Virtual Library

Abstract:
A commonly employed approach to understanding the pathogenesis of lung neoplasia is to use experimental animal models. The testing of potential chemopreventive (and chemotherapeutic) agents involves pre-clinical testing, and numerous animal models have been developed. In primary mouse lung tumor models, lung cancer develops through a predictable series of airway lesions that progress from normal epithelium to invasive cancer. Permanent genomic DNA alterations occur through either spontaneous, chemically, or environmentally-induced initiation events. The lung cancer chemoprevention field is increasingly reliant on animal studies as the results of negative, early, large scale human studies (for example, β-carotene) may have been predicted with extensive pre-clinical testing. Agents progressing to human trials now undergo extensive pre-clinical studies, and this review will focus on the commonly utilized models of adenocarcinoma (ADC) and squamous cell carcinoma(SCC). ADC: Multiple, well-characterized models of murine adenocarcinoma are available in which pulmonary adenomas progress to adenocarcinomas. These progression models also allow for the study of pre-malignant airway lesions. The most commonly studied models include initiator-promoter carcinogenesis(1), mutant KRAS(2) or EGFR(3) and the use of complete carcinogens. Urethane, a component of cigarette smoke, is a complete carcinogen because it leads to tumor development without the need for other carcinogens or promoters(4). 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) , another tobacco smoke carcinogen, is a chemically-induced model where the NNK is typically administered in drinking water or injected intraperitoneally. Tobacco smoke models also exist and they can reproducibly induce pulmonary adenocarcinomas, but they are fairly labor-intensive and do not result in robust tumor multiplicity(5). There are also multiple two-stage murine models of lung tumor promotion. Several of them use 3-methlycholanthrene (3-MCA), a polycyclic aromatic hydrocarbon, as the initiator at a low dose, followed by multiple doses of butylated hydroxytoluene (BHT). BHT is a well known antioxidant found in processed foods and packaging, however it is also an oxidant and well characterized promoter. In addition, genetically modified animal models, in which viral oncogenes or transforming ras mutants are selectively expressed in lung tissue, have been developed and extensively investigated. While there are differences between the human and murine respiratory tracts, the murine tumors derived from these models have many similarities to human adenocarcinoma, ranging from specific markers to gene expression patterns(6). SCC: Models of squamous cell lung cancer have also been developed, but they are much fewer in number. The most commonly utilized SCC model involves NTCU (N-nitroso-tris-chloroethylurea), which is applied topically and histopathological analysis of serial lung sections in this model revealed a range of lung pathology, including squamous-cell carcinoma, carcinoma in situ, and varying levels of bronchial dysplasia(7). Immunohistochemical studies on the premalignant lesions show staining that corresponds to analogous human lesions(8), and the NTCU model also induces dysplastic lesions that are similar to those found during bronchoscopy and can therefore be used to evaluate one proposed surrogate endpoint in pre-clinical studies (endobronchial dysplasia). Several positive murine chemoprevention studies examining ginseng, pomegranate fruit extract, and aerosolized budesonide +/- pioglitazone have also used NTCU (reviewed in (9)). Additional SCC models have been developed, the first consisting of a kinase dead IKKα knockin mouse (Ikkα[K44A/K44A], Ikkα[KA/KA]) that develop spontaneous SCC and marked pulmonary inflammation(10). A recently described model involved biallelic inactivation of LKB1 and PTEN in mouse lung leads to SCC that expresses the squamous markers keratin 5, p63, and SOX2(11). Chemopreventive interventions have been assessed in many of the murine preclinical models. This includes (but is not limited to): inhaled and systemic glucocorticoids; myoinositol; overexpression of prostacyclin synthase; dietary administration of the prostacyclin agonist iloprost; PPARγ overexpression; dietary administration of pioglitazone; COX inhibitors; the VEGF inhibitor vandetanib; and the anti-estrogen fulvestrant. The effect of COX inhibitors on lung cancer prevention has also been tested in murine models. It is likely the chemoprevention world will take a cue from lung cancer therapeutics by determining the altered pathways in specific premalignant lesions and employing targeted (or ‘precision’) chemoprevention in the next generation of trials. Reference List (1) Malkinson AM, Koski KM, Evans WA, Festing MF. Butylated hydroxytoluene exposure is necessary to induce lung tumors in BALB mice treated with 3-methylcholanthrene. Cancer Res 1997;57:2832-4. (2) Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 2001;410:1111-6. (3) Regales L, Balak MN, Gong Y, Politi K, Sawai A, Le C, et al. Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors. PLoS One 2007;2:e810. (4) Malkinson AM. Primary lung tumors in mice: an experimentally manipulable model of human adenocarcinoma. Cancer Res 1992;52:2670s-6s. (5) Witschi H. Tobacco smoke as a mouse lung carcinogen. Exp Lung Res 1998;24:385-94. (6) Stearman RS, Dwyer-Nield L, Zerbe L, Blaine SA, Chan Z, Bunn PA, Jr., et al. Analysis of orthologous gene expression between human pulmonary adenocarcinoma and a carcinogen-induced murine model. Am J Pathol 2005;167:1763-75. (7) Wang Y, Zhang Z, Yan Y, Lemon WJ, LaRegina M, Morrison C, et al. A chemically induced model for squamous cell carcinoma of the lung in mice: histopathology and strain susceptibility. Cancer Res 2004;64:1647-54. (8) Hudish TM, Opincariu LI, Mozer AB, Johnson MS, Cleaver TG, Malkoski SP, et al. N-nitroso-tris-chloroethylurea induces premalignant squamous dysplasia in mice. Cancer Prev Res (Phila) 2012;5:283-9. (9) Keith RL, Miller YE. Lung cancer chemoprevention: current status and future prospects. Nat Rev Clin Oncol 2013;10:334-43. (10) Xiao Z, Jiang Q, Willette-Brown J, Xi S, Zhu F, Burkett S, et al. The pivotal role of IKKalpha in the development of spontaneous lung squamous cell carcinomas. Cancer Cell 2013;23:527-40. (11) Xu C, Fillmore CM, Koyama S, Wu H, Zhao Y, Chen Z, et al. Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell 2014;25:590-604.

Abstract:
Although chemoprevention as a means of reducing cancer incidence has been successful for basal cell carcinoma of skin, breast, and prostate cancer, after three decades of research, none of the phase III trials with agents such as Beta-carotene, retinol, 13-cis-retinoic acid, alpha-tocopherol, N-acetylcysteine, acetylsalicylic acid, or selenium have demonstrated beneficial and reproducible results in preventing lung cancer, likely due to the complexity of genomic alterations in lung cancer (1). Intermediate endpoint biomarkers such as bronchial metaplasia or dysplasia have been used in Phase II trials (2). Studies on the natural history of pre-neoplastic lesions in the central airways showed that patients with high-grade dysplasia or carcinoma in-situ are more likely to develop invasive cancer at the same or another site in the lungs than those with low grade lesions. However, pre-invasive bronchial lesions may be more of a marker of lung cancer risk because more cancers developed from a separate site in the same individual than progression from an initially biopsied dysplastic site and a significant proportion of the cancers are found by CT rather than by bronchoscopy (3,4). The advantage of using bronchial metaplasia/dysplasia for phase II chemoprevention trials is that these lesions can be localized and biopsied using white light and autofluorescence bronchoscopy for histopathology confirmation. However, with a steady decline in the prevalence of centrally located squamous cell carcinomas and a shift to adenocarcinomas which are usually located in the peripheral lung beyond the range of sampling by standard flexible bronchoscopes, it has become increasingly difficult to enrol participants with bronchial dysplasia for clinical trial. With the implementation of low dose computed tomography for screening of lung cancer, alternative intermediate endpoint biomarkers, such as CT detected non-calcified lung nodules are being investigated for phase II lung cancer chemoprevention trials (5). The limitations of using CT-detected lung nodules as an intermediate endpoint are the lack of confirmation of the underlying pathology and variable growth behaviour of sub-solid nodules especially non-solid nodules (6,7). Without confirmation of the pathology (atypical adenomatous hyperplasia versus adenocarcinoma in-situ versus minimally invasive or invasive adenocarcinoma), when a nodule is first seen, volume doubling time measurement is meaningless to determine malignant behaviour. Endoscopic optical imaging tools such as combined auto-fluorescence-optical coherence tomography (8) are promising methods to localize and characterize small peripheral lung lesions for tissue or liquid biopsy for pathological diagnosis and molecular characterization (Example shown in Figure 1). The availability of accurate lung cancer risk prediction models such as the one developed by Tammemagi and co-workers (9 ) opens the possibility of using lung cancer as the endpoint for chemoprevention trials in high risk ever smokers instead of intermediate endpoint biomarkers to test chemopreventive agents that have sound biological basis. Prospective evaluation of a prototype PLCOm2012 lung cancer risk prediction model in the Pan-Canadian early Detection of Lung Cancer Study showed that a 3 years lung cancer risk of ≥2% can reliably identify a sufficient number of ever smokers who will develop lung cancer within 3 years to make it feasible to use lung cancer incidence as the endpoint for chemoprevention trials with a sample size of approximately 2500 participants. The sample size can be significantly reduced by using a nodule malignancy risk prediction model (10). There is great potential to partner with lung cancer screening programs for developing and testing biologically rationalized agents for chemoprevention clinical trials within this framework, which may lead to their eventual implementation in screening programs to improve patient outcomes. Figure 1. Autofluorescence –Optical Coherence Tomography images of a CT-detected lung nodule showing the invasive and lepidic components of the adenocarcinoma confirmed by transbronchial lung biopsy. Figure 1 Supported by the Terry Fox Research Institute, Canadian Partnership Against Cancer, the Canadian Institute of Health Research and Lung Cancer Canada. References 1. Szabo E, Mao JT, Lam S, Reid ME, & Keith RL (2013) Chemoprevention of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143(5 Suppl):e40S-60S. 2. Keith RL, Blatchford PJ, Kittelson J, Minna JD, Kelly K, Massion PP, et al. Oral iloprost improves endobronchial dysplasia in former smokers. Cancer Prev Res (Phila). 2011;4:793-802. 3. Ishizumi T, McWilliams A, MacAulay C, Gazdar A, Lam S. Natural history of bronchial preinvasive lesions. Cancer Metastasis Rev. 2010;29:5-14. 4. Jeremy George P, Banerjee AK, Read CA, O'Sullivan C, Falzon M, Pezzella F, et al. Surveillance for the detection of early lung cancer in patients with bronchial dysplasia. Thorax. 2007;62:43-50 5. Veronesi G, Szabo E, Decensi A, Guerrieri-Gonzaga A, et al. Randomized Phase II trial of inhaled budesonide versus placebo in high-risk individuals with CT screen-detected lung nodules. Cancer Prev Res 2011; 1:34-42. 6. Massion PP. Walker RC. Indeterminate pulmonary nodules: Risk for having or for developing lung cancer? Cancer Prev Res 2014;7:1173-1178. 7. Pinsky PF, Nath PH, Gierada DS, Sonavane S, Szabo E. Short- and long-term lung cancer risk associated with noncalcified nodules observed on low-dose CT. Cancer Prev Res (Phila). 2014;7:1179-85. 8. Pahlevaninezhad H, Lee AM, Shaipanich T, Raizada R, Cahill L, Hohert G, Yang VX, Lam S, MacAulay C, Lane P. A high-efficiency fiber-based imaging system for co-registered autofluorescence and optical coherence tomography. Biomed Opt Express. 2014 Aug 6;5(9):2978-87. doi: 10.1364/BOE.5.002978. eCollection 2014 Sep 1. 9. Tammemagi MC, et al. (2013) Selection criteria for lung-cancer screening. The New England journal of medicine 368(8):728-736. 10. Tammemagi MC, Lam S. Screening for lung cancer using low dose computed tomography. BMJ. 2014 May 27;348:g2253. doi: 10.1136/bmj.g2253. Review.

Abstract:
Prevention of lung cancer could lead to a significant reduction in the mortality associated with this disease. Identification of individuals at high risk for the development of invasive lung cancer is critical to establishing efficient and effective screening and prevention programs. The presence of premalignant lesions including atypical adenomatous hyperplasia/adenocarcinoma-in-situ (AAH/AIS) and bronchial dysplasia (BD), which represent precursors of adenocarcinoma and squamous cell carcinoma (SCC) respectively, provide targets that can be studied by histologic, radiographic and molecular techniques to define biologic characteristics that are indicative of risk and potential cellular activities that can be targeted for prevention. The histologic features of premalignant lesions have been well described in published WHO defined classification systems (1). Accurate histologic assessment of precursor lesions of lung adenocarcinoma prior to development of invasive cancer is limited by sampling considerations. To establish a diagnosis of premalignant AAH or AIS, the whole lesion must be examined and size criteria and histologic confirmation of lack of invasion must be documented. Because resection is generally restricted to cases of invasive cancer, tissue from AAH or AIS prior to development of invasive adenocarcinoma are rare, and most analyses of these lesions are performed on lesions that are associated with or occur as synchronous independent lesions of invasive cancer in resection specimens. However, a number of recent publications have begun to describe non-lesion associated biomarkers that can be correlated with radiographic features that appear to faithfully distinguish premalignant from invasive peripheral lung lesions. While AAH and AIS are considered to be precursors of adenocarcinomas derived from the terminal respiratory unit (TRU), a recently described premalignant lesion, mucous columnar cell change (MCCC), appears to be the precursor of a less common subset of adenocarcinomas derived from a region of the distal airways that is proximal to the TRU. This lesion has been reported to be present in up to 70% of the mucinous variant adenocarcinomas that are derived from these more central sites (2). This suggests that MCCC may be amenable to sampling at a pre-invasive stage by bronchoscopic means. In contrast, BD is detectable prior to development of invasive cancer by bronchoscopy but cannot be identified by radiographic examination. Higher rates of progression to invasive SCC and/or carcinoma-in-situ for lesions with higher grades of atypia have been suggested in a number of studies and meta-analyses (3). We have assessed the relationship between persistence of BD and risk for development of invasive lung cancer employing a numeric scoring system (1=normal; 2-7=increasing levels of precursor atypia; 8=invasive cancer). These analyses have shown that higher histologic scores on follow-up biopsies at specific sites within the airway of individuals sampled over time are associated with higher baseline histologic score, the presence of papillary angiogenic change, and current smoking status (4). Multivariable analyses including these parameters show that sites in subjects that develop SCC have mean histologic scores on follow-up biopsy that are 1.55 higher than those in patient’s without development of invasive lung cancer. On a per subject basis, the frequency of SCC was significantly increased in subjects that showed multiple sites of BD at baseline that persisted as or progressed to high grade dysplasia (moderate dysplasia or worse, histology score > 5). A 33% increase in risk for development of SCC is associated with every 10% increase in percent of sites that persist/progress to HGD corresponding to an overall hazard ratio of 17.14 (CI 2.4, 123.3) for multifocal persistent BD. These findings lend support to the importance of a field effect in lung carcinogenesis and suggest a potential role for histologic demonstration of persistent field change as an indicator of risk for the development of lung SCC. A number of biomarkers have been studied to determine their relationship with outcomes in premalignant lung lesions. Direct analyses of AAH and AIS have shown that a significant number of these lesions harbor the activating EGFR driver mutations seen in invasive adenocarcinoma of the lung. The potential of these mutational events to act as predictors of progression is under investigation, and a case report has demonstrated response to EGFR inhibitors of radiographically established multifocal premalignant disease in which an EGFR mutation was demonstrated in biopsy tissue of one of the lesions (5). Interestingly, the tumors associated with MCCC show a higher proportion of KRAS mutations. Non-lesional biomarkers of risk such as a recently reported assay measuring germline DNA repair activity that correlates decreased repair capability with increased risk for malignancy show promise for risk prediction (6). BDs, like SCC, demonstrate frequent genetic alterations in tumor suppressor genes and show characteristic associated alterations in gene methylation, loss of heterozygosity and gene copy number gains that have been associated with increased risk (7-10). In an analysis of a small series of cases in which sites with BD were observed to directly progress to invasive SCC, we have demonstrated frequent TP53 and some other mutations in precursor lesions. Furthermore, via pathway analysis of genes that we have found to be differentially expressed between persistent and regressive bronchial dysplasia, we have identified altered control of cell cycle, adhesion and immune activity (see abstract #3026) to be associated with persistence of BD. Overexpression of polo-like kinase 1 (PLK1) is the most prominent cell cycle control alteration associated with persistence and its role as a mediator of progression through the G2-M DNA damage checkpoint suggests a potential mechanism by which genomic instability can be promoted in high risk premalignant BD. PLK1 inhibitor treatment of primary cultures derived from sites of persistent BD causes an arrest of growth in S/G2 phase and induces apoptosis, neither of which occurs when PLK1 inhibitor is applied to primary cultures of normal bronchial epithelium. Histologic features and molecular biomarkers of premalignant lung lesions provide means by which risk can be assessed, appropriate targets for prevention can be identified and efficacy of preventive therapies can be measured. References 1. Travis WD, Brambilla E, Muller-Hermelink HK and Harris CC. Pathology and genetics: tumors of the lung, pleura, thymus and heart. World Health Organization Classification of tumours. Lyon: IARC; 2004. p. 9-124. 2. Weichart W and Warth A. Early lung cancer with lepidic pattern: adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant adenocarcinoma. Curr Opin Pulm Med 2014, 20:309–316 3. Ishizumi T, McWilliams A, Macaulay C, Gazdar A and Lam S. Natural history of bronchial preinvasive lesions. Cancer Metastasis Rev 2010;29:5-14. 4. Merrick DT, Haney J, Petrunich S, Sugita M, Miller YE, Keith RLet. al. Overexpression of vascular endothelial growth factor and its receptors in bronchial dysplasia demonstrated by quantitative RT-PCR analysis. Lung Cancer 2005;48(1):31-45. 5. Pastorino U, Calabro E, TamboriniE, MarchianoA, Orsenigo M, Fabbri A, Sozzi G, Novello S, and De Marinis F. Prolonged Remission of Disseminated Atypical Adenomatous Hyperplasia Under Gefitinib. J Thorac Oncol 2009;4: 266–267. 6. Sevilya Z, Leitner-Dagan Y, Pinchev M, Kremer R, Elinger D, Rennert HS, Schechtman E, Freedman LS, Rennert G, Paz-Elizur T, and Livneh Z. Low Integrated DNA Repair Score and Lung Cancer Risk. Cancer Prev Res; 7(4); 398–406. 7. Nakachi I, Rice JL, Coldren CD, Edwards MG, Stearman RS, Glidewell SC, Varella-Garcia M, Franklin WA, Keith RL, Lewis MT, Gao B, Merrick DT, Miller YE, and Geraci MW. Application ofSNPMicroarrays to theGenome-Wide Analysis of Chromosomal Instability in Premalignant Airway Lesions. Cancer Prev Res; 7(2); 255–65. 8. Massion, P., Zou, Y., Uner, H., Kiatsimkul, P.,Wolf, H. J., Baron, A. E., et al. Recurrent genomic gains in preinvasive lesions as a biomarker of risk for lung cancer. PLoS ONE 2009;4(6):e5611. 9. Wistuba, I. I., Behrens, C., Virmani, Ak, Mele, G., Milchgrub, S., Girard, L., et al. High resolution chromosome 3p allelotyping of human lung cancer and bronchial epithelium reveals multiple, discontinuous sites of 3pallele loss and three regions of frequent breakpoints. Cancer Res 2000;60:1949–1960. 10. Belinsky SA[1], Liechty KC, Gentry FD, Wolf HJ, Rogers J, Vu K, Haney J, Kennedy TC, Hirsch FR, Miller Y, Franklin WA, Herman JG, Baylin SB, Bunn PA, Byers T. Promoter hypermethylation of multiple genes in sputum precedes lung cancer incidence in a high-risk cohort. Cancer Res 2006; 66(6):3338-44.

Abstract:
The ability to intervene in the process of carcinogenesis is predicated on an understanding of the pathways leading to invasive cancer and availability of targeted tools to abrogate the resulting processes. Thus, effective chemoprevention has been hampered by the evolving understanding of lung cancer as a heterogeneous set of malignancies arising from a multitude of diverse molecular deregulations. The simplistic view that early intervention (before the evolution of multiple complex mutational events that are characteristic of tobacco-related malignancies) is more likely to be effective than late intervention has been replaced by the realization that many complex abnormalities actually do occur early and we simply do not understand which individual abnormalities or combinations of abnormalities would derail the inevitable progression to invasive and metastatic cancer. To assess efficacy, well designed clinical trials need to have end points that are informative. For phase III trials, the ideal end point would be cancer-related mortality so that cancer overdiagnosis does not cloud the issue. Realistically, cancer incidence is a more achievable and sufficiently informative end point. Phase II trials, however, depend on intermediate end points that are surrogates for cancer incidence, in a manner analogous to tumor shrinkage or progression-free survival being a surrogate for survival in phase II cancer treatment trials. Examples of end points that have been used in a variety of phase II chemoprevention trials are premalignant lesions, proliferative indices, and a variety of biomarkers of risk or malignant potential. It must be emphasized that to be useful, intermediate end points should be integrally involved in the process of carcinogenesis, differentially expressed in at-risk vs. normal epithelium, and modulated by effective interventions well above the level of spontaneous fluctuation (1). To date, no intermediate end point has been validated to replace lung cancer incidence, but such biomarkers can significantly inform drug development and decision-making for subsequent phase III trials. Nevertheless, the histologic evolution of squamous carcinogenesis, with progression from bronchial metaplasia through varying grades of dysplasia to carcinoma in situ is well described (2). This knowledge has allowed for clinical trials based on pre- and post-treatment assessment of effect of interventions on bronchial histology. However, the rate of progression of dysplasia to invasive cancer is variable even though high grade histologies are associated with higher rates of progression. Therefore, studies assessing dysplasia need to have placebo controls to correct for spontaneous and biopsy-induced regression. A recent trial of a prostacyclin analogue, iloprost, showed improvement in bronchial histology in former smokers after 6 months of treatment (3). These results will be extended in a soon-to-open trial of inhaled iloprost in a similar population and will include analyses of potential molecular predictors of histologic progression. Ongoing efforts are focusing on understanding the process of carcinogenesis by profiling premalignant lesions, both in a cross-sectional manner with regard to lesions identified at time of lung cancer resection (4) and with longitudinal follow-up. Understanding the natural history of premalignant lesions will help determine which ones progress, why they progress, and, therefore, which end points are likely to be most informative. An alternative way to approach the issue is to examine the at-risk epithelial field to identify biomarkers associated with progressive carcinogenesis. Gustafson et al. showed that the PI3K pathway is upregulated early during lung carcinogenesis and that an intervention with a drug, myo-inositol, that resulted in regression of bronchial dysplasia also inhibited PI3K activation in the histologically normal bronchial epithelium obtained by bronchial brushings (5). These data suggest that upregulated PI3K could potentially identify smokers at increased lung cancer risk and that pathway inhibition could serve as an end point for assessing treatment effect. This hypothesis is undergoing further testing in a recently finished phase II trial of myo-inositol in current and former smokers with dysplasia, where normal bronchial epithelium was collected and will be tested for PI3K activation pre- and post-treatment. Similarly, Spira et al. showed that gene expression classifiers from bronchial brushings of histologically normal epithelium obtained from individuals undergoing bronchoscopy for suspect lung cancer can aid in the diagnosis of lung cancer and can serve as lung cancer biomarkers (6,7). These classifiers have potential to be adapted to surrogate tissues further up in the aerodigestive tract, such as the nasal epithelium, and are being tested in chemoprevention ongoing clinical trials (8; NCT02123849). How do we move forward? A better understanding of the early carcinogenic processes and which processes are operative in individual persons is key to designing clinical trials that bring the prospect of precision medicine to lung cancer chemoprevention. The focus on a molecular understanding of premalignant lesions and the at-risk field is at the center of current efforts to identify informative end points for chemoprevention clinical trials. References Szabo E. Phase II cancer prevention clinical trials. Semin Oncol 2010;37:359-66. Saccomanno G et al. Development of carcinoma of the lung as reflected in exfoliated cells. Cancer 1974;33:256-70. Keith R et al. Oral iloprost improves endobronchial dysplasia in former smokers. Cancer Prev Res 2011;4:793-802. Ooi AT et al. Molecular profiling of premalignant lesions in lung squamous cell carcinomas identifies mechanisms involved in stepwise carcinogenesis. Cancer Prev Res 2014;7:487-95. Gustafson AM et al. Airway PI3K pathway activation is an early and reversible event in lung cancer development. Sci Trans Med 2010;2:26ra25. Spira A et al. Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat Med 2007;13:361-6. Silvestri GA et al. A Bronchial Genomic Classifier for the Diagnostic Evaluation of Lung Cancer. N Eng J Med 2015 May 17 [Epub ahead of print]. Zhang X et al. Similarities and differences between smoking-related gene expression in nasal and bronchial epithelium. Physiol Genomics 2010;41:1-8.

Abstract:
In the wake of the demonstrated 20% mortality reduction benefit reported from the randomized National Lung Screening Trial (NLST), the United States Preventive Services Task Forces gave a “B” recommendation for low dose CT screening of for lung cancer in high risk populations (1). This favorable endorsement in turn led the Centers for Medicare and Medicaid Service to fully reimbursement the cost of providing this service by federal and commercial insurers for high risk smokers between the ages of 55-77 who have been smoking within the last 15 years. With these provisions, national lung cancer screening is now being implemented in the United States. The protocol and screening process used for the NLST was fixed at the time of study initiation in 2002 when 4-detector scanners were the default CT device and screening management was delivered based on the existing community standard (2). In the time since the NLST was conducted there have been a number of developments that have improved the process of lung cancer screening services (3). These innovations range from the introduction of more capable CT scanners, lower medical radiation scanning protocols, more effective and efficient diagnostic work up approaches, as well as improved and more tailored surgical approaches. The aggregate effect of all of these advances is that the cost efficiency of this process is also improving (4). Further improvements with clinical management may occur as the use of quantitative CT imaging allows for more consistent measurement of suspicious pulmonary nodules, as size criteria is emerging as a key determinant guiding invasive screening work-up (5). However implementing national CT screening to ensure delivery of high quality, best-practice early lung cancer detection in the target population of tobacco-exposed individuals constitutes a profound challenge. Still the public health impact of tobacco-exposure is singularly lethal. In the United States alone over 438,000 annual deaths are related to tobacco-exposure with lung cancer being the most common cause of tobacco-related death approaching 30% of this total mortality burden. Advocacy groups have worked with academic medical centers as well as community hospitals to address this implementation challenge by creating a consortium of institutions that are conducting screening programs to systematically adopt best standard of screening practice for all components of clinical management (6). A critical aspect of the “Framework” process includes the expectation that participating institutions will prospectively acquire clinical follow-up information so that the outcomes of lung cancer screening efforts can be accessed and reported (6). This effort builds on previous models of cooperative research such as with using institutional feedback to accelerate learning curve in allowing new screening institutions to rapidly implement effective screening process. The best example to date of this approach with screening is the use of the recent I-ELCAP screening outcomes to evaluate the most favorable pulmonary nodule size to use as a threshold for a more invasive diagnostic work-up (7). Increasing the nodule size as the threshold for further diagnostic work-up markedly improves the efficiency of the screening management while reducing the rate of false positive work-ups, cost and morbidity (7). An indispensible element in the national implementation of screening is the simultaneous provision of best practice smoking cessation services for those individuals that continue to smoke. Pyenson and co-workers have reported that routine integration of smoking cessation with the annual CT screening process can improve the cost utility ratio of quality adjusted life years by close to 40% (4). Indisputably implementing national annual CT screening in high risk populations is a significant societal cost. However there are attractive opportunities to leverage this new pattern of care to further benefit health outcomes in this at-risk cohort. For example, the annual CT visit provides a scaffolding to support more intensive research to define better smoking cessation measures. In asymptomatic tobacco-exposed individuals, a growing body of research suggests that the CT scan done to evaluate for early lung cancer also commonly finds individuals with evidence of asymptomatic COPD/emphysema or coronary artery disease (8, 9). These diseases along with lung cancer account for close to 70% of the excess mortality in heavily tobacco-exposed populations. Lung cancer screening will permit additional research opportunities in this tobacco-exposed cohort including catalyzing the development for more effective drugs to manage the early stage of lung cancer. With screening, the frequency of finding early stage lung cancer is greatly increased and focusing on these early stage patients could allow for much more rapid evaluation of new targeted therapeutic agents compared to the current setting. For the same reason, lung cancer screening will also find many more early asymptomatic COPD patients and quantitative CT provides an economical biomarker to allow much more efficient COPD drug development research than is currently possible. Particular classes of drug targets such as immunomodulators could conceivably show benefit in arresting the progression of both early lung cancer and COPD. This time of initial US national screening dissemination is allowing a full national discussion not only about how to provide high quality lung cancer screening services, but also about how to thoughtfully leverage this newly reimbursed screening service to extend the utility of the thoracic imaging encounter and greatly accelerate progress with improving health outcomes in heavily tobacco-exposed populations. At the very least, evidence for one or more of these additional diseases on annual screening may heighten a smoker’s motivation to stop that habit. Other life style interventions such as diet modification and exercise are being successfully employed to manage the consequence of asymptomatic coronary calcification. Life style counseling could also emerge as integral part of the annual CT evaluation as these interventions can have markedly positive impact for a range of tobacco-dependent conditions. The emergence of lung cancer screening as a public health tool has evoked a lively global debate regarding its potential merits. While this healthy debate should continue, there are potentially unprecedented opportunities arising with this new approach to the lethality of chronic tobacco exposure that merit serious consideration. References: 1) Moyer VA. Screening for lung cancer: U.S. preventive services task force recommendation statement. Ann Intern Med. 2013 Dec 31. 2) Aberle D, Adams A, Berg C et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011; 365(5): 395-409. 3) Mulshine JL, D'Amico TA. Issues with implementing a high-quality lung cancer screening program. CA Cancer J Clin. 2014 Jun 27. 4) Villanti AC, Jiang Y, Abrams DB, Pyenson BS. A cost-utility analysis of lung cancer screening and the additional benefits of incorporating smoking cessation interventions. PLoS One. 2013 Aug 7; 8(8): e71379. PMCID: PMC3737088. 5) Mulshine JL1, Avila R, Yankelevitz D et al. Lung Cancer Workshop XI: Tobacco-Induced Disease: Advances in Policy, Early Detection and Management. J Thorac Oncol. 2015 May;10(5):762-7. doi: 10.1097/JTO.0000000000000489. 6) Rights and expectations for excellence in lung cancer screening and continuum of care.[homepage on the Internet]. Available from: http://www.screenforlungcancer.org/national-framework/. 7) Henschke CI. Definition of a positive test result in computed tomography screening for lung cancer: A cohort study. Ann Intern Med. 2013; 158(4): 246-252. 8) Zulueta J, Wisnivesky J, Henschke C, et al. Emphysema scores predict death from COPD and lung cancer. Chest. 2012; 141(5): 1216-1223. 9) Htwe Y, Cham MD, Henschke CI, et al. Coronary artery calcification on low-dose computed tomography: comparison of Agatston and Ordinal Scores. Clin Imaging. 2015 Apr 18. pii: S0899-7071(15)00098-4. doi: 10.1016/j.clinimag.2015.04.006. [Epub ahead of print]

