 2010 at the First Affiliated Hospital of Dalian Medical University. None of the patients received neoadjuvant therapy. Each tumor was reevaluated according to the current adenocarcinoma classification based on HE stains. Additional immunohistochemical staining for MUC1(Mucin-1) was used in selected cases. Cox proportional hazard regression model was used for univariate analysis. The confounding parameters were compromised by propensity score matching (PSM).

      4c3880bb027f159e801041b1021e88e8 Result

      Among 182 patients with lung adenocarcinoma, 107 patients were MUC1 low expressed, 44 patients were MUC1 moderate expressed 33 patients were MUC1 high expressed. We found the expression of MUC1 was significantly different in gender (p=0.014), smoking history (p=0.009), T stage (p=0.019), N stage (p=0.015), clinical stage (p=0.024) and the WHO classification of tumors of the lung adenocarcinoma (p=0.002). But we found all above differences among groups were no significance after PSM. Lung adenocarcinoma patients with high MUC1 expression, poorly differentiated and high pTNM stage had early relapse than the other (P≤0.05), no matter took PSM.

      Univariate analysis of clinical pathologic factors on disease-free survival risk.

      Clinical Factor

      HR

      95%CI

      P value

      Gender

      male

      1.000

      fmale

      0.732

      0.437-1.226

      0.236

      Age

      ≤67

      1.000

      >67

      0.928

      0.562 -1.534

      0.772

      History of smoking

      Out

      1.000

      Without

      1.756

      0.981 -3.140

      0.058

      Tumor size

      ≤2cm

      1.000

      >2cm

      2.100

      1.067- 4.135

      0.032

      Differentiation

      Poor

      1.000

      Moderate

      10.929

      4.734- 25.232

      0.001

      Well

      3.151

      1.376- 7.218

      0.007

      T stage

      T1

      1.000

      T2

      1.483

      0.798- 2.757

      0.213

      T3

      3.831

      2.083- 7.048

      0.001

      N stage

      N0

      1.000

      N1

      2.247

      0.879- 5.744

      0.091

      N2

      3.506

      2.047- 6.006

      0.001

      TNM stage

      I

      1.000

      II

      2.310

      0.810- 6.591

      0.118

      III

      3.823

      2.272- 6.432

      0.001

      Pathological subgroups

      MIA

      1.000

      AP

      3.414

      1.146- 10.174

      0.028

      PA

      1.486

      0.600- 3.683

      0.392

      MPA

      2.245

      0.918- 5.494

      0.076

      SOP

      5.566

      1.116- 27.754

      0.036

      MU

      5.148

      0.617- 42.923

      0.130

      Lep

      0.748

      0.090- 6.210

      0.788

      MUC1 expression

      Low

      1.000

      Moderate

      1.235

      0.604- 2.527

      0.563

      High

      2.289

      1.318- 3.974

      0.003

      MUC1 expression (PSM)

      Low

      1.000

      Moderate

      1.289

      0.557- 2.985

      0.553

      High

      2.462

      1.142- 5.312

      0.022

      8eea62084ca7e541d918e823422bd82e Conclusion

      High expression of MUC1 can be a significant independent risk factors for predicting the prognosis of lung adenocarcinoma.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-24 - Incorporation of a Molecular Prognostic Classifier Improves Conventional Non-Small Cell Lung Cancer Staging

      12:00 - 13:30  |  Presenting Author(s): Greg J. Haro  |  Author(s): Johannes R. Kratz, Nancy R. Cook, Jianxing He, Stephen K. Van Den Eeden, Gavitt A. Woodard, Matthew A. Gubens, Thierry M. Jahan, Kirk D. Jones, Il-Jin Kim, Biao He, David Mark Jablons, Michael J. Mann

      • Abstract

      Background
      Despite significant advancements in the understanding of the molecular genetics of tumor biology, the 8th Edition of Non-Small Cell Lung Cancer (NSCLC) staging adopted in 2018 remains dependent upon tumor size, nodal spread, and metastasis. The survival of patients with early stage NSCLC remains poor and further improvement in staging is needed to better inform adjuvant therapy. In this study, we explored the integration of a clinically validated, molecular prognostic classifier into conventional staging.
      a9ded1e5ce5d75814730bb4caaf49419 Method
      A novel staging system, TNMB (“B” indicating Biology), that integrates a 14-gene molecular prognostic classifier with the 8th Edition, was developed using 332 patients with non-squamous NSCLC resected at the University of California, San Francisco (UCSF). TNMB was subsequently validated on a separate multi-institutional international cohort of 1,373 patients. Reclassification metrics were evaluated from adoption of TNMB and the 8th Edition. 4c3880bb027f159e801041b1021e88e8 Result
      Adoption of TNMB improved prognostication of overall survival significantly more than adoption of the 8th Edition. TNMB resulted in Net Reclassification Improvement of 0.33 (95% CI 0.24-0.41), relative Integrated Discrimination Improvement of 22.1% (95% CI 8.8-35.3%), and Reclassification Calibration Statistic from 36 to 18 (P-Value 0.03 to 0.73). In contrast, the 8th Edition resulted in no change in Net Reclassification Improvement 0.03 (95% CI -0.00-0.06) or relative Integrated Discrimination Improvement -2.5% (95% CI -17.6-12.4%) and resulted in Reclassification Calibration Statistic from 134 to 22 (P-Value <0.01 to 0.27). 8eea62084ca7e541d918e823422bd82e Conclusion
      Incorporation of a molecular prognostic classifier offers substantial improvement to conventional staging of NSCLC and may lead to a significant impact on clinical decision-making in early stage disease where identification of high risk patients is needed to guide adjuvant therapy. Our findings may encourage application of molecular prognostic classifiers into the refinement of conventional staging for other solid tumors.

