Virtual Library

Abstract:
Over the recent decade, we witnessed important progress in the treatment of patients with advanced NSCLC in three domains. First, cytotoxic chemotherapy, where histology-directed chemotherapy with cisplatin-pemetrexed, followed by pemetrexed maintenance therapy in appropriate candidates, has resulted in a median overall survival (OS) of 16.9 months in adenocarcinoma [1]. Second, the use of tyrosine kinase inhibitors (TKIs) in tumors driven by specific molecular pathways, such as EGFR, ALK and others, has largely improved progression-free survival (PFS) compared to the one with chemotherapy in randomized studies, and had led to OS times of several years in many of these patients [2]. Third, immunotherapy with immune checkpoint inhibitors (ICI) directed against the immunosuppressive molecules programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has been in clinical trials since 2009. At present, the anti-PD-1 antibodies nivolumab (a fully human IgG4 antibody) and pembrolizumab (an engineered humanized IgG4 antibody) have been approved for NSCLC by different regulatory agencies worldwide. EMA approved nivolumab for advanced NSCLC after prior chemotherapy, and pembrolizumab for advanced NSCLC in adults whose tumors express PD-L1 and who have received at least one prior chemotherapy regimen. At the time of writing of this contribution, there were no public randomized study data on the use of these agents in 1[st] line therapy, we will therefore concentrate on the relapse therapy setting. Despite the real progress made by ICI therapy, we must realize that at present only about 20% of the patients respond to single-agent ICI treatment, while 50% have early progression (Checkmate 017 [3]; Checkmate 057 [4]). Moreover, the cost of these drugs is considerable. Hence it is important to define optimal candidates in clinical practice. Elements in this decision are a) clinicopathological factors; b) possible predictive biomarkers; and c) the availability of other treatment choices. As for (a) clinicopathological factors, there is no evidence that age, gender or ethnicity determine activity of ICIs. Smoking history, on the other hand, is strongly associated with better response rate to ICI therapy. Although EGFR oncogene pathway activation has been linked to upregulation of PD-L1 in tumor cells, response rates to ICIs in these patients are generally reported to be lower. In e.g. Checkmate 057, the overall response rate was 19%. It was 22% in smokers vs. 9% in non-smokers, 18% in EGFR-wildtype vs. 11% in EGFR-mutant tumors. Further understanding and refinement of the use of ICIs in tumor with an oncogene driver is needed. (b) A multitude of potential predictive biomarkers of response to PD-1/PD-L1 pathway inhibitors have been reported. In particular, PD-L1 expression in tumor and/or immune cells, the presence of TILs (tumor-infiltrating lymphocytes, CD8+ T-cells in particular), and the overall mutational load in the tumor cells have been linked to activity of ICIs [5]. PD-L1 expression on tumor cells, determined by immunohistochemistry (IHC) staining is by far the one most close to clinical practice for selecting optimal candidates for immunotherapy. This biomarker is quite distinct and less powerful than e.g. EGFR mutation as predictor of efficacy of EGFR TKIs. EGFR mutation is limited to the tumor, it is located in a distinct pathway, and is a yes/no phenomenon. PD-L1 IHC, on the other hand, relates to the tumor and its micro-environment, is only one of the many checkpoints in a complex interaction, and is a gradual phenomenon. Nonetheless, as can be noted from the figure, in most datasets of phase III studies – except Checkmate 017 – PD-L1 IHC predicts efficacy of ICI therapy. We added the large phase I study Keynote 001 to the figure as a very illustrative example: Over the categories of PD-L1 expression, response rate increased from 8% in the lowest to 45% in the highest category [6]. In the Keynote 010 phase III study, the hazard ratio of OS versus chemotherapy was 0.76 in the low-, but 0.54 in the high-expression group [7]. In the Checkmate 057, the OS hazard ratio even was 1.00 in all patients with tumors having PD-L1 <10%. Thus, except for the Checkmate 017 dataset, PD-L1 IHC enriches the response rate and differential OS benefit vs. chemotherapy, and can be used to designate these expensive agents to the optimal candidates. (c) Docetaxel single-agent chemotherapy was the comparator in the phase III studies on relapse therapy. In the meanwhile, progress has been made in conventional relapse therapy as well. In the LUME-Lung 1 trial, the combination of docetaxel and the triple angiogenesis inhibitor nintedanib resulted in a significantly better OS than docetaxel alone – with a difference in median OS of 2.3 months – in patients with adenocarcinoma [8]. In the REVEL study, patients treated with docetaxel plus ramucirumab, a VEGF receptor 2 inhibiting monoclonal antibody, had significantly better OS than those treated with docetaxel alone across all NSCLC histologies [9]. In conclusion, the choice of ICI therapy for relapsing NSCLC needs to be considered in the available treatment options for these patients, and this can be based on clinicopathological factors, predictive biomarkers, and comparison of efficacy of various treatments in specific subgroups. While PD-L1 is not a biomarker with the strength such as e.g. EGFR mutation, it helps to optimize the response rate and differential OS benefit of ICI therapy vs. chemotherapy, and to and can be used to designate these expensive agents to the optimal candidates. Figure Figure 1 References 1. Paz-Ares LG, De Marinis F, Dediu M et al. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after first-line treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. J Clin Oncol 2013; 31: 2895-2902. 2. Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947-957. 3. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus docetaxel in advanced squamous cell non-small cell lung cancer. N Engl J Med 2015; 373: 123-135. 4. Borghaei H, Paz-Ares L, Horn L et al. Nivolumab versus docetaxel in advanced nonsquamous non-small cell lung cancer. N Engl J Med 2015; 373: 1627-1639. 5. Rizvi NA, Hellmann MD, Snyder A et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348: 124-128. 6. Garon EB, Rizvi NA, Hui R et al. Pembrolizumab for the treatment of non-small cell lung cancer. N Engl J Med 2015; 372: 2018-2028. 7. Herbst RS, Baas P, Kim DW et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 2016; 387: 1540-1550. 8. Reck M, Kaiser R, Mellemgaard A et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): A phase 3, double-blind, randomised controlled trial. Lancet Oncol 2014; 15: 143-155. 9. Garon EB, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384: 665-673.

Abstract not provided

Abstract:
Immunotherapy (IT) has become one of the most potent new treatments for all cancers, particularly non small lung cancer. However, it has a unique toxicity profile different than most therapies (chemotherapy; biologic; targeted therapy) than most oncologists are familiar with, specifically immune related adverse events; irAE. These toxicities may be acute but also can occur weeks and months after starting or even stopping therapy. Given the prolonged duration that patients may be exposed to these drugs, they become important to manage over a short and long period. Further, given the responses and the relative milder toxicity compared with traditional chemotherapy agents, the older patient population may be exposed to these agents at a somewhat higher frequency. The use of immunomodulatory drugs to counter irAE toxicity will be discussed as to how it affects efficacy of immunotherapy. This lecture will focus on: Timeframe and monitoring for immune related toxicity (with special attention paid towards pulmonary, gastrointestinal and endocrinopathies) using the appropriate immunosuppressive drugs Management of toxicities related to IT Decision making on re-exposure to drug after iRAE Patient education Toxicities associated with combination IT drugs that may be used in the future or on clinical trials

