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Abstracts IASLC 19TH WORLD CONFERENCE ON LUNG CANCER SEPTEMBER 23–26, 2018 TORONTO, CANADA

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Against Lung Cancer!

SEPTEMBER 7–10, 2019

#WCLC2019

Book of Abstracts Content

INVITED SPEAKER SESSIONS

MINI ORAL ABSTRACT SESSIONS

Plenary Sessions

2

Monday, September 24, 2018

146

Education Sessions

5

Tuesday, September 25, 2018

178

Wednesday, September 26, 2018

224

Meet The Expert Sessions

20

Grand Round Sessions

40

Pro Con Sessions

43

Mini Symposia

60

Joint IASLC – CSCO – CAALC Session

108

CT Screening Symposium

114

POSTER SESSIONS

Poster Session 1 Monday, September 24, 2018

244

Poster Session 2 Tuesday, September 25, 2018

439

Poster Session 3 Wednesday, September 26, 2018

628

DISCLOSURE SUMMARY

794

AUTHOR INDEX

859

ORAL ABSTRACT SESSIONS

Monday, September 24, 2018

116

Tuesday, September 25, 2018

136

Wednesday, September 26, 2018

143

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ABSTRACTS IASLC 19 th World Conference on Lung Cancer

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PL02 PRESIDENTIAL SYMPOSIUM - TOP 5 ABSTRACTS TUESDAY, SEPTEMBER 25, 2018 - 08:15-09:45

PLENARY SESSIONS INVITED SPEAKER PLENARY SESSIONS

PL02 PRESIDENTIAL SYMPOSIUM - TOP 5 ABSTRACTS TUESDAY, SEPTEMBER 25, 2018 - 08:15-09:45

PL02.01 OVERALL SURVIVAL WITH DURVALUMAB VERSUS PLACEBO AFTER CHEMORADIOTHERAPY IN STAGE III NSCLC: UPDATED RESULTS FROM PACIFIC S. Antonia1, A. Villegas2, D. Daniel3, D. Vicente4, S. Murakami5, R. Hui 6, T. Kurata7, A. Chiappori1, K.H. Lee8, M. De Wit 9, B.C. Cho10, M. Bourhaba11, X. Quantin12, T. Tokito13, T. Mekhail14, D. Planchard15, Y. Kim16, C. Karapetis17, S. Hiret18, G. Ostoros19, K. Kubota20, J. Gray21, L. Paz-Ares22, J. De Castro Carpeño23, C. Faivre-Finn24, M. Reck 25, J. Vansteenkiste26, D. Spigel27, C. Wadsworth28, M. Taboada29, P. Dennis 30, M. Özgüroğlu31 H. Lee Moffitt Cancer Center & Research Institute, Tampa/FL/US, 2 Cancer Specialists of North Florida, Jacksonville/FL/US, 3Tennessee Oncology, Nashville/TN/US, 4 Hospital Universitario Virgen Macarena, Seville/ES, 5 Kanagawa Cancer Center, Yokohama/JP, 6 Westmead Hospital and the University of Sydney, Westmead/AU, 7 Kansai Medical University Hospital, Osaka/JP, 8 Chungbuk National University Hospital, Cheongju/KP, 9 Vivantes Klinikum Neukoelln, Berlin/DE, 10Yonsei Cancer Center, Yonsei University College of Medicine, Seoul/KR, 11Centre Hospitalier Universitaire de Liège, Liège/ BE, 12 CHU Montpellier and Icm Val D’Aurelle, Montpellier/FR, 13 Kurume University Hospital, Kurume/JP, 14 Florida Hospital Cancer Institute, Orlando/FL/US, 15 Gustave Roussy, Villejuif/FR, 16 Chonnam National University Hwasun Hospital, Jeonnam/KR, 17 Flinders University and Flinders Medical Centre, Bedford Park/SA/AU, 18 Ico - Site René Gauducheau, Saint Herblain/FR, 19 National Koranyi Institute of Pulmonlogy, Budapest/HU, 20 Nippon Medical School Hospital, Tokyo/JP, 21 H. Lee Moffitt Cancer Center, Tampa/FL/US, 22 Hospital Universitario 12 de Octubre, Ciberonc, Universidad Complutense and Cnio, Madrid/ES, 23 Hospital Universitario La Paz, Madrid/ES, 24 The University of Manchester and the Christie NHS Foundation Trust, Manchester/ GB, 25 Lung Clinic, Airway Rsearch Centre North (ARCN), German Center for Lung Research, Grosshansdorf/DE, 26 University Hospital KU Leuven, Leuven/BE, 27 Sarah Cannon Research Institute, Nasville/TN/US, 28 Astrazeneca, Alderley Park/GB, 29 Astrazeneca, Gaithersburg/US, 30 Astrazeneca, Gaitherburg/MD/US, 31 Istanbul University-Cerrahpaşa, Cerrahpaşa School of Medicine, Istanbul/TR

PL02.05 EFFECTS OF VOLUME CT LUNG CANCER SCREENING: MORTALITY RESULTS OF THE NELSON RANDOMISED-CONTROLLED POPULATION BASED TRIAL H. De Koning1, C. Van Der Aalst2, K. Ten Haaf 1, M. Oudkerk 3 Public Health, Erasmus MC, Rotterdam/NL, 2 Department of Public Health, Erasmus MC, Rotterdam/NL, 3 Department of Radiology, University of Groningen, University Medical Center Groningen, Groningen/NL

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This abstract is under embargo until September 25 at 08:15 Eastern Time.

PL02 PRESIDENTIAL SYMPOSIUM - TOP 5 ABSTRACTS TUESDAY, SEPTEMBER 25, 2018 - 08:15-09:45

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This abstract is under embargo until September 25 at 08:15 Eastern Time.

PL02 PRESIDENTIAL SYMPOSIUM - TOP 5 ABSTRACTS TUESDAY, SEPTEMBER 25, 2018 - 08:15-09:45

S. Liu1, A. Mansfield2, A. Szczesna 3, L. Havel4, M. Krzakowski5, M. Hochmair 6, F. Huemer7, G. Losonczy 8, M. Johnson9, M. Nishio10, M. Reck11, T. Mok12, S. Lam13, D. Shames13, J. Liu14, B. Ding13, F. Kabbinavar 13, W. Lin13, A. Sandler 13, L. Horn15 Georgetown University, Washington/DC/US, 2 Mayo Clinic, Rochester/MN/US, Mazowieckie Centrum Leczenia Chorób Płuc I Gruźlicy, Otwock/PL, 4Thomayerova Nemocnice, Pneumologická Klinika 1.Lf Uk, Prague/CZ, 5 Centrum Onkologii-Instytut Im. M. Skłodowskiej-Curie W Warszawie, Warsaw/PL, 6 Department of Respiratory and Critical Care Medicine & Ludwig Boltzmann Institute for Copd & Respiratory Epidemiology – Baumgartner Höhe, Otto-Wagner-Spital, Vienna/AT, 72Nd Department of Respiratory and Critical Care Medicine & Ludwig Boltzmann Institute for Copd & Respiratory Epidemiology – Baumgartner Höhe, Otto-Wagner-Spital, Vienna/AT, 8 Semmelweis Egyetem Áok, Pulmonológiai Klinika, Budapest/HU, 9 Sarah Cannon Cancer Research Institute/tennessee Oncology Pllc, Nashville/TN/US, 10 The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo/ JP, 11 Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research, Grosshansdorf/DE, 12 State Key Laboratory of South China, the Chinese University of Hong Kong, Sha Tin/HK, 13 Genentech, Inc., South San Francisco/CA/US, 14 F. Hoffmann-La Roche Ltd, Shanghai/CN, 15Vanderbilt University Medical Center, Nashville/TN/US 1

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This abstract is under embargo until September 25 at 08:15 Eastern Time.