      Overall Survival of Non-Small Cell Lung Cancer Patients Following Surgical Resection by 7th Edition, 8th Edition, and TNMB Staging. TNMB had distinct separation of survival by stage and larger range of survival between early and late stages compared to conventional staging.

      14531.png



      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-25 - Squamous Cell Carcinoma-Associated Bronchial Dysplasias Demonstrate Altered T-helper Lymphocyte Differentiation

      12:00 - 13:30  |  Presenting Author(s): Daniel T Merrick  |  Author(s): Elizabeth J. Donald, York E. Miller, Robert L. Keith, Moumita Ghosh, Dara L. Aisner, Kimberly Jordan, Wilbur A. Franklin, James Degregori

      • Abstract

      Background

      Persistent bronchial dysplasia (BD) is associated with an increased risk for development of invasive squamous cell carcinoma and demonstrates altered polarization of inflammatory cell subsets by gene expression analysis as compared to BD that regresses. We hypothesized that a decrease in the T-helper 1 (Th1) to T-helper 2 (Th2) lymphocyte ratio would be associated with progression to invasive squamous cell carcinoma (SCC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      VECTRA 7-color multispectral staining was applied to formalin fixed paraffin embedded (FFPE) persistent (N=12) and regressive (N=10) BD that also included four biopsies from patients that subsequently developed SCC (3 persistent and 1 regressive, 2 from the actual site of progression). inForm (Perkin-Elmer) image analysis software was used to enumerate cells that showed double positivity for Tbet-CD4 (Th1) and GATA3-CD4 (Th2) and the ratios of the percentage of Th1 and Th2 cells amongst all CD4 positive cells were calculated from multiple lesional fields for each BD (dysplastic epithelium and underlying stroma). DNA extracted from the full remaining FFPE tissue of four of these cases were sequenced employing the Oncomine Comprehensive v3 NGS panel (ThermoFisher) and the number of somatic mutations and variant allele frequencies (VAF) were determined using a threshold of at least 200 total reads and 25 variant reads per variant identified.

      4c3880bb027f159e801041b1021e88e8 Result

      A decreased Th1:Th2 ratio was seen in SCC-associated BD as compared to BD from patients that did not develop lung cancer (p=0.04; ratio = 0.04 vs. 0.68, respectively). No significant difference was seen in persistent versus regressive BD groups. There was an inverse correlation between Th1:Th2 ratios and mutational load (r2=0.21) and VAF (r2=0.28) although the small number of specimens precluded identification of a statistically significant relationship.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A decreased Th1:Th2 ratio is associated with BD from subjects that progress to SCC suggesting that alterations in T-helper lymphocyte differentiation may contribute to progression. A potential inverse relationship between Th1:Th2 ratios and mutational load or mutant clonal expansion (increased VAF) will require further study.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-26 - Tumor Immune Microenvironment in NSCLC is Predictive of Prognosis After Surgery

      12:00 - 13:30  |  Presenting Author(s): Åsa Öjlert  |  Author(s): Ann Rita Halvorsen, Ole Christian Lindgjærde, Steinar Solberg, Odd Terje Brustugun, Åslaug Helland

      • Abstract

      Background

      To investigate the tumor microenvironment in NSCLC and try to understand more about how, and why, it differs in histological and expression subtypes of NSCLC .

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Samples were collected from 399 patients who underwent surgery for stage I-IV NSCLC at Oslo university hospital 2006-16. Gene expression was assessed by using Agilent microarray on samples from adenocarcinomas (n=184) and squamous cell carcinomas (n=183) separately. RNA sequencing was performed of 32 samples. Of these 53 % (n=17) were adenocarcinomas (AD) and 47 % (n=15) were squamous cell carcinomas (SCC). Xcell(1) was used to find the proportion of different cells in the tumor microenvironment and to calculate an immunescore. All samples were assigned a gene expression subtype by using previously described nearest centroid classifiers for AD and SCC respectively (2, 3)

      4c3880bb027f159e801041b1021e88e8 Result

      For AD we found significant differences in progression free survival (PFS) between the three expression subtypes with better prognosis for TRU versus non-TRU and worse for PP versus non-PP, adjusted for stage. We found no differences in prognosis between SCC expression subtypes. Higher immune score was associated with better PFS in AD but not in SCC.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The composition of both stromal and immune cells in the tumor microenvironment will be further investigated. Differential gene expression analysis will be preformed to better understand what differentiates immunologically active from immunologically silent tumors.

