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Fred R. Hirsch

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    JCSE01 - Perspectives for Lung Cancer Early Detection (ID 779)

    • Event: WCLC 2018
    • Type: Joint IASLC/CSCO/CAALC Session
    • Track: Screening and Early Detection
    • Presentations: 20
    • Now Available
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      JCSE01.02 - Necessity for Early Detection in Lung Cancer and Initial Attempts for Early Detection (Now Available) (ID 11395)

      08:00 - 08:20  |  Presenting Author(s): Annette Maree McWilliams

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCSE01.03 - CT Screening for Early Detection (NLST, UKLS, NELSON, ITALUNG, DANTE, Others) (Now Available) (ID 11396)

      08:20 - 08:40  |  Presenting Author(s): Matthijs Oudkerk

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCSE01.04 - Risk Modeling for the Early Detection of Tin Miner Lung Cancer in China (Now Available) (ID 11397)

      08:40 - 09:00  |  Presenting Author(s): You-lin 13910410711 Qiao

      • Abstract
      • Presentation
      • Slides

      Abstract

      Result of National Lung Cancer Screening Program has demonstrated a 20% reduced lung cancer mortality with low-dose computed tomography among current or former smokers with a smoking history of 30 or more pack-years[1]. Selecting high risk population for LDCT screening is a key issue for lung cancer screening. Many studies have suggested that lung cancer risk model which incorporating these factors can be more accurate to identify high risk individuals suitable for LDCT screening than the NLST criteria[2]. Thus, more precise evaluation of association between these factors are warranted to developing lung cancer risk models.

      In this study, we developed and internal validated a lung cancer risk model with data of a occupational screening cohort in Yunnan, China with the aim to exploring potential improvement of yield of lung cancer screening with Chest X-ray and Sputum cytology due to the improved risk stratification. This study was a prospective occupational cohort study among tin miners from Yunnan Tin Corporation (YTC) initiated in 1992[3]. Participants were tin miners aged 40 or over and had at least 10 years of underground work or smelting history. Participants also had received annual lung screening from 1992 to 1999, and were annually followed up through December 31, 2001. Previous studies suggested that age, education level, smoking, occupational radon and arsenic exposure, prior chronic bronchitis were risk factors of lung cancer risk in this cohort[4-6]. During the study period, a total of 443 lung cancer deaths were confirmed among 9295 participants. To reduce the potential information bias, 69 lung cancer death with 1 year since enrollment were not included into the analysis.

      To stratified those with higher lung cancer risk, we increased the age criteria from 40 to 50 years old(model 0), then further developed three risk prediction models with multivariate logistic regression respectively, and the predicted probability of lung cancer death for each participants were also calculated based on logistic regression model respectively(table1). The goodness of fit, discrimination and calibration ability of the model performance were evaluated with -2log likelihood, area under the receiver operator characteristic curve (AUC) (C-index) and Hosmer-Lemeshow test. We found that the model incorporated age, gender, smoking, educational prior chronic bronchitis, occupational radon and arsenic had the best discrimination performance with area under ROC as of 0.821(95%CI:0.805-0.836) (figure1a). The calibration performance of this model was also good(Hosmer–Lemeshow type χ2=5.413,p=0.773)(figure1b). The areas under ROC curve of model 2 and model 3 were significantly better than those of model1 and model 0(all p<0.001), however, no difference was found between model 2 and model 3. Besides, Bootstrapping techniques were used for internal validation of the model 3 to Correct for this overfit or optimism, and discrimination C-statistic from C-statics was the same to the original data.

      We stratified the participants into 4 quintiles for the predicted risk of death from lung cancer. The cumulative lung cancer death rate from quintile 1 with lowest risk to quintile 4 having the highest risk increased from 11.51, 47.66, 625.41 to 1732.37 per 105 person-years, while only 2.5% of all lung cancer deaths were in quintile 1 and 2. Similarly, in 210 screen-detected lung cancer deaths, the proportion in quintile 1 and 2 was only 2.4%.

      In conclusion, we have developed and internal validated a lung cancer risk model based on personal and occupation covariates in this occupational population, and this model showed good accuracy for the identification of lung cancer and might assist in identifying individuals at high risk of developing lung cancer in lung cancer screening in this occupational cohort.

      [1] Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011. 365(5): 395-409.

      [2] Tammemägi MC. Application of risk prediction models to lung cancer screening: a review. J Thorac Imaging. 2015. 30(2): 88-100.

      [3] Qiao YL, Taylor PR, Yao SX, et al. Risk factors and early detection of lung cancer in a cohort of Chinese tin miners. Ann Epidemiol. 1997. 7(8): 533-41.

      [4] Lubin JH, Qiao YL, Taylor PR, et al. Quantitative evaluation of the radon and lung cancer association in a case control study of Chinese tin miners. Cancer Res. 1990. 50(1): 174-80.

      [5] Fan YG, Jiang Y, Chang RS, et al. Prior lung disease and lung cancer risk in an occupational-based cohort in Yunnan, China. Lung Cancer. 2011. 72(2): 258-63.

      [6] Yao SX, Lubin JH, Qiao YL, et al. Exposure to radon progeny, tobacco use and lung cancer in a case-control study in southern China. Radiat Res. 1994. 138(3): 326-36.

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      JCSE01.05 - Biomarkers and Liquid Biopsy for Early Detection of Lung Cancer (Now Available) (ID 11398)

      09:00 - 09:20  |  Presenting Author(s): K.C. Allen Chan

      • Abstract
      • Presentation
      • Slides

      Abstract

      The analysis of circulating DNA released by tumor cells, frequently known as liquid biopsy, provides a convenient and noninvasive way for the assessment of cancers. The most common application of liquid biopsy is to guide the choice of treatment in lung cancers. The detection of EGFR mutations in the plasma of patients with advanced lung cancers is useful for predicting the response to EGFR TKI treatment. Because of its noninvasive nature and quick turn-around time, liquid biopsy has been proposed to be a first line investigation for the assessment of EGFR mutational status. Another potential application of liquid biopsy is for the screening of early cancers. However, there is a lack of information regarding the biological feasibility of this approach as it is unclear if a small tumor would release sufficiently large amount of DNA into the circulation to allow early detection of the cancer. In this regard, we used nasopharyngeal cancer (NPC) as a model to address this biological question. As NPC is closely related to Epstein-Barr virus infection, we developed plasma EBV DNA as a marker for NPC. From 2013 to 2016, we screened over 20,000 asymptomatic men for NPC using a sensitive plasma EBV DNA assay. Subjects with positive test results were further investigated with nasal endoscopy and MRI. Through this arrangement, we identified 34 cases of NPC and almost half of them had stage I disease. Compared with historical cohorts, patients identified by screening had much improved progression-free survivial with a hazard ratio of 0.1. This study clearly demonstrates that a small early cancer can release sufficiently large amount of DNA into the circulation to allow sensitive detection by liquid biopsy. To apply these results to non-viral-associated cancers, we developed a generic cancer test based on copy number aberrations and altered methylation in plasma DNA. This test successfully detect various types of cancers, including lung cancer.

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      JCSE01.06 - Incorporating Artificial Intelligence for Early Detection of Lung Cancer (Now Available) (ID 11399)

      09:20 - 09:40  |  Presenting Author(s): Jie Hu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCSE01.09 - Cluster Trial: Ph2 Biomarker-Integrated Study of Single Agent Alpelisib, Capmatinib, Ceritinib and Binimetinib in advNSCLC (Now Available) (ID 11678)

      10:15 - 10:25  |  Presenting Author(s): Qing Zhou  |  Author(s): Yi-Long Wu, Xu-Chao Zhang, Hai-Yan Tu, Bin Gan, Bin-Chao Wang, Chong-Rui Xu, Hua-Jun Chen, Ming-ying Zheng, Zhen Wang, Xiao-Yan Bai, Yue-Li Sun, Andrea Myers, Xueting Lv, Yajnaseni Chakraborti, Sylvia Zhao, Jin -Ji Yang

      • Abstract
      • Presentation
      • Slides

      Background
      Several genetically altered signaling pathways have been profiled in NSCLC, enabling advanced management of NSCLC using targeted therapies. This study investigated the therapeutic spectrum of NSCLC with uncommon molecular alterations by allocating patients to treatment arms based on molecular aberrations; targeted therapies alpelisib (PI3Kαi), capmatinib (METi), ceritinib (ALKi), and binimetinib (MEKi) were evaluated.The study was based on the umbrella design. Key objectives: investigate feasibility of using one trial for different agents based on biomarker-integrated analysis, assess anti-tumor activity, characterize safety, tolerability and PK profiles of individual agents. Key eligibility criteria: age ≥18 years; ECOG PS ≤2; failed prior treatment/unsuitable for chemotherapy. Documentation of locally determined molecular alterations before treatment allocation was required (alpelisib, 350 mg QD: PIK3CA mutation/amplification; capmatinib, 400 mg BID (tablet): MET IHC overexpression/amplification; ceritinib, 750 mg QD: ALK or ROS1 rearrangement; binimetinib, 45 mg BID: KRAS, NRAS or BRAF mutation).Sixty-six patients with advNSCLC were enrolled (median age 58 years; 65.2% male: alpelisib, n=2; capmatinib, n=16; ceritinib, n=26; binimetinib, n=22). As of Feb 28, 2018, 10 patients in ceritinib and 2 in binimetinib arms were ongoing. Twenty-four patients had confirmed partial responses (36.4%): alpelisib, 0%; capmatinib, 18.8%; ceritinib, 73.1%; binimetinib, 9.1% (Figure). Longest mPFS (14.4 months) was in ceritinib arm. Among the most common treatment-related AEs: alpelisib: malaise, hyperglycemia, dysgeusia; capmatinib: nausea, anemia, peripheral edema, decreased appetite; ceritinib: diarrhea, vomiting, ALT/AST elevation; binimetinib: mouth ulceration, AST, blood CPK increased, rash. Most AEs were grade 1/2.

      abstract #1.jpg

      Objective responses/tumor shrinkage were observed in the study; highest ORR and mPFS were observed with ceritinib, although patient numbers differed between arms. All treatments were well tolerated; no new safety signals were observed. This study demonstrated the feasibility of an umbrella trial and importance of precision medicine in the management of advNSCLC with uncommon molecular alterations.

