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Abstract:
Background: Cancer Patient’s Association of Slovenia (CPAS) is a non-governmental organisation, connecting the patients with all cancer types as well as their relatives and health professionals. The central programme that is being offered to patients by CPAS for more than three decades is an organized self-help »On the way to recovery«, that offers support in self-help groups on 20 locations and peer-to-peer counselling in two Info centres. The lung cancer patients are entering the programme alongside the other cancer patients. The peer-to-peer support programme has developed the system of regular supervisions, initial education, the study material aimed at volunteers and the network of self-help groups spread over the Slovenia. The research analysing peer-to-peer support showed clear benefits for the patients[1,2]. Since 2014, the Lung Cancer Support Division is organised in the framework of CPAS. Its main aim is the development of the programmes for lung cancer patients and their relatives. In Slovenia, with roughly 2 million inhabitants, there are some 1230 new lung cancer patients every year, and 1100 deaths due to lung cancer[3]. Patients with lung cancer are treated in four oncological centres (Institute of Oncology Ljubljana, University Clinic Golnik, University Medical Centres Ljubljana and Maribor). Among the burdens, all cancer patients are carrying, such as confronting its own vulnerability, mortality, coping with the hardships of treatment, psychic distress often combined with the fear of recurrence, lack of social support and changes in financial situation, some are disease specific. The burdens lung cancer patients are experiencing are connected with the poor prognosis, poorer quality of life and greater symptom management needs. These are due to physical troubles, social presentation of lung cancer as death sentence, sense of guilt and stigmatisation, but are also due to the need of information regarding new treatments available[4–6]. To be able to react on the specific lung cancer patient’s needs, we have within the Lung Cancer Support Division supplemented volunteer self-help programme »On the way to recovery« with the programme »How to live with lung cancer« [7]. How to live with lung cancer is a one-day programme, which is being implemented in various also smaller places and medical institutions throughout the Slovenia. It is aimed at lung cancer patients, their relatives and also health providers. The programme is carried out through recognized consultants working with lung cancer (surgeons, medical oncologists, radiation oncologists, physiotherapists, nurses and clinical psychologists from the medical institutions treating lung cancer). Methods: All participants in the programme were given a specific designed evaluation questionnaire. We present an evaluation from the program participants in the year 2016. We analysed the participants’ responses and the evaluation will be used in further program development. Results: The participants are being highly satisfied by the programme as whole and also with the individual sets of lectures. They are highly appraising the help our programme is providing in understanding the health situation, communication with the health professionals and in understanding coping processes. The programmes main goal is to inform participants on the lung cancer diagnostics, treatment and the rehabilitation possibilities. This information is given by the relevant professional. There is a special emphasis on the new and more efficient treatment possibilities. The programme presents in depth the ways and the means for the optimal coping with the disease and its treatment and also the advices for the living with the disease. We are widening the importance of comprehensive patient treatment, informing on psycho social considerations, possibilities on entering the CPAS programmes (and also related programmes that are offered locally), we are informing on benefits of early inclusion in the palliative care thus busting the myths regarding the palliative care. Except for presenting information, the programme’s goal is also the social support for lung cancer patients, as a large amount of the time is set by for the talk and the exchange of experiences among the participants. The inclusion of different professions into the comprehensive care of cancer patients due to the patients’ needs is being represented on the symbolic level with the joint presentation, where the presenters are alternating thus rounding up the “story” of treatment and rehabilitation. Incorporated in this programme is also a chance for the patients and their relatives to have an individual conversation with the medical professionals regarding their treatment and dilemmas. While the programme is being primarily aimed at the patients and their relatives, the local medical professionals are also invited. This beside the information point of view gives them also a chance to interact with the presenters and an opportunity to discuss with them their questions and dilemmas. Through this we are trying to ensure the equal availability of treatment and to approach the people with medical and psycho social support. Conclusions: With this programme we are following all three fields where the peer support programmes have been found to be beneficial to patient. Namely, their informational needs about the cancer and its treatment, management of emotional distress and finally the facilitation of empowerment [1,2]. REFERENCE: 1. Meyer A, Coroiu A, Korner A. One-to-one peer support in cancer care: a review of scholarship published between 2007 and 2014. Eur J Cancer Care (Engl). 2015;24(3):299-312. 2. Campbell HS, Phaneuf MR, Deane K. Cancer peer support programs-do they work? Patient Educ Couns. 2004;55(1):3-15. 3. Studio N. Rak v Sloveniji 2012 Cancer in Slovenia EPIDEMIOLOGIJA IN REGISTER RAKA EPIDEMIOLOGY AND CANCER REGISTRY. 2016. 4. Missel M, Pedersen JH, Hendriksen C, Tewes M, Adamsen L. Diagnosis as the First Critical Point in the Treatment Trajectory: An Exploration of Operable Lung Cancer Patients’ Lived Experiences. Cancer Nurs. 2015;38(6):E12-21. 5. Pujol J-L, Mérel J-P, Roth C. How preconceptions about lung cancer treatment interact with medical discourse for patients who accept chemotherapy? Psychooncology. July 2016. [Epub ahead of print] 6. Pozo CLP, Morgan MAA, Gray JE. Survivorship issues for patients with lung cancer. Cancer Control. 2014;21(1):40-50. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24357740. Accessed August 21, 2016. 7. Čufer T., Simonič A., Koren P., Crnjac A, Računica K., Rajer M., Kovač V, Škufca Smrdel A. C. VPM. KAKO ZIVETI Z RAKOM_za splet-film. 2015. Available at: https://drive.google.com/file/d/0ByMyk7OmgaDSVzR3ME1vZzltbVU/view. Accessed Sept 20, 2016

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Patient involvement in the evaluation of cancer medicines; the EMA experience The European Medicines Agency (EMA) is the authority which evaluates and monitors medicines across all EU Member States. Pharmaceutical companies wishing to market a new cancer medicine in Europe are obliged to apply for a licence through the EMA. With a remit to ensure that European citizens are provided with safe and effective medicines, the EMA realised early on that patients’ experience with their disease and its treatment is a fundamental parameter to include within the evaluation of medicines. The Agency’s engagement with these stakeholders has been a progressive journey whereby a steady increase in the numbers involved (76 in 2007 to 740 during 2015) has been coupled with a diversification of methodologies ensuring opportunities all along the medicines lifecycle. Learning from experience has also been paramount to ensure that the interaction is mutually beneficial and is carried out in the most optimal manner possible. Key milestones of EMA interaction with patients and consumers: Figure 1 The “framework of interaction” adopted by the EMA management board in 2005 provides the formal basis for involving patients and consumers in Agency activities and relies on five critical elements: A network of European patients and consumers organisations A forum of exchange: EMA Working Party with Patients and Consumers’ organisations A pool of patients acting as experts in their disease and its management Interaction with the EU Regulatory Network Capacity-building focusing on training and raising awareness about EU regulatory system Today patients and consumers are systematically involved in a wide range of EMA activities: Members of EMA Management Board and scientific committees Members of the EMA ‘Patients and Consumers Working Party’ Scientific advice procedures during medicines development; Discussions on benefit/risk evaluations; Review of information (e.g. package leaflet, safety communication); Topic groups and workshops The Agency works with a large network of organisations and individuals; organisations can register with the Agency and if they meet certain eligibility criteria they are then listed on the EMA website (EMA website). Individuals are also encouraged to register to be included in the EMA “individual experts’ stakeholder database” (registration form); they then receive targeted information and can be contacted for involvement in EMA activities. Patients usually participate in person or via written procedure and are involved as either representatives of their organisation or as individual experts, depending on the nature of the activity. There are opportunities for involvement all along the medicine’s evaluation lifecycle: Figure 2 EMA continually looks to further enhance its methods for gathering patient knowledge and preferences at each stage of the process and is investigating the use of additional tools to complement those already in-house. Surveys are regularly used to elicit feedback from both regulators and patients/consumers on their involvement, its added value to the process and identify areas for potential improvement. There are inevitably challenges to overcome, for example finding suitable patients (e.g. language barrier, availability), ensuring tailored support to facilitate and enhance participation, providing a clear definition of the patient role, addressing issues around confidentiality and representation and also how to measure the impact/value of the input. Evidence, including testimonies and concrete examples, has demonstrated that ultimately patient/consumer input: Brings the everyday aspects of living with a disease into the scientific discussions; Improves the quality of patient information and communication on medicines; Increases the dissemination of EMA outcomes. Today patients and consumers are a valued and integral part of the work at the EMA and their perspectives are considered an essential element for increasing transparency in the regulatory process and ensuring more meaningful decisions for all concerned.

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Limitation by COPD for Diagnostic Procedures Ostoros, Gy. Varga, J. and Kerpel-Fronius A. National “Korányi” Institute for Pulmonology Hungary, Budapest Lung cancer and COPD are smoking dependent diseases. Smoking cessation is crucial before and during the diagnostic procedures because of the consequences of smoking (e.g. sputum retention, mucociliary dysfunction and potential other more serious complications after the procedures). Severe obstructive or restrictive pulmonary disorders limit the diagnostic possibilities in patients with malignant pulmonary diseases. The screening of lung cancer with low-dose CT has become the gold standard in the past decade. The two imaging-based phenotypes of COPD can be well distinguished by this technique. CT screening can also help to identify non-diagnosed emphysema patients and may lead to early treatment of the disease. It has been showed that non-smoker emphysema patients have a similar risk of lung cancer as smokers with emphysema. Thus, patients with emphysema may be an eligible subgroup for a more intensive lung cancer screening program. However, once a suspicious lesion is found severe COPD, it can limit the choices available for differential diagnosis seriously - CT guided lung biopsies in COPD patients carry a higher risk of haemorrhage and pneumothorax. Patients with severe COPD and respiratory failure with decreased oxygen saturation limit the indication of diagnostic bronchoscopic procedures as well. The examination of exhaled breath condensate (EBC) is a non invasive process. There are efforts to discriminate lung cancer and COPD with EBC. Lung tumours have influence on lung function. Besides the severity of COPD, the result of the lung function test (LFT) depends on the size and position of the pulmonary tumour as well. In the case of a big central tumour or a huge amount of pleural fluid, the LFT will show rather restrictive than obstructive character. A small peripheral malignancy will not change the shape and volume of the LFT. If the tumour is in the trachea or compresses it's wall, the inspiratory phase of the flow-volume chart could be flat. Sometimes the lung tumours could lead a misdiagnosis of COPD. A centrally located small tumor which is not visible on the chest X-ray but compresses the trachea or any of the pulmonary vessels can cause breathlessness, fatigue and decreased oxygen saturation. A mediastinal conglomerate of lymph nodes can cause similar symptoms. Low physical activity, obesity, smoking and comorbidities are significant negative factors for risk stratification before any pulmonary diagnostic procedure as well. Pulmonary rehabilitation can improve functional reserves if functional capacity is at borderline. Pulmonary rehabilitation has positive effect on cardiovascular function, metabolism, muscle-function and lung mechanics. As for lung function parameters, we need to focus on forced expiratory volume in one second (FEV~1~) and diffusion capacity (DL~CO~). We can follow the common agreement of minimum criteria of the European Society of Chest Surgeon and European Respiratory Society for risk stratification before a diagnostic pleuroscopy. Based on this protocol, FEV~1~ and DL~CO~ need to be >35%pred. In the case of 35%pred< FEV~1 ~and DL~CO~<75%pred, we need to consider VO~2~/kg during a cardiopulmonary exercise test. If VO~2 ~is~ ~<10 ml/kg/min, the patient need a pulmonary rehabilitation program to improve functional reserves. Regarding lung function, we need to focus on lung mechanics and lung kinematics as well. Lung mechanics can be monitored by resting functional reserve capacity (FRC) and residual volume (RV). Lung kinematics can be monitored by chest expansion. Improved resting or dynamic hyperinflation and lung kinematics of the patients with chest physiotherapy and complex pulmonary rehabilitation is also suggested. As a general effect of rehabilitation, training programs can improve the cardiovascular response, oxygen uptake and the metabolism. We may also focus on physical activity, which is a general prognostics marker. Physical activity can be monitored by pedometer. Obesity can influence the complications of the surgical procedure and it has some effect on lung mechanics as well. If we have time, in case of an obese patient we may also consider improving their body composition before the invasive procedure. To sum up, comorbidities have to be considered before an invasive diagnostic procedure of lung cancer. Patients with impaired pulmonary hemodynamics, ischemic heart disease, diabetes or obesity have to be carefully evaluated. de Torres JP. Casanova C. et al. : Exploring the impact of screening with low-dose CT on lung cancer mortality in mild to moderate COPD patients: A pilot study. Respiratory Medicine, 107, 5, 702-707. 2013. Wiener RS. Schwarcz LM. et al. Population-Based Risk of Complications Following Transthoracic Needle Lung Biopsy of a Pulmonary Nodule. Annals of Internal Medicine, 155, 3, 137-144. 2011. GOLD-www.goldcopd.org Brunelli, A. Charloux, A. et al : ERS/ESTS clinical guidelines on fitness for radical therapy in lung cancer patients Eur. Resp. J., 34, 1, 2009.

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The most common cause of death among patients with COPD is lung cancer as well as respiratory failure, and COPD often co-exists with lung cancer with a range of 40 to 70% (1). While lung cancer survival is generally very low, survival is even lower among patients with COPD, i.e. in one study, it is reported that 26% of lung cancer patients without COPD were still alive 3 years after their diagnosis compared to 15% of lung cancer patients with COPD (2). One of the reasons why prognoses of lung cancer patients with COPD are worse is that treatment options are limited due to affected lung function. For surgical treatment for lung cancer patients with COPD, post-operative residual lung function should be maintained within a certain level. Therefore, patients with severely reduced lung function may be rejected for surgical treatment, or at least they may not able to receive standard surgical procedures. For patients rejected for surgery because of poor lung function, radiotherapy is an alternative treatment option. However, radiotherapy itself affects lung function because of post treatment radiation pneumonia. For drug therapy, drug-induced lung toxicities are emerging issues, especially due to the use of EGF receptor tyrosine kinase inhibitors, ALK inhibitors or immune check point inhibitors (3). In cases whose lung function is severely affected, drug-induced lung toxicities may be lethal, and special attention should be payed to such patients. Therefore, to overcome these limitations of treatment is an urgent issue in the daily practice. For surgical treatment, assessment of preoperative lung function is essential to judge its indication. Both predicted post-operative lung function and DLco values are mainly used as parameters for the indication of surgical treatment. Therefore, optimization of these functions by medical therapy, pulmonary rehabilitation and smoking cessation may extend the opportunities of surgical treatment, resulting in better patients’ outcomes. Regarding with medical therapy, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) (4) and American Thoracic Society and the European Respiratory Society guidelines for COPD management point out the usefulness of bronchodilators as well as inhaled corticosteroids. In addition, pulmonary rehabilitations would be recommended for pre-operative lung cancer patients with poor lung function because of its safety, although there are no data clearly showing the efficacy of pulmonary rehabilitations on patients’ outcome. For radiotherapy for lung cancer patients with COPD, newly developed devices appear to show promising outcome. Both stereotactic body radiotherapy (SBRT) and ion beam radiotherapy have such a nice radiation dose distribution that high doses of irradiation are possible with low impact to normal tissues. Some reports suggest that patients’ outcomes by these treatment modalities may be not worse or sometimes better than surgical treatment (5). In addition, smoking cessation is, of course, important issue as a pre- and post- operative management. Since lung cancer patients with COPD are increasing over all area in the world, appropriate treatment should be chosen with the utmost care and attention. In addition, it is an urgent issue to establish more effective and safe treatment modalities to these patients. References 1) Young RP, Hopkins RJ, Christmas T, et al. COPD prevalence is increased in lung cancer, independent of age, sex and smoking history. Eur Respir J. 2009;34(2):380-6. 2) Kiri VA, Soriano J, Visick G, Fabbri L. Recent trends in lung cancer and its association with COPD: an analysis using the UK GP Research Database. Prim Care Respir J. 2010;19(1):57-61. 3) De Sanctis A, Taillade L, Vignot S, et al. Pulmonary toxicity related to systemic treatment of nonsmall cell lung cancer. Cancer. 2011;117(14):3069-80. 4) Rabe KF, Hurd S, Anzueto A, Barnes PJ, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176(6):532-55. 5) Chehade S and Palma DA. Stereotactic radiotherapy for early lung cancer: Evidence-based approach and future directions. Rep Pract Oncol Radiother. 2015;20(6):403-10..