Abstract:
Background: lung cancer mortality is still the leading cause of cancer death worldwide[(][1][)]. The majority of patients present with advanced disease and the current 5-year survival is only 15%. Despite treatment advances, there is little improvement of prognosis. As the American National Lung cancer Screening trial (NLST) showed that low-dose CT-scan (LDCT) screening can reduce lung cancer mortality in high risk subjects[(][2][)], the United States Preventive Task Force (USPTFS) recommends annual LDCT screening in adults who have a smoking history of at least 30 pack-years, and smoke now or have quit within the past 15 years and are between 55 and 80 years old[(][3][)]. However, there are still some important challenges, f.e. high prevalence of false-positives, overdiagnosis and the optimal screening strategy . In Europe, the sufficiently powered Dutch-Belgian lung cancer screening trial (NELSON) is still ongoing. This trial is currently in the final phase of follow-up prior to definitive analysis and reporting. Results: the NELSON trial has been setup in 2003, in which subjects at high risk for lung cancer were selected from the general population[(][4][)]. After informed consent, 15,791 participants were randomised (1:1) to the screen arm (n=7,900) or the control arm (n=7,891) (Figure 1). The screen arm participants received LDCT screening at four times: at baseline, after one year, after two years and after two and a half years, whereas the control arm participants received usual care (no screening). According to size and volume doubling time (VDT) of the nodules, three screen results were possible: negative (invitation for the next screening round), indeterminate (an invitation for a follow-up scan) or positive (referred to the pulmonologist because of suspected lung cancer). Main results of the first three screening rounds showed a favorable cancer stage distribution of the screen-detected lung cancers detected in the NELSON trial compared to the other trials and was more favorable (p<0.001) than in the NLST[(][5][)]. More than half of the screen-detected lung cancers were adenocarcinomas (51.2%) and a large proportion was localized in the right upper lobe (45.0%). Women diagnosed with lung cancer were significantly younger (58.0 vs. 62.0 years; p=0.03), had a lower BMI (23.8 vs 25.9;p=0.003) and were diagnosed at a more favorable cancer stage (p=0.028) than the men diagnosed with lung cancer. From the first screening round up to two years of follow-up after the third round scan, 34 participants were diagnosed with an interval lung cancer[(][6][, ][7][)]. Retrospectively, two-thirds of these interval cancers were visible on the last screening CT; detection errors, interpretation errors, and human errors were identified as the main causes of the failure in half of the interval cancers. Interval cancers were diagnosed at more advanced stages (p<0.001 ), and were more often small cell carcinoma (p=0.003) and less often adenocarcinomas (p=0.005) than screen-detected lung cancers. For the first three rounds combined, sensitivity was 84.6% (95% CI 79.6-89.2%), specificity was 98.6% (95% 98.5%-98.8%), positive predictive value was 40.4% (95% CI 35.9-44.7%), and negative predictive value was 99.8% (95% CI 99.8%-99.9%)[(][6][)]. For the first screening round, the sensitivity was the same, but the specificity was higher in the NELSON trial relative to the NLST: 98.3% vs. 73.4%. The positive predictive value was in our trial (40.4%) substantially higher than in other trials: f.e. 3.8% in the NLST[(][2][)]. Furthermore, our findings showed that the 2 year-probability of developing lung cancer for all included participants was 1.3% (1.2-1.5)[(][8][)]. For screened participants without any nodules this probability (more than half of the included participants) was 0.4%, which suggests that a screening interval of at least two years might be safe to apply in these individuals. In all participants with CT-detected nodules, lung cancer probability was 2.5% (2.1-2.9) but individuals’ probabilities depended strongly on nodule volume, diameter and VDT. New data: the last screening round, which took place 2.5 years after the third round, showed 46 screen-detected lung cancers, of which 58.7% were diagnosed at stage I and 23.8% at stage III/IV. More squamous-cell carcinomas (21.7% vs. 16.3%), small cell carcinomas (6.5% vs. 3.8%) and bronchioalveolar carcinomas (8.7% vs. 5.3%) were detected compared to the first three screening rounds. However, relative to the first three rounds the lung cancer detection rate was lower (0.80 vs 0.80-1.1) and lung cancer was detected at a more advanced stage (stage III/IV; 23.8% vs 8.1). Currently, we are working on the review of blinded medical files of the deceased participants to determine the cause of death, and we are collecting medical data of control arm participants. Figure 1 References 1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014 Jan-Feb;64(1):9-29. 2. National Lung Screening Trial Research T, Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011 Aug 4;365(5):395-409. 3. Moyer VA, Force USPST. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014 Mar 4;160(5):330-8. 4. van Klaveren RJ, Oudkerk M, Prokop M, Scholten ET, Nackaerts K, Vernhout R, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med. 2009 Dec 3;361(23):2221-9. 5. Horeweg N, van der Aalst CM, Thunnissen E, Nackaerts K, Weenink C, Groen HJ, et al. Characteristics of lung cancers detected by computer tomography screening in the randomized NELSON trial. Am J Respir Crit Care Med. 2013 Apr 15;187(8):848-54. 6. Horeweg N, Scholten ET, de Jong PA, van der Aalst CM, Weenink C, Lammers JW, et al. Detection of lung cancer through low-dose CT screening (NELSON): a prespecified analysis of screening test performance and interval cancers. Lancet Oncol. 2014 Nov;15(12):1342-50. 7. Scholten ET, Horeweg N, de Koning HJ, Vliegenthart R, Oudkerk M, Mali WP, et al. Computed tomographic characteristics of interval and post screen carcinomas in lung cancer screening. Eur Radiol. 2015 Jan;25(1):81-8. 8. Horeweg N, van Rosmalen J, Heuvelmans MA, van der Aalst CM, Vliegenthart R, Scholten ET, et al. Lung cancer probability in patients with CT-detected pulmonary nodules: a prespecified analysis of data from the NELSON trial of low-dose CT screening. Lancet Oncol. 2014 Nov;15(12):1332-41.

Abstract:
Future implementation of lung cancer screening programmes will require accurate identification of the population who will benefit the most, to ensure that the benefits outweigh the harms [1]. In the USA, the current criteria for Medicare reimbursement [2], for screening are: age 55 to 77, a smoking history of 30 pack-years or more and smoking within 14 years of entry [3]. However, an in-depth analysis of the NLST showed that there was marked variation in individual risk of lung cancer death, with some screened that had only a low chance of benefit: 20% of participants at lowest risk accounted for only 1% of prevented lung-cancer deaths). [4]Conversely, 88% of the prevented deaths were in the 60% of participants that were at highest risk. The only risk prediction model so far utilised in the recruitment of participants into a CT Lung Cancer Screening RCT, is the LLP~v2~ risk model in the pilot UK lung cancer screening trial (UKLS) [5]. The Liverpool Lung Project (LLP) risk model was based on a case-control study [6]. The LLP~v1~ model utilised conditional logistic regression to develop a model based on factors that were significantly associated with lung cancer (smoking duration, prior diagnosis of pneumonia, occupational exposure to asbestos, prior diagnosis of cancer family history of lung cancer (early onset <60 years) and exposure to asbestosis [6]. The multivariable model was combined with age-standardised incidence data to estimate the absolute risk of developing lung cancer. The discrimination of the LLP was evaluated and demonstrated its predicted benefit for stratifying patients for CT screening by using data from three independent studies from Europe and North America [7]. The LLP~v2~ was used to select subjects with ≥5% risk of developing lung cancer in the next five years for UKLS [8]. This method may improve cost-effectiveness by limiting screening to high-risk individuals. The UKLS approached 247,354 individuals in the two pilot sites, 75,958 people (30.7%) responded positively to the screening invitation. Demographic factors associated with positive response were: higher socioeconomic status, age 56-70 years, and ex-smokers. Those from lower socioeconomic groups and current smokers were less likely to respond. 8,729 (11.5%) positive responders were calculated as high risk of lung cancer. The high risk individuals were more often elderly, current smokers, of lower socioeconomic status and males (2.4x females). 4,055 were randomised into the UKLS. Forty two UKLS participants have been diagnosed with confirmed lung cancer, 34 of these were detected at baseline or three months, giving a baseline prevalence of 1.7% which is significantly higher than that reported by the NLST[9]or NELSON [10]trials. To date, 2.1% of all individuals screened have been diagnosed with lung cancer. 36/42 (85.7%) of the screen-detected cancers were identified at stage 1 or 2. Of those with a confirmed cancer, 17/42 (40.5%) were from the most deprived Index of Multiple Deprivation (IMD) quintile. Figure 1 Figure 1: Percentage of UKLS positive responders (n=75,958) with an LLP risk of >5%, by individual year of age. The positive response rate increased steadily with higher socioeconomic status: 21.7% of individuals in the lowest (most deprived) IMD quintile gave a positive response compared with 39.7% in the highest quintile (p<0.001;) (Figure 2). The proportion of individuals with a high LLP risk score decreased with higher socioeconomic status; ranging from 18.2% in the most deprived quintile to 8.3% in the least deprived quintile (p<0.001;). LLP risk were offset by, the socio-demographic spectrum of the individuals attending the clinic, which was in proportion to that of the original approached sample. People recruited into the UKLS trial therefore spanned all IMD quintiles in roughly equal numbers, including a representative proportion from more deprived postcodes. However, in the high risk sub group of individuals invited for screening, there was a trend towards individuals of higher socioeconomic status being more likely to consent to participate in the trial. Figure 2 Figure 2: Impact of socioeconomic status upon initial response rate (lower line), LLP risk (bars) and trial consent rate (upper line). The demographic and response data from the UKLS pilot trial enable specific recommendations to be made regarding the implementation of any future UK-wide lung LDCT screening programme. Such a programme would need to target those most at risk who may be least likely to take up offers of screening (i.e. the most deprived, current smokers, and the over 70s), and women.

Abstract:
Background Lung cancer is the leading cause of cancer death in Japan as well as western countries. To decrease the lung cancer mortality, lung cancer screening using low-dose thoracic computed tomography (CT) may be a promising measure. Several randomized controlled trials (RCTs) are being conducted in the US and Europe to evaluate the efficacy of lung cancer CT screening, and one of those trials, National Lung Screening Trial (NLST), recently reported favorable results. However, the focus of all trials has been the efficacy in smokers.　Adenocarcinomas have increased worldwide in non-smokers, especially in Japan and other Asian countries, and a powerful lung cancer screening modality for non-smokers is also desired. In a recent Japanese cohort study, mortality reduction by thoracic CT screening was suggested even in non-smokers/smokers under 30 pack-years (personal communication). Therefore, we are now conducting the JECS Study (The Japanese randomized trial for evaluating the Efficacy of low-dose thoracic CT Screening for lung cancer in non-smokers and smokers under 30 pack-years). Methods The aim of the JECS study is to assess the efficacy of lung cancer screening tests using low-dose thoracic CT once every five years, compared with chest roentgenography (XP), in people aged 50–64 with a smoking history under 30 pack-years. This study is a multi-regional prospective randomized controlled trial (RCT). The design of the RCT was described elsewhere (Jpn J Clin Oncol 42: 1219-21, 2012). Briefly, participants were recruited from people who ranged from 50-64 years old with smoking history under 30 pack-years, and underwent regular lung cancer screening using chest x-ray in the previous year (this latter requirement may be deleted after 2015). A letter for recruitment to participate in the trial was mailed to each citizen in the target municipalities, who was 50-64 years old with a smoking history under 30 pack-years. The letter explained the eligibility criteria, randomization, follow-up, possible benefit and harm including false-positive, radiation exposure and overdiagnosis. Several meetings were held for those who were interested in the trial for further explanation. People with a history of lung cancer or other malignant diseases as well as a history of thoracic CT screening were excluded. Appropriate written informed consent was completed by each participant who chose to take part in the trial. The participants were randomly assigned into one of 2 groups, a CT group and an XP group. The duration of this screening-follow-up period is 10 years. For the intervention arm, low-dose thoracic CT is provided for each participant in the first year and the sixth year. For the control arm, chest XP is provided for each participant in the first year. All of the participants are encouraged to receive annual routine lung cancer screening using chest XP in the other years. Thoracic CT findings were interpreted by two physicians, based upon the “Low-dose CT Lung Cancer Screening Guidelines for Pulmonary Nodules Management” established by the Japanese Society of CT Screening. A positive rate under 5% is preferred. The interpretation of chest XP findings is performed according to “The Manual of the Lung Cancer Screening” section in the “General rule for clinical and pathological record of lung cancer” published by the Japan Lung Cancer Society. The lung cancer incidence and mortality would be compared. The design of the trial was approved by the Institutional Review Board of the Kanazawa Medical University in 2009, and was registered on the University Hospital Medical Information Network Clinical Trial Registration (UMIN-CTR), Japan in 2011 (registration number: UMIN000005909). The sample size, 17,500 subjects for each arm, is required to detect a 60% mortality reduction after 10 years. At the first step, 3,000 subjects are needed for evaluating QOL and value of contamination of the study. Results As of March 1, 2015, local governments of 20 municipalities in 7 prefectures in Japan permitted that we sent invitation letters for the JECS Study to residents. A letter for recruitment was mailed to each of 9,268 people who were 50-64 years old with a smoking history under 30 pack-years and underwent regular lung cancer screening in the previous year. Of them, 1,812 people (19.6%) sent us a reply letter and wanted to attend one of the meetings for further explanation. One thousand five hundred people actually attended one of the meetings. Finally 1,458 people participated in the JECS Study (15.7% of people who was invited and 97.2% of people who attended a meeting). Of them, 720 people were assigned to CT group and remaining 738 people were assigned to XP group. The screening results of 48 of the 720 people who received low-dose thoracic CT screening (6.7%) were positive, whereas 20 of 738 people who underwent chest XP screening (2.7%) were positive. Until now, three lung cancer patients were diagnosed and 22 patients were under follow-up for the suspicion of having lung cancer in this whole cohort. Comments The results of the NLST demonstrated the efficacy of thoracic CT screening in smokers. However, the efficacy in non-smokers is still completely unknown. Therefore, we started to conduct a randomized trial, the JECS study, to evaluate the efficacy of low-dose thoracic CT screening for lung cancer in non-smokers/smokers under 30 pack-years. This is a first RCT in the world for not heavy-smokers. The preliminary results of this study indicated that 15.7% of the people who received the recruitment letter participated in the RCT. The compliance rate was high in comparison to that in the PLCO or the ITALUNG trial (0.3-7.2%). Over 97% of the 1,500 people who attended a meeting participated in the RCT, which was extremely high. This indicated that the letter for recruitment was effective both for excluding ineligible subjects and for explaining the contents of the trial. The compliance in the preliminary results for this study was very high, and the above RCT appears to be feasible in Japan, if the sufficient budget is obtained. This study was supported in part by the Health and Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare, Japan.

Abstract:
A leading cause of death in small cell lung cancer (SCLC) is the rapid emergence of drug resistance following an initial phase of chemotherapy and radiation sensitivity. Currently, response rates to existing second-line regimens (e.g., topotecan and other single-agent chemotherapies) are less than 20%. Because of this overall poor response to subsequent therapy, average survival for relapsed disease ranges between 4-6 months. As such, there is a critical need for the development of novel, active therapies for SCLC. Drugs that target DNA damage response (DDR), including PARP inhibitors, have shown promising activity against SCLC in pre-clinical models and in early clinical trials. Previously, we performed proteomic profiling of a large panel of SCLC cell lines which led to the observation that PARP1, Chk1, and several other DNA repair proteins are expressed at high levels in SCLC[1]. PARP1 overexpression was confirmed in patient tumors at the protein level by immunohistochemistry and at the mRNA level. Based on this finding, several PARP inhibitors were tested in pre-clinical models of SCLC. Olaparib, rucaparib, and talazoparib (previously BMN-673) all demonstrated striking single agent activity in a majority of SCLC cell lines tested. Furthermore, the addition of a PARP inhibitor to standard chemotherapies (e.g., cisplatin, etoposide and/or topotecan) and radiation further potentiated their effect[1][,][2]. In animal models including xenografts and patient-derived xenografts (PDXs), talazoparib has demonstrated significant anti-tumor activity as a single agent, comparable or superior to cisplatin[3][,][4]. Following these observations, several clinical trials were initiated to investigate the effects of PARP inhibition in SCLC patients. The first two studies to complete enrollment investigated the use of PARP inhibitors in relapsed SCLC. In the first study, single-agent talazoparib (BMN-673) was tested in an expansion cohort of patients with platinum-sensitive SCLC relapse (NCT01286987). Preliminary data from this trial demonstrated 2/23 patients with RECIST confirmed partial responses and 3/23 with stable disease lasting more than 24 weeks (clinical benefit rate of 25%). More than half of patients treated had some tumor volume reduction as their best response[5]. In the second study, the oral alkylating drug temozolomide with or without veliparib (ABT-888) was studied in 100 patients with sensitive or refractory relapse (NCT01638546). This trial recently completed enrollment and analysis of the results are ongoing. The use of PARP inhibitors in combination with chemotherapy builds upon prior pre-clinical data in lung cancer and other malignancies supporting the notion that PARP inhibitors potentiate the effect of other DNA damaging therapies. Currently, there are two studies investigating the use of veliparib (ABT-888) in combination with standard frontline chemotherapy (NCT01642251 and NCT02289690). E2511 (NCT01642251) is a Phase I/II trial of cisplatin, etoposide, and veliparib conducted through the ECOG-ACRIN Cancer Research Group in which treatment naïve SCLC patients receive the combination for up to 4 cycles. Published results from the Phase I portion support the safety and tolerability of the combination, with partial or complete responses observed in 5/7 evaluable patients[6]. More recently, another first-line study was initiated to investigate carboplatin in combination with etoposide and veliparib which will also address the question of veliparib maintenance (NCT02289690). To date, the activity of PARP inhibitors are best established in cancers with mutations in BRCA1/2 and other DNA repair genes that result in synthetic lethality in the setting of PARP inhibition (which provides a second “hit” to the DNA repair machinery). In fact, olaparib monotherapy was FDA-approved last year for patients with advanced, BRCA-mutated ovarian cancer who have received three or more lines of chemotherapy. This was based on a trial that demonstrated a response rate of 34% and a median duration of response or 7.9 months. Studies of other PARP inhibitors have also shown striking single-agent activity with this class of drugs in a mutation-selected population. However, in SCLC, the mechanism of action and identification of potential biomarkers of response to these drugs is an area of active investigation. Likely the universal loss of RB1, with resulting dependence on E2F1, plays a role, as may the PARP-trapping effects of several of these drugs which cause direct cytotoxicity[7]. Our group has demonstrated that expression levels of several DNA repair proteins – both individually and as a “DNA repair signature” – are associated with response in pre-clinical models of lung cancer[3]. However, further validation in the clinical setting is warranted. Additional DNA damage response (DDR) targets also show significant potential as therapeutic targets in SCLC. These include checkpoint kinases that are activated in response to DNA damage and facilitate S and G2 checkpoint arrest, such as Chk1 (Checkpoint kinase 1), Wee1, and ATR (Ataxia Telangiectasia and Rad3 related). Similar to PARP1, in our previous work we demonstrated elevated expression of Chk1 in SCLC[1]. SCLC may be particularly susceptible to inhibitors of Chk1 and other checkpoint kinases due to the near universal loss of TP53 in these cancers which make them dependent on other checkpoint controls in the cell cycle. Several drugs targeting these DDR proteins have entered clinical trials. For example, based on pre-clinical data demonstrating the potentiation of topoisomerase inhibitors by ATR inhibition, a Phase I/II trial of topotecan with VX970 (an ATR kinase inhibitor) has recently been initiated for SCLC (NCT02487095). Ongoing trials of PARP inhibitors and other molecules targeting DDR will help us to understand the activity of these compounds in patients with SCLC. Important questions that require further investigation include the optimal combinations of these drugs with existing therapies or other targeted inhibitors, strategies to manage associated toxicities (especially combinations with overlapping hematologic toxicities), and further development of candidate predictive biomarkers.REFERENCES 1. Byers LA, Wang J, Nilsson MB, et al. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer discovery 2012;2:798-811. 2. Owonikoko TK, Zhang G, Deng X, et al. Poly (ADP) ribose polymerase enzyme inhibitor, veliparib, potentiates chemotherapy and radiation in vitro and in vivo in small cell lung cancer. Cancer medicine 2014;3:1579-94. 3. Cardnell RJ, Feng Y, Diao L, et al. Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2013;19:6322-8. 4. Y. Feng, R. Cardnell, L.A. Byers, B. Wang, Y. Shen. Talazoparib (BMN 673) as single agent and in combination with temozolomide or PI3K pathway inhibitors in small cell lung cancer and gastric cancer models. 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (abstract) 2014. 5. Wainberg ZA, Ramanathan RK, Mina LA, Byers LA, Chugh R, Goldman JW, Sachdev JC, Matei DE, Wheler JJ, Henshaw JW, Zhang C, Gallant G, De Bono JS. Safety and antitumor activity of the PARP inhibitor BMN673 in a phase 1 trial recruiting metastatic small-cell lung cancer (SCLC) and germline BRCA-mutation carrier cancer patients. 2014 ASCO Annual Meeting; J Clin Oncol 32:5s, (suppl; abstr 7522) 2014. 6. Owonikoko TK, Dahlberg SE, Khan SA, et al. A phase 1 safety study of veliparib combined with cisplatin and etoposide in extensive stage small cell lung cancer: A trial of the ECOG-ACRIN Cancer Research Group (E2511). Lung cancer 2015;89:66-70. 7. Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer research 2012;72:5588-99.

Abstract not provided

Abstract:
Small cell lung cancer (SCLC) comprises approximately 15% of all lung cancers, and it is an exceptionally aggressive malignancy with a high proliferative index. Despite extensive basic and clinical research over the past 30 years, little progress has been made in treating this disease. A better understanding of the genomic changes in SCLC is essential to identify new therapeutic targets. However, a systematic genomic analysis of SCLC is difficult because this cancer subtype is rarely treated surgically, resulting in the lack of suitable tumor specimens for comprehensive analysis. Two reports regarding the comprehensive genomic analysis of SCLC have been published. These reports suggested that transcriptional deregulation might play a role in SCLC biology[1,2]. However, to date, attempts to develop targeted therapies toward these transcriptional deregulations have had limited success. Recently, we performed a comprehensive genomic analysis of 51 surgical resected SCLCs and found a high penetrance of genetic alterations in the PI3K/AKT/mTOR pathway[3]. MYC family amplifications are known oncogenic drivers in SCLC. PI3K/AKT/mTOR pathway alterations and MYC family amplifications were mutually exclusive in this study (Figure 1). However, the information regarding therapeutically relevant genomic alterations in advanced non-surgical SCLC is not well developed; so we performed targeted sequencing from 90 advanced SCLC. We identified that the PI3K/AKT/mTOR pathway was frequently altered in advanced SCLC in the same way as surgically resected SCLC. In advanced SCLC, PI3K/AKT/mTOR pathway alterations and MYC family amplifications were also mutually exclusive. The genomic profile of advanced SCLC was almost similar to that of resectable SCLC. To further investigate whether the PI3K/AKT/mTOR pathway could be a feasible therapeutic target in SCLC, we performed the in vitro drug sensitivity test using PI3K/mTOR dual inhibitor: NVP-BEZ235. NCI-H1048 cells harboring activating mutation in PIK3CA gene (H1047R), was the most sensitive to BEZ235, with IC50 value of 5.4 nM. Additionally, PIK3CA silencing induced a significant decrease in the proliferation of H1048 cells, suggesting that the proliferation of these cells was strongly dependent on the PI3K/AKT/mTOR pathway[3]. On the other hand, PTEN is a tumor suppressor gene working in PI3K/AKT/mTOR pathway. In murine model, Pten deletion accelerated SCLC by engineered deletion of two tumor suppressors (Rb and p53), suggesting that Pten was an important driver of tumor progression in SCLC[4]. Unlike other types of cancer, this is a unique phenomenon observed in SCLC, therefore targeting of PTEN signaling is reasonable in SCLC. There are many other reports which suggest that PI3K/AKT/mTOR pathway is the promising therapeutic target in SCLC. Although two specific inhibitors of mTORC1, everolimus and temsirolimus, have been tested against SCLC in a Phase II study, the antitumor activity was limited in unselected patients. To improve the response to these inhibitors, biomarker-based patient selection is first recommended. Secondly, the addition of PI3K inhibition might improve the response to specific inhibitors of mTORC1. The dual inhibition of PI3K and mTOR might be advantageous over the single inhibition of mTOR because of the suppression of the S6K feedback loop, which leads to the pathway reactivation. PF-05212384 is a novel potent dual inhibitor of PI3K and mTOR, which has demonstrated preliminary evidence of clinical activity in patients with solid malignancies[5]. However, dual inhibitor of PI3K and mTOR has not yet to be evaluated against SCLC in a phase II study. Thus, we planned the investigator initiated phase II study to investigate the efficacy of PF-05212384 in advanced recurrent SCLC patients harboring PI3K/AKT/mTOR pathway alteration. Key eligibility criteria include: advanced SCLC, harboring PI3K/AKT/mTOR pathway alteration, prior chemotherapy, aged ≥ 20 years, and ECOG PS 0-2. The primary endpoint is objective response rate. Patients receive weekly intravenous dose of PF-05212384 154 mg until disease progression. For screening SCLC patients harboring PI3K/AKT/mTOR pathway alteration, we use the multiplex next-generation sequencing tool enabling the analysis of about 150 genes in a single run. SCLC harboring PI3K/AKT/mTOR pathway alteration is a “Rare Cancer”. Therefore, patient recruitment is performed using the nationwide lung cancer genomic screening program, LC-SCRUM-Japan. LC-SCRUM-Japan is the largest molecular screening system in Japan. At the end of June 2015, around 180 institutes in all prefectures of Japan are participating this screening program. The prospective genomic screening of SCLC will be started in July 2015. In conclusion, the SCLC genome possesses distinguishable genetic features in the PI3K/AKT/mTOR pathway. Genetic alterations in the PI3K/AKT/mTOR pathway were noted as a top therapeutic priority in SCLC. Investigator initiated phase II study of PF-05212384 in advanced recurrent SCLC patients harboring molecular alterations in PI3K/AKT/mTOR pathway is planned to be started in January 2016.Figure 1 References 1. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nature genetics 2012; 44: 1104-1110. 2. Rudin CM, Durinck S, Stawiski EW et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nature genetics 2012; 44: 1111-1116. 3. Umemura S, Mimaki S, Makinoshima H, et al. Therapeutic priority of the PI3K/AKT/mTOR pathway in small cell lung cancers as revealed by a comprehensive genomic analysis. J Thorac Oncol 2014; 9: 1324-31. 4. McFadden DG, Papagiannakopoulos T, Taylor-Weiner A, et al. Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing. Cell 2014; 156: 1298-1311. 5. Shapiro GI, Bell-McGuinn KM, Molina JR, et al. First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer. Clin Cancer Res. 2015; 21: 1888-1895.

Abstract:
Small cell lung cancer (SCLC), which accounts for 15 – 20% of all lung cancer cases, represents one of the most aggressive subtypes based on rapid growth and early metastasis. Only limited therapeutic progress has been achieved in the recent decades and despite multiple mutations no targeted therapy for SCLC has been available by now. Based on preclinical data that revealed a relevant correlation between the immune system and SCLC the exploration of immune modulating agents appears to be attractive. First signals coming from randomized phase II trials showed an enhanced activity for the combination of the anti cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody ipilimumab with chemotherapy compared to chemotherapy alone. This combination is now under investigation in a couple of extended randomised trials. Besides ipilimumab also antibodies inhibiting the axis of programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) like nivolumab or pembrolizumab have shown encouraging results either alone or in combination with ipilimumab in heavily pre-treated patients with advanced SCLC. Ongoin or planned randomised trials will validate these signals in various therapeutic lines. A confirmation of these attractive early outcomes would have an substantial clinical impact. In particular in SCLC identification of new potential biomarkers will become of great importance because the PDL-1 status might not be the optimal predictive marker in this tumor entity.

