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Fred R. Hirsch

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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
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      Abstract not provided

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    EP1.04 - Immuno-oncology (ID 194)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.04-15 - NSCLC Response Determinants to Chemoimmunotherapy: Deep Profiling of Tumors Following Neoadjuvant Cemiplimab and Chemotherapy (Now Available) (ID 1021)

      08:00 - 18:00  |  Author(s): Fred R. Hirsch

      • Abstract
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      Background

      Clinical trials have demonstrated synergistic effects of combination chemoimmunotherapy in patients with locally advanced and metastatic non-small cell lung cancer (NSCLC), however, our understanding is limited as to why and for whom PD-1 blockade with or without chemotherapy is effective, as is our understanding of the mechanism of synergy between these therapies.

      While most patients with resectable NSCLC receive neoadjuvant or adjuvant chemotherapy, this intervention only changes the natural course of disease for ~5% of patients. Early studies have demonstrated major pathologic responses to neoadjuvant immunotherapy ± chemotherapy.

      Method

      To investigate the immunodynamic effect of PD-1 blockade and chemotherapy, and identify potentially more effective immune modifying targets or combinations, we will use novel immunophenotyping platforms to characterize the effect of this combination on the tumor. This trial will enroll 52 patients with Stage Ib-IIIa NSCLC into three cohorts receiving 2 cycles of 1) platinum-doublet chemotherapy, 2) the PD-1 antibody cemiplimab, or 3) combination chemoimmunotherapy. Following surgery, patients will receive additional adjuvant chemoimmunotherapy; in total all patients will receive 4 cycles of standard platinum-doublet chemotherapy and 8 cycles of cemiplimab. All patients will undergo pre-treatment biopsies of their tumor, and blood will be collected at 6 time-points before and after surgery.

      The primary endpoint for this clinical trial is major pathologic response, defined as ≤10% viable tumor within resection. Secondary endpoints include: delay of surgery, disease-free survival, overall response rate, overall survival, measurement of adverse events, and change in CD8 T-cell infiltration.

      Exploratory endpoints include in-depth analysis of the pre-treatment tumor biopsies and post-treatment surgical specimens, and paired blood. We will characterize proteomic and transcriptomic changes in the stromal and immune compartment of tumors at the histologic level using a multiplexed ion-beam imaging (MIBI)—a novel multiplex immunohistochemistry platform capable of analyzing >50 markers on a single section of tissue—and at the single-cell level using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITEseq), a novel platform combining the proteomic data-potential of mass cytometry (CyTOF) and the transcriptomic data-potential of single cell RNA sequencing including TCR sequencing. Feasibility of this multi-pronged approach has been demonstrated on untreated NSCLC (unpublished data, submitted as abstract to WCLC by our group).

      To probe for biomarkers correlating with response or resistance to therapy, we will perform unbiased analysis of peripheral blood lymphoid and myeloid populations by CyTOF, and measure nearly 100 soluble factors in serum using Olink.

      Result

      This trial opened to accrual April 2019.

      Conclusion

      Section not applicable.

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    IBS15 - Biology and Genetics in ICI Treatments (Ticketed Session) (ID 46)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Biology
    • Presentations: 1
    • Now Available
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      IBS15.02 - Determinants of Response to ICI (Now Available) (ID 3361)

      07:00 - 08:00  |  Presenting Author(s): Fred R. Hirsch

      • Abstract
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      Abstract

      PREDICTIVE BIOMARKERS FOR IMMUNOTHERAPY IN LUNG CANCER

      Fred R. Hirsch, MD, PhD. Professor of Medicine and Executive Director, Center for Thoracic Oncology, The Tisch Cancer Institute, Mount Sinai Health System, NY, NY. USA

      While great promise has emerged with the development of immunotherapy (IT) in lung cancer, we are still struggling with how to select the right treatment to the right patients and how to select the patients, who will benefit from IT. Only 20-30 % of the patients with NSCLC will have a clear benefit from IT compared to chemotherapy alone, and the challenge is to select those patients.