Abstract:
“How Can Immunotherapy be Implemented In a Cost-Effective Strategy?” Christoph Zielinski, Director, Clinical Division of Oncology and Chairman, Department of Medicine I, and Comprehensive Cancer Center, Medical University Vienna – General Hospital, Vienna, Austria, Central European Cooperative Oncology Group (CECOG) When talking about immunotherapy and its cost-effectiveness, the story of disharmony between the magnitude of clinical benefit and the cost-effectiveness of certain drugs clearly emerges. I will try to illustrate this by the following arguments and data: The total health care costs of cancer per person varies widely within EU countries not only concerning outpatient and primary care, but also inpatient care and particularly drug expenditures. Cancer drug-related health care costs, thus differ between less than € 10.- per person up to over € 50.- per person. This divergence has been described previously and put into context with cancer outcomes (1) as well as cancer-associated mortality (2). Therefore, the European Society for Medical Oncology decided to create a magnitude of clinical benefit scale (ESMO-MCBS) “in order to promote high quality, rational, responsible and affordable cancer care wanting to highlight treatments which bring substantial improvements to the duration of survival and/or the quality of life of cancer patients” (3). It was intended that the scale was used for accelerated reimbursement evaluation. Factors taken into account for the ESMO-MCBS were particularly overall survival and/or progression-free survival as assessed by hazard ratios, quality of life, toxicity of the compound in question and the prognosis of the individual condition. Costs were not analysed in view of their significant heterogeneity across Europe. While generating two different scales for the curative versus the non-curative setting, a couple of rules were followed regarding the performed analyses: the priority was a strong level of evidence from large phase III studies with a careful analysis of each control arm and the identification of endpoints. For the required HR, the lower limit of the 95% CI was used to take into account the variability of the estimate. Before being published, the scale and its outcomes were broadly tested and evaluated in and by various institutions. The first full-length field testing (FT-MCBS) of the ESMO-MCBS was published recently (4) in which the results of non-small cell lung cancer (NSCLC) corresponded well with the original ESMO-MCBS. Regarding the use of the immune checkpoint inhibitor Nivolumab, the FT-MCBS generated the highest grade (i.e. “5”) for squamous NSCLC according to data generated within the Checkmate 017-Trial whereas a grade “4” was given for non-squamous NSCLC, as assessed in the Checkmate 057-Trial. Thus, the immune checkpoint inhibitor Nivolumab has acquired the highest or almost highest degree in the magnitude of clinical benefit, as assessed by the FT-MCBS scale. Soon after market introduction, concerns about the financial toxic dose of immune checkpoint inhibitors emerged leading to the rejection of NICE of Nivolumab in the second-line-treatment of NSCLC, whereas – in contrast - the Scottish authorities decided to include Nivolumab into their reimbursement strategies. Very recent analyses on this very topic showed that Nivolumab was not cost effective versus Docetaxel in the second-line-treatment of NSCLC based upon data generated in Checkmate 057-Trial. However, cost effectiveness could be very well reached by including and stratifying patients according to PD-L1 testing and the use of Nivolumab in PD-L1 overexpressing tumors on one side or – in statistical models - by the reduction of drug costs on the other. Either of these strategies would improve the cost effectiveness of Nivolumab (5, 6) Scientifically, however, the doubt remains to linger whether PD-L1 would be an optimal biomarker resulting in appropriate decision making for the choice of compound optimally suitable for the treatment of NSCLC without unjustly excluding patients who might have benefitted due to other factors from treatment: Thus, it is well known that certain somatic mutations occur more frequently in very special tumors than in others (7). Along this line, the efficacy of Nivolumab correlated with higher non-synonymous mutation burden in the Checkmate 063-Trial population (8). Therefore, it seems correct to conclude that we still have a long way to go to fully understand biomarkers predictive for the outcome of an optimal treatment of NSCLC with immune checkpoint inhibitors. Accordingly, appropriate analyses necessary for biomarker identification might translate into cost effectiveness. Such analyses might result in a primarily increased diagnostic cost, but lead to an ameliorated patient selection and, thus, ameliorated cost effectiveness in the appropriate use of immune checkpoint inhibitor treatment in NSCLC. In the meantime, the scientific community remains fascinated by the insights and results which are generated by the use of these compounds in a variety of diseases including NSCLC. References 1. Jedrzejewski M. et al., The Oncologist 20: 28, 2015; 2. .Ades F. et al., Ann. Oncol. 24: 2897, 2013; 3. N.I. Cherny et al., Ann. Oncol. 26: 1547, 2015; 4. B. Kiesewetter et al., ESMO Open 1: e000066, 2016; 5. K. Matter-Walstra et al., J. Thoracic Oncol., 2016, ePub.: http://dx.doi.org/10.1016/j.jtho.2016.05.032; 6. P.N. Aguiar et al., J. Clin. Oncol. 34, abstr. 9033, 2016; 7. L.B. Alexandrov et al., Nature. 22: 415, 2013; 8. N.A. Rizvi et al., Science 2015, ePub.: pii:aaa1348

Abstract:
More than 100 million people in Latin America will be > 60 years of age by 2020. Age, smoke exposure and infectious causes of cancer (HPV, Hepatitis B, and H. pylori) will continue to drive the burden of cancer in the region. Cancer mortality rates in Latin America are approximately twice those of the United States (1). Until not so long ago, drug development and cancer clinical research were conducted almost exclusively in wealthy developed regions of the world. However, over the last 2 or 3 decades, clinical trials have been progressively incorporated in a challenging globalization process. As such, the conduct of trials in a global scale represents a major aspect to be taken into account when analyzing the future development of the area. The globalization of clinical trials, as well as multinational and multi-institutional research collaboration, represents a scenario that requires permanent and concentrated efforts by all involved if we are to achieve the fundamental objective of generating the appropriate answers to the health problems we face around the world (2). Up to the 1980s, North American and European cooperative groups mostly sponsored by the National Cancer Institute (NCI) conducted most of the pivotal practice changing trials. At that time, a progressive shift in the funding of research toward pharmaceutical companies was seen. In parallel, an increasing participation of research sites from countries outside North America and Western Europe was identifıed and has since transformed the development of new medications to what is now an increasingly globalized process (2). The number of registered clinical trials has increased in all geographic regions during this time period, with the average annual growth greatest in the Asian (30%) and Latin American/ Caribbean (12%) regions (3). Early trials seem to be conducted more frequently in North America (62%), whereas confırmatory trials are more frequent in Eastern Europe, Latin America, and Asia (4). Data from ClinicalTrials.gov shows that over 70% of the registered cancer phase I trials are conducted in the United States, whereas less than 1% are conducted in Latin America. In larger registered phase III studies, 40% are conducted in the United States, 43% in Western Europe, and 17% in Latin America (5). Involvement of investigators from developing countries in the planning phases of the trial is essential as they may provide valuable contribution while being exposed to an experience that will have long lasting effects in the future development of regional studies. Other than addressing a question that interests a pharmaceutical company, developing a reliable research infrastructure and local expertise allow researchers to expect the development of locally coordinated research addressing pertinent regional health questions benefıting the local community. As quality is a fundamental principle in the conduct of clinical research, we need to address monitoring, auditing, and inspections as a basic element in the process of globalization. In recent years, a number of independent research groups have been created in Latin America: The Chilean Cooperative Group for Oncological Research (Grupo Oncológico Cooperative Chileno de Investigación, or GOCCHI) is a nonprofit corporation registered in Chile since 1998. GOCCHI is conducting academic clinical trials in oncology based on the highest scientific, methodologic, and ethical standards (http://www.gocchi.org). The Peruvian Oncology Clinical Studies Group (Grupo de Estudios Clínicos Oncológicos Peruano, or GECOPERU) was founded in March 2005 as a nonprofit academic and research organization. It has a central operating office and partnerships with several international groups (CIBOMA, IBCSG, BIG, and others) (http://www.gecoperu.pe). Founded in 2007, the Argentine Group for Clinical Research in Oncology (Grupo Argentino de Investigación Clínica en Oncología, or GAICO [is composed of 15 cooperating groups and includes various health professionals from public and private institutions (www.gaico.org.ar). The Latin American Cooperative Oncology Group (LACOG) was founded in 2008 by medical oncologists from several Latin American countries that has developed a network of investigators in oncology for epidemiologic and clinical studies in cancer. LACOG has 47 members in 39 sites from 10 countries in the region. Currently, the group has several ongoing studies. The Brazilian Group of Thoracic Oncology (GBOT) is currently hosted at LACOG and is involved in some research initiatives (www.lacog.org.br) (www.gbot.med.br). CLICaP (Latin American Consortium for Lung Cancer Research) This consortium was created in 2010 to develop collaborative studies on the biology, diagnosis and treatment of lung cancer. CLICaP has published over 20 studies involving participants from Mexico, Costa Rica, Panama, Venezuela, Colombia, Ecuador, Peru, Chile, Argentina and Uruguay. Some of this work has established genomic differences between populations for mutations in EGFR, KRAS and ALK ROS1 following analysis of over 8500 samples (7). There are several challenges of research in South America including costs (6), regulatory issues and difficulty in recruitment but there also several advantages of performing trials in developing countries such as availability of patients, lower costs and faster accrual. As an added and very important characteristic, patients enrolled in developing countries are more frequently treatment-naive and have less, or many times, no competing trials as alternative (8) As more trials are conducted in resource-limited settings, good clinical practices and ethical assurances must be secured. Human participation in clinical research is essential to advance medicine and public health, and expanding clinical trials mandates constant oversight to ensure research quality and protection of study subjects. Some decades ago, the development of global clinical research could have been considered a dream; it is now a pressing need that should be considered unavoidable in the future (2). References: 1 Goss, P; Lee, BL; Badovinac-Crnjevic, T et al. Planning Cancer Control in Latin America and the Caribbean. Lancet Oncol 2013; 14: 391–436 2 Barrios, C; Werutsky, G and Martinez-Mesa, J. The Global Conduct of Cancer Clinical Trials: Challenges and Opportunities. ASCO Educational Book, e132- e139, 2015 3 Drain PK, Robine M, Holmes KK, et al. Trail watch: global migration of clinical trials. Nat Rev Drug Discov. 2014;13:166-167 
 4 Thiers FA, Sinskey AJ, Ernst R. Trends in the globalization of clinical trials. Nature Reviews Drug Discovery. 2008;7:13-14. 
 5 www.clinicaltrials.gov 6 Kaitin KI. The Landscape for pharmaceutical innovation: drivers of 
cost- effective clinical research. Pharm Outsourcing. 2010;2010: 
3605. 
 7 Rolfo C, Caglevic C, Bretel B et al. Cancer clinical research in Latin America: current situation and opportunities. Expert opinion from the first ESMO workshop on clinical trials, Lima, 2015. ESMO Open 2016;1 8 Smith WT. FDA requires foreign clinical studies be in accordance with 
good clinical practices to better protect human subjects. ABA Health 
eSource. 2008; 5:1-3. 