PL02.03 BRIGATINIB VS CRIZOTINIB IN PATIENTS WITH ALK INHIBITOR-NAIVE ADVANCED ALK+ NSCLC: FIRST REPORT OF A PHASE 3 TRIAL (ALTA-1L)

PL02 PRESIDENTIAL SYMPOSIUM - TOP 5 ABSTRACTS TUESDAY, SEPTEMBER 25, 2018 - 08:15-09:45

R. Camidge1, H.R. Kim2, M. Ahn3, J.C. Yang4, J. Han5, J. Lee 6, M. Hochmair7, J.Y. Li8, G. Chang 9, K. Lee10, C. Gridelli11, A. Delmonte12, M.R. Garcia Campelo13, D. Kim14, A. Bearz15, F. Griesinger 16, A. Morabito17, E. Felip18, R. Califano19, S. Ghosh20, A. Spira21, S. Gettinger22, M. Tiseo23, J. Haney24, D. Kerstein24, S. Popat25

PL02.09 NINTEDANIB + PEMETREXED/CISPLATIN IN PATIENTS WITH UNRESECTABLE MPM: PHASE III RESULTS FROM THE LUME-MESO TRIAL

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University of Colorado Cancer Center, Aurora/CO/US, Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul/KR, 3 Medicine, Samsung Medical Center, Seoul/KR, 4 National Taiwan University Hospital, Taipei/TW, 5 National Cancer Center, Goyang/KR, 6 Seoul National University Bundang Hospital, Seongnam/KR, 7 Department of Respiratory and Critical Care Medicine, and Ludwig Boltzmann Institute of Copd and Respiratory Epidemiology, Otto Wagner Hospital, Vienna/AT, 8 Queen Elizabeth Hospital, Kowloon/HK, 9 Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung/ TW, 10 Chungbuk National University Hospital, Cheongju/KR, 11 A.O.S.G. Moscati, Avellino/IT, 12 Scientific Institute of Romagna for the Study and Treatment of Cancer, Meldola/IT, 13 Complejo Hospitalario Universitario A Coruna Hospital, Coruna/ES, 14 Seoul National University Hospital, Seoul/KR, 15 Centro Di Riferimento Oncologico, Istituto Nazionale Tumori, IRCCSstruttura Operativa Complessa Oncologia Medica A, Aviano/IT, 16 Department of Hematology and Oncolory, University Department of Internal Medicine-Oncology, Pius-Hospital, Medical Campus University of Oldenburg, Oldenburg/DE, 17Thoracic Medical Oncology, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples/IT, 18Vall D’ Hebron University Hospital, Barcelona/ES, 19 Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester/ GB, 20 Guy’s and St Thomas’ NHS Foundation Trust, London/GB, 21Virginia Cancer Specialists and Us Oncology Research, The Woodlands/TX/US, 22Yale Cancer Center, New Haven/CT/US, 23 Medical Oncology Unit, University Hospital of Parma, Parma/ IT, 24 Millennium Pharmaceuticals, Inc., A Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited, Cambridge/MA/US, 25 Royal Marsden Hospital; National Heart and Lung Institute, Imperial College London, London/GB

This abstract is under embargo until September 25 at 08:15 Eastern Time. 2

PL02.07 IMPOWER 133: PRIMARY PFS, OS AND SAFETY IN A PH1/3 STUDY OF 1L ATEZOLIZUMAB + CARBOPLATIN + ETOPOSIDE IN EXTENSIVE-STAGE SCLC

IASLC 19 th World Conference on Lung Cancer ABSTRACTS

G. Scagliotti1, R. Gaafar2, A. Nowak 3, T. Nakano4, J. Van Meerbeeck5, S. Popat6, N. Vogelzang7, F. Grosso 8, R. Aboelhassan9, M. Jakopovic10, G. Ceresoli11, P. Taylor 12, F. Orlandi13, D. Fennell14, S. Novello1, A. Scherpereel15, U. Von Wangenheim16, M. Kim17, J. Barrueco18, A. Tsao19 University of Turin, Department of Oncology, S. Luigi Hospital, Torino/IT, 2 National Cancer Institute, Cairo University, Fom El Khalig, Cairo/EG, 3 National Centre for Asbestos Related Diseases, School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Crawley, Perth/AU, 4 Otemae Hospital, Osaka/JP, 5 Department of Thoracic Oncology, Antwerp University Hospital, Edegem/ BE, 6 Royal Marsden Hospital NHS Foundation Trust, London/GB, 7 Us Oncology Comprehensive Cancer Centers of Nevada, Las Vegas/NV/US, 8 Ss Antonio E Biagio Hospital, Department of Oncology, Via Venezia 16, Alessandria/IT, 9 Nasser Institute Hospital for Research and Treatment, Cairo/EG, 10 University of Zagreb, School of Medicine, University Hospital Center Zagreb, Department for Respiratory Diseases, Zagreb/HR, 11Cliniche Humanitas Gavazzeni, Department of Oncology, Bergamo/IT, 12 Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester/ GB, 13 Oncología - Health & Care Spa, Santiago de Chile/CL, 14 University of Leicester & University Hospitals of Leicester, Leicester/GB, 15 Pulmonary and Thoracic Oncology Department, CHU de Lille, Lille/FR, 16 Boehringer Ingelheim Pharma GmbH & Co. Kg, Biberach/DE, 17 Boehringer Ingelheim Korea, Seoul/KR, 18 Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield/CT/US, 19 Department of Thoracic/head and Neck Medical Oncology, Division of Cancer Medicine, University of Texas, MD Anderson Cancer Center, Houston/TX/US 1

This abstract is under embargo until September 25 at 08:15 Eastern Time.

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PL03.05 IT’S ALL IN THE TISSUE K. Kerr

