Virtual Library

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The demonstration that therapies directed at the programmed death-1 (PD-1) receptor or its ligand (PD-L1) result in durable responses and improved survival in a number of solid tumours including non-small cell lung cancer has awakened interest in cancer immunotherapy. The activity of PD-1/PD-L1 therapy in NSCLC implies that endogenous T-cells can recognize antigens on tumour cells and eliminate those cancer cells. The success of checkpoint inhibitor therapy in the metastatic setting has led to a immunotherapy trials in early stage (adjuvant) and stage lll NSCLC. This session will provide perspective on the current state and challenges facing immunotherapy in these settings. Current perspectives: The concept of using immunotherapy to prevent recurrence of NSCLC after resection of early stage NSCLC is not new. More recently, two randomized phase lll trials of therapeutic cancer vaccine strategies have been completed in resected, early stage NSCLC (MAGRIT) or after chemoradiation in stage lll disease (START). The MAGRIT trial (1) assessed the efficacy of an active, specific cancer immunotherapy (ASCI) against the MAGE-A3 cancer testis antigen in completely resected stage IB-IIIA NSCLC. Tumors from more than 13,000 patients were screened for MAGE-A3 expression and 2312 patients whose tumours expressed MAGE A3 were randomized 2:1 to MAGE-A3 (ASCI) or placebo. The MAGRIT trial failed to meet its primary end-point of improvement in disease free survival with MAGE-A3 ASCI. The START trial(2) assessed a MUC1 vaccine in stage III NSCLC patients who had response or stable disease after standard chemoradiation. The chemoradiation could have been delivered concurrently or sequentially. The modified intention to treat population included 1239 patients. The primary end-point was not met (adj. HRO .88, 95% CI 0.75 -103, p=0.123). Further development of this agent has been abandoned. The failure of these two large global phase III studies raises doubt about vaccine strategies used in isolation in early stage NSCLC. There are a number of possible explanations for these negative results (3). One of the primary reasons is that cancer vaccines , when used alone, fail to address the many immunosuppressive factors operating in the tumour microenvironment (TME). Clinical trials evaluating anti PD-1/PD-L1 therapy in early stage or locally advanced NSCLC have not yet reported results. The PACIFIC trial (NCT 20125461) is a randomized phase III trial of MEDI4736 versus placebo following concurrent chemoradiation in patients with stage III NSCLC. The primary outcome measures are OS and PFS. This trial completed accrual in April 2016 and has randomized more than 700 patients. In addition to the important efficacy outcomes, a number of exploratory objectives will assess tissue and blood for potential biomarkers. The Canadian Cancer Clinical Trials Group is assessing MEDI 4736 versus placebo in completely resected stage IB-IIIA NSCLC (NCT 02273375). This trial will randomize 1100 patients with the primary outcome measure being DFS in PD-L1 positive patients. PD-L1 positive is defined as > % positive tumour cells. Immune Based Prognostic Markers: The TME consists of stromal cells including endothelial cells and fibroblasts and a number of immune cell types. Tumours may escape immune recognition in large part by modulating the recruitment and function of various immune cells into the TME (4). A comprehensive review of the prognostic value of different immune cells in NSCLC has been reported (5). Two recent studies have separately assessed tumour lymphocytic infiltration (TLI) (6) or stromal CD8+ T-cell density (7) as potential prognostic markers in early stage NSCLC. Using the large, relatively homogenous population of curative resected NSCLC patients from the LACE-Bio collaboration, Brambilla et al examine the prognostic and predictive value of TLI. Patients were separated into discovery and validation sets. An intense TLI (>50% stromal lymphocytes in tumour bulk) was strongly prognostic of favourable overall survival and disease free survival. Based on previous work, Donner et al selected stromal CD8+ tumour infiltrating lymphocyte as the most promising immuno-based prognostic marker. Using four separate