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Globally, chronic obstructive pulmonary disease (COPD) and lung cancer are among the top 5 causes of death. The two diseases share common risk factors such as tobacco smoking, outdoor and household air pollution. COPD is associated with a two to four fold increased risk for lung cancer independent of smoking.[1,2] COPD can be defined by symptoms, lung function criteria (forced expiratory volume in one second (FEV~1~) <80% predicted for age, gender and height, FEV~1~/ forced vital capacity (FVC) <0.7, or diffusing capacity <80%.[3,4] COPD has also been defined by computed tomography (CT) changes such as pulmonary emphysema by visual examination or by quantitative measurement (percent voxels < -950 HU based on a threshold of 4.8%) or air trapping from comparison between inspiratory and expiratory CT scans.[5,6] In the PLCO~m2012 ~risk prediction model[7], self-reported COPD was significantly associated with lung cancer risk (OR 1.45, 95% CI: 1.25-1.67). The area under the ROC curve (AUC) was 0.559. The AUC of the prediction model with and without a history of COPD was 0.800 and 0.799 respectively (M. Tammemagi, personal communication). A study in British Columbia examined the incremental value of pulmonary function test in 2,596 ever smokers above 40 years of age who had smoked ≥20 pack-years. One hundred and thirty-nine participants developed lung cancer after a median follow-up of 7.7 years.[8. ]Lower FEV~1~% increased the lung cancer risk for both men and women, but did so more strongly for men than in women (interaction P <0.001). FEV~1~% was found to substantially improve lung cancer prediction in a risk prediction model that included age, sex, education level, body mass index, family history of lung cancer and smoking. In this study, although CT detected emphysema was significantly associated with lung cancer in unadjusted analysis (OR 2.22, 95% CI: 1.17 – 3.78; P=0.012), in the fully adjusted model, neither emphysema nor a history of chronic bronchitis, which were significant in other studies, approached significance. A recent case-control study showed that only air trapping on quantitative CT imaging and FEV~1~/FVC <0.7 were independent predictors of lung cancer risk in a multivariable model.[9] Thirty-five percent of lung cancer cases and 55% of the controls had no evidence of COPD on spirometry or air trapping on quantitative CT. Forty-nine percent of lung cancer patients had FEV~1~/FVC >0.7. In the Pan-Canadian lung screening study of 2,537 ever smokers between the age of 50 to 75 with a 6 year lung cancer risk of ≥2% using a prototype PLCO prediction model, 50.6% of the participants had FEV~1~/FVC <0.7 and 42.8% had FEV~1~<80%. Among those who were found to have lung cancer, 63% had FEV~1~/FVC <0.7 and 54.5% had FEV~1~<80%. In those without lung cancer, the corresponding figures were 49.5% and 42% respectively. While COPD detected by pulmonary function test(s) and/or thoracic CT identify smokers at higher risk of lung cancer, a strategy to focus CT screening using these criteria may miss a significant proportion of lung cancers. Quantitative CT imaging of air trapping requires an inspiratory and expiratory CT with added cost and radiation exposure. The US Preventive Services Task Force recommended against screening for COPD in asymptomatic adults.[10 ]Whether identification of COPD by pulmonary function test and/or quantitative thoracic CT imaging can benefit a sub-population who would otherwise not meet the current criteria for lung cancer screening with CT or reduce the frequency and duration of follow-up CTs in a population based lung cancer screening program require further study. References 1. Skillrud DM, Offord KP, Miller RD. Higher risk of lung cancer in chronic obstructive pulmonary disease. A prospective, matched, controlled study. Ann Intern Med 1986;105:503-7. 2. Turner MC, Chen Y, Krewski D, Calle EE, Thun MJ. Chronic obstructive pulmonary disease is associated with lung cancer mortality in a prospective study of never smokers. Am J Respir Crit Care Med. 2007 Aug 1;176(3):285-90. 3. Vestbo J, Hurd SS, Agustí AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013 Feb 15;187(4):347-65. 4. de-Torres JP, Marin JM, Casanova C, et al. Identification of COPD patients at high risk of lung cancer mortality using the COPD-LUCSS_DLCO. Chest 2016; 149:936-42. 5. Lynch DA, Austin JH, Hogg JC, Grenier PA, Kauczor HU, Bankier AA, Barr RG, Colby TV, Galvin JR, Gevenois PA, Coxson HO, Hoffman EA, Newell JD Jr, Pistolesi M, Silverman EK, Crapo JD. CT-Definable Subtypes of Chronic Obstructive Pulmonary Disease: A Statement of the Fleischner Society. Radiology. 2015 Oct;277(1):192-205. 6. COPDGene CT Workshop Group, Barr RG, Berkowitz EA, Bigazzi F, Bode F, Bon J, et al. A combined pulmonary-radiology workshop for visual evaluation of COPD: study design, chest CT findings and concordance with quantitative evaluation. COPD. 2012 Apr;9(2):151-9. doi: 10.3109/15412555.2012.654923. 7. Tammemagi MC, Katki HA, Hocking WG, Church T, Caporaso N, Kvale P, et al. Selection criteria for lung-cancer screening. N Engl J Med 2013;368:728-36. 8. Tammemagi M, Lam S, McWilliams A, Sin D. Incremental value of pulmonary function and sputum DNA image cytometry in lung cancer risk prediction. Cancer Prev Res (Phila). 2011 Apr;4(4):552-61. 9. Schwartz AG, Lusk CM, Wenzlaff AS, Watza D, Pandolfi S, et al. Risk of Lung Cancer Associated with COPD Phenotype Based on Quantitative Image Analysis. Cancer Epidemiol Biomarkers Prev. 2016 Sep; 25(9):1341-7. 10. US Preventive Services Task Force (USPSTF). Screening for chronic obstructive pulmonary disease. US Preventive Services Task Force recommendation statement. JAMA April 5, 2016; 315(13):1372-1377. Supported by the Terry Fox Research Institute.

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Immunotherapy in the First-Line Setting of Advanced NSCLC Lung cancer remains the leading cause of cancer-related deaths worldwide. Advances in screening, surgery and treatment have helped to improve the median survival for patients with lung cancer over the past decade, however, the five-year survival rate remains less than 20%. The majority of patients are diagnosed with advanced stage disease, who are treated with platinum-based chemotherapy, followed by targeted, combination, or immunotherapies. Given the response rates seen with the use of immunotherapy in the second-line setting, it was appropriate to begin to explore if these agents could be given to patients earlier in their treatment. Immunotherapies have been found to be better tolerated than chemotherapy and have the potential for long-term survival, thus could benefit patients as first-line therapy, as some patients will never go on to receive second-line treatment. Two agents, nivolumab and pembrolizumab, both monoclonal antibodies targeting programmed cell death protein 1 (PD-1), are approved for use in patients with non-small cell lung cancer (NSCLC) who have received prior chemotherapy. The KEYNOTE-024 randomized phase III trial of pembrolizumab vs. standard of care (platinum-based chemotherapy), demonstrated superior progression-free survival (PFS) and overall survival (OS) for first-line treatment in patients with tumors expressing high levels of programmed cell death ligand 1 (PD-L1) (tumor proportion score ≥50%). The CheckMate-026 randomized, phase III study of nivolumab vs. standard of care in treatment-naïve patients with tumors expressing ≥5% PD-L1 did not meet the primary endpoint of PFS. For this presentation, the use of predictive markers in the front-line setting will be discussed and implications for combination therapy will be reviewed.

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Background: Hu5F9-G4 is a humanized monoclonal antibody that targets CD47, blocking its anti-phagocytic “don’t eat me” signal through macrophage receptor SIRPα, leading to tumor phagocytosis. CD47 is overexpressed on human cancers and also on red blood cells (RBCs). In primate toxicology studies, Hu5F9-G4 caused a transient anemia that was improved with a single lower Priming Dose allowing higher Maintenance Doses. Materials and Methods: Relapsed/refractory solid tumors and lymphomas were included. This dose escalation study included: Part A, to determine the Priming Dose and Part B, to determine the Maintenance Dose. The maximum tolerated dose (MTD) in part A was used for the single Priming Dose in part B (Hu5F9-G4 dosed weekly). The primary objective is to determine safety and secondary objectives are to determine PK and PD. Preliminary data reported from data cutoff of July 22, 2016.Results: 25 patients have enrolled. Part A included 0.1 (N=1), 0.3 (N=2), 1 (N=6), and 3 (N=2) mg/kg. There were 2 dose-limiting toxicities (DLTs) in Part A at the 3 mg/kg dose: grade (G) 3 abdominal pain and G3 hemagglutination (H) (protocol-specific scale of G1 H on peripheral blood smear (PBS) and G2 headache). 1 mg/kg was selected as the Priming Dose, with no >G2 anemia. Pharmacodynamic studies show almost 100% RBC receptor occupancy at the Priming Dose. Treatment-related adverse event (TRAE) in Part A included: anemia (3 G1, 3 G2), hyperbilirubinemia (3 G1, 2 G2; unconjugated), headache (6 G1, 1 G2), H on PBS (8 G1), and nausea (3 G1). Part B included 3 (N = 4), 10 (N = 3), and 20 mg/kg (N=6, ongoing). There have been no DLTs in 3 patients on 10 mg/kg, and one DLT (headache with hemagglutination) in 6 patients at the 20 mg/kg maintenance dose (ongoing). Most toxicities were was associated with the initial single Priming Dose and were completely reversible. TRAE in Part B at 3 mg/kg included: anemia (2 G1, 2 G2), hyperbilirubinemia (1 G1, 1 G3), headache (3 G1), H on PBS (1 G1), retinal toxicity (G2 protocol-specific scale, asymptomatic). TRAE at 10 mg/kg included: anemia (3 G1), headache (2 G1), and nausea (1 G1). Two patients with adenoid cystic carcinoma in Part A had stable disease for 16 and 8 months. In Part B, 2 of 3 patients have had prolonged stable disease at 10 mg/kg for 8+ months (follicular thyroid cancer) and 7+ months (myoepithelioma of the head and neck). Evaluation of subjects in the 20 mg/kg cohort is ongoing. Conclusions: Hu5F9-G4 is well tolerated at 10 mg/kg weekly, with 1 mg/kg Priming Dose. Part B with a Maintenance Dose of 20 mg/kg is ongoing. Acknowledgements: Stanford Clinical and Translational Research Unit; California Institute for Regenerative Medicine; Forty Seven, Inc.Trial Registration: NCT02216409References: 1. Willingham SB, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662-7. 2. Liu J t al. Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential. PLoS One. 2015 Sep 21;10(9):e0137345. References 1. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PØ, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, van de Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, Weissman IL. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662-7. 2. Liu J, Wang L, Zhao F, Tseng S, Narayanan C, Shura L, Willingham S, Howard M, Prohaska S, Volkmer J, Chao M, Weissman IL, Majeti R. Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential. PLoS One. 2015 Sep 21;10(9):e0137345.Figure: CD47 is a myeloid-specific immune checkpoint. Figure 1Figure 2

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The treatment of lung cancer has changed dramatically in the past few years. From a time when treatment decisions were made without regard to histology or genotype, an era of personalized therapy, at least for a subset of patients with lung cancer, is a reality. The treatment of EGFR mutation-positive patients with EGFR inhibitors has resulted in significant improvements in outcomes over standard chemotherapy. Similarly, for patients with ALK- and ROS1-positive non-small cell lung cancer (NSCLC), targeted therapies have proven to be superior. However, for patients with KRAS mutations, which are seen in approximately 25-30% of lung adenocarcinomas, there is no effective targeted therapy option. For nearly 70% of patients with NSCLC, systemic chemotherapy remains the standard approach. The emergence of immune-checkpoint inhibitors has resulted in considerable change in the treatment algorithm for advanced NSCLC. These agents are now preferred salvage therapy after progression following platinum-based chemotherapy. As immunotherapy moves to the first-line therapy setting for advanced NSCLC, it is anticipated that at least 25-30% of the patients without a driver mutation will be treated with immune-checkpoint inhibitors. All of these exciting developments call for careful evaluation of ongoing and planned clinical trials, so that appropriate new priorities are established. The newly established NCI National Clinical Trials Network (NCTN) includes all the adult cancer cooperative groups (ALLIANCE, ECOG-ACRIN, SWOG, & NRG Oncology) is actively engaged in conducting the new generation of clinical trials for lung cancer. Despite, the success with targeted agents in advanced stage NSCLC, patients do not achieve a cure. Using these agents in early stage NSCLC provides the best chance for a cure. The ALCHEMIST study has been launched by the NCTN to evaluate personalized adjuvant therapy for early stage NSCLC. In this study, patients with early-stage lung cancer (stages IB, II and IIIA) are treated with systemic chemotherapy after surgical resection, as per standard of care. Subsequently, their tumor is subjected to molecular testing. Patients with ALK-positive disease are randomized to treatment with crizotinib or placebo. Patients with EGFR mutations are randomized to erlotinib or placebo. Patients who are negative for EGFR and ALK, are randomized to nivolumab or observation. These studies will evaluate the effect of the personalized adjuvant therapy on overall survival and disease-free survival. Another ongoing effort is to understand the therapeutic value of targeted strategies in patients with advanced stage squamous cell lung cancer. The lung-MAP study enrolls patients with advanced stage squamous NSCLC. Following next-gen sequencing, patients with selected targets are treated with an appropriate targeted agent. The study includes a phase 2 component, which can be rapidly adapted to phase 3 if a agent demonstrates the pre-defined level of efficacy. This trial is also designed to accelerate the development of treatments leading to full approval by the FDA by shortening timelines. These individualized treatment approaches based on genotype are likely to answer important questions in a definitive manner. As immunotherapy becomes integrated in the standard treatment paradigms, considerable changes are also warranted for patients without driver mutations. For a subset of patients, as immunotherapy becomes the first line treatment in the advanced stage disease setting, the role of platinum-based chemotherapy in the second line needs to be investigated. It is also important to evaluate the need for continued immunotherapy after disease progression when patients are switched to chemotherapy. Another key question relates to the duration of therapy for patients receiving immune checkpoint inhibitors. Appropriately designed trials to understand the optimum duration of therapy will optimize benefits, reduce toxicity, and decrease cost. Combination strategies using immune checkpoint inhibitors with chemotherapy and other targeted agents is also an important area of priority. The role of biomarkers to select therapy is another critical research priority. We should also make efforts to improve the percentage of patients enrolled to clinical trials. A major reason for this is the stringent eligibility criteria that excludes a significant proportion of patients in order to select the ‘fittest’ candidates for clinical trials. While this is certainly appropriate in early phase drug development, if patients enrolled in clinical trials do not represent the ‘real-world’ patient population, the applicability of the results are limited. The next wave of clinical trials should also take into consideration the impact of new treatments on the overall cost of care and the clinical significance of improvements in efficacy. The national Cooperative groups in the United States are committed to a collaborative approach to address key research questions and improve outcomes for lung cancer.

