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Ignacio Wistuba

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    S02 - Symposium Honoring Dr. Gazdar's Legacy (Sign Up Required) (ID 97)

    • Event: WCLC 2019
    • Type: Symposium
    • Track: Pathology
    • Presentations: 7
    • Now Available
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      S02.01 - Introduction (Now Available) (ID 3651)

      17:30 - 19:00  |  Presenting Author(s): Ignacio Wistuba

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      Abstract

      Dr. Adi Gazdar was a scientific pioneer, a groundbreaking pathologist, loyal friend and inspiring mentor.

      Dr. Gazdar was born in India; he earned his medical degree from Guy’s Hospital Medical School at the University of London and completed residencies in pathology at Peter Bent Brigham Hospital and New England Deaconess Hospital in Boston before joining the NCI in 1968. During his remarkable five-decade career, Dr. Gazdar served 23 years with the National Cancer Institute (NCI) a senior scientist and section head. His NCI experience included initially leading its Viral Pathology Section; the Human Tumor Cell Biology Laboratory for the NCI’s VA Medical Oncology Branch from 1975 to 1981; and then the Human Tumor Cell Biology Section for the NCI-Navy Oncology Branch from 1981 to 1991. His team collected, cataloged, and analyzed thousands of human cancer specimens with an emphasis on lung cancer and lymphomas. In 1991, he joined his long-time colleague Dr. John D. Minna at the University of Texas Southwestern Medical Center, Dallas, Texas, where he had a distinguished 27-year career as professor of pathology as the W. Ray Wallace Distinguished Chair in Molecular Oncology Research, and deputy director of the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research.

      Dr. Gazdar’s efforts in the laboratory yielded the first large panel lung and breast cancer cell lines, used by investigators around the world, and he developed molecular methods for detecting early lung tumors. Dr. Gazdar also identified several genes involved in the pathogenesis of different cancers. In lung cancer, he uncovered mutated genes dysregulated by mutation and DNA methylation, provided some of the first work characterizing neuroendocrine cancers such as small cell lung cancer, and played a major role in the discovery of the mutated epidermal growth factor receptor (EGFR) gene as a therapeutic target in lung cancer arising in never-smokers.

      During his long career, Dr. Gazdar published about 800 articles, book chapters and commentaries, and has been cited over 110,000 times, ranking him among the top 1% of scientists in the biomedical field. His numerous honors and recognitions include a 2004 award from the prestigious Jacqueline Seroussi Memorial Foundation for Cancer Research in Israel and the 2003 Mary J. Matthews Pathology/Translational Research from the International Association for the Study of Lung Cancer (IASLC).

      Dr. Gazdar was an inspirational role model for many young scientists mentoring over 100 post-doctoral fellows from around the world. IASLC established the Adi Gazdar Translational Research Fellowship Award on 2017 to honor his legacy in lung cancer training.

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      S02.02 - Adi Gazdar’s Legacy (Now Available) (ID 2571)

      17:30 - 19:00  |  Presenting Author(s): Peter Ujhazy  |  Author(s): Melissa Antman, Christine Burgess, James L Mulshine

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      Abstract

      Adi F. Gazdar (1937-2018) belongs to the 150 most successful scientists of all time. His impact in cancer research, virology, molecular pathology, cell biology, and many other disciplines was immense. A giant in lung cancer research, Dr. Gazdar pioneered numerous concepts and his work was seminal in the establishment of the current standard of care. He will be remembered as a prolific innovator, respected mentor, valued collaborator, and an altruistic human being. Here we will quantify the scientific legacy of Dr. Gazdar using various bibliometric analyses.

      The impact of Dr. Gazdar’s work was evaluated with the use of a panel of bibliometric tools including PubMed, iSearch, iGrants, iCite, Google Scholar, Web of Science, Clarivate Analytics, and Dimensions.

      Adi Gazdar has published more than 700 scientific publications that were cited more than 120,000 times, his H index is 171, and his most cited paper has more than 4000 citations (see Figure 1).gazdar publications.jpg His Weighted Relative Citation Ration (RCR) since 1994 is 1,283 with a mean RCR of 2.78 and median 1.33 per publication. By disciplines, most of his publications are in oncology, followed by studies on the respiratory system, cell biology, pathology, biochemistry and molecular biology, experimental medicine research, genetics, internal medicine, and biology. By scientific topics Dr. Gazdar published on lung cancer (small cell and non-small cell), tumor suppressor genes, viruses, breast cancer, allele loss, DNA methylation, risk factors, T cells, colorectal carcinoma, model systems, and growth factors and others. Many of his papers are related to drug development and testing and he published more than 10 papers on each of the following agents: decitabine, cisplatin, gefitinib, azacytidine, etoposide, insulin, doxorubicin, erlotinib, levodopa, tretinoin, and cyclophosphamide. Perhaps the most impact of Dr. Gazdar’s work had the creation and distribution of cell lines and models that allowed to characterize the retroviral particles in patients with T-cell lymphoma, test virtually all current chemo and targeted therapy agents used in the treatment of lung cancer, and define molecular subtypes of small cell and non-small cell lung cancers that are currently used in diagnosis. The National Cancer Institute US in collaboration with a team at the University of Texas Southwestern are currently assessing the tremendous impact that these cell lines had on all aspects of lung cancer research and standard of care. This Stewardship Project is led by Dr. James Mulshine from Rush University. impact of h460s.jpgThe preliminary data generated by this project indicate that Dr. Gazdar's 278 lung cancer cell lines led to 33,207 publications, which were cited 2,968,974 times, referred by 4,700 patents, linked to 422 clinical trials, and produced 14,057 supporting grants by 1,019 funders world wide. An example for the most cited cell line H460 is in Figure 2. This cell line itself had 11,124 publications cited 347,117 times, was mentioned in 1,564 patents, was linked to 118 clinical trials and 4,890 grants funded by 717 organizations.

      Doctor Adi F. Gazdar left behind an immense wealth of work that has changed cancer research and standard of care.

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      S02.03 - The Impact of Cell Line Development in Lung Cancer Research (Now Available) (ID 3653)

      17:30 - 19:00  |  Presenting Author(s): Paul A Bunn, Jr

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      Abstract

      Advances in Lung Cancer Research using patient derived cell lines and xenografts

      In the 1970s there were few lung cancer preclinical models and therapy selection was generally empiric. When the NCI established a branch to specifically study lung cancer (the NCI-VA Medical Oncology Branch) a systematic effort to establish permanent lung cancer cell lines with orthotopic implantation into athymic mice was implemented. The branch was led by Dr. John Minna and the cell line efforts were led by Dr. Adi Gazdar. The cell lines were given sequential numbers starting from NCI-H1 indicating the NCI origin and that they were human cell lines. Figure 1 shows how often these lines have been use in publications on lung cancer.