cohorts of curatively resected stage I-III patients, they established training and validation sets. Tissue microarrays were scored for stromal CD8 TLI's; stromal CD8 TIL density was found to be an independent prognostic factor and retained significant prognostic impact within each stage. The value of PD-L1 as a biomarker in NSCLC has been investigated primarily in advanced disease and focused on prediction of response and/or survival. Studies investigating the value of PD-L1 as a prognostic marker in early stage NSCLC have many limitations. These studies are small, include heterogenous populations, assess PD-L1 using different antibodies and scoring systems and included PD-L1 on tumour cells only or tumour cells and TLI's. It is not surprising that these studies show conflicting results. Based on the available evidence, the prognostic value of PD-L1 expression in early stage NSCLC remains uncertain. The adjuvant trials of anti-PD1/PD-L1 therapy currently being conducted may clarify the value of PD-L1 as both prognostic and predictive biomarkers in this setting. Challenges One of the fundamental challenges to developing effective cancer immunotherapies is our limited understanding of the human immune system in steady state and its response to stress. Animal models do not necessarily translate to humans. The Human Vaccines Project (8) is a global initiative that has as one of its primary objectives the decoding of the human immune system and providing a map of the human “immunome”. This private-public partnership uses state-of-the-art machine learning and technologies to elucidate the principles of immunogenicity to accelerate the development of new immunotherapies against infectious diseases and cancer. A second challenge is how best to target micrometastases in the adjuvant and locally advanced setting. While the primary tumor and metastatic lesions have many mutations in common, metastatic tumors possess mutations that are distinct from the primary. Do adjuvant therapies need to target the metastatic cascade and if so, which steps are the most susceptible to intervention? (9) The complex of the TME would predict that focusing on TIL’s or PD-L1 is likely to result in only modest improvements in outcome. Blank et al (10) argue that it will take a combination of biomarkers, the “cancer immunogram” , to determine the best approach in individual patients. References: Lancet Oncol 2016. 17;(8): 22-35 Lancet Oncol 2014; 15 : 59-68 Ann Oncol 2015; 26: 2213-2220 Nat Rev Immunology, 2015; 15: 73-86 Clin Cancer Res 2011; 17(16): 5247-56 J Clin Oncol 2016; 34:1223-30 Clin Cancer Res 2015; 21(11): 2635-43 Science Translational Medicine 2016; 8(334): 334-339 Nature Reviews Cancer 2015; 16: 201-218 Science 2016; 352(6286):658-660

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The targeted therapy based on genotyping has become an important treatment approach for advanced non-small cell lung cancer (NSCLC), especially adenocarcinoma. It is reported that nearly fifty to sixty percent of Asian patients with lung adenocarcinoma could have survival benefit from the first generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) and Anaplastic Lymphoma kinase (ALK)-TKI. However, the targeted therapy has apparently reached a plateau due to the drug resistance. The spatial and temporal heterogeneity of tumors are regarded as the foundation of both primary and acquired resistance. Multiple studies show that the mechanism of acquired resistance to first generation EGFR-TKI is complicated, including T790M mutation, PI3KCA mutation, c-MET amplification, and histologic transformation from NSCLC to SCLC et al, some of which could co-exist in the same patient. Although the third generation EGFT-TKI targeted at T790M mutation has been proved with dramatic efficacy, most patients become resistant after 10 months of therapy, the mechanism of which is even more complicated. Recently, by conducting next generation sequencing (NGS) through peripheral blood samples of patients treated with AZD9291 and CO1686 in clinical trials, newly drug-resistant mutations such as C797S and C693I have been found and functionally verified. This has laid a solid foundation for developing the fourth generation medicine in future undoubtedly. In the meanwhile, the resistant mechanism to