Abstract:
Introduction Small cell lung cancer (SCLC) represents approximately 13% of all lung cancer diagnoses and its incidence has reduced over the last 20 years, although the frequency is rising in women due to increased use of tobacco [1]. It is a highly malignant neuroendocrine tumor of the lung and treatment of SCLC remains challenging because of its rapid growth, early dissemination and development of drug resistance during the course of the disease [2]. Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2 to 4 months [2]. With current chemotherapy regimens survival is prolonged, however, the overall survival at 5 years is only 5% to 10% [2]. Topotecan [3] is currently the only drug licensed in Europe and the Unites States for second-line treatment of SCLC, having been shown in a phase III trial to lead to longer overall survival and better quality of life than with best supportive care. In advanced SCLC, prognosis after failure of first-line treatment is very poor. No new targeted agents have shown meaningful benefit in this disease and, therefore, an urgent need exists for new active agents [4]. Cyclin Kinase Inhibitors Cyclin dependent kinases (CDK) belong to a family of serine/ threonine protein kinases that are associated with an activating cyclin regulatory subunit. CDKs are involved in the regulation of fundamental cellular processes such as cell division cycle and gene transcription. Cell-cycle CDKs 1, 2, 4, and 6 are required for the correct timing and order of the events of the cell-division cycle. CDK7 is a component of the CDK-activating complex that contributes to the assembly of CDK1/cyclin B. In addition, CDK7 functions as a transcriptional CDK, as well as CDKs 8 and 9, which have been shown to be involved in gene transcription via regulation of RNA polymerase II activity. Deregulated CDK activity results in loss of cell-cycle checkpoint function and increased expression of antiapoptotic proteins, which has been directly linked to the molecular pathology of cancer [5]. Roniciclib (BAY 1000394) is a CDK inhibitor with low nanomolar activity against cell-cycle CDKs and transcriptional CDKs. It was evaluated in cell line-derived and patient tumor derived SCLC xenograft models. The compound strongly reduced tumor growth with T/C values between 0.12 and 0.19 showing that roniciclib was similar or even more efficacious as compared with cisplatin (T/C values between 0.06 and 0.55) [6]. In vivo, studies showed that roniciclib has more than additive efficacy when combined with cisplatin and etoposide. This compound is currently under investigation in a double-blind, placebo controlled phase II CONCEPT-SCLC trial to assess the safety and efficacy of roniciclib in combination with etoposide and cisplatin or carboplatin as first line therapy in patients with extensive SCLC after results obtained in a multicenter phase I study that evaluated 25 pre-treated SCLC patients [7]. Aurora Kinase Inhibitors The aurora kinases (A, B, and C) are serine/threonine kinases that have a key role in mitosis; in particular, aurora kinase A is essential for centrosome function and maturation, spindle assembly, chromosome alignment, and mitotic entry. Aurora kinase A localizes to the centrosomes and spindle poles and recruits the cyclin B1–CDK1 complex. Inhibition of aurora kinase A leads to abnormal spindle formation, mitotic defects, and cell death. Overexpression or amplification of this enzyme has been noted across a range of different tumor types and is linked with tumor progression and poor prognosis. Thus, inhibition of aurora kinase A is a rational target for anticancer treatment [8]. Alisertib exhibits favorable pharmacokinetic parameters and displayed tumor growth inhibition [9]. In Phase I dose escalation studies with alisertib given orally on a twice daily schedule for seven consecutive days, the maximum tolerated dose was defined predominantly by the occurrence of grade 3 or grade 4 myelosuppression and stomatitis, consistent with the antiproliferative effects of Aurora A inhibition. In a phase II study, the small-cell lung cancer cohort (see figure 1), ten (21%; 95% CI 10–35) of 48 patients had an objective response to alisertib; all responders achieved a partial response. Response-assessable patients with small- cell lung cancer received a median of 2,5 cycles (range 1−21) of alisertib, with a median time on treatment of 1,5 months (range 0,1−11,7, IQR 0,9–3,7). The median duration of response was 4,1months (95% CI 3,1 not evaluable), median progression-free survival was 2,1 months (95% CI 1,4–3,4), and median time to progression was 2,6 months (95% CI 1,4–3,8). The adverse effects of alisertib were generally manageable and included anemia, fatigue, alopecia, and various gastrointestinal disorders, and consistent with those noted in earlier trials of alisertib. Neutropenia was the most frequent drug related grade 3–4 adverse event; however, febrile neutropenia was recorded much less frequently. The antitumor activity noted in the SCLC cohort in this study (objective response 21%) seems similar to that reported with the current standard of care, topotecan (objective response 7–24%) [3]. Although the initial signal of activity noted in both the chemotherapy sensitive relapse population and in patients with refractory and chemotherapy resistant relapse is encouraging, to achieve more meaningfully improved outcomes, combinations of alisertib with other anticancer drugs should be studied. A follow-up, randomized, global phase 2 trial of alisertib plus weekly paclitaxel versus placebo plus paclitaxel as second-line treatment for small cell lung cancer is currently enrolling. References [1] Youlden DR, et al. The International Epidemiology of Lung Cancer: Geographical Distribution and Secular Trends. Journal of Thoracic Oncology, Vol. 3, No. 8, 2008, pp. 819-831. [2] Govindan R, et al. Changing Epidemiology of Small-Cell Lung Cancer in the United States over the Last 30 Years: Analysis of the Surveillance, Epidemiologic, and End Results Database, Journal of Clinical Oncology, Vol. 24, No. 28, 2006, pp. 4539-4544. [3] Ormrod D and Spencer CM, Topotecan: A Review of Its Efficacy in Small Cell Lung Cancer, Drugs, Vol. 58, No. 3, pp. 533-551. [4] Joshi M, et al.. Small-cell lung cancer: an update on targeted therapies. Adv Exp Med Biol 2013; 779: 385–404. [5] Lapenna S,et al.. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov 2009;8:547–66. [6] Siemeister G, et al. . BAY1000394, a novel cyclin –dependent kinase inhibitor, with potent antitumor activity in mono and combination treatment upon oral application. Mol Cancer Ther, 2012 Oct 11 (10): 2285-73 [7] Bahleda R, et al. A first-in-human phase I study of oral pan-CDK inhibitor BAY 1000394 in patients with advanced solid tumors: Dose escalation with an intermittent 3 days on/4 days off schedule.. J Clin Oncol 30, 2012 (suppl; abstr 3012) [8] Bolanos-Garcia VM. Aurora kinases. Int J Biochem Cell Biol 2005; 37: 1572–77.
 [9] Sells TB, et al. MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors. ACS Med Chem Lett, 2015, 6, 630-4. [10] Melichar B, et al. Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. Lancet Oncol, Vol16 April2015, 305-405 Figure 1

Abstract:
Small cell lung cancer (SCLC) accounts for nearly 15% of newly diagnosed lung cancers.[1] With the advent of tyrosine kinase inhibitors, the last decade has witnessed remarkable improvements in the outcomes of patients with non-small cell lung cancer (NSCLC). However, outcomes in patients with SCLC continue to remain dismal. Currently approved targeted therapies have minimal role in the management of SCLC, since unlike NSCLC, targetable tyrosine kinase alterations are rarely witnessed in SCLC.[2,3] Cytotoxic chemotherapy has therefore continued to remain the standard of care for SCLC. SCLC is usually very sensitive to first-line platinum based therapies.[4] Nevertheless, these responses are seldom durable and majority of patients relapse within weeks to months of treatment completion. Relapsed SCLC is a tough disease to treat and barely responds to conventional therapies. There is hence is an urgent need to develop novel therapeutic strategies that are capable of improving survival in patients with SCLC - particularly those with relapsed disease. Several new chemotherapeutic agents are currently being developed and actively studied in various solid tumors. The objective of this article is to highlight some of these newer chemotherapies and discuss their potential relevance in the management of SCLC. Eribulin mesylate is a non-taxane halichondrin B analogue derived from the marine sponge Halichondria okadaic.[5] Eribulin sequesters tubulin and inhibits mitotic spindle formation, leading to cell cycle arrest in G2-M and eventually cell death. Eribulin is currently FDA approved in the United States for the management of metastatic breast cancer in patients receiving prior treatment with at least two chemotherapy regimens, including an anthracycline and a taxane. In the phase III EMBRACE trial, as a part of which 762 women with breast cancer were randomized to receive eribulin or chemotherapy of the treating physician’s choice, overall survival (OS) was significantly improved with eribulin (13.1 vs. 10.6 months, HR 0.81 p=0.041).[6] Eribulin as single agent and in combination with erlotinib were shown to be active and well tolerated in patients with NSCLC treated with prior platinum based therapies.[7] In the study by Spira and colleauges, eribulin was dosed at 1.4mg/m2 on days 1 and 8 of a 21 day cycle (similar to breast cancer dosing schedule) and in a second cohort of patients at 1.4 mg/m2 on days 1, 8 and 15 of a 28 day schedule.[8] Among these, the 21 day dosing schedule was shown to be better tolerated and active with a median OS of 9.4 months in the second line setting for NSCLC. However, when used in combination with a second agent, the maximum tolerated dose (MTD) of eribulin was much lower. In a phase Ib/II study involving pretreated NSCLC patients, the MTD of eribulin was 0.9mg/m2, with 500mg/m2 of pemetrexed, administered on day 1 of a 21 day cycle.[9] Unfortunately, the combination was tolerable but showed no therapeutic benefit at this dose. Aldoxorubicin, formerly known as INNO-206, combines a molecular linker that allows doxorubicin to bind covalently to serum albumin upon intravenous administration.[10] This formulation releases doxorubicin in the acidic tumor microenvironment. Aldoxorubicin is currently being actively investigated in the management of soft-tissue sarcomas and glioblastoma. In a phase Ib/II study by Chawla and colleagues, the MTD of aldoxorubicin was 350mg/m2 administered every 21 days.[11] The drug showed a partial response rate of 20% and stable disease rate of 40% in 25 patients with advanced chemotherapy refractory cancers, among which most patients (68%) had soft tissue sarcomas. Aldoxorubicin was considered to be safe and efficacious in these patients. Currently, aldoxorubicin is being studied as part of an ongoing randomized phase IIb trial in patients with relapsed/refractory SCLC (NCT02200757). This study will compare progression free survival (PFS) between patients receiving aldoxorubicin at a dose of 230mg/m2 every 21 days, with those receiving topotecan. Irinotecan is a chemotherapeutic agent known to be active in SCLC. SN38 is the active metabolite of irinotecan, which through its inhibitory action on DNA topoisomerase I induces DNA breaks and inhibits repair. Etirinotecan pegol is a formulation designed to provide prolonged systemic exposure to SN38.[12] In a phase I dose escalation study, 66 patients received etirinotecan on three different dosing schedules and 115mg/m2 administered on days 1, 8 and 15 of 21 day cycles was established as the MTD. Diarrhea was observed in 5 patients at the 115mg/m2 dose level, with one patient experiencing grade 3 or higher diarrhea. The cholinergic diarrhea that is seen with irinotecan was not observed with etirinotecan. The drug was also shown to induce partial responses in patients with various cancers including SCLC. Etirinotecan was also recently reported to be active in heavily pretreated ovarian cancer patients.[13] In this study etirinotecan was administered at 145mg/m2 every 14 or 21 days, and the 21 day dosing schedule was found to be better tolerated and selected for further study. A phase II study that plans to study the effect of etirinotecan dosed every 21 days on PFS in patients with relapsed SCLC is currently recruiting (NCT01876446). Another formulation of irinotecan, MM-398, which is a nanoliposomal encapsulated formulation that packs nearly 80,000 irinotecan molecules in a 100nm liposome, is also being actively investigated in pancreatic, gastrointestinal, and other solid tumors.[14] Results from the NAPOLI-1 trial, a phase III study in which patients with metastatic pancreatic cancer who were previously treated with gemcitabine, were randomized to receive either single agent MM-398 at 120mg/m2 every 3 weeks or a combination of 5-fluorouracil (5FU), leucovorin (LV) and MM-398 at 80mg/m2, or 5-FU/LV alone, were recently presented.[15] The primary objective of this study was OS and in the intention to treat analysis, this was significantly improved in the MM-398/5FU/LV combination arm compared to the 5FU/LV arm (median OS 6.1 months vs. 4.2 months, HR-0.57, p=0.0009). Although there is currently no clinical data regarding the efficacy or safety of these newer drugs in patients with SCLC, considering that taxanes, anthracyclines, and DNA topoisomerase inhibitors are each individually active in SCLC, and that newer agents such as these have shown some positive preliminary results in other cancers - there is hope and optimism that over the next few years we will witness substantial progress in the management of SCLC. Overall, the need for developing and implementing well-designed biomarker driven clinical studies to investigate the role of these and other novel agents in SCLC is now greater than ever. References 1. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 2006;24:4539-44. 2. Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 2012;44:1111-6. 3. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 2012;44:1104-10. 4. Kalemkerian GP, Akerley W, Bogner P, et al. Small cell lung cancer. J Natl Compr Canc Netw 2013;11:78-98. 5. Scarpace SL. Eribulin mesylate (E7389): review of efficacy and tolerability in breast, pancreatic, head and neck, and non-small cell lung cancer. Clin Ther 2012;34:1467-73. 6. Cortes J, O'Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 2011;377:914-23. 7. Mok TS, Geater SL, Iannotti N, et al. Randomized phase II study of two intercalated combinations of eribulin mesylate and erlotinib in patients with previously treated advanced non-small-cell lung cancer. Ann Oncol 2014;25:1578-84. 8. Spira AI, Iannotti NO, Savin MA, et al. A phase II study of eribulin mesylate (E7389) in patients with advanced, previously treated non-small-cell lung cancer. Clin Lung Cancer 2012;13:31-8. 9. Waller CF, Vynnychenko I, Bondarenko I, et al. An open-label, multicenter, randomized phase Ib/II study of eribulin mesylate administered in combination with pemetrexed versus pemetrexed alone as second-line therapy in patients with advanced nonsquamous non-small-cell lung cancer. Clin Lung Cancer 2015;16:92-9. 10. Kratz F. A clinical update of using albumin as a drug vehicle - a commentary. J Control Release 2014;190:331-6. 11. Chawla SP, Chua VS, Hendifar AF, et al. A phase 1B/2 study of aldoxorubicin in patients with soft tissue sarcoma. Cancer 2015;121:570-9. 12. Jameson GS, Hamm JT, Weiss GJ, et al. A multicenter, phase I, dose-escalation study to assess the safety, tolerability, and pharmacokinetics of etirinotecan pegol in patients with refractory solid tumors. Clin Cancer Res 2013;19:268-78. 13. Vergote IB, Garcia A, Micha J, et al. Randomized multicenter phase II trial comparing two schedules of etirinotecan pegol (NKTR-102) in women with recurrent platinum-resistant/refractory epithelial ovarian cancer. J Clin Oncol 2013;31:4060-6. 14. Saif MW. MM-398 achieves primary endpoint of overall survival in phase III study in patients with gemcitabine refractory metastatic pancreatic cancer. JOP 2014;15:278-9. 15. Dhindsa N, Bayever E, Li C, et al. NAPOLI-1: randomized phase 3 study of MM-398 (nal-iri), with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic cancer progressed on or following gemcitabine-based therapy. Annals of Oncology (2014) 25 (suppl_2): ii105-ii117. 10.1093/annonc/mdu193.

Abstract:
Immunotherapy has recently confirmed its place as an important treatment strategy for a number of solid tumors, including melanoma and non-small cell lung cancer. Checkpoint blockade, in particular, has emerged as an ‘off-the-shelf’ immunotherapy which does not rely on known tumor antigens, costly and time-consuming individualised preparation of autologous tumor, or viral vectors. This overview will cover the history of immunotherapy in mesothelioma, recent reported clinical trials, trials in progress, and current cutting edge research with the potential for translation. Although mesothelioma is not classically considered immunogenic, there is abundant evidence that it is recognised by the immune system. Earlier studies described the relationship between tumour infiltrating lymphocytes and prognosis, occasional spontaneous remissions are seen, and there have been reports of low rates of responsiveness to a range of immunotherapies over the past 30 years. There is also a body of work demonstrating impaired immune responsiveness in people with mesothelioma and an immunosuppressive intratumoral milieu. Specifically, NK cell activity is reduced, CD4+ lymphocyte numbers are reduced, and dendritic cell function is impaired (Cornwall S, unpublished data), amongst other changes. Regulatory T cells and inhibitory cytokines within the tumour may contribute to an immunosuppressive milieu [1]. The presence of CD8+ infiltration within the tumour is a predictor of more favourable outcomes [2]. More recently, mesothelioma, in particular sarcomatoid subtype, was shown to overexpress PD-L1 and to predict poor prognosis [3] Historically, response rates below 20% have been seen in clinical trials of systemic and intrapleural interferons, generally accompanied by high toxicity [4]. Similarly, other cytokines such as Interleukin-2 or GM-CSF have shown either poor response rates, low feasibility, or excessive toxicity [5]. Gene therapy approaches have similarly shown very low response rates and are technically demanding [6]. More recent trials have focussed on antigen-specific approaches using the known tumor antigens mesothelin and WT-1, and the use of checkpoint blockade. Immunological checkpoints are inbuilt mechanisms that negatively regulate the size and duration of an immune response, both during induction of the T cell response and during the effector phase of the response, in tumor tissue. Their normal function is to prevent excessive and ongoing T cell activation which may lead to overwhelming autoimmunity. Many tumors, including mesothelioma, express ligands for these checkpoint molecules, allowing tumors to negatively regulate the anti-tumor immune response and thus evade elimination [3]. The expression of checkpoint molecules including Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and PD-1 on T cells, and the expression of ligands such as PD-L1 and PD-L2 on tumors, has allowed the development of antibody blockade which can prevent downregulation of the anti-tumor response by inhibitory signals, hence ‘taking off the brakes’ and facilitating a more effective host response to tumor. CTLA4 is expressed on T cells after activation, and counter-regulates the T cell activation which normally occurs when the co-stimulatory receptor CD28 is engaged. Whilst ligation of CTLA4 normally restricts ongoing T cell co-stimulation and activation, abrogating anti-tumour immunity[7], CTLA4 blockade using monoclonal antibody inhibitors can allow the endogenous anti-tumour response to proceed unopposed. The first report of a clinical trial of this drug class in mesothelioma was published by Calabro and colleagues in 2013 [8], with results showing some similarities to the first trials of CTLA4 blocking antibodies in melanoma. Durable partial responses were seen in two patients, with a further seven of 29 patients experiencing prolonged stable disease. The disease control rate was 31%, median progression free survival was 6·1 months, and almost 40% of participants were alive at two years. The phenomenon of early progression followed by a lengthy partial response was seen in one patient. The authors noted that the progression free survival and two year survival results were better than expected for this population, and although partial responses were uncommon they were long lasting. This study provided the rationale for the subsequent testing of tremelimumab in a large randomised phase II study in mesothelioma which has recently completed recruitment (NCT01843374). A recent presentation at the American Association for Cancer Research (AACR) reported on results from the mesothelioma cohort enrolled in the KEYNOTE-028 study. This trial used PD1 axis blockade with pembrolizumab in patients with mesothelioma selected to express the PD-L1 ligand. Of 25 patients treated, partial response was observed in 7 (28%) and stable disease in 12 (48%), giving a disease control rate of 76% with a tolerable toxicity profile. Many of the responses seen were profound and durable[9], highlighting the enormous potential of this approach in mesothelioma. Finally, mesothelin is highly expressed on mesothelioma cells, predominantly of the epithelioid subtype. A number of methods of targeting mesothelin are under development and clinical testing. The anti-mesothelin immunotoxin SS1P has been administered together with lymphodepletion using cyclophosphamide and pentostatin. Major responses were observed in a subset of patients in a small clinical trial (n=10), notably with some reports of immune pseudoprogression before eventual treatment response. Other treatments using mesothelin as a target include CRS-207, a live attenuated listeria monocytogenes strain which expresses mesothelin, and MORAb-009, a monoclonal antibody that targets mesothelin. Immunotherapy in mesothelioma remains very immature. Results of PD1 and/or PD-L1 blockade in larger numbers of treated patients are needed, and phase III studies will be important to define any benefits. Combinations of checkpoint blockade have shown outstanding efficacy in other cancer types and must be tested in mesothelioma. Underpinning these trials must be the search for biomarkers of treatment efficacy. Technologies such as tumor sequencing also have the potential to identify neoantigens with immunological reactivity in individual patients, an approach that could lead to the development of personalised vaccines, potentially in combination with other immunotherapies. References 1. Hegmans, J.P.J.J., et al., Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses. European Respiratory Journal, 2006. 27(6): p. 1086-95. 2. Yamada, N., et al., CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection. Cancer Immunol Immunother, 2010. 59(10): p. 1543-9. 3. Mansfield, A.S., et al., B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis. J Thorac Oncol, 2014. 9(7): p. 1036-40. 4. Boutin, C., et al., Intrapleural treatment with recombinant gamma-interferon in early stage malignant pleural mesothelioma. Cancer, 1994. 74(9): p. 2460-7. 5. Astoul, P., et al., Intrapleural recombinant IL-2 in passive immunotherapy for malignant pleural effusion. Chest, 1993. 103(1): p. 209-13. 6. Schwarzenberger, P., et al., Antitumor activity with the HSV-tk-gene-modified cell line PA-1-STK in malignant mesothelioma. Am J Respir Cell Mol Biol, 1998. 19(2): p. 333-7. 7. Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews. Cancer, 2012. 12(4): p. 252-64. 8. Calabro, L., et al., Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol, 2013. 14(11): p. 1104-11. 9. Alley, E.W., et al., Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-028, in Proc Am Assoc Cancer Res. 2015.

Abstract:
Mesothelin is a tumor differentiation antigen that is highly expressed in several cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. The limited expression of mesothelin on normal human tissue and its high expression in many solid tumors make it an attractive candidate for cancer therapy. Several drugs targeting mesothelin, including immunotoxins (SS1P, RO6927005), a chimeric monoclonal antibody (Amatuximab), an antibody drug conjugate (Anetumab Ravtansine), and a tumor vaccine (CRS-207), are in various stages of development to treat patients with mesothelin-expressing tumors. The first anti-mesothelin therapeutic agent to enter the clinic was the immunotoxin SS1P and it demonstrated that mesothelin could be successfully exploited as a target for cancer therapy and has led to a broad interest in developing different approaches for mesothelin immunotherapy treatment of solid tumors including malignant mesothelioma. Immunotoxins are targeted anti-cancer therapeutics that kill cancer cells by inhibition of protein synthesis using a cytotoxic bacterial toxin payload. In a phase I clinical trial SS1P had limited anti-tumor activity because it was immunogenic and patients develop antibodies to the drug limiting treatment efficacy. However, we have recently shown that co-administration of SS1P with a lymphocyte depleting regimen of pentostatin and cyclophosphamide can delay anti-drug antibody formation, increasing the number of treatment cycles that patients can receive and resulting in durable responses in heavily pre-treated mesothelioma patients. In addition, a new generation of immunotoxin molecules with reduced immunogenicity and non-specific toxicity have been developed through protein engineering techniques. RO6927005 is a next generation anti-mesothelin PE-fusion protein that has been protein-engineered to maximally reduce its immunogenicity so that patients can receive multiple cycles of the drug. In pre-clinical studies RO6927005 has increased activity compared to SS1P against mesothelioma tumor cells directly obtained from patients as well as activity in mesothelioma tumor models either alone or in combination with chemotherapy. A phase I clinical trial of RO6927005 has just been initiated for patients with mesothelin expressing cancers including malignant mesothelioma. There are other antibody based therapeutics in advanced clinical development for treatment of malignant mesothelioma including amatuximab and anetumab ravtansine. In a phase II single arm trial of unresectable, chemotherapy naïve patients with pleural mesothelioma, amatuximab with pemetrexed and cisplatin was well tolerated with objective tumor response or stable disease rate of 90% by independent radiologic review. Based on these results a registration front-line study of amatuximab with pemetrexed and cisplatin versus pemetrexed and cisplatin alone has been initiated for treatment of newly diagnosed patients with pleural mesothelioma. Anetumab Ravtansine (BAY 94-9343) is an antibody-drug conjugate in which a human anti-mesothelin monoclonal antibody is conjugated to the maytansinoid tublin inhibitor DM4. In preclinical studies it showed significant anti-tumor activity against mesothelioma cell lines as well as mesothelioma patient derived xenografts. Anetumab Ravtansine is currently being evaluated in patients with mesothelin expressing cancers who have failed standard therapies and represents a potential therapeutic option for treatment of patients with mesothelioma given the high and uniform expression of mesothelin in this tumor. Hopefully, these different approaches to exploit mesothelin for immunotherapy of malignant mesothelioma will result in new treatment options for these patients.

Abstract:
In recent years immunotherapy has become a new standard in the treatment of malignant diseases. Most clinical evaluated treatments like anti-PD1 aim to reactivate the cytotoxic T-cell response directed against the tumor (CTL-t ). A requirement for this treatment to be effective is the presence of CTL-t within the tumor as reviewed by us recently [Aerts, 2013]. CTL-t formation is dependent on a number of factors which are inhibited by tumor-derived factors and tumor-induced immune suppressive cells, precluding patients to respond to the PD-1 checkpoint blockade pathway. Knowing and bypassing these inhibition pathways of the tumor increases the number of responding patients. For instance, in melanoma it has been shown that combination treatment of anti-PD-1 and anti-CTLA-4 almost doubles the patients benefitting from checkpoint blockade inhibitors. However the number of inhibition pathways is diverse and also changeable according to the act – react principle. The blockade of one inhibitory pathway of the tumor may ultimately lead to the upregulation of another inhibitory pathway. This complex interplay inhibits the formation of new CTL-t and an exhaustion of the CTL-t present in the tumor. That is why cell based therapy, either with ex-vivo generated T-cells or stimulated dendritic cells (DC), precluding a number of inhibitory mechanisms in the patient is an alternative to increase the number of responding patients and thus the efficacy of immunotherapy. Mesothelioma is an aggressive neoplasm, with highly specific growth features making it a distinctive malignant tumor from other cancer types. One of the key immunological features in mesothelioma is the abundant immunosuppressive environment it is creating. There is a large infiltration of regulatory T-cells, immunosuppressive macrophages and myeloid derived suppressor cells (MDSC). Furthermore, the tumor milieu negatively influences immune activation for instance by the presence of hypoxic areas. , tumor metabolites (e.g. arachidonic acid), and suppressive cytokines and chemokines negatively influence the immune activation. Some early phase studies showed a possible clinical effect of immunotherapy in mesothelioma. For instance, checkpoint inhibition with anti-CTLA-4 and anti PD-1 in a subgroup of patients showed some benefit which is now further evaluated in larger studies in second and further line treatment [Calabro 2013, NCT01843374 results pending, NCT02399371 amongst others] . Although it can be questioned whether that is the right setting to determine clinical benefit in placebo controlled trials. Anti mesothelin antibodies also did show clinical efficacy which is now investigated further [Hassan 2010]. Cell based therapy may increase efficacy of immunotherapy also in mesothelioma. The choice of the tumor associated antigens (TAA) to induce a CTL-t is critical, considering the diverse and changing repertoire of TAA. Genetically altered T-cells, directed against mesothelin or Wilms tumour-1 (WT-1) have been developed and are tested in the clinic [NCT02414269 amongst others]. Also DC therapy, being the most powerful initiator of an immune response, is also tested. An advantage of DC, apart from the induction of a natural CTL-t activation, is the ability to load the DC with a pluripotent antigen mixture. DC therapy with an autologous tumor cell lysate demonstrated promosing results [Hegmans 2010] and an allogeneic tumor cell lysate is now tested as tumor associated antigen source in the clinic [NCT2395679]. In the patient stimulation of DC seems an attractive option and has been investigated but may be hampered by the immunosuppressive environment created by the tumor [Powell, 2006]. A new concept with in vivo activation of DC with mesothelin loaded listeria bacteria is now investigated in mesothelioma [NCT01675765]. DC treatment can also be optimized with the addition of different checkpoint activators or inhibitors [Lievense WCLC 2015] Apart from the immune activation strategies, investigations should focus on how to diminish the highly immunosuppressive effect of mesothelioma. Results of our trial on combination treatment with ex vivo matured DC loaded with autologous tumor cell lysate and regulatory T cell (Treg) depletion showed a reduction in circulation Treg [data submitted for publication]. We are in the field of a whole new changing treatment paradigm for mesothelioma. Immunotherapy will be one of the new treatment options. Much effort has to be invested to determine the optimal combination treatment for particular patients. Dendritic cell-based therapy seems an attractive option to generate a more robust immune response that can serve as a backbone for combination treatment.