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Abstract:
　In Japan, several cooperative study groups, such as Japan Clinical Oncology Group (JCOG), West Japan Oncology Group (WJOG), North East Japan Study Group (NEJ), Thoracic Oncology Research Group (TORG), Tokyo Cooperative Cooperative Oncology Group (TCOG), Oncology Group in Kyushu (LOGiK), Okayama Lung Cancer Study Group (OLCSG) and so on are conducting investigator initiated cooperative clinical studies for lung cancer. Phase 3 studies are mainly conducted by JCOG, WJOG and NEJ. JCOG and WJOG are conducting intergroup phase 3 studies for lung cancer. More recently, multi-group phase 3 studies are also started. 　JCOG is a multicenter clinical study group for cancer treatment fully funded by the national research grants in Japan. The goal of the JCOG is to establish effective standard treatments for various types of malignant tumors by conducting nationwide multicenter clinical trials, and to improve the quality and outcome of the management of cancer patients. JCOG consists of 16 subgroups and JCOG Lung Cancer Study Group (JCOG-LCSG) consists of 44 institutions, was established in 1982. JCOG also have JCOG Lung Cancer Surgical Study Group (JCOG-LCSSG) established in 1986. 　Only JCOG is supported by no industries but National Cancer Center and grants of Japan Agency for Medical Research and Development (AMED). Thus, JCOG studies are conducting completely independent from pharmaceutical companies. Other groups are supported by mainly pharmaceutical companies and grants of AMED. JCOG-LCSG has been conducting many randomized trials for small cell lung cancer and elderly non-small cell lung cancer. In case of JCOG-LCSG, protocol concepts are discussing in the group meeting held every 3 months. The protocol concept agreed in the group meeting will discuss in JCOG Protocol Review Committee and finally approved by JCOG Steering Committee. Kawano Y, Okamoto I, Fukuda H, et al. Current status and future perspectives of cooperative study groups for lung cancer in Japan. Respir Investig 52: 339-347, 2014.

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Background:
Immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors has emerged as a powerful tool for the treatment of lung cancer. To further enhance the antitumor efficacy of individual treatments, numerous ongoing studies are trying to identify synergistic combinations that simultaneously block more than one immunomodulatory pathway. C5aR1 is a G protein-coupled receptor activated by C5a, an anaphylatoxin released during the activation of the complement system, a major component of innate immunity. We have previously shown in a murine model of lung cancer that pharmacological blockade of C5aR1 reduces cancer progression by reversing the immunosuppressive microenvironment. Thus, we hypothesized that a combined inhibition of C5aR1 and PD-1 may have a synergistic effect in the treatment of lung cancer.

Methods:
We characterized the immunosuppressive activity of C5aR1 and evaluated the therapeutic efficacy of the dual administration of PD-1 and C5a/C5aR1 antagonists in syngeneic non-small cell lung cancer mouse models. The RMP1-14 monoclonal antibody was used to block PD-1, and a PEG-modified L-aptamer, which binds to complement C5 and C5a, was used to inhibit the C5a/C5aR1 interaction.

Results:
Kras[G12D/+] mice deficient for C5aR (Kras[G12D/+];C5aR1[Δ/Δ]) had a lower lung tumor burden and survived longer than Kras[G12D/+];C5aR1[wt/wt] littermates. Interestingly, Kras[G12D/+];C5aR1[Δ/Δ] mice showed a significant reduction of myeloid-derived suppressor cells (MDSCs), a subpopulation of immune cells that profoundly influences the effectiveness of cancer immunotherapies. We therefore evaluated whether C5a/C5aR blockade may enhance the efficacy of anti-PD-1 therapy by reversing the immunosuppressive microenvironment. In the Kras/Tp53 mutant 393P syngeneic lung cancer model, the combination of C5a and PD-1 blockade dramatically reduced in vivo tumor growth, as compared to the effect of each treatment alone. Similarly, this combination showed a remarkable synergistic antitumor effect in Lewis lung carcinoma (3LL)-bearing mice. Survival analysis confirmed the benefit of the combined treatment. Finally, the therapeutic combination significantly diminished the in vivo metastatic capacity of the highly aggressive Lacun3 lung cancer cell line in syngeneic BALB/c mice, as compared to the effect of anti-PD-1 or anti-C5a drugs as monotherapy.

Conclusion:
Our study supports the notion that the efficacy of anti-PD-1 therapy is limited by the immunosuppressive tumor microenvironment. In this context, C5a/C5aR1 blockade concomitant to anti-PD1 therapy obliterates the resistance mechanisms mediated by MDSCs, improving antitumor immune responses. These findings provide a framework for the clinical evaluation of this therapeutic strategy.

Background:
Platinum doublet chemotherapy ± bevacizumab is standard first-line therapy for patients with advanced non–small cell lung cancer (NSCLC) without genetic aberrations. Single-agent pembrolizumab exhibits robust antitumor activity in PD-L1–positive advanced NSCLC. Cohort G of the multicenter, open-label, phase 1/2 multicohort KEYNOTE-021 study (ClinicalTrials.gov, NCT02039674) evaluated the efficacy and safety of pembrolizumab + carboplatin and pemetrexed compared with carboplatin and pemetrexed in patients with treatment-naive advanced nonsquamous NSCLC with any PD-L1 expression.

Methods:
Cohort G enrollment criteria included patients with stage IIIB/IV nonsquamous NSCLC, no activating EGFR mutation or ALK translocation, no prior systemic therapy, measurable disease, ECOG performance status 0-1, and adequate tumor sample for assessment of PD-L1 status, regardless of PD-L1 expression. Patients were randomized 1:1 to 4 cycles of pembrolizumab 200 mg Q3W + carboplatin AUC 5 (5 mg/mL/min) + pemetrexed 500 mg/m[2] Q3W or carboplatin AUC 5 (5 mg/mL/min) + pemetrexed 500 mg/m[2] Q3W alone, followed by maintenance pemetrexed ± pembrolizumab. Pembrolizumab was given for ≤35 cycles. Randomization was stratified by PD-L1 expression (positive [tumor proportion score, or TPS, ≥1%] vs negative [TPS <1%]). Crossover to pembrolizumab monotherapy was allowed for eligible patients who experienced disease progression (RECIST v1.1) on chemotherapy. Response was assessed by central imaging vendor review every 6 weeks for first 18 weeks, every 9 weeks through year 1, and every 12 weeks in year 2. The primary end point was objective response rate (ORR); secondary end points included progression-free survival (PFS), duration of response, and overall survival (OS). Comparison between arms was assessed using the stratified Miettinen and Nurminen method (ORR) and stratified log-rank test (PFS, OS).

Results:
As of January 2016, 123 patients (60 in the pembrolizumab + chemotherapy arm, 63 in the chemotherapy arm) had been enrolled in cohort G. Data on ORR, duration of response, safety, and preliminary PFS and OS results will be available by August 2016.

Conclusion:
The conclusion will be updated at the late-breaking submission stage.

Background:
Immune checkpoint inhibitors are now established therapies in many advanced cancers. Preliminary studies suggest combining immune checkpoint inhibitors with platinum-based chemotherapy may enhance anti-tumour activity. The primary objective of this multi-centre study was to evaluate the safety and tolerability of durvalumab (Du), a PD-L1 inhibitor, ± tremelimumab (Tr), a CTLA-4 inhibitor, in combination with one of four standard platinum-doublet regimens (pemetrexed (pem), gemcitabine, etoposide (each with cisplatin) or nab-paclitaxel (with carboplatin)), in order to establish a recommended phase II dose (R2PD) for each combination. This abstract focuses on the pem / cisplatin cohort in non-squamous non-small cell lung cancer (NSCLC).

Methods:
Patients (pts) with advanced NSCLC (no prior treatment for advanced disease) who were eligible for treatment with cisplatin and pemetrexed were enrolled into one of four dose levels, regardless of tumour PD-L1 status. Concurrent with chemotherapy, dose level (DL) 0 added Du 15 mg/kg IV q3wks; DL1 added Du 15mg/kg q3wk + Tr 1mg/kg x1 dose; DL2a added Du 15mg/kg q3wk + Tr 1 mg/kg q6wk x multiple doses; DL2b added Du 15mg/kg q3wk + Tr 3 mg/kg q6wk (1 dose with cycle 1 and 2 doses with maintenance pem). Pemetrexed and Du maintenance continued after completion of 4-6 cycles of pemetrexed and cisplatin.

Results:
Twenty-four pts (median age=61 (range 37-78); 50% female, 95% ECOG PS≤1, were enrolled (5 pts to each of DL 0 and 1 and 7 pts each to DL2a and 2b). Thus far 121 cycles have been administered. The majority of drug-related adverse events (AEs) were ≤ grade 2. Most AEs were related to chemotherapy; other AEs were chemotherapy or immune-related (renal, hepatic, skin and pulmonary toxicity). AEs that were considered related to Du or Tr were mainly ≤ grade 2, the most common of which were fatigue (46%), nausea/vomiting (25%), anorexia (21%) and diarrhea (13%). Two pts (DL2a) had serious related AEs (febrile neutropenia related to chemotherapy and lung infection/pneumonitis related to both chemotherapy and Du + T (considered a DLT)). Seventeen of the 24 patients are currently evaluable for response. The provisional objective response rate is 52.9% (95% CI: 28 -77%).

Conclusion:
In this PD-1 unselected patient population, Du 15mg/kg q3w and Tr 1mg/kg (multiple doses q6w) or 3mg/kg (3 doses q6w) can be safely combined with full doses of platinum-doublet chemotherapy. Additional studies with this combination are being planned.

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Background:
Patients with SCLC and disease progression during/after first-line platinum-based chemotherapy have poor prognoses and limited treatment options. Nivolumab alone and in combination with ipilimumab has shown survival benefit and durable responses in multiple tumor types. Here we present updated results for the SCLC cohort of the phase 1/2 CheckMate 032 trial (NCT01928394), which was designed to evaluate nivolumab or nivolumab/ipilimumab in advanced solid tumors.

Methods:
Patients with advanced SCLC that progressed following ≥1 platinum-based chemotherapy regimens were assigned to receive nivolumab monotherapy (nivolumab-3 Q2W) or nivolumab/ipilimumab combination therapy (nivolumab-1/ipilimumab-3 or nivolumab-3/ipilimumab-1 Q3W for 4 cycles, then nivolumab-3 Q2W). Patients were eligible regardless of platinum sensitivity or tumor programmed death ligand 1 (PD-L1) expression. The primary endpoint was ORR. Additional endpoints were duration of response (DOR), OS, PFS, safety, and correlation of tumor PD-L1 expression with activity.

Results:
214 patients have been enrolled to date (nivolumab-3, n=98; nivolumab-1/ipilimumab-3, n=61; nivolumab-3/ipilimumab-1, n=55), including 96 and 118 patients treated with 1 or ≥2 prior regimens, respectively. Efficacy and safety data are shown (table). In the nivolumab-1/ipilimumab-3 cohort, ORR was 23% and 1-year OS was 43%. The proportion of patients with PD-L1–expressing tumors was substantially lower in previously treated SCLC in this study than that previously observed with pretreated NSCLC (16% vs 53%–54% with ≥1% PD-L1 expression). In SCLC, responses were observed regardless of PD-L1 expression. ORR and median OS were similar in patients treated with 1 or ≥2 prior regimens. Rate of discontinuation due to treatment-related AEs ranged from 5% to 11%; there were 3 treatment-related deaths. Figure 1



Conclusion:
Durable objective responses were observed with nivolumab and nivolumab/ipilimumab in patients with previously treated SCLC, and safety profiles were consistent with other tumor types. Updated efficacy (including 2-year OS and DOR), safety, and additional subgroup analyses will be presented from the August 2016 DBL.

Background:
Viagenpumatucel-L (HS-110) is an allogeneic whole-cell vaccine, selected for high expression of adenocarcinoma tumor antigens, transfected to secrete gp96-Ig. Prior studies with HS-110 (and related gp96-Ig vaccines) have shown a correlation between increases in CD8+ tumor infiltrating lymphocytes (TIL) and tumor response. The DURGA trial was designed evaluate the combination of HS-110 and nivolumab, in an attempt to increase tumor inflammation and improve the response rates observed with nivolumab alone. Clinical Trial identifier: NCT02439450

Methods:
Patients with advanced lung adenocarcinoma who received at least one prior line of therapy were assigned to two cohorts based on baseline levels of TIL in patient biopsies: low TIL (≤10% CD8+ T cells) or high TIL (>10% CD8+ T cells). All patients received standard of care nivolumab 3 mg/kg every 2 weeks and weekly HS-110 for 18 weeks until intolerable adverse events, disease progression, or death. Each 9-patient Phase 1b cohort could be expanded to 30 patients in Phase 2 based on exhibited efficacy. The primary endpoint was safety and tolerability. Biopsies at baseline and Week 10 were used to track changes in TIL and PD-L1 staining. Peripheral blood mononuclear cells (PBMC) were evaluated by flow cytometry for detection of circulating leukocyte subsets. ELISPOT was used to track antigen-specific immune response.

Results:
HS-110 vaccine and nivolumab combination was well tolerated with a safety profile consistent with single-agent nivolumab. Among the 8 initial patients, only 4 had optimal biopsies which showed 2 patients with high and 2 with low TILs. PD-L1 was >1% in 3 patients. IFNγ ELISPOT assay defined 4 patients as immune responders (doubling of IFNγ-secreting cells after re-stimulation with total vaccine antigen and individual cancer antigens, IR) and 4 patients as non-immune responders (NIR). The overall response rate (ORR) was 50% in the IR patients and 0% in the NIR patients. At the time of the data cutoff, 6 patients remain alive, including the 4 IR patients, with ongoing responses for 150 to 326 days. Patients with objective response also exhibited injection site reactions and maculopapular rash consistent with HS-110 mechanism of action, decreased Myeloid Derived Suppressor Cells (MDSC) in the blood, and increased markers of activated CD8+ T cell subsets by flow cytometry (CD8+CTLA-4+, CD8+Tim3+). Although the pathology specimens were sub-optimal in the two responding patients, the limited tissue available showed lower baseline TILs in both patients.

Conclusion:
Allogeneic gp96-based vaccination may have synergistic activity in combination with immune checkpoint inhibitors.

Background:
Intratumoral (IT) infiltration by activated immune effector cells is associated with a significantly better prognosis, however, tumor-associated immune suppression commonly occurs in non-small cell lung cancer (NSCLC). CD8[+ ]T cell or dendritic cell (DC) infiltration is an independent favorable prognostic indicator. CCL21 is a lymphoid chemokine that chemoattracts both lymphocytes and DC. Our aim was to investigate anti-tumor specific systemic immune responses and tumor-infiltrating CD8[+] T cells (CD8[+] TIL) in NSCLC patients in response to in situ vaccination via IT administration of autologous DC transduced with a replication-deficient adenoviral (Ad) vector expressing the secondary lymphoid chemokine (SLC/CCL21) gene. Here, we conducted a phase I trial and evaluated safety and immune responses following in situ vaccination.

