Virtual Library

Abstract:
Human being is mortal. However, people don’t want to think about death and prefer to live without considering it. Death has actually been hated in society. In general, death is thought as LOSS. Indeed, healthy body, time as a gift of life, society meaning, several experience, all achievements including money, house, family, friends, status and honor are LOST at death. In medicine which prolongation of life has been a primary purpose, death is considered as defeat. However, if we consider death as loss or defeat, theoretically goal of life itself would be futile definitely toward loss and defeat. “Human beings, who are all mortal and their own deaths are inevitable, seriously think, worry, are embarrassed and hate when they encounter death of other person. They think that death is not appropriate for them.” Gautama Buddha who was born in India 5[th] century BC thought as above, tried to find the cause of death throes and search for how to deal with terror of death throes. Teaching of Buddha from India was introduced to China in where that was developed as ZEN. Teaching of ZEN has been growing calls in the world. ZEN stresses the importance of staring DEATH. In other words, that is to learn how to live responding enough to DEATH as inquiry. It is never to pursue a world after death, just to actively find meaning of life through staring death. We would like to learn how to live while reacting DEATH that tends to evade in modern society, through historical teaching of ZEN. アジアにおける精神性 ー死から勉強するー 人は誰しも死を逃れることはできない。それにも拘わらず、人は死を見つめようとはしていない。できれば死を忘れて暮らしたいと思っている。実に死は、現代社会においても忌み嫌われていると言えよう。 一般に、死は「喪失」であると思われている。たしかに健康な肉体も、人生において与えられた時間も、社会における存在意義も、さまざまな体験も、手に入れたものすべて、貯めたお金や家、家族、友人や恋人、地位名誉などを「喪失」してしまう。 また生命を一日でも長く生かすことを考える医療において、死は「敗北」と認識されている。しかし、もしも死が「喪失」や「敗北」でしかないとしたならば、人生は「喪失」と「敗北」に向かって確実に進んでゆく空しいものとなるであろう。 「愚かな人間は、自分が死ぬものであって、また死を免れないのに、他人が死んだのを見ると、考え込んでしまい、悩み、恥じ、嫌悪している。じつは自分もまた死ぬものであって、死を免れないのに、他人が死んだのを見ては、考えこんで、悩み、恥じ、嫌悪する。このようなことは自分にはふさわしくないであろう」。 このように考えて、死の苦しみの原因を求め、死の恐怖や苦しみから如何に逃れることができるか、その道を求めたのが、紀元前五世紀にインドに生まれた、ゴータマ・ブッダであった。 ブッダの教えは、インドから中国に伝わり、中国においては「禅」という道に発展していった。「禅」の教えは、今日においても広く世界で求められている。 「禅」においては、「死」を見つめることを大切に説いている。死を問いとして、それに応えるに足る生き方を学んでいると言ってよい。それは決して死後の世界の探求ではない。あくまでも死を見つめて、積極的に生の意味を見いだすことを目指している。 現代においても、ともすれば忌避されがちな「死」について、古来の「禅」の教えを参照しつつ、「死」をどう受け止めて生きるかを学んでみたい。

