Virtual Library

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    Lunch & Poster Display session (ID 58)

    • Event: ELCC 2019
    • Type: Poster Display session
    • Track:
    • Presentations: 170
    • Now Available
    • Moderators:
    • Coordinates: 4/11/2019, 12:30 - 13:00, Hall 1
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      3P - Notable variation of molecular testing in metastatic lung cancer in the Netherlands (ID 229)

      12:30 - 13:00  |  Presenting Author(s): Chantal Epskamp-Kuijpers  |  Author(s): Michel Van den Heuvel, Lucy Overbeek, Anne Van Lindert, Ronald Damhuis, Stefan Willems

      • Abstract
      • Slides

      Background

      Adequate and timely testing for molecular alterations in NSCLC is necessary to enable treatment with tyrosine kinase inhibitors (TKI) when a certain mutation or rearrangement is present. On a nationwide basis, we aimed to assess the performance of molecular testing for EGFR and/or KRAS mutation, and ALK and ROS rearrangement in a cohort of metastatic NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      All stage IV non-squamous NSCLC from 2013 and 2015 were identified from the Netherlands Cancer Registry and matched to the Dutch Pathology Registry (PALGA). Using information extracted from pathology reports, proportions of tumors tested for EGFR and/or KRAS and ALK, and in 2015 also for ROS, within 3 months after diagnosis, were determined, and variation between 48 laboratories was assessed. In a best practice session with 4 laboratories with highest testing proportions, we tried to identify a process for the best possible flow and highest possible testing proportions.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      In total, 6,619 tumors were included (2013: N = 3,195; 2015: N = 3,424). In 2013, EGFR and/or KRAS testing was performed in 73.1% (variation between laboratories 30.6% to 91.7%) and was significantly higher in 2015: 78.9% (40.0% to 91.0%). Of the EGFR/KRAS wildtype (wt) tumors, 49.5% underwent ALK testing in 2013 (6.3% to 100%) and 77.4% in 2015 (32.5% to 100%), which was significantly higher. ROS testing was performed for 50.9% (0% to 100%) of the EGFR/KRAS wt tumors from 2015. In 2015, 6, 7 and 13 laboratories tested significantly less often for EGFR/KRAS, ALK and ROS, respectively, than the national proportion. Insufficient tissue was the most stated reason for not testing. The best practice session showed that, among other, dedicated specialized personnel, good communication with short lines, and a work culture of critical openness and honesty are essential for adequate molecular testing.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Although molecular testing proportions were significantly higher in 2015, improvement remains possible in some laboratories/hospitals, considering that some patients were possibly unjustly not eligible for TKI. Feedback on molecular testing performance was sent to individual laboratories, so they can review, and, if needed, improve their practice.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      University Medical Centre Utrecht.

      213f68309caaa4ccc14d5f99789640ad Funding

      AstraZeneca, Pfizer, Roche.

      682889d0a1d3b50267a69346a750433d Disclosure

      C. Kuijpers, S. Willems: Funding: AstraZeneca, Pfizer, Roche (these companies had no role in study design, analyses and reporting). All other authors have declared no conflicts of interest.

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      4P - Correlation between folate receptor alpha (FRα) expression and clinicopathological features in lung adenocarcinoma (Now Available) (ID 245)

      12:30 - 13:00  |  Presenting Author(s): Nobumasa Tamura  |  Author(s): Yutaka Fujiwara, Taiki Hashimoto, Hideaki Shiraishi, Shigehisa Kitano, Toshio Shimizu, Noboru Yamamoto, Noriko Motoi

      • Abstract
      • Slides

      Background

      FRα is present on the cell surface, mediates its intracellular transport via receptor-mediated endocytosis, and is also involved in cell division. FRα is expressed at high levels on various cancer cells, and it is considered that FRα could be a potential therapeutic target in FRα-expressing cancers.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We investigated the correlations between FRα expression in tissue microarray (TMA) constructed from surgical specimens of lung adenocarcinoma (LADC) and clinicopathological features including EGFR mutation retrospectively. Two TMA cores per a resected LADC specimen were created using TMA Master (3DHISTECH, Budapest, Hungary) at National Cancer Center Hospital between January 2007 and November 2016. Based on previous studies, if the percentage of stained tumor cells was greater than or equal 5%, FRα was considered as positive, and if H-score was more than or equal 60 (range, 0-300), FRα was considered as high expression.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Overall, 466 TMA cores created from 233 patients who underwent surgery for LADC were evaluated; FRα positive expression (FRα-pos)/negative (FRα-neg), 222/11; FRα high expression (FRα-HE)/low (FRα-LE), 190/43, respectively. 124 patients (53.2%) were with EGFR mutation. The median H-scores of FRα expression, rates of FRα-pos, and rates of FRα-HE for EGFR mutation and wild type were 159/104 (p = 0.0002), 97.6/92.7% (p = 0.077), and 88.7/73.4% (p = 0.0026). The median disease free survival (months) were 18.7/23.3 (p = 0.30) for FRα-pos/neg and 20.2/12.8 (p = 0.42) for FRα-HE/LE, respectively. The median overall survival were 92.9/not reached (p = 0.42) for FRα-pos/neg and 92.9/96.4 (p = 0.42) for FRα-HE/LE, respectively. FRα expression was not considered as a prognostic factor in LADC. 82 patients with EGFR mutation received EGFR-TKI after recurrence (FRα-pos/neg, 79/3; FRα-HE/LE, 71/11). Overall response rates and median progression free survival (months) of EGFR-TKI were 59.2/66.6% (p = 0.80) and 16.1/11.5 (p = 0.016) for FRα-pos/neg; 61.8/45.5% (p = 0.31) and 16.2/13.2 (p = 0.95) for FRα-HE/LE, respectively.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      FRα expression was significantly higher in LADC with EGFR mutation than that with wild-type. The efficacy of EGFR-TKI was better in FRα-pos than in FRα-neg.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      Y. Fujiwara: Research funding: AbbVie, AstraZeneca, BMS, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Incyte, Merck Serono, MSD, Novartis; Advisory role: AstraZeneca, BMS, MSD, Novartis, ONO; Speakers bureau: AstraZeneca, BMS, MSD, Novartis, ONO, Sysmex, Taiho. S. Kitano: Personal fee, grant: Eisai; Honoraria: ONO, Bristol-Myers Squibb, AstraZeneca, Chugai, Pfizer, Sanofi, Nippon Kayaku, Boehringer Ingelheim, Meiji, Taiho, Novartis, Daiichi Sankyo, MSD, Kirin, Celgene, Sumitomo Dainippon; Grant: Regeneron, Astellas, Gilead, AMED, JSPS. T. Shimizu: Advisory board: Takeda, The Consortium on Harmonization of Institutional Requirements for Clinical Research; Corporate sponsored research: Bristol-Myers Squibb, Daiichi Sankyo, Lilly, Novartis, Eisai, Takeda, PharmaMar, FivePrime, 3D-Medicine, Symbio, Chordia. N. Yamamoto: Grants: Quintiles, Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Kirin, Takeda, ONO, Janssen, Lilly, MSD, Merck; Advisory: Eisai, Takeda, Otsuka, Boehringer Ingelheim, Cimic; Speakers: BMS, Pfizer, AstraZeneca, Lilly, ONO, Chugai. N. Motoi: Personal fee (lecture, Advisory board): Bristol-Myers Squibb, Miraca Life Sciences, AstraZeneca, Chugai Pharma, MSD, Agilent, Novartis, Roche Diagnostics; Institutional research funding: Roche Diagnostics. All other authors have declared no conflicts of interest.

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      5P - The circular RNA circXPO1 promotes tumor growth in lung adenocarcinoma (Now Available) (ID 293)

      12:30 - 13:00  |  Presenting Author(s): Qi Huang  |  Author(s): Mantang Qiu

      • Abstract
      • Slides

      Background

      Circular RNAs (circRNA), a subclass of noncoding RNA characterized by covalently closed continuous loops, play emerging roles in tumorigenesis and aggressiveness. Somatic copy number variations (CNV) may drive cancer progression through both coding and noncoding transcripts. In lung adenocarcinomas, tumor stage is positively correlated with the proportion of CNV. CNV-associated circRNAs in lung cancer have rarely been reported.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      To identify critical circRNAs that contribute to lung adenocarcinoma progression, ribosomal RNA-depleted RNA sequencing was performed in 5 paired lung adenocarcinoma tissues and adjacent non-tumor tissues. Maltose-binding protein (MBP)-affinity purification and RNA immunoprecipitation (RIP) were used to identify RNA-binding proteins (RBPs) that were associated with circXPO1. Patient-derived xenograft (PDX) models were performed to assess the clinical benefits of targeting circXPO1.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      By integrating bioinformatics analyses of alerted circRNAs and focal CNV in lung adenocarcinoma, we identify a proto-oncogenic circular RNA (circXPO1), produced from the XPO1 gene at 2p15 amplicon. CircXPO1 was overexpressed in lung adenocarcinoma tissues and promoted proliferation and tumorigenesis of lung adenocarcinoma. Our mechanistic studies indicated that circXPO1 functions, at least in part, through its interaction with IGF2BP1. CircXPO1 epigenetically upregulated β-Catenin expression in lung adenocarcinoma cancer cells by interacting with IGF2BP1 to promote the stabilization of β-Catenin. Intratumor injection of cholesterolconjugated siRNA specifically targeting circXPO1 inhibited tumor growth in a patient-derived lung adenocarcinoma xenograft model.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      In summary, our study identified a CNV-associated circular RNA, circXPO1, which is overexpressed in lung adenocarcinoma tissues, due to the amplification of 2q15 locus, promotes proliferation and tumorigenesis of lung adenocarcinoma via interacting with IGF2BP1 and subsequently promote the stabilization of β-Catenin. Meanwhile, understanding the precise role of circXPO1 provides a novel therapeutic strategy for lung adenocarcinoma in the sight of circular RNAs.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Qi Huang, Mantang Qiu, Fan Yang, Jun Wang.

      213f68309caaa4ccc14d5f99789640ad Funding

      National Natural Science Foundation of China.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      6P - Correlation of epidermal growth factor receptor mutation status in plasma and tissue samples of patients with lung cancer (ID 367)

      12:30 - 13:00  |  Presenting Author(s): Choonhee Son

      • Abstract

      Background

      Somatic mutations of the gene encoding epidermal growth factor receptor (EGFR) are detected in approximately 30%–50% of patients with non-small cell lung cancers (NSCLC), so detection of EGFR mutation is the pivotal step of treatment in patients with advanced NSCLC. However, difficulty in obtaining sufficient tissue and bias from the heterogeneity of the tumor samples are the major obstacles. Although analyzing EGFR with circulating tumor DNA (ctDNA) in plasma is a breakthrough, accuracy is the problem in variable methods. Peptide nucleic acid (PNA) clamping-assisted fluorescence melting curve analysis (PANAMutyper®) is a novel and highly sensitive method of detecting EGFR mutation in tumor tissues. This study was designed to evaluate PANAMutyper® for detecting EGFR mutation with ctDNA of patients with lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      EGFR mutation status detected by PNA clamp with tissue samples and by PANAMutyper® with ctDNA was compared. Tissue biopsy was done in 158 patients with lung tumor, in which 23 cases were excluded and 135 cases were enrolled. All the plasma samples of the cases with mutant EGFR in tissue samples were verified by an already known highly sensitive method of droplet digital polymerase chain reaction (ddPCR).

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      EGFR mutation rate was 23.0% (31/135) in overall patients. The concordance rate of tissue and plasma samples was 91.9% (124/135). The sensitivity, specificity, negative predictive value, and positive predictive value were 64.5%, 100.0%, 90.4%, and 100.0%, respectively, according to the tissue samples as a standard.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      PANAMutyper® method was not inferior to ddPCR for the detection of EGFR mutation including T790M with ctDNA. These results suggest that the detection of EGFR mutation status using ctDNA in plasma by PANAMutyper® is a feasible test prior to tissue biopsy.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Choonhee Son.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      The author has declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      7P - Immunomodulatory effects of Tumor Treating Fields (TTFields) on lung cancer models (ID 436)

      12:30 - 13:00  |  Presenting Author(s): Uri Weinberg  |  Author(s): Noa Kaynan, Tali Voloshin Sela, Shiri Davidi, Yaara Porat, Anna Shteingauz, Mijal Munster, Rosa S Schneiderman, Catherine Tempel Brami, Einav Zeevi, Karnit Gotlib, Shay Cahal, Moshe Giladi, Eilon Kirson, Adrian Kinzel, Yoram Palti

      • Abstract
      • Slides

      Background

      Tumor Treating Fields (TTFields) are a clinically approved anti-mitotic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. In this study, we evaluated whether TTFields-induced cell death can be perceived as immunogenic.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Human and murine lung carcinoma cell lines were treated with TTFields using the inovitro system. Immunogenic cell death was evaluated by changes in the levels of calreticulin (CRT) on the surface of treated cells, phosphorylation of the translation initiation factor eIF2α, and secretion of ATP and High mobility group box 1 (HMGB1). Activation of immune cells was evaluated using co-culture of bone marrow derived dendritic cells (DCs) with TTFields treated cells. For in-vivo studies, mice orthotopically implanted with lung tumors were treated with TTFields, the immune checkpoint inhibitor anti-PD-1 or a combination of the two modalities. Tumor volume was monitored and flow cytometry analysis was performed for phenotypic characterization of infiltrating immune cells.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      We demonstrate that cancer cells that died under TTFields application exhibited release of HMGB1, ATP secretion from cells, and ER stress leading to CRT translocation to the cell surface, all of which are cardinal signs of immunogenic cell death. TTFields treated cells promoted in vitro phagocytosis by DCs and DC maturation as well as initiation of inflammation in vivo. The combined treatment of lung tumor-bearing mice with TTFields plus the immune checkpoint inhibitor anti-PD-1 led to a significant decrease in tumor volume compared to anti-PD-1 alone or to the control group. Significant increases in CD45+ tumor infiltrating cells were observed in the TTFields plus anti-PD-1 group. These infiltrating cells demonstrated upregulation of surface PD-L1 expression. Correspondingly, cytotoxic T-cells isolated from these tumors showed higher levels of IFN-γ production relative to untreated mice.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Our results demonstrate the potential of TTFields therapy to induce immunogenic cell death and increase the efficacy of anti PD-1 therapy by further enhancing antitumor immunity.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Novocure Israel.

      213f68309caaa4ccc14d5f99789640ad Funding

      Novocure Israel.

      682889d0a1d3b50267a69346a750433d Disclosure

      U. Weinberg, T. Voloshin Sela, Y. Porat, M. Munster, R.S. Schneiderman, C. Tempel Brami, S. Cahal, M. Giladi, A. Kinzel, Y. Palti: Full time employee: Novocure Israel; Stock options, stocks: Novocure. N. Kaynan, S. Davidi, A. Shteingauz, K. Gotlib, E. Zeevi: Full time employee: Novocure Israel; Stock options: Novocure. E. Kirson: Full time employee: Novocure Israe; Stock options, stocks: Novocure; Senior leadership position: Novocure.

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      8P - Role of chemokines in resectable non-small cell lung cancer (NSCLC) (Now Available) (ID 464)

      12:30 - 13:00  |  Presenting Author(s): Marie Drosslerová  |  Author(s): Martina Šterclová, Martina Vašáková, Alice Tašková, Vladislav Hytych, Pavel Horažďovský, Eva Richterová, Magdalena Smětáková, Libor Havel

      • Abstract
      • Slides

      Background

      Complex network of chemokines is a part of immune reaction targeted against tumor cells. Chemokines influence cancer growth. It is not clear whether the concentrations of chemokines at the time of diagnosis of NSCLC reflect extent of the disease. Aim: To compare chemokine concentrations (CCL2, CCL8, CXCL12) in plasma of patients with resectable NSCLC to those without cancer. To find out whether the chemokine concentrations differ according to stage of the disease.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We enrolled 69 patients undergoing surgery for proven/suspected NSCLC (37 males- mean age 66 years, 32 females- mean age 64 years). They underwent standard diagnostic and staging procedure to determine resectability (CT/PET-CT, bronchoscopy, ev. abdominal ultrasound), then surgery was made. We diagnosed 42 patients with NSCLC, 27 patients in the control group had benign lung pathologies (e.g. chondrohamatoma, fibrous tissue) and remained as the control group. We took plasma samples before surgery in treatment naive patients. The chemokine concentrations were assesed by ELISA LSBio Kits. The results were stated in pg/ml (CCL2, CCL8), ng/ml (CXCL12). Parametric statistics was used for results analysis.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      CCL2 (pg/ml)pCCL8 (pg/ml)PCXCL12 (ng/ml)p
      NSCLC/benign lesions169,09/146,590,34556,22/48,840,4866,32/5,30,204
      NSCLCst. I/ benign lesions177,16/146,590,31049,66/48,840,9375,08/5,30,764
      NSCLCst.II+IIIa/ benign lesions163,65/146,590,53966,34/48,840,2347,82/5,30,017

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Chemokine values did not differ in NSCLC versus control group. Patients with NSCLC stages II and IIIA had significantly higher CXCL12 concentrations than control group. This could be because CXCL12 promotes tumor growth and metastasis.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Internal grant of Thomayer Hospital.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      9P - Clinical validation of an NGS-based assay for detecting multiple genomic alterations in Chinese patients with non-small cell lung cancer (ID 487)

      12:30 - 13:00  |  Presenting Author(s): Huijuan Ge  |  Author(s): Xiaoyan Chen, Li Ruan, Qingyun Gao, Xine Yang, Weijie Shi, Xuchao Li, Guanshan Zhu

      • Abstract
      • Slides

      Background

      Patients with non-small cell lung cancer (NSCLC) often harbors driver mutations in multiple oncogenes, including EGFR, KRAS, ALK, ROS1, BRAF, HER2, RET, etc. Driver genetic alterations are used as predictive biomarkers for molecular targeted therapies. Therefore, identifying mutations in oncogenes and tailoring therapy accordingly become a standard in clinical cancer management. A genetic testing assay based on next-generation sequencing (NGS) technology, named AmoyDx Essential NGS Panel, has been developed for multiplexed and targeted deep sequencing of variants in 10 driver genes. Clinical validation was conducted in the present study.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      A total of 372 formalin-fixed and paraffin-embedded (FFPE) tissue samples collected from Chinese patients with NSCLC were detected by AmoyDx Essential NGS Panel, which enables the simultaneous detection of single-nucleotide variants (SNVs), insertions/deletions and fusions in 10 driver genes (EGFR, KRAS, NRAS, BRAF, PIK3CA, ALK, ROS1, HER2, RET, and MET) in DNA samples. DNA sequencing was performed on the Illumina platform. Golden standard Sanger sequencing as reference method was used as a reference method to test the same cohort. The concordance of variants determined with the AmoyDx Essential NGS Panel was assessed compared to the reference method.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      In total of 372 samples, 98.39% (366/372) of patients were successfully detected by both AmoyDx Essential NGS Panel and Sanger sequencing. 73.50% (269/366) were identified to shown variants by NGS as listed in the table . The overall concordance rate of mutations determined with AmoyDx Essential NGS Panel compared with reference was 98.80%.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      The NGS analysis with AmoyDx Essential NGS Panel represents an accurate and efficient approach to detect genomic alterations in 10 driver genes with high concordance rate of 98.80% compared with Sanger sequencing.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Amoy Diagnostics Co., Ltd.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      H. Ge, L. Ruan, Q. Gao, X. Yang, W. Shi, X. Li, G. Zhu: Employee: Amoy Diagnostics Co., Ltd. All other authors have declared no conflicts of interest.

      Table: 9P Variants detected by NGS

      Variant typeNumber of patientsPositive rate
      EGFR mutation21057.38%
      KRAS mutation226.01%
      NRAS mutation00.00%
      BRAF mutation71.91%
      PIK3CA mutation51.37%
      ALK fusion133.55%
      ROS1 fusion10.27%
      HER2 mutation82.19%
      RET fusion61.64%
      MET mutation10.27%
      Total26973.50%

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      10P - The prevalence and prognostic significance of JAK2 mutation subtypes in non-small cell lung cancer from Chinese populations (ID 156)

      12:30 - 13:00  |  Presenting Author(s): Wenxian Wang  |  Author(s): Chunwei Xu, Quxia Zhang, Wu Zhuang, Youcai Zhu, Zhangzhou Huang, Gang Chen, Meiyu Fang, Tangfeng Lv, Yong Song

      • Abstract
      • Slides

      Background

      Although roles of JAK2 mutations in myeloproliferative neoplasms (MPN) are well established, roles of JAK2 mutations in the pathogenesis of non-small cell lung cancer (NSCLC) remain unclear. The aim of this study is to investigate mutations and prognosis of NSCLC harboring JAK2 mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      A total of 766 patients with non-small-cell lung cancer were recruited between July 2012 and December 2016. The status of JAK2 mutations and other genes were detected by next generation sequencing.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      JAK2 gene mutation rate was 2.35% (18/766) in non-small cell lung cancer, including V617F (3 patients), L43I (2 patients), D768H (1 patient), G1066A (1 patient), W1020C (1 patient), S465R (1 patient), Q21E (1 patient), T842A (1 patient), C452* (1 patient), I404M (1 patient), P708Q (1 patient), S488* (1 patient), S1035L (1 patient), V387L(1 patient) and E575* (1 patient), and median overall survival (OS) for these patients was 19.0 months. Among them, all patients were JAK2 gene with co-occurring mutations. Briefly, patients with (n = 4) or without (n = 14) co-occurring EGFR mutations had a median OS of 23.0 months and 13.0 months respectively (P = 0.05); patients with (n = 11) or without (n = 7) co-occurring TP53 mutations had a median OS of 20.0 months and 7.0 months respectively (P = 0.01); patients with (n = 3) or without (n = 15) co-occurring ARID1A mutations had a median OS of 20.0 months and 13.0 months respectively (P = 0.32); patients with (n = 6) or without (n = 12) co-occurring KRAS mutations had a median OS of 11.5 months and 20.0 months respectively (P = 0.25).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      TP53 accompanied mutations might play a good prognosis in JAK2 gene mutation NSCLC. Next generation sequencing provides a simplified strategy and reasonably high detection rate for JAK2 mutation, which suggested application of the strategies into clinical molecular diagnostics.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      11P - Autophagy inhibition potentiates the anti-angiogenic property of multikinase inhibitor anlotinib through JAK2/STAT3/VEGFA signaling in non-small cell lung cancer cells (ID 162)

      12:30 - 13:00  |  Presenting Author(s): lijun Liang  |  Author(s): kaiyuan Hui, chenxi Hu, yixuan Wen, xiaodong Jiang

      • Abstract

      Background

      The efficacy and safety of multikinase inhibitor anlotinib has been confirmed in the treatment of advanced non-small cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by anlotinib were not fully elucidated, and the underlying mechanisms related to resistance remains largely elusive.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Cell viability, colony formation, apoptosis and tumor growth assays were performed to examine the effect of anlotinib on lung cancer cells in vitro and in vivo. The punctate patterns of LC3-I/II were detected by confocal microscopy. HUVECs migration was detected using Transwell and scratch wound-healing assay. To visualize the microvessels, tublar formation assay was performed. The expression of LC3-I/II and beclin-1 and the changes of JAK2/STAT3/VEGFA pathway were detected by western blotting. The VEGFA levels in tumor supernatant were measured by ELISA.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Anlotinib treatment decreased cell viability and induced apoptosis in Calu-1 and A549 cells. Moreover, anlotinib induced human lung cancer cell autophagy in a dose- and time-dependent manner. Blocking autophagy enhanced the cytotoxicity and anti-angiogenic ability of anlotinib as evidenced by HUVECs migration, invasion, and tublar formation assay. Co-administration of anlotinib and chloroquine (CQ) further reduced VEGFA level in the tumor supernatant, compared with that of anlotinib or CQ treatment alone. When autophagy was induced by rapamycin, the JAK2/STAT3 pathway was activated and VEGFA was elevated, which was attenuated after deactivating STAT3 by S3I-201. Further in vivo studies showed that anlotinib inhibited tumor growth, induced autophagy and suppressed JAK2/STAT3/VEGFA pathway, and CQ enhanced this effect.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Anlotinib induced apoptosis and protective autophagy in human lung cancer cell lines. Autophagy inhibition further enhanced the cytotoxic effects of anlotinib, and potentiated the anti-angiogenic property of anlotinib through JAK2/STAT3/VEGFA signaling.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      National Natural Science Foundation of China grants 81472792 and Postgraduate Research & Practice Innovation Program of Jiangsu Province grants SJCX18_0707.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      12P - Clinicopathologic characteristics of patients with TP63 mutations in Chinese non-small cell lung cancer (ID 158)

      12:30 - 13:00  |  Presenting Author(s): Quxia Zhang  |  Author(s): Chunwei Xu, Wenxian Wang, Wu Zhuang, Zhangzhou Huang, Gang Chen, Meiyu Fang, Tangfeng Lv, Yong Song

      • Abstract
      • Slides

      Background

      Variation at TP63 has recently been shown to be associated with non-small cell lung cancer patients (NSCLC) in the Chinese population. There is some clinical evidence for the use of TP63 mutations as prognostic and predictive biomarker. The aim of this study is to investigate mutations and prognosis of NSCLC harboring TP63 mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      A total of 1236 patients with non-small-cell lung cancer were recruited between July 2012 and December 2016. The status of TP63 mutations and other genes were detected by next generation sequencing.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      TP63 gene mutation rate was 2.02% (25/1236) in non-small cell lung cancer, including R643* (1 patient), H247N (1 patient), A139V (1 patient), V626F (1 patient), Q70* (1 patient), Q274E (1 patient), H615D (1 patient), R350T (1 patient), Y202Kfs*29 (1 patient), P229H (1 patient), M40V (1 patient), E409Q (1 patient), V179M (1 patient), W658* (1 patient), S365* (1 patient), T193M (1 patient), L50F (1 patient), A554E (1 patient), R226H (1 patient), Q99* (1 patient), S310N (1 patient), T169N (1 patient), R266Q (1 patient), D372H (1 patient), and P492T (1 patient), and median overall survival (OS) for these patients was 15.0 months. Among them, all patients were TP63 gene with co-occurring mutations. Briefly, patients with (n = 5) or without (n = 20) co-occurring EGFR mutations had a median OS of 22.5 months and 14.0 months respectively (P = 0.23); patients with (n = 21) or without (n = 4) co-occurring TP53 mutations had a median OS of 15.0 months and 13.0 months respectively (P = 0.33); patients with (n = 5) or without (n = 20) co-occurring BRAF mutations had a median OS of 14.0 months and 15.0 months respectively (P = 0.72); patients with (n = 5) or without (n = 20) co-occurring KRAS mutations had a median OS of 6.0 months and not up to now respectively (P < 0.01).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      TP63 is structurally and functionally similar to TP53 and their activity as transcription factors is regulated by a wide repertoire of shared and unique post-translational modifications and interactions with regulatory cofactors. EGFR, TP53 and BRAF gene accompanied may have less correlation with TP63 mutation in NSCLC patients. KRAS accompanied mutations might play a worse prognosis in TP63 gene mutation NSCLC.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      13P - The micro-environmental cross talk between mast cells and lung cancer cells through cell-to-cell contact (Now Available) (ID 348)

      12:30 - 13:00  |  Presenting Author(s): Rachel Shemesh  |  Author(s): Yaara Gorzalczany, Ronit Sagi-Eisenberg, Smadar Geva, Laila Roisman C. Roisman, Nir Peled

      • Abstract
      • Slides

      Background

      Mast cells (MCs) are key effectors in allergic reactions, but are also involved in tissue remodeling, wound healing and protection against pathogens. MCs infiltrate tumors and their number within the tumor microenvironment in certain cancer types, such as lung cancer, have been correlated with poor prognosis. The nature of crosstalk between lung cancer and MCs remain poorly resolved. In this study, we investigated the activation patterns within the MCs following cell-to-cell contact with lung cancer cells showing CD73 involvement.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Human MCs (HMC-1 and LAD-2) were exposed to Human lung cancer cells (H1299), derived membranes to recapitulate cell contact-mediated activation. Lysates of MCs were tested for protein expression and phosphorylation by targeted western blotting. We unraveled the intracellular signaling molecules that are necessary for this signaling pathway by a pharmacological approach using several inhibitors. Each condition was repeated at least three times.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      H1299 membrane exposure activated the ERK 1/2 MAP kinases in HMC-1 and in LAD-2 cells. AKT signaling was also activated in LAD-2 cells as a result of this contact. CD73 dephosphorylates AMP to adenosine within the MCs. Interestingly enough, this ERK 1/2 activation was inhibited by CD73 inhibitor and A3 receptor antagonists in HMC-1 cells. ERK 1/2 activation was inhibited by A3 receptor antagonists and PI3K in LAD-2 cells. Furthermore, we discovered that protein kinase C (PKC) inhibitor augments the activation of ERK 1/2 in LAD-2 cells. In contrast, PKC inhibitor inhibits the activation of ERK 1/2 in HMC-1 cells.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Our results suggest that H1299 membranes activate ERK 1/2 in HMC-1 cells by a mechanism that involves autocrine formation of adenosine and is mediated by CD 73 and A3 receptor. In addition, we discovered that there is an important difference between the ERK 1/2 MAP kinase signal transduction in HMC-1 and LAD-2 cells, PKC is an inhibitor of the H1299 activation of ERK 1/2 in LAD-2 cells. In contrast, the H1299 membrane activation of ERK 1/2 kinase in HMC-1 cells is mediated by PKC. This could be explained by the fact that LAD-2 MCs express wild type c-kit receptor, and HMC-1 MCs express an oncogenic constitutively active c-kit mutant.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      14P - The characteristics of MET exon 14 skipping mutations in Chinese non-small cell lung cancer: A retrospective analysis (ID 155)

      12:30 - 13:00  |  Presenting Author(s): Youcai Zhu  |  Author(s): Chunwei Xu, Wenxian Wang, Quxia Zhang, Wu Zhuang, Gang Chen, Meiyu Fang, Tangfeng Lv, Yong Song

      • Abstract
      • Slides

      Background

      MET exon 14 skipping is a potential driver alteration in lung cancer targetable. Treatment with crizotinib can cause dramatic responses in patients whose cancers have MET exon 14 skipping. The current study was aiming to determine the clinical and pathological characteristics in non-small cell lung cancers (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      A total of 2926 patients with NSCLC were recruited between July 2012 and 2015. The status of MET exon 14 skipping and other genes were detected by next generation sequencing.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      MET exon 14 skipping rate was 1.06% (31/2926) in NSCLC, including X1009_spilce (10 patients), X963_spilce (6 patients), D1010H (5 patients), D1010N (3 patients), X1008_spilce (1 patient), X1006_spilce (1 patient), X1007_spilce (1 patient), D1010Y (1 patient), Y1003S (1 patient), D1002G (1 patient), P1008A (1 patient). Among them, EGFR mutations+ MET skipping [7 patients (2 patients with 19 del+ 5 patients with L858R)], ALK fusion+ MET skipping (2 patients) and ROS1 fusion+ MET skipping (1 patient).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      MET exon 14 skipping defined a new molecular subset of NSCLC with identifiable clinical characteristics. The therapeutic crizotinib might be an alternative treatment for patients with MET exon 14 skipping NSCLC.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      15P - TTF1 status in non-small cell lung cancer adenocarcinoma: A prognostic factor (ID 377)

      12:30 - 13:00  |  Presenting Author(s): Juan Felipe Cordoba Ortega  |  Author(s): ANTONIETA Salud, SERAFIN Morales, JOEL Veas, ALVARO Rodriguez

      • Abstract
      • Slides

      Background

      Patients with thyroid transcription factor 1 (TTF1) negative lung adenocarcinoma (ADC) have been reported to have a worse prognosis and to lack epidermal growth factor receptor (EGFR) mutations. The aim of this study was to analyse the prognostic significance of TTFI status in a series of tumor samples from patients with clinically confirmed lung adenocarcinoma.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      A real-world data study of TTF1-negative ADC was performed in all lung cancer patients diagnosed in the University Hospital of Lleida from January 2011 to December 2016, using TTF1 clone 8G7G3/1(DAKO®). Each patient’s clinical history, pathology specimens and molecular results were noted. The control group consisted of 231 patients with TTF1 positive lung ADC .

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Three hundred and thirty four (334) patients with ADC were identified; TTF1 results were available in 258 (77,2%) cases. Of these, 27 (10,4%) patients were identified with TTF1-negative ADC (74% males). The median age of these patients was 66 years and their smoking history was as follows: 55,5% former smoker, 29,6% ex smokers and 14,8% never smokers. The clinical stages were as follows: stage I or II (n = 3 [11%]), stage III (n = 4 [14,8%]) and stage IV (n = 20 [74%]). Patients’ mean survival was 7,6 vs 24,4 months in ADC TTF1-negative patients versus TTF1-postive patients (P = 0,00001). When compared with the control group, TTF1-negative patients had shorter overall survival (P = 0,00001), regardless of whether patients were treated with radical or palliative intent: 34,4 vs 10, months P = 0,00001 (radical treatment) and 14,6 vs 6,7 months P = 0,007 (palliative intent). EGFR mutations were less frequent (P = 0,046) in TTF-negative tumors compared to the control group (5,5% vs 25,3%).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Patients with TTF1-negative NSCLC ADC have worse overall survival, regardless of treatment intention, and a lower frequency of EGFR mutations.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      17P - REDOXI-miRNA of Keap1/Nrf2 axis in lung tumors (ID 505)

      12:30 - 13:00  |  Presenting Author(s): Federico Pio Fabrizio  |  Author(s): Angelo Sparaneo, Stefano Castellana, Tommaso Mazza, Domenico Trombetta, Paolo Graziano, Antonio Rossi, Vito Michele Fazio, Lucia Anna Muscarella

      • Abstract

      Background

      Oxidative and electrophilic changes in cellular redox balance are mainly coordinated by the Keap1/Nrf2 axis and is strongly related to tumor progression, chemo- and radio-therapy resistance of cancer cells. In lung tumors this system is constitutively activated mainly by the loss of Keap1 or gain of Nrf2 functions due to point mutations in the key interacting domains of these two proteins. Beside of genetic lesions, Keap1/Nrf2 epigenetic abnormalities, as aberrant Keap1 promoter methylation and regulation by microRNAs were reported as emerging mechanisms of deregulation. Here we investigated the contribution of miRNA machinery on the modulations of Keap1/Nrf2 activity in lung tumors by analyzing panels of NSCLC and SCLC cell lines.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We searched for candidate miRNAs interacting with Nrf2 and Keap1 by using a combination of published data and in silico analyses performed by multiple bioinformatics tools (miRTarBase for known miRNAmRNA interactions; TargetScan, MiRanda, microRNA.org, miRBase also for predicted interactions). After this preliminary analysis we selected a list of 11 miRNAs that are experimentally validated in other tumors and/or predicted to be associated to NRF2 or KEAP1 and profiled their expression levels by real-time PCR in lung cancer cell lines and tissues.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      miR-27 family (miR-27a and miR-27b) was found to be significantly downregulated in NSCLC and SCLC cell lines. Conversely, miR-200 family (miR-200a and miR-141) was found to be significantly upregulated. Afterward, the expression data for miR-27 family and miR-200a was validated on an available training set of 29 tumor/normal paired tissues from NSCLC patients. As expected, miR- 200a was significantly up-regulated (p < 0,01, t-test), whereas miR27a and miR-27b significantly downregulated (p < 0,001, t-test) in tumors compared to normal tissues.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Since the obtained results refer to currently un-investigated miRNAs related to Keap1/Nrf2 axis in lung cancer, we plan to extend our analysis and confirm their role and impact on KEAP1/NRF2 modulation by in vitro studies. Our preliminary results suggest that redoxi-miRNA in lung cancer should add a new order of complexity to the regulation of the Nrf2/ARE pathway and will need to be more deeply explored in the future.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      AIRC.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

    • +

      18P - Immunohistochemical expression of PD-L1 in early and late stage non-small cell lung cancer: Correlation with clinicopathological and molecular features (Now Available) (ID 489)

      12:30 - 13:00  |  Presenting Author(s): Eleni Kokkotou  |  Author(s): Vassiliki Rapti, Dimitra Grapsa, Petros Bakakos, Savvas Papadopoulos, Mattheos Bobos, Kosmas Iliadis, Konstantinos Syrigos

      • Abstract
      • Slides

      Background

      The immunohistochemical expression of PD-L1 protein has been evaluated as a predictor of prognosis and response to immunotherapy, with controversial results. We herein aimed to further study its clinical relevance in patients with non-small cell lung cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      The clinical records, pathology and molecular reports of 152 patients with histologically or cytologically confirmed NSCLC, diagnosed with early-stage or metastatic disease, were retrospectively studied. The respective archival formalin-fixed, paraffin-embedded blocks were also retrieved for immunohistochemistry (IHC) testing. PD-L1 IHC was performed using the Ventana PD-L1 (SP263) assay on an automated staining system (Ventana BenchMark ULTRA), and the results were correlated with demographic, clinicopathological and molecular features of patients.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The most common subtype of NSCLC in our cohort was adenocarcinoma (82.2%). Overall, positive PD-L1 expression was observed in 47.4% of patients’ samples. EGFR and KRAS mutations and ALK rearrangement were observed in 13.0%, 7.1% and 5.4% of patients, respectively. The percentage of PD-L1 positive expression was significantly higher in cases with malignant pleural effusion (p = 0.026), more advanced disease stage (p = 0.045) and positive lymph node status (p = 0.049). PD-L1 staining showed no association with molecular data. Correlation of PD-L1 expression with the presence of pleural effusion (OR: 4.57; 95% CI: 1.20 – 17.39; p = 0.026) and positive lymph node status (OR: 1.95; 95% CI: 1.01 – 3.81; p = 0.048) was further confirmed in multivariate analysis.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Our study results support the independent correlation of positive expression of PD-L1 protein with adverse prognostic parameters and aggressive features, such as the presence of malignant pleural effusion and infiltrated lymph nodes.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      National and Kapodistrian University of Athens.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      19P - FOXP3&#x00394;3, the major isoform of FOXP3, promotes proliferation, migration, and invasion in non-small cell lung cancer (ID 515)

      12:30 - 13:00  |  Presenting Author(s): Hao JIA  |  Author(s): Haolong Qi, Jia Peng, Mingyue Li, George G Chen

      • Abstract

      Background

      Increasing evidence has shown that FOXP3 is not only expressed in immune cells but also in tumor cells. However, the results of tumor FOXP3 is inconsistent and even the opposite. Unlike mice, humans express multiple isoforms of FOXP3. However, the expression and role of FOXP3 isoforms in cancers are still largely unknown. The role of FOXP3 and FOXP3Δ3 in NSCLC remains unclear.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      The expression of FOXP3 and four FOXP3 isoforms was analyzed using the RSEM method for 32 cancer types from TCGA databases. The correlation between the expression of FOXP3 and prognosis of NSCLC patients was analyzed (http://kmplot.com/). Western blots assay, colony formation assay, MTT assay, wound-healing assay, and cell invasion assay were performed to determine the cell functions and to measure the expression of related molecules after the ectopic expression of FOXP3 and FOXP3Δ2 in NSCLC cells.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The expression of FOXP3 was upregulated in NSCLC tissues compared to adjacent non-tumor lung tissues. The FOXP3Δ3 was the most frequent FOXP3 isoform detected in NSCLC as well as in almost all types of cancers. The high expression of FOXP3 was correlated with poor prognosis in NSCLC. Tumor cells with FOXP3Δ3 were much more oncogenic than those without, and the ectopic expression of either FOXP3FL or FOXP3Δ3 could promote the proliferation, migration, and invasion of A549 and H23 cells. The ectopic expression of FOXP3 and FOXP3Δ3 downregulated E-cadherin and upregulated N-cadherin, snail, slug, MMP2, and MMP7.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      FOXP3Δ3 is the major isoform of FOXP3 in NSCLC and it may be a predictive factor for NSCLC patients.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The Chinese University of Hong Kong.

      213f68309caaa4ccc14d5f99789640ad Funding

      Research Grants Council of the Hong Kong SAR (No: CUHK462613) and the National Natural Science Foundation of China (No: 81472742).

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      20P - Atypical hyperplasia of bronchial epithelial cells induced by chronic exposure to PM 2.5 in mice (ID 301)

      12:30 - 13:00  |  Presenting Author(s): Tian Fang Hou  |  Author(s): Qian hua Chen

      • Abstract

      Background

      Air pollution is still a major environmental problem affecting the health of the respiratory system. Studies have confirmed that air pollution is closely related to the occurrence of lung cancer. Air pollution (mainly PM2.5) has been classified as a carcinogen by the International Agency for Research on Cancer. Previous evidence of the relationship between PM2.5 and lung cancer mostly comes from countries with low PM2.5 exposure level. Exposure to fine particulate matter (PM2.5) may increase the risk of lung cancer, but the underlying mechanism is still unclear.There is no direct evidence that PM2.5 can directly induce lung cancer .The aim of our study was to investigate the atypical hyperplasia of bronchial epithelial cells induced by chronic exposure to PM2.5 in mice and the possible mechanism of PM2.5 in the pathogenesis of severe atypical hyperplasia.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      30 BALB/c mice were treated with noninvasive tracheal instillation of PM2.5 suspension at different doses (2.5mg/kg, 5mg/kg, 10mg/kg) for 90 days (one time every 3 days), and the blank group and saline group were set as a control group. Tissue samples were taken at the end of the endotracheal infusion. Histopathological changes of lung tissue in mice and the expression of TTF-1, CK7 and Ki67 were detected by Hematoxylin-Eosin staining and immunohistochemical staining respectively.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Histopathological changes showed atypical hyperplasia of bronchiolo epithelia, part of glands papillary hyperplasia, some luminal glands crowded and disordered, glandular cavity back-to-back phenomenon, pulmonary septum widened, alveolar macrophages with engulfed particles and lymphocyte aggregation in bronchiole and alveolar, especially at high dose exposure group. Electron microscopic observation showed that normal structure of alveolar and bronchial epithelial cells disappeared and a large number of autophagic bodies were formed in the alveolar and bronchial epithelial cells of mice. The expression of TTF-1, CK7 and Ki67 in the lung tissue with 10mg/kg PM2.5 were positive.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Chronic exposure to PM2.5 induced severe atypical hyperplasia of the bronchial epithelial cells in mice, it suggested that the model of severe atypical hyperplasia of lung in mice was established.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      22P - Paclitaxel/ carboplatin/ bevacizumab in non-small cell lung cancer patients induces peripheral effector CD8 T cell proliferation that could be prone for treatment with checkpoint inhibitors (Now Available) (ID 384)

      12:30 - 13:00  |  Presenting Author(s): Daphne Dumoulin  |  Author(s): Pauline de Goeje, Myrthe Poncin, Koen Bezemer, Harry J.M. Groen, Egbert F. Smit, Anne-Marie C. Dingemans, Andre Kunert, Rudi Hendriks, Joachim G Aerts

      • Abstract
      • Slides

      Background

      Checkpoint inhibitors targeting programmed death receptor (PD)-1 or PD-ligand 1 (PD-L1) became the cornerstone in the treatment of advanced NSCLC. Several phase III trials showed a better overall survival by treating with combination chemotherapy and checkpoint inhibition, suggesting that addition of chemotherapy increased the response to checkpoint inhibitors. Recently, peripheral blood biomarkers such as Ki67+PD-1+CD8 cells were found to be predictive for clinical outcome with PD-1 treatment. Knowing more about immune modulatory capacities of chemotherapy can help us to design better treatment strategies. We investigated the immune-modulatory effects of paclitaxel/carboplatin/bevacizumab (PCB), focusing on known immune populations associated with response to checkpoint inhibitors in peripheral blood.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      In the NVALT 12 study, 223 patients with advanced NSCLC were enrolled to receive PCB, with or without nitroglycerin patch. At baseline and after the first and second treatment cycle, peripheral blood was drawn. By flow cytometry, the proportions of T cells and several subsets and co-inhibitory receptors of these, B cells and monocytes were determined.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      6 weeks after starting treatment with PCB, the proportions of T cells were significantly increased compared to baseline values. Within the T cells subsets, proliferation of CD4 T cells remained stable whereas proliferation of CD8 T cells (Ki67+) were significantly increased. The proliferating Ki67+ CD8 T cells expresses more PD-1 compared to non-proliferating CD8 T cells. However, patients with >2 fold increased proliferation of T cells did not show a better outcome.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Paclitaxel/ carboplatin/ bevacizumab induces proliferation of CD8 T cells which expresses more co-inhibitory checkpoint molecules. Progression free and overall survival was unchanged by this increase on its own, showing the rationale to combine PCB with checkpoint inhibition in lung cancer, as used in Impower 150.

      b651e8a99c4375feb982b7c2cad376e9 Clinical trial identification

      NCT01171170.

      7a6a3ffa2dadc03a6151ee2c4d6fa383 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      NVALT.

      682889d0a1d3b50267a69346a750433d Disclosure

      D. Dumoulin: Speakers fee: BMS, Roche, Pfizer, Novartis. A-M.C. Dingemans: Advisory boards, lectures: Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Pfizer, BMS, Amgen, Novartis, MSD, Takeda (honoraria to institution). J.G. Aerts: Advisory boards: BMS, Boehringer Ingelheim, MSD, AstraZeneca, Eli Lilly, Takeda, Amphera; Stock owner: Amphera B.V. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      23P - Immunosenescence (iSenescence) correlates with progression (PD) to PD-(L)1 inhibitors (IO) and not to platinum-chemotherapy (PCT) in advanced non-small cell lung cancer (aNSCLC) patients (pts) (ID 599)

      12:30 - 13:00  |  Presenting Author(s): Roberto Ferrara  |  Author(s): Marie Naigeon, Edouard Auclin, Boris Duchemann, Lydie Cassard, Jean Jouniaux Medhi, Lisa Boselli, Jonathan Grivel, Aude Desnoyer, Laura Mezquita, Lizza Hendriks, David Planchard, Caroline Caramella, Jordi Remon-Masip, Sabina Sangaletti, Marina Chiara Garassino, Benjamin Besse, Nathalie Chaput

      • Abstract

      Background

      iSenescence is a remodeling of immune functions with a multifactorial etiology (i.e. aging, chronic inflammation, cancer). Although the absence of CD28 and the expression of CD57 and KLRG1 on circulating T-lymphocytes are hallmarks of iSenescence, the characterization of such phenotype in aNSCLC pts and the correlation with clinical characteristics and benefit from IO or PCT are currently unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      A senescent immune phenotype (SIP) defined as % of circulating CD8+CD28-CD57+KLRG1+ T-lymphocytes was assessed by flow cytometry (FC) on fresh blood from aNSCLC pts treated with IO or PCT in a single institution. A log-rank maximization method was used to identify a SIP cut-off level and dichotomize pts accordingly. The objective was to correlate SIP with clinical characteristics and RECIST response by univariate logistic regression analysis.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      37 aNSCLC pts were evaluable for SIP before IO: 32% ≥ 65 years, 91% non-squamous, 43% KRAS mutated, 51% with PD-L1 expression ≥1%, 8% chemotherapy naïve. 43% had PD, 41% stability (SD), 16% partial response (PR). Median PFS and OS were 2.7 (95% CI 1.8; 7.3) and 13 (95% CI 4.8-NR) months, respectively, median follow-up was 9.3 (95% CI 6.2-14.9) months. SIP (% CD28-CD57+KLRG1+) median value on circulating CD8+ lymphocytes was 12.2% (min 1.7%, max 56.1%). 32% of pts had >20.47% CD8+ lymphocytes with a CD28-CD57+KLRG1+ phenotype, being classified SIP+. SIP status did not significantly correlate with age, pts’ characteristics or CT exposure. 2 (17%) of 12 SIP+ had PR/SD (DCR), vs 19 (76%) of 25 SIP- pts (p = 0.001); median PFS was significantly lower in SIP+ (1.5 months 95% CI 1;2.2) vs SIP- pts (7.4 months 95% CI 5.5, 9.3) (p = 0.001). Among 61 aNSCLC pts treated with 1st line PCT, 18% had PD, 43% SD, 39% PR. SIP median value on circulating CD8+ lymphocytes was 17.9% (min 0.89%, max 66.1%), 43% of pts were SIP+. SIP did not significantly correlate with DCR (OR: 0.82, 95% CI 0.22-3.13, p = 0.82) upon PCT.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      iSenescence, monitored by FC measurement of 3 surface molecules on circulating CD8 + lymphocytes, is observed in 32% and 43% of aNSCLC pts before IO or PCT, respectively. SIP correlated with lower DCR upon IO and not PCT.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Institut Gustave Roussy.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      24P - A new bioinformatic pipeline allows the design of small, targeted gene panels for efficient TMB estimation (Now Available) (ID 192)

      12:30 - 13:00  |  Presenting Author(s): Paolo Manca  |  Author(s): Izaskun Mallona, Daniele Santini, Giuseppe Tonini, Christian Diego Rolfo, Mark D. Robinson, Francesco Pantano

      • Abstract
      • Slides

      Background

      The tumor mutation burden (TMB) is emerging as a prognostic and predictive marker for the response to immune checkpoint blockade (ICB) drugs. We aimed to develop a new method for the definition of gene panels that can precisely estimate the TMB with a considerably lower amount of genome.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We developed a bioinformatic pipeline which allows the design of gene panels suited for TMB estimation. The method is particularly efficient in optimizing the balance between the precision of the TMB estimate and the length of the gene panel created. We tested in silico the efficiency of different panels obtained with our method in an independent cohort of patients with lung adenocarcinoma (LUAD). We also compared in the same cohort of patients the performance of our panels with the performance of existing gene panels.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      We designed a 0.080 Megabases (Mb) long gene panel which estimated TMB in an independent LUAD cohort with an acceptable precision (adjusted R2=0.745; Spearman ρ = 0.827, Pearson ρ = 0.864). The panel showed 0.89 accuracy in the identification of TMB-high patients (25/28 patients, CI: 0.73 – 0.96). Every unitary increase of our TMB estimate was associated with lower risk of disease progression (univariate analysis: HR = 0.78; CI: 0.65-0.93; p = 0.006; multivariate analysis: HR = 0.8; CI: 0.63-1.01; p = 0.0621). Different existing panels of less than 1 Mb long showed a lower adjusted R2 when compared to our gene panel (Table). Two other commercial panels of 1.9 Mb and 1.1 Mb showed a similar adjusted R2 to panels of the same lengths built with our method; nevertheless, they showed a lower accuracy in TMB-high patients definition (ROC curves AUC of 0.862, 0.870, 0.946 and 0.967 were observed, respectively, for the commercial 1.9 Mb panel, the commercial 1.1 Mb panel, our 0.080 Mb panel and our 2.0 Mb panel)

      Performance (adjusted R2) in TMB estimation of existing gene panels and gene panels built with our method of similar length.
      Other panels IDs (length)Other panels performanceOur panels performance (length)
      panel #1 (0.187 Mb)0.760.83 (0.187 Mb)
      panel #2 (0.240 Mb)0.580.85 (0.25 Mb)
      panel #3 (0.300 Mb)0.690.85 (0.25 Mb)
      panel #4 (0.98 Mb)0.810.91 (0.98 Mb)
      panel #5 (1.1 Mb)0.920.92 (1.1 Mb)
      panel #6 (1.9 Mb)0.930.93 (2.0 Mb)
      .