Methods:
Sixteen stage IIIB/IV NSCLC subjects received two vaccinations (1 x 10[6], 5 x 10[6], 1 x 10[7], or 3 x 10[7] dendritic cells/injection) by CT- or bronchoscopic-guided IT injection (days 0 and 7). Immune responses were assessed by tumor antigen-specific peripheral blood lymphocyte induction of IFN-γ in ELISPOT assays. Tumor biopsies were evaluated for CD8[+ ]T cells by immunohistochemistry (IHC).

Results:
Twenty-five percent (4/16) of patients had stable disease at day 56 follow-up by RECIST criteria. Median survival was 3.9 months. Four possible vaccine-related grade 1 adverse events (AE) occurred in 3 patients with no clear association to dose or schedule; the AE included flu-like symptoms, blood-tinged sputum after each injection, nausea, and fatigue. ELISPOT assays revealed 38% (6/16) of patients had systemic responses against tumor associated antigens (TAA). Tumor CD8[+] T cell infiltration was induced in 54% of subjects (7/13; 3.4 fold average increase in the number of CD8[+ ]T cells per mm[2]). Patients with increased intratumoral CD8[+ ]T cells following vaccination showed significantly increased PD-L1 mRNA expression (p=0.02).

Conclusion:
Intratumoral vaccination with Ad-CCL21-DC was well-tolerated and resulted in 1) induction of systemic tumor antigen-specific immune responses and 2) enhanced tumor CD8[+ ]T cell infiltration. DC-CCL21 in situ vaccination may be a promising approach to induce tumor CD8[+ ]T cell infiltration in combination with checkpoint inhibitor therapy.

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Background:
The c-Met receptor is overexpressed in ~50% of patients with NSCLC. ABBV-399 is a first-in-class ADC composed of ABT-700, an anti–c-Met antibody, conjugated to monomethyl auristatin E (a microtubule inhibitor). Preclinical data support ABBV-399 as a unique strategy to deliver a potent cytotoxin directly to c-Met+ tumor cells.

Methods:
In a 3+3 dose-escalation design, ABBV-399 was administered at doses ranging from 0.15 to 3.3 mg/kg once every 21 days to patients with advanced metastatic solid tumors (NCT02099058). ABBV-399 was then studied in a dose-expansion cohort in 16 patients with advanced c-Met+ (immunohistochemistry [IHC] H-score ≥150) NSCLC that had progressed on ≥2 prior lines of therapy. ABBV-399 was also studied in combination with erlotinib in 10 patients with NSCLC, 8 of whom were c-Met+. Overexpression of c-Met was assessed by an IHC assay utilizing the SP44 antibody (Ventana; Tucson, AZ, USA).

Results:
As of June 27, 2016, 48 patients with solid tumors received ≥1 dose of ABBV-399. The dose-limiting toxicity (DLT) for ABBV-399 was febrile neutropenia, which occurred in 2 patients (1 each at 3 and 3.3 mg/kg). There were no treatment-related deaths. Monotherapy treatment-related adverse events (AEs) occurring in ≥10% of patients (including all dose levels and all grades) were fatigue (25.0%), nausea (22.9%), neuropathy (14.6%), decreased appetite (12.5%), vomiting (12.5%), and hypoalbuminemia (10.4%). Based primarily on safety and tolerability, a 2.7-mg/kg dose was chosen for dose expansion in patients with c-Met+ advanced NSCLC. Three of 16 (19%) ABBV-399–treated c-Met+ NSCLC patients had a confirmed partial response (PR) with duration of response (DOR) 3+, 3, and 4.5 months. At week 12, 6 of 16 patients treated (37.5%) had disease control. Ten patients received ABBV-399 in combination with erlotinib. No DLTs were observed and AEs related to ABBV-399 occurring in ≥2 patients were acneiform rash (40.0%), fatigue (30.0%), and dry skin (20.0%). Three of 8 (37.5%) evaluable ABBV-399 + erlotinib-treated c-Met+ patients had a confirmed PR with DOR 2+, 4+, and 5+ months. Two of the 3 patients with PR had EGFR-mutated tumor, and previous TKI- and platinum-based chemotherapy had failed.

Conclusion:
ABBV-399 is well tolerated at a dose of 2.7 mg/kg every 21 days and has demonstrated antitumor activity in patients with c-Met+ NSCLC both as monotherapy and in combination with erlotinib. Updated data of antitumor activity and safety of ABBV-399 as monotherapy and in combination with erlotinib in c-Met+ NSCLC patients will be presented.

Background:
The sodium-phosphate transporter NaPi2b is expressed at high levels in a majority of non-squamous non-small cell lung cancers (NSCLC), suggesting it may be an attractive therapeutic target for antibody-drug conjugate (ADC) development in this disease. However, NaPi2b is also expressed at high levels in type II alveolar cells, raising the potential for normal tissue toxicity with this approach. XMT-1536 is an ADC comprised of a humanized antibody against NaPi2b and approximately 15 auristatin-derived payload molecules per antibody conjugated via a multivalent hydrophilic polymer (Fleximer). The auristatin payload is enzymatically cleaved upon ADC trafficking to the endosome/lysosome compartment, releasing a cytotoxic auristatin-derivative that is capable of bystander effect killing.

Methods:
The anti-tumor activity of XMT-1536 was evaluated in seven patient-derived xenograft models of NSCLC adenocarcinoma, chosen for high NaPi2b-expression and representing a spectrum of oncogenic driver mutations prevalent in NSCLC adenocarcinoma (including tumors without oncogenic drivers). The standard dose of XMT-1536 used across models was 3 mg/kg administered intravenously once weekly for 3 weeks (last dose on Day 14). Experiments ran until tumor growth past a pre-specified endpoint or Day 60. XMT-1536 was also evaluated for tolerability in a cynomolgus monkey study.

Results:
At the 3 mg/kg dose, XMT-1536 was active in 6/7 models: complete tumor regression in 3 models, partial tumor regression in 1 model, and significant tumor growth inhibition in 2 models. In 3 of the 4 models where XMT-1536 induced tumor regression, regressions were durable, with a majority of the animals maintaining partial or complete regression at Day 60. The antibody component of XMT-1536 is cross-reactive with cynomolgus NaPi2b with similar affinity as human NaPi2b. XMT-1536 was well tolerated up to 5 mg/kg (4294 mg/m[2] auristatin payload equivalents), the highest dose tested. There was no body weight loss, no clinical observations attributable to XMT-1536, and no evidence of neutropenia. On pathology, there was minimal mixed inflammatory cell infiltrate in the lung in 1 high dose animal at each necropsy time point, but no evidence of significant lung toxicity. Exposure to XMT-1536 indicated good conjugate stability, low exposure to free drug payload in plasma (<1 ng/mL), and supported the 3 mg/kg dose level in mouse studies as a potentially clinically-relevant dose.

Conclusion:
These results indicate XMT-1536 can achieve durable tumor regressions in murine patient-derived NSCLC adenocarcinoma models at doses associated with good tolerability in cynomolgus monkey, and support evaluation of XMT-1536 in patients with NSCLC.

Background:
Trials of anti-EGFR necitumumab and anti-PD1 pembrolizumab demonstrate the anti-tumor activity of each agent in NSCLC.

Methods:
Single-arm, multicenter Phase 1b study to investigate effectiveness and safety of necitumumab combined with pembrolizumab in patients with Stage IV NSCLC (NCT02451930). In Part A, escalating doses of necitumumab (600 mg and 800 mg IV) were administered on Day 1 and 8 every 3 weeks (Q3W) in combination with pembrolizumab (200 mg IV) on Day 1 Q3W. In the absence of dose limiting toxicity, Part B (expansion cohort) was planned with necitumumab 800 mg in 27 squamous and 27 nonsquamous NSCLC patients. Major eligibility criteria included: progression after ≥1 platinum-based chemotherapy, and ECOG PS 0-1. Study objectives were to evaluate tolerability and ORR by RECIST 1.1. PD-L1 status was centrally assessed using PD-L1 IHC 22C3 pharmDx assay (considered negative, weak positive, strong positive if <1%, 1-49%, ≥50% of tumor cells were stained, respectively).

Results:
The interim analysis population includes 34 nonsquamous patients (median age 61 years, 68% men, 21% never smokers, PD-L1 status: negative, 50% [17/34]; positive weak/strong, 15% [5/34]/15% [5/34]; unknown 21% [7/34[BJ1] ]). Median follow-up was 6.0 months. Ten patients (29.4%) had PR (confirmed and unconfirmed) (PRs by PD-L1 status: negative, 18% [3/17]; positive weak/strong, 60% [3/5]/40% [2/5]; unknown status, 2 patients). DCR was 67.6%. PFS rate at 6 months was 55.1% (95% CI, 36.2-70.6); median PFS was 6.9 months (95% CI, 2.7-NR). Most common Grade ≥3 AEs were skin rash (9%), hypomagnesemia (9%), VTE (9%) and increased lipase (9%); 1 patient died due to an AE (respiratory tract infection). Five patients (14.7%) discontinued therapy because of an AE. Figure 1



Conclusion:
Safety profile corresponds to individual profiles for both drugs, with no additive toxicities. These preliminary data suggest activity of this combination in a pretreated nonsquamous NSCLC population, irrespective of PD-L1 status.

Abstract not provided

Background:
The new 8[th] AJCC/UICC lung cancer staging system was developed and validated using the International Association for the Study of Lung Cancer (IASLC) database, which contains 94,708 lung cancer patients worldwide, but only 5% of patients in this database came from North America. The goal of this study is to validate the prognostic performance of this new staging system, focusing on the upgraded "T" and “M” parameters, in North American lung cancer patients.

Methods:
We analyzed 1,163,465 non-small cell lung cancer (NSCLC) cases collected from 2004 to 2013 in the United States in the National Cancer Database (NCDB). After excluding patients with more than one malignant primary tumor or tumor size larger than 10 cm, 545,776 NSCLC patients were included in the final data analysis. We defined 8[th] T and M parameters according to the primary coding guidelines of the Collaborative Staging Manual and Coding Instructions for the new 8[th] AJCC/UICC lung cancer staging system. Kaplan-Meier survival curves and log-rank tests were used to compare survival difference among different stage groups, and Cox regression models were used for multivariate analysis adjusting for potential confounders.

Results:
We validated that the new staging system can provide better survival prognosis for NSCLC patients in the NCDB cohort than the existing 7[th] staging system. The median survival time for T1a is 58 months (N=15,860), for T1b is 47 months (N=78,379), and for T1c is 25 months (N=79,828) (p<2e-16). The median survival time for T2a is 19 months (N=111,925), for T2b is 12 months (N=54,601), for T3 is 10 months (N=105,234), and for T4 is 7 months (N=99,949) (p<2e-16). And the median survival time for M0 is 25 months (N=411,048), for M1a is 8 months (N=49,352), for M1b is 5months (N=42,224), and for M1c is 3 months (N=15,926 cases) (p<2e-16). Multivariate analysis showed that these staging parameters are significantly associated with survival when adjusting other factors.

Conclusion:
Both upgraded “T” and “M” parameters of the 8[th] AJCC/UICC lung cancer staging systems are significantly associated with NSCLC patient survival outcomes using data from the NCDB, indicating a good validation performance in patients from North America.

Background:
The new classification for lung cancer refines the T-descriptor criteria into more categories. We examined whether this affects the accuracy of clinical staging, and how this affects the final stage of patients.

Methods:
71 patients underwent resection for primary lung cancer from January 2014 to December 2014. T-component was measured based on the maximum tumour size on CT, PET-CT and histology report. The possible effect on staging based on T-component was compared between both TNMs.

Results:
PET-CT more accurately estimates the pathological size of the tumor (mean difference from histology: CT 3mm (range -1.6 to 2.6cm) and PET-CT 1.3mm (-2 to 2.5cm). Discordance between radiological and pathological T-stage was higher with the 8th edition (7th edition concordance CT 42(59%) and PET-CT 31(43%), 8th edition CT 31(44%) and PET-CT 29(41%) (CT p=0.01; PET-CT p=0.7)). The final stage groupings was also more discrepant in the 8th edition. Concordance was for CT 7th Edition 37(54%) vs 8th Edition 21(31%) (p<0.001), and for PET-CT 34(48%) vs 19(28%) (p<0.001). The discrepancy in stage grouping is contributed significantly by T-stage discordance. In the 30 patients who were not upstaged pathologically by pleural invasion or nodal staging, there is a over 50% increase in inaccuracy of clinical staging in the 8th edition. The CT concordance was 7th edition 24(80%), 8th edition 13(43%) (p<0.001); and for PET-CT 23(77%) vs 10(33%) (p<0.001).

Conclusion:
We showed that the 8th edition TNM lung cancer staging system was associated with a significant increase in discordance between clinical and pathological staging due to differences in measurement of tumour size and consequently T-stage groupings by different modalities. This has implications for prognostication and clinical trial interpretation especially in patients who do not undergo surgery for pathological stage confirmation.Figure 1

Background:
The IASLC lung cancer staging project recently published recommendations for the 8th edition of the TNM classification of lung cancer. This recommends the same N descriptors be used, however, further analysis of an alternative system (proposed 9[th] Edition) was recommended. The aim of this retrospective study was to assess the utility of this proposed nodal staging system at a large UK tertiary lung cancer centre.

Methods:
Patients who underwent surgical resection for non-small cell lung cancer between 2011-2014 (allowing minimum of 2 years follow-up) were identified from a prospective database (n=1308). Stratification of pathological N-stage as per the IASCLC proposal was performed: N0, single station N1 (N1a), multi-statin N1 (N1b), single station N2 without N1 involvement – skip metastases - (N2a1), single station N2 with N1 involvement (N2a2), multi-station N2 (N2b) and N3. Survival data was obtained from national death registries.

Results:
There a significant effect of N-stage on mortality using Cox proportional hazards regression analysis, using pN0 (n=848) as the reference group and adjusting for sex, age and histology (table 1). There appears to be similar survival outcomes between multi-station N1 (pN1b) and single station N2 skip metastases (pN2a1), and single station N2 with N1 involvement (pN2a2) and multi-station N2 (pN2b).

Table 1.

N-stage	Hazard Ratio	95% CI	p-value
pN1a (n=146)	1.68	(1.26, 2.26)	0.001
pN1b (n=55)	2.25	(1.49, 3.39)	<0.001
pN2a1 (n=50)	2.24	(1.46, 3.45)	<0.001
pN2a2 (n=81)	2.94	(2.15, 4.03)	<0.001
pN2b (n=67)	2.99	(2.09, 4.27)	<0.001

Conclusion:
The proposed 9[th] edition N-staging classifications appear to add additional insight into prognosis. However, interpretation is limited by the small numbers of patients within the pN1/pN2 sub-groups. 65% of this large cohort were pN0 and acted as the reference group and a further 5% were pNx as no nodes were submitted. Furthermore, the accuracy of pN-staging is reliant on the quality of intra-operative lymph node sampling. Although significant improvements have been made in this timeframe at our centre (published previously), any sub-optimal performance has the potential to affect the validity of the results, particularly if multi-station N2 disease is missed.

Abstract not provided

Background:
In lung adenocarcinomas, the histologic lepidic growth pattern tends to correlate with the ground glass opacity (GGO) component, while solid components correspond with invasive adenocarcinoma. The Eighth edition of the TNM staging system suggests that the tumor size be determined according to the invasive size excluding the lepidic component. However, this new concept causes fatal confusion, i.e., tumors are classified into a same T category despite the part-solid or pure-solid appearances provided they showed a same solid component size.