Abstract not provided

Abstract not provided

Abstract:
Purpose: The purpose is to discuss how to advocate to make a Responsible Case for the Screening of lung cancer high risk group. Background and fact: Screening is looking for cancer at an early stage before a person has any symptoms. For the better screening, efficiency is determined as well as sensitivity and specificity. In these forty years, three screening tests have been studied to find if they decrease the risk of dying from lung cancer. Chest X-rays were evaluated at the earliest time in the lung cancer screening history while it is no longer recommended for screening.. Sputum cytology is a procedure in which a sample of sputum is viewed under a microscope to check for cancer cells, so it is required to good mucus that is coughed up from the lungs. Now, it is used as a non-invasive examination of a patient with a sputum symptoms rather than screening. Low-dose spiral CT (LDCT) scan is a special kind of x-ray that takes many pictures as you lie on a table that slides in and out of the machine. A computer then combines these pictures into a detailed picture of a slice of your body. In this procedure, low-dose radiation is used to make a series of very detailed pictures of areas inside the body with reduction of radiation exposure.. The National Lung Screening Trial (NLST) provided the first evidence that lung screening can reduce cancer deaths, when data from the study was published in 2011. The National Lung Screening Trial began in 2002 and enrolled more than 53,000 participants who were current or former heavy smokers, ages 55 to 74. The trial randomly assigned people to receive lung screening either by low-dose helical CT scans or chest X-rays. The trial was sponsored by the National Cancer Institute, and the University of Michigan was one of 33 places across the country to take part. U-M enrolled 850 participants. The study found that screening individuals with low-dose CT scans could reduce lung cancer mortality by 20 percent compared to chest x-ray. Now, it is concluded that the only recommended screening test for lung cancer is LD-CT, which result Medicare's decision to cover lung cancer screening in US. However, the evidence at the present time in LD-CT screening is only one report from US, the results of additional studies from Europe (NELSON) and Japan (Sagawa team) is awaited. Discussion: To raise up the efficiency of screening, It is important who is suitable as subjects. According to “ the Lung Cancer Screening Guidelines and Recommendations” by CDC, many organizations in US definite that lung cancer screening with LDCT is recommended for people of age 55 to 74 years with ≥ 30 pack year smoking history, who either currently smoke or have quit within the past 15 years while some difference of subjects who are in relatively good health or age 55 to 80 years across organizations. However, major obstacles are lying that smokers are lack of awareness or information for risks and benefits with attention to the specifics of each person making a decision about screening as well as the risk of lung cancer, in order to operate LD-CT screening effectively. GLCC poll in 2013 showed that in Australia and Great Britain current smokers are less aware of the symptoms of lung cancer than former smokers and people who have never smoked regularly. Even if screening system was developed, the risk of death due to lung cancer can not be reduced unless the people of high risk group do not visit to appropriate screening service that has been ensurring quality. In addition, Assessment of smoking and the provision of smoking cessation services must be part of any lung cancer screening program. Advocate movement based on research is urgently needed to develop approaches that will maximize cessation rates among smokers undergoing screening. Even more, it is required to enlightenment for smokers in cooperation with the international community by utilizing a variety of public relations means. In November 2014, lung cancer awareness month, Japan Lung Cancer Society approved the Kyoto Declaration. This declaration has been included that the tackle in the prevention of lung cancer and development of effective treatment by alliance with lung cancer Society, lung cancer patient, government, people, medical personnel, advocacy organizations, and healthcare industry. While the evidence from the NLST supports the implementation of lung cancer screening for high-risk individuals via LDCT, the experience to date also must validates the prior recommendations around institutional approaches to lung cancer screening, including the need for the availability of multidisciplinary clinical teams. In order to advocate making responsible case, several ways should be developed like a “Shared Decision-Making” toolkit(s) by the Lung Association that would act as a “consumers’ guide” for those considering lung cancer screening. After examine such a tool, it is also one of the ideas to take advantage according to the circumstances of each country.

Abstract:
The development and release of scientific validation and national guidelines and recommendations for lung cancer screening over the past several years has resulted in a profound paradigm shift in clinical opinion and outcomes for those at high risk for lung cancer. No other cancer is poised to realize the scale and magnitude of benefit that is now being reported for the lung cancer community. Given the import and potential of this opportunity, it was evident that there was a lack of vigor and focus by public health leadership to move aggressively and to take the next steps to develop programs and guidance to ensure the safe, responsible and equitable implementation of lung cancer screening and to bring proper health messages to those at risk. Lung Cancer Alliance (LCA), a national non-profit cancer advocacy organization, recognized this absence and stepped in to bridge these gaps and create an environment to support the adoption of best practices and consumer safety measures, as well as public service messaging about screening risk and benefit. Immediately upon the scientific validation of the mortality benefit of lung cancer screening, LCA moved rapidly to convene a multi-disciplinary team of health care professionals to devise a blueprint or framework to guide the responsible implementation of screening. The overarching goal embedded in this discussion was to ensure the public understood that they had right to know they could be risk for lung cancer and that they had a right to responsible care. This was particularly important after the National Cancer Institute (NCI) announced it was halting the National Lung Screening Trial (NLST) as the end point was reached proving at a minimum a 20% mortality benefit. And thus, the LCA National Framework for Excellence in Lung Cancer Screening and Continuum of Care was born in February 2012. Embedded within this National Framework are the following guiding principles and elements: 1. Increasing the public’s awareness about risk and their rights to responsible care, including educational resources and campaigns to spread this message; 2. Creating a framework of agreed upon best practices to guide the safe and responsible development of a screening center of excellence medical center network that then leveraged member resources to support each other; 3. Creating collaborations and relationships with other professional and advocacy societies and outreach to public and private payers to effect change at the policy level. Today, there are currently 350 hospitals within the LCA National Network of Screening Centers of Excellence who have committed to following certain best practice principles of care. Dozens of other medical centers continue to contact LCA for technical assistance and are in varying stages of program development. LCA launched an ad campaign in 2014 to raise risk awareness which received 90 million impressions through TV, print, and social media in 15 paid markets and about 20 PSA markets. In addition, LCA has helped successfully lead first-ever public health coalitions to advocate for coverage and other policy changes linking together diverse partnerships. This has included engaging the current screening centers of excellence in communication with the US Preventive Services Taskforce (USPSTF), Congress and other regulatory agencies, working with an alliance of stakeholders including ACR and STS to encourage swift action on the part of Centers for Medicare Medicaid Services (CMS) to ensure coverage for at-risk seniors, and communicating with lawmakers and encouraging them to take oversight action to ensure public health strategies by our Health and Human Services (HHS) Departmental move forward as efficiently, effectively and equitably as possible. With the finalization of the USPSTF recommendation for lung cancer screening and coverage for Medicare beneficiaries, lung cancer screening is now a covered benefit for those at high risk, with no cost sharing, co-pays or deductibles. The LCA experience is an example of how an agile and responsive patient advocacy charity can provide critical institutional support and a national public health blueprint for the scale up of a new preventive service – that is patient focused and patient driven. By creating what in effect is a national pilot program for lung cancer screening, LCA proved that responsible screening and outreach could be reproduced in medical centers all across the country at the community level. And by working closely and directly with screening centers – we have established a deeper understanding of their needs which in turn has helped us tailor our continued outreach and support to better suit their needs. Our consumer-targeted awareness campaigns have shape a culture of consciousness among the public which in turn have allowed us to better design educational materials. LCA is committed to continuing to build knowledge about the importance of screening among the at-risk public, healthcare providers, and policymakers alike. LCA is proud to have seized an important moment in time to have built a foundation for responsible care when people at risk for lung cancer needed it most. Figure 1

Abstract:
For a long period of time, lung cancer has been considered a malignancy affecting only men, but epidemiological data have shown a dramatic increase of the incidence among women and the gender gap has been narrowing steadily since the 1980s,mainly as a consequence of the huge spread of tobacco consumption during the past 60 years. Although more men are diagnosed with lung cancer, incidence is leveling off or decreasing in men, but is increasing among women.Lung cancer is the leading cause of cancer death for women in the United Statesand other countries, with about 105,600 new cases and 71,000 estimated deaths in 2015 for the female gender, whereas in European countries lung cancer is predicted to kill 87,500 women in 2015, but such predictions require caution. In Europe, for the first time in 2015 (unlike in the U.S. where it has been happening for some decades)lung cancer death rates in females are expected to overtake those of breast cancer. This trend is largely driven by women in the UK and Poland, confirming that the continuous increase in lung cancer mortality among women represents a challenge for cancer control. This disease is classified as a significant global women’s health issue. Unfortunately, women still lack awareness and knowledge about lung cancer, it is not considered a priority because most of them still believe that breast cancer is the number one cancer in women. They have misperceptions and in most cases they are not concerned because they are too young or are non-smokers. Gender differences in terms of susceptibility to carcinogens have been reported and several studies suggestthat women are more vulnerable to tobacco carcinogens than men, however this data remains controversial. Although smoking increases the risk of lung cancer dramatically, it's not the only cause. Freedman et Al reported on a cohort of nearly 500,000 individuals aged from 50 to 71 years, in which asignificant increase of cases occurred in women who never smoked, compared with male non-smokers. The rate of lung cancer in those who never smoked is higher for women in every population, counting approximately 20% of women who never smoked. The reason is unclear, but studies suggest that the hormonal status may be one potential explanation and researchers are devoting energies in this area to better understand the implication of gender differences in epidemiology, pathogenesis, prognosis and tumor response, considering that women have better survivalrates than men at any stage regardless of the type of lung cancer and the therapeutic approach. At the moment there are no gender-based approaches on diagnosis and treatment for lung cancer, but an improvement in understanding genetic, metabolic and hormonal factors could stimulate research towards further personalized gender-based investigations. Despite recent advances in treatment, lung cancer still remains a largely incurable disease with a physical impact upon women, as well as social, psychological, practical and emotional consequences. The diagnosis and subsequent treatments are traumatic events for patients and their loved ones. Serious disruptions in social and psychological aspects of their quality of life have been reported and younger women are most at risk. This type of cancer is normally associated with older people, where the disease is often diagnosed accidentally, while in young adults it is relatively rare, the incidence has been found to be around 1.2% to 6.2% (under 40 years), 5.3% (under than 45 years), and 13.4% (under 50 years),but previous reports have shown trends of increasing incidence rates of lung cancer among young patients. Unfortunately in this group this malignancy is more common in women, who are diagnosed at an advanced stage and normally receive aggressive treatments. It can be very difficult to cope with a diagnosis of lung cancer, both practically and emotionally, because the news can generate a wide range of emotions: fear, anxiety, anger, confusion, that could worsen the situation if patients are younger women because they often have to face challenges different than other patients. The worst are mothers of children or teenager, telling them the diagnosis is hard and traumatic, it means dealing with their emotions and reactions and helping them to face a daily routine affected by this event. Many feel unable to manage changes caused by lung cancer and this may create a state of distress that is increasingly recognized as a factor that can reduce the quality of life of patients. Moreover they feel hopeless, worried and sad about the uncertainty of their future and their children’s future. The disease and its treatments often may cause physical changes in the way they look, which is difficult to cope with and may affect the way women feel about themselves. Such body changes can diminish their self-esteem and change the way they relate to other people, especially family and friends. Disease progression, symptoms orside effects may force women to change the daily management of their family and house. The consequence is the inability to keep the pace of motherhood and to keep on doing things like they were used to do (for example working around the house), especially if children are young and energetic.These physical issues may also jeopardize their career and in many situations forcing them to quit job, increasing the frustration of losing their independence. Lung cancer may affect the dynamics of intimate relationships. This is connected to body image changes,in whichwomen may feelless attractive or desirable by their partner. Common symptoms of lung cancer, such as cough, fatigue or shortness of breath may affect their sexual life. Women with lung cancer have a number of unmet needs that require assistance. It is important to identify them efficiently and effectively so that patients can be provided with appropriate resources so they can find help. Physical needs are experienced by the majority of women, but emotional, psychological, social, spiritual, practical and informational needs are also present for some. Interventions must be developed to assist these women to cope with these needs and worldwide several gender focused educational and support programs have already been designed with this purpose. References: Silvia Novello & Tiziana Vavalà Lung cancer and women, Future Oncology Vol. 4, No. 5, Pages 705-716 Cancer 2010, 116(15):3656-3662. PubMed Abstract | Publisher Full Text Subramanian J, Morgensztern D, Goodgame B, Baggstrom MQ, Gao F, Piccirillo J, Govindan R: Distinctive characteristics of non-small cell lung cancer (NSCLC) in the young: a surveillance, epidemiology, and end results (SEER) analysis. J ThoracOncol 2010, 5(1):23-28. Ak G, Metintas M, Metintas S, Yildirim H, Erginel S, Alatas F: Lung cancer in individuals less than 50 years of age. Lung 2007, 185(5):279-286. Skarin AT, Herbst RS, Leong TL, Bailey A, Sugarbaker D: Lung cancer in patients under age 40. Lung Cancer 2001, 32(3):255-264. Bourke W, Milstein D, Giura R, Donghi M, Luisetti M, Rubin AH, Smith LJ: Lung cancer in young adults. Chest 1992, 102(6):1723-1729. Schnoll RA, Patterson F, Lerman C. Treating tobacco dependence in women. J Womens health 2007;16:1211-1218 Freedman ND, Leitzmann MF, Hollenbeck AR et al. Cigarette smoking and subsequent risk of lung cancer in men and women: analysis of a prospective cohort study.Lancet Oncology 2008;9:649-656 Donington JS, Colson YL. Sex and gender differences in non-small cell lung cancer. Seminars Thoracic Surgery2011;23:137-145 American Society of Cancer Oncologists. 2009. Women and Lung Cancer. Margaret I. Fitch, Rose Steele Supportive care needs of women with lung cancer- Canadian Oncology Nurses Vol 18, No 1 (2008)

Abstract:
The Community Hospital Centers of Excellence (COE) seal and program is a paradigm shift in lung cancer care to greatly increase positive patient outcomes. This necessity is driven by the reality that the 5-year patient survival rate has remained unchanged and abysmally low at approximately 16% for 40+ years. 80% of lung cancer patients in the US receive treatment by a general oncologist at community hospitals, most often without disease-specific cancer doctors. Unfortunately, generalists lack access to the most up-to-date knowledge to specifically treat lung cancer, the world’s number one cancer killer that takes more lives annually than the other top five cancer killers combined. Because of the tremendous volume and pace of scientific discovery, it is impossible for community general oncologists to stay abreast of emerging treatment options, the complexities of each disease state (lung, breast, colon, etc) and practice-changing clinical information. Due to this gap generalists cannot fully inform patients about all treatment options that exist, are expected and used every day by specialists at academic institutions where the enhanced standard of care includes molecular testing, tumor board review, clinical trials, personalized/targeted treatment, multi-disciplinary care, etc. Health literacy of physicians and patients impacts survival. The lung cancer knowledge gap especially affects patients who have limited education, are low income, ethnic minorities, recent immigrants and non-native English speakers. Knowledge and access are the currency of success and the pathway for all patients/physicians to get the right information leading to the right treatment at the right time. Information is also key for patients and their families to act as their own advocates. EVERY PATIENT NEEDS TO KNOW EVERY OPTION. ALCF acknowledges this problem and provides an innovative, first-of-its-kind solution – Community Hospital Centers of Excellence (COE) – to give all patients 360[0] care. Our solution provides community hospitals access to the same standard of care used at academic institutions to ensure that every physician and patient has access to and is educated about the newest, most effective diagnostic and therapeutic techniques, clinical resources, partners and people. Increasing lung cancer patient survival to the same high level as other cancers (breast/89.2%; prostate/98.9%) depends upon addressing disparities at the root – community hospitals – and to providing access to multi-institutional, collaborative, comprehensive care based on existing best practices. Equalizing access benefits all populations – insured, uninsured, underserved, geographically disadvantaged – fighting this disease. Physicians/hospitals in the COE national network commit to being fully informed partners with their patients in understanding, sharing and discussing treatment options. ALCF lung-specific community centers of excellence will be tracked by metrics to improve outcomes and reinforce ALCF’s belief that enhanced standard of care can extend survivability, improve quality of life, and some cases, save lives. ALCF, along with GE Healthcare and El Camino Hospital in California, has already shown success in its pilot program launched in 2012. Simultaneously, underlying research projects will be conducted to achieve milestones and increase discovery of treatment regimens for individualized therapy and survival acceleration through ALCF’s sister organization, the Addario Lung Cancer Medical Institute (ALCMI). At Centers of Excellence an on-site Patient Navigator oversees each patient’s care from the initial diagnosis. Care includes molecular testing for all patients to determine the unique genetic profile of the individual’s lung cancer. This knowledge will determine the best first-line treatment to achieve a positive outcome and will ensure that the right patient gets the right treatment at the right time. Community Hospital Centers of Excellence (COE) – Primary objectives are: ● Provide lung cancer patient program participants with multi-disciplinary, multi-institutional, collaborative, extensive, and comprehensive access to best care available. This “big picture” approach includes a Patient Navigator overseeing each patient’s care to include prospective tumor board review, molecular testing, targeted radiation therapy, and access to clinical trials, from a fully integrated team (oncologist, pulmonologist, radiologist, pathologist, immuno-oncologist, etc). ● Establish and implement improved standard of care (SOC) at community hospitals nationwide by giving patients and physicians access to the SOC used at academic institutions. This standard will be measured through patient data tracking, follow-up and patient surveys, and benchmarked against national data and statistics. In addition, ALCF will actively support the adoption and scaling of its lung cancer “standard of care” model to apply across the cancer spectrum and to other diseases and disciplines, as applicable. ● Improve progression free and overall survival rate and quality of life for patients. ● Implement best practices with expected outcomes being a new patient-centric paradigm for lung cancer patient treatment with best practices managed and documented by ALCF and findings shared with ALCF key partners and prospective Community Hospital COE sites. Because outcomes/data are essential to determine program success, tracking and measurement of all COE patients will include: Method of Diagnosis Early Detection vs. Incidental Findings Diagnosis Date Lung Cancer Type Lung Cancer Stage at Diagnosis Molecular Testing - % of Patients Received Tumor Board Review 30 Day Survival Number of ER Visits 1 and 5 Year Survival (Progression Free and Overall) Clinical Trial Referral Quality of Life (i.e. Pulmonary Function, Neuropathy, Fatigue, Appetite etc) Patient Satisfaction Survey Line of Treatment Where Applicable: Dollars Lost/Impact on Community due to Early vs. Late Stage Diagnosis Business Impact on Hospital During our pilot program's first year (El Camino Hospital, Mtn View, CA) metrics have already shown a dramatically improved standard of care (diagnosis to treatment time improved from a national average of 40+ days to 14.5 days; 100% of patients have had molecular testing; 61% have had tumor board review vs. 15% pre-program; 26% diagnosed at stage 2b or below). In adopting this collaborative, integrated standard of care, each hospital must have capacity to enroll at least 200 patients yearly. At minimum, ALCF excpects 10,000 patients will be served by 2015 end thriough 20 COEs. By equalizing physician/patient access to education and a standard of care, all populations affected by lung cancer--insured, uninsured, underserved, geographically disadvantaged--will benefit. COE will clearly be able to track outcomes and will define success through lives extended and in some cases, saved. By redesigning lung cancer patient health care delivery, COE provides an unprecedented coordination of care using technology and access to existing expertise/knowledge.

Abstract:
Background: The model of clinical trials in lung cancer has evolved quite dramatically over the past years. Expanded phase I trials in biomarker-driven populations are a new paradigm of accelerated drug approval. Enrolling patients in these clinical trials creates several new challenges. Clinical Research Nurses (CRNs) play an important role in recruitment, actual drug delivery, and monitoring of this whole process. Methods: Identify the different barriers to recruitment that CRNs face with these clinical trials. Barriers to participation can be patient-related, physician-related or tissue-related. Review of literature was the basis for the patient- and physician-related barriers. To identify the tissue barriers, we studied our own database. We also present practical tips to overcome these barriers out of own expertise in the field. Results: Patients’ barriers to participate in clinical trials include individual characteristics, practical issues, and attitudes. The most common barriers are the individual characteristics: cultural background, health literacy, ethnicity, and age. Lack of knowledge, insurance coverage, extra appointments, reimbursement, and patient ineligibility are typical practical barriers. Attitudinal barriers are reluctance to randomisation, fear for side effects, and efficacy concerns (e.g. allocation to placebo) (1-3). To overcome these barriers the trial should be explained clearly. Patient should be supported in what may be a difficult decision and should not be pressured to do so. Dedicated CRNs may help with monitoring the recruitment process, providing additional information, and obtaining informed consent (1). The process of informed consent is the optimal time to define clearly the terms of the clinical trial, and to explain the sometimes difficult to understand medical and legal terms in the informed consent document. Optimally, this should lead to good understanding by the patient of the potential benefits and risks (4). Main physicians’ barriers are lack of time due to competing priorities, insufficient staff and training to meet the ever increasing procedures from competent authorities or institutional review boards and finance departments, worry about the impact on the doctor-patient relation, concern for patients, and lack of reward and recognition. Lack of time is considered a major barrier. Doctors experience time pressure from their usual clinical practice and management duties. Recruitment, the consent process, and the follow up of clinical trials on top of that demand a large piece of extra time (1;4;5). Lack of support staff, for example CRNs, can also account for poor recruitment. A stable clinical research team is likely to be advantageous. CRNs should not only have expert clinical and well developed critical thinking skills, but be well acquainted with the complex scientific, regulatory, and ethical aspects of clinical research (6). Well trained and experienced CRNs truly are “PI-extensions”. By monitoring the clinical activity to find possible candidates for trials, they support the physician with recruitment, and later on with the follow-up of included patients. Over the last years, we saw a major progress in the treatment of advanced non-small cell lung cancer, largely due to new targeted agents, monoclonal antibodies, and immunomodulatory agents. Both in clinical practice, as well as in clinical trials, the availability of tissue for biomarker analysis – in order to make the best choice for the patient – is crucial. Tissue availability is a new important barrier to clinical trials, as we noted from our own experience (7). Moreover, central lab confirmation of an already known biomarker, is often requested before the patient is allowed to start therapy, leading to sometimes important delays. In our respiratory oncology trial unit, we analysed of our molecular database regarding this barrier (7). The mean waiting time between signing informed consent and receiving results of the biomarker analysis from the central laboratory turned out to be 25 calendar days! While delivering a tissue sample for central confirmation of molecular testing is crucial in biomarker-driven NSCLC trials, the mandatory waiting of patients to start therapy is to be discussed. Waiting times for central laboratory analysis not only lead to an important delay in treatment initiation, but even ineligibility for the trial(s) under consideration. Start of therapy based on a properly validated local test, with a posteriori central biomarker testing to guarantee the integrity of the trial, would be more rewarding for quite some patients (8). Conclusion: Recruitment in lung cancer clinical trials is a complex and vulnerable process with different types of barriers. Identifying such barriers can help clinical trial staff to develop strategies to optimize participation and cooperation. Well-trained CRNs have a unique knowledge and set of skills that allows them to make a significant contribution to the clinical research team. CRNs should follow the rapid change in clinical trials closely, so that they can be a guide for patients in their clinical trial journey. Moreover, they have an important role in minimising the patient barriers, give support in physician barriers, and facilitating tissue barriers. References (1) Ross S, Grant A, Counsell C et al. Barriers to participation in randomised controlled trials: A systematic review. J Clin Epidemiol 1999;52:1143-1156. (2) Manne S, Kashy D, Albrecht T et al. Attitudinal barriers to participation in oncology clinical trials: Factor analysis and correlates of barriers. Eur J Cancer Care 2015;24:28-38. (3) Kaplan CP, Napoles AM, Dohan D et al. Clinical trial discussion, referral, and recruitment: Physician, patient, and system factors. Cancer Causes Control 2013;24:979-988. (4) Mills EJ, Seely D, Rachlis B et al. Barriers to participation in clinical trials of cancer: A meta-analysis and systematic review of patient-reported factors. Lancet Oncol 2006;7:141-148. (5) Seruga B, Sadikov A, Cazap EL et al. Barriers and challenges to global clinical cancer research. Oncologist 2014;19:61-67. (6) Hastings CE, Fisher CA, McCabe MA et al. Clinical research nursing: A critical resource in the national research enterprise. Nurs Outlook 2012;60:149-156. (7) Lepers S, Ottevaere A, Oyen C et al. The challenge of molecular testing for clinical trials in advanced non-small cell lung cancer patients: analysis of a prospective database. J.Thorac.Oncol. 2015; 10 Suppl: Mini Oral presentation WCLC 2015. (8) Adam V, Dooms C, Vansteenkiste J. Lung cancer at the intensive care unit: The era of targeted therapy. Lung Cancer 2015;E-pub May 18.

Abstract:
This paper discusses the prevalence of distress in the lung cancer population, reviews the benefits and barriers of screening and provides practical strategies to implement psychosocial screening. Background: Lung cancer is the leading cause of death by cancer for both men and women worldwide. Most lung cancers are diagnosed at advanced stage and approximately 15% of lung cancer patients will be alive five years post-diagnosis.[1] Psychosocial distress is common for those experiencing cancer. The National Comprehensive Cancer Network (NCCN) defines psychosocial distress as ‘an unpleasant experience of an emotional, psychological, social or spiritual nature, that interferes with the ability to cope with cancer treatment, which extends along a continuum from common normal feelings of vulnerability, sadness and fear, to problems that are disabling such as true depression, anxiety, panic and feeling isolated or in a spiritual crisis’. The NCCN considers distress to be a treatable complication of cancer.[2] Lung cancer patients’ distress levels are among the highest of all cancer types with up to 60% of lung cancer patients experiencing clinical level of psychological distress compared with approximately 35% of patients with other cancer diagnoses.[3 4] These high levels of distress have been found to continue throughout the course of the illness. Prevalence of anxiety and depression in patients with lung cancer ranges from 20% to 50% [3 5] and patients with lung cancer have been identified as having one of the highest rates of suicide within the cancer population. [6] Distress has been associated with a deterioration in quality of life, higher pain levels, increased fatigue, increased family burden and reduced adherence to medical treatments. Despite high levels of distress in this population, lung cancer patients also report experiencing a significantly higher mean number of unmet needs 15.6 (95% CI 12.1–19.1), compared to 10.9 (95% CI 10.0–11.8) in other cancer patients.[7] Psychosocial distress screening Distress screening is defined as "a brief method for prospectively identifying, triaging, and educating cancer patients and their families at risk for illness-related biopsychosocial complications that undermine the ability to fully benefit from medical care, the efficiency of the clinical encounter, patient satisfaction, and safety."[2] Practice clinical guidelines recommend that all cancer patients undergo regular screening, with the American College of Surgeons (ACoS) Commission on Cancer (CoC) requiring cancer centers to implement screening programs for psychosocial distress as a new criterion for accreditation as of 2015. Without formal screening, distress may go unrecognized, clinicians could focus on the medical aspects of the illness and consider distress as a “normal” part of cancer and patients may not be offered effective biopsychosocial treatments to address distress. Without intervention for distress, the distress of lung cancer patients has been found to remain high, post six months of medical treatment.[8] Many tools exist for the screening of distress and these tools have undergone varying degrees of validation in the lung cancer patient group. The Distress Thermometer is the most popular of these tools and has been found to be both acceptable to patients with lung cancer and clinicians. In deciding which distress screening tool to employ, it is important that effective screening takes both disease (i.e. stage of illness, prognosis, side-effects, functional impairment) and demographic risk factors (i.e. age, isolation, past mental health history) into account, is easy to administer and sensitive to the identification of distress. Screening accompanied by discussion with lung cancer patients was found to be more effective than screening alone.[8] Overall, routine screening leads to improvements in communication with patient, families and staff, enhances psychosocial referrals improves symptom management and quality of life. However, some barriers may exist to the successful implementation of routine screening, including: a lack of knowledge about screening; a lack of training about how to manage distress; limited resources and time pressure; lack of institutional support; and a concern that screening may lead to ‘false positives’.[9] Implementing screening for distress recommendation The successful implementation of routing screening needs to be considered at the institutional, multidisciplinary team and individual clinician level. At an organizational level, screening and psychosocial care needs to be valued, prioritized and embedded in policy. Organizations need to ensure adequate psychosocial resources are available, staff are adequately trained and supported and that there is an ongoing evaluation of any psychosocial screening and referral process. At a multidisciplinary team level, the team needs to view psychosocial screening and treatment as part of routine care and distress needs to be assessed across the cancer trajectory, not just at a single point.[10] Treating team members need to consistently inform patients and families that the management of distress is a central part of their medical care. Teams should use a validated and easy to use instrument to assess distress and all screening should be followed by a triage discussion to help formulate treatment plans and referrals. Treatment plans must be clearly documented and communicated to the patient, family and team.[10] At an individual level, clinician should implement policy and procedures that support routine screening and access relevant training, support and supervision. Conclusion Lung cancer patients are among the most distressed and at risk cancer population. Evidence suggests that treating teams must take a person-centred approach to treatment including consideration of patients’ psychosocial needs. Routine screening allows practitioners and treating teams to appropriately consider psychosocial care and engage patients in intervention to minimize the potential negative impacts of untreated or poorly treated distress. References 1. American Cancer Society. Cancer facts and figures 2013. Atlanta, GA: American Cancer Society, 2013. 2. Network NCC. Clinical Practice Guidelines inOncology on Distress Management: National Comprehensive Cancer Network, 2011. 3. Zabora J, BrintzenhofeSzoc K, Curbow B, et al. The prevalence of psychological distress by cancer site. . Psychooncology 2001;10(1):19-28. 4. Graves KD, Arnold SM, Love CL, et al. Distress screening in a multidisciplinary lung cancer clinic: prevalence and predictors of clinically significant distress. Lung Cancer 2007;55(2):215-24 5. Linden W, Vodermaier A, Mackenzie R, et al. Anxiety and depression after cancer diagnosis. Prevalence rates by cancer type, gender, and age. J Affect Disord 2012;;141:343–51 6. Urban D, Rao A, Bressel M, et al. Suicide in lung cancer: who is at risk? Chest 2013;144(4):1245-52 doi: 10.1378/chest.12-2986[published Online First: Epub Date]|. 7. Li J, Girgis A. Supportive care needs: are patients with lung cancer a neglected population? Psycho-Oncology 2006;15(6):509-16 8. Carlson LE, Waller A, Groff SL, et al. Screening for distress, the sixth vital sign, in lung cancer patients: effects on pain, fatigue, and common problems-secondary outcomes of a randomized controlled trial. Psycho-Oncology 2013;22(8):1880-88 doi: 10.1002/pon.3223[published Online First: Epub Date]|. 9. Ristevski E, Breen S, Regan M. Incorporating supportive care into routine cancer care: the benefits and challenges to clinicians' practice. Oncology Nursing Forum 2011;38(3):E204-E11 doi: 10.1188/11.ONF.E204-E211[published Online First: Epub Date]|. 10. Pirl W, Braun I, Deshields T, et al. Implementing Screening for Distress. The Joint Position Statement from the American Psychosocial Oncology Society, Association of Oncology Social Work and Oncology Nursing Society merican Psychosocial Oncology Society, Association of Oncology Social Work and Oncology Nursing Society, 2015.

