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P.A. Bunn, Jr.

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    PL05 - Closing Plenary Session: A Life in Thoracic Oncology - Reflections from Giants on Milestones in the Treatment Advances in Lung Cancer (ID 433)

    • Event: WCLC 2016
    • Type: Plenary
    • Track:
    • Presentations: 9
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      PL05.01 - Pathology (Now Available) (ID 6914)

      A.F. Gazdar

      • Abstract
      • Presentation
      • Slides

      Abstract:
      A life in Thoracic Oncology – Reflections from a pathologist. While many regard a pathologist as a physician involved in laboratory diagnosis, by definition Pathology is the science or the study of the origin, nature and course of diseases. This broader definition of pathology, which basically encompasses all of the study of medicine, is what first attracted me to the field. After my residency I joined the NCI as a research pathologist studying viral oncology in rodents. However a few years later John Minna gave me the opportunity to return to the study of human cancer when he was appointed the head of the NCI-VA Medical Oncology Branch in Washington, DC, with a focus on lung cancer therapy. Our branch was fortunate to have an outstanding lung pathologist, Mary Matthews who taught me most of what I know about lung pathology. Mary also had a profound effect on the understanding and treatment of lung cancer. In 1973 she established that small cell lung cancer (SCLC) was almost always metastatic at the time of diagnosis, and that surgery was unlikely to be curative.[1]These observations, plus the finding that SCLC showed initial responses to the therapy then currently available, helped establish the fundamental distinction of lung cancers into SCLC and NSCLC categories. The Mary Matthew award for Pathology and Translational Research is one of the distinguished awards of the IASLC and I was fortunate and honored to be the fourth recipient in 2003. John Minna assembled an outstanding group of physicians/scientist many of whom became pioneers in the field of lung cancer. Of interest, all three past and present Chief Executive Officers of the IASLC, Heine Hansen, Paul Bunn and Fred Hirsch, spent time at the NCI-VA Medical Oncology Branch. John preached that new approaches for the therapy of lung cancer were needed, that this would require understanding biology, and to understand biology we needed preclinical models. My job was to establish such models and help “translate” them into clinical care. By the early 1980s we had established and characterized large banks of SCLC cell lines and demonstrated that they expressed the entire neuroendocrine (NE) cell program.[2] The cell lines were widely distributed to the scientific community, and in the absence of reliable tumor tissue sources, became the major source of biologic and molecular knowledge of SCLC. Within that decade our group, largely from the use of cell lines, described chromosome 3p loss, MYC family amplification, RB1 and TP53 loss as being characteristics of SCLC and also discovered the MYCL oncogene. The NCI-VA Medical Oncology Branch later relocated to the Bethesda Naval Hospital, MD. In 1991, John Minna accepted a position at the University of Texas Southwestern Medical Center, Dallas, and I was his first recruitment. Thus, during my long career I have only had two employers! I believe this continuity has helped establish strong, long term collaborations and boosted overall productivity. One of the interests of Mary Matthews and me was the heterogeneity of SCLC. It became obvious to us that the so-called oat cell variant was an ischemic artifact. However we were intrigued by the plasticity of SCLC, with a substantial percentage of cases having abnormal (“variant”) morphologies or combined with NSCLC elements, especially after therapy.[3] The variant morphology and its relationship to NEUROD1 as the driver transcription factor (as opposed to ASCL1 as the driver in typical or “classic” SCLC) has recently been highlighted.[4] By the mid 1980s, advances in SCLC biology and therapy had hit a stonewall, and funding dried up. It was time to move onto NSCLC! We established a large collection of NSCLC cell lines and these also formed much of the basis of our understanding of this disease, although tumor tissues were much more readily available. While cell lines have their pluses and minuses, they are excellent for identifying driver mutations and testing targeted therapies. They contributed to the identification of the role of EGFR mutations in lung cancer.[5, 6] Soon after this discovery we used our international fellows and contacts to perform the first large multinational study of geographic and ethnic variations in mutation frequencies, and also demonstrated that mutations were largely absent in tumors other than NSCLC.[7] The advent of Precision Medicine has highlighted the crucial role of the pathologist. Instead of the image of a pathologist looking at microscope slides in isolation in a basement office, he or she plays a crucial role as an integral part of the diagnostic and therapeutic team involved in every aspect of patient management. The pathologist assumes further responsibilities such as tissue procurement and optimal utilization, triaging scant resources for clinical trial requirements, involvement in molecular testing, performing requested or required immunostaining, establishing tissue repositories etc. Previously clinical decision making required the pathologist only to make a diagnosis of SCLC or NSCLC. Precision Medicine has highlighted the importance of accurate classification of NSCLC. Classification is required for mutation testing, therapy selection (or exclusion) and entry onto histology dependent clinical trials. While the introduction of immunostains has greatly facilitated the classification of poorly differentiated NSCLC, the SEER database indicates that up to 14% of NSCLC may remain unclassified throughout the USA. For these reasons we developed a molecular classifier for NSCLC that can be applied to formalin fixed paraffin embedded (FFPE) materials and small core biopsies.[8] The assay is highly accurate and quantitative, and also provides information on grading and survival. While SCLC languished for three decades, its recent designation as a recalcitrant cancer by the US Congress has resulted in a dramatic resurrection of interest, funding and achievement.[9] This has highlighted the importance of preclinical models for SCLC.[10, 11] I feel very humbled and privileged to have lived through and contributed to the seminal advances in our understanding of the biology and therapy of lung cancer. This would not have been possible without the many wonderful and talented people I have worked with. I am reminded of the quote of Isaac Newton: “If I have seen further than others, it is because I have stood on the shoulders of giants”. References 1. Matthews MJ, Kanhouwa S, Pickren J, et al. Frequency of residual and metastatic tumor in patients undergoing curative surgical resection for lung cancer. Cancer chemotherapy reports Part 3 1973;4:63-67. 2. Gazdar AF, Carney DN, Russell EK, et al. Establishment of continuous, clonable cultures of small-cell carcinoma of lung which have amine precursor uptake and decarboxylation cell properties. Cancer Res 1980;40:3502-3507. 3. Gazdar AF, Carney DN, Nau MM, et al. Characterization of variant subclasses of cell lines derived from small cell lung cancer having distinctive biochemical, morphological, and growth properties. Cancer Res 1985;45:2924-2930. 4. Borromeo MD, Savage TK, Kollipara RK, et al. ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs. Cell reports 2016;16:1259-1272. 5. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-1500. 6. Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7:169-181. 7. Shigematsu S, Lin L, Takahashi T, et al. Clinical and biological features associated with Epidermal Growth Factor Receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:339-346. 8. Girard L, Rodriguez-Canales J, Behrens C, et al. An Expression Signature as an Aid to the Histologic Classification of Non-Small Cell Lung Cancer. Clin Cancer Res 2016. 9. Gazdar AF, Minna JD. Developing New, Rational Therapies for Recalcitrant Small Cell Lung Cancer. J Natl Cancer Inst 2016;108. 10. Gazdar AF, Hirsch FR, Minna JD. From Mice to Men and Back: An Assessment of Preclinical Model Systems for the Study of Lung Cancers. J Thorac Oncol 2016;11:287-299. 11. Gazdar AF, Savage TK, Johnson JE, et al. The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of the lung. J Thorac Oncol 2015;10:553-564.