Abstract not provided

Abstract:
Lung cancer has the second highest absolute incidence globally as well as in developing countries and ranks fourth in developed countries. It is the most common cause of cancer death by absolute cases globally as well as in developing and developed regions. The economic burden of lung cancer care is highest relative to other cancers in the European Union. Research is at the core of achieving improved outcomes from cancer, be it in defining country-specific epidemiology of the disease, understanding the pathogenesis of disease, identifying new targets for therapeutic agents, or directing policy to achieve affordable and equitable outcomes. Cancer researchs are one of the most globally active domains of science, with more than $14 billion per annum. A critical part of the health research portfolio is the testing of interventions through randomized controlled trials. Trials can range from highly controlled explanatory trials through to pragmatic trials of new health technologies and models of service delivery. Recruitment problems also have practical and financial impacts, as they can delay completion of research or reduce its timely impact on patient health and wellbeing. Achieving appropriate levels of patient and professional participation has been a significant obstacle to evidence-based practice. Published data show that the minority of trials recruit successfully, either in terms of reaching their planned sample size, or delivering the planned sample in the expected recruitment window Despite all the diffuculties, clinical trials have become increasingly globalized due to the inclusion of more non-traditional locations, especially those in central and eastern Europe, Latin America, and Asia. The increased globalization of clinical research has arisen for several reasons, but primarily due to the need for faster and more economically efficient studies. Moves towards standardizing and harmonizing clinical research practices have facilitated the rise of globalized clinical research. However, the expansion of multinational clinical research peaked in 2009, which could reflect that the large-scale expansion of multinational clinical research effort has reached its global capacity. When the distribution of multinational clinical trials is examined after being stratified according to the condition or disease, lung cancer is not among the five most frequently studied conditions apart from Asia. The results of a bibliometric analysis of global research on lung cancer between 2004-2013 in the 24 leading countries in cancer research showed that despite a doubling of the volume of lung cancer research worldwide between 2004 and 2013, it still only accounts for a small proportion of the overall oncology research publication output (5.6%). In fact, the relative commitment (RC) to lung cancer research compared with that to total oncology research output has fallen in most countries during this period, including in the 23 countries with exception of the China. Turkey, Poland, Canada, Greece, and the United States, despite having the highest country-specific burden of lung cancer, have all seen a decrease in their RC to lung cancer research. Research from Norway, Austria, Switzerland, Belgium, and Sweden had the highest proportion of international contributors . By comparison, relative to their research output, the East Asian countries (Taiwan, India, the Republic of Korea, and Japan) and Turkey had the least amount of international collaboration. With regard to multinational studies, only 1.2% of articles had collaborators from five or more countries and 0.3% from 10 or more countries. The aim of co-operative groups in oncology is to perform multi-center clinical trials for cancer research. Research results are often conveyed to the worldwide medical community through scientific publications. In order to complete the trials within the period specified, it is obvious the need of the qualified and high-volume cancer centers. The barriers to participation of high-volume hospitals in the cooperative group trials should be determined and eliminated. Since the 1970s, centers for thoracic diseases that emerged from former tuberculosis hospitals, particularly in Europe, have focused on the diagnosis and treatment of patients with lung cancer. Traditionally, these centers were staffed by pulmonologists and thoracic surgeons, but now include an extended range of health care workers including the disciplines of radiation oncology, medical oncology, palliative care and rehabilitation medicine. These high-volume centers treat all aspects of problems affecting patients with lung cancer. In 2010, the hospitals with a median 400 new patients per year were in Albania, Belarus, Bulgaria, the Czech Republic, Poland, Romania and Slovenia. The hospitals with more than 1000 new patients with lung cancer per year were in Poland, Bulgaria, Croatia, Turkey. We have to foster the cooperative study groups in lung cancer to provide collaboration between study group and these hospitals. High-volume hospitals should be identified and hospital-based representatives should be determined. Supreme organisations as European Thoracic Oncology Platform providing collaboration among study groups and hospitals, should be able to invite the high-volume hospitals with site evaluation. These high-volume centers have to review whether adequately equipped and set up or not for participation in research projects and clinical trials. References 1- Gaga M. An Official American Thoracic Society/European Respiratory Society Statement: The role of the pulmonologist in the diagnosis and management of lung cancer. Am J Respir Crit Care Med 2013; 188(4): 503-7. 2- Blum T. G. The European initiative for quality management in lung cancer care. Eur Respir J. 2014; 43: 1254-77 3- Loddenkemper R, 100 years DGP-100 years of pneumology in Germany. Pneumologie 2010; 64:7-17. 4- Richter TA. Clinical research: A globalized network. PLoS ONE 2014; 9(12): 1-12 5- Aggarwal A. The state of lung cancer research: A global analysis. J Thorac Oncol 2016; 11(7): 1040-50