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      JCSE01.10 - A Ph3 Study of Niraparib as Maintenance Therapy in 1L Platinum Responsive Extensive Disease Small Cell Lung Cancer Patients (Now Available) (ID 11679)

      10:25 - 10:35  |  Presenting Author(s): Shun Lu  |  Author(s): Liyan Jiang, Xinghao Ai, Junling Li, Xiaorong Dong, Dan Zhang, Qi Liu

      • Abstract
      • Presentation
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      Background
      Small cell lung cancer (SCLC) accounts for 15% of lung cancer, characterized by early dissemination and rapid development of chemo-resistant disease after platinum response (60-80%). Less than 2% of extensive disease SCLC (ED-SCLC) patients survive 5 years. The bi-allelic loss or inactivation of TP53 and RB1 is common in SCLC, the poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA damage repair enzyme, is highly expressed in SCLC, and SCLC is sensitive to platinum based chemotherapy, suggesting that the defect in DNA damage repair pathways plays an important role in SCLC. ZL2306/ Niraparib is a highly selective PARP-1/2 inhibitor which was exclusively licensed for development in China by Zai Laboratory from TESARO. In SCLC PDX model, niraparib demonstrated anti-tumor activities as monotherapy. In addition, niraparib demonstrated promising tumor growth inhibition in maintenance post platinum treatment in platinum sensitive SCLC PDX models. Clinically, in phase III NOVA study, niraparib demonstrated clear clinical benefit as maintenance treatment by significantly extending progression free survival in all platinum-sensitive recurrent ovarian cancer patients regardless gBRCA or HRD status which led to the approval by FDA and EMA in ovarian cancer. It is suggested that niraparib maintenance therapy could provide potential clinical benefit in platinum responsive SCLC. ZL-2306-005 is a randomized double-blind multi-center phase 3 study to evaluate the efficacy and safety of niraparib versus placebo as maintenance therapy in ED-SCLC patients who have had responses to platinum based chemotherapy.Approximately 590 Chinese patients with histologically or cytologically confirmed ED-SCLC who have achieved either complete response or partial response to their platinum based chemotherapy to their newly diagnosed disease will be randomized (2:1) to 2 groups, receiving either ZL-2306 or placebo in ZL-2306-005 study. Patients need to complete 4 cycles of etoposide + cisplatin/ carboplatin. All patients will be stratified by gender, LDH level and history of prophylactic cranial irradiation. ZL-2306 will be started with 300mg PO QD for patients with a baseline body weight ≥77 kg and a baseline platelet count ≥150,000/μL, or 200 mg PO QD for patients with a baseline body weight <77 kg or a baseline platelet count <150,000/μL based on RADAR analysis in NOVA study. Patients will remain on treatment until disease progression or intolerable toxicity. The co-primary endpoints are PFS assessed by independent central radiologic review and OS; the secondary endpoints are PFS assessed by investigator, CFI, QoL, safety and tolerability.

      Section not applicable

      Section not applicable

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      JCSE01.11 - Dynamic ctDNA Monitoring Revealed Novel Resistance Mechanisms and Response Predictors of Osimertinib Treatment in East Asian NSCLC Patients (Now Available) (ID 14716)

      10:35 - 10:45  |  Presenting Author(s): Jianhua Chang  |  Author(s): Zhihuang Hu, Dongmei Ji, Shannon Chuai, Weina Shen, Junning Cao, Jialei Wang, Xianghua Wu

      • Abstract
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      Background

      Advanced NSCLC patients, harboring EGFR T790M, exhibit marked diversity in tumor behavior and response to AZD9291, yet a discriminable molecular profile remains elusive. In addition, although EGFRC797S was involved in 30% of AZD9291 resistance cases in Western patients, mechanisms for the rest patients remain unclear, especially for the East Asian population. We utilized circulating tumor DNA (ctDNA) profiling to conduct dynamic monitoring in patients undergoing AZD9291, thus characterizing mutational heterogeneity and genomic evolution.

      Longitudinal plasma samples were collected before, during and post of the AZD9291 treatment in Chinese NSCLC patients with acquired T790M mutation. A ctDNA panel, spanning 160KB of human genome, was used to perform capture-based targeted sequencing that comprises critical exons and introns of 168 genes. The EGFR mutation abundance and dynamic changes of allele fraction (AF) were analyzed with progression-free survival (PFS) after AZD9291 treatment.

      A total of 61 samples were collected longitudinally from 14 patients, of which 9 have experienced progressive disease (PD). Six patients exhibited a rebound of ctDNA prior to radiographic PD, suggesting the potential of ctDNA in early detection of PD. Several acquired mutations were detected with the AZD9291 resistance, including newly identified EGFR G796S, L792H/F/R/V, V802F, V843I mutations, expect for the previously reported RB1 and EGFR C797S, L718Q mutations. Patients with a higher ratio of T790M and EGFRactivating mutation at baseline had a significantly longer PFS (9.6m vs 4.5m, p=0.008). A lower ratio of EGFRactivating mutation AF compared to baseline at first follow-up was significantly correlated with a longer PFS (8.5m vs 5.0m, p=0.027). Furthermore, patients harboring other known driver mutations in addition to T790M at baseline had an inferior PFS (4.9m vs 7.8m, P=0.039).

      Several novel resistance mechanisms were identified by ctDNA monitoring in the East Asian patients treated with AZD9291. Relative AF of T790M, changes of AF after treatment and the presence of concurrent driver mutations at baseline could predict clinical benefit of AZD9291 treatment.

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      JCSE01.12 - Discussant Oral Abstracts (Now Available) (ID 11681)

      10:45 - 11:00  |  Presenting Author(s): Daniel S.W. Tan

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCSE01.13 - Discussant Poster Abstracts (Now Available) (ID 11682)

      11:00 - 11:15  |  Presenting Author(s): Bob T. Li

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCSE01.14 - Effects of Neoadjuvant Chemotherapy on the Expression of Programmed Death Ligand-1 and Tumor Infiltrating Lymphocytes in Lung Cancer Tissues (ID 14703)

      11:15 - 11:15  |  Presenting Author(s): Xu Wang  |  Author(s): Wenyu Sun, Kewei Ma

      • Abstract

      Background
      Immune checkpoints programmed death 1(PD1)and its ligand PD-L1,PD-L2 pathways can mediate negative synergistic stimulation signals.Immunotherapy combined with chemotherapy can increase the objective response rate of cancer patients,but the mechanism of combination therapy is not clear.This study aims to analyze the changes of PD-L1,PD-L2 in lung cancer tissues and the changes of TILs ( CD4+,CD8+,CD28+,and CD56+ lymphocytes ) surrounding the tumor before and after neoadjuvant chemotherapy(platinum-based),in order to provide a theoretical basis for relevant clinical studies.Tumor samples were obtained from 26 patients who confirmed primary lung cancer before and after NAC from 2009 to 2016 in the First Hospital of Jilin University. The expression of PD-L1, PD-L2 in lung cancer specimens were assessed by IHC. 5%,10%,20%,30%,50% expression thresholds were used to define PD-L1, PD-L2 positive status, respectively. Of 16 patients ( since the biopsy tissue specimens were limited, only 16 cases of biopsy and postoperative tissue specimens were collected), the expression of TILs around the tumor before and after NAC were assessed by IHC. We analyze the changes of PD-L1 and PD-L2 in lung cancer tissues before and after NAC, the correlation between the changes of PD-L1 in lung cancer tissues and tumor shrink rate, the interval from the end of NAC to operation, pathological type, gender and smoking status. Of 16 patients, the changes of TILs around the tumor before and after NAC were also evaluated. P<0.05 was considered statistically significant.

      1. When using 5%, 10%, and 20% as expression threshold to define PD-L1 positive status, PD-L1 was up-regulated after NAC (P=0.008,P=0.016,P=0.016). However, there were no obviously statistical significance about the expression of PD-L1 when using 30%, 50% expression threshold. The expression of PD-L2 were not show any statistical significance before and after NAC.

      2. Of 16 patients, the expression of CD4+, CD8+ and CD28+ lymphocytes increased after NAC (P=0.014,P=0.038,P=0.021), whereas the change of CD56+ lymphocytes was not statistical significant.

      3. There were no significant difference between the changes of PD-L1 and tumor shrink rate, interval from the end of NAC to operation, pathological type, gender and smoking status .

      1. NAC up-regulates the expression of PD-L1 in lung cancer tissues when the expression thresholds are 5%, 10%, and 20%.

      2. NAC up-regulates the expression of CD4+, CD8+, and CD28+ lymphocytes.

      3. No correlation exists between the variation of PD-L1 and tumor shrink rate, interval from the end of NAC to operation, pathological type, gender and smoking status.