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Our method allows the design of gene panels particularly suitable for the TMB estimation in patients with LUAD and outperforms existing gene panels less than 1 Mb long.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Paolo Manca.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      25P - Lung tumorspheres as a drug screening platform against cancer stem cells (ID 551)

      12:30 - 13:00  |  Presenting Author(s): Alejandro Herreros Pomares  |  Author(s): Héctor Amado, Silvia Calabuig Fariñas, Eva Escorihuela, Juan Murga, Susana Torres, Elena Durendez-Saez, Feiyu Zhang, Ana Blasco, Atilio Navarro, Cora Sampedro, Eloísa Jantus-Lewintre, Carlos Camps

      • Abstract

      Background

      Treatment resistance and metastasis are linked to cancer stem cells (CSCs). This population represents a promising target, but remains unexplored in lung cancer. The main objective of this study was to characterize lung CSCs and discover new therapeutic strategies.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      The study was performed on NSCLC cells from 8 resected patients and 12 cell lines. Suspension cultures (tumorspheres) were established for CSCs enrichment and differentiated tumor cells were cultured as monolayers (2D). The CSCs properties of tumorspheres were assessed in vitro and in vivo. The expression of 60 CSC-related genes was analyzed by RTqPCR and the expression of 12 proteins was evaluated by immunoblot (IB) and immunofluorescence (IF). High-throughput screening was performed using Prestwick and Myria libraries. Selected drugs were administered intraperitoneally to NOD/SCID mice with tumors induced by NSCLC patient and H1650 tumorspheres.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Lung tumorspheres showed unlimited exponential growth (>30 passages), great tumor initiation potential, differentiation capacity, and high resistance to chemotherapy agents, but not to salinomycin. Tumorspheres had significantly higher expression of CSC-related genes (ALDH1A1, KLF4, NANOG, CD44, CD90, CDKN1A, JUNB, MDM2), invasion promoters (MMP9, SNAI1, ITGA6), and Notch (NOTCH1, NOTCH3, DLL4, JAG1) and Wnt (CTNNB1, GSK3B) components than their paired adherent-cultured cells. IB confirmed the overexpression of proteins encoded by CD44, NANOG, CDKN1A, SNAI1, ITGA6, and NOTCH3, and IF showed different localization patterns on lung adenocarcinoma tumorspheres compared with the 2D cultures. Three novel drugs [Disulfiram (DSF), Compound 1 (COMP1) and Compound 2 (COMP2)] with greater cytotoxic potential against lung tumorspheres than monolayer cells were identified. These results were validated in vivo, demonstrating the capacity of these drugs to reduce tumor growth in mice.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Tumorspheres are a useful culture platform for CSCs characterization in a simple and cost-effective way. We found three drugs which are able to diminish the formation and viability of tumorspheres, constituting promising therapies against lung CSCs. Supported by CB16/12/00350, PI12-02838, and PI15-00753 from ISCIII.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Fundación de Investigación Hospital General Universitario de Valencia.

      213f68309caaa4ccc14d5f99789640ad Funding

      Centro de Investigación Biomédica en Red de Oncología (CIBERONC) and Instituto de Salud Carlos III (ISCIII).

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      26P - Potentialities of liquid biopsy in advanced non-small cell lung cancer (aNSCLC): Early evaluation of sentinel mutations in plasma and outcome of patients treated with immunotherapy (ID 504)

      12:30 - 13:00  |  Presenting Author(s): Laura Bonanno  |  Author(s): Elisabetta Zulato, Ilaria Attili, Alberto Pavan, Paola Del Bianco, Giorgia Nardo, Andrea Boscolo Bragadin, Lorenza Pasqualini, Fiorella Calabrese, Matteo Fassan, Giulia Pasello, Valentina Guarneri, Alberto Amadori, Pierfranco Conte, Stefano Indraccolo

      • Abstract

      Background

      The introduction of immune-checkpoint inhibitors (ICIs) in the management of aNSCLC has led to great outcome improvement, but reliable predictive biomarkers are still a need. Liquid biopsy has the potential to monitor biological effects of treatment. Aim of the study is to explore the potential predictive value of its dynamic analysis in aNSCLC treated with ICIs.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      aNSCLC patients consecutively treated with ICIs at Istituto Oncologico Veneto were prospectively enrolled and genotyped in tissue. Plasma samples were collected at baseline (T1), after three or four weeks according to the administration schedule (T2) and at the moment of the first radiological evaluation (T3). Patients carrying KRAS mutation in tissue were analyzed in plasma with droplet digital PCR (ddPCR). Semiquantitative index of fractional abundancy of mutated allele (MAFA) was used.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      aNSCLC patients (N: 54) were prospectively enrolled and tissue genotyped, 24 of them carried KRAS mutation in tissue and 11 (46%) were positive in plasma at baseline. Positivity was not associated with tumor burden or other clinical features. We evaluated the impact of the presence and the quantitative variation of MAFA during treatment on outcome in terms of progression free-survival (PFS). After a median follow-up of 10.9 months, the presence of sentinel mutation at T1 did not affect PFS, whereas the MAFA increase from baseline to T2 and to T3 were associated with shorter PFS (HR: 5.9, 95%CI: 1.2-27.7, p:0.02 and HR: 12.1, 95%CI: 2.3-23.8, p:0.003, respectively). Median PFS was 5.2 months in the presence of MAFA increase T1-2, while it was not reached in case of decreased/stable MAFA.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Increase in MAFA from baseline to three or four weeks after the start of ICI is associated with shorter PFS. Predictive value of dynamic analysis of sentinel mutations in plasma during ICIs treatment warrants further validation in aNSCLC.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Istituto Oncologico Veneto.

      213f68309caaa4ccc14d5f99789640ad Funding

      Istituto Oncologico Veneto.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      27P - Comparison of three different gene panels for determination of tumor mutational burden by next generation sequencing (ID 371)

      12:30 - 13:00  |  Presenting Author(s): Roberto Pappesch  |  Author(s): Carina Heydt, Jan Rehker, Sabine Merkelbach-Bruse

      • Abstract

      Background

      The introduction of cancer immunotherapies has improved survival rates of certain groups of patients. According to first studies, that used whole exome sequencing, the accumulation of tumor neoantigens and therefore tumor mutational burden (TMB) could be used as molecular marker for prediction. In this study, large gene panel assays of different suppliers were tested on 28 DNA samples derived from formalin fixed, paraffin-embedded (FFPE) tumor tissue with regard to implementation in routine diagnostics.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      After DNA isolation the following kits of three different suppliers have been used for library preparation: A custom SureSelectXTHS Target Assay (Agilent Technologies, Santa Clara, CA, USA), the NEOplus v2 RUO assay (New Oncology, Cologne, Germany) and the TruSight Oncology 500 kit (Ilumina, San Diego, CA, USA, TSO500) following manufacturers’ protocol. All assays were sequenced on the NextSeq 500 system (Illumina). For quality control the TapeStation 4200 System (Agilent Technologies) was used.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      All kits tested showed different final concentration after library preparation. Fragment sizes were as expected and libraries were suitable for sequencing. In terms of time needed for library preparation the NEOplus v2 RUO assay was the most laborious kit. The resulting TMB-scores showed similar picture for all kits and samples tested. For all panels access to the results of the sequenced genes and detected variants is possible. Data access differs between the developers in terms of availability and manageability. Since not all kits use unique molecular identifiers (UMI) the filtering capabilities are different.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      In this study, three different gene panel assays for TMB-determination were tested. All panels provided a similar TMB-score for the analysed samples. In terms of usage and in respect of implementation in routine diagnostics, time and efficiency are the most important parameters. Here, the TSO500 kit and the SureSelectXTHS Target Assay showed the best potential for the use in routine diagnostics.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      C. Heydt: Honoraria: AstraZeneca, BMS, Illumina. S. Merkelbach-Bruse: Honoraria: AstraZeneca; Advisory role: AstraZeneca, Roche. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      28P - Applicability of ctDNA at diagnosis and during the monitoring of EGFR-mutated patients (ID 557)

      12:30 - 13:00  |  Presenting Author(s): Silvia Calabuig Fariñas  |  Author(s): Ana Blasco, Elena Durendez-Saez, Amaya Fernández, Marais Mosqueda, Eva Escorihuela, Alejandro Herreros Pomares, Francisco Aparisi, Javier Garde, Mahmoud Shahin, Eloísa Jantus-Lewintre, Carlos Camps

      • Abstract

      Background

      Identification of activating mutations in the EGFR enabled to change the therapeutic approach for NSCLC patients as therapeutic targets. Liquid biopsy is a new option for analysis of biomarkers with valuable prognostic and predictive information, allowing the detection of EGFR mutations with a reproducible and minimally invasive approach. The aim of this study was to correlate EGFR mutational status in ctDNA at diagnosis and follow-up of NSCLC patients as a complementary/alternative to tissue-based molecular profiling.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Study included 20 patients with EGFR-mutated advanced NSCLC. Blood samples were collected at diagnosis, during follow-up and at progression. CtDNA was obtained from plasma and EGFR mutations were assessed by BEAMing dPCR (Sysmex®). Concordance between tissue and plasma EGFR mutation status was calculated as the number of positive plasma samples out of the total number of tissue samples. Cases at which T790M were first detected in blood were compared to date of progression as determined by radiological imaging in standard practice.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      A total of 262 plasma samples from 20 patients were analyzed, 75% percent of patients were females; 60% had never smoked; with a median of 18 months of follow- up (range: 5.13-61.77). The Positive Percent Agreement (PPA) at baseline for EGFR del19 and L858R mutation status between plasma and tissue was 75%; in 12 cases the clearance of the primary mutation happens during the first four to eight weeks after initiation of EGFR TKI. Furthermore, eight patients with radiological progression presented the resistance mutation T790M (66%), remarking that the majority of these tumors presented again the sensitizing mutation. In 6 of these patients plasma T790M-positivity was detected an average of 16 weeks (range: 4-24) prior to radiological progression. These results suggest that periodic monitoring of EGFR status in ctDNA could provide information regarding diagnoses, response or resistance to TKI-treatment.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Analyses of EGFR mutations in cfDNA have important clinical applicability and can be a useful alternate biomarker of diagnoses and early detection of TKIs resistance mechanisms.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Fundación de Investigación del Hospital General Universitario de Valencia.

      213f68309caaa4ccc14d5f99789640ad Funding

      Work supported in part by AstraZeneca (ISSIRES 0110); CIBERONC (CB16/12/00350); López-Trigo Grant.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      29P - Pretreatment T790M mutation detection by ultrasensitive PCR assay as predictor of efficacy in non-small lung cancer (NSCLC) patients treated with 1<sup>st</sup> or 2<sup>nd</sup> generation EGFR tyrosine kinase inhibitors (TKIs) (Now Available) (ID 477)

      12:30 - 13:00  |  Presenting Author(s): Oscar Jose Juan Vidal  |  Author(s): J. Simarro, David Lorente Estelles, G. Pérez-Simó, Nuria Mancheno, R. Murria, José Gomez Codina, Begonia Laiz, Sarai Palanca

      • Abstract
      • Slides

      Background

      T790M mutation detection previos to 1st/2nd generation EGFR TKIs treatmentis rare by conventional methods (1-8%), although PCR ultrasensitive methods increase their prevalence to 34-80%. The aim of the study is to evaluate the presence of T790M mutations by 2 different ultrasensitive assays and their impact efficacy.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      127 patients (pts) with NSCLC and EGFR mutations were analyzed. 73 of them had sufficient pretreatment tissue for T790M testing. The T790M mutation was screened by PNA Clamp TaqMan Assay (Applied Biosystems) and by ddPCR (BioRad).

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The limit of detection (LOD) of variant allele frequency was 0.081% and 0.136% for PNA Clamp and ddPCR, respectively. Prevalence of T790M mutations pretreatment was 23% (17/73) and 32% (23/71), respectively. A total of 71 samples gave a certain result in both methodologies (71/73; 95.89%). Agreement between the results of both techniques was 91.55%. Finally, 31 pts who met the eligibility criteria: diagnoses of advanced NSCLC, treated with 1st/2on generation TKIs, have pre-treatment tissue for the analysis and the result of the T790M ultrasensitive analysis was conclusive; were selected to assess the relationship between the results of T790M determined by ultrasensitive methods and the prognosis. Nine (29%) of them had pretreatment T790M+ mutation by both ultrasensitive methods. Median PFS and OS were superior for patients with T790M detected by ultrasensitive PCR assay pre-treatment with TKIs: 24,9 vs. 19,6 m (p = 0.107) and 47,3 vs. 19,9 m (p = 0.76), respectively. To evaluate the association between T790M pretreatment and in the moment of progression we selected 16 pts with T790M mutation analyzed at progression (8 T790M+ and 8 T790M-). T790M at the time of progression was detected in 7 (63,6%) of 11 T790M- diagnosis patients, whilst only 1 (20%) of 5 T790M+ diagnosis patients were positive at the time of progression.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Both methods were highly effective for detection of EGFR T790M mutation. The detection of T790M mutation pretreatment of 1st/2ndgeneration EGFR TKIs by ultrasensitive PCR assay was associated with better PFS and OS.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Precision Medicine and Biomarkers Unit. IISLAFE.

      213f68309caaa4ccc14d5f99789640ad Funding

      AstraZeneca.

      682889d0a1d3b50267a69346a750433d Disclosure

      O.J. Juan Vidal: Honoraria, advisory role: Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Roche/Genetech, AstraZeneca, Pfizer, Eli Lilly, AbbVie; Institutional research funding: Bristol-Myers Squibb, AstraZeneca. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      30P - Prognostic significance of IGF-1 signaling pathway in patients with advanced non-small cell lung cancer (Now Available) (ID 323)

      12:30 - 13:00  |  Presenting Author(s): Ioannis Kotsantis  |  Author(s): Panagiota Economopoulou, Amanda Psyrri, Eirini Maratou, Dimitrios Pectasides, Helen Gogas, Nikolaos Kentepozidis, Giannis Mountzios, George Dimitriadis, Stavroula Giannouli

      • Abstract
      • Slides

      Background

      Insulin-like growth factor 1(IGF-1) signaling pathway has been suggested as an important oncogenic mediator in various malignancies, including lung cancer. In this study, we aimed to evaluate serum levels of IGF-1, IGF-2 and IGF-Binding Protein 3 (IGF-BP3) before and after chemotherapy or chemoradiotherapy treatment in patients with locally advanced/metastatic non-small cell lung cancer (NSCLC) and their potential correlation with response to therapy and patient survival.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Seventy-three patients with stage III/IV NSCLC were included in the study. Expression of IGF1, IGF2, and IGFBP3 was evaluated in peripheral blood samples in two separate time points, at baseline and 3 months post treatment. Analysis and quantification of circulating levels of IGF-1, IGF-2, IGF-BP3 were performed by total ELISA technique. IGF-1/IGF-BP3 ratio is considered an indicator of IGF-1 bioavailability.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      In univariate analysis, the median value of IGF-1 after treatment (130.80 vs 98.00 ng/ml, p = 0.087), and the median ratio of IGF-1/IGF-BP3 (0.01044 vs 0.00678, p = 0.056) were higher in responders. Further analysis of the variation of each biomarker before and after treatment showed that the median value of IGF-1 was decreased after treatment in the total population (125.82 from 133.4 ng/ml, p = 0.087), albeit no difference was found between subgroups. In addition, the median value of IGF-1/IGF-BP3 ratio was found to be lower after treatment in the total population (0.01006 from 0.01252, p = 0.011). Importantly, the post-treatment value of the ratio was significantly reduced in responders (0.01044 from 0.01255, p = 0.02). No correlation was found between variation in biomarker values, patient OS and PFS.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      In a cohort of patients with stage III/IV NSCLC treated with chemotherapy or chemoradiotherapy, reduction of IGF-1/IGF-BP3 ratio, which is an indicator of IGF-1 bioavailability, was statistically significant in patients that responded to treatment. If validated in larger cohorts, our results support the use of IGF-1/IGFBP3 as a predictive tool for response to chemotherapy in NSCLC.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      31P - Do two lungs form an integrated immune system? Learning from BALF examination in lung cancer (ID 393)

      12:30 - 13:00  |  Presenting Author(s): Joanna Domagala-Kulawik  |  Author(s): Tomasz Skirecki, Dariusz Dziedzic, Malgorzata Polubiec-Kownacka, tomasz Kryczka, Iwona Kwiecien

      • Abstract
      • Slides

      Background

      Bronchoalveolar lavage fluid (BALF) examination was found to be useful in the evaluation of local immune status in the site of lung cancer development. This procedure may be performed during lung cancer diagnosis and repeated during therapy. It especially concerns the majority of lung cancer cases, which are beyond the possibility of resection at recognition. However, the procedure of BAL in the lung affected by cancer is often complicated. The aim of this study was an analysis of differences in the character of immune response between the lung affected by cancer versus the opposite, ’healthy‘ lung. May BALF from the lung free of tumor serve for the characterization of local immune status?

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      BALF of 36 patients was harvested from the lung affected by cancer and opposite site: the lung without tumor. BALF cells were analyzed by means of the following sets of antibodies anti: the first probe CD4, CD127, CD25, Foxp3, CTLA4, the second probe: CD3, CD16/CD56, CD45, CD19, CD8. For macrophage phenotyping the immunofluorescent method with antibodies anti: CCR7 and CD163 was used. The concentrations of 27 cytokines were analyzed in the duplicate using Bio-Plex Pro Human Cytokine Assay. The next part of the study was performed in other 32 patients by the same method with a panel of antibodies anti: CD3, CD4, CD8, CD127, CD45RA, CD69, CTLA-4, PD-1.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      By the analysis of the BALF profile we found that only the cells and cytokines involved in regulatory pathways showed significant differences between both the ’healthy‘ and the cancerous lung, being elevated in the latter. The proportion of Tregs, CTLA4+Tregs, activated and memory PD-1+ lymphocytes, CCR7lowCD163high macrophages were significantly higher in the lung with cancer than in the healthy lung. On the other hand, the proportion of effectory cells and inflammatory cytokines concentration did not differ between both lungs, which may indicate that they form an integrated immune system and individual homeostasis.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Regulatory mechanisms which are up-regulated in the tumourbearing lung affect BALF profile in the lung with cancer, while the examination of BALF from the “healthy” lung may serve for the evaluation of individual basic profile of the anti-cancer response.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      J. Domagala-Kulawik: Travel grant, consultant: BMS, MSD. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      32P - Exosomes in NSCLC: Analysis of its cargo as a source of biomarkers (ID 544)

      12:30 - 13:00  |  Presenting Author(s): Elena Durendez-Saez  |  Author(s): Silvia Calabuig Fariñas, Cristian Suarez, Marais Mosqueda, Sandra Gallach, Eva Escorihuela, Andrea Moreno, Ning Dong, Alejandro Herreros Pomares, Ernesto de la Cueva, Alicia Martinez-Romero, Eva Serna, Jesús M Paramio, Eloísa Jantus-Lewintre, Carlos Camps

      • Abstract

      Background

      Exosomes are membranous vesicles around 40-130 nm secreted by cells, carrying key information to distant tissues. Exosomes have been detected in different types of clinical samples and may play a key role in NSCLC. They intervene in several processes such as angiogenesis, metastatic niche formation, immunosuppression; being relevant in stem cell differentiation. The main objective of this study was to analyze exosomal cargo from NSCLC cell lines and primary cultures under two conditions: suspension cultures with cancer stem cells features (3D tumorspheres) and adherent cultures (2D).

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Cell cultures were established from NSCLC resected patients and cell lines. Exosomes isolation was performed by ultracentrifugation. Characterization was carried out by NTA, electron microscopy, immunoblot and flow cytometry. Exosomal DNA was extracted to determine the mutational status of EGFR and RAS genes by BEAMing dPCR (Sysmex®). Transcriptomic analysis has been carried out from exosomal RNA with Clariom D Human microarrays (Affymetrix®), (p ≤ 0.01).

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Regarding exosomes characterization, NTA and electron microscopy showed an exosome size from 108-125 nm. Exosomes surface markers were detected by immunoblot and flow cytometry. Mutational analysis of EGFR and RAS genes shown the same pattern displayed by the origin cells. Transcriptomic analysis showed an expression of mRNAs, miRNAs and precursors significantly different between 3D and 2D exosomes. Afterwards, their targets were identified and a pathway enrichment analysis was performed to know in which biological processes (cancer-related) are involved. Significant differential expressions were also found between ADC vs SCC-derived exosomes. Interestingly, 7 exosomal miRNAs (miR-200c, 29a, 339, 224, 31, 21, 33a) had already been identified as overexpressed in NSCLC tissue by our group. Moreover, miR-339 and miR-21 were related to prognosis (p < 0.05) in ADC.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Differences in exosomal cargo have been observed between: i) 3D vs 2D cultures and ii) ADC vs SCC. In addition, the same mutational pattern was detected in exosomes as compared with parental cultures. Therefore, exosomes can be a useful source for biomarkers analysis in NSCLC.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Fundación de Investigación del Hospital General Universitario de Valencia (FIHGUV).

      213f68309caaa4ccc14d5f99789640ad Funding

      Supported by grant GV/2018/026 & Asociación Española contra el Cáncer (AECC Valencia).

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      33P - Prognostic value of CD8-positive tumor stroma-infiltrating lymphocytes and PD-L1 positive tumor cells at initial biopsy in patients with locally advanced NSCLC treated with chemoradiotherapy (ID 581)

      12:30 - 13:00  |  Presenting Author(s): Kathrin Gennen  |  Author(s): Lukas Käsmann, Chukwuka Eze, Maurice Dantes, Olarn Roengvoraphoj, Julian Taugner, Jens Neumann, Amanda Tufman, Michael Orth, Simone Reu, Claus Belka, Farkhad Manapov

      • Abstract
      • Slides

      Background

      According to results of PACIFIC trial, immune checkpoint inhibitors (CPIs) are an integral part of the multimodal treatment approach for inoperable locally-advanced non-small cell lung cancer (LA-NSCLC). The purpose of this single-center study was to investigate a prognostic value of CD8-positive tumor stroma-infiltrating lymphocytes (TILs) and PD-L1 positive tumor cells at initial biopsy in patients treated with definitive chemoradiotherapy (CRT).

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We collected initial tumor tissue samples and reviewed the clinical characteristics of 36 LA-NSCLC patients treated at our center with definitive CRT between 2000 and 2004. The analyzed tumor tissue was taken before start of multimodal treatment. An experienced pathologist performed the immunohistochemistry analysis and interpretation. Tumor cells and CD8-positive tumor stroma-infiltrating lymphocytes were analyzed separately. Based on PD-L1 expression on tumor cells, patients were divided into three subgroups (0%, 1-5%, >5%). Two patient subgroups were defined according to CD8 expression in the tumor-surrounding stroma (low and high density: 0-40% vs. 41-100%).

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Thirty-six patients with LA-NSCLC were treated with definitive CRT (stage II, III and IV: 2, 30 and 4 patients). 18 (50%) patients had squamosa cell carcinoma, 14 patients (39%) adenocarcinoma and 4 patients (11%) NOS. Patients with high density of CD8 positive tumor stroma-infiltrating lymphocytes (TILS) showed a significantly reduced overall survival than patients with low density (13 vs. 19 months, one-year survival 56.5 vs. 69.2% p = 0.047); Patients without (0%) and low expression (1-5%) of PD-L1 on tumor cells showed a significantly improved overall survival compared to patients with a PD-L1 expression on tumor cells over 5% (median survival: 13.8 vs. 6.6 months, 1-year survival rate: 67.7 vs. 33.3%; p = 0.039).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      High density of CD8-positive tumor stroma-infiltrating lymphocytes and PDL1 expression on tumor cells over 5% at initial biopsy correlates significantly with reduced overall survival in patients with LA-NSCLC treated with CRT.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      34P - Impacts of HDAC2 inhibition on lung cancer treatment (ID 541)

      12:30 - 13:00  |  Presenting Author(s): Yao-Tsung Yeh  |  Author(s): Cian-Rong Wu, Jia-Chen Lai, Cheng-Hsieh Huang, Yu-Feng Wei, Ming-Shyan Huang

      • Abstract

      Background

      Approximately 80% of lung cancer is non-small cell lung cancer (NSCLC) with a median survival time of 8 to 10 months. It is critical and urgent to find the effective interventions for patients suffering from NSCLC. Histone deacetylase 2 (HDAC2) is increasingly associated with development of several solid tumors. However, its role in lung cancer remained mostly lacking.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Immunohistochemistry was used to analyze the distribution patterns of HDAC2 protein in lung cancer and the results were further statistically correlated with clinicopathological characteristics and survival rate. XTT, invasion assay, flowcytometry, immunoblotting, and immunoprecipitation were used to explore the bio-impacts and underlying mechanisms of HDAC2 and its interplay with nicotine in lung cancer cells.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The Kaplan–Meier plotter shows that 1926 lung cancer patients with high HDAC2 mRNA levels will have a poor overall survival rate (p = 0.004). Increased HDAC2 mRNA expression predicts an improved overall survival of non-smoker patient group (p = 0.018) but not that of smoker patient group. Further immunohistochemistry showed similar results (p < 0.001). Intriguingly, this association seen in smoker and non-smoker groups was demonstrated in only squamous cell lung cancer, providing the specific interplay between HDAC2 and carcinogenic content of cigarette. Treatment with nicotine induced the NO production through rapidly increasing NOS2 expression and HDAC2 was subsequently nitrosylated. Knockdown of HDAC2 reduced nicotine-induced NOS2 expression and invasive activity. Ectopic HDAC2 overexpression enhanced nicotine-mediated NOS2 induction. Interestingly, ectopic overexpression of Cys262/274Ala HDAC2 mutant, un-nitrosylated, inhibited the invasive activity. HDAC2 specific siRNA and inhibitor enhanced the cytotoxicity of cisplatin and abolished the cisplatin-mediated cyclin B1 induction.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Our results implicated that HDAC2 might be required for cigarette carcinogenic content-mediated advanced development or treatment failure in lung cancer. NOS2 provides the link between nicotine and HDAC2 in lung cancer. Inhibition of HDAC2 activity may increase therapeutic effects of cisplatin-based treatments in NSCLC.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Yao-Tsung Yeh.

      213f68309caaa4ccc14d5f99789640ad Funding

      MOST, Taiwan (R.O.C).

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      35P - Clinicopathological characteristics with genetic profiling and prognostic analysis of primary lymphoepithelioma-like carcinoma in Chinese south-eastern population (Now Available) (ID 275)

      12:30 - 13:00  |  Presenting Author(s): YInchen Shen  |  Author(s): Fang Hu, Bo Zhang, Bao-Hui Han

      • Abstract
      • Slides

      Background

      Primary lymphoepithelioma-like carcinoma (LELC) is a rare form of lung cancer, since genetic alternations participate in the carcinogenesis in lung cancer, whether critical driver genes such as ROS1 fusion, anaplastic lymphoma kinase (ALK) rearrangement and epidermal growth factor receptor (EGFR) mutation play roles in LELC remains unclear.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We collected a total of 30 LELC samples for genetic and prognosis analysis retrospectively in ShangHai Chest Hospital, EGFR gene mutation, ALK rearrangement and ROS1 fusion status were extracted from digital database. Clinicopathological characteristics with genetic profiling and survival were analyzed.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      All samples appeared negative for genes (EGFR, ALK and ROS1) alternations detection. Female gender acted as an independently prognostic factor in poorer disease-free survival (DFS) (P = 0.034), and tumors locate in the left lobe associate with worse DFS in univariate analysis (significant trend, P = 0.051), moreover, serum positive NSE level also indicate a shorter DFS after adjustment (significant trend, P = 0.057). Most of LELC are diagnosed at early stage, with 93.3% (27/30) patients obtained the opportunities for surgery.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Since no classical genetic alternations appeared in present study, more investigations of other genes distributions should be explored in the future for better understanding of this rare subtype of lung cancer. Serum positive NSE level seemed to be a prognostic biomarker for DFS in LELC patients.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      36P - Can a BALF profile distinguish hot vs cold lung tumors? (ID 389)

      12:30 - 13:00  |  Presenting Author(s): Joanna Domagala-Kulawik  |  Author(s): Dariusz Dziedzic, Malgorzata Polubiec-Kownacka, tomasz Kryczka, Iwona Kwiecien

      • Abstract
      • Slides

      Background

      Immunotherapy brings evident benefits to lung cancer patients. However, the answer to this treatment is highly individualized and seems to be better in ‘hot’ tumors than in ’cold’ ones. The vast majority of lung cancers are in their advanced stages at recognition, therefore the access to large fragments of tumor tissue and tumor environment is limited. The results of our previous studies showed the usefulness of bronchoalveolar lavage fluid (BALF) examination in the evaluation of immune status in a lung tumor site. The aim of this study was to assess if BALF may reflect the signs of ‘hot’ vs. ‘cold’ tumors.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      36 lung cancer patients were investigated. The number of lymphocytes and the proportion of following lymphocyte subtypes were analysed by flow cytometry: T, B, T helper, T cytotoxic, NK cells, CD25+Th cells, T regulatory cells, CTLA4+Tregs. The concentration of IFNγ, TNFα, VEGF, TGFβ, IL-2, IL-10 was measured by Bio-Plex Pro Human Cytokine Assay. We defined ’hot‘ tumors by the presence of cell proportion or cytokine concentration above the median value and ’cold‘ tumors where these markers were lower than the median value.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      There were 36% of BALF samples with more than 2 parameters below the median values, which may reflect ’cold‘ tumors. The indications of immune response (more than 7, e.g. 50%) were elevated in 53% samples. The majority of ’hot‘ tumors were in the type of adenocarcinoma or NOS, but without any relation to the EGFR mutations nor ALK alterations. No relation between the intensity of immune response in the BALF and the clinical stage of cancer was observed.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      BALF examination may help in distinguishing ’hot‘ and ’cold‘ lung cancer and may be useful in the characterization of local immune status before treatment. By extrapolating the results of this study we could recommend BALF as a source of useful biomarkers before immunotherapy.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      J. Domagala-Kulawik: Travel grants, consultations: BMS, MSD. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      37P - Genetic variation of lymphotoxin beta receptor (LT&#x003B2;R) rs10849448 (A/G) is associated with risk for lung cancer and metastatic spread to adrenals (ID 526)

      12:30 - 13:00  |  Presenting Author(s): Foteinos-Ioannis D. Dimitrakopoulos  |  Author(s): Anna Antonacopoulou, Anastasia Kottorou, Vassiliki Tzelepi, Nikolaos Panagopoulos, Melpomeni Kalofonou, Dimitrios Dougenis, Angelos Koutras, Thomas Makatsoris, Haralabos Kalofonos

      • Abstract

      Background

      During the last years there is an expansion of our knowledge in lung cancer immunology. In addition, there is a growing number of studies on the role of lymphotoxin beta receptor (LTβR), a member of the tumor necrosis factor (TNF) family, which plays an important role in lymphoid system formation and homeostasis as well as in immune system regulation mainly through NF-κB signaling. The aim of the current study was to investigate the clinical relevance of LTβR single nucleotide polymorphism (SNP) rs10849448 (A/G) with the susceptibility to NSCLC, the clinicopathological parameters, the relapse and the survival rates of NSCLC patients, as well as with the protein expression of LTβR.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      LTβR SNP was genotyped in 268 randomly selected NSCLC patients and 279 age- and gender-matched healthy donors. Immunohistochemical analysis for LTβR was performed on 127 NSCLC tumors. The studied cohort was under observation during a five-year period.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Genotype frequencies of rs10849448 (AA, AG, and GG) varied between healthy controls and patients, but the difference did not reach statistical significance (P = 0.054). AA homozygotes were found to have lower risk for NSCLC compared to G allele carriers in univariate as well as in multivariate analysis (both P = 0.016). Moreover, rs10849448 was associated with development of metastases with A allele carriers developing less often metastatic disease in adrenals (P = 0.013). Interestingly, rs10849448 was related to membranous LTβR protein expression (P = 0.035) in malignant cells, with AA homozygotes being associated with higher protein levels.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      The present findings suggest that the investigated SNP rs10849448 may be associated with NSCLC initiation as well as with the development of metastatic disease. More association and functional studies are needed in order to further clarify it’s role in NSCLC.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      H. Kalofonos.

      213f68309caaa4ccc14d5f99789640ad Funding

      This research was co-funded by the Hellenic Society of Medical Oncology (HeSMO) through a research funding program.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      38P - Hedgehog pathway activation might mediate pemetrexed resistance in NSCLC cells (Now Available) (ID 330)

      12:30 - 13:00  |  Presenting Author(s): Yichao Liu  |  Author(s): Rosemarie Kiefl, Rudolf M. Huber, Amanda Tufman, Diego Kauffmann-Guerrero

      • Abstract
      • Slides

      Background

      Lung cancer is the leading cause of death among all other malignancies. Despite the wide use and the high efficacy of immunotherapy, most patients with advanced or metastatic disease need chemotherapeutic treatment. Primary and acquired resistance to chemotherapeutic agents are the main cause of reduced overall survival. The Hedgehog (HH) pathway has been shown to be crucial in cell development and survival. Activated in several types of cancer it might be a potent bypass mechanism mediating chemo resistance. Thus, this study aims at investigating the role of HH signalling in chemo resistant NSCLC cells.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      HCC827 NSCLC cells were treated with increasing sub-lethal doses of pemetrexed and vinorelbine to produce pemetrexed and vinorelbine resistant cells. RNA was isolated from both chemo resistant and naive cells. RT-qPCR was performed to evaluated mRNA gene expression. To measure cell growth capacity we used a MTT assay to evaluate the impact of the HH-inhibitor vismodegib in naïve and chemo resistant cell lines.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Pemetrexed resistant cells showed clearly increased expression levels of most of HH signalling genes. The HH transcription factors GLI1, GLI2 and GLI3 were increased 3.7, 4.3 and 3.5 fold compared to non-resistant cells. The trans-membrane HH receptor PTCH1 showed to be elevated 2.4 fold and the ligand of HH signalling SSH revealed to be expressed 5.9 fold compared to naïve cells. However, vinorelbine resistant cells did not show a significant activation of HH signalling. Supporting these results pemetrexed resistant cells treated with the HH inhibitor vismodegib showed reduced proliferation compared to naïve cells treated with vismodegib.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      These are the first results of our study investigating the impact of HH signalling on chemo resistant NSCLC cells. In the case of pemetrexed resistance activation of HH pathway could play an important role to mediate this resistance. However, further investigation is needed to clarify the role of the HH pathway in NSCLC treatment.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      39P - High dose apatinib in the reversal of immunosuppressive tumor microenvironment for irradiation therapy in lung carcinoma (ID 161)

      12:30 - 13:00  |  Presenting Author(s): lijun Liang  |  Author(s): chenxi Hu, yixuan Wen, wei Zhuang, lei Wang, youyou Xia, kaiyuan Hui, xiaodong Jiang

      • Abstract

      Background

      This study aimed to investigate the potential systemic anti-tumor effects of stereotactic ablative radiotherapy (SABR) and apatinib (a novel vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor) via reversing the immunosuppressive tumor microenvironment for lung carcinoma.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Lewis lung cancer cells were injected into C57BL/6 mice in the right hindlimb (primary tumor; irradiated) and in the left flank (secondary tumor; nonirradiated). When both tumors grew to the touchable size, mice were randomly divided into eight treatment groups. These groups received normal saline or three distinct doses of apatinib (50 mg/kg, 150 mg/kg, 200 mg/kg) daily for 7 days, in combination with a single dose of 15 Gy radiotherapy or not to the primary tumor. The further tumor growth/regression of mice were followed and observed.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Only primary tumor growth could be delayed with single SABR, while both primary and secondary tumor growth could be regressed with apatinib administration in a dose-dependent propensity. When combining SABR and apatinib, significant retardation of primary tumor growth could be observed. In addition, when combining SABR and apatinib of 200 mg/kg, growth of the secondary tumors could also be significantly inhibited (P < 0.01). This result indicated the namely “abscopal effect”. Mechanism analysis suggested that increased programmed death ligand-1 expression in tumor tissue was counteract by additional apatinib therapy. Furthermore, when apatinib was combined with SABR, the composition of immune cells could be changed and tumor specific T cell activation could be induced. More importantly, this two-pronged approach evoked tumor antigen-specific immune responses and the mice were resistant to another tumor rechallenge, finally, long-term survival was improved.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Our results suggested that the tumor microenvironment could be managed with high-dose of apatinib, which was effective in eliciting an abscopal effect induced by SABR.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      This work was supported by National Natural Science Foundation of China grants 81472792 and 81702813, Postgraduate Research & Practice Innovation Program of Jiangsu Province grants SJCX18_0707, and the Technology Office Foundation of Lianyungang City (NO.SH1613).

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      40P - The metabolic phenotypes of non-small cell lung cancer cells in association with clinical treatment strategies (ID 224)

      12:30 - 13:00  |  Presenting Author(s): Ting-Chun Kuo  |  Author(s): Tzu-Hung Hsiao, Pan-Chyr Yang

      • Abstract

      Background

      In 2011, metabolic reprogramming was defined as one of the cancer hallmarks, and several drugs targeting cancer metabolism have been developed as anti-cancer drugs. To improve medication efficiency of these anti-metabolic drugs, we tried to sub-classify non-small cell lung cancer (NSCLC) cells by their glycolytic dependency and treat them by targeting different metabolism-related proteins.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We stratified NSCLC cells according to their Oxygen Consumption Rate (OCR) and Extracellular Acidification Rate (ECAR) measured by the Seahorse XF analyzer. Metformin, an inhibitor of mitochondrial respiratory complex I, was used as an example to measure the sensitivities of NSCLC cells in different metabolic subtypes to drugs targeting oxidative phosphorylation (OXPHOS) pathways.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      According to the OCR and ECAR, measured by the Seahorse XF analyser, NSCLC cells could be further separated into two metabolic subtypes, OXPHOS-dependent and glycolysis-dependent subtypes. We found that the OXPHOS-dependent subtype was sensitive to metformin, while the glycolysis-dependent subtype was resistant. To target the glycolysis-dependent subtype of NSCLC cells, monocarboxylate transporter 4 (MCT4), a proton-linked lactate transporter, was identified. MCT4 was highly expressed in the glycolysis-dependent subtype of NSCLC cells and its’ expression was important for these cells. When we knocked down the expression or blocked the function of MCT4, the proliferation of these cells was significantly inhibited.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      In this report, we established a method to sub-classify NSCLC cells and predict the sensitivity of these cells to metformin. Besides, we identified MCT4 transporter as a druggable target to inhibit the proliferation of glycolysis-dependent subtype of NSCLC.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Ministry of Science and Technology in Taiwan.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

    • +

      41P - Diagnostic accuracy of droplet digital PCR (ddPCR) and amplification refractory mutation system PCR (ARMS-PCR) for detecting EGFR mutation in cell-free DNA of advanced lung cancer: A meta-analysis (Now Available) (ID 366)

      12:30 - 13:00  |  Presenting Author(s): Caichen Li  |  Author(s): Qihua He, Hengrui Liang, Jianxing He, Wenhua Liang

      • Abstract
      • Slides

      Background

      Epidermal growth factor receptor (EGFR) mutation testing in plasma cell-free DNA (cfDNA) from advanced lung cancer patients is an emerging clinical tool. This non-invasive approach may offer genotyping information but prevent patients from the shortcomings of invasive and repeated biopsies. This meta-analysis was designed to determine the diagnostic accuracy of two common PCR systems, ddPCR and ARMS-PCR, for detecting EGFR mutation in cfDNA.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      A systematic search was carried out based on electronic databases. Data from eligible studies were extracted and pooled to calculate the sensitivity, specificity, diagnostic odds ratio (DOR), and area under the summary receiver-operating characteristic curve (AUROC), using tissue biopsy results as the standard method.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Twenty-three studies involving 4,725 cases were identified and included. The plasma testing sensitivity, specificity, DOR and AUROC, compared with the matched tumor tissues, were 71.7% (95% CI, 67.6%-75.5%), 96.4% (95% CI, 94.2%-97.9%), 39.3 (95% CI, 21.2-73.1), 0.87 (95% CI, 0.80-0.94) for ddPCR, and 65.3% (95% CI, 62.9%-67.6%), 98.2% (95% CI, 97.6%-98.7%), 52.8 (95% CI, 26.3-106.1), 0.71 (95% CI, 0.52-0.91) for ARMS-PCR, respectively. In studies simultaneously comparing the two platforms, we observed no significant difference in specificity (P = 0.473) and sensitivity (P = 0.960) between ddPCR and ARMS-PCR, regardless of EGFR mutation type, tumor stage and EGFR-TKI treatment

      Index methodIncluded studiesSensitivitySpecificityDORAUROR
      ddPCR1271.7% (95% CI, 67.6%-75.5%)96.4% (95% CI, 94.2%-97.9%)39.3 (95% CI, 21.2-73.1)0.87 (95% CI, 0.80-0.94)
      ARMS-PCR1665.3% (95% CI, 62.9%-67.6%)98.2% (95% CI, 97.6%-98.7%)52.8 (95% CI, 26.3-106.1)0.71 (95% CI, 0.52-0.91)
      Subgroup analysis of exon 19 deletion in two systems
      ddPCR973.2% (95% CI, 67.0%-78.7%)99.3% (95% CI, 98.2%-99.8%)170.8 (95% CI, 77.8-374.8)0.97 (95% CI, 0.92-1.00)
      ARMS-PCR1166.3% (95% CI, 60.9%-71.3%)99.3% (95% CI, 98.6%-99.7%)113.7 (95% CI, 39.9-323.4)0.65 (95% CI, 0.25-1.00)
      Subgroup analysis of L858R in two systems
      ddPCR1068.4% (95% CI, 61.7%-74.7%)98.8% (95% CI, 97.6%-99.5%)108.8 (95% CI, 55.3-214.3)0.97 (95% CI, 0.92-1.00)
      ARMS-PCR1161.6% (95% CI, 54.9%-68.0%)99.3% (95% CI, 98.7%-99.7%)110.1 (95% CI, 49.7-243.8)0.79 (95% CI, 0.42-1.00)
      Subgroup analysis of stage IIIB-IV and recurrence in two systems
      ddPCR472.5% (95% CI, 65.8%-78.6%)93.5% (95% CI, 89.1%-96.5%)35.1 (95% CI, 17.9-68.8)0.90 (95% CI, 0.82-1.00)
      ARMS-PCR573.7% (95% CI, 66.7%-79.8%)96.3% (95% CI, 92.1%-98.6%)52.1 (95% CI, 7.0-387.7)0.52 (95% CI, 0.00-1.00)
      Subgroup analysis of stage IA-IV in two systems
      ddPCR871.2% (95% CI, 65.8%-76.1%)98.8% (95% CI, 96.4%-99.7%)46.8 (95% CI, 16.1-136.5)0.88 (95% CI, 0.70-1.00)
      ARMS-PCR1164.2% (95% CI, 61.7%-66.7%)98.3% (95% CI, 97.7%-98.8%)60.7 (95% CI, 30.9-119.2)0.77 (95% CI, 0.55-0.99)
      Subgroup analysis of TKI-naive in two systems
      ddPCR571.7% (95% CI, 65.4%-77.4%)96.5% (95% CI, 93.9%-98.2%)51.9 (95% CI, 24.8-108.7)0.90 (95% CI, 0.81-0.99)
      ARMS-PCR563.9% (95% CI, 57.4%-70.1%)96.7% (95% CI, 94.1%-98.4%)41.9 (95% CI, 9.6-183.6)0.60 (95% CI, 0.04-1.00)
      Subgroup analysis of previous-TKI in two systems
      ddPCR774.1% (95% CI, 68.2%-79.4%)95.4% (95% CI, 87.1%-99.0%)19.9 (95% CI, 5.8-68.9)0.84 (95% CI, 0.73-95.8)
      ARMS-PCR865.4% (95% CI, 62.8%-77.9%)98.5% (95% CI, 97.9%-99.0%)72.6 (95% CI, 25.6-205.7)0.75 (95% CI, 0.49-1.00)
      .

