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  • ELCC 2017

    The 7th European Lung Cancer Conference

    Access to all presentations that took place at ELCC 2017 in Geneva, Switzerland

    Presentation Date(s):  
    • May 5 – 8, 2017
    • Total Presentations: 359

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    The role of antiangiogenic agents in NSCLC: Are we making progress? (ID 43)

    • Type: Young Oncologist session
    • Presentations: 3
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      State of the art in first and subsequent lines of the NSCLC treatment (ID 134)

      08:00 - 08:20  |  Author(s): B. Besse

      • Abstract

      Abstract not provided

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      Biomarker approaches for optimisation of antiangiogenic therapy (ID 138)

      08:20 - 08:40  |  Author(s): M. Reck

      • Abstract
      • Presentation
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      Abstract not provided

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    Management of NSCLC with resistance to first line targeted therapy (ID 21)

    • Type: Educational session
    • Presentations: 5
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      Management of T790M positive disease after EGFR TKI failure (ID 84)

      09:00 - 09:20  |  Author(s): L. Horn

      • Abstract
      • Presentation
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      Management of T790M negative disease after EGFR TKI failure (ID 85)

      09:20 - 09:40  |  Author(s): M. Krebs

      • Abstract
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      Management of drug resistance in ALK positive NSCLC (ID 86)

      09:40 - 10:00  |  Author(s): D.S. Tan

      • Abstract

      Abstract not provided

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      Management of resistance in other targets beyond ALK and EGFR (ID 87)

      10:00 - 10:20  |  Author(s): L. Friboulet

      • Abstract
      • Presentation
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      Abstract not provided

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    SCLC and early stage NSCLC (ID 62)

    • Type: Proffered Paper session
    • Presentations: 7
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      44O - Validation of the prognostic value of 8th edition revisions of the AJCC staging system for non-small cell lung cancer: A SEER database analysis (ID 494)

      09:00 - 09:12  |  Author(s): O. Abdel-Rahman

      • Abstract
      • Presentation
      • Slides

      Background:
      The 8[th] edition of the American Joint Committee on Cancer (AJCC) staging system for non-small cell lung cancer (NSCLC) has been released. The current study seeks to validate the prognostic significance of the new system among patients registered within the surveillance, epidemiology and end results (SEER) database.

      Methods:
      SEER database (2010-2013) has been accessed through SEER*Stat program and AJCC 8[th] edition stages were reconstructed utilizing the collaborative stage descriptions. Overall and lung cancer-specific survival analyses according to both 7[th] and 8[th] editions were conducted through Kaplan-Meier analysis and multivariate analysis was conducted through a Cox proportional hazard model.

      Results:
      A total of 127096 patients with NSCLC were identified in the period from 2010-2013. For overall survival assessment according to the 8[th] edition, P values for all pair wise comparisons among different stages were significant (<0.0001) except for the comparison between stage IIA and stage IIB (P = 0.102). For lung cancer-specific survival according to the 8[th] edition, P values for all pair wise comparisons among different stages were significant (<0.0001). Among patients with stage I disease, multivariate analysis for factors affecting overall and lung cancer-specific survival among patients with stage I disease was conducted. The following factors were associated with worse overall and lung cancer-specific survival (age ≥ 70 years, more advanced stage, male gender, squamous histology, no surgery and no radiotherapy) (P < 0.0001 for all factors).

      Conclusions:
      This SEER analysis supports the prognostic significance of the added sub-stages described within AJCC 8[th] edition stages I and III. Further work is needed to incorporate molecular markers and personalize the future editions of the AJCC staging system.

      Clinical trial identification:


      Legal entity responsible for the study:
      Omar Abdel-Rahman

      Funding:
      Omar Abdel-Rahman

      Disclosure:
      The author has declared no conflicts of interest.

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      59O - The impact of EGFR mutations on the prognosis of resected non-small cell lung cancer: A meta-analysis of literatures (ID 372)

      09:12 - 09:24  |  Author(s): W. Liang, Q. He, W. Wang, J. He

      • Abstract
      • Presentation
      • Slides

      Background:
      Epidermal growth factor receptor (EGFR) mutation represents a favorable prognostic factor in advanced-stage non-small cell lung cancer (NSCLC), which is predominantly contributed by its good response to EGFR-tyrosine kinase inhibitor. However, its impact on the prognosis of resectable NSCLC after complete surgery, which more closely reflects its natural course, remains controversial. Diverse results have been reported partially due to the small sample size of these studies; small studies bring bias especially in postoperative setting. Therefore, we sought to pool all current evidence to show the true effects.

      Methods:
      Electronic databases were searched for eligible studies. The primary endpoint was disease free survival (DFS), which will be less influenced by subsequent treatments after recurrence. The DFS between EGFR mutated and wild-type patients were compared with special interest in stage I patients who are rarely subjected to adjuvant therapy. In addition, DFS of patients with 19 exon deletion (19del) and 21 exon L858R mutation (L858R) were compared. Random effects models were used.

      Results:
      A total of 13 studies involving 2,652 cases were included; 1033 (39.0%) patients were EGFR-mutated, 47.7% were 19del and 44.1% were L858R. Most studies detected EGFR mutations with PCR-based methods. The DFS of EGFR-mutated patients were similar to wild type patients in overall population (HR 0.87, 95% CI 0.65 to 1.16) and stage I subgroup (HR 0.82, 95% CI 0.40 to 1.69). DFS of 19del patients was potentially inferior to L858R patients but the difference was not significant (HR 1.38, 95% CI 0.76 to 2.52).

      Conclusions:
      EGFR-mutated patients showed no significant difference in postoperative disease-free survival compared with wild-type resected NSCLC. There is still no sufficient evidence to support different postoperative treatment strategy (especially for stage I) for mutated and wild-type patients. However, 19del might be an adverse factor through indirect reasoning, which might require more intensive management. Thus, we strongly encouraged reporting specific prognostic impacts of different mutation types compared with wild-type patients in the following studies.

      Clinical trial identification:


      Legal entity responsible for the study:
      The clinical research center of the first affiliated hospital of Guangzhou Medical Univeristy

      Funding:
      The 1st Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

      Disclosure:
      All authors have declared no conflicts of interest.

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      60O - The benchmark of examined lymph node count in node positive NSCLC patients: A populational validation with SEER database (ID 518)

      09:24 - 09:36  |  Author(s): W. Liang, J. He, G. Rocco, T. D’amico, C.S.H. Ng, A. Brunelli, C. Liu, R.H. Petersen, J. He

      • Abstract
      • Presentation
      • Slides

      Background:
      Based on SEER database and a Chinese multicenter registry, we previously identified a benchmark for indicating sufficient lymph node (LN) examination among node negative NSCLC patients (Liang et al. J Clin Oncol 2016). Due to variability of LN examination practice, some patients with less than 16 examined LNs might be understaged and therefore have worse survival outcome. This benchmark agrees with the reported mean LN being harvested during complete pulmonary and mediastinal LN exploration, which could serve as a sign for adequate systematic LN sampling and theorectically be applicable to node positive patients as well. We sought to determine its prognostic value among node positive patients using SEER database.

      Methods:
      The United States Surveillance, Epidemiology, and End Results (SEER) database on stage I to IIIA completely resected NSCLC (1990-2010) were extracted. Patients were dichotomized according to examined LN count (<16 vs. > =16). Multivariate Cox regression model was used to compare the overall survival (OS) and cancer specific survival (CSS) between groups under adjustment for other prognostic factor.

      Results:
      A total of 12,407 cases met the inclusion criteria with complete data were studied. The median followup was 7.6 years (range 0.1 to 10.0). Patients with <16 examined LNs remained a significant unfavorable factor in terms of both OS (HR 1.34, 95% CI 1.27 to 1.43, P < 0.001) and CSS (HR 1.36, 95% CI 1.27 to 1.45) when compared to those with at least 16 LNs, after adjusting for diagnostic year, sex, age, tumor size, differentiation, pathology and positive LN count. Different subgroups showed consistent trends.

      Conclusions:
      This study confirmed that 16 exmamined LNs could also be considered a benchmark for systematic LN examination among node positive NSCLC patients despite the number of positive LNs. Node positive NSCLC with less than 16 LNs being harvested should be cautiously evaluated for the quality of LN examination and indication for subsequent treatment.

      Clinical trial identification:


      Legal entity responsible for the study:
      The 1st Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

      Funding:
      The 1st Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

      Disclosure:
      T. D’Amico: Consulting or Advisory Role: Scanlan International. C.S.H. Ng: Leadership: Johnson & Johnson; Honoraria: J&J, Covidien, Medtronic; Consulting or Advisory Role: J&J, Covidien, Medtronic; Speakers’ Bureau: J&J, Covidien, Medtronic; Research Funding: J&J, Covidien, Medtronic. A. Brunelli: Honoraria: Bard Medical. C-C. Liu: Honoraria: Johnson & Johnson Consulting or Advisory Role: Johnson & Johnson Travel, Accommodation, Expenses: Johnson & Johnson (I). R.H. Petersen: Honoraria: Medtronic, Ethicon, Medela. J. He: Consulting or Advisory Role: Johnson & Johnson. All other authors have declared no conflicts of interest.

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      Invited Discussant 44O, 59O and 60O (ID 545)

      09:36 - 09:51  |  Author(s): W.E.E. Eberhardt

      • Abstract
      • Presentation
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      Abstract not provided

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      51O - Early limited-stage small cell lung cancer: Sub-group analysis of the concurrent once-daily versus twice-daily radiotherapy (CONVERT) trial (ID 474)

      09:51 - 10:03  |  Author(s): A. Salem, L. Ashcroft, A. Dagnault, C. de Metz, M. Hatton, I. Locke, I. Monnet, L. Padovani, F. Blackhall, C. Faivre-Finn

      • Abstract
      • Presentation
      • Slides

      Background:
      There is little evidence to guide the management of early limited-stage small cell lung cancer (LS-SCLC). We examined outcome of early LS-SCLC patients treated within a contemporary trial.

      Methods:
      This is an exploratory analysis of early (TNM stage I-II) LS-SCLC patients included in the CONVERT trial. This is a randomized phase III trial that compared twice-daily (45 Gray (Gy) in 30 twice-daily fractions over 3 weeks) and once-daily (66 Gy in 33 daily fractions over 6.5 weeks) radiotherapy starting on day 22 of chemotherapy cycle 1 in good performance score (PS) patients. Chemotherapy consisted of 4-6 cycles of cisplatin and etoposide. Prophylactic cranial irradiation (PCI) was offered if indicated. Radiotherapy was delivered using three-dimensional conformal or intensity modulated technique.

      Results:
      Between 2008 and 2013, 547 patients were recruited to this trial. Five hundred and thirteen patients were eligible for this analysis and 87 (17%) had early disease. Staging flurodeoxyglucose positron emission tomography (FDG-PET) use (68% versus 55.4%, p = 0.05) and baseline PS (PS0 57.5% versus 43.2%, p = 0.04) were different between early and non-early LS-SCLC patients, respectively. Early patients achieved longer overall survival (median 50 versus 25 months, p = 0.001) and time to local (median 40 versus 17 months, p = 0.0017) and metastatic progression (median 49 versus 16 months, p = 0.0004) compared to non-early patients, irrespective of treatment arm. In early patients, there was no significant overall survival difference between treatment arms, p = 0.31. Radiotherapy compliance was significantly higher in early patients (p = 0.004) and these patients were less likely to experience grade ≥3 acute oesophagitis, compared to non-early patients (11% versus 21%, p < 0.005).

      Conclusions:
      Early LS-SCLC patients achieve good long-term survival with minimal acute side-effects following chemo-radiotherapy and PCI. This study guides practice and provides a benchmark for future studies comparing a surgical to a non-surgical approach in this patient cohort.

      Clinical trial identification:
      ISRCTN91927162, NCT00433563

      Legal entity responsible for the study:
      MAHSC-CTU, The Christie NHS Foundation Trust, Manchester, UK

      Funding:
      Cancer Research UK

      Disclosure:
      All authors have declared no conflicts of interest.

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      LBA2_PR - Use of G-CSF and prophylactic antibiotics with concurrent chemo-radiotherapy in limited-stage small cell lung cancer: Results from the Phase III CONVERT trial (ID 501)

      10:03 - 10:15  |  Author(s): F. Gomes, C. Faivre-Finn, F. Fernandez-Gutierrez, D. Ryder, A. Bezjak, F. Cardenal, P. Fournel, J. Van Meerbeeck, F. Blackhall

      • Abstract
      • Presentation
      • Slides

      Background:
      Concurrent chemo-radiotherapy (CTRT) is the optimal treatment for limited-stage small cell lung cancer. The use of granulocyte colony stimulating-factor (G-CSF) in this context is controversial and its routine use is not recommended after a report of higher toxicity but the safety data is scarce. The use of prophylactic antibiotics is also not standardised.

      Methods:
      In a phase 3 trial, 547 patients (pts) were randomised between once-daily RT (66Gy 33 fractions) or twice-daily (45Gy 30 fractions) with chemotherapy (cisplatin/etoposide). The use of prophylactic G-CSF and antibiotics was permitted.

      Results:
      33% of pts received at least 1 cycle of prophylactic G-CSF and 41% received prophylactic and/or therapeutic G-CSF. Its use increased from 11% at cycle 1 to 27% at cycle 4. Prophylactic antibiotics were used in 48% of pts but its use decreased from 41% to 20%. The use of antibiotics and/or G-CSF was similar in both arms. The incidence of grade 3/4 thrombocytopenia was higher in pts with G-CSF (29.4% vs. 13%; p 

      Conclusions:
      The use of G-CSF with modern radiotherapy techniques during CTRT does not result in an increased risk of severe acute esophagitis or pneumonitis. Despite an increased incidence of severe thrombocytopenia and anaemia, the use of G-CSF was not detrimental in PFS or OS.

      Clinical trial identification:
      ISRCTN91927162 / NCT00433563

      Legal entity responsible for the study:
      The Christie NHS Foundation Trust

      Funding:
      The Christie NHS FT, Cancer Research UK, EORTC, GECP, GFPC, IFCT.

      Disclosure:
      All authors have declared no conflicts of interest.

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      Invited Discussant 51O and LBA2_PR (ID 546)

      10:15 - 10:30  |  Author(s): S. Popat

      • Abstract
      • Presentation
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      Abstract not provided

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    Is there a role for second-line immunotherapy in patients with PD-L1 negative NSCLC? (ID 22)

    • Type: Controversy session
    • Presentations: 4
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      Introduction and first vote (ID 89)

      09:15 - 09:25  |  Author(s): M. Reck

      • Abstract

      Abstract not provided

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      Yes (ID 90)

      09:25 - 09:45  |  Author(s): R. Herbst

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    • +

      No (ID 91)

      09:45 - 10:05  |  Author(s): B. Besse

      • Abstract

      Abstract not provided

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      Second vote and conclusions (ID 92)

      10:05 - 10:15  |  Author(s): L. Paz-Ares

      • Abstract

      Abstract not provided

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    Molecular understanding of lung cancer: The role of the host and environment (ID 23)

    • Type: Educational session
    • Presentations: 5
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    SCLC: New insights (ID 25)

    • Type: Educational session
    • Presentations: 5
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      What is the optimal thoracic radiotherapy in limited stage SCLC? (ID 103)

      11:00 - 11:20  |  Author(s): C. Faivre-Finn

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      Can brain control be improved beyond PCI? (ID 104)

      11:20 - 11:40  |  Author(s): E. Gkika

      • Abstract

      Abstract not provided

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      New therapies, new era? (ID 105)

      11:40 - 12:00  |  Author(s): N. Reguart

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      What can CDX models teach us? (ID 106)

      12:00 - 12:20  |  Author(s): C. Dive

      • Abstract

      Abstract not provided

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    What should non-surgeons expect from surgeons? (ID 24)

    • Type: Educational session
    • Presentations: 5
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      Minimal requirements for surgical participation in CT screening programmes (ID 98)

      11:00 - 11:20  |  Author(s): G. Veronesi

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      Surgeon-led randomised trials: The case of mesothelioma (ID 99)

      11:20 - 11:40  |  Author(s): J. Edwards

      • Abstract

      Abstract not provided

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      The approach of surgeons towards N2 NSCLC (ID 100)

      11:40 - 12:00  |  Author(s): G. Massard

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      The impact of international surgical registries on multidisciplinary decisions: The case of thymic tumours and NET (ID 101)

      12:00 - 12:20  |  Author(s): P.L. Filosso

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    Poster Display Session (ID 63)

    • Type: Poster Display Session
    • Presentations: 142
    • Moderators:
    • Coordinates: 5/07/2017, 12:30 - 13:00, Hall 1
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      4P - PD-L1 in NSCLC cytology (ID 446)

      12:30 - 12:30  |  Author(s): M. Kovacevic, I. Kern, S. Gabrič

      • Abstract

      Background:
      PD-L1 is a predictive biomarker for NSCLC, which is determined by immunohistochemistry. Significant number of NSCLCs are diagnosed from cytology samples. No study of PD-L1 expression in NSCLC cytology samples was published to date. The aim of this study was to evaluate possiblity of immunocytochemical determination of PD-L1 status in primary and metastatic NSCLC.

      Methods:
      We examined 50 consecutive cytology samples from 50 patients (19 TBNAs of mediastinal lymph nodes, 9 FNABs of peripheral lymph nodes, 15 TBNAs of lung, 4 pleural effusions, 2 FNABs of subcutaneous mass and one US – guided FNAB of liver). Methanol – fixed cytospins were prepared for immunocytochemistry using PD-L1 mouse monoclonal antibody (clone 22C3, Dako, USA) on an automated staining platform (Benchmark, Ventana/Roche, USA). Samples containing 100 or more tumor cells were considered representative. PD-L1 expression was evaluated on tumor cells with membranous staining. PD-L1 positivity was defined by cutoff value of 1%. 18 patients had concurrent histology samples used for PD-L1 immunohistochemistry (FFPE sections, same PD-L1 antibody clone and platform).

      Results:
      We found 37 (74%) adenocarcinomas, 7 (14%) squamous cell carcinomas, while 6 (12%) remained NSCLC-NOS. 74% of all NSCLC samples showed positive immunocytochemical reaction with PD-L1. 27 (73%) of all adenocarcinomas, 4 (57%) of all squamous cell carcinomas and 6 (100%) of all NSCLC-NOS showed positive immunocytochemical reaction with PD-L1. In patients with both cytology and histology samples, concordance in PD-L1 expression was 78%. All types of cytology samples examined in the study showed to be representative for evaluation. Most problems occurred in evaluation of pleural effusion due to nonspecific cytoplasmic staining for PD-L1 in histiocytes.

      Conclusions:
      Cytology samples are adequate for evaluation of PD-L1 expression in primary and metastatic NSCLC.

      Clinical trial identification:


      Legal entity responsible for the study:
      University Clinic Golnik

      Funding:
      University Clinic Golnik

      Disclosure:
      All authors have declared no conflicts of interest.

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      5P - Repeated biopsy for mutational analysis on EGFR-mutated non-small cell lung cancer (EGFR-NSCLC): Feasibility and safety (ID 493)

      12:30 - 12:30  |  Author(s): G. Anguera, M. Riudavets, A. Torrego, V. Pajares, A. Gimenez, L. López-Vilaró, E. Martínez, J.C. Trujillo-Reyes, E. Lerma, M. Majem

      • Abstract

      Background:
      The majority of non-small cell lung cancer (NSCLC) patients (pts) with epidermal growth factor receptor (EGFR) mutation develop resistance to EGFR tyrosine kinase inhibitors, in 50-60% of the cases, mediated by the EGFR T790M-mutation. Repeated biopsy (Bx) is necessary after progression on initial therapy to check T790M status. The aim of this study is to evaluate the feasibility and safety of repeated Bx in clinical practice.

      Methods:
      Retrospective analysis of 110 repeated biopsies (Bxs) performed in 74 pts with advanced NSCLC during the last 4 years, 30 of them with EGFR-NSCLC underwent to 42 Bxs. The technical success rates for the repeated Bx and the adequacy rates of specimens were evaluated. Bx-related complications were recorded. Clinical details were collected.

      Results:
      42 repeated Bxs were performed in 30 pts with EGFR-NSCLC (6 men (20%), 24 women (80%)). Mean age 62 (36-82). Mean number of repeated Bxs per patient: 1 (1-3). At diagnosis (dx), exon 19 mutation was detected in 20 pts (66,7%) and exon 21 mutation in 10 (33,3%). The main reasons for repeated Bx were: mutational analysis at dx 5 (16,7%), insufficient material at dx 4 (13,3%) and detection of T790M at the moment of progression 21 (70%). The technical success rate for Bx was 35/42 (83.3%), and postprocedural complications occurred in 2/42 cases: 1 pneumothorax and 1 low bleeding. Bx specimens came mostly from primary tumor (25/42, 59,5%, followed by: lymph nodes (2/42, 4,8%), pleural fluid (3/42, 7,15%), liquid Bx (3/42, 7,15%), metastasis sites (9/42, 21,4%): bone 2, liver 2, spinal fluid 2, pleural 2, adrenal gland 1. The most used technique was bronchoscopy (19/42, 45,2%), followed by: percutaneous biopsy (11/42, 26,2%), thoracocentesis (4/42, 9,5%). Other techniques: liquid Bx 3 cases (7,15%), surgery 3 (7,15%) and lumbar puncture 2 (4,8%). Results from repeated Bx were used to select the next line of treatment in 28/42 procedures (66,7%), and 16 of them (57,1%) allowed to include the patient in a clinical trial.

      Conclusions:
      Our data demonstrate that repeated Bx in EGFR-NSCLC is safe and clinically feasible. Findings from repeated biopsy were used to direct subsequent treatment in 66.7% of pts and 16 of them (57,1%) allowed to include the patient in a clinical trial.

      Clinical trial identification:


      Legal entity responsible for the study:
      Hospital de la Santa Creu i Sant Pau

      Funding:
      Hospital de la Santa Creu i Sant Pau

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      6P - Metformin sensitizes lung cancer cells to treatment by the tyrosine kinase inhibitor erlotinib (ID 315)

      12:30 - 12:30  |  Author(s): X. Wang, Y. Xiang, B. Gao

      • Abstract

      Background:
      Lung cancer is one of the deadliest malignant tumors with limited treatment options. Although targeted therapy, using tyrosine-kinase inhibitors, such as erlotinib, has shown therapeutic benefit, only 15% patients with mutated epidermal growth factor receptor (EGFR) in lung cancer cells are sensitive. Therefore, additional therapeutic strategy should be developed. Metformin (Met) has been used to treat type 2 diabetes (T2D) for nearly 60 years. Met reduces circulating glucose and insulin levels by inhibiting gluconeogenesis in the liver. Recently Met class drugs have been shown their anticancer properties, including in combination therapy, in which Met inhibits the growth of tumor initiating cells in breast cancer cell lines and prevents the relapse of tumors in vivo when combining with chemotherapy.

      Methods:
      The effects of Met to sensitizing wild type EGFR lung cancer cells to erlotinib were examined in vitro by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT), flow cytometry analysis, Western blot analysis, chemotaxis assay, as well as in vivo experiments.

      Results:
      We found that MET sensitized lung cancer cells bearing wild-type EGFR to erlotinib treatment by enriching cancer cells expressing higher levels of EGFR with persistent phosphorylation. As a consequence, combination of MET and erlotinib more efficiently inhibited the growth of lung cancer cells both in vitro and in mice with xenografted tumors.

      Conclusions:
      These results suggest a novel approach to treating lung cancer cases which are originally resistant to erlotinib.

      Clinical trial identification:


      Legal entity responsible for the study:
      Shanghai Ruijin Hospital

      Funding:
      This project was supported in part by Shanghai Municipal Health and Family Planning Commission Research Grants (Youth) 20154Y0089.

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      7P - Population-level effect of targeted therapy in patients with advanced pulmonary adenocarcinoma: A Swiss prospective cohort study (ID 453)

      12:30 - 12:30  |  Author(s): C. Schwegler, D. Kaufmann, O. Gautschi, S. Aebi, J. Diebold, D. Pfeiffer

      • Abstract

      Background:
      Large cancer centres in the USA demonstrated that molecular diagnosis and targeted therapy improved overall survival (OS) of patients with advanced pulmonary adenocarcinoma (Kris, JAMA 2014). We validated this finding in a rural area of Switzerland, served by private practices, community hospitals, and a tertiary referral centre.

      Methods:
      We conducted a prospective cohort study with the Cancer Registry of Central Switzerland, established in 2010, covering 4 cantons and 517'000 inhabitants. We enrolled all residents newly diagnosed with stage IV pulmonary adenocarcinoma from 2010 until 2014. From the registry, the central pathology and the residents’ offices, we obtained the date of diagnosis and death, gender, smoking, tumour histology and stage, molecular testing (on demand), and therapy. We used the Kaplan-Meier method and a log-rank test to compare OS, and Cox proportional hazards model for association with age, gender and smoking. The cutoff date was February 2016. No adjustment was made for multiple testing. The study was approved by the IRB.

      Results:
      348 patients were included in the study. Median age at diagnosis was 66 years (range, 30-94), 190 (55%) patients were men, 197 (57%) were smokers or former smokers. Molecular testing (PCR, IHC and FISH) was performed in 279 (80%), 132 (38%) had oncogenic driver mutations (ODM): KRAS (17%), EGFR (12%), ALK (6%), HER2 (2%), BRAF (1%), RET (0,5%) or MET (0,5%). 56 patients with an ODM, mostly EGFR (34) and ALK (12), received genotype-matched targeted therapy, at least 25 (45%) of whom in a clinical trial or named patient program. Median OS was 18 months for patients with ODM and targeted therapy, 8 months for patients with ODM and conventional therapy, and 10 months for patients with no ODM and conventional therapy. For patients with ODM and targeted therapy, OS was significantly better than for patients with ODM and conventional therapy (HR 0.64, p = 0.04).

      Conclusions:
      Rigorous testing combined with optimal access to targeted therapy in clinical trials, improved the prognosis of patients with advanced pulmonary adenocarcinoma and EGFR mutation or ALK rearrangement. For patients with tumours lacking actionable mutations, further advances are expected with immunotherapy.

      Clinical trial identification:


      Legal entity responsible for the study:
      J. Diebold, Institute of Pathology, Cantonal Hospital Lucerne, Lucerne, Switzerland

      Funding:
      Cancer League of Central Switzerland, Lucerne, Switzerland

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      8P - Expression of genes associated with anti-viral response in EGFR mutant non-small cell lung cancer (NSCLC) (ID 346)

      12:30 - 12:30  |  Author(s): N. Karachaliou, A. Giménez-Capitán, A. Drozdowskyj, E. Aldeguer, M. González Cao, A.F. Cardona, G. López-Vivanco, J.M. Sánchez, M.D.L.L. Gil, R. Rosell

      • Abstract

      Background:
      Up-regulation of endogenous retroviruses induces interferon response ("viral mimicry") and potentiates response to immune checkpoint therapy. Pattern-recognition receptors (PRRs), including retinoic acid-inducible gene-I (RIG-I), could up-regulate interferon pathway activating signal transducers and activators of transcription (STAT1), which ultimately induces CD274 (PD-L1) mRNA expression. We assume that alterations in the interferon pathway could be present in EGFR mutant NSCLC. Activation of STAT3 stimulates DNMT1 repressing PRRs. We recently identified YAP1 as a compensatory mechanism of resistance to gefitinib and osimertinib in EGFR mutant cells. Activation of YAP1 up-regulates CXCL5, a chemokine attracting myeloid-derived suppressor cell.

      Methods:
      Total RNA from 53 EGFR mutant NSCLC patients (pts), was reversed transcribed and analyzed by qRT-PCR. RIG-1, STAT1, CD274, DNMT1 and CXCL5 mRNA were examined with specific primers/probes in triplicates. Progression-free survival (PFS) and overall survival (OS) were estimated.

      Results:
      Fifty-three EGFR mutant NSCLC pts treated with erlotinib were analyzed, 65% were female, 65% never-smoked, 32% had brain metastases, 37% had bone metastases and 68% had exon 19 deletion. A close correlation was found between the RIG-1 and STAT1 mRNA levels (r = 0.42, p = 0.02). An anti-correlation trend was noted between DNMT1 and STAT1. Median PFS was 22 mo, 12.9 mo and 8.6 mo for pts with high, intermediate and low PD-L1 mRNA, respectively (P = 0.04). Median PFS was numerically longer for pts with low levels of DNMT1, RIG1 STAT1 and CXCL5, although the differences were not statistically significant. A similar trend was observed for OS.

      Conclusions:
      CD274 (PD-L1) mRNA could be a prognostic marker in EGFR mutant NSCLC pts. Down-modulation of CD274 indicates alterations in PRRs or downstream interferon signaling factors. The pathway dysregulation is multifactorial, and the role of STAT3 and YAP1 hyperactivation merits further research. DNMT1 overexpression ablates STAT1. Since the cyclin-dependent kinase 4 (CDK4) interacts with DNMT1, therapies with CDK4 inhibitors can directly neutralize the main defects in the interferon "viral mimicry" pathway.

      Clinical trial identification:


      Legal entity responsible for the study:
      Institut d\'Investigació en Ciències Germans Trias i Pujol, Badalona, Spain Institut Català d\'Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain

      Funding:
      Institut d\'Investigació en Ciències Germans Trias i Pujol, Badalona, Spain Institut Català d\'Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      9P - Knockdown of MFN2 gene expression inhibits lung adenocarcinoma cell proliferation (ID 254)

      12:30 - 12:30  |  Author(s): Y. Lou, Y. Zhang, J. Xu, P. Gu, W. Zhang, X. Zhang, H. Zhong, L. Jiang, B. Han

      • Abstract

      Background:
      Mitofusin-2(MFN2) was initially identified as a hyperplasia suppressor in hyper-proliferative vascular smooth muscle cells of hypertensive rat arteries, which has also been implicated in various cancers. There exists a controversy in whether it is an oncogene or exerting anti-proliferative effect on tumor cells. Our previous cell cycle analysis and MTT assay showed that cell proliferation was inhibited in MFN2 deficient A549 human lung adenocarcinoma cells. MFN2-knockdown induced gene expression changes in A549 cells was analyzed by microarray assay and then functional pathway enrichment analysis revealed that six pathways were enriched in deregulated genes including Cell cycle, DNA replication, ECM-receptor interaction, Focal adhesion, MAPK signaling pathway and Chemokine signaling pathway, as we previously reported.

      Methods:
      MFN2 expression at protein level was examined in 30 pair lung adenocarcinoma/adjacent normal lung samples with immunohistochemistry staining. Then MFN2 knockdown was performed in human lung adenocarcinoma cells A549 with lentiviral-mediated shRNA strategy. The expression changes of downstream factors were determined in A549 cells by western blot. Furthermore, tumor models in nude mice were generated and tumor formation and progression in these mice were analysed.

      Results:
      As compared to adjacent normal lung tissues, MFN2 expression was significantly higher in lung adenocarcinoma tissues with positive MFN2 signals in 90% (27/30) lung adenocarcinoma tissues and only in 26.7% (8/30) adjacent normal tissues. The downregulation of RAP1A and upregulation of RALB and ITGA2 identified in MFN2-knockdown cells by microarray analysis were confirmed by western blot. In vivo, tumor models in nude mice were generated. Tumor formation and progression in nude mice suggested that MFN2 knockdown reduced tumorigenesis of A549 cells.

      Conclusions:
      The current study confirmed the anti-proliferative effect of MFN2 deficiency and its risk in lung adenocarcinoma.

      Clinical trial identification:


      Legal entity responsible for the study:
      Shanghai Chest Hospital

      Funding:
      This work was supported by the National Natural Science foundation of China (81572249 and 81201839).

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      10P - In vivo evaluation of combertestatin A-4 phosphate for lung cancer by bioluminescence imaging and multispectral optoacoustic tomography (ID 293)

      12:30 - 12:30  |  Author(s): L. Liu, S. Kumari, J. Campbell, R.P. Mason, L. Zhang

      • Abstract

      Background:
      Vascular disrupting agents (VDA) promise significant therapeutic efficacy against solid tumors by selectively destroying tumor vasculature. Combretestatin A-4 phosphate (CA4P) is a well-characterized VDA that inhibits microtubule polymerization by binding to the colchicine-binding site of beta-tubulin [1,2]. This disruption causes a decrease in blood flow, leading to ischemia and cell death. Photoacoustic tomography (PAT) is a non-invasive technique which allows for high-resolution (∼100μm) spectral imaging. The iThera Multispectral Optoacoustic Tomography inVision 256-TF (MSOT) system allows for high throughput, in vivo imaging of small animals. The MSOT has access to a range of frequencies (680-980nm) with 1nm resolution and so is able to differentiate between numerous different contrasts agents simultaneously.

      Methods:
      Female and male nude mice (each group n = 6) were implanted with 2x10[6] H1299 lung cancer cells subcutaneously. Ten days after implantation, the mice image were acquired in transaxial sections through the tumor region using nine wavelengths ranging from 700-880 nm by MSOT device and bioluminescence images (BLI) were taken by IVIS Spectrum at different time points. Images were reconstructed and processed using manufacturer’s software. Percentage of hemoglobin saturation (%SO~2~) was calculated as %SO~2~ = [HbO~2~/(HbO~2~+Hb)]*100.

      Results:
      VDA caused significant perfusion reduction and hypoxiation at 1 and 3 hours post VDA and mostly recovered at 24 hours. The %SO~2~ of tumor peripheral vessels was decreased from 42.5% at baseline to 33% and 28% at 1 and 3 hours respectively. The %SO2 of the tumor core reduced from 43% at baseline to 27% and 12% at 1 and 3 hours respectively. There was no change in %SO2 of normal tissue (spine). Similarly, BLI signal was reduced by > 90% within 3 hours after administration of CA4P indicating vascular disruption which was confirmed by histology.

      Conclusions:
      We demonstrated the feasibility of MSOT to detect changes in oxyhemoglobin and deoxyhemoglobin based on their unique absorption spectra in order to further elucidate the mechanism of action. CA4P caused significant reduction of perfusion and oxygenation within the tumor. The results indicate strong rationale for further development, particularly in combination with additional therapies.

      Clinical trial identification:


      Legal entity responsible for the study:
      Li Liu

      Funding:
      CPRIT RP160617

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      11P - Prognostic significance of different immunohistochemical markers in small cell lung cancer (ID 407)

      12:30 - 12:30  |  Author(s): E. Gkika, S. Beitinger, S. Adebahr, T. Schimek-Jasch, S. Wiesemann, C. Waller, A. Grosu, U. Nestle, G. Kayser

      • Abstract

      Background:
      To evaluate the role of different immunohistochemical markers concerning the overall and progression free survival in patients with small cell lung cancer (SCLC).

      Methods:
      A total of 104 consecutive patients with histologically proven SCLC (limited and extensive disease) treated with chemotherapy and radiotherapy at the University Hospital of Freiburg, between 2005 and 2012 and available pathologic slices, were included in the analysis. The expression of different immunohistochemical markers from the tissue biopsy such as CD56, CD44, Chromogranin, Synaptophysin, TTF-1, GLUT-1, Hif-1 alpha, PD-1 und PD-L1 and MIB-1/KI-67 as well as the LDH und NSE from the initial blood sample were correlated with the overall survival (OS) and progression free survival (PFS) using the Kaplan Meier Method and Cox proportional hazards ratio. Furthermore, for CD44, Hif-1 alpha and GLUT-1 H-Scores were generated for further analysis.

      Results:
      Of the included 104 patients, 48 had limited disease (LD) and 53 extensive disease (ED) at diagnosis. The median overall survival calculated from diagnosis was 21 (95%CI 19-23) months for patients with LD and 13 (95%CI 11-15) months for patients with ED. Patients with higher LDH (HR: 1.003 95% CI 1.001-1.005, p < 0.001) and NSE (HR:1.004, 95%CI: 1.002-1.007, p < 0.001) at diagnosis had a worse OS. These factors correlated also with a worse PFS (HR: 1.002 95% CI 1.000-1.003 p = 0.011 and HR: 1.004, 95% 1.001-1.006, p = 0.002, respectively). Concerning the immunohistchemical markers only the expression of Synaptophysin correlated with a worse OS (HR 1.890, CI 95% 1.067-3.346, p = 0.029) but not with the PFS (HR: 1.761, 95% CI 0.963-3.222, p = 0.066). All other markers did not correlate with OS or PFS.

      Conclusions:
      A positive immunhistochemical staining of synaptophysisn in patients with SCLC correlated with worse prognosis.

      Clinical trial identification:


      Legal entity responsible for the study:
      University of Freiburg

      Funding:
      N/A

      Disclosure:
      All authors have declared no conflicts of interest.

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      12P - Thyroid transcription factor-1 as a prognosticator in patients with metastatic lung adenocarcinoma without EGFR sensitizing mutations (ID 335)

      12:30 - 12:30  |  Author(s): J.Y. Park, S.H. Jang, J. Kim, S. Park, Y.I. Hwang, K. Jung, J.W. Seo

      • Abstract

      Background:
      Thyroid transcription factor-1 (TTF-1) expression is known not only as a diagnostic marker but also a good prognosticator among patients with lung adenocarcinoma. However, good prognosis of TTF-1 expression might be due to epidermal growth factor receptor (EGFR) sensitizing mutations because of the positive correlation between TTF-1 expression and EGFR mutations. The purpose of this study was to explore prognostic impact of TTF-1 expression according to EGFR sensitizing mutation status in lung adenocarcinoma.

      Methods:
      This is a retrospective analysis of patients with 1) stage IV lung adenocarcinoma having available TTF-1 immunohistochemistry result, 2) ECOG performance status 0-2, and 3) receiving systemic anti-cancer treatment. The data were extracted from the registry of Hallym University Sacred Heart Hospital in Korea, between March 2006 and March 2016.

      Results:
      Of the 697 patients with lung adenocarcinoma, 144 patients were included for analysis. The mean age was 65.2 ± 11.6 years (female; 42.4%). EGFR sensitizing mutations were detected in 72/144 (50.0%) patients. TTF-1 was positive in 116/144 (80.6%) patients, and it had a significant correlation with EGFR sensitizing mutations (p < 0.001). Patients with TTF-1 positive lung adenocarcinoma had longer overall survival (OS) than TTF-1 negative (21.4 vs. 6.5 months, p < 0.001). In Cox regression analysis, TTF-1 positivity (hazard ratio [HR] 0.50; 95% CI: 0.31-0.83; p = 0.007), Stage IV, M1a (HR 0.62; 95% CI, 0.40–0.97; p = 0.034), good performance status (ECOG=0; HR 0.52; 95% CI, 0.33–0.82; p = 0.005) and EGFR sensitizing mutations (HR 0.62; 95% CI, 0.39–0.97; p = 0.038) were independently associated with prolonged OS. In the subgroup of patients with wild type EGFR adenocarcinoma, TTF-1 positivity was also good prognosticator for OS (HR 0.58; 95% CI: 0.33-0.99; p = 0.046), and for progression-free survival (PFS) of the first-line cytotoxic chemotherapy (HR 0.43; 95% CI, 0.24–0.78; p = 0.006). (Table).rnTable: 12PCox proportional hazard model of overall survival for 72 patients with lung adenocarcinoma harboring wild type EGFRrn

      rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn
      CovariateUnivariate analysisMultivariate analysis
      P valueHR (95% CI)P valueHR (95% CI)
      Age < 70 vs. ≥ 700.9860.995 (0.607-1.633)0.5631.175 (0.680-2.030)
      Female vs. male0.0060.425 (0.231-0.780)0.4700.563 (0.119-2.676)
      Never smoker vs. ever smoker<0.0010.443 (0.248-0.790)0.9800.981 (0.222-4.330)
      Stage IV, M1a vs. M1b0.0620.602 (0.353-1.027)0.0460.569 (0.327-0.991)
      ECOG 0 vs. 1-20.0160.529 (0.316-0.887)0.0760.587 (0.325-1.057)
      TTF-1 positive vs. negative0.0600.607 (0.360-1.022)0.0460.575 (0.334-0.991)
      Pemetrexed, 1[st] line vs. non-pemetrexed containing regimen0.8620.956 (0.576-1.587)0.4800.829 (0.492-1.395)
      rnHR=Hazard ratio; CI=confidence intervals, ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; TTF-1 = thyroid transcription factor 1.rn

      Conclusions:
      TTF-1 expression was a good prognosticator for OS and PFS in patients with stage IV lung adenocarcinoma without EGFR sensitizing mutations.

      Clinical trial identification:


      Legal entity responsible for the study:
      Hallym University Sacred Heart Hospital Institutional Ethics Committee

      Funding:
      N/A

      Disclosure:
      All authors have declared no conflicts of interest.

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      13P - Characterizing the DNA damage response in putative stem cells of resected normal lung and matched NSCLC patient samples (ID 462)

      12:30 - 12:30  |  Author(s): T.M. Marti, C.C. Tièche, R. Peng, S.R.R. Hall, L. Froment, P. Dorn, S. Berezowska, R.A. Schmid

      • Abstract

      Background:
      More than 80% of lung tumors are non-small cell lung cancers (NSCLC). Tumor initiation and propagation are mediated by tumor initiating cells (TICs). In NSCLC and glioblastoma, TICs are characterized by high glycine decarboxylase (GLDC) expression. The DNA damage response (DDR) network evolved to maintain genome integrity and its dysregulation is associated with TICs and therapy resistance. Our aim was to establish a protocol to characterize the DDR status in NSCLC TICs.

      Methods:
      We evaluated a small cohort of eleven consenting patients who underwent elective surgery for lung cancer. Dissection of the tumor and non-adjacent normal lung tissue was performed by a pathologist. Tissue was dissociated to a single cell suspension, which was stained and analyzed by multicolor flow cytometry (FACS).

      Results:
      Based on EpCAM and GLDC expression, we identified four distinct subpopulations within the lineage negative compartment (live cells/CD31-/CD45-). In normal lung samples, a rare subpopulation was characterized by increased expression of the epithelial marker EpCAM and GLDC. Relative GLDC expression was increased in matched tumor samples. In normal samples, GLDC expression was associated with proliferation as indicated by Ki-67 staining, which was increased in matched tumor samples. Basal activation of the DDR as indicated by H2AX phosphorylation was increased in tumor versus normal samples. Upon DNA damage induction in both normal and cancer samples, H2AX was phosphorylated in the majority of the EpCAM+/GLDC+/- cells, in a smaller fraction of the EpCAM-/GLDC+ cells and absent in EpCAM-/GLDC- cells. Interestingly, the relative increase in basal versus DNA damage-induced H2AX phosphorylation was significantly higher in normal compared to matched cancer subpopulations. Further, variation in H2AX phosphorylation levels was higher in cancer samples. A larger cohort will be required to correlate DDR activation with the mutational status of the NSCLC samples.

      Conclusions:
      We established a FACS-based protocol allowing us to analyze DDR activation in normal versus tumor tissue and bulk versus cancer stem cells. This protocol can easily be adapted for the analysis of other types of patient tissue samples.

      Clinical trial identification:


      Legal entity responsible for the study:
      University Hospital Bern

      Funding:
      This work was supported by the Bernese Cancer League and the Swiss Cancer Research (KFS-3530-08-2014) to TMM.

      Disclosure:
      All authors have declared no conflicts of interest.

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      14P - Histone H2AX phosphorylation increases apoptosis of lung cancer cells by miR-3196/PUMA pathway (ID 213)

      12:30 - 12:30  |  Author(s): C. Lu, C. Xu, L. Zhang, L. Duan

      • Abstract

      Background:
      Increasing amount of studies indicate that histone H2AX acts as a novel tumor suppressor, but the detailed mechanism of apoptosis in tumor cells regulated by H2AX remains elusive.

      Methods:
      Microarray assay was performed to analyze differentially expressed apoptosis-related miRNAs regulated by H2AX in lung cancer cells. The flow cytometry (FCM) assay was performed for detection of apoptosis. Quantitative RT-PCR (qRT-PCR) was used to detect miR-3196 expression. Chromatin immunoprecipitation (ChIP) together with qRT-PCR was used to evaluate the binding of gamma-H2AX and RNA polymerase II to the miR-3196 promoter, and H3K27 trimethylation level in the promoter region of miR-3196. H2AX, BIRC7, PUMA and β-actin protein levels were determined by western blotting. The miR-3196 binding to PUMA mRNA at the 3′-UTR and miR-3196 promoter activity were evaluated by luciferase assay. Lipofectamine 2000 was used for transfection of vectors and miR-3196 mimics or miR-3196 inhibitor.

      Results:
      The data from microarray assay demonstrated that histone H2AX was involved in regulation of miRNAs expression during lung cancer cell apoptosis. H2AX knockdown affected the expression of 16 miRNAs, resulting in the downregulation of 1 and the upregulation of 15 miRNAs. Among the upregulated miRNAs, miR-3196 was identified as a target of H2AX and shown to inhibit apoptosis in lung cancer cells by targeting p53 upregulated modulator of apoptosis (PUMA). Phosphorylated H2AX (gamma-H2AX) was shown to bind to the promoter of miR-3196 and regulate its expression. In addition, H2AX phosphorylation increased H3K27 trimethylation in the promoter region of miR-3196 and inhibited the binding of RNA polymerase II to the promoter of miR-3196, leading to the inhibition of miR-3196 transcription. Taken together, these results indicated that miR-3196 is inhibited by H2AX phosphorylation and attenuates lung cancer cell apoptosis by downregulating PUMA.

      Conclusions:
      Histone H2AX phosphorylation increases apoptosis of lung cancer cells via the miR-3196/PUMA pathway.

      Clinical trial identification:
      This study does not contain clinical trial.

      Legal entity responsible for the study:
      Air Force General Hospital (PLA)

      Funding:
      National Natural Science Foundation of China

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      15P - PLGF regulates crosstalk between non-small cell lung cancer cells and tumor-associated macrophages in cancer vascularization and growth (ID 253)

      12:30 - 12:30  |  Author(s): W. Zhang, Y. Lou, B. Yan, Y. Zhao, S. Cui, L. Jiang, B. Han

      • Abstract

      Background:
      The growth and invasion of non-small cell lung cancer (NSCLC) require assistance of tumor-associated vascularization, the underlying molecular mechanisms of which remain eluted. Recently, we reported that placental growth factor (PLGF) was expressed by NSCLC cells, and promoted the metastasis of NSCLC cells. Here, we showed that NSCLC cells produced and secreted PLGF to signal to tumor-associated macrophages (TAM) through the surface expression of the receptor for PLGF, Flt-1, on macrophages.

      Methods:
      Ten week-old male NOD/SCID mice were used for transplantation of 10[7] AAV-transduced/labeled A549 cells by tail vein injection. Bones from 12-week-old male C57BL/6 mice were flushed with macrophage culture media. Isolated bone-marrow-derived macrophages (10[5]) were co-cultured either with equal number of A549 cells (10[5]) with/without of 10µmol/l SB431542, or with/without recombinant PLGF (100ng), or with/without of 10 µg/l sFlt-1. Two days after co-culture, the changes in A549 cell number were determined with an MTT assay, and the macrophage subtypes were determined by flow cytometry.

      Results:
      In a transwell co-culture system, PLGF secreted by NSCLC cells triggered macrophage polarization to a TAM subtype that promote growth of NSCLC cells. Moreover, polarized TAM seemed to secrete transforming growth factor β 1 (TGFβ1) to enhance the growth of endothelial cells in a HUVEC assay.