      1. Aran D, Hu Z, Butte AJ. xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome Biol. 2017;18(1):220.

      2. Wilkerson MD, Yin X, Walter V, Zhao N, Cabanski CR, Hayward MC, et al. Differential pathogenesis of lung adenocarcinoma subtypes involving sequence mutations, copy number, chromosomal instability, and methylation. PLoS One. 2012;7(5):e36530.

      3. Wilkerson MD, Yin X, Hoadley KA, Liu Y, Hayward MC, Cabanski CR, et al. Lung squamous cell carcinoma mRNA expression subtypes are reproducible, clinically important, and correspond to normal cell types. Clin Cancer Res. 2010;16(19):4864-75.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-27 - Somatic BRCA1/2 Mutations in Advanced NSCLC Patients: Description of a Sub-Population from the Ongoing Unicancer SAFIR02-Lung / IFCT-1301 Trial

      12:00 - 13:30  |  Presenting Author(s): Jordi Remon  |  Author(s): Etienne Rouleau, Fabrice Barlesi, Alexandra Leary, Ivan Bièche, Bastien Job, Ludovic Lacroix, Aurélie Auguste, Marjorie Mauduit, Clarisse Audigier-Valette, Judith Raimbourg, Anne Madroszyk, Stefan Michiels, Mohammed Amine Bayar, Marta Jimenez, Jean-Charles Soria, Benjamin Besse

      • Abstract

      Background

      Molecular profiling is considered standard of care in advanced NSCLC. Identification of druggable molecular alterations may enhance the percentage of patients suitable for personalized treatment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From 04/2014 to 03/2017, 602 newly diagnosed,advanced NSCLC patients (pts) were enrolled in SAFIR02-Lung trial (NCT02117167). Molecular profile provided information on copy number alterations and mutations on 71 oncogenes and tumor suppressor genes. The profile was performed for 420 pts (70%) on archival tissue or frozen tissue collected from a new biopsy performed before the 3rd cycle (tissue or liquid) of chemotherapy. The frequency of BRCA mutation (mut) was assessed and clinicopathologic data collected. A homologous recombinant deficiency (HRD) score was performed on the copy number variations (CNV) data and the germline status was based on blood analysis. The BRCAshare database was the reference for the variants classification.

      4c3880bb027f159e801041b1021e88e8 Result

      18 pts were identified with BRCA alterations. BRCA variants of unknown significance were detected in 11 pts (2.6%). Response to chemotherapy according to RECIST 1.1 by investigator was: 6 stable disease (SD), 1 partial response, and 4 progressive disease (PD). CNV profile was evaluable for HRD in 6 out of 11 pts, with 50% positive.

      Seven pts (1.7%) were identified with deleterious BRCA-mut. 2 pts (0.5%) harboured germline BRCA2-mut (1 with breast cancer familiar history). Both pts had SD to chemotherapy. Somatic BRCA-mut was identified in 5 pts (1.2%, 2 BRCA1- and 3 BRCA2-mut). All were male, 100% adenocarcinoma, 75% smokers of 40 pack/year, 1 pt with familial cancer history, and 80% of pts had bone metastases. Response to chemotherapy was: 4 SD, and 1 PD. Three of 7 corresponding CNV profiles were evaluable for HRD score analysis with 100% positive.

      N=420

      BRCA alterations (N=18)

      BRCA VUS

      N=11

      BRCA deleterious

      N=7

      Somatic

      6

      5

      Germline

      5

      2

      HRD positive- Somatic

      Germline

      3/6*

      2

      1

      3/3*

      3

      0

      VUS: variants of unknown significance

      *Amongst patients with available samples for analysis

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pathogenic BRCA1/2 mutations occur in 1.7% of advanced NSCLC with 71% of somatic mutations suggesting its value for exploring new therapeutic strategies in this population

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-28 - LKB1 Mutation Status is Associated with Poor Radiation Outcome in Patients with Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Piyada Sitthideatphaiboon  |  Author(s): Ana Galan Cobo, Alissa Poteete, Fahao Zhang, Diane Lui, Waree Rinsurongkawong, John V Heymach

      • Abstract

      Background

      Previously, we reported that the upregulation of the NRF2/KEAP1 pathway in non-small cell lung cancers (NSCLC) bearing co-mutations in KRAS and LKB1 is critical to maintain redox homeostasis which contribute to radiation resistance in these tumors. Here, we explore the role of the LKB1 mutation as a potential predictor radiation outcome in NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively analyzed the patients undergoing definitive treatment for newly diagnosed NSCLC who were enrolled in the prospectively collected MD Anderson Lung Cancer Moon Shot GEMINI database according to LKB1 mutation status. Cox regression analysis and log-rank tests were used to correlate with radiation outcomes according to LKB1 mutation status and/or KRAS mutation subgroup. We then investigated the mechanisms of radiation resistance in these tumors in preclinical models.