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      This study demonstrates that both ddPCR and ARMS-PCR have a high specificity with a practical sensitivity for detecting EGFR mutation in cfDNA of advanced lung cancer patients, which supports their application as a supplement or an alternative to tissue biopsy in clinical practice for genotyping.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The First Affiliated Hospital of Guangzhou Medical University.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      44P - Temporal trends in treatment (Tx) and overall survival (OS) among patients (pts) with incident NSCLC in the UK: A real-oncology database analysis from the I-O Optimise initiative (ID 514)

      12:30 - 13:00  |  Presenting Author(s): Michael Snee  |  Author(s): Sue Cheeseman, Matthew Thompson, Majid Riaz, Laure Lacoin, Will Sopwith, Carlos Chaib, Melinda Daumont, John R Penrod, John C O'Donnell, Geoff Hall

      • Abstract
      • Slides

      Background

      As part of I-O Optimise, a multinational research platform providing real-world insights into the management of lung cancers, temporal trends for initial Tx and OS are reported for pts diagnosed with NSCLC at Leeds Teaching Hospitals Trust (LTHT), hosting one of the largest integrated cancer centres in the UK.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      A retrospective cohort study using longitudinal data collected from electronic medical records at LTHT, including all adult pts diagnosed with NSCLC from Jan 2007 to Aug 2017 (follow-up to Mar 2018). Initial Tx was the 1st Tx received after diagnosis (categorised as surgery, radiotherapy or systemic anti-cancer therapy [SACT]). In this analysis, 2 diagnostic periods were compared: 2007–2012 and 2013–2017. Kaplan–Meier methods were used for OS.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Among 3739 pts with incident NSCLC, TNM stage distribution was: I, 19.2% (this increased noticeably from 14.0% in 2007–2012 to 24.8% in 2013–2017); II, 11.6%; IIIA, 12.5%; IIIB, 9.0%; and IV, 47.7%. Overall, 29.7% had non-squamous cell carcinoma (NSQ), 21.9% had squamous cell carcinoma (SQ), 11.7% had NSCLC NOS (this decreased noticeably from 18.8% in 2007 to 8.4% in 2016) and 2.4% had other histology; 34.3% of pts were diagnosed without pathology. Tx patterns for NSQ and SQ pts are shown by stage and year of diagnosis (Table). Between 2007–2012 and 2013–2017, median OS (in months) increased noticeably in stage I–IIIA NSQ (28.7 to 50.0) and SQ pts (17.4 to 32.1), but not in stage IIIB–IV NSQ (4.1 to 5.0) or SQ pts (5.3 to 4.8)

      Temporal changes in initial Tx (within 6 months of diagnosis) by pathology, TNM stage and year of diagnosis*
      Stage IStage IIStage IIIAStage IIIBStage IV
      2007-20122013-20172007-20122013-20172007-20122013-20172007-20122013-20172007-20122013-2017
      NSQn = 64n = 159n = 61n = 51n = 51n = 57n = 49n = 40n = 296n = 281
      Treatment (%)
      Surgery alone56.367.341.037.313.712.30.00.02.0M
      Surgery + SACT/RTMM21.321.69.817.50.00.0MM
      RT alone29.722.613.121.60.014.020.417.518.623.8
      SACT + RT0.00.09.8M21.633.324.530.016.217.1
      SACT aloneMMMM13.714.024.537.522.031.0
      Untreated (%)7.83.111.5M15.7M30.615.039.226.3
      SQn = 58n = 69n = 58n = 74n = 91n = 72n = 68n = 49n = 161n = 118
      Treatment (%)
      Surgery alone43.162.329.329.715.411.10.00.0MM
      Surgery + SACT/RTMM10.317.6MM0.00.0MM
      RT alone39.733.341.429.741.833.336.832.724.226.3
      SACT + RTM0.0M10.824.231.936.832.726.720.3
      SACT aloneM0.00.0MM11.111.814.316.821.2
      Untreated (%)MM13.810.813.28.314.718.429.227.1

      Data for patients with only clinical diagnosis and patients with initial treatment >6 months after diagnosis are not shown.

      M, masked as < 5 patients; RT, radiotherapy.

      .

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      OS improved in stage I–IIIA pts over time, most likely due to an increased proportion diagnosed at stage I and the evolution of initial Tx through the study period. In contrast, among stage IIIB–IV pts, SACT use remains relatively low and OS outcomes remain unchanged. Future analyses will help assess the impact of new therapies, including immunotherapy and 2nd-generation tyrosine kinase inhibitors, on Tx patterns and OS in the UK.

      b651e8a99c4375feb982b7c2cad376e9 Editorial acknowledgement

      Editorial assistance was provided by Richard Daniel, PhD, of Parexel and funded by Bristol-Myers Squibb.

      934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study

      Bristol-Myers Squibb.

      213f68309caaa4ccc14d5f99789640ad Funding

      Bristol-Myers Squibb through an EU wide RWD initiative called IO-Optimize sponsored by BMS.

      682889d0a1d3b50267a69346a750433d Disclosure

      M. Snee: Grants, personal fees: IQVIA, during the conduct of the study. L. Lacoin: Consultant epidemiologist contracted by Bristol-Myers Squibb. W. Sopwith: Personal fees: IQVIA, during the conduct of the study and outside the submitted work. C. Chaib: Employee: Bristol-Myers Squibb; Bristol-Myers Squibb (BMS) is funding this work through an EU wide RWD initiative called IO-Optimize sponsored by BMS. J.R. Penrod: Employment, stock ownership: Bristol-Myers-Squibb. J.C. O’Donnell: Employee, shareholder: BMS. All other authors have declared no conflicts of interest.

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      45P - Treatment (Tx) patterns and overall survival (OS) in patients (pts) with stage IIIB&#x02013;IV NSCLC in Portugal: An IPO-PORTO database analysis from the I-O Optimise initiative (ID 210)

      12:30 - 13:00  |  Presenting Author(s): Marta Alexandra Silva Soares  |  Author(s): Luis Antunes, Patricia Redondo, Marina Borges, Ruben Hermans, Dony Patel, Fiona Grimson, Robin Munro, Carlos Chaib, Laure Lacoin, Melinda Daumont, John R Penrod, John C O'Donnell, Maria Jose Bento, Francisco Rocha Goncalves

      • Abstract
      • Slides

      Background

      Understanding Tx patterns and related outcomes in the rapidly changing NSCLC landscape informs clinical decision-making. As part of I-O Optimise, a multinational research platform providing real-world insights into the management of lung cancers, Tx patterns and OS are reported for pts with NSCLC prior to immunotherapy reimbursement in Portugal.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      IPO-Porto, Portugal’s largest oncology hospital, has a research database linked to the RORENO cancer registry, covering northern Portugal. This database has collected data on 1524 adult pts with NSCLC since 2012; the current analysis includes pts diagnosed at stage IIIB–IV from Jan 2015 (when systemic anticancer therapy [SACT] data became available) to Dec 2016 (follow-up to Jun 2017). Tx patterns are shown for the first 3 Tx lines. Kaplan–Meier methods were used for OS and time to next Tx or death (TTNT) from SACT initiation.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Of 595 pts diagnosed at stages I–IV in 2015–2016, 54 (9.1%) had stage IIIB and 338 (56.8%) had stage IV NSCLC (median age, 65 yrs [range: 27–90; 9.2% ≥80]; male, 77.3%; brain metastases, 16.3%; non-squamous [NSQ], 73.7%; squamous [SQ], 21.2%). Of the 372 NSQ/SQ pts, 284 (76.3%) had 1st-line SACT; 101 (27.2%) had 2nd-line, and 20 (5.4%) had 3rd-line (Table). Median OS from SACT initiation was 12.6 (NSQ) or 10.3 (SQ) months. Median OS was longer in stage IV pts without brain metastases (11.6 vs 7.6 months), and in treated NSQ pts with EGFR/ALK alterations vs wild type (14.4 vs 9.3 months). Most NSQ pts with EGFR/ALK alterations (73.0%) had a 1st-line tyrosine kinase inhibitor (TKI). Median TTNT was 11.0 months in NSQ pts on 1st-line TKI and 6.3 (NSQ) or 7.3 (SQ) months in pts on 1st-line platinum chemotherapy

      SACT regimen (%)Non-squamousSquamous
      1st-line Txn = 221n = 63
      Platinum-based chemotherapy72.987.3
      Non-platinum single agent4.512.7
      TKI (any)22.60.0
      Erlotinib12.70.0
      Crizotinib2.30.0
      Gefitinib7.70.0
      Anti-PD-1/anti-PD-L1 checkpoint inhibitors0.00.0
      2nd-line Txn = 82n = 19
      Platinum-based chemotherapy13.421.1
      Non-platinum single agent59.873.7
      TKI (any)24.40.0
      Erlotinib9.80.0
      Crizotinib11.00.0
      Other TKI3.60.0
      Anti-PD-1/anti-PD-L1 checkpoint inhibitors2.45.3
      3rd-line Txn = 17n = 3
      Platinum-based chemotherapy35.30.0
      Non-platinum single agent41.2100.0
      TKI (any)11.80.0
      Erlotinib5.90.0
      Crizotinib0.00.0
      Anti-PD-1/anti-PD-L1 checkpoint inhibitors11.80.0

      PD-1, programmed death-1; PD-L1, programmed death-ligand 1

      .

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Pts with advanced NSCLC have a high burden of disease, with most diagnosed at stage IV and a short OS from SACT initiation. Future analyses will assess the post-reimbursement impact of immunotherapies (and new TKIs) on Tx and OS in Portugal.

      b651e8a99c4375feb982b7c2cad376e9 Editorial acknowledgement

      Professional medical writing assistance was provided by Richard Daniel, PhD, of Parexel and funded by Bristol-Myers Squibb.

      934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study

      Bristol-Myers-Squibb.

      213f68309caaa4ccc14d5f99789640ad Funding

      Bristol-Myers-Squibb through an EU wide RWD initiative called IO-Optimize sponsored by BMS.

      682889d0a1d3b50267a69346a750433d Disclosure

      M.A.S. Soares: Advisory boards, talks: Roche; Lilly, BMS, MSD; Boehringer Ingelheim, Pfizer, AstraZeneca, Novartis, outsider the submitted work. L. Antunes, P. Redondo, M.J. Bento: Grants: IQVIA, during the conduct of the study. M. Borges: Grants: IQVIA to IPO Porto, during the conduct of the study. R. Hermans, F. Grimson, R. Munro: Employee: IQVIA Real-World Insight Solutions (vendor paid by BMS). D. Patel: Personal fees: BMS, during the conduct of the study. C. Chaib: Employee: Bristol-Myers Squibb. L. Lacoin: Consultant epidemiologist contracted by Bristol-Myers-Squibb. All other authors have declared no conflicts of interest.

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      46P - Evolution of overall survival (OS) in patients (pts) with incident NSCLC in Denmark and Sweden: A SCAN-LEAF study analysis from the I-O Optimise initiative (ID 460)

      12:30 - 13:00  |  Presenting Author(s): Jens Benn Sørensen  |  Author(s): Simon Ekman, Odd Terje Brustugun, Pia Horvat, Dony Patel, Mats Rosenlund, Anne Mette Kejs, Ariadna Juarez-Garcia, Melinda Daumont, Laure Lacoin, John R Penrod, John C O'Donnell, Maria Planck

      • Abstract
      • Slides

      Background

      As part of I-O Optimise, a multinational research platform providing real-world insights into the management of lung cancers, the SCAN-LEAF study aims to describe the epidemiology, clinical care, and outcomes for pts with NSCLC in Scandinavia. Here, we report temporal OS trends among pts diagnosed with incident NSCLC from 2005 to 2015 in Denmark and Sweden.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      The SCAN-LEAF Danish and Swedish cohorts were established by linking respective national registries and include all adult pts diagnosed with incident NSCLC from Jan 2005 to Dec 2015 (follow-up to Dec 2016). The Kaplan–Meier method was used to estimate OS at 1, 3, and 5 yrs by histology (non-squamous cell [NSQ] or squamous cell [SQ]), TNM stage, and yr of diagnosis; changes in OS over time were assessed using the Cochrane–Armitage test.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      31,939 pts in Denmark and 30,067 pts in Sweden were diagnosed with NSCLC from 2005 to 2015. Most were diagnosed at stage IV (51.6% and 48.4%, respectively) and had NSQ histology (54.4% and 60.4%). Statistically significant trends (P < 0.05) for improved OS accompanied by an absolute OS rate increase of > 5% over the analysis period were seen for NSQ pts at 1 yr for all stages in both countries (Table); at 3 yrs for stages I–IIIB in Denmark (P ≤ 0.027), and stages I–II (P ≤ 0.0013) in Sweden; and at 5 yrs for stages I–II (P ≤ 0.026) in both countries. For SQ pts, this was seen only at 1 yr for stage IIIA in Denmark and stage I in Sweden (Table), and at 5 yrs for stage IIIA in Denmark (P = 0.02)

      1-yr survival probability*Year of Diagnosis
      P value for trend
      20052006200720082009201020112012201320142015
      DENMARK
      NSQ (n = 16,535)
      Stage I82%85%88%92%91%91%92%93%92%91%92%0.0001
      Stage II77%80%79%77%72%86%80%88%84%88%83%0.007
      Stage IIIA67%71%76%57%67%69%72%74%74%70%75%0.017
      Stage IIIB43%46%41%41%36%49%53%50%47%47%51%0.032
      Stage IV23%25%21%23%24%24%25%26%27%27%31%<0.0001
      SQ (n = 7987)
      Stage I80%79%82%79%85%85%87%85%83%86%83%0.114
      Stage II68%59%71%74%73%60%69%77%74%67%72%0.276
      Stage IIIA42%55%57%50%58%57%62%62%59%59%57%0.014
      Stage IIIB32%39%38%38%31%40%41%45%38%43%42%0.060
      Stage IV25%23%21%22%21%22%19%20%21%29%25%0.501
      SWEDEN
      NSQ (n = 16,847)
      Stage I87%91%87%92%90%92%93%94%93%94%95%<0.0001
      Stage II77%71%77%69%64%78%72%76%88%82%83%0.002
      Stage IIIA63%65%68%70%60%65%65%66%72%77%71%0.019
      Stage IIIB41%39%42%42%40%47%50%58%51%48%56%<0.0001
      Stage IV21%24%25%25%27%30%29%32%29%31%34%<0.0001
      SQ (n = 6574)
      Stage I77%88%82%74%81%83%85%85%86%87%89%0.024
      Stage II53%61%56%83%67%69%69%71%66%60%73%0.305
      Stage IIIA51%55%47%52%58%51%51%55%49%59%59%0.216
      Stage IIIB40%39%38%37%39%46%46%34%46%47%40%0.224
      Stage IV19%19%19%22%18%19%24%23%21%20%25%0.088

      Includes only patients with valid TNM staging classification at diagnosis. TNM, tumour, nodes, and metastasis.

      .

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Despite some improvements between 2005 and 2015, mainly in the short-term survival of pts with early-stage NSCLC, long-term OS rates for pts with late-stage disease did not change significantly and remained low. Even in pts with early-stage disease, OS outcomes were suboptimal, with a particular unmet need in the SQ population. Future analyses including data after 2015 will evaluate the potential impact on OS of increased use of new TKIs and immune checkpoint inhibitors.

      b651e8a99c4375feb982b7c2cad376e9 Editorial acknowledgement

      Professional medical writing assistance was provided by Richard Daniel, PhD, of Parexel funded by Bristol-Myers Squibb.

      934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study

      Bristol-Myers Squibb.

      213f68309caaa4ccc14d5f99789640ad Funding

      Bristol-Myers Squibb.

      682889d0a1d3b50267a69346a750433d Disclosure

      S. Ekman: Grants: BMS, during the conduct of the study. P. Horvat: Employee: IQVIA. D. Patel: Personal fees: BMS, during the conduct of the study. M. Roselund, A. Mette-Kejs: Fees for service to institution (IQVIA) during the conduct of this study: BMS; Employee: IQVIA. A. Juarez-Garcia: Employee: BMS. L. Lacoin: Consultant epidemiologist contracted by Bristol-Myers-Squibb for the SCAN-LEAF Project. All other authors have declared no conflicts of interest.

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      47P - Treatment (Tx) patterns and overall survival (OS) in patients (pts) with NSCLC in Sweden: A SCAN-LEAF study analysis from the I-O Optimise initiative (ID 446)

      12:30 - 13:00  |  Presenting Author(s): Simon Ekman  |  Author(s): Jens Benn Sørensen, Odd Terje Brustugun, Pia Horvat, Dony Patel, Mats Rosenlund, Anne Mette Kejs, Ariadna Juarez-Garcia, Melinda Daumont, Laure Lacoin, John R Penrod, John C O'Donnell, Maria Planck

      • Abstract
      • Slides

      Background

      As part of I-O Optimise, a multinational research platform providing real-world insights into the management of lung cancers, the SCAN-LEAF study aims to describe the epidemiology, clinical care and outcomes for pts with NSCLC in Scandinavia. We report initial Tx and OS for pts with NSCLC prior to the availability of immunotherapies in Sweden.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      The analysis includes all adult pts diagnosed with NSCLC at Uppsala and Karolinska (Stockholm) University Hospitals from 2012 to 2015 (follow-up to Dec 2016). Electronic medical record data were extracted using Pygargus CXP software and linked with national registries. Bespoke rule-based algorithms were applied to describe Tx patterns; Kaplan–Meier methods were used to estimate OS.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      2779 pts were diagnosed with incident NSCLC (median age, 70 yrs [range: 22–96; 14.2% ≥80]; male, 48.5%; histology: non-squamous (NSQ), 70.9%, squamous (SQ), 17.7%, other, 11.4%; stage distribution: I, 19.3%; II, 7.7%; IIIA, 12.3%; IIIB, 7.2%; IV, 51.2%). Initial Tx (≤6 months from diagnosis) by stage and yr of diagnosis is shown in the table. Median OS (months) for NSQ and SQ pts: not reached and 52.8 in stage I, 43.2 and 23.6 in stage II, 26.7 and 20.4 in stage IIIA, 12.5 and 12.9 in stage IIIB, and 7.6 and 6.1 in stage IV, respectively. Among stage IIIB–IV pts, 60.7% (NSQ) and 53.5% (SQ) had ≥1 line of systemic anti-cancer therapy (SACT); median OS was 12.2 (NSQ) and 10.4 (SQ) months in pts on SACT, and 3.1 (NSQ) and 3.7 (SQ) months in pts not on SACT. Ongoing analyses will assess factors associated with SACT receipt in stage IIIB–IV pts

      Initial Tx following diagnosis (≤6 months) based on TNM stage and year of diagnosis*, %
      Stage I
      Stage II
      Stage IIIA
      Stage IIIB
      Stage IV
      2012–201420152012–201420152012–201420152012–201420152012–20142015
      NSQN = 263N = 100N = 97N = 32N = 136N = 61N = 67N = 29N = 736N = 267
      Surgery only52.950.027.815.68.83.30.00.00.30.0
      Surgery + SACT or RT6.57.025.843.810.316.40.00.00.40.8
      RT alone27.022.012.418.811.83.317.910.318.613.5
      Chemoradiation3.43.020.69.452.259.00.00.00.00.0
      SACT + RT in stage IIIB–IV0.00.00.00.00.00.038.837.920.516.9
      SACT alone2.73.06.26.38.19.823.931.037.646.8
      Not treated**7.615.07.26.38.88.219.420.722.622.1
      SQN = 65N = 19N = 35N = 18N = 60N = 31N = 44N = 23N = 123N = 38
      Surgery only44.636.825.716.73.33.20.00.00.80.0
      Surgery + SACT or RT7.75.314.316.810.16.50.04.30.00.0
      RT alone36.931.628.650.011.712.920.521.719.510.5
      Chemoradiation3.15.320.05.650.051.60.00.00.00.0
      SACT + RT in stage IIIB–IV0.00.00.00.00.00.038.747.813.021.1
      SACT alone3.110.55.711.111.76.527.38.734.144.7
      Not treated**4.610.55.70.013.319.413.617.432.523.7

      Data shown for 2244 pts receiving Tx within 6 months of diagnosis. Data for pts with initial Tx administered more than 6 months after diagnosis or who did not have a valid TNM stage are not shown.

      No record of surgery, RT, or SACT during follow-up.

      RT, radiotherapy; TNM, tumour, nodes, and metastasis.

      .

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Swedish pts with NSCLC had a high burden of disease, with most diagnosed at stage IV and a median OS of ∼1 yr in late-stage pts receiving SACT. There is also scope for improved prognosis in pts diagnosed at early stages, particularly in SQ pts. Future analyses will assess the potential impact of recent improvements in diagnostics and therapeutics on Tx patterns and OS in Swedish NSCLC pts.

      b651e8a99c4375feb982b7c2cad376e9 Editorial acknowledgement

      Professional medical writing assistance was provided by Richard Daniel, PhD, of Parexel funded by Bristol-Myers Squibb.

      934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study

      Bristol-Myers Squibb.

      213f68309caaa4ccc14d5f99789640ad Funding

      Bristol-Myers Squibb.

      682889d0a1d3b50267a69346a750433d Disclosure

      S. Ekman: Grants: BMS, during the conduct of the study. P. Horvat, A. Mette Kejs: Employee: IQVIA. D. Patel: Personal fees: BMS, during the conduct of the study. M. Rosenlund: Employed: BMS, during the conduct of the study. A. Juarez-Garcia: Employed: BMS, outside the submitted work. L. Lacoin: Consultant epidemiologist contracted by Bristol-Myers-Squibb for the SCAN-LEAF Project. All other authors have declared no conflicts of interest.

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      48P - Education and lung cancer: A Mendelian randomisation study (Now Available) (ID 189)

      12:30 - 13:00  |  Presenting Author(s): Huaqiang Zhou  |  Author(s): Yaxiong Zhang, Jiaqing Liu, Yunpeng Yang, Wenfeng Fang, Shaodong Hong, Gang Chen, Shen Zhao, Zhonghan Zhang, Jiayi Shen, Wei Xian, Yan Huang, Hongyun Zhao, Li Zhang

      • Abstract
      • Slides

      Background

      Education has been shown to be inversely associated with the incidence of lung cancer at several conventional observational studies. However, this association may be biased owing to the methodological limitations of traditional observational study-confounding, reverse causation, and measurement error. Therefore, we aimed to investigate whether more years spent in education is causally associated with risk of lung cancer through a two sample mendelian randomisation study.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      The main analysis used publicly available genetic summary data from two large consortiums (International Lung Cancer Consortium (ILCCO) and Social Science Genetic Association Consortium (SSGAC)). Genetic variants used as instrumental variables for lung cancer and years of education were derived from two large genome wide association studies: ILCCO and SSGAC, respectively. Finally, genetic data from three additional consortia (TAG, GLGC, GIANT) were analyzed to investigate whether longer education can causally alter the common lung cancer risk factors. The exposure was the genetic predisposition to higher levels of education, measured by 73 SNPs from SSGAC. The primary outcome was the risk of lung cancer (11348 events in ILCCO). Secondary outcomes based on different histologic subtypes were also examined.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Genetic predisposition towards 3.6 years of additional education was associated with a 52% lower risk of lung (odds ratio 0.48, 95% confidence interval 0.34 to 0.66; p = 1.02 × 10−5). Sensitivity analyses were consistent with a causal interpretation in which major bias from genetic pleiotropy was unlikely. The Mendelian randomisation assumptions did not seem to be violated. Genetic predisposition towards longer education was additionally associated with less smoking, lower body mass index, and a favorable blood lipid profile.

      Mendelian randomisation estimates of the associations between education attainment and risk of lung cancer overall and histologic types

      OutcomeIVW method
      MR-Egger
      Weighted median method
      OR (95% CI)P valueOR (95% CI)P valueOR (95% CI)P value
      Lung cancer overall0.48 (0.34-0.66)1.02e-05*0.61 (0.12-3.17)0.560.52 (0.35-0.77)1.08e-03*
      Adenocarcinoma0.64 (0.41-1.00)4.97e-02*0.89 (0.09-8.48)0.920.59 (0.32-1.08)8.94e-02
      Squamous cell carcinoma0.41 (0.27-0.62)2.57e-05*0.32 (0.04-2.63)0.290.55 (0.30-1.01)5.24e-02

      : P value < 0.05; IVW: inverse-variance weighted; OR: odds ratio; CI: confidence interval.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Our present mendelian randomisation study provided strong evidence to support that higher education attainment plays a causal role in lowering the risk of lung cancer. Furthermore, more work is needed to elucidate the potential mechanisms which mediate the association between education and lung cancer.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      National Key R&D Program of China (Grant No. 2016YFC0905500, 2016YFC0905503).

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      49P - A Mendelian randomization study of the effects of Crohn&#x02019;s disease on lung cancer (ID 299)

      12:30 - 13:00  |  Presenting Author(s): Jiaqing Liu  |  Author(s): Huaqiang Zhou, Yaxiong Zhang, Wenfeng Fang, Yunpeng Yang, Shaodong Hong, Gang Chen, Shen Zhao, Jiayi Shen, Wei Xian, Yan Huang, Hongyun Zhao, Li Zhang

      • Abstract
      • Slides

      Background

      Crohn’s disease is associated with increased lung cancer risk in observational studies, but the causality of this association is uncertain. Here we conducted a two-sample Mendelian randomisation (MR) study to examine whether Crohn’s disease is causally related to lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We used the summary data of the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC, 5,956 cases and 14,927 controls; European ancestry) and International Lung Cancer Consortium (ILCCO, 11348 lung cancer cases and 15861 controls; European ancestry). 52 single nucleotide polymorphisms (SNPs) associated with Crohn’s disease were used as instrumental variables in the MR analysis. We utilized various MR methods (inverse-variance weighting (IVW), MR Egger, weighted median regression) to explore the causality. To investigate whether the effect of Crohn’s disease is associated with the histology of lung cancer, we also performed similar analyses on two different histologic subtypes of lung cancer (adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC).

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Crohn’s disease was not significantly associated with risk of lung cancer (odds ratio [OR], 1.01; 95% confidence interval [CI], 0.97-1.04; p = 0.76, IVW method). Weighted median (OR, 1.03; 95% CI, 0.98-1.07; p = 0.26) and MR Egger analysis (OR, 1.03; 95% CI, 0.95-1.11; p = 0.49) showed similar effect estimates of Crohn’s disease on lung cancer. The MR-Egger regression analysis showed that there was no evidence for the presence of horizontal pleiotropy (intercept β=-0.005, p = 0.532). Our leave-one-out analysis revealed that no single SNP strongly drove the overall effect of Crohn’s disease on lung cancer. The similar causal trend was observed in both LUAD and LUSC (LUAD, OR 0.99, 95% CI 0.94-1.04, p = 0.67, IVW method; LUSC, OR 0.98, 95% CI 0.94-1.03, p = 0.47, IVW method).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Our findings indicated that Crohn’s disease might not be causally associated with lung cancer, although patients with Crohn’s disease were at increased lung cancer risk in observational studies. Our study suggested there might be other risk factors associated with lung cancer in patients Crohn’s disease, which needs to be confirmed in the further study.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      National Key R&D Program of China (2016YFC0905500).

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      50P - Reduced-, and no-dose thin-section radiologic examinations: Comparison of capability for nodule detection in patients having pulmonary nodules (ID 247)

      12:30 - 13:00  |  Presenting Author(s): Wei Tang  |  Author(s): Qin Peng, Yao Huang, Ning Wu, Han Ouyang

      • Abstract

      Background

      To evaluate the capability of pulmonary MR imaging with zero echo time (ZTE) in pulmonary nodules assessments, using low-dose computed tomography (LDCT) as the reference standard.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Institutional review board approval and informed consent were obtained. Eight-nine consecutive patients (51 males: mean age, 69 years and 38 females: mean age, 71 years) with various pulmonary nodules were examined with chest LDCT and pulmonary MR imaging with ZTE. The interval between two examinations was within two weeks for each patient. Lung images were visually scored by two experienced radiologists who assessed the probability of nodule presence in comparison with LDCT. To compare nodule detection capability of the two methods, consensus for performances was evaluated by means of kappa statistics and χ2 test, and receiver operating characteristic analyses were used to compare diagnostic performance of both methods.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      There was no significant difference (F = 0.75, P = 0.56) in figure of merit between methods (LDCT, 0.84 Vs. MR imaging with ZTE, 0.86). Intermethod agreements between ZTE MR imaging and LDCT were significant (0.70 ≤ κ ≤ 0.98; P < 0.001). Areas under the curve for pulmonary nodules on LDCT were significantly larger than those on MR imaging with ZTE (P = 0.02).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Pulmonary thin-section MR imaging with ZTE was useful in nodule detection, and it is considered at least as effective as low-dose thin-section CT.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      51P - Invasive diagnostic investigation-related complications and its impact on treatment initiation in lung cancer patients in a rapid access lung lesion clinic in regional Australia (ID 403)

      12:30 - 13:00  |  Presenting Author(s): Katherine Mccann  |  Author(s): Wasek Faisal

      • Abstract

      Background

      Rapid Access Lung Lesions Clinic (RALLC) is designed to expedite the diagnostic pathway of suspected lung cancer, to allow treatment in a timely fashion. Invasive investigations (i.e. bronchoscopy, EBUS biopsy, CT-guided biopsy) are the usual tools to obtain tissue for histological diagnosis and each carries a small procedure-related complications risk, which could potentially delay definitive treatment initiation until the complication resolves.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Data was prospectively collected of all patients referred to a RALLC clinic in a tertiary cancer centre in regional Australia between July 2017 and December 2018. The need and choice of invasive investigation was determined based on tumour location, clinical suspicion of malignancy and multidisciplinary recommendation. Time to treatment was calculated from the date of diagnostic investigation to the first date of treatment (i.e. chemo/radio/immunotherapy, surgery). All data were analysed using descriptive statistics.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Over 18-months 202 patients were referred to the RALLC clinic for evaluation. 105 patients underwent invasive investigation [CT-guided lung biopsy 46 (44%), Bronchoscopy 32 (30%), EBUS biopsy 22 (21%) & Surgical biopsy 5 (5%)]. Malignancy was confirmed in 89 patients (85% diagnostic yield), 80 being lung cancer. The only investigation-related complication was pneumothorax, which occurred in 15 of the CT-guided lung biopsy (33%) with 11 patients needing hospital admission. The median time to first treatment for the overall cohort of lung biopsy patients was 28 days (mean 28.3, range 0-72). In the non-pneumothorax group, the median was 27 days (mean 27.7, range 0-65) while the pneumothorax group was 29 days (mean 29.8, range 5-72).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Although CT-guided lung lesion biopsy resulted in a significant number of pneumothorces in our cohort of patients, ultimately this did not significantly delay definitive treatment compared to the overall cohort. However, the high pneumothorax rate increases health care burden and additional invasive management procedures for the patient. Further investigation is warranted to explore factors associated with this.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Ballarat Health Services, Ballarat, Victoria, Australia.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

    • +

      52P - Concordance, decision impact, and satisfaction for a computerized clinical decision support system in treatment of lung cancer patients (Now Available) (ID 395)

      12:30 - 13:00  |  Presenting Author(s): K. Adam Lee  |  Author(s): Winnie Felix, Gretchen Jackson

      • Abstract
      • Slides

      Background

      Treatment options for lung cancer patients are progressing rapidly. A clinical decision support system (CDSS) which affords first-line treatment recommendations for cancer patients was implemented at Jupiter Medical Center, on March 1, 2017. This pilot analysis studied system performance and its impact on patients and providers.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Lung cancer cases managed in the CDSS between October 2017 and November 2018 were incorporated. CDSS results were viewed by providers, discussed in tumor board, and shared with the patients. Navigators directed a survey about CDS impact and user satisfaction to clinician and patients at conclusion of visits. Summary responses were calculated.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Thirty cases were processed by the CDSS; 23 surveys were completed. The treatment team agreed completely with CDSS recommendations for 18 cases (78.3%) and partly for 4 (17.4%). Clinicians reported that the CDSS impacted the treatment decision 9 (39.1%) cases and saved time in treatment design for 17 (73.9%). The CDSS confirmed the treatment plan for 16 cases (69.6%), recommended an option that was designated for 5 (21.7%), and offered a useful option not chosen for 1 (4.3%). For most cases, clinicians conveyed they were pleased with the CDSS results (n = 22; 95.7%), realized the system easy to use (n = 21; 91.3%), and would use it again (n = 22; 95.7%). For most cases, clinicians responded that they strongly agreed or agreed that the CDSS provided information that was relevant (n = 22, 95.7%), easy to understand (n = 21, 95.6%), and actionable (n = 21, 95.6%). Most patients answered that they were pleased with the CDSS analysis of their treatment plan (n = 19; 82.6%) and would want their provider to use the system in the future (n = 19; 82.6%).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      This study provides initial evidence that a CDSS can positively support and influence the care of lung cancer patients. Treatment teams agreed with CDSS recommendations in most cases, and the CDSS impacted treatment conclusions. Providers and patients were pleased with the CDSS and reported being willing to use it again.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Jupiter Medical Center.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      53P - Pulmonary tuberculosis: A hurdle to overcome for early lung cancer diagnosis in TB burden countries (Now Available) (ID 586)

      12:30 - 13:00  |  Presenting Author(s): Mst Shamima Akter  |  Author(s): Sharif Ahmed

      • Abstract
      • Slides

      Background

      Bangladesh is ranked 6th among the Tuberculosis high burden countries. Sometimes, pulmonary tuberculosis (PTB) mimics the early symptoms of lung cancer. Developing countries like Bangladesh, with limited diagnostic facilities, often misdiagnose early lung cancer as smear negative PTB. According to national guidelines for PTB, smear negative PTB is defined as the cases diagnosed on the basis of X-ray abnormalities or suggestive histology and extra pulmonary cases without laboratory confirmation. This observational study has been done to find out the ratio of misdiagnosis of lung cancer as Smear Negative PTB.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      This observational study was done between June, 2017 to January, 2018 at OPD of NIDCH (National Institute of Diseases the Chest & Hospital), Dhaka, Bangladesh. Inclusion criteria for the confirmation of PTB were: symptoms not improving after 3 weeks of anti-TB treatment; non-improving chest X-ray; new symptoms; no prior anti-TB treatment; smear negative PTB. For confirmation of AFB (Acid fast bacillus) smear test, CT scan of chest, GeneXpert of sputum, Mycobacterium culture and histological confirmation were performed. During this period, 172 cases were included in the study. After confirmation of the diagnosis, every case was treated according to national TB guidelines and refered to other tertiary specialized hospitals. After changing of the treatment protocol, 3-weekly follow up was done for 2 months with chest X-ray and other blood parameters.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The investigations mentioned above were performed in all cases included in the study: 35 cases (20.34%) were diagnosed as lung cancer by histological confirmation. 81 cases were (47.09%) diagnosed as multidrug-resistant TB and 2 cases (1.16%) were diagnosed as extensively drug-resistant TB. Other cases (31.39%) were confirmed as PTB.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      In countries with a high tuberculosis burden and lack of facilities for guided biopsy or fine needle aspiration, except in tertiary hospitals, plays an important role in delay of early diagnosis of lung cancer. In addition, flexible national guidelines and DOT (direct observed therapy) of anti-TB drugs are given at no cost to patients are also contributory factors. In this short observational study, it was found that a number of patients received anti-TB drug based on clinical diagnosis has been diagnosed as Lung cancer that were previously diagnosed as Smear negative PTB on clinical ground and Chest X-ray. This finding suggests that national policy makers should consider that patients with smear negative PTB (clinical diagnosed PTB) need close follow up and proper referral to specialized & tertiary hospitals where there are facilities for confirming the diagnosis. To make and change in national guideline this observational study should be run in multi center in the country.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      NIDCH.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      56P - CT image standardization is superior to larger but heterogeneous data for robust radiomic models (ID 433)

      12:30 - 13:00  |  Presenting Author(s): Diem Vuong  |  Author(s): Marta Bogowicz, Jan Unkelbach, Robert Foerster, Sarah Denzler, Alexandros Xyrafas, Miklos Pless, Sandra Thierstein, Solange Peters, Matthias Guckenberger, Stephanie Tanadini-Lang

      • Abstract

      Background

      Radiomics is a promising tool for identification of new prognostic biomarkers. Radiomic models are often based on single-institution data however multi-centric data, highly heterogeneous due to different scanning protocols, reflect better the clinical reality. Robustness studies are crucial to find features robust to e.g. scanner settings. We study if a CT radiomics overall survival (OS) model trained on multi-centric data with robust feature pre-selection can achieve a similar performance as a model on standardized data.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Pre-treatment CT data from 121 IIIA/N2 NSCLC patients from a prospective multi-centric randomized trial (SAKK 16/00, neoadj. chemo- or radiochemotherapy prior to surgery) were used to calculate 1404 radiomic features on the primary tumor. Two OS radiomic models were trained on (1) a sub-cohort with standardized imaging protocol (native CT, standard kernel, n = 84) and on (2) the entire heterogeneous cohort but with robust radiomic feature pre-selection. Robust features were extracted from four robustness studies (contrast, convolution kernel, motion, delineation) using the intra-class correlation coefficient (> 0.9 considered stable). Seperately for each model, principal component (PC) analysis was performed and PCs describing in total 95% data variance were selected. The feature with highest correlation to the PCs were used for the multivariate Cox model with backward selection. Model performances were quantified using Concordance Index (CI), verified with 10-fold cross-validation and compared using bootstrap with resampling.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Robustness studies revealed 113 stable features. The convolution kernel was the largest influence on the feature stability. Final OS model on the entire heterogeneous data consisted of four and on standardized data of six features (all identified as unstable). The model on standardized data showed significant better prognostic performance compared to the model with robust feature pre-selection based on the entire heterogeneous data (CI = 0.64 and 0.61, p < 0.05, resp.).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      For our prognostic NSCLC radiomic models image protocol standardization appears superior to using larger but heterogeneous imaging data combined with robust feature pre-selection.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Swiss National Science Foundation (SNSF) Swiss Group for Clinical Cancer Research SAKK.

      682889d0a1d3b50267a69346a750433d Disclosure

      M. Guckenberger: Board member: European Society for Therapeutic Radiation Oncology (ESTRO). All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

    • +

      57P - Non-small cell lung carcinoma (NSCLC) patients with baseline brain imaging: A prospective observational study (Now Available) (ID 334)

      12:30 - 13:00  |  Presenting Author(s): GUNDU NARESH  |  Author(s): Prabhat Singh Malik, Sachin Khurana, Sushmita Pathy, Mukesh Yadav, Deepali Jain, HARISH Kancharla

      • Abstract
      • Slides

      Background

      Brain metastases in NSCLC patients is the major cause of the poor survival and quality of life. Symptomatic brain metastasis at baseline are present in 5-10% of NSCLC and over the time course about 40% patients develop brain metastasis. Screening for asymptomatic brain metastasis in advanced NSCLC is controversial. Here we present our initial experience of mandatory brain imaging of all NSCLC patients irrespective of CNS symptoms and stage.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      It is a prospective observation study of NSCLC patients with mandatory baseline brain imaging. Data was analysed for patients enrolled in the study from Jan 2018- Nov 2018. All patients with histology proven NSCLC were incuded irrespective of stage. Brain imaging was performed by CECT. A comprehensive CNS examination was performed at diagnosis. All statistical analysis was done by STATA version 13.Univariate analysis was done by Cox regression model.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      There were 238 patients enrolled. Median age was 58yrs (range 26-83yrs) with male predominance (n = 183 , 76.9%). Smokers were 65.1% ( n = 153) and majority had ECOG PS 1&2 (82%). Most common histology was adenocarcinoma - 64.6% (n = 151) . EGFR mutation could be tested in 98 of adenocarcinoma patients and was positive in 32 (32.6%). ALK (IHC-D5F3) was tested in 78 patients and was positive in 11 (14.1%) . Majority patients had stage 4 disease, 74.8% (n = 176). There was upstaging to stage 4 after brain imaging in 8% (n = 20) patients. Brain metastases was present in 22.7% (n = 54) of which 52% (n = 28) were asymptomatic. Majority had solitary lesion - 48% (n = 26), predominatly located supratentorially - 66% (n = 36). Majority of these patients received chemotherapy - 46.2% (n = 25), TKI -27.7% (n = 15), WBRT -14.8%(n = 8), BSC -22.2% (n = 12). Univariate analyses was done for age, sex, histological subtype, EGFR and ALK status, out of which younger age (<40 yrs) and adenocarcinoma histology were found to be significant predictors for presence brain metastases.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Brain metastasis with mandatory baseline brain imaging (atleast CECT) were found in 22.7% patients in our study and resulted in upstaging of disease in 8%. Frequency of brain metastasis were significantly higher in adenocarcinoma histology and younger age (<40 yrs).

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      All India Institute of Medical Sciences.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      58P - Evaluation of a care path for patients with lung tumors and co-existing interstitial lung disease (ID 300)

      12:30 - 13:00  |  Presenting Author(s): Merle Ilona Ronden-Kianoush  |  Author(s): Esther J. Nossent, Chris Dickhoff, Suzan F.M. Nijman, Idris Bahce, Suresh Senan, Femke O.B. Spoelstra

      • Abstract
      • Slides

      Background

      Patients with lung cancer and co-existing interstitial lung disease (ILD) are at increased risk of treatment-related toxicity after both surgery and radiotherapy. A care path was implemented at our institution for patients presenting to the lung tumor board with a possible ILD, and we report on our experience using this structured approach.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Since 2015, patients with possible lung cancer and ILD were referred to the general ILD clinic for assessment. In 2017, a dedicated ILD lung tumor board was established in order to facilitate quick assessment of treatment-related risks. An ethics-approved institutional database containing details of all these patients was accessed.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      24 patients with lung tumors and a co-existing ILD were identified (Table). The mean interval between referral to, and consultation at our ILD-board was 2 weeks. A prior diagnosis of ILD was available in 9 of 17 (53%) patients, but review led to a re-classification of the ILD subtype in 8 of the former. Treatments for lung cancer included radiotherapy alone (n = 14), surgery (n = 6), sequential chemoradiation (n = 3), and concurrent CRT followed by salvage surgery (n = 1). 6 patients developed progression of ILD after radiation; of these, 2 had received nintedanib during treatment. One patient died because of progressive ILD and in another 3 patients ILD-related deaths could not be excluded.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      A dedicated care path for ILD patients resulted in a fast evaluation of lung cancer patients. A previous ILD-diagnosis was revised in a majority of patients, a process which can allow for a better understanding of treatment-related risks in different subgroups of ILD patients, and also assess the role of ILD-directed therapies.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      S. Senan: Grants, during the conduct of the study: ViewRay Inc.; Personal fees, outside the submitted work: Varian Medical Systems. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      59P - Comparison of internal target volume delineation using CT datasets of four-dimensional computed tomography in lung cancer radiotherapy (Now Available) (ID 320)

      12:30 - 13:00  |  Presenting Author(s): SABHEEN BUSHRA  |  Author(s): Anil Tibdewal, Naveen Mummudi, Rajesh Kinhikar, Yogesh Ghadi, Jai Prakash Agarwal

      • Abstract
      • Slides

      Background

      Precise tumour volume delineation is a major challenge in lung cancer radiotherapy (RT) because of respiration induced motion. Four-dimensional computed tomography (4DCT) using maximum intensity projection (MIP) dataset is commonly used method to generate internal target volume (ITV). This study compared ITV generation by tumour delineation on MIP and on all phases of the respiratory cycle.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Thirty consecutive patients who underwent 4DCT from Jan 2014 to Mar 2017 were included. After 4DCT image acquisition, ITV was generated by tumour delineation on MIP (ITVMIP) and on all ten phases of respiratory cycle(ITV10). The Correlation between ITVMIP and ITV10 was analysed using Matching index (M.I=overlapping/encompassing volume) and 3D centroid shift. M.I >0.8 was considered as good agreement. Time required to generate ITVMIP and ITV10 was also documented. Mann Whitney test was used for analysis and p < 0.05 was considered significant.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Mean volume of ITV10 was 134 cc (range 13 -627) and ITVMIP was 113 cc (range 11 - 569)(p < 0.001). Median volume of ITVMIP not getting covered by ITV10 was 4 cc (5.2%) and vice versa was 19.5cc (19%). The mean M.I between ITVMIP and ITV10 was 0.76 (SD = 0.08, range 0.57-0.88). For 15 patients with tumour close to high density structures like mediastinum, mean MI was 0.73 and for peripheral tumours was 0.78 (p = 0.003). Mean M.I was 0.75 for both tumour ≤5 and >5 cm. For peripheral and ≤ 5 cm tumours, M.I was 0.8. The average time for ITVMIP and ITV10 delineation was 9 and 96 minutes respectively. The centre of mass of ITV10 and ITVMIP was same 0.15 cm in sup/inf axis, 0.11 cm in medio/lateral axis and -0.06 and -0.04 cm in ant/post axis respectively when compared with free breathing CT. The 3D Centroid shift between ITVMIP and ITV10 was 0.01 cm.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      ITV delineation using MIP is significantly smaller and may be imprecise in tumours adjacent to mediastinum, chest wall and diaphragm. This difference is likely due to difficulty in delineating tumour edges caused by blurring of images. However, delineation using MIP dataset is significantly less time consuming, hence, we recommend its continued use in peripheral tumour and advises caution in central tumours.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      TMC Intramural.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      60P - Nomogram for patients with stage I small cell lung cancer: A competing risk analysis (ID 277)

      12:30 - 13:00  |  Presenting Author(s): Jiaqing Liu  |  Author(s): Huaqiang Zhou, Yaxiong Zhang, Wenfeng Fang, Yunpeng Yang, Shaodong Hong, Gang Chen, Shen Zhao, Xi Chen, Zhonghan Zhang, Wei Xian, Jiayi Shen, Yan Huang, Hongyun Zhao, Li Zhang

      • Abstract
      • Slides

      Background

      Small-cell lung cancer (SCLC), accounting for about 15% of all lung cancers, is a subtype of lung cancer with poor prognosis. It has a 5-year survival rate of 7% and kills an estimated 250,000 people worldwide annually. Although many studies have estimated the prognosis of SCLC, most of them were conducted without considering competing risks. This study aimed to evaluate the probability of cause-specific death for patients with stage I small cell lung cancer (SCLC) with a competing risk analysis.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We identified patients with stage I SCLC between 2004 and 2010 in the Surveillance Epidemiology, and End Results (SEER) database. We calculated the cumulative incidence function (CIF) for all the SCLC patients, and the differences in CIF between subgroups were estimated by Gray’s test. Proportional subdistribution hazard model was constructed to predict cancer-specific death for patients with stage I SCLC. We also built a competing risk nomogram based on Fine and Gray’s model to predict the 3-year, the 5-year prognosis of SCLC patients. We evaluated the model performance by the c-index and calibration plot using a bootstrap cross-validation method with 200 resamples. All statistical analyses and visualization were performed on R statistical software version 3.4.4 (Institute for Statistics and Mathematics, Vienna, Austria). Statistical significance was set as a 2-sided p < 0.05.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      We identified 864 stage I SCLC patients. The 5-year cumulative incidence of cause-specific death for stage I SCLC was 56.2% and 13.7% for other causes of death. Predictive factors for the prognosis of stage I SCLC included age, surgery, chemotherapy, and radiotherapy (Table). Fine and Gray competing risk regression model indicated that age at diagnosis, surgery treatment, and radiotherapy could be independent predictive factors of SCLC cause-specific death. Those who were diagnosed with SCLC at an older age were more like to die of lung cancer, with a subdistribution hazard ratios (sdHR) of 1.02 (95% CI, 1.012-1.03). Patients without treatment were at an elevated risk of SCLC cause-specific death except for chemotherapy, with an sdHR of 2.85 (95% CI, 2.29-3.54) and 1.89 (95% CI, 1.53-2.33) for patients without surgery and radiotherapy, respectively. No statistical significance was detected between chemotherapy and SCLC cause-specific death. The competing risk nomogram based on the Fine and Gray’s model was established to predict the 3-year and 5-year cause-specific death. The c-index for SCLC cause-specific mortality model was 0.66, and the calibration curves suggested that the nomogram was well-calibrated.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      In the study, we performed a competing risk analysis in patients with stage I SCLC based on the SEER database. We discovered independent predictive factors of death due to SCLC and built a nomogram to calculate the 3- and 5-year cause-specific mortality. The competing risk nomogram might be a convenient tool to evaluate crude mortalities of stage I SCLC, and help clinicians to choose appropriate treatment strategies.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      National Key R&D Program of China (2016YFC0905500).