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      PL05.02 - Surgery (Now Available) (ID 6915)

      P. Goldstraw

      • Abstract
      • Presentation
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      Abstract:
      WCLC2016 Abstract for Closing Plenary Session A Life in Thoracic Oncology - Reflections on Treatment Advances: Surgery The speaker began his training in Cardiothoracic surgery in 1973 and was appointed as a Consultant in 1979. He will introduce this topic by describing a typical case undergoing surgical treatment for lung cancer in the 1970s, the patient journey and outcomes at that time. From that basis he will detail the changes in the surgical treatment of lung cancer in the last 40 years. This will include: · Changes in the epidemiology of lung cancer. · Improvements in pre-operative selection. · Improvements in the staging process prior to surgery, during surgery and post-surgery. · Differences in surgical approach and the anatomical extent of resection. · Changes in the stage classification over that period. · The establishment of effective adjuvant therapy. · Improved outcomes in morbidity, mortality and survivorship. None of these improvements has been of itself a game changer but collectively they amount to a fundamental change in the surgical management of this disease. A brief mention will be made of advances in the surgical treatment of other thoracic malignancies. Peter Goldstraw

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      PL05.03 - Radio-Oncology (Now Available) (ID 6916)

      D. Ball

      • Abstract
      • Presentation
      • Slides

      Abstract:
      When I commenced training in radiation oncology in 1973, there were no CT scanners, calculations were done with slide rules, and chemotherapy, let alone combined modality therapy, had no established role in the treatment of non-small cell lung cancer. An influential trial published in the Lancet in 1971(1) had shown no difference in survival whether patients were randomized to radiotherapy, chemotherapy, a combination of the two or a policy of wait-and–see. Yet within 30 years, the standard of care for patients with inoperable lung cancer being treated for cure, both small cell and non-small cell, had, ironically, become, and remains, concomitant chemotherapy and radiotherapy. The outlook for patients generally regarded as incurable at the outset of my career is that up to one in three selected patients can now expect to live five years as a result of chemoradiation. Patients with stage I non-small cell lung cancer can have their cancer successfully ablated by non-invasive stereotactic radiotherapy in 90% of cases. The developments which led to these changes can be grouped according to three main themes: the impact of the computer revolution; a better understanding of the natural history and biology of the disease, and the introduction of mutimodality therapy. The computer revolution: imaging, treatment planning and delivery Better identification and delineation of the tumor are critical to the success of radiotherapy, in particular avoidance of the catastrophic “geographic miss”. Without computers, the CT and hybrid PET/CT scanners could not have been possible. These dramatically improved the accuracy of staging as well as providing 3D information on the relationship of the soft tissue target to the nearby dose-limiting organs at risk. As computing power increased it became possible to create 4D images of moving tumours, and to image the target with on-board CT scanners attached to the linac immediately before treatment, so making image guided stereotactic ablative radiotherapy possible. Powerful computerised treatment planning systems are now able to create complex dose distributions conforming to the irregularities of any target volume, and to provide dose-volume metrics predictive of risks of normal tissue damage. Improved understanding of the natural history and biology of the disease The recognition that the central nervous system is a sanctuary site which can harbour metastatic disease leading to treatment failure in spite of successful chemotherapeutic eradication of extracranial disease, particularly in small cell lung cancer, led to the introduction of prophylactic cranial irradiation. The British study of continuous hyperfractionated accelerated radiotherapy (CHART) which was given over 12 days to patients with inoperable non-small cell lung cancer resulted in better survival than treatment given over six weeks, even though the total dose was lower. This trial provided clinical support for the notion of treatment induced accelerated repopulation, and reinforced the principle that total treatment times should be kept short in both small cell and non-small cell lung cancer, both when radiotherapy is used alone, and when in combination with chemotherapy. Multimodality therapy The limitations of single modality therapy for a disease with a high propensity for developing genetically determined resistance have long been recognised, and have stimulated the development of strategies simultaneously employing non-cross resistant therapies to maximise tumor cell kill, in line with the principles espoused by Goldie and Coldman.(2) The use of concomitant platinum based chemotherapy with high dose radiotherapy is now well established by meta analysis as improving survival of both non-small cell and small cell lung cancers, but it is also more toxic. Amelioration of these toxicities represents a major challenge for the future. Future directions It is likely that the technical progress in radiation treatment planning and delivery is close to a plateau, and that future progress will depend more on understanding the biology of the disease and its response, and that of the normal tissues, to radiation damage. Biomarkers of response and toxicity, so spectacularly harnessed to advantage by our medical oncology colleagues, are desperately needed to tailor the radiotherapy prescription to the needs of each individual and their cancer. Finally, it is evident that in many jurisdictions, including industrialised wealthy nations, that many patients are either receiving substandard radiotherapy that might increase their chances of cure, or are not receiving treatment at all.(3) Unless these problems can be addressed, the benefits of the remarkable advances in technology and biology documented above will shamefully be restricted to only a fraction of those afflicted with locoregional disease. 1. Durrant KR, Berry RJ, Ellis F, Ridehalgh FR, Black JM, Hamilton WS. Comparison of treatment policies in inoperable bronchial carcinoma. Lancet. 1971;1(7702):715-9. 2. Goldie JH, Coldman AJ, Gudauskas GA. Rationale for the use of alternating non-cross-resistant chemotherapy. Cancer Treat Rep. 1982;66(3):439-49. 3. Vinod SK. International patterns of radiotherapy practice for non-small cell lung cancer. Semin Radiat Oncol. 2015;25(2):143-50.

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      PL05.04 - Translational Lung Cancer Research (Now Available) (ID 6917)

      N. Saijo

      • Abstract
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      Abstract:
      Lung cancer is a leading cause of cancer death in the world. The survival benefit of chemotherapy was rarely observed in NSCLC until the development of Cisplatin. Platinum doublets including 2nd/3rd generation cytotoxic drugs showed minor prolongation of survival but the effect reached a plateau. JCOG conducted key RCTs to develop new standards against SCLC but a breakthrough has not been observed yet. Two recent major therapeutic advancements in NSCLC are immunotherapies to inhibit immune checkpoints and development of targeted drugs for driver mutations. Translational Research in Immune Checkpoint inhibitors Immunotherapy of cancer has a long history without success because of wrong strategy of immune stimulation with non-specific immunostimulators, biological response modifiers and recently by peptide antigens. After introduction of idea on immune checkpoint inhibition by Dr. James Allison, the studies of this fields were dramatically activated. Currently two anti-PD-1 antibodies such as Nivolumab and Pembrolizumab have been approved for the treatment of NSCLC based on reproducible effects of tumor shrinkage and survival benefit. In second line treatment, both antibodies significantly improved survival compared with standard care of cytotoxic chemotherapy irrespective of patient selection. Recent press release announced that Nivolumab failed to demonstrate benefit for PFS compared to cytotoxic chemotherapy (CheckMate-026), on the other hand Pembrolizumab demonstrated superior PFS and OS (KEYNOTE-024). Both of the trials patient selection was done based on PD-L1 expression in lung cancer cells. In spite of positive data on survival, RR in various trials against advanced NSCLC with or without prior chemotherapy ranges from 15-25% for both drugs and median survival is almost same in anti-PD1 Ab and cytotoxic drugs. The most important issue will be how to concentrate responsive patient population or how to eliminate in effective patients. Although there is a tendency of correlation between PD-L1 expression and objective response/survival, responders to Ab are experienced even in PD-L1 negative patients. There are many problems in PD-L1 screening. There is no comparative data of various PD-1 tests used in various clinical trials. Each PD-1 test uses different antibody. Each test uses a different definition and cut off point that defines PD-1 positivity. There is no data on best sample, paraffin-fixed vs fresh tissue, primary site tumor vs metastatic tissue. PD-1 expression is not stable and influenced by many factors. There is no reliable validation and standardization. In tumor cells, mutation burden may influence on antigenicity. In colorectal cancer, microsatellite instability has related with response to anti-PD-1 antibody, but it is not yet clear whether mutation burden really increases antigenicity. CD8 lymphocytes infiltration is also considered to be one of the biomarkers for anti-PD-1 Ab response. However, it is too objective and seems to be quite difficult to quantify CD 8 lymphocytes infiltration. The most important thing will be the function of killer T lymphocytes which can respond to target antigens and to kill tumor cells. The best method may be quantitative measurements of cytotoxicity in killer T cell on tumor cells. The techniques to demonstrate this process are mandatory for successful patient selection in the treatment with anti-PD-1 antibody. Translational Drug Development for Precision Medicine Recent development of molecular target drugs in lung cancer really reflects progress of translational studies. EGFR-TKIs are one of the most important drugs and changed concept of treatment of lung cancer. Finding on many rare driver mutations forced to reclassify lung cancer to various genomic subtypes. Innovative technologies for genomic medicine changes one size fit medicine to precision medicine. For discovery of drugs to each genomic subtype of lung cancer, nationwide and global screening network should be mandatory. In Japan LC-SCRUM Japan leaded by Dr. Koichi Goto, National Cancer Center Hospital East, started in February 2013 to find out new seeds against lung cancer by the support of government.. At the beginning, tumor tissues were analyzed for ALK/ROS1/RET fusions using RT-PCR in EGFR –Mt negative patients and the detected fusions were confirmed by FISH. From March 2015, multiplex diagnostic kit using NGS was introduced and this project expanded as SCRUM-Japan including other histological types of lung cancer such as SQ and SM as well as GI malignancy. 14 pharmaceutical companies started to support this project. No. of institutions joined in the network increased to 200 In Non-SQ NSCLC, 159 and 96 for SQ and SM, respectively on March, 2016. More than 2,500 samples were analyzed. Rare mutations including ROS(91), RET(54) and ALK(40) fusions, ERB2 mutation/amplification(48), BRAF mutation(16), MET amplification/ex14 skip(16) and PIK3A mutation(22) have been screened in 287 Non-SQ-NSCLC patients and 67(23%) have been accrued to more than 12 clinical trials. In LURET trials against RET fusion gene + patients, 19 patients have been accrued and 17 are eligible. The response rate of vandetanib was 53%and PFS was 4.7 months. In 0012-01 trial against ROS fusion gene + patients, 129 patients (74 from china, 26 from Japan, 15 from Taiwan and 12 from Korea)has been accrued. Response rate of crizotinib was 69%in 127 evaluable patients. J-AlEX trial was a phase III randomized controlled trial comparing alectinib(ALE) and crizotinib(CRI) in ALK-positive NSCLC. Response rates for ALE and CRI were 85.4% and 70.2% respectively. PFS was not reached and 10.2 months(P<0.0001), respectively. Other clinical trials are ongoing. Samples from SQ and SM are increasing and interesting mutations and amplifications have been detected in these materials. Accordingly this nationwide and population enrichment screening system enabled various rare driver mutations to be efficiently detected in lung cancer, contributing to the rapid accrual of matched patients in translational clinical trials.