      4c3880bb027f159e801041b1021e88e8 Result

      wclc 2018 picture.jpgOf the 173 patients with stage III NSCLC treated with definitive radiotherapy, with or without chemotherapy were analyzed according to LKB1 mutation status demonstrated that LKB1 mutation had statistically significantly higher rate of loco-regional recurrence, and shorter disease-free survival than in patients with wild type LKB1 (P = 0.013 and P = 0.037, respectively). Moreover, additional loss of either LKB1 or TP53 in KRAS-mutant tumors renders these tumors higher loco-regional recurrence after radiation (P interaction = 0.045). We identified that LKB1 loss is associated with radio-resistance in part by KEAP1/NRF2 pathway activation. Re-expression of LKB1 or NRF2 pathway suppression (via KEAP1 expression) enhanced radiotherapy sensitivity in vivo.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results suggest that LKB1 mutation is a potential predictive impact on radiation outcome of patients with NSCLC. The upregulation of the KEAP1/NRF2 pathway in NSCLC bearing co-mutations in KRAS and LKB1 is critical to maintain redox homeostasis and determine the sensitivity for radiation.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-29 - The Prognostic Effect of Tumor Mutation Burden and Smoking History in Resected EGFR Mutant Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Hadas Sorotsky  |  Author(s): Michael Cabanero, Mor Moskovitz, Jessica Weiss, Melania Pintilie, Natasha B Leighl, Penelope Bradbury, Geoffrey Liu, Alborz Kia, Trevor J. Pugh, Dax Torti, Jonathon Torchia, Ming Sound Tsao, Frances A Shepherd

      • Abstract

      Background

      Although EGFRm NSCLC occurs mainly in non-smoking patients, most series report 20%-35% of cases in current or previous smokers. Broad molecular profiling of EGFRm NSCLC in smokers has not been reported.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Surgically resected primary EGFR exon 19, 20 and 21 mutated NSCLC tumors from 106 patients were molecularly profiled by whole exome sequencing using the Illumina HiSeq2000 platform. Alignment and variant discovery analysis was performed according to GATK best practices workflow; 74 sequenced to a mean coverage of 65.1x. Demographics and outcomes were compared for smokers and non-smokers (non-S), and by mutation profile.

      4c3880bb027f159e801041b1021e88e8 Result

      Among 53 non-smokers and 21 smokers (5 current/recent within 10 years), 70% were female, 51% non-Asian, 40.5% >65 years of age and 58.1% had EGFR exon 19. Of the 74 patients, 51% were stage I, 19% stage II and 30% stage III+. Smoking was associated with male sex (p= 0.011) and non-Asian ethnicity (p=0.00002) but not age, stage or EGFR exon 19/20/21 subtype. Multiple “driver” mutations occurred in tumors of 23.8% smokers and 26.4% non-S. TP53/EGFR co-mutation occurred in 52.4% smokers and 47.2% non-S. There was no significant difference seen for TMB in smokers: median TMB in smokers 3(1.4-7.46) versus 2.7(0.96-3.95) in non-S (p=0.11). The strongest prognostic factor for OS and DFS was stage (I, II, III+) (p<0.0001 for each compared to stage I). Smoking history did not have a significant effect on survival: HR 1.61 (CI 0.78-3.32, p=0.2) or probability of relapse: HR 0.9 (CI 0.46-1.77, p=0.77). Smoking within 10 years of NSCLC diagnosis was not associated with shorter OS/DFS. Neither EGFRm subtype nor TP53/EGFR co-mutation was associated with probability of relapse or OS. High TMB was significantly associated with shorter survival: HR above vs below the median 2.37 (CI 1.12-5.01, p=0.024), but not probability of relapse: HR 1.67 (CI 0.88-3.19, p=0.12). A subset analysis found the effect of TMB on survival was significant in patients >65 years (p=0.004), but not in patients <65 years (p=0.95).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Stage remains the strongest prognostic factor for survival and probability of relapse in completely resected EGFRm NSCLC. TMB appears to have an effect on survival outcomes, unlike smoking status, and this effect may be greater in patients older than 65 years.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.03-30 - Clinical Significance of Urothelial Carcinoma Associated 1 in Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Hongyu Wu

      • Abstract

      Background

      Lung cancer is a leading cause of death worldwide. Long non-coding RNAs have been documented aberrantly expressed and exerted crucial role in variety of cancers. Urothelial carcinoma associated 1 (UCA1) is a potential new type of biomarkers for tumor diagnosis and exerts oncogenic effect on various human cancers. In previous work of our lab, we demonstrated that UCA1 exerts oncogenes activity in lung cancer, acting mechanistically by up-regulating HMGB1 expression through ‘sponging’ miR-193a. However, the contributions of this pathway in lung cancer remain largely unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this study, we sought to dissect the role of UCA1/miR-193a/HMGB1 pathway in progression of lung cancer. Firstly, we detected the expression profile of UCA1/miR-193a/ HMGB1 pathway in 50 pairs of lung cancer and adjacent normal tissues and meanwhile, plas­ma samples from 50 healthy controls, 50 lung cancer patients before and after tumor removal.