ALK-TKI is also very complex. Multiple drug-resistant mutations could not only occur in ALK kinase domain, but also in alternative signal pathways. Therefore, we should establish a real-time, dynamic and quantitative detecting system for multiple targetable genes to fulfill detecting and monitoring the drug resistance during treatment, and on the other hand, to explore novel drug-resistant mutations through NGS of peripheral blood samples in future. Checkpoint inhibitors have been studied and utilized in various cancers, which has changed the perennially stagnant situation of immunotherapy and opened a new chapter in the treatment of cancers. Studies have shown an objective response rate of approximately 20%-30% with a prolonged survival period of 3-6 months to a series of programed death (PD1)/ programed death-ligand 1(PD-L1) inhibitors immunotherapy in lung cancer patients, with adenocarcinomas, squamous cell carcinomas and small cell carcinomas. While the biggest challenge of immunotherapy currently is to establish a powerful predictive system for efficacy. The existing researches mostly focus on exploring whether the PD-L1 expression or tumor infiltrating lymphocytes (TIL) status could predict the efficacy of PD1/PD-L1 inhibitors. The results varied from different agents of PD1/PD-L1 inhibitors and results of different trails. For instance, PD-L1 expression was associated with response to Nivolumab in patients with lung adenocarcinoma, while this kind of relationship was not observed in squamous cell NSCLC. The inconsistency between different trails may be attributed to the heterogeneity of PD-L1 expression, the unstandardized sample collecting and storing, and issue in IHC evaluation system. So the future investigation should lay more emphasis on overcoming tumor heterogeneity, standardization and optimization of detection techniques and sample collections, based on which we are looking forward to more effective predictive biomarkers. Both tumor and host microenvironment should be equally important as the foundation of precision medicine for cancer. More and more studies show that mutation loads of somatic cells contribute to immunogenicity of tumors, so as to be associated with the efficacy of checkpoint inhibitors. One research showed that different types of mutations, such as EGFR mutation, ALK fusion gene and PI3KCA mutation, possess different levels of mutation loads. And another research indicated that lung adenocarcinoma with higher neoantigen-load responded better to checkpoint inhibitors than the lower ones. There has been a study to calculate mutation loads and neoantigens in adenocarcinoma or squamous carcinoma by whole Exome sequencing based on the Cancer Genome Atlas (TCGA). The future studies should pay close attention to exploring the dynamic change patterns of mutation loads and neoantigens prior and during the treatment strategies, including PD-1/PD-L1 inhibitors immunotherapy, targeted therapy and traditional chemotherapy, and also to investigate the relationship between regulatory immune factors in the microenvironment, to further establish the predictive system for immunotherapy integrating PD-L1、PD-L2, TIL mutation loads of somatic cells, and neoantigens which are in great expectations.

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Targeted therapies or immune checkpoint inhibitors may be the adequate treatment in some patients with advanced non-small cell lung cancer (NSCLC). So far, certain biomarkers are known which may predict tumor response to these drugs. Of major importance is the detection of activating epidermal growth factor receptor (EGFR) mutations. They occur more frequently in the asian compared to the caucasian population and are usually found within exon 18-20 of the EGFR gene. Most of them are either a deletion at exon 19 or the L858R point mutation at exon 21. Activating EGFR mutations are predominantly detected in female patients with adenocarcinoma histology and never (or low) smoking history. The efficacy of first (erlotinib, gefitinib) and second (afatinib) generation EGFR tyrosine kinase inhibitors (TKI) in patients with advanced NSCLC and an activating EGFR mutation was demonstrated in several clinical studies. However, at some time during treatment with a first- or second generation TKI