Methods:
Between 2008 and 2012, we retrospectively evaluated 719 surgically resected cN0 lung adenocarcinomas that measures 30mm or less in total dimension to assess the prognostic impact on the presence of GGO among the Eighth TNM classification. According to the new T category, it was defined based on the solid component size as follow: Tis; 0 cm (pure-GGO), T1mi; ≤ 5 mm, T1a; 6-10 mm, T1b; 11-20 mm, T1c; 21-30mm. Furthermore, all tumors were classified into 2 groups, i.e., GGO or Solid arms based on the presence of GGO component.

Results:
Of the cases, 133 (18%) were categorized in Tis, 88 (12%) in T1mi, 121 (17%) in T1a, 244 (34%) in T1b and 133 (19%) in T1c, respectively. Multivariate analysis revealed that both a presence of GGO and solid component were independently significant prognostic factors (p=0.007, 0.002). The 5y-overall survival (OS) was 99.2% in Tis, 95.8% in T1mi, 96.5% in T1a, 81.8% in T1b and 66.4% in T1c (p=0.038) with a median follow-up period of 56 months. When we evaluated the impact of T category based on GGO presence, the 5y-OS was significantly different between GGO and Solid arm in each T categories (T1a; 99.0% vs. 95.7%, p=0.045, T1b; 89.8% vs. 73.3%, p=0.004, T1c; 90.0% vs. 62.6%, p=0.046). Furthermore, clinical T categories significantly separated the OS in Solid arm (p=0.015) (T1a vs. T1b; p=0.090, T1b vs. T1c; p=0.037). In contrast, the 5y-OS was approximately 90% or more in GGO arm despite their T categories. Moreover, regarding radiological and pathological correlations, the rates of AIS was only 65% in Tis, and 51% showed invasive adenocarcinoma even in T1mi.

Conclusion:
Clinical T category should be considered based on the presence of GGO on thin-section CT, and tumor size should be applied exclusively to radiological solid lung cancer. In contrast, oncological outcomes of the tumor with GGO component were excellent despite their T categories, which should be described as Tis for pure-GGO, and T1a for part-solid tumor.

Background:
Central tumour location is considered as an independent risk factor for occult mediastinal metastases in patients with non­-small cell lung cancer (NSCLC) after negative computerized tomography (CT) and integrated positron emission tomography/CT. However, the distinction between a central and a peripheral tumour has not been codified, some authors consider any tumour in the inner­third of the hemithorax to be central, and others in the inner two­thirds. The objective of this study is to identify the best centrality tumour definition for detecting occult mediastinal metastasis.

Methods:
We retrospectively reviewed our thoracic surgery database for cases between January 2011 and December 2015. It was identified patients with potentially operable NSCLC screened by CT and PET/CT and they were classified according to tumour location in the inner third, middle third or outer third. The prevalence of occult mediastinal lymph node metastases was analysed in relation to tumour location. Statistical analysis for best centrality definition was performed. Univariable analysis was performed using the Fisher exact test and multivarible analysis using logistic regression.

Results:
A total of 359 patients with clinical operable NSCLC were included in our study. Seventy­-five (20.9%) tumours were located in the inner­third, 137 (38.2%) in the middle­third and 147 (40.9%) in the outer­third. It was detected 23 patients with N2 disease and negative TC and PET/CT, 8/38 (21.1%) in the inner­third, 6/121 (5.0%) in the middle­third and 9/122 (7.4%) in the outer­third. Defining centrality as tumour located in the inner­third of the hemithorax the incidence of occult N2 was 21.1% and 6.2% for central and peripheral tumour respectively. And defining centrality as tumour located in the inner two­thirds the incidence of occult N2 was 8.8% for central tumours and 7.4% for peripheral. Univariable analysis shows statistical differences in occult N2 involvement between central or peripheral defining central lesion as innerthird (p=0.002), but not for central definition of innternal twothirds (p=0.651). In multivariable analysis considering centrality possible defenition, histology, Clinical T factor and Clinical N1 affection, only innerthird as centrality definition was statistical significance predictor factor for occult mediastinal lymph node involvement (p= 0.027)

Conclusion:
Considering the results of our study the best definition for central tumour location is limited to the inner­third of the hemithorax. Given the low rate of occult N2 disease in the middle third location, the systematic evaluation of the mediastinum by ecobronchoscopy and/or mediastinoscopy in this group of patients is not justified.

Background:
False-negative 18F-fluorodeoxyglucose (FDG) uptake can be divided into those cases related to technological limitations of positron-emission tomography (PET) and others related to inherent properties of neoplasms. We aim to clarify possible factors causing false-negative (FN) PET results in solid-type pulmonary adenocarcinomas (PAs).

Methods:
From 01/2007 to 12/2014, among 255 Stage-I NSCLCs we retrospectively review PET/CT-records, clinical information, preoperative thin-section CT-images, and pathological features (classified by the IASLC/ATS/ERS subtyping criteria) of 94 consecutive solid-type Stage-I PA undergone surgical resection at Our Institution. Univariate and multivariate logistic analysis were used to identify and weigh the independent predictors of PET-findings: body weight, blood glucose level, tumor-size, and histological classification.

Results:
There were 58 males and 36 females (mean age= 68.7 yrs, range 42-85). Seventeen lesions (18.1%) were judged as PET-negative and 77 lesions (81.9%) as PET-positive. Overall, mean SUVmax was 8.0 (range 0-35) with higher SUVmax-values (p<0.001) in PA>2cm (mean SUVmax=10.6) than PA<2cm (mean SUVmax=4.8). PET false-negative (FN) results were also differently distributed (27.9% in PA <2cm vs 9.8% in PA>2 cm, p=0.023). When clustering the PA in 2 histological classes (Class-A [“colloid/mucinous/lepidic”] vs Class-B [“micropapillary/solid/acinar/papillary”]), the radiometabolic patterns were significantly different [mean SUVmax 3.8 in Class-A vs 9.9 in Class-B, p<0.001], as reported in Figure 1. Similarly, a different distribution of PET FN-cases was observed (38.7% FN in Class-A vs 7.9% FN in Class-B, p=0.001). Table 1 shows the results of multivariate logistic analysis. Both the tumor-size (cut-off=2cm) and IASLC/ATS/ERS aggregated clusters were clinically relevant factors for determining whether PET results were negative or positive, but only histology was statistically significant (OR:6.1, 95%CI: 1.85-20.15, p=0.003). Figure 1



Conclusion:
Among solid-type lung adenocarcinoma, tumor-size and histopathological findings were significantly associated with FDG-uptake. In particular, it warrants attention that lesions ≤2cm and “colloid/mucinous/lepidic” adenocarcinomas have a tendency for negative PET-findings.

Abstract not provided

Background:
Immune check-point inhibitors (ICPIs) exert their activity by blocking inhibitory signaling and therefore enhancing T-cell activity against tumor cells; however, this peculiar mechanism of action might lead to many difficulties in evaluating clinical response with the usual CT imaging due to inflammatory patterns that could confuse the evaluation. The aim of this study was to assess the role of FDG-PET to support clinical decision based on CT scan.

Methods:
From May 2015 to April 2016, 74 patients with advanced pretreated NSCLC received at least one dose of nivolumab (3 mg/Kg every 14 days) within a single-institutional translational research trial. Among these, 58 patients were evaluable for response assessment. The patients underwent CT scan and FDG-PET every four cycles and, in case of progressive disease, an additional evaluation was performed after two further cycles in order to confirm it. We evaluated the response to treatment by CT scan with RECIST criteria, Immuno-related Response Criteria (irRC), WHO criteria and immunoRECIST criteria, while the metabolic response has been determined with PERCIST criteria. Finally, we determined the concordance in terms of response between CT evaluation criteria and metabolic response obtained with PERCIST; concordance was calculated with kappa value.

Results:
Our findings showed a low concordance of all CT scan evaluation criteria to PERCIST, the best concordance being between PERCIST and RECIST (K=0.500) and the worst agreement being between PERCIST and irRC (K=0.295) . In particular, PERCIST seems to underestimate the progressive disease (PD). In fact, between 46% and 55% of patients, defined in progression with CT evaluation criteria were considered in stable metabolic disease (SMD) by PERCIST; among these, 50% of patients in the RECIST PD group and 80% of RECIST SD patients were alive at 6 months. Furthermore, in our sample, between 9% and 18% of patients were considered in progression with CT evaluation criteria when they were in partial response with PERCIST; these patients were still alive with a survival similar to those who defined in partial response with RECIST (>9 months).

Conclusion:
FDG-PET evaluation by PERCIST could not be helpful when SMD is reported, in fact, patients that have a RECIST PD maintain a poor prognosis compared to RECIST SD between the patients define as SMD. Conversely, PERCIST evaluation could be informative when it define a partial response, specially when RECIST criteria show a PD.

Background:
Nivolumab is approved for treatment of squamous and non-squamous advanced NSCLC. Since nivolumab restores antitumor immunity, it is not clear whether 18F-FDG-PET/CT is able to distinguish response from tumor progression. We evaluated early metabolic patterns of response to nivolumab in advanced NSCLC patients.

Methods:
We retrospectively reviewed PET/CT scans and paired CT scans from 22 patients with advanced NSCLC who received nivolumab 3mg/kg every 2 weeks and performed PET/CT before and after 4 infusions of nivulomab. Total Lesion Glycolysis (TLG) and Metabolic Tumor Volume (MTV) of every lesion up to 5 per patient were measured on baseline and follow-up PET/CT. Percentage changes in MTV (ΔMTV) and TLG (ΔTLG) between the two PET/CT were calculated. Patients were classified into responders (nivolumab for >6 months), non responders (nivolumab ≤6 months) or having pseudo-progression (PP, nivolumab and clinical benefit >6 months despite initial progressive disease according to RECIST criteria)

Results:
Among 22 patients, 6 (27%) were responders, 15 (68%) were non-responders and 1 (4.5%) had PP. Baseline MTV and TLG were significantly lower in responders than in non-responders (medians 27 vs. 63 mL, p=0.03 and 124 vs. 254 g, p=0.04, respectively). After 4 infusions of nivolumab, metabolic parameters were significantly lower in responders than in non-responders (median MTV : 2 vs. 148 mL, p=0.001 and median TLG : 6 vs. 835 g, p=0.002). Mean ΔMTV and ΔTLG were both -88% in responders, and +236% and +312% respectively in non-responders, which was significantly different (p=0.0005). The only patient with PP had lower ΔMTV (+11%) and ΔTLG (+41%) than non-responders patients.

Conclusion:
In NSCLC, objective response and disease progression upon nivolumab usually translate into early and clear-cut patterns of change in PET/CT. Early PET/CT may help to distinguish progression from pseudo-progression.

Background:
Immune check-point inhibitors have dramatically changed the management of advanced non-small cell lung cancer (NSCLC); however, their mechanism of action creates concerns on the most appropriate method to determine radiological responses to this drug class. The aim of this study is to compare a set of different evaluation criteria for patients receiving nivolumab for advanced NSCLC.

Methods:
Patients with pre-treated advanced NSCLC were enrolled in a single-institutional translational research study in the San Martino Hospital – National Institute for Cancer Research, Genova, Italy and received nivolumab (3 mg/kg every 14 days). Computed tomography (CT) was performed at baseline and after every 4 administrations. The assessments were performed according to Immune-related response criteria (irRC), response evaluation criteria in solid tumors (RECIST 1.1), World Health Organization (WHO), and immune-related RECIST (irRECIST), which are recently proposed based on the original RECIST with the following differences derived by irRC: 1) new lesions do not automatically define progressive disease (PD), but are added to the target lesions count; 2) PD has to be confirmed with a subsequent CT-scan after 2 additional cycles. The concordance among the different criteria was determined with Cohen’s kappa coefficient (K).

Results:
Fifty-two patients were eligible: median age= 70 years (44-85); male/female: 70%/30%; current or former smokers= 87%; non-squamous/squamous histology= 79%/21%; median number of cycles= 6 (4-29). The following responses were observed:

	Partial Response	Stable Disease	Progressive Disease
	First evaluation (4 cycles)
RECIST 1.1	4 (7.7%)	19 (36.5%)	29 (55.8%)
irRC	3 (5.8%)	23 (44.2%)	26 (50%)
WHO	3 (5.8%)	20 (38.5%)	29 (55.8%)
irRECIST	4 (7.6%)	24 (46.2%)	24 (46.2%)
	Best Response
	Partial Response	Stable Disease	Progressive Disease
RECIST 1.1	9 (17.3%)	14 (26.9%)	29 (55.8%)
irRC	8 (15.4%)	19 (36.5%)	25 (48.1%)
WHO	7 (13.5%)	17 (32.7%)	28 (53.8%)
irRECIST	11 (21.2%)	18 (34.6%)	23 (44.2%)

Generally, the concordance between first evaluation and best response was good for all the criteria (K ranging from 0.783 to 0.839); the concordance between irRECIST and irRC was high (K= 0.828) and RECIST 1.1 had a good concordance with IRC (K= 0.734), irRECIST (K= 0.767), and WHO (0.766).

Conclusion:
The different response assessment methods were generally concordant. Since response is more easily assessed with irRECIST than with irRC, the former might be proposed as an appropriate method of response evaluation.

Abstract not provided

Background:
Conventionally, the classification of lung cancer and many other malignancies is determined by the histology of a tumor. Large cell neuroendocrine carcinoma (LCNEC) is traditionally classified as a histological variant of large cell carcinoma (LCC), which is a subtype of non-small cell lung cancer (NSCLC). However, LCNEC exhibits differential cytological, morphological, clinical and biological features than those of classic LCC, thus rendering controversies regarding its classification. In 2015, with the integration of immunohistochemical analyses, the World Health Organization (WHO) has re-classified LCNEC under neuroendocrine tumors. Due to the rareness of LCNEC, few studies have been conducted on the molecular genetic profiling of LCNEC. In this study, we characterized molecular signature associated with a cohort of LCNEC, SCLC and LCC using capture-based targeted sequencing.

Methods:
We performed capture-based targeted sequencing on 30 surgically resected samples from patients with lung cancer using BurningRock Biotech’s OncoScreen Panel. This panel, consisting of all exons and critical introns of 295 genes, covering multiple classes of somatic mutations, including single nucleotide variation (SNVs), rearrangements, copy number variations (CNVs) and insertions and deletions (INDELs), can be used to detect genetic alterations both qualitatively and quantitatively. Among the 30 patients, 15 of them were diagnosed with LCNEC, 5 with LCC and 10 with small cell lung cancer (SCLC).

Results:
While no statistically significant difference was observed in total number of mutations among the three subtypes, LCC carries the most number of somatic mutations followed by LCNEC then SCLC. Overall, we identified 331 mutations with TP53 being the most frequently mutated gene in all three subtypes. Genes with recurrent somatic mutations detected in LCNEC, but not in LCC or SCLC include RUNX1, ERBB4, BRCA1, and EPHA3. Copy number analysis revealed a higher prevalence of CNV in LCNEC, with 60% of cases harboring such alteration. There is no common CNVs shared among all three subtypes. NFкBIA amplification is the only common CNV found in both LCNEC and LCC; and AKT2 amplification is shared by LCNEC and SCLC. Most CNVs are subtype-specific. Interestingly, one RET-fusion was discovered in one LCC sample and one EGFR exon 19 deletion accompanied by EGFR copy number amplification was discovered in one LCNEC sample.

Conclusion:
Targeted deep sequencing reveals distinct genetic profile for LCNEC compared to LCC and SCLC. LCNEC harbors more CNV and contains a panel of genes, including RUNX1, ERBB4, BRCA1 and EPHA3 that are more frequently mutated comparing to LCC and SCLC.