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      PL05.05 - Chemotherapy (Now Available) (ID 6918)

      T. Le Chevalier

      • Abstract
      • Presentation
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      Abstract:
      Chemotherapy has long been the only available systemic treatment for Non-Small Cell lung Cancer. In the late 70’s, there were a multitude of triplets and quadruplets with response rates ranging from 20-35% in patients with stage IV disease. In 1980, cisplatin, a cytotoxic agent initially developed for germ-cell tumors, showed some activity, mostly when combined with a vinca-alkaloïd or with etoposide. At the time Vinorelbine was registered by the FDA in 1994, alone or in combination with cisplatin, only 3 drugs were approved for NSCLC, nitrogen mustard, methotrexate and doxorubicin! Metastatic Disease The individual data-based meta-analysis published in 1995 established the superiority of chemotherapy over supportive care in patients with advanced NSCLC. These results have been recently updated and confirmed in 2714 patients from 16 trials with an overall survival benefit of 9% at 1 year. Chemotherapy also improves quality of life and symptom control in patients with good performance status. It is classically recommended to use platin compounds (mostly cisplatin and carboplatin) in combination with third generation agents including vinorelbine, gemcitabine, taxanes (paclitaxel, docetaxel, nab-paclitaxel) or pemetrexed (in non-squamous NSCLC). Integrating palliative care at an early stage of the treatment also prolongs survival and improves quality of life. Second line chemotherapy with docetaxel or pemetrexed has also been demonstrated active even if the benefit on overall survival remains modest. The use of biological markers such as ERCC1, RRM1, beta-tubulin or thymidilate synthase has not yet proven efficacy on the choice of cytotoxic agents. Maintenance: Up to 2009, it was generally accepted that 4 to 6 cycles of induction chemotherapy followed by a rest till progression were the standard. The switch to a new drug as maintenance after 4 cycles of a platin-based doublet showed a benefit for PFS and OS. Maintenance is now considered a standard in the management of metastatic NSCLC. Chemo-radiotherapy for locally advanced disease: The benefit obtained with radiotherapy and chemotherapy given sequentially in locally advanced inoperable NSCLC is modest but significant and well established. Several randomized trials comparing radiotherapy-chemotherapy given sequentially or concomitantly have suggested a better outcome when both modalities were given early and simultaneously. A meta-analysis based on individual patient data from published and unpublished randomised trials which compared radiotherapy alone with the same radiotherapy combined with concomitant cisplatin- or carboplatin-based chemotherapy was recently performed. The analysis was based on 9 trials including 1764 patients. The hazard ratio of death among patients treated with radio-chemotherapy compared to radiotherapy alone was 0.89 (CI 95%: 0.81-0.98; P = 0.02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years. There was some evidence of heterogeneity among trials and sensitivity analyses did not lead to consistent results. The available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy in combination with radiotherapy. Adjuvant chemotherapy: In the meta-analysis published in 1995, a 13% reduction in the risk of death was observed, suggesting an absolute benefit of 5% at 5 years with adjuvant chemotherapy. These results constituted the rationale for a new generation of randomized studies with platinum-based regimens. The LACE meta-analysis, which was reported at ASCO 2006, pooled a total of 4584 patients accrued in the five largest cisplatin-based adjuvant trials launched after the results of the meta-analysis. It confirmed the benefit of adjuvant chemotherapy with a 5.3% improvement of survival at 5 years (p=0.0043). Disease-free survival was also improved (5.2% at 5 years, p<0.0001). There was a negative effect of adjuvant chemotherapy for stage IA. The risk reduction was 8% for stage IB, 17% for stages II and III. The effect of chemotherapy did not vary according to age, gender, PS, type of surgery and histology. In parallel, the adjuvant UFT meta-analysis also confirmed a significant advantage of the drug compared to control in 2003 Japanese patients (p<0.001). The individual-data-based meta-analysis was updated in 2007. It confirmed the significant effect of postoperative chemotherapy, with or without postoperative radiotherapy. Neoadjuvant chemotherapy : Several phase II trials have been carried out in the 80’s to evaluate the benefit of preoperative chemotherapy in operable NSCLC with encouraging results. In the mid 90’s, two randomized phase III trials had a significant impact on the medical community due to their impressive results. Both trials randomized 60 stage IIIA patients and were interrupted after positive interim results were observed. Only two published randomized phase III studies comparing front-line surgery to pre-operative chemotherapy followed by surgery accrued the number of patients that were initially planned: a French study that included 373 patients and the Medical Research Council LU22 trial that included 519 patients. None of the large randomized studies could demonstrate a significant advantage in favor of pre-operative chemotherapy. A recent individual patient data-based meta-analysis of pre-operative chemotherapy trials has included 2385 patients from 15 trials. A HR of 0.87 (CI 95%: 0.7_–0.96, p=0.007) was observed, equivalent to an absolute improvement in survival of 5% at five years, similar to the benefit observed with postoperative chemotherapy. Preoperative or postoperative chemotherapy? A comparison of preoperative versus postoperative chemotherapy has been did not show any difference. In fact, the key issue may be to determine which patients should be treated with adjuvant and/or neo-adjuvant therapy. The neo-adjuvant approach offers a unique opportunity to test new drugs and to compare the tumor characteristics prior to and following induction therapy. Developing molecular based therapeutic strategies will certainly be one of the major challenges over the next few years. Several randomized adjuvant studies have recently been initiated in Europe and in America, based on the molecular characteristics of patients tumor. In conclusion, chemotherapy remains the main systemic treatment for most patients with lung cancer and the only one able to increase the cure rate. Unfortunately, very few drugs have been developed in the last decade in spite of a clear unmet medical need. A better individual selection of drugs/drug combinations according to pharmacogenomic data might encourage the community to optimize the use of cytotoxic agents.