Department of Pathology, Aberdeen Royal Infirmary, Aberdeen/GB

Lung cancer therapy has been transformed in recent years, especially for patients with advanced stage non-small cell lung cancer (NSCLC). Our biological understanding of diverse lung cancer types has been enhanced by pathological investigation and molecular analysis of tumours, in turn driving and refining tumour classification. Biological features have become targets of therapy. Eestablished therapeutic approaches of surgery, radiotherapy and chemotherapy still prevail, but their usage has been refined by a better understanding of pathology. New treatment approaches include the inhibition of receptor kinases and therapies which enable an existing but constrained immune response to attack the tumour. All of this progress has been driven by research conducted on tumour tissue. In the lung there are (at least) two pathways of carcinogenesis, involving transformation within two different stem cell populations in the bronchial and peripheral terminal respiratory unit (TRU) epithelium respectively. Our understanding of preneoplasia and its morphological progression has informed ideas about adenocarcinogenesis in particular, and improved radiological diagnosis of early lung cancer, and impacted lung cancer screening. These concepts also underpinned understanding of the pathology of squamous cell carcinoma, and adenocarcinoma, and tumours allied to these sub-type genres, and drove changes in the 2015 WHO classification of lung cancer. In 2008, the JMDB trial demonstrated superiority of pemetrexed/ platinum in advanced ‘de facto’ adenocarcinomas, rather than squamous cell carcinoma, making accurate subtyping of NSCLC an issue for the pathologist. Differences in immunohistochemical profiles of lineage markers reflecting tumour origin from bronchial or TRU epithelium became a method of predicting NSCLC subtype when morphology was insufficient. This diagnostic approach features in practice recommendations, and is now standard of care. All of this progress has been driven by research conducted on tumour tissue. The use of tyrosine kinase inhibitors in mutant EGFR oncogene-addicted adenocarcinomas was the first major step in the expansion of personalised, precision medicine in the treatment of advanced stage NSCLC. Targeting ALK fusion gene proteins followed soon after, when it was recognised that ALK tyrosine kinase inhibitors were effective in treating adenocarcinomas bearing an ALK gene rearrangement identified by FISH analysis or multiplex PCR testing to demonstrate abnormal mRNA fusion gene products. Then came the realization that these molecular events were associated with a modest elevation in tumour cell ALK protein, which is the oncological effector driving the tumour, and which is also the target of the drugs. The presence of the protein is associated with, and probably required for, efficacy of these drugs. The same scenario is now unfolding for ROS1 gene rearrangement, its protein product and the use of ROS1 tyrosine kinase inhibitors. BRAF V600 mutation are the latest genetic alteration to be regarded, in many guidelines, as a mandatory test in advanced NSCLC due to the efficacy of BRAF kinase inhibitors. Other targets in a predominantly non-squamous cell carcinoma patient population remain on the ‘waiting list’ and these may become mandatory pending trial data convincing for efficacy, and approval by appropriate regulatory authorities. The alterations, which have inhibitors targeting kinase activity include MET exon 14 skipping mutations, high levels of MET amplification, RET and NTRK gene rearrangements, and HER2 gene mutations. Some of these alterations represent extremely rare genomic drivers but still represent sufficient patient numbers to justify their investigation. Squamous cell carcinoma presents a rather different scenario. The dominance of tobacco carcinogenesis in this cell type means oncogenic addictive drivers are exceptionally unusual. Most squamous cell carcinomas have a complex genome, exhibiting many mutations, many of which cause loss-of-function in tumour suppressor genes, an unpromising situation for therapeutic intervention. All of this progress has been driven by research conducted on tumour tissue and furthermore, the vast majority of the trial biomarker data and clinical detection if these genomic alterations is based upon detection in tumour tissue samples. Immunotherapy, particular the use of anti-PD1 and antiPD-L1 agents, has had a major impact on standard of care treatment in advanced stage NSCLC, and biomarker testing to enrich treatment populations for clinical benefit has had a major impact on pathological diagnosis. The principle clinical trial-validated and approved biomarker for these drugs is PD-L1 immunohistochemistry (IHC). Whilst the testing algorithms for the approved drugs, or those drugs in advanced stage of trial validation, all consider PD-L1 expression in tumour cells, the algorithm for atezolizumab also includes expression on tumour-infiltrating immune cells. Other assessments of the tumour microenvironment and tumour inflammation are poorly developed in context of immunotherapy biomarker assessment but there is plenty of scope for pursuing this in the future. A little data exists for NSCLC using mRNA immune gene expression signatures but there is almost nothing based upon morphological assessment of tumour inflammation. Tumour mutation burden, as a

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surrogate for neoantigenicity is another emerging biomarker in this arena, and is also capable of enriching for effective response. Once again, the vast majority of the trial data, and all validated clinical biomarker assessment is based upon examination of the tumour tissue. Lung cancer pathology has ‘come of age’ in the last 10 years. Of course, pathologists can rightly argue that it always was important and relevant, but it is only in recent years that it has taken such a pivotal role in predictive biomarker assessment to facilitate personalized, precision medicine for patients with NSCLC. More or less everything we know about lung cancer biology comes from pathological analysis of tumour tissue. Although the so called ‘liquid biopsy’ is an attractive source of biomarker data, it cannot provide detailed, structural (spatial) pathological information about the patients disease, suffers from sensitivity issues which means it does not work for all patients, and is as abstract assessment – it is presumed findings in the blood relate to the patients tumour, but this may not always be so. In the field of immunotherapy is particular, the tumour microenvironment and cellular relationship are set to assume importance. Pathologists need to work to maximize the amount of data that can be derived from the limited tissue samples that we usually have available.

INVITED SPEAKER PLENARY SESSIONS

PL03 CALL TO ACTION - CHALLENGES AHEAD WEDNESDAY, SEPTEMBER 26, 2018 - 08:15-09:45

Keywords: tissue diagnosis, biomarkers

PL03 CALL TO ACTION - CHALLENGES AHEAD WEDNESDAY, SEPTEMBER 26, 2018 - 08:15-09:45

PL03.06 THE FUTURE OF TARGETED THERAPY T. Mitsudomi

Thoracic Surgery, Kindai University Faculty of Medicine, Osaka-Sayama/JP

It is a standard of care to treat patients with non-small cell lung cancer (NSCLC) harboring driver oncogenes with respective tyrosine kinase inhibitors(TKI). The list of the driver genes started with the EGFR gene and now it is further expanding to include ALK, ROS1 and BRAF. Survival of NSCLC patients with EGFR mutations has greatly prolonged since the advent of EGFR-TKI. At the turn of the 21st century, the median survival time of patients with metastatic lung cancer was around on year. However, overall survival of patients with EGFR mutation exceeds 3 years and in some studies, it is close to 4 years. However, acquisition of resistance against EGFR-TKI is almost inevitable and it is exceptional to see patients whose disease are cured. Therefore, although introduction of inhibition of oncogenic tyrosine kinases into lung cancer care was a great progress, it is still on the way from the viewpoint of conquering lung cancer. What is needed for further improving patients’ outcome? Identification of new targets In addition to above-mentioned driver genes to which each targeted therapy is approved by the regulatory agencies, RET, MET, HER2, NTRK1 gene mutations are emerging molecular targets and clinical trials to test each inhibitor for clinical activities are actively conducted. Gene alterations such as KEAP1/ Nrf1 whose mutations are relatively frequent in NSCLC is also sought for possibilities to become a therapeutic target other than receptor tyrosine kinase. Development of strategies to cope with KRAS Although KRAS gene mutation in NSCLC was found nearly 40 years ago and is frequently mutated in NSCLC especially those occurring Caucasian patients. However despite the fact that KRAS mutation is mutually exclusionary with other driver gene mutations., strategies to treat these lung cancers have been unsatisfactory. For example, recent large-scale, SELECT-1 study failed to show a superiority of addition of selumetinib to docetaxel in patients with KRAS mutation. This is partly because not all KRAS mutated cancer cells are fully addicted to mutated KRAS function. Considering the magnitude of the patient population, efficient strategies to treat KRAS lung cancer including the development of small molecules and immunotherapy are eagerly awaited. Development of mutationspecific and wild-type sparing TKI Osimertinib is the first thirdgeneration EGFR-TKIs that is active for both activating EGFR mutations as well as T790M resistant mutations yet sparing wild-type EGFR function. As a result, it showed superior activity over chemotherapy for lung cancer with acquired resistance due to T790M. Following this, the Flaura study showed longer PFS compared with gefitinib/erlotinib. OS result is immature but promising. Because of low activity against wild-type EGFR, adverse events are in general less frequent. This will make it easier for this compound to combine with other modality of therapy, although the incidence of interstitial lung disease was high when combined with durvalumab in the Tatton study. In the case of ALK, alectinib showed prominent superiority in terms of PFS to crizotinib in the J-ALEX and ALEX studies, with better tolerability. These facts clearly indicate that newer drugs that have a higher activity against mutated version but not against wild-type version further prolong patient survival. Development of combination strategies To maximize patients’ benefit, we have to understand the biology of oncogene-driven lung cancer more in detail. When EGFR mutations were initially discovered, NSCLC harboring EGFR mutations were thought to behave similarly in the patients. However, we soon knew that different EGFR mutations may result in different biological/clinical consequences. For example, exon 19 deletion (Del

ABSTRACTS IASLC 19 th World Conference on Lung Cancer

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INVITED SPEAKER PLENARY SESSIONS