Abstract:
In order to keep up with the rapid development of world cancer treatment exploring, Chinese clinical oncology professionals, relevant enterprises and public institutions voluntarily constituted a non-profit professional academic group which is known as The Chinese Society of Clinical Oncology (CSCO) in April 1997. The CSCO organization not only pay attention to international collaboration such as establishing reciprocal memberships with American Society of Clinical Oncology (ASCO) , European Society for Medical Oncology (ESMO), Clinical Oncological Society of Australia (COSA) and participating rotation of presidency organization of Asia Clinical Oncology Society (ACOS), but also committed to Chinese Oncology development. The CSCO annual meeting delivered the latest advancements and research fruit from home and abroad which offered a great academic exchange platform for vast amount of Chinese oncologists. CSCO also organize experts to make tumor diagnosis and treatment standardized guideline. Up to date, CSCO has launched dozens of guidelines regarding many major cancers in china, including non-small cell lung cancer, colorectal cancer and hepatocellular carcinoma. The newly made guideline about non-small cell lung cancer has fully considered Chinese special situation, not only disease characteristics, but also social economic factors, which made a good example of better suiting Chinese oncologists and patients. Other than this, CSCO developed multi-center clinical researches which offered solid evidence for Chinese cancer patients and made contribution to world cancer diagnosis and treatment. Most of clinical researches were carried out by Study Group majored in different cancers, such as Chinese Thoracic Oncology Group (CTONG), Chinese Breast Cancer Study Group (CBCSG) and Chinese Gastrointestinal Oncology Group (CGOG). The CSCO also keeps an open mind and follows the trend of hot spot, such as building expert committee on cancer biomarkers and precise medicine, even making consensus on standard of driver gene mutation test, standard of operation procedure and so on. Of all the Study Groups in CSCO, CTONG is the most active and fruitful committee. CTONG is also the most active organization in lung cancer field in China. Through the great effort of four top experts majored in lung cancer (Yi-Long Wu, Li Zhang, Shun Lu and Cai-Cun Zhou), CTONG was successfully established in 2007. With the goal of designing and developing multi-center clinical trials in the field of chest tumor, especially for lung cancer, providing high level of evidence for clinical practice of thoracic tumor, promoting standardization, modernization and internationalization of clinical and research work in thoracic tumor area and finally improving the level of diagnosis and treatment of chest tumor in China, as well as international status, CTONG has actually made massive efforts and achieved great success. Up to date, CTONG has 31 members from 15 provinces and municipality cities and has successfully performed 47 clinical trials in China. Half of these clinical trials established China lung cancer treatment modalities. Take CTONG 0802 study (OPTIMAL) for example, the multicenter open-label randomized phase II study compared erlotinib with combination of gemcitabine and cisplatin in first-line treatment of patients with EGFR mutation-positive NSCLC[1], Median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy (13.1 [95% CI 10.58-16.53] vs 4.6 [4.21-5.42] months; hazard ratio 0.16, 95% CI 0.10-0.26; p<0.0001). Chemotherapy was associated with more grade 3 or 4 toxic effects than was erlotinib (including neutropenia in 30 [42%] of 72 patients and thrombocytopenia in 29 [40%] patients on chemotherapy vs no patients with either event on erlotinib), which suggested that erlotinib is important for first-line treatment of patients with advanced EGFR mutation-positive NSCLC. The results of CTONG0802 was orally presented on ESMO2010, WCLC 2011, discussed on ASCO 2011 and published on Lancet Oncology. CTONG 0901 study compared erlotinib with gefitinib in patients with EGFR mutation positive stage IIIb/IV NSCLC and found no PFS or OS difference between these two regimens which offered solid evidence for clinical choice[2]. CTONG also paid attention to first-line maintenance therapy, second-line treatment, Another well-known study of CTONG is FASTACT-II (CTONG0902) proved that erlotinib maintenance therapy after first-line gemcitabine combined with cisplatin improves overall survival of stage IIIB/IV NSCLC patients[3]. CTONG 0806 study suggested improvement in PFS and an improved OS trend with pemetrexed compared with gefitinib as second-line setting treatment of EGFR wild-type advanced non-squamous NSCLC[4]. There were also many studies focused on palliative treatment, brain metastasis and peri-operative treatments and achieved meaningful results in these fields. Additionally, CTONG has initiated the very first real-world study in China targeting 1st line treatment pattern of advanced non-squamous NSCLC patients, the study concern difference between scientific achievements and clinical practice in China and set a great beginning of caring for patients’ actual profits. The currently ongoing reform for new drug approval of CFDA provides great chances for the development of clinical trials in China and domestic drug innovation such as icotinib and apatinib. CTONG and other study groups also face more opportunities. CTONG, as the successful example of CSCO study groups, is expected to make more contributions to china lung cancer treatment. Hopefully, CSCO achievements will finally benefit more Chinese cancer patients and make more contribution to world cancer control. Reference: 1. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735-742. 2. Yang JJ, Zhou Q, Yan HH, et al. A Randomized Controlled Trial of Erlotinib versus Gefitinib in Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations (CTONG0901). J Thorac Oncol 2015;10(2), S321(ABSTRACT MINI 16.03) 3. Wu YL, Lee JS, Thongprasert S, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013 Jul;14(8):777-86. 4. Zhou Q, Cheng Y, Yang JJ, et al. Pemetrexed versus gefitinib as a second-line treatment in advanced nonsquamous nonsmall-cell lung cancer patients harboring wild-type EGFR (CTONG0806): a multicenter randomized trial. Ann Oncol. 2014 ;25(12):2385-2391.

Abstract not provided

Abstract not provided

Abstract:
Non small cell lung cancer(NSCLC) with sensitive epidermal growth factor receptor (EGFR) mutations invariably develop resistance to EGFR tyrosine kinase inhibitors (TKIs). 20%-30% of NSCLC patients haboring sensitive mutations have no good initial clinical response to EGFR-TKIs, which is defined as having intrinsic resistance to EGFR-TKIs; while the rest of patients with activating mutations who are initially responsive to EGFR-TKIs eventually develop acquired resistance after 10–12 months of consistent clinical beneft, followed by disease progression. The drug resistance is a really tough and urgent clinical problem. Part of resistant mechanisms have been reported, including BIM deletion polymorphism, combined with other bypass signal pathway activation, epithelial-mesenchymal transition (EMT) for primary resistance; T790M, cMET amplification, SCLC transformation for acquired resistance. However, partial resistant mechanisms still unknown. In contrast to acquired resistance to EGFR-TKIs, intrinsic resistance is more complicated. Next-generation sequencing (NGS) is a promising tool for analysis of tumor mutations. We aimed to investigate the intrinsic resistant mechanisms to EGFR-TKIs by NGS, further to optimize treatment strategies and improve clinical outcome in EGFR activating mutant patients having intrinsic resistance to EGFR-TKIs. At present, the study is underway, and the results will be presented at the 2016 WCLC.