      These lines were initially used to study various chemotherapy agents and combinations such as the etoposide/cisplatin in small cell lung cancer (SCLC) xenografts. The expression of multiple proteins such as CD56 and many neuropeptides distinguished these SCLC cell lines from NSCLC cell lines. Originally it was recognized that most SCLC cell lines grew as floating aggregates but that s minority grew attached to the plastic. These later cell lines were termed “variant” lines were as the floaters were called “classic”. Essentially all of the lines had p53 mutations and loss of Rb. More recent studies indicated that the classic lines highly expressed neuroendocrine features. The variant lines more often had amplified myc. a new model of SCLC subtypes defined by differential expression of four key transcription regulators: achaete-scute homologue 1 (ASCL1); neurogenic differentiation factor 1 (NeuroD1), yes-associated protein 1 (YAP1) and POU class 2 homeobox 3 (POU2F3). These high NE SCLC cell lines and tumors also expressed NKX2-1, the entire range of NE markers, and lacked expression of the neuronal and NE repressor REST. The low NE subtype had undergone epithelial mesenchymal transition (EMT) and had activated the Notch, Hippo and TGFβ pathways and MYC oncogene. Recent studies found that 16% of human SCLC tumors and 10% of SCLC cell lines were of the low NE subtype, as well as cell lines from the GEM model. Synaptophysin was a more commonly expressed marker for variant SCLC cell lines, which rarely showed Dopa decarboxylase activity.

      These cell lines and patient samples were also used to describe the expression of N-Myc and L-Myc in small cell lung cancers. Reports demonstrated that 6 of 31 independently derived human small-cell lung cancer (SCLC) cell lines had 5- to 170-fold amplified N-myc gene sequences. A third myc-related gene (L-myc) cloned from SCLC DNA with homology to a small region of both the c-myc and N-myc genes. SCLC cell lines may prove useful in defining patients most likely to benefit from immunotherapy. For example, human SCLC cells, in contrast to other lung cancer types, are characterized by greatly reduced transcription of HLA-A,B,C and beta 2m genes, which suggests the existence of a mechanism for evading the host immune response to the tumor and of an E1a-like product in this type of tumor cell. Cell lines with myc amplification were shown to be especially sensitive to aurora kinase inhibitors.

      The human lung cancer cell lines were also used to define many of the genetic, proteomic and transcription features of lung adenocarcinomas, squamous carcinomas and large cell carcinomas. Early studies demonstrated a significant correlation between EGFR gene copy number, EGFR gene mutations, and gefitinib sensitivity. EGFR protein was necessary but not sufficient for predicting sensitivity. Gefitinib-sensitive lines showed a G(1) cell cycle arrest and inactivation of downstream signaling proteins; resistant cell lines had no changes. The in vivo effects mirrored the in vitro effects.

      Cell lines have also been used to study EGFR exon 20 mutations and HER2 mutations. HER2(YVMA) mutations were shown to activate cellular substrates more potently than HER2(WT); and that lung cancer cells expressing this mutation remain sensitive to HER2-targeted therapies but insensitive to EGFR TKIs. HER2 mutations were in-frame insertions in exon 20 and target the identical corresponding region as did EGFR exon 20 insertions.HER2 exon 20 insertions were shown to be sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib.

      EGFR-mediated bypass signaling has been reported after ALK and ROS1 blockade as well as RET and NTRK1 blockade. EGFR signaling provided a critical adaptive survival mechanism that allows cancer cells to evade oncogene-specific inhibitors, providing a rationale to co-target

      The RAS-MAPK dependence was shown to be a hallmark of EML4-ALK lung adenocarcinoma and provided a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes.

      Dr. Gazdar and colleagues also developed a method to reproducibly generate continuously replicating human bronchial epithelial cell (HBEC) lines that provide a novel resource to study the molecular pathogenesis of lung cancer and the differentiation of bronchial epithelial cells.

      In summary, human lung cancer cell lines have contributed greatly to the development of novel biomarkers and therapies for lung cancer and much of the work stemmed from early development by Dr. Gazdar and his team at the NCI.cell line pubs.png

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      S02.04 - Dr. Gazdar as a Mentor (Now Available) (ID 3654)

      17:30 - 19:00  |  Presenting Author(s): Tetsuya Mitsudomi

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      It was September in 1989 when I joined the NCI-Navy Medical Oncology Branch as a postdoctoral fellow. At that time, I was in my 10th year as a surgeon. The reason why I wanted to join the NCI-Navy was that I was greatly fascinated by the book entitled “The Biology of Lung Cancer” published by Marcel Dekker authored by many of the NCI-Navy MOB investigators. Especially, I was attracted by experimental works that used many lung cancer cell lines established by Adi’s group.

      When I first met Adi, my impression was that he was a calm and quiet person. My first project was to characterize peripheral airway cell phenotype in the adenocarcinoma cell lines by examining the expression of surfactant proteins as well as class II MHC. But I did not like this project and after 2 months or so, he agreed to change my theme to KRAS or TP53 mutations in lung cancer cell lines. He never pushed me to do or not to do something and never became emotional.

      I was deeply immersed in the research to look for the clinical and pathologic significance of those genetic abnormalities in lung cancer. This was what is called “translational research” today. I thought I could find what I should pursue throughout my life as a lung cancer doctor. It is obvious that without this experience and Adi, my life would have been so different. In addition, human network owing to Adi has been a precious treasure for me.

      One day in 1990, he gave me a paraffin block of bronchial biopsy sample and told me to search for TP53 mutation. It is currently a routine diagnostic workup to examine genetic alterations in the biopsy samples when you see lung cancer patients. It was as if he had known what would be the future diagnostic workup before 30 years. During this fruitful time of my life, I am so proud that I was able to co-authored 18 papers with Adi.

      After coming back to Japan, I saw Adi occasionally but periodically at various meetings such as the AACR, ASCO, ELCC and especially WCLC. Every time, he encouraged me to pursue my goal and gave some suggestions on my experiments. When Adi was to edit a special issue on Lung Cancer in Never Smokers in Translational Lung Cancer Research in 2018, he invited me to write about GGO lesions in never smokers. It was the last homework that he assigned to me.

      I am going to organize the Annual meeting of the Japanese Lung Cancer Society in December 2019. When I talked to him and his wife Celia at the Toronto WCLC meeting in 2018, Adi promised me to come to Japan to give a lecture. That was our last conversation. The promise has been broken and I really miss him. Adi. Please rest in peace. There are many of your children all over the world who have inherited your spirit as a lung cancer researcher.

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      S02.05 - The Importance of Elucidating Genomic Events is Lung Premalignancy (Now Available) (ID 3655)

      17:30 - 19:00  |  Presenting Author(s): Kwun M Fong

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      Abstract

      In contrast to the dramatic explosion of knowledge for cancer genomics such as trunk/branch; driver/passenger; intrinsic/acquired mutations from rapid technological developments, much work is still needed in the study of preneoplasia. Very sadly, lung cancer research around the world in 2018 lost a legend in preneoplasia research, Dr Adi Gazdar, who has either trained or worked with many of the scientists contributing to recent lung preneoplasia research. This is in addition to his enduring contributions establishing globally used lung cancer cell line resources and making lung cancer pathology discoveries.