      PD-L1 protein expression demonstrated by immunohistochemistry (IHC) has been pursuit as primary selection biomarker in the clinical trial development. However, the major challenge for evaluation of PD-L1 and top compare the results from one study to another was the use of different antibodies/assays and processing by the different companies. A comparison of the different PD-L1 assays was performed in the “PD-L1 Blueprint Project”, and three antibodies/assays was found to be performing similarly and could be interchangeable (1,2). While higher PD-L1 expression seems to be associated with gradually increased outcome of IT, a tumor proportion score (TPS) ≥ 50% seems to be useful in the choice of IT (e.g. pembrolizumab) monotherapy versus IT plus chemotherapy (CT). The results (PFS/OS) of IT monotherapy for patients with high PD-L1 expression is not significantly different than for IT+CT, although not directly compared, while for patients with tumors having lower PD-L1 expression, the combination of IT+CT seems better (3, 4). Thus, the predictive role of PD-L1 expression might be different between IT alone and IT+CT. The prognostic role of PD-L1 (e. g. association to outcome without any therapy) is still not clear with conflicting reported outcomes in the literature.

      Tumor mutation burden (TMB) has in some clinical trials demonstrated to be of predictive value, both based on tissue and plasma (5, 6, 7). In several studies it has been shown that the patient population with high TMB has little overlap with the patient population with high PD-L1 expression (6). Prospective clinical trials arer today performed evaluating plasma TMB as predictive biomarker (b-FIRST). However, also challenges related to TMB reports occur; different assay platforms have been used in different clinical trials, different definitions (e. g cut-offs) have been applied in the definition of high TMB vs low TMB, and also for TMB an comparison of results /assays seems to be needed. Such comparison studies are on-going both in the US (i.e. Friends of Cancer) and in Europe.

      On this stage, it is not clear whether TMB can replace PD-L1 IHC in treatment decisions; who will benefit from IT or not? Some studies (i.e. CheckMate 227) (8), indicate also that the two predictive assays are not “competing” but complementary. It has been shown that for patients having tumors with low (≤1%)- or no PD-L1 expression, but high TMB a treatment option of combined therapy with nivolumab+ ipilumumab seems justified. There are also conflicting results reported on the prognostic role of TMB associated to no systemic therapy or predictive role associated to chemotherapy alone.

      Other candidate biomarkers are under investigations and will be discussed.

      REFERENCES:

      Hirsch FR et al. J Thorac Oncol 2017 (2): 208-222

      Tsao MS et al: J Thorac Oncol 2018 (9): 1302-1311

      Gandhi L et al; N Engl J Med 2018 378(22): 2078-2092

      Reck M et al; N Engl J Med 2016 375(19): 1823-1833

      Carbone DP et a;; N Engl J Med 2017 376(25): 2415-2426

      Gandara DR et al. Nat Med 2018 (9): 1441-1448

      Samstein RM et al; Nat Genet 2019 (2): 202-206

      Hellman MD et al; N Engl J Med 2018 378(22): 2093-2114

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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): Fred R. Hirsch

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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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    OA04 - Immuno Combinations and the Role of TMB (ID 126)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      OA04.01 - A Phase III Randomized Study of Nivolumab/Ipilimumab vs Nivolumab for Previously Treated Stage IV Squamous Cell Lung Cancer (Now Available) (ID 872)

      15:15 - 16:45  |  Author(s): Fred R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background

      Lung-MAP is a master protocol for patients (pts) with stage IV previously treated SqNSCLC. S1400I enrolled pts who were not eligible for a biomarker-matched sub-study. (Lung-MAP Sub-Study S1400I, NCT02785952)

      Method

      S1400I is phase III randomized trial for immunotherapy-naïve patients with ECOG 0-1 not selected by PD-L1 expression. Pts were assigned 1:1 to nivolumab and ipilimumab (N+I) vs nivolumab (N). N was given at 3 mg/kg q 2w, I was given at 1 mg/kg q 6w. The primary endpoint was overall survival (OS). Secondary endpoints: investigator-assessed progression-free survival (IA-PFS), response by RECIST 1.1, and toxicity.

      Result

      From December 18, 2015 to April 23, 2018, 275 pts enrolled and 252 determined eligible (125 N+I and 127 N). Median follow up for patients still alive was 17.4 months. The study was closed for futility at an interim analysis. Baseline characteristics were similar across arms. mOS was 10.0 m (8.0-12.8) and 11.0 m (8.2-13.5) for N+I and N. HR 0.97 (0.71-1.31), p 0.82. mPFS was 3.8 m (2.3-4.2) and 2.9 m (1.8-3.9) for N+I and N. HR 0.84 (0.64-1.09), p 0.19. The response rate was 18% (12-25) in N+I and 17 % (11, 24) in N. Outcomes were similar across TMB subgroups and PD-L1 expression levels. Most AE were low grade. There were 5 grade 5 AE in N+I arm and 1 in N arm. Grade ≥3 treatment-related AEs occurred in 48(39%) of pts on N+I vs 38(31%) on N. irAE reported in 39% of pts on N+I and 34% of patients on N. Drug-related AEs led to discontinuation in 25% of pts on N+I and 16% of pts on N.