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      Five-year cumulative incidences of death among patients with stage I SCLC

      CharacteristicsN (%)Event (%)Cause-specific death
      Death from other causes
      5 year (%) (95% CI)p5 year (%) (95% CI)p
      Total86468056.2 (52.9-59.5)13.7 (11.5-16.1)
      Age (years)<0.0010.127
      <65257 (29.7)178 (26.2)48.5 (42.2-54.4)12.5 (8.8-16.9)
      65+607 (70.3)502 (42.9)59.5 (55.5-63.3)14.2 (11.6-17.1)
      Sex0.2030.373
      Male407 (47.1)332 (52.9)59.2 (54.2-63.8)15.4 (12.0-19.1)
      Female457 (52.9)348 (40.8)53.6 (48.9-58.1)12.3 (9.5-15.5)
      Race0.0960.096
      White772 (89.4)609 (89.6)55.8 (52.2-59.2)14.4 (12.0-17.0)
      Black68 (7.9)49 (7.2)58.2 (45.3-69.0)6.0 (1.9-13.5)
      Others/Unknown24 (2.8)22 (3.2)65.2 (41.0-81.5)13.0 (3.0-30.6)
      Surgery< 0.0010.548
      Yes305 (35.3)187 (27.5)39.2 (33.7-44.6)11.5 (8.2-15.4)
      No559 (64.7)493 (72.5)65.6 (61.5-69.3)14.9 (12.1-18.0)
      Chemotherapy< 0.0010.719
      Yes567 (65.6)433 (63.7)53.1 (48.9-57.1)13.1 (10.4-16.0)
      No297 (34.4)247 (36.3)62.3 (56.5-67.5)15.0 (11.1-19.3)
      Radiotherapy0.0040.035
      Yes399 (46.2)313 (46.0)52.2 (47.1-56.9)15.1 (11.8-18.8)
      No465 (53.8)367 (54.0)59.8 (55.1-64.1)12.6 (9.7-15.8)

      SCLC: Small cell lung cancer; CI: confidence interval

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      61P - Value of post-radiotherapy for limited stage small cell lung cancer on basis of a prognostic scoring model (Now Available) (ID 292)

      12:30 - 13:00  |  Presenting Author(s): Jing Yu  |  Author(s): Wen Ouyang, Jing Hu, Junhong Zhang, Conghua Xie

      • Abstract
      • Slides

      Background

      Small cell lung carcinoma (SCLC) rarely underwent surgical treatment. The aim of the study was to investigate the value of postoperative radiotherapy for limited stage small cell lung cancer based on a prognostic scoring model.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We searched the Surveillance, Epidemiology, and End Results (SEER) database for all cases of limited stage SCLC treated by surgical resection and chemotherapy between 2004-2014. A prognostic scoring model was built to evaluate the prognostic value of postoperative radiotherapy on the basis of a Cox proportional hazards model. Overall survival (OS) and cancer-specific survival (CSS) was compared in the different risk groups.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Multivariable analysis of the association between clinical variables and overall survival (N = 767)

      OS
      VariablesHR (95%CI)P
      Age (>65 vs ≤ 65 y)1.35 (1.17-1.57)<0.001
      Race (White vs non-white)1.18 (0.90-1.55)0.238
      Sex (Male vs Female)1.33 (1.15-1.54)<0.001
      Grade (Poor/ undifferentiated vs Well/Moderately/NOS0.99 (0.86-1.15)0.922
      Lymph Node Stage (N+ vs N-)1.36 (1.17-1.58)0.001
      T stage (T3/4 vs T1/2)1.31 (1.08-1.58)0.005
      Laterality (Left vs Right vs NOS)1.04 (0.91-1.19)0.55
      Primary lobe (Main bronchus vs Upper vs Middle vs Lower vs Overlapping lesion of lung or NOS)1.01 (0.94-1.09)0.717

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      On the basis of the prognostic scoring model, postoperative-radiotherapy in addition to surgery provides better outcomes than surgery alone for limited stage SCLC in high risk group. Prospective studies are needed to validate these results.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Jing Yu.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      62P - External validation of a survival score for limited stage small cell lung cancer treated with chemoradiotherapy (Now Available) (ID 570)

      12:30 - 13:00  |  Presenting Author(s): Lukas Käsmann  |  Author(s): Reem Abdo, Julian Taugner, Chukwuka Eze, Maurice Dantes, Olarn Roengvoraphoj, Claus Belka, Farkhad Manapov

      • Abstract
      • Slides

      Background

      In 2016, a survival score for limited stage small cell lung cancer (LS-SCLC) patients was developed to characterize prognostic sub-groups who underwent multimodal treatment. Herein, we validate the score in an independent external patient cohort.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We reviewed the medical charts of 78 LS-SCLC patients treated with CRT at our institution. The survival score was calculated by independent prognostic factors: gender, Karnofsky performance status (50-70% vs. 80-100%), Tumor sub-stage (very limited vs. limited disease) and hemoglobin level before the start of radiation (<12 g/dl vs. ≥12 g/dl). Scoring points were derived from 2-year survival rates divided by 10 and the individual values for each prognostic factor were tallied. Three risk subgroups were defined (high, intermediate vs. low-risk: 9-13, 14-18 vs.19-26 points).

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Median overall survival in the validation cohort was 17 months (range: 1-123months). The 2-year survival rates were 0% in the high, 35% in the intermediate and 43% in the low-risk subgroup, respectively (p = 0.018). The difference in 2-year survival between the high and intermediate risk subgroups was significant (p = 0.007), whereas the 2yr-OS between the intermediate and low risk was not (p = 0.602). After stratification for the concurrent treatment mode, 2-year survival rates were 0% in the high, 60% in the intermediate and 58% in the low-risk subgroups, respectively (p = 0.004).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      The survival score was reproducible to estimate 2-year survival rates of patients with LS-SCLC, especially in the high and intermediate-risk subgroups. In order to better characterize the prognostic difference between intermediate and low-risk patients, the scoring system needs further optimization.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      63P - Real-life experience with the implementation of DLL3 staining and the subsequent treatment with rovalpituzumab tesirine in heavily pretreated SCLC patients (ID 530)

      12:30 - 13:00  |  Presenting Author(s): Maximilian Johannes Hochmair  |  Author(s): Christoph Weinlinger, Hannah Fabikan, Renate Koger, Dagmar Krenbeck, Florian Huemer, Oliver Mark Illini, Melisa Kulaksiz, Arschang Valipour, Otto Chris Burghuber

      • Abstract

      Background

      Around 15% of newly diagnosed lung cancer patients are characterized as SCLC mostly with extensive stage disease. While SCLC may be responsive to 1st or 2nd line chemotherapy, there is no approved drug for the 3rd line with guidelines recommending best supportive care. Rovalpituzumab Teserine (Rova-T) is a novel first–in-class antibody-drug conjugate and targets the delta-like protein 3 (DLL3), a newly discovered target highly expressed in SCLC and other high-grade neuroendocrine carcinomas. ROVA-T showed an encouraging single-agent anti-tumor activity and manageable safety profile in Phase 1 and 2 studies. The present study is a retrospective analysis to evaluate DLL3 testing and real-life experience with ROVA-T for patients with an unmet medical need after failure of at least 2 systemic treatments.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      DLL3 Immunohistochemistry (VENTANA DLL3 (SP347) Assay) was performed for 68 Patients with high grade neuroendocrine carcinoma (61 SCLC and 7 LCNEC). The percentages of stained tumor cells was determined - TC-counts of < 25% were interpreted as negative, counts of ≥ 25 to < 75% as positive and ≥75% as highly positive. 16 patients were eligible for treatment with Rova-T and received at least 1 of 2 planned cycles with a dose of 0.3 mg/kg.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      DLL3 staining was seen in most of the patients with high grade neuroendocrine carcinoma, 49 specimens (72.1%) were interpreted as highly positive, 10 specimens (14.7%) were considered positive. 9 (13.2 %) were considered negative, 4 (5,9%) of them showed no staining for IHC. All eligible patients had an ED with an ECOG of 0-1. 2 of the treated patients were DLL3 negative, 4 positive and 10 were highly positive. Of the 2 planned cycles 7 patients received both and 9 received only one due to disease progression or adverse events. Overall, 4 patients (25%) showed a PR, 4 (25%) had SD and 8 developed disease progression (50%). Side effects were manageable.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      DLL3 staining is frequent in SCLC patients but further studies are needed to proof it to be a useful predictive biomarker. Rova-T seems to be an option for ED SCLC patients in later lines with a high unmet need for treatment and showed a clinical benefit in selected patients with a manageable safety profile.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      64P - Timing of treatment with concurrent chemoradiotherapy (CRT) and impact on progression free survival (PFS) in limited stage small cell lung cancer (LSSCLC) (ID 601)

      12:30 - 13:00  |  Presenting Author(s): Lynda M McSorley  |  Author(s): Caitriona Marie Goggin, Nihal Elhadi, Pauline O'Dea, Jane Sze Yin Sui, Deirdre catherine Kelly, Claire Brady, Deirdre O'Mahony

      • Abstract

      Background

      SCLC is an aggressive cancer subtype, with early metastatic spread and poor prognosis. We review Irish patient outcomes, outside of a clinical trial setting, to determine if patients who commenced radiotherapy (RT) within 30days of chemotherapy (CT) had a longer PFS.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      SCLC cases diagnosed between 2006-2016 were identified from a prospectively maintained lung cancer registry at a tertiary referral centre. Electronic patient records, paper charts, and pathology reports were reviewed to extract relevant data. In order to detect a statistical difference between the two groups with 95% confidence interval and a 5% margin of error, a sample size of 125 patients with SCLC was needed, and a sample size of 56 with LSSCLC. A two-sided t-test was used where data was normally distributed. A p value of < 0.05 was accepted. Kaplan-Meier analysis was used to assess progression free survival and a Mann-Whitney test to assess differences between groups.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      265 patients identified, 70 with LSSCLC, 44 had concurrent treatment. Median time to starting CT was 20 days (95%CI; 15.8-24.2days). The median time between diagnosis and CT was 28days, from CT to RT was 28.5 days. 21 patients started RT within 30 days of commencing CT; median time 19days. 19 patients started RT more than 30 days post CT; median time 67days. Median time from diagnosis to CT was 12days in this group. Median PFS where the time from day1 CT to day1 of RT was less than 30days was 12.1months. For patients where the treatment interval was greater than 30 days, median PFS was 10.6months. Using a non-parametric Mann-Whitney test to evaluate the median PFS produced a U value of 127, and a P-value of 0.41.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      This study reports real-world outcomes in patients with LSSCLC over a 10-year period. Although not reaching statistical significance there is a numerical difference in PFS favouring shorter time to combination CRT. We have also identified areas where there is room to improve our practice. Further attention will focus on strategies to reduce both the interval between histological diagnosis and commencing CT, and the interval between CT and RT in this setting. A study expansion is planned.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

    • +

      65P - Experience of prophylactic cranial irradiation in extensive stage small cell lung cancer at a regional cancer center in India (ID 536)

      12:30 - 13:00  |  Presenting Author(s): RANJEET RAM Jat  |  Author(s): Rahul Kumar Rai, Shankar Lal Jakhar, Surendra Kumar Beniwal, Neeti Sharma, H S Kumar

      • Abstract

      Background

      We conducted this randomized trial at our center to assess benefits of prophylactic cranial irradiation (PCI) in cases of extensive stage small cell lung cancer (eSCLC), who showed complete or partial response to 4 cycles of cisplatin and etoposide chemotherapy-based regime.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      For the study, 71 patients of histology proven SCLC with extensive stage (with no symptomatic and radiological brain metastasis) on clinico-radiological examination were randomized into two arms (Arm A and Arm B). Patients in Arm A were treated with PCI whilw those in Arm B were kept on observation, patient in both arms were followed for 1 year. Primary endpoint of the study was to assess the time of onset of symptomatic brain metastasis in both arms. Computer Tomography (CT scan) or Magnetic Resonance Imaging (MRI) was performed in patients who had any symptom suggestive of brain metastasis.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Patients in both arms (36 in Arm A and 35 in Arm B) were comparable for baseline characteristics. Patients in Arm A had significantly low risk of symptomatic brain metastasis then Arm B (p value = <0.005). The risk of brain metastasis in Arm A was 19.4% and in Arm B it was 51.4%. Mean duration for freedom from symptomatic brain metastasis in Arm A was 8.36 months while it was 4.49 months for Arm B. Overall 1 year median survival rate in Arm A was significantly higher in Arm A then Arm B (8 months vs 4 months). Patients in Arm A had higher toxicities, but they were mostly manageable and were not associated with poor quality of life.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      PCI is associated with significantly low risk of symptomatic brain metastasis and higher overall survival without affecting quality of life in eSCLC.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Aacharya Tulsi Regional Cancer Treatment and Research Center, Bikaner.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      66P - Treatment (tx) characteristics and clinical outcomes in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC) treated with carboplatin (carbo) or cisplatin (cis) in combination with etoposide (etop) in US clinical practice (ID 309)

      12:30 - 13:00  |  Presenting Author(s): Martin Sebastian  |  Author(s): Fabrice Barlesi, Raffaele Califano, Aaron S. Mansfield, Fiona Helen Blackhall, Evelyn M. Flahavan, Jessica Davies, Phil Arnold, Stefanie Morris, Martin Reck

      • Abstract
      • Slides

      Background

      For pts with ES-SCLC, guidelines recommend carbo or cis + etop as first-line (1L) tx. However, real-world data (RWD) on tx patterns and outcomes are limited. Here, we describe pt characteristics, tx duration and clinical outcomes associated with these 2 regimens.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Pts with ES-SCLC diagnosis (or limited-stage [LS] SCLC who initiated second-line [2L] tx) between 1 Jan 2013 and 31 Aug 2017 (follow-up to 31 Aug 2018) were identified from the US-based Flatiron Health electronic health record–derived database. Pts receiving tx with either carbo + etop or cis + etop were included in the analysis.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      RWD on 2161 pts from 156 tx centres were included; 84% of pts received carbo + etop. See table below for pt characteristics. The median tx duration was 3.4 mo (95% CI: 3.4, 3.4) with carbo + etop and 3.0 mo (95% CI: 2.8, 3.4) with cis + etop. The distribution of tx cycles administered was similar between carbo and cis, with 20% and 28% of pts completing 4 or 6 cycles, respectively. Median overall survival (OS) was 8.3 mo (95% CI: 8.1, 8.7) with carbo + etop and 9.7 mo (95% CI: 9.3, 11.0) with cis + etop. The 1-yr OS rates were 30% (95% CI: 28, 33) and 41% (95% CI: 36, 47), respectively. In pts with Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and ≥ 2, median OS was 9.3 mo (95% CI: 8.6, 9.9) and 7.1 mo (95% CI: 6.3, 8.3), respectively. Pts with unknown ECOG PS had a median OS of 8.4 mo (95% CI: 8.0, 8.9).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Tx duration was similar between the 2 regimens. Pts who received cis + etop had numerically increased OS vs pts who received carbo + etop, as did pts with ECOG PS 0-1. However, these findings may be due to pts receiving cis + etop being fitter (younger and lower ECOG PS) at baseline.

      b651e8a99c4375feb982b7c2cad376e9 Editorial acknowledgement

      Medical writing assistance for this abstract was provided by Steffen Biechele, PhD, of Health Interactions and funded by F. Hoffmann-La Roche, Ltd.

      934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study

      F. Hoffmann-La Roche, Ltd.

      213f68309caaa4ccc14d5f99789640ad Funding

      F. Hoffmann-La Roche, Ltd.

      682889d0a1d3b50267a69346a750433d Disclosure

      M. Sebastian: Honoraria, consulting: AZ, BI, BMS, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche; Honoraria: Pierre Fabre; Consulting: Celgene. F. Barlesi: Personal fees/clinical trials (inst.): AZ, BMS, BI, Lilly, Roche, Novartis, Merck, MSD, Pierre Fabre, Pfizer, Takeda; Clinical trials (inst.): AbbVie, ACEA, Amgen, Bayer, Eisai, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Medimmune, Sanofi-Aventis. R. Califano: Honoraria/consult: BI; Stock: Christie Private Care; Grants/nonremunerated activities: Clovis, AbbVie; Leadership (nonrem): ESMO; Nonrem membership: EORTC; Honoraria/consult/grants/nonrem activities: AZ, Roche, Pfizer, Lilly, MSD, Takeda, Novartis, BMS. A.S. Mansfield: Research funding (inst.): Novartis, Verily; Honoraria/Ad board (inst.): Genentech, AbbVie, BMS Mesothelioma Applied Research Foundation; Board member (non-rem.) ASCO; Lung Cancer Education Committee member (non-rem). F.H. Blackhall: Grant/research: Roche, BI, AZ, Cellmedica, AbbVie, Pfizer; Advisory board: AZ, Cellmedica, AbbVie, Ipsen, Takeda, Roche; Consulting/speakers: Takeda; Honoraria: Takeda, Roche, AbbVie, Ipsen; Study, editorial support: Roche. E.M. Flahavan: Employee: Roche; Stock: Lilly, Roche; support of parent study and funding of editorial support: Roche. J. Davies: Employee: Roche. P. Arnold: Employee: Roche; Stock: Novartis Pharma AG. S. Morris: Employee, Stock: Roche. M. Reck: Support of parent study, funding of editorial support: Roche; Honoraria for lectures and consulting: Amgen, AbbVie, BI, BMS, Celgene, Merck-Serono, MSD, Lilly, Novartis, Pfizer, Roche.

      Characteristics

      Carbo + EtopCis + Etop
      Pts, n1815346
      Age, median (IQR), y68 (61-74)64 (58-69)
       35-64, n (%)663 (37)189 (55)
       65-69, n (%)357 (20)77 (22)
       ≥ 70, n (%)795 (44)80 (23)
      Male, n (%)919 (51)184 (53)
      White race, n (%)1383 (76)259 (75)
      Baseline ECOG PS, n (%)
       0-1716 (39)144 (42)
       ≥ 2296 (16)29 (8)
       Not provided803 (44)173 (50)
      Type of ES-SCLC, n (%)
       1L tx of ES-SCLC1757 (97)335 (97)
       2L tx of LS-SCLC58 (3)11 (3)

      IQR, interquartile range.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      67TiP - ADRIATIC: A phase III trial of durvalumab &#x000B1; tremelimumab after concurrent chemoradiation for patients with limited stage small cell lung cancer (ID 237)

      12:30 - 13:00  |  Presenting Author(s): Suresh Senan  |  Author(s): Norah Shire, Gabriel Mak, Wenliang Yao, Haiyi Jiang

      • Abstract
      • Slides

      Background

      Limited stage small-cell lung cancer (LS-SCLC), which represents ∼30% of newly diagnosed SCLC, remains an area of high unmet medical need. Standard of care, which has not changed for several decades, consists of curative intent platinum-based chemotherapy concurrent with radiotherapy (cCRT) followed by prophylactic brain irradiation (PCI) and observation. Despite good response to cCRT, outcomes remain poor, with median progression-free survival (PFS) ∼15 months and overall survival (OS) ∼25 months. Durvalumab (D) is a selective, high-affinity, human IgG1 monoclonal antibody (mAb) that blocks programmed cell death ligand-1 binding to programmed cell death-1 and CD80. Tremelimumab (T) is a selective human IgG2 mAb against CTLA-4. D demonstrated a PFS and OS advantage over placebo in locally advanced NSCLC following cCRT. D and D + T demonstrated a tolerable safety profile and antitumour activity in pretreated extensive stage SCLC. The ADRIATIC trial (NCT03703297) will assess if treatment with D ± T is beneficial vs placebo in patients (pts) with LS-SCLC who have not progressed following cCRT.

      a9ded1e5ce5d75814730bb4caaf49419 Trial design

      ADRIATIC is a Phase 3, randomised, double-blind, multicentre, placebo-controlled international trial. Pts (N∼600) will be randomised 1:1:1 to receive D + placebo T, D + T, or dual placebo, stratified by Stage (I/II vs III) and receipt of PCI at the investigator’s discretion (yes vs no). Eligible pts must have confirmed inoperable Stage I–III LS-SCLC; WHO/ECOG PS 0/1; and completed 4 cycles of cCRT with a response of stable disease or better within 1–42 days prior to randomisation. Pts will receive the assigned treatment until clinical, RECIST v1.1-defined progressive disease, intolerable toxicity or for a maximum of 24 months, whichever comes first. Primary objectives are PFS and OS for D ± T vs placebo. Key secondary endpoints include health-related quality of life, and safety and tolerability. Recruitment is ongoing

      ArmDoseInitial regimen (first 4 cycles)Continuation regimen (up to 24 months)
      D + placebo TD = 1500 mg (intravenous [i.v.])D + placebo T q4wD q4w alone after the final dose of D + placebo T
      D + T combinationD = 1500 mg (i.v.)T = 75 mg (i.v.)D + T q4wD q4w alone after the final dose of D + T
      Placebo D + placebo Ti.v. salinePlacebo D + placebo T q4wPlacebo D q4w
      .

      d9b324a48b043b3d87bc9b3fe620f260 Clinical trial identification

      NCT03703297.

      7a6a3ffa2dadc03a6151ee2c4d6fa383 Editorial acknowledgement

      Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Craig Turner, MSc, of Cirrus Communications, an Ashfield company (Macclesfield, UK), and was funded by AstraZeneca.

      934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study

      AstraZeneca PLC.

      213f68309caaa4ccc14d5f99789640ad Funding

      AstraZeneca.

      682889d0a1d3b50267a69346a750433d Disclosure

      S. Senan: Departmental research grant: AstraZeneca, Varian Medical Systems, ViewRay Inc.; Advisory boards: AstraZeneca, MSD, Eli Lilly, Celgene. N. Shire: Employment, stock: AstraZeneca, outside the submitted work. G. Mak W. Yao, H. Jiang: Employment, stock: AstraZeneca, outside the conduct of the study.

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      73P - Utilization rates of stereotactic body radiation therapy for the treatment of stage I NSCLC in three European countries (ID 445)

      12:30 - 13:00  |  Presenting Author(s): Ronald Damhuis  |  Author(s): Suresh Senan, Aamir Khakwani, Susan Harden, Aaslaug Helland, Trond-Eirik Strand

      • Abstract
      • Slides

      Background

      Stereotactic body radiation therapy (SBRT) has become increasingly accepted as a treatment for patients with inoperable early stage lung cancer. We studied the patterns of treatment utilization for stage I non-small cell lung cancer (NSCLC) in three European countries in patients diagnosed in 2015-2016.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Information from population-based registries in England, Norway and the Netherlands were retrieved, and treatment patterns and two-year survival for patients with clinical stage I were analysed.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Resection rates were higher in Norway (55%) and England (53%) than in the Netherlands (47%). SBRT use was highest in the Netherlands (41%), followed by Norway (29%) and England (12%). Failure to perform curative intent treatment was more common in England (26%) than either Norway (13%) or the Netherlands (9%). In patients treated with SBRT, pathology confirmation of diagnosis was more common in Norway (70-73%) than in England (44-51%) or the Netherlands (47-50%). Two-year survival rates were better for surgery than for SBRT or conventional radiotherapy and treatment-specific survival was higher in Norway than in the other two countries.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      For clinical stage I NSCLC, SBRT has largely replaced conventional radiotherapy in both Norway and the Netherlands, while just 67% of radiotherapy patients in England receive SBRT. The proportion of patients not receiving any curative treatment was higher in England, especially in the elderly.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      S. Senan: Research grants: Varian Medical Systems, ViewRayInc; Membership of advisory boards: AstraZeneca, MSD. All other authors have declared no conflicts of interest.

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      74P - Is there any prognostic significance of the level of change in SUVmax after SBRT in patients with early stage NSCLC? (Now Available) (ID 355)

      12:30 - 13:00  |  Presenting Author(s): Gokhan Yaprak  |  Author(s): Alaattin Ozen, Fuzuli Tugrul, Sule Ozugur, Naciye Isik

      • Abstract
      • Slides

      Background

      Stereotactic body radiotherapy (SBRT) is a standard treatment for early stage non-small cell lung cancer (esNSCLC) patients who are not eligible for surgery. We aimed to evaluate the prognostic significance of the level of change in SUVmax (ΔSUVmax) between pre and post-treatment PET/CT in esNSCLC patients treated with SBRT.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Between November 2009-February 2018, pathologically proven esNSCLC patients (T1-2N0M0) treated with CyberKnife as primary treatment alone and had pre and post-treatment PET/CT (in 3 weeks before and 12-16 weeks after SBRT) were retrospectively identified. The ΔSUVmax was calculated using formula ΔSUVmax. The area under the curve (AUC) was used to verify the accuracy; the product of maximum sensitivity and specificity was chosen as the cutoff value. Then, we stratified the study cohort above and below AUC and the survival data were estimated by Kaplan Meier method. Univariate and multivariate analyses were carried out by use of a Cox proportional hazards model.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      All patients’ clinicopathological and treatment characteristics are presented in the table. Median dose was 45 Gy/3 fr (range: 45-60 Gy/3-5 fr). According to EORTC metabolic response criteria, 8 (16.7%) patients achieved complete, and 35 (72.9%) patients achieved partial response. AUC was calculated as 0.62 for cutoff ΔSUVmax (sensitivity 79%, specificity 45%). ΔSUVmax was ≥0.62 in 7 of 8 patients with complete response and <0.62 in progressive 2 patients. At a median follow-up of 23 (range: 6-92) months local, regional and distant relapse had developed in 16 (33.3%), 11 (22.9%), and 16 (33.3%) patients, respectively. 29 (60.4%) patients were still alive at the time of analysis. Median PFS was 15 vs 59 months (p=.012) and median OS was 36 vs 70 months (p=.045). In univariate analysis, we could not find any significant effect of sex, age, KPS, T stage, and BED10 on PFS, and OS. In both univariate and multivariate analysis, the lower ΔSUVmax (as both dichotomous and continuous variable) was determined as a negative prognostic factor on PFS (p=.02, .003 for univatiate and .013 and .003 for multivariate) and it has been showed that the lower ΔSUVmax (only as a dichotomous variable) is a negative prognostic factor on OS in multivariate analysis (p=.009)

      Clinicopathological and treatment characteristics

      ΔSUVmax
      p
      <0.62 n (%)≥0.62 n (%)
      Gender Female Male2 (6.5) 29 (93.5)2 (11.8) 15 (88.2)NSD
      Age at diagnosis (years) Median Range67 54-8467 56-82NSD
      KPS Median Range90 60-10080 60-90NSD
      Tumor Size (mm) Median Range27 15-4320 11-45NSD
      T stage T1 T221 (67.7) 10 (32.3)13 (76.5) 4 (23.5)NSD
      NSCLC histology Squamous Adenocarcinoma Other / unidentified13 (41.9) 8 (25.8) 10 (32.3)9 (52.9) 5 (29.4) 3 (17.6)NSD
      BED10 (Gy) Median Range112.5 100 - 180112.5 100 - 151NSD
      Local Failure Yes No12 (38.7) 19 (61.3)4 (23.5) 13 (76.5)0.04
      Regional Failure Yes No9 (29.0) 22 (71.0)2 (11.8) 15 (88.2)0.02
      Distant Failure Yes No14 (45.2)) 17 (54.9)2 (11.8) 15 (88.2)0.02
      Last Situation Alive Exitus16 (51.6) 15 (48.4)13 (76.5) 4 (23.5)0.04
      .

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      ΔSUVmax is a prognostic factor in esNSCLC patients treated with SBRT and patients with higher ΔSUVmax (≥0.62) have better PFS and OS.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      75P - Thoracic ultrasound can be a trustable tool in untouchable lung nodule surgery (ID 400)

      12:30 - 13:00  |  Presenting Author(s): Hongbin Zhang

      • Abstract

      Background

      Localization of ground-glass opacifications (GGOs) with more than 1cm distance to the pleura are still a challenge to thoracic surgeons during video-assisted thoracoscopic surgery (VATS). Efficiency, damage avoidance, and safety are uppermost factors to be considered when choosing the location technique. Our center tested the thoracoscopic ultrasound (US) as a complementary method during VATS GGOs surgery.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We evaluated 40 patients with GGOs divided into group A (VATS-US) and group B (VATS). We used positive pressure in the chest cavity during surgery in group A to decrease the time needed to collapse the lung. With the same excision standard between the two groups, we recorded and compared the time needed, ratio of converting to thoracotomy, blooding volume, and any complications observed.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      We found that the use of ultrasound during VATS surgery could improve the success rate of localization (p < 0.05), especially in patients where it was difficult to conduct preoperative CT guided localization (p < 0.01). There were no statistically significant differences between the two groups in operation time, bleeding during the operation, or postoperative complications (p > 0.05).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      We concluded that thoracoscopic ultrasound could be an excellent supplement to preoperative CT localizing technique for localization of GGOs, if not a replacement at present.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Hongbin Zhang.

      213f68309caaa4ccc14d5f99789640ad Funding

      Peking University International Hospital.

      682889d0a1d3b50267a69346a750433d Disclosure

      The author has declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      76P - Endobronchial surgery and photodynamic therapy for early central lung cancer treatment (ID 573)

      12:30 - 13:00  |  Presenting Author(s): Sergey S Pirogov  |  Author(s): Larisa Telegina, Victor Sokolov, Tatiana Karmakova, Elena Filonenko, Oleg Pikin, Andrey Kaprin

      • Abstract

      Background

      Development of endoscopic therapeutic methods for early central lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      During the period from 1984 to 2019 in P.A.Hertsen Moscow Research Oncologic Institute has accumulated clinical experience in endoscopic diagnostics and treatment of early central lung cancer in 129 patients (176 tumors). X-Ray negative ECLC was observed in 86% of cases. As a treatment approach - electrocoagulation was in used from 1984 to 1993 in 73 patients (91 tumors) with ECLC, PDT and argon plasma coagulation (APC) were used from 1992 to 2019 in 56 patients (85 tumors). The following agents for used for PDT: radachlorine, photohem, photosense photolon. Endoscopic methods in 90% of cases was selected due to unfeasibility of the conventional surgery.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      In the group of patients with ECLC treated by electrocoagulation the complete tumor regression was observed in 89% of cases. The tumor recurrence observed only in 17% of cases. In the patients who received PDT and APC the results were determined by the tumor size. When the tumor size was not greater than 1 cm, complete regression was achieved in 100% of cases. When the tumor size ranged from 1 to 1.5 cm complete resorption was achieved in 75% of cases. and with the tumor size up to 2.5 cm complete regression was achieved in 29% of cases. In 9% of cases the recurrences were diagnosed. Follow-up period lasted up to 15 years. Median survival was 5.05 years. Five year survival rate was 50±12 %.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Intraluminal endoscopic treatment methods - photodynamic therapy and argon-plasma coagulation in early central lung cancer patients, declined of conventional surgery, provides complete tumor regression in most of cases. 5-year disease-free survival achieved in half of patients group.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

    • +

      77P - The prognostic impact of the international association for the study of lung cancer (IASLC) definitions on completeness of surgical resection for non-small cell lung cancer (NSCLC) (ID 380)

      12:30 - 13:00  |  Presenting Author(s): Matteo Gagliasso  |  Author(s): Carlotta Francesca Cartia, Alessandro Maraschi, Roberta Rapanà, Simona Sobrero, Alberto Sandri, Giuseppe Migliaretti, Francesco Ardissone

      • Abstract
      • Slides

      Background

      To reappraise the prognostic significance of the IASLC definitions of complete, uncertain, and incomplete resection in NSCLC surgery.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Single-institution retrospective review of 1052 consecutive patients surgically treated for NSCLC between 2008 and 2017. Complete resection was defined by absence of residual disease; systematic nodal dissection; no extracapsular extension in lymph nodes removed separately or those at lung specimen margin; negativity of distal mediastinal lymph nodes. An uncertain resection was defined by free resection margins, but one of the following applied: inadequate lymph node assessment; positivity of distal mediastinal lymph nodes; presence of carcinoma in situ at bronchial margin; positive pleural lavage cytology. A resection was defined incomplete by presence of residual disease; extracapsular extension in distal mediastinal lymph nodes or those at lung specimen margin; positive cytology of pleural or pericardial effusions. Follow-up was complete and overall survival (OS) was assessed using the Kaplan-Meier method and Cox proportional hazard modeling.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Eight hundred eighty-six (84.2%) patients had a complete resection, 131 (12.5%) an uncertain resection, and 35 (3.3%) an incomplete resection. Median follow-up was 44.9 months (range, 0.1 to 132.3). Complete resection was associated with significantly better survival compared to uncertain and incomplete resection (adjusted hazard ratio, 1.84 and 2.31, respectively; both p = 0.0001). Median OS and 5-year survival rate were 102.3, 32.9, 23.3 months and 62.3%, 33.5%, 24.3% in patients undergoing complete, uncertain, and incomplete resection, respectively. Additional significant predictors for OS in the multivariable Cox model were patient age and Charlson Comorbidity Index; tumor diameter, histology and pathologic TNM stage; and the occurrence of postoperative adverse events.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Our current experience confirms that in NSCLC surgery, significant differences exist in long-term survival following complete, uncertain, and incomplete resection, as defined by the IASLC.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      78P - Lung resection for cancer in patients with heart disease: Management and postoperative outcome (Now Available) (ID 385)

      12:30 - 13:00  |  Presenting Author(s): Fatmir Spiro Caushi  |  Author(s): Ilir Skenduli, Alban Hatibi, Arjan Mezini, Sofiela Telo, Silvana Bala, Eljana Shima, Alma Cani

      • Abstract
      • Slides

      Background

      Patients with lung cancer sometimes presents with concomitant heart disease. That kind of patients represents a high risk group necessitating prompt diagnosis and treatment. As lung resection still is the treatment of choice for early stages of lung cancer, its feasibility depends on the severity of the cardiac impairment. The aim of this study was to analyze the results of lung resection in patients with heart disease in terms of 30 day postoperative mortality, hospital stay and 5 year survival.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      This was a retrospective analysis of 161 patients with lung cancer who underwent complete lung resection between January 2011 and January 2014 at our department.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Surgery consisted in 140 lobectomies, 21 pneumonectomies. 24,2% of patients (39) of this study had a cardiac disease as co-morbidity where 14 of them was suffering from hyper tension of second stage, 10 of them from chronic atrial fibrillation, 14 patients (8.7%) with coronary artery disease where 10 of them have been treated previously by CABG or PTCA revascularization procedure meanwhile in 4 patients the disease was diagnosed in routine examinations. One patient had undergone a cardiac surgery for mitral valve replacement. In both of 4 patients that were diagnosed with coronary disease was not required myocardial revascularization despite presented a medium-high cardiac risk and the surgery was performed under the continuous control of cardiologists. The mortality rate was 3%. There was one intraoperative death because of cardiac arrhythmia, and 4 deaths in first 30 days post operation (one of them because of heart attack in a pre-treated coronary disease by PTCA and 3 others by severe pneumonia). Hospital stay was longer for patients who had cardiac co-morbidity (12.3±4 vs. 8.5±3 days). The overall 5-year survival rate was 60%. In patients cardiopulmonary co-morbidity the 5-year survival rate was 40%.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Lung resection in patients with cardiac disease is feasible. Careful preoperative evaluation can identify patients who might benefit from myocardial revascularization prior to surgery. A careful cardiac treatment and follow-up of such patients its necessary to achieve better results regarding mortality and 5-year survival.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Fatmir Caushi.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      79P - Tissue microarray analysis on prognostic value of coexpression of RUNX3 and trimethylated histone H3 lysine 27 in surgically resected patients with stage I non-small cell lung cancer (Now Available) (ID 442)

      12:30 - 13:00  |  Presenting Author(s): Xiaohui Chen  |  Author(s): Yujie Deng, Yi Shi

      • Abstract
      • Slides

      Background

      Lung cancer is still the leading cause of cancer-related deaths in both sexes in China and worldwide. Although many surgically resected patients shared the same histology and pathologic TNM stage, their prognosis had varied a lot. For within the stage-Ipatients who had received radical surgery of lung cancer, nearly one-third of them suffered from postoperative relapse or distant metastasis. In the present study, we sought to investigate the potential interrelationships of expression of RUNX3, H3K27me3 and its methyltransferase EZH2 in NSCLC patients, their correlation with clinicopathologic parameters, and the prognostic significance as well.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      A total of 208 NSCLC patients and block samples who had never received other therapies before were collected and built into tissue microarrays (TMA). Protein level of RUNX3, H3K27me3, EZH2 were detected and evaluated with immunohistochemistryand western blotting to determine their expressions and mutual correlations.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Co-expression of RUNX3 and H3K27me3 stood a vital significance in the prediction of better outcome and longer OS in early-stage NSCLC, especially pTNM stage-I(P = 0.0124). Correlation analysis demonstrated that non-coexpression of RUNX3 and H3K27me3 was significantly associated with male sex (P = 0.037), high ECOG PS (P = 0.000), smoker (P = 0.001), postoperative relapse (P = 0.000), postoperative distant metastasis (P = 0.048), non-nuclear expression of RUNX3 (P = 0.000) and low EZH2 expression (P = 0.016) while had nothing to do with age (P = 0.918), histology (P = 0.145), BMI (P = 0.300), lymphatic vessels involvement (P = 0.246), pleural involvement (P = 0.811), vascular involvement (P = 0.144), T staging (P = 0.189), lymph node involvement (P = 0.152), mediastinal lymph node involvement (P = 0.608), M staging (P = 0.667), TNM staging (P = 0.227, P = 0.231), resectibility (P = 0.850), depth of invasion (P = 0.245), serum CEA level (P = 0.174) or Ki-67 expression (P = 0.947).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Coexpression of RUNX3 and H3K27me3 is a good marker as survival gain to discriminiate whether or not TNM stage-INSCLC patients would have a better survival.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      80P - High blood platelets levels (BPL): A prognostic factor in patients with early or locally advanced non-small cell lung cancer (NSCLC) (ID 543)

      12:30 - 13:00  |  Presenting Author(s): Juan Felipe Cordoba Ortega  |  Author(s): ANTONIETA Salud, SERAFIN Morales, JOEL Veas, ALVARO Rodriguez

      • Abstract
      • Slides

      Background

      Patients with high blood platelets levels (BPL) have been reported to attenuate the efficacy of platinum-based chemotherapy and to have a worse prognosis when treated with surgery and postoperative adjuvant chemotherapy. This study describes a series of sample tumors from patients with clinically confirmed lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      In all non-small cell lung cancer (NSCLC) patients diagnosed in the University Hospital of Lleida from January 2011 to December 2016, a real world data study of blood platelets levels (BPL) was performed. Each patient’s clinical history, pathology specimens and molecular results were noted. Four hundred and forty-five patients with low BPL formed the control group.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The blood platelet levels (BPL) was analyzed in seven hundred and seventy-five (775) patients with an average of 290 mcL (24 - 995). In 330 patients (42%) a platelet level greater than 290 mcL was observed (22,1% females). The media age was 67 years. The smoking history was as follows: 57,2% former, 31,5% ex smokers and 11,2 never smokers. The clinical stages and histology were as follows: stage I and II: 17%, stage III: 30% and stage IV 53%; 43% of patients had adenocarcinoma histology, 36% squamous and 21% other. In patients treated with radical intention (surgery or chemotherapy plus radiotherapy) the median overall survival was 49 vs 36 months in patients with BPL ≥ 290 mcL (P = 0,00001), when they were compared with the control group, patients with high BPL (≥ 290 mcL) had overall shorter survival (P = 0,00001), regardless of histology, age or smoking history.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Patients treated with radical intention and high BPL (≥ 290 mcL), have worse overall survival, regardless of histology, age or smoking history.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      81P - Higher PD-L1 expression correlates with lymphocyte infiltration in early non-small cell lung cancer (ID 396)

      12:30 - 13:00  |  Presenting Author(s): Pedro Rocha  |  Author(s): Maite Rodrigo, Laura Moliner, Max Hardy-Werbin, David Casadevall Aguilar, Xavier Durán, Oriol Arpí, Sergi Clavé, Marta Salido, Xenia Riera, Silvia Menendez, Álvaro Taus, Lara Pijuan, Laura Comerma, Edurne Arriola Aperribay

      • Abstract
      • Slides

      Background

      Patients with advanced NSCLC (Non-small cell lung cancer) benefit from ICIs (immune checkpoint inhibitors) as part of their treatment strategy. This benefit might also be observed in earlier stages. The aim of our work was to characterize the immune contexture of early NSCLC and assess the impact on outcome of immune biomarkers.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Formalin-fixed paraffin embedded (FFPE) 1 mm cores from patients that underwent curative surgical treatment between 2006 and 2018 at Hospital del Mar (Barcelona, Spain), and did not received neoadjuvant therapy were included in a tissue microarray. PD-L1 expression as well as CD3, CD4, CD8, CD80 and CD103 were evaluated by immunohistochemistry. We report the percentage of positive cells for each marker from all nucleated cells. We evaluated the association between clinicopathological and molecular characteristics and immune biomarkers (Mann-Whitney, Kruskal-Wallis and Spearman correlation) and their impact on survival outcomes (Cox regression).

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Samples from 195 patients were included (Adenocarcinomas N = 130, Squamous cell carcinoma N = 61, Other histology N = 4). In our cohort, 74.9% of the cases were males, predominantly smokers (87.2%). Tumor size was less or equal than 40mm in 72.3% of the cases. Stage I, II, III and IV tumors represent 44.6%, 25.1% and 26.7% of all cases included in our study, respectively. PD-L1 expression was <1%, 1 - <50% and ³50%, in 46.7%, 29.2% and 24.1% of the cases respectively. PD-L1 expression was positively correlated with higher percentage of CD4 (rho=0.195), CD8 (rho=0.3272), CD80 (rho=0.2152) and CD103 (rho=0.4237) (all p-values<0.05). CD103 expression was positively correlated with CD80 expression (rho=0.514; p < 0.001). A higher percentage of lymphocytes measured by CD3 expression in tumor tissue was correlated with better overall survival (p = 0.045; HR = 0.98 (0.96-0.99)) when adjusted by TNM 8thedition stage and adjuvant chemotherapy. No correlations with clinicopathological features were observed.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Immune biomarker expression is highly heterogeneous in early NSCLC. Lymphocyte infiltration is associated with higher PD-L1 expression. Evaluation of immune biomarkers might better inform the choice of adjuvant treatment for NSCLC patients.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      82TiP - IMpower030: Phase III study evaluating neoadjuvant treatment of resectable stage II-IIIB non-small cell lung cancer (NSCLC) with atezolizumab (atezo) &#x0002B; chemotherapy (ID 183)

      12:30 - 13:00  |  Presenting Author(s): Solange Peters  |  Author(s): Anthony W. Kim, Benjamin Solomon, David R. Gandara, Rafal Dziadziuszko, Alessandro Brunelli, Marina Chiara Garassino, Martin Reck, Lijia Wang, Iris To, Shawn W. Sun, Barbara J. Gitlitz, Alan Sandler, Naiyer Rizvi

      • Abstract

      Background

      A standard of care for resectable early-stage NSCLC is surgery alone or in combination with adjuvant or neoadjuvant platinum-based doublet chemotherapy (PT-DC). Still, 30%-70% of patients develop recurrence and die from disease progression, highlighting the need for more effective treatments. Atezo, an anti–programmed death-ligand 1 (PD-L1) antibody that restores anti-tumour immunity, has shown promising efficacy as monotherapy and in combination with chemotherapy in advanced NSCLC. It is hypothesised that the combination of atezo and PT-DC may provide clinical benefit in the neoadjuvant setting by enhancing cancer cell killing and eradicating micrometastases, reducing the risk of disease recurrence. The objective of IMpower030 (NCT03456063) is to evaluate the efficacy and safety of atezo in combination with PT-DC as neoadjuvant treatment for patients with resectable early-stage NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Trial design

      IMpower030 is a global, Phase III, double-blind, randomized study in patients with histologically or cytologically confirmed, resectable stage II, IIIA, or select IIIB (T3N2) NSCLC (per AJCC/UICC, 8th ed). Study inclusion requires measurable disease per RECIST v1.1, ECOG PS of 0/1 and eligibility for R0 resection with curative intent and PT-DC. Patients who had received prior therapy for lung cancer or present with nonsquamous NSCLC with activating EGFR mutations or ALK translocation are excluded. Patients will be randomized to receive 4 cycles of neoadjuvant atezo (1200 mg Q3W, Arm A) or placebo (Arm B) in combination with an investigator-selected PT-DC regimen. Following unblinding, patients in Arm A will receive adjuvant atezo treatment for ≤ 16 cycles or until disease recurrence or unacceptable toxicity, and patients in Arm B will receive best supportive care and scheduled observational follow-up. Endpoints will include major pathological response (≤ 10% residual viable tumour tissue at time of resection), investigator-assessed event-free survival and disease-free survival per RECIST v1.1, OS, ORR, pathological complete response and patient-reported outcomes. Exploratory biomarkers will also be evaluated.

      d9b324a48b043b3d87bc9b3fe620f260 Clinical trial identification

      NCT03456063.

      7a6a3ffa2dadc03a6151ee2c4d6fa383 Editorial acknowledgement

      Medical writing assistance for this abstract was provided by Jessica Men, PharmD, of Health Interactions and funded by F. Hoffmann-La Roche, Ltd.

      934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study

      F. Hoffmann-La Roche, Ltd.

      213f68309caaa4ccc14d5f99789640ad Funding

      F. Hoffmann-La Roche, Ltd.

      682889d0a1d3b50267a69346a750433d Disclosure

      S. Peters: Ad board, honoraria: Daiichi, Debiopharm, FoundMed, Janssen, Merrimack, PharmaMar, Regeneron, Sanofi, Seattle Genetics; Ad boad, honoraria, talk: Lilly, Takeda; Talk, honoraria, investigation in trials: AZ, BI, BMS, Clovis; Ad board, honoraria, talk, investigation in trials: Roche, Merck, Novartis, Pfizer; Ad board, honoraria, investigation in trials: Illumina. A.W. Kim: Full-time employee: University of Southern California; Advisory board: Medtronic, Genentech; Other (support of parent study, funding of editorial support): F. Hoffmann-La Roche. B. Solomon: Support of parent study, funding of editorial support: Roche. D.R. Gandara: Research grants: AstraZeneca, Genentech, Novartis, Merck; Consultant/Advisory board: AstraZeneca, Celgene, CellMax, Genentech, Guardant Health, Inivata, IO Biotech, Lilly, Liquid Genomics, Merck, Samsumg Bioepis; Parent study, medical writing support: Roche. R. Dziadziuszko: Advisor/Board member: Roche, Novartis, Pfizer, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb; Speaker’s Bureau: Roche, Pfizer, Foundation Medicine; Support of parent study, funding of editorial support: Roche. A. Brunelli: Support of parent study, funding of editorial support: F. Hoffmann-La Roche. M.C. Garassino: Grants/research support: MSD, BMS, AZ, Roche, Celgene, Medimmune; Advisory board/Speakers’ bureau: MSD, BMS, AZ, Roche, Celgene, Medimmune, Incyte, Ignyta; Other (support of parent study, funding of editorial support): Roche. M. Reck: Speakers bureau, consulting, advisory role: Roche, Lilly, Pfizer, BI, AZ, MSD, BMS, Merck, Novartis, Celgene; Other (support of parent study, funding of editorial support): Roche. L. Wang, I. To, S.W. Sun, B.J. Gitlitz: Employee: Genentech; Other (support of parent study, funding of editorial support): Roche. A. Sandler: Employee: Genetech; Stock: Roche; Other (support of parent study, funding of editorial support): Roche. N. Rizvi: Consulting: AbbVie, AstraZeneca, BMS, EMD Sorono, Genentech, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron; Advisory boards: Bellicum, Brooklyn Immunotherapeutics, Neogenomics, Gritstone; Equity: Bellicum, Brooklyn Immunotherapeutics, Gritstone, ARMO Board of Director (2017-2018) with Stock options vested with company acquisition by Lilly (June 25, 2018); Royalties: Personal Genome Diagnostics: Royalties related to patent filed by MSKCC, Determinants of cancer response to immunotherapy (PCT/US2015/062208); Research funding: BMS, Merck; Institutional financial interests: Clinical research: AstraZeneca, BMS, Genentech, GSK, Merck, Regeneron.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      87P - Time-series of peripheral blood biomarkers as biomarkers for immunotherapy in advanced non-small cell lung cancer (aNSCLC) patients (Now Available) (ID 503)

      12:30 - 13:00  |  Presenting Author(s): Arsela Prelaj  |  Author(s): SARA ELENA Rebuzzi, PAMELA Pizzutilo, MASSIMO Bilancia, MICHELE Montrone, FRANCESCO Pesola, VITO Longo, GABRIELLA Del Bene, VITTORIA Lapadula, FLAVIO Cassano, PATRIZIA Petrillo, DANIELA Bafunno, NICCOLO' Varesano, VITO Lamorgese, ANGELICA Mastranrdea, DONATELLA Ricci, ANNAMARIA Catino, DOMENICO Galetta

      • Abstract
      • Slides

      Background

      Immune-checkpoint inhibitors (ICIs) as second-line therapy showed an overall survival (OS) benefit, but only 18-20% of aNSCLC patients respond with a median progression-free survival (mPFS) of 2-4 months. The identification of biomarkers to select patients most likely to benefit from ICIs is still an unmet need in clinical practice.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We conducted a retrospective monocentric analysis in 154 aNSCLC patients receiving single-agent nivolumab or pembrolizumab as second-line (68%) and >3rd line (32%) therapy. We recorded complete blood cell count at baseline (T0), before second (T1) and third cycle (T2), assessing neutrophil-lymphocyte ratio (NLR), derived-NLR (dNLR) and lymphocyte-monocyte ratio (LMR). Statistical analyses (univariate and multivariate analysis) were performed to evaluate the correlation between overall response rate (ORR), PFS and OS and the change from baseline of NLR, dNLR and LMR at second (T0-T1) and third cycle (T0-T2). We divided biomarker time-series into two groups of > 30% increase and <30% increase or decrease from baseline value.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The only biomarker statistically significantly associated with survival outcomes was NLR. An increase of > 30% of NLR from baseline to the second cycle (NLR T0-T1) was associated with a worse PFS (3.7 vs 4.9 months, HR 1.52 95% CI 1.02 – 2.24; p = 0.04). We also observed a statistically significant correlation between ORR and the >30% increase of LMR from baseline to the second (LMR T0-T1; p < 0.001) and the third cycle (LMR T0-T2; p = 0.001).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      According to the prognostic value of time-series of biomarkers at second and third cycle from baseline, patients who experienced an increase of > 30% of NLR after the first ICI cycle were associated with a worse PFS; also, an increase of > 30% of LMR after the first and second ICI administration lead to a better ORR.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      D. Galetta: Medical advisor: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      89P - Treatment patterns and long-term survival for unresected stage III non-small cell lung cancer patients: A nationwide register study in Denmark (ID 214)

      12:30 - 13:00  |  Presenting Author(s): Anders Green  |  Author(s): Karen Ege Olsen, Mette Bliddal, Helene Nordahl Christensen, Erik Jakobsen

      • Abstract
      • Slides

      Background

      Patients with stage III non-small cell lung cancer (NSCLC) is a heterogeneous population with resectable or unresectable tumors. Current standard of care for unresectable disease has since long been either curatively intended chemoradiotherapy (CRT) followed by active surveillance, or palliative treatment for CRT ineligible patients. Recently, published data have shown survival benefit of CRT followed by immunotherapy (durvalumab). The aim was to investigate long-term survival, treatment patterns, and characteristics for unresected stage III NSCLC patients in a real-life setting.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      This nationwide study identified all stage III NSCLC patients diagnosed in Denmark during 2006-2015 in the Danish Cancer Registry. Patient and tumor data were linked with data on resection, CRT, radiotherapy only [RT], chemotherapy only [CT] and comorbidity from the National Patient Registry. Survival rates were estimated from date of diagnosis until death, migration, or end of study (2016) using Kaplan-Meier curves.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      During the study period, 33,747 patients were diagnosed with NSCLC, of which 7390 (22%) had stage III disease. Of these, 5919 (80%) patients were unresected, and they were older (mean age 69.2 vs. 65.8 years), more frequently men (55.0% vs. 51.5%), and had more comorbidity (39.8% vs. 33.6% ≥one comorbidity) compared to the resected patients. Among the unresected patients, 40.5% received CRT, 15.1% RT, 15.6% CT, and 28.8% had no treatment. Patients receiving CRT were younger and had less comorbidity than patients receiving RT or CT only. The 5-year overall survival rates in the unresected group were: 10.6% CRT, 4.5% RT, and 3.6% for patients treated with CT. Among the resected stage III NSCLC patients, 42% survived ≥5 years.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      The poor long-term survival rates observed among unresected stage III NSCLC patients indicate a high unmet need for more effective therapy. New treatment strategies, including CRT followed by immunotherapy, might improve long-term outcomes for these patients. Increased utilization of biomarkers and correctly targeted therapies has the potential to personalize and improve treatment of stage III NSCLC.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Institute of Applied Economics and Health Research Aps, Copenhagen, Denmark.