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      JCSE01.15 - Molecular Characteristics of ALK Primary Point Mutations Non-Small-Cell Lung Cancer in Chinese Patients (ID 14704)

      11:15 - 11:15  |  Presenting Author(s): Chunwei Xu  |  Author(s): Jinhuo Lai, Wenxian Wang, Quxia Zhang, Wu Zhuang, Yunjian Huang, Youcai Zhu, Yanping Chen, Gang Chen, Meiyu Fang, Tang Feng Lv, Yong Song

      • Abstract
      • Slides

      Background
      Anaplastic lymphoma kinase (ALK) gene rearrangements have been identified in lung cancer at 3-7% frequency, thus representing an important subset of genetic lesions that drive oncogenesis in this disease. While the genetic locus of ALK primary point mutations NSCLC patients is unclear. The aim of this study is to investigate mutations and prognosis of NSCLC harboring ALK primary point mutations.

      A total of 339 patients with non-small-cell lung cancer were recruited between July 2012 and December 2015. The status of ALK primary point mutation and other genes were detected by next generation sequencing.


      ALK gene primary point mutation rate was 8.55% (29/339) in non-small cell lung cancer, including V163L (3 patients), F921Gfs*16 (2 patients), K1416N (2 patients), A585T (2 patients), P1442Q (1 patient), A348T (1 patient), K1525E (1 patient), S737L (1 patient), P115L (1 patient), Q515E (1 patient), E314D (1 patient), R395H (1 patient), S1219F (1 patient), S341G (1 patient), P1543S (1 patient), G129V (1 patient), Q167H (1 patient), L550F (1 patient), T1012M (1 patient), D302Y (1 patient), H755Q (1 patient), H331Q (1 patient), G1474E (1 patient) and E119D (1 patient), and median overall survival (OS) for these patients was 20.0 months. Among them, 27 patients with co-occurring mutations had a median OS of 20.0 months, and median OS of the 2 patients without complex mutations was 8.5 months. Statistically significant difference was found between the two groups (P=0.02). Briefly, patients with (n=8) or without (n=21) co-occurring EGFR mutations had a median OS of 24.0 months and 20.0 months respectively (P=0.73); patients with (n=21) or without (n=8) co-occurring TP53 mutations had a median OS of 20.0 months and 17.0 months respectively (P=0.83).

      EGFR and TP53 gene accompanied may have less correlation with ALK primary point mutation in NSCLC patients. Results of ongoing studies will provide a platform for further research to offer individualized therapy with the purpose of improving outcomes.

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      JCSE01.16 - Positive Correlation Between Whole Genomic Copy Number Variant Scoring and the Grading System in Lung Non-Mucinous Invasive Adenocarcinoma  (ID 14705)

      11:15 - 11:15  |  Presenting Author(s): Zheng Wang  |  Author(s): Shenglei Li, Lin Zhang, Lei He, Di Cui, Chenglong Liu, Yuyan Gong, Bi Liu, Xiaoyu Li, Wang Wu, David Cram, Dongge Liu

      • Abstract
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      Background
      Grading systems of Lung adenocarcinoma have been proposed by Sica and Kadota in stage I tumors,but the predominant architectural subtypes grading system is applicable for resection samples mostly. The correlation between the histological subtypes and grading with whole genomic copy number variation(WGCNV) is unknown, and was investigated in lung non-mucinous invasive adenocarcinoma (LNMIA) at this study.The predominant histological subtype from 58 resection specimens of LNMIA and 20 para-cancerous lung tissues were collected by laser microdissection from HE staining FrameSlides PEN-Membrane slides.7 of 58 specimens,two predominant subtypes in one cancerous nodule were collected simultaneously. Whole genome amplification followed by high-throughput sequencing was used to deteted WGCNV with the para-cancerous lung tissues as normal reference set and WGCNV was scored by a particular formula.
      abstract #1.jpgabstract #2.jpg

      The letters above the figure show the results of Chi-squared test, and same letters mean no significant difference.

      WGCNV median scores of 5 histological subtypes of LNMIA with three tiered architectural grades are shown in Table1. The WGCNV scores have a positive correlation with either histological subtypes and architectural grading system (Figure1 A and B). The differences of WGCNV scores are detected betweem two predominant subtypes in one cancerous nodule.

      GWCNV scores display a positive correlation with three tiered architectural grading system and may has a potential value to predict prognosis in LNMIA.

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      JCSE01.17 - Weekly Nab-Paclitaxel Plus Carboplatin as Neoadjuvant Therapy for IIIA-N2 Lung Squamous Cell Carcinoma: A Prospective Phase II Study (ID 14706)

      11:15 - 11:15  |  Presenting Author(s): Changli Wang  |  Author(s): Yu Zhang, Jian Quan Zhu, Dongsheng Yue, Xiaoliang Zhao, qiang Zhang, Hui Chen

      • Abstract
      • Slides

      Background
      To evaluate the safety and antitumor activity of weekly nab-paclitaxel combined with carboplatin in patients with advanced stage IIIA-N2 NSCLC patients with squamous histologyFrom April 2015 to August 2017, 36 treatment-naive, pathologically diagnosed IIIA-N2 lung squamous cell carcinoma patients were enrolled and given two cycles of weekly nab-paclitaxel (100mg/m2, day1,8,15 of a 21-day cycle) plus Carboplatin (AUC = 5 at day 1, q3w) as neoadjuvant therapy. Then resectability was assessed and surgery was performed for resectable lesions. Post-operative adjuvant chemotherapy regimens is the combination of Nab-paclitaxel (100mg/m2, qw x 6) and carboplatin (AUC 5, Q3W x 2) for patients with PD, adjuvant chemotherapy regimen will be changed. The primary objective is the safety and efficacy, and the secondary objectives are quality of life and the role of prognostic biomarker SPARC.

      Of 36 patients, 3 stopped treatment due to patient decision. 33 were finally evaluated and 1 is still on treatment. Significant tumor volume shrinkage was seen in some patients after the neoadjuvant therapy. 66.7% patients achieved partial response (PR), 21.2% patients achieved stable disease (SD). Disease control (PR +SD) rate was 87.9%. Finally, 23 patients underwent surgical resection, the respectability rate was 69.7%. 12.1% occurred disease progress and failed to achieve resection, including 3 with local progress and 1 with pulmonary metastatic nodule; Among 22 PR pts, 4 failed to achieve resection, in which 1 was due to heart function, the other 3 due to personal unwillingness. 2 of 7 with stable disease failed to achieve resection; the pathological improvement in T stage and N stage before and after treatment was 81.8% (18/22) and 50% (11/22) respectively. The major adverse event was neutropenia (grade I and II) and no serious AE was found.

      Nab-paclitaxel in combination with Carboplatin showed promising ORR rate and resection rate in of IIIA-N2 lung squamous cell carcinoma. The regimen could be a new chemo option as the neoadjuvant treatment. PFS and OS data will be reported after follow up completing.

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      JCSE01.18 - A Multicenter Survey of One Year Survival Among Chinese Patients with Advanced Nonsquamous Non-Small Cell Lung Cancer (CTONG1506) (ID 14707)

      11:15 - 11:15  |  Presenting Author(s): Qing Zhou  |  Author(s): Ping Yu, Yong Song, Xin Zhang, Gongyan Chen, Yi Ping Zhang, Jianhua Chen, Zhuang Yu, Yi Hu, Xia Song, Diansheng Zhong, Guosheng Feng, Lulu Yang, Lujing Zhan, Luan Di Yao, Yun Chen, Yue Gao, Yi-Long Wu

      • Abstract
      • Slides

      Background
      Previous results of CTONG1506 study showed that gene aberration test rate was increasing in Chinese NSCLC patients and first-line treatment was standardized accordingly. This survey further described one year survival of patients with different gene aberration status and under different first-line treatments.

      CTONG1506 was a two-year series cross-sectional study. Patients with advanced nonsquamous NSCLC who were admitted from August 2015 to March 2016 and who received first-line anti-cancer treatment at one of 12 tertiary hospitals across China were included. Data extracted from medical charts were entered into medical record abstraction forms, which were collated for analysis. Survival information was collected one year after patients were admitted to hospital. One year survival rate and its 95% confidence interval were analysed by Kaplan-Meier method.

      A total of 707 patients were analysed, with mean age of 57 years and 56.7% were male. Among the 487 patients who had survival data, 192 were EGFR- mutation positive (86 mutated in exon 19 [one year survival rate 0.90, 95% CI: 0.81-0.94] and 88 mutated in exon 21 [one year survival rate 0.84, 95% CI: 0.75-0.90]), 27 patients were ALK positive and 164 patients were EGFR and ALK wild type. Most EGFRmutation positive patients (128/192) received tyrosine kinase inhibitors (TKIs) as first-line treatment and most EGFR wild type patients (155/175) received first-line chemotherapy (Chemo). Pemetrexed was the most common non-platinum chemotherapy-backbone agent (120/155) in platinum doublet regimens. One year survival rates are shown in the table.

      abstract 12337 ctogn1506 one-year survival.png

      This national-wide real world study of tertiary hospitals in China revealed that a majority of (>75%) advanced nonsquamous NSCLC patients survived more than one year and was comparable to well-controlled clinical trial results, indicating survival benefits by gene aberration status guided standard of care. This result may be further validated by our on-going two-year survey.