      OS and PFS based on TMB and PD-L1

      N+I

      Median in months

      N

      Median in months
      HR p
      OS PD-L1 ≥5 14.1 (5.8-17.5) 12.0 (8.2-19.8) 1.06 (0.58-1.92) 0.86
      OS PD-L1 <5 8.3 (6.0-10.7) 10.3 (6.3-13.5) 1.01 (0.62-1.65) 0.97
      OS TMB ≥10 13.1 (9.3-17.0) 11.4 (8.2-16.1) 0.86 (0.56-1.32) 0.48
      OS TMB <10 7.6 (5.7-10.2) 10.0 (6.3-15.2) 1.08 (0.68-1.71) 0.74
      PFS PD-L1 ≥ 5 3.9 (1.7-7.1) 2.9 (1.8-4.7) 0.65 (0.38-1.08) 0.10
      PFS PD-L1 <5 4.4 (2.1-6.0) 1.6 (1.5-3.0) 0.64 (0.41-1.01) 0.06
      PFS TMB ≥ 10 4.2 (3.4-5.9) 3.4 (1.8-5.3) 0.75 (0.52-1.10) 0.15
      PFS TMB < 10 1.9 (1.5-4.1) 2.7 (1.6-3.3) 0.92 (0.62-1.39) 0.70

      Conclusion

      S1400I failed to show improvement in outcomes with N+I. Study was closed for futility at interim analysis. Toxicities were not different between two arms. Molecular correlates will be presented at the meeting.

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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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      OA13.01 - SPECS2 Lung Cancer Consortium Prospective Multicenter Validation of Prognostic Signature for Early Stage Squamous Lung Cancer (Now Available) (ID 2723)

      11:30 - 13:00  |  Author(s): Fred R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background

      Squamous Lung Cancer (SC) which constitutes 30% of all non-small cell lung cancers (NSCLC) has few targeted therapy options for advanced disease. Surgery for early SC is the best treatment strategy; however, even patients who undergo surgery for stage IA or IB disease are still at a substantial risk for recurrence and death. Adjuvant therapy is not currently indicated for stage I SC smaller than 4 cm. Prior reports suggest gene expression-based signatures that may predict recurrence in patients with stage I SC, but none has been validated or is in clinical use. The SPECS2 Lung Cancer Consortium was assembled to compare and attempt to validate previously published prognostic signature(s) according to the guidelines proposed by Subramanian and Simon (J Natl Cancer Inst 2010; 7:327).

      Method

      The multi-institutional team assembled 249 frozen SC samples representing six participating institutions (cohort 1). These samples were fully annotated in a redcap database hosted by the independent statistical core. Cohort 2 was assembled utilizing 234 frozen SC samples from a prospective multi-institutional NCTN lung biobanking protocol (NCT00899782). RNA was extracted and profiled with U133A microarrays (Affymetrix) in independent core facilities. The data was transferred directly to the SPECS2 Lung statistical core in collaboration with the Alliance Statistical core and the performance of 6 most promising candidate signatures was evaluated relative to a base model that included only age, gender and AJCC stage (editions 6, 7, 8).

      Result

      Analysis of Cohort 1 demonstrated that only one signature (Raponi et al, Cancer Res 2006; 66:7466) significantly enhanced prognosis relative to the base model, independent of AJCC edition. This was also observed in Cohort 2, where Uno’s C index associated with AJCC 8th edition stage, sex and age (0.561; 0.468-0.654) was significantly (p <0.05) increased when the prognostic signature was added to the model (0.683; 0.611-0.755).

      Conclusion

      The SPECS2 Lung Cancer Consortium was successful in validating a previously published prognostic molecular signature for early stage SC using rigorous experimental design. To our knowledge, this is the first unbiased validation of a lung cancer prognostic signature using multi-institutional prospective specimens. These results support a clinical trial designed to evaluate the potential role of adjuvant therapy in completely resected early stage SC.