      Conclusions:
      Thus, our studies suggest that the cross-talk between TAM and NSCLC cells via PLGF/Flt-1 and TGFβ receptor signaling may promote the growth and vascularization of NSCLC.

      Clinical trial identification:


      Legal entity responsible for the study:
      Shanghai Chest Hospital

      Funding:
      This work was supported by the National Natural Science foundation of China (81402378).

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      16P - Carvacrol induces growth inhibition and circumvents chemoresistance via inhibition of STAT3/Skp2/p27 pathway in non-small lung cancer cells (ID 269)

      12:30 - 12:30  |  Author(s): K. Kim, C. Lee

      • Abstract

      Background:
      S-phase kinase-associated protein 2 (Skp2) which constitues SCF complex and plays a role to recognize the substrates has been known to act as a proto-oncogene. In this study, we examined the effect of carvacrol, an active compound of oregano, on Skp2 inactivation and the underlying mechanisms in non-small lung cancer cells.

      Methods:
      Reagents and antibodies. Carvacrol was obtained from Sigma-Aldrich. A549 and H460 cells were purchased from the ATCC. For Western blot analysis, specific antibodies against Skp2, phospho-STAT3, STAT3, p21, p27, and GAPDH, as well as secondary antibodies were obtained from Santa Cruz Biotechnology.rnCell viability measurement. Cells were treated with carvacrol for 24 h and stained wtih 0.4% Trypan blue solution. Dye-excluding viable cells were counted under the microscope.rnClonogenic assay. Cells were seeded into 24 well plates and treated with carvacrol and then cultured for the next 7 to 10 days to form colonies. Colonies of > 50 cells were stained with crystal violet.rnEctopic expression of Skp2. To ectopically express Skp2, the recombinant plasmid, pcDNA3-Skp2-myc, was constructed and transfected into cells using Lipofectamine 2000. To establish stable cell lines, the transfected cells were cultured in the presence of 400 μg/ml of G418.rnsiRNA transfection. To reduce Skp2 expression, cells were transfected with siRNA targeting Skp2 or control siRNA.

      Results:
      Carvacrol treatment of A549 as well as H460 cells caused to reduce Skp2 protein level in dose-dependent manner. RT-PCR assay was also found that Skp2 mRNA level was reduced by carvacrol, suggesting the transcriptional down-regulation of Skp2 expression by carvacrol. We next found that the cytotoxic effect of carvacrol was attenuated in Skp2 overexpression in A459 cells and further observed its synergistic anti-proliferative effect in cells transfected with Skp2 specific siRNA. In addition, carvacrol was found to result in apoptotic cell death.

      Conclusions:
      Taken together, these data indicate that carvacrol targets Skp2 to inhibit cell proliferation and to cause apoptotic cell death in non-small lung cancer cells.

      Clinical trial identification:


      Legal entity responsible for the study:
      Yeungnam University College of Medicine, Republic of Korea

      Funding:
      Yeungnam University College of Medicine, Republic of Korea

      Disclosure:
      All authors have declared no conflicts of interest.

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      19P - Domestic cooking fuel as a risk factor for lung cancer in women: A case control study (ID 227)

      12:30 - 12:30  |  Author(s): S.S. Katpattil

      • Abstract

      Background:
      Tobacco smoking is the most common risk factor for lung cancer. But a significant proportion of lung cancer occurs in non-smokers. Indoor pollution due to domestic fuels has been recently implicated as a causative agent in lung cancer especially in women. We conducted a case control study to find out the role of domestic cooking fuel as a risk factor for lung cancer in Indian women.

      Methods:
      In a case control study 67 women with proven lung cancer were recruited. Forty-six females having a non-malignant respiratory disease constituted the control group. The patients and controls were asked about the exposure in various cooking fuels using a questionnaire.

      Results:
      There were 50(74.6%) non-smokers and 17(25.4%) smokers among the female cancer cases (p = 0.016). Adenocarcinoma was the commonest histological type of malignancy (n = 26, 38.8%) in the whole group and was the predominant form in the non-smoking females. Tobacco smoking was the most important risk factor for lung cancer with OR of 4.87 (95% CI 1.34-17.76). Among non-smokers out of all the cooking fuels the risk of development of lung cancer was highest for biomass fuel exposure with an odds ratio of 5.33 (95% CI 1.7-16.7). Use of mixed fuels was associated with a lesser risk (OR = 3.04, 95% CI 1.1-8.38).

      Conclusions:
      This study indicated that domestic cooking fuel exposure is an important risk factor in the causation of lung cancer among women in addition of exposure to tobacco smoke.

      Clinical trial identification:
      NA

      Legal entity responsible for the study:
      Al Iqbal Hospital

      Funding:
      Al Iqbal Hospital

      Disclosure:
      The author has declared no conflicts of interest.

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      21P - The efficacy of combination therapy with varenicline and bupropion for smoking cessation (ID 329)

      12:30 - 12:30  |  Author(s): D.A. Johns

      • Abstract

      Background:
      Extended use of combined pharmacotherapies to treat tobacco dependence may increase smoking abstinence. The objective of this study was to evaluate smoking abstinence by using bupropion alone, varenicline alone and combination of both.

      Methods:
      We conducted a randomized, prospective, double-blind, trial with 300 smokers enrolled. Group 1 bupropion alone (150 mg twice daily), group 2 varenicline alone (1 gm twice daily), group 3 varenicline + bupropion (1 gm twice daily+ 150 mg twice daily). The drugs were given for 12 weeks. Main outcome measures: The primary outcome was carbon monoxide-confirmed continuous abstinence rates (CAR) and the assessment of nicotine withdrawal symptoms. Nicotine dependence was assessed with the 6-item Fagerstrom Test for Nicotine Dependence scores ≥ 6 indicate high dependence. During the treatment phase, the Minnesota Nicotine Withdrawal Scale was used to assess withdrawal symptoms.

      Results:
      Subjects in the group 1,2 and 3 (n = 100 each) were comparable in age, smoking history, number of daily smoked cigarettes, and nicotine dependence. After the treatment there was reduced cigarette cravings (17.5 ± 1.1vs 15 ±3 vs 13.1 ± 1) and total nicotine withdrawal symptoms (17.8 ± 4.3 vs 15.4 ± 5.1 vs13.2 ± 2.1) during the treatment period. As compared to B and VR monotherapy, VR+B produced significant increases in CAR at 6 months (OR, 1.63; CI, 1.10-2.20, OR, 1.52; CI, 1.00-2.30 and OR, 1.72; CI, 1.06-2.67, respectively); results were similar, but somewhat stronger, when 7PP was used at 10 weeks (OR, 1.69; CI, 1.05-2.53, OR, 1.57; CI, 1.03-2.41 and OR, 1.82; CI, 1.09-2.83, respectively)All medications were well tolerated, but participants in the VR groups experienced more fatigue, digestive symptoms (e.g., nausea, diarrhea), and sleep-related concerns (e.g., abnormal dreams, insomnia). The frequency of serious adverse events did not differ between groups.

      Conclusions:
      Dual medication was found to enhance success in the early phases of quitting.

      Clinical trial identification:
      REF/2017/03/013652

      Legal entity responsible for the study:
      Abhilash Clinic

      Funding:
      N/A

      Disclosure:
      The author has declared no conflicts of interest.

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      23P - Pictorial warning on cigarette packets and its role in tobacco cessation: Questionnaire survey among cigarette smokers in Chennai (ID 320)

      12:30 - 12:30  |  Author(s): C.J.K. Francis

      • Abstract

      Background:
      Warning labels on cigarette packages are meant to communicate such smoking-associated risks. The study is designed to find out the effectiveness of pictorial warnings present on cigarette packets in India for tobacco cessation among cigarette smokers.

      Methods:
      A questionnaire was distributed to 800 current smokers attending an outpatient department of a college. Statistical analysis was done to find association between socioeconomic status and effectiveness of pictures to quit cigarette smoking.

      Results:
      48% smokers perceive text warning is an efficient method to create awareness. 56% emphasized the importance of pictorial warning and greater area to be covered. 43% felt that warning on cigarette packets helped them to quit smoking.

      Conclusions:
      Though pictorial warning is an effective method to improve the awareness among smokers on the ill effects of smoking, the size, area covered and the position of the picture on cigarette packets needs to be reviewed to improve the quit rate.

      Clinical trial identification:
      na

      Legal entity responsible for the study:
      N/A

      Funding:
      C.J.K. Francis

      Disclosure:
      Nestle India Limited

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      25P - Tobacco consumption pattern among auto rickshaw drivers in Chennai city, Tamil Nadu, India (ID 310)

      12:30 - 12:30  |  Author(s): D.L. Francis

      • Abstract

      Background:
      Tobacco use is a major preventable cause of premature death and diseases, currently leading to five million deaths worldwide which are expected to raise over eight million deaths worldwide by 2030. India is the second largest consumer of tobacco in the world. This study is contemplated with an aim to assess the prevalence of tobacco consumption and the associated factors involved in its consumption, as this group of the population is under constant pressure and account for the workforce of the country. So through this study we could be able to know the awareness of ill effect, reasons & amount of consumption.

      Methods:
      Across sectional descriptive study was conducted among Auto Rickshaw Drivers in Chennai City. Auto drivers who were working for more than two years and present on the day of examination and who were willing to participate in the study were included. Cluster random sampling technique was used. 400 samples were selected from 40 auto stands of various parts of Chennai City. Data was collected using a Survey Proforma which comprised of a Questionnaire which can assess the frequency of consumption, age of initiation, the amount of consumption, mental stress, economic factors, any past history of disease and most importantly the awareness towards oral cancer. Age, tobacco consumption pattern, reasons of consumption, amount of consumption, harmful effects of tobacco are the variables.

      Results:
      Prevalence among auto rickshaw drivers for consumption of tobacco products was very high (87%). Auto rickshaw drivers were mostly used tobacco in the form of Gutkha (72%) and bidi (40%) in comparison to other products. It also shows that they use cheap tobacco products. Most of the auto rickshaw drivers start using tobacco products in age less than 18 years (80%) and associated factors for tobacco use are due to friends and their influence (78%). Awareness level among auto rickshaw driver was high (70%) but still uses tobacco products because of its addiction (66%). In the opinion of auto rickshaw drivers increase in tax may reduce it consumption and the majority of drivers (70%) think that tobacco must be banned.

      Conclusions:
      Prevalence of tobacco use among auto rickshaw drivers was very high. They are in definite need of tobacco cessation activities.

      Clinical trial identification:
      NA

      Legal entity responsible for the study:
      N/A

      Funding:
      N/A

      Disclosure:
      The author has declared no conflicts of interest.

    • +

      26P - Smoking habits and awareness about anti-smoking acts among general public in Gurgaon, Haryana, India (ID 319)

      12:30 - 12:30  |  Author(s): C.J.K. Francis

      • Abstract

      Background:
      India is the world’s third largest tobacco-growing country. The Indian scenario as far as tobacco consumption is concerned is far worse because of the prevalence of the tobacco chewing habit which covers a wide spectrum of socioeconomic and ethnic groups and is spread over urbanized area as well as remote village. Despite the facts, that the harmful effects of tobacco chewing and smoking are widely known, many young people start smoking during adolescence, largely because they believe that smoking will boost their social acceptability and image. This study was contemplated with an aim to assess tobacco/smoking habits and awareness about anti-smoking act among general public in Gurgaon, Haryana, India.

      Methods:
      A structured questionnaire consisting of 14 questions related to tobacco/smoking habits and awareness about anti-smoking act were asked to general public and their response was recorded. Random sampling method was used and data was collected from a cross-sectional survey. Anti-tobacco counselling was given on the spot and followed.

      Results:
      The study population consisted of total 430 individuals, male 364 (84.65%) and females 66 (15.34%). Then the questionnaires were asked and statistically analyzed. Around 286 (78.57%) from 364 males were indulged in some form of tobacco usage (smoker =32.86%, tobacco chewer = 16.78%, both =11.18%, alcohol +tobacco user =21.67%). In the present study, most common cause of tobacco use was pleasure 40.5%, inducing factor were friends 53.1% followed by parents and siblings.

      Conclusions:
      36.20% patients used tobacco as second hand exposure in job places. 54.8% were aware about the anti-smoking act in public places, so only 8.6% people from all males enrolled, were smoking in public places.

      Clinical trial identification:
      na

      Legal entity responsible for the study:
      N/A

      Funding:
      C.J.K. Francis

      Disclosure:
      Nestle India Limited

    • +

      27P - Factors causing treatment delays and its impact on treatment outcome in patients of lung cancer: An analysis (ID 214)

      12:30 - 12:30  |  Author(s): D. Kumar, S. Singh

      • Abstract

      Background:
      Delays in diagnosis and treatment are undesirable in cancer management. In this analysis, we tried to identify factors causing delay in diagnosis and subsequently its effect on outcome in patients of lung cancer presenting to the oncology department.

      Methods:
      55 patients with proven histopathological diagnosis of lung cancer were interviewed. Results were analysed statistically.

      Results:
      M:F=3:1.Mean age 49 years (32-65 years).NSCLC:SCLC=4:1, majorly adenocarcinoma. The duration of symptoms ranged from 1 month to 2 years. The number of illiterate patients presented mainly in advanced stages as compared to their educated counterparts and the difference was statistically significant (P<0.001). The number of patients presenting directly to the department was 8, those diagnosed outside and referred to us was 29 while those diagnosed and received some form of oncologic treatment outside and referred thereafter was 18. The difference in the primary delay between patients presenting directly to the institute versus those diagnosed outside was significant (P=0.01). The mean time to starting definitive treatment after presentation to the outpatient was 3 days (range 0-15 days) and was very significantly (P< 0.001) less than the secondary delays caused to the other two subsets of patients. The most important patient reasons for the delay in diagnosis were - financial constraints (20/55, 28.3%), ignorance about disease (9/55, 16.36%); dependency to escort (5/55, 9.0%), far off native place (7/55,12.7%), faith in local practitioner (3/55, 5.4%), family occasions (2/55, 3.6%), fear of death (2/55, 3.6%). 4/55 (7.2%) were initially diagnosed as tuberculosis and hence the delay, and 3/55 (5.4%) had no reason cited. Stages at diagnosis were stage II (4/55, 7.2%), stage III (41/55, 74.5%), stage IV (10/55,18.1%). Advanced stage disease patients had statistically significant poorer outcomes compared with those with earlier stage disease.

      Conclusions:
      Factors causing delayed presentation are both patient and system related. Awareness regarding the early signs and symptoms of lung cancer should be encouraged through various media channels. At the same time, the system needs to intensify its efficiency to avoid secondary delays that adversely affect the treatment outcome.

      Clinical trial identification:
      not applicable

      Legal entity responsible for the study:
      N/A

      Funding:
      None

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      28P - Impact of a pharmaceutical consultation: Review of a pilot study (ID 382)

      12:30 - 12:30  |  Author(s): E. Clou, J. Gaudas, K. Ahmed, D. Avenin, A. Esteso, G. Galula, J. Fillon, J.P. Lotz, I. Debrix

      • Abstract

      Background:
      The development of oral anticancer drug has resulted in several challenges. Prescriptions require a specific monitoring of the patient during his treatment. The objective of this work, resulted from collaboration among health professionals, was to assess the feasibility of setting up a pharmaceutical consultation in department of medical oncology. In addition, we aimed to evaluate the impact of this consultation in reducing prescription errors, drug-drug interactions finding, the early detection of adverse events (AEs) and in the patients’ adherence to both their treatments and the present approach.

      Methods:
      Before the initiation of oral chemotherapy, the oncologist proposed to the patient at participating in a pharmaceutical consultation. Following the patients’ agreement, the pharmacist collected several datas (medical history, community pharmacy medical prescriptions, treating physician) and agreed to an appointment with him. This process allowed to obtain the Best Possible Medication History and establish with the patient the treatment plan. During consultation, the resident assessed the patients’ compliance (with Morisky Scale questionnaire) and informed about the preventive and corrective measures to be implemented in case of AEs. All this datas were related in a specific notebook. A telephone follow-up was proposed to the patient. At last, a report containing all the pharmaco-therapeutic analysis was sent to the oncologist.

      Results:
      The pharmaceutical consultations allowed follow-up of 17 patients. Of the 19 pharmaceutical interventions conducted during the consultations, 94% involved drug-drug interactions. All patients participated to the telephone follow-up. 49 telephones calls allowed the detection of 25 AEs, half of which were referred to other health professionals. For 2 patients, anticancer drug had to be stopped for a bad tolerance finding telephone follow-up. Compliance remained constant over time for all patients. An average score of 9.4/10 was noted by patients for global satisfaction with the activity.

      Conclusions:
      Those results have showed that pharmaceutical consultation could enhance quality management of patients treated by oral anticancer drugs. It highlighted the major interest of this new health professional’s collaboration.

      Clinical trial identification:


      Legal entity responsible for the study:
      Isabelle Debrix

      Funding:
      Hospital Tenon (Paris 20ème)

      Disclosure:
      All authors have declared no conflicts of interest.

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      29P - Baseline characteristics of participants in pl-208: A multi-center trial of the prolung test™ (Transthoracic Bioconductance Measurement) as an adjunct to CT chest scans for the risk stratification of patients with pulmonary lesions suspicious for lung cancer (ID 334)

      12:30 - 12:30  |  Author(s): R.C. Yung, D. Ost, M. Simoff, C. Reddy, A. Goyal, I. Barjakarevic, M. Garff, K. Larson, J. O'Driscoll, S. Makani

      • Abstract

      Background:
      Lung cancer screening with low dose CTs shows numerous indeterminate pulmonary lesions (IPLs). Followup evaluation entail additional radiation (full dose CT/PET) or invasive biopsies. Alternative, novel adjunctive risk-stratification pathways are needed. Volume-averaged thoracic bioconductance, is a non-invasive technology measured transcutaneously by ProLung’s Electro-Pulmonary Nodule Scan (EPNS). A single center study had demonstrated potential to risk stratify such lesions.[1] with sensitivity/specificity of 90%/92% respectively and ROC >0.90. We present interim patient data of PL-208, a pivotal multicenter EPNS validation study.

      Methods:
      This is IRB approved and prospectively enrolled IPNs being evaluated. It is a two-phase study consisting of 350 subjects, 200 in the algorithm stabilization phase and 150 subjects in a subsequent algorithm validation phase. EPNS is performed within 60 days of the CT and pre tissue biopsies. In this prospective study, all study subjects & investigators are blinded to the EPNS results.

      Results:
      We present data on the initial 133 subjects in the table comparing data between the earlier feasibility study FML204[1] and PL208. 46(35%) subjects were asymptomatic; the rest had symptoms leading to imaging. Diagnoses include: 84 (63%) lung cancers, 4 (3%) non-primary lung cancers, 20 (15%) benign by biopsy, and 25 (19%) benign by CT follow-up.

      Conclusions:
      PL-208 cohort has a similar gender and age distribution to the PL204 feasibility study using EPNS as a risk-stratifying tool in evaluating suspicious IPLs. PL-208 includes asymptomatic nodules detected during LDCT screening, and hence more subjects with small T1a IPLs (17% Vs 7%), but overall a majority of subjects have IPNs < 3 cm (59%/56%). Of LCs diagnosed, 38%/41% are in stages I/II. [1]Yung et al. Transcutaneous Computed Bioconductance Measurement. J Thorac Oncol 2012; 7:681–9.\r\nTable: 29PComparison FML-204 and PL-208 patient characteristics\r\n

      \r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n
      SUBJECTSFML-204PL-208
      Age Mean(range)64 (34-80)65 (22-85)
      Male (%)22 (54%)68 (51%)
      Symptomatic41 (100%)87 (65%)
      COPD diagnosis19 (46%)27 (20%)
      NODULE FEATURES\r\n\r\n
      Solitary/multiple17(41%)/24 (59%)45 (34%)/88 (66%)
      0-10 mm (T1a)2 (7%)23 (17%)
      11-20 mm (T1b)13 (32%)35 (26%)
      21-30 mm (T1c)7 (17%)21 (16%)
      31-50 mm (T2a)9 (22%)25 (19%)
      > 50 mm (T2b/c)8 (20%)22 (17%)
      Solid37 (90%)111 (83%)
      Part solid/GGO3 (7%)/1 (2%)13 (10%)/9 (7%)
      DIAGNOSIS\r\n\r\n
      Benign by biopsy/CT-fu9 (22%)/3 (7%)20 (15%)/25 (19%)
      Small cell lung cancer2 (5%)10 (8%)
      Adenocarcinoma20 (49%)51 (38%)
      Squamous cell carcinoma6 (15%)17 (13%)
      Carcinoid1 (2%)6 (5%)
      Non-lung malignancy0 (0%)4 (3%)
      STAGE\r\n\r\n
      I11 (38%)20 (24%)
      II1 (3%)12 (14%)
      III6 (21%)23 (27%)
      IV11 (38%)20 (24%)
      Other0 (0%)9 (11%)
      \r\n

      Clinical trial identification:
      NCT01566682

      Legal entity responsible for the study:
      ProLungDx

      Funding:
      ProLungDx

      Disclosure:
      R.C. Yung: Conducted study with ProLung (corporate) sponsorship of study. Lead author also on ProLung Advisory Board, have received consultation fees and travel support (to meetings). Have been offered stock options. D. Ost: Conducted study with ProLung (corporate) sponsorship of study. Have received consultation fees on Advisory Board. M. Simoff, C. Reddy, A. Goyal, I. Barjakarevic: Conducted study with ProLung (corporate) sponsorship of study. M. Garff: Employee of ProLungDx. K. Larson: Employee of ProLung. J. O\'Driscoll: Chief Medical Officer and member of the Board of Directors for ProLungDx. S. Makani: Funded corporate sponsored research from ProLungDx.

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      31P - Targeted therapy for patients with ALK positive NSCLC: Results from the transalpine cohort (ID 332)

      12:30 - 12:30  |  Author(s): C. Britschgi, M. Rechsteiner, R. Delaloye, M. Früh, G. Metro, O. Gautschi, S.I. Rothschild, R.A. Stahel, P.J. Wild, A. Curioni-Fontecedro

      • Abstract

      Background:
      Anaplastic lymphoma kinase (ALK) rearrangements occur in 3-5% of lung adenocarcinoma. ALK tyrosine kinase inhibitors (ALK-TKIs) are used for the treatment of these patients as standard of care, in clinical trials or in expanded access programs. The aim of this study was to analyze the clinical characteristics of response and progression to different ALK-TKIs and to study mechanisms of resistance using next generation sequencing (NGS).

      Methods:
      This collaborative study was performed in five institutions in Switzerland and Italy. Clinical data from patients diagnosed with ALK positive NSCLC (i.e. break in 2p23 in FISH) in the palliative setting were collected and analyzed. If available, biopsies both before starting ALK-TKI and at progression were subjected to NGS using the Ion AmpliSeq Comprehensive Cancer Panel.

      Results:
      We collected clinical data of 139 patients. 117 have so far undergone first-line treatment with chemotherapy (ChT) (n = 87, 74%), ALK-TKIs (n = 29, 25%) or other (n = 1, 1%). Second-line therapy was given in 92 patients; 16 received ChT (17%), 68 ALK-TKIs (74%), 8 immuno- (I-O) and other therapies (9%). 55 patients underwent third-line therapy comprising ChT (n = 11, 20%), ALK-TKIs (n = 40, 75%), or I-O and others (n = 3, 5%). Fourth-line treatment was given to 24 patients; ChT (n = 8, 33%), ALK-TKIs (n = 15, 63%) and other treatments (n = 1, 4%). 11 patients have received five or more lines of therapy. Crizotinib was given to 102 patients (81% in first- or second-line) resulting in a median PFS of 11.7 months (95% confidence interval [CI] 8.2-13.1). Ceritinib was given to 37 patients (76% in third- or later line) with a median PFS of 6.5 months (95% CI 3.7-9.4). 26 patients received alectinib (85% in third- or later line) with a median PFS of 12.4 months (95% CI 8.4-17.0). So far, NGS has been performed in 5 patients before and after ALK-TKI therapy. Two secondary ALK mutations were detected (ALK p.I1171S and p.C1156Y) conferring responsiveness to further ALK-TKIs.

      Conclusions:
      This study confirms the activity of ALK-TKIs in ALK positive NSCLC and allowed the documentation of important clinical data in the real-life setting. Moreover, an in-depth molecular analysis of resistance mechanisms was performed, which will now be expanded to more patients from the cohort.

      Clinical trial identification:


      Legal entity responsible for the study:
      University Hospital Zurich

      Funding:
      University Hospital Zurich, Novartis

      Disclosure:
      S.I. Rothschild: Compensation (to the institution) for advisory boards from Novartis, Pfizer and Roche. Compensation (to the institution) for invited talks from Pfizer and Roche. All other authors have declared no conflicts of interest.

    • +

      32P - Effects of BTK inhibitor on gefitinib-resistance non-small cell lung cancer (ID 162)

      12:30 - 12:30  |  Author(s): T. Hong, Y. Fang, Y. Chen

      • Abstract

      Background:
      Lung cancer is the most frequent cause of cancer death in the world. EGFR-mutant lung cancer is a subtype of non–small cell lung cancer (NSCLC) that exhibits sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib (Iressa); however, acquired resistance was developed after a median of 9–14 months. In our previous study, we used two primary TKI-resistant lung cancer cell lines (CL25 and CL100) and a genome-wide human kinase and phosphatase RNAi screening and found that silencing Bruton tyrosine kinase (BTK) significantly inhibited the NSCLC viability. BTK is a non-receptor tyrosine kinase of the Tec kinase family and plays an important role in B-cell receptor signaling. Therefore, we wanted to combine primary TKI (Iressa) with BTK inhibitors (Ibrutinib and CC-292) as a cancer treatment for EGFR TKI-resistant NSCLC patients.

      Methods:
      First, we verified that BTK knockdown decreased cell viability in EGFR TKI-resistant CL25 cells and enhanced the sensitivity to Iressa treatment. Second, we test the 50% inhibitory concentration (IC50) of BTK inhibitors (Ibrutinib and CC-292) in NSCLC cells by WST-1 assay. Next, we analyzed the effects of BTK inhibitors on the downstream signaling of BTK by western blot. Furthermore, we investigated the mechanism of growth inhibition triggered by BTK inhibitors in CL25 cells. The cell cycle distribution and cell death were examined. Finally, we tried to understand whether BTK inhibitors could enhance the gefitinib -induced cell death in EGFR TKI-resistant CL25 cells by combined treatment with gefitinib and BTK inhibitors.

      Results:
      By a genome-wide human kinase and phosphatase RNAi screening and found that BTK may contribute to the primary resistance. Knockdown of BTK expression decreased the NSCLC cell viability in a dose dependent manner and increased the gefitinib-induced cell death in both EGFR TKI-resistant CL25 and CL100 cells. BTK knockdown increased the levels of apoptotic and autophagic markers and cyclinD1 by western blot analysis. Moreover, BTK inhibitors affected BTK, NFkB, PI3K/AKT and EGFR signaling in EGFR TKI-resistant CL25 cells. Besides, treatment with Ibrutinib or CC-292 at the concentration of 4 fold IC50 induced G1 arrest in CL25 cells. Finally, combination of BTK inhibitors and gefitinib could not enhance the gefitinib-induced cell death.

      Conclusions:
      According to above results, we found that BTK may be a candidate contributing to the primary EGFR-TKI resistance in NSCLC cells. Knockdown of BTK induces the autophagic cell death and the G1 arrest in primary EGFR TKI-resistant CL25 cells and enhances the gefitinib-induced cell death while BTK inhibitors induce G1 arrest but cannot enhance the gefitinib-induced cell death.

      Clinical trial identification:


      Legal entity responsible for the study:
      National Cheng Kung University

      Funding:
      Ministry of Science and Technology, Taiwan.

      Disclosure:
      All authors have declared no conflicts of interest.

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      33P - The screening and characterization of aptamer against gefitinib-resistant cells (ID 161)

      12:30 - 12:30  |  Author(s): Y. Chen, J. Wu, T. Hong

      • Abstract

      Background:
      The EGFR tyrosine kinase inhibitor (TKI) gefitinib serves as first-line drug for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutation. The challenge of this target therapy is the acquired resistance due to T790M mutation after gefitinib treatment. Aptamers are single-strand DNA molecules that form 3D structures and specifically bind to target components. In this study, we wanted to isolate aptamers with recognition ability for gefitinib-resistant NSCLC cells and look for another mechanism that contributes to the acquired resistance that is not caused by T790M mutation.

      Methods:
      We used PC9 (gefitinib-sensitive cells) and PC9-IR (gefitinib-resistant cells with no T790M mutation) cells to select specific aptamers that bound to membrane proteins which were overexpressed in PC9-IR cells. We used suction-type microfluidic control module to perform cell-systematic evolution of ligands by exponential enrichment (Cell-SELEX) and obtained some aptamers that had more affinity to bind to PC9-IR. We examined the specificity of the aptamers and observed whether aptamers could bind to cell membranes of PC9-IR. In addition, we tested the cell cytotoxicity of the aptamers.

      Results:
      We obtained the aptamer, AP16-23F, which had greater affinity to bind to PC9-IR. In order to test whether AP16-23F could recognize the cells with gefitinib resistance, we used AP16-23F to isolate cells from PC9 by fluorescence-activated cell sorting (FACS). The results showed that the cells selected by AP16-23F were more resistant to gefitinib.

      Conclusions:
      We have isolated an aptamer with specificity for binding and capturing gefitinib-resistant NSCLC cells. This aptamer may be useful for drug resistance detection and may have the potential to deliver anti-cancer drug to gefitinib-resistant cells in the future.

      Clinical trial identification:


      Legal entity responsible for the study:
      National Cheng Kung University

      Funding:
      Ministry of Science and Technology, Taiwan

      Disclosure:
      All authors have declared no conflicts of interest.

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      34P - Discovery of 1,3,5-triazine-monastrol based novel EGFR-tyrosine kinase inhibitor against human lung carcinoma (ID 371)

      12:30 - 12:30  |  Author(s): U.P. Singh, J.K. Shrivastava, A. Verma, H.R. Bhat

      • Abstract

      Background:
      In India, the number of new lung cancer cases has been increased with an annual rise of 15-20%. This poses a significant burden on already struggling healthcare services of the country. Thus, more efforts have been directed towards the easy access of the medicines and development of novel cost effective drug for the under-privileged. Consequently, introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has led to dramatic clinical improvement in non-small cell lung cancer (NSCLC). However, resistance to these inhibitors either via intrinsic and acquired resistance, put a selective pressure on the development of novel inhibitors. Therefore, the present study was aimed to develop novel 1,3,5-triazine derivatives as EGFR-TKIs for lung carcinoma.

      Methods:
      The 1,3,5-triazine-monastrol compounds were synthesized via multi-component reaction. The compounds were tested for determination of anticancer activity three human NSCLC cell lines A549, H157 and H52. The compounds were also tested for effect on cell growth inhibition and apoptosis through cell cycle arrest assay. The docking analysis was also carried out with EGFR-TK domain (PDB ID: 1M17) to elucidate vital structural residues necessary for bioactivity.

      Results:
      The cytotoxicity studies results suggest that, synthesized derivatives exhibit considerable inhibition with average IC~50~ for compound 7a were found to be 3.21, 6.32 and 11.05 µmol/l. It has been found that, 7h showed augmention in the number of cells in G0–G1 phase, with a subsequent decrease in the cells belonging to S and G2–M phase. It also causes modulation of tumor cell apoptosis in a concentration-dependent way. In docking study, it has been found that, compound 7h, 7l, 7m, 7e were found to be the most efficient analogues to attenuate EGFR-TKs via creating MET769, ASP831, LYS721 and CYS773 amino acids comparable to erlotinib.

      Conclusions:
      In conclusion, 1,3,5-triazines-monstrol conjugates has shown promising antitumor activity via inhibition EGFR-TK in lung carcinoma and my find serve as a lead for further research.

      Clinical trial identification:


      Legal entity responsible for the study:
      SHUATS

      Funding:
      SHUATS

      Disclosure:
      All authors have declared no conflicts of interest.

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      35P - CDK7 inhibition as a promising therapeutic strategy in lung squamous cell carcinoma with SOX2 amplification (ID 188)

      12:30 - 12:30  |  Author(s): J.C. Lee, J.Y. Hur, J.K. Rho, H.R. Kim, C. Choi

      • Abstract

      Background:
      Molecular targeted therapy has much improved the survival of lung adenocarcinoma while few advances have been made in the treatment of lung squamous cell carcinoma (SCC). SOX2 amplification is one of the most common genetic alterations in SCC. We investigated the effects of THZ1, a potent inhibitor of cyclin-dependent kinase 7 (CDK7) which plays a key role in gene transcription, on SCC cell lines with SOX2 amplification.

      Methods:
      SOX2-amplified SCC cell lines (H520, H1703, HCC95) and SCC cell lines without SOX2 amplification (H226, SK-MES1, H1975) were used. Along with the general drug efficacy of THZ1 and the effect of SOX2 knockout by CRISPR on cell growth, the differential gene expression following THZ1 treatment was evaluated by microarray analysis.

      Results:
      Genetic inhibition of SOX2 by CRISPR resulted in the suppression of cell growth in SOX2-amplified SCC cell lines. The treatment of THZ1 led to the suppression of cell growth and apoptotic cell death only in SOX2-amplified SCC cell lines while the modest growth-inhibitory effect of cisplatin was not different according to the status of SOX2 amplification. The phosphorylation of carboxyl-terminal domain (CTD) of RNAPII and the expression of SOX2 and survivin were decreased by THZ1 in Western blotting. Accordingly, the expression of transcription-associated genes including SOX2 was down-regulated by THZ1 in SOX2-amplified SCC cell lines.

      Conclusions:
      THZ1 could effectively control the proliferation and survival of SOX2-amplified SCC cells with the decrease of global transcriptional activity. It suggests that CDK7 inhibition leading to suppression of transcription may be considered as one of promising therapeutic options in lung SCC with SOX2 amplification.

      Clinical trial identification:


      Legal entity responsible for the study:
      Jae Cheol Lee

      Funding:
      Asan Medical Center

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      36P - Circulating tumor DNA (ctDNA) as predictive biomarker in NSCLC patients treated with nivolumab (ID 401)

      12:30 - 12:30  |  Author(s): F. Passiglia, A. Perez, A. Listì, M. Castiglia, E. Musso, C. Ancona, S. Rizzo, M. Alù, L. Blasi, A. Russo

      • Abstract

      Background:
      Nivolumab is a programmed death-1 (PD-1) inhibitor recently approved for the treatment of NSCLC patients who failed prior chemotherapy. Searching for predictive biomarkers of immunotherapy efficacy is an area of intensive investigation for translational research. Monitoring circulating tumor DNA (ctDNA) during nivolumab treatment could help clinicians to predict the immunotherapy efficacy and ultimately improve the management of patients.

      Methods:
      From August 2015 to January 2017, 25 NSCLC patients receiving intravenous nivolumab 3 mg/kg every two weeks were included within a translational study. All the patients underwent CT-scan every 6 cycles and responses were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST). Peripheral blood samples were obtained from the patients at baseline and after 4 cycles of therapy and the quantification of ctDNA (ng/µL plasma) was performed by qubit dsDNA HS assay and confirmed by qPCR evaluating a 115 bp fragment of ALU repeat. The Mann Whitney test was used for intergroup comparisons of two independent samples. A p-value <0.05 was used as a threshold for statistical significance. Survival analysis was performed using Kaplan–Meier method, providing median and p-value.

      Results:
      Among the 20 patients included, 13 experienced progression disease (PD) at the first CT-scan, 3 partial response (PR), 4 stable disease (SD); 7 patients are still alive at the time of analysis. In 20 patients evaluable for ctDNA analysis at baseline, median ctDNA was significantly higher in patients with time to progression (TTP) < 3 months as compared to TTP > 3 months (p: 0.03). Similarly, in 17 patients evaluable for ctDNA analysis after 4 cycles, median ctDNA was significantly higher in patients with time to progression (TTP) < 3 months as compared to TTP > 3 months (p: 0.042). A not significant trend toward a TTP benefit was observed in patients with baseline ctDNA < 0.49 ng/µL as compared to ctDNA > 0.49 ng/µL (5 vs 3 months; p: 0.06); however, ctDNA after 4 cycles < 0.56 ng/µL was significantly associated with an improved TTP as compared to ctDNA > 0.56 ng/µL (p: 0.05). No significant differences in overall survival (OS) have been observed between these subgroups of patients.

      Conclusions:
      The preliminary results of this study showed that high ctDNA plasma levels are associated with early PD in NSCLC treated with nivolumab, suggesting a potential role of ctDNA as early predictor of response to immunotherapy. These preliminary data need to be explored and confirmed by prospective studies including larger cohorts of patients.

      Clinical trial identification:
      N.A

      Legal entity responsible for the study:
      Palermo University Hospital

      Funding:
      Palermo University Hospital

      Disclosure:
      All authors have declared no conflicts of interest.

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      37P - Can we perform subtyping of non-small cell lung cancer patients by use of lung tissue metabolic fingerprinting? (ID 477)

      12:30 - 12:30  |  Author(s): M. Ciborowski, J. Kisluk, K. Pietrowska, P. Samczuk, E. Parfieniuk, T. Kowalczyk, M. Kozlowski, A. Kretowski, J. Niklinski

      • Abstract

      Background:
      In case of NSCLC patients targeted agents (TAs) and newer chemotherapeutics yielded differences in outcomes according to histologic subgroups. About 62% of adenocarcinoma (ADC) patients have driver mutations in targeted oncogenes and TAs can be successfully administrated to these patients. Similar mutations are rarely observed in squamous cell carcinoma (SCC) and TAs are currently unavailable for this group of patients. A correct histologic classification is important for treatment planning and novel therapeutic options are awaited for SCC patients. Metabolomics has potential for revealing metabolic pathways altered by disease and for biomarkers discovery. The purpose of this study was to evaluate whether LC-MS metabolomics of lung tumor tissue can be used to classify NSCLC patients according to histological subtype: ADC, SCC or large cell carcinoma (LCC).

      Methods:
      The study was performed in the group of 25 NSCLC patients (62±8 years old, BMI=25±2, 32% females) who underwent curative tumor surgery. The patients were classified as ADC (n = 8), LCC (n = 4), and SCC (n = 13). Metabolites were extracted from tumor and adjacent control lung tissue and analyzed by LC-QTOF-MS. Differences between tumor and control tissue were evaluated by paired t-test or Wilcoxon rank test. One-way ANOVA was used to select metabolites discriminating NSCLC subtypes. Multivariate analysis was used for samples classification.

      Results:
      Control and tumor tissue samples were well separated on OPLS-DA model (R2=0.96, Q2=0.86). The main metabolites responsible for separation were lysophospholipids (+51-384%, p-value 0.02-0.0004) and acylcarnitines (+59-477%, 0.05-0.0007). PLS-DA model showed good separation of NSCLC subtypes (R2=0.99, Q2=0.7). Among metabolites responsible for this separation sphingosine (p = 0.03), four acylcarnitines (p-value 0.03-0.001), Lyso PEs 18:1 (p = 0.04) and 16:0 (p = 0.03) as well as Lyso PC 16:1 (p = 0.01) can be mentioned.

      Conclusions:
      NSCLC subtypes can be discriminated based on tumor tissue metabolic fingerprinting. Obtained results are preliminary and require further validation in a larger group of patients.

      Clinical trial identification:
      This study is a research project which was approved by the Ethics Committee of the Medical University of Bialystok (No. R-I-003/262/2004).

      Legal entity responsible for the study:
      Medical University of Bialystok

      Funding:
      National Science Centre, Poland (2014/13/B/NZ5/01256).

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      38P - Flow cytometry immunophenotyping of pleural fluid cytology in patients with diffuse large B-cell lymphoma (DLBCL) and malignant pleural effusion (ID 377)

      12:30 - 12:30  |  Author(s): F. Lumachi, P. Ubiali, R. Tozzoli, S.C. Sulfaro, S.M. Basso

      • Abstract

      Background:
      Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL and comprises up to 35% of cases. In patients with DLBCL the clinical presentation varies widely. Malignant pleural effusion (MPE) represents a common occurrence in cancer patients with either thoracic and extra-thoracic malignancies, often requiring invasive diagnostic procedures, including video-assisted thoracoscopic surgery (VATS)-guided biopsy. Approximately 20% of patients with DLBCL may develop MPE. The aim of this study was to demonstrate the usefulness of flow cytometry phenotyping (FCP) of pleural cytology (PC) in patients with MPE due to DLBCL.

      Methods:
      A retrospective chart review of 40 (15 (37.5%) males and 25 (62.5%) females, median age 69 tears, range 46-85 years) patients with histologically confirmed MPE was performed at a tertiary referral Medical Center. All patients underwent PC and FCP before VATS-guided biopsy. For the FCP, the FACSCanto II system and the FACSDiva software (BD Biosciences, Franklin Lakes, USA) were used. Compensation beads were obtained with single stains of each antibody to determine the compensation settings, and the settings were applied in FlowJo software (Tree Star, Ashland, USA) after data collection. Sample cells were stained with a panel of antibodies, including CD5, CD10, CD19, CD23, Kappa, Lambda, and CD45 (Dako, Glostrup, Denmark). In the presence of a T-cell population with aberrant phenotypes or a B-cell population with monotypic light chains, the diagnosis of DLBCL-related pleural effusion was made.

      Results:
      Final histology showed 5 (12.5%) patients with DLBCL and 35 (87.5%) with MPE from other malignancies (mainly breast cancer and lung cancer). The age (68.0±10.1 vs. 67.5±14.2 years; p = 0.94) and the male to female ratio (p = 0.64) did not differ between groups. The results are reported in the Table. The sensitivity and negative predictive value of FCP reached 100%, the specificity was the same as obtained with the PC alone, but the accuracy was superior (97.5% vs. 85%; p = 0.003).rnTable: 38PResults of flow cytometry phenotyping and pleural cytologyrn

      rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn
      ResultsFlow cytometry immunophenotypingPleural fluid cytology
      Sensitivity100%0%
      Specificity97.1% (95% CI: 91.6-100)97.1% (95% CI: 91.6-100)
      Negative predictive value100%97.2%
      Clinical accuracy97.5%85.0%
      Prevalence12.5%12.5%
      False positive rate2.9%2.9%
      False negative rate0%14.3%
      Likelihood ratio positive350
      Likelihood ratio negative01.3
      rn

      Conclusions:
      FCP of PC has great value in confirming (or excluding) the relationship between pleural effusion and malignancy, including lymphoma, exhibiting a significantly higher accuracy that that of PC alone. FCP should be performed in all patients with a history of DLBCL who exhibit suspicious MPE.

      Clinical trial identification:


      Legal entity responsible for the study:
      Università degli Studi di Padova

      Funding:
      Università degli Studi di Padova

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      39P - Efficacy of Tumor Treating Fields (TTFields) and anti-PD-1 in non-small cell lung cancer (NSCLC) preclinical models (ID 457)

      12:30 - 12:30  |  Author(s): U. Weinberg, T. Voloshin, O.T. Yitzaki, N. Kaynan, M. Giladi, A. Shteingauz, M. Munster, S. Cahal, E.D. Kirson, Y. Palti

      • Abstract

      Background:
      Tumor Treating Fields (TTFields) are an effective anti-neoplastic treatment modality delivered via non-invasive application of low intensity, intermediate frequency, alternating electric fields. TTFields is approved for the treatment of both newly diagnosed and recurrent glioblastoma. TTFields interrupt mitosis in cancer cells by disrupting microtubules and septin filaments, which play key roles in mitosis. The mitotic effects of TTFields include abnormal chromosome segregation that trigger different forms of cell death. We evaluated TTFields’ effect on immunogenic cell death and its efficacy when combined with an immune checkpoint inhibitor (αPD1) in NSCLC.

      Methods:
      Murine Lewis lung carcinoma (LLC) cells were treated with TTFields using the inovitro[TM] system. Levels of cell surface calreticulin (CRT) and intracellular ATP levels were evaluated using flow cytometry. High mobility group box 1 (HMGB1) secretion was measured using an ELISA assay. Mice inoculated with LLC cells were treated with isotype control, TTFields, αPD-1, or TTFields + αPD-1. Tumor volume monitoring and intra-tumor immune cell profiling were performed.

      Results:
      TTFields induced elevated cell surface expression of CRT, decreased ATP levels, and promoted HMGB1 secretion. In vivo, the combined treatment of TTFields + α-PD-1 led to a significant decrease in lung tumor volume compared to all three other groups (P < 0.001). Significant increase in CD45+ tumor infiltrating cells was observed in the TTFields + αPD-1-treated mice. Infiltrating cells demonstrated a significant upregulation of surface PD-L1 expression. Both F4/80+CD11b+ cells and CD11c+ cells exhibited higher tumor infiltration and elevated PD-L1 expression, as compared to the control group. These findings indicate enhanced inflammatory antitumor environment conferred by the combination of TTFields + αPD-1.

      Conclusions:
      Our results demonstrate that TTFields treatment potentiates immunogenic cell death in NSCLC cancer cells. Combining TTFields with specific immunotherapies such as anti-PD-1 may enhance antitumor immunity and result in increased tumor control. A phase III clinical study on TTFields in combination with either PD-1 inhibitors or docetaxel in NSCLC is underway.

      Clinical trial identification:
      Not applicable. Preclinical research.

      Legal entity responsible for the study:
      Novocure Ltd

      Funding:
      Novocure Ltd

      Disclosure:
      U. Weinberg: Full time employee of Novocure. T. Voloshin, O.T. Yitzaki, N. Kaynan, M. Giladi, A. Shteingauz, M. Munster, S. Cahal, E.D. Kirson: Full time employee of Novocure Ltd. Y. Palti: Shareholder at Novocure Ltd, NY.

    • +

      40P - Antitumoral effect and reduced systemic toxicity in mice after intra-tumoral injection of an in vivo solidifying calcium sulfate formulation with docetaxel (ID 201)

      12:30 - 12:30  |  Author(s): M. Sandelin, S. Grudén, V. Rasanen, P. Micke, M. Hedeland, N. Axén, M. Jeansson

      • Abstract

      Background:
      Docetaxel is a cytostatic agent approved for treatment of non-small cell lung cancer as well as other cancers. Its effectiveness in clinical practice is associated with a variety of acute and long term side effects. To reduce the systemic side effects, a local slow-release depot formulation based on calcium sulfate with docetaxel for intra-tumoral administration was developed.

      Methods:
      Two formulations with a twofold difference in docetaxel drug load (corresponding to 12.5 and 25.0 mg/kg body weight) were manufactured with the calcium sulfate based NanoZolid™ technology. The formulations were injected intra-tumorally as a paste which solidified within the tumor. The effects of the two local depot formulations were tested in female mice (n = 60) inoculated with subcutaneous Lewis lung carcinoma cells. The slow-release depots were compared to systemic intraperitoneal injections of docetaxel (25.0 mg/kg) and a calcium sulfate placebo formulation. Tumor volumes were measured and systemic side effects were evaluated using body weight and cell counts from whole blood as well as plasma concentrations. In addition, a histological evaluation was performed.

      Results:
      Both docetaxel formulations showed a significantly higher antitumor efficacy compared to placebo, which was comparable to that of systemic administration of docetaxel. Moreover, the intra-tumoral depot formulations with docetaxel showed reduced systemic toxicity compared to systemic treatment, including less weight loss and no decrease in blood cell counts. The extracellular deposits of calcium sulfate, observed in all groups with intra-tumoral injections, did not lead to significant inflammatory changes.