      4c3880bb027f159e801041b1021e88e8 Result

      We found that UCA1 and HMGB1 were up-regulated and miR-193a down-regulated in cancer sample from tissues and plasma. Then, the relationships between UCA1/miR-193a/ HMGB1 pathway and clinical features and overall survival were analyzed. The results demonstrated that high expression of UCA1, HMGB1 and low expression of miR-193a were associated with LMN, higher pT category, advanced TNM stages (P < 0.01) and worse survival time than those with low expression of UCA1, HMGB1 and high expression of miR-193a (P = 0.038). Furthermore, plasma levels of UCA1 and HMGB1 in lung cancer patients were significantly higher than those of controls (P = 0.017). In addition, we displayed the significant difference in plasma level of UCA1, miR-193a and HMGB1 between samples taken before and after surgery (P = 0.048).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The expression profile of UCA1/miR-193a/ HMGB1 pathway is related to prognosis in lung cancer and served as a potential biomarker for early diagnosis and dis­ease monitoring of lung cancer patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

  • +

    P3.04 - Immunooncology (Not CME Accredited Session)

    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Moderators:
    • +

      P3.04-01 - Combined Plasma cfDNA Mutations and a Serum Proteomic Signature may Identify Non-Responders to Anti PD-1 Treatment in NSCLC

      12:00 - 13:30  |  Presenting Author(s): Arno Amann  |  Author(s): Gabriele Gamerith, Alexander Bader, Westen Hahn, Cherie Tschida, Tristin Wolff Cope, Audrey Audetat, Hestia Mellert, Gary Pestano, Heinz Zwierzina

      • Abstract

      Background

      Predictive scoring systems, for example the status of programmed death-ligand 1 (PD-L1), provide physicians a tool to prescribe immune checkpoint inhibitors for patients diagnosed with non-small cell lung cancer (NSCLC). However, a significant percentage of patients do not respond to these therapies. Additional predictive biomarkers, which further define subpopulations that will benefit from these drugs, are needed.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Serum/plasma samples, clinical and survival data were available for 20 patients with NSCLC that received anti PD-1 therapy either in first (n=1) or second line or later (n=19). Serum/plasma samples were acquired on the day when immunotherapy was administered the first time and at the timepoint of first staging, following initiation of therapy. Plasma samples were analysed for circulating KRAS (G12C, G12D, G12V) and EGFR (E746-A750, L858R, T790M) mutation status by droplet digital PCR (the GeneStrat test). Furthermore, matrix assisted laser desorption/ionization (MALDI) mass spectra were acquired from the matched serum samples using a proteomic test (the VeriStrat test). VeriStrat creates a profile of eight protein features and uses a supervised machine learning algorithm to define outcome subgroups.

      4c3880bb027f159e801041b1021e88e8 Result

      Four patients were found to harbour either EGFR or KRAS mutations or a combination of both in circulation. Two patients displayed a mutation in KRAS G12D and EGFR del19 simultaneously. The other two patients exhibited only a mutation in KRAS (either G12V or G12C). Interestingly, three patients harbouring driver mutations displayed a VeriStrat status of poor at first staging and did not benefit from anti PD-1 therapy. The two patients harbouring both EGFR and KRAS mutations had VeriStrat good labels before start of treatment, which switched to poor results at first staging. Only one patient, displaying a single KRAS mutation and a VeriStrat good status before start of treatment showed a partial response at first staging. Of the 16 patients for whom no circulating mutation was present we found no change in VeriStrat status from before start of treatment to first staging.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Integrated analysis of circulating genomic and proteomic markers for patients that will receive therapy aimed at the inhibition of anti-PD1 and anti-PD-L1 axis may further define patient cohorts that will not respond to immunotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.04-02 - Early Plasma ctDNA Response Anticipates Clinical Response to First-Line Immunotherapy in Advanced NSCLC

      12:00 - 13:30  |  Presenting Author(s): Mark M. Awad  |  Author(s): Christine A Lydon, Anika Adeni, Safiya Subegdjo, Greg Jones, Vincent Plagnol, John Beeler, Geoffrey R. Oxnard

      • Abstract

      Background

      Shedding of circulating tumor DNA (ctDNA) into plasma can be an independent prognostic indicator in lung cancer, and changes in plasma ctDNA levels correlate with response to targeted therapy. We hypothesized that serial assessment of plasma ctDNA by next generation sequencing (NGS) would enable early detection of response to immunotherapy in NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with advanced NSCLC who received first-line treatment with pembrolizumab alone or in combination with platinum doublet chemotherapy at the Dana-Farber Cancer Institute were enrolled in this study. Plasma collected from patients prior to starting therapy and again at 3 and 3 weeks after starting therapy was analyzed by NGS using enhanced tagged-amplicon sequencing of hotspots and coding regions from 36 genes (InVisionSeq). The trends of the ctDNA allele frequency were correlated with radiographic responses to therapy.