Abstract:
Lung cancer is still the leading cause of cancer-related death in both men and women with 80% to 85% of cases being non-small-cell lung cancer (NSCLC).[1]Over the past years, the IASLC Staging and Prognostic Factors Committee has collected a new database of 94,708 cases of lung cancer as the backbone for the upcoming 8[th] edition of the TNM classification for lung cancer due to be published late 2016 [2,3]. The 8[th] edition will significantly impact lung cancer staging with CT and/or PET-CT due to the subclassification of T1 and T2 into a,b and c categories, the reclassification of tumors more than 5 cm but not more than 7 cm in greatest dimension as T3, the reclassification of tumors more than 7 cm in greatest dimension as T4, the grouping of the involvement of the main bronchus as a T2 descriptor, regardless of distance from the carina, but without invasion of the carina, the grouping of partial and total atelectasis or pneumonitis as a T2 descriptor, the reclassification of diaphragm invasion as T4 and the elimination of mediastinal pleura invasion as a T descriptor [2,3]. Moreover, the upcoming 8[th] edition will also lead to a novel classification of distant metastasis, in which single extrathoracic metastasis will be classified as M1b whereas multiple extrathoracic metastasis are classified as M1c. The changes made within the proposal of the 8[th] edition of the TNM will be discussed within the presentation using clinical examples. Beside the accurate staging of patients with lung cancer early detection using CT screening with novel low radiation dose CT technologies will also be discussed. Within this context, a special focus will be given on novel methods that may improve a more accurate characterization of detected lung nodules using deep machine learning and Radiomics. Radiomics refers to the comprehensive quantification of lung nodule and tumour phenotypes by applying a large number of quantitative image features that are standardized collected with specific software algorithms. Radiomics features have the capability to further enhance imaging data regarding prognostic tumour signatures, detection of tumour heterogeneity as well as the detection of underlying gene expression patterns which is of special interest in patients with metastatic disease. The third part of the presentation will focus on novel techniques in lung cancer imaging. The past fifteen years have brought significant breakthroughs in the understanding of the molecular biology of lung cancer. Signalling pathways and genetic driver mutations that are vital for tumour growth have been identified and can be effectively targeted by novel pharmacologic agents, resulting in significantly improved survival of patients with lung cancer[4]. Parallel to the progress in lung cancer treatment, imaging techniques aiming at improving diagnosis, staging, response evaluation, and detection of tumour recurrence have also considerably advanced in recent years[5]. However, standard morphologic computed tomography (CT) and magnetic resonance imaging (MRI) as well as fluor-18-fluorodeoxyglucose ([18]F-FDG) positron emission tomography CT (PET-CT) are still the currently most frequently utilized imaging modalities in clinical practice and most clinical trials [6,7]. Novel state-of-the-art functional imaging techniques such as dual-energy CT (DECT), dynamic contrast enhanced CT (DCE-CT), diffusion weighted MRI (DW-MRI), perfusion MRI, and PET-CT with more specific tracers that visualize angiogenesis, tumour oxygenation or tumour cell proliferation have not yet been broadly implemented, neither in clinical practice nor in phase I–III clinical trials. In this context, Nishino et al.[4] published an article on personalized tumour response assessment in the era of molecular treatment in oncology. The authors showed that the concept of personalized medicine with regard to cancer treatment has been well applied in therapeutic decision-making and patient management in clinical oncology. With regard to imaging techniques, however, it was criticized that the developments in tumour response assessment that should parallel the advances in cancer treatment are not sufficient to produce state-of-the-art functional information that directly reflect treatment targets. Functional information on tumour response is highly required because there is growing evidence that the current objective criteria for treatment response assessment may not reliably indicate treatment failure and do not adequately capture disease biology. Molecular-targeted therapies and novel immunotherapies induce effects that differ from those induced by classic cytotoxic treatment including intratumorale haemorrhage, changes in vascularity, and tumour cavitation. Thus, conventional approaches for therapy response assessment such as RECIST or WHO criteria that exclusively focus on the change in tumour size are of decreasing value for drug response assessment in clinical trials[8,9]. In summary, the aim of of this presentation is to provide an overview on the changes made within the upcoming 8[th] of the TNM classification as well as to provide an overview on state-of-the-art imaging techniques for lung cancer screening, staging, response evaluation as well as surveillance in patients with lung cancer. The various techniques will be discussed regarding their pros and cons to further provide functional information that best reflects specific targeted therapies including anti-angiogenetic treatment, immunotherapies and stereotactic body radiation therapy. Literature: 1. Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg 2009;15:4-9. 2. Asamura H, Chansky K, Crowley J, et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the N Descriptors in the Forthcoming 8th Edition of the TNM Classification for Lung Cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2015;10:1675-84. 3. Rami-Porta R, Bolejack V, Crowley J, et al. The IASLC Lung Cancer Staging Project: Proposals for the Revisions of the T Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2015;10:990-1003. 4. Rengan R, Maity AM, Stevenson JP, Hahn SM. New strategies in non-small cell lung cancer: improving outcomes in chemoradiotherapy for locally advanced disease. Clin Cancer Res 2011;17:4192-9. 5. Miles K. Can imaging help improve the survival of cancer patients? Cancer Imaging 2011;11 Spec No A:S86-92. 6. Nishino M, Jackman DM, Hatabu H, Janne PA, Johnson BE, Van den Abbeele AD. Imaging of lung cancer in the era of molecular medicine. Acad Radiol 2011;18:424-36. 7. Nishino M, Jagannathan JP, Ramaiya NH, Van den Abbeele AD. Revised RECIST guideline version 1.1: What oncologists want to know and what radiologists need to know. AJR Am J Roentgenol 2010;195:281-9. 8. Oxnard GR, Morris MJ, Hodi FS, et al. When progressive disease does not mean treatment failure: reconsidering the criteria for progression. J Natl Cancer Inst 2012;104:1534-41. 9. Stacchiotti S, Collini P, Messina A, et al. High-grade soft-tissue sarcomas: tumor response assessment--pilot study to assess the correlation between radiologic and pathologic response by using RECIST and Choi criteria. Radiology 2009;251:447-56.

Abstract:
The treatment of lung adenocarcinomas has improved with the identification of driver gene mutations and the development of drugs tackling the altered driver gene proteins [1]. The interrogation of EGFR mutations as well as ALK and ROS1 translocations is nowadays part of the routine diagnostic workup of lung adenocarcinomas. Further therapies aiming at mutations in driver genes like RET, HER2, BRAF and MET are emerging. The main techniques currently employed in molecular pathology laboratories for mutation detection are mutation specific PCR, conventional capillary (Sanger) sequencing and next generation sequencing (NGS) [2]. The basic principles of these methods, advantages and disadvantages with a special emphasis on NGS and its potency for cancer diagnostics will be discussed. Recently the detection of driver gene mutations in DNA that is derived from cancer cells and released into the blood has become feasible (so-called „liquid biopsy“) [3]. It has already entered routine diagnostics with the detection of the T790M mutation in circulating tumor DNA of primary EGFR mutated lung cancers, that developed resistance to first or second generation tyrosine kinase inhibitors [4]. The verification of a T790M mutation either by liquid biopsy or the analysis of tumor tissue is a prerequisite for therapy of lung adenocarcinomas with third generation tyrosine kinase inhibitors like osimertinib. The principles of liquid biopsy, employed techniques and potential applications will be introduced. The recent advent of cancer immunotherapy that interferes with immune checkpoint molecules like programmed death 1 (PD-1) offers a new treatment for subgroups of lung cancer patients. A biomarker that would predict responsiveness to this expensive therapy is greatly needed. The expression of the PD-1 ligand (PD-L1) by tumor or immune/stromal cells is a potential biomarker, however its utility is heavily debated [5]. The confusion on PD-L1 as a biomarker is partly caused by technical difficulties in the determination of expression, such as the antibody used for immunohistochemistry and the determination of a treshold of expression that correlates with response [6]. A further biomarker that is determined by immunohistochemistry is the expression of EGFR in lung squamous cell carcinoma. A therapy with the recently approved anti-EGFR antibody necitumumab requires the demonstration of EGFR expression by the cancer cells [7]. The methods and pitfalls in PD-1 and EGFR immunohistochemistry will be presented. The requirement for biomarkers increases. This poses a challenge for diagnostics in respect to availabiltity of techniques, infrastructure and budget. Particularly in lung cancer often very little tissue is available, but different assays should be run. To fulfill the increasing demand for a plethora of biomarker analysis multiplexing techniques that simultaneously interrogate a large number of gene mutations, gene fusions, gene amplification and deletions, as well as RNA and protein expression will be needed. An outlook on available and emerging multiplexing techniques will be provided. References 1. The Cancer Genome Atlas Research N (2014) Comprehensive molecular profiling of lung adenocarcinoma. Nature 511 (7511):543-550. doi:10.1038/nature13385 2. Buermans HP, den Dunnen JT (2014) Next generation sequencing technology: Advances and applications. Biochimica et biophysica acta 1842 (10):1932-1941. doi:10.1016/j.bbadis.2014.06.015 3. Diaz LA, Jr., Bardelli A (2014) Liquid biopsies: genotyping circulating tumor DNA. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 32 (6):579-586. doi:10.1200/JCO.2012.45.2011 4. Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, Lai Z, Markovets A, Vivancos A, Kuang Y, Ercan D, Matthews SE, Cantarini M, Barrett JC, Janne PA, Oxnard GR (2015) Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med 21 (6):560-562. doi:10.1038/nm.3854 http://www.nature.com/nm/journal/v21/n6/abs/nm.3854.html - supplementary-information 5. Sunshine J, Taube JM (2015) PD-1/PD-L1 inhibitors. Current opinion in pharmacology 23:32-38. doi:10.1016/j.coph.2015.05.011 6. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn M-J, Felip E, Lee J-S, Hellmann MD, Hamid O, Goldman JW, Soria J-C, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L (2015) Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer. New England Journal of Medicine 372 (21):2018-2028. doi:doi:10.1056/NEJMoa1501824 7. Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK, Balint B, Losonczy G, Kazarnowicz A, Park K, Schumann C, Reck M, Depenbrock H, Nanda S, Kruljac-Letunic A, Kurek R, Paz-Ares L, Socinski MA (2015) Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. The Lancet Oncology 16 (7):763-774. doi:10.1016/s1470-2045(15)00021-2