      Conclusions:
      It was shown that intra-tumoral slow-release depots of calcium sulfate with docetaxel were well tolerated and released docetaxel at amounts sufficient for satisfactory local antitumor effect and for a low level plasma detection. The use of such depots can be an alternative to intravenous injection as an efficient antitumoral treatment with reduced systemic toxicity.

      Clinical trial identification:


      Legal entity responsible for the study:
      Uppsala University, Department of Immunology, Genetics and Pathology, Marie Jeansson

      Funding:
      This study was supported by an IGP Young Investigator grant (MJ), the Swedish Research Council (521-2012-865, MJ), Åke Wiberg Foundation (738866289, MJ), Magnus Bergvalls Foundation (24942-1-2013, 2014-00055, MJ), and Ture Stenholms Foundation for Surgical Research (MS)

      Disclosure:
      S. Grudén: Consultant for LIDDS AB. N. Axén: Consultant for LIDDS AB and have equity interests in LIDDS AB. All other authors have declared no conflicts of interest.

    • +

      41P - Development of novel 1,2,4-triazole-thiol derivatives as dual PI3K/mTOR inhibitor against the non-small cell lung cancer (NSCLC) (ID 435)

      12:30 - 12:30  |  Author(s): A. Verma, V. Kumar, U.P. Singh

      • Abstract

      Background:
      PI3K catalyzes the ATP-dependent phosphorylation of the 3'-hydroxyl group of phosphatidylinositols and plays an important role in cell growth and survival. However, most of the inhibitors in this signaling pathway have inhibitory effect against both PI3K and mammalian target of rapamycin (mTOR) kinases. It is well known that the mTOR, regulate cell proliferation, apoptosis, angiogenesis, and metabolism through both AKT-dependent and AKT-independent mechanisms. Agents targeting PI3Ks with additional mTOR kinase inhibitory have more advantageous than alone inhibition. Our efforts to identify potent and efficacious PI3K/mTOR dual inhibitors resulted in the discovery of a series of substituted 1,2,4-triazole-thiol derivatives.

      Methods:
      The entire set of the designed compounds were assessed on the Lipinski rule of five for drug-likeness prediction using Molinspiration and synthesized via novel synthetic procedure. The anticancer activity was evaluated against panel of three human NSCLC cell lines A549, H157 and H52 together with effect on cell cycle. The compounds were also evaluated for inhibitory activity against PI3K and mTOR via kinase inhibitory assay together with molecular docking experiments (PI3K; 3s2a.pdb) to rationalize the mechanism of action.

      Results:
      The compounds were developed in excellent yield and found to be significantly activity against the panel of the cell lines. The most active compound 6b showed significant inhibitory activity with IC50 of 4.56, 7.23 and 9.21 µmol/l against A549, H157 and H52, respectively, with highest activity against A549 (IC50 = 1.13 µmol/l). The compound 6b causes a significant arrest of G2/M phase and induces tumor cell apoptosis in a concentration dependent manner. In a PI3K/mTOR inhibition assay, 6b showed IC50 of 1.43±0.21 µM and 2.32±0.12 against PI3Ks and mTOR, respectively. Moreover, the docking results showed that 6b efficiently inhibit PI3Ks via channeling in ATP pocket with Ki of 436.57 nM. It showed to interact with Met804, ILE831, ILE879.

      Conclusions:
      In conclusion, a novel series of 1,2,4-triazole-thiol derivatives has been developed as potent inhibitor of PI3K/mTOR against lung cancer with favorable drug likeness profile.

      Clinical trial identification:


      Legal entity responsible for the study:
      SHUATS

      Funding:
      SHUATS

      Disclosure:
      All authors have declared no conflicts of interest.

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      42P - Dual inhibitory effects of novel naringenin analogue in tobacco-carcinogen induced lung cancer via inhibition of PI3K/Akt/mTOR pathway (ID 337)

      12:30 - 12:30  |  Author(s): V. Kumar, A. Verma, P.C. Bhatt

      • Abstract

      Background:
      Phosphoinositide 3- kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathways is considered as the signalling pathway which activates the diverse cellular function viz., survival, cell expansion, vesicular transport and proliferation and found frequently dysregulated pathway in lung cancer. Consequently, flavonoids based inhibitors play a key kinase role in the pathway including mTOR, PI3K and AKT, have been extensively scrutinized in targeting the oncology in recent years. The common pathway to PI3K-Akt-mTOR used to target during the lung cancer therapy. Therefore, the current study was aimed to peruse the naringenin as dual PI3K/mTOR for lung cancer.

      Methods:
      In the current experimental study mice were randomly divided into 7 groups with 12 mice in each groups The oxidative stress was evaluated in term of antioxidant parameters such as myeloperoxidase (MPO) and superoxide dismutase (SOD), respectively. The proinflammatory cytokines viz., interleukin (IL)-1β, tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were measured via using the standard enzyme-linked immunosorbent assay kits. The concentration of PI3K, P-PI3K, mTOR, P-mTOR Akt and P-Akt were determined via using the Western blot techniques. We also performed the histopathological study to identify the changes during the disease.

      Results:
      Naringenin significantly suppressed the oxidative stress via improving the status of endogenous antioxidant parameters such as SOD and MPO in a dose dependent manner. disease control group mice confirmed the change in protein levels of PI3K/Akt/mTOR pathway in lung as compared to normal control, which were significantly down-regulated by the naringenin in a dose dependent manner. In the histological study, we observed that the naringenin substantially reduced the benzopyrene induced neutrophils in lung tissue.

      Conclusions:
      It can be concluded that naringenin has shown promising anticancer effect via attenuation of PI3K/Akt/mTOR against lung cancer and signifies the potential therapeutic relevance for further development.

      Clinical trial identification:


      Legal entity responsible for the study:
      SHUATS

      Funding:
      SHUATS

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      43P - A phase I-II clinical trial to evaluate the safety, pharmacokinetics and efficacy of high dose intravenous ascorbic acid synergy with mEHT in Chinese patients with stage III-IV non-small cell lung cancer (ID 225)

      12:30 - 12:30  |  Author(s): J. Ou, X. Zhu, Y. Lu, C. Zhao, H. Zhang, X. Gui, X. Wang, X. Zhang, T. Zhang, C.L.K. Pang

      • Abstract

      Background:
      Ascorbic acid (AA) infusion and modulated electrohyperthermia (mEHT) have been widely used by integrative cancer practitioners for many years. However, there are no safety and pharmacokinetics data in Chinese cancer patients.

      Methods:
      Blood ascorbic acid in the fasting state was obtained from 35 NSCLC patients; selecting from them 15 patients with stage III-IV entered the phase I -II study. They were randomized allocated into 3 groups, and received doses 1.0, 1.2, 1.5g/kgAA infusions. Pharmacokinetic profiles were obtained when they received solely IVAA at concentrations of 1g/kg, 1.2g/kg, and 1.5g/kg, and when IVAA in combination with mEHT. The process was applied 3 times a week (every other day, weekend days off) for 4 weeks. Participants in the first group received intravenous AA (IVAA) when mEHT was finished; in the second group IVAA was administered simultaneously with mEHT; and in the third group IVAA was applied first, and followed with mEHT. All patients started the trial doses of 1 g/kg for 8 treatments. When there was no DLT observed, the test dose for patients increased to 1.2 g/kg continuously for 8 treatments, and then the test dose for patients was escalated to 1.5 g/kg continuously for 8 treatments. DLT was defined as any reversible grade ≥3 adverse events, whether haematological or non-haematological.

      Results:
      Fasting plasma AA levels were significantly correlated with stage of the disease. Peak concentrations of AA were significantly higher in the simultaneous treatments than in other combinations with mEHT or in solely IVAA-managed groups. The average scores for the functioning scales continuously increased and the symptoms gradually decreased over the full cycle of the study. 3/7 patients with squamous cell lung cancer were CR, 4/7 were PR. 1/8 patient with adenocarcinoma cell lung cancer was PR, 5/8 were SD, and 2/8 died.

      Conclusions:
      IVAA synergies with simultaneous mEHT is safe and the concomitant application significantly increases the plasma AA level for NSCLC patients. QOL is improved when they receive the above treatments. Patients diagnosed with squamous cell lung cancer were sensitive to the above two treatments.

      Clinical trial identification:
      NCT02655913

      Legal entity responsible for the study:
      Junwen Ou

      Funding:
      Clifford Hospital

      Disclosure:
      All authors have declared no conflicts of interest.

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      47P - Multi detector CT evaluation of suspicious malignant lung masses with its combined wash-in & wash-out features and their histopathological correlation (ID 237)

      12:30 - 12:30  |  Author(s): S. Khanduri, S. Bhagat

      • Abstract

      Background:
      Lung cancer is the leading cause of cancer death in the world. Detection of malignancy at an early stage and with precision is the utmost objective of radiological evaluation. The final diagnosis of lung cancer is histopathological evaluation of the mass by biopsy or fine needle aspiration cytology (FNAC) only. This study was carried out with an aim of evaluating the suspected malignant masses by Multidetector CT (MDCT) along with their contrast wash-in & wash-out characterisctics with their histopathological correlation.

      Methods:
      After obtaining ethical approval, 50 cases of suspected lung cancer, by clinical and radiographic evaluation, were enrolled in the study. These patients underwent CT thorax (non contrast, contrast & delayed scans) on 384 slice Siemens Somatom Force®. After undergoing the radiological evaluation, biopsy of the mass was performed either using CT guidance or bronchoscopy guidance. Radiological and histopathological findings were correlated.

      Results:
      Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy of MDCT against histopathology were 97.3%, 76.9%, 92.3%, 90.9%, and 92.0%, respectively. Sensitivity and specificity calculated through receiver operating characteristic curve for wash-in (Net early enhancement) for >17.00 HU were found to be 97.3% and 76.9% while that of wash out characterization of lung mass - Relative wash-out at < 18.83% were 97.3% and 93.3%, and absolute washout at < 65.48% were 97.3% and 93.3% in predicting malignancy.

      Conclusions:
      MDCT serves as an excellent tool for early diagnosis of lung cancer and it is an important tool for cases where biopsy or FNAC is not possible. Faster and newer CT techniques such as contrast wash-in and wash out have greater diagnostic accuracy than the conventional diagnostic techniques. So a combination of conventional and newer techniques can further increase the diagnostic accuracy of MDCT in diagnosing lung cancers and obviate the need for invasive methods for biopsy/FNAC.

      Clinical trial identification:


      Legal entity responsible for the study:
      Era\'s Lucknow Medical College & Hospital

      Funding:
      Era\'s Lucknow Medical College & Hospital

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      48P - Evaluation of neoplasms incidentally detected by preoperative FDG-PET/CT for primary lung cancer (ID 362)

      12:30 - 12:30  |  Author(s): Y. Noda, H. Matsudaira, S. Arakawa, K. Yoshida, T. Morikawa

      • Abstract

      Background:
      Fluorodeoxyglucose Positron emission tomography/computed tomography (FDG-PET/CT) is an effective modality generally used in preoperative evaluation for primary lung cancer. In some cases, FDG-PET/CT found incidental neoplastic lesions and also detected unexpected pre-malignancy or second malignancy. Our study aimed to examine incidental findings detected by preoperative PET/CT and its impact on management for lung cancer.

      Methods:
      From April 2010 until August 2015, 149 patients underwent surgery for primary lung cancer at Katsushika Medical Center and 111 patients of them acquired preoperative PET/CT were evaluated retrospectively. Incidental findings were followed up by some imaging test, clinician feedback, pathological examination and various endoscopy.

      Results:
      The objects included 32 women and 79 men. The mean age was 70.6±8.46 years old. Excluding known diseases and thoracic cage lesions, abnormal FDG uptakes on PET/CT observed at 40 patients (36%). 8 cases (7.2%) of them required other modalities for further evaluation and the sites of abnormal uptake were prostate, larynx, thyroid gland, 3 cases of colon, bone and lymph node each.3 cases (2.7%) of colon had an indication for treatment. 2 cases were colon polyp and the other case was colon cancer. 2 cases underwent endoscopic mucosal resection. The other case underwent surgery for the colon cancer before treatment for the lung cancer because of neoplastic obstruction. This case was pointed out liver metastasis 6 months later from surgery of the colon cancer. We diagnosed liver lesion as colon cancer metastasis and we are doing chemotherapy to this case.

      Conclusions:
      A malignant or pre-malignant lesion was found in 0.9% and 1.8%, respectively. Colon was major lesion of abnormal uptake of FDG in our study, and 1 case required colon resection before lung cancer. The case had a significant change in management for treatment. We conclude preoperative FDG PET/CT might be useful modality in identifying second primary cancers or pre-malignancy lesions in patients with primary lung cancer. Further investigations are needed to evaluate incidental findings detected by preoperative FDG PET/CT.

      Clinical trial identification:


      Legal entity responsible for the study:
      Jikei University School of Medicine

      Funding:
      Jikei University School of Medicine

      Disclosure:
      All authors have declared no conflicts of interest.

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      49P - Computed tomographic features of pulmonary sarcomatoid carcinoma (ID 499)

      12:30 - 12:30  |  Author(s): M. Attia, K. Abdelmoula, H. Neji, M. Affes, S. Hantous-Zannad, A. Mekkaoui, I. Baccouche, K. Ben Miled-M'rad

      • Abstract

      Background:
      Pulmonary sarcomatoid carcinoma is a rare tumor. It is subdivided into 5 subtypes and representing approximately 0.4% of non-small cell lung cancer. The aim of our work is to illustrate the computed tomography (CT) features of this tumor.

      Methods:
      This was a retrospective case series of 18 consecutive patients with a pulmonary sarcomatoid carcinoma, collected between January 2011 and December 2016. All patients had undergone a CT scan for the diagnosis, staging and therapeutic response evaluation. CT- guided percutaneous biopsy and a histological analysis were performed in all cases for the pathological confirmation.

      Results:
      The mean age of patients was 56.8 years (range, 46-73 years). The CT appearance of the tumor was similar for all our patients: Large mass, peripheral, heterogeneous density, with massive necrotic tissue component that strongly heightened after contrast injection; tumor had a locoregional extension with parietal and bone invasion (n = 5) and a distance extension (n = 4) to the adrenal glands. Pathological examination found a pleomorphic carcinoma (n = 3), a giant cell carcinoma (n = 1) and a carcinosarcoma (n = 2). Sarcomatoid carcinoma diagnosis was increased for the remaining patients without precision of histological subtype.

      Conclusions:
      Pulmonary sarcomatoid carcinoma seems to have CT scan characteristics that distinguish it from other non-small cell lung cancers, specifically: diagnosis size, peripheral necrosis and increased vascularization of its fleshy portion with a local aggressiveness and a high metastatic potential.

      Clinical trial identification:


      Legal entity responsible for the study:
      Abderrahmen Mami Hospital

      Funding:
      Abderrahmen Mami Hospital

      Disclosure:
      All authors have declared no conflicts of interest.

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      50P - Usefulness of F-18 FDG PET/CT to identify metastatic mediastinal lymph node in NSCLC patients with bilateral benign mediastinal lymph node hyperplasia (ID 272)

      12:30 - 12:30  |  Author(s): Y.S. Kim, S.H. Yoon, B.S. Son, D.H. Kim, K. Kim, S. Kim

      • Abstract

      Background:
      F-18 FDG PET/CT is superior to CT imaging in identifying metastatic mediastinal lymph node (MLN) involvement in NSCLC. However, the accuracy of F-18 FDG PET in nodal staging is substantially reduced by false increases in F-18 FDG uptake in the inflammatory nodes. The efficacy of this technique is controversial because of reactively increased F-18 FDG uptake in the mediastinum, especially in regions endemic for the granulomatous disease. Here, we determined the qualitative and quantitative parameters of F-18 FDG-PET/CT for evaluation of mediastinal nodes to distinguish between malignant and benign lesions.

      Methods:
      27 patients with pathologically documented NSCLC who showed bilateral F-18 FDG-avid MLNs on pre-treatment staging PET/CT image were included. 104 MLNs were pathologically analysed through EBUS-TBNA or MLN dissection. The MLN with prominent F-18 FDG uptake compared with other F-18 FDG-avid LNs via visual assessment was qualitatively considered as metastasis. The maximum standardized uptake value (SUVmax) of LN and SUVmax of LN to the liver and blood pool were calculated for quantifying F-18 FDG uptake. SUVmax/contra was obtained to identify metastatic MLNs.

      Results:
      The qualitative evaluation showed sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for separating metastatic LN from benign reactive hyperplasia of 66.7%, 87.0%, 74.3%, and 88.2%, respectively. SUVmax of LN and normalized SUVmax of LN to the liver and blood pool did not significantly differ; however, SUVmax/contra was significantly higher for metastatic LNs than benign lesions. Receiver-operating-characteristic derived SUVmax/contra cut-off was 1.18 (AUC, 0.734). The quantitative evaluation showed sensitivity, specificity, PPV, and NPV of 66.7%, 75.3%, 77.4%, and 86.4%, respectively.

      Conclusions:
      Qualitative interpretation of F-18 FDG PET/CT was superior to quantitative parameters in discriminating metastatic LNs from benign reactive hyperplasia in patients with bilateral F-18 FDG-avid mediastinal LNs. We suggest SUVmax/contra may aid in the interpretation of mediastinal nodal staging in patients with NSCLC.

      Clinical trial identification:


      Legal entity responsible for the study:
      None

      Funding:
      N/A

      Disclosure:
      All authors have declared no conflicts of interest.

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      52P - Combined chemotherapy with etoposide, irinotecan plus cisplatin compared with topotecan monotherapy as the second-line treatment in sensitive relapsed small cell lung cancer: A retrospective analysis (ID 308)

      12:30 - 12:30  |  Author(s): H. Wang

      • Abstract

      Background:
      Topotecan is currently the only drug approved by US Food and Drug Administration (FDA) for treatment of relapsed small-cell lung cancer (SCLC) patients. We did this study to attempt to investigate whether combined chemotherapy with etoposide, irinotecan plus cisplatin (PEI) was superior to topotecan alone as second-line treatment for sensitive relapsed SCLC patients.

      Methods:
      Between January 2009 and November 2015, a total of 82 relapsed SCLC patients were admitted to the affiliated Cancer Hospital of Zhengzhou University in this retrospective analysis. Among them, 44 patients were treated with combined PEI chemotherapy, while 38 patients were treated with topotecan monotherapy. Disease control rates (DCR), progression-free survival (PFS), overall survival (OS) and adverse reaction were recorded.

      Results:
      A total of 82 patients were analyzed. The patients treated with combined chemotherapy had longer median overall survival (OS) (16.3 months vs 10.1 months) than those treated with topotecan (P = 0.001), and median progression-free survival (PFS) time was slightly but significantly longer (6.2 months vs 4.1 months), than the topotecan group. Compared with the topotecan group, more common grade 3 or 4 adverse events were recorded for the combination chemotherapy group, including leucopenia, anaemia, thrombocytopenia. Grade 3-4 non-hematological toxicity was not common. When compared with younger patients, combined chemotherapy-treated patients (≥ 68 years of age) experienced higher rates of leucopenia, anemia, thrombocytopenia and fatigue. Serious adverse events were reported in two patients in the topotecan group and seven patients in the combination group. Two treatment-related deaths (one each of pulmonary infection and pneumonitis) occurred in the combination group, one treatment-related death (pneumonitis) occurred in the topotecan group.

      Conclusions:
      Combined chemotherapy with etoposide, irinotecan plus cisplatin (PEI) is not inferior to topotecan monotherapy as the second-line treatment.

      Clinical trial identification:
      none

      Legal entity responsible for the study:
      None

      Funding:
      The National Natural Science Foundation of China (No.81272600)

      Disclosure:
      The author has declared no conflicts of interest.

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      53P - Systematic literature reviews of second and third-line treatments used for small-cell lung cancer (SCLC) (ID 246)

      12:30 - 12:30  |  Author(s): R. Goulding, M. Lorenzi, Y. Yuan, S. Bobiak, N. Hertel, B. Korytowsky, J.R. Penrod, J. Jansen

      • Abstract

      Background:
      While SCLC is initially sensitive to first-line chemotherapy and radiotherapy, most patients relapse, and outcomes with second-line treatments remain bleak. The purpose of this study was to gather evidence and assess appropriate methodologies for evidence synthesis of the following clinically relevant outcomes: efficacy, safety, and health-related quality of life (HRQoL) in adult patients treated with existing second and third-line SCLC treatments, including immunotherapy, which was recently recommended in the NCCN SCLC treatment guidelines.

      Methods:
      A systematic literature search was conducted using MEDLINE, EMBASE, and the Cochrane Register of Controlled Clinical Trials, and carried out by 2 independent reviewers. Manual searches of clinicaltrials.gov, the WHO International Clinical Trials Registry Platform, and 5 relevant conferences (ASCO, AACR, ESMO, WCLC, and ELCC) were performed to identify unpublished randomized clinical trials (RCTs) potentially eligible for inclusion. RCTs that reported outcomes of interest, including overall survival, progression-free survival, objective response rate, and/or HRQoL, for the treatments and population of interest, were identified for this review. Corresponding trial, patient baseline characteristics, and outcome data were extracted for all included studies.

      Results:
      17,550 citations were identified, including 970 conference abstracts and 25 clinical trial registry entries. Nine SCLC RCTs were identified studying treatments of interest, including cisplatin, carboplatin, etoposide, amrubicin, irinotecan, gemcitabine, and topotecan; however, there were a lack of RCTs for innovative treatments including nivolumab.

      Conclusions:
      A lack of RCT evidence for all relevant treatments in the target population may result in disconnected treatment networks, such that trial comparisons involving all treatments of interest may not be feasible using the standard network meta-analysis methodology. Alternative methods that incorporate single-arm evidence may be required to estimate the relative clinical efficacy, safety, and HRQoL outcomes of second- and third-line treatments of relevant SCLC comparators.

      Clinical trial identification:


      Legal entity responsible for the study:
      Bristol-Myers Squibb and Precision Health Economics

      Funding:
      Bristol-Myers Squibb

      Disclosure:
      R. Goulding: Employee of Precision Health Economics, funding from Bristol-Myers Squibb for the work on the abstract. Y. Yuan, S. Bobiak, N. Hertel, B. Korytowsky, J.R. Penrod: Employee of Bristol-Myers Squibb with stock/ownership options. J. Jansen: Employee of Precision Health Economics and reports that Precision Health Economics received funding for this work. All other authors have declared no conflicts of interest.

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      54P - Up front chemotherapy dosing and relative dose intensity in extensive stage small cell lung cancer (ID 344)

      12:30 - 12:30  |  Author(s): A.W. Mølby, B.E. Laursen, U. Falkmer, T. McCulloch, N.A. Jensen, L.Ø. Poulsen

      • Abstract

      Background:
      Extensive-stage small cell lung cancer (ES-SCLC) is an extremely aggressive malignant disease where patients often present with a poor performance status (PS), high age and several comorbidities. Reduced dose up front is a possibility for these patients. We investigated the impact of reduced dose up front and the impact of Relative dose intensity (RDI), age and comorbidity on overall survival (OS).

      Methods:
      Data of a real-time registration study of a consecutive cohort, of patients treated with carboplatin and etoposide for ES-SCLC during 2012 and 2013 in the North Denmark Region, were analyzed. Patients only treated with one cycle of chemotherapy were excluded. Comorbidity was assessed according to the Charlson Comorbidity Index (CCI). Area Under the Curve (AUC), for carboplatin dose, was used for analysis of RDI. All dose reductions were made simultaneously in both carboplatin and etoposide. Multivariate statistical survival analysis was made using Cox Regression analysis calculating a Hazard Ratio (HR) for OS.

      Results:
      In all, data from 75 patients were analyzed; mean age was 68 years; 44/75 (59%) were in PS 0-1 and 37/75 (49%) had 1 or more comorbidities. Reduced dose at baseline was applied to 25/75 (33%) of the patients. These patients had a HR 1.82, p-value = 0.070. RDI of 85% or below, was applied to 42/75 (56%) and showed a HR of 0.66, p-value = 0.228. Compared to PS 0-1, PS 2 showed a HR of 2.35 (p = 0.014) and PS 3-4 a HR of 8.40 (p < 0.000). Age, CCI, polypharmacy and LDH ≥ 300 U/L showed no statistical significant impact on OS. Hematological toxicity was the main reason for dose reductions and delays during chemotherapy, which occurred 19/75 (25%) and 47/75 (63%), respectively. Five patients died due to febrile neutropenia/sepsis. Fourteen long-term survivors were seen with an OS of more than 20 months.

      Conclusions:
      These results suggest that full dose chemotherapy should be applied up front, though poor PS is a major limiting factor, whereas high age should not be. RDI showed no impact on OS, but larger studies are needed. Data concerning fourteen long-term survivors will be presented at the meeting.

      Clinical trial identification:


      Legal entity responsible for the study:
      Aalborg University Hospital, Department of Oncology

      Funding:
      N/A

      Disclosure:
      All authors have declared no conflicts of interest.

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      55P - Clinical significance of EBUS-TBNA in patients with small cell lung cancer (ID 433)

      12:30 - 12:30  |  Author(s): Y.M. Lee

      • Abstract

      Background:
      Small cell lung cancer (SCLC) is associated with rapid tumor growth and early dissemination. A mass in or adjacent to the hilum/mediastinum is particularly characteristic of SCLC. Transbronchial needle aspiration (TBNA) is minimally invasive and safe method for the evaluation of lung masses. The diagnostic sensitivity of TBNA is particularly high for SCLC (64-93%). The addition of endobronchial ultrasound (EBUS) guidance to TBNA (EBUS-TBNA) has greatly enhanced the diagnostic yield and safety of the procedure. The aim of this retrospective study was to assess the clinical characteristics of SCLC diagnosed by EBUS-TBNA and its clinical significance.

      Methods:
      From January 2011 to December 2015, SCLC diagnosed by EBUS-TBNA were enrolled. For each patient, we documented patients characterisitics, size and locations of L/Ns, bronchoscopic findings and clinical courses. All patients underwent routine clinical assessment and a CT scan prior to EBUS-TBNA.

      Results:
      A total of 100 patients (64[64%] with limited-stage and 36[36%] with extensive-stage disease) were included in this study. Sex and Age distribution was M: F = 92.8 with a mean age 66.3±16.2 years. The most common chief complains were cough (n = 51), dyspnea (n = 18), chest pain (n = 15), blood tinged sputum (n = 10) and hoarseness (n = 6). The majority of patients was smokers (n = 95, 95%) and heavy smoker (>40pack.yr) was 74 (74%). 26 patients (26%) had hilar/mediastinal masses without a primary parenchymal lesion. Tumor marker CEA mean value was 16.4 in LD and 27.6 in ED. In bronchoscopy findings, 79 (79%) cases show only bronchial obstruction by external compression. The median size of target lesion examined by EBUS-TBNA was 33mm (range 11.5-74mm). Of the 100 EBUS-TBNA samples, 100(100%) samples yielded a diagnosis of SCLC. The most common target lymph node was at station 4R, followed by 7 and 11R. The median number and duration of aspirates per lesion was 2 (range 1-5) and 13mins (10-33). The most common distatant metastasis organ was bone (n = 30), follow by liver (n = 15), adrenal gland (n = 7) and brain (n = 6). The most common comorbidity was COPD (n = 34) followed by Heart disease (n = 15) and DM (n = 13) and DILD (n = 7). 30 patients of SCLC were not received chemotherapy. In chemotherapy group, overall response rate was 78.5% (LD: 88%, ED: 55%). No procedure-related complications were noted.

      Conclusions:
      EBUS-TBNA is a safe and highly accurate procedure for the diagnosis of SCLC. It is recommended a first diagnostic test if a patient is clinically suspected with SCLC.

      Clinical trial identification:


      Legal entity responsible for the study:
      Busan Paik Hospital

      Funding:
      Busan Paik Hospital

      Disclosure:
      The author has declared no conflicts of interest.

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      56P - Pro-GRP in small cell lung cancer (ID 288)

      12:30 - 12:30  |  Author(s): S. Cavalieri, F. Nichetti, D. Morelli, F. de Braud, A. Martinetti, E. Sottotetti, K. Dotti, M. Prisciandaro, F. Corti, M. Platania

      • Abstract

      Background:
      NSE was historically the recommended tumor marker for SCLC. It stains up to 80% of SCLCs in tissue examinations but is also elevated in the sera of 20–30% of patients with NSCLC. NSE has low sensitivity, particularly in patients with limited disease (LD). Recently, pro-gastrin-releasing peptide (pro-GRP) became available as a sensitive, specific and reliable tumor marker for patients with SCLC.

      Methods:
      We retrospectively analyzed pro-GRP in pts with SCLC and NSCLC treated from 2015 to 2016 at our Center. Serum pro-GRP level was measured with electrochemiluminescence method at our laboratory; it was considered elevated if higher than 77.8 pg/ml. Statistical tests used to study differences between pro-GRP medians were Mann-Whitney U test for SCLC vs NSCLC and Fisher’s exact test for DD vs LD. To calculate sensitivity (Sn), specificity (Sp), positive and negative predictive values (PPV and NPV respectively) we considered: SCLC with elevated pro-GRP as true positive (TP), NSCLC with normal pro-GRP as true negative (TN), SCLC with normal pro-GRP as false negative (FN), NSCLC with elevated pro-GRP as false positive (FP).

      Results:
      A total of 46 pts were studied (33 men, 13 women), whose median age was 67 years (range 20-78). 20 pts had SCLC (16 DD, 4 LD) and 26 metastatic or unresectable advanced NSCLC. Median pro-GRP level was 1398 pg/ml (range 43-50000) in SCLC and 26 pg/ml (range 6-119.2) in NSCLC (difference 1372 pg/ml; SCLC/NSCLC ratio 53.76; p < 0.01). TPs were 18, FNs 2, TNs 25, FP 1. Sn was 90%, Sp 96.15%, PPV 94.73% and NPV 92.59%. All the TPs had diffuse disease, the 2 FNs had limited disease, the only FP had a poorly differentiated adenocarcinoma. Median pro-GRP was 182.25 pg/ml (range 43-642) in LD pts and 2522 pg/ml (range 88-50000) in those with DD (absolute difference 2339.75 pg/ml; ratio DD/LD 13.83; p = 0.026). Pro-GRP was elevated in all DD pts and in half of LD pts (2/4): Both of them had a high burden of loco-regional disease.

      Conclusions:
      Our data confirm that pro-GRP is sensitive for SCLC diagnosis and that it might help to discriminate DD from LD. Since high marker levels are related to a high disease burden, pro-GRP may have a negative prognostic significance. Follow up is required to define its role in clinical practice in monitoring response to treatment.

      Clinical trial identification:
      Not applicable

      Legal entity responsible for the study:
      Fondazione IRCCS Istituto Nazionale dei Tumori

      Funding:
      Fondazione IRCCS Istituto Nazionale dei Tumori

      Disclosure:
      All authors have declared no conflicts of interest.

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      57P - small cell lung cancer: Retrospective review of an institution (ID 508)

      12:30 - 12:30  |  Author(s): A. Silva, I. Guerreiro, C. Castro, M. Brandao, A. Rodrigues, C. Oliveira, I. Pousa, J. Oliveira, I. Azevedo, M. Soares

      • Abstract

      Background:
      Small cell lung cancer (SCLC) account for 10 to 15% of lung cancers. Despite the high rate of response to chemotherapy and radiotherapy, it is characterized by a rapid growth and development of widespread metastases.

      Methods:
      Retrospective review of patients with SCLC with diagnosis between January 2013 and December 2016 in our institution - Portuguese Oncology Center, Porto. Descriptive analysis and survival evaluation by Kaplan-Meier method. Evaluation of differences between survival curves by log rank test.

      Results:
      From the 144 patients included, 115 (79.9%) were male and the mean age was 65 years (range 42-87). The majority of patients had an ECOG PS 0-1 at diagnosis (n = 91, 64.1%). History of smoking was present in 115 patients (79.8%). Ki-67 was analyzed in 38 patients (36.4%) and was ≥50% in 30 patients. 108 patients (75%) had metastatic disease at diagnosis, more frequently bone (n = 61, 42.4%) and liver (n = 50, 34.7%) metastasis. Initial treatment had palliative intent in 118 patients (81.9%), and 41 (28.5%) underwent only symptomatic treatment. The most commonly used chemotherapy regimen was the doublet of platinum and etoposide (n = 98, 95.1%). The overall response rate (ORR) was 64%. Median overall survival (OS) was 5.5 months (95% confidence interval (CI) 2.9-7.9). Within patients submitted to radical treatment (n = 26, 18.1%), there was relapse in 15 (57.7%), with a median disease free survival of 10.5 months (95% CI: 9.4-11.7). Within patients submitted to palliative treatment there was progression in 43 (not evaluated in 28), with a median progression free survival of 6.3 months (95% CI: 5.9-6.7). The median OS of the patients without metastatic disease at diagnosis was significantly higher than those with metastatic disease (median 15.9 months, 95% CI: 12.3-19.4 versus 3.1 months (95% CI: 2.1 -4.1, p < 0.001).

      Conclusions:
      The results obtained in our sample are in agreement with the existing literature. The discovery of predictive and predictive biomarkers as well as new forms of treatment is urgently needed.

      Clinical trial identification:


      Legal entity responsible for the study:
      Instituto Portugues de Oncologia do Porto (Portuguese Oncology Institute of Porto, Portugal)

      Funding:
      Instituto Portugues de Oncologia do Porto (Portuguese Oncology Institute of Porto, Portugal)

      Disclosure:
      All authors have declared no conflicts of interest.

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      58TiP - IMpower133: Phase I/III trial of first-line atezolizumab with carboplatin and etoposide in ES-SCLC (ID 421)

      12:30 - 12:30  |  Author(s): M. Reck, A.S. Mansfield, S.V. Liu, T.S.K. Mok, X. Tang, S. Lam, F. Kabbinavar, A. Lopez-Chavez, A. Sandler, L. Horn

      • Abstract

      Background:
      Platinum-based chemotherapy (chemo) with etoposide is the current first-line standard of care for the majority of patients (pts) with ES-SCLC. However, survival outcomes remain poor (median OS, < 1 year) despite initial response rates ranging from 50%-70%. Atezolizumab (atezo) is an anti–PD-L1 mAb that prevents the interaction of PD-L1 with its receptors, PD-1 and B7.1, and restores antitumor T-cell activity. Tolerable safety with promising durability of response has been shown with atezo in pts with ES-SCLC: confirmed ORR was 6% (n = 1/17 [partial response]; DOR of 7 mo) by RECIST v1.1 and 24% by immune-related response criteria (irRC; n = 4/17, with 2 pts on atezo for ≥ 12 mo). Preliminary data also indicate the potential synergy between atezo and platinum-based chemo in NSCLC whereby durable responses may translate into improved survival compared with atezo alone. IMpower133 (NCT02763579), a global, Phase I/III, randomized, multicenter, double-blinded, placebo-controlled trial, will evaluate the efficacy and safety of 1L atezo + carboplatin + etoposide compared with placebo + carboplatin + etoposide in treatment-naive pts with ES-SCLC.

      Trial design:
      Eligibility criteria include ES-SCLC, measurable disease (RECIST v1.1), ECOG PS 0-1 and no prior systemic anticancer treatment. Exclusion criteria include untreated CNS metastases and history of autoimmune disease. Submission of tumor tissue is a study requirement but pts will be enrolled regardless of biomarker status. Stratification factors are sex, ECOG performance status and presence of treated brain metastases. Eligible pts will be randomized 1:1 to receive four 21-day cycles of atezo (1200 mg IV) or placebo in combination with carboplatin (AUC 5 mg/mL/min IV, d 1) and etoposide (100 mg/m[2] IV, d 1-3), followed by maintenance therapy with atezo or placebo until PD per RECIST v1.1. Pts can continue with treatment until persistent radiographic PD, symptomatic deterioration or unacceptable toxicity. Co-primary endpoints are investigator-assessed PFS per RECIST v1.1 and OS. Secondary efficacy endpoints include investigator-assessed ORR and DOR. Safety and tolerability will also be assessed. Approximately 400 pts will be enrolled.

      Clinical trial identification:
      NCT02763579

      Legal entity responsible for the study:
      F. Hoffmann-La Roche Ltd/Genentech Inc.

      Funding:
      F. Hoffmann-La Roche Ltd/Genentech Inc.

      Disclosure:
      M. Reck: Honoraria for lectures and consultancy with Boehringer-Ingelheim, Hoffmann-La Roche, Lilly, MSD, BMS, AstraZeneca, Celgene, Merck, Pfizer. A.S. Mansfield: Advisory Board: Genentech, BMS, and Trovagene. S.V. Liu: Advisory board/consultant for: Genentech, Pfizer, Ariad, Celgene, Boehringer Ingelheim, Lilly. T.S.K. Mok: Grant/Speaker/AdBoards: AZ, BI, Pfizer, Novartis, SFJ, Roche, MSD, Clovis, BMS, Eisai, Taiho, Lilly, Merck, ACEA, Vertex, BMS, geneDecode, OncoGenex, Celgene, Ignyta, Taiho; Stock: Sanomics; Board: IASLC, CLCRF, CSCO, HKCTS. X. Tang: Roche employee. S. Lam: Roche/Genentech: employee, stock. F. Kabbinavar, A. Lopez-Chavez, A. Sandler: Employee, stock: Roche/Genentech. L. Horn: Advisory board: Genentech; Consulting: Abbvie, Merck, Lilly, Xcovery and EMD Serono.

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      62P - Risk factors associated with early vs late recurrence in stage I lung adenocarcinoma (ID 436)

      12:30 - 12:30  |  Author(s): J. Qian, J. Xu, S. Wang, W. Yang, F. Qian, B. Zhang, R. Wang, X. Zhang, H. Wang, B. Han

      • Abstract

      Background:
      Patients with stage I lung adenocarcinoma (ADC) develop recurrences after complete surgical resection, both early and over the long term. This study aimed to identify and compare risk factors for early and late recurrence after surgery in stage I lung ADC patients.

      Methods:
      We analyzed recurrences among 5904 patients with stage I lung ADC who underwent curative operations at Shanghai Chest Hospital between January 1, 2008 and December 31, 2014. Recurrences were classified as within 2 years (early), and more than 2 years (late) after surgery. The clinicopathologic findings were compared between patients with early and late recurrences. Both univariate and multivariate analyses were performed, incorporating factors of gender, age at diagnosis, operation type, tumor location and size, pathologic subtype, cell differentiation, lymphovascular invasion, visceral pleural invasion, and smoking history.

      Results:
      Recurrence occurred in totally 628 (10.6%) patients, with early and late recurrence in 300 and 328 patients, respectively. Early and late recurrences shared common risk factors of advanced age at diagnosis (P = 0.013 and P = 0.006, respectively), poorly cell differentiation (both P = 0.000), larger tumor size (both P = 0.000), and visceral pleural invasion (both P = 0.000). Early recurrence was additionally associated with male (HR, 1.327; 95%CI, 1.042-1.690; P = 0.022), sublobar resection (HR, 2.353; 95%CI, 1.634-3.387; P = 0.000), tumor located in the right middle lobe (HR, 1.711; 95%CI, 1.634-3.387; P = 0.005) and solid, micropapillary or variant subtypes (HR, 5.437; 95%CI, 1.258-23.509; P = 0.023).

      Conclusions:
      These findings suggest the existence of different risk factors accounting for early vs late recurrences among patients with stage I lung ADC.

      Clinical trial identification:


      Legal entity responsible for the study:
      Shanghai Chest Hospital

      Funding:
      Shanghai Chest Hospital

      Disclosure:
      All authors have declared no conflicts of interest.

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      63P - Diabetes predisposes patients to atrial fibrillation after robotic-assisted video-thoracoscopic pulmonary lobectomy (ID 514)

      12:30 - 12:30  |  Author(s): S. Reynolds, J. Glover, M. Echavarria, E. Ng, F. Velez-Cubian, C. Moodie, J. Garrett, J. Fontaine, E. Toloza

      • Abstract

      Background:
      Pre-existing diabetes has been described as a risk factor for the development of atrial fibrillation (AFib) following non-cardiac surgery. This study aimed to determine if diabetes and associated comorbidities increase the risk of AFib following robotic-assisted pulmonary lobectomy and improve risk stratification of diabetics.

      Methods:
      Excluding patients with preoperative history of AFib, 353 consecutive patients who underwent robotic-assisted video thoracoscopic (RAVTS) lobectomy by one surgeon from October 2010 to August 2016 were retrospectively analysed. Patients were studied with respect to the presence of diabetes, coronary artery disease, heart failure, kidney failure, peripheral vascular disease, and other known associated comorbidities. Chi-Square (X[2]), Fisher’s exact test, and Student’s t-test were used to compare variables, with significance at p ≤ 0.05.

      Results:
      In this study, 64 patients with diabetes were identified, 11 (17.2%) of whom developed AFib following RAVTS lobectomy. Patients with diabetes were at higher risk of developing of AFib following surgery (OR 2.52, 95% CI 1.15 to 5.50, p = 0.02). The average age of diabetics who developed AFib was 72.7 years and 68.4 years for those who did not (p = 0.07). Known comorbidities in patients with diabetes did not confer additional risk, including hypertension (p = 1.00), hyperlipidaemia (p = 1.00), cardiomyopathy (p = 0.17), coronary artery disease (p = 0.27), and obesity (p = 0.67). There was a trend toward increased risk in diabetics with kidney disease, although it failed to reach significance (p = 0.07). Being a former smoker was the only independent risk factor identified, as 90.9% of diabetics with AFib were former smokers (OR 10.38, 95% CI 1.24 to 86.95, p = 0.03). Pack-years did not increase risk for AFib, with 47.2 pack-years on average being reported in those who developed AFib, while patients without AFib averaged 49.6 pack-years (p = 0.87). Furthermore, there was no significant difference in pre-operative percent forced expiratory volume in 1 second of diabetics who did and did not develop AFib (87.0% vs 80.4%, p = 0.45).

      Conclusions:
      Patients with diabetes are at higher risk for developing AFib after RAVTS lobectomy. Known comorbidities of diabetes, including obesity, hyperlipidaemia, and kidney disease, did not confer an increased risk for the development of AFib after surgery; however, being a former smoker puts diabetics at 10-times greater risk than current or never smokers with diabetes.

      Clinical trial identification:
      Not applicable.

      Legal entity responsible for the study:
      Eric M. Toloza, M.D., Ph.D.

      Funding:
      Moffitt Cancer Center and University of South Florida Health Morsani College of Medicine

      Disclosure:
      J. Fontaine, E. Toloza: Honoraria as robotic thoracic surgery observation site and proctor for Intuitive Surgical Corp. All other authors have declared no conflicts of interest.

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      64P - Smoking history as a risk factor for atrial fibrillation following robotic-assisted video-thoracoscopic pulmonary lobectomy (ID 515)

      12:30 - 12:30  |  Author(s): J. Glover, S. Reynolds, M. Echavarria, E. Ng, F. Velez-Cubian, C. Moodie, J. Garrett, J. Fontaine, E. Toloza

      • Abstract

      Background:
      Smoking history has been correlated to the development of atrial fibrillation (AFib) after noncardiac thoracic surgery, increasing hospital length of stay, post-operative mortality, and costs. This study sought to determine the effects of smoking history and pulmonary function on the development of AFib following robotic-assisted pulmonary lobectomy to allow for more targeted dispositioning of post-lobectomy patients.

      Methods:
      We retrospectively analysed 353 consecutive patients without history of AFib who underwent robotic-assisted video thoracoscopic (RAVTS) lobectomy by one surgeon from October 2010 to August 2016. Patients were analysed with respect to smoking status, pack-years, months of smoking cessation, and pulmonary function. Chi-Square (X[2]), Fisher’s exact test, and Student’s t-test were used to compare variables, with significance at p ≤ 0.05.

      Results:
      In our study, 17 of 144 men (11.8%) and 16 of 209 women (7.7%) experienced new-onset AFib following RAVTS lobectomy (p = 0.19). The average age of people who developed AFib was 72.8 years (yrs) and 66.4 yrs for those who did not (p < 0.001). Former smokers represented 72.7% of new AFib cases, current smokers 21.2%, and never smokers 6.1% (p = 0.009). Former smokers were at higher risk than both never (OR 5.30, 95% CI 1.22 to 23.09, p = 0.03) and current smokers (OR 2.62, 95% CI 1.09 to 6.31, p = 0.03). Former smokers who developed AFib also were older (74.6 vs. 69.1 yrs, p = 0.004) and more often diabetic (OR 3.27, 95% CI 1.31 to 8.17, p = 0.01). There was no difference in AFib rates for light (≤15 pack-years) and heavy (>15 pack-years) smokers (p = 0.21). Never smokers fared better than light (p = 0.02) but not heavy (p = 0.13) smokers. There was no difference in pack-years for former and current smokers who developed AFib (p = 0.11). For all groups, the development of AFib was independent of pre-operative pulmonary function as measured by percent of predicted forced expiratory volume in 1 second and percent of predicted diffusion capacity of the lung for carbon monoxide (p = 0.09 and 0.63, respectively). The development of AFib was also unaffected by the presence of COPD (p = 0.80).

      Conclusions:
      Former and light smokers are at higher risk than both current and never smokers for developing AFib after RAVTS lobectomy, independent of pack-years and pre-operative pulmonary function. Duration of smoking cessation prior to lobectomy does not change the likelihood of developing AFib.

      Clinical trial identification:
      Not applicable.

      Legal entity responsible for the study:
      Eric M. Toloza, M.D., Ph.D.

      Funding:
      Moffitt Cancer Center and University of South Florida Health Morsani College of Medicine

      Disclosure:
      J. Fontaine, E. Toloza: Have received honoraria as robotic thoracic surgery observation site and proctor for Intuitive Surgical Corp. All other authors have declared no conflicts of interest.

    • +

      65P - Lymph node metastases in clinically node negative peripheral non-small cell lung cancer (ID 207)

      12:30 - 12:30  |  Author(s): T. Mehmood

      • Abstract

      Background:
      Small lung cancers are increasingly detected with the advent of low dose spiral computed tomography and lung cancer screening programme, and these lesions are frequently subsolid and low risky pN+ disease. Integrated positron emission tomography/computed tomography (PET/CT) is widely used in lymph node staging with higher accuracy and sublobar resection may be appropriate in cN0 NSCLC. This retrospective study was designed to identify the risk factors and pattern of lymph node metastases in NSCLC.

      Methods:
      107 consecutive cN0 patients with 1 cm to 2 cm peripheral NSCLC who underwent PET-CT scans followed by curative-intent resections in our hospital were enrolled in this study. Clinical and pathological data were analyzed by multivariate analysis retrospectively, including tumor size, tumor SUVmax, ratio SUVmax tumor/SUVmax liver. Lymph nodes of metastases were analyzed in pN+ patients.

      Results:
      8.5% (9/107) PET-CT diagnosed N0 NSCLC cases had pathological lymph node metastases, including 8 N1 and 3 N2 involvement (1 skipping N2 metastases). Univariable and multivariable analysis of clinicopathological factors (including tumor size, ratio SUVmax tumor/liver) found no independent risk factor for lymph node metastases. All N(+) cases were adenocarcinoma while 66.7% (6/9) of the N(+) cases were single station metastases. The lymph node metastasis rate of solid NSCLC and GGO were 10.7% and 0% (P=0.224), respectively.