Abstract:
The Buddhist traditions are rich in meditation practices, utilizing them for their spiritual development as a tool towards enlightenment, and also for physical, emotional and mental wellbeing. For centuries, these practices were only for a select group of yogis in caves or nuns and monks in monasteries, but globalization and other movements of the Twentieth century helped bring these practices to a wider population, including people with illnesses such as cancer. This presentation will focus on how some of the philosophical Buddhist concepts, like the understanding of our own mortality or impermanence, and some of the meditation practices had been applied in a non-religious way as part of the offerings for cancer patients and their caregivers within contemporary western clinical settings in our Integrative Medicine Center at MD Anderson Cancer Center in Houston. George Engel’s seminal 1977 paper in Science provides the background for a bio-psycho-social approach at our Integrative Medicine Center that is now part of the Department of Palliative, Rehabilitation and Integrative Medicine at MD Anderson. In other words, a healing focused not just on the physical (i.e., bio) but also on the psycho-social-spiritual aspects of the person, which sometimes seems to be forgotten in conventional allopathic medicine. The bio-psycho-social approach is very much in accordance to the Buddhist approach, and palliative care and integrative medicine are optimal settings. I will share how we bring these into our group classes as well as individual clinic sessions, where people with different kinds of cancers, including lung cancer, participate. In particular I will address cases of people with lung cancer, and issues of stigma, of facing one’s own mortality, and how the concepts and practices that stem from a Buddhist perspective can have positive impact in their quality of life, overall survival, and better relationship to others, in particular their family members and caregivers. In addition I will share the results of a single arm clinical study of Tibetan Yoga (meditation and simple movements) for people with lung cancer and their caregivers that was held at MD Anderson Cancer Center in collaboration with the Ligmincha Texas Center for the Tibetan Meditative and Healing Arts. The purpose of this study was to establish feasibility and preliminary efficacy of a mind-body intervention in lung cancer patients and caregivers. Patients with stage I-III non-small cell lung cancer undergoing radiotherapy and their family caregiver participated in a 15-session Tibetan Yoga (TY) program that included breathing exercises, guided visualizations, and gentle movements. This single-arm trial assessed pre/post intervention levels of mental health (CESD; BSI), fatigue (BFI), sleep disturbances (PSQI), spiritual well-being (FACT-SP) and overall QOL (SF-36). Patients (mean age: 73 yrs., 62% male, 85% stage III) and caregivers (mean age: 65 yrs., 73% female, 85% spouses) completed a mean of 12 TY sessions (range: 6-15) and 95.5% of them rated the program as useful or very useful. Paired t-tests revealed a significant increase in spiritual well-being (P=.03; d=1.12) for patients and decrease in fatigue (P=.03; d=.87) and anxiety (P=.04; d=.91) for caregivers. This first couple-based Tibetan yoga program appears to be a safe, feasible, acceptable and subjectively useful supportive care strategy for patients and their caregivers. Based on these promising preliminary findings regarding treatment gains, the next step is to conduct a randomized controlled pilot trial. Furthermore, based on this and other Tibetan meditation and Tibetan yoga studies with other cancer populations (namely, lymphoma and women with breast cancer), we have incorporated this as a new class of Tibetan meditation and movement as part of our free offerings for people with cancer and their caregivers in our Integrative Medicine Center.