      This research area owes much to pioneering work started over 20 years ago when Dr Gazdar, Dr John Minna and colleagues started thinking about preneoplastic molecular changes and field cancerisation (Smith, Hung et al. 1996, Yashima, Litzky et al. 1997). Subsequently, he and his former-post-doctoral Fellow Igancio Wistuba, another world renowned pathologist, summarised the main morphologic forms of preneoplastic lung lesions recognize then; squamous dysplasias, atypical adenomatous hyperplasia, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, and highlighted different molecular pathways for adenocarcinoma: smoking-associated activation of RAS signaling, and nonsmoking-associated activation of EGFR signaling; the latter is detected in histologically normal respiratory epithelium (Wistuba and Gazdar 2006).

      It is clear that there has been steady progress in lung preneoplasia research, with the hope of translation to human benefit through prevention and/or early diagnosis. Many scientists in the field of lung preneoplasia have been influenced by the foundational work from Dr Adi Gazdar, scientist, pathologist, teacher and friend to many of us. The ability to diagnose pre- neoplasia at its earliest stages will help enable the development of novel diagnostic, prevention strategies and therapeutics during the process of carcinogenesis when clinical intervention could be curative; a laudable goal in lung cancer where most cancers are now clinically diagnosed in advanced stages.

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      S02.06 - New Developments in SCLC and Neuroendocrine Tumors (Now Available) (ID 3656)

      17:30 - 19:00  |  Presenting Author(s): Lauren Averett Byers

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      Abstract

      In an IASLC memorial earlier this year, Dr. Gazdar was very appropriately described as “a true giant in the field of lung cancer.” Dr. Gazdar’s profound impact on our field continues to be felt both in the clinic and at the bench. As a world-renowned molecular and clinical pathologist, he played a key role in setting the standards for classifying human lung cancers. As a scientist, he established ~400 human cancer cell lines. These included a large number of molecularly-annotated non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines that have led to countless, practice-changing biological discoveries. As a founding-father of lung cancer research, he had a remarkable depth of knowledge in lung cancer biology and pathology. He shared his expertise through hundreds of publications. However, he also gave generously of himself (and his knowledge) to collaborators and mentees – serving as an advisor and teacher to almost everyone in the field who had the opportunity to be around him.

      Having contributed to key discoveries over five decades, Dr. Gazdar intuitively understood which new developments were likely to make the biggest impact and what questions we should be asking next. This was especially true for small cell lung cancer (SCLC) and other neuroendocrine tumors, where despite years of research there had been relatively few advances in the clinic. In a review published a year before his death, Dr. Gazdar and his co-authors shared their excitement for the recent worldwide resurgence of SCLC research – which they describe as “The Second Golden Age” of SCLC research.1 Several new developments in SCLC and neuroendocrine tumors have contributed to a better understanding of the disease and have shown promise for translational application. These include the discovery of (1) significant heterogeneity between patients with SCLC, (2) the plasticity of SCLC over time, (3) the role of intra-tumoral heterogeneity in metastasis and resistance, and (4) the identification of new therapeutic targets, immunotherapy approaches, and candidate biomarkers for SCLC. Going forward, opportunities and unmet needs in SCLC include enrolling patients onto clinical trials that can identify therapeutic vulnerabilities among specific SCLC subtypes; deeply profiling relapsed SCLC (through new models and patient specimen profiling); and extending our understanding of the immune microenvironment in SCLC. Given the pace and impact of recent discoveries in SCLC, it is no surprise that Dr. Gazdar and his co-authors concluded that “…while the past has been bleak, the future offers great promise.”

      1. Gazdar AF, Bunn PA, Minna JD. Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer 2017;17:725-37.

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      S02.07 - Dr. Gazdar as a Friend and Final Remarks (Now Available) (ID 3657)

      17:30 - 19:00  |  Presenting Author(s): Fred R. Hirsch

      • Abstract
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      Abstract not provided

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    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA11.09 - Increased Frequency of Bystander T Cells in the Lungs Is Associated with Recurrence in Localized Non-Small Cell Lung Cancer (Now Available) (ID 955)

      14:00 - 15:30  |  Author(s): Ignacio Wistuba

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      Background

      Non-small cell lung cancer (NSCLC) exhibits a high mutational burden. As a result, patients afflicted by this tumor type experience greater responses to immune checkpoint blockade. This is largely due to the ability of T cells to destroy tumor cells on the basis of antigens recognized by their T cell receptor (TCR). However, the lungs are exposed to carcinogens and pathogens which can also trigger a T cell response distinct from cancer. Therefore, a better understanding of the T cell repertoire in the lungs is needed to improve upon the success of current immunotherapies in NSCLC.

      Method

      We obtained peripheral blood, tumors, and adjacent uninvolved lungs from a cohort of 236 early stage NSCLC patients. Whole exome sequencing, RNA microarray, immunohistochemistry (CD3, CD4, CD8, CD57, CD68, FoxP3, CD45RO, GzmB, PD-1, and PD-L1) and T cell repertoire sequencing were performed in NSCLC patients and lungs from organ donors and COPD patients. Antigen specificity was predicted using the Grouping of Lymphocyte Interactions by Paratope Hotspot (GLIPH) algorithm. Single cell TCR and RNA sequencing as well as sequencing of the virome are underway.

      Result

      Clonality was associated with CD8 T cells (r=0.31; p=0.0003), GzmB (r=0.29; p=0.001) and IFN-γ (r=0.52; p<0.0001) production as well as with tumor mutational burden (r=0.19; p=0.015), HLA-B (r=0.29; p=0.0005) and β2-m expression (r=0.20; p=0.018). Patients with classical EGFR mutations exhibited lower T cell clonality (p=0.003) even after adjustment for TMB, highlighting the impact of this driver mutation on the T cell response. Surprisingly, clonality was higher in the adjacent uninvolved lung than tumor (p<0.0001), suggesting an active antigenic response outside the tumor. Comparison of the composition of the T cell repertoire between the uninvolved lung and tumor revealed 57% of the top 100 T cells in the tumor were also found in the adjacent normal lung, highlighting certain parallels in the ongoing antigenic responses. Deeper analysis suggested that shared T cells may have been reactive against mutations shared between the normal lung and tumor (r=0.23, p=0.028) or viruses (p<0.0001). Accordingly, patients with a more reactive T cell repertoire outside the tumor (i.e. bystanders) exhibited shorter disease-free survival (p=0.036) suggesting these responses against shared mutations and/or viruses may detract from the anti-tumor T cell response.

      Conclusion

      Our findings highlight the importance of understanding the specificity of the T cell repertoire in the lungs in patients with NSCLC treated with immunotherapy. As a high proportion of bystander T cells appear to reside in the lungs, their reactivation could contribute to the impaired responses and/or increased toxicity observed in certain patients with NSCLC treated with immunotherapy.