      Conclusions:
      The lymph node rate of 1 cm to 2 cm NSCLC is relatively high and intrapulmonary lymph nodes were higher risk than mediastinal lymph nodes. However, no predictors of lymph node metastases were detected in this population. Sublobar resection can be an alternative procedure for GGO lesions as no lymph node metastases were found, but for solid NSCLC, thorough lymph node sampling should be performed to rule out lymph node metastases before making the decision of segmentectomy.

      Clinical trial identification:


      Legal entity responsible for the study:
      SKMH, Lahore

      Funding:
      SKMH, Lahore

      Disclosure:
      The author has declared no conflicts of interest.

    • +

      66P - Effect of age on risk for atrial fibrillation following robotic-assisted video-thoracoscopic pulmonary lobectomy (ID 517)

      12:30 - 12:30  |  Author(s): J. Glover, S. Reynolds, E. Ng, M. Echavarria, F. Velez-Cubian, C. Moodie, J. Garrett, J. Fontaine, E. Toloza

      • Abstract

      Background:
      Aging is a known risk factor for several post-operative comorbidities, including atrial fibrillation (AFib), leading to increased length of stay and mortality. This study was designed to investigate the effect of age and related comorbidities on new-onset atrial fibrillation after robotic-assisted pulmonary lobectomy to better identify patients at greatest risk.

      Methods:
      We conducted a retrospective analysis of 353 consecutive patients without history of preoperative AFib who underwent robotic-assisted video-thoracoscopic (RAVTS) lobectomy by one surgeon from October 2010 to August 2016. Patients were analysed with respect to age and associated comorbidities, such as hypertension, hyperlipidaemia, and diabetes. Chi-Square (X[2]), Fisher’s exact test, and Student’s t-test were used to compare variables, with significance at p ≤ 0.05.

      Results:
      The average age of participants who developed post-operative AFib (n = 33) was significantly higher, 72.8 years (yrs) vs. 66.4 yrs (p < 0.001). There was a decreased risk in patients under 70 yrs, with only 11 (5.3%) developing AFib (OR 0.31, CI 0.14-0.66, p = 0.002). By contrast, 22 (15.3%) of the elderly (age ≥70 yrs) experienced new-onset A-fib (OR 2.54, 95% CI 1.19 to 5.41, p = 0.02). Those under 60 yrs were at least risk (OR 0.10, 95% CI 0.01 to 0.75, p = 0.02), and those ≥80 yrs were at greatest risk (OR 2.74, 95% CI 1.03 to 7.28, p = 0.04). While the elderly in our cohort had a higher rate of many well-described comorbidities, including hypertension, hyperlipidaemia, coronary artery disease, and cardiomyopathy, none of these conferred an increased risk of post-operative AFib. Among those over 70 yrs, only BMI, particularly an obese BMI (≥30 kg/m[2]), led to a higher risk (p = 0.02 and p = 0.003, respectively). Among the elderly, obese patients developed AFib at 2.3 times the rate of those with normal or overweight BMI’s (OR 4.21, 95% CI 1.66 to 10.68, p = 0.002). Conversely, only being a former smoker increased the risk of AFib in those under 70 yrs (OR 4.79, 95% CI 1.23 to 18.70, p = 0.02). The risk in former smokers was independent of pack-years and duration of cessation prior to surgery. Furthermore, the risk of AFib was not significantly affected by intra-operative complications in either group.

      Conclusions:
      Patients aged 70 years or older are at increased risk of AFib after RAVTS lobectomy, particularly if they are obese. Those under 70 years are at increased risk if they are former smokers.

      Clinical trial identification:
      Not applicable.

      Legal entity responsible for the study:
      Eric M. Toloza, M.D., Ph.D.

      Funding:
      Moffitt Cancer Center and University of South Florida Health Morsani College of Medicine

      Disclosure:
      J. Fontaine, E. Toloza: Have received honoraria as robotic thoracic surgery observation site and proctor for Intuitive Surgical Corp. All other authors have declared no conflicts of interest.

    • +

      67P - CT-guided fine-needle aspiration biopsy of pulmonary lesions under 15 mm of diameter: Results on 68 consecutive patients (ID 303)

      12:30 - 12:30  |  Author(s): D. Tosi, A. Palleschi, L. Rosso, P. Mendogni, I. Righi, R. Carrinola, F. Damarco, M. Cattaneo, L. Santambrogio

      • Abstract

      Background:
      Most reports on lung fine needle aspiration cytology (FNAC) demonstrate that the diagnostic accuracy tends to decrease with the size of the lesions, and that the frequency of complications increases as the size of lesions decreases. The aim of this prospective study was to describe the accuracy and incidence of complications related to FNAC of solitary pulmonary nodules (SPNs) of 15 mm or less in diameter. Moreover, we evaluated how this procedure during the initial evaluation of patients with SPN can reduce the number of unnecessary surgery.

      Methods:
      From January 2012 to December 2014, 225 patients with an SPN between 7-15 mm in diameter were referred to our Institution. Patients with risk factors such as ASA 3, FEV1 <70% of predicted, cardiac comorbidity or previous chest surgery were enrolled. A total of 68 patients were candidate to CT guided FNAC.

      Results:
      The prevalence of malignant pathology in the whole population was 61%. Forty-nine out of 68 smears (72%) were considered adequate for diagnosis. Sensitivity was 83%, specificity was 100%. Positive and negative predictive values were 83% and 100%. Out of the total number, 16 patients (23%) avoided surgery. A post-biopsy pneumothorax was detected in 27 cases (39%). The pneumothorax rate was significantly affected by the number of passages (p = 0.01).

      Conclusions:
      In our experience the diagnostic accuracy value was high. Subjecting patients with undiagnosed pulmonary lesions to FNAC during the initial evaluation significantly reduces the number of unnecessary surgical procedures.

      Clinical trial identification:
      None

      Legal entity responsible for the study:
      Fondazione Ca\' Granda Policlinico - Milan

      Funding:
      Fondazione Ca\' Granda Policlinico - Milan

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      68P - Circulating tumor cells spillage after lung nodule biopsy (ID 497)

      12:30 - 12:30  |  Author(s): M. Sarfaty, N. Abdel-Rahman, A. Moore, J. Pfannkuche, C. Chudak, M.R. Kramer, N. Peled

      • Abstract

      Background:
      Lung cancer has high recurrence rate even when diagnosed at an early stage. Biopsy is currently the procedure of choice for the investigation of pulmonary lesions, yet it is unclear whether the biopsy itself releases tumor cells into the circulation and attributes to the late distal recurrence. Studies of various malignancies show the ability to identify circulating tumor cells (CTC) even in early stage cancer. The number of CTC correlates with disease outcome. The aim of this study was to quantify the spillage of tumor cells after nodule biopsy in early lung cancer.

      Methods:
      Patients with pulmonary nodules undergoing computed tomography biopsy enrolled into this study. CellCollector[TM] (GILUPI, Germany) was used for CTC detection before and after the procedure. This filtration device isolates CTC in-vivo through a standard cannula inserted to the cubbital vein for thirty minutes via epithelial cell adhesion molecule antibodies. Patients served as their own controls. Trans thoracic biopsy was done by a 19G needle with a standard procedure of one pass. The study was approved by the institutions' ethics committee.

      Results:
      13 patients were enrolled to between 02/2016 and 08/2016. Five patients were excluded due to partial procedure. Eight patients were eligible for analysis. Three had benign diseases (Granuloma, Interstitial pneumonitis. and five had lung cancer (Adenocarcinoma -4; Squamous-1); 3 had an elevation of the CTC count (0->2, 0->3, 2->8) and 2 had a depletion (8->2, 5->2). All 5 patients were male, with a median age of 65 years (range 54-72), four of them were past smokers and one never smoker. No adverse events were reported.

      Conclusions:
      With the limitation of low number of participants, this preliminary data shows that trans thoracic biopsy may increase CTC in some patients with lung cancer. The study is ongoing and the enlarged cohort will be presented.

      Clinical trial identification:


      Legal entity responsible for the study:
      Rabin Medical Center Ethics Comittee

      Funding:
      GILUPI

      Disclosure:
      J. Pfannkuche: Managing director at GILUPI, which provided the kits for this study. C. Chudak: Marketing & Sales Manager at GILUPI, which provided the kits for this study. All other authors have declared no conflicts of interest.

    • +

      69P - CT-Guided radiofrequency ablation of early stage NSCLC (ID 168)

      12:30 - 12:30  |  Author(s): X. Zhang

      • Abstract

      Background:
      To prospectively evaluate the safety and efficacy of radiofrequency (RF) ablation of early stage NSCLC with diameter of less than 30 mm.

      Methods:
      Forty patients (24 men and 16 women; age range, 35–78 years; mean age, 58 years) with early stage NSCLC (40 lesions) which were conformed by biopsy were enrolled in during 2014-2016. RF ablation was performed in tumors by CT guidance, each with a diameter of less than 30 mm (mean deviation, 14 mm). Written informed consent was obtained in this prospective study that was approved by the local ethics committee. Follow-up CT scans were obtained within 48 hours after treatment and at 2 and 6months thereafter to evaluate treatment outcome and complications. Lung spirometry measurements were obtained before and 2 months after RF ablation.

      Results:
      Forty successful RF ablation treatments were performed. The complications occured in the periprocedural period were 9 cases of minor pneumothorax and 4 cases of sputum cruentum. There were 35 lesions of reduced size, 13 lesions of stabilized lesion size, and 2 lesions of increased size on the follow-up Contrast-enhanced CT images at 6-month. There was no modification of respiratory function was found between the spirometry measurements before the treatment and 2 months after (P < 0.05).

      Conclusions:
      RF ablation is a safe and effective method to treat early stage NSCLC with diameter of less than 30 mm. Larger studies are necessary to fully evaluate its potential combination with other treatment techniques.

      Clinical trial identification:


      Legal entity responsible for the study:
      Xiaobo Zhang

      Funding:
      The Radiology Department of Chinese PLA General Hospital

      Disclosure:
      The author has declared no conflicts of interest.

    • +

      70P - A retrospective analysis to explore the value of gemcitabine combined with cisplatin as adjuvant chemotherapy of NSCLC (ID 375)

      12:30 - 12:30  |  Author(s): D. Ma, J. Wang, X. Hao, Y. Wang, X. Hu, P. Xing, J. Li

      • Abstract

      Background:
      To evaluate the value of gemcitabine combined with cisplatin (GP) as adjuvant chemotherapy in radical resection of non-small cell lung cancer (NSCLC).

      Methods:
      This study reviewed the 100 patients’ charts with radical resection of NSCLC treated with cisplatin/gemcitabine as adjuvant chemotherapy between June 2007 and December 2010 in CAMS (Chinese Academy of Medical Sciences).

      Results:
      Among the 100 cases, eighty-two (82%) was male and the median age was 59 years (range, 36-73 years). Forty-two (42%) patients were adenocarcinoma, while fifty-five (55%) were squamous cell carcinoma. Most patients had pathologic IIB (29%) and IIIA (44%) stage disease, whereas others were IA (2%), IB (14%), IIA (6%), and IIIB (5%). Surgical methods included sleeve resection (12%), pneumonectomy (14%), and lobectomy (73%).The completion rate of 4 cycles of chemotherapy was 85%, of which 76 case (76%) completed the planned full-dose chemotherapy. And the main reason for the reduction in gemcitabine doses in thirteen patients were grade 3/4 myelosuppression, mainly neutropenia and thrombocytopenia. The median dose and dose intensity were 8377.1 mg/m[2] and 708 mg/(m[2]·week) for gemcitabine, and 293.38 mg/m[2] and 25.24 mg/(m[2]·week) for cisplatin respectively. With good compliance to treatment, toxicities observed were tolerable and managable. During a median follow-up duration of 73.1 months, the median disease-free survival(DFS) was 33.8 months (95%CI: 15.938-51.676). Patients with the squamous cell carcinoma (HR 0.404, 95% CI 0.241-0.676, P = 0.001) and pathologic stage I (HR 4.379, 95% CI 1.721-11.142, P = 0.002) were associated with better DFS from univariate and multivariate analyses. The survival rate at 1 year, 2 years and 5 years was 94%, 77% and 55%, while the survival rate without recurrence was 64%, 53% and 39% respectively.

      Conclusions:
      As one of the adjuvant chemotherapy regimens, gemcitabine combined with cisplatin is well tolerated. Patients with squamous cell carcinomas or stage I can benefit from it better.

      Clinical trial identification:


      Legal entity responsible for the study:
      None

      Funding:
      None

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      71TiP - A randomized, phase 3 trial with anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) versus placebo for patients with early stage NSCLC after resection and completion of standard adjuvant therapy (EORTC/ETOP 1416-PEARLS) (ID 399)

      12:30 - 12:30  |  Author(s): L. Paz-Ares, B. Hasan, U. Dafni, J. Menis, E. De Maio, K. Oselin, I. Albert, M. Faehling, P. Van Schil, M.E.R. O'Brien

      • Abstract

      Background:
      In the last 5 years no major advances have been made in the treatment of early stage NSCLC. Checkpoint inhibitors have shown promising clinical efficacy in advanced, refractory non-small cell lung cancer (NSCLC), but they have not yet been explored in the adjuvant setting. PEARLS (NCT02504372) is international, triple-blinded, placebo-controlled, randomized phase III trial to compare pembrolizumab versus placebo after complete resection of stage IB (T ≥ 4 cm), II and IIIA NSCLC, followed by standard adjuvant chemotherapy, if appropriate as per local guidelines, in patients who have signed the informed consent.

      Trial design:
      Eligible patients are those with completely resected stage IB (T ≥ 4 cm), II and IIIA NSCLC that have or have not received adjuvant platinum-based chemotherapy and whose PD-L1 status is known: negative (TPS=0%) versus weak positive (TPS = 1-49%) versus strong positive (TPS≥50%). Co-primary endpoints are disease-free survival in the PD-L1 strong positive subgroup and in the overall population. An HR = 0.78 is targeted for the whole population with 640 disease free survival events from a sample size of 1380 randomized patients. Secondary endpoints include disease-free survival in the PD-L1 positive subgroup, overall survival in each subpopulation and in the overall population, lung cancer specific survival, and safety and tolerability. The exploratory endpoints will assess pharmacokinetics, immunogenicity, quality of life and potential biomarkers of treatment response. Recruitment started in January 2016 and is currently ongoing. As of November 17, 2016, among the 102 randomized patients so far, 44 (43.1%), 32 (31.4%) and 26 (25.5%) patients have negative, weak positive and strong positive PD-L1 status respectively.

      Clinical trial identification:
      (EudraCT number 2015-000575-27) (NCT02504372)

      Legal entity responsible for the study:
      MSD EORTC, ETOP

      Funding:
      MSD

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      75P - Predictive value of CT texture analysis in lung cancer patients undergoing nivolumab (ID 231)

      12:30 - 12:30  |  Author(s): V. Nardone, P. Tini, E. Aldi, P. Pastina, L. Sebaste, G. Battaglia, S.F. Carbone, V. Ricci, L. Pirtoli, P. Correale

      • Abstract

      Background:
      Nivolumab is a human mAb to PD-1 with significant antitumor activity in a number of solid malignancies including NSCLC, kidney cancer and melanoma. At the present, no predictive factor has been identified for this drug, thus its administration is mostly empirical, at price of frequent adverse events and high costs. In this context, we evaluated whether baseline CT texture analysis (TA) could be used to identify advanced NSCLC patients who will benefit by Nivolumab treatment, by taking in consideration that the therapeutic effects PD-1 blockade depends by its ability of reactivating a pre-existing immuneresponse, whose activity is strictly related to the presence of necrosis, hypoxia, and inflammation in the tumor sites, which can be evaluated by imaging assessments.

      Methods:
      A retrospective analysis was performed on a sample of seventeen NSCLC patients who received salvage therapy with Nivolumab 3 mg/kg every 15 days between October 2015 and January 2017 with a median follow up of twelve months. The gross primary tumor volume before treatment (baseline) was contoured on pre and post contrast CT sequences. TA parameters were extrapolated by using LifeX Software ©, tested for reliability and then correlated with patients’ outcome, in particular with early failure defined as a confirmed disease progression or death within 6 months (7 patients), by means of univariate and multivariate analysis.

      Results:
      We found a significant correlation among TA parameters and patients’ outcome at univariate analysis. In fact, early vs longer responders showed differences in term of volume in voxel (p:0.049), entropy (p:0.046), compacity (p:0.033), GLCM-contrast (p: 0.018), GLCM-dissimilarity (p:0.017), LRHGE (p:0.019), coarseness (p:0.036), contrast (0.020), ZP (p:0.025), pre contrast: GLCM-contrast (p:0.031), GLCM-dissimilarity (p:0.035), contrast (p:0.038), SZE (p:0.029), ZP (p:0.040). Multivariate analysis (Logistic regression) confirmed a significant correlation between early failure and post contrast GLCM dissimilarity (p:0.011, OR: 3.30, AUC: 0.800; 95% CI 0.578-1.00).

      Conclusions:
      Our results, if confirmed on a larger series, suggest that TA may predict early failure, and therefore may help the selection of patients who may benefit by Nivolumab treatment.

      Clinical trial identification:


      Legal entity responsible for the study:
      Azienda Ospedaliera Universitaria Senese

      Funding:
      Azienda Ospedaliera Universitaria Senese

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      76P - Interpretation and prognostic value of PET-CT after induction chemotherapy with or without radiation in IIIA-N2 non-small cell lung cancer patients who receive curative surgery (ID 200)

      12:30 - 12:30  |  Author(s): J.H. Lee

      • Abstract

      Background:
      We evaluated the correlation of clinical staging on positron emission tomography-computed tomography (PET-CT) and pathologic staging and the prognostic value of PET-CT after induction chemotherapy in patients with locally advanced non-small cell lung cancer (NSCLC).

      Methods:
      We analyzed 42 cases of clinical stage IIIA-N2 NSCLC who received 2 to 4 cycles of pre-operative chemotherapy with or without radiation followed by curative resection. The maximum standard uptake value (SUVmax) of the suspected lesion on PET-CT was recorded. PET-CT findings after induction chemotherapy were compared with those of initial PET-CT and pathology after surgery.

      Results:
      The accuracy of PET-CT in restaging of the primary tumor after induction chemotherapy was 50.0%. 18 (42.8%) of 42 patients were underestimated ycT stage, and 3 (7.1%) of 42 patients was overestimated ycT stage by PET-CT scan. The accuracy of PET-CT in restaging of the nodal disease was 71.4%. 6 (14.3%) of 42 patients were underestimated ycN stage, and 6 (14.3%) of 42 patients were overestimated ycN stage as compared with pathologic staging. The 2-year overall survival (OS) and relapse-free survival (RFS) rate were 68.5% and 40.9%, respectively. Complete responders (ycT0N0M0) on PET-CT after induction chemotherapy had a significantly longer RFS time than did incomplete responders (28.3 months versus 9.1 months, P = 0.021).

      Conclusions:
      Complete response on PET-CT after induction chemotherapy with or without radiation was a good prognostic indicator for RFS in stage IIIA-N2 NSCLC patients who received surgery. However, response evaluation on PET-CT after induction chemotherapy should be interpreted with caution due to its unacceptable accuracy.

      Clinical trial identification:
      None declared.

      Legal entity responsible for the study:
      Jong Hoon Lee

      Funding:
      None

      Disclosure:
      The author has declared no conflicts of interest.

    • +

      77P - Bronchoscopic photodynamic therapy for treatment of microscopic residual disease post resection in non-small cell lung cancer (ID 257)

      12:30 - 12:30  |  Author(s): A. Biswas, A. Khokar, S. Fernandez-Bussy, M.A. Jantz, H.J. Mehta

      • Abstract

      Background:
      The goal of lung cancer surgery is a complete tumor resection (R0 resection) with tumor-free resection margins. However, 4-5% of lung cancer resections have evidence of microscopic residual disease which is associated with worse prognosis as compared to complete resection. Definitive management for such patients is re-operation and resection of residual tumor. However, a significant percent of patients may not be able to tolerate another surgery and for those patient’s definitive management is not well studied. We treated these patients with stage I cancer and mucosal residual disease with bronchoscopic PDT (photoynamic therapy) and report our experience here.

      Methods:
      We conducted a retrospective analysis of patients who underwent definitive surgery for early stage lung cancer. All patients with R1 resection, stage I disease with mucosal residual tumor and or carcinoma in situ along the stump site were treated with bronchoscopic photodynamic therapy and were studied. Patient characteristics, histology, type and site of surgery, pattern of recurrence, recurrence status, and survival data were evaluated. Adverse events were recorded.

      Results:
      A total of 11 patients (Table) with mucosal R1 resection were treated with PDT along the stump site between 2007 and 2013. The breakdown according to the pattern of residual disease was as follows: CIS in 3 and MRD in 8 patients. One patient (9%) had local recurrence 1 year after treatment and was treated with radiation along the stump site. Four patients (36%) had no evidence of recurrence to date after a median follow up of 4 years and other 6 patients had evidence of regional (16%) or distant (45%) and were treated appropriately for the same. Local control rate was 91%. The median overall survival and progression free survival in our cohort of patients were 45 and 26 months respectively. One patient developed pneumonia and one patient has evidence of photosensitivity reaction.rnTable: 77Prn

      rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn rnrn
      Patient #AgeSexOperationHistologyType of residual diseaseSite of treatmentPattern of recurrencePFS monthsOverall survival monthsAlive
      153MLobectomyAdeno caMRDLLLregional4966Y
      280FLobectomySCCaCISLULn/an/a45N
      380FSegmentectomyAdeno caMRDRMLDistant1011N
      457MLobectomySCCaCISRLLn/an/a70Y
      566MLobectomySCCaMRDLLLDistant2832N
      640MLobectomyAdeno caMRDRULregional3659N
      766FLobectomyAdeno caMRDRLLn/an/a86Y
      867FLobectomySCCaMRDRMLDistant2634N
      976MSleeve lobectomySCCaMRDLLLn/an/a39N
      1072FSegmentectomySCCaCISRULLocal2473Y
      1174FLobectomySCCaMRDLULDistant2125N
      rn

      Conclusions:
      Conclusion: Bronchoscopic photodynamic therapy (PDT) is a nonthermal ablative technique that can be used to treat central airway disease in adults. In conclusion, based on our findings, PDT is a safe and effective alternative therapy for patients with mucosal residual disease post R1 resection. Although this was a retrospective evaluation with a small sample, our data suggest that selected NSCLC patients after R1 resection may benefit from bronchoscopic PDT.

      Clinical trial identification:
      This is not a clinical trial.

      Legal entity responsible for the study:
      University of Florida

      Funding:
      None

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      78P - Comparison of chemoradiotherapy treatment strategies in stage III non-small cell lung cancer among elderly patients from multiple data sources (ID 365)

      12:30 - 12:30  |  Author(s): H. Pang, T. Stinchcombe, P. Cheng, A.W. Lee, V.H. Lee, E.E. Vokes, X. Wang

      • Abstract

      Background:
      Comparative effectiveness research can benefit from combining data from multiple sources. This analysis integrally evaluated the survival benefits of combined modality therapies (CMTs) in locally advanced non-small cell lung cancer (NSCLC) based on individual patient data from US and Chinese populations.

      Methods:
      Two patient populations were included. SEER-Medicare cohort consists of 65 years or higher who were diagnosed with stage III (IIIA/IIIB) NSCLC from 2006 to 2010 and received combined modality treatment. Queen Mary Hospital cohort from Hong Kong for aged 65 or higher who were diagnosed with stage III (IIIA/IIIB) NSCLC from 2007 to 2016. The four CMTs of interest were concurrent (CMT-ONLY), sequential chemotherapy followed radiation (CMT-SEQ), induction followed by concurrent (CMT-IND) and concurrent followed by consolidation (CMT-CON) chemoradiation. The primary endpoint for was overall survival. Patients hospitalized for neutropenia were ascertained through inpatient claim with the claim occurring within 130 days after the first chemotherapy. Stepwise multivariable regression models and propensity score adjusted models were used to control confounding variables. We also compared the findings with our previous study based on clinical trials data.

      Results:
      2682 locally advanced NSCLC patients were included. For CMT-ONLY, CMT-SEQ, CMT-IND, and CMT-CON respectively, their corresponding median overall survivals were 13.0 (95% CI 12.0-14.0), 13.0 (95% CI 12.0-16.0), 17.0 (95% CI 15.0-20.0), and 15.4 (95% CI 14.0-17.0) months. CMT-IND and CMT-CON had survival benefit over CMT-ONLY and CMT-SEQ. Patients receiving CMT-SEQ were relatively healthier patients in this study based on the Charlson comorbidity weights. 7.9%, 2.8%, 8.6%, and 9.5% were hospitalized for neutropenia for CMT-ONLY, CMT-SEQ, CMT-IND, and CMT-CON, respectively. CMT-SEQ had a lower hospitalization for neutropenia rate than the other CMTs.

      Conclusions:
      The findings on efficacy and toxicity are quite consistent with previously reported studies based on clinical trials or observational databases.

      Clinical trial identification:


      Legal entity responsible for the study:
      Duke University

      Funding:
      NIH, HMRF

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      79P - Long term survival of stage IIIB non-small cell lung cancer (NSCLC) patients treated with concurrent chemoradiation (ID 208)

      12:30 - 12:30  |  Author(s): T. Mehmood

      • Abstract

      Background:
      The optimal treatment strategy for Stage IIIB NSCLC patients with a T4N0-1 tumor is a matter of debate. In prospective combined modality series including surgery, the median overall survival (OS) is approximately 24 months. We hypothesized that results comparable to regimens including surgery can be achieved with concurrent chemoradiation in this patient group.

      Methods:
      In our retrospectively collected database of NSCLC patients, all patients with T4 (mediastinal invasion) N0-1 NSCLC receiving concurrent chemoradiation were included. One patient had a recurrence after previous pneumonectomy. All patients were given 3 cycles of chemotherapy (cisplatin and etoposide). Radiotherapy (RT) was started at the 2nd course of chemotherapy. OS was calculated from date of diagnosis (Kaplan-Meier method). Toxicity was scored according to CTCAEv3.0.

      Results:
      42 patients (8 females, 34 males) with a median age of 62.5 ± 9 years (44-80 years) were included from January 2005 until December 2009. Stage distribution: 86% T4N0 (n = 36), 14% T4N1 (n = 6). The maximal tumor dose was 66 Gy using conventional fractionation. The median prescribed mean lung dose was 15 ± 4.4 Gy (5.03 -19.9 Gy). Acute toxicity: 1 patient experienced grade 3 dyspnea during RT. Grade 3 dysphagia occurred in 5 patients (12%) during RT requiring tube feeding in 3 of these patients (7%). Dysphagia persisted later than 1 month after RT in 1 patient (2%). Grade 3 dysphagia only occurred in patients treated concurrently. Grade 3 cough occurred in 1 patient during RT, no patient experienced grade 3 cough 1 month after RT. 2 patients died within 3 months after start of RT, one due to myocardial infarction, one of unknown causes. Severe late toxicity was not present: no grade 3 complications more than 3 months after the end of radiotherapy. With a median follow-up of 42 months, the median OS for the whole group is 34 months (95% CI 24-43 months). 2-year OS survival is 55%.

      Conclusions:
      Concurrent accelerated chemoradiation using an individualized dose prescription is a valid treatment strategy for stage IIIb, T4N0-1 NSCLC patients yielding very promising OS results with low toxicity.

      Clinical trial identification:


      Legal entity responsible for the study:
      SKMH, Lahore

      Funding:
      SKMH, Lahore

      Disclosure:
      The author has declared no conflicts of interest.

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      80TiP - A feasibility trial evaluating the addition of nivolumab to standard first-line chemo-radiotherapy in locally advanced stage IIIA/B NSCLC: The ETOP 6-14 NICOLAS trial (ID 455)

      12:30 - 12:30  |  Author(s): S. Peters, R..A. Stahel, M. Kassapian, M. Guckenberger, E. Felip, A..J. De Langen, R.M. Huber, H. Roschitzki-Voser, A. Piguet, D. De Ruysscher

      • Abstract

      Background:
      Sequential or concomitant chemo-radiotherapy is the treatment of choice for stage III NSCLC. One attempt to improve the long-term survival is an immunotherapeutic strategy. The monoclonal antibody nivolumab targets and inhibits PD-1, an immune receptor on activated T-cells and responsible for abrogating anti-cancer immune response. The role of immune-checkpoint inhibitors is currently being evaluated in this indication as monotherapy or in combination with chemotherapy as well as after completion of chemo-radiotherapy but it has not yet been assessed in combination with radiotherapy. While anecdotal data of concurrent therapy suggests an acceptable toxicity profile, a formal prospective assessment is required before embarking on trials comparing concurrent versus sequential checkpoint inhibitors and radiotherapy.

      Trial design:
      NICOLAS is a phase II feasibility trial evaluating the administration of nivolumab concomitantly with standard first-line chemo-radiotherapy for locally advanced stage IIIA/B NSCLC. Additional inclusion criteria include adequate organ function and performance status 0-1. Chemotherapy consists of three cycles of cisplatin plus vinorelbine, etoposide or pemetrexed. Radiotherapy to the chest will be delivered either sequentially to or concurrently with chemotherapy. The initial nivolumab dose is 240 mg Q2W for eight cycles in the sequential, and 360 mg Q3W for four cycles in the concurrent chemo-radiotherapy schedule, followed by 480 mg Q4W for maximum one year for both regimens. A total of 43 patients will be recruited into the trial. The primary endpoint is grade > =3 pneumonitis observed up to 6 months after radiotherapy. The goal is to reject a 6-month pneumonitis-free rate of < =67%, tested at a rate of 85%, with 85% power and 5% one-sided alpha. An interim analysis will be performed after 21 patients have completed a 3-month follow-up on nivolumab treatment. Safety is closely monitored by the ETOP IDMC at their regular meetings every three months. NICOLAS is sponsored by ETOP with financial support of Bristol-Meyers Squibb. Accrual is ongoing and as of January 2017, 18 patients have been enrolled.

      Clinical trial identification:
      EudraCT: 2014-005097-11

      Legal entity responsible for the study:
      European Thoracic Oncology Platform (ETOP)

      Funding:
      Bristol-Meyers Squibb

      Disclosure:
      R.A. Stahel: Honoraria as consultant at advisory boards from Abbvie, Astra Zeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Pfizer and Roche and as speaker from Astellas, Astra Zeneca, Lilly, MSD, Novartis and Roche. R.M. Huber: Honoraria as consultant at advisory boards from BMS. All other authors have declared no conflicts of interest.

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      97P - Brigatinib in crizotinib-refractory ALK+ NSCLC: Updates from the pivotal randomized phase 2 Trial (ALTA) (ID 247)

      12:30 - 12:30  |  Author(s): M.J. Hochmair, M. Tiseo, K.L. Reckamp, H.L. West, H.J. Groen, C.J. Langer, W. Reichmann, D. Kerstein, D. Kim, D.R. Camidge

      • Abstract

      Background:
      In a phase 1/2 trial (NCT01449461), the investigational next-generation anaplastic lymphoma kinase (ALK) inhibitor brigatinib (BRG) showed promising activity in crizotinib-treated ALK-positive non–small cell lung cancer (ALK+ NSCLC) patients (pts); because tumor responses and adverse events (AEs) varied with starting dose, two BRG regimens were evaluated in ALTA (NCT02094573).

      Methods:
      Pts with crizotinib-refractory advanced ALK+ NSCLC were stratified by presence of brain metastases and best response to prior crizotinib and randomized 1:1 to receive BRG at 90 mg qd in arm A or 180 mg qd with a 7-day lead-in at 90 mg in arm B. Investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1 was the primary endpoint.

      Results:
      222 pts were enrolled (112 in arm A, 110 in arm B); median age was 54 years, 57% were female, 74% had received chemotherapy, and 69% had brain metastases. As of 29 February 2016, 57%/69% of pts in arms A/B were receiving BRG, with 7.8/8.3-month median follow-up. Investigator-assessed efficacy by arm and subgroup is shown below. Per independent review committee, as of 16 May 2016, confirmed ORR was 48%/53% and median PFS was 9.2/15.6 months in arms A/B. Treatment-emergent AEs with ≥25% overall frequency (A/B, n = 109/n=110 treated) were nausea 33%/40%, diarrhea 19%/38%, headache 28%/27%, and cough 18%/34%; grade ≥3 events with ≥3% frequency were hypertension 6%/6%, increased blood creatine phosphokinase 3%/9%, pneumonia 3%/5%, and increased lipase 4%/3%. A subset of pulmonary AEs with early onset (median onset: Day 2) occurred in 14/219 (6%) treated pts (3%, grade ≥3); no such events occurred after escalation to 180 mg in arm B, and 7/14 pts were successfully retreated.

      Conclusions:
      BRG yielded substantial efficacy, with an acceptable safety profile, in both arms. 180 mg with 90 mg lead-in showed an improvement in efficacy endpoints, particularly PFS, with no increase in early pulmonary AEs, compared with 90 mg. Investigator-Assessed Efficacy by Subgroup.rnTable: 97PDrn

      rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn rnrn
      rnArm A n = 112Arm B n = 110Total N = 222
      Confirmed ORR, n/N (%)rnrnrn
       All pts[a]50/112 (45)59/110 (54)109/222 (49)
       Racernrnrn
        Asian18/39 (46)18/30 (60)36/69 (52)
        Non-Asian32/73 (44)41/80 (51)73/153 (48)
       Prior chemotherapyrnrnrn
        Yes35/83 (42)44/81 (54)79/164 (48)
        No15/29 (52)15/29 (52)30/58 (52)
       Best response to prior crizotinibrnrnrn
        CR or PR36/71 (51)47/73 (64)83/144 (58)
        Other14/41 (34)12/37 (32)26/78 (33)
       Baseline brain metastasesrnrnrn
        Yes31/80 (39)43/74 (58)74/154 (48)
        No19/32 (59)16/36 (44)35/68 (51)
      Median PFS, monthsrnrnrn
       All pts9.212.911.1
       Racernrnrn
        Asian8.811.111.1
        Non-Asian9.212.911.8
       Prior chemotherapyrnrnrn
        Yes8.812.911.8
        No9.28.19.2
       Best response to prior crizotinibrnrnrn
        CR or PR11.115.615.6
        Other7.412.99.2
       Baseline brain metastasesrnrnrn
        Yes9.211.811.1
        No7.415.615.6
      rnCR = complete response, ORR = objective response rate, PFS = progression-free survival, PR = partial responsernaPrimary endpointrn

      Clinical trial identification:
      NCT02094573

      Legal entity responsible for the study:
      ARIAD Pharmaceuticals, Inc.

      Funding:
      ARIAD Pharmaceuticals, Inc.

      Disclosure:
      M. Tiseo: Consulting or advisory role (AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Novartis, Otsuka, Pierre Fabre), research funding (ARIAD). K.L. Reckamp: Consulting or advisory role (ARIAD), research funding (ARIAD). H.L. West: Consulting or advisory role (ARIAD, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Merck, Novartis, Pfizer, Roche/Genentech, Trovagene), speakers’ bureau (ARIAD, Eli Lilly, Roche/Genentech). H.J. Groen: Consulting or advisory role (Eli Lilly, MSD, Novartis, Pfizer, Roche). C.J. Langer: Honoraria (BMS, Lilly/ImClone, Roche/Genentech), consulting or advisory role (Abbott, ARIAD, AstraZeneca, Bayer/Onyx, BMS, Cancer Support Community, Celgene, Clarient, Clovis Oncology, Lilly/ImClone, Merck, Millennium, Roche/Genentech), research funding (Advantagene, ARIAD, Celgene, Clovis Oncology, GSK, Inovio, Merck, Roche/Genentech). W. Reichmann, D. Kerstein: Employment, stock and other ownership interests (ARIAD). D.R. Camidge: Honoraria (ARIAD), research funding (ARIAD). All other authors have declared no conflicts of interest.

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      98P - Retrospective indirect comparison of alectinib phase II data vs ceritinib real-world data in ALK+ NSCLC after progression on crizotinib (ID 379)

      12:30 - 12:30  |  Author(s): J. Davies, M. Martinec, R. Martina, P. Delmar, M. Coudert, W. Bordogna, S. Golding, G. Crane

      • Abstract

      Background:
      Approvals of second-line ALK inhibitors (ALKi) ceritinib and alectinib are based on single-arm trials that lack comparative efficacy data to support health technology assessments. We assessed if real-world data (RWD) could provide this by acting as an external control for single-arm studies by comparing data generated from alectinib trials and ceritinib patient data.

      Methods:
      We retrospectively analysed patients (pts) with ALK+ advanced NSCLC receiving an ALKi after crizotinib failure. The alectinib arm (ALC; n = 183) included pts from the phase II NP28673/NP28761 studies. To generate the ceritinib control arm (CER; n = 67) eligibility criteria similar to the alectinib trials was applied to the Flatiron Health’s electronic health record database. A propensity score based on prognostic factors was generated and applied by inverse probability treatment weighting. A multivariate Cox model was used to evaluate the association of ALC compared with CER on overall survival (OS) adjusting for age, sex, prior treatment, race and stage at diagnosis. Summary data from the CER trial ASCEND-2 were re-digitised to compare with CER RWD.

      Results:
      Prior to re-weighting, the arms were heavily imbalanced. Key differences between the arms included age, prior treatments and baseline CNS metastases (median: 53 vs 61 yrs, 36% vs 13% [≥3 lines], 61% vs 35%, ALC vs CER). After weighting, balance was achieved across all key prognostic factors with a standardised mean difference <10% for all factors. A multivariate Cox model showed ALC was associated with lower risk of death (HR 0.65; 95% CI 0.48–0.88). Adjusted median OS was 24.2 months for ALC (95% CI 17.5–NR) vs 15.6 months for CER (95% CI 15.5–18.6). Median OS in the RWD CER group was similar to that reported in the CER ASCEND-2 trial (14.9 months).

      Conclusions:
      The results show that ALC is associated with prolonged OS vs CER, which was consistent through numerous sensitivity analyses. CER RWD median OS was similar to that observed in ASCEND 2, validating this analysis. For single-arm studies, RWD can serve as an external control for producing comparative data.

      Clinical trial identification:
      NP28673 NP28761

      Legal entity responsible for the study:
      F. Hoffmann-La Roche

      Funding:
      F. Hoffmann-La Roche

      Disclosure:
      J. Davies, G. Crane: Employee at Roche Products Ltd. P. Delmar, M. Coudert: Employee at F. Hoffmann-La Roche, Ltd. M. Martinec, W. Bordogna, S. Golding: Employee: F. Hoffmann-La Roche; Stock ownership: F. Hoffmann-La Roche. All other authors have declared no conflicts of interest.

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      99P - Efficacy of gefitinib in advanced squamous cell lung cancer harboring epidermal growth factor receptor mutations: A pooled analysis of individual patient data (ID 300)

      12:30 - 12:30  |  Author(s): D. Tao, N. Zhang, Y. Wang

      • Abstract

      Background:
      Gefitinib has demonstrated clinical benefits for patients suffering from lung adenocarcinoma with activating mutation of epidermal growth factor receptor (EGFR). However, the efficacy of gefitinib for advanced squamous cell lung cancer (SqCLC) harboring EGFR mutation is still unclear.

      Methods:
      We conducted a pooled analysis of individual patient data based on the published reports that included patients with advanced SqCLC harboring EGFR mutation who were treated with gefitinib. The patients selected for the analysis were advanced SqCLC patients harboring EGFR mutations who were treated with gefitinib and described in reports containing the data of the histology, EGFR mutation status and type, response to gefitinib, and outcome of these patients.

      Results:
      Tweenty-six patients were selected from ten reports for the pooled analysis. One patient obtained a complete response (CR) and five patients obtained a partial response (PR); the response rate (RR) was 23.1%. The median progression-free survival (mPFS) and overall survival (mOS) was 3.1 months and 10.8 months, respectively. The RR and PFS were significantly inferior in the SqCLC patients harboring EGFR mutations to non-SqCLC patients harboring EGFR mutations selected from the same published reports (RR: 23.1% vs. 62.2%, P < 0.001; PFS: 3.1 vs. 9.2 months, P < 0.001, respectively). While no significant difference in OS was observed between the two groups (OS: 10.8 vs. 17.7 months, P = 0.082).

      Conclusions:
      The efficacy of gefitinib was inferior in advanced SqCLC harboring EGFR mutation as compared to non-SqCLC harboring EGFR mutation. The underlining mechanisms of resistance to EGFR-TKI in SqCLC with EGFR mutation should be deeply explored in the further studies.

      Clinical trial identification:


      Legal entity responsible for the study:
      Chongqing Cancer Hospital & Cancer Institute

      Funding:
      Chongqing Cancer Hospital & Cancer Institute

      Disclosure:
      All authors have declared no conflicts of interest.

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      100P - Afatinib vs gefitinib for treatment-naïve patients with EGFRm+ NSCLC (LUX-Lung 7): Analysis of time to treatment failure and impact of afatinib dose adjustment (ID 356)

      12:30 - 12:30  |  Author(s): J.C. Yang, L. Paz-Ares, E. Tan, K. O'Byrne, L. Zhang, M. Boyer, T. Mok, V. Hirsh, J. Fan, K. Park

      • Abstract

      Background:
      PFS was significantly improved in LUX-Lung 7 with afatinib (A) vs gefitinib (G). Time to treatment failure (TTF) was a co-primary endpoint to reflect clinical practice of continuing TKI tx beyond radiologic progression in the absence of clinical deterioration. An analysis of TTF and a post-hoc analysis of the impact of dose adjustment of A on PFS and AEs are reported here.

      Methods:
      Patients (pts) were randomized to A 40mg/d or G 250mg/d until progressive disease (PD) or beyond if deemed beneficial. The dose of A could be reduced by 10mg decrements to a minimum of 20mg in the event of selected drug-related (DR) AEs. TTF was analyzed using a stratified log-rank test and Kaplan-Meier methods. PFS was compared between pts who had a dose reduction within 6 mos and those who received ≥40mg for 6 mos. Incidence/severity of common AEs before/after dose reduction was assessed.

      Results:
      319 pts were randomized (160 A, 159 G). At data cut-off (21 Aug 2015), 87.5% A and 93.7% G pts had discontinued tx, mostly due to radiologic PD (69.4 vs 74.8%) or toxicity (11.3 vs 10.7%). 35.0% A and 29.6% G pts with clinical benefit continued tx beyond radiologic PD. Pts remained on tx significantly longer with A vs G (median TTF 13.7 vs 11.5 mos; HR 0.73 [95% CI 0.58–0.92]; p = 0.007; pts on tx at 2 yrs: 25.0 vs 13.2%). TTF subgroup analyses favored A. Risk of tx failure was reduced with A vs G regardless of EGFRm type or race. Median tx duration beyond PD with A and G was 2.7 and 2.0 mos, respectively. 63 pts (39%) treated with A had a dose reduction to 30mg; 21 (13%) had further reduction to 20mg. There was no significant difference in PFS in pts who received <40 mg or ≥ 40 mg (median 12.8 vs 11.0 mos; HR 1.3 [95% CI 0.9–2.0]; p = 0.14). Dose reduction of A reduced the incidence/severity of DR AEs: grade ≥3 diarrhea, rash/acne and stomatitis were reduced from 25.4%, 20.6% and 7.9%, to 9.5%, 3.2% and 3.2%, respectively.

      Conclusions:
      TTF was significantly improved with first-line A vs G in EGFRm+ NSCLC, which testifies to the tolerability of A, and suggests that it may confer additional clinical benefit in pts who continue tx beyond PD. Dose adjustment of A reduced the frequency/intensity of DR AEs without compromising efficacy.

      Clinical trial identification:
      LUX-Lung 7: EudraCT No: 2011-001814-33

      Legal entity responsible for the study:
      Boehringer Ingelheim

      Funding:
      Boehringer Ingelheim

      Disclosure:
      J.C-H. Yang: Ad board and honoraria: BI, Lilly, Bayer, Roche/Genentech/Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono pharmaceutical Daiichi, Sankyo, and AZ. L. Paz-Ares: Honoraria from Pfizer, Bristol-Myers Squibb, MSD, Novartis, Roche, Eli Lilly, Boehringer lngelheim, Clovis Oncology, AstraZeneca, and Amgem. K. O\'Byrne: Ad board, speaker bureau, travel to international conferences and honoraria: AZ, BMS, Roche-Genentech, MSD, Pfizer, BI. Ad board and speaker bureau: Novartis. 3 Patents: 1 on novel drugs, 2 on biomarkers, IP held by Queensland University of Technology. M. Boyer: Ad board: BMS, Merck Sharpe and Dohme, Pfizer Board of Directors: IASLC Research: Pfizer, Genentech, BI, AZ, Novartis, Merck Sharpe and Dohme, Clovis Honoraria: Merck Sharpe and Dohme, BI, BMS, AZ. T. Mok: Receipt of grants/research supports: AstraZeneca, BI, Pfizer, Novartis, SFJ, Roche, MSD, Clovis Oncology, BMS; Receipt of honoraria or consultation fees: AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, Merck Serono, MSD, Janssen, Clovis Oncology, BioMarin, GSK, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Inc., Vertex Pharmaceuticals, BMS, AVEO & Biodesix, Prime Oncology, Amgen; Participation in a company sponsored speaker’s bureau: AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, MSD, Amgen, Janssen, Clovis Oncology, GSK, Novartis, BMS, PrIME Oncology; Stock shareholder: Sanomics Limited. V. Hirsh: Honoraria for participating on advisory boards for Boehringer Ingelheim, AstraZeneca, Roche, Merck, Eli Lilly, Pfizer, Amgen, and Bristol-Myers Squibb. K. Park: Participated on advisory boards for Astellas, AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Eli Lilly, Hanmi, MSD, Novartis, and Roche. All other authors have declared no conflicts of interest.

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      101P - Association between time to progression and subsequent survival in previously treated BRAF V600E-mutant metastatic non-small cell lung cancer (ID 416)

      12:30 - 12:30  |  Author(s): M. Sasane, J. Li, J. Zhang, J. Zhao, M.L. Ricculli, S. Redhu, J. Signorovitch

      • Abstract

      Background:
      Time to progression (TTP) has been associated with prolonged post-progression survival (PPS) in ALK positive non-small cell lung cancer (NSCLC). However, such associations have not yet been assessed among previously treated metastatic NSCLC patients with BRAF V600 mutation who received BRAF-specific targeted therapies. This study evaluated the TTP-PPS association among previously treated BRAF V600E-mutant metastatic NSCLC patients receiving the BRAF inhibitor dabrafenib as a single agent or in combination with the MEK inhibitor trametinib.

      Methods:
      Patients who experienced disease progression in an open-label, non-randomized, Phase II study (NCT01336634) of 2nd-line or later treatment with dabrafenib monotherapy or combination therapy with trametinib were included. Progression was defined per RECIST v1.1. Time from progression to death (PPS) was studied in a Kaplan-Meier analysis with patients stratified by shorter (< 6 months) versus longer TTP (≥ 6 months). The association between TTP and PPS was also quantified in Cox proportional hazards models.