19) and L858R are sensitizing mutations, exon 20 insertion mutations are resistant against existing TKIs. Other rarer mutations, so-called uncommon mutations are not that as sensitive as Del19. Furthermore, even though with the same EGFR mutation, lung cancer never behaves same in each patient. There is a great heterogeneity in terms of progression-free survival within patients with the same EGFR mutations when treated with EGFR-TKI. This heterogeneity is now being understood as effects of co-occurring genetic alterations (co-drivers). For example, several investigators found that PFS of patients with EGFR mutation plus TP53 mutation has a shorter PFS than those without. These co-occurring alterations that negatively affect PFS include those of CDK2/4, HER2, TP53. Therefore it is clear that EGFR TKI alone will not be able to achieve long-term disease control, necessitating combination strategy. Recently, NEJ009 trial suggested that carboplatin with pemetrexed followed by pemetrexed maintenance plus gefitinib might prolong overall survival up to over 4 years. This illustrates the importance of chemotherapy as well as EGFR-TKI even for patients with driver gene alterations, probably through inhibition of some activities mediated by co-drivers. Role of immunotherapy for NSCLC with driver gene mutations PD-1 blockade by pembrolizumab is a standard of care for NSCLC with high PD-L1 expression except those with driver mutations. This is because PD-1/ L1 antibodies could not derive benefit for the patients with EGFR/ALK alterations over docetaxel, resulting in omission of these patients in the first-line trial except in the case of atezolizumab. IMpower 150 study showed the superiority of carboplatin/paclitaxel/bevacizumab(CPB) plus atezolizumab over CPB not only in wild-type patients but in EGFR/ALK+ cohorts after first-line TKI therapy. It is not very clear this is because of combination with chemotherapy or bevacizumab or both at this point, and also the mechanism of this efficacy is not known. This study re-opened the door to immunotherapy for these patients, which was once almost closed, In this talk, I would like to envision what has to be done in the next 10 years to further improve the outcome of the patients with driver gene and ultimately to cure their disease. Keywords: Targeted therapy, driver oncogene, combination therapy

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IASLC 19 th World Conference on Lung Cancer ABSTRACTS

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World Congress of Thoracic Imaging Proceedings, Journal of Thoracic Imaging, accepted for oral presentation, 2017. [4] Avila R, Jirapatnakul A, Subramaniam R, Yankelevitz D, “A new method for predicting CT lung nodule volume measurement performance,” SPIE Medical Imaging Proceedings, 2017.

ES01 ADVANCES IN LUNG CANCER SCREENING THROUGH IMAGING MONDAY, SEPTEMBER 24, 2018 - 13:30-15:00

Keywords: “lung cancer screening”, “Image Quality”

ES01.01 IMAGE QUALITY CHARACTERISTICS AND NODULE GROWTH MEASUREMENT, MEDICAL PHYSICS AND MACHINE PARAMETERS

ES01 ADVANCES IN LUNG CANCER SCREENING THROUGH IMAGING MONDAY, SEPTEMBER 24, 2018 - 13:30-15:00

INVITED SPEAKER EDUCATION SESSIONS

EDUCATION SESSIONS

R. Avila

Accumetra, Llc, Clifton Park/US

Modern CT scanners are routinely being used to determine the malignancy potential of small sub-centimeter pulmonary nodules. Increasingly, this involves CT scanning and quantitative volume measurement of lung nodules over short time intervals (e.g. 3 or 6 months) to determine whether a change in nodule size consistent with malignant growth has occurred. Although it may appear that current CT scanners are more than capable of reliably performing these quantitative measurements with high quality due to their ability to obtain submillimeter resolution lung images, many clinical sites are not taking the steps needed to achieve consistent high quality small lung nodule measurement results. A study of volume measurement performance in a phase II clinical trial observed multiple clinical sites using CT scanners which resulted in errors in volume change measurements as high as 43% [1]. In addition, a 2016 crowd-sourcing study of CT scanner image quality performance using the site’s low dose CT lung cancer screening acquisition protocol revealed that 37% of sites used insufficient slice thickness (90% long-term local control rates and minimal morbidity in multiple histologies of intrathoracic metastases, including thymic tumors.10 Lastly, palliative RT should be considered whenever surgical management or definitive radiation treatment options are not feasible. Conventional palliative RT is an important modality to improve quality of life by alleviating pain, treating SVC syndrome,

ABSTRACTS IASLC 19 th World Conference on Lung Cancer

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INVITED SPEAKER MEET THE EXPERT SESSIONS

airway compression and other symptoms. 1. Fernandes AT, Shinohara ET, Guo M, et al. The role of radiation therapy in malignant thymoma: A surveillance, epidemiology, and end results database analysis. Journal of Thoracic Oncology. 2010;5(9):1454-1460. 2. Rimner A, Gomez DR, Wu AJ, et al. Failure patterns relative to radiation treatment fields for stage II-IV thymoma. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2014;9(3):403409. 3. Rimner A, Yao X, Huang J, et al. Postoperative Radiation Therapy Is Associated with Longer Overall Survival in Completely Resected Stage II and III Thymoma-An Analysis of the International Thymic Malignancies Interest Group Retrospective Database. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2016;11(10):1785-1792. 4. Modh A, Rimner A, Allen PK, et al. Treatment Modalities and Outcomes in Patients With Advanced Invasive Thymoma or Thymic Carcinoma: A Retrospective Multicenter Study. American journal of clinical oncology. 2016;39(2):120-125. 5. Ahmad U, Yao X, Detterbeck F, et al. Thymic carcinoma outcomes and prognosis: results of an international analysis. J Thorac Cardiovasc Surg. 2015;149(1):95-100, 101.e101-102. 6. Omasa M, Date H, Sozu T, et al. Postoperative radiotherapy is effective for thymic carcinoma but not for thymoma in stage II and III thymic epithelial tumors: the Japanese Association for Research on the Thymus Database Study. Cancer. 2015;121(7):1008-1016. 7. Ruffini E, Detterbeck F, Van Raemdonck D, et al. Thymic carcinoma: a cohort study of patients from the European society of thoracic surgeons database. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2014;9(4):541-548. 8. Gomez D, Komaki R. Technical advances of radiation therapy for thymic malignancies. Journal of Thoracic Oncology. 2010;5(10 SUPPL. 4):S336-S343. 9. Gomez D, Komaki R, Yu J, Ikushima H, Bezjak A. Radiation therapy definitions and reporting guidelines for thymic malignancies. Journal of Thoracic Oncology. 2011;6(7 SUPPL. 3):S1743-S1748. 10. Baschnagel AM, Mangona VS, Robertson JM, Welsh RJ, Kestin LL, Grills IS. Lung metastases treated with image-guided stereotactic body radiation therapy. Clinical oncology (Royal College of Radiologists (Great Britain)). 2013;25(4):236-241. Keywords: Thymoma, radiation, pleural recurrence

MTE07 MANAGEMENT OF PLEURAL RECURRENCE (TICKETED SESSION) MONDAY, SEPTEMBER 24, 2018 - 07:00-08:00

MTE07.02 FROM SURGICAL PERSPECTIVE R. Korst

Thoracic Surgery, Mount Sinai Health System, New York/NY/US

The pleural space represents the most common location for recurrence following resection of thymic epithelial tumors (TET). The rationale to include surgical resection in the management plan for these patients is based on small case series and reports, many of which demonstrate long periods of survival following pleural metastasectomy. Two large, retrospective series of patients with pleural disease have been recently published, both of which reflect pooled data from multiple institutions; one from Europe and the other from Japan1,2. Despite this, little prospective data address this issue. In addition, the management strategy for pleural disease in patients with TET is extrapolated from the management of primary TET in the mediastinum, where surgical resection plays an important role. Prognostic factors after surgical resection for pleural disease mirror those that are most consistently reported for primary mediastinal TET. Most case series of patients undergoing resection for pleural disease (either recurrence or initial presentation) suggest that the ability to completely resect the disease is an important prognostic factor. Indeed, both of the aforementioned larger series confirm that complete resection is associated with enhanced survival1,2. The Japanese report of 136 cases of pleural dissemination of thymoma at initial presentation (not recurrence) also determined that lower disease burden in the pleural space positively affects survival2. Although the large European Society of Thoracic Surgery (ESTS) Thymic Working Group Project (152 patients with either pleural recurrence and pleural disease at initial presentation) did not report disease burden, it confirmed the importance of complete resection in maximizing survival1. This later study also determined that thymic carcinoma patients experienced significantly shorter survival after resection of pleural disease than patients with thymoma. Thymic carcinoma, pleural disease burden and the ability to perform a complete resection can all be considered surrogates for individual tumor biology, which may be the most important underlying prognostic factor. Surgical approaches for patients with TET that has spread to the pleural space include metastasectomy and extrapleural pneumonectomy (EPP). The surgeon’s goal is the complete gross resection of disease, which is dependent on the burden and location of disease. In cases of pleural recurrence, the surgical approach is typically through a lateral thoracotomy since this incision provides the best exposure of the entire pleural space and the mediastinal tumor has already been resected at an earlier time. More recently, video assisted