      4c3880bb027f159e801041b1021e88e8 Result

      Serial plasma samples were collected on 21 patients with the following characteristics: 67% female, median age 62, 90% adenocarcinoma, 10% squamous cell carcinoma. Pembrolizumab was administered as monotherapy to 18 (86%) patients and in combination with platinum/pemetrexed in 3 (14%) patients for a median of 6 cycles. Among the 8 (38%) patients with no detectable ctDNA at baseline, 5 patients who maintained no detectable ctDNA during serial analyses responded to treatment, and 3 patients with emergence of ctDNA within the first 6 weeks of treatment initiation experienced progressive disease. In the 13 (62%) patients with detectable ctDNA at baseline, radiographic responses were preceded by earlier changes in ctDNA allele frequency. Six of 7 patients with >50% decreases in ctDNA allele fraction responded to treatment while 4 of 6 patients with progressive disease had increases in ctDNA within 6 weeks.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In advanced NSCLC treated with first-line immunotherapy, rapid decreases and clearance of ctDNA correlated with clinical benefit, while increasing or newly detectable ctDNA was a harbinger of progressive disease. These results suggest a potential role for ctDNA as an early pharmacodynamic biomarker of response or resistance to immunotherapies.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.04-03 - Association of Functional Polymorphism in CTLA-4 Gene with Survival in Non-Small Cell Lung Cancer: A Brazilian Study

      12:00 - 13:30  |  Presenting Author(s): Marcelo L. Balancin  |  Author(s): Juliana Machado-Rugolo, Alexandre Todorovic Fabro, Edwin Roger Parras Cuentas, Vanessa Karen De Sá, Claudia Aparecida Rainho, Maria Aparecida Nagai, Vera Luiza Capelozzi

      • Abstract

      Background

      Blockade of immune checkpoints with monoclonal antibodies has recently emerged as a novel therapy against cancer. Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) is a potent immunoregulatory molecule which regulate T- cell activation and proliferation. The most studied +49A/G polymorphism (rs231775) of the CTLA-4 gene has been associated with several autoimmune diseases and cancer.This study aimed to investigate the relationship between +49A/G polymorphism can predict the prognosis of patients with early stage non-small cell lung cancer (NSCLC) after surgical resection in Brazilian population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Genomic DNA (gDNA) was extracted from fresh-frozen NSCLC tissue using the QIAamp DNA Mini Kit (Qiagen, Valencia, USA) following the manufacturer’s recommendations. The CTLA-4 gene was customized in a amplicon-based assay for targeted resequencing by TruSeq Custom Amplicon v1.5kit (TSCA, Illumina) on an Illumina MiSeq instrument (Illumina, San Diego, CA, USA). SNPs with minor allele frequency (MAF) of 0.05 or higher were included. X2 test was used to assess the association between CTLA-4 49A/G SNP and categorical clinicopathologic parameters. The overall survival (OS) estimates were calculated using the Kaplan-Meier method. p <0.05 was considered as statistically significant.

      4c3880bb027f159e801041b1021e88e8 Result

      Seventy-five patients with diagnosed NSCLC have been enrolled into this study. According to the pathological reports, the samples included adenocarcinoma (AC,n=52), adenosquamous carcinoma (ASC,n=5), squamous cell carcinoma (SCC,n=15) and large cell carcinoma (LCC, n=3). The CTLA-4 +49A/G genotype frequencies in NSCLC patients were detected with the following disposition: the frequencies of AA, AG and GG genotype were 53,3% (40/75), 33,3% (25/75) and 13.4% (10/75), respectively. We observed that patients with the GG-genotype of CTLA-4 rs231775 had longer OS compared with patients with an AG or AA genotype.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study suggests that CTLA-4 rs231775 could potentially be used as a prognostic biomarker.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.04-04 - Prognostic Value of MHC-I, PD-L1 and CD8+ TILs Expressions in Patients with Surgically Resected Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Xu Wang  |  Author(s): Xiao Ding, Jiuwei Cui

      • Abstract

      Background

      Lung cancer is the most commonly diagnosed cancer and also the leading cause of cancer death globally. Chemotherapy showed limited improvement in the survival of surgically resected non-small cell lung cancer (NSCLC) patients. There was no effective prognostic indicators in surgically resected NSCLC. The expression levels of tumor surface molecules, such as major histocompatibility complex class I (MHC-I), programmed cell death-ligand 1 (PD-L1) and CD8+ tumor infiltrating lymphocytes (TILs) were detected in this study to investigate the potential prognostic markers in the patients with surgically resected NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tissue of 125 patients with surgically resected NSCLC were obtained from the First Hospital of Jilin Universtiy. MHC-I, PD-L1 and CD8+ TILs expressions were detected with immunohistochemistry. The association between their expression levels and patients’ prognosis was analyzed by SPSS 17.0 software (SPSS, Chicago, IL).

      4c3880bb027f159e801041b1021e88e8 Result

      MHC-I was down-expressed, PD-L1 was up-regulated in NSCLC compared with the adjacent tissues. CD8+ TILs could be seen in tumor stroma and nest. With univariate analysis, we found that the down-expression of MHC-I had an association with poor relapse-free survival (RFS) and overall survival (OS) in NSCLC patients (P = 0.007 and P = 0.001). RFS and OS in PD-L1− group tended to be longer than that of PD-L1+ group, but the difference was not significant (P > 0.05). Based on the distribution of CD8+ TILs, patients were divided into three groups: immune-inflamed group, immune-excluded group and immune-desert group. RFS and OS of patients with the immune-inflamed phenotype (CD8inflamed) were longer than patients with the immune-excluded and immune-desert phenotype (CD8non-inflamed) (P = 0.013 and P = 0.015). Besides, patients were divided into four subgroups based on the PD-L1 and CD8+ TILs expression: PD-L1+/CD8inflamed, PD-L1+/CD8non-inflamed, PD-L1−/CD8inflamed, and PD-L1−/CD8non-inflamed. Statistical differences were achieved both in RFS and OS (P = 0.012 and P = 0.032). RFS and OS in patients with PD-L1+/CD8inflamed and PD-L1−/CD8inflamed were longer than patients with PD-L1+/CD8non-inflamed and PD-L1−/CD8non-inflamed. Patients with PD-L1+/CD8non-inflamed experienced the worst RFS and OS. With multivariate analysis, we found that MHC-I and CD8+ TILs might be independent prognostic factors in surgically resected NSCLC.