      213f68309caaa4ccc14d5f99789640ad Funding

      AstraZeneca.

      682889d0a1d3b50267a69346a750433d Disclosure

      H.N. Christensen: Employed: AstraZeneca. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      90P - Real-world treatment patterns, clinical practice and outcomes for locally advanced, non resectable, non-small cell lung cancer from the French ESME Lung database (ID 525)

      12:30 - 13:00  |  Presenting Author(s): Nicolas Girard  |  Author(s): Maurice Pérol, Gaetane Simon, Clarisse Audigier Valette, Radj Gervais, Didier Debieuvre, Roland Schott, Xavier Quantin, Bruno Coudert, Herve Lena, Matthieu Carton, Mathieu Robain, Thomas Filleron, Christos Chouaid

      • Abstract

      Background

      Approximately 30% of patients (pts) with non-small-cell lung cancer (NSCLC) are diagnosed with locally advanced disease, which is often unresectable. The historical standard of care (SoC) has been platinum-based chemoradiotherapy (CRT), based on data from clinical trials conducted in selected populations. As immunotherapy is being integrated in the treatment strategy, real-world evidence aiming at understanding the current management of those patients is missing.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      This study is an analysis of the Epidemio-Strategy and Medical Economics (ESME) Lung Data Platform, a multi-center real-life database using a retrospective data collection process. This database compiles data from patient’s Electronic medical records (EMR), inpatient hospitalisation records and Pharmacy records. 8514 pts from 20 centres with lung cancer treated between January 1st, 2015 and December 31st, 2016, were included.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      822 pts with unresectable locally advanced NSCLC - 69% male, median age 65y, 61% ECOG PS0-1, 60% non-squamous histology - were included in the analysis. Treatment was initiated in 736 pts (analysis population): 39% concurrent CRT (cCRT), 17% sequential CRT (sCRT), 26% chemotherapy (CT) alone, 16% radiotherapy (RT) alone and 2% other therapy. For cCRT, 95% of pts received induction chemotherapy before the concurrent phase, based on taxanes (32% of pts), vinorelbine (42% of pts), or pemetrexed (16% of pts); 35% of patients received consolidation chemotherapy. For sCRT, preferred platinum doublet chemotherapy regimens were based on taxanes (39% of pts), vinorelbine (26% of pts), or pemetrexed (17% of pts). Radiotherapy was delivered to a total dose of 60-66 Gy for 84% (cCRT) and 71% (sCRT). After a median follow-up of 17 months, progression rate was 62%; progression occurred in the thorax, the brain, or at other sites in 42%, 19% and 38% of pts, respectively. Median PFS was 8.0 months (m) for the analysis population, 9.3 m (cCRT) and 11.6 m (sCRT). 24-month OS rate was 51%, 60%, and 52%, respectively.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Real world data support the use of CRT in locally advanced NSCLC, with similar outcomes than in landmark clinical trials.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      UNICANCER.

      213f68309caaa4ccc14d5f99789640ad Funding

      AstraZeneca.

      682889d0a1d3b50267a69346a750433d Disclosure

      N. Girard: Fees for attending scientific meetings, speaking, organizing research or consulting: AstraZeneca, Boehringer Ingelheim, Roche, SBMS, MSD, Lilly, Novartis, Pfizer, Amgen. M. Pérol, R. Gervais: Symposium, advisory board: AstraZeneca. C. Audigier Valette: Consultancy, Advisory board membership: AstraZeneca, Pierre Fabre. C. Chouaid: Fees for attending scientific meetings, speaking, organizing research or consulting: AstraZeneca, Boehringer Ingelheim, GSK, Roche, Sanofi Aventis, BMS, MSD, Lilly, Novartis, Bayer, Pfizer, Takeda, Amgen. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      91P - Prognosis of EGFR-mutant advanced lung adenocarcinoma patients with different intrathoracic metastatic patterns (Now Available) (ID 273)

      12:30 - 13:00  |  Presenting Author(s): Fang Hu  |  Author(s): Bo Zhang, Changhui Li, Jianlin Xu, Huimin Wang, Ping Gu, Xiaoxuan Zheng, Wei Nie, Yinchen Shen, Hai Zhang, Ping Hu, Xueyan Zhang

      • Abstract
      • Slides

      Background

      Lung cancer diagnosed solely with intrathoracic metastases are classified as M1a, but intrathoracic metastases can be further divided into different patterns. The objective of our study was to analyze the survival difference between different metastatic patterns of intrathoracic metastases in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      EGFR-mutant patients diagnosed only with intrathoracic metastasis between March 2011 and October 2016 were collected. Prognosis was analyzed according to metastatic patterns based on univariate and multivariate analysis.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      A total of 137 patients (60 patients who only had pleural metastasis [Group A], 44 patients who only had contralateral lung metastasis [Group B] and other 33 patients had both pleural and contralateral lung metastasis with or without pericardial effusion [Group C]) were included in the study. The median OS (overall survival) times were 38.1(95%confidence interval [CI]: 27.8-48.4), 35.7(95%CI: 23.4-48.0), and 29.7(95%CI: 22.8-36.6) months for Group A, Group B, and Group C, respectively (p = 0.037). Multivariate analysis demonstrated that Group A and Group B had longer OS than Group C (hazard ratio [HR]=0.524, 95%CI: 0.307-0.894, p = 0.018; HR = 0.473, 95%CI: 0.241-0.931, p = 0.030, respectively) among lung adenocarcinoma patients with EGFR mutation. With regard to patients with pleural or contralateral metastasis only, OS benefit (p = 0.579) was not significant between the two groups. Subgroup analysis demonstrated that the OS benefit of Group A was significant in patients with N0-1 disease and 21L858R mutant but not in EGFR exon 19 deletion, N2-3 stage and T3-4 stage disease patients.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      The prognosis of EGFR-mutant lung adenocarcinoma patients diagnosed only with intrathoracic metastasis is different, indicating that M1a may should be refined in the future.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      National Natural Science Foundation of China (No.81502450) and Science and Technology Commission of Shanghai Municipality, China (No.18441904700).

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      92P - A prospective study on the association of dose-volume histogram parameters with oesophagitis, radiation pneumonitis, radiation induced pulmonary fibrosis after receiving chemoradiation for NSCLC (ID 241)

      12:30 - 13:00  |  Presenting Author(s): SAIKAT Bhowal  |  Author(s): KOUSHIK Chatterjee, JOYITA Dey

      • Abstract

      Background

      The aim of this study was to assess the relationship between pulmonary V30, age, gender, smoking history, tumor location & incidence, grade of oesophagitis, radiation pneumonitis (RP) and radiation induced pulmonary fibrosis (RIPF) (within radiotherapy portals) in NSCLC patients treated with chemoradiation.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      A hospital-based prospective study of 64 NSCLC patients treated (between November 2017–2018) with chemoradiation (paclitaxel & carboplatin + total 60 Gy in 30# i.e. 2Gy once daily) was conducted. Relationship between pulmonary V30, age, gender, smoking history, tumor location & incidence, grades of oesophagitis, RP, RIPF (HRCT confirmed) with a median follow up of 7 months was analysed using Spearman's rank correlation coefficient in SPSS software (multivariate analysis). Kruskal Wallis test was used to test significance. Ethical clearance was obtained from the local ethics committee.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      1) Oesophagitis of grade 0,1,2,3,4 was diagnosed in 23,30,8,2&0 patients respectively. Corresponding mean V30 values were 33.8%,34.5%,37.2%,39.6& 41.2% 2) RP of grade 0,1,2,3,4 was detected in 18,19,24,2&1 patients respectively. Corresponding mean V30 values were 21.3%, 22.4%,26.8%,30.0%& 36.2%. 3) RIPF of grade 0,1,2,3,4 was detected in 32,26,8,0&0 patients respectively. Corresponding mean V30 values were 31.2%,34.4%,35.9%,38% &38.6%. 4) Significant correlation was detected between V30≥30%& incidence & grade 2 oesophagitis (p = 0.02, r = 0.86), grade 2 radiation pneumonitis (p = 0.001, r = 0.74), grade 1 RIPF (p = 0.01, r = 0.88). 5) Increasing age (p = 0.03), smoking history (p = 0.04), tumor location i.e. upper vs middle/lower lobe (p = 0.02) had a significant correlation with incidence and grades of oesophagitis, RP, RIPF.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Hence, the incidence and grades of oesophagitis, RP, RIPF are significantly related to lung V30≥30%, age, smoking history, and tumor location.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Institute of Post Graduate Medical Education & Research & SSKM Hospital, Kolkata.

      213f68309caaa4ccc14d5f99789640ad Funding

      Institute of post graduate medical education & research & SSKM Hospital, Kolkata.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      93P - Heterogeneity score in inoperable stage III non-small cell lung cancer patients treated with definitive chemoradiotherapy: A single centre analysis (ID 563)

      12:30 - 13:00  |  Presenting Author(s): Julian Taugner  |  Author(s): Lukas Käsmann, Chukwuka Eze, Maurice Dantes, Olarn Roengvoraphoj, Kathrin Gennen, Monika Karin, Amanda Tufman, Claus Belka, Farkhad Manapov

      • Abstract

      Background

      Inoperable stage-III non-small cell lung cancer (NSCLC) represents a very heterogeneous disease in terms of patient and tumor characteristics. A simple heterogeneity score may help to personlize multimodal therapy.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      The data of 99 patients with performance status ECOG 0-1 treated with chemoradiotherapy (CRT) for inoperable stage III NSCLC, treated between 2011 and 2016 at our hospital were analyzed. Patient- and tumor-related factors were evaluated, and factors showing a significant negative association with patient survival were scored with one point each. Three subgroups with a low, intermediate and high-risk (0-1, 2-3 and 4-5 points) score were defined. The results were validated in a prospective cohort of 35 patients.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Concurrent CRT was administered in 78% (n = 78) of patients and sequential CRT in 11% (n = 11), 10 Patients were treated with radiotherapy alone. 53% (n = 53) of patients received induction chemotherapy. Median overall survival (mOS) for the entire cohort was 20.8 months. Age (p = 0.020), gender (p = 0.007), cumulative tobacco pack years (PY) (p = 0.015), tumor-associated atelectasis (p = 0.004) and histology (p = 0.011) had a significant impact on survival in univariate analysis. 12, 59 and 28 patients had low, intermediate and high-risk score. MS, 1-, 2- and 3-year survival rates were as follows: not reached, 100%, 83% and 67% in the low, 22.9 months, 80%, 47% and 24% in the intermediate and 13.7 months, 57%, 25% and 18% in the high-risk score subgroup. Prospective validation of the score demonstrated one-year survival of 100% for patients in the low-risk subgroup, 93% in the intermediate-risk subgroup, and 69% in the high-risk subgroup (p = 0.100).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      This simple heterogeneity score was developed for inoperable stage III NSCLC patients with good performance status receiving multimodal therapy. The score may aid physicians to infer clinical outcomes and optimize decisions concerning treatment strategies, as well as planning of prospective studies.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      94P - Challenges in the management of stage III non-small cell lung cancer (NSCLC) within multidisciplinary team (MDT): A lung cancer center experience (Now Available) (ID 562)

      12:30 - 13:00  |  Presenting Author(s): Kaouther Harbegue  |  Author(s): Nesrine Mejri, Houda El Benna, Soumaya Labidi, Nouha Daoud, Hammouda Boussen

      • Abstract
      • Slides

      Background

      We aimed to report patterns of care and difficulties during the management of patients with newly diagnosed stage III NSCLC who were presented at our MDT meeting.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Medical records of 88 patients diagnosed with stage III NSCLC between 2011-2017 presented at least once at our weekly lung cancer MDT meeting, were reviewed. Tumor characteristics and treatment receipt were described.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Median age was 61 years old, with a disease stage: IIIA in 48 % and IIIB 52% before MDT meeting. We observed 27.3% of patients referred without histological diagnosis; median delay time from first visit to having a histological diagnosis was 17 days. Median time from first visit to presentation at MDT meeting was 11.8 days (SD = 15.3), and to the start of first therapy was 21.4 days (DS = 43.5). TNM stage was reconsidered after the MDT meeting in 16 % of cases. Treatment decision was upfront surgery in 20%, neoadjuvant chemotherapy (NACT) in 59 %, concurrent chemoradiation (CCRT) in 20%. MDT indications were in adherence to ESMO guidelines in 90 %. Treatment receipt was 81 % for surgery, 84% for NACT and 44% for CCRT. For NACT, the median delay between MDT presentation and start of therapy was 19 days, 15 days for surgery and 19 days for CCRT. Discordance between the planned and administered treatment was recorded in 58% of cases. The reasons for discordance were: 14% patient’s refusal, 8% patient’s general condition decline, 4% of cases for medical contraindications, 8% for the delay in radiation therapy initiation, and lost to follow up in 33 % of cases. Progression occurred during the planned treatment in 23% of cases and 10% of patients died before the end of the planned therapy. The MDT meeting was consulted for the same patient twice in 41% of cases, 3 times 1%. We observed a statistically significant difference between patients who had their treatment as decided by the MDT meeting with 49 months median overall survival versus 22 months in non-adherent patients (p < 0.01).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Management of stage III NSCLC within a MDT showed a role in staging assessment and was characterized by a relatively rapid start of therapy and high impact on survival but a low receipt rate for CCRT.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Medical Oncology Department Abderrahmen Mami Hospital.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      95P - The role of patient performance status and its changes before and after completion of multimodal treatment for inoperable stage III NSCLC (Now Available) (ID 584)

      12:30 - 13:00  |  Presenting Author(s): Lukas Käsmann  |  Author(s): Julian Taugner, Chukwuka Eze, Olarn Roengvoraphoj, Maurice Dantes, Kathrin Gennen, Monika Karin, Amanda Tufman, Claus Belka, Farkhad Manapov

      • Abstract
      • Slides

      Background

      The Eastern Cooperative Oncology Group performance score (ECOG-PS) is used in clinical routine to quantify patients’ general condition. We evaluated ECOG-PS before, after and its changes in the course of chemoradiotherapy (CRT) in patients with inoperable stage III NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      The data of ninety-nine patients with NSCLC UICC stage IIIA/B (TNM 7th edition) were evaluated. ECOG-PS before treatment, at first follow-up and the difference was examined for their impact on overall survival (OS) from initial diagnosis and event-free survival (EFS) from the first day of radiation.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Median survival for the entire cohort was 20.8 (range: 15.3-26.2) months. Before the start of multimodal treatment, ECOG-PS was 0 in 48% and 1 in 52% of patients; median OS, 1- and 2-year survival rates were 26.4 months, 85% and 53% for ECOG-PS 0 and 18.9 months, 69% and 37% for ECOG-PS 1 patients (p = 0.1). After completion of CRT 65% of patients had the same or better and 35% worse ECOG-PS: 0 in 34%, 1 in 46%, 2 in 18% and 3 in 2% of patients. Median OS, 1- and 2-year survival rates were 40.3 months, 88% and 64% for ECOG-PS 0; 19.3 months, 82% and 40% for ECOG-PS 1; 11.9 months, 50% and 28% for ECOG-PS 2 and 7.6 months, 0% and 0% for ECOG-PS 3 (p < 0.001). Deterioration of ECOG-PS after multimodal treatment significantly impaired survival in the initial ECOG-PS 0 (p = 0.005, median 19.1 vs 31.4 months) and 1 (p = 0.001, median 22.9 vs 11.1 months) subgroups. Median EFS was 9.6, 9.0, 7.9 and 3.5 months for patients with ECOG-PS 0, 1, 2, 3 after completion of CRT (p = 0.018). EFS was not affected by initial ECOG-PS but was significantly impaired by deterioration of ECOG-PS after completion of multimodal therapy with a median time of 9.4 vs 7.7 months (p = 0.049), respectively.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Deterioration of ECOG-PS after completion of primary multimodal treatment is a significant negative prognostic factor.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      96P - Impact of thrombocytosis and neutrophil-to-lymphocyte ratio before start of chemoradiotherapy on patient survival in inoperable stage III NSCLC (ID 587)

      12:30 - 13:00  |  Presenting Author(s): Michael Hoffmann  |  Author(s): Julian Taugner, Olarn Roengvoraphoj, Chukwuka Eze, Lukas Käsmann, Claus Belka, Farkhad Manapov

      • Abstract

      Background

      We aimed to evaluate an impact of thrombocytosis and neutrophil-to-lymphocyte ratio (NLR) before start of multimodal treatment on survival of patients with inoperable locally advanced non-small cell lung cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Retrospective data of 99 patients (ECOG 0-1) with inoperable NSCLC stage III receiving definitive chemoradiotherapy (CRT) between 2010 and 2016 at our institute were analyzed. Complete blood count and neutrophil- to- lymphocyte ratio (NLR) before initiation of multimodal treatment were evaluated and correlated with EFS and OS.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The median age was 67 years and 63 % of patients were male. Median follow-up for the entire cohort was 17 months (range: 2 – 92). Patients with initial thrombocytosis (>401 x 109/L) demontrated a significantly shorter median EFS (7 vs. 14.5 months, p < 0.001, log-rank test) and OS (11 vs. 23 months, p = 0.002, log-rank test) vs. patients with normal platelet count. Patients with NLR >3.5 before start of multimodal treatment had a significantly worse prognosis than patients with lower initial NLR (0.78 – 3.5), (17.2 vs 29.3 months, p = 0.041, log-rank test).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Initial thrombocytosis and NLR > 3.5 were associated with shorter survival in patients with inoperable stage III NSCLC treated with definitive CRT.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

    • +

      97P - Pattern of first-site failure and salvage treatment in patients with inoperable stage III non-small cell lung cancer after chemoradiotherapy (ID 590)

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

      • Abstract

      Background

      The standard of care treatment for inoperable stage III NSCLC is concurrent chemoradiotherapy (CRT) followed by consolidation with durvalumab. Loco-regional and distant recurrences remain common. Herein, we examine pattern of first-site failure and salvage treatment.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We analysed the medical charts of 99 patients treated with CRT. Scans from date of first-site failure were fused with the delivered treatment plans. Recurrences were identified as in-field recurrence (IFR), out-of-field recurrence (OFR) [outside 50Gy isodose line] and distant metastases (DM). Using the Kaplan-Meier method with log-rank test for univariate analysis, the effect of salvage surgery (S), radiotherapy (sRT), chemotherapy (sCT) and immunotherapy (sIO) on overall survival (OS) was evaluated.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      With a median follow-up of 17.2 months, the mOS for all patients was 20.8 months. 26 patients (26%) with IFR had a mOS of 19.3 months. In patients who survived at least 12 months from initial diagnosis (74%), IFR was a significant negative prognosticator (mOS 19.3 vs 40.0 months; p < 0.001). 25 (25%) patients developed OFR with no significant impact on survival (27.1 vs 20.8 months, p = 0.313). 3 (12%) patients with OFR underwent salvage surgery (p = 0.057) and were still alive at the time of this analysis. 5 (20%) patients underwent sRT with a mOS of 71.2 vs 19.1 months (p = 0.014). 13 (52%) patients with OFR received sCT; mOS 26.4 vs 32.7 mo. (p = 0.644;) and 4(16%) pts received sIO (mOS: 64.6 vs 26.4 months; p = 0.222). Distant and brain relapse were detected in 42 (42%) and 16 (16%) patients; mOS 19.1 vs. 22.9 months (p = 0.819) and 19.1 vs 20.8 mo. (p = 0.635), respectively. 15 (94%) patients with brain relapse received cranial radiotherapy: 7 (47%) whole brain irradiation and 8 (53%) stereotactic radiosurgery (mOS 15.3 vs. 37.8 mo.; p = 0.064).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      IFR was a significant negative predictor of OS in patients, who survived >1 year after initial diagnosis. Patients with OFR benefit most from salvage operation and/or radiotherapy. Furthermore, we observed survival benefit in patients who received SRS vs. WBRT for brain relapse.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

    • +

      98P - Implications for UK practice of the use of durvalumab in stage III NSCLC (ID 559)

      12:30 - 13:00  |  Presenting Author(s): Muhammad Shahid Iqbal  |  Author(s): Philip Atherton, Carol Macgregor, Andrzej Wieczorek, Julian Singer, Julie Walther, Felicity Little, Susan Harden, Clive Peedell, Abby Cyriac, Subhra Chowdhury, Mike Bayne, Kent Yip, Anna Britten, Ceri Powell, Juliet Brock, Sudipta Datta, Timothy Sevitt, Ajay Mehta, Alastair Greystoke

      • Abstract

      Background

      The PACIFIC trial showed a survival benefit in patients receiving Durvalumab after concurrent chemoradiotherapy (CRT) in stage III Non-Small Cell Lung Cancer (NSCLC). Key inclusion criteria were platinum doublet chemotherapy with no chemotherapy delivered after concurrent phase. Dose delivered was 54 - 66Gy and treatment started within 42 days of completing radiotherapy. European licence is restricted to patients with PDL1 positive tumours. Previous UK audits have shown a number of CRT regimens in routine use. We assessed the implications to UK practice of adding durvalumab after CRT.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      A 9 point questionnaire was sent by email to all 50 radiotherapy centres delivering chemoradiotherapy for NSCLC in the UK.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      21 responses were received (42%) at the time of submission. Rates of concurrent treatment ranged from 10 - 90% (median 40%, IQR 25-60%) with median surgery rates for N2 disease of 10%. Doses delivered ranged from 55 to 66 Gy (median 60, IQR 55 – 64 Gy) in a median of 30 fractions (IQR 20 to 32). 10 centres used hypofractionated regimens. The most common chemotherapy back-bone was cisplatin and vinorelbine (1 centre used carboplatin and 1 etoposide routinely). 11 centres prescribe chemotherapy post concurrent treatment. Currently only 3 centres scan within the 6 week window after completion of treatment. The majority of centres are now planning to avoid giving consolidative chemo after concurrent CRT and will scan early after CRT. 13 centres are already testing PDL1 in this context. Durvalumb will be supervised in 16 centres by a clinical oncologist, in 2 by medical oncologist with the remaining 3 undecided.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      The implementation of consolidative Durvalumab in stage III NSCLC post concurrent CRT will require changes in practice in the majority of UK centres. Most centres have already implemented some changes but more work needs to be done to standardise practice and ensure equality of access for patients.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

      • Abstract
      • Slides

      Background

      Platinum-based adjuvant chemotherapy (CT) improves survival in surgically resected non-small-cell lung cancer (NSCLC) patients (pts). However, cisplatin and vinorelbine (PV), the most studied regimen, is often associated with increased rates of grade 3-4 toxicities. We aimed to study the efficacy and safety of adjuvant CT in NSCLC pts in a real-world scenario.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We performed a retrospective analysis of NSCLC pts treated with surgery with curative intent between 2009 and 2018 in an academic cancer center. After surgery, pts were accessed to receive adjuvant CT, based on physicians’ discretion. Electronic records were reviewed and data were collected for pts and tumor characteristics, treatments, outcomes (overall survival [OS] and disease-free survival [DFS]), and toxicities. OS and DFS were estimated by the Kaplan-Meier method, and curves were compared by log-rank. Prognostic factors were evaluated using Cox regression.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      250 consecutive pts were studied: 80 adjuvant CT and 170 observation; 55/80 received PV. Median age 65 years, 62% adenocarcinoma and 28% squamous cell carcinoma. The observation group differed from the adjuvant CT group in terms of type of surgery (lobectomy, 88% vs 76%; p = .020), 7th ed TNM staging (I, 50% vs 2%; II, 29% vs 45%; III, 20% vs 42%; p < .001), and lymph node status (N0, 71% vs 31%; p < .001). After a median follow-up of 24 months (mo), median DFS was 56.0 vs 39.3 mo in CT and observation groups, and median OS was 61.4 vs 58.5 mo, respectively. In an adjusted analysis, adjuvant CT was associated with improved DFS (HR 0.36, IC 95% 0.23-0.58; p < .001) and OS (HR 0.47, IC 95% 0.28-0.78; p .004). Toxicities were high in the PV group: 49% of the pts required hospitalization, 45% discontinued treatment, and 89% presented grade 3-4 toxicities, including 29% of febrile neutropenia. Five pts (9%) had treatment-related deaths.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Our study supports both the OS and DFS benefits of NSCLC adjuvant CT in the real world scenario. However, PV was associated with alarming rates of treatment-related toxicities and deaths, suggesting that new adjuvant avenues are warranted.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      100P - A new PET-CT score for locally-advanced inoperable NSCLC stage III patients treated with chemoradiotherapy (Now Available) (ID 580)

      12:30 - 13:00  |  Presenting Author(s): Olarn Roengvoraphoj  |  Author(s): Chukwuka Eze, Julian Taugner, Arteda Gjika, Amanda Tufman, Lukas Käsmann, Indrawati Hadi, Erik Mille, Claus Belka, Farkhad Manapov

      • Abstract
      • Slides

      Background

      FDG-PET/CT is an integral part of staging and radiation treatment planning for patients with stage III non-small cell lung cancer (NSCLC). In this study, we analysed the correlation between different PET parameters and survival in NSCLC patients treated with chemoradiotherapy (CRT).

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Ninety-nine consecutive patients with NSCLC stage IIIA-B and good performance status, who underwent FDG-PET-CT before the start of CRT were analysed. Maximum standardized uptake value of primary tumor (SUVmax_PT) and range between the two most distant PET-positive (SUV≥3) lymph nodes in two directions (cranio-caudal and transversal) were analysed for their correlation with patient survival. The cranio-caudal distance was defined as A- and the transversal as B-line. The area under the ROC curve (AUC) as well as the cut-off SUVmax, A- and B-lines were calculated.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Median survival for the entire cohort was 20.8 months (95% CI: 15.3-26.3). Patients with SUVmax_PT ≥ 8 had poor overall survival (OS) (19 vs. 40 months in patients with SUVmax ≥ 8 and <8, p < 0.0001). A-line was not associated with OS, whereas B-line < 3.7 cm improved OS significantly (30 vs. 16 months in patients with B-line < 3.7 and ≥3.7cm, p = 0.001). The sum of A- and B-lines with the cut-off at 6.7cm correlated with overall survival significantly (29 vs. 18 months in patients with sum < 6.7 and ≥6.7cm, p = 0.04). The PET-CT score was generated on the basis of PET parameters correlated with OS in univariate analysis. The patients were divided into 4 subgroups. The low-risk subgroup (0 points) included patients with SUVmax_PT< 8, B-line < 3.7 cm and the sum of A- and B-lines < 6.7 cm (n = 20, 21.3%). Twenty-eight patients (29.5%) had 1 point (intermediate risk), 20 (21.3%) had 2 points (high) and 26 patients (27.7%) had 3 points (very high risk). Median OS in terms of low/intermediate/high and very high risk subgroups was 40 (95% CI: 0-83)/27 (95% CI: 15-39)/26 (95% CI: 15-37) and 14 months (95% CI: 13-14), (p = 0.0001).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      A new PET-CT score was developed for patients with inoperable stage III NSCLC treated with definitive CRT. Initial SUVmax_PT < 8, B-line < 3.7 cm and PET-CT score were predictors of patient long-term outcome.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      101TiP - PACIFIC-R: First real-world study of patients with unresectable, stage III NSCLC treated with durvalumab after chemoradiotherapy (ID 236)

      12:30 - 13:00  |  Presenting Author(s): Nicolas Girard  |  Author(s): Françoise Mornex, Daniel Christian Christoph, Ranier Fietkau, Andrea Riccardo Filippi, John K. Field, Pilar Garrido Lopez, Fiona McDonald, Solange Peters, Alyssa B. Klein, Muriel Licour, Marina Chiara Garassino

      • Abstract

      Background

      Approximately 30% of patients (pts) with non-small-cell lung cancer (NSCLC) are diagnosed with Stage III disease, which is often unresectable. Historically, the standard of care (SoC) has been platinum-based chemoradiotherapy (CRT), but outcomes have been poor. Durvalumab is a selective high-affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80. In the phase 3 PACIFIC trial of durvalumab versus placebo in pts with unresectable, Stage III NSCLC without progression after concurrent CRT (cCRT), both primary endpoints progression-free survival (PFS) and overall survival (OS) were met and significantly improved with durvalumab (HR for PFS, 0.52; 95% CI 0.42–0.65; P < 0.001; HR for OS, 0.68; 99.73% CI 0.47–0.997; P = 0.0025) with similar safety between treatments (Antonia et al, NEJM 2017; 2018). Based on these findings, the PACIFIC regimen (durvalumab following CRT) is becoming the SoC. PACIFIC-Real World (PACIFIC-R) will assess if durvalumab treatment after cCRT shows similar efficacy and safety in a large, real-world population.

      a9ded1e5ce5d75814730bb4caaf49419 Trial design

      PACIFIC-R is an international, observational study that will enroll ∼1200 NSCLC pts who have received durvalumab as part of early access programs (EAPs) between Sept 2017 and Dec 2018. In the EAP, eligible pts are adults with histologically or cytologically documented unresectable, Stage III NSCLC, regardless of tumor PD-L1 expression, who have not progressed after definitive CRT. Pts received durvalumab (10 mg/kg intravenously) every two weeks. Pts will be enrolled in the PACIFIC-R study after discontinuation of the EAP in participating countries. Data will be abstracted from pts’ medical records at several time points within the 5 year study period. Primary endpoints are PFS (investigator assessed) and OS. Secondary endpoints include PFS and OS in pt subgroups; time to distant metastases; sites of disease progression; adverse events of special interest leading to treatment interruption, discontinuation or medical intervention; and descriptive analyses of demographic and clinical characteristics of pts treated with durvalumab in a real-world setting. Recruitment for this study is ongoing.

      d9b324a48b043b3d87bc9b3fe620f260 Clinical trial identification

      NCT03798535.

      7a6a3ffa2dadc03a6151ee2c4d6fa383 Editorial acknowledgement

      Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by James King of Cirrus Communications (Macclesfield, UK), an Ashfield company, and was funded by AstraZeneca.

      934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study

      AstraZeneca AB.

      213f68309caaa4ccc14d5f99789640ad Funding

      AstraZeneca AB.

      682889d0a1d3b50267a69346a750433d Disclosure

      N. Girard: Personal fees: AstraZeneca, MSD, BMS, Roche, during the conduct of the study. F. Mornex, D.C. Christoph, R. Fietkau, J. Field, P. Garrido Lopez: Conflict of Interests not immediately avaliable, will be following up with congress directly to provide as soon as possible. A.R. Filippi: Personal fees: AstraZeneca during the conduct of the study. McDonald: Personal fees: AstraZeneca, Elekta; Research grants: MSD, outside the conduct of the study. S. Peters: Personal fees: AbbVie, Amgen, AZ, Bayer, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F Hoffman-LaRoche, Foundation Medicine, Illumina, Janssen, Merck, Merrimack, Novartis, PharmaMar, Pfizer, Regeneron, Sanofi. A.B. Klein, M. Licour: Employment, stock: AstraZeneca outside the conduct of the study. M.C. Garassino: Personal fees: MSD, BMS, AstraZeneca, Roche, outside the conduct of the study.

      cffcb1a185b2d7d5c44e9dc785b6bb25

    • +

      121P - Risk of not receiving second-line therapy is high in EGFR mt&#x0002B; patients: Real-world data of certified lung cancer centers on treatment sequence in EGFR mt&#x0002B; patients (ID 316)

      12:30 - 13:00  |  Presenting Author(s): Julia Roeper  |  Author(s): Anne Christina Lueers, Markus Falk, Stefanie Schatz, Markus Tiemann, Claas Wesseler, G.H. Wiest, Sandra Sackmann, Dieter Ukena, Lukas Heukamp, Frank Griesinger

      • Abstract
      • Slides

      Background

      Recently FLAURA study demonstrated significant PFS and numeric OS benefit for Osimertinib 1st line vs. 1st gen. TKI’s Erlotinib/Gefitinib. The number of pts switching from 1st gen. to 3rd gen. TKI (30%) appeared to be low and it is questionable whether these data represent real world sequencing treatment patterns. Therefore, we investigated the sequence pattern, i.e. the percentage of 2nd line therapy in EGFR mt+ pts in 3 certified lung cancer centers in Germany.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Data of 912 of 1477 pts tested for EGFR mt+ were analyzed between 2009-2017. 140/144 pts with an activating EGFR mutation (16%) and treated with systemic therapy (4 pts received no therapy) were identified and their treatments were captured as well as their outcome. 36 pts were treated before accessibility to 3rd gen. TKI and 104 pts after accessibility to 3rd gen.TKI.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      130/140 pts were treated with 1st line TKI and 10 received 1st line chemotherapy. 17 pts are still on 1st line TKI, 8 pts were lost to follow-up, 3 pts died while on 1st line TKI. 112 pts were candidates for 2nd line therapy. 34/112 (30%) of these pts did not receive 2nd line therapy. Causes for not receiving 2nd line therapy were pts refusal (n = 2), bad PS (n = 26) frequently due to CNS metastases, fast progression and death (n = 6). After accessibility of 3rd gen. TKI, 20 of 66 (30%) pts did not receive 2nd line therapy. Median OS of the overall cohort was 27 months (n = 140), median OS of pts receiving 2nd line (n = 78) vs. no 2nd line (n = 62) was 36 vs. 14 months (p < 0.0001). After accessibility of 3rd gen. TKI 30/104 pts (29%) receive a 3rd gen. TKI after 1st line or 2nd line therapy. Median OS of pts receiving (n = 30) and not receiving 3rd gen. TKI (n = 110) was 55 months vs. 22 months (p < 0.0001).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      In real world, a significant number of pts treated with 1st or 2nd gen. TKI do not reach 2nd line therapy even when 3rd gen. TKI were accessible. Reasons for not receiving 2nd line therapy are in most cases deterioration of PS and lack of possibility to test for T790M in the minority of cases (n = 28/66, 42% were not tested). These data, although favorable for the small and very selected cohort of pts treated with Osimertinib, might argue for the most effective therapy in 1st line for pts with EGFR mt+ tumors.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      F. Griesinger.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      J. Roeper: Honorary: Boehringer Ingelheim, Roche. M. Falk: Honorary: BMS, Boehringer Ingelheim, MSD. L. Heukamp: Advisory board: BMS, Boehringer Ingelheim, Roche, Novartis. F. Griesinger: Advisory boards, travel support: ARIAD, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Clovis, Lilly, MSD, Novartis, Pfizer, Roche; Scientific support: AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      122P - Osimertinib as first-line (1L) treatment for epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer (NSCLC): Final efficacy and safety results from two phase I expansion cohorts (ID 404)

      12:30 - 13:00  |  Presenting Author(s): James Chih-Hsin Yang  |  Author(s): Suresh S Ramalingam, Chee Khoon Lee, Takayasu Kurata, Dong-Wan Kim, Thomas John, Naoyuki Nogami, Yuichiro Ohe, Yuri Rukazenkov, Moira Murphy, Pasi Antero Jänne

      • Abstract
      • Slides

      Background

      Osimertinib is a 3rd-generation, CNS-active EGFR-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitising (EGFRm) and EGFR T790M resistance mutations. Earlier results from the Ph I AURA (NCT01802632) and Ph III FLAURA (NCT02296125) studies have established 1L osimertinib efficacy. We report final efficacy and safety data from two Ph I expansion cohorts who received 1L osimertinib 80 or 160 mg for advanced EGFRm NSCLC in AURA.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Treatment-naïve pts with locally advanced/metastatic EGFRm NSCLC received osimertinib 80 or 160 mg once daily. Endpoints included objective response rate (ORR), progression-free survival (PFS) and safety evaluation. EGFRm status was confirmed via local and/or central laboratory testing. Key eligibility criteria included measurable disease and WHO performance status 0/1. Pts with stable asymptomatic CNS metastases were eligible. Data cutoff: 1 May 2018.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Overall, 60 patients (pts) were enrolled at two doses (80 mg, n = 30; 160 mg, n = 30): 75% female; 72% Asian; 43% with EGFR ex19del; 48% with L858R. Five pts were EGFR T790M mutation-positive by central test at study entry. Median follow up: 19.1 mo. ORR (95% CI): 67% (47, 83) in the 80 mg cohort, 87% (69, 96) in the 160 mg cohort, 77% (64, 87) overall. Median duration of response (95% CI): 19.3 mo (12.2, 24.7) in the 80 mg cohort, 16.7 mo (9.7, 29.0) in the 160 mg cohort, 18.0 mo (12.5, 24.7) overall. Median PFS (95% CI): 22.1 mo (12.3, 30.2) in the 80 mg cohort, 19.3 mo (11.1, 26.0) in the 160 mg cohort, 20.5 mo (13.7, 26.1) overall (78% maturity). 42% (95% CI 29, 54) and 14% (95% CI 6, 26) of pts were progression free at 24 and 48 mo, respectively. Dose reductions occurred in 27% and 60% of pts at 80 mg and 160 mg, respectively. Most common adverse events overall: (% [Grade ≥3]) diarrhoea (80 mg, 63% [3%]; 160 mg, 87% [7%]), stomatitis (80 mg, 47% [0]; 160 mg, 53% [3%]), paronychia (80 mg, 37% [0]; 160 mg, 57% [10%]).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Consistent with previously reported results, 1L osimertinib for EGFRm advanced NSCLC results in prolonged PFS at both doses and better tolerability at the 80 mg dose.

      b651e8a99c4375feb982b7c2cad376e9 Clinical trial identification

      NCT01802632 (25 February 2013).

      7a6a3ffa2dadc03a6151ee2c4d6fa383 Editorial acknowledgement

      Medical writing support was provided by Natasha Cary BSc, from iMed Comms, an Ashfield Company and funded by AstraZeneca.

      934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study

      AstraZeneca.

      213f68309caaa4ccc14d5f99789640ad Funding

      AstraZeneca.

      682889d0a1d3b50267a69346a750433d Disclosure

      J.C-H. Yang: Honoraria: BI, Roche, MSD, AstraZeneca, Novartis; Consulting/advisory: BI, Novartis, AstraZeneca, Roche/Genentech, Clovis Oncology, Lilly, MSD, Merck Serono, Celgene, Astellas Pharma, Bayer, Pfizer, Ono Pharmaceutical, Bristol-Myers Squibb, Yuhan, Hansoh. S.S. Ramalingam: Advisory boards: AbbVie, Amgen, AstraZeneca, BMS, Celgene, Genentech, Lilly, Merck, Roche, Nektar, Loxo, Takeda; Research grants: Merck, Tesaro. C.K. Lee: Advisory boards: AstraZeneca, Roche, Norvatis, Pfizer. Research funding to institution: AstraZeneca for the trials in which I am currently involved. T. Kurata: Research grants: AstraZeneca, MSD; Honoraria: AstraZeneca, MSD, Ono, Bristol-Myers Squibb, Chugai, Eli Lilly. D-W. Kim: Advisory board membership, personal expenses: Novartis. T. John: Consultancy: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Takeda, Pfizer, Novartis, Merck, Roche. N. Nogami: Honoraria: AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan K.K., MSD, ONO Pharmaceutical, Pfizer Japan Inc., Taiho Pharmaceutical. Y. Ohe: Honoraria, consulting, research funding: AstraZeneca, Chugai, Dainippon Lilly, Ono, BMS Japan, Daiichi Sankyo, BI, Bayer, Ignyta, Pfizer, MSD, Taiho, Novartis, Kyorin, Kyowa Hakko Kirin, Takeda, Celltrion. Y. Rukazenkov: Employee and shareholder: AstraZeneca. P.A. Jänne: Consultancy: AstraZeneca, BI, Pfizer, Merrimack, Roche/Genentech, Chugai, AceaBiosciences, ARIAD Pharma, Ignyta, LOXO Oncology; Stock ownership: Gatekeeper Pharma; Research funding: Astellas, AstraZeneca; IP: EGFR mutations licensed to Lab Corp. All other authors have declared no conflicts of interest.

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      123P - Long term survival analysis of osimertinib in stage IV NSCLC patients harbored acquired EGFR T790M mutation: A real-word study in China (ID 459)

      12:30 - 13:00  |  Presenting Author(s): Shuyuan Wang  |  Author(s): Baohui Han

      • Abstract

      Background

      Aura studies have demonstrated the efficacy of osimertinib in advanced NSCLC patients harbored acquired EGFR T790M mutation. However, the real word data remains rare in China.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      This retrospective study was conducted in Shanghai Chest Hospital. We collected data form stage IV NSCLC patients diagnosed with acquired EGFR T790M mutation. The whole median overall survival (OS) and OS from osimertinib, progression free survival (PFS) of osimertinib were observed.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      A total of 584 patients were tested positive for EGFR T790M mutation either by tissue or blood from Jan 2012 to Dec 2017. Finally, 238 patients (60.1% female, 62.2% 19del, 19.7% smokers) received osimertinib and have enough data to analysis. The median whole OS and OS from osimertinib were 54.8 and 24.33 month, respectively. And PFS of osimertinib was 11.0 month. Patients with 19del have better PFS, OS and whole survival from osimertinb (12 vs 10month, P = 0.054; 24.4 vs 20.27month, P = 0.012; 42.7 vs 60.9month, P = 0.056). The therapy line and EGFR T790M mutation detection methods (tissue or blood) had no impacts on PFS and OS. Additionally, in 63 patients with brain metastases (BM), osimertinib plus local therapy could contribute to the OS (61.3 VS 47.8, p = 0.086). After osimertinib failure, 39 patients benefited from rebiopsy.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      This study gave us information that osimertinib could be a standard therapy in patients with EGFR T790M mutation, these patients have a better prognosis and an indolent progress. In addition, although osimertinib showed good control of BM, local therapy although show be taken into consideration for patients with BM.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      124P - The effect of proton pump inhibitors (PPI) on dacomitinib (DACO) pharmacokinetics and efficacy in non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutation (ID 322)

      12:30 - 13:00  |  Presenting Author(s): Jerry Li  |  Author(s): Dana J Nickens, Keith Wilner, Weiwei Tan

      • Abstract

      Background

      Concomitant use of PPIs has been shown to decrease DACO AUClast and Cmax by approximately 39% and 51% in a healthy volunteer study. ARCHER-1050 (A1050) was a phase 3 study to evaluate DACO as first-line treatment for patients with EGFR-positive advanced NSCLC. A considerable number of patients in A1050 used concomitant PPIs. This analysis evaluates the effects of concomitant PPI use on DACO exposure and progression free survival (PFS) in NSCLC patients treated with DACO using data from A1050.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Steady-state DACO trough concentrations (Ctrough) were collected on Day 1 of Cycles 2-6 (1 cycle = 28 days). Patients started DACO at 45 mg once daily (QD), but were permitted to dose reduce to 30 then 15 mg QD. The geometric mean of Ctrough (CGM) for each patient per dose level was calculated to represent the patient’s Ctrough. Patients who reported using PPIs at least one dose before and at least one dose after starting DACO treatment were grouped as PPI users, while all other patients were grouped as non-PPI users. The DACO exposure, measured as geometric mean of CGM, was compared between the 2 groups. Statistical analyses were performed using the Kaplan-Meier method and Cox Regression adjusted for several confounding factors. All data processing and analyses were conducted in R, version 3.5.1 (R studio).

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Of the 227 patients who were treated with DACO, baseline characteristics were similar between PPI user (n = 28) and non-PPI user (n = 199) groups, except that PPI user group had a higher percentage of non-Asian patients (61% vs. 20%) than the non-PPI use group. DACO exposure was similar in the 2 groups for each dose level. The median PFS values for PPI users and non-users were 13.1 and 14.9 months, respectively. The Cox Regression Model demonstrated no statistically significant difference in PFS (p > 0.05) between the 2 groups.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      PPI use appeared to have no impact on DACO exposure or on PFS in patients with EGFR-positive advanced NSCLC treated with DACO.

      b651e8a99c4375feb982b7c2cad376e9 Clinical trial identification

      The data used in this abstract were from the multinational, multicenter, randomized, open-label, phase III ARCHER 1050 study (NCT01774721).

      7a6a3ffa2dadc03a6151ee2c4d6fa383 Legal entity responsible for the study

      Pfizer.

      213f68309caaa4ccc14d5f99789640ad Funding

      Pfizer.

      682889d0a1d3b50267a69346a750433d Disclosure

      D.J. Nickens, K. Wilner, W. Tan: Employee: Pfizer. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      125P - Elderly patients treated with afatinib in clinical practice: Results from the prospective non-interventional study GIDEON (ID 294)

      12:30 - 13:00  |  Presenting Author(s): Wolfgang Brückl  |  Author(s): Eckart Laack, Cornelius Kortsik, Harald Schaefer, Martin Reck, Angela Maerten, Christopher Hoffmann

      • Abstract

      Background

      Elderly patients are often underrepresented in clinical trials, leading to uncertainties in the treatment of these patients in the clinical routine.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      The prospective non-interventional study GIDEON allows analyzing a German real world patient collective treated with afatinib according to label. This analysis focusses on patients older than 70 years.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Patients older than 70 years account for 44% of the GIDEON study population (n = 67). Main EGFR mutation in this population was Del.19 (n = 43, 64%), followed by L858R und rare mutations (both n = 12, 18%). Brain metastases at baseline were detected in 22% of patients (n = 15). Afatinib dose was reduced in 55% (n = 37) of all patients older than 70 years and in 58% of patients younger than 70 years. The percentage of patients who received a starting dose of afatinib lower than 40mg was higher in the elderly population (n = 25, 37%) compared to patients younger than 70 years (18%). Main Afatinib related side effects of grade 3 or higher were independent of age, with diarrhea (18% in patients <70 years and 15% in patients ≥70 years) as the most frequent adverse drug reactions. Overall response rate was 78% and disease control rate was 93% in the elderly population. PFS rate at one year was 62%.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      With 44% of the whole study population, elderly patients (>70 years) are well represented in GIDEON. Therefore, these data provide important information for the routine clinical use of afatinib in these patients. With an overall response rate of 78% and a PFS-rate of 62% after one year, these data support the use of afatinib in elderly patients. Adverse drug reactions of grade 3 or more were not significantly higher in the elderly group.

      b651e8a99c4375feb982b7c2cad376e9 Clinical trial identification

      NCT02047903.

      7a6a3ffa2dadc03a6151ee2c4d6fa383 Legal entity responsible for the study

      Boehringer Ingelheim.

      213f68309caaa4ccc14d5f99789640ad Funding

      Boehringer Ingelheim.