Abstract:
I am going to introduce the medical care for cancer and nursing for cancer in Japan. Starting from 1981, cancer claimed 1[st] place of the cause of death, and it currently account for approximately 30% of the cause of death. About 900,000 people are annually affected by the cancer. The per category death rate is in the order of lung cancer in 1[st] place, stomach cancer in 2[nd] place, and colorectal cancer in 3[rd] place. The per category affected subject rate is in the order of stomach cancer in 1[st] place, colorectal cancer in 2[nd] place, and lung cancer in 3[rd] place. As you can see from the above, cancer is a serious health problem for Japanese, and although Japan implemented countermeasure for cancer starting from the 60’s, “Cancer Control Act” was established in 2006, and “Basic Plan to Promote Cancer Control Program” was also setup to promote such Act. The purpose of the countermeasure is to do the following: 1.Reduce cancer death (Reduce age-adjusted mortality under 75 years, 2.reduction of burden and improvement of quality of life among cancer patients and their families, 3.Buliding a society in which cancer patients can live peacefully. Based on such backdrop, the role of nurses are further increased. To enhance the specialization of nursing for cancer, “Japanese Society of Cancer Nursing” was established in 1987, and it is now celebrating its 30[th] anniversary. This establishment has been supporting activities such as education and research. Nurses with certification such as “Certified Cancer Nurse Specialist” that can be obtained with completion of master’s course at graduate school, and “Certified Nurse” that can be obtained with 600 hours of education for those with over 5 years of nurse experience are taking active role in the fields of Palliative Care, Cancer Chemotherapy Nursing, Cancer Pain Management Nursing, Breast Cancer Nursing, Radiation Therapy Nursing, etc. Such active role is making positive contribution toward the enhancement of specialization in the clinical field. A variety of issues surrounds the medical care for cancer such as being able to correspond to the advancement of medical technology, increase of cancer survivor, and aging of patients. There is much anticipation for the good use of specialization in the cancer-nursing for team medicine to support the life of patient and to respect the decision-making of patient. I would like to introduce these types of initiatives that are specific to the condition surrounding the nursing for cancer and enhancement of specialized nursing in Japan.

Abstract:
Background Exercise has been introduced to improve physical capacity (VO~2peak~ and 1RM) and quality of life and to reduce symptoms and side-effects of treatment in patients with cancer, mostly investigated in patients with breast cancer (1,2). Against this background a feasibility study was developed to investigate the safety and feasibility of a preoperative and postoperative exercise program in patients undergoing surgery for lung cancer (3). The study concluded that the preoperative exercise program was not feasible. However, initiation of exercise two weeks postoperatively for patients with NSCLC was safe and feasible. A randomized clinical trial (PROLUCA) was therefore developed to investigate the efficacy of a postoperative exercise intervention in a non-hospital setting. Objectives The objective of the presented study was to explore operable lung cancer patient experiences with the postoperative exercise intervention from a longitudinal perspective according to patient motivation and patient perceived benefits and barriers of exercise. Methods This qualitative component formed part of the randomized control trial (PROLUCA) comparing the efficacy of early initiated postoperative exercise (initiated two weeks after surgery) with the effect of exercise initiated 14 weeks after surgery (usual care). NSCLC patients referred for surgery at the Department of Thoracic Surgery, Copenhagen University Hospital, were recruited for the exercise intervention. More details on the RCT study can be found in the published protocol by Sommer et al. (3). Nineteen patients enrolled in the exercise intervention two weeks post-surgery participated in qualitative interviews at three time points; the day after surgery, 7 weeks post-surgery and 4 months post-surgery. An analysis based on Ricoeur’s theory of interpretation was conducted in a phenomenological hermeneutical approach (4). Results The patient sample’s mean age was 63 years (range 48–75). Patients underwent video-assisted thoracoscopic surgery (VATS) with intent to cure. The majority (79 %) had comorbidities, including chronic obstructive pulmonary disease (26 %), cardiovascular disease (26 %) and hypertension (26%). Pre-illness physical activity levels of the patients showed that 47 % had not met the national recommendation for physical activity. Patients started exercising 15 days following surgery (median) (range 14–41 days). Delay was due to postoperative complications (pain, pneumothorax, pneumonia, atrial fibrillation, general discomfort). Eight participants dropped out of the intervention. Reasons for non-adherence included chemotherapy side effects (nausea, fatigue) (n=3), other reasons (n=1), fractured arm (n=1), work (n=1), terminally ill husband (n=1) and death (n=1). The mean attendance rate for the 11 participants who completed the intervention was 82 % (range 58–100 %). No patients experienced severe adverse events (e.g. heart- or respiration stop) during or following exercise. The interview findings are organized into three themes reflecting the timespan related to the patients’ treatment trajectory: 1) Pre-intervention motivation for participation; 2) Benefits and barriers of the intervention; 3) Overall experiences with the intervention. Motivation for participation included patients’ expectations of physical benefits and the security of having professionals present. Patients experienced physical and emotional benefits and affirmed their social identity, including improved breathing and increased well-being and energy level. Group training had social benefits and the patients experienced a sense of belonging. Exercising with others in a similar circumstance was meaningful to the patients and created a sense of community. Barriers were primarily related to side-effects of chemotherapy. The intervention put the patients on track to a healthier lifestyle regarding physical activity and smoking, and regaining vitality and energy increased the participants’ faith in the future. The patients were satisfied with the exercise intensity level, contents and variation and felt that after 12 weeks of two 60-min weekly sessions they had regained a good amount of strength and energy. Two of the eight patients who were undertaking adjuvant chemotherapy started training on completion of their treatment, while three other patients exercised while being treated. Discussion To our knowledge, this is the first study that addresses operable NSCLC patient perspectives on participating in an exercise intervention during the immediate post-surgical period and subsequent chemotherapy. The sample of the 19 patients included in the interview study appears to be a select group of operable lung cancer patients. So far it has not been possible to compare the interview sample with the larger sample of the trial and therefore not possible to discuss representativeness of the selected sample. However, when comparing the interview study sample with other operable lung cancer patients, it appears that the study patients are a little younger, better educated, have early stage disease, good performance status and are used to physical activity. Although this sample is comparable with other lung cancer exercise samples (5), this suggests social inequality related to the intervention’s design. This might also explain why the operable lung cancer patients consented to participate in the intervention and changed their behaviour—a finding that is not comparable with the general lung cancer population reported to have particularly low levels of physical activity during the post-treatment period (6) and with patients engaged in light physical activity (7). Despite the fact that the studied sample might be a select group, the diagnosis appears to represent “a teachable moment” as discussed by Demark-Wahnefried and colleagues (8), and the intervention seem to assist the patients by increasing their physical function and energy, their well-being and improve their social capital. Eleven of the patients completed the intervention with a mean attendance rate of 82 %, which is comparable with other exercise intervention studies (9). This result underscores the patients’ desire and ability to complete the intervention. Reasons for dropping out of the intervention were due to external conditions unrelated to the intervention or due to chemotherapy side effects. Conclusion This study contributes to the literature by taking into account patient perspectives of exercise interventions. The supervised intervention was undertaken safely by operable lung cancer patients initiated 2 weeks after surgery. This select group of lung cancer patients experienced physical and emotional benefits and affirmed their social identity. This qualitative study indicates that exercise is beneficial for lung cancer patients in the postsurgical trajectory and especially for those who were physically active and motivated pre-illness. References 1. Adamsen L, Quist M,Andersen C, Moller T, Herrstedt J, Kronborg D et al (2009) Effect of a multimodal high intensity exercise intervention in cancer patients undergoing chemotherapy: randomised controlled trial. BMJ 339:b3410 2. Mishra SI, Scherer RW, Snyder C, Geigle PM, Berlanstein DR, Topaloglu O (2012) Exercise interventions on health-related quality of life for people with cancer during active treatment. Clin Otolaryngol 37(5):390–392 3. Sommer MS, Trier K, Vibe-Petersen J, Missel M, Christensen M, Larsen KR et al (2014) Perioperative rehabilitation in operation for lung cancer (PROLUCA)—rationale and design. BMC Cancer 14:404-2407–14-404 4. Ricoeur P (1976) Interpretation Theory. Discource and the surplus of meaning. TCU Press, Texas 5. Jones LW, Eves ND, Spasojevic I,Wang F, Il'yasova D (2011) Effects of aerobic training on oxidative status in postsurgical non-small cell lung cancer patients: a pilot study. Lung Cancer 72(1):45–51 6. Coups EJ, Park BJ, Feinstein MB, Steingart RM, Egleston BL, Wilson DJ et al (2009) Physical activity among lung cancer survivors: changes across the cancer trajectory and associations with quality of life. Cancer Epidemiol Biomarkers Prev 18(2):664–672 7. Lin YY,Wu YC, RauKM, Lin CC (2013) Effects of physical activity on the quality of life in Taiwanese lung cancer patients receiving active treatment or off treatment. Cancer Nurs 36(4):E35–E41 8. Demark-Wahnefried W, Aziz NM, Rowland JH, Pinto BM (2005) Riding the crest of the teachable moment: promoting long-term health after the diagnosis of cancer. J Clin Oncol 23(24):5814–5830 9. Kjaer TK, Johansen C, Ibfelt E, Christensen J, Rottmann N, Hoybye MT et al (2011) Impact of symptom burden on health related quality of life of cancer survivors in a Danish cancer rehabilitation program: a longitudinal study. Acta Oncol 50(2):223–232

Abstract:
Background This paper will reflect upon some of the ethical challenges in conducting clinical research into lung cancer and mesothelioma. Lung cancer care, treatment and research operate in a complex environment. Characteristics of lung cancer that contribute to this complexity are that, in comparison to other cancer sites, it has a limited evidence base, high mortality, late presentation, diagnosis at advanced stage, few curative treatments, complex trial designs and nihilistic attitudes regarding treatment and research. As a result, people delay reporting lung cancer symptoms because of fear, fatalism and poor knowledge of treatment.[1] Such beliefs and attitudes may also influence decisions or prevent people from participating in research. When they are asked to participate, they are often in a situation of advanced illness with fear and/or fatalism in their minds. As such, they may be desperate volunteers.[ 2] Desperate Volunteers An example of a study involving desperate volunteers might be a surgical intervention for mesothelioma, such as the procedures in Mesothelioma And Radical Surgery (MARS)Trial[3] study or the new feasibility study of MARS 2. Treatment options in lung cancer and mesothelioma are increasing, but remain limited, especially regarding curative treatment. In mesothelioma, surgery will not be curative, but might be seen as the only palliative treatment that can make a substantial inroad into the disease pogression. Research treatments may therefore be seen as “the only treatment in town”. Both the multidisciplinary team and the patient may not see any other viable treatment. If the intervention is only available within research then research emerges as the only option. So what are the ethical challenges here? The ethical principle of voluntariness comes into play. Might recruitment into a trial be experienced as coercive – even if this is not the intention of the person recruiting? Is the experience of being approached about trial participation seen as coercive, or is it a decision in difficult circumstances? We need to ensure it is the later. It may be a decision taken under pressure, but needs to be made in a voluntary capacity. Other factors that will impact on levels of desperation, and the balance between coercion or decision, include whether the intervention is available outside the trial or not, and the trial design i.e. does it involve randomisation. Both these things will impact on someone’s readiness to participate in research and whether they will seek treatment outside of a trial. Finally it is necessary to consider whether the level of distress or desperation is impacting upon mental capacity.[4] Trials for all As previously stated, the evidence base for lung cancer is limited when compared to other cancer sites. There is also a drive in the UK cancer and health research community to ensure all patients have a right to access any appropriate trial. In the historical context of lung cancer being the “poor relation” in terms of research activity, caution is required to avoid being over-zealous in putting this right. People have the right to have access to appropriate trials but this does not mean every patient should be on a trial. There are many reasons why people will not want to embark on the journey of being a research participant. This should be respected. There is a theoretical argument that an over-zealous “trails for all” approach could have two other impacts. First, it may lead a desperate volunteer to misinterpret or inflate what the trial may offer in terms of treatment, cure or symptom impact; second it may change perceptions of equipoise. Equipoise Clinical equipoise provides the ethical basis and justification for medical research which involves assigning or randomising patients to different treatment arms of a trial. The term was first used by Benjamin Freedman in 1987.[5] If clinical equipoise exists there is genuine uncertainty over whether a treatment will be beneficial. It follows that it is reasonable for a clinician in equipoise to assign a patient to one arm or the other of a randomised trial. The challenge lies in deciding whether equipoise exists and whose interpretation it is based upon. Usually the decision is made according to the best evidence.[6] An ethical window of opportunity will exist within which it is justified to conduct a randomised trial. That is until evidence is generated to demonstrate whether an intervention is better than standard treatment or not. However, there is a value-based element to equipoise. As such equipoise may vary between researcher, clinician, and patient – and between different patients. For example, on the basis of best evidence it may be justified to randomise between a surgical intervention and standard care, as clinical equipoise is seen to exist. However, if standard treatment is NO treatment, will the patient view equipoise in the same way as the scientist? Implications The above challenges will apply in different ways to different patients and contexts. However This paper focuses on some key messages for clinical and research practice. These can be summarised as: · Information and consent: The process of providing participants with sufficient information, and obtaining informed consent, need to be actively managed in these complex situations. Sufficient time needs to be allowed in times of heightened emotion and a cooling off period is recommended in between information and consent. Also, consent should be approached in a staged or continuous manner, where willingness to continue participation in research is verified at different stages in the study. [· ]Research designs: Where possible, patient preference trial designs should be considered.[7,8] · Availability of research intervention outside of the trial: Consider the impact of this at the design stage. Is an agreement possible to cease delivery outside of a trial until evidence is generated? · Equipoise: Whose equipoise is the trial based on? It is necessary to consider patient/participant values as well as the judgements of the scientist and clinician. · Patient experience: It is worth including a qualitative component in trials to understand what is going on for the participants, and trial staff, in terms of decisions to participate and be randomised, response to allocation, and experience of intervention. 1. Tod AM. Allmark P. Craven J. Diagnostic delay in lung cancer: a qualitative study. Journal of Advanced Nursing. 2008. 61(3), 336-343 2. Allmark P (2006) Should desperate volunteers be included in randomised controlled trials? JMedEth 32, 548-53 3. Treasure T, et al. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol. 2011 Aug;12(8):763-72. doi: 10.1016/S1470-2045(11)70149-8. Epub 2011 Jun 30. 4. Mental Capacity Act Code of Practice (2005) online Chapter 11 5. Freedman B (1987) Equipoise and the ethics of clinical research NEJM 317(3), 141-5 6. Kurzrock J, Stewart D (2014) Equipoise abandoned? Randomization and clinical trials. Ann Onc 24(10), 2471-74 7. Ismalia A, Walter S 2014 Review of designs for accommodating patients' or physicians' preferences in randomized controlled trials. In Montfort K van. et al Developments in Statistical Evaluation of Clinical Trials Sedgwick P (2013) What is a patient preference trial? BMJ 347:f5970

Abstract:
An individual is considered a cancer survivor from the time of diagnosis, through the balance of his or her life (NCSI –Survivorship definitions 2004) . In the UK Lung cancer survival has improved over the past two decades .In 1990 17% of male and female lung cancer patients were alive after one year compared with 29% of men and 33% of women diagnosed with lung cancer in 2010 . (The National Cancer Intelligence Network – public health England 2013).Such noticeable improvement in survival rates illustrates the improvements in Lung cancer care from diagnostics, treatments and configuration of cancer services. However variations and gaps in the delivery of lung cancer care nationally and internationally reinforce concerns around survivorship care. Lung cancer is a diagnosis associated with heavy disease burden and survivors may experience a myriad of concerns related to diagnosis and or treatment with high levels of physical and psychological distress affecting the quality of life for both patients and carer’s. Maguire et al (2012) reported that many people with a lung cancer diagnosis feel that supportive care needs are not being met, they have significantly more unmet supportive care needs compared to other cancer types. They are also less aware of supportive care elements available and have limited information to resources. (Steele and Fitch, 2008) The American Cancer Society (ACS)’s has set one of its 2015 goals for the nation as establishing “..Measurable improvement in the quality of life from the time of diagnosis and for the balance of life for all cancer survivors” Recent years have seen the growth of a new trends in medicine that are based entirely on data obtained from patients own assessment of their symptoms and ability to function “normally” Widely known in the cancer fields as a self-evaluation of health status or outcomes assessment. Such assessments were directed primarily towards patient evaluation and came to be known as health-related quality of life (HRQOL) in order to distinguish it from the quality of life of the general population. HRQOL refers to multidimensional assessments that include physical, psychological, social domains and also include other domains such as cognitive functioning, sexuality and spirituality. While single areas such as performance status or symptoms may be components of HRQOL they are, by themselves, insufficient to constitute a complete HRQOL assessment. In addition, the assessment of HRQOL does not usually include some other patient reported assessments, such as needs assessment and satisfaction with care. Thus, patient-reported outcomes (PROs) a more inclusive term, was proposed to include any data that may be reported directly by the patient without an intermediary such as a family member or a healthcare professional (Willke et al. 2004). The process of obtaining PRO data is commonly referred to as PRO measurement (PROM)s (Osoba 2011) The National cancer survivorship Initiative, (NCSI) launched in 2007, initially had limited evidence around the needs of cancer survivors. Taking action to improve outcomes (NCSI 2013)collected information on quality of life (QoL) through the use of PROMS and identified that many cancer survivors had unmet needs. Following on from the success of this National Cancer Survivorship Initiative, The Living With and Beyond Cancer (LWBC) Programme was set up in June 2014. This two year partnership between NHS England and Macmillan Cancer Support is aimed at entrenching NCSI findings and recommendations ensuring that those living with and beyond cancer get the care and support they require to lead as healthy and active a life as possible, for as long as possible. There are a number of key recommendations, including the introduction of an integrated package of interventions, “The Recovery Package”, which includes • Structured Holistic Needs Assessment and Care Planning, • Treatment Summaries and Cancer Care reviews • Patient education and support events (Health and Wellbeing Clinic) • Advice about and access to schemes that support people to undertake physical activity and healthy weight management. The collaboration of multi-disciplinary working involved in such interventions will enable improved outcomes for cancer survivors, through creating a shared understanding between patient and professionals about the issues important to the individual patient, identifying any needs to be addressed in an appropriate and timely manner. It has been designed to complement the stratified care pathway (NHS Improvement 2012) which enables individualised follow-up care as a supported self-management programme, shared care or complex care. REFRENCES National Cancer Institute –Survivorship definitions 2004 The National Cancer Intelligence Network – public health England 2013) One-year survival for lung cancers diagnosed in England 1990-2010 Maguire,R. et al. What is the value of the routine use of patient-reported outcome measures toward improvement of patient outcomes, processes of care, and health service outcomes in cancer care? A systematic review of controlled trials. J Clin Oncol. 2014 May 10;32(14):1480-501 Steele R, Fitch MI. Why patients with lung cancer do not want help with some needs. Support 2008 Mar;16(3):251-9. The American Cancer Society 2015 Organisational outcomes Willke, R.J., Burke, L.B. and Erickson, P. (2004) Measuring treatment impact: a review of patient reported outcomes and other efficacy endpoints in approved product labels. Control Clinical Trials 25: 535_552. Osoba,D. Health-related quality of life and cancer clinical trials Advance Medical Oncology (2011) 3(2) 57_71 The National cancer survivorship Initiative Living with and beyond cancer: Taking action to improve outcomes (2013) The Recovery Package, National Cancer Survivorship Initiative, NHS Improvement 2012 Innovation to implementation: Stratified pathways of care for people living with or beyond cancer- NHS Improvement 2012

Abstract:
With the dramatic clinical benefit that can be observed using tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC) harbouring activating mutations in EGFR, there has understandably been a focus on the use of these agents in this subset of NSCLC. However, EGFR mutation positive NSCLC represents only approximately 10 – 15 % of all non-squamous NSCLC in non-East Asian patients, and a substantial proportion of East Asian patients do not harbour this mutation. Thus, world-wide, the vast majority of those with NSCLC are so-called “wild-type” for EGFR. For these patients, it is clear from randomized clinical trials that the treatment of choice in the first-line metastatic setting is platinum-doublet chemotherapy. Increasing data suggest that chemotherapy may be preferred in the second-line setting. Is there any role for the use of EGFR TKIs in the wild-type population? Randomized data in which an EGFR TKI is compared to placebo in both the maintenance and refractory settings suggest that there may be. NCIC Clinical Trials Group study BR21 [1] which randomized 731 unselected patients to either erlotinib or matching placebo, was designed and conducted prior to the discovery of activating mutations. Patients had received 1 (50 %) or > 2 (50 %) lines of prior therapy; > 90 % had received a platinum-doublet. An improvement in median survival (6.7 versus 4.7 months [HR 0.70, p < 0.001]) was also associated with a quality of life benefit. This benefit was consistent across subgroups, including in the 50 % of patients with non-adenocarcinoma histology. In a separate analysis of ever-smokers with squamous histology, patients highly unlikely to harbour an EGFR mutation, the magnitude of survival benefit was the same as in the overall study population (median 5.6 versus 3.5 months [HR 0.66, p=0.009])[2]. The SATURN trial [3] randomized 889 patients who had not progressed after 4 cycles of platinum-doublet chemotherapy to either erlotinib or placebo. While of debatable clinical relevance, there was a statistically significant one month prolongation of median survival with the use of erlotinib (HR 0.81, p=0.009). A similar effect was observed in the 44 % of patients with known EGFR wild-type status (HR 0.77, p=0.02). In a pre-planned subgroup analysis [4], a greater magnitude of benefit was observed in those patients whose best response to induction chemotherapy was stable disease (median overall survival 11.9 versus 9.6 months [HR 0.72, p=0.002]), with a similar effect noted in those patients with squamous histology (HR 0.67, p=0.01), and those known to be EGFR wild-type (HR 0.65, p=0.004). Maintenance erlotinib has been shown to not negatively impact quality of life [5], and when used in those with stable disease, to be cost effective [6]. Meta-analyses of placebo-controlled trials of EGFR TKIs in the maintenance setting have confirmed a modest progression-free survival benefit in squamous [7] and known wild-type [8] patients. Multiple trials have compared an EGFR TKI to either docetaxel or pemetrexed in the second-line setting. The TAILOR trial [9], the only trial to prospectively determine and enrol only wild-type patients, showed a clear PFS advantage to docetaxel, and a trend towards improved overall survival. However several other trials that enrolled patients who were unselected with regard to EGFR status had a substantial number of wild type patients, and none of these trials demonstrated a difference in overall survival in wild-type patients between an EGFR TKI and chemotherapy. While these were retrospective analyses on only a subset of enrolled patients with available tissue, wild-type patient numbers in many trials approached (and in one exceeded) the number of patients enrolled to TAILOR. Further, unlike other trials, TAILOR prohibited crossover, which may have impacted survival results, particularly for patients with squamous carcinoma in the erlotinib arm. Taken together these trials suggest that a treatment strategy that includes both chemotherapy and an EGFR TKI sequentially, irrespective of order, will lead to a similar length of survival provided patients receive both lines of therapy. In platinum-pretreated patients who are fit it is likely preferred to use chemotherapy and then at progression move on to an EGFR TKI, as the chance of patients receiving both treatments is higher. Additional data to suggest that EGFR TKIs may have activity in wild-type patients comes from several small, randomized phase II trials comparing second-line chemotherapy with the same chemotherapy with intercalated EGFR TKIs. These studies have shown prolonged PFS in patients treated with the combination. What these trials demonstrate is that EGFR TKIs appear to have a modest treatment effect in EGFR wild-type patients. In these days of targeted therapies leading to substantial treatment effects in a variety of tumours with oncogenic drivers, is this magnitude of benefit sufficient? In lung cancer, many other treatments have been adopted for a similar magnitude of benefit. Although objective response rates to EGFR TKIs are low in wild-type patients, they are also low to standard cytotoxic chemotherapies beyond first-line, and it seems possible that there is a larger proportion of patients with stabilization of disease and / or slowing of progression that is clinically relevant. Not all oncologists or patients will feel that a trial is warranted, but an EGFR TKI is a reasonable choice as last-line therapy when the option is no further treatment, or as maintenance treatment in patients with squamous histology following a best response of stable disease to induction platinum-based chemotherapy. EGFR “wild-type” is a heterogeneous, not homogeneous, population, and as with any therapy, only a subgroup of patients will benefit from treatment. However a consistent reproducible biomarker for benefit in the wild-type subgroup has not yet been discovered. EGFR protein expression, gene copy number, Kras status and serum proteomics have all been evaluated with at times conflicting results, due to limited samples and the retrospective nature of the analyses. The development of rash may be a pharmacodynamic predictor of greater efficacy [10]. Additional work is required to determine which wild-type patients may derive benefit from an EGFR TKI, to avoid needless toxicity and improve cost-effectiveness. References 1. Shepherd et al. N Engl J Med 353: 123-132, 2005 2. Clark et al. Clin Lung Cancer 7:389-394, 2006 3. Cappuzzo et al. Lancet Oncol 11:521-529, 2010 4. Coudert et al. Ann Oncol 23:388-394, 2012 5. Juhasz et al. Eur J Cancer 49:1205-1215, 2013 6. Walleser et al. Clinicoeconomics Outcomes Res 4:269-275, 2012 7. Ameratunga et al. Asia-Pacific J Clin Oncol. 10:273-278, 2014 8. Vale et al. Clin Lung Cancer 16:173-182, 2015 9. Garassino et al. Lancet Oncol 14:981-988, 2013 10. Ding et al. Contemp Clin Trials 29:527-536, 2008

Abstract not provided

Abstract not provided

Abstract:
Great advantages of next generation sequencing have been published so far, and many new genetic alterations were found with whole genome sequencing. Targeted sequencing using next generation sequencing technique can analyze FFPE small biopsy specimens, but may be equivalent or less than the current selected testing, such as EGFR and ALK testing. Although the targeted sequencing can actually analyze multiple genes, most diagnostic panels include the genes that are frequently altered in cancer generally, thus practically useful genes are limited in terms of lung cancer, such as EGFR, ALK, ROS1, and RET. In contrast, whole exome sequencing is potentially useful, as it can comprehensively examine mRNA expression on tumor cells. In general, mRNA in clinical samples well represents tumor genetic status even with significant dilution with the normal cells, which are less active in transcription. However, it is difficult to perserve high quality RNA with clinical samples, and it is unclear that the whole exome sequencing is constantly clinically applicable for small biopsy specimens. Furthremore, there are some cases that show discrepant results between DNA and RNA based assays. As EGFR transcript is suppressed in SCLC, EGFR mutation cannot be detected with the exome sequencing in SCLC transformed as a resistant mechanism to EGFR-TKI treatment. On the other hand, current selected testing for EGFR and ALK has been confirmed with clinical trials and are adjusted to clinical demands, e.g., short turnaround time and high sensitivity.

Background:
Resminostat, an oral hydroxamate-type inhibitor of class I and II histone deacetylases, has shown a broad spectrum of anti-tumor activity against human cancer cell lines, and synergetic or additive effects in combination with docetaxel in non-small cell lung cancer (NSCLC) cell lines. We initiated a phase I/II study to evaluate the safety and efficacy of combining resminostat and docetaxel in patients (pts) with NSCLC pretreated with platinum-based therapy. The purpose of the phase I portion was to evaluate dose-limiting toxicities (DLTs) in the first cycle, estimate the maximum tolerated dose (MTD) of resminostat when administered in combination with docetaxel, and determine the recommended dose (RD) for the phase II portion. Here, we report the results of the phase I portion.