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    MA17 - Molecular Mechanisms and Therapies (ID 143)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Biology
    • Presentations: 1
    • Now Available
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      MA17.10 - Lactate Transporter Blockade as a Strategy to Overcome VEGF Inhibitor-Resistance in LKB1-Deficient NSCLC (Now Available) (ID 2647)

      15:45 - 17:15  |  Author(s): Ignacio Wistuba

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      Background

      STK11/LKB1 alterations are found in 20-30% of NSCLC and used to co-occur with KRAS mutations. Because LKB1 activates AMPK, many of the best known functions of LKB1 are attributed to its ability to control metabolic alterations in cells. Our laboratory have previously reported that loss of LKB1 promotes enhanced glycolysis and elevated lactate production and more recently we demonstrated that STK11/LKB1 mutations are the strongest predictors of de novo resistance to immunotherapy in NSCLC. Prior studies have revealed an association between alterations in the LKB1/AMPK pathway and worse clinical outcomes in NSCLC and in patients treated with chemotherapy and bevacizumab. Given the roles of LKB1 in the regulation of cell metabolism and resistance to immunotherapy, it is feasible that LKB1 also impacts on the response to anti-angiogenic therapies.

      Method

      Xenograft mouse models were established by subcutaneous injection of H460 cells (LKB1-deficient) and H460 LKB1-expressing in nude mice and LKR10 (KRASG12D) LKB1 wild-type (K) or LKB1- knockout (KL) into 129Svmice. Mice were randomized to vehicle or B20-4.1.1 anti-VEGF antibody. Glycolytic activity of LKB1-intact and -deficient NSCLC cells was measured by Seahorse assay. We analyzed gene expression of SLC16A3 (MCT4) by qPCR and Western blot. Genetic disruption of MCT4 in the K and KL cell lines was done using CRISPR-Cas9 and mouse models were established by subcutaneous injection into mice.

      Result

      Mice bearing LKB1-expressing H460 xenografts treated with anti-VEGF antibody showed a significant decrease in tumor volume (p<0.05) compared with their vehicle-treated counterparts. However, mice bearing LKB1-deficient H460 xenografts showed markedly reduced efficacy of anti-VEGF therapy compared with that in LKB1-expressing xenografts. Anti-VEGF therapy significantly reduced growth of LKR10 K tumors (p<0.001) but not in LKR10 KL tumors. Microvascular density was not increased in KL tumors following anti-VEGF treatment compared to K. Human isogenic LKB1-deficient cells showed a significantly increased rate of glycolysis and lactate secretion compared with cells expressing LKB1. Human and murine LKB1-deficient cells also had increased MCT4 expression compared to K cells. Immunofluorescence and RPPA analysis of tumor samples from the K and KL mouse models showed that KL tumors upregulated MCT4 protein expression compared with K tumors (p<0.0001). The genetic disruption of MCT4 KL tumors significantly improved tumor volume reduction to anti-VEGF therapies in vivo (p<0.001).

      Conclusion

      LKB1 loss is associated with increased lactate secretion and resistance to VEGF inhibition in NSCLC. The targeting of the lactate transporter MCT4 enhance the sensitivity of LKB1-deficient NSCLC to anti-VEGF therapy.

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    MA21 - Non EGFR/MET Targeted Therapies (ID 153)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA21.03 - The International Association for the Study of Lung Cancer (IASLC) Global Survey on Molecular Testing in Lung Cancer (Now Available) (ID 1198)

      14:30 - 16:00  |  Author(s): Ignacio Wistuba

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      Background

      Evidence-based standards for molecular testing of lung cancer have been established, but the global frequency and practice of testing are not well understood. The IASLC conducted an international survey to evaluate current practice and barriers to molecular testing.

      Method

      Distributed to IASLC members and other healthcare professionals, content included: 7-question introduction, 32 questions for those requesting tests/treating patients, 45 questions on performing/interpreting assays, and 24 questions on tissue acquisition. All respondents were asked to provide 3-5 barriers to implementing/offering molecular testing.

      Respondents’ countries were grouped by geography or developing/developed using IASLC and World Bank criteria. Surveys were available in 7 languages. Regional comparisons used the Chi-squared test or ANOVA; free-text was analyzed with Nvivo.

      Result

      We obtained 2,537 responses from 102 countries. Respondents were 45% Medical Oncologists, 12% Pulmonologists, 12% Thoracic Surgeons, 9% Pathologists, and 22% scientists or other. 56% of responses were from developing countries, 44% developed. Regions included: 52% Asia, 19% Europe, 11% Latin America, 11% US/Canada, 7% Other.

      1683 (66%) chose the requesting/treating track (50% government, 42% academic, 8% other). 61% reported most patients in their country do not receive molecular testing, with the lowest rates in Latin America/Other (p<0.0001). 39% were not satisfied with the conditions of molecular testing in their country. Indications for requesting testing included: adenocarcinoma (89%), never-smoker (61%), female (57%), and young (54%) (variable by region, p<0.0001). 99% ordered EGFR, 95% ALK, 84% PDL1, 79% ROS1, all other tests <50%. 56% typically received results within 10 days. Only 67% were aware of CAP/IASLC/AMP guidelines, least frequently in Asia/Other (p=0.041). 37% have trouble understanding molecular testing result reports, most of whom cited a need for more technical and scientific knowledge. 75% had multidisciplinary tumor boards, but 23% met <1/month.

      The 316 (12%) testing track respondents were from laboratories that were 49% academic, 35% government, and 16% private/other. 94% of laboratories offered EGFR, 83% ALK, 69% KRAS, 68% BRAF, 64% ROS1, 56% HER2, and others <50%; 68% tested for PDL1. 57% offered Multiplex assays, less frequently in Latin America/Asia (p=0.0294). 69% tested blood-derived DNA, less frequently in US/Canada/Other (0.0013). 23% of respondents reported >10% of cases are rejected due to inadequate samples; however, 47% stated there is no policy or strategy to improve the quality of the tissue samples in their country. 52% reported patients/physicians are not satisfied with the state of molecular testing in their country. Respondents performing/interpreting assays (334, 14%) were typically informed of biopsy results (91%), and notified when the sample was inadequate (84%).

      The most frequent barrier to molecular testing in every region was cost, followed by quality/standards, turnaround-time, access, and awareness. After cost, time was the most common barrier in developed countries, while it was quality in developing countries. The second largest barrier was quality in Asia, access in Europe/Latin America/Other, and turn-around time in US/Canada.

      Conclusion

      These preliminary analyses show molecular testing usage varies across the globe. Barriers vary by region, and one-third of respondents were unaware of evidence-based guidelines. Global and regional strategies should be developed to address barriers.

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    MS17 - Pathology of the Future (ID 80)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Pathology
    • Presentations: 1
    • Now Available
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      MS17.04 - Multiplex Immunohistochemistry (Now Available) (ID 3540)

      14:30 - 16:00  |  Presenting Author(s): Ignacio Wistuba

      • Abstract
      • Presentation
      • Slides

      Abstract

      Multiplexed imaging platforms to simultaneously detect multiple epitopes in the same tissue section emerged in the last years as very powerful tools to study tumor immune contexture. These revolutionary technologies are providing a deep methodology for tumor evaluation in formalin-fixed and paraffin-embedded (FFPE) to improve the understanding of tumor microenvironment, new targets for treatment, prognostic and predictive biomarkers, and translational studies. Multiplexed imaging platforms allow the identification of several antigens simultaneously from a single tissue section, core needle biopsies, and tissue microarrays. In recent years, multiplexed immunohistochemistry, immunofluorescence, mass spectometry and other imaging modalities have improved the abilities to characterize the different types of cell populations in malignant and non-malignant tissues, and their spatial distribution in relationship to clinical outcomes. Multiplexed technologies associated with digital image analysis software offer a high-quality throughput assay to study cancer specimens, inc;luding lung cancer, at multiple timepoints before, during and after treatment. The aim of this resentation is to provide a review of multiplexed tissue imaging applied to lung cancer focusing in the use of multiplex immunofluorescence with tyramine signal amplification staining for lung cancer immune profiling and translational research.