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      PL05.06 - Targeted Therapy (Now Available) (ID 6922)

      F. Shepherd

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      PL05.07 - A Wise Man’s Conclusion (Now Available) (ID 6919)

      L. Einhorn

      • Abstract
      • Presentation
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      Abstract:
      The past decade has seen more advances in diagnosis and management of lung cancer than were available in the previous 30 years. Fifty years ago, the association of cigarette smoking in lung cancer was firmly established by the Surgeon General's report in the United States. During the past decade, major efforts by IASLC and other organizations have greatly reduced the use of tobacco and, thus, we will be seeing a decrement in morbidity and mortality from lung cancer. However, in the United States last year, there were still 228,000 new cases and 160,000 deaths from lung cancer. It remains the number one cause of cancer death in both American men and women, and the same is true in most developed and developing countries. Over 28% of all cases of cancer death in the United States are due to lung cancer. IASLC has been a leader in updating the TNM classification for non-small cell lung cancer. This allows for uniformity of data results in surgical and adjuvant studies. Cisplatin-based adjuvant chemotherapy has been demonstrated to improve the surgical cure rate by 5-10%. In the future, we hope to be able to identify by molecular, rather than just clinical characteristics, those patients with resected lung cancer who are cured with surgery and do not need to be subjected to adjuvant chemotherapy, as has been similarly accomplished in breast cancer. Also, we hope to have better definition of tumors that are inherently platinum resistant and, therefore, would need alternative strategies to try to improve the surgical cure rate. For the last two decades of the 20th century, chemotherapy has been the backbone for treatment of stage IVB lung cancer. Most studies have been built around platinum combination chemotherapy. Earlier studies pre-platinum utilized inactive drugs such as cyclophosphamide and doxorubicin. In the 1980s, cisplatin and etoposide was a common platinum doublet, and in the 1990's, carboplatin + paclitaxel. A review of phase III trials in North America from 1973-1994 demonstrated very sobering results. Thirty-three trials in 8,434 patients were performed and 23 of these 33 included a platinum compound. Only 5 of the 33 trials demonstrated a statistically significant difference in survival with a median increase of 2 months (range 0.7 to 2.7 months). It thus became clear that we need to personalize therapy rather than giving all patients the same chemotherapy. Modest success was seen by adding Bevacizumab to carboplatin + paclitaxel. Major advances have been made during the past decade with the identification of specific mutations that can be therapeutically exploited. EGFR and ALK were the first to be identified and subsequently ROS-1. Molecular targeted agents demonstrated spectacular responses in the great majority of patients, compared to the usual 25% brief responses that were achieved previously with platinum-based combination chemotherapy. These driver mutations were predominantly in adenocarcinomas and non-smokers or never smokers. More recent mutations have included smokers and non-smokers such as BRAF V600E and MET Exon-14 skipping mutation which can be seen in smokers as well as non-smokers. During the past five years, immunotherapy has been an exciting new addition to the armamentarium for treatment of patients with metastatic lung cancer. Immune checkpoint inhibitors are still in the nascent phase and the optimal duration of therapy for stage IVB disease, combination with other immunotherapeutic agents, chemotherapy, or radiotherapy, as well as use of adjuvant therapy, will be awaited with eager anticipation. Exciting new technology such as CRISPR-cas9 to gene edit PD-1 holds great potential future promise to make these immune checkpoint inhibitors more effective in a larger percentage of patients with lung cancer, as well as those responses being more durable.

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      PL05.08 - Welcome to Yokohama for WCLC 2017 (Now Available) (ID 6920)

      H. Asamura

      • Abstract
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      Abstract not provided

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      PL05.09 - Farewell (Now Available) (ID 6921)

      R. Pirker

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      Abstract not provided

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    SC17 - Lung Cancer: A Global Cancer with Different Regional Challenges (ID 341)

    • Event: WCLC 2016
    • Type: Science Session
    • Track: Regional Aspects/Health Policy/Public Health
    • Presentations: 6
    • Now Available
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      SC17.01 - Lung Cancer in Russia: Challenges and Perspectives (Now Available) (ID 6666)

      V. Gorbunova

      • Abstract
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      • Slides

      Abstract:
      Background Cancer is set to become a major cause of morbidity and mortality in coming decade in every region of the world.Methods The mortality, morbidity and treatment variants in Russia were evaluated.Results The incidence of lung cancer morbidity in Russia in 2014 numbered 57 685, mortality – 49 730. Standardized index incidence rate demonstrates improvement of men since year 2009. It was 55,0 on 100 000 population in 2009; 49,15 in 2013 and 49,0 in 2014. It means a 10,9% decrease since 2009 to 2014. It takes stable first place in men. In women the same years showed different values: 7,0; 7,17; 7,3 at 2009, 2013 and 2014 years respectively, that means + 4,3%. It takes 10-12 places of all malignant diseases among women. Among men lung cancer is on the first place (26,6%) in mortality rates. A non-interventional, prospective cohort study included 838 patients, average age 58,7; male – 78,4%; female – 21,6%, smokers – 26,5%; ex-smokers – 24,1%, current smokers – 49,4%. Disease stages at diagnosis were: stage I-II – 36,8%; stage III – 37,8%; stage IV – 25,4%. It was squamous-cell carcinoma – 54,3%; adenocarcinoma – 31%; BAR – 6,4%; LCC – 2,9%, adenosquamous carcinoma – 2,3%, other – 3,1%. Proportion of EGFR positive tumors constitutes 10,1% (85/838) pts. Surgery was performed for 393 pts (46,9%). Radiotherapy was administered to 145 pts (17,8%). 370 pts (44,2%) underwent first-line CT and 96 (11,8%) – second-line. The treatment depends on the morphology type of the tumor. We consider four main types NSCLC (AdenoCa and SCC), LCLC and NETs. NETs group included typical and atypical carcinoids, LCNEC, SCLC. We participated in 53 different multicenter international trials in lung cancer, including 930 patients. Outside of these protocols we analyzed 567 pts with advanced NSCLC: 255 pts with squamous cell cancer (SCC) and 250 pts with non-SCC for 1st line chemotherapy (CT). ORR was 20-25% for platinum-duplets, 1-year survival – 27,5-37,5 month. The 1-year survival showed best results in absolute figures with paclitaxel and platinum compounds in SCC and gemcitabine and platinum compounds in non-SCC, but the value was not statistically significant neither for 1-year nor for median survival. For SCLC new combination with irinotecan and platinum compound showed ORR – 55,1% and stabilization of disease in 24,3% of pts.Conclusions Nowadays the treatment approaches to lung cancer in Russia depends from morphological type of tumors, IGC results and needs further investigations.

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      SC17.02 - Lung Cancer in China: Challenges and Perspectives (Now Available) (ID 6667)