Methods:
NSCLC pts with failure of a platinum-based therapy were eligible for the study. Patients were treated with docetaxel on day 1 and resminostat on days 1 to 5 every 21 days. Phase I was an open-label, 3+3 cohort, dose-escalation study. While the docetaxel dose was fixed at 75 mg/m[2], the resminostat dose was escalated from 400mg (Dose Level 1: DL1) to 600 mg (DL2). DLT was defined as follows: grade 4 thrombocytopenia, grade 4 neutropenia lasting >7 days, febrile neutropenia lasting >3 days, and any other clinically significant grade 3/4 non-hematological toxicity.

Results:
A total of 9 pts (DL1: 3 pts, DL2: 6 pts) were enrolled in the phase I portion: male/female, 6/3; median age, 60 yr (50-71 yr); histologically proven adenocarcinoma/squamous cell carcinoma, 7/2; performance status, 0/1 in 7/2 pts. No DLTs were observed at DL1 or DL2. The most frequent grade 3/4 adverse events in any cycle were neutropenia (8 pts, 88.9%), leukocytopenia (8 pts, 88.9%), and febrile neutropenia (4 pts, 44.4%). These events were transient and resolved prior to the next cycle. No pharmacokinetic (PK) interaction between resminostat and docetaxel was observed. A partial response was observed in 1 pts (DL1) and stable disease in 3 pts (DL2).

	DL1 N=3		DL2 N=6
PK parameters (Geometric Mean)	Resminostat	Docetaxel	Resminostat	Docetaxel
C~max ~(ng/mL)	3,010	2,840	5,610	3,140
T~max ~(h)	1.78	1.00	1.47	1.03
AUC~inf~(h∙ng/mL)	11,800	3,030	25,500	3,280
t~1/2~ (h)	2.98	8.21	3.02	8.73

Conclusion:
The combination of resminostat and docetaxel was tolerable up to DL2 (docetaxel 75 mg/m[2], resminostat 600 mg); the MTD was not reached. Dose Level 2 was determined as the RD for the phase II portion of this study, which is currently ongoing.

Background:
It is considered that there is a population of “fit-elderly” patients, but how to select this population is undetermined. Two-drug regimen consisted of carboplatin (CBDCA) + weekly paclitaxel (PTX) in elderly patients with non-small cell lung cancer (NSCLC) was reported to be active but to have 4.4% of toxic deaths. When considering to add bevacizumab (BEV) to the two-drug regimen, meta-analysis of BEV-related adverse events taught that congestive heart failure (CHF) and arterial thromboembolic events increased in elderly patients. In this phase II study, we employed exclusion criteria of having both congestive heart failure (CHF) and diabetes mellitus (DM), which relates to arterial thromboembolism.

Methods:
Elderly (≥70 years old) patients with chemotherapy-naive, stage IIIB/IV or recurrent non-squamous NSCLC, ECOG-PS 0-1, measurable target lesion, and adequate organ functions were eligible for this study. Pts with CHF (i.e. those with brain natriuretic peptide (BNP) ≥ 100 pg/ml and ejection fraction (EF) ≤ 50%) and with DM (i.e. those with HbA1c ≥ 7.0%) were excluded. Treatment included CBDCA at AUC 5 on day 1, PTX at 90 mg/m[2] on days 1 and 8, and BEV at 15 mg/kg on day 1 of each 21-day cycle for up to 4 cycles, followed by maintenance BEV.

Results:
Thirty-six eligible patients (14 male, 22 female; median age, 75 years) were enrolled between February 2012 and September 2014. Fifteen and 21 patients had ECOG-PS of 0 and 1, respectively. The median number of CBDCA + weekly-PTX + BEV treatment cycles received was 4, and that of BEV maintenance dosing was 5. Grade 3/4 non-hematological and hematological toxicities were observed in 13 (36.1%) and 20 pts (55.6%), respectively. The most common grade 3/4 AEs included neutropenia (52.8%), hypertension (11%), anemia (8.3%), and infection (8.3%). No fatal AE was observed. The response rate, the primary endpoint of this study, was 69.4% (95% CI = 51.9–83.7), and median progression free survival was 9 months.

Conclusion:
CBDCA + weekly PTX + BEV followed by BEV was a feasible and effective first-line regimen for selected elderly non-squamous NSCLC patients. BNP, EF, and HbA1c may aid in selecting “bevacizumab-fit” elderly patients.　 Clinical information: UMIN000006622.

Background:
The combination of epigenetic drug decitabine with genistein, a natural isoflavone, produces synergistic responses in preclinical studies with particular activity shown in lung cancer cell lines. Our phase I dose-escalation study of decitabine with a fixed dose of genistein to treat advanced solid tumor was followed by a phase II study in advanced lung cancer patients.

Methods:
In phase I, decitabine was administered over 10-hours at increasing doses (60, 120, 240 mg/m[2]) with continuous administration of genistein 300 mg/day orally. The MTD was 120 mg/m[2] with neutropenia as DLT. Decitabine at 120 mg/m[2 ]and genistein produced plasma levels of 0.62±0.06 µM and 8.5±5.6 µM, respectively.

Results:
The drug combination was well tolerated and produced stable disease for more than 6 months (7-14 months) in 5/10 patients. One gastric cancer patient had a 50% reduction in tumor burden after 6 months of therapy. Stable disease was also achieved in patients with desmoplastic small round cell tumor, oncocytic carcinoma, follicular thyroid carcinoma and bladder cancer. The phase II study was focused on nine patients with non-small cell lung cancer refractory to 3-4 lines of therapy. Eight progressed within the first radiologic evaluation at week 6. One NSCLC patient remains on therapy with SD after 3 months of treatment. A total of 60 adverse events were reported during the study with all patients experiencing at least one AE. Grade 3 & 4 treatment related toxicities were observed in 6/9 patients (66%) : neutropenia (4) anemia (2) febrile neutropenia (1) and hypertension (1).

Conclusion:
This combination of genistein with decitabine was well tolerated in advanced patients with solid tumors. The activity of the combination seen in some patients with tumors of more indolent biology was modest in the phase II cohort of heavily pretreated NSCLC patients. The efficacy profile observed in this trial suggests that tumors with slower tumor kinetics might benefit more from this type of epigenetic therapy.

Background:
Endostar [TM ](rh-endostatin, 7.5mg/m[2], 3-hour intravenous infusion (IV) daily for 14 days) was approved by Chinese FDA for treatment of advanced NSCLC in 2005. Considering continuous intravenous infusion (CIV) may be a more favorable way to deliver Endostar, we designed the phase I study to evaluate pharmacokinetics, tolerability and efficacy of Endostar CIV at different doses combined with pemetrexed and carboplatin in untreated advanced non-squamous NSCLC patients.

Methods:
In phase Ia, 19 patients were assigned to 4-6 cycles (21 days/cycle) of pemetrexed (500mg/m[2], day 1), carboplatin (AUC 5, day 1), and CIV Endostar from day 2 to day 21 at doses of 7.5mg (8 patients), 15mg (6 patients), 30mg (5 patients) /m[2]/d, respectively. Serum samples were obtained 0h、1h、2h、4h、8h、24h、48h、72h、96h、120h、122h、124h、128h、132h and 144h after the Endostar infusion. In phase Ib, another 21 patients received CIV Endostar at doses of 7.5mg (10 patients) or 15mg (11 patients) /m[2]/d with pemetrexed + carboplatin.

Results:
The AUC~0-120h~ of Endostar 7.5mg/m[2] CIV and 7.5mg/m[2] 3-hour IV daily were comparable (12.6±7.6 vs 13.3±8.8 ug/mL × hour). C~max~ (ng/ml) (7.5mg: 152.4±83.7; 15mg: 287.2±122.6; 30mg: 398.2±52.6) and AUC~0-120h~ (ug/mL × hour) (7.5mg: 12.6±7.6; 15mg: 21.2±10.8; 30mg: 33.4±8.5) were linear with dose. In phase Ia, the most common adverse events were anemia (78.9%, G3/4 10.5%), neutropenia (68.4%, G3/4 31.6%), thrombocytopenia (63.2%, G3/4 10.5%), LDH increase (47.4%), aminotransferase increase (42.1%), and supraventricular arrhythmia (26.3%). No grade 3 or 4 non- hematologic adverse event was observed. The incidence of supraventricular arrhythmia in 30mg cohort (40%) was higher than the other two cohorts. Thus 30mg cohort was excluded in Ib phase. Totally, 15 patients in 7.5mg cohort and 17 patients in 15mg cohort were evaluable for treatment response. The DCR and ORR were 80.0% and 60.0% in 7.5mg cohort, 94.1% and 76.5% in 15mg cohort, respectively.

Conclusion:
The pharmacokinetics of Endostar CIV and daily IV were comparable. At doses of 7.5mg and 15mg/m[2]/d, Endostar CIV was well tolerated with encouraging anti-tumor efficacy. Increasing dose of Endostar might lead to better response.

Abstract not provided

Background:
There is little evidence supporting the efficacy of third-line systemic therapy in non-small cell lung cancer (NSCLC) patients (p) with advanced (a) disease, except for erlotinib, and its role is unclear in unselected population. Nonetheless, further-line chemotherapy(CT) is frequently offered in daily clinical practice. We retrospectively analyzed the clinical, pathological characteristics and outcomes of p with aNSCLC who received >3 CT regimens to identify subsets of patients more likely to benefit. The presence of underlying molecular alterations has also been evaluated.

Methods:
The study included data from all consecutive p diagnosed with aNSCLC in our Institution from January 2008 to December 2013. Median overall survival (mOS) and progression free survival (PFS) were evaluated with Kaplan-Meier curves and groups were compared using the Log-rank test. Variables analyzed included p tumor and treatment characteristics. Overall response rate(ORR) was calculated according to the RECIST criteria.

Results:
A total of 486 p were included .175 p (36%) received >3 lines (group3+). Table 1 summarized p characteristics. Group 3+included more females (35.4%vs22.8%; p= 0.0041),younger p (58.9vs61.9;p =0.0016), more never-smoker p (26.9%vs18%;p=0.015), less lung (10.9%vs22.2%;p= 0.0020) and heart (4%vs11.6%;p=0.0020) comorbidities, a higher proportion of molecular alterations (EGFR/ALK) (25.7%vs12.9%; p= 0.0005), more adenocarcinoma (68.6%vs55%;p=0.0045) and less brain metastasis (14.3%vs23.5%;p=0.018). ORR to first line was higher in group 3+ (45.8%vs 29%;p=0.0009). 82.3% non-squamous histology were tested for at least one molecular alteration. There were no differences in PFS between both groups. The mOS of p in group 3+ was longer [24.3 m vs. 7.7 m, p<0.0001)], including p with EGFR/ALK/ROS1 wild-type or unknown [21.6 m vs. 7.4 m, p<0.0001) ]. OS was also longer in the group 3+ harboring a molecular alteration [32.2 m vs 12.7m;p=0.0002]. In the univariate analysis the presence of a molecular alteration were related to longer PFS. In univariate analysis having received >3, female gender, age<65 and the presence of molecular alterations were associated with longer OS. In the multivariate analysis >3 therapeutic lines and the presence of molecular alterations were related to longer OS.

Conclusion:
P treated with >3 systemic treatments were more likely to respond better, progress later and live longer. This better prognosis could be related to the presence of molecular alteration. However p without or unknown molecular alteration could benefit from receiving subsequent lines.

Background:
A recent study has shown pretreatment sodium levels to be a predictive and prognostic marker in NSCLC patients treated with erlotinib. The objective of this study was to evaluate the prognostic impact of pretreatment sodium levels on progression free survival (PFS) and overall survival (OS) in patients of NSCLC treated with pemetrexed-platinum doublet chemotherapy.

Methods:
Stage IIIB/ IV NSCLC patients aged ≥ 18 years treated between January 2011 to November 2014 at our centre were included in this retrospective study. Patients received pemetrexed 500 mg/m[2] with either cisplatin 75 mg/m[2 ]or car­boplatin (AUC 5) on day 1 of a 21 day cycle for 6 cycles followed by maintenance pemetrexed till progression. Electronic medical record (EMR) database of our hospital was used to retrieve demographic data, pretreatment sodium levels, PFS and OS data. LSS was defined as serum sodium < 136mEq/L. Survival analysis was performed using Kaplan-Meier curves and compared between LSS and normal serum sodium (NSS) groups using Log-Rank test and proportional hazard model.

Results:
Figure 1Data was available for 256 patients (M/F = 172/84) with median age of 53 (25-79) years. Majority had ECOG PS of 1 (0 = 34, 1 = 172, 2 = 44, 3 = 6). Stage IIIB = 24 (9%), stage IV = 232 (91%). Pretreatment LSS was observed in 75 (29%) patients while 181 (71%) had NSS. Median duration of follow-up was 17 months. Patients with NSS had significantly longer PFS (10.7 vs. 7.4 months; P < 0.05) and OS (17.6 vs. 13.4 months; P < 0.05) compared to LSS group. Cox-proportional hazard model has shown LSS was an independent prognostic biomarker for poor survival (P < 0.05).



Conclusion:
Pretreatment serum sodium level is an important prognostic marker in stage IIIB/ IV NSCLC patients. The simple possibility of testing coupled with low cost makes it an attractive marker to implement in clinical practice.

Background:
Non-small-cell lung cancer (NSCLC) accounts for >80% of all lung cancers, and the risk of lung cancer clearly increases with advancing age. Because of the progressive aging of population, the number of elderly patients with NSCLC is increasing and the desease is becoming an increasing public health problem worldwide. We previously reported a phase I study that recommended a dose of carboplatin (Cb, area under the curve = 5) plus pemetrexed (PEM, 500 mg/m[2]) for elderly (≥75-years-old) patients with non-squamous NSCLC. Furthermore, PEM maintenance therapy, following the combination therapy, was also found to be well tolerated. Therefore, we conducted a multicenter phase II trial to evaluated the efficacy and safety of Cb (area under the curve = 5) plus PEM (500 mg/m[2]) followed by maintenance PEM for elderly (≥75-years-old) patients with non-squamous NSCLC.

Methods:
Treated patients received 4 courses of Cb plus PEM, followed by maintenance PEM, without showing disease progression or severe toxicities. The primary endpoint was the 1-year overall survival (OS) rate, and the secondary endpoints were OS, progression free survival (PFS), response rate (RR), and safety.

Results:
Thirty four patients were enrolled between June 2012 and May 2013. All patients had an ECOG performance status 0 or 1, and adenocarcinoma. The median patient age was 77 years (75-84 years). Twenty four patients were male and ten patients were female. Three patients harbored activating epidermal growth factor recepter mutation (exon19 or 21). The median observation time was 22.7 months. In clinical outcome, the overall RR was 41.2%, and the disease control rate was 85.3%. No patient showed a complete response, 14 showed partial responses, 15 showed stable disease, 4 showed disease progression, and 1 was not evaluated. The maintenance therapy rate was 58.8%. The median PFS for all patients was 5.7 months (95% confidence interval, 3.3–8.5 months), whereas the median OS was 20.5 months (95% confidence interval, 7.8–25.4 months). The 1-year OS rate was 58.0%. In adverse events (total phase of this study), hematological adverse events ≥grade 3 were leucopenia (in 23.5% of patients), neutropenia (55.9%), anemia (35.3%), and thrombocytopenia (20.6%), and major non-hematological adverse events ≥grade 3 were febrile neutropenia (in 8.8% of patients), increased levels of aminotransferase (5.9%), infection (23.5%), and anorexia/fatigue (5.9%). There was 1 treatment-related death due to interstitial lung disease.

Conclusion:
The combination of Cb plus PEM followed by maintenance PEM was effective and reasonably well tolerated in chemotherapy-naïve elderly (≥75-years-old) patients with non-squamous NSCLC. This data was promising and valuable to conduct the phase III study compared with docetaxel (DOC) monotherapy in the first-line setting. Now, the phase III trial compared Cb plus PEM followed by maintenance PEM with DOC for chemotherapy-naïve elderly (≥75-years-old) patients with non-squamous NSCLC (JCOG1210/WJOG7813L: UMIN000011460) is ongoing and the result is warranted. Clinical trial information: UMIN000004810

Background:
Recent trials suggested that maintenance treatments improve outcomes for patients not progressing after first-line therapy for advanced NSCLC. However, physicians have little guidance on selecting which patients benefit the most and what drug or regimen is optimal. Here, we report a systematic review and network meta-analysis (NMA) of current evidence assessing relative efficacies of maintenance options in unselected populations, as well as in subgroups determined by EGFR mutation, histology, and response to induction.

Methods:
PubMed and conference proceedings were reviewed and individual study relative efficacy measures were meta-analyzed in a Bayesian hierarchical model. The primary and secondary outcomes, Overall Survival (OS) and Progression Free Survival (PFS), respectviely, were evaluated in terms of (i) posterior surface under cumulative ranking curve (SUCRA), (ii) probability of being best treatment, (iii) probability of outperforming no maintenance, and (iv) posterior median hazard ratios with 95% credible intervals, in an unselected population, as well as by EGFR mutation status, histology, and response to induction. Secondary outcomes were overall survival (OS) and adverse events.

Results:
Twelve trials evaluating eight maintenance treatments in 3,850 patients were included in NMA. Selected maintenance treatments showed substantial PFS and OS benefits with probabilities ≥99% and ≥92% respectively of outperforming no maintenance. Results suggest the following strategy for optimal OS and PFS: (i) switch to or continue pemetrexed or switch to anti-EGFR TKI for nonsquamous patients, (ii) continue gemcitabine for squamous patients, (iii) switch to docetaxel or continue gemcitabine for responders to previous induction, and (iv) switch to or continue pemetrexed or switch to anti-EGFR TKI for patients with stable disease post-induction.

Conclusion:
Maintenance treatments improve PFS and OS in good performance status patients with stage IIIb/IV NSCLC not progressing after first-line chemotherapy. Benefits are optimized by targeting specific maintenance treatments to selected patient groups guided by histology and response to previous induction.

Abstract not provided

Background:
Pemetrexed and cisplatin (P-C) has become the standard 1st line chemotherapy in NSCLC patients with wild-type EGFR. The recommended drugs in the 2nd line are docetaxel, docetaxel plus ramucirumab, gemcitabine or EGFR TKIs. Gemcitabine and vinorelbine have good clinical efficacies and low toxicity profiles, so this two drug combination therapy is challenged for their clinical efficacy as 2nd line treatment. The optimal 2nd line chemotherapy following failure of 1st line P-C treatment in advanced NSCLC patients with wild-type EGFR is not yet defined. Therefore, we evaluated the optimal 2nd line chemotherapy in P-C non-responders with advanced NSCLC.

Methods:
We conducted a retrospective analysis of patients with stage IIIB or IV NSCLC who had been treated with P-C as a first line treatment from February 2010 to May 2014. Patients who had EGFR mutation or were on pemetrexed maintenance therapy were excluded. We compared the progression free survival, overall response rate and adverse effects of each regimen.

Results:
Among 110 patients, 52 were eligible for the study. 28 received EGFR TKI (gefitinib or erlotinib); 13 received docetaxel monotherapy; 11 received gemcitabine-vinorelbine (G-V) combination therapy. Median age was 64.5, 61 and 63 years, respectively. All patients showed adenocarcinoma type histology except two in docetaxel and G-V group with large cell type histology. Best response rates were 15.4% in docetaxel group, 18.1% in G-V group and 11% in EGFR TKIs group. Median progression free survival time was 62 days(95% CI 54-70) in EGFR TKIs group, 63 days (95% CI 30-96) in docetaxel group, and 83 days (95% CI 55-111) in G-V group (P=0.17). In pairwise comparisons, p-value was 0.54 for EGFR TKI versus docetaxel group, 0.08 for TKI versus G-V group, and 0.23 for docetaxel versus G-V group. There were no difference in progression-free survival and response rate among the groups. There was a higher rate of grade 3/4 neutropenia in the Docetaxel group.

Conclusion:
Despite the absence of statistical significance, there was a trend that G-V combination therapy had longer progression-free survival outcome compared to EGFR TKI or Docetaxel groups. G-V as well showed better toxicity profiles compared to Docetaxel group. A larger study is required to confirm the efficacy of cytotoxic chemotherapy, especially G-V, as a second line treatment in EGFR mutation negative NSCLC patients.

Background:
In advanced non-small cell lung cancer (NSCLC) decisions regarding palliative treatment are based on tumor response, increasingly combined with patient reported outcomes, especially quality of life (QoL). However, considering treatment decisions in this manner ignores patients’ own opinion about (change in) QoL. A more patient-oriented view regarding therapy could offer valuable information in the process of shared decision-making about treatment initiation or continuation with chemotherapy. We assessed patients’ satisfaction with the received chemotherapy using the Cancer Therapy Satisfaction Questionnaire (CTSQ) in relation with QoL during treatment.

Methods:
In a prospective observational multi-center study, patients with stage IIIB or IV NSCLC receiving pemetrexed (PEM)-based chemotherapy as first or second line treatment were enrolled. Prior to and after four cycles of chemotherapy, patients completed the WHO Quality of Life-BREF (WHOQoL-BREF) and EORTC-Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30), which both contain one item measuring overall QoL on a 1-5 and 1-7 scale, respectively. After four cycles patients also completed the CTSQ, which consists of 16 items scored on a 1-5 scale and is divided in three domains, including the domain satisfaction with therapy (SWT). Linear transformation of the domain score results in a score range 0-100, with a higher score representing a better treatment satisfaction. Items of special interest were Question 7 (Q7) “Chemotherapy was worth taking even with side effects”, Question 16 (Q16) “If given the choice again, would you decide to take this chemotherapy treatment” and Question 2 (Q2) “Chemotherapy would cure the cancer”. From all patients tumor response measurements were obtained according to RECIST 1.1.

Results:
Of the 88 patients receiving four cycles of PEM-based chemotherapy, 65 patients completed the WHOQoL-BREF, EORTC-QLQ-30 and the CTSQ. The majority of these patients had stage IV NSCLC (87.7%) and received PEM-based therapy as first line treatment (92.3%). Treatment resulted in stable disease (53.8%), partial response (40.0%) and progressive disease (6.2%). Eighteen patients often (13.8%) or always (13.8%) expected chemotherapy would cure the cancer. During therapy, overall QoL measured by WHOQoL-BREF increased (1.3±0.6), remained stable (0±0) and decreased (-1.4±0.7) in respectively 15 (23.1%), 30 (46.2%) and 20 (30.8%) patients. The SWT domain score (77.5±12.3 vs. 83.8±13.1) and single item scores Q7 (4.1±0.9 vs. 4.4±0.8) and Q16 (4.4±0.7 vs. 4.5±0.6) in patients with decrease vs. increase of overall QoL did not differ significantly between the groups (p> 0.05). Change in overall QoL measured by the EORTC-QLQ-C30 related to SWT, Q7 and Q16 showed similar results.

Conclusion:
Despite a decrease of QoL during chemotherapy, patients still consider the treatment as worth taking and would decide to receive the chemotherapy again. Since the majority of patients understand that the treatment has no curative intentions, it is unlikely that the satisfaction with treatment only reflects false expectations of cancer cure. Our results represent a group of patients who mainly established disease stabilization, which could have influenced our findings. In shared decision-making on palliative treatment, patients’ QoL cannot be used as a single decision criterion because it does not reflect patients’ satisfaction with treatment. This study is funded by ZonMw, the Netherlands

Background:
Randomized clinical trials have demonstrated the benefits of chemotherapy in carefully selected NSCLC patients. How generalizable these results are to the general population of NSCLC patients, who often have multiple comorbidities that would have rendered them ineligible for licensing trials, is unresolved.

Methods:
The outcomes of unselected patients with stage IV NSCLC who did not participate in a clinical trial and who were treated with standard chemotherapy regimens (paclitaxel/carboplatin; gemcitabine/carboplatin; pemetrexed/carboplatin; paclitaxel/carboplatin/bevacizumab) as first line therapy between 2002 and 2012 at a tertiary teaching hospital were compared to the reported outcomes observed in the licensing trials supporting the use of these drug regimens.

Results:
Results are summarized in Table 1 Patients treated with three-weekly paclitaxel plus carboplatin at recommended dosages had a median progression free survival of 4.9 months for patients responding to this regimen and an overall survival of 13.1 months for responders vs 9.2 months for non-responders. In patients’ treated with gemcitabine plus carboplatin on a three or four week cycle the median progression free survival was 4.8 months for patients responding to the regimen and overall survival of 13 months for responders vs 8.9 months for non-responder group of patients. For patients receiving pemetrexed plus carboplatin the median progression free survival was 7.1 months for patients responding to the regimen with an overall survival of 15.5 months for responders vs 5.9 months for non-responders. Those patients’ treated with paclitaxel plus carboplatin plus bevacizumab the median progression free survival was 7.3 months for patients responding to treatment and overall survival was 16.7 months vs 14.6 months for those patients who did not respond to this regimen as initial treatment. Table I: Patient demographics and results for each regimen

	paclitaxel and carboplatin N=105	Gemcitabine and carboplatin N=35	pemetrexed and carboplatin N=26	paclitaxel and carboplatin and bevacizumab N=28
Age 70>	15.2%	31.4%	26.9%	25.0%
< 70	84.8%	68.6%	73.1%	75.0%
Gender Male Female	64.8% 35.2%	51.4% 48.6%	57.7% 42.3%	60.7% 39.3%
Smoker	89.2%	91.2%	84.6%	71.4%
ECOG 0	12.6%	12.1%	8.7%	23.1%
1	68.9%	63.6%	47.8%	76.9%
2	17.5%	24.2%	43.5%	0.0%
3	1.0%	0.0%	0.0%	0.0%
PFS (months)	4.9	4.8	7.1	7.3
OS (months) PR PD	13.1 9.2	13 8.9	15.5 5.9	16.7 14.6

Conclusion:
Progression free survival in an unselected population of NSCLC patients was similar to that reported in clinical trials supporting the approval of these drugs and regimens. The present analysis provides further support for the use of combination chemotherapy in patients with stage IV NSCLC, including those who would have been ineligible for many clinical trials due to comorbidities. Further analysis is ongoing.

Background:
The current available method to monitor response to treatment in lung cancer patient is by Computerized Tomography (CT) scans. However, time intervals between consecutive CT scans might be too long to allow early identification of treatment failure. The aim of this study is to examine the use of breath sampling as a tool for monitoring response to anti-cancerous treatment in patients with advanced lung cancer.

Methods:
In a prospective study, repeated exhaled breath samples were collected from patients with advanced lung cancer before and under systemic therapy. VOCs[1] profiles were determined by GC-MS[2] and nanomaterial-based array of sensors and correlated with response to therapy, assessed by CT scans as Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD). [1] Volatile Organic Compounds [2] gas-chromatography/mass-spectrometry

Results:
One hundred forty three breath samples were collected from 39 patients with stage III/IV lung cancer. GC-MS anaylsis identified 3 VOCs as significantly indicating PR/SD samples. One of them was also significantly discriminated between PR/SD and PD. Further, the NA-NOSE signals were able to alarm per a change in tumor response across therapy, i.e. indicating lack of further response to therapy, or developement of resistance to therapy. PR/SD was detected in a sensitivity of 93%, specificity of 85% and accuracy of 89% and ppositive/negative predictive values (PPV; NPV) of 86% and 92% respectively. PD was detected with 100% specificity and 92% accuracy, but the sensitivity was only 28%. The PPV and NPV were 100% and 91%, respectively. The achieved results indicate high reliability in predicting a progression of the disease and detecting patient's lack of response to treatment (i.e., PD).

Conclusion:
Breath analysis may serve as a serogate marker for response to systemic therapy in lung cancer. Such a monitoring tool can provide the oncologist with a quick and simple method to identify patient's response to anti-cancerous treatment in shorter intervals than currently available by CT scans.

Abstract not provided

Background:
Treatment of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is the standard therapy for advanced non-small cell lung cancer (NSCLC) with common EGFR mutations such as exon 19 deletions or L858R mutations. However, the efficacy of EGFR-TKIs in patients with uncommon EGFR mutations remains unclear.

Methods:
We have retrospectively surveyed a consecutive database of NSCLC patients with EGFR mutations at Kinki-chuo Chest Medical Center, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases. We analyzed the collect data of NSCLC patients with uncommon mutations including single or complex (uncommon plus uncommon mutations, or uncommon plus common mutations) mutations, treated with gefitinib or erlotinib between July 2007 and September 2014.

Results:
Forty-one patients who had any EGFR uncommon mutations were analyzed in this study. By the Response Evaluation Criteria in Solid Tumors criteria, the overall response rate (RR) was 22.0% with 9 partial response (PR) in all patients with uncommon mutations. Among uncommon single mutations, RR was 12.5% with 3 PR in patients with G719X mutation and 33.3% with 2 PR in patients with L861Q mutation. As for complex mutations, there were no patients in PR with uncommon plus uncommon mutations but RR was 50.0% with 4 PR in patients with uncommon plus common mutations. Median progression-free survival (PFS) was 3.5 months in all patients with uncommon mutations. Among uncommon single mutations, PFS in patients with G719X (median PFS: 1.8 months) was shorter than PFS in patients with L861Q mutation (median PFS: 7.6 months). Furthermore, there was a difference in the efficacy of EGFR-TKIs among patients with each G719X mutation (median PFS in G719A: 8.2 months, median PFS in G719C: 1.1 months, median PFS in G719S: 1.7 months).Figure 1



Conclusion:
First generation EGFR-TKIs are less effective in NSCLC patients with uncommon mutations than in those with common mutations. However, they had favorable response in patients with L861Q or G719A mutations, compared with G719C or G719S mutations.