Background:
Tumor mutational load (TML) by whole-exome sequencing (WES) is a potential determinant of response to immune checkpoint blockers. The use of PD-L1 as a predictive biomarker for use of PD-1/PD-L1 inhibitors is limited. To date, there are few data concerning TML in puNETs.

Methods:
WES was performed in fresh-frozen tumor-normal pairs from 35 typical carcinoid (TC), 4 atypical carcinoid (AC) and 9 large-cell neuroendocrine carcinoma (LCNEC) consecutively collected. Exome enriched libraries were sequenced on an Illumina HiSeq 2000 with a paired-end 2 x 100 bp protocol. Reads were aligned to the reference hg19 using an implementation of the Burrows-Wheeler Aligner, and a BAM file was produced for each tumor and normal sample using the Picard pipeline. The MuTect algorithm was used to identify SSNVs in WES data. We used a minimal allelic fraction cutoff of 0.1. Patients' characteristics and TML were described (median and interquartile for quantitative variables and frequencies for qualitative variables). To evaluate the effect of some factors on the TML, an analysis of variance was used. A log transformation was performed according to the distribution of the TML. The median follow-up was estimated using the Schemper's method. The number of relapses and deaths was reported.

Results:
Cohort included 24 male and 24 female. Median age at diagnosis was 57 [Q1= 46; Q3= 70] years, 38% of carcinoids (TC+AC) and 89% of LCNEC were smokers, 26 (54%) stage I, 16 (34%) stage II, 3 (6%) stage III and 3 (6%) stage IV. All patients underwent surgery and 5 (10%) received neoadjuvant treatment. Median follow-up was 32.6 (min= 4.4; max= 179.9) months; there were 8 (17%) relapses (6/9 LCNEC, 2/39 carcinoids) and 10 deaths. On average, 11.6 Gb of sequence were produced per sample, aiming a mean coverage of 72X. Overall median TML was 0.31/Mb [Q1= 0.22; Q3= 0.67], significantly lower in carcinoids tumors than LCNEC (0.28 [Q1= 0.20; Q3= 0.38]/Mb vs. 2.98 [Q1= 1.20; Q3= 4.84]/Mb, respectively, p<0.0001). Similar findings were observed among smoker vs. non-smoker patients (0.28 [Q1= 0.18; Q3= 0.38]/Mb vs. 0.60 [Q1= 0.28; Q3= 2.98]/Mb, respectively, p=0.04). Both variables were found to be independently correlated with TML within the ANOVA test (p=0.0016).

Conclusion:
Our findings provide a unique portrait of puNETs, revealing different histotype mutational burden. Continued work in harnessing immunological data in puNETs are needed for better understanding immunotherapy-treatment option in this orphan disease.

Background:
Insulinoma-associated protein 1 (INSM1) is expressed predominantly in embryonic developing neuroendocrine (NE) tissues, and the expression is significantly reduced/restricted in adult tissues. We previously revealed that INSM1 is expressed exclusively in small cell lung cancer (SCLC) compared to non-small cell lung cancer (NSCLC). The significance of the expression of INSM1 in lung cancer has been largely unknown. We investigated the utility of INSM1 as a novel immunohistochemical marker and researched the biological significance in lung cancer cell lines.

Methods:
We compared INSM1 as an immunohistochemical marker for NE tumours of the lung to conventional markers (chromogranin A (CGA), synaptophysin (SYP), and CD56). To elucidate the biological function of INSM1 in the NE differentiation pathway, we conducted INSM1 gene knockdown/overexpression experiments using human lung cancer cell lines.

Results:
INSM1 was expressed in 100% of SCLCs (44/44), Large cell neuroendocrine cell carcinomas (7/7), and Carcinoids (11/11), but was not expressed in NSCLCs (90 adenocarcinomas and 47 squamous cell carcinomas). This novel immnohistochemical marker showed high sensitivity and specificity when compared to conventional NE markers. We demonstrated that knockdown of INSM1 expression resulted in significant reduction of NE molecules in SCLC cell lines, and overexpression of INSM1 induced NE differentiation in NSCLC cell lines.

Conclusion:
INSM1 was a superior NE immunohistochemical marker when compared to conventional markers. Furthermore, our biological molecular experiments revealed that INSM1 is a critical upstream regulator of the NE differentiation pathway in SCLC cell lines. The elucidation of the significance of INSM1 expression in lung cancer strongly supports the diagnosis of NE tumours of the lung and promotes the understanding of the molecular biology of these tumours.

Abstract not provided

Background:
Circulating-tumor DNA (ctDNA) is emerging as a key potential biomarker for post-diagnosis surveillance but it may also play a crucial role in the detection of pre-clinical cancer. Small-cell lung cancer (SCLC) is an excellent candidate for early detection given there are no successful therapeutic options for late-stage disease, and it displays universal inactivation of TP53 (Peifer and Fernandez-Cuesta et al., Nat Genet 2012; George et al., Nature 2015).

Methods:
We assessed the presence of TP53 mutations in the cell-free DNA (cfDNA) extracted from the plasma of 51 SCLC cases and 123 non-cancer controls. The results were further validated in an independent series of 102 non-cancer controls. We identified mutations using Needlestack (Delhomme et al., in preparation; https://github.com/IARCbioinfo/needlestack), a pipeline specifically designed to accurately detect variants at very low allelic fractions (AF).

Results:
We detected TP53 mutations in the cfDNA of 49% of the SCLC patients (35.7% of the stage I-II). While statistically significant in cases versus controls (p-value=6x10[-9]), TP53 mutations were also detected in the cfDNA of 11.4% of the non-cancer controls, and these results were confirmed in the replication series (10.8%). The presence of TP53 mutations in controls was not correlated with age, smoking, or alcohol-intake status. There was a statistically significant difference between the mutational patterns found in cases versus controls (p-value=0.008): within controls the fraction of nonsense, indel, or splicing mutations was lower than in cases. The median AF of the TP53 mutations detected in the five stage I-II SCLC (0.9%) was not significantly different from that found in controls (1.2%; p-value=0.64), while it differed from the median AF of stage III-IV SCLC tumors (8.2%; p-value=2x10[-6]). Finally, we sequenced the DNA extracted from the white-blood cells (WBC) of 39 cfDNA TP53-positive patients, from which material was available (19 cases and 20 controls). Four cfDNA TP53 mutations (1 case and 3 controls) were detected in the WBC DNA, with similar AFs to those found in the cfDNA. These AFs, below 11%, are consistent with a somatic origin in both cfDNA and WBC DNA.

Conclusion:
The detection of TP53 mutations in 11% of the 225 non-cancer controls suggests that somatic mutations in cfDNA among individuals without any cancer diagnosis is a common occurrence, and poses serious challenges for the development of ctDNA screening tests for the early diagnosis of cancer (Fernandez-Cuesta, Perdomo, and Avogbe et al., EBioMedicine 2016). We will discuss these results as well as follow-up analyses in retrospective and prospective series.

Background:
Patients with extensive stage small cell lung cancer (ES-SCLC) who progress after frontline platinum-based chemotherapy are often considered “platinum-sensitive” (progression ≥ 90 days from last platinum dose) or “platinum-refractory” (progression < 90 days), as each group reportedly has differential overall survival (OS) outcomes. In a pooled analysis of recent SWOG trials of second and/or third-line targeted therapy, we showed that platinum-sensitivity status may no longer be as strongly associated with OS (Lara et al, JTO 2015). We assessed post-progression survival (PPS) following frontline platinum-based therapy in the context of platinum sensitivity status in ES-SCLC patients treated on SWOG 0124, a phase III trial of Irinotecan/Cisplatin vs Etoposide/Cisplatin.

Methods:
Data from 657 patients enrolled in S0124 were pooled. PPS was calculated as OS from the reported progression date. Crude PPS was evaluated according to platinum-sensitivity status. Hazard ratios (HRs) for PPS accounting for platinum-sensitivity and baseline clinical covariates (i.e., measured at the time of first line therapy) were calculated using single and multivariable Cox Proportional Hazard models. Baseline covariates were included in a logistic regression model to identify predictors of platinum-sensitivity. Recursive partitioning analysis (RPA) was performed to define prognostic risk groups.

Results:
Of 657 patients, 534 had a progression date and thus included in the analysis: 162 (25%) were platinum-sensitive and 372 (75%) refractory. Fewer patients with PS 0 (32% vs. 41%) and more patients with weight loss > 5% (40% vs. 31%) were seen in the refractory group. Crude unadjusted PPS was higher in platinum-sensitive vs refractory patients (median PPS 7.5 vs. 4.3 months; HR=1.64, p <0.001, 95%CI 1.356, 1.981). A multivariable Cox model showed that baseline elevated serum lactate dehydrogenase (LDH; HR=0.66, p<0.001) and platinum-sensitivity status (HR=1.54, p<0.001) were independently associated with PPS. None of the baseline covariates predicted for platinum-sensitivity. Prognostic groups with differential PPS based on platinum-sensitivity status, gender, and LDH were identified by RPA.

Conclusion:
PPS was significantly higher for S0124 patients categorized as platinum-sensitive vs. refractory. Limitations of this work include lack of relevant clinical data at the time of progression and number and type of post-progression therapies. These data have implications for the development of ES-SCLC trials in the salvage setting. [Supported by NIH/NCI/NCTN grants to SWOG: CA180888, CA180819, and in part by Pharmacia & Upjohn, a subsidiary of Pfizer. ClinicalTrials.gov Identifier: NCT00045162]

Background:
PARP1 is overexpressed in small cell lung cancer (SCLC) and represents a novel therapeutic target for this disease. Preclinical data indicates that combining veliparib (an oral PARP-1/2 inhibitor) and temozolomide (TMZ) results in synergistic tumor growth delay or regression. In this study, we investigated whether adding veliparib to TMZ would improve outcomes in patients with relapsed sensitive and refractory SCLCs. Candidate predictive biomarkers, including SLFN11, were then explored.

Methods:
SCLC patients previously treated with 1 or 2 prior regimens were enrolled in the trial and randomized 1:1 to receive oral TMZ 150-200mg/m[2]/day (D1-5) with either veliparib or placebo 40mg twice daily, orally (D1-7) (NCT01638546). Primary endpoint was 4-month progression free survival (PFS). Data were analyzed in patients with platinum sensitive (progression >60 days after 1st line therapy) or refractory disease (progression ≤60 days after 1st line therapy, or in need of 3rd line treatment). Archived tissue was available for 53 patients for biomarker analysis.

Results:
104 patients were enrolled and 100 patients were treated. Baseline characteristics were balanced between treatment arms: 52% female; median age 62.5 (range, 31-84); 59% refractory disease; 33% needing 3rd-line therapy. Progression free survival at 4-months was similar between the two arms, 36% vs. 27% (p=0.39). However, in 93 evaluable pts, response rate was significantly higher in pts treated with veliparib/TMZ compared to TMZ alone (39% vs 14%, p =0.016). Median overall survival: 8.2 mos (95% CI: 6.4-12.2) in veliparib arm and 7 mos (95% CI: 5.3-9.5) in placebo arm, p = 0.50. Grade 3/4 thrombocytopenia and neutropenia more commonly occurred in the veliparib/TMZ arm: 50% vs 9% and 31% vs 7%, respectively. Levels of SLFN11, a marker of SCLC response to PARP inhibition in preclinical models, were assessed by immunohistochemistry. High SLFN11 in patient tumors (obtained at original diagnosis) was associated with a trend towards better overall survival in the veliparib/TMZ arm, but no difference in outcome in the TMZ alone arm. Additional correlative studies are ongoing, including assessment of MGMT promoter methylation, and will be available at the time of presentation.

Conclusion:
The combination of veliparib/TMZ increased response rates significantly, compared to TMZ alone. Hematologic toxicities of the combination may have impacted PFS (which was not significantly different between the arms) by limiting dosing. Biomarkers such as SLFN11, ATM, or MGMT promoter methylation could potentially help guide patient selection in the SCLC population.

Abstract not provided

Background:
For patients with SCLC, response to chemotherapy is monitored by computed tomography (CT) scans, which can be costly and inconvenient. A previous study showed that baseline levels (>100 pg/ml) of the tumor marker, ProGRP, were positively correlated with advanced SCLC, and a decline in ProGRP levels during treatment was associated with response.[1] However, the best approach to fully exploit ProGRP for monitoring treatment response is still unknown. The objective of this study was to determine if progression could be ruled out solely by combining the changes in ProGRP levels over two chemotherapy cycles.

Methods:
Patients with SCLC receiving first-line platinum-based doublet chemotherapy or a single-agent cytotoxic in any subsequent treatment line were included from six centers in Europe and China. Samples were collected prospectively and ProGRP levels were measured in serum or plasma samples using a fully automated ProGRP assay at baseline and after chemotherapy cycles 1 and 2. Only patients with blood samples taken at these time points and with elevated baseline ProGRP >100 pg/ml were eligible for this analysis. A logistic regression model was calculated to incorporate changes after the first cycle (i.e. from baseline to the end of cycle 1) and in between cycles (i.e. end of cycle 1 to the end of cycle 2). Progression was ascertained with CT scans. A non-progressor was defined as a patient with complete response, partial response, or stable disease, according to the RECIST v1.1 or WHO criteria. Progressors were patients with progressive disease only.

Results:
Overall, 123 patients (n=108 non-progressors, n=15 progressors) satisfied the eligibility criteria. Median age was 62.0 years (range 36.0–83.0), 56% were male, and 78% reported to be current or past smokers. In this population, a decline in ProGRP from both baseline to cycle 1 and from cycle 1 to cycle 2 was associated with non-progression (AUC 91.5%; 95% CI: 85.3−97.8; sensitivity 100%; specificity 71%). All patients who experienced a >25% relative decline in ProGRP levels after the first chemotherapy cycle, followed by any further decrease (>0%) after the second cycle, were found to be non-progressors.

Conclusion:
By measuring the change in ProGRP levels at baseline and after each of the two subsequent chemotherapy cycles, we were able to identify patients with non-progressive disease. This might reduce the need for interim CT scans. References 1. Muley, et al. Journal of Thoracic Oncology 2015; 10(9) Supplement 2:MINI27.13

Background:
Small cell lung cancer (SCLC) that has progressed after 1[st] line therapy has few effective treatments and no new class of approved therapies in over 20 years. Paired tumor-normal exome and transcriptome sequencing efficiency, coverage, cost, and analytics has improved over the last decade and has begun to be applied in the clinic. In this prospective study, we used genome-wide strexome (exome+structural variation) plus whole transcriptome sequencing (NGS) to identify genomic events and associated expression changes in advanced SCLC and attempt to prescribe systemic therapy based on the results (NCT02297087, study was funded by SU2C).

Methods:
After informed consent a prospective fresh frozen tumor biopsy was obtained. Germline DNA was extracted from PBMC and reference normal tissue RNA was obtained commercially. Strexome and RNA-seq libraries were prepped and NGS, data analysis, and reporting were performed in a CLIA-certified CAP accredited environment.

Results:
The study completed its accrual goal of 12 evaluable patients. There was one screen failure due to anticipated inadequate sample yield because of tumor location. The cohort included 10 women, median age was 56.5 years and had 3 never smokers. All patients received prior platinum-based chemotherapy and were receiving >1[st] line systemic treatment while awaiting NGS results. The minimum tumor content for successful NGS was 20%. The median turnaround time from sample collection to report was 27 days (range 21-38). Average strexome coverage was 420X (tumor), 200X (germline), with an average of 277 million RNA reads generated for tumors. All patients had ³2 clinically actionable targets identified (associated with a commercially available, FDA-approved drug by predefined rules), median 4 targets (range 2-8). Three patients received treatment identified by NGS. One has continuing partial response by RECIST 1.1 >8 months on a clinical trial involving PD-1 inhibitor+irinotecan (MLH1 mutation); treatment linked to NGS was already initiated prior to the report becoming available. One is too early to evaluate on olaparib (PARP1 mutation), and one had disease progression on dasatinib (KIT overexpression) as best overall response. One patient has not yet received NGS recommended therapy, and the remaining 8 evaluable patients had clinical deterioration or died before NGS recommended therapy was initiated.