      8eea62084ca7e541d918e823422bd82e Conclusion

      MHC-I and CD8+ TILs expression had a close association with patients prognosis in this study. The combination of PD-L1 and CD8+ TILs, instead of PD-L1 alone, suggested impressive prognostic values in NSCLC patients. It worth further study to confirm the clinical value of MHC-I, PD-L1 and CD8 TILs expressions in the patients with surgically resected NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.04-05 - Programmed Death-Ligand 1 of Cytology Specimens as a Promising Method for Maker Evaluation in Patients of Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Zhengwei Dong

      • Abstract

      Background

      Measuring programmed death-ligand 1 (PD-L1) expression has been commonly used to classify the promising patients for immunotherapy. PD-L1 heterogeneous expression has been elucidated within the tumor. Therefore, we questioned whether small tissue samples, such as cytology samples, sufficiently represented PD-L1 expression in non-small cell lung cancer(NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Paired cytological cell block and surgical resection before systemic therapy was assessed. PD-L1 expression was quantified by using both 28-8 and SP142 assays. Feasibility of PD-L1 expression in cell blocks was compared with that in matched surgical resection with various cutoffs.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 112 pairs of specimens were collected at the time of initial diagnosis, including 79(63.2%) adenocarcinomas and 28(25.0%) squamous cell carcinomas. PD-L1 expression showed fair to substantial concordance between cytology specimens and surgical resection for both antibodies’ staining ( 8eea62084ca7e541d918e823422bd82e Conclusion

      PD-L1 expression of cytology specimens with high tumor cells showed concordance with surgical resection. These findings suggested that cytology specimens might be adequate representative for PD-L1 expression of patients with NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.04-06 - Prognostic Significance of Serum CXCL12 Level in Patients with Surgical Resected Lung Adenocarcinoma

      12:00 - 13:30  |  Presenting Author(s): Jung-Jyh Hung  |  Author(s): Wen-Hu Hsu

      • Abstract

      Background

      Lung cancer is the leading cause of cancer-related death in the world. Cytokines are a heterogeneous group of soluble small polypeptides or glycoproteins. The tumor microenvironment is rich in cytokines and other inflammatory mediators that influence immunosuppression, cancer cells growth, tissue remodeling and angiogenesis. In this study, we determined the prognostic value of selected cytokines or chemokines in patients with lung adenocarcinoma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Sixty-three patients undergoing surgical resection for lung adenocarcinoma were enrolled in this study. A total of 63 serum samples from these patients were used for study. The levels of cytokines/chemokines in these serum samples were determined by cytometric bead array according to manufacture’s instruction. The following cytokines/chemokines have been examined, including interleukin-1b (IL-1b), IL-6, IL-8, IL-10, CXCL9, CXCL10, CXCL12, CCL19, CCL21, and CCL25.

      4c3880bb027f159e801041b1021e88e8 Result

      With a median follow-up time of 62.3 months (range, 0.7 to 94.1 months), the 5-year overall survival rate was 88.1%. To determine the expression of cytokines/chemokines in lung adenocarcinoma serum samples, cytometric bead array was performed in 63 lung adenocarcinoma serum samples. Univariate analysis indicated that stage II and III (vs. stage I) (P = 0.016) was a significant prognostic factor for worse overall survival. Poor differentiation (P = 0.062) and CXCL12 overexpression (P = 0.052) tended to be significant prognostic factors for worse overall survival. IL-1b, IL-6, IL-8, IL-10, CXCL9, CXCL10, CCL19, CCL21, and CCL25 were not significant prognostic factors for overall survival. The advanced stage (II and III vs. I) (hazard ratio [HR], 7.775; 95% confidence interval [CI], 1.243 to 48.618; P = 0.028), poor differentiation (HR, 7.995; 95% CI, 1.092 to 58.547; P = 0.041) and CXCL12 overexpression (HR, 7.307; 95% CI, 1.163 to 45.899; P = 0.034) were still significant prognostic factors for worse overall survival in multivariate analysis. Male sex (P = 0.007) was significantly associated with CXCL12 overexpression.