      L. Zhang

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Lung cancer is still the leading cause of cancer death in China. The estimated new lung cancer cases and deaths were 733,300 and 610,200 in 2015, respectively. Non-small cell lung cancer (NSCLC) remains the predominant form of the disease in China, with majority of patients being diagnosed at advanced stages. Thus this presentation will focus on advanced stage NSCLC. Current treatment strategy The current treatment algorithm for wild-type non-squamous and squamous NSCLC were shown in Figure 1 and 2, respectively. Figure 1 Figure 1. Treatment algorithm for non-squamous NSCLC (wild-type) Figure 2 Figure 2. Treatment algorithm for advanced squamous NSCLC For patients with activating EGFR mutations, EGFR-TKIs therapy will be used as front-line therapy. Commercial available EGFR-TKIs in China include Gefitinib, Erlotinib and Icotinib. For patients harbouring an ALK rearrangement, crizotinib will also be considered as first-line treatment. When failed from EGFR-TKIs or ALK-Inhibitor therapy, patients will be treated according to clinical model of disease progression. For patients with asymptomatic progression, continuing EGFR-TKIs or ALK-Inhibitor is recommended. For patients with local progression, EGFR-TKIs or ALK-Inhibitor will also be continued with additional local therapy such as whole brain radiation. However, for patients with aggressive progression, EGFR-TKIs or ALK-Inhibitor will be substituted by chemotherapy. Unfortunately, it is difficult to overcome drug resistance according to molecular mechanism because novel agents such as Osimertinib and Alectinib haven’t been approved by Chinese FDA. Challenge and perspective 1. Genetic alterations assays Genetic alterations are frequent in Chinese NSCLC patients. According to PIONEER study (NCT01185314), which is a prospective molecular epidemiology study in newly diagnosed advanced lung adenocarcinoma, the EGFR active mutation rate is 50.2% in Chinese patient population. The incidence of EGFR mutations in patients who never smoked can be as high as 59.6%. ALK rearrangement is also common in this patient population. In a large cross-sectional study enrolled 1160 NSCLC patients, the incidence of ALK rearrangements is 8.1%. Noteworthy, 44% of patients younger than 30 years old harbor ALK rearrangements. However, genetic alterations test rate used to be low in China. According to a large national survey, the EGFR mutation test rate was only 9.6% in 2011. However, as the turnover time shortens, the testing fee decreases, and ctDNA testing becomes available, the EGFR/ALK assays have turned into routine practice in China. Moreover, NGS platforms detecting panels of mutations are commonly used in some leading centers now. 2. Novel agent availability There is severe delay in the approval for novel agents by Chinese FDA. For instance, Bevacizumab was approved by FDA for treatment of NSCLC in 2006, while it was approved by Chinese FDA 9 years later. To improve availability of novel agents, Chinese oncologists are active in participation in international multi-center clinical trials. In addition, more and more innovative drugs have been developed by domestic pharma industry and entered clinical trials (Table 1). Moreover, Chinese FDA makes new policies to encourage innovative drugs and accelerating new drug application.

      Agent ID Classification Indication Phase
      Avitinib Mutation selected EGFR-TKI EGFR T790M Mutation Phase I
      Apatinib VEGFR-TKI Nonsquamous NSCLC in 3L Phase III
      Famitinib VEGFR-TKI Nonsquamous NSCLC in 3L Phase III
      Theliatinib EGFR inhibitor EGFR amplification Phase I
      Volitinib c-MET inhibitor c-MET amplification Phase I
      SHR-1210 PD-1 antibody NSCLC in 2/3L Phase I
      Table 1. Innovative drugs from China in clinical trials 3. Lung cancer prevention The incidence rate of lung cancer remains high in China between 2000 and 2011. Factors that have contributed to this issue include tobacco smoking and air pollution. 50% adult Chinese men were current smokers in 2010. In addition, smoking rates in adolescents and young adults are still rising in China. To reduce tobacco use in China, the government enact a strict smoking control law in Beijing in June 2015. However, the air pollution is still a severe problem and needs to be improved urgently. 4. Economic burden There are several factors which have contributed to the heavy economic burden of lung cancer patients in China. First, the residents’ income is still low in China. In 2015, per capita disposable income (one year) was only $3300. Second, the cost of anti-cancer drugs is very high (Crizotinib/cycle $8500, Gefitinib/cycle $2200, Pemetrexed/cycle $3000, and Bevacizumab/cycle $4500). Moreover, only 20% of whole medical expense can be covered by insurance, and majority of targeted drugs can’t be covered.





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      SC17.03 - Lung Cancer in India: Challenges and Perspectives (Now Available) (ID 6668)

      D. Behera

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Lung cancer is the commonest type of cancer in males and the leading cause of cancer death in both sexes world-wide. It is also the commonest in men in India accounting for 11.3% of all new cancers and also is the most common cause of cancer death (13.7%). In contrast to a decline trend in men in developed countries with a plateau for females, in India, the incidence continues to rise for both males and females. Data from the population based cancer registries developed under the National Cancer Registry Program of the Indian Council for Medical Research(ICMR) indicates that there is wide geographical variability in the incidence of this disease in different parts of the country. The highest age adjusted incidence rates of 45 per 100000 population are seen in the North-East region of India and are similar to areas reporting the highest incidence rates in some parts of the US and Europe. In other areas of India, especially the Western region, the age adjusted incidence rates are as low as 2 per 100000 population. The demographic profile including age, gender, stage, histology and even the molecular epidemiology (prevalence of EGFR mutations and ALK rearrangements) varies considerably in different parts of India. However, the overall incidence is much lower than that compared to many western countries. The demographic profile of lung cancer seen in India needs special mention. In the past, a single-centre large series of 1009 patients presenting to our institute from 1977-86 had shown squamous histology to the commonest (34.3%) followed by adenocarcinoma (25.9%) and small cell lung cancer (SCLC; 20.3%). Subsequent analysis of 250 patients presenting to us three decades later (2007-09), we found that the histological pattern was largely unchanged with squamous still being the commonest (34.8%) followed by adenocarcinoma (26.0%) and SCLC (18.4%). The male-female ratio as well as the current/ex-smoker to never-smoker ratio was also similar between the two cohorts. A possible reason for the lack of change in demographic profile of lung cancer was thought to be related to the fact that ‘bidi’ and NOT cigarette is the most common form of tobacco smoking in India. The ratio of bidi to cigarette smoking in India ranges from 2.5:1 to 7.0:1 in different parts of India and unlike cigarette making, there has been no change in the process of bidi manufacturing which is primarily a cottage industry. The other important aspect related to its association of quantified tobacco smoke exposure. The smoking index (SI; number of combined bidis and cigarettes smoked per day multiplied by number of years smoked) has been developed for this purpose. Patients can be categorized as either never-smokers (SI=0), light to moderate smokers (SI=1-300) and heavy smokers (SI≥301). In a cohort of 520 non-small cell lung cancer (NSCLC) patients, we observed that age, gender, histological type and stage differed significantly between the three groups. Never-smokers had significantly more females (52%), were younger (mean age 54.5 years), lesser squamous histology (28%), more advanced stage (IIIB/IV; 92%), more metastatic disease (67.4%) and more extra-thoracic metastases (42%) while group of heavy smokers had more males (98%), were older (mean age 61.2 years), more squamous histology (58%), lesser advanced stage (81%), lesser metastatic disease (39%) and lesser extra-thoracic metastases (17%). We have identified another risk factor in women to be the exposure to Biomass fuel. Majority of patients (approximately 83% of NSCLC histology at our centre) present with advanced stage(IIIB/IV) at the time of diagnosis and are managed non-surgically. Misdiagnosis as tuberculosis and empirical treatment with anti-tubercular drugs prior to referral to higher centre is one of the important causes for delayed diagnosis of this disease in India. Developing and under-developing countries are often constrained with regards to availability of health care and other resources necessary for appropriate management of the health related requirements of their population and this holds true for lung cancer as well. Some of the challenges in resource constrained settings include: · Large population with high population density · Illiteracy and poor health awareness · Sub-optimal economic and infrastructure inputs for health care · Suboptimal ratios of doctor and nurses for population · Overburdened hospitals and health care facilities · Huge burden of TB that hinders differentiation by the primary physician with lung cancer Important issues in resource constrained settings include choosing the platinum agent as well as the non-platinum agent. Decision on dose intensity may also be influenced by similar factors (efficacy, tolerance, toxicity profile and packaging strengths of marketed drugs). A list of some of the important factors influencing decision are shown below.