Abstract:
This paper discusses the prevalence of burnout in oncology settings and strategies that can be implemented at both an individual and organizational level to maintain and create a healthy workforce. Background Lung cancer is the leading cause of death by cancer for both men and women worldwide. Most lung cancers are diagnosed at advanced stage and approximately 16% of lung cancer patients will be alive five years post-diagnosis [1]. Working in lung cancer can be gratifying and very rewarding; however it requires high levels of emotional engagement. Oncology professionals work intensively with patients, they provide sophisticated treatments, emotional support, and comfort to patients and their family across the cancer trajectory [2]. Burnout, which refers to feeling emotionally and physically exhausted is common in oncology settings. In a random sample of 1000 US oncologists, 56% experienced burnout at some point in their career [3]. In an Australian sample, 33% of staff with direct patient contact and 27% of staff with non-direct patient contact displayed high levels of emotional exhaustion [4]. Oncology staff who are younger, female, isolated and who work longer hours are more likely to experience burnout [5]. Predictors of stress and burnout include increased work demands, staff shortages, lack of communication training, lack of control or autonomy and dissatisfaction with leave arrangements [6]. Burnout has serious consequences for oncology professionals including elevated rates of mental and physical health concerns, suicidal ideation, difficulties sleeping, frequent bouts of illness, and addiction, intimacy and relationships problems. As a result, patient care is often compromised due to increased errors, turnover and absenteeism and reduced empathetic care. Assessment and strategies to combat burnout A number of tools can assist in better understanding levels of burnout in oncology staff. The most frequently used tool to determine rates of burnout is the Maslach Burnout Inventory (MBI-HSS). The MBI-HSS is a 22-item self-report questionnaire. It measures three distinct dimensions of burnout: (1) emotional exhaustion (EE) characterised by feeling emotionally overextended; (2) depersonalisation, which includes feeling disconnected, detached; and (3) personal accomplishment, the negative judgements one makes about their career and levels of success [7]. Assessing burnout can lead to early identification and interventions for stress management. To reduce burnout, both individual and organisational factors need to be implemented. Developing personal resilience is essential for combating stress and burnout. A number of individual strategies that can assist in developing and maintaining resilience, include creating a work-life balance and adopting self-care and relaxation routines [8]. At an organisational level, coping can be enhanced by the provision of supports such as supervision, professional development opportunities, and the development of work schedules that promote team engagement and address staff shortages and adequate leave arrangements. Furthermore, formal education on how to better manage stress, including mindfulness-based stress reduction, cognitive behaviour therapy and communication training interventions can improve stress management and staff wellbeing [8]. Conclusion Working in oncology can be very rewarding, but can also be emotionally and physically exhausting. The workforce is the most important resource in any organization and burnout needs to be addressed both at the individual and organisational level. At an individual level, oncology professionals need to acknowledge stress, create a work-life balance and adopt self-care and relaxation practices. To maintain a healthy workforce, organizations need to ensure adequate staffing, leave arrangements and provide access to appropriate training, professional and emotional supports. References 1. Cancer Australia. Lung cancer statistics: Australian Govenrment; 2017 2. Diggens J, Chesson T. Do factors of emotion-focussed patient care and communication impact job stress, satisfaction and burnout in radiation therapists? Journal of Radiotherapy in Practice 2014;13(1):4-17. doi: 10.1017/S146039691300006X 3. Whippen DA, Canellos GP. Burnout syndrome in the practice of oncology: results of a random survey of 1,000 oncologists. Journal Of Clinical Oncology: Official Journal Of The American Society Of Clinical Oncology 1991;9(10):1916-20. 4. Girgis A, Hansen V, Goldstein D. Are Australian oncology health professionals burning out? A view from the trenches. European Journal Of Cancer (Oxford, England: 1990) 2009;45(3):393-99. doi: 10.1016/j.ejca.2008.09.029 5. Kamal AH, Bull JH, Wolf SP, et al. Prevalence and Predictors of Burnout Among Hospice and Palliative Care Clinicians in the U.S. Journal Of Pain And Symptom Management 2016;51(4):690-96. doi: 10.1016/j.jpainsymman.2015.10.020 6. Isikhan V, Comez T, Danis MZ. Job stress and coping strategies in health care professionals working with cancer patients. European Journal Of Oncology Nursing: The Official Journal Of European Oncology Nursing Society 2004;8(3):234-44. 7. Maslach C, Jackson S E, P. LM. Maslach Burnout Inventory Manual, 3rd edition. Mountain View, CA: CPP Inc, 1 1996:1–52. 8. Gillman L, Adams J, Kovac R, et al. Strategies to promote coping and resilience in oncology and palliative care nurses caring for adult patients with malignancy: a comprehensive systematic review. JBI Database Of Systematic Reviews And Implementation Reports 2015;13(5):131-204. doi: 10.11124/jbisrir-2015-1898