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    OA13 - Ideal Approach to Lung Resection and Novel Perioperative Therapy (ID 146)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      OA13.07 - Neoadjuvant Atezolizumab in Resectable NSCLC Patients: Immunophenotyping Results from the Interim Analysis of the Multicenter Trial LCMC3 (Now Available) (ID 1755)

      11:30 - 13:00  |  Author(s): Ignacio Wistuba

      • Abstract
      • Presentation
      • Slides

      Background

      The immune mechanisms dictating response and resistance to PD-(L)1 blockade are not well understood in early stage non-small cell lung cancer (NSCLC). Understanding these mechanisms will be key to improve outcomes and identify the next generation of predictive biomarkers of response to these therapies. Here, we present updated immunophenotyping at time of interim analysis of LCMC3, a multicenter trial of neoadjuvant atezolizumab in resectable NSCLC (NCT02927301).

      Method

      Patients received 2 cycles of atezolizumab before resection. Tumor, LN biopsies and PB were obtained pre-atezolizumab and at surgery. Paired PB, screening and surgical LN were analyzed using IMMUNOME flow cytometry. Plasma-based cytokine arrays were performed on a subset of patients. Immunophenotypic analyses were correlated with treatment effect, major pathologic response (MPR, primary endpoint) and preoperative treatment-related adverse events (preop-TRAE).

      Result

      We report on 55 patients with paired PB samples (analyzed within 72h after collection) and completed surgery. We observed preop-TRAE in 32/55 patients (18 grade 1, 13 grade 2, 1 grade 3). CD1c+ and CD141+ myeloid cells (MC) were lower at baseline in patients developing preop-TRAEs, while monocytic M-MDSCs were higher in those patients. Senescent T cells decreased in patients with preop-TRAE and increased in patients with non-preop-TRAE. After treatment, the absolute cell counts of late activated CD4+and CD8+T cells decreased in patients achieving MPR. LN IMMUNOME data, cytokine data and 12-month follow-up (DFS, OS) will be reported.

      table 1-page-001.jpeg

      Conclusion

      Preliminary immunophenotyping data from the interim analysis showed significantly lower baseline immunosuppressive cell subsets in patients with preop-TRAE and decreased late activated CD4+and CD8+T cells from PB in patients with MPR.These results, together with additional LN IMMUNOME and cytokine analyses, may improve our understanding of immunophenotypic features associated with outcome, and changes induced by neoadjuvant atezolizumab in early stage NSCLC patients.

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    OA15 - Targeted Agents and Immunotherapy for Small Cell Lung Cancer (ID 152)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
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      OA15.04 - Genomic and TCR Intratumor Heterogeneity of Small-Cell Lung Cancer by Multiregion Sequencing: An Association with Survival (Now Available) (ID 1458)

      14:30 - 16:00  |  Author(s): Ignacio Wistuba

      • Abstract
      • Presentation
      • Slides

      Background

      Small cell lung cancer (SCLC) is an aggressive cancer. Although sensitive to initial therapy, recurrence is almost inevitable. The molecular mechanisms underlying recurrence are unknown. We have previously demonstrated that complex genomic and T cell receptor (TCR) intratumor heterogeneity (ITH) was associated with increased risks of relapse in non-small cell lung cancers (NSCLC). Genomic ITH and TCR architecture of SCLC and its clinical impact have not been well studied, largely due to lack of tumor specimens as surgery is rarely used to treat SCLC.

      Method

      We performed multiregion whole-exome sequencing and TCR sequencing of 49 tumor samples from 18 resected limited-stage SCLCs to delineate the immunogenomic ITH of SCLC. We compared the results to those in NSCLC and assessed the association of genomic and TCR attributes with patient’s survival.

      Result

      On average, 544 mutations/sample were detected. The median proportion of trunk mutations (mutations identified in all regions within the same tumors) was 80.4% versus 70% in NSCLC (TRACERx, Jamal-Hanjani, NEJM, 2017, p=0.08) and all TP53 and RB1 mutations were trunk mutations, suggesting these mutations were early events during carcinogenesis of this cohort of SCLCs. A higher non-synonymous tumor mutational burden (TMB) was associated with a higher T cell density (infiltration) in the tumor (r=0.46, p=0.005). Compared to the TCR repertoire of NSCLC (Reuben, WCLC, 2017), these SCLC tumors demonstrated significantly lower T-cell density (0.05 versus 0.24, p<0.0001), richness (diversity, 1,043 versus 3,666, p<0.0001) and clonality (reactivity, average 0.02 versus 0.15, p<0.0001) despite similar non-synonymous TMB (average 187 in SCLC versus 176 mutations/sample in NSCLC). Only 0.2% to 14.6% of T cells were detectable across all regions from the same tumors, suggesting substantial TCR ITH. Jaccard index (JI), a parameter quantifying TCR ITH was significantly lower in SCLC than in NSCLC (0.06 versus 0.1, p<0.0001) implying higher level of TCR ITH in SCLC than NSCLC. Interestingly, higher T-cell density, richness or clonality appeared to be associated with lower risk of recurrence numerically. Furthermore, higher TCR JI (less degree of ITH) was associated with significantly longer overall survival (HR=0.15, p=0.04).

      Conclusion

      Limited-stage SCLC tumors have distinct TCR repertoire and genomic ITH architecture. Overall, SCLC may have a more pronounced immunosuppressive microenvironment and higher level of TCR repertoire ITH than NSCLC. Nevertheless, higher degree of T cell infiltration and clonal expansion as well as more homogeneous T cell response may be associated with more favorable clinical outcome in patients with limited-stage SCLC.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 3
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-07 - Immune Suppressive Microenvironment and Highly Clonal Concordance of TCR Repertoire in Brain Metastases from Non-Small Cell Lung Cancer (ID 2018)

      09:45 - 18:00  |  Author(s): Ignacio Wistuba

      • Abstract
      • Slides

      Background

      The tumor immune microenvironment (TIME) of lung cancer brain metastasis is largely unexplored. We performed immune profiling and sequencing analysis of paired resected primary tumors and brain metastases of non-small cell lung carcinoma (NSCLC).

      Method

      TIME profiling of archival formalin-fixed and paraffin embedded specimens of paired primary tumors and brain metastasis from 39 patients with surgically resected NSCLCs was performed using a 770 immune gene expression panel (NanoString Technologies, Seattle, WA) and by T cell receptor beta repertoire (TCRß) sequencing (Adaptive Biotechnologies, Seattle, WA). Immunohistochemistry was performed for validation. Targeted sequencing was performed to catalog hot spot mutations in cancer genes (ThermoFisher Scientific, Waltham, MA).

