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Tetsuya Mitsudomi

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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

      • 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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      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

      • Abstract
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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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      Abstract

      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
      • Presentation
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      Abstract not provided

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Author of

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    IASLC General Assembly (ID 364)

    • Event: WCLC 2019
    • Type: General Assembly
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/10/2019, 08:00 - 08:45, Tokyo (1982)
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      GA01.01 - Welcome (Now Available) (ID 3909)

      08:00 - 08:45  |  Presenting Author(s): Tetsuya Mitsudomi

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OC01 - Opening Ceremony (ID 82)

    • Event: WCLC 2019
    • Type: Opening Ceremony
    • Track:
    • Presentations: 1
    • Now Available
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      OC01.02 - IASLC Distinguished Awards (Now Available) (ID 3553)

      19:00 - 20:30  |  Author(s): Tetsuya Mitsudomi

      • Abstract
      • Presentation

      Abstract not provided

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-55 - Comparison of PD-L1 Expression Status Between Pure-Solid Versus Part-Solid Tumors in Lung Adenocarcinomas (ID 169)

      09:45 - 18:00  |  Author(s): Tetsuya Mitsudomi

      • Abstract

      Background

      Recent studies have reported clinicopathological and prognostic differences between lung adenocarcinomas with ground-glass opacity (GGO) versus those without GGO (pure-solid tumors). However, it is unknow if the expression status of PD-L1 protein differs between these two groups.

      Method

      One-hundred twenty-four stage IA – IB lung adenocarcinoma patients who received pulmonary resection between 2007 – 2009 were included in this study. PD-L1 staining was performed in our previous study using E1L3N antibody. PD-L1 status was classified as positive if 1% or more tumor cells showed membrane staining; and was classified as strong positive if 50% or more tumor cells did so.

      Result

      Among 124 lung adenocarcinoma patients, 45 had lung adenocarcinomas with GGO and 79 had pure-solid lung adenocarcinomas. We observed no significant differences between these two groups in terms of clinical factors (gender, age, and smoking status). However, the rates of PD-L1 positive tumors (4% vs 25%, p < 0.01) and PD-L1 strong positive tumors (2% vs 16%, p = 0.02) were significantly lower in lung adenocarcinomas with GGO. In multivariate analyses, these correlations between the presence / absence of GGO and PD-L1 expression status were still evident as shown in Table 1.table 1..png

      Conclusion

      Lung adenocarcinomas with GGO were less frequent to express PD-L1 compared to pure-solid lung adenocarcinomas.

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    P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.18-02 - The AEGEAN Phase 3 Trial of Neoadjuvant/Adjuvant Durvalumab in Patients with Resectable Stage II/III NSCLC (ID 1375)

      09:45 - 18:00  |  Author(s): Tetsuya Mitsudomi

      • Abstract

      Background

      For patients (pts) with early stage non-small cell lung cancer (NSCLC) (Stages I–IIIA) surgery is the primary treatment. Adjuvant and neo-adjuvant chemotherapy (CTx) are both accepted approaches for resectable NSCLC, and result in modest but clinically meaningful improvements in overall survival (OS) compared with surgery alone; nevertheless, recurrence rates remain high and improved therapies are needed. Checkpoint inhibitors that block programmed death 1 (PD-1)/PD ligand 1 (PD-L1) have shown benefit as monotherapy and in combination with CTx in NSCLC. Durvalumab (durva), a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, significantly improved progression-free survival and OS in pts with unresectable Stage III NSCLC who did not progress following chemoradiotherapy (Antonia et al, NEJM 2017; 2018). The AEGEAN study (NCT03800134) will assess the activity and long-term clinical outcomes of durva plus CTx prior to surgery, as well as further administration of durva post-surgery, in pts with resectable Stages II and III NSCLC.

      Method

      The AEGEAN trial is a Phase 3, double-blind, placebo-controlled, multi-center study. Approximately 300 pts with resectable Stage II and III NSCLC will be randomized 1:1 to receive either durva (1500 mg intravenously) or placebo every 3 weeks (wks) alongside platinum-based CTx (4 cycles) prior to surgery, followed by either durva or placebo alone every 4 wks for an additional 12 cycles post-surgery. Pts will be stratified by disease stage and PD-L1 expression levels (<1% vs ≥1%); the number of pts with EGFR/ALK mutations will be capped at 20%. Tumor size (according to RECIST v1.1 criteria) will be evaluated at completion of neo-adjuvant CTx prior to surgery, every 12 wks for the first year; every 24 wks for 2–4 years; then yearly thereafter. The primary endpoint is major pathological response (≤10% residual viable tumor in the resected primary lung tumor after neoadjuvant treatment) in the full analysis set (FAS). Secondary endpoints include safety assessments, a range of efficacy measures including complete pathological response (FAS and PD-L1-TC ≥1%) and OS, pt-reported outcomes, durva pharmacokinetics and immunogenicity. This trial is currently recruiting.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P2.17 - Treatment of Early Stage/Localized Disease (ID 189)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.17-41 - Treatment Outcomes of Pulmonary Resection in NSCLC Patients with Autoimmune Diseases (ID 3102)

      10:15 - 18:15  |  Author(s): Tetsuya Mitsudomi

      • Abstract

      Background

      Surgical resection for early stage non-small cell lung cancer (NSCLC) patient with autoimmune disease(s) is a relatively rare occasion. Most of such patients have received steroid therapy with/without immunosuppressant agent for a long period before the surgery. However, short-term or long-term treatment outcomes of NSCLC patients with autoimmune disease are unclear.