Abstract not provided

Abstract not provided

Abstract:
Global tobacco control is like a gigantic cake, with innumerable slices dedicated to different tobacco control initiatives in different parts of the world. Each slice is vitally important, responsible for advancing our collective cause just that bit further. Each slice is in fact essential as the magnitude of the task simply demands a multitude of efforts and the complexity of the task – not knowing where or when the next breakthrough will occur (or where or when it will be halted due to tobacco industry interference) means that we need to simultaneously commit to a broad range of strategies. Up until a few years ago, there was, however, one slice missing - the slice that involved the finance sector. Never before had the global finance sector, and its almighty power, been leveraged in tobacco control efforts. In fact business as usual for the finance sector saw it working against every other slice of the cake. This situation was largely unintentional, simply a result of ‘doing things the way they had always been done’. Most pension funds invest in tobacco companies. Most banks lend them money. It’s been like that for about a hundred years. Professionally engaging with global finance leaders, asking them to learn about the tobacco epidemic and to reconsider commercial relationships with the tobacco industry, has seen significant changes implemented in the business models of banks, insurers, pension funds and fund managers. Since Tobacco Free Portfolios began in 2012, approximately USD $6 billion has been shifted from investment in the tobacco industry by financial institutions in ten different countries. Several banks have ceased lending money to tobacco companies and several insurers have ceased providing insurance. There is increasing acknowledgement of the significant reputational risk faced by financial organisations if they continue to maintain links with tobacco companies – companies that make products that kill two out of three of their best customers. To proceed with a tobacco-free investment decision, many conditions need to be in place. An open door to the CEOs office; willingness to consider the issue and to learn about something that sits outside the traditional paradigm of the finance sector; a country where public support of tobacco control is strong - where there is awareness of the cost-burden of tobacco, and understanding of the future financial risks associated with tobacco companies, spanning regulation, litigation and scrutiny of supply chains. Some individual finance leaders are more open to the tobacco-free conversation than others but interest is growing rapidly. Tobacco Free Portfolios is working towards a world where the global finance sector is aligned with the global health and governments sectors on tobacco. Our vision is for tobacco-free investment to be the baseline expected standard. With a forecast of one billion tobacco-related deaths this century, tobacco is a problem so profound that it cannot be adequately addressed unless every sector of society contributes to the solution. The changes witnessed in recent years are hopefully the start of a new frontier in truly comprehensive global tobacco control.

Background:
AURA3 (NCT02151981) showed osimertinib, a third-generation EGFR-TKI, significantly prolongs progression‑free survival and improves response rate vs platinum‑pemetrexed in patients with T790M-positive advanced NSCLC, whose tumors had progressed on first-line EGFR-TKI therapy. Using patient baseline samples, we report concordance between plasma circulating tumor DNA (ctDNA) and tissue for the detection of EGFR mutations (T790M, exon 19 deletions [Ex19Del], L858R) using three distinct plasma detection technologies.

Method:
Tumor tissue biopsy samples were taken following progression on first-line EGFR‑TKI treatment. Baseline central confirmation of EGFR mutation status was by cobas[®] EGFR Mutation Test (Roche Molecular Systems). Where possible, baseline blood samples for plasma ctDNA screening were collected from patients in the osimertinib treatment group and analyzed using allele specific (AS)‑PCR (cobas[®] EGFR Mutation Test v2), ddPCR (Biodesix) and next generation sequencing (NGS, Guardant Health).

Result:
Figure 1 ctDNA was undetectable (negative for all three EGFR mutations [T790M, Ex19Del, L858R]) in 51/228 (22%) patients by AS-PCR, 58/211 (27%) by ddPCR, and 54/230 (23%) by NGS. Robust correlations (Spearman’s Rank) were observed for EGFR mutant allelic fractions (AFs) between ddPCR and NGS assays: T790M R[2] 0.9129 (n=201), Ex19Del R[2] 0.9384 (n=201), L858R R[2] 0.8090 (n=200). Discordant results between ddPCR and NGS were observed in 24/201 (12%) samples for T790M, 17/201 (8%) Ex19Del and 11/200 (6%) L858R. All discordant samples had AFs ≤1% by both assays.



Conclusion:
Using cobas tissue test as a reference, sensitivity for the detection of plasma T790M appeared higher for ddPCR and NGS assays compared with AS-PCR. Robust correlations were observed between quantitative ddPCR and NGS assays for determination of AFs across all three mutations. About 25% of AURA3 patients did not appear to shed ctDNA, as evidenced by absence of all three EGFR mutations across the three platforms.

Background:
Leptomeningeal metastases (LM) are more frequent in non-small cell lung cancer (NSCLC) with EGFR mutations. Resistance mechanisms of LM remained unclear due to limited access to leptomeningeal lesions.