      Results:
      A total of 84 patients who progressed on dabrafenib monotherapy or combination therapy were included in this study, with 77% having ECOG performance score > 0 at screening. Prior to progression, 57 received dabrafenib monotherapy and 27 received combination therapy with trametinib. Among all patients included, 60 (71%) died during post-progression follow-up. Patients with TTP ≥ 6 months experienced significantly longer PPS compared to those with TTP < 6 months (median PPS: 9.5 vs. 2.7 months, log-rank p-value < 0.001). In the proportional hazards model for the full cohort, each 3 months of longer TTP was associated with a 32% lower hazard of death following progression (hazard ratio [95% confidence interval]: 0.68 [0.57, 0.83]). A similar positive association between TTP and PPS was observed in each treatment group (monotherapy: 0.70 [0.57, 0.88]; combination therapy: 0.57 [0.34, 0.97]).

      Conclusions:
      A longer duration of TTP after treatment with dabrafenib monotherapy or combination therapy was significantly associated with a longer duration of PPS.

      Clinical trial identification:
      NCT01336634

      Legal entity responsible for the study:
      Novartis

      Funding:
      Financial support for the study were provided by Novartis.

      Disclosure:
      M. Sasane: Employee of Novartis and own Novartis stock or stock options. J. Li: Employed by Analysis Group, Inc., payment from Novartis for participation in this research. J. Zhang: Employee of Novartis and own Novartis stock or stock options. J. Zhao: Employed by Analysis Group, Inc., payment from Novartis for participation in this research. M.L. Ricculli: Employed by Analysis Group, Inc., payment from Novartis for participation in this research. S. Redhu: Employee of Novartis and own Novartis stock or stock options. J. Signorovitch: Employed by Analysis Group, Inc., payment from Novartis for participation in this research.

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      102P - LUX-Lung 8 phase III trial: Analysis of long-term response to second-line afatinib in patients with advanced squamous cell carcinoma (SCC) of the lung (ID 355)

      12:30 - 12:30  |  Author(s): J.C. Yang, G. Goss, E. Felip, S. Lu, A. Ardizzoni, S.M. Gadgeel, V. Georgoulias, N. Dupuis, E. Ehrnrooth, J. Soria

      • Abstract

      Background:
      In LUX-Lung 8, afatinib (A; 40mg/day) significantly improved OS (median 7.9 vs 6.8 months, p = 0.008) and PFS (2.6 vs 1.9 months, p = 0.010) versus erlotinib (E; 150mg/day) in pts with pretreated SCC of the lung (n = 795). 12-month (36 vs 28%; p = 0.016) and 18-month survival (22 vs 14%; p = 0.013) were significantly higher with A than E, indicating that some pts derive prolonged benefit from A. This is a post-hoc analysis of baseline characteristics and efficacy/safety of A in long-term responders (LTRs; treatment for ≥12 months). Archived tumor samples and serum were analyzed to identify potential biomarkers.

      Methods:
      Tumor samples were retrospectively analyzed using next-generation sequencing (NGS); EGFR expression was determined by IHC. Pre-treatment serum samples were analyzed with VeriStrat[®] and classified as VeriStrat-Good or VeriStrat-Poor.

      Results:
      21/398 pts treated with A were LTRs. Six pts were still on treatment at the time of data cut-off. The median duration of treatment was 17.6 months (range: 12.3–27.6). Baseline characteristics were similar to the overall dataset (median age: 64 y [range: 54–81]; male: 76%; Asian: 29%; ECOG 0/1: 33%/67%; best response to chemotherapy CR or PR/SD: 48%/52%; current and ex-smokers: 90%). Median PFS was 16.6 months (range: 2.8–25.8); median OS was 21.1 months (12.9–31.6). The most common treatment-related AEs (all grade/grade 3) were: diarrhea (81%/5%); rash/acne (71%/5%); stomatitis (29%/5%). AEs generally occurred soon after treatment onset. Six pts had dose reductions due to related AEs. NGS data in ten LTRs will be presented. Genomic aberrations in the ErbB gene family were identified in 50% of these pts (overall dataset: 26.5%). Of 17 pts assessed by VeriStrat, 88% were VeriStrat-Good (overall dataset: 62%). IHC data were available for only one LTR (EGFR-).

      Conclusions:
      Baseline characteristics of LTRs to A were similar to the overall dataset. A conferred median OS of almost 2 years in this subgroup. A was well tolerated with predictable, transient AEs. Though biomarker data look promising, the cohort was too small to identify any clear NGS/VeriStrat predictive signals; further studies are required.

      Clinical trial identification:
      LUX-Lung 8: EudraCT No: 2011-002380-24

      Legal entity responsible for the study:
      Boehringer Ingelheim

      Funding:
      Boehringer Ingelheim

      Disclosure:
      J.C-H. Yang: Ad board and honoraria: BI, Lilly, Bayer, Roche/Genentech/Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono pharmaceutical Daiichi, Sankyo, and AZ. G. Goss: Participated on advisory boards for AstraZeneca, Boehringer Ingelheim, Pfizer, Eli Lilly, Bristol-Myers Squibb, and Celgene. E. Felip: Participated on advisory boards for Eli Lilly, Pfizer, Roche, MSD, and Boehringer Ingelheim. Felip has receieved lecture fees from AstraZeneca, Bristol-Myers Squibb, and Novartis. A. Ardizzoni: Received honoraria and participated on advisory boards for Bristol-Myers Squibb, MSD, Eli-Lilly, and Boehringer Ingelheim. Ardizzoni has received honoraria from Pfizer and Bayer. S.M. Gadgeel: Participated on advisory boards for Boehringer Ingelheim, Pfizer, Genentech, ARIAD, AstraZeneca, Bristol-Myers Squibb, and Roche. N. Dupuis: Employee of and owns stock in Biodesix. E. Ehrnrooth: Employee of Boehringer Ingelheim. J-C. Soria: Astrazeneca, Astex, GSK, Gammamabs, Lilly, MSD, Merus, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Symphogen, Takeda. All other authors have declared no conflicts of interest.

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      103P - Re-biopsy for advanced non-small cell lung cancer after EGFR tyrosine kinase inhibitor therapy: CT characteristics of patients with T790M mutation and the use of various re-biopsy procedures (ID 385)

      12:30 - 12:30  |  Author(s): H.J. Koo, M.Y. Kim, C. Choi, J.C. Lee, S. Park

      • Abstract

      Background:
      Re-biopsy for mutation analysis of non-small cell lung cancer (NSCLC) after EGFR-tyrosine kinase inhibitor treatment is important to determine further chemotherapy regimen. There have been no studies about the radiologic characteristics of NSCLC with T790 mutation and the use of the various re-biopsy procedures.

      Methods:
      Between January and December 2016, 78 patients underwent re-biopsy for mutation analysis of NSCLC, and among them, 76 were assessed with adequate specimen. Patients’ treatment course, serial CT scans and pathologic reports were retrospectively reviewed. Re-biopsy methods are varied: EBUS or BFS-guided (n = 27), CT-guided (n = 18), fluoroscopy-guided (n = 5) biopsies, US-guided supraclavicular lymph node (n = 6) or other sites (n = 6) biopsies and pleural fluid analysis (n = 14). CT images obtained at the time of initial biopsy and re-biopsy were compared between patients with and without T790M mutation. Re-biopsy associated complications were assessed.

      Results:
      Among 76 patients, 40 (52.6%) presented T790M mutation on re-biopsy. Progression free survivals between patients with and without T790M mutation were not statistically different (322 and 389 days, respectively). On initial CT, pleural retraction (odds ratio (OR), 4.1; p = 0.03) and the presence of pleural metastasis (OR, 3.4; p = 0.03) were significant factors that related to the positive T790M mutation by multivariate logistic analysis. Pleural retraction (OR, 26.8, p = 0.03) and pleural metastasis (OR, 11.4; p = 0.004) are also shown as significant factors that related to the positive T790M mutation on CT obtained at the time of re-biopsy. Three patients developed pneumothorax, and two were managed by chest tube insertion. One patient who was negative T790M mutation on pleural fluid analysis finally diagnosed as positive T790M mutation by following CT-guided biopsy.

      Conclusions:
      Pleural retraction and pleural metastasis were significantly associated factors to positive T790M mutation in NSCLC patients who underwent re-biopsy. Negative T790M on pleural fluid analysis could not give a guarantee for true negative, and further core biopsy might be recommended.

      Clinical trial identification:


      Legal entity responsible for the study:
      None

      Funding:
      N/A

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      104P - Efficacy of ceritinib in a "real-world" population of crizotinib-refractory ALK-positive NSCLCs: Results of the Italian compassionate use program (ID 422)

      12:30 - 12:30  |  Author(s): G. Metro, A. Passaro, G. Lo Russo, V. Gregorc, R. Giusti, E. Capelletto, O. Martelli, F.L. Cecere, L. Bonanno, R. Chiari

      • Abstract

      Background:
      Ceritinib has been approved by EMA for the treatment of patients (pts) with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) who progress on crizotinib. Nevertheless, this drug is not reimbursed in Italy by the National Health Care System as of January 2017. The aim of this study was to assess the efficacy of ceritinib administered within a compassionate use (CU) program made available to crizotinib-refractory patients.

      Methods:
      This collaborative study involved multiple institutions in Italy. Clinical data from crizotinib-refractory pts with ALK-positive NSCLC who were requested ceritinib compassionate use (CU) were collected and analyzed.

      Results:
      Twenty-four centres took part to the study, for a total of 70 pts who were requested ceritinib CU. Of these, 63 pts received at least one dose of ceritinib 750 mg/d from July 2014 to January 2017. Pts characteristics were as follows: median age 56 years (22-86), 34/63 (54%) female, 43/63 (68%) never smokers, 12/63 (19%) ECOG PS ≥ 2, 13/63 (21%) pretreated with ≥ 2 lines of chemotherapy, 49/63 (78%) metastatic to the brain. Median time on prior crizotinib was 370 days (51-1644). The most common any grade treatment-related adverse events (TRAEs) were nausea (60%, 6% grade 3 or 4), vomiting (49%, 5% grade 3 or 4), diarrhea (51% 2% grade 3 or 4), ALT elevation (48%, 17% grade 3 or 4), AST elevation (49%, 17% grade 3 or 4), and fatigue (59%, 8% grade 3 or 4). Dose reduction due to TRAEs occurred in 31/63 pts (49%). Out of 31 pts, 15 pts (49%) reduced the dose to 600 mg/d, 10 pts (32%) to 450 mg/d, and 6 pts (19%) to 300 mg/d. Unusual TRAEs consisted of an increase in serum creatinine in 3 pts. Of the 55 patients who were evaluable for response, 21 pts (38%) responded to treatment. Overall, at a median follow-up of 6.2 months (0.5-26), median progression-free survival (PFS) was 7.6 months and 6-month PFS was 59%.

      Conclusions:
      The ceritinib CU program in Italy confirms the efficacy of the drug in a "real-world" setting, with a safety profile that is similar to that observed in clinical trials. A high rate of dose adjustments due to TRAEs was observed, which, however, did not appear to influence the activity of the drug.

      Clinical trial identification:
      NA

      Legal entity responsible for the study:
      N/A

      Funding:
      Associazione Italiana per la Ricerca contro il Cancro

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      105P - Prognostic factors in crizotinib (CRZ)-resistant anaplastic lymphoma kinase (ALK+) non-small cell lung cancer (NSCLC) patients (Pts) (ID 469)

      12:30 - 12:30  |  Author(s): K.L. Reckamp, J. Lee, J. Huang, I. Proskorovsky, W. Reichmann, M. Krotneva, D. Kerstein, H. Huang

      • Abstract

      Background:
      The aim of this analysis was to assess prognostic factors in patients with CRZ-resistant ALK+ NSCLC associated with progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) based on the Phase 2 ALTA Trial (NCT02094573) of brigatinib.

      Methods:
      Analyses used data from ALTA Arm B (180 mg qd with a 7-day lead-in at 90 mg, N = 110). Potential prognostic factors were evaluated using univariate and multivariate Cox proportional hazards models for PFS and OS, and logistic regression for ORR. Potential prognostic factors included age, sex, race, ECOG performance status, prior radiotherapy (RT), prior RT to brain, prior chemotherapy, prior platinum-based chemotherapy, smoking status, number of prior regimens, best response to prior CRIZ, number of metastatic sites, and active brain lesions. ALTA trial was not powered to detect differences in outcomes by these factors, thus a threshold of p < 0.5 was used to select variables into all models. Factors with hazard ratios >1.30 or < 0.77 were also included in the final models for PFS and OS.

      Results:
      As of February 29, 2016, median follow-up was 8.3 months, and independent review committee (IRC) assessed median PFS was 15.6 months [95% CI: 11.0, NR] (31 events). Median OS was not reached (17 deaths). IRC-assessed ORR was 52.7% [95% CI: 43.0%, 62.3%]. Prognostic factors are shown in the table.rnTable: 105PImportant prognostic factors in CRIZ-resistant ALK+ NSCLC treated with brigatinib 180 mg qd with a 7-day lead-in at 90 mg (N = 110)rn

      rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn
      Prognostic FactorPFS (HR [95% CI])*OS (HR [95% CI])*ORR (OR [95% CI])**
      Age (per 1-year increase)0.98 [0.95, 1.01]
      Sex Male vs female1.79 [0.84, 3.79]
      Race Asian vs non-Asian1.29 [0.55, 3.04]0.15 [0.02, 1.25]1.87 [0.73, 5.00]
      ECOG performance status 1 vs 0 2 vs 00.72 [0.33, 1.58] 3.24 [0.99, 10.60]2.56 [0.72, 9.06] 4.02 [0.73, 22.14]0.64 [0.26, 1.53] 0.19 [0.02, 1.07]
      Prior chemotherapy Yes vs no0.42 [0.19, 0.95]0.34 [0.11, 1.04]1.90 [0.71, 5.24]
      Best response to prior CRIZ CR/PR vs any other status or unknown0.56 [0.25, 1.27]0.74 [0.24, 2.33]1.88 [0.77, 4.70]
      Prior radiotherapy to brain Yes vs no2.21 [1.02, 4.78]0.51 [0.17, 1.57]
      Active brain lesions Yes vs no0.45 [0.15, 1.39]
      Smoking status Never vs current/former/unknown0.49 [0.14, 1.67]2.45 [1.04, 5.97]
      Number of metastatic sites 3 vs 1-2 4+ vs 1-21.05 [0.20, 5.58] 2.66 [0.59, 12.03]0.34 [0.10, 1.08] 0.81 [0.27, 2.36]
      rnAbbreviations: PFS = progression-free survival; OS = overall survival; ORR = objective response rate; HR = hazard ratio; OR = odds ratio; CI = confidence interval; CR = complete response; PR = partial response; ECOG = Eastern Cooperative Oncology Group;rn*HR < 1 indicates lower risk of progression or death vs reference group;rn**OR > 1 indicates higher odds of response vs reference grouprn

      Conclusions:
      In this analysis of CRZ-resistant ALK+ NSCLC patients, a history of prior chemotherapy was associated with longer PFS, while prior radiotherapy was associated with shorter PFS, both likely due to unmeasured patient characteristics. Never smokers had more than double the odds of response, versus current or former smokers. ECOG status 2 was nominally associated with shorter PFS and OS and lower ORR, and presence of active brain lesions was associated with longer OS.

      Clinical trial identification:
      The trial protocol number is NCT02094573.

      Legal entity responsible for the study:
      Evidera Inc.

      Funding:
      ARIAD Pharmaceuticals

      Disclosure:
      K.L. Reckamp: Consulting or advisory role (ARIAD), research funding (ARIAD). J. Lee, M. Krotneva: Employee of Evidera Inc., which provides consulting services to pharmaceutical organizations. Evidera Inc. received funding from ARIAD pharmaceuticals. J. Huang: Employment, consulting or advisory role (ARIAD). W. Reichmann, D. Kerstein, H. Huang: Employment, stock shareholder (ARIAD). All other authors have declared no conflicts of interest.

    • +

      106P - Brain metastases (BM) development in molecular selected non-small cell lung cancer (NSCLC) patients included in clinical trials (ID 305)

      12:30 - 12:30  |  Author(s): S. Cedres, N. Pardo, A. Navarro-Mendivil, A. Martinez, A. Martinez de Castro, J. Remon, F. Amair, J. Zeron, M. Vilaro, E. Felip

      • Abstract

      Background:
      The molecular profiling of patients (p) with advanced NSCLC identifies several oncogenic drivers that can be targeted with selective inhibitors. We aimed to assess the characteristics and brain development of p with molecular alterations at our center treated with targeted agents.

      Methods:
      EGFR, KRAS, HER2 mutated p and ALK, ROS1 and RET rearrangements positive p enrolled onto clinical trials between 2009 and 2015 at our center were included in this analysis. A cohort of wild type (WT) adenocarcinoma p was selected as comparator. Overall survival (OS) was estimated by the Kaplan Meier method.

      Results:
      200 p were collected (76 WT, 45 EGFR, 51 ALK, 21 KRAS, 3 ROS1, 2 HER2 and 2 RET). Median age 57 years (26-82), 52% men, 60% performance status (PS) 1, 59% smokers, 98% stage IV and 92% adenocarcinoma. First treatment was selective inhibitor in 73% of EGFR and 58% of ALK p. Median follow up was 23 months (m) (95% CI 1.6-104.6). The OS (immature with 58% of deaths) was 33m for all p and 57m EGFR, 40m ALK, 31m KRAS and 19m WT. We found differences in OS for molecular selected population vs WT (55m vs 19 m p < 0.001), women (55m vs 23m, p = 0.002), PS 0/1 vs PS2 (21 vs 7m, p < 0.001) and non-smokers (51 vs 23 m smokers, p = 0.002). Brain metastases were detected in 86 p (36 ALK, 25 WT, 14 EGFR, 8 KRAS, 2 ROS and 1 RET) and 87% received local therapy. BM were more frequent in women, non-smokers and ALK p (p < 0.001). BM developed at a median of 6m from diagnosis of NSCLC (6m molecular selected and 5m WT, p = 0.44) and median OS after development of BM was 14m (28m EGFR, 26m ALK and 8m WT, p < 0.001). No differences in OS were detected in p with or without BM (p > 0.05). Independently of target agent, we did not found significant differences in OS p with BM treated with local therapy vs systemic treatment (p > 0.005). P who initiated the EGFR and ALK inhibitors after diagnosis of BM had greater benefit than those p who began treatment before diagnosis of BM (86m vs 57m for EGFR and 55m vs 35m for ALK respectively, p > 0.05 in both).

      Conclusions:
      Molecular selected p treated with targeted agents have prolonged survival. Brain metastases is a frequent site of disease progression, but the prognosis of these p is impressive independently of local therapies.

      Clinical trial identification:
      not aplicable

      Legal entity responsible for the study:
      N/A

      Funding:
      N/A

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      107P - The real world experience of first generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) in patients with advanced lung cancer: Explorative analysis of big data from national health insurance service of Korea (ID 437)

      12:30 - 12:30  |  Author(s): B.S. Kwon, J.C. Lee, S. Kim, M.Y. Kim, C. Choi

      • Abstract

      Background:
      Although the effectiveness of EGFR-TKI in patients with advanced lung cancer has been proven in previous trials, the real-world efficacy of EGFR-TKI has not been investigated. The object of this study was to evaluate the outcomes of first-generation EGFR-TKI in female patients with advanced lung cancer using big data analysis.

      Methods:
      We retrospectively reviewed the Korean health insurance service data of advanced lung cancer patients from January 2004 to December 2013. Patients older than 20 years in palliative setting were grouped into three categories: Group A received 1st-generation EGFR-TKI ≥6 months, group B given EGFR-TKI < 6 months, and group C was treated with cytotoxic chemotherapy alone. For each group, we determined progression-free survival (PFS) and overall survival (OS).

      Results:
      Of 11,045 patients enrolled in the study, 6,170 (55.8%) received EGFR-TKI at least 1 month, and 4,875 (44.2%) never treated with EGFR-TKI. 2,572 were in the group A and 3,598 were in the group B. In the group C, platinum based doublet agent or monotherapy such as docetaxel, gemcitabine and pemetrexed was administered. The median OS of patients treated with EGFR-TKI was significantly longer than that of EGFR-TKI naïve patients (19.1 months [95% confidence interval (CI) 18.5-19.7] vs 9.5 months [95% CI 9.1-9.8]; p < 0.0001). In subgroup analysis, the median OS was 30.3 months [95% CI 29.5-31.2] in the group A, compared with 12.3 months [95% CI 11.9-12.7] in the group B and 9.5 months [95% CI 9.1-9.8] in the group C (p < 0.001). Patients age < 65 years, treated with EGFR-TKI ≥ 6months, and received docetaxel, pemetrexed chemotherapy were independent predictors of longer OS (Hazard ratio (HR) 0.78 [95% CI 0.74-0.81]; p = 0.002, HR 0.41 [95% CI 0.38-0.43]; p < 0.001, HR 0.81 [95% CI 0.77-0.85]; p < 0.001, HR 0.77 [95% CI 0.74-0.81]; p < 0.001, respectively). Median PFS was 15.8 months [95% CI 15.1-16.3] in group A and 3.7 months [95% CI 3.5-3.8] in group B (p < 0.001).

      Conclusions:
      The current study demonstrated that EGFR-TKI conferred a significant PFS and OS benefit in female patient with advanced lung cancer in real-world.

      Clinical trial identification:


      Legal entity responsible for the study:
      Asan Medical Center

      Funding:
      None

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      108P - NSCLC patients harbouring a rare or complex EGFR mutation are more often smokers and might not benefit from first line TKI therapy (ID 479)

      12:30 - 12:30  |  Author(s): D. Kauffmann-Guerrero, K. Kahnert, S. Reu, A. Jung, Z. Synyaeva, P. Mertsch, R.M. Huber

      • Abstract

      Background:
      TKI therapy is definitely standard in first line treatment of patients with advanced NSCLC harbouring a classic EGFR mutation (Exon 19 deletion or Exon 21 L858R). However, a certain percentage of patients have rare or complex EGFR mutation with unknown relevance regarding prognosis and response to TKIs. For those patients, therapy decisions remain challenging.

      Methods:
      343 patients with NSCLC, who underwent EGFR mutation testing, were analysed in this study with regard to epidemiological characteristics as age, sex and smoking status as well to EGFR mutation status classified into wild type, classic, rare, synonymous, T790M and complex mutations. Further rare and complex mutations of 12 patients who received TKI therapy were analysed regarding to response to TKI treatment.

      Results:
      282 (82%) of all patients were EGRF wild type, whereas 61 (18%) harboured an EGFR mutation. Most of them appeared to be classic mutations 32 (9%), followed by rare (16 (5%)) and complex (7 (2%)) mutations. Synonymous and T790M resistance mutations were found in 3 and 4 patients respectively. EGFR mutations were significantly more frequent in women than in men. It was noticeable that patients with rare or complex mutations were significantly more often smokers compared to classic EGFR mutations. Further the rare and complex mutations showed to be less responsive to TKI therapy.

      Conclusions:
      Smoking seems to enhance the probability of rare or complex EGFR mutations. Besides, those mutations might not benefit from first line TKI therapy, so that the presence of EGFR mutation alone should not necessarily lead to induction of a TKI therapy and in case of TKI treatment to close surveillance. In fact, type of mutation, reports of response and patient characteristic as performance status should lead the decision.

      Clinical trial identification:


      Legal entity responsible for the study:
      Department of Internal Medicine V, University Munich

      Funding:
      Department of Internal Medicine V, University of Munich

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      109P - Sequential administration of EGFR-TKI and pemetrexed achieved a long period of response in advanced NSCLC patients with EGFR-mutant tumors (ID 322)

      12:30 - 12:30  |  Author(s): Y. Chen, Q. Zhu, L. Dai, Z. Ding

      • Abstract

      Background:
      The study aimed to explore the efficacy of sequential administration of EGFR TKI and pemetrexed doublet chemotherapy (P), two effective therapies, in advanced NSCLC patients with EGFR mutant tumors.

      Methods:
      This was a retrospective study where patients prescribed with EGFR-TKI (gefitinib or icotinib) from Jan 2013 to Jan 2016 were screened. Patients must have metastastic diseases harboring TKI-sensitizing EGFR mutation. They must be older than 18 years, and have evaluable target lesions. Whether TKI or P was used in the first line, it must be switched to the other in the second line. PFS in both first line (PFS1) and second line (PFS2) was collected.

      Results:
      We screened totally 550 patients (gefitinib n = 455, icotinib n = 95) to enroll a cohort of 37 patients. However, 1 patient was found to subject adjuvant TKI therapy and therefore was excluded. They were all adenocarcinoma except 1 adenosquamous carcinoma. Gender, good PS, mutation type were equally distributed (male n = 19 vs female n = 17, PS:0 n = 21 vs PS:1 n = 15, exon 19 del n = 14 vs L858R n = 14 vs other type n = 8). The median age was 50.5 years. For the whole cohort, the total PFS (PFS1+PFS2) was 18.1 m (95%CI: 15.2-21.1 m). For the patients receiving first-line TKI, PFS1 and PFS2 were 10.3 m and 6.6 m. And for those receiving first-line P, PFS1 and PFS2 were 3.4 m and 11.5 m.

      Conclusions:
      Our results argued the sequential usage of TKI and P achieve a long period of response in advanced NSCLC patients with EGFR-mutant tumors, comparable to that of synchronous administration (15.4 m, JMIT study).

      Clinical trial identification:
      NA

      Legal entity responsible for the study:
      West China Hospital, Sichuan University

      Funding:
      West China Hospital, Sichuan University

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      110P - Afatinib for patients with advanced NSCLC pretreated with chemotherapy and an EGFR tyrosine kinase inhibitor: Retrospective analysis of the Swiss Afatinib Named Patient Program (ID 505)

      12:30 - 12:30  |  Author(s): M. Ehmann, L. Wannesson, M. Pless, M. Früh, O. Gautschi, A. Curioni-Fontecedro, D. Betticher, M. Mark, A. Ochsenbein, S.I. Rothschild

      • Abstract

      Background:
      Epidermal growth factor receptor (EGFR) mutations are found in 12-15% of lung adenocarcinoma patients in European countries. Afatinib is a second-generation EGFR tyrosine kinase inhibitor (TKI) and is approved for stage IV NSCLC patients with common EGFR mutations. Based on the LUX-Lung 1 trial a named patient program for afatinib was initiated in Switzerland. We thus aimed to evaluate afatinib activity in patients which where previous treated with chemotherapy and first-generation TKIs.

      Methods:
      This multicentre retrospective analysis was performed in 11 institutions in Switzerland. We reviewed clinical records of patients included in the afatinib NPP.

      Results:
      Between 03/2011 and 04/2014 a total of 69 patients were included in the NPP. Baseline characteristics were obtained from all these patients. Follow-up data were accessible from 41 patients. Median age of the population was 63 years (range, 46-79). 68% of patients were female and 28% were never smoker. Adenocarcinoma was the predominant histological subtype (93%). 56 patients (81%) had a proven EGFR mutation. Of those, 29 patients (52%) had a deletion 19, 16 patients (29%) had a L858R mutation in exon 21. A T790M mutation was detected in 10 patients (18%). 50 patients (73%) received treatment with erlotinib and 14 patients (20%) with gefitinib before inclusion in the NPP. 31 patients were evaluable for response assessment by RECIST 1.1. One patient (3.2%) achieved a complete remission, 4 patients (12.9%) showed a partial remission and 3 patients (9.7%) disease stabilization. Mean duration of afatinib therapy was 200 days (95% CI 146-255). Mean overall survival (OS) from diagnosis of metastatic NSCLC was 17.2 months (95%CI 11.9-22.6). In multivariate analysis, EGFR mutation was associated with response to afatinib.

      Conclusions:
      This study confirms the activity of afatinib in pretreated lung adenocarcinoma. The benefit is larger in patients with EGFR mutation positive tumors and mainly in those with classical mutations (deletion 19 or point mutation L858R in exon 21).

      Clinical trial identification:


      Legal entity responsible for the study:
      N/A

      Funding:
      Unrestricted educational grant by Boehringer-Ingelheim

      Disclosure:
      S.I. Rothschild: Advisory Board Boehringer-Ingelheim (honorary paid to the institution). All other authors have declared no conflicts of interest.

    • +

      111P - Pharmacist led proactive follow-up algorithm for advanced EGFR positive NSCLC patients on afatinib (ID 513)

      12:30 - 12:30  |  Author(s): P.K. Cheema, A. Thawer, J. Leake, S.Y. Cheng, S. Khanna, J.C. Victor

      • Abstract

      Background:
      Afatinib is a standard first-line therapy for advanced EGFR positive NSCLC. We implemented a pharmacy led proactive follow-up algorithm for pts prescribed afatinib to identify and manage early adverse events (AEs) (Table). Management of AEs was standardized.

      Methods:
      This was a retrospective chart review of all advanced EGFR positive NSCLC pts at the Sunnybrook Odette Cancer Centre from April 1, 2015 to July 31, 2016 that received afatinib following institution of our algorithm. This study evaluated the impact of our algorithm and characteristics of real world AEs.

      Results:
      We included 33 pts. Median age was 64 and 55%, 79%, 59%, 27% and 88% were female, PS < 2, Asian, smokers, and treated as 1st line, respectively. Median follow up was 249 days (d). Median time on afatinib was 157 d (IQR: 27 to 304). Prophylactic use of topical hydrocortisone/clindamycin was 55% and 46% for an oral tetracycline. All pts had 1 drug related AE, 18% were grade 3/4. Most common AEs were diarrhea 88%, rash 82%, stomatitis 58%, paronychia 46%, nausea 39% and fatigue 39%. Median time to 1st drug related AE was 17 d (IQR: 7 to 126), with early median time to onset of diarrhea 8 d, stomatitis 13 d, rash 15 d, fatigue 18 d and nausea 25 d and late onset of paronychia 75 d, transaminitis 114 d and anorexia 133 d. Median dose of afatinib was 40 mg/daily, 34% of pts had > or = 1 dose reduction and 9% discontinued afatinib due to AEs. Proactive calls identified 37% of all drug related AEs, 33% of grade 3/4 AEs, 58% of first drug related AEs and identified 2 patients that were noncompliant. Only 3% of AEs were identified by an ER visit/urgent clinic visit.rnTable: 111PPhamacist led follow-up algorithm for pts prescribed afatinibrn

      rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn rnrn
      Time on drugDay 1Day 5Day 10Day 14Day 17
      InterventionVisit with pharmacyProactive pharmacy callProactive pharmacy callRoutine clinic visit with medical oncologyProactive pharmacy call
      Variables assessedPatient education of side effects and consent obtained for proactive callsAdherence Rash Diarrhea StomatitisAdherence Rash Diarrhea Stomatitis Paronychia Nausea FatigueClinical assessment and laboratory monitoring of CBC, creatinine and liver function testsAdherence Rash Diarrhea Stomatitis Paronychia Nausea Fatigue Anorexia
      rn

      Conclusions:
      Our algorithm resulted in early identification and management of AEs with a low rate of urgent assessments and discontinuation due to toxicity while maintaining the ideal dose of afatinib. This algorithm provides a tool for centres prescribing afatinib.

      Clinical trial identification:


      Legal entity responsible for the study:
      Dr. Parneet Cheema, PI and Sunnybrook Health Sciences Centre

      Funding:
      Boehringer Ingelheim

      Disclosure:
      P.K. Cheema: Advisory board and research grants: Boehringer Ingelheim. A. Thawer: Advisory board and research grant: Boehringer Ingelheim. S.Y. Cheng, S. Khanna: Advisory board: Boehringer Ingelheim. All other authors have declared no conflicts of interest.

    • +

      112P_PR - Immune response and adverse events to influenza vaccine in cancer patients undergoing PD-1 blockade (ID 502)

      12:30 - 12:30  |  Author(s): S.I. Rothschild, C. Balmelli, L. Kaufmann, M. Stanczak, M. Syedbasha, D. Vogt, O. Gautschi, A. Egli, A. Zippelius, H. Laeubli

      • Abstract

      Background:
      Immune checkpoint inhibitors have been introduced into standard clinical practice. Since cancer patients are at risk to develop complications when infected with seasonal influenza viruses – in particular patients with lung cancer that often have pre-existing lung disorders – it is recommended to vaccinate oncological patients. Concerns have been raised about the safety of influenza vaccination in patients undergoing checkpoint blockade. It is feared that immune stimulation via PD-1/PD-L1 blockade might induce an overshooting immune response.

      Methods:
      Patients undergoing checkpoint blockade were vaccinated with a trivalent influenza vaccination between October and November 2015. For an age-matched control cohort, the partners of the patients were vaccinated and included in our analysis as healthy controls. Safety and frequency of immune-related adverse events were evaluated. Antibody titers against antigens and strains that were included in the trivalent influenza vaccination were measured by hemagglutination inhibition assay in patients undergoing PD-1 blockade and age-matched controls. Cytokine/chemokine profile and changes in peripheral immune cells in a cohort of cancer patients undergoing immunotherapy with PD-1/PD-L1 blockade were also studies.

      Results:
      We included 23 patients at two institutions in Switzerland (University Hospital Basel and Cantonal Hospital Lucerne). Most patients have been treated with PD-1 blocking antibodies for at least 6 weeks at the time of vaccination. The frequency of irAEs was at 52.2% and 6 of 23 patients (26.1%) hat severe grade 3 or 4 irAEs. This frequency is significantly higher than in our general experience at our center (all grades 25.49%, grade 3 or 4 9.8%). There was no major difference over time in the generation of antibody titers in all three viral lines tested. Peripheral leukocyte counts and also cytokine/inflammatory chemokine levels did not change significantly shortly after vaccination.

      Conclusions:
      While the vaccination against seasonal influenza viruses seems to produce good serological protection and no short term toxicity of the vaccination could be observed, the increased rate of immunological toxicity is concerning and should be studied in a larger patient population.

      Clinical trial identification:


      Legal entity responsible for the study:
      N/A

      Funding:
      University Hospital Basel

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      113P - Clinical outcomes and quality of life (QoL) in adults with advanced refractory non-small cell lung cancer (NSCLC) patients receiving nivolumab (Nivo) as 2+ line treatment: Interim analysis of expanded access program (ID 391)

      12:30 - 12:30  |  Author(s): K.K. Laktionov, L.V. Bolotina, V.V. Breder, A.S. Danilova, F.V. Moiseenko, T.P. Nikitina, R.V. Orlova, E.A. Filippova, S.A. Protsenko, T.I. Ionova

      • Abstract

      Background:
      Therapy with immune checkpoints changed the paradigm of treatment in many solid tumors including NSCLC. Recently several drugs of this group were approved in second and first line. Still the data on their use in NSCLC is quite limited. The aim of this study was to evaluate benefits/risks of Nivo treatment within the expanded access program in refractory NSCLC patients both from physician’s and patient’s perspective. We report interim analysis on response rates, safety and QoL.

      Methods:
      Adult pts with advanced refractory NSCLC received Nivo 3 mg/kg q2w in accordance with expanded access program. Tumor response was assessed using RECIST v. 1.1. Adverse events (AEs) were evaluated by NCI CTCAE v3.0. QoL was assessed by RAND SF-36, symptom severity – by ESAS-R. Group comparisons were made using Mann-Whitney test.

      Results:
      From July of 2015 to December of 2016 with the median follow-up time of 11 weeks 141 pts were enrolled in 7 centers in RF. Clinical characteristics: 64.5% – males; median age – 60.5 (29 − 79); ECOG PS 0-1/2-3 – 78.3%/21.3%; former or current smokers – 71%; non squamous NSCLC – 65.2%; ≥2 lines of previous systemic treatment – 54%. At baseline pts had poor QoL comparing with healthy controls – 0.283 vs 0.505 (p < 0.001); 68.8% had moderate-to-severe symptoms. The most dramatic QoL worsening was observed for physical functioning and role functioning, p < 0.001. During 4 weeks of treatment Integral QoL index increased by 50% in 53% of pts. Efficacy was evaluated in 51 pts (median first evaluation – 9 weeks), PR – 6/51, SD – 30/51, PD – 15/51. Early deaths from cancer occurred in 7 pts; early deaths not related to cancer – 2 pts. 15 pts discontinued Nivo prematurely (<2 mos) because of rapid clinical worsening. 66 pts were not evaluated for response on cut-off. AEs were registered in 35 pts (median of Nivo treatment – 7 weeks); among them 8 with grade 3-4 AEs.

      Conclusions:
      QoL is dramatically compromised in advanced refractory NSCLC pts. Early data from this study supports that Nivo is effective and well tolerated by this patient population.

      Clinical trial identification:


      Legal entity responsible for the study:
      Multinational Center for QoL Research

      Funding:
      The study was supported by the grant of BMS

      Disclosure:
      K.K. Laktionov, L.V. Bolotina, V.V. Breder, A.S. Danilova, F.V. Moiseenko, T.P. Nikitina, R.V. Orlova, E.A. Filippova, S.A. Protsenko, T.I. Ionova: Study supported by the grant of BMS

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      114P - Phase II study of nivolumab in patients with advanced non-small cell lung cancer (NSCLC) in Korea (ID 441)

      12:30 - 12:30  |  Author(s): E.K. Cho, J.H. Kang, J. Han, J.S. Lee, D. Kim, S. Kim, Y.J. Min, K.H. Lee, J. Kim, K. Park

      • Abstract

      Background:
      Nivolumab (BMS-936558/ONO-4538), a fully human IgG4, PD-1 immune-checkpoint inhibitor antibody, has shown durable clinical activity in several tumor types. Recently, two phase III studies (CheckMate-017 and -057) demonstrated that nivolumab improved overall survival (OS) than docetaxel in second-line of squamous (SQ) and non-squamous (NSQ) Non-Small Cell Lung Cancer (NSCLC), respectively. Here, we report the results of a phase II study to evaluate the efficacy and safety of nivolumab in Korean patients (pts) with previously treated advanced SQ and NSQ NSCLC.

      Methods:
      This study requires pts aged ≥ 20 years with ECOG Performance Status (PS) of 0 or 1, stage IIIB/IV or recurrent NSCLC and at least one prior chemotherapy including platinum containing regimen. Pts received nivolumab 3 mg/kg IV Q2W until progression or unacceptable toxicity. The primary endpoint in this study was the objective response rate (ORR) (RECIST v1.1).

      Results:
      Nivolumab was administered to 100 NSCLC pts (SQ: 44, NSQ: 56), male/female: 78 (SQ: 44, NSQ: 34)/22 (SQ: 0, NSQ: 22); PS 0/1: 14 (SQ: 6, NSQ: 8)/86 (SQ: 38, NSQ: 48); aged 29 to 80 [median: 66.5] years (SQ: 40 to 80 [median: 69.5], NSQ: 29 to 77 [median: 63.5]); Stage IIIB/IV/recurrence: 6 (SQ: 5, NSQ: 1)/91 (SQ: 37, NSQ: 54)/3 (SQ: 2, NSQ: 1)). In SQ and NSQ NSCLC, ORR was 15.9% (7/44) and 23.2% (13/56), respectively. Median progression-free survival was 2.6 mo and 5.3 mo, respectively. Complete Response was observed in 2.3% (1/44) and 1.8% (1/56), respectively. Median OS was 12.3 mo and 16.3 mo, respectively. Median follow-up was 8.9 mo and 12.3 mo, respectively. Most common adverse drug reaction (ADR) was decreased appetite 15.9% (7/44), followed by pyrexia 9.1% (4/44) in SQ NSCLC, and decreased appetite 12.5% (7/56), followed by pruritus 10.7% (6/56), fatigue 8.9% (5/56), pyrexia 5.4% (3/56) and nausea 5.4% (3/56) in NSQ NSCLC. Grade 3-4 ADR was observed in 6.8% (3/44) and 10.7% (6/56) of SQ and NSQ NSCLC, respectively. No interstitial lung disease and no grade 5 ADRs were observed in this study.

      Conclusions:
      Nivolumab was considered to be effective and used safely in Korean pts with SQ and NSQ NSCLC as well as in non-Korean pts with SQ and NSQ NSCLC.

      Clinical trial identification:
      NCT02175017

      Legal entity responsible for the study:
      Ministry of Food and Drug Safety in Korea

      Funding:
      Ono Pharmaceutical

      Disclosure:
      J.H. Kang: Honoraria; Bristol-Myers Squibb, Boehringer Ingelheim Consulting or Advisory Role; Bristol-Myers Squibb, Amgen Research Funding; AstraZeneca, Lilly. K. Park: Consulting or Advisory Role; Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Lilly, Hanmi, Kyowa Hakko Kirin, Novartis, Ono Pharmaceutical, Roche, Speakers\' Bureau; Boehringer Ingelheim Research Funding: AstraZeneca. All other authors have declared no conflicts of interest.

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      115P - Immune related adverse events (irAE) and disease response with nivolumab in pre-treated advanced non-small cell lung cancer (NSCLC) (ID 428)

      12:30 - 12:30  |  Author(s): E. Connolly, G. Mallesara, I. Nordman

      • Abstract

      Background:
      IrAE with nivolumab are recognised. Incidence in practice and correlation with disease response in NSCLC has not been well characterised.

      Methods:
      A retrospective, descriptive analysis was carried out on 40 patients who received nivolumab on a compassionate access program from July 2015 to November 2016. Disease response was assessed by RECIST criteria.

      Results:
      The median age of patients was 63 years (range 28-80). 24 patients were female (60%). 17 received nivolumab as second line therapy, 12 as third line, 9 as fourth line, and 2 as fifth line. Best response included partial response (PR) in 15% (n = 6), stable disease (SD) in 40% (n = 16), progressive disease (PD) in 38% (n = 15) and unknown in 8% (n = 3). Treatment is ongoing in 30% (n = 12) (mean 6 months, range 2-18 months). 70% (n = 28) had irAE of any grade. Development of rash (n = 11; 28%) and pruritis (n = 10; 25%) were the most frequent irAE experienced. Grade 3 pruritus, pneumonitis, hepatitis, rash, arthralgia, and fatigue were seen. 2 patients developed grade 3 biopsy proven immune related colitis. Treatment requiring endocrinopathies occurred; hypothyroid (13%; n = 5), hyperthyroid (5%; n = 2) and hypoadrenal (5%; n = 2). Therapy was ceased due to grade 4 rash (n = 1), grade 3 hepatitis (n = 1), progressive neurological symptoms (n = 1) and psychiatric symptoms requiring hospital admission with no prior history of psychiatric illness (n = 1). The psychiatric and neurological symptoms resolved with treatment cessation and both patients have ongoing disease control on observation. A death occurred from suspected immune related hepatitis. Importantly, 5 of 6 patients who had PR developed grade 3 and above irAE. Of 13 patients who received treatment for greater than 3 months with SD, 11 developed irAE (85%). Of 10 patients on treatment for greater than 6 months with disease control (PR or SD); 7 developed grade 3 irAE or treatment requiring endocrinopathies. Of 10 non responders (PD within 3 months) 40% (n = 4) developed irAE; all grade 1. Clinically there appears to be a trend between response and development of irAE.

      Conclusions:
      The irAE are in line with published data however are of higher incidence and severity in this case series. There may be a trend of response and development of irAE.

      Clinical trial identification:
      not applicable

      Legal entity responsible for the study:
      Calvary Mater Newcastle

      Funding:
      Study conducted by Calvary Mater Newcastle. Nivolumab received on compassionate access programme from Bristol-Myers Squibb (BMS) however BMS have not been involved in data collection or interpretation.

      Disclosure:
      All authors have declared no conflicts of interest.

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      116P - A randomized study to evaluate safety of DCVAC/LUCA added to chemotherapy with carboplatin and pemetrexed vs. chemotherapy alone in patients with stage IV non-small cell lung cancer (ID 239)

      12:30 - 12:30  |  Author(s): H. Zhong, R. Zhong, B. Yan

      • Abstract

      Background:
      DCVAC/LuCa is an active autologous cellular immunotherapy consisting of autologous dendritic cells (DCs) loaded with NSCLC antigens (whole tumor cell antigens of tumor cell lines, like Her2/neu, MAGE-A3 and Survivin, et al.). DCVAC has the ability to induce an immune response, including cytotoxic CD8+ T cells, against tumor-associated antigens expressed by patients’ cancer cells. However, advanced-stage NSCLC with a heavy tumor burden establishes a harsh landscape for immunotherapy due to immune tolerance towards tumor antigens. Combination of DC treatment and chemotherapy is anticipated to achieve stronger immune responses than either of the treatments alone. AEs were collected in this study to evaluate the safety of DCVAC/LuCa added to chemotherapy with pemetrexed and carboplatin vs. chemotherapy alone in patients with stage IV non-small cell lung cancer.

      Methods:
      This is a randomized, open-label study. A total of 20 newly diagnosed stage IV, non-squamous, wild-type EGFR, ALK-negative or unknown NSCLC patients treated between January 2016- December 2016 in Shanghai Chest Hospital were enrolled.10 patients were randomized to group A: DCVAC/LuCa + chemotherapy (4-6 cycles of pemetrexed/carboplatin followed by pemetrexed as maintenance therapy); 10 patients were randomized to group B: 4-6 cycles of pemetrexed/carboplatin followed by pemetrexed as maintenance therapy.Patients in the group A started with DCVAC/LuCa (5 × 106 DCs/aliquots) treatment on Day 15 (+/- 3 days) of chemotherapy Cycle 3.The initial 5 doses of DCVAC/LCa were administered at a 3-week interval. The DCVAC/LuCa was then injected every 6 weeks up to the maximum number of 15 doses (75 × 106 DCs/15 aliquots). AEs were collected and analyzed.

      Results:
      The common adverse events in both group were chemotherapy related leukopenia, hemoglobin decrease etc. All AEs were grade 1 or 2 according to CTCAE V4.03, and there were no grade 4 toxicities or treatment-related deaths. One patient in group A got non-infectious fever and returned to normal without treatment.

      Conclusions:
      In patients with stage IV NSCLC, DCVAC/LuCa therapy was well tolerated with the favorable safety profile.

      Clinical trial identification:


      Legal entity responsible for the study:
      Shanghai Chest Hospital

      Funding:
      Sotio Medical Research (Beijing) Co., Ltd

      Disclosure:
      All authors have declared no conflicts of interest.

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      117P - Symptomatic pneumonitis in the irradiated lung after nivolumab: Three case studies (ID 295)

      12:30 - 12:30  |  Author(s): O. Roengvoraphoj, C. Eze, M. Li, F. Manapov

      • Abstract

      Background:
      Nivolumab is a feasible therapy option in patients with advanced NSCLC who progress after first-line conventional treatment. There is limited information about an overlapping toxicity of nivolumab when applied after primary multimodality treatment. Here, we describe symptomatic pneumonitis in the irradiated lung in patients undergoing second- or third-line nivolumab therapy.

      Methods:
      Case 1: A 66-year-old female patient who presented with squamous NSCLC stage ypT2a pN2 cM0 underwent adjuvant thoracic irradiation. Nivolumab was started 6 months’ post-radiotherapy when recurrent disease was detected on restaging CT. Twelve days after the first nivolumab treatment, the patient developed grade 2 dyspnea and cough.rnCase 2: A 76-year-old male patient with non-squamous NSCLC stage cT1a cN2 cM1b (single metastatic brain tumor) recieved intracranial stereotactic radiosurgery followed by thoracic RT to a total dose of 66Gy. Second-line nivolumab was started 6 months later and after the fourth cycle (70 days after the first nivolumab treatment), the patient developed grade 2 dyspnea and cough.rnCase 3: A 56-year-old female patient with metastatic NSCLC was treated with Cisplatin/Pemetrexed followed by irradiation to the brain and thorax. Due to systemic progression, second-line chemotherapy with docetaxel/nintedanib. Six months later, the patient was started on nivolumab. After 6 cycles (77 days after the first cycle of nivolumab), the patient developed grade 2 coughing and dyspnea.