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      JCSE01.19 - ALTER-0303 Study: Tumor Mutation Index (TMI) For Clinical Response to Anlotinib in Advanced NSCLC Patients at 3rd Line (ID 14708)

      11:15 - 11:15  |  Presenting Author(s): Baohui Han  |  Author(s): Jun Lu, Wei Zhang, Bo Yan, Lele Zhang, Jie Qian, Bo Zhang, Shuyuan Wang

      • Abstract
      • Slides

      Background

      Anlotinib is an effective multi-targeted receptor tyrosin kinase inhibitor (TKI) for refractory advanced Non-Small Cell Lung Cancer (NSCLC) therapy at 3rd line. ALTER-0303 clinical trial has been revealed that Anlotinib significantly prolongs progression free survival (PFS; Anlotinib: 5.37 months vs Placebo: 1.40 months) and overall survival (OS; Anlotinib: 9.63 months vs Placebo: 6.30 months) with the objective response rate (ORR) of 9.18% and the disease control rate (DCR) of 80.95%. Here, we sought to understand the gene mutation determinants for clinical response to Anlotinib via next generation sequencing (NGS) upon cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) at baseline.

      Totally 437 advanced NSCLC patients enrolled in ALTER-0303 study, and 294 patients received Anlotinib therapy. Of the 294 patients, 80 patients were analyzed in the present study. Capture-based targeted ultradeep sequencing was performed to obtain germline and somatic mutations in cfDNA and ctDNA. Response analyses upon discovery cohort (n = 62) and validation cohort (n = 80) were performed by use of germline and somatic (G+S) mutation burden, somatic mutation burden, nonsynonymous mutation burden, and unfavorable mutation score (UMS), respectively. Based on the above independent biomarkers and their subtype factors, tumor mutation index (TMI) was developed, and then used for response analysis.

      Our data indicated that the patients harbouring less mutations are better response to Anlotinib therapy (G+S muatation burden, cutoff = 4000, Median PFS: 210 days vs 127 days, p = 0.0056; somatic mutation burden, cutoff = 800, Median PFS: 210 days vs 130 days; p = 0.0052; nonsynonymous mutation burden, cutoff = 50, Median PFS: 209 days vs 130 days; p = 0.0155; UMS, cutoff = 1, Median PFS: 210 days vs 131 days; p = 0.0016). TMI is an effective biomarker for Anlotinib responsive stratification (Median PFS: 210 days vs 126 days; p= 0.0008; AUC = 0.76, 95% CI: 0.62 to 0.89) upon discovery cohort and validation cohort (Median PFS: 210 days vs 127 days; p = 0.0006). Lastly, integrative analysis of TMI and IDH1 mutation suggested a more promising result for Anlotinib responsive stratification upon validation cohort (Median PFS: 244 days vs 87 days; p < 0.0001; AUC = 0.90, 95% CI: 0.82 to 0.97).This study provide a biomarker of TMI to stratify Anlotinib underlying responders, that may improve clinical outcome for Anlotinib therapy on refractory advanced NSCLC patients at 3rd line. Clinical trial information: NCT02388919.

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      JCSE01.20 - Outcome in Small Cell Lung Cancer Patients with Cerebral Recurrence After Prior Prophylactic Cranial Irradiation  (ID 14710)

      11:15 - 11:15  |  Presenting Author(s): Lei Zhao  |  Author(s): Jindong Guo, Xuwei Cai, Xiaolong Fu

      • Abstract
      • Slides

      Background
      Prophylactic cranial irradiation (PCI) is a standard therapy for both limited small cell lung cancer (SCLC) and extensive SCLC patients with good responses to first-line treatment. The aim of this study was to examine outcomes in SCLC patients in a single institution who underwent cerebral recurrence after prior PCI.

      We retrospectively examined the medical records of 219 consecutive SCLC patients who had initially received PCI(25 Gray in 10 fractions) between June 2007 to June 2017. Data were analyzed with regard to age, sex, smoking status, treatment, disease stage, data of PCI, time to cerebral recurrence, site of cerebral recurrence, re-irradiation after cerebral recurrence and time to death. Survival was estimated by the Kaplan-Meier method. Multivariate analyses were performed by the log-rank and Cox’s proportional hazard model test.

      Of the 219 patients undergoing PCI, 180(82.2%) were LD-SCLC and 39(17.8%) were ED-SCLC. The median age was 59 years and the median follow-up time was 23.7 months. The median overall survival (OS) of all patients from the time of diagnosis was 39.0 months (95%CI, 29.6–48.4), in LD-SCLC it was 47.0 months (95%CI, 35.4–58.6), and in ED-SCLC it was 19.0 months (95%CI, 17.0–21.0). The difference was statistically significant with P=0.000.

      Forty-six patients (21.0%) were diagnosed with cerebral recurrence. 30(65.2%) of these presented with oligometastatic disease and 16(34.8%) had non-oligometastatic disease. Cox multivariate analysis identified disease stage (P=0.043) was the only significantly favorable prognostic factor for cerebral recurrence. The median survival time from PCI was 21.0 months (95%CI, 12.5–29.5), in oligmetastatic disease it was 35.0 months (95%CI, 19.0–51.0), and in non-oligometastatic disease it was 16.0 months (95%CI, 12.1–19.9). The difference was statistically significant with P=0.007. Meanwhile, the median time from PCI to cerebral recurrence was 11.0 months (95%CI, 9.5–12.5), in oligmetastatic disease it was 11.0 months (95%CI, 6.7–15.3), and in non-oligometastatic disease it was 10.0 months (95%CI, 8.4–11.6). There was no statistical significance between the two.

      Among forty-six patients with cerebral recurrence, 34 patients underwent re-irradiation using either Re-WBRT (11patients, 23.9%) or SRS /SRT (23patients, 50.0%), another 12 patients (26.1%) did not accept radiotherapy to brain. The median survival time from cerebral recurrence was 10 months (95%CI, 4.1-16.0) for re-irradiation and 4 months (95%CI, 2.3-5.8) for no radiotherapy group, respectively. The difference was statistically significant with P=0.000.

      PCI remains standard therapy for SCLC patients with good responses to first-line treatment. Cerebral recurrence is inevitable, however, cerebral re-irradiation after recurrence is proven to be beneficial for survival.


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      JCSE01.21 - Different Responses to Osimertinib in Primary and Acquired EGFR T790M-Mutant NSCLC Patients (ID 14711)

      11:15 - 11:15  |  Presenting Author(s): Shuyuan Wang  |  Author(s): Bo Zhang, Baohui Han

      • Abstract
      • Slides

      Background
      Primary EGFR T790M could be occasionally identified by routine molecular testing in tyrosine kinase inhibitor TKI-naive non-small cell lung cancer (NSCLC) patients. This study was aimed to compare clinical characteristics of primary and acquired T790M mutations and their responses to Osimertinib in NSCLC patients.
      We collected clinical characteristics of patients diagnosed with epidermal growth factor receptor (EGFR) mutation from 2012 to 2017 in Shanghai Chest Hospital. For patients with primary and acquired T790M mutations, the responses to Osimertinib were analyzed.Primary T790M was identified in 1.03% (61/5900) of TKI-naive patients. Acquired T790M was detected in 45.50% (96/211) of TKI-treated patients. T790M always coexisted with sensitizing EGFR mutations. Primary T790M was always coexisted with 21L858R (45/61) whereas acquired T790M was coexisted with 19del (61/96). Among them, 18 patients with primary T790M mutation acquired Osimertinib and 75 patients with acquired T790M mutation received Osimertinib. The median progression-free survival (mPFS) of Osimertinib in primary T790M group was greatly longer than that in acquired T790M group (18.0 months:95% CI:15.0-21.0 VS 10.0months:95% CI:8.3-11.7, P=0.016). The DCR of both groups were 89.3% and 100%. In primary T790M group, the mPFS of concomitant occurrence of 20 T790M and 21 L858R or 19del were 15.7m and 24.0 m, respectively. In acquired T790M group, the mPFS of concomitant occurrence of 20 T790M and 21 L858R or 19del were 11.0m and 10.0m, respectively.

      Primary and acquired T790M-mutation patients showed different molecular characteristics. Both of them may respond to Osimertinib. However, primary T790M patients showed greater survival benefits from Osimertinib than acquired T790M patients.

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      JCSE01.22 - Differential Molecular Mechanisms Associated with Dramatic and Gradual Progression in NSCLC Patients with Intrathoracic Dissemination (ID 14713)

      11:15 - 11:15  |  Presenting Author(s): Ying Chen  |  Author(s): Bao Hua, Wei Li, Chao Zhang, Wen-Fang Tang, Ao Wang, Xue Wu, Jing-Hua Chen, Jian Su, Yang W. Shao, Yi-Long Wu, Wen-Zhao Zhong

      • Abstract
      • Slides

      Background
      Lung cancer is a highly heterogeneous disease with diverse clinical outcomes. The pleural cavity is a frequent metastasis site of proximal lung cancer. Better understanding of its underlining molecular mechanisms associated with dramatic and gradual progression of pleural metastasis in patients with non-small cell lung cancer (NSCLC) is essential for prognosis, intervention and new therapy development.We performed whole-exome sequencing (WES) of matched primary lung adenocarcinoma and pleural metastatic tumors from 26 lung cancer patients with dramatic progression (DP, n=13) or gradual progression (GP, n=13). Somatic alterations at both genome-wide level and gene level were detected. Kaplan-Meier survival analysis and multivariate Cox regression models were applied to analyze the association between different somatic alterations and clinical parameters.We first analyzed the differences in somatic alterations between AP and RP group in the primary tumors, and identified higher somatic copy number alteration (SCNA) level in DP group compared to GP group, which is significantly (p=0.016) associated with poorer progression-free survival (PFS). More specifically, patients with chromosome 18q loss in the primary tumor showed a trend (p=0.107) towards poorer PFS. PTEN (p=0.002) and GNAS (p=0.002) mutations are enriched in the primary tumors of DP group, and are associated with poorer PFS. Furthermore, pleural metastatic tumors harbor a relatively higher level of mutation burden (p=0.105) and significantly increased SCNA (p=0.035) compared to the primary tumors.NSCLC patients in the attenuated progression group have more stable genomes. High level of genomic instability, GNAS and PTENmutations, as well as chromosome 18q loss are associated with rapid progression.