      682889d0a1d3b50267a69346a750433d Disclosure

      W. Brückl: Fees for consulting and/or lectures: AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Pfizer, Roche, Stratifyer. M. Reck: Honoraria for lectures and consultancy: Hoffmann-La Roche, Lilly, Amgen, Boehringer Ingelheim, Abbot, AstraZeneca, Celgene, BMS, MSD, Merck, Novartis, Pfizer. A. Maerten, C. Hoffmann: Employee: Boehringer Ingelheim. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      126P - Regional retrospective analysis of outcomes of EGFR mutated non-squamous non-small cell lung cancer (NSCLC) patients in West Yorkshire (Now Available) (ID 435)

      12:30 - 13:00  |  Presenting Author(s): Darshan Sharma  |  Author(s): Finbar Slevin, Katy Clarke, Kevin Nicholas Franks, Michael Snee, Pooja Jain

      • Abstract
      • Slides

      Background

      In the UK approximately 10% of all patients diagnosed with NSCLC harbour an Epidermal Growth Factor Receptor (EGFR) mutation. Tyrosine kinase inhibitors (TKI) have been used as first-line treatment for this group of patients since 2009. We performed a retrospective analysis of our regional cohort to assess patient outcomes and document changes in practice over the years.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Electronic paperless notes system (PPM) was used to collect data on 210 patients diagnosed with EGFR mutation positive NSCLC within West Yorkshire from 2009-2018. Information regarding patient characteristics, stage of cancer, treatment, toxicity and outcome was obtained. Descriptive statistics were performed and Graphpad Prism® was used to determine overall survival. Subgroup analyses were performed for exon mutation, performance status, TKI received and year treated.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Of 150 evaluable patients, 114 received first-line TKI, 3 received second-line TKI and 33 received no TKI. Median age was 72 (interquartile range 62-77). 10, 43 and 61 patients had exon 18, 19 and 21 mutations respectively. 93 patients treated with TKI were performance status (PS) 0-2 and 21 PS 3. 49 patients were treated 2009-13 and 65 2014-2018. Of the 33 patients who did not receive a TKI, 14 had no residual disease following another radical treatment modality, 14 were inappropriate for systemic treatment based on PS or EGFR resistance mutation and 2 declined any treatment. Median overall survival for the full cohort was 15.6 months. Statistically non-significant trends towards improved overall survival were seen in patients with PS ≤ 2 versus (vs.) PS 3 (17.8 vs. 9.9 months); exon 19 vs. 21 (19.1 vs. 14.3 months); treatment with Afatinib vs. Gefitinib or Erlotinib (21.3 vs. 12.8 and 13.8 months) and patients treated 2014-2018 vs. 2009-2013 (18.4 vs. 9.9 months). Compared to 2009-2013, in patients treated 2014-2018 Gefitinib use decreased (40 vs. 23) whilst Erlotinib (9 vs. 18) and Afatinib (0 vs. 24) use both increased.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Our real-world data supports the published literature by demonstrating improved outcomes with TKI treatment in patients with exon 19 mutations, better PS and treatment more recently with second generation TKIs.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The Leeds Teaching Hospitals NHS Trust.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      127P - Obesity has an impact on the efficacy of EGFR-TKI in NSCLC patients harbouring EGFR mutation: A real-world study (ID 485)

      12:30 - 13:00  |  Presenting Author(s): Zhen-Yu Ding  |  Author(s): Yue-Yun Chen, Ye Hong, Yang Fu, Li-Ping Tong, Qing Li, Pan-Pan Lin

      • Abstract

      Background

      EGFR-TKI has become the standard-of-care therapy for advanced NSCLC harbouring EGFR mutation. However, the efficacy varies widely, suggestive of other confounding factors. Obesity is related to the etiology, morbidity, and mortality of cancer. However, its impact on the efficacy of EGFR-TKI remains unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      This was a multi-center, real-world study conducted in 3 tertiary referring medical centers. Treatment-naive metastatic NSCLC patients harbouring EGFR mutation who were prescribed with TKI (gefitinib, erlotinib, or icotinib) were enrolled. Body Mass Index (BMI) was proposed as the indicator of obesity. The PFS of all patients were collected and analyzed.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The training cohort (n = 321) consisted consecutive patients in West China Hospital from Sept 2010 to Jul 2018. The total PFS was 12.1m (95%CI: 11.2-13.0m). Those with a high BMI (>22.8) achieved a longer PFS than their counterparts (10.9 and 13.8 m, HR 0.68, 95% CI: 0.54-0.86, P = 0.001). Although the cut-off value was set-up by ROC analysis, the superiority was irrespective of the artificially-defined cut-off value (median 22.9, quadrant value 22.5 or 25). Additionally, the difference was confirmed in an independent validation cohort (n = 108) in 3 tertiary referring medical centers. The PFS was 11.3 and 13.7 m (HR 0.74, 95% CI: 0.61-0.91, P = 0.004). Interestingly, the influence of obesity was restricted in men (HR 0.45, 95% CI: 0.31-0.65, P<0.0001), while not in women (HR 0.89, 95% CI: 0.66-1.2, P = 0.47).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      High BMI is associated with improved outcomes in advanced NSCLC, primarily in men.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      128P - Frequency and types of EGFR mutation in Moroccan patients with non-small cell lung cancer (Now Available) (ID 512)

      12:30 - 13:00  |  Presenting Author(s): mohamed lemine sow  |  Author(s): HIND El Yacoubi1, BADREDDINE Moukafih, SALIF Balde, GLORIA Akimana, SIHAM Elkhoyaali, HALIMA Abahssain, HIND Mrabti, IBRAHIM Elghissassi, HASSAN Errihani

      • Abstract
      • Slides

      Background

      Mutations in the epidermal growth factor receptor (EGFR) gene are commonly observed in non-small-cell lung cancer (NSCLC), particularly in adenocarcinoma histology (aNSCLC). The frequency of EGFR mutations is ethnicity-dependent, with a higher proportion in Asian populations than Caucasian populations. Yet there is a lack of data of these mutations among North African patients. The aim of this study was to report the frequency and types of EGFR mutations in a group of NSCLC Moroccan patients.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Tumor specimens from Moroccan patients with NSCLC were collected, between November 2010 and December 2017 to determine frequency and types of EGFR mutations. Tumors were tested for EGFR by polymerase chain reaction and sequencing of exons 18, 19, 20, and 21.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      A total of 334 patients were consequently enrolled: 242 (72.5%) males and 92 females (27.5%), with a mean age of 61.9 years. 56.9% had a history of smoking, and only the adenocarcinoma histology are considered .EGFR testing of 334 (100%) demonstrated wild typein 261 (78.1%) and mutated EGFR in 73 (21.9%).Mutations were mainly detected in the exon 19 (65.8%), followed by exon 21 L858 (17.8%),exon 21codon (5.5%) and exon 18 (6.8%), whereas mutations in the exon 20 were less frequent(4.1%). In patients with aNSCLC, the detection of EGFR mutation was independently associated with gender (41,3% females Vs.14,5% males; p < 0.001) and smoking status (34.8% non-smokers Vs. 12.9%, p < 0.001).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Our findings confirm the genetic heterogeneity of NSCLC worldwide, reporting frequency of EGFR mutations in NSCLC Moroccan patients intermediate between Asian (50%) and Caucasian (15%) populations. The substantial lack of data from several large geographic regions of the world, notably our region, highlights a potential lack of routine mutation testing and consequent access to EGFR targeted agents, suggesting the need for further research implementations in Morocco.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      129P - Anlotinib can overcome acquired resistance to EGFR-TKIs via FGFR1 signaling in non-small cell lung cancer (Now Available) (ID 336)

      12:30 - 13:00  |  Presenting Author(s): Zengzhi Lian  |  Author(s): Wenwen Du, Jianjie Zhu, Yuanyuan Zeng, Liu zeyi, Jian-an Huang

      • Abstract
      • Slides

      Background

      As a novel multitarget receptor tyrosine kinase inhibitor, anlotinib has been demonstrated to be effective in inhibition of tumor angiogenesis and growth. Interestingly, a subset of advanced non-small cell lung cancer (NSCLC) patients who are refractory to EGFR-TKIs are sensitive to anlotinib treatment, the underlying molecular mechanism remained unclear. Herein, we mainly focus on elucidating the regulatory mechanism treated with anlotinib in overcoming acquired resistance to EGFR-TKIs in NSCLC and thus may develop novel therapeutic strategies for anlotinib aiming at improving the prognosis of patients resistant to TKIs.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      High throughput sequencing analysis, western blot analysis, real-time quantitative reverse transcriptase PCR, RNA interference, CCK-8 and flow cytometry were performed on human NSCLC EGFR-resistant cell lines.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Based on high-throughput sequencing analysis, FGFR1 was highly expressed in gefitinib-resistant cell line when compared to HCC827. In line with the data, anlotinib application obviously inhibitied cell viability, proliferation and promoted apoptosis in HCC827GR cell line. Knockdown of FGFR1 can reverse gefitinib resistance. Research into possible mechanisms indicated that anlotinib treatment down-regulated the phosphorylation levels of Erk and Akt.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Anlotinib can overcome acquired resistance to EGFR-TKIs via inhibiting FGFR1 signaling pathway, which provide a mechanism evidence for the treatment of NSCLC patients.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The First Affiliated Hospital of Soochow University.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      130P - Relationship of clinicopathological characteristics, EGFR genotyping and prognosis in non-small cell lung cancer patients with malignant pleural effusion (Now Available) (ID 469)

      12:30 - 13:00  |  Presenting Author(s): Jing Zhang  |  Author(s): zhang shao Zhou, yun cui Su, tao qi Yu

      • Abstract
      • Slides

      Background

      To investigate the relationship of the clinical characteristics, EGFR genotyping and prognostic factors of malignant pleural effusion associated with non-small cell lung cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      A total of 321 patients hospitalized in Guangxi Medical University Affiliated Tumor Hospital from November 2013 to December 2017 who were pathologically or cytologically confirmed NSCLC with malignant pleural effusion (MPE) were enrolled in the study. The information including clinical features at baseline, pleural effusion status, EGFR genomic alternation, treatment and prognosis for patients were retrospectively extracted and analyzed. The data were analyzed by SPSS 21.0 software. Chi-square test was used for comparison between groups, and Fisher’s exact probability method was used for correction. Survival curves were drawn by Kaplan-Meier method, and the differences between groups were compared by log-rank test. P < 0.05 was considered as statistical significance.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      There were significant differences in M staging, ECOG score and bone metastasis between patients with malignant pleural effusion at initial diagnosis and those with malignant pleural effusion at diseases progression (P < 0.05). The median overall survival for EGFR exon 19 deletion mutation, exon 21 L858R mutation and wild type in MPE patients were 21.8 months, 19.5 months and 11.6 months respectively (P = 0.005). The median overall survival for patients with EGFR sensitizing mutations treated with first- and second- generation EGFR-TKIs and those without TKI treatment was 21.9 months and 12.9 months respectively (P = 0.001). The median overall survival for wild type EGFR patients with simultaneous liver metastasis and non-liver metastasis was 5.8 months and 12.2 months respectively (P = 0.031).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Through comparing clinicopathological characteristics, EGFR genotyping and prognosis in MPE patients, those whose MPE were identified at the time of diagnosis are more frequently a higher incidence of ECOG score and bone metastasis, a longer OS in patients with EGFR mutation and treated with EGFR-TKI, and a significantly lower OS in patients with wild-type EGFR and liver metastasis.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      131P - Upfront whole brain radiotherapy for multiple brain metastases in patients with EGFR-mutant lung adenocarcinoma (Now Available) (ID 268)

      12:30 - 13:00  |  Presenting Author(s): Changhui Li  |  Author(s): Jindong Guo, Lei Zhao, Fang Hu, Wei Nie, Huimin Wang, Xiaoxuan Zheng, Yinchen Shen, Ping Gu, Yujun Zhang, Xueyan Zhang

      • Abstract
      • Slides

      Background

      This study aimed to evaluate the efficacy of upfront whole-brain radiotherapy (WBRT) in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma with multiple brain metastases (BM).

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      195 patients with EGFR mutations who had multiple BM at preliminary diagnosis were included and retrospectively reviewed in this study. Patients were administered for following treatments in a multi-disciplinary setting: upfront WBRT followed by EGFR-TKI, concurrent EGFR-TKI and WBRT and upfront EGFR-TKI followed by WBRT. A disease specific graded prognostic assessment (GPA) was performed for all the patients. The treatment response and overall survival (OS) were evaluated.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The median OS of these patients was 27 months. Objective response rate (ORR) was much better in upfront WBRT group than other two groups (P = 0.004). Moreover, patients receiving upfront WBRT (n = 67) had longer OS than the concomitant group (36 vs. 25 months; P = 0.006) and the upfront EGFR-TKI group (36 vs. 25 months; P < 0.0001). The prognosis of patients with different GPA scores significantly differed (p < 0.0001). In subgroup of concomitant and upfront EGFR-TKI groups, patients with higher GPA scores (2-3) had more favorable prognosis compared with those with lower scores (0-1.5) (27 versus 25 months; P = 0.023). Patients receiving EGFR-TKI concurrently with WBRT had superior OS than those receiving upfront EGFR-TKI with high GPA scores. (37 versus 17 months; P = 0.023).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      The use of upfront WBRT in EGFR-mutated lung adenocarcinoma patients with multiple BM improves ORR and OS. More importantly, patients with high GPA scores are recommended to receive WBRT soon after EGFR-TKI therapy.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      National Natural Science Foundation of China (No.81502450) and Science and Technology Commission of Shanghai Municipality, China (No.18441904700).

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      132P - New insights into acquired resistance mechanisms to third-generation EGFR tyrosine kinase inhibitor therapy in lung cancer (ID 307)

      12:30 - 13:00  |  Presenting Author(s): Jana Fassunke  |  Author(s): Carina Heydt, Sebastian Michels, Bianca Van Veggel, Fabienne Müller, Marina Keul, Marcel A. Dammert, Anna Schmitt, Egbert F. Smit, Stefan Kast, Jürgen Wolf, Reinhard Buettner, Martin L. Sos, Daniel Rauh, Sabine Merkelbach-Bruse

      • Abstract

      Background

      The emergence of acquired resistance (AR) against third-generation epidermal growth factor receptor tyrosine kinase inhibitors (TKI) remain a major clinical challenge in lung adenocarcinoma patients. Here we characterized the role of acquired resistance mechanism with a focus on inter-individual heterogeneity and co-occurring genetic aberrations. We could analyze pre- and post-treatment samples of patients treated with third-generation EGFR TKIs.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We characterized 128 patients, which are EGFR p.T790M positive to early generation EGFR TKIs within thedatabases of the Network Genomic Medicine (NGM), the NOWEL network, the Department of Thoracic Oncology of the Netherlands Cancer Institute and the Vall d’Hebron University Hospital. In 60 patients, corresponding analyses of third generation EGFR TKI treatment outcomes and molecular analyses were practicable.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Co-occurring aberrations were found in 75% of the samples with acquired resistance to early-generation TKI. TP53mutations were the most frequent aberrations detected. In MET, copy number variants were found (n = 6). In a subgroup, we identified 4 patients with the new EGFRresistance mutation p.G724S after third-generation TKI treatment. Still, loss of the EGFRp.T790M mutation and METamplification are the most common aberrations after third-generation TKI treatment.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      EGFR inhibitors represent a powerful tool for precision cancer medicine in genetically selected patients. We could show in this study that additional genetic aberrations are frequent in the setting of AR to EGFR TKIs and may mediate innate and acquired resistance to third-generation EGFR TKIs. Amplification of METwas strongly associated with primary treatment failure and thus the strongest factor in innate resistance. AR to third-generation EGFR TKI (p.G724S) can possibly be overcome with second-generation EGFR TKI.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Deutsche Forschungsgemeinschaft, Cluster of Excellence RESOLV, the Bundesministerium für Bildung und Forschung, Else Kröner-Fresenius Stiftung, Deutsche Krebshilfe, European Union, (NRW) as part of the EFRE initiative (EMODI, grant no. EFRE-0800397 to R.B. and M.L.S.) and by the German Ministry of Science and Education (BMBF) as part of the e:Med program (grant no. 01ZX1303A to R.B. and J.W). E.F. received funding by the Instituto de Salud Carlos III (PI17/00938), NEGECA, ITMC of TU Dortmund.

      682889d0a1d3b50267a69346a750433d Disclosure

      J. Fassunke: Honoraria: AstraZeneca. C. Heydt, S. Merkelbach-Bruse: Speaking honoraria: AstraZeneca. J. Wolf: Consulting, lecture fees: AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Ignyta, Lilly, MSD, Novartis, Pfizer, Roche; Funding for scientific research: BMS, Johnson&Johnson, MSD, Novartis, Pfizer. R. Buettner: Employee: Targos Molecular Pathology. M.L. Sos: Commercial research grant: Novartis. D. Rauh: Consultant, lecture fees: AstraZeneca, Merck-Serono, Takeda, Pfizer, Novartis, Boehringer Ingelheim, Sanofi-Aventis. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      133P - A study evaluating the different treatment modalities for EGFR mutation positive advanced NSCLC patients that acquire c-MET amplification after EGFR TKI therapy resistant (Now Available) (ID 176)

      12:30 - 13:00  |  Presenting Author(s): Jingjing Qu  |  Author(s): Li Liu, Jianfu Heng, Chunhua Zhou, Yi Xiong, Wenjuan Jiang, Nong Yang

      • Abstract
      • Slides

      Background

      c-MET amplification was one of the major important mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Whereas, once the patient acquired c-MET amplification combined with EGFR mutation after EGFR-TKI resistant, the most optimal treatment strategy is remains controversial. Our study proposed an optimal treatment strategy for EGFR mutant NSCLC patients who acquired c-MET amplification after EGFR TKI resistance.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Patients with EGFR mutant NSCLC acquiring c-MET amplification, detected from a re-biopsy performed after progression on EGFR-TKI, were identified in Hunan Cancer Hospital. Clinical data were retrospectively collected.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Between March 2015 and July 2018, 393 patients were screened and 30 of them were enrolled. EGFR status prior to the initiation of first line therapy was not associated with sex, age and smoking status. After patients developed resistance to EGFR-TKI, the re-biopsy was performed. 30 patients with c-MET amplification and EGFR mutation and received different treatment. The median PFS between c-MET inhibitors(c-METi) combined EGFR-TKI versus c-MET inhibitors were 4.0 months and 1.5 months (HR:0.07; 95% CI, 0.01 to 0.35; P = 0.003), respectively. The PFS in the chemotherapy group was 3.0m and without significance compared to c-METi combined EGFR-TKI group or c-METi monotherapy group. The objective response rates for patients treated with a combination of c-METi and EGFR-TKI, chemotherapy alone and c-METi alone were 58.8%, 14.3% and 16.7%, respectively.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      This study, comparing the ORR and PFS of EGFR-mutant patients after acquiring c-MET as the major resistance of EGFR-TKI, suggests that a combination of c-METi and EGFR-TKI maybe the best optimal treatment.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Hunan Provincial Tumor Hospital.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      134P - Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors (ID 297)

      12:30 - 13:00  |  Presenting Author(s): Svenja Wagener  |  Author(s): Carina Heydt, Juliane Sueptitz, Sebastian Michels, Markus Falk, Christina Alidousty, Jana Fassunke, Markus Tiemann, Lukas Heukamp, Jürgen Wolf, Reinhard Buettner, Sabine Merkelbach-Bruse

      • Abstract

      Background

      Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors Over the past years, EGFR tyrosine kinase inhibitors (TKI) revolutionized treatment response. 1st-generation (reversible) EGFR TKI later the 2nd –generation irreversible EGFR TKI Afatinib was aimed to improve treatment response. Nevertheless, diverse resistance mechanisms develop within the first year of therapy. Here, we evaluate the prevalence of acquired resistance mechanisms towards reversible and irreversible EGFR TKI.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Rebiopsies of patients after progression to EGFR TKI therapy (>6months) were targeted to histological and molecular analysis. Multiplexed targeted sequencing (NGS) was conducted to identify acquired resistance mutations (e.g. EGFR p.T790M). Further, Fluorescence in situ hybridisation (FISH) was applied to investigate the amplification status of bypass mechanisms like, MET or HER2.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      123 rebiopsy samples of patients that underwent firts-line EGFR TKI therapy ( PFS >6months) were histologically and molecularly profiled upon clinical progression. The EGFR p.T790M mutation ist the major mechanism of acquired resistance in patients treated with reversible as well as irreversible EGFR TKI. Nevertheless a statistically significant difference for the acquisition of T790M mutation has been idientified: 45% of afatinib- vs 65% of reversible EGFR TKI treated patients developed a T790M mutation (p-value 0.02). Progression free survival (PFS) was comparable in patients treated with irreversible EGFR irrespective of the sensitising primary mutation or the acquisition of p.T790M.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      The EGFR p.T790M gatekeeper mutation ist he most prominent mechanism of resistance to reversible and irreversible EGFR TKI therapy. Nevertheless there is a statistically significant prevalence of p.T790M acquisition between the two types of TKI, which might be of importance for clinical therapy decision.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Boehringer Ingelheim.

      682889d0a1d3b50267a69346a750433d Disclosure

      S. Wagener-Ryczek: Honoraria: Boehringer Ingelheim. C. Heydt: Honoraria: AstraZeneca, BMS, Illumina. S. Michels: Honoraria: Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim; Advisory roles: Boehringer Ingelheim, Pfizer; Research funding: Pfizer, Novartis, BMS; Travel support/accommodations: Novartis. J. Fassunke: Honoraria, advisory role: AstraZeneca. M. Tiemann: Honoraria: Pfizer, Novartis, Roche. L. Heukamp: Co-founder: Neo New Oncology. J. Wolf: Honoraria: AstraZeneca, BMS, Clovis Oncology, Lilly, MSD, Novartis, Pfizer, Roche; Advisory roles: AstraZeneca, BMS, Clovis Oncology, Lilly, MSD, Novartis, Pfizer, Roche, Amgen. R. Buettner: Co-founder, Chief Scientific Officer: Targos Molecular Pathology; Honoraria: Roche, Pfizer, Novartis, AstraZeneca, Qiagen, MSD, BMS, Lilly. S. Merkelbach-Bruse: Honoraria: AstraZeneca; Advisory roles: AstraZeneca, Roche. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      135P - EGFR &#x00026; PD L1: An (im)perfect union (ID 566)

      12:30 - 13:00  |  Presenting Author(s): Ullas Batra  |  Author(s): Mansi Sharma, Parveen Jain, Sneha Bothra, Sunil Pasricha

      • Abstract

      Background

      EGFR inhibitors are associated with durable responses in patients harboring EGFR mutations. Also, Immune checkpoint inhibitors are associated with higher response rates with increasing PDL1 levels. PDL1 positivity in EGFR mutant metastatic non small cell lung cancer(mNSCLC) is known to portend poor prognosis due to resistance to TKI. However, the data regarding the same is scarce. This study was done as a retrospective analysis of treated cases of EGFR mutant mNSCLC with PDL1 levels done on the archival biopsy (first biopsy) specimen, which was used for diagnosis.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      The study was conducted on 121 NSCLC patients who had previously been diagnosed with EGFR mutation by RT PCR method. PDL1 testing was carried out by SP 263 kit.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The median age of presentation was 57 years, and 47% (n = 57) patients were aged 40-60 years. There were with 55 % males (n = 67), 86 % (n = 104) of all patients were non smokers. PDL1 was positive in 38.8 % (n = 47) patients, with 12.4 % (n = 15) patients having PDL1 ≥ 50%. PDL1 positivity was not significantly different among gender, smoking status or age or various EGFR mutations. Of all the patients, 15 patients did not take therapy. So survival analysis was possible only for 106 patients. Progression free survival (PFS) for PDL1 negative patients was 11 months (95% C.I. 8.6-13.6 months), while for PDL1 positive patients was 13 months (95% C.I. 6.3-19.6 months) p = 0.986 (not significant). The analysis also showed that PFS in patients with PDL1 positive with DEL 19 mutation was 15 months v/s7 months in L858R mutation(p = 0.09). In PDL1 negative patients, PFS was 12 months v/s 10 monthsin Del 19 v/s L858R mutation.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      The present study showed a higher PDL1 positivity rate in EGFR mutant patients than what is previously reported. Also, the median PFS was not stastically different in PDL1 negative vs PDL1 positive patients. This is in contradiction to data previously presented. However, it could also be due to the fact that most of our patients were non smokers and could also represnt a geographic variation in PDL1 expression. Further studies are warranted to clarify this data.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Ullas Batra, Sunil Pasricha.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      136P - Correlation of molecular status and anatomic sites of metastases at diagnosis of EGFR positive non-small cell lung cancer (NSCLC): A single institution experience (ID 462)

      12:30 - 13:00  |  Presenting Author(s): Kristina Krpina  |  Author(s): Bernard Budimir, Suzana Kukulj, Ante Marušić, Marko Jakopović, Miroslav Samaržija

      • Abstract

      Background

      A significant proportion of NSCLC patients carry mutations in the epidermal growth factor receptor (EGFR) kinase domain, in most cases with the presence of a deletion mutation in exon 19 or L858R point mutation. The aim of our analysis was to examine the patterns of metastatic spread in IV stage nsclc and whether it varies by EGFR mutation status.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      All patients (pts) with stage IV NSCLC from 2014-2017, without a recent history of cancer, were diagnosed at our department in which anatomic sites of metastasis, before initial treatment, were recorded. Tumor tissues were further processed, and data on molecular testing (EGFR; ex19, ex 20, ex21 L858R) were extracted. Correlation between molecular status and anatomic sites of mets was assessed.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      We reviewed 206 pts with stage IV NSCLC, EGFR positive. Further molecular analysis: Ex 19 (n = 118 + 57.2%), Ex 20 ( n = 20 + 9.7%) , Ex 21 L 858R (n = 69; 33.4%). Most frequent mets sites were bone (28.2%), lung (27.9%), brain (22.8%) and supraclavicular lmph (18.2%). Pts with Ex20 had more brain mets (38.9% ) than pts with ex21 (7%), for ex 20 no significant result. Statistic significance was Ex20 with lymp supraclavicular (p = 0.006), Ex20 with effusion pericardi (p = 0.021). Interesting Ex21 L858R with meta hepatis (p = 0.044) and Ex19with meta hepatis (p = 0.083).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Molecular status of NSCLC is associated with biological behavior. Most frequent meta site were bone, at diagnosis 39.2% of EGFR + pts. Because of better prognosis for EGFR+ pts screening and prevention of skeletal-related events in NSCLC pts is reasonable.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Kristina Krpina.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      137P - Detection and clinicopathologic features of ctDNA in T790M-positive advanced lung adenocarcinomas patients after failure of treatment with first- and second-generation EGFR-TKIs (ID 359)

      12:30 - 13:00  |  Presenting Author(s): wei he  |  Author(s): zhang shao Zhou, tao qi Yu, hua wen Zhao, yun cui Su, ping ai Zeng

      • Abstract
      • Slides

      Background

      We aimed to detect ctDNA in patients with advanced lung adenocarcinomas after failure of treatment with first- and second-generation EGFR-TKIs and to analyze it’s clinicopathologic features in a subset of patients harbouring the T790M mutation.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We retrospectively collected data from November 2016 to October 2018 in patients with lung adenocarcinomas who had been analysed by Next-Generation Sequencing or ddPCR after progression on EGFR-TKIs at GuangXi Medical University Affiliated Tumor Hospital. Statistical analyses were performed to examine the associations between clinicopathologic features and acquired T790M mutation in patients.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      A total of 72 plasma samples were collected, of which 17 had matched tissue biopsies. Of these patients, 48 were analysed by NGS and the rest by ddPCR. The T790M mutation was detected in 43 cases (59.7%). We found this mutation was higher than that of mPFS>11.5 months (79% vs. 44%; odds ratio, 4.516; 95%CI, 1.53 to 13.30; p=0.006), and in which longer median PFS (13.0 months vs. 9.0 months; p = 0.042). Those who received chemotherapy before EGFR-TKIs were more likely to have the T790M mutation (80% vs. 53%, p=0.03) compared to those who received EGFR-TKIs in the first-line. In this study, the occurrence of T790M mutation in patients with L858R mutation was higher than seen in patients with 19-del (65% vs.57%; p=0.809). Among 17 patients who were sequenced by NGS in both samples, 7 had T790M positive blood samples and 8 were T790M positive in tissue biopsies. The coincidence rate was 94%.10 cases after the progression of the third generation TKI treatment. Three cases of T790M with C797S cis-mutation were detected and 3 cases with PIK3CA, BRAF V600E and MAP2K1 mutations, respectively. Secondary resistance mutations were not detected by NGS in 4 cases.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Patients with advanced lung adenocarcinomas harbouring the T790M mutation who failed with first- or second-generation EGFR-TKIs were more likely to have longer mPFS. In this study, NGS testing using ctDNA was a feasible means for monitoring acquired resistance mutations during or after progression on targeted therapy.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Cancer Hospital of Guangxi Medical University.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      138P - PD-L1 confers primary resistance to EGFR-TKI in EGFR mutant non-small cell lung cancer via inducing EMT phenotype (Now Available) (ID 356)

      12:30 - 13:00  |  Presenting Author(s): Yang Zhang  |  Author(s): Ting Liu, Yuanyuan Zeng, Jianjie Zhu, Wenwen Du, Liu zeyi, Jian-an Huang

      • Abstract
      • Slides

      Background

      There were approximately 30% of patients with epidermal growth factor receptor (EGFR)-activating mutations do not respond to EGFR- tyrosine kinase inhibitors (TKIs) (primary resistance). However, little is known about the molecular mechanism involved in primary resistance to EGFR-TKIs in EGFR-mutant non-small-cell lung cancer (NSCLC). Programmed death ligand-1 (PD-L1) (B7-H1, CD274) is an important immune co-signaling molecule from the B7/CD28 family, it not only negatively regulates T cell functions through its PD-1 and CD80 interactions, but also plays important regulatory roles in intracellular functions and leads to acquired resistance to EGFR-TKIs in NSCLC. Here, we investigated that mechanistic role of PD-L1 in primary resistance to EGFR-TKIs in EGFR-mutant NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      The mRNA expression level of PD-L1 was detected using real-time quantitative reverse transcriptase PCR. Molecular manipulations (overexpression or silencing) were performed to investigate the effect of PD-L1 expression on sensitivity to gefitinib in vitro, and a xenograft mouse model was used for in vivo confirmation. Migration and invasion assay were used to determine EMT phenotype.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The mRNA expression level of PD-L1 was consistent with IC50 value for gefitinib in H1975, HCC827 and PC-9 cell line. Overexpression of PD-L1 decreased the sensibility to gefitinib, in addition, knockdown of PD-L1 increased the sensibility to gefitinib in vitro. Furthermore, Overexpression of PD-L1 attenuated sensitivity to gefitinib in a xenograft mouse model. Overexpression of PD-L1 leaded to primary resistance to gefitinib through inducing EMT phenotype.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      PD-L1 contributes to primary resistance to EGFR-TKI in EGFR mutant non-small-cell lung cancer, which may be mediated by inducing EMT phenotype.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The First Affiliated Hospital of Soochow University.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      139P - Real-world immuno-oncology (IO) therapy treatment patterns and outcomes in patients with anaplastic lymphoma kinase positive (ALK&#x0002B;) non-small cell lung cancer (NSCLC) in the United States (ID 382)

      12:30 - 13:00  |  Presenting Author(s): Xiaoyun Pan  |  Author(s): Mark M Lin, Yu Yin, Peijie Hou, Pia Baumann, Mohammed Jahanzeb

      • Abstract
      • Slides

      Background

      Cancer immunotherapies are new treatment options in advanced NSCLC. Evidence of IO therapy efficacy in tumors with activating mutations, such as ALK rearrangements, is lacking. This retrospective study describes the characteristics of ALK+ NSCLC patients treated with IO therapy and assesses treatment outcomes (time to treatment discontinuation, real-world progression-free survival [rwPFS], overall survival [OS]).

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      The Flatiron Health Electronic Health Record (EHR)−derived database (Jan 2011−Sep 2017) was used to identify patients with advanced ALK+ NSCLC who had received ≥1 ALK TKI and IO therapies (nivolumab, pembrolizumab, atezolizumab). Discontinuation of IO therapy was defined as switch to an ALK TKI or chemotherapy, death, or gap between last IO therapy administration and last follow-up date of > 120 days. rwPFS was estimated as the time from treatment initiation to progression (abstracted from clinician notes and radiology reports) or death. Time to discontinuation, rwPFS, and OS were analyzed using Kaplan-Meier methods.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Of 335 ALK+ NSCLC patients with follow-up between Jan 2015−Sep 2017, 32 (9.5%) patients were treated with IO therapy. Median age was 62.5 years, with 78.1% of patients diagnosed at stage IV, and 24 patients receiving nivolumab. Of the 32 IO treated patients, 15.6% received IO therapy before first ALK TKI, and 59.4% were treated with IO therapy after ≥2 ALK TKIs. Median (95% CI) time to discontinuation of IO therapy was 1.88 months (0.95 − 2.80), rwPFS was 2.17 months (1.18 − 2.93), and OS was 6.71 months (2.80−NE).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      We identified ALK+NSCLC patients who received IO therapy; most of whom were treated post ALK TKI. Time to discontinuation of IO therapy was short, and real-world effectiveness (rwPFS and OS) was limited. These results point to IO therapy’s relative futility in ALK+ NSCLC patients. Compared to IO therapy, several approved ALK inhibitors have shown better effectiveness in both first and later lines of therapy. However, the optimal sequencing of ALK inhibitors with other therapies, including chemotherapy and IO therapy, remains unclear.

      b651e8a99c4375feb982b7c2cad376e9 Editorial acknowledgement

      Jane Kondejewski, PhD of SNELL Medical Communication, Inc.

      934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study

      Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

      213f68309caaa4ccc14d5f99789640ad Funding

      Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

      682889d0a1d3b50267a69346a750433d Disclosure

      M.M. Lin: Employer: Millennium Pharmaceuticals, Inc. a wholly owned subsidiary of Takeda Pharmaceutical Company limited, which funded this study. X. Pan, Y. Yin, P. Hou, P. Baumann: Employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited which funded this study. M. Jahanzeb: Research Grant: Lilly, Boehringer Ingelheim, Callisto; Research Grant, consultant: Millennium/Takeda, Novartis, Ipsen, Roche/ Genentech, Pfizer.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      140P - Brigatinib experience on the ALK project (ID 576)

      12:30 - 13:00  |  Presenting Author(s): Fabio Gomes  |  Author(s): Nadza Tokaca, Kent Yip, Sharmistha Ghosh, Thomas Newsom-Davis, Alastair Greystoke, Henrietta Mills, Samreen Ahmed, Amelie SM Harle, Gareth Ayre, Riyaz Shah, Sanjay Popat, Fiona Helen Blackhall, Yvonne Summers

      • Abstract

      Background

      The ALK Project established a network across the UK with the aim to analyse treatment patterns/outcomes and promote collaborations and research. The treatment pathway for ALK+ patients has been revolutionised in recent years.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      A multicentre retrospective analysis across 32 NHS hospitals/trusts identified 196 ALK+ non-small cell lung cancer (NSCLC) patients who were offered treatment by Dec-2018. Patients who received brigatinib during their treatment pathway were selected. The primary aims were 2-years overall survival (OS) and median OS from start of brigatinib. The secondary aims were objective response rate (ORR), incidence of grade 3-4 toxicity and 5-years/median OS from diagnosis of advanced NSCLC.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      A total of 50 patients were included with 48% being males, 70% never smoked tobacco and the median age at diagnosis was 50 years. 66% of patients developed brain metastasis at some point during their care and 52% had brain metastasis at the start of brigatinib. Brigatinib was used as the first, second or subsequent ALK inhibitor in 18%, 50% and 32% of cases, respectively. 82% of patients were exposed to other ALK inhibitors during their treatment pathway and 46% received chemotherapy prior to the start of any ALK inhibitor. On a median follow-up (since start of brigatinib) of 10 months, patients stayed on brigatinib for a median of 9 months (95% CI, 3.1-14.9), reaching 14 months (95%CI 11.0-19.9) if no brain metastasis (p = 0.15). The overall ORR was 64% and the incidence of grade 3-4 toxicity was 16%. Median OS from start of brigatinib was not reached and the 2-years OS according to brain metastasis was 61% or 83%, in favour of those without brain metastasis (p = 0.037). The median OS from diagnosis of advanced NSCLC was not reached and the 5-years OS was 55%.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Brigatinib is well tolerated and an effective treatment even in heavily pre-treated patients or in those with brain metastasis. A nationwide collaboration is possible and revealed the remarkable survival improvements for ALK+ patients with the development of newer generations of ALK inhibitors.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The Christie NHS Foundation Trust.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      141P - Effect of central nervous system (CNS) metastases in a real-world multicenter cohort study of Spanish ALK-positive non-small cell lung cancer (NSCLC) patients (p) (ID 565)

      12:30 - 13:00  |  Presenting Author(s): Laura Angelats  |  Author(s): Maria Rosario Garcia Campelo, Reyes Bernabe Caro, Edurne Arriola Aperribay, Virginia Calvo de Juan, Andrés Barba Joaquín, Nuria Vinolas Segarra, Maria de los llanos Gil Moreno, Laia Vilà Martinez, Oscar Jose Juan Vidal, Noelia Vilariño Quintela, Manuel Cobo, Elia Sais, Manuel Domine Gomez, Natalia Fernandez Nuñez, Juan Coves Sarto, Raquel Marse Fabregat, Ana Maria Esteve Gomez, Delvys Rodríguez-Abreu, Enric Carcereny Costa

      • Abstract
      • Slides

      Background

      CNS is a common site of metastases in patients with ALK-positive NSCLC. CNS metastases are associated with a number of deleterious effects, such as reduction in quality of life. However, the relationship between brain metastases and prognosis remains unclear. We aimed to evaluate the effect of CNS metastases on overall survival (OS) in a multicenter cohort of Spanish ALK-positive NSCLC patients diagnosed between 2008 and 2017.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We included patients with stage IV at diagnoses, followed up to April 2018; OS (months [m]) was estimated with the Kaplan-Meier method. Survival curves were compared between groups of patients using the log-rank test. Hazard risk (HR) to death was estimated with multivariable Cox model.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Out of 163 patients in the cohort, a total of 116 were evaluated, with a median of follow-up of 29.2 m and 59 deaths reported. Characteristics at diagnosis were a median age of 58 years, 50% female, 58.6% never-smokers, 54.3% with comorbidities, PS by ECOG 0-1 93.1%. CNS metastases (median number of lesions 6) were present in 43.1% of patients and 34% of patients with CNS metastases were treated with local therapy (11.8 % local radiotherapy and 76.5% holocraneal radiotherapy). ALK inhibitors as first line and second line treatment were administered to 45.5% and 78.6% of patients, respectively. The median OS was 39 months; OS in patients with CNS metastases at diagnosis was 34.4 m and 39.0 m in those without CNS metastases at diagnosis (p=.9). In patients without CNS metastases at baseline (n=60), 22 developed CNS, with a median OS greater than in those without CNS metastases during follow-up, although the difference is not significant (45.5 m vs 33.3 m; p=.9). There were 81 patients who presented with metastases in more than one organ and 33 patients with metastases in a single organ. The risk of death increased as the number of metastatic organs at diagnoses increased (HR=1.26, p=.0305), with worse OS in those presenting with liver metastases at diagnoses (21.1%, OS: 20 m), compared to those without tumor involvement (OS: 45.4 m; p =.008).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      OS was similar for ALK-positive NSCLC patients with and without CNS metastases at diagnoses. OS was worse as the number of metastatic organs at diagnosis increased, with liver metastases being associated with the highest risk of mortality.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Catalan Oncology Institute.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      142P - Clinical management of advanced lung adenocarcinoma with ALK rearrangement: Real-world treatment outcomes and long-term survival (ID 546)

      12:30 - 13:00  |  Presenting Author(s): Bo Zhang  |  Author(s): Shuyuan Wang, Jianlin Xu, Yanwei Zhang, Xueyan Zhang, Jie Qian, Jun Lu, RONG Qiao, Wei Nie, Lele Zhang, Yiming Zhao, Minjuan Hu, Wei Zhang, Bao-Hui Han

      • Abstract

      Background

      Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have been demonstrated to be effective in ALK-rearranged, advanced lung adenocarcinoma patients. However, data from a real-world setting is very limited. The aim of the study was to: a) determine long-term survival in these patients and investigate factors associated with their prognosis; and b) analyze the clinical outcomes of patients who were sequentially treated with next-generation ALK-TKIs.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      ALK-rearranged, advanced lung adenocarcinoma patients who were treated with crizotinib were included between January 2013 and December 2016. Progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method. The hazard ratio (HR) for the risk of progression or death was calculated using multivariate Cox regression model.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      A total of 5286 patients were screened and 176 eligible patients were included. Median PFS and OS were 12.4 months (95% CI, 10.3-14.6 months) and 45.6 months (95% CI, 37.6-53.7 months), respectively. 36.3% of patients were 5-year survivors. Extrathoracic metastasis before crizotinib treatment was independently associated with worse PFS (HR, 1.77, 95% CI, 1.24-2.53, P < 0.01) and OS (HR, 1.61, 95% CI, 1.02-2.54, P = 0.04). 45 patients were sequentially treated with newer-generation ALK-TKIs, obtaining a statistically longer OS (54.8 months, 95% CI, not calculable) than patients who were solely treated with crizotinib during clinical management (36.6 months, 95% CI, 29.2-43.9 months, P < 0.01).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Our study provides useful information about ALK-rearranged, advanced lung adenocarcinoma patients treated with ALK-TKIs in a real-world setting.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      143P - Role of radiotherapy in management of brain metastases in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC): A single-center retrospective study (ID 257)

      12:30 - 13:00  |  Presenting Author(s): Yiming Zhao  |  Author(s): Bo Zhang, Yanwei Zhang, Shuyuan Wang, Jie Qian, Bao-Hui Han

      • Abstract

      Background

      Targeted therapies provide benefits in ALK-rearranged patients with brain metastases (BM). However, role of radiotherapy in these patients hasn’t been established. This study sought to determine if upfront radiotherapy in combination with targeted therapies can impact patient outcomes.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      A total of 60 ALK-rearranged patients with BM were included for analysis. 34 patients developed BM prior to TKIs: 20 patients received radiotherapy followed by crizotinib and 14 received upfront crizotinib. 26 patients developed BM while receiving crizotinib: 13 patients were treated with crizotinib beyond progression after brain radiotherapy and 13 received next-generation TKIs with or without radiotherapy. Overall survival (OS) and intracranial time to progression (IC-TTP) were calculated from the date of BM.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Among patients with BM prior to TKIs, upfront radiotherapy cohort had longer IC-TTP (22.9 vs 8.9 months; p = 0.022) and longer OS (28.6 vs 23.3; p = 0.024) compared to upfront crizotinib cohort. Of patients who developed BM while receiving crizotinib, continuation of crizotinib plus radiotherapy for those without extracranial progression can give another intracranial progression-free time. However, next-generation TKIs cohort showed superior median IC-TTP compared to crizotinib beyond progression (11.4 vs 7.2 months; p = 0.006). Patients treated with radiotherapy followed by second TKIs even had much longer IC-TTP (21.8 vs 7.2 months; p = 0.009), though median IC-TTP of second TKIs without radiotherapy failed to reach statistical significance compared with crizotinib beyond progression (10.4 vs 7.2 months; p = 0.1).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Upfront radiotherapy provided better outcomes for ALK-positive patients who developed BM before TKIs and during treatment of crizotinib, and should be considered.

      b651e8a99c4375feb982b7c2cad376e9 Editorial acknowledgement

      We would like to acknowledge all the patients and their families for their contributions to this study.