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IASLC 19 th World Conference on Lung Cancer ABSTRACTS

thoracic surgery (VATS) approaches have been used selectively to approach these patients depending on the expertise of the operator. The surgeon wishes to perform the least amount of resection possible while still rendering the patient grossly disease free. Metastasectomy may range from the resection of a single pleural lesion to an extensive parietal pleurectomy with or without pulmonary resection(s) for visceral pleural involvement of metastatic deposits. On occasion, the surgeon may explore the chest of a patient with the intent of performing metastasectomy, but instead encounters diffuse innumerable visceral and parietal pleural metastatic deposits. In this case, EPP may be the only option to render the patient grossly disease free. The surgeon should always be prepared for this development whenever operating on a patient for metastatic TET, so that an educated decision can be made to proceed with EPP at the time of exploration, if necessary. EPP, however, may not be a good option for patients with thymic carcinoma that has metastasized to the pleural space given the magnitude of this approach combined with the significantly worse survival after resection in patients with metastatic pleural disease, when compared to thymoma. Pleural treatments used as an adjunct at the time of surgical resection for patients with pleural metastases from TET are becoming more popular. Heated intrapleural chemotherapy (HIPC) represents the most commonly used modality in this regard. After resecting all gross disease, the surgeon perfuses the hemithorax with heated chemotherapy for a period of time ranging from one to two hours. This strategy has been demonstrated to be safe with an acceptable complication rate in several small case series of patients with TET3. Although survival rates appear to be encouraging, definitive data demonstrating a survival benefit to HIPC are lacking. Intrathoracic photodynamic therapy (PDT) has also recently been reported for patients with TET that has metastasized to the pleural space4. Although the use of neoadjuvant chemotherapy has been reported in several case series of patients with pleural metastases at the time of initial presentation5, data are lacking specifically in the scenario of pleural recurrence. The rationale for this approach mimics that for locally advanced TET in the mediastinum – to reduce the disease burden in hopes of increasing the likelihood of complete resection. Once again, this strategy appears to be safe and associated with encouraging rates of complete resection and survival, but definitive data confirming a benefit are lacking. In summary, the surgical resection of pleural recurrence of TET is associated with prolonged survival in selected patients, as reported in many case series. However, given the lack of controlled studies, it is unclear if prolonged survival is a direct result of the surgical approach or simply selection of patients with more forgiving tumor biology. Despite this, a rational approach may be to invoke a surgical approach as the initial strategy in patients with thymoma whose disease appears to be resectable. Once surgical options have been exhausted, or the disease is clearly unresectable, systemic therapy and/or radiotherapy can be utilized to achieve further disease control. References: 1. Moser B, et al. Surgical therapy of thymic tumours with pleural involvement: an ESTS Thymic Working Group project. Eur J Cardiothorac Surg 2017;52:34655. 2. Okuda K, et al. Thymoma patients with pleural dissemination: Nationwide retrospective study of 136 cases in Japan. Ann Thorac Surg 2014;97;1743-9. 3. Maury J-M, et al. Intra-thoracic chemo-hyperthermia for pleural recurrence of thymomas. J Thorac Dis 2017;9:E1137-9. 4. Chen K-C, et al. Pleural photodynamic therapy and surgery in lung cancer and thymoma patients with pleural spread. PLOS one 2015;10:e0133230. 5. Shapiro M, et al. Surgical Approaches for stage IVa thymic epithelial tumors. Front Oncol 2014;3:332. Keywords: Thymoma, Surgical resection, pleural recurrence

MTE08 ENHANCING THE NURSE’S ROLE IN TOBACCO PREVENTION AND CESSATION: NEW CHALLENGES (TICKETED SESSION) MONDAY, SEPTEMBER 24, 2018 - 07:00-08:00

MTE08.01 ENHANCING THE NURSE’S ROLE IN TOBACCO PREVENTION AND CESSATION: NEW CHALLENGES L. Sarna

School of Nursing, University of California, Los Angeles, Los Angeles/CA/US

The purpose of this presentation is to discuss strategies for enhancing the nurses’ role in tobacco control, including the implementation of smoking cessation interventions in oncology practice settings as part of routine care. The experiences of the Tobacco Free Nurses Initiative to accelerate nursing involvement in tobacco control in multiple countries will be used to illustrate key strategies. Healthcare professionals are effective in increasing quit attempts and long-term cessation; however, few patients receive the necessary support. Although more healthcare providers are identifying smoking status in the patient record and providing advice to quit, fewer actively assist patients who smoke with a quit attempt and arrange for follow-up. During this presentation, an evidence-based smoking cessation intervention based on the 5 As (i.e., Ask, Advise, Assess, Assist and Arrange) will be reviewed along with strategies for facilitating implementation in the clinical setting. The

WWW.IASLC.ORG

Title

Organization

Information

Agency for Healthcare Research and Quality

Treating Tobacco Use and Dependence: 2008 Update https://www. ahrq.gov/professionals/ clinicians-providers/guidelines-recommendations/ tobacco/index.html

Section for clinicians and system decision makers, including systems change information for integration of tobacco dependence in clinical practice

American Society of Clinical Oncology

Tobacco cessation tools and resources https://www.asco.org/ practice-guidelines/ cancer-care-initiatives/ prevention-survivorship/ tobacco-cessation-control

Comprehensive information regarding the 5 As for a cessation intervention and wide-ranging tobacco control policies

Centers for Disease Control and Prevention

Health Care Providers: How you can help patients quit https://www.cdc.gov/ tobacco/campaign/tips/ partners/health/hcp/index. html

Provides general information for healthcare providers based on the Tips for Former SmokersRCampaign

Smoking cessation and cancer https://www.cdc. gov/tobacco/campaign/ tips/diseases/cancer.html

Specific examples of the impact of smoking and exposure to second-hand smoke on cancer. Videos from the TIPs campaign with cancer to promote motivation to quit

State telephone support lines for smoking cessation http://www.naquitline.org/

Provides information about availability and details of telephone quitlines for smoking cessation across the United States including electronic referral, other resources, and availability of nicotine replacement

Centers for Disease Control and Prevention

North American Quitline Consortium

WWW.IASLC.ORG

Oncology Nursing Society

Tobacco control policy recommendationsfor oncology nurses https:// www.ons.org/advocacy-policy/positions/policy/ tobacco

Also endorsed by the International Society of Nurses in Cancer Care

Smokefree partner toolkit

Smoke-free.gov https:// smokefree.gov/help-others-quit/health-professionals

Provides comprehensive list of evidence-based resources, guides and government reports aimed for clinicians, including smokefree mobile interventions

SRNT, Society for Research on Nicotine and Tobacco

Resources for Clinicians https://www.srnt. org/?page=Resources_Clinicians

Provides many science-based resources and a searchable index for abstracts related to cardiovascular disease

Tobacco Free Nurses

Resources for nurses to enhance to tobacco control https://tobaccofreenurses.org

Multiple webcasts in different languages, including many focused on oncology nursing and tobacco control

University of Wisconsin- Center for Tobacco Research and Intervention

Providers overview of tobacco dependence treatment https://ctri.wisc. edu/providers/providers-overview/