      Result

      Somatic hot spot mutations were mostly shared between both tumor sites (28/39 patients; 71%). We identified 161 differentially expressed genes, indicating inhibition of dendritic cell maturation, Th1, and leukocyte extravasation signaling pathways, in brain metastases compared to primary tumors (p < 0.01). The proinflammatory cell adhesion molecule vascular cell adhesion protein 1 was significantly suppressed in brain metastases compared to primary tumors. Brain metastases exhibited lower T cell and elevated macrophage infiltration compared with primary tumors (p < 0.001). T cell clones were expanded in 64% of brain metastases compared with their corresponding primary tumors. Further, while TCR repertoires were largely shared between paired brain metastases and primary tumors, T cell densities were sparse in the metastases.

      Conclusion

      We present findings that the TIME in brain metastases is immunosuppressed when compared to matched primary tumors in NSCLC patients, and that thus may help guide immunotherapeutic strategies for NSCLC brain metastases.

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      P1.04-11 - Depicting the Intra-Tumoral Viral and Microbial Landscape of Localized NSCLC Using Standard Next Generation Sequencing Data (ID 1126)

      09:45 - 18:00  |  Author(s): Ignacio Wistuba

      • Abstract
      • Slides

      Background

      Studies from our group and others have shown that bacteria and viruses present in the tumor may impact therapeutic responses. In the specific context of non-small cell lung cancer (NSCLC), intra-tumoral viral DNA and bacteria have been reported previously to be linked to therapeutic outcomes. However, the interplay between intra-tumoral microorganisms and the host immune response in NSCLC remains unknown. Moreover, the prognostic and predictive therapeutic value of localized NSCLC-specific microbial composition has yet to be defined.

      Method

      RNA-sequencing (RNA-seq) (n=82) and whole exome sequencing (WES) (n=80) was performed on surgically resected (pTNM I-III) tumors from lung cancer patients enrolled in the ImmunogenomiC prOfiling of NSCLC (ICON) project. Intra-tumoral bacteria, viruses and fungi were queried with MetaPhlAn2, a bioinformatical analysis pipeline which employs unique clade-specific marker genes, using reads from RNA-seq and WES that did not map to the human genome/transcriptome. Generated data were correlated to patients’ clinicopathologic parameters as well as immune profiling using previously validated multiplex IHC panels based on Vectra 3.0™ multispectral microscopy IHC panels and image analysis (InForm™ 2.2.1 software).

      Result

      Our analyses revealed that 18.29% (n=15/82) of tumors contained bacterial signatures. The most frequent bacterial signature was related to Escherichia (n=9/15). Moreover, 6.49% (n= 5/77) of tumors had evidence of human viral signatures, including the Epstein-Barr virus (n=1/5). No tumors contained fungal signatures. Preliminary clinicopathologic analyses suggested that patients whose tumors harbor bacterial signatures had a trend towards decreased overall survival (p=0.12). Tumors from former smokers were also more likely to contain bacterial signatures (p=0.11). Preliminary multiplex immune cell IHC analyses did not highlight statistically significant associations with the presence of intra-tumoral bacteria.

      Conclusion

      Our results suggest that a significant proportion of localized NSCLC tumors may harbor components of the human microbiome. Further studies using larger cohorts and dedicated intra-tumoral microbiome and virome methodologies will be needed to better define these findings and to delineate associations with the local immune infiltrate.

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      P1.04-79 - CD73 Expression in Lung Adenocarcinomas and Immunological and Molecular Associations (ID 2412)

      09:45 - 18:00  |  Author(s): Ignacio Wistuba

      • Abstract

      Background

      Immune checkpoints inhibitors (ICI), in monotherapy or combination with chemotherapy, are the standard of care for lung adenocarcinoma (ADC) patients. Unfortunately, only a restricted number of patients will respond to ICI. Combination therapies such as CD73 inhibitors, are being studied with the goal to achieve synergic effects. CD73 is a membrane-bound protein with immunosuppressive functions. We previously reported that higher immune cell infiltration was associated mainly to CD73 basolateral (BL) expression, in this abstract, we show the correlation of CD73 expression at luminal (L) and BL membrane of ADC malignant cells (MCs), with annotated clinicopathological characteristics, immune and molecular biomarkers.

      Method

      CD73 IHC expression (clone D7F9A) was evaluated in 106 archived ADCs from patients that underwent surgical treatment without neoadjuvant therapy between February 1999 and February 2012 at MD Anderson Cancer Center (Houston, Texas, USA). We scored % and H-score of CD73 expression at the luminal (L) and basolateral (BL) membrane, we calculated the Total (T) CD73 as the average of L and BL, and classified ADCs in three groups: ‘T High’ (TH) (upper quartile for all tumors); ‘T Low’ (TL); ‘T Neg’ (TN) (<1%). We correlated T, L and BL expression and the three groups with clinicopathological characteristics, mutational status of KRAS and EGFR, TP53, STK11 and Tumor mutation burden (TMB), and cell densities of CD3, CD8, CD68, CD45RO, FOXP3, and Granzyme B, and PD-L1 expression (clone E1L3N) in MCs.

      Result

      T CD73 expression was found in 76%; BL in 60% and L in 57%; among ADCs with luminal membrane present (n=72), L CD73 was present in 83%. T+ and L+ expression was more frequent in never smokers (p=0.02 and p=0.003). Also higher frequency of L+ was found in older patients (>65) (p=0.01), tumors with non-solid histology patterns (p<0.001), EGFR mutation (p=0.048), non-mutated p53 (p=0.002), negative PD-L1 (p=0.03), and low TMB (<10 mut/MB) (p=0.001). Higher levels of L expression were found in KRAS mutated tumors (p=0.049). Higher BL expression positively correlated with p53 mutated tumors (p=0.038), PD-L1+ in MCs (p=<0.0001), and higher TMB (p=0.040).

      Our group analyses revealed that TH and TN were associated with ADCs from patients with >30 pack-year of smoking history (p=0.04), presence of any-solid histology pattern (p=0.03), p53 mutation (p= 0.005) and higher TMB (p=0.003) compared with TL. TH also had higher frequency of PD-L1+ tumors, and a higher cell density of CD3 (p=0.0001), CD8 (p=0.001), CD68 (p=0.048), CD45RO (p=0.036), FOXP3 (p=0.053), and Granzyme B (p=0.024) compared to TL and TN. TN showed higher frequency of STK11 mutation (p=0.034).

      Conclusion

      Based on the CD73 expression we defined subsets of lung adenocarcinomas that have distinct histological, molecular and immunological characteristics that may play a role in the response to ICI.

      Our characterization could help us to understand patient’s response to ICI, and identify patients that could potentially benefit from combination therapies.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-17 - Genomic Evolution During TKI Treatment in Non-Small Cell Lung Cancer Patients With or Without Acquired T790M Mutation (ID 2988)

      09:45 - 18:00  |  Author(s): Ignacio Wistuba

      • Abstract

      Background

      EGFR-mutant non-small-cell lung cancer (NSCLC) patients inevitably develop drug resistance when treated with EGFR tyrosine kinase inhibitors (TKIs). Clonal and clinical analyses of genetic alterations at baseline and progressive disease (PD), as well as differences between acquired T790M and T790M-negative patients in drug-resistant mechanisms, have not been systematically studied.