usually resistance to these drugs occurs which is mediated by the EGFR T790M mutation in about 50%. Recent trials demonstrated that third generation EGFR TKIs like osimertinib and olmutinib may be effective in T790M mutation positive patients with an overall objective tumor response rate of about 60%. Another molecular aberration which is of importance for treatment decision in patients with advanced NSCLC is the rearrangement of the anaplastic lymphoma kinase (ALK) gene. It was demonstrated that patients with an ALK rearrangment do benefit from therapy with the ALK inhibitor crizotinib. Second generation ALK inbibitors (e.g. alectinib, brigatinib, ceritinib) can overcome resistance which may be mediated by secondary ALK mutations. Moreover, third generation ALK inhibitors (e.g. lorlatinib) were developed and are currently being tested. Similar to patients with an ALK rearrangement also patients with a ROS1 rearrangement may benefit from treatment with crizotinib. The relevance of other molecular characteristics like KRAS or BRAF mutations, c-met amplification and HER2 abnormalities as potential biomarkers for targeted therapies is currently under investigation. Programmed death 1 (PD-1) immune checkpoint inhibitor antibodies like nivolumab or pembrolizumab are used in the clinical routine, however, only about 20% of patients do benefit from this treatment. To use resources as effective as possible, a biomarker to predict tumor response to these type of drugs would be enormous helpful in order to save costs. So far, the impact of expression of the PD ligand 1 (PD-L1) regarding clinical benefit to PD1 and PD-L1 inhibitor therapy was, besides efficacy of these drugs in comparison to chemotherapy, investigated in several randomized clinical trials. While in the CheckMate 017 study the overall survival of squamous cell carcinoma patients treated with nivolumab was independent from PD-L1 expression on tumor cells, in the CheckMate 057 study there seems to be some association between the PD-L1 expression level and the overall survival of adenocarcinoma patients treated with nivolumab. In the KEYNOTE-010 trial especially patients (both squamous cell and adenocarcinoma histology) with high (≥ 50% score) PD-L1 expression on tumor cells did benefit from treatment with pembrolizumab. PD-L1 expression on tumor cells as well as on tumor infiltrating immune cells were investigated in patients treated with the PD-L1 inhibitor atezolizumab in the POPLAR study. The overall survival benefit from atezolizumab increased with increasing PD-L1 expression on tumor cells, tumor infiltrating immune cells or both. Overall, currently the impact of PD-L1 expression and the use of certain cut-off levels to predict response to PD-1 and PD-L1 inhibitors is still under discussion. Different findings may, at least partly, be explainded by the use of variables regarding tissue fixation and storage as well as by different antibodies for detection of PD-L1. Alternative biomarker approaches are currently being investigated. In particular, the mutational load as well as the number of predicted neoantigens may be of importance. An association between a higher nonsynonymous mutation burden in tumors and an improved objective reponse, durable clinical benefit as well as progression-free survival in patients treated with pembrolizumab was reported and, in addition, the efficacy was associated with the molecular smoking signature, higher neoantigen burden and DNA repair pathway mutations. Overall, additional studies are necessary to definitely define the impact of PD-L1 expression as biomarker for PD-1 and PD-L1 inhibitors as well as to investigate the value of alternative biomarkers. In conclusion, strong biomarkers are able to predict response to certain therapies. Thus, ineffective treatment strategies may be prevented and resources including costs may be saved. So far, a few biomarkers are known which are very well established in the clinical routine and are important for treatment decisions in NSCLC patients. Regarding immunotherapy, it seems that the expression of PD-L1 may has some impact to predict response to PD-1 and PD-L1 inhibitors, however, its role needs to be completely clarified. Several candidate biomarkers exist, however, their impact needs to be futher investigated.