      Results:
      In all patients comprehensive radiological and functional diagnostic as well as bronchoscopy were performed after onset of respiratory symptoms. Imaging analysis was strongly consistent with parenchyma changes in the irradiated lung volume receiving 15 to 20Gy. Nivolumab treatment was interrupted and patients were treated with systemic corticoids for one to two months with rash alleviation of symptoms.

      Conclusions:
      Three cases of symptomatic pneumonitis in patients with advanced NSCLC treated with nivolumab were described. Interruption of immunotherapy and systemic corticosteroid therapy for several weeks was necessary. Future prospective investigation of the described phenomenon is urgently indicated.

      Clinical trial identification:


      Legal entity responsible for the study:
      Deparment of Radiation Oncology LMU Munich

      Funding:
      N/A

      Disclosure:
      All authors have declared no conflicts of interest.

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      118P - Early onset of endocrine alterations during PD-1 blockade in advanced NSCLC patients (ID 381)

      12:30 - 12:30  |  Author(s): C.E. Onesti, A. Botticelli, M. Occhipinti, F.R. Di Pietro, I. Zizzari, C. Napoletano, M. Nuti, S. Lauro, F. Mazzuca, P. Marchetti

      • Abstract

      Background:
      Immune checkpoint inhibitors have been widely studied in recent years for solid tumors treatment, including lung cancer. Despite advantages observed in term of survival, new toxicities, such as endocrinopathies, have been observed. The most common are thyroid dysfunctions, hypophysitis and adrenal insufficiency. Diabetes mellitus and low level of testosterone are observed with anti-CTLA4 antibodies, but no data for anti-PD-1 and anti-PD-L1 are reported so far.

      Methods:
      Patients with histological diagnosis of squamous NSCLC, eligible for treatment with nivolumab, with ECOG PS 0-2 and adequate organs function were enrolled in our observational prospective study. All patients underwent blood sampling before starting treatment, after one and two months. All samples were analyzed for adeno-pituitary hormones (LH, FSH, ACTH, PRL, TSH) and for hormones secreted by target glands (FT3, FT4, 17-β-estradiol, testosterone, cortisol).

      Results:
      We enrolled 11 patients (6 M, 5 F; median age 65 y, range 44-82 y) affected by squamous NSCLC, receiving nivolumab in second line treatment. Three patients had hypothyroidism treated with levothyroxine in past medical history. The majority of patients (72.7%) showed endocrine alterations during treatment, three of which were symptomatic. Three males showed a reduction of testosterone level, in one case associated with decreased libido. A woman had a raised testosterone with hirsutism. Two patients experienced an increase in LH and FSH level and one patient a reduction. Moreover, we observed two cases of hyperthyroidism, one of which symptomatic in a patient with hypothyroidism in past medical history, two cases of increased ACTH level, one case of PRL reduction, one of 17-β-estradiol raise, one of cortisol reduction and one of cortisol raise. In all the cases endocrine alterations onset early during the treatment.

      Conclusions:
      We observe high rate of endocrine alterations in patients receiving nivolumab, in most cases asymptomatic. Many alterations observed are not usually evaluated and symptoms are often underestimated. More and wider studies could help to manage symptoms for a better quality of life and to investigate the mechanisms underlying endocrine disorders.

      Clinical trial identification:
      Not Applicable

      Legal entity responsible for the study:
      \"Sapienza\" University of Rome, Department of Medical Oncology

      Funding:
      \"Sapienza\" University of Rome, Department of Medical Oncology

      Disclosure:
      All authors have declared no conflicts of interest.

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      119P - A phase 2 randomized open-label study of ramucirumab (RAM) plus first-line platinum-based chemotherapy in patients (pts) with recurrent or advanced non-small cell lung cancer (NSCLC): Final results from squamous pts (ID 174)

      12:30 - 12:30  |  Author(s): S. Thomas, R.C. Doebele, D. Spigel, M. Tehfe, M. Reck, S. Verma, A. Zimmermann, E. Alexandris, P. Lee, P. Bonomi

      • Abstract

      Background:
      Vascular endothelial growth factor receptors (VEGFR) and their ligands are key regulators of angiogenesis and implicated in pathogenesis of NSCLC. RAM, a human IgG1 monoclonal antibody, specifically binds to VEGFR-2 thereby preventing receptor activation and angiogenesis. In a phase 2 trial (NCT01160744) addition of RAM to platinum-pemetrexed chemotherapy demonstrated clinical activity and acceptable safety in pts with advanced non-squamous NSCLC; here we report data from squamous (SQ) NSCLC pts treated with RAM in combination with first-line gemcitabine plus platinum chemotherapy.

      Methods:
      Eligible pts had Stage IV SQ NSCLC, ECOG PS ≤ 2, and no prior VEGF/VEGFR therapy nor chemotherapy for stage IV disease. Pts were randomized 1:1 into either Arm C: gemcitabine 1000 mg/m[2] + carboplatin AUC=5/cisplatin 75 mg/m[2] (GEM + Cb/Cis) or Arm D: ramucirumab 10 mg/kg + gemcitabine + carboplatin/cisplatin (RAM + GEM + Cb/Cis). Pts received first-line therapy from 4 to 6 cycles (21-day cycle); patients in Arm D, in absence of progressive disease, entered a maintenance phase with RAM alone. Primary objective was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), change in tumor size (CTS), duration of response and safety.

      Results:
      140 pts were randomized (GEM + Cb/Cis: 69; RAM + GEM + Cb/Cis: 71). The median PFS was 5.4 m GEM + Cb/Cis and 5.6 m for RAM + GEM + Cb/Cis; HR 0.88 (90% CI, 0.64, 1.22; p = 0.52). Median OS was 11.3 m for GEM + Cb/Cis and 10.4 m for RAM + GEM + Cb/Cis; HR 0.93 (90% CI, 0.68, 1.27; p = 0.68). ORR was significantly improved in RAM + GEM + Cb/Cis (46.5%) compared to GEM + Cb/Cis (24.6%) (p = 0.007). No statistically significant difference was observed in DCR and CTS between the two arms. Grade ≥ 3 adverse events occurring in > 10% of pts on RAM administered arm were: anemia, neutropenia and thrombocytopenia.

      Conclusions:
      The primary endpoint of PFS was not met. The addition of RAM to GEM + Cb/Cis significantly improved ORR in pts with SQ NSCLC with no new unexpected safety findings.

      Clinical trial identification:
      NCT01160744 JVBL

      Legal entity responsible for the study:
      Eli Lilly and Company, Indianapolis, IN

      Funding:
      Eli Lilly and Company, Indianapolis, IN

      Disclosure:
      R.C. Doebele: Grants from Ignyta, Threshold Pharmaceuticals, Strategia; patent from NTRK1 FISH; royalties paid to Abbott Molecular; Licensing fees for biologic materials Ariad, Loxo, Chugai, Blueprint Medicines; other from Ariad, Trovagene, Guardant Health, AstraZeneca. D. Spigel: Novartis Speakers Bureau (uncompensated). M. Tehfe: Advisory board committee and Honoraria for speaker: Lilly, Celegene, BMS, Merck. M. Reck: Personal fees from Boehringer-Ingelheim, Hoffmann-La Roche, Lilly, MSD, BMS, AstraZeneca, Celgene, Merck, Pfizer, outside the submitted work. A. Zimmermann, E. Alexandris, P. Lee: Employee and stockholder of Eli Lilly and Company. P. Bonomi: Personal fees from Eli Lilly, Roche Genentech, Pfizer, Celgene, Bristol Myers Squibb, Astra Zeneca, Merck, outside the submitted work. All authors have declared no conflicts of interest.

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      120P - Subgroup analysis of adenocarcinoma patients refractory to first-line chemotherapy from REVEL: A randomized phase III study of docetaxel with ramucirumab or placebo for second-line treatment of stage IV non–small cell lung cancer (NSCLC) (ID 423)

      12:30 - 12:30  |  Author(s): M. Reck, L. Paz-Ares, D. Moro-Sibilot, F.A. Shepherd, F. Cappuzzo, K.B. Winfree, E. Alexandris, A. Sashegyi, R. Varea, M. Pérol

      • Abstract

      Background:
      In the phase III REVEL trial, ramucirumab plus docetaxel significantly improved median overall survival (OS), median progression-free survival (PFS), and objective response rate (ORR) in patients with advanced NSCLC who progressed after first-line platinum therapy, independent of histology. The REVEL trial also showed that ramucirumab plus docetaxel therapy improved median OS, median PFS, and ORR in adenocarcinoma patients who were refractory to first-line platinum therapy and in patients categorized as rapid progressors. Here, we report safety and quality of life (QoL) outcomes in refractory adenocarcinoma patients who participated in the REVEL trial.

      Methods:
      Patients were refractory if they had a best response of progressive disease to first-line treatment. Patients were randomized 1:1 to receive docetaxel 75 mg/m[2] in combination with either ramucirumab 10 mg/kg or placebo every 21 days until disease progression, unacceptable toxicity, or death. Treatment-emergent adverse events (TEAEs) were assessed according to the NCI-CTCAE, version 4.0. Quality of life was measured by the Lung Cancer Symptom Scale (LCSS).

      Results:
      Of the 1253 patients randomized (ramucirumab + docetaxel: 628; docetaxel + placebo: 625), 17% (ramucirumab + docetaxel: 9%; docetaxel + placebo: 8%) were adenocarcinoma patients refractory to first-line therapy. The safety overview and LCSS scores are presented in the table.rnTable: 120PSafety and QoL Outcomes of Refractory Adenocarcinoma Patients Treated in REVELrn

      rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn
      TEAEs, n (%)Ramucirumab + Docetaxel N = 111Placebo + Docetaxel N = 101
      Any TEAE108 (97)101 (100)
      Grade ≥3 TEAEs82 (74)73 (72)
      Serious TEAEs47 (42)48 (48)
      TEAEs leading to discontinuation6 (5)4 (4)
      TEAEs leading to death4 (4)11 (11)
      LCSS scores, time to deteriorationHazard Ratio (95% CI)
      Loss of appetite1.45 (0.91, 2.32)
      Fatigue0.90 (0.58, 1.41)
      Cough1.29 (0.77, 2.14)
      Dyspnea1.06 (0.64, 1.76)
      Hemoptysis1.55 (0.59, 4.07)
      Pain1.14 (0.71, 1.84)
      Symptom distress1.12 (0.69, 1.81)
      Activity level1.01 (0.64, 1.59)
      Global QoL0.98 (0.63, 1.52)
      Total LCSS0.81 (0.47, 1.41)
      ASBI0.83 (0.46, 1.50)
      rnNote: The primary LCSS analysis was time to deterioration, defined as the time from randomization to the first 15 mm increase. ASBI, average symptom burden index; CI, confidence interval; LCSS, Lung Cancer Symptom Scale; QoL, quality of life; TEAE, treatment-emergent adverse event.rn

      Conclusions:
      Our analysis did not identify any new safety concerns or increased detriment in QoL for this subgroup of patients. Safety outcomes for refractory adenocarcinoma patients were consistent with the outcomes for refractory patients with all histologies and the intent-to-treat population.

      Clinical trial identification:
      NCT01168973

      Legal entity responsible for the study:
      Eli Lilly and Company

      Funding:
      Eli Lilly and Company

      Disclosure:
      M. Reck: Personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Hoffmann-La Roche, Merck Sharp & Dohme, Novartis, and Pfizer. L. Paz-Ares: Personal fees from AMGEM, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, CLOVIS, Eli Lilly and Company, Hoffmann-La Roche, Merck Sharp & Dohme, Novartis, and Pfizer. D. Moro-Sibilot: Personal fees from AMGEN, Ariad, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Hoffmann-La Roche, Merck Sharp & Dohme, Novartis, and Pfizer. F.A. Shepherd, M. Pérol: Personal fees from Eli Lilly and Company. F. Cappuzzo: Personal fees from AstraZeneca, Hoffmann-La Roche, and Pfizer. K.B. Winfree: Employee of Eli Lilly and Company and reports personal fees from Eli Lilly and Company. E. Alexandris: Employee of Eli Lilly and Company. A. Sashegyi, R. Varea: Employee and shareholder of Eli Lilly and Company.

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      121P - Safety and efficacy of bevacizumab in "fragile" patients with advanced non-small cell lung cancer (ID 492)

      12:30 - 12:30  |  Author(s): C. Maragkos, D. Grapsa, G. Koumakis, A. Polyzos, K. Syrigos

      • Abstract

      Background:
      Bevacizumab is the first antiangiogenic agent approved for treatment of advanced non-squamous NSCLC. Elderly or other “fragile” patients, such as those with poor performance status (PS), comprise the majority of the NSCLC population, but are typically underrepresented in clinical trials. The primary aim of this study was to investigate the efficacy and safety of first-line bevacizumab in “real-world” patients with advanced NSCLC.

      Methods:
      The medical records of all patients with histologically or cytologically confirmed advanced-stage non-squamous NSCLC, treated with first-line bevacizumab (plus chemotherapy) at the Oncology Clinic of “Sotiria” Athens University Hospital between January 2008 and December 2012 were retrospectively reviewed. Selected patients were stratified according to age, i.e. elderly (> 70 years) vs non-elderly (≤70 years), ECOG PS (0-1 vs 2-3) and other demographic, clinicopathological and treatment data. Main outcome measures were overall survival (OS) and treatment-related toxicity.

      Results:
      A total of 145 cases (mean age/SD=61.7 ± 10.6 years) were included. 23,4% of patients were elderly, while 15.8% had poor PS (2-3). Maintenance bevacizumab (with or without pemetrexed) was administered in 24.1% of all cases, including only patients with good PS, and mainly non-elderly. The presence of comorbidities was significantly associated with poor PS and age> 70 years. No statistically significant difference with regard to OS, or type and frequency of side effects was observed between elderly and non-elderly patients. A similar toxicity profile was also observed between patients with good versus poor PS. Absence of maintenance bevacizumab and poor PS were both significantly associated with reduced OS, both in univariate [HR (95% CI): 0.45 (0.22-0.9); p = 0.023 and HR (95% CI): 2.16 (1.29-3.64); p = 0.004, respectively] and in multivariate analysis [[HR (95% CI): 0.47 (0.22-0.99); p = 0.048 and HR (95% CI): 1.76 (1.04-3.00); p = 0.036, respectively].

      Conclusions:
      Our findings suggest that first-line bevacizumab may show similar efficacy and toxicity in elderly versus non-elderly patients with advanced NSCLC. Further prospective data are needed to confirm these observations.

      Clinical trial identification:


      Legal entity responsible for the study:
      University of Athens

      Funding:
      University of Athens

      Disclosure:
      All authors have declared no conflicts of interest.

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      122P - Response to Metabolically Supported Chemotherapy (MSCT) with weekly carboplatin/paclitaxel in advanced stage/metastatic (Stage IV) non-small cell lung cancer: A survival, efficacy and tolerability analysis (ID 184)

      12:30 - 12:30  |  Author(s): M.S. Iyikesici, A. Slocum, A.K. Slocum, E. Turkmen, F.B. Berkarda

      • Abstract

      Background:
      Metabolically supported chemotherapy (MSCT), is defined as the application of standard chemotherapy protocols concomitant to the administration of pharmacological doses of regular insulin and the development of hypoglycemia, and following fasting starting the previous day. This study aims to evaluate the efficacy and the tolerability of MSCT combining carboplatin and paclitaxel in the treatment of advanced/metastatic non-small cell lung cancer (NSCLC).

      Methods:
      This study is a retrospective single center analysis of all patients diagnosed with metastatic (stage IV) NSCLC that received MSCT combining carboplatin and paclitaxel at our clinic between March 2010 and June 2015.

      Results:
      44 patients were included in our study. While 39 (88.6%) of the patients were male, their median age was 65 years (range 35-87). Adenocarcinoma was diagnosed in 34 (77.3%) of the patients. 18 (40.9%) of the patients had brain metastases and ECOG PS was ≥2 in the case of 36 (81.8%) of the patients. When the response evaluation for this study was carried out at the end of 6 cycles of treatment, 42 out of 44 patients included in this analysis remained alive. Statistical analysis revealed a mean overall survival (OS) of 43.4 months, mean progression-free survival (PFS) of 41.8 months and 1-year survival rate of 86.1%.

      Conclusions:
      This study demonstrates that a metabolically supported form of applying weekly paclitaxel at a dose of 75 mg/m[2] combined with weekly carboplatin at a dose of AUC 2 may bring about remarkable improvements in the survival rates of patients with advanced and metastatic NSCLC.

      Clinical trial identification:


      Legal entity responsible for the study:
      Kemerburgaz University Bahcelievler Medical Park Hospital and ChemoThermia Oncology Center

      Funding:
      N/A

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      123P - A retrospective study in Chinese patients: Is there a role of nanoparticle albumin bound paclitaxel in advanced NSCLC? (ID 393)

      12:30 - 12:30  |  Author(s): Y. Zhu, P. Xing, L. Shan, S. Chen, X. Hao, J. Li

      • Abstract

      Background:
      We aimed to report the safety and short-term efficacy of nanoparticle albumin bound paclitaxel (Nab-PTX) in advanced non-small cell lung cancer (NSCLC) in Chiina as a second line and later treatment, and explored its efffcacy affected by previous paclitaxel treatment wether or not.

      Methods:
      Advanced NSCLC patients who failed in prior treatment and received weekly Nab-PTX regimen on days 1, 8 (a dose of 130 mg/m2/week) treatment were included. The primary efficacy endpoint was progression-free survival (PFS). Toxicity was evaluated with NCI-CTCAE 3.0.

      Results:
      A total of 98 patients at the Cancer Institute & Hospital of the Chinese Academy of Medical Sciences (Beijing, China) between June 2010 and July 2015 were enrolled. The median PFS and overall survival (OS) were 4.34 months (95% CI 3.508 to 5.165 months) and 11.73 months (95% CI 9.211 to 14.247 months), respectively. PFS was no significant difference between patients with previous paclitaxel treatment and without previous paclitaxel treatment (median, 4.11 versus 4.53 months, respectively, p = 0.195). OS was also no significant difference between the two arms (median, 9.69 versus 14.62 months, respectively, p = 0.190). The objective responses rate (ORR) and disease control rate (DCR) of all patients were 22.4% and 74.5%, respectively. The ORR and DCR were 23.0% and 70.5%, respectively in one arm with previous paclitaxel treatment, while in another arm without previous paclitaxel treatment, the results were 21.6% and 81.1%. No significant difference in ORR (p = 0.533) and DCR (p = 0.244) between the two arms. Grade 3 or higher adverse events (AEs) of all patients was neutropenia (25.5%), leukopenia (12.4%), peripheral neuropathy (5.1%), myalgia/arthralgia (5.1%), anaemia (3.1%), and fatigue (1.0%), respectively.

      Conclusions:
      The Nab-PTX was effective and well tolerated as second line or later treatment in advanced NSCLC patients. Even used paclitaxel treatment previously did not affect the efficacy and PFS of Nab-PTX.

      Clinical trial identification:
      Preview and Finish

      Legal entity responsible for the study:
      Junling Li

      Funding:
      Junling Li

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      124P - Driverless lung carcinoma: Impact of expanded RNA and protein-based testing on detection of actionable biomarkers (ID 396)

      12:30 - 12:30  |  Author(s): Z. Gatalica, J. Xiu, W. Chen, T. Maney, A. Voss, N. Plowman

      • Abstract

      Background:
      In recent years, massively parallel-gene sequencing (NGS) has improved the detection of targetable mutations in lung cancer (NSCLC). We have identified NSCLC cases that, despite extensive DNA sequencing and targeted in-situ hybridizations (ISH) for ROS1, ALK and cMET alterations, have no druggable target or conventional lung cancer pathogenic mutation identified ("driverless" cancer). Expanded platform testing (RNA and protein-based) was performed on these driverless cases in order to assess the ability of these technologies to identify actionable drug targets.

      Methods:
      A review of 522 NSCLC cases (Caris Life Sciences, Phoenix, AZ) tested with NGS (592 gene sequencing panel, Agilent SureSelectXT; Illumina NextSeq) and ISH yielded 21 patients (F:M=12:9) without characteristic genetic alterations. Expanded testing included an RNA-based fusion panel (52 genes, Archer FusionPlex) and protein-expression (IHC) testing for EGFR, TS and PD-L1.

      Results:
      Expanded platform profiling identified targetable NTRK gene fusions (NTRK3:ETV6 and NTRK1:TPM3) in 2 cases and c-MET exon 14 skipping in 1 case. IHC identified PD-L1 expression in 7 (3 low and 4 high TPS), EGFR over-expression (H-score>200) in 7, and TS under expression in 13 cases. Initial NGS panel identified 2 low allele frequency pathogenic mutations (PIK3CA and GNAS), and 3 gene amplifications (MDM2, CDK4 and CDKN2A), as potential non-characteristic drivers in 4 cases. Total mutational load (TML) range was 1-10/Mb (mean 5.2/Mb).

      Conclusions:
      With the routine use of NGS a small proportion of cases (4.2%) remain without standard biomarker-guided therapy recommendation. They are characterized by a lower TML (5.2/Mb) than reported for NSCLC (e.g. TCGA mean: 8.9/Mb). A significant benefit from expanded multiplatform testing (RNA- and protein-based) included detection of biomarkers for immune check point inhibitors (33% eligible) and targeted therapies (23% eligible: NTRK and c-Met inhibitors). Over-expression of EGFR and under expression of TS (57% and 72%. respectively) could provide additional information for therapy guidance in specific cancer types.

      Clinical trial identification:
      Not applicable

      Legal entity responsible for the study:
      Caris Life Sciences

      Funding:
      Caris Life Sciences

      Disclosure:
      Z. Gatalica, A. Voss: Employment: Caris Life Sciences. J. Xiu, W. Chen, T. Maney: Employment: Caris LIfe Sciences. All other authors have declared no conflicts of interest.

    • +

      125P - Clinical research platform into molecular testing, treatment and outcome of non-small cell lung carcinoma Patients (CRISP): A prospective German registry in stage IV NSCLC, AIO-TRK-0315 (ID 388)

      12:30 - 12:30  |  Author(s): F. Griesinger, W.E.E. Eberhardt, N. Marschner, M. Jänicke, A. Fleitz, J. Sahlmann, A. Karatas, A. Hipper, M. Sebastian, M. Thomas

      • Abstract

      Background:
      Treatment in NSCL is quickly evolving and new agents make it to the routine practice at a rapid pace. Whether outcome and PRO data generated in clinical trials with often narrow inclusion and exclusion criteria will hold up in the routine practice is of high interest, especially due to the increasing costs of new drugs. Therefore, registry data are of ever increasing importance to patients, physicians and reimbursement institutions.

      Methods:
      Therefore, we have started a prospective, clinical registry for patients with metastatic NSCLC. The purpose of CRISP is to set up a national clinical research platform to document representative data on molecular testing, sequences of systemic therapies and other treatment modalities, course of disease in patients with advanced or metastatic NSCLC in Germany not amenable to curative treatment. A particular focus is on molecular biomarker testing of patients before the start of 1[st] -line treatment. The data shall be used to assess the current state of care and to develop recommendations concerning topics that could be improved. PRO assessment will provide large-scale data on quality of life and anxiety/depression for real-life patients in routine practice. In addition, two questionnaires (concerning individual quality of life and patient-caregiver communication) will be validated in German patients with metastatic NSCLC. Furthermore, CRISP will set up a decentral tissue annotation for future collaborative, investigational scientific biomarker testing. This study will be carried out in up to 150 representative cancer centers in all therapeutic sectors in Germany. More than 8000 patients will be recruited and followed up to a maximum of 3 years, respectively until death.

      Results:
      The first patients have been included in Dec. 2015. As of Jan. 2[nd] 2017, 71 centers are recruiting patients and 529 patients have been recruited. Preliminary data will be presented at the meeting for molecular testing, demographic data as well as treatment stratification in the 1[st] line setting.

      Conclusions:
      The registry CRISP will be the first to present representative real life data, covering all treatment settings of patients with NSCLC in Germany.

      Clinical trial identification:
      NCT02622581

      Legal entity responsible for the study:
      AIO-Studien-gGmbH

      Funding:
      CRISP is supported by Grants from AstraZeneca GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Bristol-Myers Squibb GmbH & Co. KGaA, Celgene GmbH, Lilly Deutschland GmbH, MSD Sharp & Dohme GmbH, Novartis Pharma GmbH, and Pfizer Pharma GmbH.

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      126P - The clinical impact of multiplex ctDNA gene analysis in lung cancer (ID 476)

      12:30 - 12:30  |  Author(s): S. Geva, T. Twito, A. Dvir, L. Soussan-Gutman, M. Ilouze, L.C. Roisman, E. Dudnik, A. Zer, R.B. Lanman, N. Peled

      • Abstract

      Background:
      Next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) enables a non-invasive option for comprehensive genomic analysis of lung cancer patients. In this study, we evaluated the clinical utility of ctDNA sequencing on treatment strategy.

      Methods:
      In this retrospective study, data was collected from files of 109 NSCLC patients at the Thoracic Cancer Unit at Rabin Medical Center, Israel, between 2014-2017. Plasma samples from advanced non-small cell lung cancer (NSCLC) patients were analyzed by a commercial test (Guardant 360[TM]), using massively parallel paired-end synthesis to sequence a targeted gene panel. This test allows the detection of somatic alterations such as point mutations, indels, fusions and copy number amplifications.

      Results:
      109 consecutive NSCLC patients were included in this study. Median age at diagnosis was 63 years, 81% had adenocarcinoma. 39% (43/109) performed ctDNA analysis before 1[st] line therapy (Group A) and 61% (66/109) on progression (Group B), among them 42% (28/66) after progression on EGFR TKI (Group B1). ctDNA analysis yielded lung cancer related actionable mutations in 40% (44/109) of the patients; 32% (14/43) in group A and 45% (30/66) in group B; 71% (20/28) in group B1. Treatment decision was taken toward targeted therapy subsequent to NGS analysis in 27% of patients. 68 individual actionable genomic alterations were found (table).rnTable: 126PGenetic alterations frequencies among groups A, B and B1rn

      rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn
      Group A: Upfront NGS (n = 43, 19 individual mutations)Group B: NGS on progression (n = 66, 49 individual mutations)Group B1: NGS on progression on EGFR TKIs (n = 28, 34 individual mutations)
      EGFR Sensitizing52% (10/19)EGFR Sensitizing45% (22/49)EGFR Sensitizing59% (20/34)
      MET16% (3/19)MET25% (12/49)EGFR T790M23% (8/34)
      ERBB210.5% (2/19)EGFR T790M16% (8/49)MET12% (4/34)
      BRAF V600E10.5% (2/19)RET6% (3/49)ERBB23% (1/34)
      RET10.5% (2/19)ERBB26% (3/49)ALK3% (1/34)
      rnrnALK2% (1/49)rnrn
      rnrnResponse assessment (RECIST) for 20 patients with evaluable response to targeted therapy showed complete response in 5% (1/20), partial response in 35% (7/20), stable disease in 25% (5/20) and progressive disease in 35% (7/20). Response rate was 20% (1/5) for group A, 47% (7/15) for group B, among them 67% (6/9) for group B1. Total objective response rate (ORR) was 40%.

      Conclusions:
      Comprehensive ctDNA testing revealed possible treatment options for 40% of patients analyzed. The highest impact was seen in the progressors on EGFR therapy. These positive results emphasize the utility of liquid biopsy analysis to guide clinicians to select the right therapy for the right patient.

      Clinical trial identification:


      Legal entity responsible for the study:
      Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petach Tikva, Israel.

      Funding:
      Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petach Tikva, Israel.

      Disclosure:
      S. Geva: Travel grant from Teva Pharmaceuticals. Honorarium from Guardant Health, Inc. T. Twito, A. Dvir, L. Soussan-Gutman: Employee of Oncotest (subsidiary of Teva pharmaceuticals), the distributor of Guardant360 in Israel. E. Dudnik: Consultant of BI. Honorary lectures for BI, Roche, AstraZeneca and MSD. R.B. Lanman: Employee with stock ownership in Guardant Health, Inc. N. Peled: Consultant for Pfizer, BI, Roche, AZ, MSD, BMS, Lilly, Novartis, and NovellusDx. All other authors have declared no conflicts of interest.

    • +

      127P - Prognostic significance of advanced lung cancer inflammation index (ALI) In untreated and treated stage IV non-small cell lung cancer (NSCLC): An Australian cancer centre experience (ID 172)

      12:30 - 12:30  |  Author(s): H. Mandaliya, M. Jones, C. Oldmeadow, I. Nordman

      • Abstract

      Background:
      The role of advanced lung cancer inflammation index (ALI) at diagnosis is increasingly explored as an independent prognostic factor of survival in stage IV NSCLC. Post-treatment changes in ALI and the potential impact on survival are not clear in this group of patients. We aimed to evaluate prognostic role of ALI in stage IV NSCLC at diagnosis as well as post treatment.

      Methods:
      A retrospective descriptive study was conducted for patients with stage IV NSCLC actively treated at Calvary Mater Newcastle, Australia from 2010 to 2015. Advanced lung cancer inflammation index (ALI = BMI x Albumin/NLR; BMI=Body mass index, NLR=Neutrophil-to-lymphocyte ratio, Albumin=Serum albumin g/dl) values calculated at diagnosis and post first cycle chemotherapy/targeted treatment. Demographic variables summarised and estimates of Kaplan-Meier (KM) survival distribution for overall survival (OS) generated. Extended Cox regression used to derive OS hazard ratios of predictive variables. Project approved by Research Ethics Committee.

      Results:
      A total of 279 patients with Stage IV NSCLC were treated during the study time. Baseline ALI was available for 276 patients and post first treatment cycle for 189 patients. The Cox PH model suggested ALI was a prognostic factor for OS, hazard ratio = 0.982 (95% CI: 0.973-0.991). Post first-cycle treatment, individuals with mean baseline ALI, had a hazard ratio = 0.391 (95% CI: 0.211-0.629) that was also increasing multiplicatively as a function of baseline ALI. At baseline, KM estimate suggested median survival was 6.23 months (95% CI: 4.83-9.27) for patients with ALI < 18 compared to 14.70 months (95% CI: 11.63-18.20) for those with ALI > 18. Post first-cycle treatment, not adjusted for baseline, patients with ALI < 18 median survival was 5.23 months (95% CI: 3.27-9.07) compared to 12.67 months (95% CI: 10.47-15.13) for ALI > 18.

      Conclusions:
      ALI has a strong association with survival from baseline and post first-cycle treatment adjusted for baseline ALI. High pretreatment and post treatment ALI predicts for a longer survival while low pretreatment and post treatment ALI predicts for a shorter survival.

      Clinical trial identification:


      Legal entity responsible for the study:
      Hunter New England Human Research Ethics Committee

      Funding:
      Department of Medical Oncology, Calvary Mater Newcastle, Australia Hunter Medical Research Institute, Australia

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      128P - Serum DKK-1 as a clinical and prognostic factor in non-small cell lung cancer patients with bone metastases (ID 192)

      12:30 - 12:30  |  Author(s): R. Qiao, T. Chu, B. Han, R. Zhong, Q. Chang, J. Teng, J. Pei

      • Abstract

      Background:
      The Wnt/β-catenin pathway plays a crucial role in tumor pathogenesis, specifically in cell proliferation, angiogenesis, motility and invasiveness. The activity of Wnt family ligands is antagonized by several secreted factors including Dickkopf (DKK). A member of the Dickkopf family, DKK-1, is a 35 kDa secreted protein that is a potent inhibitor of Wnt/β-catenin signaling. The study was designed to evaluate the association between serum Dickkopf-1(DKK-1) and non- small cell lung cancer(NSCLC) bone metastases.

      Methods:
      Serum DKK-1and CEA levels were quantified in 318 NSCLC patients, 140 with osseous metastases and 178 with extraosseous metastases. We used receiver operating characteristics (ROC) to evaluate the predictive qualities of these parameters for bone metastases.

      Results:
      Serum DKK-1 levels were significantly higher in patients with osseous metastases compared with patients with extraosseous metastases (P < 0.001). ROC curves showed that the optimum cutoff was 311.8 ng/ml (area under curve [AUC] 0.791, 95% confidence interval [CI] 0.739–0.843, sensitivity 77.1% and specificity 71.4%). ROC analysis also showed that testing both DKK-1 and CEA increased the detection accuracy for NSCLC bone metastases compared with CEA alone (AUC 0.797, 95% CI 0.746–0.848, sensitivity 82.9% and specificity 68.9%; DKK-1 plus CEA vs. DKK-1 alone P = 0.370; DKK-1 plus CEA vs. CEA alone P = 0.0001). Thus, serum DKK-1 correlated with the number of bone lesions (P = 0.042). In osseous metastases group, Kaplan–Meier analysis showed that patients with high serum DKK-1 levels had poorer overall survival than patients with low serum DKK-1 levels (P = 0.025), and multivariable analyses showed serum DKK-1 to be an independent prognostic factor for overall survival (P = 0.029).

      Conclusions:
      Our data shows that serum DKK-1 levels are increased in NSCLC patients with bone metastases. More importantly this is the first report to show that high serum DKK-1 levels are associated with the extent of bone metastases and poor survival in NSCLC patients with bone metastases.

      Clinical trial identification:


      Legal entity responsible for the study:
      Shanghai Chest Hospital

      Funding:
      The Science and Technology Development Fund of Shanghai Chest Hospital (Grant No. 2014YZDC10101)

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      129P - Procathepsin D as a novel diagnostic marker for malignant pleural effusion of lung cancer (ID 341)

      12:30 - 12:30  |  Author(s): C.Y. Lee, J.Y. Hong, M. Lee, S.H. Jang

      • Abstract

      Background:
      Approximately 20% of pleural effusions are due to malignancy, and 50% of these are due to primary lung cancer. However, the etiology of the effusions is often obscure and various diagnostic procedures may be required in order to find their cause. Cathepsin D (CD) as a lysosomal aspartic protease is one of the most important intracellular enzymes considered to be substantially involved in tumor invasion. Procathespin D (pCD) is overexpressed and secreted by cells of various tumor types. The aim of this study is to evaluate the serum and pleural fluid levels of CD and pCD as a differential diagnostic tool in patients with pleural effusion caused by malignant or benign process.

      Methods:
      Patients and pleural fluid collection: The present study included 85 patients (40 patients with lung cancer, 30 patients with tuberculosis, 10 patients with parapneumonic effusion, 5 patients with transudate effusion) who underwent thoracentesis and pleural biopsy. Clinical and pathology data, including tumor type were acquired for all patients. Analysis of CD and pCD: Amounts of CD in the pleural fluid and serum were determined with a cathepsin D ELISA kit and pCD with a sandwich ELISA method.

      Results:
      Concentration of pleural CD was not significantly different in patients with malignant pleural effusion compared with non malignant effusion (mean 13.34 vs. 16.72 ng/ml; p > 0.05), and also the concentration of serum CD was not significantly different (mean 41.34 vs. 36.52 ng/ml; p > 0.05). Plasma pCD of malignant pleural effusion and non malignant effusion were 42.03 ng/ml and 38.59 ng/ml, respectively (p > 0.05) but pleural pCD of malignant pleural effusion and non malignant effusion were 84.24 ng/ml and 33.82 ng/ml, respectively with significance (p < 0.05).

      Conclusions:
      In this small cohort, the pleural pCD of lung cancer patients showed elevated levels compared with that of non malignant effusion. The pleural fluid levels of pCD could be a diagnostic marker of malignant effusion with lung cancer and further prospective studies might shed more light on the value of CD and pCD in the diagnostics of pleural effusion.

      Clinical trial identification:


      Legal entity responsible for the study:
      Chang Youl Lee

      Funding:
      Hallym University Medical Center

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      130P - EGFR mutations in lung adenocarcinoma and brain metastases: A Croatian single institution experience (ID 512)

      12:30 - 12:30  |  Author(s): K.B. Sreter, S. Kukulj, S. Smojver-Jezek, S. Seiwerth, M. Jakopovic, M. Samarzija

      • Abstract

      Background:
      The brain, bones and lungs are common sites of metastasis in non-small cell lung cancer. We aimed to investigate the metastatic pattern of epidermal growth factor receptor (EGFR) mutations by analyzing the incidence of different metastatic sites in EGFR positive (+) lung adenocarcinoma patients with brain metastases (BM).

      Methods:
      Data from medical records at the Clinic for Respiratory Diseases "Jordanovac" were collected for this retrospective cohort study. Caucasian Croatian patients with primary lung adenocarcinoma (PLA) and EGFR+ mutation status (2014-2015) were included.

      Results:
      Of 116 EGFR+ patients, 24 (21.0%) were diagnosed with BM. The majority of EGFR+ patients (n = 17, 70.8%) were less than 65 years old at BM diagnosis. There were fewer males (n = 4, 16.7%) than females. Only four patients (all female, 16.7%) were active smokers at diagnosis of PLA. Median age at diagnosis of BM was 62 years (range: 43-78 years). Most patients (n = 20, 83.3%) had good performance status (PS, ECOG 0-1) and normal to increased body mass index (n = 17, 70.8%). Weight loss at presentation was reported by 10 patients (41.6%). The majority (n = 16, 66.7%) initially presented to the emergency department. In 8 patients (33.3%), symptoms related to BM appeared prior to or at the same time as the PLA. Oral tyrosine kinase inhibitor (TKI) treatment was received in second line (n = 8, 33.3%) after progression of disease following first line chemotherapy. Most patients with multiple BM (n = 18, 75.0%) received whole brain palliative radiotherapy; three could not due to poor PS. The main extracranial sites of metastases were bone (n = 16, 66.7%), liver (n = 7, 29.2%) and pleura (n = 19, 79.2%). The most common EGFR mutations were single exon 19 deletion (n = 13, 54.2%) and exon 21 L858R (n = 5, 20.8%). One patient (4.2%) had a double mutation (exon 19 and 21) and another (4.2%) had a rare single exon 18 mutation. Exon 20 T790M mutation occurred in 16.7% of patients (n = 4). The median overall survival (mOS) was 7.7 months versus 20.1 months from time of diagnosis of BM versus from PLA, respectively.

      Conclusions:
      Early diagnosis of BM and extracranial metastases in EGFR mutant PLA patients is key to improving clinical outcomes, quality of life, and overall survival.

      Clinical trial identification:


      Legal entity responsible for the study:
      University Hospital Centre Zagreb, Clinic for Respiratory Diseases \"Jordanovac\"

      Funding:
      N/A

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      131P - T790M co-exists with other secondary resistance mechanisms in EGFR mutation positive NSCLC and are associated with inferior outcomes (ID 159)

      12:30 - 12:30  |  Author(s): R. Teng, A. Takano, W. Tan, M. Ang, C. Toh, Q. Ng, W. Lim, E. Tan, T. Lim, D.S. Tan

      • Abstract

      Background:
      Compared to conventional chemotherapy, NSCLC adenocarcinoma patients with EGFR-activating mutations (M+) have superior response to EGFR TKIs. However, all patients develop acquired resistance (AR) to TKIs, most commonly through T790M mutation. Due to intratumour heterogeneity, additional non-T790M mechanisms of AR could coexist with the T790M mutation. Little is known about the prevalence and clinical outcomes of patients with co-existing mechanisms of AR.

      Methods:
      145 patients with EGFR M+ NSCLC underwent a repeat biopsy after developing AR to TKI therapy. All specimens underwent histological review, while 116 (80%) underwent molecular profiling with multiple parallel high-sensitivity assays (including a 29-gene NGS panel) to detect genetic aberrations linked to TKI resistance. Kaplan Meier survival curves were plotted and compared with the log-rank test.

      Results:
      53.4% TKI-resistant patients (n = 57/106) were T790M-positive, while 61% patients had a non-T790M mechanism of AR including CMET polysomy or amplification, PTEN Loss, PIK3CA substitution and small cell change. 10 patients had lost their original EGFR-activating mutation. Up to 42% (n = 34/80) had a mutation in an NSCLC driver gene (including BRAF, DDR2, NRAS) detected by a 29-gene panel. 51% patients treated with 1[st]-generation gefitinib or erlotinib (n = 101) were T790M-positive, compared to only 20% of patients treated with 2[nd]-generation afatinib (n = 15). There was also a difference (p = 0.071) in T790M prevalence between patients treated with TKI post-progression (37/67, 55%) and those treated with chemotherapy (15/41, 36.5%). Notably, almost half the T790M-positive subjects harboured co-existing non-T790M mechanisms of AR (28/57, 49.1%). These patients had inferior OS of 42 months (95% CI 36.9-47.1) compared to patients with solely T790M (58 months, 95% CI 36.5-132.8).

      Conclusions:
      While T790M is widely-accepted as the predominant mechanism of AR, the spectrum of mutations can vary greatly depending on the type of prior therapy. Moreover, other mechanisms of AR could coexist with T790M and portend inferior clinical outcomes, suggesting that targeting other mechanisms of AR beyond T790M may be clinically-relevant.

      Clinical trial identification:


      Legal entity responsible for the study:
      Ministry of Health Singapore

      Funding:
      National Cancer Centre Singapore

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      132P - Real world treatment patterns and outcomes for mNSCLC patients receiving second and third-line therapy in Germany (ID 349)

      12:30 - 12:30  |  Author(s): N. Yu, I. Reyes-Rivera, J. Hipp, M. Zou, N. Pillai, S. Hammerschmidt

      • Abstract

      Background:
      Metastatic non-small cell lung cancer (mNSCLC) is the leading cause of cancer death worldwide. Recent approvals of targeted therapies, especially immunotherapies, may change the treatment landscape, but little is known about their real-world impact. This study (MO39087) assessed real world treatment patterns and outcomes of patients (pts) receiving second- (2L) and/or third-line (3L) therapy for mNSCLC in Germany.

      Methods:
      A retrospective, non-interventional, observational study was performed with secondary data from the German Oncology Network of outpatient treatment centres. Participating office-based oncologists across Germany provided de-identified longitudinal patient-level data via electronic case report forms for mNSCLC pts. Pts were followed from start of 2L and 3L (index dates) until death/loss to follow up. Pt characteristics and treatment patterns were described. Overall survival (OS) and progression-free survival (PFS) from index dates were calculated using the Kaplan-Meier method.

      Results:
      Of pts diagnosed between Jan 2007–Jul 2016, 340 and 123 pts started 2L and 3L therapy, respectively. Of these, 56% in 2L and 59% in 3L were treated in 2014 or later. The top 3 regimens in 2L were monotherapies of docetaxel (n = 55, 16%), vinorelbine (n = 41, 12%) and pemetrexed (n = 40, 12%). In 3L, the top 3 regimens were monotherapies of docetaxel (n = 19, 15%), vinorelbine (n = 17, 14%) and gemcitabine (n = 11, 9%). Since 2014, an increase in pts on targeted therapies was seen in 2L (25%, 47/192, n = 15 for immunotherapy) vs before 2014 (14%, 20/148). The same trend was also seen in 3L (since 2014, 25%, 18/72, n = 9 for immunotherapy; before 2014, 16%, 8/51). Median OS and PFS was 8 mths (95% CI 6.6–8.9) and 5 mths (95% CI 4.2–5.3) for 2L, and 9 mths (95% CI 6.4–10.3) and 4 mths (95% CI 3.0–5.9) for 3L.

      Conclusions:
      Despite a trend of increased uptake of 2/3L targeted therapies since 2014, prescription levels were still low and single agent chemotherapy still dominates. Given the small number of pts and short observation time, especially for immunotherapy, further studies will be needed when a broader uptake of immunotherapy is expected, to fully assess the impact on treatment patterns and survival.

      Clinical trial identification:
      M039087

      Legal entity responsible for the study:
      Roche Pharmaceutical

      Funding:
      Roche Pharmaceutical

      Disclosure:
      N. Yu: Roche employee. I. Reyes-Rivera: Employee: F. Hoffmann-La Roche Ltd., Stock ownership: F. Hoffmann-La Roche Ltd. J. Hipp: Employee: Roche Pharma AG, and Stock ownership: F. Hoffmann La-Roche. M. Zou: Corporate-sponsored research by Roche. S. Hammerschmidt: Advisory board or board of directors: Astra Zeneca, Boehringer-Ingelheim, BMS, Novartis, Pfizer, Roche. All other authors have declared no conflicts of interest.

    • +

      133P - The influence of body composition on TTFields intensity in the lungs (ID 466)

      12:30 - 12:30  |  Author(s): U. Weinberg, N. Urman, H.S. Hershkovich, Z. Bomzon, E.D. Kirson, Y. Palti

      • Abstract

      Background:
      Tumor Treating Fields (TTFields) are low intensity, alternating electric fields in the intermediate frequency range that disrupt mitosis. The therapy is FDA approved for the treatment of glioblastoma, and a pivotal study testing the efficacy of TTFields in non-small cell lung cancer is planned. TTFields are delivered through two pairs of transducer arrays (TL) placed on the patient's skin. Since the efficacy of TTFields increases with intensity, it is important to identify factors that influence field intensity in the lungs. Therefore, it is important to understand how body shape and composition influence the field intensity. Here we present a computer-simulation-based study investigating the effect of body size, shape and composition on the field distribution in the lungs.

      Methods:
      The study was performed using the Sim4Life software package and realistic computational phantoms of a female (ELLA), male (DUKE) and obese male (FATS). Various array layouts were placed on the models, and the distribution of TTFields within their lungs were calculated and compared.

      Results:
      For all models, uniform field distributions within the lungs were obtained when the arrays were axially-aligned with the parenchyma as much as anatomically possible. The layouts that generated the highest average field intensities were those in which one pair of arrays delivered an electric field from the anterolateral to the posterior-contralateral aspect of the patient, with the second pair inducing the field from the antero-contralateral to the posterolateral aspect of the patient. In all models, these layouts led to average field intensities in the lungs of above the therapeutic threshold (>1 V/cm). The highest field intensities developed in DUKE's lungs and the lowest field intensities developed in FATS's lungs. Analysis suggests that field attenuation was caused primarily by layers of fat. Hence, the lower field intensities in the lungs of ELLA and FATS can be largely attributed to the thick layers of fat present in FATS and the fatty tissue in ELLA's breasts.

      Conclusions:
      This study provides insights into how TTFields distribution in the lungs is influenced by body composition. These insights will help to optimize TL placement and design in the future.

      Clinical trial identification:


      Legal entity responsible for the study:
      Novocure

      Funding:
      Novocure

      Disclosure:
      U. Weinberg, N. Urman, H.S. Hershkovich, E.D. Kirson: Employee of Novocure. Z. Bomzon: Paid employee of Novocure Ltd. Y. Palti: The author is a shareholder in Novocure.

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      134P - Applicable CT-guided percutaneous radiofrequency ablation (RFA) in the treatment of unresectable Lung Ground Glass Opacity (GGO) (ID 348)

      12:30 - 12:30  |  Author(s): Y.T. Wei

      • Abstract

      Background:
      Radiofrquency ablation (RFA) is a locoregional therapeutic for variable unresectable malignancies and currently used for lung cancer (either primary or metastatic). It is minimally invasive and accurate for percutaneous RFA under CT guidance. This study was to investigate the safety and efficacy of RFA in the treatment of unresectable lung Ground Glass Opacity (GGO).