Abstract:
Early adaptive resistance in EGFR mutant NSCLC Rafael Rosell Small molecule inhibitors are the current treatment for non-small-cell lung cancer (NSCLC), especially for tumours harbouring an active mutation of epidermal growth factor receptor (EGFR). Approximately 90% of EGFR mutations are exon 19 deletions or exon 21 single-point L858R substitutions and are associated with sensitivity to EGFR tyrosine kinase inhibitors (EGFR TKIs), like gefitinib or erlotinib. However, less than 5% of EGFR-mutant NSCLC patients achieve a complete response to EGFR TKI and the overall median progression-free survival is no longer than 9-11 months. Accumulated studies report several mechanisms of early adaptive resistance that can occur as early as two hours after starting EGFR TKI therapy. The activation of signal transducer and activator of transcription 3 (STAT3) signalling is among these mechanisms of resistance. Furthermore, EGFR blockage enriches lung cancer stem cells through Notch3-dependent signalling pathway. We have previously demonstrated that NF-κB contributes to gefitinib resistance in EGFR-mutant NSCLC. The efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is jeopardized by the activation of signalling pathways. We examined the relevance of co-targeting EGFR, signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signalling. We conducted clinical and preclinical studies of key components of signalling pathways limiting EGFR TKI efficacy in EGFR-mutant NSCLC. High levels of STAT3 or YAP1 mRNA expression were associated with worse outcome to EGFR TKI in two independent cohorts of EGFR-mutant NSCLC patients. In the initial cohort of 64 patients, median progression-free survival was shorter among the patients with high STAT3 than among those with low STAT3 (hazard ratio [HR] for disease progression, 3·02; 95% confidence interval [CI], 1·54-5·93; P=0·0013). Median progression-free survival was shorter among the patients with high YAP1 than among those with low YAP1 (HR for disease progression, 2·57; 95%CI, 1·30-5·09; P=0·0067). The results were similar in the validation cohort of 55 patients. We demonstrated that gefitinib augments STAT3 signalling in EGFR-mutant NSCLC cells. Gefitinib with TPCA-1 (STAT3 inhibitor) blocked STAT3, but not the YAP1 phosphorylation on tyrosine residue 357 by Src family kinases (SFKs) that occurs downstream of IL-6. The triple combination of gefitinib, TPCA-1 and AZD0530 (SFK inhibitor) ablated both STAT3 and YAP1 phosphorylation and markedly and safely suppressed tumour growth. Added value of our research: We found that EGFR TKI therapy activates STAT3 and that EGFR blockage enriches lung cancer stem cells with up-regulation of the YAP1 and Notch downstream effectors connective tissue growth factor (CTGF) and hairy-enhancer of split-1 (HES1), respectively. We sought to demonstrate that EGFR TKI treatment cannot abrogate STAT3 and Src-YAP1-Notch activation in EGFR-mutant NSCLC cell lines, leading us to examine whether the combination of gefitinib with compounds targeting STAT3 and Src, supresses the mechanisms of resistance. Nine days after gefitinib treatment, STAT3 mRNA level was significantly increased, as well as the fraction of ALDH positive cells. TPCA-1, a compound that targets STAT3, increases sensitivity to gefitinib in PC-9 and H1975 cells; however, neither gefitinib nor TPCA-1 inhibits Src or YAP1. The addition of the Src inhibitor, saracatinib, to the doublet of gefitinib and TPCA-1, was highly synergistic and abrogated STAT3, and Src-YAP1-Notch signalling. Implications: Treatment with single EGFR TKI can no longer be considered adequate for patients with EGFR mutant NSCLC. Our findings ultimately suggest that a clinical trial evaluating the co-targeted inhibition of STAT3 and Src is warranted. As a result, STAT3 and YAP1 mRNA levels could become important predictive biomarkers. References: We searched PubMed for English language reports published up to December, 2015 using the terms “non-small-cell lung cancer”, “STAT3”, “interleukin-6”, “NF-κB”, “aldehyde-dehydrogenase (ALDH)”, “integrin-linked kinase (ILK)”, “glycoprotein 130 (gp130)”, “Src-homology 2 domain-containing phosphatase 2 (SHP2)”, “the complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing protein-1 (CDCP1)”, “AXL”, “ephrin type-A receptor-2 (EphA2)”, “Src family kinases (SFK)”, “YES-associated protein 1 (YAP1)”, “Notch”, “cell migration, invasion and metastases” and “STAT3 inhibitors”.