      Characteristic Relative importance
      Disease related
      Age ++
      Gender +
      Histology +++
      Molecular profile of tumor ++
      Stage +
      Performance Status +++
      Unrelated to disease
      Co-morbid illnesses +
      Socio-economic background/financial constraints +++
      Medical reimbursement/insurance issues +++
      Wishes of patient/family members ++
      Frequency of hospital visits ++
      Dr. D. Behera Senior Professor & Head, Dept. of Pulmonary Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh - 160012 (INDIA) Email: dirlrsi@gmail.com Select References and suggested reading 1. Behera D, Balamugesh T. Lung cancer in India. Indian J Chest Dis Allied Sci 2004; 46 : 269-81 2. Behera D. Managing lung cancer in developing countries: difficulties and solutions. Indian J Chest Dis Allied Sci 2006; 48: 243-4 3. Jindal SK, Behera D. Clinical spectrum of primary lung cancer: review of Chandigarh experience of 10 years. Lung India 1990; 8: 94-98 4. Singh N, Aggarwal AN, Gupta D, Behera D, Jindal SK. Unchanging clinico-epidemiological profile of lung cancer in North India over three decades. Cancer Epidemiol 2010; 34: 101-4. 5. Behera D, Balamugesh T. Indoor air pollution as a risk factor for lung cancer in women. J Assoc Physicians India 2005; 53: 190-2. 6. Singh N, Aggarwal AN, Gupta D, Behera D, Jindal SK. Quantified smoking status and non-small cell lung cancer stage at presentation: analysis of a North Indian cohort and a systematic review of literature. J Thorac Dis 2012; 4: 474-84. 7. Singh N, Behera D. Lung cancer epidemiology and clinical profile in North India: Similarities and differences with other geographical regions of India. Indian J Cancer 2013; 50: 291 8. Singh N, Aggarwal AN, Behera D. Management of advanced lung cancer in resource constrained settings : a perspective from India. Expert Rev Anticancer Ther 2012: 12: 1479–95. 9. Maturu VN, Singh N, Bal A, Gupta N, Das A, Behera D. Relationship of epidermal growth factor receptor activating mutations with histologic subtyping according to International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society 2011 adenocarcinoma classification and their impact on overall survival. Lung India 2016; 33: 257-66. 10. Bal A, Singh N, Agarwal P, Das A, Behera D. ALK gene rearranged lung adenocarcinomas: molecular genetics and morphology in cohort of patients from North India. APMIS 2016 Aug 8; DOI: 10.1111/apm.12581 [Epub ahead of print]

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      SC17.04 - Lung Cancer in Latin America: Challenges and Perspectives (Now Available) (ID 6669)

      E. Richardet

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      SC17.05 - Lung Cancer in Africa: Challenges and Perspectives (Now Available) (ID 6670)

      R.M. Gaafar

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Lung cancer has been the most common cancer in the world for several decades. The number of new cases estimated in 2012 is 1.8 million cases (12.9% of the total), 58% of which occurred in the less developed regions. The disease remains as the most common cancer in men worldwide (1.2 million, 16.7% of the total) with the highest estimated rates in Nothern America (33.8%) and Northern Europe (23.7%), a relatively high rate in Eastern Asia (19.2) and the lowest rates in Western and middle Africa (1.1 and 0.8 respectively). In developing countries, lung cancer is the most common cancer among males and the third most common cancer among females. Lung cancer is the most common cause of death from cancer worldwide estimated to be responsible for nearly one in 5 (1.59 million deaths, 19.4% of the total) (1). Temporal analyses reveal that significant reductions in lung cancer mortality have been observed in developed countries due to increased awareness of the harmful effects of smoking , asbestos and other factors The role of early detection is also evident. (2). In contrast, lung cancer incidence and mortality rates have increased in some low and medium resourced countries (3). The regional differences are mainly due to increased tobacco smoking in the developing countries , smoking waterpipe, cannabis or even passive and secondary smoke and in the mean time there is lack of proper tobacco control. There are also occupational risk factors such as asbestos exposure, dust, fumes, nickel ,silica and insecticides and up till now there are areas that have not banned asbestos or succeeded to control occupational and environmental exposure and incidence of mesothelioma is increasing. (4) Many studies have shown that cases have genetic susceptibility to develop lung cancer specially in North Africa. Another important factor specially the Middle East North Africa is the increase in the elderly population that may be attributed to better infection control and improvement of general health care . As life expectancy continues to increase throughout the African continent, the burden of cancer is likely to increase. Given that an estimated 32,640 new lung cancer cases will be seen in Africa in 2015 ( 5) .We have to remember also that cancer diagnosis rate in Africa is relatively low and patients present usually in an advanced stage so underreporting may be another factor . Accordingly, it is essential to know the magnitude of lung cancer in different regions in Africa by having cancer registry for the countries . So, obstacles to the global fight against lung cancer include lack of registry in some parts of Africa, low public awareness of lung cancer and absence of screening for the high risk cases , overburdened treatment centers and insufficient financial support. The ways to combat all these obstacles start by setting strategies for prevention and earlier detection in the low income countries. Public health awareness of the risk factors that cause lung cancer and the importance of avoiding / stopping smoking and banning asbestos should be clear and this is the role of public health authorities, medical journals and public media. The war against tobacco companies should start and everyone should understand the danger of smoking. This is done also by cooperation of scientific organizations of governmental and non governmental organizations. Also, we should reduce air pollution and regulate the occupational exposure of the employees to avoid the appearance of lung cancer and mesothelioma. As for early detection , screening can help in high risk patients and many authorities and NGOs can help to catch the early cases. In the mean time there should be ways to access modern imaging techniques to detect the cancer and use the minimal requirements for diagnosis and care . Accordingly it is essential to set the treatment guidance protocols to facilitate the management of the patients and to educate and train the doctors that should acquire degree granting programs and get certificates in the oncological field. It is mandatory to to lower the cost of health care to encourage the patients to go for treatment and to get the proper care. There should be special dealing for the economic pressure and avoidance of financial toxicities for the patient. The last point that have to be ameliorated in Africa developing countries is research through International collaboration as studying genetic polymorphism and relation to smoking and changing patient concept about drugs received in clinical trials that use new drugs, proper investigations and lower the cost of treatment and may get better outcome. References 1- Globocan 2012 (IARC): Estimated cancer incidence, mortality and prevalence worldwide, section of cancer surveillance 2- Jemal A, Center MM, DeSantis C, Ward EM (2010) Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev 19: 1893-1907. 3- Sankaranarayanan R, Jayant K, Brenner H 2011: An overview of cancer survival in Africa, Asia, the Caribean and central America: the case for investment in cancer health services. IARC Sci Publ: 257-291. 4- Gaafar RM, Eldin NH (2005) Epidemic of mesothelioma in Egypt. Lung Cancer 49: S17-S20. 5- Tao Z, Shi A, Lu C, Song T, Zhang Z, etal. 2014: Breast cancer : Epidemiology and Etiology. Cell Biochem Biophysi

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      SC17.06 - Lung Cancer in Low and Middle Income Countries: A Comprehensive Cancer Control Approach (Now Available) (ID 7171)

      N. Enwerem-Bromson

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    JCES01 - Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session (ID 413)

    • Event: WCLC 2016
    • Type: Joint Chinese / English Session
    • Track:
    • Presentations: 1
    • Now Available
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      JCES01.07 - North American Perspective (Now Available) (ID 6817)

      P.A. Bunn, Jr.

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      OA23.07 - Analysis of Outcomes in US IRESSA Clinical Access Program (ICAP) Patients on Gefitinib for More Than 10 Years (Now Available) (ID 3731)

      P.A. Bunn, Jr.

      • Abstract
      • Presentation
      • Slides

      Background:
      In 2011, following gefitinib (IRESSA[®]) NDA voluntary withdrawal, US patients benefiting from gefitinib were eligible to continue gefitinib through the IRESSA Clinical Access Program (ICAP), an IRB-approved protocol. A subset of ICAP investigators subsequently collected additional retrospective data on their ICAP patients through another IRB-approved project (“chart-review subset”).

      Methods:
      For all enrolled ICAP patients, demographic and serious adverse event (SAE) reports were reviewed. All ICAP investigators were invited to participate in chart review; 47 accepted and collected data on patient/tumor characteristics and safety/tolerability of prolonged gefitinib therapy among their 79 ICAP patients.