Background:
Erlotinib, gefitinib and afatinib, tyrosine kinase inhibitors directed at EGFR signalling (EGFR-TKI), are currently used for the treatment of patients with advanced-stage non-small cell lung cancer (NSCLC). A considerable progress in the field of molecular oncology and cancer genomics in recent years has let to identification of several gene alterations predicting clinical outcome of patients treated with EGFR-TKIs. Activating EGFR mutations are widely recognized predictors of good response to EGFR-TKI treatment. While the predictive role of common EGFR mutations (exon 19 deletions and exon 21 L858R point mutation) is well described, very little clinical evidence data exist on the role of rare EGFR mutation types. The aim of this study was to assess the distribution of common and rare EGFR mutations in patients with NSCLC and to evaluate the efficacy of EGFR-TKIs for patients harboring rare and common EGFR mutations.

Methods:
Clinical data of 305 patients with advanced-stage NSCLC (IIIB or IV) treated with EGFR-TKIs having EGFR mutation positive primary tumors at the time of diagnosis were evaluated in a retrospective setting. The therapy included erlotinib, gefitinib or afatinib as recorded in a Czech national lung cancer registry – TULUNG. The relative frequency and survival data (PFS and OS) were evaluated for individual EGFR mutation types.

Results:
The common activating EGFR mutations (exon 19 deletion and exon 21 L858R point mutation) were found in a total of 249 (81.6%) patients. Rare EGFR mutations were found in 56 (18.4%) patients, the most frequent of which was exon 18 - G719X mutation found in 29 patients (9.5%), followed by mutations in exon 20 found in 28 patients S768I in 3 patients (0.98%) and insertion 3 mutations in 16 patients (5.2%). Patients with exon 19 deletion had median median OS 11.0 months, patients with exon 21 point mutation L858R median OS 9.4 months,respectively. Patients with rare EGFR mutations median OS 12.5 months.Comparing frequent and rare mutations, there were no differences in sex, age, PS, stage of disease and adverse effects of first line gefitinib therapy, the group of patients with rare mutations were more frequently smokers, duration of gefitinib therapy was shorter, response rate and PCR, PFS and OS were worse than in patients having frequent EGFR mutations. There were no significant differences in characteristics, PFS and OS between exon 19 deletion and exon 21 L858R point mutation tumour patients.

Conclusion:
While patients with frequent EGFR sensitive mutations have significant benefit from gefitinib therapy, patients with G719X mutation on exon 18 have marginal PFS and OS benefit, while pagtients with exon 20 insertion mutations have no demonstrable benefit from targeted therapy.Next generation tyrosinkinase inhibitors may prolong survival in some of rare EGFR mutated tumour patients.

Background:
Rociletinib (CO-1686) is a novel, oral, irreversible mutant selective tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC). Rociletinib has demonstrated efficacy against activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. A maximum tolerated dose was not identified in Phase 1 with 1000 mg BID the highest dose studied. Here we assess the efficacy and safety of the three doses of rociletinib (500 mg BID, 625 mg BID and 750 mg BID) selected for Phase 2 study.

Methods:
TIGER-X (NCT01526928) is a Phase 1/2 open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with advanced EGFR mutant NSCLC progressing after ≥1 EGFR tyrosine kinase inhibitor (TKI). Efficacy is assessed using RECIST. Safety is evaluated using standard adverse event (AE) reporting.

Results:
As of April 2015, a total of 231 central T790M positive patients were evaluable for efficacy and 343 for safety (any T790M). All patients were enrolled in the USA (85%), Europe (9%) and Australia (6%). Baseline characteristics were similar in each dose group. The median number of prior therapies was 2. 85% had EGFR TKI as their most recent prior therapy and 10% had a history of diabetes/hyperglycemia. Immature ORRs are 53% (500 mg BID), 52% (625 mg BID) and 43% (750 mg BID), with disease control rates of 89% (500 mg BID), 87% (625 mg BID) and 82% (750 mg BID). The most common ≥grade 3 treatment-related AE was hyperglycemia [16% (500 mg BID), 25% (625 mg BID) and 35% (750 mg BID)] which was managed with oral hypoglycemic agents. Only one patient discontinued the study for hyperglycemia. Grade 3 QTc prolongation was uncommon, occurring in 2% (500 mg BID), 7% (625 mg BID) and 10% (750 mg BID) of patients, and demonstrated a relationship to dose. There were no clinically relevant cutaneous toxicities with 7 cases of grade 1 rash and 4 cases of grade 1 stomatitis (no dose relationship) and no paronychia.

Conclusion:
All 3 Phase 2 doses of rociletinib are active and well tolerated in a Western patient population with advanced NSCLC. The lack of cutaneous toxicities confirms the selectivity of rociletinib for mutant forms of EGFR and is an important contributor to QOL and maintaining dose intensity (Lacouture et al. 2011). Overall, the adverse event frequency appears to be related to dose, but antitumor activity does not, thus the risk/benefit profile may be optimal at the lowest dose studied.

Background:
Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) with activity against the activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. TIGER-X (NCT01526928) is a Phase I/II open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with advanced EGFR mutation-positive NSCLC with progressive disease after ≥1 EGFR tyrosine kinase inhibitor (TKI). An overall response rate of 67% has previously been reported in this trial for T790M positive patients treated with the 500 and 625 mg BID doses (Soria 2014). Here we provide preliminary data on the activity of rociletinib in the subgroup of patients with a history of CNS disease.

Methods:
Patients with a history of CNS disease were permitted if asymptomatic and stable, as defined by steroid requirements. The primary activity endpoint was RECIST overall response rate. However, patients who developed progressive disease (PD) while on study treatment were allowed to continue therapy with rociletinib if deemed clinically beneficial by the investigator.

Results:
As of 16 March 2015, a total of 401 patients received therapeutic dose levels of rociletinib (500, 625 and 750 mg BID) including 170 (42%) patients with a history of CNS metastases. Based on this interim analysis, the RECIST overall response rate among these patients with a history of CNS disease is 41%. To date, 42 patients with a history of CNS disease have continued therapy with rociletinib post-progression. Of those who continued for at least 14 days the average treatment duration beyond PD was 89 days (range: 14 - 336 days). Twenty-two of the 42 patients with a history of CNS disease with PD also received brain radiation and continued rociletinib treatment for an average of 120 days (range: 22 – 336 days) after PD. Rociletinib is held on radiation days only. Progression-free survival data for these subgroups is not yet mature. The three most common adverse events in the patient population with a history of CNS disease are similar to those found in the general TIGER-X patient population: hyperglycemia, diarrhea and nausea.

Conclusion:
In patients with a history of CNS disease, a factor associated with poor prognosis, rociletinib is active with a RECIST response rate of 41%. Local CNS radiation has been administered safely with rociletinib held on radiation days and continued afterwards. Prolonged use of rociletinib post CNS radiation suggests ongoing systemic benefit is still experienced by these patients. The role of rociletinib in NSCLC patients with CNS involvement is being further explored in the ongoing TIGER clinical development program.

Abstract not provided

Background:
AZD9291 is an oral, potent, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selective for both EGFR-TKI-sensitizing (EGFRm) and T790M resistance mutations. The Phase I AURA study was a dose escalation/expansion study in patients with EGFRm positive advanced non-small cell lung cancer (NSCLC) who had progressed after EGFR‑TKI treatment. The 80 mg once daily (qd) dose was chosen for further evaluation in a Phase II extension cohort of the AURA study, and in an additional Phase II study (AURA2). Here we report efficacy and safety of AZD9291 from the AURA study Phase II extension cohort (NCT01802632) in patients pre-treated with EGFR-TKI and with centrally confirmed T790M positive advanced NSCLC.

Methods:
Eligible patients had measurable disease, World Health Organization performance status (WHO PS) 0 or 1, and acceptable organ function; stable brain metastases were allowed. A mandatory tumor sample was taken after disease progression on the most recent line of therapy, for prospective confirmation of T790M positive status by central laboratory testing (cobas™ EGFR Mutation Test). Patients received AZD9291 at 80 mg qd until disease progression. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 (assessed by independent central review, ICR). Secondary objectives included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), investigator-assessed ORR, and safety. Planned enrollment was 175 patients to give an estimate of the ORR with 95% CI within ±8%. Data cut-off was January 9, 2015 after all patients should have undergone the second tumor assessment.

Results:
201 patients were dosed in the extension cohort of the study; two patients without measurable disease at baseline by ICR were excluded from the evaluable-for-response set. By central testing, EGFR mutation subtypes were: T790M, 98%; Ex19del, 71%; L858R, 25%; other, 3%. Median age was 62 years; female, 66%; Asian, 57%; WHO PS 0/1/2, 34%/66%/1%; second/≥third-line, 30%/70%. At the data cut-off, median treatment exposure was 4.9 months and 168 patients remain on treatment. ORR by ICR was 58% (115/199; 95% CI 51, 65) and DCR was 92% (95% CI 87, 95). ORRs were similar across lines of therapy (second-line, 59.0% [36/61] vs ≥third-line, 57.2% [79/138]). Investigator-assessed ORR was 68% (137/201; 95% CI 61, 75). Median DoR and median PFS have not been reached (maturity 2% and 21%, respectively). The most common all-causality adverse events (AEs) were diarrhea, 41% (0.5% Gr≥3) and grouped rash terms 37% (0.5% Gr≥3); 42 (21%) patients experienced Gr≥3 AEs. Interstitial lung disease grouped terms were reported in five (2.5%) patients, one of which was fatal (0.5%) and considered possibly causally related to AZD9291 by the investigator. Eight patients (4%) discontinued treatment due to an AE. Updated results from a later data cut-off will be available for presentation.

Conclusion:
In the AURA study Phase II extension cohort, AZD9291 80 mg qd demonstrates clinical activity, manageable tolerability, and a low discontinuation rate in patients with centrally confirmed EGFR T790M positive advanced NSCLC that has progressed on or after EGFR‑TKI treatment. These data provide further validation of the results from the Phase I study cohorts.

Background:
AZD9291 is an oral, potent, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) selective for both EGFR-sensitizing (EGFRm) and T790M resistance mutations. It has shown anticancer activity and manageable tolerability in patients with EGFRm advanced NSCLC that had progressed after EGFR‑TKI treatment.

Methods:
In this first-line expansion cohort (AURA, NCT01802632), patients received AZD9291 at 80 or 160 mg/day, in sequential dose groups. EGFRm status was determined locally and/or by central testing using the cobas EGFR Mutation Test. Other inclusion criteria included measurable disease, World Health Organization performance status (WHO PS) 0 or 1, and acceptable organ function; stable brain metastases were allowed. Safety, tolerability, and anticancer activity were assessed in these cohorts, to evaluate AZD9291 in the first-line treatment setting. The data cut-off was December 2, 2014.

Results:
Sixty treatment-naïve patients were enrolled; 30 patients in each dose group (80 or 160 mg/day). By central testing, EGFR mutation subtypes were: L858R 40%; exon 19 deletion, 37%; other EGFR-sensitizing mutations, 3%; and T790M, 8%. Baseline median age was 63.5 years; 25% of patients were male; 57%/43% had WHO PS 0/1, respectively; 72% were Asian and 23% Caucasian. Median treatment exposure at the 80 and 160 mg dose levels was 260 and 171 days, respectively. Fifty-two out of 60 patients remained on treatment at the data cut-off. Anticancer activity of AZD9291 is shown in Table 1. One-third (33%) of patients experienced Grade ≥3 adverse events; two patients had Grade 3 diarrhea and one patient had Grade 3 skin rash. New data from a 2015 data cut of the AURA first-line expansion will be available for presentation.

Table 1. Anticancer activity findings in AURA first-line expansion

Endpoint	Finding
Objective response rate:
Overall	70% (95% CI 57, 81)
AZD9291 80 mg/160 mg	60%/80%
Disease control rate:
Overall	97% (95% CI 89, 100)
AZD9291 80 mg/160 mg	93%/100%
Progression-free survival:
Median	Not yet reached
3-month/6-month	93%/87%
Events to date	7/60 (12% mature)

Conclusion:
AZD9291 has a manageable tolerability profile and is associated with promising anticancer activity in treatment-naïve patients with EGFRm advanced NSCLC. A Phase III study (FLAURA, NCT02296125) has been initiated to assess the efficacy and safety of AZD9291 in comparison with a standard-of-care EGFR-TKI (gefitinib or erlotinib) in the first-line setting.

Background:
The epidermal growth factor receptor (EGFR) T790M mutation is found in about half of patients who have developed resistance to EGFR-tyrosine kinase inhibitors (TKIs), gefitinib or erlotinib. AZD9291 is an oral, potent, irreversible EGFR-TKI selective for both EGFR-sensitizing (EGFRm) and T790M resistance mutations. In the Phase I AURA study, AZD9291 80 mg (dose selected for further evaluation) was found to be clinically active, with an acceptable tolerability profile. This ongoing AURA2 Phase II study (NCT02094261) investigates the efficacy and safety of AZD9291 80 mg once daily after previous EGFR-TKI treatment in patients with EGFRm and T790M positive advanced NSCLC.

Methods:
AURA2 (NCT02094261) is a global, open-label, single-arm Phase II study. To be eligible, all patients had a mandatory tumor sample taken after disease progression on the most recent line of therapy, for confirmation of T790M positive status by central laboratory testing using the cobas™ EGFR Mutation Test. Further inclusion criteria included measurable disease, World Health Organization performance status (WHO PS) 0 or 1, and acceptable organ function; stable brain metastases were allowed. Patients receive AZD9291 at 80 mg once daily until disease progression. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 (assessed by independent central review, ICR). Secondary objectives included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), and safety. Planned enrollment was 175 patients to give an ORR with 95% confidence interval (CI) within ±8%. The data cut-off was January 9, 2015.

Results:
Recruitment is complete and 210 patients were enrolled; 12 patients did not have measurable disease at baseline by ICR and are excluded from the evaluable-for-response set. By central testing, in addition to T790M, patients had background EGFR mutation: Ex19del, 65%; L858R, 32%; other, 3%. Baseline characteristics: median age, 64 years; female, 70%; WHO PS 0/1, 40%/60%; Asian, 63%; second-/≥third-line, 32%/68%. Median treatment exposure was 4.0 months and 183 patients remain on treatment at the data cut-off. ORR by ICR was 64% (127/198; 95% CI 57, 71) and DCR was 90% (95% CI 85, 94). Investigator-assessed ORR was 64% (135/210; 95% CI 57, 71). Median DoR and median PFS have not been reached (maturity 6% and 20%, respectively). The estimated proportion of patients who are alive and progression free is 82% and 70% at 3 and 6 months, respectively. The most common all-causality adverse events (AEs) were diarrhea, 34% (1% Gr≥3) and grouped rash terms 40% (0.5% Gr≥3); 38 (18%) patients experienced Gr≥3 AEs. Interstitial lung disease grouped terms were reported in four (1.9%) patients, one of which was fatal (0.5%) and considered possibly causally related to AZD9291 by the investigator. Eight patients (4%) discontinued treatment due to an AE. Updated results from a later data cut-off will be available for presentation.

Conclusion:
AZD9291 80 mg once daily demonstrates clinical activity and manageable tolerability in patients with EGFRm, T790M mutation positive advanced NSCLC that has progressed on or after EGFR‑TKI treatment. AZD9291 is being investigated in the randomized AURA3 Phase III study (NCT02151981) in comparison with platinum-based doublet chemotherapy.

Background:
Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) exhibits sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib; however, acquired resistance eventually develops in most patients. The most common mechanism of TKI resistance is a second-site mutation in the EGFR kinase domain, T790M. AZD9291 is an oral, potent, irreversible EGFR-TKI with potency against both T790M resistance and sensitizing EGFR mutations. In the ongoing Phase I AURA study (NCT01802632), AZD9291 induced durable responses in patients with acquired resistance to EGFR-TKIs. We report results of paired biopsy cohorts of the AURA trial, reviewing modulation of key molecular biomarkers of AZD9291 activity in patient tumor samples.

Methods:
Two cohorts of patients on the AURA trial were consented for collection of paired tumor biopsies. These patients had a pre-study tumor biopsy with T790M positive tumor status confirmed by central laboratory EGFR testing (Cobas™ EGFR Mutation Test). Following 8 to 15 days of once daily AZD9291 treatment (80 or 160 mg), a post-dose tumor biopsy was obtained. Baseline and post-dose tumor tissue was processed for routine histology and pathologic evaluation. More than 100 viable tumor cells per sample were required for subsequent biomarker scoring. Formalin-fixed paraffin-embedded tumor biopsies were profiled by immunohistochemistry with a suite of key pathway and tumor-relevant markers (phospho[p]-EGFR, pERK, pAKT, pS6, PD-L1, CD8). Matching plasma pharmacokinetic samples were also obtained for PK-PD correlations.

Results:
As of February 2015, 58 potential patients with an evaluable baseline biopsy were identified as candidates for post-dose biopsy collection. Sixteen of these patients did not proceed to an on-study biopsy as the identified lesions had regressed too substantially or were no longer considered suitable for re-biopsy, one patient was medically excluded from re-biopsy, and one patient’s sample was not available. In total, 40 patients supplied matched pre- and on-treatment biopsies. As of March 2015, paired tumor samples were available for QC from 26 of these 40 patients. Ten of these 26 biopsy specimens subsequently failed QC due to inadequate tumor content, leaving 16 paired tumor samples available for biomarker analyses, of which five have thus far been evaluated. AZD9291 treatment resulted in the inhibition of EGFR pathway components in the majority of post-treatment tumor biopsies. Tissue biomarker analyses are ongoing and updated data on evaluable biopsy pairs will be reported at the time of the congress.

Conclusion:
The completion of a paired biopsy cohort within the AURA trial was challenging due to the rapid onset of anti-tumor effects of AZD9291. Approximately 29% (17/58) of potentially eligible patients were unsuitable for the post-dose biopsy procedure due to tumor regression and 38% (10/26) of available post-dose biopsies were found to contain too little tumor for analysis. In the evaluable tumor pairs, pharmacodynamic modulation of the EGFR pathway was evident. Further biomarker analyses, including evidence of modulation of immune system markers, may help inform future combination strategies.

Abstract not provided

Background:
Afatinib, an irreversible tyrosine kinase inhibitor (TKI), has shown clinical benefits and prolonged progression free survival in EGFR mutated patients. HGF, a ligand of c-MET, may be involved in resistance to EGFR-TKIs.

Methods:
A total of 66 patients with advanced lung adenocarcinoma (stage IIB and IV) and documented progression to first-line chemotherapy were enrolled to receive afatinib 40 mg/day. Mutational EGFR and HER-2 status were assessed by RT-PCR. HER2 amplification was evaluated by FISH. Plasma HGF levels were measured by ELISA before and 2 months after the start of treatment with afatinib. We assessed the change in plasma HGF levels and the association with objective response rate (ORR), progression free survival (PFS) and overall survival (OS). The protocol is registered in ClinicalTrials.gov (NCT01542437).

Results:
We identified 2 patients carrying a HER2 mutation and both presented stable disease (SD). HER2 amplification was not detected. HGF-positive plasma reduction status had a significant higher ORR (75.0% vs 44.1% p= 0.011), and was strongly associated with longer PFS (HR 0.40 [95% CI 0.18 - 0.87], p= 0.02) and OS (HR 0.31 [0.13 - 0.71] p=0.006). A stratified multivariate analysis in EGFR mutated patients showed that the HGF plasma levels reduction remains as a significant and independent factor associated with longer PFS (HR 0.34 [95% CI 0.13 - 0.89] p= 0.04) and OS (HR 0.34 [95% CI 0.13 - 0.88] p= 0.02).

Conclusion:
HGF plasma levels reduction is strongly related to better outcomes with afatinib therapy, irrespective of EGFR mutation status. The lack of reduction might allow the identification of a subgroup of patients who will not expected to respond and could benefit with the use of drugs targeting the HGF-c-Met axis. Further studies are warranted.

Background:
The phenomenon of small cell lung cancer(SCLC) transformation in EGFR mutated adenocarcinoma had been previously identified as a resistant mechanism. However, this phenomenon was only reported in single case and a repeat biopsy patient cohort. Moreover, the underlying molecular mechanism remains unclear. Previous study found that the inactivation of TP53 and Rb1 could efficiently transform neuroendocrine and alveolar type 2 cells into SCLC. We inferred that TP53 and Rb1 might also play an important role in SCLC transformation. So we use the sh-RNA mediated depletion of RB1 adenocarcinoma cell line, that also have TP53 inactivation in nature, to investigate the molecular mechanism of SCLC transformation.

Methods:
Both primary and metastatic tissue were analyzed on 3 SCLC transformation patients by whole genome sequencing (WGS). We knock down RB1 in TP53 inactivation cell lines, PC-9, HCC-827 and H1975. Western blot and immunohistochemistry (IHC) were used to confirm RB1 knock down and expression of neuroendocrine (NE) markers. Trans well cell invasion assay and softer agar clone formation test were investigated the change of invasion and migration. CCK8 kit was used to evaluate relative viability of cells after RB1 knock down. Cell cycle and apoptosis were determined by folw cytometry. And we use balb/c mice for cell line tumorgenesis.

Results:
① Pathological analysis of the 3 patients’ primary lesion and the consistent EGFR mutation status confirmed the phenomenon of SCLC transformation. WGS showed the copy number variation of primary tumor and transformed metastasis was distinct. RB1 is lost in 100% of the three transformed cases but occur in one patient’s primary tissue in extremely low frequency(<5%). ② PC-9, HCC827 and H1975 cell line showed up-regulation of NE markers after sh-RNA mediated RB1 depletion, which presented more capable of invasion and migration. Cell folw cytometry showed more cells was in G2 and S phase after RB1 knock down. The expression of Bik and puma that belong to Bcl-2 family was up-regulated after RB1 inactivation compared with the control group.

Conclusion:
The NE differentiation and changes in invasion, migration, apoptosis and cell cycle indicated that the loss of TP53 and RB1 promote the process of SCLC transformation. TP53 and RB1 deficiency may be a necessary event for SCLC transformation to emerge, but is still insufficient to induce SCLC transformation.

Background:
For non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations, preclinical data showed the superiority of exon 19 mutations to exon 21 mutations in both response to EGFR tyrosine kinase inhibitors (TKIs) and survival. Meanwhile, retrospective studies demonstrated that erlotinib was significantly superior to gefitinib in progression-free survival (PFS) for advanced NSCLC patients with EGFR mutations. However, no randomized controlled trials compared erlotinib to gefitinib in advanced NSCLC patients with EGFR exon 19 or 21 mutations.

Methods:
We conducted a randomized controlled trial (CTONG 0901；NCT01024413) comparing erlotinib to gefitinib in advanced NSCLC harboring EGFR exon 19 or 21 mutations from July 2009 to July 2014. Eligible patients were randomized to receive erlotinib (150 mg, qd) or gefitinib (250 mg, qd) at the ratio of 1:1 in any line settings. The primary endpoint was PFS, and the secondary endpoints included overall survival (OS), objective response rate (ORR), post-progression survival (PPS), and toxicities.

Results:
The last follow-up was on March 30, 2015. Totally, 256 patients (148 with exon 19 mutations and 108 with exon 21 mutations), of whom 165, 83 and 9 were in the first, second or further-line settings respectively, were randomized to receive erlotinib or gefitinib. Median PFS was 12.4 (95%CI: 10.6~14.1) months in erlotinib arm and 10.4 (95%CI: 8.8~11.9) months in gefitinib arm, HR=0.80 (0.61~1.05), p=0.100; ORR, median PPS and OS were 56.3% versus 52.3% (p=0.530), 6.9 (95%CI: 4.3~9.5) versus 6.9 (95%CI: 4.5~9.2) months (p=0.784), and 22.4 (95%CI: 17.9~27.0) versus 20.5 (95%CI: 17.1~23.8) months (HR=0.90 [0.67~1.22]; p=0.496) respectively. There were no significant differences in toxicities between the two arms, p＞0.05. In the four subgroups (the first-line, second or further-line setting, exon 19 and 21 mutations), except for median PFS being 11.4 versus 7.9 months (HR=0.58 [0.37~0.90], p=0.015) in the second or further-line setting, no significant differencs were observed in median PFS and OS respectively between the two arms, p＞0.05. Receiving erlotinib or gefitinib treatment, EGFR exon 19 mutant patients were superior to those with exon 21 mutations in terms of ORR (62.2% versus 43.5%, p=0.003), median PPS (9.1 [95%CI: 7.0~11.2] versus 4.6 [95%CI: 3.4~5.8] months, p=0.011 ) and OS (24.8 [95%CI: 20.9~28.8] versus 17.7 [95%CI: 15.1~20.3] months, HR=0.66 [0.48~0.89], p=0.006) respectively, even though there was no significantly difference in median PFS (11.4 [95%CI: 9.6~13.2] versus 11.1 [95%CI: 9.4~12.9] months, HR=0.80 [0.60~1.05], p=0.101). Multivariant Cox regression analysis showed that subsequent EGFR TKIs, combination of subsequent EGFR TKIs and local treatment, as well as subsequent chemotherapy were prognostic factors for OS, p＜0.05.

Conclusion:
Erlotinib was not significantly superior to gefitinib in advanced NSCLC with either exon 19 or 21 mutations in response and survival, with similar toxicities. However, EGFR exon 19 mutant patients had remarkably increased ORR, PPS and OS than those with exon 21 mutations after taking erlotinib or gefitinib. Subsequent treatments after failure to EGFR TKIs were significantly prognostic factors for OS.

Background:
Patients with EGFR-mutant lung cancers treated with EGFR tyrosine kinase inhibitors (TKI) develop clinical resistance, often associated with acquisition of EGFR T790M. Upregulation of JAK/STAT signaling is involved in resistance to EGFR TKIs and JAK inhibition is a proposed treatment strategy in the setting of acquired resistance by restoring sensitivity to erlotinib. Ruxolitinib is an FDA-approved oral JAK1/2 inhibitor given at 20mg twice daily for hematologic malignancies with a largely non-overlapping toxicity profile with erlotinib.

Methods:
We evaluated the toxicity and efficacy of once daily oral erlotinib and twice daily oral ruxolitinib in patients with EGFR-mutant lung cancers and acquired resistance to erlotinib therapy (NCT02155465). Using a 3+3 dose escalation, we assessed escalating doses of ruxolitinib (10mg BID, 15mg BID, 20mg BID) with erlotinib 150mg daily for 21 day cycles. Response was evaluated by RECIST 1.1. Tissue and peripheral blood samples were obtained; exosomes will be extracted from peripheral blood and molecular and proteomic analyses will be performed.

Results:
From May 2014 to February 2015, 12 patients (pts) were enrolled. Median age: 60; Women: 7 (58%); never-smokers: 6 (50%); EGFR L858R=4 (33%) and Exon 19 deletion=8 (67%). Two of twelve (17%) were EGFR T790M positive at rebiopsy at the time of acquired resistance. Of 12 pts treated, 3 received ruxolitinib 10mg BID, 3 received 15mg bid and 6 received 20mg BID with erlotinib 150mg daily. No dose limiting toxicities were seen. The recommended phase 2 dose is ruxolitinib 20mg BID with 150mg erlotinib daily. Treatment-related AEs were all grade 1-3. The most frequent treatment related clinical adverse events (all grade 1-3) were anemia (25%), diarrhea (25%), rash (25%), pain (17%), fatigue (8%), and pneumonitis (8%). The most frequent treatment-related laboratory adverse events (all grade 1-2) were anemia (33%), elevated ALT (17%), elevated AST (17%), and hyperbilirubinemia (8%). Of the 12 pts treated, 2 (17%) required a dose reduction of erlotinib for treatment emergent toxicities; both subjects were on lower doses of erlotinib than 150mg daily prior to study enrollment. There were no dose reductions of ruxolitinib. Of 12 evaluable patients, no partial responses were seen. The median-progression free survival is 3 months. Two patients remain on study. One patient has been on study for 10 months with ongoing stable disease. Nine patients (75%) came off study for progression, 1 (8%) for toxicity. One person discontinued treatment on study for grade 3 pneumonitis, possibly related to the combination of erlotinib and ruxolitinib. The symptoms resolved with discontinuation of erlotinib and ruxolitinib.

Conclusion:
Combination erlotinib and ruxolitinib is well-tolerated. The phase 2 dose of ruxolitinib is 20mg BID in combination with erlotinib. There were no partial responses, but durable disease control was seen in some patients. The phase 2 study of erlotinib and ruxolitinib in this population is ongoing.

Abstract not provided

Background:
We have proposed that synergistic epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-chemotherapeutic interaction in lung cancer cells has 3 essentials: no platinum, cells not or no more sensitive to EGFR-TKI, and using a synergistic chemo partner, e.g., pemetrexed (P) (Tsai, et al. Lung Cancer 82:305, 2013).

Methods:
GENIUS study (NCT01579630) was a phase II, multicenter, randomized, open-label prospective trial comparing maintenance G/P versus P in patients with metastatic lung adenocarcinoma (mLADC) harboring no sensitizing EGFR mutations (sEGFRm) detected by high sensitivity methods following a 4-cycle P/Platinum induction therapy in frontline setting. Patients with no disease progression (PD) were 1:1 randomized to receive P (500 mg/m[2], 3-week cycle) ± G (250 mg, daily) until PD or treatment failure, and stratified by study site and response. The primary endpoint was progression free survival (PFS) by both independent radiologist review (IRR) and investigator assessment (IA), secondary endpoints included time to treatment failure (TTF), overall survival (OS), safety and toxicity profile.