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      JCSE01.22a - Tislelizumab Combined With Chemotherapy as First-Line Treatment in Chinese Patients With Advanced Lung Cancer (ID 14702)

      11:15 - 11:15  |  Presenting Author(s): Jie Wang  |  Author(s): Jun Zhao, Zhijie Wang, Zhiyong Ma, Jiuwei Cui, Yongqian Shu, Zhe Liu, Ying Cheng, Shiang Jiin Leaw, Jian Li, Fan Xia

      • Abstract

      Background
      Immune checkpoint inhibitors have shown efficacy in patients with NSCLC as monotherapy and in combination with chemotherapy. Tislelizumab is a humanized IgG4 monoclonal antibody to PD‑1 specifically engineered to minimize FcϒR binding on macrophages, possibly minimizing negative interactions with other immune cells. In a phase 1 study, tislelizumab was generally well tolerated and showed antitumor activity; 200mg IV Q3W was established as the recommended dose.

      This multi-arm phase 2 study, consisting of safety run-in and dose-extension phases, assessed tislelizumab in combination with platinum-based chemotherapy (by tumor histology) as a potential first-line treatment for Chinese patients with lung cancer. All patients received tislelizumab at 200mg Q3W in combination with 4–6 cycles of platinum-doublet until disease progression. Nonsquamous (nsq) NSCLC patients received pemetrexed + platinum Q3W for 4 cycles followed by pemetrexed maintenance, while squamous (sq) NSCLC patients received paclitaxel + platinum (A) or gemcitabine + platinum (B) Q3W, and small-cell lung cancer (SCLC) patients received etoposide + platinum Q3W. Tumor response (RECIST v1.1) and safety/tolerability were evaluated.

      As of 21 Feb 2018, 48 patients (median age, 62 years [range: 36–75], 71% male, 71% current/former smokers) received tislelizumab treatment (median, 3 cycles [range: 1–7]); 44 patients remain on the study. Across the four cohorts, confirmed and unconfirmed partial responses were observed in 13 and 9 patients, respectively (Table). The most frequent AEs were chemotherapy-related hematologic toxicities. The most commonly reported grade ≥3 treatment-related AEs were neutropenia (20.8%) and anemia (12.5%); the most common grade 3 immune-related AEs were pyrexia (6.3%) and rash (6.3%). One sq‑NSCLC patient experienced a fatal myocarditis/myositis following one cycle of paclitaxel/cisplatin; all other treatment-related AEs were managed/resolved by study-drug interruption (n=15) or discontinuation (n=4) and appropriate treatment.

      Best Overall Response (Patients With ≥1 Post-Baseline Tumor Assessment)

      nsq-NSCLC (n=9)

      sq-NSCLC [A] (n=12 )

      sq-NSCLC [B] (n=5 )

      SCLC (n=8)

      Total

      (N=34)

      PR

      4 (44.4)

      9 (75)

      4 (80)

      5 (62.5)

      22 (64.7)

      Confirmed PR

      1 (11.1)

      4 (33.3)

      4 (80)

      4 (50)

      13 (38.2)

      Unconfirmed PR

      3 (33.3)

      5 (41.7)

      0 (0)

      1 (12.5)

      9 (26.5)

      SD

      3 (33.3)

      2 (16.7)

      1 (20)

      2 (25)

      8 (23.5)

      PD

      1 (11.1)

      0 (0)

      0 (0)

      1 (12.5)

      2 (5.9)

      NE

      1 (11.1)

      1 (8.3)

      0 (0)

      0 (0)

      2 (5.9)

      Data presented as n (%).

      Abbreviations: nsq-NSCLC, non-squamous non-small cell lung cancer; NE, not evaluable; PD, progressive disease; PR, partial response; SCLC, small cell lung cancer; SD, stable disease; sq-NSCLC, squamous non-small cell lung cancer.

      Tislelizumab, in combination with platinum doublets, demonstrated preliminary antitumor activity and was generally well tolerated in patients with advanced lung cancer.



Author of

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    MA04 - Novel Approaches with IO (ID 900)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 1
    • Now Available
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      MA04.10 - Comprehensive Peripheral Blood Immunophenotyping and T-Cell Clonal Analysis During Neoadjuvant Immunotherapy with Atezolizumab in NSCLC (Now Available) (ID 13118)

      14:35 - 14:40  |  Author(s): Fred R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background

      Immune-checkpoint blockade targeting PD-L1/PD-1 to activate anti-tumor immunity is associated with improved response rates and survival compared to chemotherapy in selected metastatic NSCLC patients. Evaluation of the pre-therapeutic immune profile and its treatment-related evolution associated with clinical benefit will guide future immunotherapy development and support clinical decision-making. Here, we present an analysis of peripheral blood (PB) immunophenotyping and T-cell-receptor (TCR) clonality before and after immunotherapy from an ongoing 180-patient phase II study of atezolizumab as neoadjuvant therapy with stage IB-IIIB resectable NSCLC (NCT02927301; LCMC3).

      Method

      As of February 5th datacut, the first 54 enrolled and dosed patients are presented. The biomarker evaluable population (BEP) further subset to patients with paired PB samples analyzed within 72 hours after collection and a major pathological response (MPR) assessment. Comprehensive immune cell phenotyping (10-color flow cytometry, IMMUNOME) and TCR-Vß-analysis by flow cytometry were performed. Immunoprofile analyses were correlated with atezolizumab treatment, pathological response and PD-L1 expression.

      Result

      In this ongoing analysis, BEP included 31 patients. 5 patients (16%, 95% CI (5%, 34%)) had a MPR; all of which stained positive for PD-L1 by IHC using 22C3 (TPS≥1%) and SP142 (PD-L1 expression on ≥1% tumor cells (TC) and/or tumor infiltrating immune cells (IC)) at baseline. We observed significant increases in natural killer (NK) cells (p=0.005) and CD8+ T-cells (p=0.031) and a Th1-response related dendritic cell (DC) subpopulation (p=0.031) and significant decreases in B-cells (p=0.015) after treatment.

      Patients who achieved MPR show lower baseline levels of degranulated CD8+ T-cells (p=0.015), late-activated NK-cells (p=0.043), memory CD4+ (p=0.048) and memory CD8+ T-cells (p=0.032); changes in PB NK-cells (p=0.041), a decrease in M-MDSCs and a Th-2 and Th-17-response related DC subpopulation (p=0.043) in response to treatment were noted in patients with MPR versus non-MPR.

      Among the 16 patients with TC/IC 1/2/3 (> 1% PD-L1 expression) the following significant differences were observed compared to TC0/IC0 (7 patients): higher levels of late-activated CD4+ T-cells (p=0.025) and mid-activated CD8+ T-cells (p=0.044) at baseline, decrease of senescent T-cells (p=0.041), monocytic myeloid-suppressor cell subpopulations (M-MDSCs) and an increase in a Th1-response related DC subpopulation (p=0.026) after treatment.

      TCR clonality analysis showed expansions in Vß-subtypes after atezolizumab treatment.

      Conclusion

      Immunophenotyping and TCR-Vß-repertoire analysis in peripheral blood samples from NSCLC patients treated with neoadjuvant atezolizumab show differences in immune cell subsets in baseline samples and changes after treatment.

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    MA11 - Biomarkers of IO Response (ID 912)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 1
    • Now Available
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      MA11.05 - Indoleamine 2,3-Dioxygenase Expression in Non-Small-Cell Lung Cancer: Analyses of Prevalence, Clinical Correlations and Prognostic Impact (Now Available) (ID 13309)

      11:00 - 11:05  |  Author(s): Fred R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background

      Indoleamine 2,3-dioxygenase-1 (IDO-1) is a cytosolic enzyme involved in the catabolism of tryptophan; IDO-1-related immune suppression is due to decreased tryptophan availability and to the generation of tryptophan metabolites, culminating in substantial suppression of T-lymphocytes. Here we investigate IDO-1 expression in a cohort of non-small-cell lung cancer (NSCLC) specimens, both in tumor cells and in immune infiltrate, with correlation of IDO-1 to PD-L1 expression, clinical patient demographics and outcomes.

      Method

      A cohort of 1.200 NSCLC samples were obtained from 437 patients who underwent surgical lung resections at Austin Health, Melbourne, Australia. IDO-1 expression was evaluated by immunohistochemistry. Correlations were assessed using Spearman and Kendall tests. A Cox proportional hazards (PH) model was used to assess if overall survival (OS) was associated with IDO-1 positivity in univariate and multivariable settings.