      Results:
      Across 137 US sites, 191 patients enrolled in ICAP. As of September 2016, 75 (39%) remain on gefitinib; discontinuations were due to progression (36%), death (34%), AEs (13%), or other (17%). Sixty-four (34%) patients reported 162 SAEs; 5 (2.6%) patients had 12 SAEs considered to be gefitinib-related by investigators. The chart-review subset included 79 (41%) patients with median age of 69 years at ICAP enrollment, who were predominantly female (70%) and white (84%); 95% had a confirmed NSCLC diagnosis. Due to the evolving understanding of genetic mutations in NSCLC at the time of gefitinib initiation, the majority of patients (79%) never had EGFR sequencing performed. Although tissue is not available for EGFR status confirmation, we assume these patients are nearly exclusively EGFR mutation-positive. Median total length of gefitinib was 11.1 years (6.5-15.1; Table). Long-term gefitinib was well-tolerated; 5% discontinued due to a gefitinib-related AE. Ten-year survival rate from first-ever initiation of gefitinib was 86% and 15-year was 59%. Table. Gefitinib treatment patterns and tolerability among ICAP chart-review patients.

      Parameter n, % Observed Population (N=79)
      Total time on gefitinib, prior to and during ICAP
      Median duration, y, range 11.1 (6.5-15.1)
      Prior to ICAP
      Median duration, y, range 7.8 (5.4-10.9)
      Starting dose 250 mg/day 67 (84.8)
      No dose changes due to AEs 75 (94.9)
      During ICAP
      Median duration, y, range 3.5 (0.04-4.7)
      Dose: 250 mg/day 76 (96.2)
      Treatment-related AEs Grade 1-2 Grade ≥3 Grade unknown 13 (16.5) 1 (1.3) 2 (2.5)
      Dose reductions due to treatment-related AEs 1 (1.3)
      Discontinuations due to treatment-related AEs 4 (5.1)
      Discontinuations due to progressive disease 11 (28.9)


      Conclusion:
      The majority of this subset of patients who participated in ICAP based on long-term clinical benefit from gefitinib continue to do well with gefitinib, demonstrating good tolerance of therapy and survival for a median duration of more than 10 years.

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    P2.06 - Poster Session with Presenters Present (ID 467)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
    • Presentations: 2
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      P2.06-019 - A Phase II Study of Atezolizumab as Neoadjuvant and Adjuvant Therapy in Patients (pts) with Resectable Non-Small Cell Lung Cancer (NSCLC) (ID 4642)

      P.A. Bunn, Jr.

      • Abstract

      Background:
      There is no curative treatment for patients with NSCLC who develop metastatic disease after resection. Trials of neoadjuvant and adjuvant chemotherapy have demonstrated an absolute survival benefit of 5% for patients with stages IB, II, and IIIA disease. Clearly, developing new treatment strategies to improve survival following resection is critical to improving outcomes for this patient population. Immunotherapy with checkpoint inhibitors such as antibodies to PD-1 and PD-L1 has demonstrated superior survival compared to chemotherapy in randomized clinical trials. PD-L1 expression is being investigated as a predictive biomarker for these therapies, but its ability to predict response has varied in published trials. Atezolizumab is a humanized IgG1 monoclonal PD-L1 antibody that was recently evaluated in the POPLAR trial (NCT01903993), a phase II randomized trial of patients with NSCLC who progressed on platinum based chemotherapy. Atezolizumab therapy improved overall survival compared with docetaxel (12.6 months vs. 9.7 months, HR 0.73 [95% CI 0.53 – 0.99]) with a manageable safety profile. Improvement in survival correlated with PD-L1 immunohistochemistry expression of tumor and tumor-infiltrating immune cells.

      Methods:
      Trial design: This phase II, open-label, single-arm study is designed to evaluate the efficacy and safety of atezolizumab as a neoadjuvant therapy in patients with Stage IB, II, or IIIA NSCLC prior to curative-intent resection. Approximately 180 patients with NSCLC will be enrolled in this study at 15 academic medical centers in the United States. There are two parts to this study: the first/primary part will evaluate the ability of neoadjuvant atezolizumab to produce objective pathologic responses in patients with early stage NSCLC. Atezolizumab 1200 mg IV will be given every 3 weeks for two doses. Surgical resection of tumors following treatment will allow determination of pathologic response rates and potential predictive biomarkers. Part 2 is exploratory and will evaluate atezolizumab adjuvant therapy for up to 12 months in patients who demonstrate clinical benefit (evidence of pathologic response or absence of radiographic progression) in Part 1. After surgical resection, patients may receive SOC adjuvant chemotherapy (with or without radiation) before starting atezolizumab adjuvant therapy in Part 2. The primary objectives are safety and major pathologic response based on surgical resection. Secondary objectives include overall response rate based on PD-L1 status, mutational load, antigen burden, and RNA-sequencing. This trial presents a unique opportunity to evaluate exploratory biomarkers, including pre- and post-treatment biopsy assessment of evolution of immune related markers associated with response.

      Results:
      Section not applicable

      Conclusion:
      Section not applicable

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      P2.06-032 - Oral Pioglitazone for the Chemoprevention of Lung Cancer in Current and Former Smokers (ID 4395)

      P.A. Bunn, Jr.

      • Abstract

      Background:
      Clinical Trial with Data Analysis in Progress

      Methods:
      Subjects (n=90) were selected for the trial if they met one the following criteria: current or former smoker (> 10 pack years); biopsy proven endobronchial dysplasia; airflow obstruction (FEV1/FVC < 0.70); or at least mild sputum cytologic atypia. Fluorescent bronchoscopy was performed at trial entry with biopsy of 6 standard endobronchial sites and all other abnormally appearing areas. Subjects also had pulmonary function testings and quantitative high resolution CT scans at the start and completion of the trial. Subjects were then randomized to oral pioglitazone or placebo for 6 months, followed by a second fluorescent bronchoscopy with repeat biopsy of all the central airway areas sampled on the first bronchoscopy. The endobronchial biopsies were scored on a 1-8 scale based on WHO criteria. The primary endpoint for the study is change in maximum (worst) endobronchial histology.

      Results:
      Final data analysis is pending

      Conclusion:
      clinical trial with data analysis in progress

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      P3.02b-084 - Rational Combinations to Improve Outcome for EGFR-TKIs in NSCLCs with EGFR Mutations (Now Available) (ID 6002)

      P.A. Bunn, Jr.

      • Abstract
      • Slides

      Background:
      Background: EGFR-TKIs produce high response rates in tumors with EGFR activating mutations as first line therapy and after development of T790M resistance. But complete responses are rare and all patients progress. We conducted serial RNAseq analyses of EGFR mutant cell lines exposed to gefitinib and osimertib. We found a rapid induction of gene reprogramming indicative of WNT signaling and EMT signaling that developed within 72 hours of drug exposure and lasted through at least 57 days. Important genes involved included E-cadherin, vimentin, ZEB1&2, axin2, IL8 and others. We therefore elected to determine if inhibitors of Wnt or EMT reprograming would produce synergistic growth inhibition in EGFR mutant cell lines exposed to osimertib. Prior clinical studies indicated that the HDAC inhibitors can safely be combined with EGFR-TKIs.

      Methods:
      Methods: Growth inhibition in the HCC4006 line by osimertib (10-100nM) in combination with the WNT/Bcatenin inhibitors AZD1366, ICG01, E7449 (30-270nM), WntC59, IWP2-V2, LGK974 (90-810nM), and with the HDAC inhibitors etinostat (300-1000nM), panobinostat (10-50nM) and romidepsin (1-6nM) was assessed by 5 day MTT assays. Growth inhibition by osimertib (2.5-20nM) + etinostat (60-300nM) was also evaluated in the PC9, HCC827, H3255 and PC9T790M EGFR mutant lines. Analysis of the combined drug effects was by the median-drug effect method using the CalcuSyn program to determine the combination indices (CI). CI values of < 1 are indicative of drug synergy.