      Methods:
      From June 2015 to June 2016 a total of 68 patients (29 males and 39 females with a median age of 46 y, range, 29-78 y) with 83 lesions (GGO) have been enrolled in this study. As approved by institutional review board, all patients were informed and signed the consent forms beforehand. All the preselected lesions were proven by needle biopsy under CT guidance percutaneously prior to the procedure. In total 60 malignancies were ultimately included and CT-guided percutaneous RFA was serially performed with pre-set power of 40-80w and ablation time of 12-25 min. Imaging follow-up served as evaluation method.

      Results:
      All of the procedures were performed to completion. There were 18 patients with pneumothorax postoperatively and of those 6 needed a closed thoracic drainage. 8 patients showed slight bleeding during the procedures. Follow-up CT scanning at 30-, 90-, and 180-day postoperatively have shown that 56 of 60 lesions turned consolidated and with volume diminished. 4 of 60 were without significant dimensional change at 30-day follow-up, 3 of the 4 with accentuation were detected on 90-day CT follow-up and needed a reoperation of RFA.

      Conclusions:
      CT-guided percutaneous RFA is safe and effective. It offers good control and is well-tolerated as a viable option for unresectable GGO.

      Clinical trial identification:


      Legal entity responsible for the study:
      Chinese PLA General Hospital

      Funding:
      Chinese PLA General Hospital

      Disclosure:
      The author has declared no conflicts of interest.

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      135P - Coxsackievirus type B3 is a potent oncolytic virus against KRAS-mutant non-small cell lung cancer (ID 242)

      12:30 - 12:30  |  Author(s): H. Deng, T.D. Sliva, Y. Xue, Y. Mohamud, J. Zhang, W. Lockwood, H. Luo

      • Abstract

      Background:
      Lung cancer is one of the most leading causes of cancer-related death worldwide. Over 85% of lung cancers are non-small cell lung cancer (NSCLC), for which the 5-year survival rate is extremely low (∼15.9%). Most NSCLCs are caused by the accumulation of genomic alterations, among which epidermal growth factor receptor (EGFR) mutation and KRAS mutation are two of the most predominant types. Although patients with EGFR-mutant NSCLCs have manifested a good response to EGFR inhibitors, there is a paucity of effective treatments for the KRAS-mutant NSCLCs and new strategies are urgently needed. Coxsackievirus type B3 (CV-B3) is a non-enveloped, human-pathogenic enterovirus that causes mild flu-like symptoms in adults. Due to its highly lytic nature, CV-B3 has yielded an increased efficacy of viral-mediated oncolysis as compared to other viruses, which makes it as a good candidate for cancer treatment.

      Methods:
      Seven NSCLC cell lines (A549, H2030, H23, H1975, PC-9, H3255 and HCC4006) and three normal lung epithelial cells (HPL1D, HAE and BEAS2B) were selected for this study. Cells were infected with CV-B3 (MOI 0.01) for 48hrs. Cytopathic effects caused by virus infection were observed by light microscope, followed by crystal violet staining. MTS assay were conducted to examine the resistance of normal lung epithelial cells upon CVB3 infection. The supernatants were collected to determine the virus titres by plaque assay. Coxsackievirus and adenovirus receptor (CAR) expression was examined via western blot.

      Results:
      Our studies found that CV-B3 treatment led to a significant reduction of cell survival in KRAS-mutant NSCLCs but not EGFR-mutant NSCLCs nor normal lung epithelial cells. MTS assay results demonstrated CV-B3 infection didn’t lead to a significant enhancement of cell death in normal lung epithelial cells. Furthermore, we showed that virus titres within the supernatants of KRAS-mutant NSCLCs are significantly higher than both EGFR-mutant NSCLCs and normal lung epithelial cells. Finally, we demonstrated that CAR expression levels were significantly increased in KRAS-mutant NSCLCs.

      Conclusions:
      Our study found that CV-B3 is an effective and safe oncolytic virus against KRAS-mutant NSCLCs.

      Clinical trial identification:


      Legal entity responsible for the study:
      Center for Heart and Lung Innovation, St. Paul’s Hospital, Department of Pathology and Laboratory Medicine, University of British Columbia

      Funding:
      British Columbia Lung Association

      Disclosure:
      All authors have declared no conflicts of interest.

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      136P - Long-term safety and efficacy of darbepoetin alfa in subjects with stage IV NSCLC receiving multi-cycle chemotherapy (ID 357)

      12:30 - 12:30  |  Author(s): P. Gascón, R. Nagarkar, M. Šmakal, K. Syrigos, C.H. Barrios, J. Cárdenas Sánchez, L. Zhang, D. Henry, D. Tomita, C. De Oliveira Brandao

      • Abstract

      Background:
      Darbepoetin alfa (DA) is an erythropoiesis-stimulating agent (ESA) that has been shown to increase hemoglobin levels and reduce the rate of transfusions in patients with chemotherapy-induced anemia (CIA). Most studies have not shown an association between ESA use and poor outcomes, but some clinical trials have reported increased mortality and/or tumor progression. This trial was therefore designed to address the safety of DA for CIA in patients with non-small cell lung cancer (NSCLC).

      Methods:
      Study 20070782 is a randomized, double-blind, noninferiority trial to compare DA with placebo, and is enrolling patients with NSCLC with CIA. Eligible patients are ≥ 18 years old with Eastern Cooperative Oncology Group (ECOG) status ≤ 1, stage IV NSCLC, no prior adjuvant/neoadjuvant NSCLC therapy, ≥ 2 cycles first-line chemotherapy planned (≥ 6 weeks total), and screening hemoglobin ≤ 11 g/dL. Approximately 3,000 patients from up to 500 global sites will be randomized 2:1 to DA (500 mcg) or placebo every 3 weeks (Q3W) until disease progression or end of chemotherapy. At hemoglobin > 12 g/dL, study drug is withheld until hemoglobin ≤ 12 g/dL. Transfusions are allowed when necessary. Endpoints include overall survival (OS; primary) and progression-free survival (PFS; secondary), and will be analyzed when ∼2,700 deaths have occurred. Additional safety endpoints include tumor response and rate of thromboembolic events. Superiority of DA to placebo in transfusion rates will be tested if noninferiority is achieved for OS and PFS.

      Results:
      As of January 1, 2017, a total of 2,447 patients have enrolled. The independent data monitoring committee has conducted 10 reviews of unblinded data (which included a planned formal interim analysis at 60% of planned total number of 2,700 deaths to test for harm), and has recommended continuation of the trial without changes.

      Conclusions:
      Study 20070782 is the largest clinical trial in NSCLC to date, and will provide comprehensive data on the safety and efficacy of DA in patients with CIA.

      Clinical trial identification:
      NCT00858364

      Legal entity responsible for the study:
      Amgen Inc.

      Funding:
      Amgen Inc.

      Disclosure:
      C.H. Barrios: Pfizer, Novartis, Amgen, AstraZeneca, Boehringer Ingelheim, Roche, Lilly, Sanofi, GSK, Taiho, Mylan, Merrimack, Merck, Abbvie, Astellas, Biomarin, BMS, Daiichi Sankyo, Abraxis, AB Science, Asana, Medivation, Daiichi Sankyo, Exelixis, ImClone, LEO. L. Zhang: Investigator/consultant: AstraZeneca, Pfizer, Lilly, BMS, Roche, Boehringer Ingelheim. D. Tomita, C. De Oliveira Brandao: Employee and shareholder of Amgen Inc. All other authors have declared no conflicts of interest.

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      137P - Cost-effectiveness of afatinib versus erlotinib for the treatment of squamous non-small cell lung cancer in France after a first-line platinum based therapy (ID 176)

      12:30 - 12:30  |  Author(s): M. Pignata, K. Le Lay, L. Luciani, C. McConnachie, J. Gordon, C. Chouaid, S. Roze

      • Abstract

      Background:
      Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and has an extremely poor prognosis. Among the different histologies, squamous NSCLC represents 20 to 30% of them. Afatinib is an irreversible ErbB family blocker approved in Europe for squamous NSCLC after a first-line platinum based therapy. The objective of the present study was to evaluate the cost-effectiveness of afatinib versus erlotinib in this setting in France.

      Methods:
      The study population was taken from the LUX-Lung 8 trial which compared afatinib with erlotinib in patients with squamous NSCLC. The analysis was performed from the perspective of healthcare funders and affected patients in France. A state transition model was developed to evaluate cost-effectiveness based on progression-free survival and overall survival in the trial. Life expectancy, quality-adjusted life expectancy and direct costs were evaluated over a 10-year time horizon. Future costs and clinical benefits were discounted at 4% annually. Deterministic and probabilistic sensitivity analyses were performed.

      Results:
      Model projections indicated that patients-treated with afatinib benefitted from longer life expectancy than those treated with erlotinib (0.94 years versus 0.78 years respectively) translating to an increase of 0.094 quality-adjusted life years (QALYs). The total cost of treatment over a 10-year time horizon was higher for afatinib than erlotinib, EUR 12,364 versus EUR 9,510, leading to an incremental cost-effectiveness ratio of EUR 30,277 per QALY gained for afatinib versus erlotinib. Sensitivity analyses showed that the base case findings were stable under variation in a range of model inputs.

      Conclusions:
      Based on data from the LUX-Lung 8 trial, afatinib was projected to improve clinical outcomes versus erlotinib, with an 89% probability of being cost-effective assuming a willingness to pay of EUR 50,000 per QALY gained, following a first-line platinum based therapy for patients with squamous NSCLC in France.

      Clinical trial identification:


      Legal entity responsible for the study:
      HEVA HEOR

      Funding:
      Boehringer Ingelheim

      Disclosure:
      M. Pignata, C. McConnachie, S. Roze: The study was supported by funding from Boehringer Ingelheim. K. Le Lay: Employee of Boehringer Ingelheim. L. Luciani: Employee of Boehringer Ingelheim. J. Gordon: Employee of Boehringer Ingelheim. C. Chouaid: In the past 5 years, received fees for attending scientific meetings, speaking, organizing research or consulting from AstraZeneca, Boehringer Ingelheim, and Hoffman la Roche.

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      138TiP - An open-label phase 3b/4 safety trial of flat-dose nivolumab plus ipilimumab in patients with advanced non-small cell lung cancer (NSCLC) (ID 164)

      12:30 - 12:30  |  Author(s): L. Paz-Ares, B. Lash, I. Albert, G. Gagnon, C. Chakmakjian, N. Ready, W. Hu, L. Krug, J. Fairchild, R.N. Pillai

      • Abstract

      Background:
      The combination of nivolumab and ipilimumab, immune checkpoint inhibitors with distinct but complementary mechanisms of action, is approved as first-line therapy for metastatic melanoma and has shown encouraging clinical activity in other tumors, including NSCLC. In CheckMate 012, a multi-cohort phase 1 trial in chemotherapy-naïve patients with NSCLC, nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) yielded objective response rates of up to 47%; discontinuation rates due to treatment-related adverse events were similar to those with nivolumab monotherapy. Data indicate comparable pharmacokinetic, safety, and efficacy profiles for 240 mg flat-dose nivolumab and 3 mg/kg nivolumab. This open-label phase 3b/4 study (ClinicalTrials.gov identifier: NCT02869789) will characterize the safety of flat-dose nivolumab plus ipilimumab in patients with advanced NSCLC. This study will also evaluate this combination in special patient populations who are typically excluded from NSCLC trials.

      Trial design:
      Adult patients with stage IV/recurrent NSCLC and no prior systemic anticancer therapy (cohort A; n = 400), or with stage IIIb/IV NSCLC and recurrence or progression during or after one prior platinum doublet chemotherapy regimen (cohort B; n = 400) will be enrolled. Patients are required to have assessment of programmed death-1 ligand 1 expression, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1, and no untreated brain metastases, carcinomatous meningitis, autoimmune disease, or active malignancy requiring concurrent intervention. A third cohort (A1; n = ∼200) with no prior systemic therapy will have ECOG PS 2 or one or more of the following: asymptomatic untreated brain metastases, renal or hepatic dysfunction, and/or HIV. All patients will receive flat-dose nivolumab (240 mg every 2 weeks) plus weight-based ipilimumab (1 mg/kg every 6 weeks). Endpoints are shown in the table.rnTable: 138 TiPStudy endpointsrn

      rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn rnrn
      PrimarySecondary
      Number and percentage of patients with high-grade treatment-related select and immune-mediated adverse eventsProgression-free survival
      Objective response rate
      Duration of response
      Patient-reported outcomes based on the Functional Assessment of Cancer Therapy-Lung (FACT-L)
      rn

      Clinical trial identification:
      NCT02869789

      Legal entity responsible for the study:
      Bristol-Myers Squibb

      Funding:
      Bristol-Myers Squibb

      Disclosure:
      L. Paz-Ares: Medical advisor for: Lilly, Roche, MSD, BMS, Celgene, Pfizer, Boehringer Ingelheim, Bayer, Clovis, and Astra Zeneca. C. Chakmakjian: Speaker\'s Bureau for: BMS. N. Ready: Honoraria from: BMS, Merck; Consultant for: BMS, Merck, Novartis, Abbvie. W. Hu, L. Krug, J. Fairchild: Bristol-Myers Squibb employee. All other authors have declared no conflicts of interest.

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      139TiP - A non-interventional biomarker study in patients (pts) with non-small cell lung cancer (NSCLC) of adenocarcinoma histology who are treated with nintedanib according to the approved label (LUME-BioNIS) (ID 260)

      12:30 - 12:30  |  Author(s): M. Reck, A.J. Staal-Van den Brekel, A. Mellemgaard, N. Morsli, A. Ellingboe, R. Kaiser, K. Pietzko, T. Kitzing, J. Braunger, K. Kerr

      • Abstract

      Background:
      Nintedanib+docetaxel significantly improved overall survival (OS) of pts with advanced adenocarcinoma NSCLC. There are currently no validated tumour- or serum-derived biomarkers to predict the efficacy of antiangiogenic therapy. The objective of this study is to investigate whether tumour-based gene/protein expression patterns or genomic markers, alone or combined with clinical covariates, could predict treatment effect in pts with adenocarcinoma NSCLC receiving nintedanib (Vargatef[®]).

      Trial design:
      In this non-interventional study at 86 mainly European sites, new biomarker data and clinical characteristics will be collected from ∼300 pts who receive nintedanib as part of routine treatment. Pts must be eligible for nintedanib+docetaxel, i.e. have advanced adenocarcinoma NSCLC after first-line chemotherapy, and will receive nintedanib 200 mg twice daily (Days 2–21 of 21-day cycle) and docetaxel (75 mg/m[2]; Day 1). The primary outcome is OS in relation to exploratory biomarker assessment, including gene expression profile, tumour genomic alterations and protein analysis. Tumour tissue samples obtained prior to first-line therapy are required along with informed consent. Mutation analysis of nintedanib target genes (VEGFR1–3, FGFR1–3, PDGFR α/β) and driver genes (EGFR, KRAS, ALK, BRAF, PIK3CA) will be conducted, as well as evaluation of tumour protein expression (e.g. PD-L1, CD133) and proliferation (Ki-67) markers by immunohistochemistry. One ∼2 mL blood sample (or a buccal swab) will be collected at baseline or after nintedanib initiation alongside routine blood sampling to analyse the potential influence of genetic variants in angiogenesis-related genes (e.g. single nucleotide polymorphisms in VEGFR1). Pts will be followed up every 6 months. The primary outcome will be analysed after 250 deaths. Gene expression patterns and tumour genomics in relation to efficacy will be analysed using univariate and multivariate regression models. Adverse events will be assessed. All analyses will be exploratory and considered hypothesis-generating. The study is ongoing (NCT02671422).

      Clinical trial identification:
      NCT02671422

      Legal entity responsible for the study:
      Boehringer Ingelheim Pharma GmbH & Co. KG

      Funding:
      Boehringer Ingelheim Pharma GmbH & Co. KG

      Disclosure:
      M. Reck: Author reports personal fees from Boehringer-Ingelheim, Hoffmann-La Roche, Lilly, MSD, BMS, AstraZeneca, Celgene, Merck and Pfizer. K. Kerr: Personal fees from Boehringer Ingelheim, during the conduct of the study. All other authors have declared no conflicts of interest.

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      140TiP - CheckMate 384: A phase 3b/4 dose-frequency optimization trial of nivolumab in advanced or metastatic non-small cell lung cancer (ID 261)

      12:30 - 12:30  |  Author(s): N. Reinmuth, R. Harris, P. Mitchell, E.B. Garon, J. Zhu, I. Chang, G. Selvaggi, E. Pichon

      • Abstract

      Background:
      Nivolumab, an anti-programmed death-1 antibody, is approved for the treatment of various cancers. Based on efficacy and safety findings across multiple tumor types, the approved dose of nivolumab was, until recently, 3 mg/kg every 2 weeks (Q2W). In September 2016, the approved nivolumab dose in non-small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma was modified in the United States to a flat dose of 240 mg Q2W. Reducing the frequency of nivolumab administration may increase convenience and compliance while maintaining efficacy and safety in patients receiving long-term nivolumab therapy. CheckMate 384, a randomized, open-label phase 3b/4 trial (NCT02713867) was designed to evaluate less frequent nivolumab dosing (480 mg every 4 weeks [Q4W] vs 240 mg Q2W) in patients with advanced/metastatic NSCLC following up to 12 months of prior treatment with nivolumab 3 mg/kg or 240 mg Q2W.

      Trial design:
      Eligible patients are adults with advanced/metastatic squamous or non-squamous NSCLC and Eastern Cooperative Oncology Group performance status 0–2 who received prior intravenous nivolumab 3 mg/kg or 240 mg Q2W for up to 12 months and achieved a complete or partial response or stable disease confirmed on 2 consecutive assessments. Patients with untreated, symptomatic central nervous system metastases are not eligible. Patients are randomized 1:1 to receive intravenous nivolumab in 1 of 2 flat-dose schedules: 240 mg Q2W or 480 mg Q4W. Randomization is stratified by histology and response to pre-study nivolumab treatment (complete/partial response vs stable disease). Endpoints are shown in the table. The primary objective is to compare 6-month and 1-year progression-free survival (PFS) rates between patients who received nivolumab 480 mg Q4W and those who received 240 mg Q2W. Planned enrollment is 620 patients.rnTable: 140TiPStudy endpointsrn

      rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn rnrn
      PrimarySecondary
      PFS rates at 6 months and 1 year after randomization (co-primary)PFS rate at 1 year after randomization by tumor histology and by response to pre-study nivolumab before randomization
      PFS rate at 2 years after randomization
      Overall survival rate
      Safety and tolerability, as assessed by incidence and severity of adverse events
      rn

      Clinical trial identification:
      NCT02713867

      Legal entity responsible for the study:
      Bristol-Myers Squibb

      Funding:
      Bristol-Myers Squibb

      Disclosure:
      N. Reinmuth: Personal fees (speakers and consulting honoraria): Bristol-Myers Squibb, Hoffmann-La Roche, Lilly, Novartis, Boehringer-Ingelheim, AstraZeneca, Amgen, Pfizer, MSD. R. Harris: Consultant (personal fees): Bristol-Myers Squibb. P. Mitchell: Advisory board member: AstraZeneca, Roche, Boehringer-Ingelheim, BMS, MSD, Celgene; Honoraria: Roche; Travel grants: Roche, BMS. E.B. Garon: Research Funding (received by my institution): AstraZeneca, BMS, Merck, Genentech, Eli Lilly, Pfizer, Novartis, Boehringer Ingelheim, Mirati. J. Zhu, I-F. Chang: BMS Employment and BMS Stock Ownership. S. Selvaggi: Bristol-Myers Squibb employee and shareholder and has received travel, accommodation, and expense assistance from Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

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      141TiP - ASTRIS: A multicenter, real world treatment study of osimertinib in EGFR T790M positive non-small cell lung cancer (NSCLC) (ID 278)

      12:30 - 12:30  |  Author(s): P.K. Cheema, Y. Chen, F. de Marinis, H.C. Freitas, S. Kim, A. Milner, M. Provencio, J. Rigas, Y. Wu

      • Abstract

      Background:
      EGFR tyrosine kinase inhibitors (TKIs) are the first-line treatment for patients with EGFR mutation positive advanced NSCLC. Resistance develops due to a secondary EGFR T790M mutation in approximately 60% of cases. Osimertinib is an oral, irreversible, central-nervous system (CNS) active, EGFR-TKI selective for both EGFR-TKI sensitising and T790M resistance mutations. In a Phase III trial versus platinum-based doublet chemotherapy in patients with T790M positive NSCLC (AURA3), osimertinib provided a significantly longer progression-free survival (PFS; median 10.1 mths vs. 4.4 mths; hazard ratio 0.30; 95% CI 0.23, 0.41; p < 0.001) and higher response rates (71% vs 31%; odds ratio 5.39; p < 0.001) (Mok et al, New Engl J Med 2016). Currently, there is limited evidence of the efficacy of osimertinib outside of clinical trials.

      Trial design:
      ASTRIS is a Phase III open-label, single-arm, multi-national, real world treatment study assessing the efficacy and safety of osimertinib in patients with advanced T790M mutation positive NSCLC, who have previously received an EGFR-TKI. Approximately 3500 patients will be enrolled across Asia, Europe and North and South America on a rolling basis. Country level enrolment is to stop within 6 months of market licence approval or national reimbursement. Key inclusion criteria are adults with locally advanced or metastatic NSCLC having a confirmed T790M mutation who received a prior EGFR-TKI and have World Health Organization performance status 0 − 2. T790M status must be confirmed by an appropriately validated test. Patients with asymptomatic CNS metastases, not requiring an increasing corticosteroid dose within 2 weeks prior to osimertinib administration, are allowed. Osimertinib 80 mg will be administered orally once daily for as long as the patient continues to receive clinical benefit, as judged by the investigator. The primary efficacy outcome is overall survival: secondary outcomes include investigator assessed response rate, PFS, and time to treatment discontinuation. Baseline demographics and disease characteristics, T790M mutation testing results and safety will also be reported.

      Clinical trial identification:
      NCT02474355 (27 May 2015)

      Legal entity responsible for the study:
      AstraZeneca

      Funding:
      AstraZeneca

      Disclosure:
      P.K. Cheema: Advisory board: Astrazeneca, Bristol Myers Squibb, Novartis, Boehringer Ingelheim, Pfizer, Merck Research sponsors: Astrazeneca, Hoffmann La Roche, Boehringer Ingelheim. Y-M. Chen: Advisory board of AstraZeneca, Boehringer Ingelheim, Roche and Merck Sharp & Dohme. H.C. Freitas: Member of ASTRIS steering committee, a research program supported by Astra Zeneca. A. Milner: Employee of AstraZeneca, who sponsored the study. M. Provencio: Honoraria for consultancy work from MSD, Bristol-Myers Squibb, Roche and Astrazeneca. J. Rigas: Consultant, through Kelly Service, for AstraZeneca in Global Medical Affairs on osimertinib (TAGRISSO). Y-L. Wu: Speaker fees from AstraZeneca, Roche, Eli Lilly. All other authors have declared no conflicts of interest.

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      142TiP - A prospective multi-center study to investigate the EGFR-TKI resistance profile, treatment algorithm and clinical outcome in Chinese patients with advanced EGFRm+ NSCLC who have received prior first generation EGFR TKI (PRECENT study, CCTC-1601, NCT02988141) (ID 280)

      12:30 - 12:30  |  Author(s): W. Liang, L. Wu, L. Wang, Y. Huang, R. Xu, L. Zhang, J. He

      • Abstract

      Background:
      The resistance mechanism is impactful to make treatment strategy after prior first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) failure and the profile has well established in western population; while without solid data among Asian population. In addition, methods used in determining previously reported resistance profiles are flawed in failing to detect concomitant or heterogeneous mechanisms. High throughput next-generation sequencing (NGS), which allows parallel multiplex genotyping with tissue or plasma sample, can help in addressing these issues. Furthermore, little was known about the treatment algorithms and clinical outcomes of different mechanisms in China. Thus, the study aims to investigate the resistance mechanism, treatment strategy and clinical outcome for those patients with prior EGFR-TKI in China.

      Trial design:
      We are going to perform a prospective, multi-center study to obtain: a) the biomarker profile of EGFR-TKI acquired resistance detected based on paired tissue and blood respectively; b) concordance of T790M detection by NGS in blood sample with that in tissue sample as reference; c) the clinical outcomes (ORR, DCR, PFS of subsequent treatment and OS) of patients with different resistance mechanisms by NGS in tissue samples and blood samples. All the paired re-biopsy tissue and blood samples will be collected and subjected to NGS panel testing by central lab. Treatment strategy will be summarized and described. The assessment will be performed every 6 weeks until objective disease progression as defined by RECIST1.1. Survival follow-up will be conducted every 6 weeks until death, lost to follow-up, withdrawal of consent or the DCO (data cut off). A sample size of 100 patients will provide 80% power to detect at least 1 case of resistance mechanism with a proportion of 1.5% and a precision of 9% for an assumed concordance 70% of T790M mutation between tissue and blood samples. First subject will be enrolled in Feb 2017.

      Clinical trial identification:
      NCT02988141

      Legal entity responsible for the study:
      Guangdong Association of Thoracic Disease (China)

      Funding:
      AstraZeneca

      Disclosure:
      L. Zhang: Member on an advisory board and receives lecture fees from AstraZeneca. All other authors have declared no conflicts of interest.

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      143TiP - IMpower110: Phase III trial of 1L atezolizumab in PD-L1–selected chemotherapy-naive NSCLC (ID 364)

      12:30 - 12:30  |  Author(s): J. Jassem, F. de Marinis, D.R. Spigel, S. Lam, S. Mocci, A. Sandler, A. Lopez-Chavez, Y. Deng, G. Giaccone, R.S. Herbst

      • Abstract

      Background:
      Despite poor survival and toxicities, chemotherapy is the standard of care and remains the main first-line option for patients (pts) with advanced NSCLC non-squamous (non-sq) and squamous (sq) histology without genetic driver alterations. Immunotherapies targeting PD-L1/PD-1 are available for 2L+ NSCLC but remain to be fully studied in the 1L setting. Atezolizumab (atezo), an anti–PD-L1 mAb, prevents PD-L1 interacting with PD-1 and B7.1, restoring tumor-specific T-cell immunity. Significant and clinically relevant survival benefit has been shown with atezo in previously treated NSCLC, regardless of PD-L1 expression on tumor cells (TC) and/or tumor-infiltrating immune cells (IC). IMpower110 (NCT02409342), a global Phase III randomized, multicenter, open-label trial, will evaluate efficacy and safety of 1L atezo vs cisplatin (cis)/carboplatin (carbo) + pemetrexed (pem) or gemcitabine (gem) in PD-L1–selected chemotherapy-naive pts with advanced non-sq or sq NSCLC, respectively.

      Trial design:
      Inclusion criteria include stage IV non-sq or sq NSCLC, measurable disease (RECIST v1.1), ECOG PS 0-1, no prior chemotherapy for advanced NSCLC and centrally assessed PD-L1 expression of ≥ 1% on TC or IC (TC1/2/3 or IC1/2/3 with VENTANA SP142 IHC assay; expected prevalence, ≈ 65%). Exclusion criteria include active or untreated CNS metastases, prior immune checkpoint blockade therapy or autoimmune disease. Pts will be randomized 1:1 to receive atezo or cis/carbo + pem (non-sq)/gem (sq) (4 or 6 21-day cycles are allowed). Pts receiving atezo may continue until loss of clinical benefit, while pts in the comparator arm can receive pem maintenance (non-sq) or best supportive care (sq) until disease progression. Stratification factors are sex, ECOG PS, histology (non-sq vs sq) and centrally assessed PD-L1 expression by IHC. Co-primary endpoints are PFS and OS. Key secondary endpoints are ORR, DOR, IRF-assessed PFS (RECIST v1.1) and TTD in pt-reported lung cancer symptoms. Safety and PK will also be evaluated. Tumor biopsies at progression will be assessed for immunologic biomarkers associated with responses to atezo and to differentiate unusual responses from radiographic progression. Approximately 570 pts will be enrolled.

      Clinical trial identification:
      NCT02409342

      Legal entity responsible for the study:
      F. Hoffmann-La Roche Ltd/Genentech Inc., a member of the Roche Group

      Funding:
      F. Hoffmann-La Roche Ltd/Genentech Inc., a member of the Roche Group

      Disclosure:
      J. Jassem: Speaker: AstraZeneca, Roche, Pfizer; Advisory roles: AstraZeneca, Boehringer, BMS, Celgene, G1 Therapeutics, Merck, Pfizer, Pierre Fabre, Roche; Travel support: Roche, Boehringer. F. de Marinis: Consultation fees received from Roche/BMS/Boehringer/Novartis/Pfizer/MSD/Astrazeneca. D.R. Spigel: Consulting/Advisory Role: Genentech (uncompensated); Travel, accommodation, expenses: Genentech. S. Lam, S. Mocci, A. Sandler, A. Lopez-Chavez, Y. Deng: Employee, stock: Roche/Genentech. G. Giaccone: Consulting or Advisory Role: Clovis, Boehringer-Ingelheim; Celgene; Research grants: Karyopharm, Astra-Zeneca; Eli-Lilly. R.S. Herbst: Consultant and research support from Genentech

    • +

      144TiP - CheckMate 227: A randomized, open-label phase 3 trial of nivolumab, nivolumab plus ipilimumab, or nivolumab plus chemotherapy versus chemotherapy in chemotherapy-naïve patients with advanced non-small cell lung cancer (NSCLC) (ID 394)

      12:30 - 12:30  |  Author(s): L. Paz-Ares, J. Brahmer, M.D. Hellmann, M. Reck, K. O'Byrne, H. Borghaei, W.J. Geese, H. Lu, F.E. Nathan, S. Ramalingam

      • Abstract

      Background:
      Platinum-based chemotherapy is standard-of-care first-line therapy for most patients with advanced NSCLC, but the clinical benefit is modest. Although first-line nivolumab, an immune checkpoint inhibitor antibody, did not improve progression-free survival or overall survival (OS) versus chemotherapy in patients with advanced NSCLC and ≥5% programmed death-1 ligand 1 (PD-L1) expression, OS compared favorably with historical controls of first-line platinum-based chemotherapy. Combining nivolumab with chemotherapy in this setting may increase the durability of tumor responses and broaden the population of patients to derive benefit. In a multi-cohort phase 1 study (CheckMate 012) in chemotherapy-naïve patients with advanced NSCLC, nivolumab plus chemotherapy had promising clinical activity, regardless of tumor PD-L1 expression, and a manageable safety profile. CheckMate 227 is a 2-part, randomized, open-label phase 3 trial (NCT02477826), evaluating first-line nivolumab, nivolumab plus ipilimumab, or nivolumab plus chemotherapy versus chemotherapy in patients with advanced NSCLC.

      Trial design:
      Part 1 of CheckMate 227, which has completed accrual, enrolled adult patients with stage IV/recurrent NSCLC, no prior systemic anticancer therapy, and assessment of PD-L1 expression at screening. Patients with ≥1% PD-L1 expression were randomized 1:1:1 to nivolumab, nivolumab plus ipilimumab, or chemotherapy arms; those with <1% PD-L1 expression were randomized 1:1:1 to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy arms. In part 2, ∼480 previously untreated patients with advanced NSCLC, regardless of PD-L1 expression level, will be randomized 1:1 to receive histology-based platinum doublet chemotherapy alone or in combination with nivolumab. Part 2 of CheckMate 227, which is the focus of this presentation, allows for the evaluation of first-line nivolumab plus chemotherapy in a broad group of patients with advanced NSCLC across the PD-L1–expressing continuum.

      Clinical trial identification:
      NCT02477826

      Legal entity responsible for the study:
      Bristol-Myers Squibb

      Funding:
      Bristol-Myers Squibb

      Disclosure:
      L. Paz-Ares: Served as a medical advisor for the following companies: Lilly, Roche, MSD, BMS, Celgene, Pfizer, Boehringer-Ingelheim, Bayer, Clovis, and AstraZeneca. J. Brahmer: Received research grants and served as an uncompensated advisory board member for Bristol-Myers Squibb. M.D. Hellmann: Received grants from Genentech and Bristol-Myers Squibb. Received personal fees from Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, Novartis, and Janssen. M. Reck: Received consultant fees and served on speaker\'s bureau for the following companies: Roche, Lilly, Bristol-Myers Squibb, MSD, AstraZeneca, Pfizer, Boehringer-Ingelheim, and Celgene. K. O\'Byrne: Received honoraria, speaker bureau and/or travel and registration support for national and international meetings from BMS, Boehringer-Ingelheim, Astrazeneca, Lilly Oncology, Novartis, MSD, Roche-Genentech and Pfizer. H. Borghaei: The institution has a clinical trial agreement w/BMS. Consultant/advisory board member for: BMS, Lilly, Genentech, Celgene, EMD-Serono, Merck, Pfizer, Trovagene, Millenium, & Boehringer-Ingelheim. Received grants from: Millenium, Merck, & Celgene. W.J. Geese, H. Lu: BMS Employee and stock holder. F.E. Nathan: BMS employee. S. Ramalingam: Served on ad hoc scientific advisory board meetings the following companies: Astra Zeneca, BMS, Boehringer Ingelheim, Celgene, Ariad, Amgen, Lilly, Merck, Genentech. Also received honoraria from BMS.

    • +

      145TiP - TTFields combined with PD-1 inhibitors or docetaxel for 2nd line treatment of non-small cell lung cancer (NSCLC): Phase 3 LUNAR study (ID 408)

      12:30 - 12:30  |  Author(s): U. Weinberg, O. Farber, M. Giladi, Z. Bomzon, E.D. Kirson

      • Abstract

      Background:
      Tumor Treating Fields (TTFields) are a non-invasive, anti-mitotic treatment modality. TTFields disrupt the formation of the mitotic spindle, and dislocation of intracellular constituents. TTFields significantly extend the survival of newly diagnosed glioblastoma patients when combined with temozolomide. Efficacy of TTFields in NSCLC has been shown preclinically and in a phase I/II pilot study with pemetrexed, where overall survival (OS) improved by > 5 months vs historical controls.

      Trial design:
      We hypothesize that adding TTFields to 2nd line therapies in advanced NSCLC will increase OS. Patients (N = 512) with squamous or non-squamous NSCLC are enrolled in this Phase 3 study LUNAR [NCT02973789]. Patients are stratified by 2[nd] line therapy (PD-1 inhibitor or docetaxel), histology (squamous vs. non-squamous) and geographical region. Key inclusion criteria are 1st disease progression (RECIST 1.1), ECOG 0-1, no prior surgery or radiation therapy, no electronic medical devices in the upper torso, and absence of brain metastasis. Docetaxel or PD-1 inhibitors (either nivolumab or pembrolizumab) are given at standard doses. TTFields are applied to the upper torso for at least 18 hours/day, allowing patients to maintain daily activities. TTFields are continued until progression in the thorax and/or liver according to the immune-related response criteria (irRC). Follow up is performed once q6 weeks, including CT scans of the chest and abdomen. On progression in the upper torso, patients are followed monthly for survival. The primary endpoint is superiority in OS between patients treated with TTFields in combination with either docetaxel or PD-1 inhibitors, compared to docetaxel or PD-1 inhibitors alone. A co-primary endpoint compares the OS in patients treated with TTFields and docetaxel to those treated with PD-1 inhibitors alone in a non-inferiority analysis. Secondary endpoints include progression-free survival, radiological response rate based on the irRC, quality of life based on the EORTC QLQ C30 questionnaire and severity & frequency of adverse events. The sample size is powered to detect a HR of 0.75 in TTFields-treated patients versus control group.

      Clinical trial identification:
      NCT02973789

      Legal entity responsible for the study:
      Novocure Ltd

      Funding:
      Novocure Ltd

      Disclosure:
      U. Weinberg, O. Farber, M. Giladi, Z. Bomzon: Full time employee of Novocure. E.D. Kirson: Full time employee of Novocure Ltd

    • +

      146TiP - EXalt3: A phase III study of ensartinib (X-396) in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) (ID 473)

      12:30 - 12:30  |  Author(s): L. Horn, Y. Wu, M. Reck, C. Liang, F. Tan, K. Harrow, V. Oertel, G. Dukart, T.S.K. Mok

      • Abstract

      Background:
      Ensartinib is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. Ensartinib has demonstrated activity in ALK treatment naïve and previously treated patients and has a generally well tolerated safety profile.

      Trial design:
      eXalt3 (NCT02767804) is a global, randomized, open-label phase III study comparing the efficacy and safety of ensartinib to crizotinib in ALK- positive TKI naïve non-small cell lung cancer (NSCLC) patients. It is being conducted in > 100 sites in North America, South America, Europe, and the Asia/Pacific region. Enrollment began in 2016. The primary efficacy endpoint is progression free survival (PFS) assessed by independent radiology review. Secondary efficacy endpoints include overall survival, response rates (overall and central nervous system [CNS]), PFS by investigator assessment, time to response, duration of response, and time to CNS progression. Approximately 270 patients with ALK+ NSCLC who have received no prior ALK TKI and up to one prior chemotherapy regimen will be randomized 1:1 to ensartinib 225 mg QD, or crizotinib 250 mg BID, with stratification based on prior chemotherapy, ECOG performance status (PS), CNS metastases and geographic region. Eligibility includes patients ≥ 18 years of age, stage IIIB or IV ALK+ NSCLC. Patients are required to have measurable disease per RECIST 1.1, adequate organ function, and an ECOG PS of ≤ 2. Adequate tumor tissue (archival or fresh biopsy) must be available for central testing. The study has >80% power to detect a superior effect of ensartinib over crizotinib in PFS at a 2-sided alpha level of 0.05.

      Clinical trial identification:
      NCT02767804

      Legal entity responsible for the study:
      Xcovery Holding Company

      Funding:
      Xcovery Holding Company

      Disclosure:
      L. Horn: Consulting for Xcovery Holding Company, BMS, BI, Abbvie, Genentech, Merck. Y-L. Wu: Speaker fees from AstraZeneca, Roche, Eli Lilly. M. Reck: Honoraria for lectures and consultancy: Hoffmann-La Roche, Lilly, BMS, MSD, AstraZeneca, Merck, Celgene, Boehringer-Ingelheim, Pfizer, Novartis. C. Liang, K. Harrow, V. Oertel, G. Dukart: Full-Time Employee- Xcovery Holding Company. F. Tan: Manager- Xcovery Holding Company Chief Medical Officer- Betta Pharmaceuticals. T.S.K. Mok: Grant/Research Support from AstraZeneca, BI, Pfizer, Novartis, SFJ, Roche, MSD, Clovis Oncology, BMS, Eisai, Taiho; Speaker’s fees with: AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, MSD, Novartis, BMS, Taiho; Major Stock Shareholder in: Sanomics Ltd.; Advisory Board for: AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, Clovis Oncology, Merck Serono, MSD, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Inc., Vertex Pharmaceuticals, BMS, geneDecode Co., Ltd., OncoGenex Technologies Inc., Celgene, Ignyta, Inc.; Board of Directors: IASLC, Chinese Lung Cancer Research Foundation Ltd., Chinese Society of Clinical Oncology (CSCO), Hong Kong Cancer Therapy Society (HKCTS).

    • +

      148P - Metastatic site location may influence the diagnostic accuracy of plasma EGFR-mutation testing in NSCLC: A pooled analysis (ID 406)

      12:30 - 12:30  |  Author(s): F. Passiglia, A. Listì, N. Barraco, A. Galvano, D. Fanale, L. Incorvaia, V. Bazan, C. Rolfo, A. Russo

      • Abstract

      Background:
      Recent studies evaluated the potential role of EGFR mutation testing by using circulating tumor DNA (ctDNA) isolated from plasma of NSCLC patients, overall showing a lower sensitivity compared with the standard tissue genotyping. However, it’s less clear if the presence of extrathoracic (M1b) disease may enhance the ability to identify EGFR mutations in plasma. This pooled analysis aims to evaluate the association between metastatic site location and sensitivity of ctDNA analysis.

      Methods:
      Data from all published studies, that evaluated the sensitivity of plasma-based EGFR-mutation testing, stratified by metastatic site location (extrathoracic (M1b) vs intrathoracic (M1a)) were collected by searching in PubMed, Cochrane Library, American Society of Clinical Oncology, and World Conference of Lung Cancer, meeting proceedings. Pooled Odds ratio (OR) and 95% confidence intervals (95% CIs) were calculated for the ctDNA analysis sensitivity, according to the metastatic site location.

      Results:
      A total of seven studies, with 1233 patients, were eligible. Pooled analysis showed that the sensitivity of EGFR-mutation testing by ctDNA was significantly higher in patients with extrathoracic disease (M1b) compared to patients with intrathoracic (M1a) disease (OR: 4.29; 95% CIs: 2.20 – 8.38).

      Conclusions:
      These data suggest that the location of metastatic sites significantly influences the diagnostic accuracy of ctDNA analysis. Particularly the ability to identify EGFR activating mutations in plasma of NSCLC patients is significantly higher in the presence of M1b vs M1a disease. These observations could influence the clinical management of EGFR-mutated patients.

      Clinical trial identification:
      N.A

      Legal entity responsible for the study:
      Palermo University Hospital

      Funding:
      Palermo University Hospital

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      149P - PD-L1 expression patterns in the metastatic tumors to the lung: A comparative study with the primary non-small cell lung cancer (ID 251)

      12:30 - 12:30  |  Author(s): Z. Gatalica, J. Senarathne, S. Vranic

      • Abstract

      Background:
      Immune check point inhibitors (anti-PD-1/PD-L1) therapy has revolutionized cancer treatment of several, advanced and chemotherapy resistant malignancies. PD-L1 expression on tumor (TC) and/or inflammatory cells (IC) has been associated with a more favorable therapy response. We compared PD-L1 distribution in a large cohort of advanced tumors metastatic to the lungs and compared it with the primary lung non-small cell carcinomas (NSCLC).

      Methods:
      The study groups included 176 metastatic cancers and 81 NSCLC. Expression of PD-L1 was assessed using immunohistochemistry (SP142, Ventana). PD-L1 positivity was defined as 2+ intensity at ≥ 5% in TC or IC cells. All cases were further stratified into 4 categories based on the expression presence or absence of PD-L1 expression on tumor or IC cells. PD-L1 expression was correlated with total mutational load (TML) measured in tumors using NGS.

      Results:
      Overall TC PD-L1 positivity was significantly higher in NSCLC compared with metastatic tumors (28% vs. 14%, p = 0.009) although some metastatic cancers (e.g. triple-negative breast and head/neck carcinomas, melanoma) exhibited higher TC PD-L1 expression. In contrast, overall IC PD-L1 expression was predominantly observed in metastatic tumors (28% vs. 0%, p < 0.001). The IC PD-L1 expression ranged from 0% for metastatic renal cell carcinomas to 36-38% in the metastatic breast and colon carcinomas and melanoma. Consequently, the stratification based on PD-L1 distribution (TC vs. IC), resulted in significantly different patterns between the primary and metastatic tumors (p < 0.001, Table). Mean TML (±SD) for NSCLC (10±5.6) differed significantly from metastatic carcinomas from other sites (6.6±2.7) (p = 0.013).

      Conclusions:
      Our study indicate that a substantial proportion of metastatic tumors to the lung exhibit PD-L1 expression on either tumor or inflammatory (immune) cells and are potentially amenable for the treatment with immune check point inhibitors.rnTable: 149Prn

      rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn
      HistotypesTME categories (PD-L1 expression)Total
      TC+/IC+TC-/IC-TC+/IC-TC-/IC+
      NSCLC05823081
      Metastatic tumors81111641176
      Total81693941257
      rn

      Clinical trial identification:


      Legal entity responsible for the study:
      None

      Funding:
      Caris Life Sciences

      Disclosure:
      Z. Gatalica: Employee of Caris Life Sciences. J. Senarathne: Jude Senarathne is an employee of Caris Life Sciences. S. Vranic: Received honoraria from Caris Life Sciences.

    • +

      150P - Immunohistochemical characteristics of brain metastases and corresponding primary lung cancer (ID 360)

      12:30 - 12:30  |  Author(s): D. Marinova, Y. Slavova, S. Nachev, D. Dimitrova, E. Mekov, M. Mihailov, D. Kostadinov, V. Youroukova

      • Abstract

      Background:
      About 40% of patients with lung cancer (LC) develop brain metastases (BM). The prognosis is poor. The study of BM is important for better understanding of the biology of LC.

      Methods:
      Surgically resected BMs and corresponding primary LCs from 30 patients (men n = 25, 83%; age 55±9) were studied: adenocarcinoma (AC)-21, squamous cell carcinoma (SCC)-5, small cell lung carcinoma (SCLC)-4. The histological subtype and immunohistochemical expression of TTF-1, p63, cytokeratin 7, synaptophysin, Ki-67 (proliferative activity) and CD31 (number intratumoral microvessels-NIM) were evaluated.

      Results:
      The histology of LC compared with BM is different in half of the AC and without difference in SCC and SCLC. ACs are mainly with acinar (53% cases) and solid (37%) components. Metastatic ACs are more often with papillary (47%) component. In 47% of AC BM has different histological structure than LC. The acinar AC are predominantly papillar in 70% of BM showing that the papillary component metastasize most frequently. TTF-1 is expressed in greater number of lung AC (n = 20, 95%), but with lower mean levels of expression, while the corresponding BM express the marker less frequently (n = 16, 76%), but when it is presented it has higher mean values of expression (45.44 vs73.88, p = 0.011). P63 is expressed in high percentage in all SCC (n = 5,100%); there is no difference in expression between LC and BM (80.6 vs 81.6, p = 0.68). Cytokeratin 7 is expressed in all AC equally regardless of the site - primary or metastatic. Ki-67 proliferative index (PI) is higher in SCLC than in lung AD (p = 0.008), in SCLC BM than in AD BM (p < 0.001), in SCLC BM than in SCC BM (p = 0.008). It was found that the Ki-67 PI BM is higher than that of AC LC (30 vs. 17, p = 0.003), in SCC (35 vs.27, p = 0.048) but without difference in SCLC (p = 0.141). CD31 establish vascular invasion in LC – NIM is higher in AC than in SCLC (55vs.31, p = 0.003), in SCC than in SCLC (61vs.31, p = 0.009), no difference between AC and SCC (66 vs.61, p = 0.467). There were no significant differences between LC and BM.

      Conclusions:
      There are differences between primary LC and corresponding BM – in histology structure, in immunohistochemical expression, and in proliferative activity.

      Clinical trial identification:


      Legal entity responsible for the study:
      Medical University, Sofia.

      Funding:
      Supported by Grant 360/2015-Contract Nr.76/2015 funded by Medical University, Sofia.

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      151P - Predictors of survival in patients with bone metastasis of lung cancer (ID 354)

      12:30 - 12:30  |  Author(s): S. Jagadeesan

      • Abstract

      Background:
      In non-small cell lung cancer patients (NSCLC), median survival from the time patients develop bone metastasis is classically described being inferior to 6 months. We investigated the subcategory of patients having skeletal-related-event revealing NSCLC. The purpose of this study was to assess the impact of bone involvement on overall survival and to determine biological and tumoral prognosis factors on OS.

      Methods:
      We assessed the survival rates after bone metastasis and prognostic factors in 28 patients with bone metastases from lung cancer. We first assessed the survival rates and explored various prognostic factors of 28 patients with bone metastasis from lung cancer. We then preliminarily ascertained in a small group of patients whether treatment with an EGFR inhibitor had the potential to influence survival.