Conclusion:
SCLC after 1[st] line therapy tends to have more rapid progression and deterioration making NGS application for systemic therapy challenging. Either applying NGS earlier in the earlier stages of disease course or further improvements in turnaround time may better address these challenges.

Background:
Hippocampal avoidance (HA) during whole brain radiotherapy (WBRT) is performed to prevent neural stem-cell injury causing decreased neurocognitive function. Nevertheless, the estimated risk for metastases in HA area in small cell lung cancer (SCLC) patients is unknown. The current study aimed to characterize the metastatic distribution within the brain relative to the hippocampus and estimate the incidence of hippocampal metastasis in SCLC patients and also identify clinical and radiographic variables that may be associated with the presence of metastases within the HA area.

Methods:
SCLC patients treated with WBRT between January 2010 and December 2015 were reviewed. T1-wighted, post-contrast axial MRI (1.5 or 3 Tesla) images obtained just before therapeutic cranial irradiation were retrieved and reviewed for each patient. The HA area was generated by expanding the hippocampal contour by 5 mm volumetrically to account for necessary dose fall-off between the hippocampus (HP) and the whole brain planning target volume. Metastatic lesions within HP or HA area were defined as HP metastasis. HP metastasis rate was evaluated and characteristics of patients with HP metastasis were analyzed and compared to patients without HP metastasis.

Results:
54 patients evaluated with cranial MRI were enrolled. HP metastasis rate was 32% (17 patients). 4.4% of all metastases involved the HP and HA area (2.2% of metastases each) Figure 1. The most common location of metastasis was frontal lobe followed by cerebellum and temporal lobe. Having diabetes mellitus (OR: 12.1, 95% CI: 1.1-137.4, p=0.045) and being younger than 65 years of age (OR: 4.8, 95% CI: 1-23.2, p=0.049) were found to be independent risk factors for HP metastasis.



Conclusion:
HP metastasis might be more common in SCLC patients. Reducing the dose to the HP by HA-WBRT plan in SCLC may be risky for the development of HP metastasis compared with other malignant solid tumors.

Abstract not provided

Background:
The use of new, emerging techniques in the search of tailored patient therapies is rapidly becoming a reality. Here we describe the optimization and implementation of next generation sequencing for treatment predictive mutation screening in parallel with gene fusion status of ALK, RET and ROS1 in non-small cell lung cancer (NSCLC) patients.

Methods:
The Illumina TruSight tumor 26-gene NGS panel was validated in 81 clinical routine FFPE or cytology specimens and implemented in 533 diagnostic NSCLCs during one year of clinical analysis. In parallel, a RNA-based NanoString method was evaluated in 169 cases for gene fusion status of ALK, RET and ROS1.

Results:
We have successfully established a streamlined workflow with a 5-day turnaround time from specimen arrival to mutation report. The concordance in the validation cohort was 99% for comparable variants. In the 533 diagnostic samples, 1-2 variants were detected in 79% of the cases. Most frequently mutated genes included TP53, KRAS, EGFR, STK11, and BRAF, all with differences in mutational patterns between histological subgroups. The RNA-based NanoString assay was successfully established and validated. The success rate in the 169 cases was 80% and 10 gene fusions were found (five ALK fusions, three RET fusions and two ROS1 fusions) all in adenocarcinomas. Integration of mutation and gene fusion status revealed that 68% of adenocarcinomas, 13% of SqCCs and 56% of NSCLC-NOS harbored ≥1 actionable alteration ALK, RET, ROS1, EGFR, KRAS, PIK3CA, BRAF, NRAS, MAP2K1, ERBB2 or AKT1. Specifically, in 13.2% of the adenocarcinomas where no EGFR or ALK alteration was detected emerging targeted therapy may be considered in addition to the 15.3% of patients that was eligible for EGFR or ALK inhibitors. The corresponding proportions for SqCCs were 5.5% in addition to the 2.2%, and for NSCLC-NOS 2.5% in addition to the 11.2% eligible for EGFR or ALK inhibitors.

Conclusion:
Next generation sequencing in combination with the NanoString technology is time- and cost efficient in the diagnostic routine for treatment predictive mutation screening and gene fusion status detection. The techniques represent valuable tools for pinpointing patients eligible to standard targeted therapies in addition to new emerging therapies.

Background:
Our laboratory has a unique cohort of patients with pre-invasive lung squamous cell carcinoma (SqCC) lesions, within which there is a clear discrepancy between the prevalence of pre-invasive lesions and the incidence of lung cancer, suggesting that not all pre-invasive lesions progress to cancer. Using gene expression microarrays we identified 1846 genes significantly differentially expressed between progressive and regressive pre-invasive SqCC lesions. The macrophage metalloelastase MMP12 gene was found to be highly expressed in progressive lesions, and we hypothesised that it plays a role in epithelial-to-mesenchymal transition (EMT). Conversely, the actin binding protein LIM-domain only 7 (LMO7) gene was highly expressed in regressive lesions, and we postulated that it may be protective against EMT due to its role in the maintenance of epithelial architecture. Initial studies using three SqCC cell lines (A431, H357 and H376) with MMP12-shRNA knockdown showed a significant decrease in migration and invasion compared to non-silencing shRNA controls. LMO7-shRNA knockdown in HBECs was found to significantly increase migration. The aim of this study is to further characterise the function and signalling of MMP12 and LMO7 in lung SqCC development.

Methods:
Eight-week-old NOD/SCID mice were used for tumorigenesis experiments. A431 and H357 MMP12-shRNA knockdown and non-silencing shRNA cells were injected in a suspension of one million cells in a total of 200μl, subcutaneously in the right and left flank, respectively. Tumours were measured every 2–5 days. Adhesion assays were carried out to assess the roles of MMP12 knockdown or LMO7 overexpression on cell adhesion. Cell signalling mechanisms were assessed using western blotting, qPCR and immunostaining.

Results:
We observed that MMP12 knockdown decreases tumorigenicity in an immunocompromised mouse model. Both A431 and H357 MMP12 knockdown cells produced significantly smaller tumours compared with non-silencing shRNA cells. We found that MMP12 knockdown decreases cell adhesion, which is currently being further investigated along with effects on integrin signalling pathways. Levels of EMT markers were assessed in MMP12 knockdown and LMO7 overexpressing cells using qPCR, western blotting and immunostaining. Results indicate that higher MMP12 expression is associated with a mesenchymal phenotype, whereas higher LMO7 expression is associated with an epithelial phenotype.

Conclusion:
Our results suggest that MMP12 is a key driver of migration and invasion in SqCC and its high expression may contribute to EMT, whereas LMO7 is a putative tumour suppressor with a crucial role in maintaining epithelial cell architecture. MMP12 and LMO7 may be potential therapeutic markers for lung cancer at an early stage.

Abstract not provided

Background:
Patients with COPD and/or emphysema have an increased risk of non-small cell lung cancer (NSCLC). COPD and lung cancer are both characterised by increased oxidative stress associated with mitochondrial dysfunction. We hypothesise that mitochondrial dysfunction is a driving mechanism for the increased risk of NSCLC in COPD. We determined whether there is dysregulated expression of mitochondrial-related proteins in NSCLC arising in COPD, and if so, their clinical significance.

Methods:
To determine the clinical relevance of mitochondrial related gene expression, we examined a database containing transcriptomic data of more than 1, 000 human NSCLC samples and with survival outcomes (https://precog.stanford.edu/). Immunohistochemistry for PGAM5 and FUNDC1 was performed on cancer and background (‘normal’) tissue from lung cancer resections from non-smokers, healthy smokers (without COPD) and COPD/ emphysema patients. Protein expression was assessed using a semi-quantitative immunohistochemical scoring system (H score). Specific gene expression was further correlated with outcome in dataset GSE 72194, containing transcriptomic data of NSCLC cases and patient survival.

Results:
25 mitochondrial-related genes were linked to survival in NSCLC. Of those 25, we chose to study further the expression of PGAM5 and FUNDC1, which are regulators of mitochondrial degradation (mitophagy). In background lung tissue, PGAM5 and FUNDC1, only expressed in alveolar macrophages, were most highly expressed in COPD (H score: 180 ± 58 and 23 ± 9, respectively) compared to healthy smokers (146 ± 58 and 20 ± 8) and non-smokers (68 ± 48 and 3.3 ± 1.4) (p<0.05). In cancerous tissue, only the malignant epithelial cells and associated macrophages, at the periphery of the cancer, expressed PGAM5 and FUNDC1. PGAM5 was also expressed in pre-neoplastic epithelium (squamous dysplasia and carcinoma in situ). There was no difference in expression across the 3 groups, although the macrophages, at the edge of cancer, from COPD patients tended to show higher expression of PGAM5 and FUNDC1, compared to those from the other groups. When the expression of PGAM5 was compared with that of 50 known macrophage transcriptomic signatures within NSCLC samples, there was a positive correlation between PGAM5 and 9 macrophage signatures (r= 0.27 - 0.44, p<0.05), with one a determinant of patient survival.

Conclusion:
PGAM5 expression in pre-neoplastic tissue and NSCLC, but not in normal epithelium, suggests it plays a role in the transformation of malignant epithelial cells. PGAM5 and FUNDC1 may contribute to the pathogenesis of both COPD and NSCLC, possibly through mitophagic processes.

Background:
We and others have reported the prognostic impact of tumor spread through air spaces (STAS) in lung adenocarcinomas. The goal of this study is to investigate preoperative predicting factors for STAS and to determine whether STAS can be detected by intraoperative frozen section analysis.

Methods:
In a cohort of 874 patients with small (≤2cm) stage I adenocarcinoma (1995-2012), we reviewed preoperative computed tomography (CT) and positron emission tomography (PET) scans. According to the 2016 Fleischner Society’s criteria, radiological whole tumor size, consolidation size, as well as C/T ratio (consolidation/whole tumor diameter) were determined using thin slice (<3mm) CT scans where available (n=174). Clinico-radiological prediction of STAS was evaluated by logistic regression model. Using the frozen section slides with adequate adjacent lung parenchyma surrounding tumor without artifact (n=48), the presence of STAS was evaluated by five pathologists who are unaware of the radiological findings or the pathological information on permanent slides. The kappa statistic was calculated to measure the agreement between two pathologists.

Results:
In univariable model for predicting STAS, current smoker, larger consolidation tumor size, C/T ratio, and SUVmax were significant variables. In multivariable model, current smoker and C/T ratio were independent risk factors for the presence of STAS (p=0.027 and p<0.001, respectively; Table 1a). The sensitivity and the specificity of frozen section for prediction of STAS were 71% (95% confidence interval: 52-91%), 92.4% (81-100%) respectively, and the accuracy was 80% (71-89%). The kappa statistics were 0.40-0.74 (Table 1b) with 8/10 being moderate or substantial agreement.

Conclusion:
Smoking status and C/T ratio were independent predictors for the presence of STAS in patients with small lung adenocarcinomas. Frozen section prepared with adequate surrounding normal lung tissue may help identify STAS intraoperatively. Figure 1

Background:
Tumor spread through air spaces (STAS) is a recently recognized pattern of invasion in lung adenocarcinoma, however, the incidence of and prognostic importance of STAS have not yet been defined in squamous cell carcinoma (SCC).

Methods:
In a cohort of 445 patients with p-stage I-III lung SCC, cumulative incidence of recurrence and lung cancer-specific death (LCSD) was evaluated by competing risks analysis and overall survival (OS) by Cox models.

Results:
76% of patients were >65 years of age. 273 patients died during follow up, one third (91, 33.3%) died of lung cancer whereas two thirds died of competing events or unknown cause. STAS was present in 132 (30%). The cumulative incidence of any, distant, and locoregional recurrence as well as LCSD were significantly higher in patients with STAS compared to those without STAS (Figure), whereas there was no statistically significant difference in OS. STAS was an independent predictor for both recurrence and LCSD in multivariable analysis (p=0.034 and 0.016, respectively, Table).

Conclusion:
STAS was present in one third of resected lung SCC and it was an independent predictor of recurrence and LCSD, supporting our proposal that STAS is a clinically important pattern of invasion and not an artifact. Figure 1 Figure 2

Abstract not provided

Background:
In early-stage lung adenocarcinomas, high-grade micropapillary (MIP) and solid (SOL) predominant pathology is known to be associated with worse prognosis. The aim of this study is, in addition to predominant patterns, to investigate clinical impact of the presence of small amounts (≥5%) as well as increasing percentage of high-grade patterns.

Methods:
Invasive tumors from early-stage lung adenocarcinoma patients who underwent curative-intent resection with no induction therapy were investigated (N=2017; 1995-2012) (8[th] edition TNM pStage I=1390, II=357, III=270). In 388 cases, synchronous lymph node (LN) metastases were available. Histological subtype (lepidic [LEP], acinar [ACI], papillary [PAP], MIP, or SOL) percentages were stratified into 4 groups; 0-4%, 5-24%, 25-49%, and 50-100%. The association between increasing percentage of patterns of primary tumor and the incidence of lymphatic/vascular invasion, necrosis, tumor spread through air spaces (STAS) as well as estimated 5-year cumulative incidence of recurrence (CIR) were analyzed. The differences in distribution of each pathological variable between 4 groups was analyzed by Chi-square test. The percentages of histological pattern were compared between primary tumor and LN metastasis.

Results:
Increasing percentage of MIP pattern is associated with increasing incidence of lymphatic/vascular invasion, STAS, as well as 5-year CIR (Figure 1a, p<0.001). Increasing percentage of SOL pattern is associated with increasing incidence of necrosis and 5-year CIR (p<0.001). Presence (≥5%) of SOL pattern is associated with higher incidence of lymphatic/vascular invasion and STAS (p<0.001) compared to the absence (<5%) of SOL pattern, but no significant relationship between lymphatic/vascular invasion and proportion of SOL pattern. The percentage of SOL pattern in LN metastasis is higher than that in synchronous primary tumors (Figure 1b).

Conclusion:
In early-stage lung adenocarcinomas, presence (≥5%) of MIP or SOL patterns as well as increasing percentages is associated with poor prognostic clinicopathological variables and incidence of recurrence. Figure 1

Background:
Clinical significance of 2015 WHO classification histological subtype of early-stage lung adenocarcinoma (LADC) has been well documented; the incidence and significance of histological subtypes in autologous metastatic tumors is unknown.

Methods:
Histological subtyping was performed on paired primary and metastatic LADC tumor samples from patients who underwent resection of metastases (N=203, 1996-2012). 57 cases with inadequate tumor specimen and 4 cases diagnosed as local recurrence were excluded.

Results:
Location of metastatic sites were – brain 51 (35.9%), lung 48 (33.8%), lymph node 14 (9.9%), pleura 10 (7.0%), and adrenal gland 5 (3.5%). Metastatic tumors demonstrated more frequent solid histological pattern than primary tumors (first predominance: 51% vs. 24%; second predominance 29% vs. 17%, Figure 1). Among all histological subtypes, solid subtype showed the highest concordance between primary and metastatic tumors (Figure 2). In addition, analysis of all available clinicopathological factors showed significantly higher percentage of solid subtype in both primary and metastatic tumors was observed in patients with smoking history (p=0.003 and p=0.004, respectively).