Offers tobacco treatment training through webinars, onsite videos or online programs. Updates on the evidence for electronic cigarettes, including vaping regulations by state

INVITED SPEAKER MEET THE EXPERT SESSIONS

oncology team needs adequate knowledge and skills in the delivery of a tobacco dependence treatment intervention. Although many healthcare providers may know about the devastating health effects of smoking and tobacco use, including lung cancer, few received the necessary training to deliver an evidence-based intervention. Many educational resources are available as listed in Table 1. Basic content of educational programs to support delivery of a smoking cessation intervention includes information about health risks of smoking and exposure to secondhand smoke, nicotine dependence and withdrawal, health benefits of quitting, evidence-based methods for supporting tobacco dependence treatment including behavioral interventions (i.e., social support and skills training), identification of triggers for relapse and how to manage withdrawal symptoms and cravings, and knowledge of FDA-approved pharmacotherapy, including side effects and toxicity. With the advent of the electronic medical record (EMR), tobacco use is often included as core information at patient intake with reminders to providers increasing the rates of advice and assessment. The EMR may be tailored to include easy-to-use prepopulated “Smart sets” for intervention with information about approved medications and referral options as well as downloadable materials for patients and families. The EMR can push alerts to clinicians to prompt treatment. Inpatients who are identified as smokers can be offered nicotine replacement therapy (NRT) to alleviate withdrawal symptoms, regardless of their desire to quit long-term. Changes in the healthcare environment also can support implementation of these recommendations. These include adopting smoke-free policies in healthcare settings, beyond the inpatient hospital, and supporting quit efforts of healthcare providers. Although smoking is declining among healthcare providers, this may be an issue in some settings and in some geographic areas. Smoking of the healthcare provider has been associated with decreased interventions and confidence in providing a patient with intervention. Promoting the smoking cessation support services provides an opportunity to support the quit efforts of healthcare providers as well. Providers’ support of patient quit efforts is essential regardless of the smoking status of the individual clinician. Table 1. Resources to support implementation of tobacco dependence treatment in oncology clinical settings

References Treating Tobacco Use and Dependence:2008 Update. Clinical Practice Guideline.https://www.ahrq.gov/professionals/cliniciansproviders/guidelines-recommendations/tobacco/index.html EK, Strouse R, Hall J, Kovac M, & Schroeder SA. (2010). National survey of U.S. health professionals’ smoking prevalence, cessation practices, and beliefs. Nicotine Tob Res, 12 (7), 724–733. doi: 10.1093/ntr/ntq071. Sharpe T, Alsahlanee A, Ward K & Doyle F. (2018). Systematic review of clinicianreported barriers to provision of smoking cessation interventions in hospital inpatient settings. J Smok Cessat, 1-11. Doi.10.1017/jsc.2017.25 Sarna L, Bialous SA, Ong MK, Wells M, Kotlerman J. Increasing nursing referral to telephone Quitlines for smoking cessation using a webbased program. Nurs Res. 2012 Nov-Dec;61(6):433-40. doi: 10.1097/ NNR.0b013e3182707237. Thomas D, Abramson MJ, Bonevski B, George J. System change interventions for smoking cessations. Cochrane Database Syst Rev.2017 Feb 10;2:CD010742. doi: 10.1002/14651858. CD010742.pub2. Boyle R, Solberg L, Fiore M. Use of electronic health records to support smoking cessation. . 2014 Dec 30;(12):CD008743. doi: 10.1002/14651858.CD008743.pub3. Review. PMID 25547090 Rigotti NA, Regan S, Levy DE, Japuntich S, Chang Y, Park ER, Viana JC, Kelley JH, Reyen M, Singer DE. Sustained care intervention and postdischarge smoking cessation among hospitalized adults: a randomized clinical trial. JAMA.2014 Aug 20;312(7):719-28. doi: 10.1001/jama.2014.9237 Keywords: Cancer, tobacco, smoking, nurses

MTE09 MANAGEMENT OF ADVANCED WILD-TYPE LUNG CANCER IN SPECIAL SITUATIONS (TICKETED SESSION) MONDAY, SEPTEMBER 24, 2018 - 07:00-08:00

MTE09.01 EVIDENCE BASED MANAGEMENT OF THE PATIENT OVER 80 E. Quoix

Pneumology, University Hospital, Strasbourg/FR

Lung cancer is the first cause of death by cancer in the entire world. In US the estimated number of new lung cancer cases in 2018 is 234030 with an estimated number of deaths of 154050 (25% of all cancer deaths) (1). Due to the conjunction of two factors (increased incidence of cancer with age and increase of life expectancy), median age at diagnosis is now 70 years in the US. The probability of developing a lung cancer is 6.1% after 70 years of age in males and 4.8% in females to be compared with respectively 1.9% and 1.4% between 60 and 69 years (1). Seventy years is also the cutoff most frequently used to define older adults in clinical trials of systemic treatments (2) (3) (4) Although, octogenarians represent a non negligible part of the patients, lung cancer is most frequently diagnosed among people aged 65-74 years (33.4% of the cases) whereas

ABSTRACTS IASLC 19 th World Conference on Lung Cancer

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INVITED SPEAKER MEET THE EXPERT SESSIONS

26.8% are diagnosed between 75 and 84 years and 9.4% after 84 years (https//seer.cancer.gov/statfacts/html/lungb.html) . Non-small cell lung cancer (NSCLC) represent 85% of the cases whatever the age of diagnosis and, between 2007 and 2013, 57% of them were diagnosed at a metastatic stage (1). Thus systemic treatment to be applied in older patients is of paramount importance. Patients without targetable mutations and with a PDL1 expression 50% should be considered for immunotherapy by Pembrolizumab as first line therapy (5). Recommendations for fit patients with no targetable mutations are to give a platin-based doublet (4 to 6 cycles ) followed by a maintenance therapy in patients with no progressive disease at the end of the induction cycles. In non-squamous cell carcinoma, bevacizumab may be added in the absence of contra-indication (5). Regarding chemotherapy for older adults, we have some specific trials (table 1). The first point of these studies is that elderly patients do beneficiate of chemotherapy. Second point is that a non platin-based doublet does not provide any survival benefit compared to single agent therapy and third, carboplatin-based doublet (especially monthly carboplatine + weekly paclitaxel) provides an important survival benefit over single agent alone for elderly patients with PS 0-2 (4). In this study subgroup analysis showed that the survival benefit of a doublet compared to single agent therapy was also observed in the octogenarians. We have no data regarding maintenance therapy in elderly patients. The benefit/risk ratio is not in favor of bevacizumab after 70 years (6). The case of immunotherapy in elderly patients is of importance as the increased incidence of cancers in this population may be due to immune dysfunction (7). However, we do not have studies dedicated to elderly patients and data are obtained from subgroup analyses of studies with no upper limit of age (with the risk of selection biases). Pembrolizumab was compared to chemotherapy in patients with PDL1 expression > 50% and resulted in a survival benefit (8). Moreover in a recently published trial, addition of Pembrolizumab to chemotherapy as first-line therapy resulted also in a survival benefit compared to chemotherapy alone (9). Although there were some patients aged 80 years and more in these trials, specific studies are lacking and should be implemented. With reference to second line treatment, there are also no specific trials for elderly patients although erlotinib was due as second line therapy in one randomized trial (10) with similar results as observed in the pivotal study (BR21 comparing placebo to erlotinib after a first line consisting in a platin-based doublet). Regarding immunotherapy as second line, 4 phase III trials (docetaxel versus nivolumab in squamous and non-squamous cell carcinoma, docetaxel versus pembrolizumab and docetaxel versus atezolizumab) which are all in favor of the immunotherapy, included some elderly patients but with a median age around 62-64 years and although the eldest patients were 85 years old the proportion of patients aged 75 and more was below 12%. Thus, if recommendations regarding chemotherapy in elderly patients are now clear, there is a need for specific studies of immunotherapy in elderly patients especially those aged over 75 years either in first line therapy or second line therapy. Table I Randomized trials dedicated to elderly patients with advanced NSCLC