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    P1.12 - Small Cell Lung Cancer/NET (ID 179)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.12-05 - Microenvironment Characterization of Small Cell Lung Cancer Xenografts Implanted in Hematopoietic Humanized Mice (ID 2022)

      09:45 - 18:00  |  Author(s): Fred R. Hirsch

      • Abstract

      Background

      With the high mutational burden seen in small cell lung cancer (SCLC) there is the theoretical potential to improve SCLC outcome through immunotherapy. Recent immunotherapeutic clinical trials in SCLC have demonstrated promising results. However, to better understand the immune response and the potential role of immunotherapy in SCLC, immunocompetent models are needed. To this end, we have applied a hematopoietic humanized mouse model, Hu-CB-BRGS to investigate the mechanisms underlying SCLC immunotherapy and develop novel strategies to improve therapeutic efficacy.

      Method

      BALB/c-Rag2nulllll2rynullSIRPαNOD (BRGS) pups were humanized through transplantation of cord blood (CB)-derived CD34+ cells. SCLC flank tumors were initiated in BRGS mice using two characterized SCLC cell lines (CDX) and 1 patient derived xenograft (PDX). Upon verification of human T-cell chimerism in the Hu-CB-BRGS mice, SCLC tumors grown in BRGS mice were engrafted into the flanks of Hu-CB-BRGS mice by trocar transfer. Tumor growth was quantified by twice weekly measurement and harvested on reaching 1200 mm3. At harvest, tumor tissue as well as host immune organs (lymph node, spleen) were collected for immunological assessment. Humanized immune system and tumor were evaluated by flow cytometry and immunohistochemistry (IHC).

      Result

      Flank tumors from two CDX tumors (H82 and H187) and one PDX tumor (LX-95) were successfully developed in the Hu-CB-BRGS mice with take rates averaging 82%. SCLC tumor growth rate in Hu-CB-BRGS mice was comparable to that seen in BRGS mice. Although human T cells were well represented in the lymph nodes and spleens of the Hu-CB-BRGS mice, we detected very few tumor infiltrating immune cells in the engrafted SCLC tumors by IHC and flow cytometry as defined by CD45 and CD3, which is consistent with the observations in SCLC patient tumor tissue. Tumor cells, identified by EpCAM expression, expressed low levels of MHC class I, II and PD-L1. PD-1 was expressed by human T cells found in the lymph nodes and spleen of Hu-CB-BRGS mice, while the SCLC xenografts expressed varying levels.

      Conclusion

      We demonstrate that both SCLC PDX and CDX tumors can be grown in the context of a humanized immune system within mouse recipients. SCLC Hu-CB-BRGS mice demonstrate persistence of human immune cells, including T cells and B cells in the immune organs. The xenograft tumor microenvironment included variable human immune infiltrates. The SCLC Hu-CB-BRGS mouse model may be a valuable preclinical platform for testing human specific immune-oncology therapeutics for SCLC patients.

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      P1.12-09 - RNA Sequencing in Small Cell Lung Carcinoma Reveals Change in Neuroendocrine Pattern in Primary Tumor Versus Lymph Node Metastases (ID 2820)

      09:45 - 18:00  |  Author(s): Fred R. Hirsch

      • Abstract
      • Slides

      Background

      Recent preclinical cell line data presented at World Conference on Lung Cancer 2018 suggest that neuroendocrine (NE) pattern of small cell lung cancer (SCLC) has strong therapeutic relevance. NE high tumors are associated with immune desert and NE low tumors are considered immune oasis phenotype.

      Method

      Targeted RNA-sequencing of 2560 genes was performed on 32 matched surgically resected SCLC patients primary tumors and lymph node (LN) metastases. We performed a cluster analysis and heat map to divide patients into NE high and NE low subtypes by using the top NE associated genes.

      Result

      Cluster analysis clearly identified SCLC NE subtypes according to primary tumor (NE high vs. low, 20 vs. 12, respectively) and LNs (NE high vs. low, 23 vs. 9, respectively). In case of five patients, a change in NE pattern was observed, suggesting a possible inter-tumor heterogeneity regarding NE differentiation. Moreover, a significant downregulation of NE associated genes CAV1, CAV2 and ANXA3 was found in LN metastases compared to primary tumor. A lower expression of NE associated key RNA genes REST and Myc, and the higher expression of DLL3 in NE high subtype are in accordance with the preclinical findings, and confirms the accuracy of the cluster analysis performed.

      Conclusion

      Our data confirm the results of preclinical studies and show NE low and high differentiation clusters in SCLC. NE pattern of the LN metastatic lesions might not reflect the NE phenotype of the primary tumor, consequently, treatment decisions including immunotherapy administration needs to be further investigated.

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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): Fred R. Hirsch

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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