      934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      144P - Clinical and treatment features associated with improved 5-year survival rate in ALK-positive lung cancer treated with ALK-TKIs (ID 329)

      12:30 - 13:00  |  Presenting Author(s): Antonio Passaro  |  Author(s): Arsela Prelaj, Gianluca Spitaleri, Ester Del Signore, Giovanna Rossi, Elena Guerini-Rocco, Massimo Barberis, Chiara Catania, Filippo de Marinis

      • Abstract
      • Slides

      Background

      ALK rearrangement predicts for prolonged survival in pts with metastatic NSCLC treated with ALK TKIs. Long-term survival, however, remains undefined in a real-world population. The objective of this study was to determine the 5-years survival in these patients and identify clinical factors associated with OS improvement.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Pts with ALK-rearranged metastatic NSCLC who had been treated with ALK TKIs at European Institute of Oncology between 2013 and 2018 were retrospectively reviewed and analyzed for efficacy outcomes.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Among 105 pts, mPFS and mOS were 13.6 mos (95% CI: 9.8 – 17.3) and 40.4 mos (95% CI: 33.6 – 47.1), respectively. 5-year survival rate was 21%, and more than half of overall pts population (51.4%) were treated with different ALKis for more than 3 yrs. The 55.2%, 42.8% and 2% of pts received one, two or three TKIs, respectively. In 99 pts, crizotinib was the first ALKi used with a mPFS of 13.6 (9.8 - 17.3) mos. Univariate analysis showed a positive correlation between mOS and age (< vs ≥ 65 yrs) (42.9 vs 36.3 mos; HR = 0.58, 95% CI: 0.34 – 0.98, p = 0.042), ECOG PS 0/1 vs 2 (44.4 vs 18.4 mos; HR = 0.23, 95% CI: 0.12 – 0.44, p < 0.001) and absence of baseline brain metastases (44.5 vs 22.9 mos; HR = 0.59, 95% CI: 0.35 – 0.97, p = 0.04). Multivariate analysis, adjusted for age, sex, smoking status and ECOG PS, showed that over young age (< 65) and good ECOG PS (0/1), the number of the metastatic sites (< 3 vs ≥ 3) (54.1 vs 36.3 mos; HR = 0.58, 95% CI: 0.34 – 0.98, p = 0.045) and the use of RT for oligoprogression/palliative management (48.4 vs 36.3 mos; HR = 0.58, 95% CI: 0.35 – 0.95, p = 0.033) were significantly associated with prolonged OS. Median IC-PFS was 40 (23.6 – 56.3) mos. Pts without baseline brain metastases reported a significantly longer IC-PFS (55.0 vs 17.3 mos, IC95% HR 0.51, p = 0.029).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      In this broad real-world population, the clinical benefit was consistent with a 5-year survival of 21%. The absence of brain metastases, the use of palliative RT and the tumour burden resulted as independent positive prognostic factors associated with a statistically significant improvement of prolonged survival. Based on these findings, clinicians can gain an enhanced estimation of long-term outcomes in this population.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      145P - Clinicopathological characteristics and outcome of advanced ROS1-positive non-small cell lung cancer in Asian patients (ID 332)

      12:30 - 13:00  |  Presenting Author(s): Cleon Kho  |  Author(s): Darren Wan-Teck Lim, Daniel Shao Weng Tan, Wan Ling Tan, Tanujaa Rajasekaran, Amit Jain, Chee Keong Toh, Mei-Kim Ang, Eng Huat Tan, Quan Sing Ng

      • Abstract

      Background

      ROS1 rearrangement is a rare and distinct molecular subset of non-small cell lung cancer (NSCLC), sensitive to tyrosine kinase inhibitors (TKI) targeting the ROS1 kinase domain. We describe the prevalence, clinicopathological characteristics and clinical outcomes of advanced ROS1 positive NSCLC patients (pts), including concomitant mutations and brain metastases.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We reviewed 1733 consecutive NSCLC pts from the Lung Cancer Consortium Singapore database, reflex tested for ROS1 rearrangement using break-apart fluorescence in situ hybridization. Clinical data including pts characteristics, concomitant mutations, incidence of brain metastasis, response to chemotherapy or TKIs, were retrospectively analyzed.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      We identified 34 pts (2.0%) with ROS1 positive NSCLC; median age 52 years (range 28-76), 19 males (55.9%), 26 pts (76.5%) never smoked. A patient with stage I was excluded from outcome analysis. All had adenocarcinoma histology. 8 pts (23.5%) had brain metastases at diagnosis and 6 developed brain metastases during treatment. 6 pts (17.6%) harbored concomitant EGFR mutations; 2 (9.1%) had cMET mutations; 1 had EGFR L858R, cMET and ROS1 alterations simultaneously. 8 of 13 pts (61.5%) had PD-L1>1%. Median overall survival (OS) for all pts was 29.3 months (mths). In the first line, 13 pts received chemotherapy; 11 pemetrexed-based with a response rate (RR) of 78% and 2 gemcitabine-based with a RR of 50%. Progression free survival (PFS) was 9.8 mths and OS was 30.6 mths. Ten pts received ROS1 TKIs (9 crizotinib, 1 entrectinib) as first line with RR 80%, PFS 9.9 mths, and OS 23.7 mths. For second line, 7 pts received chemotherapy, 4 were pemetrexed-based (RR 100%) and 3 were gemcitabine-based (RR 0%), 8 pts received ROS1 TKIs (6 crizotinib, 2 ceritinib) (RR 57%). 3 pts with PD-L1>1% received pembrolizumab without objective response.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      ROS1-positive NSCLC has unique clinicopathological characteristics, high rate of brain metastases and concomitant mutations. Despite effective and durable responses to ROS1 TKI and pemetrexed chemotherapy, optimal treatment sequence remains to be explored and the role of immune checkpoint inhibitors is uncertain.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      146P - Clinical significance of ROS1 5&#x02019; deletions detected by FISH and response to crizotinib (ID 399)

      12:30 - 13:00  |  Presenting Author(s): Filippo Gustavo Dall'Olio  |  Author(s): Giuseppe Lamberti, Elisa Capizzi, Elisa Gruppioni, Francesca Sperandi, Annalisa Altimari, Francesca Giunchi, Michelangelo Fiorentino, Andrea Ardizzoni

      • Abstract

      Background

      ROS1-rearranged non-small cell lung cancer (NSCLC) patients (pts) are eligible for crizotinib therapy. Diagnosis is based on break-apart fluorescence in situ hybridization (FISH), as for ALKrearrangements, and include 5’ deletions. We report assessment of ROS15’ deletion by FISH and next-generation sequencing (NGS) and outcome of crizotinib treatment.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We included all consecutive NSCLC pts treated at our Institution with: i) diagnosis of 5’ ROS1 gene fusion by break-apart FISH (≥15% of tumor cells with any 5’ deletion pattern); ii) availability in the samples of at least 50 ng of extracted RNA with at least 50% tumor cell enrichment; iii) treatment with crizotinib for at least 4 weeks following the diagnosis of ROS1fusion; iv) availability of clinical and radiological response data after therapy. FISH assay was performed using the Zytolight SPEC ROS1 Dual Color Break Apart Probe (ZytoVision, Germany). NGS was performed on Ion Torrent Personal Genome Machine (Thermo Fisher Scientific). The RNA panel identified rearrangements in 23 genes including ROS1 rearrangements with EZR, CD74 and SCD4.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Eight patients were included. No patient had brain metastasis at diagnosis. Five pts were never-smoker, 2 light former smoker and 1 (case #1) a current heavy smoker (50 pack-year). Crizotinib therapy lasted for a mean of 11.0 months (range 2-31). The median overall survival was not reached at a median follow-up of 11.1 months (15.7 months for censored only). In 4 of the 8 cases (cases #2, 3, 7, 8; 50%), NGS confirmed a ROS1 fusion: 3 of them with the partner EZR and 1 with SCD4. All of these pts showed an objective response to crizotinib, 2 of them being complete responses according to RECIST v1.1 criteria. All these pts were alive at the time of last follow-up. In the other 4 pts (cases # 1, 4 ,5 ,6), NGS analysis did not detect ROS1 fusions. Of these, objective response to crizotinib was observed in only 2 pts, including one (case #5) with a concomitant EML4-ALKrearrangement, confirmed by FISH. The two other patients experienced rapid progressive disease.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      FISH-detected ROS15’ deletion is associated with a high response probability to crizotinib, similarly to classical ROS1 gene rearrangement. However, confirmation with at least one other method, e.g. NGS, is recommended, in order to exclude possible false positive results.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      This work was in part supported by the Pallotti fund to Michelangelo Fiorentino.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

    • +

      147P - Impact on KRAS-subtypes and TP53 mutations on the prognostic value of KRAS/KEAP1 comutations in non-small cell lung cancer (NSCLC) (Now Available) (ID 493)

      12:30 - 13:00  |  Presenting Author(s): Matthias Scheffler  |  Author(s): Rieke Frank, Michaela A. Ihle, Diana SY Abdulla, Sophia Koleczko, Lucia Nogova, Alessandra Holzem, Tamanna Chanra, Richard Riedel, Sebastian Michels, Rieke Nila Fischer, Anna Kron, Sabine Merkelbach-Bruse, Reinhard Buettner, Jürgen Wolf

      • Abstract
      • Slides

      Background

      Recent studies suggest a devastating impact of KEAP1 mutations on survival in systemically treated advanced NSCLC for both KRAS-comutated and KRAS-wildtype patients. KRAS G12C mutations differ in their co-mutational properties from other KRAS mutations, and TP53 mutations affect the outcome in a subset of NSCLC like ALK-positive NSCLC. We set out this analysis to determine the impact of both KRAS G12C and co-occurring TP53 mutations on the prognostic value of KRAS/KEAP1 comutations.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We pooled the data from three different analyses between 2013 and 2018 and looked for patients with stage IV NSCLC for whom survival data was available and who received systemic therapy. The patients had to be diagnosed by a comprehensive next-generation sequencing panel, comprising at least KRAS, KEAP1and TP53 mutations. Median overall survival (mOS) was assessed using Kaplan Meier statistics.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      We identified 35 patients with KRAS/KEAP1 comutation and available survival data. G12C was detected in 22 patients (62.9%). A co-occurring TP53 mutation could be found in 15 patients (42.9%), and 11 patients (31.4%) presented with both aberrations beside a KEAP1 mutation. 15 patients (42.9%) had neither comutation. The mOS for the whole cohort was 9.8 months (95% CI, 6.3-13.3 months). Neither the presence of a G12C mutation (mOS 9.8 months [5.7-13.4], log rank p = 0.724) nor the presence of a co-occurring TP53 mutation (mOS 9.0 months [5.8-12.2], log rank p = 0.407) had a significant influence on the outcome. For G12C/TP53 beside KEAP1 mutations, there was hardly any difference to the comparison cohort (mOS 9.8 months [5.4-14.2], log rank p = 0.998). Patients without G12C and TP53 had an mOS of 10.4 months (3.6-17.2 months, log rank p = 0.467).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      The comutation status of TP53 mutations and/or the presence of the KRAS G12C subtype have no impact on the prognostic value of KRAS/KEAP1-mutated stage IV NSCLC. Further investigations are ongoing to reveal the influence of the mode of systemic therapy in larger cohorts to confirm these findings.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      148P - KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic non-squamous NSCLC (Now Available) (ID 368)

      12:30 - 13:00  |  Presenting Author(s): Marika Cinausero  |  Author(s): Noemi Laprovitera, Giovanna De Maglio, Lorenzo Gerratana, Mattia Riefolo, Marianna Macerelli, Michelangelo Fiorentino, Elisa Porcellini, Vanessa Buoro, Francesco Gelsomino, Anna Squadrilli, Giampiero Fasola, Marcello Tiseo, Manuela Ferracin, Andrea Ardizzoni

      • Abstract
      • Slides

      Background

      Programmed cell death -1 (PD-1) PD-ligand 1 (PD-L1) inhibitors represent a novel therapeutic option for advanced chemotherapy-pretreated non-small cell lung cancer (NSCLC) patients, leading to a significant improvement in median and long-term survival. However, about 50% patients do not benefit from therapy and experience rapid disease progression. PD-L1 expression and tumor mutational burden (TBM) have been proposed as biomarker of benefit to anti-PD-1/PD-L1 therapy. However, PD-L1 is not an ideal biomarker and TMB calculation is hardly obtainable for all patients. Here, we planned to test specific NSCLC genetic alterations as potential predictive factors of response to immunotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Tumor DNA was obtained from advanced NSCLC patients treated with anti PD-1 monoclonal antibody nivolumab (N = 44) or pembrolizumab (N = 3). The mutational status of 22 genes was assessed by targeted next-generation sequencing using Oncomine™ Solid Tumour DNA assay (Thermo Fisher).

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The most frequently mutated genes were TP53 (49%), KRAS (43%), ERBB2 (13%), SMAD4 (13%), DDR2 (13%), STK11(9%), ERBB4 (6%), EGFR (6%), BRAF (6%) and MET (6%). We observed that KRASmut patients have a better response to PD-1 inhibitors, showing a longer progression-free survival (PFS) and overall survival (OS) than KRASwt patients. Additionally, we observed that patients with ERBB-family, including EGFR, ERBB2 and ERBB4, mutations all failed to respond to PD-1 blockers, independently from KRAS status.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      These results suggest that the analysis of the mutational status of KRAS and ERBB-family genes is a potential molecular biomarker of response to PD-1 inhibitors that could be used in clinical practice.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Associazione Italiana per la Ricerca sul Cancro (AIRC).

      682889d0a1d3b50267a69346a750433d Disclosure

      M. Tiseo: Advisory boards, speakers’ fee: BMS, MSD. A. Ardizzoni: Grants, personal fees: BMS; Grants: Celgene; Personal fees: MSD, Eli Lilly, Boehringer Ingelheim, Pfizer, outside the submitted work. All other authors have declared no conflicts of interest.

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      149P - Efficacy of tyrosine kinase inhibitors (TKIs) in advanced lung adenosquamous carcinoma (ID 291)

      12:30 - 13:00  |  Presenting Author(s): Minjuan Hu  |  Author(s): Bo Zhang, Shuyuan Wang, Yinchen Shen, Jie Qian, Yiming Zhao, Bao-Hui Han

      • Abstract

      Background

      Adenosquamous carcinoma (ASC) is a rare type of lung cancers, with components of both squamous carcinoma and adenocarcinoma comprising to at least 10% of the tumor. EGFR-TKIs are playing an increasingly important role in the treatment of mutation-positive lung adenocarcinoma. However, the frequency and efficacy of multi-line EGFR-TKIs for ASC patients with sensitive EGFR mutations remain unclear.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      From January 2010 to January 2018, patients pathologically diagnosed as lung ASC in Shanghai Chest Hospital were screened. The effectiveness of EGFR-TKIs in advanced ASC patients with EGFR mutation is retrospectively analyzed.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      A total of 268 ASC patients were screened and 189 patients were tested for the presence of EGFR mutation. 101 positive patients were identified (53.0%, 95% CI, 46.3-60.6%), of which there are 43 19del, 44 21L858R mutations, 6 compound mutations or rare mutations, the rest lack of specific information. A higher frequency of EGFR mutation was found in younger, female patients who were non-smokers. We retrospectively collected consecutive survival data of 67 advanced ACS patients with EGFR-TKI therapy of different generations. Forty-six (46/52, 88.5%) patients had disease progression after first-generation EGFR-TKI treatment, with a median progression free survival (PFS) of 10.7 months (95% CI, 8.6-12.8 months) and a median duration of treatment (MDT) of 13.1 months (95% CI, 8.4-17.8 months). Median PFS for 15 eligible patients received third-generation TKI treatment was 10.2 months (95% CI, 8.3-12.1 months). Median overall survival (OS) for 14 eligible patients with multi-line EGFR-TKIs treatment was 42.1 months (95% CI, 15.7-68.5 months), compared to median OS of patients without third-generation treatment (25.1 months, 95% CI, 10.7-39.4) months.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Our data suggests the detection of EGFR mutations in patients with ASC, especially in young, female, non-smoking patients. The third-generation EGFR-TKI treatment could be a better choice to improve outcomes of advanced patients after progression of first-generation TKI.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Minjuan Hu.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      150P - Characterization of patients with metastatic non-small cell lung cancer obtaining long term benefit from immunotherapy (Now Available) (ID 321)

      12:30 - 13:00  |  Presenting Author(s): Giulia Galli  |  Author(s): Claudia Proto, Diego Signorelli, Martina Imbimbo, Roberto Ferrara, Arsela Prelaj, Alessandro De Toma, Giovanni Randon, Benedetta Trevisan, Monica Ganzinelli, Nicoletta Zilembo, Marina Chiara Garassino, Giuseppe Lo Russo

      • Abstract
      • Slides

      Background

      The indications of Immunotherapy (IO) for metastatic Non Small Cell Lung Cancer (mNSCLC) are broadening. Although different studies have proved the efficacy of IO in this setting, only a minority of patients (pts) gains advantage from IO and predictive variables of Long Term Benefit (LTB) are incompletely understood.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We retrospectively collected data about all consecutive mNSCLC pts treated with IO at Istituto Nazionale dei Tumori, Milan, Italy, from 04/2013 to 07/2017. We defined pts with LTB as those obtaining a Complete Response (CR), a Partial Response (PR) or a Stable Disease (SD) as best response from IO and maintaining it for ≥12 months (mos). Pts were defined to have a Short Term Benefit (STB) if they obtained a CR, a PR or a SD as best response but maintained it for <12 mos. Pts were defined as Progressors (P) If they obtained a progression as best response. Fisher’s test was used to compare variables. Multivariate analyses were performed with logistic regression. Survival was estimated with Kaplan-Meier method.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      One hundred forty-seven pts were identified. IO was an antiPD1 in 87 cases, an antiPDL1 in 52 cases, a combination antiPDL1/PD1 + antiCTLA4 in 7 cases, an antiCTLA4 in 1 case. First line IO was administered in 19 pts, II line IO in 63 pts, ≥III line IO in 64 pts. After a median follow up of 28.5 mos, 35 pts obtained LTB from IO. A higher proportion of LTB pts compared with controls (STB + P) showed CR/PR as first (12/35 vs 10/112, p = 0.0007) and best response (19/35 vs 14/112, p < 0.0001) to IO. More LTB pts than controls had a neutrophil/lymphocyte ratio<5 (p = 0.0378) and did not receive steroids (p = 0.0023), but only the evidence of a CR/PR during IO retained association to LTB at multivariate analyses (p = 0.0002). All other clinical and pathologic variables appeared unremarkable. A second analysis comparing pts with LTB and STB confirmed this result (odds ratio for CR/PR vs SD: 2.629, 95%CI: 1.051-6.579; p = 0.0427).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Objective response appears to be a central factor in predicting LTB from IO, irrespective of all other variables. If confirmed, this observation could help in identifying the pts with mNSCLC candidate to gain the highest advantage from IO.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      151P - Safety and tolerability of pembrolizumab or placebo plus pemetrexed and platinum as first-line therapy in Japanese patients (PTS) with metastatic non-squamous non-small cell lung cancer (NSCLC) enrolled in the phase III KEYNOTE-189 study (ID 484)

      12:30 - 13:00  |  Presenting Author(s): Hidehito Horinouchi  |  Author(s): Naoyuki Nogami, Hideo Saka, Makoto Nishio, Takaaki Tokito, Toshiaki Takahashi, Kazuo Kasahara, Yoshihiro Hattori, Eiki Ichihara, Noriaki Adachi, Takeshi Sawada, Takashi Shimamoto, Kazuo Noguchi, M. Catherine Pietanza, Takayasu Kurata

      • Abstract
      • Slides

      Background

      The global, randomized, double-blind, phase 3 KEYNOTE-189 study (NCT02578680) showed significantly improved OS and PFS with pembrolizumab (pembro) + pemetrexed (pem) + platinum compared with placebo + pem + platinum with a manageable safety profile in pts with previously untreated metastatic nonsquamous NSCLC without targetable EGFR/ALK aberrations|. We present safety and tolerability data from Japanese pts enrolled in KEYNOTE-189.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Eligible pts enrolled in Japan during the global or extension study of KEYNOTE-189 were randomized 2:1 to pembro 200 mg Q3W or placebo for up to 35 cycles (∼2 y); all pts received pem 500 mg/m2 (until progressive disease or intolerable toxicity) and 4 cycles of carboplatin AUC 5 or cisplatin AUC 75 mg/m2. Safety and tolerability were assessed by clinical review of all relevant parameters; adverse events (AEs) and laboratory abnormalities were graded per NCI CTCAE v4.0.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Of 40 pts enrolled in Japan (global study, n = 10; extension study, n = 30), 25 were randomized to the pembro arm, and 15 to the placebo arm. There were no meaningful differences in baseline characteristics, apart from a smaller proportion of pts with brain metastases (16% vs 33%), and larger proportion with PD-L1 TPS <1% (56% vs 40%) and cisplatin recipients (72% vs 53%) in the pembro vs placebo arm, respectively. The median (range) follow-up was 5.6 (2.4–12.9) mo and 7.0 (2.4–19.8) mo in the pembro and placebo arms, respectively. There were no deaths due to AEs. Grade 3/4 AEs occurred in 13 pts (52%) in the pembro arm and 8 (53%) in the placebo arm. 6 (24%) vs 3 pts (20%) had immune-mediated AEs and infusion reactions, with no events of pneumonitis reported in the pembro arm vs 2 (13.3%) in the placebo arm. Overall, AEs led to treatment discontinuation in 4 (16%) pts in the pembro vs 3 (20%) pts in the placebo arm.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Pembro + pem + platinum demonstrated a tolerable and manageable safety profile in Japanese pts, generally consistent with the overall pt population in the global KEYNOTE-189 study. No new safety concerns were identified in Japanese pts.

      b651e8a99c4375feb982b7c2cad376e9 Clinical trial identification

      NCT02578680.

      7a6a3ffa2dadc03a6151ee2c4d6fa383 Editorial acknowledgement

      Medical writing assistance was provided by Shilpa Aggarwal, PhD, of C4 MedSolutions, LLC (Yardley, PA, USA), a CHC Group company and was funded by funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

      934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study

      Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

      213f68309caaa4ccc14d5f99789640ad Funding

      Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

      682889d0a1d3b50267a69346a750433d Disclosure

      H. Horinouchi: Corporate-sponsored research: MSD, Eli Lilly, BMS. N. Nogami: Honoraria: Pfizer Inc., Chugai Pharmaceutical Co. Ltd, Eli Lilly, Taiho Pharmaceutical Co. Ltd., AstraZeneca, Kyowa Hakko Kirin, Ono Pharmaceutical Co. Ltd., MSD. H. Saka: Grants/research support: AstraZeneca, MSD, Ono Pharmaceutical; Honoraria: AstraZeneca, MSD, Ono Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, Kyorin Pharmaceutical. M. Nishio: Grants and personal fees: Ono Pharmaceutical, Bristol-Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Boehringer-Ingelheim, MSD, Novartis; Personal fees: Daiichi Sankyo Healthcare, Merck Serono; Grants: Astellas, outside the submitted work. T. Tokito: Honoraria: AstraZeneca, MSD, Ono, Chugai. T. Takahashi: Grants, personal fees: Ono Pharmaceutical Co., Ltd., MSD K.K., AstraZeneca KK, Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K.; Grants: Pfizer Japan Inc.; Personal fees: Boehringer Ingelheim Japan, Inc, Roche Diagnostics K.K. K. Kasahara: Grants, honoraria: Boehringer Ingelheim; Honoraria: Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceuticals, AstraZeneca, MSD. Y. Hattori: Research funding: MSD, Ono; Honoraria: AstraZeneca, Boehringer Ingelheim, Chugai, Eli Lilly, MSD, Novartis, Ono, Taiho. E. Ichihara: Research grants: Eli Lilly, MSD. N. Adachi, T. Sawada, T. Shimamoto, K. Noguchi: Employee: MSD K.K., Tokyo, Japan. M.C. Pietanza: Employee: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. T. Kurata: Research grants: AstraZeneca, MSD; Honoraria: AstraZeneca, MSD, Ono, Bristol-Myers Squibb, Chugai, Eli Lilly.

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      152P - Correlation among different KRAS alterations, genetic co-mutations and PD-L1 expression in patients treated with immunotherapy in metastatic NSCLC (Now Available) (ID 365)

      12:30 - 13:00  |  Presenting Author(s): Letizia Gianoncelli  |  Author(s): Gianluca Spitaleri, Antonio Passaro, Caterina Fumagalli, Pamela Trillo Aliaga, Ester Del Signore, Valeria Stati, Emanuela Ferraro, Elena Guerini-Rocco, Chiara Matilde Catania, Massimo Barberis, Filippo de Marinis

      • Abstract
      • Slides

      Background

      No molecularly driven strategy against KRAS demonstrated convincing activity in clinical trials. The introduction of immune checkpoints inhibitors (IO) represents a paradigm shift in treatment of NSCLC without gene target. Considering the association with smoke, the high mutational burden, the high PDL1 expression and the abundance of T-cell infiltrating lymphocyte, KRAS mutant tumors have been considered an attractive target for IO.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Patients (pts) with stage IV NSCLC harboring KRAS mutation treated with IO in our Institution between 2016 and 2018 were retrospectively identified by electronic medical record review. All pts provided written informed consent for the collection of clinical, demographic and molecular data.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      A total number of 328 consecutive pts with KRAS mutant NSCLC were identified, of them 32 received IO. All eligible pts had PDL1 testing and in 21 cases (65.6%) NGS was available. Median age was 63 (range 44-78). Male/female were 17/15. Most pts had an adequate ECOG PS (0/1 18.7%/65.6% respectively). 29 pts (90.6%) were smokers. According to the setting, 10 pts were treated in 1st-line, 9 in 2nd-line and 13 in further lines. Between the 9 subtypes of KRAS mutation identified in our cohort, G12C was the commonest (14, 43.8%). 15 pts (46.9%) had PDL1≥50%, 10 (31.2%) had PD-L1 between 1-49%, and 7 (21.9%) were negative. 8 pts (25%) had co-occurring gene mutations. With a median follow-up of 5.1 mos (0.4-28.6), the mPFS and mOS for ITT population were 4.47 (95% CI 2.5-6.4) and 7.73 (95% CI 6-14.5) mos.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Our preliminary results, contrary to findings in other oncogene driven NSCLC, showed that the presence of KRAS mutations seems to be irrelevant for the selection of patients for IO. Furthermore, neither the association of co-mutation (found in the 25% of cases) nor the type of KRAS variant or the treatment setting (1st vs further lines) seems to have an impact on the effectiveness of IO in KRAS NSCLC pts. Data about clinical efficacy according to PD-L1 expression will be presented at the meeting.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      153P - Chemotherapy with immune-checkpoint inhibitors in first-line treatment metastatic NSCLC patients: Systematic review and literature-based meta-analysis (Now Available) (ID 179)

      12:30 - 13:00  |  Presenting Author(s): Alfredo Addeo  |  Author(s): Giuseppe Luigi Banna, Giulio Metro, Massimo Di Maio

      • Abstract
      • Slides

      Background

      Checkpoint inhibitors plus platinum-based chemotherapy have shown superiority compared to chemotherapy alone as first-line therapy in advanced non–small cell lung carcinoma (NSCLC), but little is known about the real benefit within the different PDL1 expression subgroups. Our aim was to estimate the relative benefit in term of Overall Survival (OS) and Progression-free Survival (PFS) of checkpoint inhibitors plus chemotherapy versus chemotherapy alone, overall and in subgroups defined by PDL1 expression.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      This meta-analysis searched PubMed and checked references of articles to identify trials that combined checkpoint with chemotherapy versus chemotherapy in the first-line setting. For each trial included in this study, the trial name, year of publication or conference presentation, patients’ clinic-pathological characteristics, type of chemotherapy, type of checkpoint inhibitor and PDL1 expression were extracted. Data collection took place from October 1th to October 24th, 2018. A random-effects model was applied.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Eight trials with advanced NSCLC were included in this meta-analysis. Checkpoint inhibitors plus chemotherapy were associated with prolonged OS, compared with chemotherapy in the ITT population (HR, 0.61; 95% CI, 0.61-0.66; P<.000001). OS was prolonged in the PDL1 0% group (HR, 0.78; 95% CI, 0.67-0.90; P<.0007) and in the PDL1 high (HR, 0.61; 95% CI, 0.48-0.78; P<.00001) but not in the PDL1 low (HR, 0.77; 95% CI, 0.55-0.107; P < 0.12). Chemotherapy plus pembrolizumab showed OS benefit (HR, 0.56; 95% CI, 0.40-0.78; P<.00007)in low PD-L1 low, unlike atezolizumab backbone trials (HR, 0.92; 95% CI, 0.62-1.37; P < 0.69). Checkpoint inhibitors plus chemotherapy were associated with prolonged PFS in the ITT (HR, 0.61; 95% CI, 0.56-0.66; P < 0.00001) across PDL1 subgroups.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Checkpoint inhibitors plus chemotherapy compared to chemotherapy, are associated with prolonged OS and PFS in first-line therapy in NSCLC. In low PDL1 subgroup the benefit was statistically significant only in the pembrolizumab backbone trials. The findings of this meta-analysis could assist in the design and interpretation of future trials and in economic analyses.

      b651e8a99c4375feb982b7c2cad376e9 Editorial acknowledgement

      none

      934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      A. Addeo: Consulting role: MSD, Roche, Pfizer, Astrazeneca, BMS, Boehringer Ingelheim; Research grant: Boehringer Ingelheim; Travel grant: Roche, MSD. M. Di Maio: Honoraria for lectures in meeting, participation in Advisory boards: Astellas, Janssen. All other authors have declared no conflicts of interest.

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      154P - Renal toxicity from platinum/pemetrexed and pembrolizumab in the era of combination therapy (Now Available) (ID 558)

      12:30 - 13:00  |  Presenting Author(s): Daphne Dumoulin  |  Author(s): Sabine Visser, Robin Cornelissen, Joachim G Aerts

      • Abstract
      • Slides

      Background

      Recently, the phase 3 keynote-189 trial showed that in previously untreated patients with advanced non-squamous NSCLC without targetable mutations, the progression-free and overall survival were significantly longer with addition of pembrolizumab to chemotherapy than with chemotherapy alone. Both chemotherapy and pembrolizumab can give renal toxicity, which can be a major challenge in the clinical setting.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      In a prospective multicenter observational real-life cohort study [Visser Eur Respir J 2018], we evaluated the incidence of acute/chronic kidney disease (AKD/CKD), its related treatment discontinuation frequency and associated clinical variables with AKD in patients with stage IIIB/IV NSCLC treated with platinum/pemetrexed. In addition, the Keynote 189 toxicity data was used for the combination treatment. We thereafter reviewed literature to generate an algorithm for diagnosis and treatment in increased creatinine levels.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      149 patients received pemetrexed platinum, of whom 44 patients (30%) continued maintenance. During induction therapy 48 patients (50%) treated with cisplatinum/pemetrexed developed AKD and 15 patients (29%) treated with carboplatin/pemetrexed. During maintenance 13 patients (30%) developed AKD, leading to CKD and treatment discontinuation in eight patients (62%). In the Keynote 189 trial combining pembrolizumab with chemotherapy, nephritis has been reported in 1,7% of patients in any grade (1,5% grade 3-4). However, when looking at an increased blood creatinine in the group that was treated with carboplatin, a total of 12,2% of patients showed any increase (0,7% grade 3-4).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Increased blood creatinine levels from pemetrexed and pembrolizumab is a common entity, probably more common in a real-life setting. This elevation is clinically challenging in a population that receives three agents that can cause a creatinine increase. Currently, there are no markers to distinguish between renal failure due to chemotherapy of immunotherapy. We will present an algorithm based on current knowledge for clinicians as guidance for renal dysfunction in patients treated with chemotherapy and pd-(l)1 checkpoint inhibitors.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      D. Dumoulin: Speakers fee: BMS, Roche, Pfizer, Novartis. R. Cornelissen: Consultancy: Roche, Boehringer Ingelheim, BMS, MSD; Speakers fee: Roche, Pfizer, Boehringer Ingelheim, Novartis, BMS. J.G. Aerts: Advisory boards: BMS, Boehringer Ingelheim, MSD, AstraZeneca, Eli Lilly, Takeda, Amphera; Stock owner: Amphera B.V. All other authors have declared no conflicts of interest.

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      155P - Association of immune-related adverse events (irAEs) and immunotherapy (IT) benefit in advanced non-small cell lung cancer (NSCLC) (Now Available) (ID 577)

      12:30 - 13:00  |  Presenting Author(s): Cristina Saavedra Serrano  |  Author(s): Arantzazu Barquín García, Elena Corral de la Fuente, Juan José Serrano Domingo, Victor Albarrán Artahona, Roberto Martin Huertas, Ana Gómez Rueda, María Eugenia Olmedo García

      • Abstract
      • Slides

      Background

      IT has improved outcomes in advanced NSCLC. However, this therapy can yield significant toxicity secondary to immune activation. Several retrospective studies have reported a direct relationship between IT efficacy and the development of irAEs, in Response Rate (RR) and survival.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We retrospective reviewed our experience with anti-PD1/anti-PDL1 as single agent in advanced NSCLC patients treated between February 2014 and August 2018. Patient and tumor features, irAEs, concomitant and subsequent treatments were collected. Stata 14.1 was used for the analysis.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      98 patients were included. Mean age was 62 years (41-85). 73.5% were men. 73.5% had > 30 smoked pack-years. 64.3% were adenocarcinoma, of which 41% showed KRAS mutation; PDL1 was known in 50% of patients (11.2% <1%, 13.3% 1-49%, 25.5% >50%). IT was administered mainly as a second line (61%) and third or later (24.5%). Most employed drug was nivolumab (52%). RR was 33% (partial response 28%, complete response 5%). Disease control rate (DCR) was 55% and progression rate 34% as better response, 67% at the moment of the analysis. irAEs were reported in 30.6%. The table summarizes irAEs. We found a significant association between irAEs and RR (OR 3.71 p 0.005 IC 1.49 - 9.23) and DCR (OR 5.06 p 0.002 IC 1.84 - 13.98). An impact of irAEs in progression-free survival (PFS) (1.7 vs 7.7 months (m) HR 0.44 p 0.002 IC 0.26 - 0.73) and overall survival (OS) (6.1 vs 15.7 m HR 0.53, p 0.026, IC 0.31- 0.93) was found too. Most of the patients requiring steroid therapy during IT was due to an irAE. There was not detrimental effect of steroids in RR (OR 3.17 p 0.01 IC 1.3 - 7.76), DCR (OR 6.17 p 0.000 IC 2.33 - 16.34), PFS (1.6 vs 6 m HR 0.36 p 0.000 IC 0.22 - 0.62) or OS (6.2 vs 13.3 m HR 0.61 p 0.057 IC 0.36 - 1.01).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      The development of irAEs appears to be associated with efficacy of IT in our retrospective review. The use of steroids during IT had no negative impact in RR, DCR or survival. Still, we need prospective studies in order to confirm this hypothesis.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      156P - Peripheral blood biomarkers as prognostic factors for immunotherapy in advanced non-small cell lung cancer (aNSCLC) patients (Now Available) (ID 579)

      12:30 - 13:00  |  Presenting Author(s): Arsela Prelaj  |  Author(s): SARA ELENA Rebuzzi, PAMELA Pizzutilo, MASSIMO Bilancia, MICHELE Montrone, FRANCESCO Pesola, VITO Longo, GABRIELLA Del Bene, VITTORIA Lapadula, FLAVIO Cassano, PATRIZIA Petrillo, DANIELA Bafunno, NICCOLO' Varesano, VITO Lamorgese, ANGELICA Mastranrdea, DONATELLA Ricci, ANNAMARIA Catino, DOMENICO Galetta

      • Abstract
      • Slides

      Background

      Second-line immunotherapy showed an overall survival (OS) benefit, but only a low percentage of aNSCLC patients (pts) respond to therapy. The identification of new biomarkers to select patients for immunotherapy (IO) is a crucial topic. In our study we aim to investigate the role of peripheral blood biomarkers (PBBs) that can predict response and outcome in aNSCLC pts treated with IO.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We conducted a retrospective analysis on 154 aNSCLC patients receiving single-agent nivolumab or pembrolizumab as second-line (68%) and >3rd line (32%) therapy. We recorded complete blood cell count at baseline (T0), at second (T1) and third cycle (T2), assessing absolute blood count and their ratio such as neutrophil-lymphocyte ratio (NLR), derived-NLR (dNLR) and lymphocyte-monocyte ratio (LMR). Univariate and multivariate analysis were performed to evaluate the correlation between overall response rate (ORR), PFS and OS and PBBs.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The univariate analysis for PFS and OS showed that, at T1 and T2, ANC≥7000/µL, AMC≥900/µL, NLR≥4, dNLR>2.2 were statistically significantly associated with worse survival outcomes and increased LMR>1.8 with better survival outcomes. ALC≥1200/µL was associated with higher PFS and OS at T1; AEC<100/µL was associated with worse PFS and OS at T1 and only PFS at T2. The multivariate analysis for PFS confirmed as statistically significant independent predictive factors ANC, ALC and dNLR at both T1 and T2, and AEC at T1, AMC and LMR at T2. The multivariate analysis for OS confirmed as statistically significant independent prognostic factors ANC, ALC, AMC and LMR at both T1 and T2 while dNLR only at T1 and NLR at T2.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      In conclusion, factors such as high ANC, AMC, NLR and dNLR level can be considered as negative prognostic factors, and high AEC and LMR as positive prognostic factors in NSCLC patients treated with immunotherapy in ≥ second line setting and their change after IO could help monitoring the response and outcome. Further prospective analyses are needed.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      157P - Prognostic impact of the use of antibiotics in patients with advanced non-small cell lung cancer (NSCLC) receiving PD-(L)1 targeting monoclonal antibodies (ID 242)

      12:30 - 13:00  |  Presenting Author(s): Anne Schett  |  Author(s): Sacha I Rothschild, Laetitia Arja Mauti, Sabine Schmid, Christina Appenzeller, Alessandra Curioni-Fontecedro, Martin Frueh, Markus Joerger

      • Abstract

      Background

      Anti-PD-(L)1 monoclonal antibodies (mAb) have changed the therapeutic landscape in patients with advanced NSCLC, still 35-40% of these patients derive no benefit from anti-PD-(L)1 mAb. Antibiotics alter gut microbiota diversity and composition, and may affects antitumor immune responses following immune checkpoint inhibitors (ICI) in NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We retrospectively included 218 patients with advanced NSCLC receiving anti-PD-(L)1 mAb. Overall survival (OS) (primary endpoint), progression free survival (PFS) and radiological response was compared between patients who received antibiotics within 2 months prior to the start of immunotherapy (ATB+) and patients who did not (ATB-). Assuming a rate of antibiotic comedication of 20% of all patients included, the study had a power of 70% to detect a 35% OS improvement in ATB- patients.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Patients are well balanced with the exception of PD-L1 immunohistochemical expression that was more frequent in ATB+ compared to ATB- (30% vs. 19%, P = 0.05). ATB+ compared to ATB- was associated with a significantly shorter OS (median OS, 10.6 vs 29.9 months, HR 2.7, 95% CI 1.7-4.1, P < 0.001) and shorter PFS (median PFS 1.4 vs 5.8 months, HR 2.2, 95% CI 1.5-3.4, P < 0.001). In the adjusted model for OS, the following 4 parameters retained a statistically significant prognostic value : ATB+ vs. ATB- (HR 2.8, 95% CI 1.7-4.5, P < 0.001), ECOG performance score >1 vs. 0-1 (HR 2.3, 95% CI 1.4-3.7, P = 0.001), squamous-cell vs. Non squamous-cell histology (HR 2.1, 95% CI 1.4-3.2, P < 0.001) and no prior radiotherapy vs. prior radiotherapy (HR 1.7, 95% CI 1.2-2.6, P = 0.006). ATB+ compared to ATB- was significantly associated with an increased risk of progressive disease as best radiological response (73% vs 41%, P = 0.002).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Antibiotic treatment is associated with a reduced clinical benefit from therapy with anti-PD-(L)1 mAb. The negative prognostic value of antibiotics was independent from known prognostic factors. However, further investigation is required on the mechanism behind this observation, with emphasis on the role of the gut microbiota composition in the context of anticancer immune response.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      M. Joerger.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      158P - Immune-related adverse events (irAEs) in advanced non-small cell lung cancer (aNSCLC): Platelet-to-lymphocyte ratio (PLR) predicts the risk of development and relapse (ID 288)

      12:30 - 13:00  |  Presenting Author(s): Alberto Pavan  |  Author(s): Lorenzo Calvetti, Alessandro Dal Maso, Ilaria Attili, Giulia Pasello, Giuseppe Aprile, Valentina Guarneri, Pierfranco Conte, Laura Bonanno

      • Abstract

      Background

      Immune checkpoint inhibitors (ICIs) have radically changed the treatment of aNSCLC patients (pts). IrAEs are mainly reversible but they require timely recognition and management and may be potentially life-threatening. No predictive markers are available to predict the onset of irAEs and their risk of recurrence. Aim of the study was to evaluate the potential role of circulating markers in predicting the development of irAEs.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We retrospectively reviewed clinical data of aNSCLC pts consecutively treated with ICIs at Istituto Oncologico Veneto (Padua, Italy) and at San Bortolo General Hospital (Vicenza, Italy) between August 2013 and August 2018. We collected data on the type, grading (G) and timing of irAEs and calculated NLR and PLR before first ICI administration and at the onset of the irAEs. The values were dichotomized for analysis in two groups: high (H-) and low (L-) NLR and H- and L-PLR using pre-identified cut-offs of 3 and 180, respectively.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The analysis included 194 pts. ICIs were administered as first-line treatment in 29 (15%) pts. Median number of ICIs cycles was 6 (range: 1-66). Median PFS and OS were 4.6 months (m) (95% CI: 3.3-5.9) and 8.7m (95% CI: 6.1-11.4). Seventy-two pts (37%) developed irAEs, mainly G1-2 (68%), with permanent discontinuation of ICI in 23 (32%) cases; 15 pts (20.8%) experienced more than one irAE. Median time to irAE onset was 77 days (7-751 days). Pts with baseline L-NLR and L-PLR values had a higher risk of irAE development (OR = 1.98, 95% CI: 1.09-3.61, p = 0.025 and OR = 2.15, 95% CI: 1.16-3.98, p = 0.016). Multivariate analysis confirmed PLR as independent predictive marker (OR = 2.01, 95%CI: 1.02-3.96; p = 0.045). Among pts who experienced irAE, L-PLR at time of irAE onset was associated with the risk of irAE recurrence or second irAE development (OR = 4.5, 95% CI: 1.11-18.16, p = 0.035).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Baseline evaluation of NLR and PLR may be a tool to predict the risk of irAE onset and to personalize clinical follow-up during and after treatment with ICIs. The evaluation of PLR at the time of irAE onset might predict the risk of further toxicity. If validated, PLR value may support the clinical decision of re-introducing ICIs after discontinuation.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Istituto Oncologico Veneto (IOV), Padua, Italy.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      159P - Initial serum tumor marker dynamics predict progression-free and overall survival in single PD-1/PD-L1 inhibitor treated advanced NSCLC (Now Available) (ID 218)

      12:30 - 13:00  |  Presenting Author(s): David Lang  |  Author(s): Andreas Horner, Elmar Brehm, Kaveh Akbari, Benedikt Hergan, Klaus Langer, Christian Asel, Mario Scala, Bernhard Kaiser, Bernd Lamprecht

      • Abstract
      • Slides

      Background

      Routine measurement of serum tumor markers (STM) is not recommended in advanced non-small cell lung cancer (NSCLC). However, immune checkpoint inhibitor (ICI) treated patients may initially present with indeterminate radiological response, demanding additional biomarkers aiding clinical decisions.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Carcinoembrionic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), cytokeratin 19 fragments (CYFRA 21-1) and neuron specific enolase (NSE) were routinely measured at primary NSCLC diagnosis. The marker with the highest initial elevation above the upper limit of normal (“leading STM”) was used for follow-up. Relative leading STM changes between ICI initiation and first radiological restaging were retrospectively evaluated regarding their impact on progression-free survival (PFS) and overall survival (OS). Comparatively, we calculated PFS and OS for the corresponding computed tomography results according to response evaluation criteria in solid tumors (RECIST).

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Among 84 patients (61% men, mean age 68 years) included, median PFS was significantly (p < 0.001) longer, when the leading STM decreased (11months(M) (7,19), N = 37) than in case of marker increases (<2-fold: 6M (3,8), N = 31; ≥2-fold: 2M (1,2), N = 16). Patients with initial leading STM decrease also had significantly (p < 0.001) longer median OS (not reached) than patients with STM increase (<2-fold: 14M (12,26); ≥2-fold: 4M (3,7)). In the group with stable or progressive disease (PD/SD) according to RECIST at first restaging, PFS and OS were significantly (p < 0.001) longer upon leading STM decrease (PFS: 8M (4,14); OS: 18M (10,-); N = 24) than in case of increase (PFS: 2M (2,4); OS: 10M (6,13); N = 42).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Leading STM decrease at first restaging is predictive of longer PFS and OS in single PD-1/PD-L1 inhibitor treated NSCLC. Such tumor marker response identifies a subgroup with favorable further treatment outcomes among initial radiological non-responders.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      D. Lang, A. Horner: Travel/accommodation funding: Roche. E. Brehm: Speakers fees, consultant/advisor: Roche, Merck Sharp & Dohme, Bristol-Myers Squibb; Travel/accommodation funding: Roche, Merck Sharp & Dohme. B. Lamprecht: Speakers fees, consultant/advisor: Roche, Merck Sharp & Dohme, Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      160P - EPSILoN score: Validation cohort of a prognostic score in advanced non-small cell lung cancer (aNSCLC) patients treated with immunotherapy (Now Available) (ID 494)

      12:30 - 13:00  |  Presenting Author(s): Arsela Prelaj  |  Author(s): Giuseppe Lo Russo, Diego Signorelli, Roberto Ferrara, Martina Imbimbo, Giulia Galli, Alessandro De Toma, Giovanni Randon, MARTA Brambilla, Benedetta Trevisan, Monica Ganzinelli, Nicoletta Zilembo, FILIPPO De Braud, Marina Chiara Garassino, Claudia Proto

      • Abstract
      • Slides

      Background

      Despite the benefit in overall survival (OS), only 18-20% of aNSCLC patients (pts) respond to immunotherapy (IO) in second-line (2nd) with a median progression-free survival (mPFS) of 2-4 months (mo). We previously reported the role of EPSILoN score (Ecog-Ps, Smoke, lIver, Ldh, Nlr) as a clinical and biochemical prognostic score of survival in 154 pts treated with 2nd IO. In this study we aim to validate the EPSILoN score in a different patient population group treated with IO in the same setting.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We enrolled 193 eligible patients at the National Cancer Institute of Milan, Italy. From 193 aNSCLC patients receiving single-agent anti-PD-(L)-1 as 2nd (61%) and ≥ 3rd line (39%) we collected baseline complete blood cell count and estimated their ratio such as neutrophil-lymphocyte ratio (NLR). Also we evaluated baseline LDH level. Survival analyses using Kaplan–Meier method and multivariate analysis (Cox progression model) were performed to identify and confirm independent variables.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Of 193 pts mPFS and mOS were 2.3 and 7.6 mo, respectively. Univariate and multivariate analyses for PFS adjusted for age, sex, smoke status, ECOG-PS, histology, disease site, confirmed heavy smoking status (≥40 pack/years) (HR 0.71, p = 0.036) and baseline LDH <400 mg/dl (HR 0.66, p = 0.026) as independent positive factors while ECOG-PS 2 (HR 1.79, p < 0.001), baseline liver mets (HR 1.48, p = 0.04) and NLR≥4 (HR 1.49, p = 0.029) as negative factors. The five baseline clinical and blood biomarkers (smoking status, ECOG PS, liver metastases, LDH and NLR), were included in the EPSILoN score to validate it in this cohort. Finally, three different survival groups defined as high, intermediate and low for PFS (6.0 vs 3.8 vs 1.9 mo respectively, HR 1.94 95% IC 1.51–2.48, p < 0.001) and OS (24.5 vs 8.9 vs 3.4 months, respectively HR 2.40, 95% IC 1.82–3.17, p < 0.001) were identified.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      EPSILoN score which combine five baseline clinical and blood biomarkers may help identify patients who most likely will benefit or not from IO in clinical practice in aNSCLC patients treated with second-line IO. Furthermore, it seems to play an important role in both PFS and OS.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      M.C. Garassino: Consultancies, honoraria: AstraZeneca, Roche, Boehringer Ingelheim, BMS, MSD, Eli Lilly, Novartis, Bayer, Pfizer, Sanofy, Italfarmaco. D. Signorelli: Consultancies, honoraria: AstraZeneca. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      161P - Tumor mutational burden assessed by a targeted NGS assay predicts clinical benefit from immune checkpoint inhibitors in non-small cell lung cancer (ID 556)

      12:30 - 13:00  |  Presenting Author(s): Philip Jermann  |  Author(s): Ilaria Alborelli, Katharina Leonards, Sacha I Rothschild, Laura Leuenberger, Spasenija Savic Prince, Kirsten Mertz, Severin Poechtrager, Alfred Zippelius, Luca Quagliata, Lukas Bubendorf

      • Abstract
      • Slides

      Background

      In non-small cell lung cancer (NSCLC) immune checkpoint inhibitors (ICIs) significantly improve progression-free survival (PFS) and objective response rate. Biomarkers capable of predicting response to ICIs are highly desired. Assessment of tumor mutational burden (TMB) by whole-exome sequencing has been associated with outcome in patients treated with ICIs. Recently, being more suited for clinical applications, targeted sequencing has also proven its ability to reliably assess TMB. Our study is the first to evaluate the predictive power of TMB measured through the Oncomine Tumor Mutational Load (TML - Thermo Fisher Scientific) assay in 64 NSCLC patients treated with ICIs.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      TMB was assessed retrospectively in patients with metastatic NSCLC exposed to ICIs. Clinical data (RECIST 1.1) were collected and patients were characterized as either having clinical benefit (CB = complete/partial response (CR/PR) or stable disease (SD)) or having no clinical benefit. TMB was assessed using the TML assay, covering 409 genes. Differences in TMB between responders and non-responders were examined using Mann-Whitney test.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      TMB assessed by the TML assay was significantly higher in patients with CB compared to patients with no CB (median TMB = 5.9 versus 8.4 mutations/Mb, Mann-Whitney p = 0.028). TMB predicts CB by receiver operating characteristic (ROC, AUC = 0.66). 67% of patients with high TMB (cutoff = 3rd tertile, TMB = 8.7) were responders (CB), compared to only 24% of patients with low TMB (cutoff = 1st tertile, TMB = 5). TMB-high patients were characterized by a significantly higher progression-free survival (PFS) compared to patients with low mutational load (log rank for trend, p = 0.024). Finally, the highest response rate was observed in PD-L1 positive samples with high tumor mutational load (73%), whereas the PD-L1 negative and TMB-low population consisted of only 11% responders.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Our results show that the TML panel is an effective tool for patient stratification for ICI treatment. Since we observed the highest response rate in PD-L1 positive patients with a high mutational load, we believe that a combinatorial use of biomarkers will maximize the precision of patient selection.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      University Hospital Basel.

      213f68309caaa4ccc14d5f99789640ad Funding

      Bristol-Myers Squibb, Thermo Fisher Scientific.

      682889d0a1d3b50267a69346a750433d Disclosure

      P. Jermann: Bristol-Myers Squibb provides funding in the form of a research grant. Thermo Fisher Scientific provides next-generation sequencing reagents and access to analysis software and technical support. All other authors have declared no conflicts of interest.