28

Author (year)

Drugs

N° patients

Response rate (%)

Median survival (months)

1-year survival rate (%)

P

Gridelli (1999)

VNR BSC

76 75

19.7 ------

6.5 4.9

32 14

0.03

Frasci (2000)

VNR VNR+Gem

60 60

15 22

4.5 7

13 30

90% of a cohort of both limited and extensive stage SCLC patients making it a highly suitable tool for patient monitoring. In 2014 we pioneered the development of CTC derived patient explant (CDX) models in immune compromised mice (3) which faithfully recapitulate the donor patients’ tumour morphology and genomic landscape, and mimic their response to cisplatin-based chemotherapy. The models also display patient-relevant metastatic tissue tropism and cell subpopulations are competent for vasculogenic mimicry (4). We are currently interrogating phenotypic heterogeneity in our panel of 45 CDX models and using them to test novel drug combinations including DNA damage repair and cell cycle checkpoint inhibitors (5). CDX cells can be cultured ex vivo for short periods, genetically manipulated and re-implanted in vivo for hypothesis testing studies (6) and most recently we have witnessed progress in culturing CTCs directly from patients’ blood samples. These ex vivo approaches allow therapy screening (CDX cultures) or real time viability assays tailored to small cell numbers (CTC cultures) that ultimately may be able to inform patient treatment. All of the aforementioned applications of liquid biopsies in SCLC will be discussed and reviewed. References 1. Hou JM, Krebs MG, Lancashire L, Sloane R, Backen A, Swain RK, et al. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J Clin Oncol. 2012;30(5):525-32. 2. Carter L, Rothwell DG, Mesquita B, Smowton C, Leong HS, Fernandez-Gutierrez F, et al. Molecular analysis of circulating tumor cells identifies distinct copynumber profiles in patients with chemosensitive and chemorefractory small-cell lung cancer. Nat Med. 2017;23(1):114-9. 3. Hodgkinson CL, Morrow CJ, Li Y, Metcalf RL, Rothwell DG, Trapani F, et al. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nat Med. 2014;20(8):897-903. 4. Williamson SC, Metcalf RL, Trapani F, Mohan S, Antonello J, Abbott B, et al. Vasculogenic mimicry in small cell lung cancer. Nat Commun. 2016;7:13322. 5. Lallo A, Frese KK, Morrow CJ, Sloane R, Gulati S, Schenk MW, et al. The combination of the PARP inhibitor olaparib and the Wee1 inhibitor AZD1775 as a new therapeutic option for small cell lung cancer Clin Cancer Res. in press. 6. Lallo A, Warpman Berglund U, Frese KK, Potter DS, Helleday T, Dive C. Ex vivo culture of circulating tumour cell derived explants to facilitate rapid therapy testing in small cell lung cancer. European Association for Cancer Research Annual Conference; Manchester, U.K.2016. Keywords: SCLC, CDX, liquid biopsies

Notch pathways and EMT were greatly upregulated. These and other findings were predicted to impact on the potential responses of the two subtypes to chemotherapy, radiotherapy, and multiple targeted therapies. Differences limited to tumors and absent in cell lines: Despite having a high mutational burden, SCLC is considered to be an “immunological desert”, with few infiltrating immune or inflammatory cells, low or absent PDL-1 expression, and modest responses to PD-1 blockade. While the high NE tumors fitted this description most of the low NE tumors had strands of fibrosis encircling tumor islets, with varying numbers of inflammatory cells in the fibrous strands. Major differences at multiple steps were present in the low NE subtype involving the over 200 genes regulating the Cancer-Immunity Cycle, including the major cytokine families, toll like receptors, the inflammasome pathway, the JAK/STAT pathway, HLA antigens, CD47 antigen, perforin and granzymes. These changes were accompanied by highly significant increases in the relative numbers of multiple types of infiltrating immune and inflammatory cells. In addition, the low NE subtype had increased expression of PDL-1 and the interferon gamma signature, suggesting enhanced responses to immunotherapy. Conclusions: SCLC tumors and cell lines can be divided into high and low NE subtypes and these subtypes have major differences in lineage specific transcription factors, expression of the NE program, as well as some oncogenes and pathways, predicting them to respond very differently to conventional and targeted therapies. In addition, very different infiltrating cellular and gene expression patterns of immune responses were present in the low NE tumors, involving multiple aspects of Innate and Adaptive Immunity, and predicting that the low NE subtype tumors are more likely to respond to immunotherapy. In addition, several possibilities of combining cytotoxic, targeted and immunotherapies are suggested from our findings. I thank my collaborators for their invaluable contributions: Ling Cai, Tao Wang, Guanghua Xiao, Luc Girard and John Minna. 1. Zhang W, Girard L, Zhang YA, et al. Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes. Transl Lung Cancer Res 2018;7(1):32-49. Keywords: Small cell lung cancer, Heterogeneity, Neuroendocrine differentiation

MS32 SCLC - FROM BENCHSIDE TO BEDSIDE - CLINICAL SCIENCE SESSION WEDNESDAY, SEPTEMBER 26, 2018 - 13:30-15:00

MS32.05 TARGETING DNA DAMAGE AND REPAIR MS32 SCLC - FROM BENCHSIDE TO BEDSIDE - CLINICAL SCIENCE SESSION WEDNESDAY, SEPTEMBER 26, 2018 - 13:30-15:00

L. Byers

MS32.04 MOLECULAR PHENOTYPES OF SCLC

Small cell lung cancer (SCLC) remains one of the most recalcitrant cancer types, with a 5 year survival less than 10% across all stages. At the genomic level, SCLC is characterized by loss of p53 and RB1 function and frequent amplification or overexpression of MYC family members1. These molecular hallmarks of SCLC contribute to high rates of replication stress and genomic instability which, in turn, may make SCLC tumors more susceptible to drugs targeting DNA damage response (DDR). Previously, we found that PARP1, Chk1, Wee1, and other proteins regulating DNA repair are highly expressed in SCLC, as compared to other lung cancers2. Based on this finding, several DDR inhibitors have now been tested in SCLC models as single agents or in combination with other DDR inhibitors or chemotherapy. Pharmacologic inhibitors of PARP, Chk1, Wee1, and ATR (alone or in combination) have shown promising activity in SCLC cell lines and mouse models (as reviewed in Sen, Gay, and Byers, TLCR 2018)3. Interestingly, in SCLC, response to PARP inhibitors and other DDR inhibitors has not been associated with mutations in BRCA1/2, other gene defects in homologous recombination (HR), or with higher HR deficiency scores. Rather, several novel biomarkers have been identified that define subsets of SCLC with enhanced sensitivity to specific DDR inhibitors. These include high SLFN11 expression as a predictor of PARP inhibitor sensitivity and MYC amplification or overexpression as a predictor for Chk1 and aurora kinase targeting. Many of these biomarkers are associated with pathways that contribute to replication stress (e.g., high MYC activity) or that promote replication arrest following DNA damage (e.g., high SLFN11)4,5. This supports the hypothesis that SCLC tumors under greater replication stress may be more susceptible to DDR inhibitors. Several PARP inhibitors (e.g., olaparib, rucaparib, niraparib) are now approved for the treatment of breast and ovarian cancer and inhibitors that hit other DDR targets are in various stages of clinical development. The availability of these agents – together with the preclinical data – has led to several clinical trials investigating DDR inhibitor targeting in SCLC. Results from a recently published randomized Phase 2 trial of temozolomide (TMZ) with either veliparib (PARP inhibitor) or placebo in 104 relapsed SCLC patients did not meet its primary endpoint of 4-month progression free survival (PFS)6. However, response rates were three times as high in the veliparib-treated patients (39% TMZ/ veliparib vs. 19% TMZ/placebo, p=0.016). Furthermore, when patients were stratified by biomarker status, those patients with SLFN11-positive tumors (as measured by IHC) who received the PARP inhibitor had