      8eea62084ca7e541d918e823422bd82e Conclusion

      CXCL12 overexpression was a significant prognostic factor for worse overall survival in patients with surgical resected lung adenocarcinoma. Male sex was significantly associated with CXCL12 overexpression. CXCL12 overexpression has the potential to be used as a predictor of worse outcome in lung adenocarcinoma patients after surgical resection.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.04-07 - Correlation Between PD-L1 Expression and Expression of CDK4 and SPOP in Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Masaaki Inoue  |  Author(s): Junichi Yoshida, Soichi Oka, Yohei Honda, Daisei Yasuda

      • Abstract

      Background

      Immunotherapy that targets programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) has emerged as a novel treatment modality for cancers. Clinical trials have reported durable responses and long-term remissions using PD-1/PD-L1 inhibitors, and the expression level of PD-L1 at the tumor cells was correlated with a response to PD-1/ PD-L1 inhibitors. However these inhibitors are only effective in a subset of lung cancer patients, and the underlying molecular mechanisms are not well understood. Recently, it has been reported that PD-L1 expression can be regulated at both transcriptional and post-translational levels, such as cyclinD-CDK4 and the cullin 3-SPOP (phosphorylation of speckle-type POZ protein) E3 ligase. In this study, we focus on the regulation of PD-L1 expression in lung cancer, and we investigated the association between the expression of PD-L1 and biomarkers in regard to clinical outcomes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We invested CDK4, CDK6 and SPOP expression of lung cancer, and CD4 and CD8 expression of tumor-infiltrating lymphocytes (TILs) by immunohistochemistry of 36 non-small cell lung cancers, those had undertaken an operation or chemotherapy from March 2007 to January 2018 and analyzed PD-L1 expression (negative:0%, low expression:1-49%, high expression:≥50%). The staining intensity of CDK4, CDK6 and SPOP was scored as 0 (negative), 1 (weak), 2 (medium), and 3 (strong). Extent of staining was scored as 0 (0-10%), 1 (11-25%), 2 (26-50%), 3 (51-75%), and 4 (76-100%) according to the percentages of the positive staining areas in relation to the whole cancer area. For CD4+ and CD8+ cells, a maximum numbers of stained cell were counted semi-quantitatively in high-powered fields for the scoring as 1-4. The observed protein expression levels and TILs counts were analyzed for correlation to PD-L1 expression, clinicopathological parameters and the responses of PD-1 inhibitors.

      4c3880bb027f159e801041b1021e88e8 Result

      PD-L1 expression was observed in 15 (48%) patients of lung cancer, 8 (26%) of low expression and 7 (23%) of high expression. Positive expression rates of SPOP were 56.3% of negative expression of DP-L1, 50.0% of low expression and 28.6% of high expression. That of CDK4 and CDK6 was 43.8%, 25.0%, 16.6%, and 43.8%, 62.5%, 51.7%, respectively. The positive rate of SPOP (p=0.67), CDK4 (p=0.16) and CDK6 (p=0.37) in PD-L1 positive group was lower than that of PD-L1 negative group, but significant. CD8+ cell count was positive relation to PD-L1 expression.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our data supported previous findings that inhibition of CDK4 and CDK6 increases PD-L1 protein levels and SPOP-deficiency correlated with increased PD-L1 protein abundance.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P3.04-08 - Identifying Resistance to Immune Checkpoint Inhibitors by Screening for PD-L1 and MHC I Expression on CTCs in Pts with NSCLC

      12:00 - 13:30  |  Presenting Author(s): Ticiana A. Leal  |  Author(s): Jennifer L. Schehr, Alexander Kamisnki, Toby Campbell, Anne Traynor, Joshua M Lang

      • Abstract

      Background

      PD-L1 expression on tumor predicts benefit to immune checkpoint inhibitors (ICIs) in patients with advanced NSCLC. However, there are a significant number of patients whose tumor test positive for PD-L1 expression that do not derive benefit from ICIs, suggesting the existence of intrinsic resistance mechanisms. PD-L1 blockade aims to trigger tumor cell recognition and lysis by CD8+ T cells, but this process requires concordant expression of MHC I by tumor cells. Recently, MHC I negativity was observed in 49% of patients with lung carcinoma, and correlated with a lack of CD8+ T cell infiltration, emphasizing the importance of screening for MHC I in combination with PD-L1.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      For the purposes of both screening and the detection of acquired resistance, we developed a minimally invasive diagnostic test using Circulating Tumor Cells (CTCs). CTCs were captured and stained on the ExtractMax system (Gilson, Inc.) with Exclusion-Based Sample Processing (ESP) technology (Salus Discovery, LLC). With automation, the ExtractMax simplifies complex multi-step procedures, reduces variability, and ensures gentle manipulation of rare cell targets for optimal yield and viability.

      4c3880bb027f159e801041b1021e88e8 Result

      A range of PD-L1 and MHC I expression levels were detected on CTCs captured from a cohort of patients with NSCLC, with two patients showing no MHC 1 expression and all others with heterogeneous expression of MHC 1. PD-L1 expression was variable across all samples tested with subset of patients with PD-L1 positive CTCs but MHC I negative, suggesting intrinsic resistance to PD-L1 targeted therapies.

      abstract_14173.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      This data supports the feasibility of using an automated CTC processing system to detect and monitor PD-L1 and MHC I expression in patients with NSCLC. Ongoing efforts include expanding this patient cohort in larger clinical trials and transitioning this test into a clinical laboratory testing facility for regulatory approval and use as a clinically actionable diagnostic tool.

      6f8b794f3246b0c1e1780bb4d4d5dc53