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Tobacco Control Tobacco is the biggest preventable cause of cancer in the world. Estimates suggest that approximately one-third of all cancers are caused by tobacco use. Although 80%–90% of all lung cancers are attributable to tobacco, it also has a causative role in malignancies of the mouth, larynx, pharynx, nose and sinuses, oesophagus, stomach, liver, pancreas, kidney, bladder, cervix, and bowel as well as on one type of ovarian cancer and some types of leukaemia. Tobacco is a widely and legally available product which, through the drug nicotine, is highly addictive and is promoted by a powerful and highly profitable industry. It has several marketing advantages over other addictive drugs. Other addictive drugs are mostly illegal, their method of administration is often by injection, they are socially disruptive, and they have very low social acceptability. In contrast, tobacco use has been the norm in the past and still has social acceptability in certain societies. Thousands of harmful chemicals are present in tobacco and particularly in tobacco smoke, which has documented serious adverse health effects. There are 70 known carcinogens in cigarette smoke including nitrosamines, polycyclic aromatic hydrocarbons, benzene, cadmium, toluidine, and vinyl chloride Industry access to policymakers Tobacco control policies, and therefore the health of the public, suffer when policy-makers maintain connections with the Transnational Tobacco Companies (TTC), as this provides a direct avenue for policy influence. TTCs still meet with and hope to influence government officials responsible for tobacco control policy in many countries. This is in direct violation of those countries commitments under the FCTC which is a legally binding WHO treaty. Through these contacts, industry has been able to offer ‘help’ to national governments to negotiate e.g. a later excise harmonization deadline and influence the speed of increase to meet these requirements. Political links such as this contravene the FCTC Article 5.3, which seeks to protect policymaking from industry influence. What can we do to reduce death and disability from Tobacco use? The prevalence—at approximately 29% of the adult population—remains stubbornly high in Europe and is increasing among females in some European countries. This despite the fact that effective and cost effective interventions to control and eliminate tobacco use exist and are well known. The World Health Organization (WHO) has validated several strategies which are effective in curtailing the use of tobacco .These approaches include using increased price, through taxation, as a tool to reduce tobacco use. The use of smoke-free legislation to prevent exposure to second-hand smoke (SHS) in the workplace is also important in preventing cancer because SHS is also a known carcinogen. The banning of advertising, sponsorship, and promotion of tobacco is an effective and a widespread intervention to help reduce tobacco use and the use of strong antismoking advertising has also been shown to be effective. WHO recommends the monitoring of smoking and the provision of cessation programs to help smokers stop smoking. This treatment of tobacco dependence is particularly covered by Article 14 of the FCTC. In Art.14 of the FCTC governments are urged to ‘facilitate accessibility and affordability for treatment of tobacco dependence’ (World Health Organization, 2015). According to the 2014 FCTC implementation report, the implementation of services to support cessation of tobacco use in line with Article 14 can and should be significantly improved (World Health Organization, 2014). Yet there seems to date to be little progress. Price as a control intervention The relationship between a rise in price and a fall in tobacco consumption is clear; however, a number of important aspects of this relationship must be considered. Lower socioeconomic groups and younger people are most sensitive to price increase as a deterrent, whereas in higher socioeconomic groups, price is not necessarily a determining factor. The use of price as an instrument to reduce tobacco use is usually opposed by the tobacco industry and its allies. The industry and its representatives usually try to persuade finance ministers that a price increase will lead to a loss of revenue through an increase in smuggling, although the evidence from many studies is that a rise in tobacco price leads to an increase in revenue and a reduction in cigarette consumption. Taxation is an effective, highly cost-effective and very powerful tool available to governments if they want to prevent cancer and the many other diseases which are caused by tobacco. Smoke free policies Since Ireland introduced its comprehensive national smoke-free legislation in 2004, many European countries have followed Ireland’s lead, but not all of those have introduced laws as comprehensive as Ireland’s. Nevertheless, all 27 EU member state countries have initiated some form of smokefree strategy. To date, 14 EU member states have enacted laws which ban smoking in all indoor workplaces including bars, restaurants, and clubs; however, a number of countries with significant populations such as Germany and Poland have only limited smoke-free laws. It is encouraging that Russia, where smoking prevalence is very high (more than 50%), introduced its smoke-free measure on June 1, 2013, banning smoking in airports, train stations, stadiums, schools, playgrounds, hospitals, government institutions, beaches, and places of employment. Tougher smoking fines were signed into law by President Vladimir Putin on October 21, 201 The importance of smoke-free policies for cancer prevention is high. SHS is a definite cause of cancer and is defined as Class 1 carcinogen by the International Agency for Research on Cancer. The number of cancers caused by SHS can be calculated, but smoke-free policies have other cancer prevention benefits. They discourage young people from starting to smoke, encourage smokers to quit, and help former smokers stay off smoking and promote an attitude of denormalisation of smoking. Smoking has often been regarded as a normal social activity despite the fact that it is addictive, is a cause of great inequality, and contributes significantly to disease, disability, and death. Smoke-free policies can achieve their positive effect by educating about the health benefits, limiting opportunities to smoke, and promoting an attitude of denormalisation of smoking.

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