Results:
Between 03/2011 and 11/2013, 55 patients were randomized, G/P 26, P 29. Baseline characteristics were balanced between arms (age 57; female 42%; never smoker 55%; ECOG1 91%; ≥2 metastatic sites 38.2%; ALK+ 16%). Median follow-up was 20.4 mo. Median cycle of treatment was G/P 9.5 (range 1-32) and P 4 (2-21). Median PFS was substantially longer for G/P than P, both by IRR (3 deemed as PD at randomization were excluded; n = 25 v 27): 8.4 v 3.8 mo; HR [95% CI] 0.42 [0.23-0.79]; p = 0.0057, and by IA: 8.7 v 2.9 mo; HR 0.38 [0.21-0.70], p = 0.0013. Response with induction therapy, age, and smoker had interactions with treatment for PFS. Median TTF: 7.0 v 2.9 mo; HR 0.46 [0.25-0.83], p = 0.0085. OS was also better for G/P than P by IRR (undefined v 29.3 mo; HR 0.44 [0.20-0.97]; p = 0.037) and IA (undefined v 21.7 mo; HR 0.46 [0.22-0.97]; p = 0.038). There were more treatment-related diarrhea, liver and skin toxicities on G/P v P, but generally mild. Two G/P patients were off-study due to liver toxicity.

Conclusion:
This proof of concept ph 2 study first demonstrated survival benefit of EGFR-TKI plus chemo in the maintenance phase of frontline treatment for patients with mLADC harboring no sEGFRm. This strategy deserves phase III study to confirm.

Background:
Advanced NSCLC pts with Zubrod PS2 are often excluded from clinical trials and platinum-based therapy. In SWOG 0341, erlotinib in PS 2 pts yielded progression-free (PFS) and overall survival (OS) of 2.1 and 5 months respectively. In a trial of erlotinib versus carboplatin/paclitaxel in PS2 pts (Lilenbaum, JCO 2008), PFS for erlotinib and chemotherapy were 1.9 and 3.5 months, respectively. Early reports suggested a potential role for serum proteomics in predicting erlotinib benefit beyond that of EGFR mutational status. We therefore conducted a prospective trial of erlotinib +/- chemotherapy in NSCLC pts with PS2 enriched by serum proteomics (Veristrat assay).

Methods:
Metastatic NSCLC pts with PS2, acceptable end-organ function, and “good” classification by serum proteomics were randomized to either Arm A (erlotinib 150 mg orally QD) or Arm B (erlotinib 150 mg orally QD on days 2-16 plus carboplatin AUC 5 IV day 1 and paclitaxel 200 mg/m2 IV day 1 x 4 cycles, followed by erlotinib 150 mg orally QD). Cycle length was 3 weeks. Arm B agents were “pharmacodynamically separated” to mitigate potential antagonism. The arm with superior observed median PFS would be selected for further evaluation, but only if ≥ 3 months. A sample size of 98 pts was based on a variety of assumed PFS probabilities for each arm. The trial was prematurely closed after the FDA determined midway through accrual that an IDE application was required for the proteomics assay; however SWOG had limited resources available for such filing.

Results:
Of 156 pts screened, 83 (59%) were classified as “good” by serum proteomics. 59 of 83 pts (60%) met trial eligibility and were randomized. Treatment-related grade 4 adverse events were seen in 2 pts in Arm A (thrombosis, hypomagnesemia) and 5 pts in Arm B (neutropenia -5, febrile neutropenia-1, leukopenia -1), with no treatment related deaths. Figure 1



Conclusion:
In Zubrod PS2 pts with advanced NSCLC and “good” classification by serum preoteomics, pharmacodynamically-separated erlotinib plus chemotherapy had better observed median PFS/OS versus erlotinib alone and surpassed the protocol-specified benchmark of PFS >= 3 months required for further study. Updated data will be presented.

Background:
National Comprehensive Cancer Network Guidelines recommend using VeriStrat, a blood proteomics test to determine using erlotinib instead of chemotherapy as second-line treatment for patients with non-small cell lung cancer (NSCLC). However, VeriStrat has not been evaluated in a first-line setting within a randomized trial.

Methods:
TOPICAL was a double-blind randomised placebo-controlled trial, for 670 chemotherapy-naive NSCLC patients (stage IIIb/IV) considered unsuitable for chemotherapy, mainly due to poor performance status (ECOG ≥2) or co-morbidities. They were randomized to receive best supportive care plus oral placebo or erlotinib (150mg/day) until disease progression/toxicity. Although there was no overall survival (OS) benefit among all patients, patients on erlotinib who developed first-cycle rash had improved OS, compared to placebo: hazard ratio (HR 0.76), p=0.006; unlike those without rash (HR 1.30, p=0.017). Pre-treatment serum samples were available for 477 of 670 (70%) TOPICAL patients. They were sent as anonymised aliquots to Biodesix for VeriStrat testing.

Results:
VeriStrat testing classified 52% (250/477) as having good outcomes, 46% (221) poor outcomes, and 6 unknown. In all patients, VeriStrat classification was associated with OS (good vs. poor: HR=0.58, 95%CI 0.47-0.73; P<0.0001) and PFS (HR=0.72; 95% CI 0.53-0.97; P=0.002), after allowing for gender, histology, stage, treatment and first-cycle rash (unadjusted HRs were similar, as were those ignoring rash). In all erlotinib patients, median OS was 4.9 (good) vs. 3.1 months (poor); HR=0.63, 95% CI 0.47-0.85, p=0.002. The corresponding results among all placebo patients were: 5.3 (good) vs. 2.9 months (poor), HR=0.53, 95% CI 0.39-0.73, p<0.001. Similar results were found for PFS: median 3.1 (good) vs. 2.2 (poor) months (HR=0.72; 95% CI 0.53-0.96, P=0.027) for erlotinib patients; and 2.8 vs. 2.4 months for placebo patients (HR=0.72, 95% CI 0.53-0.97, p=0.033). Among all patients, VeriStrat was not predictive: OS HR for erlotinib vs. placebo was 1.02 (95% CI 0.79-1.31) in the ‘good’ group, and 0.86 (95% CI 0.66-1.12) for ‘poor’; interaction p-value=0.38. Corresponding PFS HRs were 0.86 (95% CI 0.67-1.10) and 0.84 (95% CI 0.65-1.10); interaction p-value=0.92. VeriStrat was also not predictive when allowing for first-cycle rash (Table 1). However, among patients who had rash, those with ‘good’ classification had longer OS (p<0.001) and PFS (p=0.001) than those classified as ‘poor’. Figure 1



Conclusion:
Our large randomized trial among NSCLC patients considered unsuitable for chemotherapy shows that VeriStrat status was prognostic for OS and PFS; but it was not predictive for OS nor PFS, in relation to erlotinib vs. placebo as first-line treatment.

Background:
Erlotinib in 2[nd] line improves survival in patients with recurrent/progressive NSCLC, is also active in squamous cell NSCLC, as reported in a BR.21 study subgroup. So far, no prospective non interventional study has specifically evaluated patients with this histological subtype treated with erlotinib. We present the final results of PEPITA cohort.

Methods:
PEPITA is a French multicenter, prospective cohort study assessing erlotinib modalities of use in daily practice in squamous NSCLC. The primary endpoint was progression-free survival (PFS); secondary endpoints included patients’ characteristics, overall survival (OS), safety and quality of life. EGFR mutation was tested in 41 patients (28.5%) reason why exploratory analyses assessing EGFR genotyping and smoking status were also performed.

Results:
Between June 2012 - May 2013, 152 patients were included and 146 patients were analyzed for efficacy; median follow-up was 5.31 months (0.03-17.65).

Patients characteristics at baseline	Efficacy population (n=146)	EGFR tested (n=41)	EGFR not tested* (n=103)	p-value
Mean age (±SD), years Men	67.7 (±8.6) 90.4%	67.4 (±8.9) 87.8%	67.8 (±8.6) 92.2%	0.79 0.52
ECOG PS 0/1 ECOG PS 2/3	17.5% / 43.8% 33.6% / 5.1%	n=39 20.5% / 56.4% 23.1% / 0	n=96 16.7% / 38.5% 38.5% / 6.3%	0.09
Current smoker Former smoker Never smoker	28.8% 63.7% 7.5%	24.4% 63.4% 12.2%	31.1% 63.1% 5.8%	0.39
Comorbitities : Cardiovascular Endocrinological Pulmonary	63.0% 23.3% 19.9%	65.9% 22.0% 19.5%	62.1% 23.3% 20.4%	0.68 0.86 0.91

* 2 patients without EGFR mutation status Efficacy and genotyping results were:

	EGFR mutation not tested n=103	EGFR mutation tested n=41	Non-smoker n=11	Smoker/Ex-smoker n=135	Efficacy population n=146
PFS
Event (progression or death)	95 (92.2%)	34 (82.9%)	8 (72.7%)	123 (91.1%)	131 (89.7%)
Median (months)	2.8 [2.3;3.2]*	4.4 [2.9;5.8]*	3.3 [0.7;ND]*	3.0 [2.7;3.5]*	3.0 [2.7;3.5]*
Survival rates at 12 months	7.0% [3.1;13.1]*	10.7% [3.1;23.6]*	27.3% [6.5;53.9]*	6.3% [2.9;11.6]*	8.0% [4.2;13.4]*
OS
Event (progression or death)	79 (76.7%)	22 (53.7%)	6 (54.5%)	96 (71.1%)	102 (69.9%)
Median (months)	5.5 [4.0;6.4]*	9.1 [4.4;ND]*	8.0 [1.6;ND]*	5.8 [4.5;7.1]*	5.8 [4.7;7.1]*
Survival rates at 12 months	22.4% [14.5;31.3]*	37.1% [20.9;53.5]*	43.6% [14.7;69.9]*	24.8% [17.2;33.0]*	26.3% [18.9;34.3]*

*[95% CI] In the safety population (n=152 patients), 158 adverse events (AEs) were reported in 70 patients (46.1%), including 48 grade ≥ 3 AEs in 31 patients (20.4%). The most frequent AEs related to erlotinib were skin rash (all grades [23,7%], grade ≥ 3 [5,2%]) and diarrhea (all grades [11,8%], grade ≥ 3 [2.0%]); 19 serious adverse events (SAEs) were reported in 12 patients (7.9%), including 16 grade ≥ 3 SAEs in 10 patients (6.6%). There were 6 SAEs leading to death (3.9% patients), but none SAE was related to erlotinib.

Conclusion:
PEPITA is the first non-interventional study assessing modalities of use in daily practice of patients with stade IIIb/IV squamous NSCLC treated in 2[nd] line with erlotinib. This final analysis show similar efficacy and safety results to those observed in clinical trials. Clinical profile may drive EGFR genotyping.

Abstract not provided

Background:
The REVEL trial demonstrated that second-line treatment with ramucirumab (RAM) plus docetaxel (DOC) significantly improved overall survival (OS) compared to placebo (PBO) plus DOC in the intent-to-treat (ITT) population (N=1253) of patients with stage IV non-small cell lung cancer. The REVEL trial also significantly improved progression-free survival (PFS) and objective response rates (ORRs). Results from the East Asia (EA) subgroup (Taiwan and Korea) analysis are presented.

Methods:
Subgroup analyses were performed in the EA ITT population, which consisted of all patients who were randomized in Taiwan (n=27) and Korea (n=62). Endpoints evaluated in the EA subgroup were OS, PFS, ORR, and safety. OS and PFS were analyzed using the Kaplan-Meier method and Cox proportional hazard model. Response was compared using the Cochran-Mantel-Haenszel test. ClinicalTrials.gov number NCT01168973.

Results:
In the 89 ITT EA patients, median OS was 15.44 months for the RAM plus DOC arm (n=43) and 10.17 months for PBO plus DOC arm (n=46) (HR: 0.762, 95% CI: 0.444–1.307). Median PFS was 4.88 months for the RAM plus DOC arm and 2.79 months for the PBO plus DOC arm (HR: 0.658, 95% CI: 0.408–1.060). The ORRs were 25.6% (95% CI: 13.5–41.2) in the RAM plus DOC arm and 9% (95% CI: 2.4–20.8) in the PBO plus DOC arm. Approximately two years after the enrollment of the first patient, in May 2012, the independent data monitoring committee recommended a reduction in the dose of DOC from 75 mg/m[2] to 60 mg/m[2] for newly enrolled EA patients, based on a higher incidence of neutropenia and febrile neutropenia associated with 75 mg/m[2] in EA patients compared to non-EA patients. This amendment resulted in a reduction in the toxicity associated with the original treatment regimen (Table). Table: Select grade ≥3 treatment-emergent adverse events, regardless of causality, by treatment arm and DOC dose in EA patients

Preferred term	RAM plus DOC (75 mg/m[2]) (n = 32)	PBO plus DOC (75 mg/m[2]) (n = 33)	RAM plus DOC (60 mg/m[2]) (n = 11)	PBO plus DOC (60 mg/m[2]) (n = 13)
Any	31 (96.9)	26 (78.8)	6 (54.5)	7 (53.8)
Neutropenia*	26 (81.3)	24 (72.7)	6 (54.5)	5 (38.5)
Febrile neutropenia	14 (43.8)	4 (12.1)	0	1 (7.7)

Data are n (%). *Consolidated term.

Conclusion:
Although not statistically powered to demonstrate significant improvement, the improved OS, PFS, and ORR observed in the EA subgroup treated with RAM plus DOC is consistent with the treatment effect observed in the overall ITT population in the REVEL trial. A dose reduction in DOC from 75 mg/m[2] to 60 mg/m[2] was associated with an improved safety profile and a reduction in the incidence of febrile neutropenia in the EA subgroup.

Background:
Nintedanib is a triple angiokinase inhibitor of receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor and fibroblast growth factor. The randomized, placebo-controlled, Phase III LUME-Lung 1 study (NCT00805194; 1199.13) investigating nintedanib/docetaxel was the first trial of an antiangiogenic agent to demonstrate significant overall survival (OS) benefit in previously treated patients with non-small cell lung cancer (NSCLC) of adenocarcinoma histology; nintedanib/docetaxel is approved in the European Union for the treatment of patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma histology after 1[st]-line chemotherapy. Here we report LUME-Lung 1 data from the adenocarcinoma population who received 1[st]-line chemotherapy containing bevacizumab, pemetrexed or taxanes.

Methods:
In LUME-Lung 1, 1314 patients with Stage IIIB/IV recurrent NSCLC received either nintedanib/docetaxel or placebo/docetaxel. Primary endpoint was centrally assessed progression-free survival (PFS); OS was a key secondary endpoint. Prior treatment with anti-VEGF agent bevacizumab was a stratification factor. Analyses of the adenocarcinoma population (n=658) according to prior treatment with bevacizumab (n=45 in either arm), pemetrexed (1[st]-line [n=126] or maintenance [n=27]) or taxanes (n=142) were performed to determine if 1[st]-line regimens could influence subsequent outcomes for nintedanib/docetaxel.

Results:
Patient characteristics were generally well-balanced across prior-treatment subgroups. For the adenocarcinoma population, there was no interaction between 1[st]-line treatment with bevacizumab, pemetrexed or taxanes and treatment outcome with nintedanib/docetaxel. Independent of pretreatment, nintedanib/docetaxel-treated adenocarcinoma patients had an OS benefit (Table). In the overall patient population, efficacy outcomes for these subgroups were also similar regardless of prior treatment. Furthermore, there was no significant effect on nintedanib/docetaxel outcomes for the few adenocarcinoma patients who received maintenance pemetrexed. The adverse event (AE) profile for nintedanib/docetaxel in each subgroup was consistent with that reported for the adenocarcinoma population in LUME-Lung 1, with diarrhea and reversible liver enzyme elevations among the more frequently reported AEs. Among patients who received nintedanib/docetaxel, there was no difference between prior-treatment subgroups in the frequency of AEs commonly associated with the prior treatment, such as hypertension with bevacizumab, mucositis with pemetrexed and peripheral neuropathy with taxanes.

Conclusion:
In LUME-Lung 1, regardless of whether a patient with NSCLC of adenocarcinoma histology received 1[st]-line chemotherapy containing bevacizumab, pemetrexed or taxanes, subsequent treatment with nintedanib/docetaxel led to improved OS.

Table: OS results in patients with NSCLC of adenocarcinoma tumor histology stratified by ± prior 1st-line bevacizumab, pemetrexed or taxanes treatment

	No BEV		BEV		No PEM		PEM		No TAX		TAX
	N/D	Pl/D	N/D	Pl/D	N/D	Pl/D	N/D	Pl/D	N/D	Pl/D	N/D	Pl/D
Patients, n	298	315	24	21	261	271	61	65	245	271	77	65
Median OS, months	12.6	10.6	14.9	8.7	13.4	10.8	12.0	8.0	12.2	10.3	15.1	11.6
HR (95% CI)	0.85 (0.71–1.01)		0.61 (0.31–1.20)		0.83 (0.68–1.00)		0.79 (0.53–1.18)		0.86 (0.71–1.05)		0.75 (0.51–1.11)
Interaction p-value	p=0.24				p=0.90				p=0.61

BEV, bevacizumab; CI, confidence interval; HR, hazard ratio; N/D, nintedanib/docetaxel; NSCLC, non-small cell lung cancer; OS, overall survival; PEM, pemetrexed; Pl/D, placebo/docetaxel; TAX, taxanes.

Background:
Nintedanib (N; Vargatef[®]), a triple angiokinase inhibitor, is approved in the EU in combination with docetaxel (D) for the treatment of patients with advanced NSCLC of adenocarcinoma histology (ACH) after 1[st]-line chemotherapy. In the randomized, placebo-controlled, Phase III LUME-Lung 1 study (NCT00805194; 1199.13), N+D significantly improved overall survival (OS; secondary endpoint) vs D in patients with ACH (median OS: 12.6 vs 10.3 months (m); HR: 0.83 [95% CI: 0.70–0.99]; p=0.0359) and in patients who progressed either during or within 9 m of 1[st]-line therapy (time[T]<9m) (median OS: 10.9 vs 7.9 m; HR: 0.75 [95% CI: 0.60–0.92]; p=0.0073). We explored the impact of on tumor growth over time as a treatment effect of N+D, with a specific focus on early progressors (T<9m) and patients who had progressive disease as best response to 1[st]-line therapy (PD-FLT).

Methods:
Tumor growth was evaluated using all available tumor measurements. Mixed-effects models were used to quantify the non-linear individual relationships between time from randomization and tumor burden, measured as the sum of longest diameter of target lesions (SLD) and assessed by independent central review (RECIST 1.0). Analyses were conducted for the entire population of patients with ACH, T<9m and PD-FLT.

Results:
Estimated mean baseline SLD was 82.5 mm in all patients with ACH, 88.3 mm in T<9m and 98.1 mm in PD-FLT. N+D showed a significant reduction of tumor growth over time (p<0.0001) in patients with ACH compared to D. Treatment difference at 6 months (SLD D group – SLD N+D group) for patients with ACH was 9.7 mm. This treatment difference was even more pronounced in the T<9m group (16.8 mm) and in patients with PD-FLT (19.7 mm). Tumor growth over time for N+D showed a non-linear J-shaped curve, indicating a decline in SLD at the beginning of treatment, which was maintained over time followed by a linear increase (see Figure for curves for the T<9m group). This relationship was consistently observed between populations. For patients treated with D, a linear increase in SLD from baseline over time in all ACH patients, T<9m and PD-FLT was observed. Figure 1



Conclusion:
In the LUME-Lung 1 study, N+D significantly decreased tumor burden and decelerated tumor growth over time compared to D in all patients with ACH and in the groups of patients with the poorest prognosis.

Abstract not provided

Background:
Metastatic non-small cell lung cáncer (NSCLC) is associated with a poor prognosis, and palliative chemotherapy is the mainstay of treatment. However, long-time survival has been observed in oligometastatic patients treated with locally ablative therapies to all sites of tumoral disease. Oligometastatic NSCLC with unresectable primary tumor at diagnosis represents a therapeutic challenge, and nowadays there is limited evidence about the benefit of the treatment with radical intention of both primary tumor and metastases.

Methods:
Retrospective study of patients with oligometastatic (3 or less lesions, in a unique location) and unresectable NSCLC treated with radical chemo-radiotherapy at primary tumor and with surgery or stereotactic radiation therapy to the metastases. We have done a systematic review of clinical histories from NSCLC advanced patients diagnosed between October 2011 and March 2015. The aim of our study is to analyze the safety and efficacy of this treatment strategy in terms of response rate, progression free survival (PFS) and overall survival (OS).

Results:
Twenty-three patients met inclusion criteria. Median age 57 year, eighteen male (78,3%) and ECOG (0-1) 95,7%. Histology: 15 adenocarcinoma (65,2%), 5 squamous carcinoma (5%), and 3 (13%) others. All patients had unresectable mediastinal lymph nodes infiltration. Location of metastases included the brain (n=12, 52.2%), lung metastases (n=6, 26,1%), bone metastases (n= 3, 13%), adrenal (n=1, 4,3%) and lymph node (n=1, 4,3%). Chemotherapy: 9 CDDP-Pemetrexed (39,1%), 9 CDDP-Vinorelbina (39,1%), 3 Carboplatin-paclitaxel, 1 CDDP-Gemcitabina (4.3%), 1 CDDP-Docetaxel (4.3%). Ten patients (43.5%) received sequential thoracic radiotherapy and 12 (52.2%) concomitant. Metastases treatment: 12 stererotactic radiation (52.2%), 7 external radiotherapy (30, 4%), 3 surgery (13%), 1 radiofrequency (4.3%). Toxicity: four patients (17,39%) developed G3 toxicity (2 hematological, 1 pneumonitis, 1 esophagitis). Median follow up was 15 months, median OS 18 m, median PFS 11 months. The 1-year OS were 73.9%, 2-year OS 21,7% and 3-year OS 8.7%.

Conclusion:
Radical treatment of oligometastatic and unresectable NSCLC patients is a safe therapeutic strategy. Despite the limited data and the small numbers of our study, it could be contemplated as an effective therapeutic alternative for selected patients.

Background:
Stage IV non-small cell lung cancer (NSCLC) patients are considered incurable and mainly treated with palliative intent. The overall survival (OS) and disease free survival (DFS) of this patient group is considered as poor. The purpose of this study was to investigate the OS and DFS of NSCLC patients, diagnosed with synchronous oligometastatic disease treated with curative intent of the intrathoracic disease as well as the metastases.

Methods:
Patients treated between 2008 and 2014 were included in this retrospective cohort analysis. Main inclusion criteria were: synchronous presentation of NSCLC and oligometastatic disease at diagnosis, and multidisciplinary consent on a radical treatment of both the intrathoracic disease and the metastases. Besides systemic treatment. The intrathoracic disease was radically irradiated (> 55 Gy biological effective dose) or resected. Treatment of the metastases consisted of: radical/stereotactic radiotherapy, surgical resection or radiofrequency ablation (RFA).

Results:
A total of 56 patients, 31 men and 25 women, were included. The mean age was 61 years (range 36-79) and all were in good condition (WHO 0-1). Most patients had a solitary metastasis (brain (22), bone (17), adrenal gland (6), lymphe node (3), liver (2), soft tissue (1), pulmonary (1), thyroid gland (1) and breast (1)). Two patients had 2 metastases (liver and bone / pleural and bone). The intrathoracic tumor stage,ignoring M-status, was IA in 3 patients, IB in 2 patients, IIA in 8 patients, IIB in 4 patients, IIIA in 24 patients and IIIB in 15 patients. Fifty patients were treated with radiotherapy and 4 patients had a surgical intervention for the primary tumor; 2 patients only received systemical treatment for the intrathoracic disease. Fifty patients received chemotherapy (89%), of which 5 (10%) concurrent with the radiotherapy of the intrathoracic disease and 45 (90%) sequential. The metastases were treated with ablative/stereotactic radiotherapy (45), surgical intervention (2), only systemical treatment (5), combination of surgical intervention and radiotherapy (3) and RFA (1). The mean follow-up was 21 months (range 4-69). Forty-one (73%) patients developed recurrent disease of whom 29 (52%) died. Only 8 (20%) recurrences occurred within the irradiated area. Most recurrences where brain (13) and pulmonary metastases (11). For the whole group, the median DFS was 14 months (range 2-69, 95% CI 11-17) and the median OS was 32 months (range 4-69, 95% CI 16-48). The 1- and 2-year OS was 86% and 58%, respectively. The 1- and 2-year DFS was 66% and 30%, respectively.

Conclusion:
Radical local treatment of a highly selected group of NSCLC patients in good condition presenting with synchronous oligometastatic stage IV disease (maximum 2 metastases) resulted in excellent local control, and also in favorable long-term DFS and OS.

Background:
Stage IV Non-Small Cell Lung Cancer (NSCLC) is considered as an incurable disease with median survival of 6 to 12 months. Palliative platinum based chemotherapy is the standard therapy. It has been suggested that patients with one synchronous isolated metastasis (SIM) suitable for local therapy have longer survival.

Methods:
Database of the Multidisciplinary Thoracic Oncology Group of our centre was retrospectively screened from 1993 to 2012. Consecutive NSCLC of any stage were included. Median overall survivals (OS) between stage III and stage IV (SIM and non SIM) were compared with log-rank test. For the multivariate analyses Cox models were performed.

Results:
4917 patients were registered, 85 were excluded because of missing data. Among the study population, 1335 (27.6%) patients were stage III NSCLC, 1483 (31%) non SIM stage IV and 109 (2%) SIM stage IV. SIM site were mainly brain (n=70, 64%) and adrenal gland (n=16, 15%). Clinical and histological data differed substantially between each stage (Table 1). Median OS was significantly longer in SIM stage IV compared to non-SIM stage IV (18 [IQR, 9-33] months vs 6 [IQR, 2-13] months respectively, p-value<10[-4]) and not significantly different between SIM stage IV and stage III (14 months [IQR, 6-31], p-value=0.05). In multivariate analysis (Table 2), we still observed that median survival of SIM stage IV and stage III were not significantly different (p-value= 0.47).Figure 1 Figure 2





Conclusion:
OS of SIM stage IV is remarkably improved compared to non SIM stage IV, and comparable to stage III. This data supports aggressive treatment in the subgroup of SIM stage IV.

Background:
We retrospectively investigated the survival outcomes of stage III non-small-cell lung cancer (NSCLC) patients presenting with isolated brain failures (IBF) after definitive concurrent chemoradiotherapy (C-CRT) and treated with whole brain radiotherapy (WBRT) ± stereotactic radiosurgery (SRS) or surgery.

Methods:
A total of 162 patients with stage III NSCLC who were treated with platinum based C-CRT between January 2007 and December 2012 and presented with proven IBF with/without locoregional failures were included in this retrospective analysis. All patients received WBRT of 20-30 Gy (3-4 Gy/fx) ± SRS of 16-22 Gy or surgery. The primary and secondary end points were overall survival (OS) and identification of factors associated with longer survival.

Results:
Median follow-up was 12.7 months from the IBF diagnosis.IBF occurred at median 7.8 months (range: 1.7-46.4) from the commencement of C-CRT.WBRT was the sole local intervention in 78 patients whereas 55 and 29 patients received additional SRS or surgery mostly prior to WBRT. Median and 3-year survival rates were 11.7 months and 20.4%, respectively. In univariate analysis, controlled primary (20.3 vs. 6.4 months; p<0.001) and absence of extracranial metastasis development during follow-up (23.3 vs. 10.6 months; p<0.001) were determined to be significantly associated with longer OS times, which also retained their independent significance in multivariate analysis. Addition of SRS or surgery was related with better brain control rates but not OS in overall population. However, in patients presenting with ≤3 brain lesions and controlled lung primary the addition of SRS or surgery to WBRT was associated with significantly superior OS times than WBRT alone (25.8 vs. 8.2 months; p<0.001).

Conclusion:
Present results demonstrated that controlled lung primary and absence of extracranial metastasis development during follow-up period were the factors positively associated with longer OS after WBRT ± SRS or surgery in stage III NSCLC patients presenting with IBF after platinum based C-CRT.Additionally, our results suggested superior survival with addition of SRS or surgery to WBRT in patients with 1-3 brain lesions and controlled lung primaries.

Background:
The effectiveness of pulmonary metastasectomy for non-small cell lung cancer(NSCLC) is controversial. The aim of this study is to report the overall survival after pulmonary metastasectomy for NSCLC and to determine prognostic factors for survival.

Methods:
Between June 2003 and July 2007, 39 patients underwent pulmonary metastasectomy in single center. Data from first time of pulmonary metastasectomy were included and data from more than second time of pulmonary metastasectomy were excluded.

Results:
There were 24 men and 15 women, and the median age at pulmonary metastasectomy was 64.0 years. The median recurrence free time from initial pulmonary resection to pulmonary metastasectomy was 18.5 months. The overall 5-year survival rate was 67.2%. In univariate analysis, ager under 70 years, recurrence free time over 24 months, adenocarcinoma and normal CEA level were prognostic factors for overall survival. Gender, initial TNM stage, operation type of pulmonary metastasectomy, number and size of pulmonary nodule and distance from nodule to margin were not associated with overall survival.

Conclusion:
In selected patients, pulmonary metastasectomy for NSCLC may confer a good survival. It appears reasonable that such patients should be considered as surgical candidates.

Abstract not provided