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      162P - Monitoring of blood serum amyloid (SAA) to predict outcome of first-line pembrolizumab (P) in patients (pts) with advanced non-small cell lung cancer (ANSCLC) (ID 451)

      12:30 - 13:00  |  Presenting Author(s): Vincenzo Pio Di Noia  |  Author(s): Ettore D'Argento, Emanuele Vita, Miriam Ferrara, Paola Damiano, Marta Ribelli, Antonella Cannella, Antonella Virtuoso, Giampaolo Tortora, Emilio Bria

      • Abstract

      Background

      In melanoma pts, SAA inhibits the anti-tumor immune response by the expansion of IL-10-secreting neutrophils. We previously found that baseline high SAA was associated with early progressive disease (PD) in small cohort of ANSCLC pts receiving up-front P. Here we explored the relationship between dynamic monitoring of SAA and survival outcomes in an enlarged cohort.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Pts with ANSCLC (PD-L1 ≥50%) receiving upfront P at our institution, were prospectively evaluated for blood SAA and radiological response at baseline and every 9 weeks during the treatment. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS) and PD rate. The most accurate SAA cut-off to predict PFS was established with a ROC-analysis.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      We enrolled 37 consecutive pts. Pts characteristics: male/female (70/30%), number of sites <3/≥ 3 (30/70%), ECOG PS 0/≥ 1 (38/62%); never/former or current smokers (54/46%); median age 72.5 (range 59-86) years. Baseline SAA was > the ROC-derived cut-off (73.9 mg/L, AUC 0.77, 95% CI 0.6-0.9,p=0.002) in 11 (30%) pts. After a median follow-up of 11.5 months (m), pts with pre-treatment high SAA achieved worse PFS (1.4 vs not reached [NR], HR 0.11, 95%CI 0.03-0-41, p < 0.0001) andOS(7.2 vs NR, HR 0.07, 95%CI 0.01-0.37, p < 0.0001) compared with those having lower level. Baseline high SAA was also related to PD (p < 0.05). Combining SAA at baseline and the dynamic monitoring, the median PFS was 1.4 m (95%CI 0.6-4.4) when SAA remained high (n = 10) while was not reached at-12 m when SAA remained low (n = 12) or changed (n = 7)(p < 0.0001).The SAA monitoring was also associated with OS (p = 0.0003);the worst prognosis (median 7.2 m, 95%CI 5.4-13.6) was observed in pts maintaining high SAA.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Baseline high SAA predicts poor outcome in ANSCLC pts receiving 1stline P, supporting the potential immunosuppressive role. Considering the strong relationship between SAA monitoring and survival outcomes, the acquired resistance to P could be early and easily detected with a simple blood test. This prospective study is currently ongoing to increase the power and to confirm the predictive role of SAA including a control group.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Catholic University of Sacred Heart.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      163P - Immuno-oncological treatment and tumor load in non-small cell lung cancer (NSCLC): Case-control analysis of overall survival (OS) in routine clinical practice (ID 476)

      12:30 - 13:00  |  Presenting Author(s): Martin Faehling  |  Author(s): Birgit Schwenk, Marcel Kopp, Sabine Fallscheer, Sebastian Kramberg, Robert Eckert

      • Abstract

      Background

      Immuno-oncological (IO) therapies such as PD-1 and PD-L1-antibodies have been introduced in the treatment of advanced NSCLC since 2015 based on randomized trials showing unprecedented advantages in OS with hazard ratios (HR) often between 0.5 and 0.6. The impact of these treatments on survival in routine clinical practice and the role of tumor load have not been studied.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      1334 patients diagnosed with NSCLC in our certified lung-cancer center from 2006 – September 2018 were studied. OS of immuno-oncologically treated patients (“IO-patients”) who received treatment with a PD-1 antibody (nivolumab [n = 76] or pembrolizumab [n = 51]) or a PD-L1-antibody (atezolizumab [n = 4] or durvalumab [n = 12]) was compared to historic controls treated in our center before availability of IO-treatment using case-control analysis. IO-patients and historic controls were individually matched for stage, performance state, histology, smoking history, gender, age, and initial treatment mode (palliative vs. curative). Matching was performed blinded to patient number, treatment, and survival. The study was approved by the local ethics committee (Landesärztekammer Baden-Württemberg F-2017-004).

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      IO-patients had significantly longer OS than historic controls (21.8 vs. 10.7 months, HR 0,55, CI 0.40 - 0.75, p = 0.0002). The benefit was more pronounced in patients with lower tumor stage (HR 0.364 [stage III], 0.407 [IVA], 0.605 [IVB]) or smaller tumor size (HR 0.32 [RECIST < 65], 0.38 [RECIST 65-100], 0.56 [RECIST 101-145], 0.86 [RECIST > 145]).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      IO-patients in routine clinical practice showed significant benefit in OS with hazard ratios comparable to that reported in phase III trials. The benefit was greater in patients with lower tumor load.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      M. Faehling: Advisory boards: AstraZenenca, BMS, MSD, Roche. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      164P - PD-L1 expression affect the efficacy of pemetrexed maintenance therapy in real-world patients with advanced non-squamous NSCLC (ID 278)

      12:30 - 13:00  |  Presenting Author(s): Yi Qin  |  Author(s): Lili Jiang, Yanying Li, Li Ren, Yongsheng Wang, Youling Gong, Feng Peng, Jiang Zhu, Zhenyu Ding, Yongmei Liu, Min Yu, You Lu, Meijuan Huang

      • Abstract
      • Slides

      Background

      It has been demonstrated that pemetrexed maintenance therapy is an effective and well tolerated option for patients with advanced non-squamous non-small cell lung cancer (NSCLC). This study aimed to investigate the impacts of clinical features, gene status and PD-L1 expression on the efficacy of pemetrexed maintenance therapy in real-world.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      The clinicopathological characteristics and prognostic data of 102 patients with advanced non-squamous NSCLC who received pemetrexed maintenance therapy between May 2011 and October 2017 were retrospectively analyzed. Kaplan-Meier method with Log-rank test was used for survival analysis. Multivariate Cox regression were used to identify variables associated with median progression free survival (mPFS).

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      102 patients completed 485 cycles of induction chemotherapy and 509 cycles of maintenance chemotherapy, with a mPFS of 11.9 months (95%CI 9.95-13.84). The mPFS of ALK-positive patients was superior to negative patients (18.3 vs. 11.4 months; P = 0.032). Patients with PD-L1 expression ≥50% had significantly prolonged mPFS compared with PD-L1 <50% (17.5 vs. 11.4 months; P = 0.034). Bivariate correlation showed that PFS was significantly positively related to PD-L1 expression (R = 0.359, P = 0.001). No differences were found between EGFR positive and negative patients. The independent beneficial prognostic factors for PFS were age ≥65 years old (HR, 0.328; 95% CI, 0.137-0.787; P = 0.013) and ALK rearrangements (HR, 0.120; 95% CI, 0.027-0.533; P = 0.005).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Pemetrexed has been shown to be efficacious in patients with advanced non-squamous NSCLC. ALK rearrangements and high PD-L1 expression are more likely to have longer PFS of pemetrexed maintenance therapy.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      165P - Clinical benefit of anti PD-1/PD-L1 plus chemotherapy versus chemotherapy alone in first-line treatment in advanced non-small cell lung cancer: A meta-analysis (Now Available) (ID 383)

      12:30 - 13:00  |  Presenting Author(s): Thierry Landre  |  Author(s): Gaetan Des Guetz, Alain Vergnenegre, Christos Chouaid

      • Abstract
      • Slides

      Background

      First-line therapy for advanced non–small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Combination of anti-PD-1/PD-L1 to chemotherapy (CT) offers a new therapeutic option for this population.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We performed a meta-analysis of randomized trials that compared PD-1/PD-L1 inhibitor plus CT with CT alone in first line of treatment for advanced NSCLC. The outcomes included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). A fixed-effect or random-effects model was adopted depending on between-study heterogeneity.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The eight eligible studies included 4401 patients (3097 males, mostly smokers (81%), median age 64 years), with 3037 nonsquamous (69 %) and 1330 squamous tumours (30%). One study evaluated nivolumab + CT (CheckMate 227), four studies evaluated atezolizumab + CT (IMpower 130,131,132 and 150), and three studies pembrolizumab + CT (Keynote 021, 189 and 407). The combination PD-1/PD-L1 inhibitor + CT was significantly associated with improvement of OS (hazards ratio [HR], 0.72; 95% CI 0.61–0.85; p < 0.0001), PFS (HR, 0.63; 95% CI 0.58–0.68; p < 0.0001) and ORR (relative ratio [RR], 2.08; 95% CI 1.69–2.55; p < 0.0001), irrespective of PD-L1 expression level. For patients with low (<1%) or undetectable PD-L1 expression, OS benefit was statistically significant (HR, 0.75; 95% CI 0.63-0.89; p < 0.0008).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      The combination of PD-1/PD-L1 inhibitor to chemotherapy, compared with chemotherapy alone, is associated with significantly improved OS, PFS, and ORR in first-line therapy in NSCLC. This strategy appears as a new standard of care for patients with untreated NSCLC, including for those with low or undetectable PD-L1 expression.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      APHP.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      166P - Correlation of various clinical, imaging and laboratory parameters with outcome in patients with metastatic non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs): Results from a prospective, observational, single institution study (Now Available) (ID 491)

      12:30 - 13:00  |  Presenting Author(s): Konstantinos Rounis  |  Author(s): Chara Papadaki, Dimitris Makrakis, Alexia Monastirioti, Lampros Vamvakas, Konstantinos Kalbakis, Dimitrios Mavroudis, Sophia Aggelaki

      • Abstract
      • Slides

      Background

      PDL1 expression in the tumor is used as a biomarker predictive of benefit from ICIs in NSCLC. We prospectively evaluated clinical, imaging and laboratory parameters to identify additional factors that could be used for patient (pt) selection.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Pt and disease characteristics, sites (brain, liver, bones) and extent (1 vs ≥ 2) of metastases, concomitant use of steroids, antibiotics, or chronic use of proton pump inhibitors, neutrophil to lymphocyte ratio and LDH were prospectively collected from pts with NSCLC treated with ICIs in the 2nd or 3rd line. Response rate ( RR ), Progression free survival ( PFS ) and overall survival ( OS ) data were prospectively recorded.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Forty-four pts, median age 69 years, 50% squamous, 50% non-squamous, were included in the analysis. Performance status was 0-1 in 75% and 2 in 25% of pts, 92.7% were active/former smokers and PDL1 was ≥1% in 62% of pts with available PDL1 status. Partial response was recorded in 20% of pts, 30% had stable and 50% progressive disease. Median PFS and OS were 2.7 and 7.6 months, respectively. Prolonged (≥14d, either within 30d pre- or during treatment) use of antibiotics (p = 0,007) and concurrent steroids (p = 0,047) were inversely correlated with response. In multivariate analysis, liver metastases [HR = 4 (CI: 1,6 – 9,9; p = 0.003)], prolonged antibiotic use [HR = 2,76 (CI: 1,8 – 6,4; p = 0,02)] and concurrent steroids [HR = 3,3 (CI: 1,4 – 8,1; p = 0,009)] were independent predictors of shorter PFS, whereas, only antibiotics had a negative impact on OS [HR 4,6 ( CI: 1,7-12, p = 0,003 )].

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      To our knowledge this is the first prospective evaluation of routine clinical parameters potentially associated with outcome from ICIs in NSCLC. Our data are in accordance with previous retrospective reports regarding the adverse effect of antibiotics and steroids in the outcome of pts. Moreover, we show that in these pts liver metastases are predictive for inferior outcomes.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      University Hospital of Heraklion, Crete, Greece.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      167P - Prognostic significance of neutrophil/lymphocyte ratio in patients undergoing treatment with nivolumab for recurrent non-small cell lung cancer (ID 513)

      12:30 - 13:00  |  Presenting Author(s): Bernardo L. Rapoport  |  Author(s): Daniel A. Vorobiof, Lizanne Langenhoven, Jacqueline May Hall, Ronwyn Irene Van Eeden, Teresa Smit, Sze Wai Chan, Michiel Christoffel Botha, JOHANNES ISAAC Raats, Margreet De Necker, Hennie Duvenhage

      • Abstract
      • Slides

      Background

      Neutrophil-to-lymphocyte ratio (NLR) has prognostic value in several types of cancers. We investigated the influence of NLR in patients undergoing treatment with PD-1 checkpoint inhibitors for recurrent Non-Small Cell Lung Cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Study CA 209-8C3, is a multicenter, non-interventional retrospective data analysis, which include patients who were previously treated for recurrent (unresectable or metastatic) NSCLC. Retrospective data was collected from 5 participating oncology centers.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      We analyzed data of 56 patients treated with nivolumab, 32 (57%) were male with a median age of 65 (46-86). Thirty-two (57%) had NSCLC specified as adenocarcinoma. Fifty (89%) patients had an ECOG performance status (PS) of 0 or 1, and 6 (11%) had an ECOG PS of 2. A ≥ 4 cut-off value for NLR was calculated using the receiving operating characteristic (ROC) curves. The median OS was 11 months. One and two-year survival was 45% (95% CI 32% - 58%) and 32% (95% CI 20% - 45%) respectively. Median progression-free survival (PFS) was 6 months (95% CI 4 – 8). Univariate analysis found the number of metastatic sites and a higher NLR to be associated with shorter OS. Patients with ≤2 metastatic sites had a median OS of 11.4 months and patients with >2 sites 6.10 months (HR = 3.29 [95% CI 1.23-8.78], p = 0.0174). Patients with NLR ≥4 at 5-weeks post treatment had a median OS of 8.13 months, with median OS not reached for patients with NLR <4 (HR = 4.18, p < 0.001). NLR ≥4 at 9-weeks post treatment were also significantly correlated with shorter OS (HR = 4.15, p = 0.001) with median OS of 7.28 months, median OS for NLR <4 not reached. In a Cox multiple regression model with age, gender, race, ECOG PS, diagnosis, smoking status and NLR at 3-, 5- and 9-weeks, NLR ≥4 at five-weeks post nivolumab was the only factor that retained significance (HR = 5.41 95% p < 0.001). Clinically relevant grade ≥3 toxicities include pneumonitis (n = 5), severe skin rash (n = 1), colitis (n = 1) and other (n = 3).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Elevated NLR is associated with a poor outcome in patients with recurrent metastatic NSCLC treated with nivolumab.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      BMS: Study CA 209-8C3.

      682889d0a1d3b50267a69346a750433d Disclosure

      B.L. Rapoport: Contract research, Advisory boards, Speaker: BMS, MSD, Roche South Africa, AstraZeneca; Research grant: BMS, Roche South Africa. All other authors have declared no conflicts of interest.

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      168P - Dynamic changes of patelet-to-lymphocyte ratio predict efficacy of PD-1/PD-L1 inhibitors in NSCLC (ID 545)

      12:30 - 13:00  |  Presenting Author(s): Fei Zhou  |  Author(s): Anwen Xiong, Caicun Zhou

      • Abstract

      Background

      Baseline neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are markers of host inflammation and have been reported as prognostic factors in advanced cancer patients, but have not been analyzed extensively in lung cancer in the era of immunotherapy, especially the dynamic changes of these markers.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Patients who were treated with immune checkpoint inhibitors (ICIs) either as a standard of care or on a clinical trial at Shanghai Pulmonary Hospital were enrolled. Baseline complete blood count [defined as the results obtained at the time (−3/0 days) of initiating ICIs, including white blood cell (WBC), absolute neutrophil count (ANC), platelet count and absolute lymphocyte count (ALC) to calculate the NLR and PLR] were extracted from medical records. Derived NLR (dNLR) was calculated as dNLR = ANC/(WBC−ALC). C3 complete blood count (defined as the results obtained before Cycle 3 of ICIs) was also collected and calculated.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Ninety-five patients were identified in the present study. 49 (51.6%) of patients received ICI monotherapy, and 46 (48.4%) received ICI-based combination therapy. Baseline NLR, dNLR, PLR were not associated with clinical outcomes of ICI therapy (ORR or PFS). Using 5 as a C3 NLR cut-off value, patients with C3 NLR <5 had better ORR and PFS than those with C3 NLR ≥5. Furthermore, patients who had increased NLR (n = 29) had inferior ORR (17.2% versus 41.0%, P = 0.026) and median PFS (5.5 versus 8.5 months, P = 0.022) than those who had decreased NLR (n = 61). Patients with C3 dNLR <3 had better ORR and median PFS than those with C3 dNLR ≥3. Patients who had increased dNLR (n = 26) had lower ORR (15.4% versus 40.3%, P = 0.027) and inferior median PFS (5.6 versus 8.4 months, P = 0.150) than those who had decreased dNLR. There was a trend towards better ORR and median PFS in patients lower C3 PLR. Interestingly, patients who had decreased PLR (n = 47) had better ORR (42.6% versus 23.3%, P = 0.052) and median PFS (11.8 versus 5.5 months, P = 0.003) than those who had increased PLR (n = 43). Multivariate analysis revealed dynamic changes of PLR as an independent predictive factor for PFS (HR: 2.27, 95% CI, 1.10-4.71, P = 0.027).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Dynamic change of PLR has a potentially predictive role of the efficacy of ICI therapy.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      169P_PR - Benefit of immunotherapy (IT) in advanced non-small cell lung cancer (NSCLC) in elderly patients (EP) (Now Available) (ID 582)

      12:30 - 13:00  |  Presenting Author(s): Elena Corral de la Fuente  |  Author(s): Arantzazu Barquín García, Cristina Saavedra Serrano, María Eugenia Olmedo García, Roberto Martin Huertas, Juan José Serrano Domingo, Victor Albarrán Artahona, Ana Gómez Rueda

      • Abstract
      • Slides

      Background

      Despite EP (aged ≥70 years) represent the majority of patients with advanced NSCLC, the efficacy and toxicity rates of IT remain poorly described, as they are under-represented in clinical trials. Furthermore, the age-related decline in the immune system might affect efficacy of IT.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We retrospectively reviewed advanced NSCLC patients treated with IT (antiPD-1, anti-PD-L1) monotherapy as first, second and subsequent-line settings, between 2014 and 2018 in our hospital. Patient and tumor features, irAEs, concomitant and subsequent treatments were collected. Stata 14.1 was used for the analysis.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      98 patients were included. Mean age was 62 years (41-85). 73.5% were men. 73.5% had >30 smoked pack-years (py), 64.3% were adenocarcinoma (ADC), of which 41% were KRAS mutated; and 25.5% were squamous (SCC). PDL1 was known in a 50% of patients (11% <1%, 13% 1-49%, 25% >50%). IT was administered mainly as a second line (61%) and third or later (24.5%). Most employed drug was nivolumab (52%) (Table). Response Rate (RR) was 32.7% (partial response 28%, complete response 5%). Disease control rate (DCR) was 55%. Overall Survival (OS) was significantly lower in EP compared to patients aged <70 years (5.5 vs 13 months (m) HR 3.86; IC 2.073- 7.214; P < 0.0001). Progression-free survival (PFS) was significantly worse for EP than for younger patients (1.8 vs 3.6m, HR 2.1; IC 1.181 - 3.744; P = 0.012). Regarding toxicity, 30.6% irAEs were reported. There were no statistically significant differences in terms of irAEs between EP and younger patients (P = 0.535). The development of irAEs was associated with better PFS in younger patients (13.3 vs 5.5m, HR 0.45; IC 0.244 - 0.840; P = 0.012) without significant impact on OS.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Our results suggest that EP could have worse survival outcomes than younger patients, without differences in terms of toxicity, but prospective trials are needed to confirm this hypothesis.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Elena Corral de la Fuente.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      170P - Advanced non-small cell lung cancer patients with low tumor mutation burden might derive benefit from anti-programmed cell death (PD)-1 and anti-programmed deathligand 1 (PD-L1) blockade (ID 194)

      12:30 - 13:00  |  Presenting Author(s): Wei Nie  |  Author(s): Mi-Die Xu, Lu Gan, Yi Zhang, Bao-Hui Han

      • Abstract

      Background

      We aimed to investigate the association between tumor mutation burden (TMB) and survival in non-small cell lung cancer (NSCLC) patients with anti–programmed cell death (PD)-1 and anti--programmed cell deathligand 1 (PD-L1) blockade.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Five retrospective cohorts using PD1/PDL1 blockades and The Cancer Genome Atlas (TCGA) lung cancer data set were included in this study. The restricted cubic spline (RCS) analysis was used to explore the association between TMB and survival. The cut-off values for TMB were determined by X-tile software. Primary outcomes were overall survival (OS) and progression-free survival (PFS). The associations between TMB and intratumor heterogeneity, number of segments, fraction of genome alterations, aneuploidy score, and T cell populations were also investigated.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      TMB showed an inverted J-shaped curve with survival risk in RCS plot. Two cut-off values were determined by X-tile software in each cohort. In addition to high TMB, low TMB was an independent prognostic indicator for OS and PFS in NSCLC patients treated with PD1/PDL1 blockades. Objective response rate (ORR), disease control rate (DCR), and 1-year OS rate in the low TMB group were higher than that in the medium TMB group. In TCGA lung cancer data set, low TMB was also associated with longer OS in comparison with medium TMB. Furthermore, NSCLC patients with low TMB had significantly lower intratumor heterogeneity, number of segments, fraction of genome alterations, aneuploidy score, T helper type 2 (Th2) cells, and CD8+ T cells, but higher levels of Th1 and Th17 cells.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      NSCLC patients with low TMB might benefit from anti-PD1/PDL1 immunotherapy.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      171P - Previous exposure to bevacizumab indicated inferior benefits from PD-1/PD-L1 inhibitors in nonsquamous NSCLC (ID 344)

      12:30 - 13:00  |  Presenting Author(s): Fei Zhou  |  Author(s): Yingying Pan, Caicun Zhou

      • Abstract

      Background

      Bevacizumab is known to enhance the effects of immunotherapy. The landmark IMPOWER150 has demonstrated that the addition of atezolizumab to bevacizumab plus chemotherapy significantly improved survival outcomes among patients with metastatic nonsquamous NSCLC. However, the impact of previous use of bevacizumab on the efficacy of PD-1/PD-L1 inhibitors remained unclear.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Between Oct 2016 to Sep 2019, 113 patients who were treated with PD-1/PD-L1 inhibitors either as a standard of care or on a clinical trial at Shanghai Pulmonary Hospital were identified. Patients who had prior exposure to immunotherapeutic agents, or death within 4 weeks from the first dose of ICIs treatment were excluded from the analysis. The information regarding previous exposure to bevacizumab was reviewed in electronic medical record.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The median age of enrolled patients was 63 years (range, 29 to 82). Regarding histology, 59.2% (67/113) had nonsquamous NSCLC and 40.8% (46/113) had squamous cell carcinoma. Overall, 16 patients (14.2%) previously received bevacizumab therapy, all of whom had nonsquamous NSCLC. Interestingly, patients who were previous exposure to bevacizumab had shorter PFS than those who were not (1.9 versus 4.3 months, P = 0.017). We then divided patients into 3 groups: arm 1 (16 patients, previous exposure to bevacizumab), arm 2 (51 patients, nonsquamous NSCLC who were not previous exposure to bevacizumab), arm 3 (46 patients, squamous cell carcinoma). The PFS was significantly different between arm 1 and arm 2 (1.9 versus 4.3 months, P = 0.023) or arm 3 (1.9 versus 4.2 months, P = 0.045), but not arm 2 and arm 3 (4.3 versus 4.2 months, P = 0.736). Patients in arm 1 also had inferior ORR (14.3% versus 29.4% versus 29.5%, P = 0.342) and DCR (42.9% versus 70.6% versus 68.2%, P = 0.05) compared with arm 2 and arm 3. Multivariate analysis identified previous exposure to bevacizumab as being independently associated with poorer PFS (HR = 1.9, 95%CI, 1.01-3.59, P = 0.048).

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Previous use of bevacizumab indicated inferior benefits from PD-1/PD-L1 inhibitors in nonsquamous NSCLC.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      172P - A multi-center, randomized, double-blind, parallel, two-group phase III clinical study on the efficacy and safety of QL1101 or bevacizumab in combination with paclitaxel and carboplatin in the first-line treatment of non-squamous non-small cell lung cancer (ID 437)

      12:30 - 13:00  |  Presenting Author(s): Baohui Han  |  Author(s): Kai Li, Tianqing Chu, Minghong Bi, Helong Zhang, Yan Yu, Jianhua Shi, Xiaochun Zhang, Zhendong Chen, Cuicui Han, Tao Bai

      • Abstract

      Background

      QL1101 is a biosimilar molecule of bevacizumab (BEV,Avastin®) which is a monoclonal antibody (mAb) that binds and inhibits vascular endothelial growth factor (VEGF). The main purpose of the study is to evaluate whether the effectiveness of QL1101 is equivalent to that of Avastin®; the secondary purpose is to estimate the safety and immunogenicity.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      The study planed the recruitment of 512 patients with locally metastatic or recurrent non-squamous cell non-small cell lung cancer (NCT03169335). into QL1101 (test group) or Avastin® (control group) in combination with paclitaxel/carboplatin (paclitaxel 175mg/m2, carboplatin AUC=5) at a 1:1 ratio. QL1101 and Avastin (15mg/kg respectively) combined with chemotherapy, were given every 3 weeks as one treatment cycle for 6 cycles, then followed by QL1101 single-drug maintenance treatment. The primary endpoint was the best objective response rate (ORR) at week 18 evaluated by the blind independent imaging review committee.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      A total of 675 subjects were screened and 532 were eventually treated, including 266 in the trial group and 266 in the control group. At week 18, the ORR of the QL1101 group and Avastin group, evaluated by the blind independent imaging review committee, were 52.26% (CR:0, PR:139) .and 56.02% (1 cases CR, 148 PR), respectively. Risk ratio (RR) value and 90%CI was 0.933(0.818-1.064), which met the prespecified equivalence margins (0.75-1.33).The median progression-free survival in the two groups was 7.72 and 8.25 months, respectively (HR: 1.111 (0.919—1.342)). The adverse reverse incidence of CTCAE ≥ 3 in the two groups were: 31.20 % in the experimental group and 24.06 % in the control group, respectively (P = 0.0808). The immunogenicity of the two groups was similar, and no neutralizing antibodies were detected.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      QL1101 and Avastin are equivalent in clinical efficacy in non-squamous cell non-small cell lung cancer patients, and the safety profile (including immunogenicity) is similar. There are no unexpected serious adverse reactions found.

      b651e8a99c4375feb982b7c2cad376e9 Clinical trial identification

      NCT03169335; May 30, 2017.

      7a6a3ffa2dadc03a6151ee2c4d6fa383 Legal entity responsible for the study

      Qilu Pharmaceutical Co., Ltd, Shandong, People’s Republic of China.

      213f68309caaa4ccc14d5f99789640ad Funding

      Qilu Pharmaceutical Co., Ltd, Shandong, People’s Republic of China.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      173P - Stereotactic radiotherapy concurrent to immune or targeted therapy for oligometastatic NSCLC: Clinical scenarios affecting survival (ID 193)

      12:30 - 13:00  |  Presenting Author(s): Stephanie G.C. Kroeze  |  Author(s): Corinna Fritz, David Kaul, Oliver Blanck, Klaus Kahl, Falk Roeder, Shankar Siva, Joost J.C. Verhoeff, Anca L. Grosu, Markus M. Schymalla, Markus Glatzer, Marcella Szuecs, Michael Geier, Georgios Skazikis, Irina Sackerer, Fabian Lohaus, Franziska Eckert, Matthias Guckenberger

      • Abstract
      • Slides

      Background

      Oligometastatic NSCLC pts. may benefit from a more aggressive treatment approach. However, the concept of “oligometastasis” is complex: e.g. limited progression or resistance of disease to systemic treatment. This study evaluated the outcome of stereotactic radiotherapy (SRT) to oligoprogressive or oligoresistant NSCLC in pts. receiving concurrent immuno- or targeted therapy.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      The international register study (TOaSTT) collected data on metastatic NSCLC pts. receiving SRT concurrent (≤30d) to immuno- or targeted therapy. Pts. were grouped in: SRT of ≤ 5 metastases without additional metastases (oligoprogression), SRT of ≤ 5 progressive metastases with controlled disease of all other metastases (oligopersistent), and SRT of ≤ 5 metastases with otherwise mixed response/ uncontrolled disease. OS, PFS, LC and time to systemic therapy-switch after SRT were analyzed using Kaplan-Meier survival curves and log rank testing. Toxicity was scored using CTCAE.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      SRT of 192 lesions in 108 pts. was performed between 7/2009 - 5/2018. Median age was 63y (range 33-80). Driver mutations were: EGFR 41%, ALK 14%, other 21%, unknown/no 24%. Median FU was 18.7 (range 1-102) mo. 90% were ECOG 0-1. Median 1 (range 1-5) metastasis was treated. Targeted therapies were started before SRT in 69%, during SRT in 8%, and after SRT in 23%. 60% received an ALK- or EGFR-TKI, 31% PD-L1/PD-1 inhibitors, 8% bevacizumab. Oligoprogressive and oligopersistent pts showed improved OS compared to advanced metastatic disease (p = 0.008) (Fig.1). PFS was best in oligoprogressive patients; median 20.1 vs 7 and 4.4 mo. (p = 0.006). LC was median 21.0, 12.0 und 9.0mo: no sign. difference between groups. After 1y, 86%, 47% and 39% continued the same immuno- or targeted therapy as before SRT. Severe acute toxicity were observed in 7%, late toxicity in 4%.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      An excellent survival with limited toxicity was observed when definitive SRT to a limited number of metastases was combined with targeted- or immunotherapy in oligoprogressive and oligopersistent NSCLC patients. SRT of metastatic sites allowed continuation of targeted-, or immunotherapy in many patients. These observations need to be further evaluated in prospective trials.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Matthias Guckenberger.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      174P - NSCLC stages IIa-IIIc: Tumor related IGRT yields better local control than kV-guidance to anatomic structures (ID 173)

      12:30 - 13:00  |  Presenting Author(s): Franz Zehentmayr  |  Author(s): Josef Karner, Karl Wurstbauer, Romana Elisabeth Wass, Gerd Fastner, Lukas Rettenbacher, Michael Studnicka, Christian Pirich, Felix Sedlmayer, Peter Kopp

      • Abstract
      • Slides

      Background

      The prognosis for patients with LA-NSCLC (UICC stages IIa - IIIc) is still very limited with 5-year overall survival rates (OS) of approximately 20%. The meta-analysis published by Auperin et al. published in 2010 gives evidence that improved local control (LC) translates into better OS.Concurrent chemoradiotherapy – the standard of care treatment regimen – achieves LC around 65% at two years. The aim of the current single centre analysis was a comparison of LC after tumor related image guided radiotherapy (IGRT) versus kV-IGRT to central anatomic structures.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      122 patients with LA-NSCLC treated between January 2010 and December 2014 were eligible. After induction chemotherapy patients were treated with dose-differentiated accelerated radiotherapy (DART-bid) with total doses ranging between 73.8 and 90.0 Gy. In group A (69 patients) image guidance was either performed by matching to the tumor (with cone beam CT or fiducials) whereas in group B (53 patients) two orthogonal kV-images were acquired for subsequent matching to central mediastinal structures. With respect to baseline characteristics patients in group B had a higher ECOG, more loss of weight and a higher probability of a centrally located tumor. KV-imaging was used more frequently in the years 2010 and 2011, with a shift towards tumor related IGRT thereafter. Irradiation techniques changed from 3D target splitting to IMRT by the end of 2013.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      With a minimum follow-up of 3.5 years LC for all patients amounted to 73% and 59% at year 1 and 2 respectively. The difference between group A and B was insignificant (log-rank p-value = 0.080). Yet in the subgroup of 81 patients with peripheral lung cancer, tumor related IGRT led to a significantly better 1- and 2-year LC compared to kV-imaging: 84% and 72% versus 70% and 35% respectively (log-rank p-value: 0.010). Multivariate analysis (Cox regression, forward stepwise) showed that tumor related image guidance was the only significant prognosticator (p = 0.017, HR 0.279; 95%-CI 0.097 – 0.798) for LC.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Tumor related image guidance is the IGRT method of choice for patients with peripherally located tumors in order to improve local control.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      175P - Permanent pleural catheter (PPC) for malignant pleural effusion (PE) in advanced non-small cell lung cancer (NSCLC) (Now Available) (ID 215)

      12:30 - 13:00  |  Presenting Author(s): MIREIA Martinez Kareaga  |  Author(s): Nerea Urbieta-Macazaga, Cristina Sanchez-Vieco, Laura Tomás-López, Iratxe Intxaurbe-Etxebarria, Beatriz Mareque, Nuria Torrego, Alicia Narro, Laura Puntí, Iosune Guillen

      • Abstract
      • Slides

      Background

      Pleural effusion (PE) is a relatively frequent complication in patients (p) with advanced NSCLC that causes refractory symptoms such as pain and dyspnea. These patients frequently need repeated thoracocentesis to relieve symptoms.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      From May 2008 to September 2018, 30 consecutive patients of our hospital with advanced NSCLC who overwent to PPC implantation were retrospectively evaluated. Baseline characteristics, acute and late complications and outcome were retrospectively collected. Overall survival (OS) was calculated from the date of the PPC implantation to the date of death.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Thirty patients were evaluated, 20 were male and 10 female. All patients were death at the cut-off date, the 1st October 2018. Median age at PPC implantation was 66y (range: 47-91) and 80% presented ECOG PS 2. Adenocarcinoma was the most frequent histology (22p). Mean hospital stay was 7 days (range 1-28). Mean catheter duration was 60 days (range 3-181). Median OS was 14.3 weeks (IC 95%, range 1.3-59.1). Four patients (13%) suffered an acute complication: 1 pleuro-cutaneus fistula, 1 empyema, 1 hematoma and 1 needed surgical intervention because the catheter guided was at pleural cavity. After hospital discharge, one p presented a complication, with pleural liquid exit pericatheter. Twenty-five p (83%) presented clinical relief and 11p (37%) received chemotherapy after PPC implantation. Citology of pleural liquid was performed in 23p (77%) and resulted positive for malignancy in 14 cases.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      PPC implantation is a safe technique that can cause symptomatic relief in most patients with malignant pleural effusion. However, mean catheter duration and survival after PPC implantation are still low. Therefore a better selection of patients is mandatory.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      176P - Real-world treatment patterns for metastatic non-small cell lung cancer at IRST Italy (ID 499)

      12:30 - 13:00  |  Presenting Author(s): Mattia Altini  |  Author(s): Ilaria Massa, William Balzi, Nicola Gentili, Flavia Foca, Valentina Danesi, Silvia Manunta, Marco Angelo Burgio, Paola Cravero, Flavia Ejzykowicz, Sheenu Chandwani, Angelo Delmonte

      • Abstract

      Background

      This study sought to describe treatment patterns in terms of real world first-line (1L) and second-line (2L) treatment of metastatic non-small cell lung cancer (NSCLC) prior to the availability of Immunotherapies (IOs) in Italy.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Metastatic NSCLC pts who initiated anti-cancer systemic treatment at IRST from Jan 2014 to Jun 2017 were included in this retrospective analysis based on electronic health records database, including information on demographics, clinical, tumor, molecular characteristics and treatment(s) administered.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      In total, 440 pts for 1L and 152 for 2L were analyzed. Median age was 69.5 and 65.9 yrs for the 1L and 2L, respectively.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      In this real world population prior IOs approval in Italy, treatments were largely in line with NSCLC treatment guidelines. As expected, the most frequent type of regimen in 1L setting was platinum doublet and in 2L was single agent chemo.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      Merck & Co., Inc.

      213f68309caaa4ccc14d5f99789640ad Funding

      Merck & Co., Inc.

      682889d0a1d3b50267a69346a750433d Disclosure

      F. Ejzykowicz, S. Chandwani: Employee, shareholder: Merck & Co, Inc. All other authors have declared no conflicts of interest.

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      177P - Real-world experience of ALK positive NSCLC from India (Now Available) (ID 296)

      12:30 - 13:00  |  Presenting Author(s): Mridul Malhotra  |  Author(s): Vanita Noronha, Amit Joshi, Vijay Patil, Shweta Malhotra Wadhwa, Kumar Prabhash

      • Abstract
      • Slides

      Background

      ALK gene rearranged lung cancer is a rare subset of NSCLC. However, treatment with ALK inhibitors leads to a drastic improvement in outcomes. In this study, we have audited the outcomes of patients with ALK-rearranged NSCLC at our institute.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We conducted an audit of patients with ALK-rearranged NSCLC diagnosed between November 2011–December 2017 from a prospective database of lung cancer patients maintained by the authors. The basic demographic characteristics, treatment received, and the outcomes were noted. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan Meier method. This study was approved by the institutional ethics committee and was carried out in accordance with good clinical practice guidelines and the Declaration of Helsinki.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      We diagnosed 318 ALK-positive patients during November 2011–December 2017. The median age was 50 years (23-77 years); 189 patients (59.4%) were male and 129 (41.6%) were female. Only 57 (17.9%) were smokers. The ECOG PS was 0-1 in 195 patients (61.3%), 2 in 46 (14.5) and 3-4 in 33 (10.4%). Data on PS was missing in 44 patients (13.8%). The median number of sites of metastasis was 2 (0-7); brain metastases were seen in 38 patients (11.9%). The first line treatment received was as follows: crizotinib (either upfront or as a switch after a few cycles of doublet chemotherapy) in 202 patients (63.5%), pemetrexed platinum in 72 (22.6%), taxane platinum in 5 (1.6%), gemcitabine platinum in 5 (1.6%) and others in 33 (10.7%). The median PFS and median OS for the entire cohort was 11.0 months and 34.2 months, respectively. The hazard ratio (HR) favoured using crizotinib upfront (0.5, 95% CI 0.38-0.67, p < 0.001). Patients receiving upfront crizotinib had better PFS compared to those who received crizotinib as a switch after a few cycles of chemotherapy (HR: 0.66 (0.44-0.99) p-0.040). However, the median OS was similar between the two treatment strategies for crizotinib (p-0.964). The median OS in patients who never received crizotinib was 11.0 months while OS was not reached in patients who received crizotinib in any line (p< 0.001). The 5-year OS in patients receiving crizotinib in any line was 50.0%.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Crizotinib substantially improves outcomes in patients with ALK-rearranged NSCLC and is a suitable option where other ALK inhibitors are not available.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      IEC, TMH.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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      178P - Feasibility of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for treatment monitoring of brain metastases in lung cancer patients (ID 561)

      12:30 - 13:00  |  Presenting Author(s): Diana SY Abdulla  |  Author(s): Maximillian Ruge, Matthias Scheffler, Lucia Nogova, Sophia Koleczko, Thorsten Persigehl, Stefan Grau, Alexander Drzezga, Carsten Kobe, Reinhard Buettner, Norbert Galldiks, Jürgen Wolf

      • Abstract

      Background

      Brain metastases (BMs) occur frequently in patients with advanced lung cancer. So far, intracranial efficacy of systemic lung cancer treatment is nearly unpredictable. Contrast-enhanced magnetic resonance imaging (MRI) is considered gold standard for response assessment but lacks potential to discriminate between malignant or active tumor lesions from benign or postinflammatory signal alterations. O-(2- [18F]fluoroethyl)-L-tyrosine (FET)-positron emission tomography (PET) has shown additional diagnostic value over standard MRI in glioma patients. We set out this analysis to determine the feasibility of FET PET in lung cancer patients.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      FET with a mean activity of 200 MBq was produced and FET PET performed 20-40 minutes post injectionem at Research Center Juelich (Forschungszentrum Jülich). Patients with cerebral metastasized lung cancer underwent at least one tomography, and tumor volume and activity were assessed by both standard uptake values (SUVs) or tumor-to-brain ratios. A lesion-brain ratio in the standard uptake value (SUV) of more than 2 was considered pathological.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      From 2015 to 2018, 48 patients received at least one FET PET, whereof 11 patients (22.9%) underwent two scans and one patient three serial FET PETs. All scans could be analyzed for the assessment of tumor activity. The patients did not suffer of adverse events related to the tracer or the procedure. In most cases, FET PET was performed to discriminate between scar tissue and new tumor activity in singular metastases treated stereotactically. In a smaller number of patients, FET PET was used to assess treatment response in systematically treated patients.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      FET PET is feasible in patients with brain metastases of lung cancer and might provide additional information to MRI for treatment decisions in these patients. Validation of the results and the reproducibility is ongoing.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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      179P - Treatment (tx) characteristics of patients (pts) with locally advanced or metastatic non-small cell lung cancer (NSCLC) receiving atezolizumab (atezo) monotherapy in US clinical practice (ID 227)

      12:30 - 13:00  |  Presenting Author(s): Martin Frueh  |  Author(s): Osama E. Rahma, Russell K. Pachynski, Julien Mazieres, Jerome Goldschmidt Jr., Thanh G.N. Ton, Shivani K. Mhatre, Ching-Yi Chuo, Jorge Martinalbo, Jessica Davies, Rosalyn Juergens

      • Abstract
      • Slides

      Background

      In the randomised Ph III OAK study, atezo (anti–PD-L1) significantly improved survival vs docetaxel, regardless of PD-L1 levels, and was approved by the FDA and EMA as 2L+ tx for advanced NSCLC. Given limited real-world data (RWD) on atezo in clinical practice, we describe here tx and characteristics of pts receiving atezo in clinical practice.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Pts diagnosed with advanced NSCLC on or after Jan 1, 2011, and who initiated 2L+ atezo before Jul 1, 2017, were identified from the Flatiron Health database of electronic health records from US-based hospitals and community practices. Time-on-treatment (TOT) was defined as time from first to last atezo dose, plus 1 cycle. Median TOT was calculated using the Kaplan-Meier methods. Data from the OAK registrational trial (NCT02008227) are provided.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      122 pts met selection criteria (Table). 105 pts (86%) had 2L+ atezo without prior anti–PD-1 tx, while 17 pts (14%) had prior anti–PD-1 tx. Median TOT was 3.9 mo (95% CI: 2.9, 4.9), similar to OAK. A median of 4 cycles was administered for both non-squamous (IQR 1-22) and squamous (IQR 1-17) histology. Progression was the most common reason for atezo discontinuation.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      TOT with atezo in the US RW setting was similar to the OAK clinical trial setting, although pts treated in RW were older and 22% had ≥ 3 lines of previous therapy.

      b651e8a99c4375feb982b7c2cad376e9 Editorial acknowledgement

      Medical writing assistance for this abstract was provided by Steffen Biechele, PhD, of Health Interactions and funded by F. Hoffmann-La Roche, Ltd.

      934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study

      F. Hoffmann-La Roche, Ltd.

      213f68309caaa4ccc14d5f99789640ad Funding

      F. Hoffmann-La Roche, Ltd.

      682889d0a1d3b50267a69346a750433d Disclosure

      M. Frueh: Consulting/advisory: BMS, MSD, AZ, BI, Roche; Research funding: MSD. O.E. Rahma: Advisory board: Celgene, Leerink, PRMA Couns., Outcomes4me, Puretech; Consulting: Alcimed SAS, GFK, Merck, Five Prime, Defined Health Honorarium: Merck, Clinical Care Option, Mi Bioresearch, Alaunusglobal; Other (study/editorial support): Roche. R.K. Pachynski: Grants/research support: Ferring, Janssen; Consultant: AZ, BMS, EMD Serono, Exelixis, Dendreon, Jounce, Pfizer; Speakers: AZ, GNE/Roche, Dendreon, Genomic Health, Sanofi, Merck; Other (support of parent study and funding of editorial support): Roche. J. Mazieres: Financial relationship: Roche, BMS, MSD, AstraZeneca, Pfizer, Novartis: consulting fees; Contracted research: Roche, BMS. J. Goldschmidt Jr.: Consulting/advisory role/honorarium: Amgen; Speakers bureau: BMS, Celgene; Support of parent study, funding of editorial support: Roche. T.G.N. Ton: Full time employee with self-managed stock: Genentech/Roche. S.K. Mhatre: Genentech, Inc./F. Hoffmann-La Roche: full time employee F. Hoffmann-La Roche: Stock shareholder (self managed) C-Y. Chuo: Full time employee, stock, support of parent study, funding of editorial support: Roche/Genentech. J. Martinalbo, J. Davies: Full time employee: F. Hoffmann-La Roche. R. Juergens: Honoraria: Amgen, AZ, BI, BMS, Lilly, Merck Sharp & Dohme, Roche Canada; Consulting or advisory role: Amgen, AZ, BI, BMS, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche Canada; Research funding: AZ/MedImmune, BMS, Merck Sharp & Dohme, Novartis.

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      180TiP - An open-label, randomized, phase I/II trial of IO102 and pembrolizumab, or IO102, pembrolizumab and chemotherapy, as first-line treatment for patients with metastatic non-small cell lung cancer (ID 208)

      12:30 - 13:00  |  Presenting Author(s): James Spicer  |  Author(s): Mariano Provencio, Pilar Garrido Lopez, Joaquim Bosch-Barrera, Francisco Javier de Castro Carpeño, Enriqueta Felip, José Trigo, Santiago Viteri, Elisabeth Coart, Emmett Schmidt, Anita Vedel Christiansen, Mai-Britt Zocca, Mads Hald Andersen, Eva Ehrnrooth, Luis Paz-Ares

      • Abstract
      • Slides

      Background

      Immunotherapy has significantly changed the treatment landscape of non-small cell lung cancer (NSCLC) with no driver mutations. However, despite the addition of anti-PD-1/PD-L1 therapies to the clinical armamentarium only a subset of patients derives durable benefit. IO102 is a novel, second generation, HLA-A unrestricted immune modulating T-win® vaccine targeting IDO. IO102 has a dual mode of action; remodulation of the tumour micro-environment through elimination of immune suppressive cells and induction of CD8 T-cell mediated killing of IDO-expressing tumor cells. Our first-generation IDO vaccine (IO101) has shown promising antitumor activity and a favorable safety in heavily pretreated NSCLC patients (Iversen, CCR 2013).

      a9ded1e5ce5d75814730bb4caaf49419 Trial design

      Phase I/II, international, multicenter, open-label, randomized trial with two parallel cohorts. Cohort A: IO102 (100µg s.c.) and pembrolizumab (200 mg) (PD-L1 ≥ 50%); Cohort B: IO102, pembrolizumab and carboplatin plus pemetrexed (PD-L1 < 50%). The maximum treatment duration is 35 cycles (app. 2 years). Key eligibility criteria include metastatic NSCLC or non-squamous NSCLC (cohort B) with no prior treatment for metastatic NSCLC and no driver mutations. Phase I is a non-randomized safety run-in with 6 patients per cohort investigating one dose level of the experimental arms. Only one DLT is allowed in each cohort. Phase II is following Sargent’s two-stage, three-outcome optimum design (Sargent, ClinTrial2001) with a 2:1 randomization in the cohorts. Cohort A: IO102 and pembrolizumab versus pembrolizumab alone; Cohort B: IO102, pembrolizumab and chemotherapy vs. pembrolizumab and chemotherapy. Provision of blood and tumour tissue is required for biomarker studies. The primary endpoint is safety and objective response rate (ORR) per RECIST 1.1 in Phases I and II, respectively. Secondary endpoints include ORR per iRECIST, duration of response, progression free survival, overall survival, and biomarkers including immunoscore in tissue, tumour mutational burden and immunomonitoring in blood. The study is enrolling in Europe and US: EudraCT Number 2018-000139-28 / IND Number 018081.

      d9b324a48b043b3d87bc9b3fe620f260 Clinical trial identification

      EudraCT 2018-000139-28 / IND Number: 018081.

      7a6a3ffa2dadc03a6151ee2c4d6fa383 Legal entity responsible for the study

      IO Biotech.

      213f68309caaa4ccc14d5f99789640ad Funding

      IO Biotech.

      682889d0a1d3b50267a69346a750433d Disclosure

      J. Spicer: Research funding, honoraria (institutional): Achilles, AstraZeneca, Bayer, BerGenBio, Boehringer Ingelheim, BMS, Celgene, Curis; Genmab, Roche, Shionogi, Starpharma, Taiho; Co-founder, shareholder: IGEM Therapeutics. P. Garrido Lopez: Consulting, advisory: I4, MSD, BMS, Boerhinger Ingelheim, Pfizer, AbbVie, Guardant Health, Novartis, Lilly, AstraZeneca, Janssen, Sysmex, Blueprint Medicines, Takeda; Speaker: Roche, MSD, BMS, Pfizer, Novartis, Boerhinger Ingelheim. J. Bosch-Barrera: Advisory board: MSD. E. Felip: Advisory: Blue Print Medicines, Celgene, Guardant Health, Janssen; Advisory, speaker: AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Merck KGaA, MSD, Novartis, Pfizer, Roche, Takeda; Consultant: Boehringer Ingelheim. J. Trigo: Advisory board: Takeda, BMS, Boehringer; Speaker: BMS, Boehringer, Roche, AstraZeneca. S. Viteri: Speaker fees: BMS, Roche; Travel fees: Servier, Roche, Merck Serono; Advisory fees: Roche, AbbVie; Research fees: Roche, BMS, Servier, Merck Serono, AbbVie, Janssen. E. Schmidt: Employed: Merck & Co., Inc. A.V. Christiansen, E. Ehrnrooth: Employed: IO Biotech; Member of the Safety Monitoring Committee for the IO102-012/KN-764 trial. M-B. Zocca: Chief Executive Officer, founder: IO Biotech; Member of the Safety Monitoring Committee for the IO102-012/KN-764 trial. M.H. Andersen: Chief Scientific Officer, founder, member of BoD: IO Biotech. L. Paz-Ares: Advisory board: Roche, Lily, MSD, BMS, Boehringer Ingelheim, Novartis, AstraZeneca, Amgen, Pfizer. All other authors have declared no conflicts of interest.

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      181TiP - Phase II study of crizotinib in Japanese patients with advanced non-small cell lung cancer harboring a MET gene alteration: Co-MET study (ID 170)

      12:30 - 13:00  |  Presenting Author(s): Motostugu Shimokawa  |  Author(s): Kaname Nosaki, Takashi Seto, Kadoaki Ohashi, Masahiro Morise, Yutaka Fujiwara, Jun Sakakibara, Haruyasu Murakami, Seiji Yano, Miyako Satouchi, Shingo Matsumoto, Koichi Goto, Kiyotaka Yoh