      Results:
      The cumulative survival rates after bone metastasis from lung cancer were 59.9% at 6 months, 31.6% at 1 year, and 11.3% at 2 years. The mean survival was 9.7 months (median, 7.2 months; range, 0.1–74.5 months). A favorable prognosis was more likely in women and patients with adenocarcinoma, solitary bone metastasis, no metastases to the appendicular bone, no pathologic fractures, performance status 1 or less, use of systemic chemotherapy, and use of an epithelial growth factor receptor inhibitor.

      Conclusions:
      Bone metastases are a common problem in advanced lung cancer. While the benefits of bone-targeted therapies have been demonstrated, their use is limited in non-trial populations. If better predictive markers of individual risk were available this might increase the appropriate use of bone-targeted agents.

      Clinical trial identification:


      Legal entity responsible for the study:
      S. Jagadeesan

      Funding:
      N/A

      Disclosure:
      The author has declared no conflicts of interest.

    • +

      152P - Relationship between overall survival and preoperative parameters in patients with colorectal cancer and synchronous liver and lung metastases (ID 451)

      12:30 - 12:30  |  Author(s): F. Lumachi, S.M. Basso, U. Zuccon, F. Maffeis, A. Del Conte, P. Ubiali

      • Abstract

      Background:
      The overall survival (OS) of patients with synchronous colorectal cancer (CRC) and pulmonary metastases (PMs) is significantly shorter, but the optimal surgical strategy, including simultaneous colorectal and liver resection vs. delayed liver metastasectomy, has not been defined. The aim of this retrospective study was to evaluate the relationship between OS and preoperative parameters, including age, number and median size of metastases, in patients with PMs from CRC and synchronous or metachronous liver metastases (LMs).

      Methods:
      The medical charts of a group of 20 patients (9 man, 11 women, median age 60 years, range 31-75) who underwent curative surgery for CRC and developed both PMs and synchronous or metachronous LMs were reviewed. Eleven patients aged <65 years, whilst 9 patients aged 65 years or older. Written informed consent was obtained from all the participants. The Pearson correlation coefficient (R) and the linear regression equation calculation was obtained. Because the data were not normally distributed, the Mann-Whitney U-test was used to evaluate statistical significance of correlations.

      Results:
      The median OS was 12.0 months (range 1-58 months) and the overall disease-free interval (DFI) was 2.7±1.9 months. The OS showed a difference in favor of the older (≥65 years) patients (43.3±21.3 vs. 20.1±23.3, p = 0.036). As expected, a strong direct linear relationship between OS and DFI (R = 0.8469, p < 0.000001) was found. There was no significant correlation between OS and both median size (R=−0.3976, p = 0.8256, regression line equation: mm = 21.820349609352-0.20184496105481OS) and number of metastases (R=−0.2975, p = 0.2025, regression line equation: Number=3.294978403666-0.039208413596717OS). Surprisingly, a direct strong relationship between OS and the age of the patients (R = 0.6098, p = 0.0043, regression line equation: age=52.147836178944 + 0.46213761830125OS) was found.

      Conclusions:
      Our results suggest that patients with both PMs and LMs from CRC aged ≥65 years should undergo metastasectomy (in lack of contraindication to surgery) regardless of other parameters, including number and size of metastases, because OS directly correlates with age.

      Clinical trial identification:


      Legal entity responsible for the study:
      Università degli Studi di Padova

      Funding:
      Università degli Studi di Padova

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      153P - Predictive markers of survival in patients with pulmonary metastases and malignant pleural effusion (ID 404)

      12:30 - 12:30  |  Author(s): F. Lumachi, S.M. Basso, R. Tozzoli, A. Del Conte, U. Zuccon, P. Ubiali

      • Abstract

      Background:
      Lung metastases (LMs) can be identified in up to 30-50% of all cancer patients, and represent the result of metastatic spread to the lungs from the several cancers. The presence of LMs seriously affects overall survival (OS), and the onset of pleural effusion further reduces the life expectancy of the patients. The aim of this retrospective study was to evaluate the usefulness of carcinoembryonic antigen (CEA), lactate dehydrogenase (LDH), and C-reactive protein (CRP) measurement in the pleural fluid of patients with LMs and malignant pleural effusion (MPE).

      Methods:
      The medical records of 22 patients (median age 68 years, range 46-86) with LMs (mainly from breast, urinary tract, and colorectal cancers) and MPE were analyzed. There were 13 (59.1%) males and 9 (40.9%) females. All patients underwent video-assisted thoracoscopic (VAT)-assisted thoracentesis and subsequent pleural fluid examination, including CEA, LDH, and CRP, which were measured using a chemiluminescent (CLIA) immunoassay (sandwich CLIA with native CEA coated to magnetic microbeads), a spectrophotometric assay (L-lactate as substrate), and an immunonephelometric assay (polystyrene particles coated with anti-human CRP monoclonal antibodies), respectively.

      Results:
      The OS was 6.7±5.2 months (range 1-23 months), and the levels of pleural markers were 10.4±21.6 ng/mL (CEA), 418.4±342.9 U/L (LDH), and 6.2±9.1 mg/L (CRP). No relationship was found between OS and the age of the patients (R = 0.14, p = 0.542), LDH (R=-0.31, p = 0.169) or CRP (R=-0.33, p = 0.136). There was a significant direct correlation between OS and CEA (R = 0.66, p = 0.0007). The relative regression line equations are reported in the table.rnTable: 153Prn

      rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn
      ParameterRegression line equation
      Age of the patientsOS = 63.323797651973 + 0.23725477330884 age
      CEAOS = 2.0616207417742-4.4634344843623 CEA
      LDHOS = 470.3738751303-20.900941750959 LDH
      CRPOS = 12.210673177537-0.84687826996861
      rn

      Conclusions:
      In patients with MPE and LMs, only CEA pleural levels significantly related to OS, and can be considered a useful predictive factor. Further studies will eventually confirm our results.

      Clinical trial identification:


      Legal entity responsible for the study:
      Università degli Studi di Padova

      Funding:
      Università degli Studi di Padova

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      154P - Analysis of factors affecting survival in patients with simultaneous liver and pulmonary metastases from colorectal cancer (ID 450)

      12:30 - 12:30  |  Author(s): F. Lumachi, S.M. Basso, U. Zuccon, F. Maffeis, A. Del Conte, P. Ubiali

      • Abstract

      Background:
      In patients with colorectal cancer (CRC) the presence of simultaneous liver (LMs) and pulmonary metastases (PMs) is uncommon, but may significantly affect overall survival (OS). The aim of this study was to identify the prognostic factors (PFs) influencing OS in such a group of patients.

      Methods:
      We retrospectively reviewed the medical records of 36 patients (mean age 62.2±10.5 years) with CRC who underwent curative surgical resection and developed PMs during follow up requiring video-assisted thoracoscopic (VATS) metastasectomy. There were 21 (58.3%) males and 15 (41.7%) females. Twenty (55.6%) patients had already LMs at the time of VATS. Survival curves were estimated by Kaplan-Meyer method and compared with log rank testing. Cox proportional hazard model (HR) calculation (stepwise logistic regression) was used in the multivariate analysis, to identify the independent variables. A p-value of < 0.01 (two-tailed) was considered statistically significant.

      Results:
      The OS of the entire population ranged widely (30.6±25.1 months), according to patient age (p = 0.004), presence of involved mesenteric (p = 0.0003) or thoracic (p = 0.0001) lymph nodes, number of the involved nodes (p = 0.006), and simultaneous LMs and PMs (p = 0.0002). There was no relationship between gender (p = 0.67) or the mean size of metastases (p = 0.53) and OS. A tendency towards a correlation between age and the presence of lymph node involvement (p = 0.050) was also observed. The regression analysis showed that the number of LMs (HR = 1.37, 95% CI: 1.14-1.67, p = 0.0011), and the presence of node involvement, both thoracic (HR = 11.49, 95% CI: 1.49-88.58, p = 0.0191) and mesenteric (HR = 5.79, 95% CI: 1.27-26.30, p = 0.0230), were independent parameters affecting OS.

      Conclusions:
      In patients with CRC with both LMs and PMs only lymph node involvement and their number should be considered as negative PFs. In conclusion, the results of liver metastasectomy are independent of age, gender, and size of metastases, and thus this therapeutic approach should be suggested in all node-negative patients suitable for surgery, regardless of other PFs.

      Clinical trial identification:


      Legal entity responsible for the study:
      Università degli Studi di Padova

      Funding:
      Università degli Studi di Padova

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      155P - Combination of hepatic surgery and minimally invasive thoracic surgery using a subxyphoid approach through an abdominal incision (ID 323)

      12:30 - 12:30  |  Author(s): M. Lim, D.H. Kim

      • Abstract

      Background:
      If an intrathoracic mass is found in a patient scheduled for open hepatic surgery, combined surgery is not recommended because of the high risk. If combined surgery is essential, the thoracic approach must be minimally invasive. We here introduce a subxyphoid approach through an abdominal incision to minimize the invasiveness of combined thoracic and hepatic surgery.

      Methods:
      From April 2012 to December 2016, 17 patients requiring combined hepatic and thoracic surgery were treated via the subxyphoid approach through an abdominal incision. We retrospectively analyzed the clinical data and evaluated the feasibility of the procedure.

      Results:
      The hepatic lesions included 7 cases (41.2%) of colon cancer metastases and 10 cases (58.8%) of primary hepatocellular carcinoma. The types of liver resection performed included two wedge resections (11.8%), two multiple wedge resections (11.8%), eight segmentectomies (47.1%), three lobectomies (17.5%), and two other procedures (11.8%). Unilateral, mediastinal, and bilateral subxyphoid approaches toward thoracic surgery were employed in 11 (64.7%), 2 (11.8%), and 4 (23.5%) cases, respectively. The thoracic surgeries included six cases (35.3%) of wedge resection, five cases (29.4%) of multiple wedge resection, two (11.8%) segmentectomies, and four (23.5%) mediastinal mass excisions. The mean number of lung masses excised was 1.7±1.0 (range 1–5). No lung-related morbidities were noted; one patient died as a result of the abdominal procedure. The mean thoracic and total operation times were 79.7±63.0 min (range, 20–205 min) and 411.0±109.0 min (range, 255–635 min), respectively. Mean ICU and mean hospital stay did not differ between the patients described above and others who underwent open hepatic surgery during the same period.

      Conclusions:
      The subxyphoid approach through an abdominal incision allows aggressive treatment of intrathoracic masses in patients scheduled for open hepatic surgery. This approach did not have a significant impact on the time of operation and the period of the recovery. The approach is especially suitable for patients with bilateral lung lesions.

      Clinical trial identification:


      Legal entity responsible for the study:
      Department of Cardiovascular and Thoracic Surgery, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital

      Funding:
      Department of Cardiovascular and Thoracic Surgery, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      156P - Clinical outcome of cyberknife radiosurgery in brain metastases of non-small cell lung cancer: A single institutional experience (ID 444)

      12:30 - 12:30  |  Author(s): S. Lee, Y. Kim, Y.K. Won, S.J. Lee, J.H. Hong, Y.N. Kang, J.H. Kang, S. Hong, S.J. Kim, Y.K. Kim

      • Abstract

      Background:
      Stereotactic radiosurgery is a less invasive therapeutic modality for brain metastasis of non-small cell lung cancer (NSCLC). We retrospectively reviewed a single institutional experience using Cyberknife radiosurgery (CKRS).

      Methods:
      The patients diagnosed with brain metastasis of NSCLC who were treated with CK-RS from 2006 to 2016 in Seoul St. Mary’s Hospital were analyzed. Total 304 targets from 150 patients were included. The histology of NSCLC patients was as follows: adenocarcinoma (85%), squamous cell carcinoma (9%), and others (7%). Median 22 Gy (range: 17-30Gy, 1-8 fx) was given. Median 2 targets (range: 1-7 targets) were treated per patient. Whole brain radiotherapy (WBRT) was given to 44.7% of the patients. Total 68 patients (45.5%) were mutation positive and targeted therapy was given to 95 patients (63.3%).

      Results:
      Median follow-up time was 11.4 mo (range: 0-94.6 mo) from the last day of CKRS. Response to CKRS was observed in 86.1% of the targets. Median time to response was 2.9 mo (range: 0.2-58.8 mo). At the time of analysis, there were 14 recurrences (4.6%) and median time to recurrence was 13.3 mo (range: 4.1-62.6 mo). Intracranial failure defined as appearance of new metastasis other than sites previously treated with CKRS was observed in 81 patients (54.7%) at median 8.9 mo (range: 7-10.8 mo). The 1-year intracranial failure rates of the patients who received targeted therapy were 64.8% versus 55.3% of those who did not, respectively (P = 0.38). The 1-year intracranial failure rates of the patients who received CKRS alone were 64% versus 58.3% of those who received both CKRS and WBRT, respectively (P = 0.58). Radiation-associated change on MRI was observed in 98 targets (32.3%) at median 7.0 mo (range: 0.4-68.8 mo). Eleven patients (7.3%) required steroids for symptom alleviation at median 21 days (range: 7-42 days). Five patients (3.0%) underwent surgery after median 7.0 mo (range: 2.8-74.2 mo). The patients survived median 12.6 mo (range: 0.3-94.8 mo) after CKRS.

      Conclusions:
      According to our institutional experience, CKRS achieved adequate local control with tolerable toxicity in patients with brain metastasis of NSCLC.

      Clinical trial identification:


      Legal entity responsible for the study:
      The institutional review board reviewed and approved of the study.

      Funding:
      N/A

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      157P - Mediastinal masses: A study of our cases by transthoracic needle biopsy (TTNB) versus open surgery as a diagnostic procedure (ID 187)

      12:30 - 12:30  |  Author(s): F. Gradica, L. Lisha, D. Argjiri, A. Cani, A. Leka, F. Kokici, S. Gradica, Y. Vata, F. Gradica, V. Rexha

      • Abstract

      Background:
      Mediastinal tumors are an uncommon abnormalities found in clinical practice. Transthoracic needle biopsy (TTNB) is done with imaging guidance and most frequently by a radiologist but and by a thoracic surgeon, for the aim is to diagnose a defined mass. It is integral in the diagnosis and treatment of many thoracic diseases, and is an important alternative to more invasive surgical procedures. Open biopsy is done by chamberlein procedures under general anesthesia.

      Methods:
      We evaluate the different malignant mediastinal mass (MMs) in various age groups and the sensitivity and early mortality rate of open biopsy 2004 to 2013 and transthoracic needle biopsy (TTNB) and core needle biopsy (CNB) 2013-2016. This was a prospective study of 80 patients who were consulted for MMs and underwent open biopsy from 2004 to 2013 and 20 patients underwent by thoracic surgeon TTNB and CNB under guidance of ultrasound or computed tomography (CT) scan from 2013 to 2016. Cytology and histological examinations were evaluated in all patients.

      Results:
      Among 80 cases, 63 were male and 17 were female were diagnosed by open biopsy from 2004 to 2013. Among 20 cases, 13 males and 7 females were diagnosed by TTNB. Mean age of presentation was 57 years old (ranging from 50-75 years old). Metastatic carcinoma and nonHodgkin's lymphoma are the common AMMs. Adequate tissue material by open biopsy was obtained in 80 cases and 17 of 20 cases (85%) by TTNB. Of these 17 patients, 15 (88,2%) cases were diagnosed correctly by TTNB, whereas 3 (11,8%) cases were not diagnosed definitely by TTNB. The sensitivity of TTNB for MMs was 85%, and no mortality whereas open biopsy were correctly diagnosed in 77 of 80 cases (96.25%) patients and operative mortality rate 2 patients (2.5%) and operative major compliactions in 3 (3.7%) patents had massive operative bleeding. Three cases (3.7%) had died after several mounths after open biopsy with out histological diagnosis. There is no significant difference of TTNB and open biopsy in carcinoma patients (P > 0.05). Operative mortality rate was higher for open biopsy in carcinomatous patients (3.7%) than for TTNB (0%).

      Conclusions:
      CT scan-guided TTNB and CNB in combination with FNAC are safe, minimally invasive, and cost-effective procedure, with low morbitity rate and major complications, which can provide a precise diagnosis in the MMs, and may obviate the need for invasive surgical approach. Invasive surgical approach should be performed whenever the diagnosis by TTNB or CNB is suspected of carcinoma but not established.

      Clinical trial identification:
      -

      Legal entity responsible for the study:
      N/A

      Funding:
      N/A

      Disclosure:
      All authors have declared no conflicts of interest.

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      158TiP - Open label, multi-center, prospective study to investigate the efficacy and safety of osimertinib in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI (APOLLO Study, NCT02972333) (ID 250)

      12:30 - 12:30  |  Author(s): L. Wang, L. Xing, L. Cao, L. Wang, X. Wang, J. Feng, Y. Shu, Y. Shi, Y. Song, J. Yu

      • Abstract

      Background:
      The development of EGFR-TKI have led to significant advances in patients with tumors harboring EGFR mutations (EGFRm). However, increasing incidence of central nervous system (CNS) metastasis (∼40%), including leptomeningeal metastasis (LM) and brain metastasis (BM), has been reported, particular in EGFR mutant NSCLC receiving EGFR TKI treatment. Due to limited blood brain barrier (BBB) penetration of current EGFR inhibitors (i.e. 1st generation EGFR TKIs such as gefitinib, erlotinib or icotinib and 2nd generation TKIs e.g. afatinib), these drugs can only exhibit limited efficacy on CNS metastasis. Furthermore, the acquiring resistance may commonly occur due to the development of EGFR T790M mutation. Osimertinib is a novel oral, potent and irreversible inhibitor of both EGFRm sensitizing and T790M resistance mutants. In a combined analysis from AURA (NCT01802632) and AURA2 (NCT02094261) study, the ORR of pts with CNS metastases was 56%, whilst 64% in pts without CNS metastases, demonstrating the potential benefits of osimertinib in pts with BM.

      Trial design:
      This is an open label, multi-center, prospective study to investigate the efficacy and safety of osimertinib in pts with BM. Pts with confirmed EGFR T790M positive NSCLC who received prior therapy with an EGFR-TKI and concurrent with brain metastasis will be enrolled. All eligible patients will have access to osimertinib 80mg once-daily as long as they show clinical benefit as judged by the investigator and in the absence of discontinuation criteria. All consenting pts will be required to provide CSF and blood samples pre-treatment, 6 weeks after treatment and at PD. All pts receiving osimertinib will be followed for clinical outcomes (tumor response, survival, etc) and patient reported outcomes at baseline and every 12 weeks (± 7days investigator per RECIST 1.1 until objective disease progression, intolerant toxicity, loss of follow up). A sample size of 100 patients will provide 80% power to evaluate the treatment profile of Osimertinib and its impact on the molecular evolution. The First subject in is on 11[th] January, 2017.

      Clinical trial identification:
      APOLLO Study (protocol number: NCT02972333) was released on November 23, 2016.

      Legal entity responsible for the study:
      Jinming Yu, Shandong Cancer Hospital

      Funding:
      AstraZeneca

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      159TiP - TTFields and radiosurgery for 1-10 brain metastases from NSCLC: The Phase 3 METIS study (ID 409)

      12:30 - 12:30  |  Author(s): M.P. Mehta, V. Gondi, P.D. Brown

      • Abstract

      Background:
      Tumor Treating Fields (TTFields) are non-invasive, loco- regional, anti-mitotic treatment modality, based on low intensity alternating electric fields. Efficacy of TTFields in non-small cell lung cancer (NSCLC) has been demonstrated in multiple in vitro and in vivo models, and in a phase I/II clinical study. TTFields treatment to the brain was shown to be safe and to extend overall survival in newly-diagnosed glioblastoma patients.

      Trial design:
      The study objectives are to test the efficacy, safety and neurocognitive outcomes of TTFields in this patient population. Patients (N = 270) with 1-10 brain metastases (BM) from NSCLC are randomized in a ratio of 1:1 to receive stereotactic radio surgery (SRS) followed by either TTFields or supportive care alone. Patients are followed-up every two months until 2[nd] cerebral progression. Patients in the control arm may cross over to receive TTFields at the time of 2[st] cerebral progression. Key inclusion criteria: Karnofsky performance status (KPS) of 70 or above, 1 inoperable or 2-10 brain lesions amenable to SRS, optimal standard therapy for the extracranial disease, no brain-directed therapy, no signs of significantly increased intracranial pressure, and no electronic implantable devices in the brain. Endpoints: Time to 1[st] cerebral progression based on the RANO-BM Criteria or neurological death (primary); time to neurocognitive failure based on the following tests: HVLT, COWAT and TMT; overall survival; radiological response rate; quality of life; adverse events severity and frequency (secondary). Treatment: Continuous TTFields at 150 kHz for at least 18 hours per day are applied to the brain within 7 days of SRS. The treatment system is a portable medical device allowing normal daily activities. The device delivers TTFields to the brain using 4 Transducer Arrays, which may be covered by a wig or a hat for cosmetic reasons. Patients receive the best standard of care for their systemic disease. Statistical Considerations: This is a prospective, randomized, multicenter study for 270 patients. The sample size was calculated using a log-rank test (based on Lakatos 1988 and 2002) and has 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57.

      Clinical trial identification:
      NCT02831959

      Legal entity responsible for the study:
      Novocure

      Funding:
      Novocure

      Disclosure:
      M.P. Mehta: Grants/research support: Novocure; Cellectar (both to institution, not to self) Advisor/board member: Board of Directors of Pharmacyclics Consultant: Cavion, Novocure, Varian, Agenus, Insys, Remedy, IBA Stock shareholder: Pharmacyclics. V. Gondi: Educational honoraria: Novocure Consultant: INSYX Therapeutics. All other authors have declared no conflicts of interest.

    • +

      160P - BAP1 in advanced sporadic malignant pleural mesothelioma (ID 304)

      12:30 - 12:30  |  Author(s): A. El Bastawisy, R. Shehab, A. Bahnassy, N. Sabri

      • Abstract

      Background:
      BAP1 mutation has been previously described in familial malignant pleural mesothelioma (MPM), however a little is known about its role in sporadic MPM.

      Methods:
      This is a prospective study including all eligible cases of MPM presenting to NCI, Cairo University, Egypt during the years 2013-2016. BAP1 analysis was done by PCR. Patients received first line chemotherapy (Pemetrexed/platinum). Primary objective was to evaluate the rate of BAP1 mutation in MPM, secondary objectives: To evaluate the correlation of BAP1 mutation and objective response rate (ORR), progression free survival (PFS) and overall survival (OS) in advanced MPM.

      Results:
      Among 120 cases, 38.5% showed positive BAP1 mutation.56.5% in the mutated group showed overall clinical benefit (CR+PR+SD) versus 46.2% in the wild group. (P = 0.34). One year PFS in the mutated group was 50.5% versus 38.5% in the wild group. (P = 0.31). One-year OS in the mutated group was 54.5% versus 47.6% in the wild group. (P = 0.67).

      Conclusions:
      BAP1 mutation is present in high frequency in a Caucasian population however it was not associated with clinical outcome after first line platinum based chemotherapy.

      Clinical trial identification:


      Legal entity responsible for the study:
      National Cancer Institute and Faculty of Pharmacy, Cairo University, Egypt

      Funding:
      National Cancer Institute and Faculty of Pharmacy, Cairo University, Egypt

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      161P - DKK1 stabilization as a new malignant pleural mesothelioma therapeutic avenue (ID 490)

      12:30 - 12:30  |  Author(s): A. Guazzelli, E. Bakker, F. Sotgia, M. Listanti, M. Krstic-Demonacos, L. Mutti

      • Abstract

      Background:
      Malignant Pleural Mesothelioma (MPM) is a cancer with a hypoxic microenvironment. Hypoxic niches favor “stemness” in cancer cell formation and therefore represent a novel therapeutic target. DKK1 (dickkopf) abrogates WNT signaling via lipoprotein-related protein 5/6 (LRP5/6) and secreted frizzled related proteins (sFRPs)-mediated interference. Doxycycline (DXC) has the potential to be a repositioned drug with potent inhibition of mitochondrial biogenesis, targeting cancer stem-like cell (CSC) generation. The aim of this study has been to assess the effect of DXC on DKK1 expression and MPM-CSC generation.

      Methods:
      We have conducted a microarray analysis in MPM cell lines in normoxic and hypoxic (1% O~2~) conditions and on the basis of this experiment we have performed Western blot analysis of DKK1 and assessed MPM-CSCs generation (meso-spheres) in the same conditions before and following treatment with Doxycycline.

      Results:
      Microarray analysis showed a significant increase in DKK1 following treatment with DXC (7.56 fold). However, hypoxic conditions showed progressive DKK1 degradation compared to normoxic conditions (as assessed by Western blotting), thus confirming the role of WNT signaling in hypoxia. Treatment with DXC promoted DKK1 stabilization in both normoxia and hypoxia and significantly prevented CSC generation via hampering DKK1 degradation in hypoxic conditions.

      Conclusions:
      We have identified that both hypoxia and doxycycline exert differential cell-specific effects on DKK1 expression in cell monolayers, thus identifying DKK1 as a potential target for therapeutic development. DKK stabilization by DXC in hypoxic conditions paves the avenue of new therapeutic approaches aimed at WNT signaling regulation.

      Clinical trial identification:
      N/A

      Legal entity responsible for the study:
      Luciano Mutti\'s research group at the University of Salford

      Funding:
      G.I.Me. – Gruppo Italiano Mesotelioma and University of Salford

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      162P - Targeting the RON/MET/TAM signalling network in mesothelioma (ID 447)

      12:30 - 12:30  |  Author(s): A. Baird, M. Jarzabek, L. Shiels, S. Raeppel, S. Finn, S. Cuffe, H.I. Pass, I. Schmitt-Opitz, A.T. Byrne, S.G. Gray

      • Abstract

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer, with limited treatment options and poor survival rates. Simultaneously targeting the RON/MET/TAM family of receptor tyrosine kinases (RTK) may provide an effective novel therapeutic strategy for this disease.

      Methods:
      Expression of RON/MET/TAM and associated ligands were assessed in a cohort of patient samples and MPM cell lines. In vitro and in vivo experiments were undertaken to determine the efficacy of single and multi RTK targeting agents (LCRF0004, RXDX-106, BMS-777607).

      Results:
      mRNA expression of the RON/MET/TAM family was detected in a large panel of normal pleural and MPM cell lines. In a cohort of patient samples, mRNA levels of flRON, sfRON, c-MET, Axl and Tyro3 were increased in MPM tumour samples compared with benign pleural (p < 0.05). There was no difference detected in MERTK expression. In addition, MSP was also elevated in tumour tissue (p < 0.05), whereas GAS6 was not. Furthermore, no MET Exon 14 skipping mutations were detected. All RTK targeting agents displayed in vitro efficacy in terms of reduced proliferation and increased apoptosis. In an in vivo SQ xenograft model the multi-target TKI (BMS-777607) demonstrated superior anti-tumour activity compared with a single targeting agent (LCRF0004).

      Conclusions:
      Data suggests that a multiple TKI, targeting the RON/MET/TAM signalling network, is superior to selective RTKi as an interventional strategy in MPM.

      Clinical trial identification:
      N/A

      Legal entity responsible for the study:
      St. James\'s Hospital

      Funding:
      HRB

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      164P - Heart radiation dose as a risk factor for dyspnea worsening after multimodality treatment for non-small cell lung cancer and pleural mesothelioma: An exploratory analysis (ID 500)

      12:30 - 12:30  |  Author(s): A. Botticella, C. Billiet, G. Defraene, C. Draulans, K. Nackaerts, C. Deroose, J. Coolen, P. Nafteux, D. De Ruysscher

      • Abstract

      Background:
      The purpose of our study is to quantify the influence of heart dose on the early and late onset of dyspnea in a cohort of radiotherapy (RT)-treated non-small cancer patients (NSCLC) and malignant pleural mesothelioma (MPM) patients after multimodality treatment, according to the type of surgery.

      Methods:
      In 121 patients with multimodality-treated NSCLC and MPM the maximal dyspnea score (CTCAE 4.0) before RT and at an early (≤6 months) and a late (7-12 months) time point were obtained. Included patients needed to be clinically and radiologically progression-free 9 months after the end of RT. The difference (Δ) between the maximal dyspnea at ≤ 6 months and the pre-RT dyspnea or the maximal dyspnea at 7-12 months and the pre-RT dyspnea was calculated.

      Results:
      Our results show that 44% (50/113) of patients developed an early worsening of at least 1 point in their dyspnea score (Δdyspnea ≥1) after the end of RT. As independent predictors of an early worsening, we identified the MHD (for Δdyspnea ≥1: OR = 1.032, p = 0.04) and the dyspnea score before RT (for Δdyspnea ≥1: OR = 0.40, p = 0.0001; for Δdyspnea ≥2: OR = 0.35, p = 0.05). At a later timepoint, only the dyspnea score before RT (OR: 0.40, p = 0.001) was identified as predictor of for Δdyspnea ≥1.

      Conclusions:
      Our results, albeit exploratory, suggest that heart dose may play a role in the early worsening of the dyspnea in a heterogeneous cohort of multimodality treated RT patients.

      Clinical trial identification:


      Legal entity responsible for the study:
      KUL UHasselt-ZOL-Jessa

      Funding:
      This study is part of the Limburg Clinical Research Program (LCRP) UHasselt-ZOL-Jessa, supported by the foundation Limburg Sterk Merk, province of Limburg, Flemish government, Hasselt University, Ziekenhuis Oost-Limburg and Jessa Hospital. This work was partly funded by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no 601826 (REQUITE). CB is supported by the Cancer foundation Limburg and a grant from ‘Kom op tegen kanker’. AB is supported by a grant from the Stichting tegen kanker/Fondation contre le cancer (CA/2014/354) and by Kom op Tegen Kanker (Stand up to Cancer, The Flemish Cancer Society).

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      165P - Malignant pleural mesothelioma: A systematic review of first-line chemotherapy and analysis of Hong Kong cohort (ID 281)

      12:30 - 12:30  |  Author(s): H. Pang, J. Ji, K. Yan, C.C. Leung, D. Lam

      • Abstract

      Background:
      Malignant pleural mesothelioma (MPM) is a rare but aggressive cancer. Although the standard first-line chemotherapy for MPM has been established, many different treatments are still under investigation. Additionally, epidemiologic analysis of MPM patients in Hong Kong has not been conducted in recent years.

      Methods:
      To review the progress in first-line chemotherapy treatment for MPM patients between 2010 and 2016, and to study the epidemiology and prognostic factors of Hong Kong MPM patients from 2002 to 2015. A thorough literature search was performed on PubMed and Cochrane Library (CENTRAL), restricted to English papers released between January 2010 and May 2016. Hong Kong MPM patients were identified from Pneumoconiosis Medical Board (PMB) by reviewing medical records. Kaplan-Meier and log-rank tests were used to compare survival between categories. Prognostic factors were identified by Cox regression analysis.

      Results:
      22 studies were included in the review. Pemetrexed/cisplatin is the recommended first-line regime now. Studies suggested that carboplatin plus pemetrexed can be an alternative regimen to reduce toxicity. The addition of bevacizumab to pemetrexed/cisplatin showed promising results and may become a new paradigm. Gemcitabine plus cisplatin, especially administrated in low dose prolonged infusion, showed comparable efficacy with lower cost. From the Hong Kong PMB clinic, 102 MPM patients were identified, with male predominance, mean age of 69.1 years at diagnosis, mean latency of 49 years, median overall survival of 11.7 months and mainly epithelioid histological subtype. Other possible prognostic factors like symptoms of chest pain and dyspnea were explored.

      Conclusions:
      Cisplatin plus pemetrexed, has been supported in routine practices settings. Carboplatin can substitute cisplatin to reduce toxicity. Bevacizumab plus cisplatin-pemetrexed triplet with appropriate management of treatment-related toxicity is the most promising first-line treatment. Hong Kong MPM patients share similarities in terms of prognostic factors with those in the literature.

      Clinical trial identification:


      Legal entity responsible for the study:
      HKU

      Funding:
      Pneumoconiosis Compensation Fund Board

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      166P - Thymoma and thymic carcinoma: A real-life retrospective analysis (ID 472)

      12:30 - 12:30  |  Author(s): I. Attili, S. Frega, A. Pavan, G. Pasello, V. Polo, G. Zago, F. Rea, F. Calabrese, P. Conte, L. Bonanno

      • Abstract

      Background:
      Thymic epithelial tumors (TETs) include thymoma and thymic carcinoma, a group of rare and heterogeneous thoracic cancers. The management is primarily surgical, but pre- and post-operatory chemotherapy and radiotherapy are to be evaluated. Recurrences after surgery occur in 10-15% of resected tumors.

      Methods:
      We retrospectively collected TETs consecutively treated at our center between 2005 to 2016 and analyzed clinical and pathological features, response to treatment and patterns of relapse. Patients with uncomplete records or with less than 12-month follow-up were excluded from survival analysis.

      Results:
      Study population included 57 TETs. Median age was 55 years, male: female ratio was 1:1, all were ECOG PS 0-1 at diagnosis. Histologic subtype A to B1 thymoma was 21%, B2-B3 47.4%, thymic carcinoma 21%, others 11%. Paraneoplastic syndromes were present at diagnosis in 1/3 of the cases (85% myasthenia gravis), mainly less differentiated histologies (85% B2 thymoma or higher). C-kit immunohistochemistry has been evaluated only in 30 cases, 1/3 resulting positive, 80% associated to thymic carcinoma. 50 cases were included in survival analysis: median follow up was 52 months (m) (95%CI: 30-74m), median overall survival (OS) has not been reached (121m- NA) and was not affected by recurrences (p: 0.34). Treatments and relapse patterns are summarized in table. 66% of patients developed disease relapse (51% pleura) regardless of histology and radical surgery, median time to first relapse was 30 m (95% CI: 6-54m), median OSr (OS from first relapse) was not reached (47m-NA) and was significantly worse for thymic carcinomas (p: <0.0001); OSr was not affected by treatment type, number or site of relapse; the only variable able to affect time to relapse was histology: ῃ[2] 0.27.rnTable: 166PTreatment and relapse patterns in TETs [s: surgery; rt: radiotherapy; c: combined; r: relapse]rn

      rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn
      rnLocal treatment (s: rt: c)Systemic treatmentSystemic+ Local (s: rt: c)Best supportive care
      1[st] diagnosis (N:57)27 (12: 0: 15)327 (8: 4: 15)0
      1[st] r (N:33)14 (5: 2: 7)106 (1: 2: 3)3
      2[nd] r (N:17)9 (6: 1: 2)53 (1:1: 1)0
      3[rd] r (N:9)1 (1: 0: 0)51 (0: 0: 1)2
      4[th] r(N:4)1 (0: 0: 1)11 (0: 0: 1)1
      TOT5224386
      rn

      Conclusions:
      Real-life management of TETs include multidisciplinary evaluation, which is essential also at relapse to integrate local and systemic treatment.

      Clinical trial identification:


      Legal entity responsible for the study:
      Istituto Oncologico Veneto

      Funding:
      Istituto Oncologico Veneto

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      167P - Role of surgery in the treatment of thymic carcinoma based on a 5-year experience (ID 325)

      12:30 - 12:30  |  Author(s): F.F. Caushi, I. Skenduli, J. Shkurti, D. Xhemalaj, A. Hatibi, R. Kortoci, B. Gega, H. Hafizi

      • Abstract

      Background:
      Invasive thymomas and thymic carcinomas are relatively rare neoplasms, which together represent about 0.2-1.5% of all malignancies. Thymic carcinomas account for only 0.06% of all thymic neoplasms and have extremely poor prognosis. In about 50% of the patients, thymic carcinomas are detected by chance with plain-film chest radiography. Nowadays the surgery is going to earn more and more space in their multimodality treatment because of new techniques and new technology.

      Methods:
      We reviewed all cases with histologically confirmed thymic carcinoma treated between 2011 and 2016. This study was performed to investigate the tumor characteristics, treatment approach, and prognosis of patients with thymic carcinoma.

      Results:
      There were 47% males and 53% females in this study. Mean age was 45,4 years. Thymic carcinoma was diagnosed in 13% of patients with mediastinal tumors, as opposed to 60% for thymoma. None of the thymic carcinoma patients had concomitant myasthenia gravis. All of the patients received surgical intervention and the diagnosis was made by pathologic study. The pathologic subtypes of thymic carcinoma included 40% squamous cell carcinomas, 35% undifferentiated carcinomas, 20% carcinoid tumors, and the rest other types of tumors. Surgery performed was en-bloc resection of the tumor in 22% of cases accompanied by partial resection of superior vena cava, total resection of the left innominate vein and partial pericardectomy, and debulking surgery in 18%. In all other cases surgery was undertaken for diagnostic purposes. No perioperative deaths occurred. All cases were treated postoperatively with adjuvant radio and/or chemotherapy. The mean of hospitalized days after surgery was 12±2.

      Conclusions:
      Owing to the paucity of cases, optimal management of thymic carcinoma has yet to be defined, but one thing is for sure, that it requires multimodality treatment. Our experience supports the pivotal role of surgery in managing thymic carcinoma. En-bloc resection of the tumor is an essential treatment for favorable outcomes of locally advanced thymic tumors, while debulking surgery may be considered for patients in advanced stages because it minimizes the tumour size and area for irradiation postoperatively.

      Clinical trial identification:


      Legal entity responsible for the study:
      Fatmir Caushi

      Funding:
      Fatmir Caushi

      Disclosure:
      All authors have declared no conflicts of interest.

    • +

      168P - Clinical and prognostic characteristics of primary pulmonary non-Hodgkin’s lymphoma: A retrospective analysis of 38 cases in a Chinese population (ID 194)

      12:30 - 12:30  |  Author(s): R. Qiao, B. Han, R. Zhong, Y. Zhao, T. Chu, L. Jiang, H. Zhong

      • Abstract

      Background:
      Primary pulmonary non-Hodgkin’s lymphoma(NHL) is very rare, and although the prognosis is favorable, clinical features, beneficial diagnostic procedures, prognostic factors and optimal management have not been clearly defined.

      Methods:
      In this study, thirty-eight cases of primary pulmonary NHL treated in Shanghai Chest Hospital during a 10-year period were retrospectively reviewed, and clinicopathological features and prognosis were analyzed.

      Results:
      There were twenty-eight patients with mucosa-associated lymphoid tissue (MALT) lymphoma, three with diffuse large B-cell lymphoma, one with peripheral T-cell lymphoma, one with mantle cell lymphoma and five with unclassified B-cell lymphoma. The cohort consisted of 21 male and 17 female patients with a median age of 57.5 years. At presentation, 36.8% of patients were asymptomatic, and unilateral tumors occurred more frequently than bilateral and predominantly in the right lung. Thirty-three patients underwent surgical resection single or combination chemotherapy, and five patients received combination chemotherapy alone. Overall survival(OS) was significantly longer in patients with MALT lymphoma than that of non-MALT lymphoma (129.9 vs. 71.5 months, P = 0.019 by log-rank test). Patients who had received surgical resection had a better OS (126 vs. 65.4 months, P = 0.036 by log-rank test). Additionally, multivariate analysis showed that elevated serum lactate dehydrogenase (LDH) level was independently associated with a poor OS (P = 0.048).

      Conclusions:
      Primary pulmonary NHL has atypical clinical manifestations and non-specific imaging changes. Surgical resection is vital in clarifying the diagnosis and obtaining a favorable prognosis. Serum LDH level was an independent prognostic factor.

      Clinical trial identification:


      Legal entity responsible for the study:
      Shanghai Chest Hospital

      Funding:
      Shanghai Chest Hospital

      Disclosure:
      All authors have declared no conflicts of interest.

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      169P - Pulmonary carcinoid tumors: Experience from an oncology center (ID 454)

      12:30 - 12:30  |  Author(s): L. Bei, A. Silva, A.L. Cunha, C. Franco, J. Oliveira, I. Azevedo, I. Pousa, A. Rodrigues, M. Soares, D. Pereira

      • Abstract

      Background:
      Pulmonary carcinoid (PC) tumors are a rare group of pulmonary neoplasms, characterized by neuroendocrine differentiation and indolent clinical behavior. Typical carcinoid (TC) account for the majority of cases, are low-grade and rarely metastasizes. Atypical carcinoid (AC) have worse prognosis, with greater tendency to metastasize and recur locally.

      Methods:
      Retrospective analysis of histologically confirmed PCs diagnosed between 2008 and 2016. Descriptive analysis of the main demographic, clinical and prognostic characteristics was performed. Overall survival (OS) was evaluated using the Kaplan-Meier.

      Results:
      We identified 55 patients (PTS). TC 58.2% (n = 32), AC 36.4% (n = 20), not other specified 3.6% (n = 2) and one case of combined TC and AC (bilateral). Female 56.4% (n = 31), male 43.6% (n = 24). Median age 62 years (range 18-83). Current smoker (SMK) 10.9% (n = 6), ex-SMK 10.9% (n = 6) and non-SMK 58.2% (n = 32). Secondary malignancies in 27.3% (n = 15) of PTS: thyroid (n = 4), breast (n = 3), prostate (n = 3), colorectal (n = 2), endometrium (n = 1), cervix (n = 1) and non-small lung cancer (n = 1). Staging (AJCC 7th Ed.): I (65.5%, n = 36), II (7.3%, n = 4), III (7.3%, n = 4), IV (16.4%, n = 9). Surgery was performed in 38 (86.3%) PTS with localized disease: lobectomy 78,9% (n = 30) pneumonectomy 13.2% (n = 5) and segmentectomy 7.9% (n = 3) and the majority (>90%) had systematic nodal dissection. One PT had adjuvant chemotherapy (CT) - stage IIIA. Recurrence was documented in 5 PTS submitted to complete resection. For advanced or recurrent disease, first line systemic treatment (Tx) was proposed in 9 PTS: somatostatin analogues (SA) (n = 3), CT (n = 3) and SA + CT (n = 3). The CT regimens were platinum + etoposide, streptozocin (STZ) + 5-FU and STZ + doxorubicin. Two PTS were treated after disease progression with further CT, one of them received 177Lutetium DOTA octreotide. 4 PTS underwent radiotherapy in palliative setting. Radioembolization was used to treat liver metastasis in 3 PTS. 5-year OS was 76,2%.

      Conclusions:
      PC’s diagnosis and Tx require an experienced multidisciplinary team. Our results corroborate the literature data regarding epidemiology, high percentage of localized disease amenable for surgery and OS. Despite the emergence of new therapies, advanced disease remains with limited Tx options.

      Clinical trial identification:


      Legal entity responsible for the study:
      Instituto Português de Oncologia do Porto

      Funding:
      Instituto Português de Oncologia do Porto

      Disclosure:
      All authors have declared no conflicts of interest.

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      170TiP - LUME-Meso: Randomised phase II/III study of nintedanib (N) + pemetrexed/cisplatin (PEM/CIS) followed by maintenance N or placebo (P) in chemo-naïve patients with malignant pleural mesothelioma (MPM) (ID 274)

      12:30 - 12:30  |  Author(s): S. Popat, R. Gaafar, A. Nowak, A. Tsao, J. Van Meerbeeck, N. Vogelzang, T. Nakano, D. Velema, N. Morsli, G. Scagliotti

      • Abstract

      Background:
      PEM/CIS is the standard first-line treatment for MPM, with median overall survival (OS) of ∼1 year. N is a triple angiokinase inhibitor of vascular endothelial growth factor (VEGF) receptors 1–3, platelet-derived growth factor (PDGF) receptors α/β and fibroblast growth factor receptors 1–3, as well as Src and Abl kinases. VEGF and PDGF overexpression are associated with poor prognosis in MPM, and N has demonstrated efficacy in preclinical MPM models. We performed a randomised Phase II trial of N or P + PEM/CIS in MPM followed by maintenance N or P; progression-free survival (PFS) was the primary endpoint. An internal Data Monitoring Committee recommended the study be expanded to include a confirmatory Phase III part. With regulatory authority guidance, the Phase II data were unblinded, demonstrating a PFS benefit with N (hazard ratio 0.56, 95% confidence interval 0.34–0.91; p = 0.017); these data assisted in planning the Phase III part including sample size estimation, and N was granted U.S. Food & Drug Administration orphan drug designation for the treatment of MPM in December 2016. The Phase III part (NCT01907100) is recruiting.

      Trial design:
      For Phase III, 450 chemo-naïve patients worldwide (>100 sites in 27 countries) aged ≥18 years with unresectable MPM of epithelioid histology and Eastern Cooperative Oncology Group performance score 0–1 will be randomised 1:1 to receive up to 6 21-day cycles of PEM (500 mg/m[2])/CIS (75 mg/m[2]) on Day 1 plus N or P (200 mg twice daily, Days 2–21), followed by N or P monotherapy until disease progression or undue toxicity. The primary endpoint is PFS; the key secondary endpoint is OS. An adaptive design will be used at the time of the primary PFS analysis to reassess the number of OS events for sufficient OS power. Other secondary endpoints are objective response and disease control (using modified Response Evaluation Criteria in Solid Tumors). The frequency/severity of adverse events and health-related quality of life will also be assessed. An exploratory analysis of predictive/prognostic biomarkers is planned.

      Clinical trial identification:
      NCT01907100

      Legal entity responsible for the study:
      Boehringer Ingelheim Pharma GmbH & Co. KG

      Funding:
      Boehringer Ingelheim Pharma GmbH & Co. KG

      Disclosure:
      S. Popat: Acknowledges NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden and the ICR, and is consultant to and has received honoraria from Boehringer Ingelheim and Eli Lilly. A. Nowak: Acknowledges funding from the National Health and Medical Research Council of Australia to the National Centre for Asbestos Related Diseases. A. Tsao: Received honoraria from Eli Lilly, Roche, Novartis, AstraZeneca, Ariad, Boehringer Ingelheim, Genentech, BMS, Seattle Genetics, and has received research funding from Eli Lilly, AstraZeneca, Millennium, BMS, Seattle Genetics, and Polaris. J. Van Meerbeeck: Received institutional funding through research grants from the Belgian Foundation against Cancer and Flemish Kom op tegen Kanker Fund. N. Vogelzang: Received an honorarium from Boehringer lngelheim for services on the steering committee of this study. D. Velema: Employee of Boehringer Ingelheim. N. Morsli: Employee of Boehringer Ingelheim. G. Scagliotti: Consultant for Eli Lilly and has received honoraria from Eli Lilly, Roche, Pfizer, Novartis, AstraZeneca, and Clovis Oncology. All other authors have declared no conflicts of interest.

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    Industry Satellite Symposium 6 (ID 57)

    • Type: Industry Satellite Symposium
    • Presentations: 1
    • Moderators:
    • Coordinates: 5/07/2017, 13:00 - 14:00, Room A
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      Treatment of advanced NSCLC: State of the art today & promises for the future (ID 570)

      13:00 - 14:00  |  Author(s): S. Peters

      • Abstract

      Abstract not provided

  • +

    Industry Satellite Symposium 7 (ID 58)

    • Type: Industry Satellite Symposium
    • Presentations: 1
    • Moderators:
    • Coordinates: 5/07/2017, 13:00 - 14:00, Room C
    • +

      Sharing our knowledge in NSCLC: Case interchange of real-world experience (ID 571)

      13:00 - 14:00  |  Author(s): R..A. Stahel

      • Abstract

      Abstract not provided