A. Gazdar

UT Southwestern Medical Center, Dallas/US

Heterogeneity of neuroendocrine (NE) differentiation in small cell lung cancer (SCLC) determines very different molecular phenotypes Background and Purpose: SCLC is usually regarded as a homogenous tumor treated in a standard fashion. We have established and validated a 50 gene expression quantitative scoring system for NE lung tumors, consisting of both positive and negative scores [1]. While almost all carcinoid tumors have positive scores, SCLC and large cell neuroendocrine carcinomas have positive and negative subpopulations. Methodology: We utilized the NE gene expression score to demonstrate intertumor heterogeneity of gene expression patterns and their relationship to signaling pathways and to immune and inflammatory response. We used cluster analysis to divide the SCLC samples into high and low NE subtypes. We studied two public SCLC tumor data sets (n = 140) as well as 70 cell lines established by us and a pair of high/ low sublines established from a single SCLC cell line. Results: The NE score cluster analysis indicated that ~10% of cell lines and ~20 of SCLC tumors were of the low NE subtype. The low NE subtype samples had RB1 mutations or low or absent RB1 expression, confirming their SCLC origin. Differences between the high and low subtypes were divided into those common to tumors and cell lines and those largely or entirely limited to tumors. Differences common to tumors and cell lines. At least three different lineage specific transcription factors were expressed by SCLC tumors and cell lines. Most NE high cells expressed ASCL1 in conjunction with NKX2-1. NEUROD1, occasionally with ASCL1, was expressed by a smaller subset of NE high and occasionally by NE low cells. POU2F3 was expressed by most of the NE low subtypes, and about half of these also expressed ASCL2. However, about 4% of tumors and cell lines (all belonging to the NE low subtype) lacked an identified lineage specific transcription factor. The NE high subtype expressed all of the classic NE markers, as well as numerous neural markers covering neural and glial differentiation. In addition they selectively expressed markers for DNA damage, the FGFR pathway, calcium signaling and Notch inhibitors. The NE low subtype lacked all or most of the NE cell program, NKX2-1 and DLL3 expression, while MYC and REST expression, the Hippo, TGFb and

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IASLC 19 th World Conference on Lung Cancer ABSTRACTS

Thoracic/Head & Neck Medical Oncology, UT MD Anderson Cancer Center, Houston/ TX/US

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INVITED SPEAKER MINI SYMPOSIA

significantly higher PFS and overall survival (OS) than biomarker-negative patients (interaction p-value 0.009). For example, SLFN11-positive patients treated with TMZ/veliparib had a median OS of 12.5 months as compared to 7.5 months in SLFN11-negative patients (p=0.014). In contrast, there was no difference in PFS or OS based on biomarker status in patients in the placebo (TMZ only) arm, supporting that the biomarker was in fact predictive of benefit from PARP inhibitor treatment. An ongoing study combining the PARP inhibitor olaparib with TMZ is further exploring this combination in relapsed SCLC patients (NCT02446704). In addition, two trials have now been conducted investigating veliparib in combination with frontline platinum-etoposide chemotherapy (NCT01642251 and NCT02289690). SLFN11 biomarker analysis from the first of these studies will be presented at this meeting. Other DDR inhibitors in clinical investigation include the Chk1 inhibitor prexasertib and the Wee1 inhibitor AZD1775 (alone or in combination with other DDR inhibitor or chemotherapy). DDR targeting may also potentiate the effect of immunotherapy. In other cancer types, recent reports describe enhanced activity of immune checkpoint inhibitors in cancers with inherent DDR deficiencies such as BRCA1 mutations. Clinical trials in multiple tumor types including lung cancer are underway investigating whether treatment with a DDR inhibitor could enhance response to immunotherapy. Emerging preclinical data suggests activity of DDRimmune targeting in SCLC. REFERENCES 1. George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature 2015;524:47-53. 2. Byers LA, Wang J, Nilsson MB, et al. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer Discov 2012;2:798811. 3. Sen T, Gay CM, Byers LA. Targeting DNA damage repair in small cell lung cancer and the biomarker landscape. Transl Lung Cancer Res 2018;7:50-68. 4. Sen T, Tong P, Stewart CA, et al. CHK1 Inhibition in Small-Cell Lung Cancer Produces Single-Agent Activity in BiomarkerDefined Disease Subsets and Combination Activity with Cisplatin or Olaparib. Cancer Res 2017;77:3870-84. 5. Steward, AC, Tong P, Cardnell RJ, et al. Dynamic variations in epithelial-to-mesenchymal transition (EMT), ATM, and SLFN11 govern response to PARP inhibitors and cisplatin in small cell lung cancer. Oncotarget 2017;8:28575-87. 6. Pietanza MC, Waqar SN, Krug LM, et al. Randomized, Double-Blind, Phase II Study of Temozolomide in Combination With Either Veliparib or Placebo in Patients With Relapsed-Sensitive or Refractory Small-Cell Lung Cancer. J Clin Oncol 2018:JCO2018777672. Keywords: Small cell lung cancer (SCLC), DNA damage repair, Biomarkers

MS32 SCLC - FROM BENCHSIDE TO BEDSIDE - CLINICAL SCIENCE SESSION WEDNESDAY, SEPTEMBER 26, 2018 - 13:30-15:00

MS32.06 EPIGENETIC TARGETS J. Poirier

Memorial Sloan Kettering Cancer Center, New York/NY/US

Lung cancer remains the most common cause of death in men and women, responsible for more deaths than colon, breast and prostate cancer combined. Lung adenocarcinoma (a type of NSCLC) and small cell lung cancer (SCLC) comprise two of the major subgroups within lung cancer and collectively contribute to a high degree of cancer mortality year after year. Despite recent success in developing and implementing targeted therapeutics for several prominent driver oncogenes in NSCLC, SCLC remains a critical unmet medical need in the cancer field, in part due to a relative paucity of actionable mutations and well-defined biomarkerdirected therapies. New therapeutic strategies are desperately needed to improve clinical outcomes for patients with SCLC. Despite lacking known driver oncogenes, such solid tumors have been shown to have frequent inactivating mutations in epigenetic remodeling enzymes – the “reader” and “writers” of the epigenome – which collectively play a role in the regulation of transcription, cellular plasticity and the ability of cancer to adapt or resist therapeutic interventions. Known to be central to the role in regulation of gene expression are the SWI/SNF family of chromatin remodeling enzymes (also know as “BAF”), the Polycomb Repressive Complexes (PRC1/2), the p300-CBP transcriptional coactivator family, BRD4, LSD1-NuRD, MLL and others. These transcriptional rheostats have a central role in dynamic process of opening and closing chromatin to the access of transcription and elongation factors. It is increasingly appreciated that SCLC is particularly sensitive to perturbations in transcription. Small molecules now exist to target the catalytic function of many of these epigenetic targets and are proceeding to clinical testing for patients with molecularly defined cancers, offering a therapeutic opportunity in an otherwise barren space. Keywords: EZH2, Epigenetic, LSD1

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ABSTRACTS IASLC 19 th World Conference on Lung Cancer

107

JOINT IASLC – CSCO – CAALC SESSION

JCSE01 PERSPECTIVES FOR LUNG CANCER EARLY DETECTION SUNDAY, SEPTEMBER 23, 2018 - 07:30-11:15

JCSE01.04 RISK MODELING FOR THE EARLY DETECTION OF TIN MINER LUNG CANCER IN CHINA Y. Qiao

Department of Cancer Epidemiology, Cancer Institute/hospital, Chinese Academy of Medical Sciences, Beijing/CN

INVITED SPEAKER JOINT IASLC - CSCO - CAALC SESSION

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 χ 2=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