      Result

      Samples from 437 patients were analyzed for IDO-1 expression, with 111 (25.4%) determined as positive (H-Score 1) and 326 patients (74.6%) as negative (H-Score: 0). IDO-1 expression was determined to be greater in tumor immune infiltrate, with 406 patients (93.8%) determined as positive, while just 27 (6.2%) were IDO-1 negative. There was a significant positive correlation between IDO-1 positive tumor cells and immune cells (0.2167, p < 0.001). Both continuous and binary versions of tumor H-Score showed a significant positive correlation with the amount of tumor immune infiltrate (0.1806 and 0.1698, p < 0.0001, respectively). None of the analyzed variables (age, sex, histology, stage, EGFR, KRAS and PD-L1 status) were found to display a significant correlation with IDO-1 positivity in tumor and immune cells. IDO-1 positivity in tumor cells was found to be significantly associated with OS in the univariate setting and in the multivariable model where variables age, sex, histology, stage, EGFR, KRAS and PD-L1 status were included [P-value = 0.009 and 0.021, respectively; HR: 0.72 (95% CI: 0.55-0.95)]. IDO-1 positivity in immune cells was found to be significantly associated with OS in the univariate setting and was borderline significant in the multivariable model [P-value = 0.006 and 0.053, respectively; HR: 0.798 (95% CI: 0.635-1.003)].

      Conclusion

      To our knowledge, this is the most extensive analysis of IDO-1 expression in NSCLC patients reported in the literature. Our results suggest the possible prognostic role of IDO-1 expression in tumor and immune cells, highlighting the relevance of IDO-1 detection in tumor tissue. Since new compounds targeting IDO-1 are actually under investigation, the identification of potential prognostic and predictive biomarkers will be needed.

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    MS21 - Giants in Thoracic Oncology (ID 869)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track:
    • Presentations: 1
    • Now Available
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      MS21.07 - The Growing Role of Biomarkers in Treatment Selection: “The Tissue is the Issue” (Now Available) (ID 13380)

      16:15 - 16:25  |  Presenting Author(s): Fred R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Abstract

      Much progress has occurred in the treatment of lung cancer over the last decades. A main reason for this progress is due to technology developments, which make it possible to identify new targets and develop new active drugs targeting the molecular abnormalities. However, developing predictive biomarkers for selection of the right group of patients to the right treatment has been crucial in this progress.

      The detection of EGFR mutations as predictive biomarkers for EGFR TKIs paved the way for biomarker development and was shortly followed by the detection of Anaplastic Lymphoma Kinase fusions and the development of ALK-inhibitors. Later, many other targets have been identified (i.e. ROS1, BRAF, RET, TRAKS) and specific targeted drugs developed with impressive clinical effect in biomarker defined subgroups, particularly of NSCLC (1).

      The International Association for the Study of Lung Cancer (IASLC) has together with the College of American Pathologists (CAP) and the Association for Molecular Pathology (AMP) developed guidelines for molecular testing of patients with advanced NSCLC, which second edition has recently been published (2). Those guidelines have been the role model for several other guidelines globally.

      Assay developments have been crucial in the biomarker development. While traditional immunohistochemistry (IHC) is still relevant for selection of patients to certain targeted therapies, e.g. ALK- inhibitors, more technological advanced assays based on DNA or RNA have become more” relevant” as multiplexed marker analysis seems in many cases “mandatory” as (sparse) “Tissue is the Issue” (3). The last revision of the CAP/IASLC/AMP guidelines recommend the use of Next Generation Sequencing (NGS) if possible, as this assay gives more information and detect mutations as well as fusions. Today only a limited number of targets are linked to FDA approved drugs for treatment of lung cancer and the use of NGS gives a broad molecular profiling of the patients’ tumor. This knowledge gives the patient opportunity to seek clinical trials, of which many are ongoing, including a broad range of molecular targets.

      Many molecular targets have seen several generations of specific targeted drugs, e.g. EGFR and ALK and more knowledge has emerged on resistance mechanisms, a knowledge, which in some cases, leads to targeted agents specifically targeting the resistance mechanisms. The third generation EGFR TKI represented by osimertinib targeting T790 M mutation is the best example. This development has paved the way for the need for biopsy at progression, which is a change in the current “culture”. However, acquiring tissue at this stage can often be challenging, and the development of liquid biopsy is rapidly emerging. The IASLC has just published a consensus report on the role of liquid biopsy in the management of patients with NSCLC (4). The liquid biopsy technology has the capability to be applied to NGS and several other DNA and RNA assays with high specificity (90-100%) and increasing high sensitivity (70-90%).

      The progress with immunotherapy has been remarkable for patients with lung cancer; however, the role of predictive biomarkers in immunotherapy has been challenging. PD-L1 has been pursued by the relevant pharmaceutical companies, but, unfortunately, with the development of their own proprietary assays that differ with regard to antibodies, processing platforms, and with different cut-off points for definition of “high’- versus “low” PD-L1 expression in the clinical trials. IASLC has compared the analytical performances of the different assays in order to see if harmonization is possible, and the results of the “Blueprint Project” indicate that three assays (Dako’s 28-8 and 22C3 and Ventana’s SP 263) perform very similar and seem to be interchangeable when the same clinical cut-offs for the different categories are used (5,6). Tumor mutation burden has also emerged as a predictive biomarker for immunotherapies (7); however, the tumor mutation burden assays need to be compared and standardized as well. Much research today is devoted to try to identify new and better predictive biomarker(s) for immunotherapy. While we have primarily focused on “single” biomarker assays for immunotherapy thus far, it might be time to look into the role of “combined” biomarkers or assays for the most optimal selection of patients, who benefit from immunotherapy.

      In conclusion, a tremendous development of biomarkers and assays have been seen over the last decade(s), which has made it possible to identify subgroups of patients with dramatic effect of new targeted therapies. Future drug development needs to ensure the biomarker development occurs simultaneously in the clinical development to ensure validation and proper selection of subgroups of patients, who will benefit from the new agents. Development of “masterprotocols” seems to be one mechanism for speeding up this development (8).

      REFERENCES:

      1.Hirsch FR, Scagliotti GV, Mulshine JL et al: Lung Cancer: Current Therapies and New Targeted Treatments. Lancet 389 (10016); 299-331, 2017.

      2.Lindeman NI, Cagle PT, Aisner DL et al: Updated Molecular Testing Guidelines for Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors. Guideline from the College of American Pathologists, The International Association for the Study of Lung Cancer and the Association for Molecular Pathology. J Thorac Oncol 142(3); 321-346, 2018.

      3.Hirsch FR, Wynes MW, Gandara DG, Bunn PA: “The Tissue is the Issue”. Clin Cancer Res 16 (20); 4909-4911. 2010

      4.Rolfo C, Mack PC, Scagliotti GV et al: IASLC Statement Paper: Liquid Biopsy for Advanced Non-Small Cell Lung Cancer. J Thorac Oncol , June 6th, 2018 (E-pub ahead of time).

      5.Hirsch FR, McElhinny A, Stanforth D et al; PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase1 of the Blueprint PD-L1 Comparison Project. J Thorac Oncol 12(2); 208-222, 2017.

      6.Tsao MS, Kerr KM, Kockx M et al: PD-L1 Immunohistochemistry Comparison Study in Real-Life Samples; Results from Blueprint Phase 2 Project. J Thorac Oncol , May 22, 2018 (Epub ahead of time).

      7.Hellman MD, Callahan MK, Awad MM: Tumor Mutation Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilumumab in Small Cell Lung Cancer. Cancer Cell 14(33): 853-861, 2018.

      8.Malik SM, Pazdur R, Abrams JS et al: Consensus Report from a Joint NCI Thoracic Malignancy Steering Committee- FDA workshop on strategies for integration of biomarkers into clinical development of new therapies for lung cancer leading to inception of “Masterprotocols” in lung cancer. J Thorac Oncol 9 (10); 1443-1448. 2014

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    OA03 - Advances in Lung Cancer Pathology (ID 897)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
    • Now Available
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      OA03.03 - Phase 2B of Blueprint PD-L1 Immunohistochemistry Assay Comparability Study (Now Available) (ID 14530)

      10:50 - 11:00  |  Author(s): Fred R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background
      PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each developed as predictive biomarker for specific anti PD1/PD-L1 immunotherapies. The Blueprint (BP) phase 1 comparability study demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells (TPS), while the SP-142 PD-L1 assay appeared to stain a lower percentage of tumor cells when compared to the other assays. The first part of BP phase 2 (BP2A) re-affirmed these findings in a larger cohort of ‘real life’ specimens scored by 24 experienced pulmonary pathologists, and also showed that the 73-10 assay developed for avelumab showed greater sensitivity than all other assays to detect PD-L1 on tumour cells. BP2A also demonstrated generally excellent inter-observer agreement for tumor cell PD-L1 scoring using both glass slides and digital images, with slightly lesser agreement for the cytology samples included in the study cohort. Inter-observer agreement for immune cell scoring on glass or digital slides was poor. Phase 2B of Blueprint (BP2B) aimed to compare PD-L1 scoring on triplet samples representing large tumor resection blocks, small biopsy samples and fine needle aspirate cell blocks prepared from the same tumor. Method
      Triplet samples of large resected tumor block, small biopsy sample and fine needle aspirate cell block (the latter two taken from the resected tumour specimen) were gathered from 31 resected primary lung cancers (17 adenocarcinomas, 12 squamous cell carcinomas, and 2 large cell carcinomas). Sections from all 93 blocks were stained with the pharmDx 28-8 and 22C3, the FDA-approved SP142 and SP263, or clinical trial associated 73-10 PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. All H&E and PD-L1 IHC slides were scanned and digital images were used to score all cases by the same 24 pathologists involved in BP2A. As before, tumor cells PD-L1 staining were scored as continuous variable and into 7 cut-off-defined categories, as used in various immune checkpoint inhibitor trials. Immune cells were not scored. Result
      The data reaffirm the relative comparability of 28-8, 22C3 and SP263 assays across the range of scores; SP142 assay scores were lower, those for 73-10 higher. Inter-observer agreement between readers ranged from moderate to near perfect (Kappa-Fleiss (K-F) scores generally >0.7); best overall agreement was on aspirates. Overall, the agreement between scores on the different sample types from the same tumor was good (most K-F scores >0.7); aspirates showed no significant difference from biopsy samples or whole surgical blocks. In contrast to biopsies and surgical blocks, scores could, however, not be rendered in about 14% of aspirate sections. Conclusion
      The results of BP2B confirms earlier results and also demonstrate comparable performance for fine needle aspirates in those cases where TPS scores were possible.