Abstract:
Immune checkpoint inhibitors in cancer immunotherapy. Programmed death receptor-1 (PD-1) is a type 1 membrane protein of the immunoglobulin superfamily that has an important role in restrincting immune-mediated tissue danage secondary to inflammation and/or infection (1). The clinical advantage of antibodies that target either PD-1 or PD-L1 to block this ligand-receptor interface, allowing cancer killing by T cells became clear when CTLA4, an antagonist against the T-cell, such as ipilimumab, and afterward PD-1, showed an increase survival in patients with metastatic melanoma (2). Clinical investigations in lung cancer have demonstrated the benefit of PD-1 inhibitors pembrolizumab in advanced non–small cell lung cancer (NSCLC) and nivolumab in advanced squamous and nonsquamous NSCLC; both approved as second-line therapies by the US Food and Drug Administration (FDA) (3-5). Others PD-L1 inhibitors such as atezolizumab and durvalumab have demonstrated effectiveness in several tumor types (6-7) but they were not approved for clinical use until now. PD-1 inhibitors induce around of 20% of complete response frequency in patients with NSCLC, and persistent response in a subgroup of patients treated by immune checkpoint inhibitors. Garon et al (3) showed that tumors with PD-L1 expression ≥ 50% by immunohistochemistry (IHC) were significantly more expected to respond to pembrolizumab than those with less than 50% malignant cell expression. In contrast, response rates to nivolumab are significantly greater in patients with nonsquamous NSCLC, showing ≥ 1% tumor cell positivity (5). These differences are related to the combination of antibody clone and detection system as a companion diagnostic for selecting lung cancer patients for pembrolizumab therapy. Previous investigations reported response taxes in PD-L1–positive tumors of 31% to 52%, but particularly more than 16% of PD-L1–negative tumors also showed treatment response (1). This finding indicates that PD-L1 expression improves for responders but the absence of expression is not a complete indicator of advantage. PD-L1 expression did not predict differential response to nivolumab in lung squamous cell carcinoma as compared with docetaxel (4).Immunohistochemical Assessment of Immune Checkpoint Inhibitors. PD-L1 in NSCLC is expressed on the membrane of tumor cells, and/or on immune infiltrating cells dendritic cells, antigen-presenting cells and T lymphocyte. PD-1, the PDL1 receptor, is expressed on tumor infiltrating lymphocytes, mainly CD4 T cells, T and B regulatory, NK, monocytes and DC. Concerning PD-L1 binding, PD-1 inhibits kinases involved in T cell activation. Two potential mechanisms are involved in expression of immune checkpoints on tumor cells and their immune stromal component: oncogenic signaling, and response to inflammatory signals (8). Tumor cells express multiple ligands and receptors and antitumor immune response can be enhanced by multi-level blockade of immune checkpoints. PD-1/PD-L1 commitment leads to HSP-2 phosphatase activity which dephosphorylates Pi3K and thus downregulate AKT (8). The positive score on tumor cells has not been evaluated nor enhanced or standardized (3; 8). Brambilla and Ming (8) assessed a score of positivity for prognosis analysis using E1L3N Cell Signaling antibody commercially available. They found that 20% of lung tumors cell expressed PD-L1 (≥ 20% intensity 2+3+), and 29% the immune stromal cells (T, macrophages, DC ) ≥ 10% intensity 2+3+. PD-L1 positivity in both tumor and immune cells were seen in only 9% of NSCLC, 20,7% were both negative. There was no prognostic relevance of PD-L1 (tumor cells or stroma) whatever cut off by 10% increment or linear scoring was used. Only immune PD-L1 expression was correlated with a highly intense immune infiltrations. Previous published evaluations of prognostic value were discordant likely because immune checkpoints modulators play both positive and negative roles in the immune inhibitory pathways with some redundancy, and patients series and assays were not comparable. The two meta-analyses with different antibodies, cutoffs, patient series, ethnicities and contribution of oncogene driven cancers, initial resection sample or contemporary biopsy rendered their interpretation extremely problematic. Global result was supporting a poor prognosis of “PD-L1 positivity” on tumor cells.PD-L1 as a Predictive Biomarker for Checkpoint Inhibitors. Most of phase I trials works with four antibodies targeting PD-1 or its primary ligand PD-L1, response taxes appear higher in patients with increased tumor PD-L1 membrane expression by IHC. However, different antibody assays, absence of standardization, different score to determine PD-L1 positivity, companion test type, and a short number of specimens available for testing, accopled to the variability of the intervals between biopsy and test, has certainly disadvantaged the conclusion and prevent consensus to be reached (10). The best threshold was provided by Garon et al, with ≥ 50% of tumor cells PD-L1 positive to allow the highest response rate of 45% to pembrolizumab (3). In most trial series, biopsies or resected specimen were used and considerable difference between these samples occurs due to tumor heterogeneity. The reliability of small biopsy samples is questioned (10). Indeed lung tumor heterogeneity is characteristic and PD-L1 is typically heterogeneous in its distribution in the tumor majority as is PD-L1 positive immune cells. Multiple questions are still addressed before PD-L1 is considered as a definitive molecular predictor of effectiveness. As for prognostic evaluations, thresholds of ≥ 1%, ≥ 5%, ≥ 10%, ≥ 50% or continuous H score have been used. In addition, in a few trials, PD-L1 expression in TILs was predictive more than PD-L1 on tumor cells but the best cut off was not revealed.Conclusion. PDL1 expression predicts response to immune checkpoint inhibitors. Concordant results showing a better response if PDL1 + in several trials, using drug specific test and for Nivolumab also histology specific. We should evaluate membranous staining in tumor sample with at least 100 tumors cells and immune cells. Perspective for upgrading includes: 1) heterogeneity of the expression of PDL1 within tumor, primitive vs metastases number and size of samples; 2) surgical tissue versus biopsy and 3) archival versus new biopsy and 4) standardize the assays. Published abstracts showed high rates of concordance between primary and metastases (81%). Obtaining multiple biopsies from different areas of the tumor would enhance the validity of the results of IHC evaluation (160 patients=48% discordance).References 1. Sholl LM, Aisner DL, Allen TC, Beasley MB, Borczuk AC, Cagle PT, Capelozzi V, Dacic S, Hariri L, Kerr KM, Lantuejoul S, Mino-Kenudson M, Raparia K, Rekhtman N, Roy-Chowdhuri S, Thunnissen E, Tsao MS, Yatabe. Programmed Death Ligand-1 Immunohistochemistry--A New Challenge for Pathologists: A Perspective From Members of the Pulmonary Pathology Society. Arch Pathol Lab Med. 2016;140(4):341-4. 2.Couzin-Frankel J. Breakthrough of the year 2013: cancer immunotherapy. Science 2013;342:1432–1433. 3.Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non–small-cell lung cancer. N Engl J Med 2015;372:2018–2028. 4.Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123–135. 5.Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373: 1627–1639. 6. Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014; 515:563–567. 7.Stewart R, Morrow M, Hammond SA, et al. Identification and characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. Cancer Immunol Res 2015;3:1052–1062. 8. Brambilla E, Le Teuff G, Marguet S, Lantuejoul S, Dunant A, Graziano S, Pirker R, Douillard JY, Le Chevalier T, Filipits M, Rosell R, Kratzke R, Popper H, Soria JC, Shepherd FA, Seymour L, Tsao MS. Prognostic Effect of Tumor Lymphocytic Infiltration in Resectable Non-Small-Cell Lung Cancer. J Clin Oncol. 2016;34:1223-30. 9. Soria JC, Marabelle A, Brahmer JR, Gettinger S. Immune checkpoint modulation for non-small cell lung cancer. Clin Cancer Res. 2015;21: 2256-62. 10. Kitazono S, Fujiwara Y, Tsuta K, Utsumi H, Kanda S, Horinouchi H, Nokihara H, Yamamoto N, Sasada S, Watanabe S, Asamura H, Tamura T, Ohe Y. Reliability of Small Biopsy Samples Compared With Resected Specimens for the Determination of Programmed Death-Ligand 1 Expression in Non--Small-Cell Lung Cancer. Clin Lung Cancer 2015;16:385-90.

Abstract not provided

Abstract not provided

Abstract:
Figure 1Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) are the standard therapy for patients with Non-Small-Cell Lung Cancer (NSCLC) harboring activating EGFR mutations. During the last 10 years several trials demonstrated that first and second generation EGFR-TKIs such as erlotinib, gefitinib or afatinib are superior to standard platinum-based chemotherapy in terms of efficacy and tolerability and quality of life. Development of EGFR-TKIs led to a dramatic change in mentality of physicians treating NSCLC. For many years NSCLC has been treated with chemotherapy and platinum-based doublets were offered to all patients irrespective of biological characteristics. Knowledge in the field of molecular biology were limited and even a small cytological sample was sufficient for defining the therapy. Tumor biopsy was recommended only at the time of initial diagnosis and changes in tumor biology as a consequence of therapy exposure were largely unknown. Discovery of EGFR mutations and the impressive activity observed with EGFR-TKIs in EGFR mutated patients led clinicians to understand the relevance of patient selection based on biomarker assessment and therefore the importance of tumor tissue analysis. Since EGFR-TKI approval, EGFR testing entered onto clinical practice and today several biomarkers are routinely tested in NSCLC patients for defining the best therapeutic strategy. In addition to EGFR, other biomarkers such as ALK or ROS1 rearrangements or PD-L1 expression are guiding physician for therapy choice and additional tests are expected to reach the clinic in the next future. As a consequence, tumor biopsy and tissue collection become relevant in clinical practice and also in trial design, since modern studies often claim for tumor tissue. In addition, identification of mechanisms responsible for acquired resistance led to repeat tumor biopsies. Unfortunately, in NSCLC, the amount of tissue obtained at the time of primary diagnosis is often not abundant and tumor re-biopsy if feasible in the minority of patients. Such limitations are leading to development of the so-called “liquid biopsy”, allowing physicians to obtain biomarker information in circulating tumor DNA. In addition, new technologies are implementing the possibility to test for multiple biological events using a single experiment, with a significant reduction in amount of tissue needed, reducing time and costs. Development of EGFR inhibitors also led to a different approach for treating lung cancer. For the first time physicians faced with oligo-progressing diseases, consisting in disease slowly progressing under EGFR-TKI therapy. Often the disease remains asymptomatic and it is still partially sensitive to the therapy. The possibility to control disease outcome by continuing the targeted agent led to the concept of “treatment beyond progression”, an approach that is preserving patient quality of life with also a favorable impact on duration of life. Finally, anti EGFR therapies also highlighted the new opportunity for treating brain metastases. Brain metastases (BM) are a frequent complication of NSCLC, with 25–40% of patients developing BM during the course of the disease, often within the first 2 years after the primary tumor diagnosis. A review of 1,127 NSCLC patients found that those with EGFR mutations were more likely to develop BM than those without such mutations. The frequency of BM was thus 31.4% for the mutation-positive patients but only 19.7% for the negative ones. Improvements in neurologic symptoms and performance status have been reported with whole-brain radiation therapy (WBRT) in combination with steroid therapy in these patients. However, due to their poor performance status, many patients with BM are not eligible for surgery or radiosurgery. Furthermore, the role of systemic chemotherapy for the treatment of BM is controversial due to the impenetrable nature of the blood brain barrier (BBB), with reported response rates to chemotherapy ranging from 15–30% (overall survival [OS] 6–8 months). Response rates of brain metastases to EGFR tyrosine kinase inhibitor (TKI) treatment (e.g. gefitinib, erlotinib, afatinib) in patients with NSCLC harboring EGFR mutations reach 60–80%, with a complete response rate as high as 40%. Median OS is 15–20 months, and progression-free survival in the brain reaches 6.6–11.7 months, demonstrating improved clinical outcome (Table I). Nevertheless, first and second generation EGFR-TKI may have limited BBB penetration. New EGFR-TKIs including the third-generation EGFR-TKI osimertinib and AZD3759, an oral reversible inhibitor of EGFR activating mutations, recently showed impressive activity in presence of BM. The possibility to obtain a long lasting brain disease control together with the positive impact on duration of life is also impacting on the strategy of BM treatment, with preference for therapies not or modestly impacting on cognitive functions, such as stereotaxic radiotherapy, and a lower usage of WBRT. Reference: 1. Porta R, et al. Eur Respir J 37: 624-631, 2011. 2. BPark SJ, et al. Lung Cancer 77: 556-560, 2012. 3. Li Z. J Clin Oncol 29 (Suppl): abstract e18065, 2011. 4. Kim JE, et al. Lung Cancer 65: 351-354, 2009. 5. Welsh JW, et al. J Clin Oncol 31: 895-902, 2013. 6. Iuchi T, et al. Lung Cancer 82: 282-287, 2013. 7. Hoffknecht P, et al.. J Thorac Oncol 10: 156-163, 2015.