      Method

      We performed targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients. Ten additional patients were sequenced using whole exome sequencing to infer the clonal evolution patterns.

      Result

      We observed new co-occurring alterations and pathways limiting EGFR-inhibitor response, including 9p34.3/19p13.3 (NOTCH1/STK11) co-deletion and TGF-beta pathway alterations. Besides acquired T790M mutation, chromosomal instability (CIN) related genes including AURKA and TP53 alterations were the most frequently acquired events. CIN significantly increased with TKI treatment in T790M-negative patients. Transcriptional regulators including HNF1A, ATRX and NKX2-1 acquired alterations were enriched in T790M-positive patients, and diverse oncogenic pathway alterations were more common in T790M-negative patients. T790M-positive patients had improved PFS compared to T790M-negative patients. We further identified subgroups within T790M-positive or T790M-negative patients with distinct PFS. Clonal evolution analysis indicated progression of T790M-positive patients depends on competition between T790M and non-T790M resistant subclones.

      Conclusion

      Our study is the first attempt to identify co-occurring copy number events to stratify patients resistant to TKI treatment. Besides acquired T790M mutation, chromosomal instability (CIN) related genes were identified as the most frequently acquired events. Clonal evolution analysis indicated indicate that higher competitive advantage of T790M was associated with improved PFS.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-19 - Neoadjuvant Chemotherapy Is Associated with Immunogenic Cell Death and Increased T Cell Infiltration in Early-Stage NSCLC (ID 1122)

      10:15 - 18:15  |  Author(s): Ignacio Wistuba

      • Abstract
      • Slides

      Background

      Recent success using immune checkpoint blockade (ICB) in the metastatic setting has raised the need to understand the immune microenvironment (IME) in early-stage disease. Moreover, pre-clinical evidence suggests that cytotoxic agents can modulate this IME. A recent study conducted by our group showed that non-small cell lung cancer (NSCLC) patients who received neoadjuvant chemotherapy followed by surgery (NCT), as compared to patients who received upfront surgery (US), had higher densities of CD3+ lymphocytes and CD68+ tumor-associated macrophages (TAMs). CD3+CD4+ lymphocytes and TAMs also correlated with better clinical outcomes. In this study, we explored the relationships between NCT and the IME by harvesting tumor samples of multiple surgical NSCLC cohorts.

      Method

      The PROSPECT microarray database was queried in NCT (n=45) and US (n=200) patients to investigate differentially expressed genes related to immunogenic cell death (ICD), susceptibility to CD8+ T cell and NK cell cytotoxicity, priming of antigen presenting cells, immunosuppressive enzymes and intra-tumoral cytokines. Available data from the ImmunogenomiC prOfiling of NSCLC (ICON) and other surgical NSCLC cohorts was evaluated to determine: 1) differential immune profiling using FACS (NCT=17; US=39) and multiplex IHC imaging (NCT=10; US=72); 2) plasma circulating cytokines (NCT=18; US=73); 3) tumor mutational burden (TMB) (NCT=40; US=61). Participants who received NCT or US were excluded according to these criteria: 1) concurrent treatment in addition to NCT; 2) sarcomatoid and small cell histologies; 3) clinical or pathological TNM Stage 4 disease; 4) synchronous malignancies other than lung.

      Result

      PROSPECT NCT patients expressed increased damage-associated molecular pattern (DAMP) genes (HSPA2, HSPA4, HSPE1, and S100A2; p<0.05) and T cell-related chemotaxis and antigen presentation genes (CXCR7, CD1A; p<0.05). Concordantly, the ICON cohort FACS results showed that NCT patients display increases in: 1) infiltration of CD8+ T cells (p=0.004); 2) proliferating Ki67+CD8+ T cells (p=0.02); 3) tissue resident memory CD8+CD103+ (p=0.02) and CD4+CD103+ non-Treg cells (p=0.01). Trends from the ICON multiplex IHC also highlighted increases in CD8+ T cells (p=0.09), CD20+ cells (p=0.08), as well as PD-L1+ malignant cells (p=0.08) and PD-L1+ TAMs (p=0.08) in NCT patients, the latter finding being supported by increased circulating MCP-1 (p=0.03). TMB was similar between NCT and US groups (p=0.912).

      Conclusion

      Our data provides the first evidence of ICD (i.e., increased DAMP gene expression) following NCT in human early-stage NSCLC. Furthermore, our data highlights the association of NCT with a favorable IME (i.e., increased T cell infiltration), supporting the rationale of NCT and ICB combinations in localized NSCLC.

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      P2.04-88 - Surgical Outcomes of a Multicenter Phase II Trial of Neoadjuvant Atezolizumab in Resectable Stages IB-IIIB NSCLC: Update on LCMC3 Clinical Trial (ID 1817)

      10:15 - 18:15  |  Author(s): Ignacio Wistuba

      • Abstract
      • Slides

      Background

      The role of immune checkpoint inhibitors in resectable NSCLC remains undefined. We report the updated safety results of the first multicenter trial assessing neoadjuvant atezolizumab (a PD-L1 inhibitor) for resectable NSCLC.

      Method

      Eligible patients with clinical stage IB-IIIB resectable NSCLC received 2 cycles of neoadjuvant atezolizumab (1200 mg, days 1, 22) followed by surgical resection (day 40±10). Pre- and post-treatment PET/CT, pulmonary function tests (PFT), and bio-specimens were obtained. Adverse events (AE) were recorded according to CTCAEv.4.0. Preoperative treatment-related TRAE (preop-TRAE) and postoperative TRAE (postop-TRAE) defined as AE onset on, or after date of surgery, were analyzed.

      Result

      Follow-up data to post-surgery visit were analyzed for 101 patients out of planned 180: mean age: 64.6 years; male: 47/101(46.5%); current smokers: 23/101(22.8%); non-squamous histology: 66/101(65.3%); and clinical stages IB(10.9%), IIA(15.8%), IIB(27.7%), IIIA(38.6%), and IIIB(6.9%). Two cycles of atezolizumab were not completed in 5/101(5.0%) patients due to grade 1 or 2 AEs. Surgery was not performed in 11/101(10.9%) patients: 5 demonstrated disease progression, and 6 for ‘other’ reasons. 6/101(5.9%) patients were deemed unresectable. Surgery was delayed (outside of 10-day window) in 10/90(11.1%) patients by an average of 11(1-39) days. Two of these delays were due to TRAEs (hypothyroidism and pneumonitis), 3 were patient-elected delays, 2 were surgeon-related, and 3 for ‘other’ reasons. Intraoperative vascular complications occurred in 2/90(2.2%) and extensive hilar fibrosis was noted in 20/90(22.2%) patients. Overall, there was insignificant mean change in the PFTs pre- vs. post-atezolizumab therapy. Only 3/101(3.0%) patients had treatment-related dyspnea, dyspnea on exertion, or pneumonitis.