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    P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.04-23 - Expression of Emerging Immunotherapy Targets in Early-Stage Squamous Lung Carcinoma (Now Available) (ID 13520)

      16:45 - 18:00  |  Author(s): Fred R. Hirsch

      • Abstract
      • Slides

      Background

      Anti-PD1/PD-L1 immunotherapy has demonstrated response in approximately 20% of unselected advanced non-small cell lung cancer (NSCLC) patients. Strategies involving combination immunotherapies are under investigation to improve the overall response to immunotherapy. The objective of this study was to identify the expression of emerging immune targets in a cohort of early-stage squamous lung carcinoma (SqLC), which may be used to design combinatorial immunotherapy approaches.

      Method

      202 early stage (I-II) SqLC resected patient tumors and corresponding clinical data were collected from 6 cancer centers as part of the SPECS II program. Fourteen emerging immune targets or targeted axis were selected based on their advanced stage of development in preclinical/clinical studies. The mRNA expression level of these targets and PD-1/PD-L1 were determined by Affymetrix U133A gene expression profiling. The correlations among these targets and the overall survival were evaluated.

      Result

      The mRNA levels of the immune molecules which were grouped on PD-L1 protein expression in early stage SqLC are shown in Figure 1. No correlation was found between the mRNA level of PD-L1 and the other immune targets expressed on APC/tumor cells, except PD-L2 (r2= 0.41, p<0.00001). We found that the immune cell receptor, CD226, correlated with CD96 and CD112R respectively (r2= 0.514, p<0.00001; r2= 0.476, p<0.00001), and CD96 correlated with CD112R (r2= 0.644, p<0.00001) as well. In addition, higher expression of GAL-9, CD48 and ICOS were associated with better prognosis [p= 0.0358, HR=0.249 (0.068, 0.912); p= 0.0309, HR=1.61 (1.04, 2.49); p= 0.0429, HR=2.47 (1.03, 5.93)].

      figure 1.tif

      Conclusion

      Several emerging immune targets were expressed at higher levels than PD-L1 in this early stage SqLC cohort. The mRNA levels of all immune targets evaluated were independent of PD-L1 expression, except PD-L2. The expression of GAL-9, CD48 and ICOS were identified as prognostic. These results may provide important information in the design of future combination immunotherapies for early-stage SqLC.

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    P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.04-13 - The Immune Checkpoint, HVEM Contribute to Immune Escape in Non Small Cell Lung Cancer of Lacking PDL1 Expression (ID 13116)

      16:45 - 18:00  |  Author(s): Fred R. Hirsch

      • Abstract

      Background

      Herpes Virus Entry Mediator (HVEM) is an important immune checkpoint in cancer recognition. HVEM expressed on tumor cell membranes activates immune cell signaling pathways leading to either inhibition of activity (BTLA) or activation of immune activity (LIGHT). The aim of this study is to investigate the prevalence of HVEM expression and its association with PDL1 expression in NSCLC.

      Method

      A TMA of 527 resected NSCLC samples and 53 NSCLC cell lines were evaluated for HVEM and PD-L1 expression. The IHC assay for HVEM was optimized on the Dako Link48 autostainer using a polyclonal antibody from R&D Systems(AF356). PD-L1 IHC was performed on the Dako Link48 autostainer using the PD-L1 22C3 pharmDx kit. Scoring HVEM employed the H-score system while for PD-L1 the tumor proportion score (TPS) was used.

      Result

      HVEM expression in the NSCLC resected samples and cell lines revealed a positive H-score more than 1 was18.6%(77/415) and 45.3%(24/53) respectively. HVEM expression was significantly higher in patients with lymph node N2 metastasis (25.5% vs 7.9% vs 17.5%, P=0.046) when comparing with N1 or no lymph node metastasis, and was marginally significantly higher in patients with stage III/IV disease (24.5% vs 16.4%, P=0.059). Subgroup analysis showed that HVEM (median 45 vs 36 months, p=0.706) and PD-L1 expression (median 45 vs 48 months, p=0.178) status was not predictive of overall survival. HVEM was found to have a significant negative correlation with PD-L1 expression (r=-0.232, p=0.002, Figure 1A) in patients with NSCLC and also have a negative correlation in NSCLC cell lines(r=-0.055, p=0.764,Figure 1B).

      figure 1.tif

      Conclusion

      HVEM was found to be overexpressed in patients of NSCLC with advanced disease or lymph node metastasis and has a negative co-relationship with PD-L1 expression, while, it did not have a prognostic role in patients with NSCLC.

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      P2.04-15 - Heterogeneity and Correlation Between Immune Markers in Lung Cancers: Analysis of Treatment-Naïve Lesions (ID 11288)

      16:45 - 18:00  |  Author(s): Fred R. Hirsch

      • Abstract

      Background

      Immunotherapies are becoming a new standard of care for patients with lung cancers. Although a few immune-checkpoints are currently used as therapeutic targets and/or as predictive biomarkers, the complex correlation between immune-checkpoints is not well understood. Expression level of immune-checkpoint molecules is affected by numerous factors including tumor cells themselves, patients’ immunological characteristics, tumor microenvironment (metastatic sites), and previous treatments. To effectively investigate correlations of immune-checkpoints across multiple lesions, we analyzed gene expression data obtained from treatment-naïve autopsied patients.

      Method

      Our cohort of 5 lung cancer patients included thirty specimens of both primary and metastatic lesions. RNA sequencing reads were mapped to the hg19 reference genome using the TopHat/Cufflinks workflow and transcripts were quantified using the FPKM method. Expression data for immune-checkpoints and total numbers of detected mutations were compared.

      Result

      We observed substantial inter-tumor heterogeneity in immune-checkpoint expression between lesions obtained from each patient. No consistent correlation was found by comparison of primary vs. metastatic lesions or between primary vs. specific metastatic sites. Evaluation of immune-checkpoints expressed by tumor cells and/or antigen presenting cells revealed a positive correlation between GAL9 and PD-L2 (R = 0.79) and GAL9 and HVEM (R = 0.69; Figure 1A). We also observed a strong correlation between these markers when lesions obtained from each patient were correlated to each other (Figure 1B and C). Comparisons between immune-checkpoints expressed by immune cells identified a positive correlation between PD-1 and LAG3 (R = 0.77). No correlation was found between immune-checkpoint expression and mutation burden.

      figure for abstract..tif

      Conclusion

      We observed substantial inter-tumor heterogeneity in immune-checkpoints expression in each patient. We also found several positive correlations between immune-checkpoints which were consistent within the small cohort of patients. Further functional evaluation is warranted.

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    P2.09 - Pathology (Not CME Accredited Session) (ID 958)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.09-01 - Tumor-Associated Immune Cell Infiltration Patterns in Early Stage Squamous Lung Carcinoma (Now Available) (ID 13456)

      16:45 - 18:00  |  Author(s): Fred R. Hirsch

      • Abstract
      • Slides

      Background

      With the recent clinical success of immunotherapy in non-small cell lung carcinoma, the character of the inflammatory infiltrate associated with these tumors is now the subject of increasing interest. Molecular studies have suggested that tumors can be stratified by the character of their inflammatory infiltrate. We now describe the detailed histological appearances of a multi-institutional series of early stage squamous carcinomas and correlate them with mutation burden, PDL1 expression patterns and clinical outcome.

      Method

      Histologic sections of from 250 tumors were evaluated by two pathologists independently for squamous subtype (WHO classification), percentage and character of intratumoral inflammatory cells, percentage and character of para-tumoral infiltrate and presence or absence of scalloping at tumor cell/stromal interface by inflammatory cells along the edges of tumor cell nests, a feature possibly related to existing immune reaction. The ratios of infiltrating inflammatory cells to tumor cells were estimated in 10% increments by microscopic inspection. Quantity and character of infiltrates was assessed by Kaplan-Meir testing for effect on survival and by Pearson bivariate testing for relationships among variables.

      Result

      The character and extent of inflammatory infiltrates were highly heterogeneous. The infiltrates could be divided into intratumoral and paratumoral patterns according to their location in relation to microscopic tumor cell nests. Intratumoral infiltrates could be further subdivided into two patterns: one consisted exclusively lymphocytes, usually few in number; a second polymorphous pattern contained many inflammatory cell types including polymorphonuclear leukocytes (PMNs). In paratumoral tissue, three patterns could be discerned: lymphocytic, plasmacytic and polymorphous. Inflammatory cell infiltrate quantity or character did not correlate with survival for either intratumoral or paratumoral infiltrates and there was no evident relationship to mutational burden or to PDL1 expression by IHC. Scalloping at the tumor cell stromal interface was also not prognostically significant.

      Conclusion

      The inflammatory infiltrates in early stage squamous lung carcinoma are highly heterogenous and are not associated with outcome. However, the complexity of tumor infiltrating inflammatory cells is worthy of further evaluation in future immunotherapeutic trials.