Abstract:
Performance status (PS) captures a patient’s ability to perform daily activities and provides a measure of impairment as a function of tumor burden. The Eastern Cooperative Oncology Group (ECOG) scale is the most frequently used and ranges from 0 (fully ambulatory without symptoms) to 5 (dead). Typically, patients with an ECOG PS of 0 and 1 are labeled as “good PS”, are typically treated with combination regimens, and are the focus of the majority of the clinical trials. Patients with “poor PS”, mostly ECOG 2, but also 3 and occasionally 4, have been largely excluded from clinical trials. Patients with a PS of 2 account for approximately 30-40% of patients diagnosed with advanced non-small cell lung cancer (NSCLC) in clinical practice (1). As a result of the lack of dedicated research, current guidelines are equivocal with respect to the optimal therapy for these patients and their management remains inconsistent, ranging from best supportive care to combination chemotherapy. Cooperative group studies in the 1980’s and 1990’s suggested that poor PS patients (ECOG ≥2) derived little or no benefit from systemic chemotherapy and had high rates of treatment-related morbidity and mortality (2). This perspective permeated clinical research and clinical practice for over 2 decades. While concerns about safety and benefit remain appropriate, the advent of better supportive care, along with more effective and tolerable carboplatin-based doublets have led to new trials in this subset of patients. Two large phase III randomized trials in PS 2 patients in the mid-2000’s provide insights into this heterogeneous cohort. In one trial, 400 patients were assigned to standard carboplatin plus paclitaxel or carboplatin plus another formulation of paclitaxel (3). In the other trial, 400 patients were assigned to single agent gemcitabine or vinorelbine (4). The identical eligibility criteria led to a separate publication comparing single agent vs. combination chemotherapy (5). The response rate (38 versus 16 percent) and the median time to progression (4.6 versus 3.5 months) were statistically superior with combination chemotherapy. Overall survival trended in the same direction, but the difference was not significant (8.0 versus 6.6 months). Toxicity, as expected, was higher with combination chemotherapy. The question of single agent vs combination chemotherapy was addressed in a definitive manner by a phase III randomized trial that compared pemetrexed alone or in combination with carboplatin in 205 eligible patients with PS 2 (6). Respectively, the response rates were 10% vs 24%; the median progression free survival was 2.8 vs. 5.8 months; and the median survival was 5.3 vs. 9.3 months, all statistically significant in favor of the combination regimen. Toxicity was manageable but 4 treatment-related deaths were observed in the combination arm. This trial has set a new standard for treatment of advanced NSCLC patients with a PS of 2. The advent of targeted agents led to the exploration of these agents as a “gentler approach” to PS 2 patients, irrespective of the presence or absence of the mutation. In a phase II randomized trial, patients were assigned to either erlotinib or a combination of carboplatin and paclitaxel (7). Patients treated with erlotinib had a significantly shorter median survival compared to chemotherapy (6.5 vs 9.7 months, HR 1.73, 95% CI 1.09-2.73). As shown in other trials, EGFR inhibitors should not be given to untreated patients without the mutation, regardless of the PS. Guidelines from the American Society of Clinical Oncology (ASCO) state that the data for patients with PS 2 are insufficient to make a strong recommendation for combination chemotherapy, and single agent therapy may be appropriate if the perception of risk outweighs the perception of benefits (8). The European Society of Medical Oncology (ESMO), after reviewing the same body of data, came up with a straightforward recommendation for carboplatin-based combinations to all eligible PS 2 patients (9). The National Comprehensive Cancer Network (NCCN) merged PS 2 patients into the PS 0-1 group for recommendations regarding first line therapy, with no obvious distinction between the subsets (10). This progressive approach recognizes the advances made in the management of PS 2 patients in the past decade and extends the benefits of systemic therapy to a large group of patients who were, until recently, offered inferior treatments. References: Lilenbaum RC, Cashy J, Hensing TA, et al. Prevalence of poor performance status in lung cancer patients: implications for research. J Thorac Oncol 2008; 3:125 Sweeney CJ, Zhu J, Sandler AB, et al. Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a Phase II trial in patients with metastatic nonsmall cell lung carcinoma . Cancer 2001; 92:2639 Langer CJ, O'Byrne KJ, Socinski MA, et al. Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. J Thorac Oncol 2008; 3:623 O'Brien ME, Socinski MA, Popovich AY, et al. Randomized phase III trial comparing single-agent paclitaxel Poliglumex (CT-2103, PPX) with single-agent gemcitabine or vinorelbine for the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. J Thorac Oncol 2008; 3:728 Lilenbaum R, Villaflor VM, Langer C, et al. Single-agent versus combination chemotherapy in patients with advanced non-small cell lung cancer and a performance status of 2: prognostic factors and treatment selection based on two large randomized clinical trials. J Thorac Oncol 2009; 4:869 Zukin M, Barrios CH, Pereira JR, et al. Randomized Phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small cell lung cancer and Eastern Coopertaive Group performance status of 2. J Clin Oncol 2013; 31:2849–2853 Lilenbaum R, Axerold R, Thomas S, et al. Randomized Phase II Trial of Erlotinib or Standard Chemotherapy in patients with Advanced Non-Small Cell Lung Cancer and a Performance Status of 2. J Clin Oncol 2008; 26:863-869 Masters GA, Temin S, Azzoli G, et al. Systemic therapy for stage IV non-small cell lung cancer: American society of clinical oncology clinical practice guideline update. J Clin Oncol 2015; 62:1342 Reck M, Popat S, Reinmuth N, et al. Metastatic non-small cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment, and follow-up. Ann Oncol 2014; 25 (suppl 3): iii27 National Comprehensive Cancer Network. Non-Small Cell Lung cancer (Version 4.2016). http://www.nccn.org/professionals/physician_gls/pdf/bone.pdf. Accessed September 15, 2016

Abstract not provided