      Table 1

      Treatment Related Adverse Events

      (TRAE)

      Preoperative TRAE

      (N = 101)

      Postoperative TRAE

      (N = 90)

      All AEs

      Any grade

      55 (54.5%)

      20 (22.2%)

      Grade 1

      29 (28.7%)

      7 (7.8%)

      Grade 2

      24 (23.8%)

      9 (10.0%)

      Grade 3

      2 (2.0%)

      4 (4.4%)

      Grade 4

      0

      0

      Grade 5

      0

      0

      Specific AEs

      Dyspnea

      1 (1.0%; grade 2)

      3 (3.3%; grade 1)

      Dyspnea on exertion

      1 (1.0%; grade 1)

      0

      Myalgia

      4 (4.0%; grade 1 or 2)

      0

      Hyperthyroidism

      3 (3.0%; grade 1 or 2)

      1 (1.1%; grade 1)

      Hypothyroidism

      0

      1 (1.1%; grade 2)

      Pneumonitis

      1 (1.0%; grade 3)

      3 (3.3%; grade 2 or 3)

      Transaminitis (AST or ALT)

      8 (7.9%; grade 1 or 2)

      3 (3.3%; grade 1 or 2)

      Post-atezolizumab Change in Pulmonary Function Tests

      PFT factor

      Mean change (95% Confidence Interval)

      FEV1 (N = 72)

      -0.6% (-2.6% to 1.3%)

      FVC (N = 72)

      0.0% (-1.8% to 1.8%)

      DCLO (N = 64)

      -1.2% (-4.1% to 1.7%)

      Conclusion

      Treatment with neoadjuvant atezolizumab in resectable stage IB-IIIB NSCLC was well tolerated, with minimal delay to surgery, and few treatment associated AEs. This trial continues to accrue and assess MPR, survival, and other long-term endpoints.

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    P2.09 - Pathology (ID 174)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.09-24 - IASLC Global Survey for Pathologists on PD-L1 Testing for Non-Small Cell Lung Cancer (ID 906)

      10:15 - 18:15  |  Author(s): Ignacio Wistuba

      • Abstract
      • Slides

      Background

      PD-L1 immunohistochemistry (IHC) is now performed for advanced non-small cell lung cancer (NSCLC) patients to examine their eligibility for pembrolizumab treatment, as well as in Europe for durvalumab therapy after chemoradiation for stage III NSCLC patients. Four PD-L1 clinical trial validated assays (commercial assays) have been FDA/EMA approved or are in vitro diagnostic tests in multiple countries, but high running costs have limited their use; thus, many laboratories utilize laboratory-developed tests (LDTs). Overall, the PD-L1 testing seems to be diversely implemented across different countries as well as across different laboratories.

      Method

      The Immune biomarker working group of the IASLC international pathology panel conducted an international online survey for pathologists on PD-L1 IHC testing for NSCLC patients from 2/1/2019 to 5/31/2019. The goal of the survey was to assess the current prevalence and practice of the PD-L1 testing and to identify issues to improve the practice globally. The survey included more than 20 questions on pre-analytical, analytical and post-analytical aspects of the PDL1 IHC testing, including the availability/type of PD-L1 IHC assay(s) as well as the attendance at a training course(s) and participation in a quality assurance program(s).

      Result

      344 pathologists from 310 institutions in 64 countries participated in the survey. Of those, 38% were from Europe (France 13%), 23% from North America (US 17%) and 17% from Asia. 53% practice thoracic pathology and 36%, cytopathology. 11 pathologists from 10 countries do not perform PD-L1 IHC and 7.6% send out to outside facility. Cell blocks are used by 75% of the participants and cytology smear by 9.9% along with biopsies and surgical specimens. Pre-analytical conditions are not recorded in 45% of the institutions. Clone 22C3 is the most frequently used (61.5%) (59% with the commercial assay; 41% with LDT) followed by clone SP263 (45%) (71% with the commercial assay; 29% with LDT). Overall, one or several LDTs are used by 57% of the participants. A half of the participants reported turnaround time as 2 days or less, while 13% reported it as 5 days or more. Importantly, 20% of the participants reported no quality assessment, 15%, no formal training session for PD-L1interpretation and 14%, no standardized reporting system.

      Conclusion

      There is marked heterogeneity in PD-L1 testing practice across individual laboratories. In addition, the significant minority reported a lack of quality assurance, formal training and/or standardized reporting system that need to be established to improve the PD-L1 testing practice globally.

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    S02 - Symposium Honoring Dr. Gazdar's Legacy (Sign Up Required) (ID 97)

    • Event: WCLC 2019
    • Type: Symposium
    • Track: Pathology
    • Presentations: 1
    • Now Available
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      S02.01 - Introduction (Now Available) (ID 3651)

      17:30 - 19:00  |  Presenting Author(s): Ignacio Wistuba

      • Abstract
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      Abstract

      Dr. Adi Gazdar was a scientific pioneer, a groundbreaking pathologist, loyal friend and inspiring mentor.

      Dr. Gazdar was born in India; he earned his medical degree from Guy’s Hospital Medical School at the University of London and completed residencies in pathology at Peter Bent Brigham Hospital and New England Deaconess Hospital in Boston before joining the NCI in 1968. During his remarkable five-decade career, Dr. Gazdar served 23 years with the National Cancer Institute (NCI) a senior scientist and section head. His NCI experience included initially leading its Viral Pathology Section; the Human Tumor Cell Biology Laboratory for the NCI’s VA Medical Oncology Branch from 1975 to 1981; and then the Human Tumor Cell Biology Section for the NCI-Navy Oncology Branch from 1981 to 1991. His team collected, cataloged, and analyzed thousands of human cancer specimens with an emphasis on lung cancer and lymphomas. In 1991, he joined his long-time colleague Dr. John D. Minna at the University of Texas Southwestern Medical Center, Dallas, Texas, where he had a distinguished 27-year career as professor of pathology as the W. Ray Wallace Distinguished Chair in Molecular Oncology Research, and deputy director of the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research.

      Dr. Gazdar’s efforts in the laboratory yielded the first large panel lung and breast cancer cell lines, used by investigators around the world, and he developed molecular methods for detecting early lung tumors. Dr. Gazdar also identified several genes involved in the pathogenesis of different cancers. In lung cancer, he uncovered mutated genes dysregulated by mutation and DNA methylation, provided some of the first work characterizing neuroendocrine cancers such as small cell lung cancer, and played a major role in the discovery of the mutated epidermal growth factor receptor (EGFR) gene as a therapeutic target in lung cancer arising in never-smokers.

      During his long career, Dr. Gazdar published about 800 articles, book chapters and commentaries, and has been cited over 110,000 times, ranking him among the top 1% of scientists in the biomedical field. His numerous honors and recognitions include a 2004 award from the prestigious Jacqueline Seroussi Memorial Foundation for Cancer Research in Israel and the 2003 Mary J. Matthews Pathology/Translational Research from the International Association for the Study of Lung Cancer (IASLC).

      Dr. Gazdar was an inspirational role model for many young scientists mentoring over 100 post-doctoral fellows from around the world. IASLC established the Adi Gazdar Translational Research Fellowship Award on 2017 to honor his legacy in lung cancer training.

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