Conclusion:
Analysis of a large cohort of primary and autologous metastatic LADC tumors demonstrated a higher percentage of solid histological pattern metastases, even in cancers with a low solid component in the primary site of disease. Figure 1Figure 2

Abstract not provided

Background:
The goal of this study is to investigate comprehensive comparative pathological analyses of both primary tumor and metastatic lymph node (LN) and correlate with lung cancer-specific death (LC-death) in patients with LN-positive lung adenocarcinoma.

Methods:
PN1/2 lung adenocarcinoma patients who underwent R0 resection without induction therapy (n=402, 2000-2012) were included in the study. In primary tumor, lymphatic/vascular/pleural invasion, necrosis, tumor spread through air spaces (STAS), as well as histologic subtypes according to 2015 WHO classification were evaluated. In metastatic LN, metastatic tumor size, extracapsular invasion, histologic subtypes were evaluated. Recurrence and LC-death were analyzed by Cox model.

Results:
Micropapillary and solid predominant subtypes were more frequent in LN metastases than in primary tumors (Figure). In multivariable analyses, adjuvant chemotherapy, pleural invasion, extracapsular invasion of LN metastasis, micropapillary predominant subtype in LN metastasis were independent factors for recurrence; adjuvant chemotherapy, pleural invasion, tumor STAS, and extracapsular invasion were for LC-death (Table).

Conclusion:
In lung adenocarcinoma lymph node metastases, predominant micropapillary pattern and extracapsular invasion indicate high risk for recurrence and lung cancer-specific death. Figure 1 Figure 2

Background:
No studies have reported any survival benefit in recurrent MPM. We examined the effect of nivolumab, in patients who presented with progressive disease and agreed to have biopsies taken before and during treatment.

Methods:
In this single center, phase II study, patients received nivolumab (3mg/kg q2w) until progression or toxicity. The primary endpoint was an improvement of disease control rate at 12 weeks of 20 to >40% compared to historic control according to a Simon two-stage design. A total of 33 patients were planned with paired biopsies at week -1 and 6 according to treatment start. PD-L1 status and other biomarkers were analyzed.

Results:
From 09-2015 until 06-2016, 38 patients were included with 33 having paired biopsies; 4 were not evaluable. There were no treatment related death and DCR at 12 weeks was 50%. Five patients had a confirmed PR; 12 had SD and 17 PD. Three patients showed pseudo-progression. Grade 3 toxicity occurred in 8 patients leading to discontinuation of the treatment in 4. The table shows the patients/tumor details. PD-L1 ≥1% was expressed in 9/32 evaluable patients with 2/9 having a confirmed PR at 12 weeks.

Conclusion:
Nivolumab in 2[nd] or later lines in recurrent MPM met the primary endpoint. The toxicity was mild and long lasting results were observed. A clear correlation between PD-L1 expression and response was obeserved.

	Outcome
Age	mean 66 yrs (51-81)
M/F	28 / 6
Epithelial/mixed/non epithelial	28 / 4 / 2
PR/SD/PD	5 / 12 / 17
PD-L1 + (1-10; 10-25; 25-50; >50%)	2 / 1 / 3 / 3
Correlation PR/SD/PD according to PD-L1 expression	<1% : 3/8/12 1 - 10% : 0/1/1 10-25% : 0/0/1 25-50% : 1/1/1 > 50% : 1/1/1
Correlation PR/SD/PD with histology	Epithelioid : 4/9/15 Mixed : 1/2/1 Non-epithelial : 0/1/1

Background:
Pembrolizumab showed significant activity in PD-L1+ MM in a phase IB study (Alley, 2015). We are conducting a phase II trial (NCT02399371) of pembrolizumab in previously-treated MM patients to further characterize its activity in a larger, non-selected population, determine a PD-L1 expression threshold, and interrogate the microenvironment.

Methods:
Eligible patients have histologically-confirmed pleural or peritoneal MM, measurable disease, PS 0-1, disease progression on/after pemetrexed/platinum, 1-2 prior regimens, normal organ function, and available tissue. Patients receive 200 mg pembrolizumab IV Q21 days and CT scans Q9 weeks. Primary objectives: 1) determine the objective response rate in: A] an unselected population and, B] a PD-L1 positive population; 2) determine the optimal threshold for PD-L1 expression using the 22C3 antibody-based IHC assay (Qualtek). Exploratory correlatives profile the inflammatory microenvironment via: a) multi-color immunofluorescence of tumor infiltrating lymphocytes (TILs) and macrophages, b) RNA-based inflammation signatures/pathway activation, c) characterizing underlying mutations/copy number changes. Proceeding to a 2[nd] stage requires ≥3 responses in 35 patients. If an optimal threshold for PD-L1 expression is determined, the 2[nd] stage only enrolls above that threshold.

Results:
35 patients enrolled 5/15-2/16. 1 withdrew. Male 82%; median age 63 (range 26-85); PS 0/1 63%/37%; epithelial/sarcomatoid/biphasic/NOS: 69%/26%/3%/3%; pleural/peritoneal 86%/14%; 1 prior regimen: 60%. Mean cycles: 8.5 (range 1-18). Median progression-free survival: 6.2 months (95% CI: 3.2, 8.2). Median overall survival has not been reached. Partial response: 7 (21%), stable disease (SD): 19 (56%); progression: 6 (18%); early death: 2 (6%). Ten patients received treatment beyond progression; 20% subsequently achieved SD. Grade 3/4 toxicity: pneumonitis 6%, fatigue 6%, adrenal insufficiency 6%, colitis 3%, confusion 3%, hyponatremia 3%, neutropenia 3%. Grade 1/2 immune-related toxicities: hypothyroidism 17%, rash 14%, pruritus 11%, diarrhea 9%, uveitis 6%, arthralgia 6%, hepatitis 3%, infusion reaction 3%, mucositis 3%. Grade 5 toxicities: autoimmune hepatitis 3%, unknown 3%. PD-L1 expression by tumor proportion score (N=31): none (< 1%): 55%; low (1%-49%): 19%; high (≥ 50%): 26%. PD-L1 expression did not correlate with response (ROC area 0.62; 95% CI: 0.32, 0.94).

Conclusion:
Pembrolizumab has robust activity in PD-L1 unselected, previously-treated MM patients, with a response rate of 21% and a disease control rate of 76%. An optimal PD-L1 threshold could not be established in this small sample. The 2nd stage is enrolling an additional 30 patients without PD-L1 pre-selection. Correlative studies including CD8 TILs, macrophage characterization, and presence of T-regulatory cells will be presented. Funded by a grant from the Mesothelioma Applied Research Foundation.

Background:
Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with poor prognosis and limited treatment options after progression on platinum-containing chemotherapy. Pembrolizumab, a humanized anti–programmed death 1 (PD-1) antibody, has demonstrated robust antitumor activity and a favorable safety profile in multiple tumor types. Here, we present long-term overall survival (OS) data for patients with malignant pleural mesothelioma enrolled in the KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) study.

Methods:
KEYNOTE-028 is a nonrandomized, multicohort phase 1b trial of pembrolizumab in patients with PD-L1–positive advanced solid tumors. 25 patients with MPM were treated with pembrolizumab in the mesothelioma cohort. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or intolerable toxicity, death, withdrawal of consent, or physician decision. Response was assessed per RECIST v1.1 by investigators every 8 weeks for the first 6 months and every 12 weeks thereafter. Primary end point was objective response rate (ORR; per RECIST v1.1, investigator assessed). Secondary end points included safety, tolerability, progression-free survival (PFS), and OS.

Results:
As of June 9, 2016, median duration of follow-up was 18.7 months (range, 1.5-24.6 months), and 4 patients (16%) are still on treatment. ORR was 28% (n = 7); 12 (48%) patients had stable disease, resulting in a disease control rate of 76%; median duration of response was 9.2 months (range, 2.4-20.5+ months); median PFS was 5.8 months (95% CI, 3.4-8.2 months), with 6- and 12-month PFS rates of 50% and 25%, respectively. Median OS was 18.0 months (95% CI, 9.4 months-not reached) with 6- and 12-month OS rates of 83.5% and 62.6%, respectively. No new safety signals have been identified. Sixteen (64%) patients experienced a drug-related adverse event (DRAE), and 5 (20%) experienced grade 3/4 DRAEs. Three patients required dose interruption because of immune-related adverse events (1 each, ALT increased, iridocyclitis, and pyrexia/arthralgia]). There was no treatment-related mortality or discontinuation due to DRAE.

Conclusion:
Single-agent pembrolizumab has significant clinical activity in patients with PD-L1–positive MPM. Responses from pembrolizumab in patients with MPM are durable; the 62.6% 12-month OS rate in this mostly pretreated patient population warrants further investigation. Long-term administration of pembrolizumab is feasible in patients with MPM, and no new safety signals were identified.

Abstract not provided

Background:
The genomic landscape of malignant pleural mesothelioma (MPM) is not well understood. Advanced high-throughput sequencing technologies allow comprehensive characterization of genetic alterations. Knowledge of the somatic mutations and the immune microenvironment in patients with MPM will help to develop effective targeted therapies.

Methods:
We examined biopsy specimens from 12 MPM patients (8 epithelioid and 4 biphasic) that were removed during maximal cyto-reductive surgery. Specimens from 3 different sites (anterior, posterior and diaphragm, a total of 36 tissue samples) were studied through whole exome sequencing, T cell receptor (TCR) repertoire analysis of tumor-infiltrating T cells (TILs), and expression levels of immune-related genes. We also performed in silico prediction of potent neoantigens derived from non-synonymous somatic mutations in each specimen. For the comparison of tumor tissues from 3 different sites, we performed hierarchical clustering to assess the tumor heterogeneity and differences in immune environment.

Results:
High mutation/neoantigen load was significantly correlated with higher clonal expansion of TILs (R=0.46) and high expression levels of immune-associated cytolytic factors, granzyme A (R=0.25) and perforin 1 (R=0.48), in tumor tissues. In the clustering analysis, heterogeneous MPM cases revealed unique neoantigens and clonotypes of TILs that were restricted to each of tumor site, suggesting infiltration of the neoantigen-specific T cells. Further sub-analysis according to histologic types showed that biphasic tumors had higher mutation/neoantigen load and stronger oligo-clonal T cell expansion (p=0.01) than epithelioid tumors.

Conclusion:
Our analysis demonstrated a significant correlation between somatic mutation/neoantigen load, clonality of TILs, and the immune-related tumor microenvironment in MPM. Our findings suggest that high mutation/neoantigen load in tumor cells might promote effective expansion and infiltration of functional (tumorocidal) T cells into the tumor bed. These findings provide a rationale for selecting MPM patients who can benefit from treatment with immune checkpoint blockades. This may accelerate development of the neoantigen targeting TCR-engineered T cell therapy for MPM.

Background:
Mesothelioma is an aggressive malignancy without curative treatment options. We have previously shown promising activity of dendritic cell (DC) immunotherapy loaded with autologous tumor cell lysate (Hegmans 2013, Cornelissen 2016). Because of quality and quantity issues (availability, standardization etc) with the autologous lysate, we have developed an off-the-shelf allogenic tumor cell lysate from human mesothelioma cell lines (Pheralys.[®]).

Methods:
Patients (pts) with advanced mesothelioma, either treatment naive, or non-progressing after chemotherapy, were included. Leucapheresis was performed to obtain an enriched monocyte fraction from which immature DC were generated which were loaded with the allogenic lysate. The DC were matured, frozen and stored. In subsequent cohorts of 3 pts 10, 25, or 50 × 10[6 ]DC were administered IV and intradermally, 3 times at a bi-weekly interval and after 3 and 6 months. Primary endpoint was toxicity occurring within 8 weeks after the first vaccination. Secondary endpoints were response rate (RR), progression free survival (PFS) and overall survival (OS). PFS and OS were determined from time of registration in the trial. Immunological read-outs were performed (DTH skin testing, peripheral blood testing).

Results:
Nine pts (median age 69yrs, 8 male, 1 female) were included. All patients developed transient grade 1-fever and a grade 1-2 injection site reaction. No dose limiting toxicities or autoimmunity signs were observed. In 2 pts (22%), both treated with 25 ×10[6] cells, a partial response (PR) was observed, the other 7 pts had stable disease as best overall response. All patients are alive with a median follow up of 11.9 months after trial inclusion(range 7.6-16.5 months). Median PFS was 8.3 months (95% confidence interval (CI) 3.7-not yet reached), PFS at 12 months was 33% (95% CI 8%-62%). Data on immunological read outs are pending.

Conclusion:
DC immunotherapy with allogenic tumor cell lysate is safe and clinically active. Data on PFS and OS are promising and still maturing. The recommended dose for future studies will be 25 * 10[6] cells based on the responses and logistic reasons (the number of monocytes obtained during leucapheresis to generate 5 vaccinations). A randomized trial comparing DC therapy with Pheralys versus best supportive care as maintenance treatment after chemotherapy is planned to start in Q1 2017.

Background:
Malignant pleural mesothelioma (MM) remains an almost universally fatal disease with limited treatment options. Preclinical models indicate the preferential oncolytic activity of the modified vaccine strain measles virus carrying the gene for the human sodium-iodine symporter (NIS) – MV-NIS. Intraperitoneal and intravenous administration of MV-NIS was recently found to be potentially effective in patients with refractory ovarian cancer and multiple myeloma. However, whether MV-NIS is directly oncolytic or triggers an anti-tumor immune response remains unclear.

Methods:
We conducted a phase I dose escalation study with 3+3 design and ongoing maximal tolerated dose (MTD) expansion cohort. MV-NIS was administered as first or second line therapy via a tunneled intrapleural catheter to patients with MM. MV-NIS dose ranged from 10[8] TICID~50~ to 9 x 10[9] TICID~50~. In the absence of dose limiting toxicity and disease progression, patients received up to 6 cycles of MV-NIS therapy (Phase I). Currently additional patients are being randomized between a single and multiple cycles. MV-NIS infection and replication are monitored by Iodine[123] SPECT/CT (Phase I only) as well as by RT-PCR and/or plaque-assay. Anti-tumor immunity is monitored in the blood and pleural fluid and patients are followed clinically by chest CT using the modified RECIST criteria.

Results:
Twelve patients (3/dose level) received MV-NIS therapy. There were no dose limiting adverse events and therapy was well tolerated. The best therapeutic response was stable disease, which was achieved at 1 month by 8/12 evaluable patients (67%). Median overall survival was 449 days (95%CI: 221, 484) (~15 months) (4/12 patients remain alive), and median progression free survival was 63 days (95% CI: 33, 174) (~2 months). MV infection and replication were detectable by RT-PCR and plaque assay in the pleural fluid between 24-72 hours after treatment. I[123] SPECT-CT demonstrated only marginal viral gene expression in a single patient treated with the highest dose level. MV-NIS therapy effectively boosted pre-existing anti-MV neutralizing antibody responses in the plasma and pleural fluid of most patients. We observed a transient inflammatory response in the pleural space after MV-NIS administration. In addition, induction or boosting of anti-tumor antibody responses was observed.

Conclusion:
The intrapleural administration of MV-NIS is safe, resulted in stable disease for 67% of patients and may be associated with favorable overall survival in MM. While there was only transient infection and viral replication, we observed the induction of anti-tumor immune responses supportive of potential long-term therapeutic impact. The study continues with the MTD expansion cohort.

Abstract not provided