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      P2.09-24 - MERS67 is a Novel anti-NaPi2b Antibody and Demonstrates Differential Expression Patterns in Lung Cancer Histologic Subtypes (ID 12636)

      16:45 - 18:00  |  Author(s): Fred R. Hirsch

      • Abstract

      Background

      NaPi2b is a sodium-dependent phosphate transporter expressed in lung, ovarian, and thyroid cancers. Prior studies have suggested an enrichment of expression in lung adenocarcinoma (ACA).

      XMT-1536 is a NaPi2b targeting ADC (Antibody Drug Conjugate) comprised of a humanized antibody (XMT-1535) conjugated with 10-15 auristatin F-HPA (AF-HPA) payload molecules via the Dolaflexin platform. AF-HPA is capable of controlled bystander-effect killing, resulting in efficacy in models with heterogeneous antigen expression, and is metabolized intra-tumorally to an active non-permeable metabolite to enable greater systemic tolerability. Previously, we demonstrated pre-clinical activity of XMT-1536 in human primary xenograft models of non-small cell lung cancer (NSCLC).

      MERS67 is a human-rabbit chimeric antibody derived from XMT-1535. MERS67 has been formatted for use as an immunohistochemical reagent by multiple methods and expression has been shown to correlate with response in an unselected series of primary ovarian cancer xenografts. (AACR-EORTC, 2017)

      We evaluated MERS67 to see if it would preferentially stain lung adenocarcinoma (ACA), as has been demonstrated using other NaPi2b antibodies.

      Method

      An immunohistochemical assay for MERS67 was established on a Leica BondRx Instrument. The assay was performed on tissue microarrays (TMA), including NSCLC and small cell lung cancer (SCLC) cell line arrays, and a NSCLC human tumor array. Tumors in the NSCLC array had previously been classified based on morphologic features only. All arrays were scored based on the H-score method.

      To characterize the primary tumors further, the tumor TMA was stained with TTF-1 and p40, markers of ACA and squamous cell carcinoma (SqCC), respectively. Results of this staining were compared to MERS67 staining patterns.

      Result

      H-Scores in the NSCLC cell line TMA ranged from 0-260, and from 0-100 in the SCLC TMA. Within the tissue microarray, 99 individual cases were evaluable. By morphologic classification 63 cases were SqCC, and 23 cases were ACA. Using an arbitrary cut point of H=50, there was a statistically significant difference in the number of NaPi2b positive ACA cases (19/23) vs SqCC (3/63). Among 43 cases where p40 and TTF-1 were evaluable and were in agreement with morphologic diagnosis, 7/7 cases of ACA were positive for NaPi2b, while 0/36 SqCC were positive.

      Conclusion

      MERS67 is an anti-NaPi2b antibody that frequently demonstrates immunoreactivity in lung ACA. MERS67 is a chimeric antibody related to XMT-1536, a proprietary anti-NaPi2b ADC. Target expression using MERS67 is being evaluated in an ongoing XMT-1536 Phase 1 clinical trial enrolling non-squamous NSCLC patients.

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    P2.11 - Screening and Early Detection (Not CME Accredited Session) (ID 960)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.11-08 - Tumor Autoantibody Panel Can Improve the Accuracy of Early Diagnosis in Lung Cancer Presenting with GGNs /Solid Nodules  (ID 14324)

      16:45 - 18:00  |  Author(s): Fred R. Hirsch

      • Abstract

      Background

      Autoantibody is an attractive diagnostic approach for early detection of malignant tumors. We performed this study to validate the performance of an autoantibodies (TAAs) panel (p53,PGP9.5,SOX2,GAGE7,GBU4-5,MAGE A1,CAGE) to aid early diagnosis of lung adenocarcinoma with ground-glass nodules (GGNs) and/or solid nodules in Chinese population and to find an effective simple blood test which can be used in further assessing the risk of lung cancer being present GGNs and/or nodules.

      Method

      A prospective audit was conducted on 540 individuals known to have GGNs and/or lung nodules. These patients included 311 pulmonary malignant or borderline lung diseases, 229 lung benign GGNs and/or nodules. We detected TAAs quantitation by ELISA method.

      Result

      The sensitivity and specificity of autoantibody assay were 48.6% and 92.7% respectively. In lung invasive adenocarcinoma, the sensitivity of autoantibody assay was 51.9%. When the seven-autoantibody panel test was combined with CT imaging in patients with GGNs and/or nodules, the accuracy was increased to 90.42%.

      table.png

      Conclusion

      The greatest impact of using the new seven-autoantibody panel was the highly significant improvement in the sensitivity and specificity of the test in the clinical setting. Our study suggested that the seven-autoantibody panel can be combined with CT imaging to aid diagnosis of lung cancer with GGNs and/or solid nodules.

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-45 - SHERLOC: A Phase 2 Study of Seribantumab in Combination with Docetaxel in Patients with Heregulin Positive, Advanced NSCLC (Now Available) (ID 11349)

      16:45 - 18:00  |  Author(s): Fred R. Hirsch

      • Abstract
      • Slides

      Background

      HER3 and its ligand, heregulin (HRG), have been identified as a critical activator of PI3K and Akt signaling and a key pro-survival pathway in cancer cells. Seribantumab (MM-121) is a fully human, monoclonal IgG2 antibody that binds to the HRG domain of HER3, blocking HER3 activity. Preclinical data suggest that seribantumab reverses HRG-mediated drug resistance across multiple cancer models. In retrospective analyses of prior seribantumab Phase 2 studies, high levels of HRG mRNA appeared to predict poor outcome to standard of care (SOC) treatment. Addition of seribantumab to SOC appeared to improve progression-free survival (PFS) in patients with HRG positive (HRG+) tumors, consistent with the hypothesis that the blockade of HRG-induced HER3 signaling by seribantumab can restore drug sensitivity.

      Method

      In the current randomized, open-label, international, Phase 2 study, patients with locally advanced or metastatic NSCLC histologically classified as adenocarcinoma are screened for HRG using an RNA in situ hybridization assay on a recent biopsy tissue sample. Approximately 100 HRG+ patients will be enrolled and randomized in a 2:1 ratio to receive seribantumab plus docetaxel (experimental treatment Arm), or docetaxel alone (control Arm). Eligible patients must have no EGFR and ALK mutations and have progressed following one to two SOC for locally advanced and/or metastatic disease, including platinum-based therapy and anti-PD-1/PD-L1 therapy where available and clinically indicated. Primary trial endpoint is PFS. Secondary endpoints include overall survival, objective response rate, time to progression, and pharmacokinetic profile. The study has ≥ 80% power to detect a 3-month improvement in median PFS over 3 months (hazard ratio ≤ 0.50), using a one-sided, stratified log-rank test at a significance level of 0.025. Study is ongoing and enrolling patients in seventy nine sites worldwide. Clinical trial information: NCT02387216

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P3.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 978)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.12-13 - Expression of the Immune Checkpoint Axis-PVR/TIGIT in Small Cell Lung Cancer (Now Available) (ID 13994)

      12:00 - 13:30  |  Author(s): Fred R. Hirsch

      • Abstract
      • Slides

      Background

      The poliovirus receptor (PVR) is an immune checkpoint protein expressed on tumor cells. It has been reported to mediate activation of T cells via CD226 or inhibition through binding to T-cell Ig and ITIM domain (TIGIT). TIGIT competes with CD226 for binding to PVR, and exhibits stronger affinity for PVR. Recently we have found that PVR is highly expressed in SCLC cell lines. Characterizing the expression and significance of the PVR-TIGIT axis in SCLC will help us to better understand the immunology of SCLC and may lead to novel therapeutic strategies to combine checkpoint blocking agents for improved SCLC immunotherapy.

      Method

      Immunohistochemistry (IHC) was performed to evaluate PVR protein expression in a TMA of 39 SCLC cell lines and a cohort TMA of 77 limited stage SCLC patients with clinical data. We analyzed both PVR and TIGIT in an independent cohort of 27 resected, limited-stage SCLC tumors.

      Result

      Thirty-seven cell lines (95%, 37/39) demonstrated staining for PVR and of those, 4 cell lines (10.3%, 4/39) showed strong staining (H-score ≥ 270). In the 77 SCLC patients cohort, PVR expressed predominantly in the membrane of tumor cells, with minimal expression observed on immune cells. PVR expression in the SCLC patient cohort was 82% with an arbitrary H-score cut-off of ≥ 50. Higher PVR expression was found for male patients (P=0.040). The expression of PVR increased with the tumor progressing from stage I to stage III (p =0.007). SCLC patients who had higher PVR expression demonstrated poorer prognosis and the difference was near statistically significant (p=0.050). Using the same cut-off (H-score ≥ 50) in the independent SCLC cohort, the prevalence of high PVR expression was 89% (24/27).

      In the independent SCLC cohort, TIGIT was found to be expressed membranous or cytoplasm on the immune cells with weak to moderate staining. Immune cells with TIGIT staining were typically seen as variable size and aggregated toward the periphery of the tumor nest. TIGIT protein staining was demonstrated in 20 cases (74%). No association was found between PVR H-score and TIGIT expression by Fisher’s test (p=0.093).

      Conclusion

      PVR is broadly expressed in SCLC cell lines and tumor tissues. The expression of TIGIT protein was also found in SCLC patients with weak to moderate staining. Blockade of the PVR-TIGIT pathway may represent a possible future target to immunotherapy in SCLC patients.

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