      Results:
      Results: The CI values from combining 30nM osimertib with the midrange concentration of the WNT pathway inhibitors and HDAC inhibitors in the HCC4006 line varied from 0.18 to 1.2 and most were ≤ 0.75. The tankyrase inhibitor AZD1366 produced the most synergistic effect with CI = 0.18. CI values of ≤ 0.5 were observed with WntC59 and ICG01. The HDAC inhibitors all produced CI values of ≤ 0.75 with the lowest value of 0.23 for etinostat. CI values of osimertib combined with panobinostat and romdidepsin were 0.51 and 0.73 respectively. CI values for 30 nM osimertib combined with etinostat in the other EGFR mutant cell lines were also synergistic ranging from 0.37 in PC9 to 0.96 in the H3255 line. Synergy was also observed with romidepsin and panobinostat in these lines.

      Conclusion:
      Conclusions: The combination of WNT pathway inhibitors or HDAC inhibitors with EGFR-TKIs produce synergistic growth inhibition and may prevent EMT and survival pathways in EGFR mutant lung cancers.

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    SC31 - Together Against Lung Cancer - A Strategy for Success in the 21st Century (ID 355)

    • Event: WCLC 2016
    • Type: Science Session
    • Track: Regional Aspects/Health Policy/Public Health
    • Presentations: 1
    • Now Available
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      SC31.01 - The Role of Scientific Organizations (Now Available) (ID 6731)

      P.A. Bunn, Jr.

      • Abstract
      • Presentation
      • Slides

      Abstract:
      WCLC Extended Abstract: The Role of Scientific Organizations Paul A. Bunn, Jr, MD, FASCO The goal of scientific organizations is to facilitate progress in a specific area through promotion of research, training and education. In some instances the scientific area may be a single discipline such as medical, surgical or radiation oncology, pathology, radiology and so on. In some instances the scientific area may be a single geographic region such as Europe, North America or Asia. Examples of such organizations would be the European Respiratory Society (ERS), the American College of Radiology, the College of American Pathology (CAP) and many, many others. In some instances the organization might focus its efforts on training and research grants and in other instances the organization might focus on education of the public and in public programs such as prevention. In some instances the organization may conduct research or may solely sponsor research to be done by others. Some scientific organization chose to develop guidelines for clinical care. All of these efforts are important and different organizations focus on different aspects of a problem. In this presentation I will focus my attention on The International Association for the Study of Lung Cancer (IASLC) since it is the sponsor of the World Conferences on Lung Cancer and since is programs are dedicated to reducing the world wide burden of thoracic cancers. Lung Cancer is the leading cause of cancer death worldwide and the most preventable. When the IASLC was organized in 1974 it was recognized not only that lung cancer was the leading cancer killer but also that it would take an international and multidisciplinary effort to make progress. The very international and multidisciplinary nature of the IASLC are what set it apart from other organizations. Many of the unique contributions of the IALSC rely on these differentiating aspects. For example, the IASLC has contributed all the cases and evaluation of the world wide lung cancer, mesothelioma and thymoma TNM staging classifications. The IASLC Pathology committee has formulated all of the changes to the pathologic classification of thoracic cancers. The IASLC has worked with other organizations such as the College of American pathology and Association of Molecular Pathology to develop guidelines on molecular characterization of lung cancer. To enhance worldwide collaboration and education the IASLC began the World Conferences on Lung Cancer and rotated these conferences to different regions around the world. Originally, these conferences were held every 3 years as progress was slow but as research and research advances have quickened, the WCLCs are ow held annually. In addition the IASLC sponsors regional meetings on a routine basis including the European Lung Cancer Conference (ELCC), the Latin America Lung Cancer Conference (LALCA), the Asia Pacific Lung cancer conference and the Chicago Multidisciplinary Lung Cancer conference. The IASLC also sponsors workshops on various timely topics such as a conference on Small cell lung cancer held in 2015. To support its educational and research missions the IASLC publishes a scientific journal entitled Journal of Thoracic Oncology which has continually increased its circulation and impact factor. More recently, the IALSC has reinstituted a weekly newsletter and has published monographs on time issues such as ALK and PD-L1 testing. The IASLC has sponsored research grants especially for junior faculty and fellows to support and nurture their research careers. The IASLC has also sponsored travel fellowship awards for junior investigators and for young faculty from developing countries. The IASLC had worked with advocacy groups from around the world to provide information and support to these groups and to individuals and families afflicted by lung cancer. These efforts have led to a sharing of efforts and to publications directed to patients and their families. The IASLC’s tobacco committee has worked tirelessly to combat the worldwide tobacco epidemic. References: Tan DS, Yom SS, Tsao MS, Pass HI, Kelly K, Peled N, Yung RC, Wistuba II, Yatabe Y, Unger M, Mack PC, Wynes MW, Mitsudomi T, Weder W, Yankelevitz D, Herbst RS, Gandara DR, Carbone DP, Bunn PA Jr, Mok TS, Hirsch FRThe International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation-Positive Non-Small Cell Lung Cancer: Status in 2016.. J Thorac Oncol. 2016 Jul;11(7):946-63. doi: 10.1016/j.jtho.2016.05.008. Epub 2016 May 23. Review Bunn PA Jr, Minna JD, Augustyn A, et al. Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes?J Thorac Oncol. 2016 Apr;11(4):453-74. doi: 10.1016/j.jtho.2016.01.012. Epub 2016 Jan 30. Review Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE, Nicholson AG, Groome P, Mitchell A, Bolejack V; International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee, Advisory Boards, and Participating Institutions. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer.J Thorac Oncol. 2016 Jan;11(1):39-51. doi: 10.1016/j.jtho.2015.09.009 Hirsch FR.International Association for the Study of Lung Cancer (IASLC): celebrating 40 years with scientific and educational achievements!J Thorac Oncol. 2014 Oct;9(10):1424-5. doi: 10.1097/JTO.0000000000000340. Bhora FY, Chen DJ, Detterbeck FC, Asamura H, Falkson C, Filosso PL, Giaccone G, Huang J, Kim J, Kondo K, Lucchi M, Marino M, Marom EM, Nicholson AG, Okumura M, Ruffini E, Van Schil P; Staging and Prognostic Factors Committee; Advisory Boards. The ITMIG/IASLC Thymic Epithelial Tumors Staging Project: A Proposed Lymph Node Map for Thymic Epithelial Tumors in the Forthcoming 8th Edition of the TNM Classification of Malignant Tumors. J Thorac Oncol. 2014 Sep;9(9 Suppl 2):S88-96. doi: 10.1097/JTO.0000000000000293. Tsao MS, Travis WD, Brambilla E, Nicholson AG, Noguchi M, Hirsch FR; IASLC Pathology Committee. Forty years of the international association for study of lung cancer pathology committee..J Thorac Oncol. 2014 Dec;9(12):1740-9. doi: 10.1097/JTO.0000000000000356. Leighl NB, Rekhtman N, Biermann WA, Huang J, Mino-Kenudson M, Ra malingam SS, West H, Whitlock S, Somerfield MR. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the study oflung cancer/association for molecular pathology guideline. J Clin Oncol. 2014 Nov 10;32(32):3673-9. doi: 10.1200/JCO.2014.57.3055. Epub 2014 Oct 13 Hung JJ, Yeh YC, Jeng WJ, Wu KJ, Huang BS, Wu YC, Chou TY, Hsu WH. Predictive value of the international association for the study of lung cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma in tumor recurrence and patient survival. J Clin Oncol. 2014 Aug 1;32(22):2357-64. doi: 10.1200/JCO.2013.50.1049. Epub 2014 May 5 Detterbeck FC, Asamura H, Crowley J, Falkson C, Giaccone G, Giroux D, Huang J, Kim J, Kondo K, Lucchi M, Marino M, Marom EM, Nicholson A, Okumura M, Ruffini E, van Schil P, Stratton K; Staging and Prognostic Factors Committee; Members of the Advisory Boards; Participating Institutions of the Thymic Domain The IASLC/ITMIG thymic malignancies staging project: development of a stage classification for thymic malignancies. J Thorac Oncol. 2013 Dec;8(12):1467-73. doi: 10.1097/JTO.000000000000001

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