      Method

      Between January 2007 to December 2018, thirty-nine NSCLC patients with autoimmune disease(s) received pulmonary resection with curative intent in our department. Patients with interstitial lung disease were excluded from this study. Patient clinical and pathological characteristics and treatment outcomes were evaluated.

      Result

      There were 17 males and 22 females in out cohort. The median age was 68 years old (39 – 84), and thirty patients were smokers. Twenty-three patients had rheumatoid arthritis, and among them, three patients had additional autoimmune disease (autoimmune hepatitis, Sjogren syndrome, or polyneuropathy). Other autoimmune diseases included Hashimoto disease (n = 4), systemic lupus erythematosus (n = 3), Behcet’s disease (n = 2), primary biliary cirrhosis (n = 2), and others. Only three patients received limited resections (2 partial resections and one segmentectomy), and 36 patients received lobectomy or bi-lobectomy. At the post-operative pathological diagnosis, there were 13 patients with squamous cell carcinomas, 21 patients with adenocarcinomas, four patients with pleomorphic carcinomas, and one patient with adenosquamous cell carcinoma. Post-surgical complications included pneumonia (n = 1, 3%), prolonged air leakage (n = 1, 3%), and no patient experienced bronchopleural fistula or empyema. The median post-surgical hospital stay was eight days ( 4 – 28 days).

      Conclusion

      Pulmonary resection for NSCLC patients with autoimmune disease(s) were safely performed. We will also report the long-term outcome for this cohort at the conference.

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    PL01 - New Questions with Imaginative Answers (ID 88)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      PL01.03 - Will the Immunotherapy with Newer Biomarkers, Combination Therapy or New Technology Eventually Cure Lung Cancer? (Now Available) (ID 3582)

      08:15 - 09:45  |  Presenting Author(s): Tetsuya Mitsudomi

      • Abstract
      • Presentation
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      Abstract

      The recent introduction of immune checkpoint therapy has greatly changed the clinical practice of non-small cell lung cancer (NSCLC). A battery of clinical trials showed the superiority of either PD-1 antibody monotherapy or PD-1/L1 antibody combined with chemotherapy as a first-line treatment of NSCLC over standard platinum doublet chemotherapy that has long been a standard of care. Hence, most if not all of NSCLC patients receive PD-1/L1 antibodies unless contraindicated due to coexisting immune-related comorbidities.

      The recent update of the Keynote-001 trial showed that 5-year survival of the high expressors of PD-L1 treated with pembrolizumab as a first-line treatment was 23%. Especially, the 5-year survival rate of patients who received the first-line pembrolizumab more than 2 years was 79%. This really indicates that at least some of the NSCLC patients may be cured by monotherapy of PD-1 antibodies.

      Conversely, about three fourth of patients, even with high expression of PD-L1 cannot survive for more than 5 years. This is natural considering the complexity of immunologic mechanisms against cancer. To be eliminated effectively by PD-1/L1 treatment, cancers should express their unique antigens typically generated by somatic mutations in the context of MHC. Therefore, the adequate quantity as well as the adequate quality of somatic mutations and intact antigen presentation, are prerequisite for immune response. When abnormal peptide is recognized by immune cells, adaptive expression of PD-L1 on the tumor cells occurs by secretion of interferon γ by T cells as a negative feedback that dampens antitumor immunity, Upon binding of PD-L1 with PD-1 on T cells downregulates T cell function. This tumor microenvironment (TME) is the best candidate for anti-PD-1/PD-L1 therapy. However, not all cancer has this TME. Besides PD-1/L1 systems, there are many other molecules such as CTLA4, TIGIT, TIM3, LAG3, etc. that negatively regulate the immune response. Regulatory T cells and myeloid-derived suppressor cells (MDSC) are also major players of immunosuppressive TME

      To overcome these immunologic evasions, many strategies are being extensively sought. To enhance immune recognition of mutations and to prime new response, polypeptide or RNA-based vaccines that contain mutation-derived epitopes are being tested. For tumor cells that lost HLA molecules, enhancement of NK cell activities through NKG2A antibody or anti KIR antibody may be effective. To overcome adaptive immune resistance by molecules other that PD-1, use of blocking antibodies against above-mentioned other co-inhibitory molecules or agonistic antibodies against co-stimulatory molecules such as ICOS, GITR, 4-1BB, OX40, etc. is a rational way. Finally, to reverse immune suppressive TME, use of antibodies against CSF-1R and CCR4 to suppress MDSC and regulatory T cells, respectively, may be effective. Antagonists for immunosuppressive molecules such as adenosine A2AR, IDO, TGFb, etc are also expected to enhance tumor immunity.

      Will the Immunotherapy eventually cure lung cancer? Currently, I have to say "Yes, for some but not sure for every patient". In this talk, I would like to discuss ongoing efforts to further improve outcomes of immune-therapy of lung cancer and future perspectives.

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      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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