Method:
Primary tumor, cerebrospinal fluid (CSF) and plasma in patients with suspected LM of NSCLC were tested by Next-Generation Sequencing with 168 genes panel. Thirty patients diagnosed as LM and harboring EGFR mutation were enrolled in this cohort, and CSF cfDNA and plasma of two patients and CSF precipitates of another two patients were not available

Result:
Driver genes were detected in 100% (28/28) , 85.7% (24/28) and 75% (21/28) patients of CSF cfDNA, CSF precipitates and plasma, respectively; and 92.9% (26/28) patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA when compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were privately detected in CSF cfDNA, and CNVs in patients after TKI failure were more complicated when compared to those TKI naïve before LM. MET copy number gain identified in 44.0% (11/25) patients was the most frequent one, other CNVs included ERBB2, KRAS, ALK, MYC and FGFR1. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 67.9% (19/28) CSF cfDNA, which was much higher than that in plasma (2/28, 7.1%; p<0.001), and there was a trend towards higher rate of concomitant resistance mutations in patients with TP53 LOH than those without one (70.6% vs. 25%; p=0.036 ). EGFR T790M was identified in 28% (7/25) patients with progression to TKIs in CSF cfDNA.

Conclusion:
CSF cfDNA could reveal the unique genetic profiles of LM, and it should be the most representative medium of liquid biopsy for LM in NSCLC harboring EGFR mutations.

Background:
Liquid biopsy for plasma circulating tumor DNA (ctDNA) next generation sequencing (NGS) is now commercially available and increasingly adopted in clinical practice with a paucity of evidence based guidance. We set out to prospectively determine the utility of plasma ctDNA NGS in the lung cancer clinic.

Method:
Patients (pts) with advanced NSCLC who were driver unknown or resistance mechanism unknown were eligible. Pts were enrolled prospectively at Memorial Sloan Kettering (NY, USA) and Northern Cancer Institute (Sydney, Australia). Peripheral blood was collected in Streck tubes (10-20mL) and sent to Resolution Bioscience (Bellevue, WA) for targeted NGS of extracted DNA using a bias corrected hybrid capture 21 gene assay in a CLIA laboratory with unique reads at 3000x and sensitive detection at variant allele frequency above 0.1%. Clinical endpoints included detection of oncogenic drivers, turnaround time, comparison to tissue NGS when available, and ability to match pts to targeted therapy along with their treatment outcomes.

Result:
Seventy-six pts were prospectively accrued. Plasma NGS detected an oncogenic driver in 36% (27/76) of pts, of whom 14% (11/76) were matched to targeted therapy; including pts matched to clinical trials for HER2 exon 20 insYVMA, BRAF L597Q and MET exon14. Of the 10 evaluable pts, 10 partial responses were observed. Mean turnaround time for plasma was 6 days (3-12) vs 21 days (16-30) for tissue (P <0.0001). Plasma ctDNA was detected in 60% (46/76) of pts; detection rate was 46% (16/35) if blood was drawn on active therapy and 73% (30/41) if drawn off therapy, either at diagnosis or progression (Odds ratio 0.31, 95% CI 0.12 – 0.81; P=0.02). Of the 25 concurrent tissue NGS performed to date, there was a 96% plasma concordance with tissue and a 60% tissue concordance with plasma for driver mutations.

Conclusion:
In pts who were driver or resistance mechanism unknown, plasma NGS identified a variety of oncogenic drivers with significantly shorter turnaround time compared to tissue NGS, and matched patients onto targeted therapy with clinical benefit. Plasma ctDNA is best detected at diagnosis of metastatic disease or at progression. A positive finding of an oncogenic driver in plasma is highly specific and can immediately guide treatment, but a negative finding may still require tissue biopsy. Our findings provide evidence to support the incorporation of plasma NGS into practice guidelines.

Abstract not provided

Background:
Molecular characterization of tumor can guide the choice of therapy for NSCLC patients. However, tumors are complicated by spatial heterogeneity and sometimes may not be of sufficient quality and quantity for analysis. NGS using plasma cell-free DNA (cfDNA) input may capture temporal and spatial heterogeneity, and enable genomic profiling in patients without adequate available tumor tissue. Targeted gene panels allow for robust detection of known oncogenic drivers, but may not be comprehensive enough to screen for novel biomarkers or mechanisms of acquired resistance. Whole exome sequencing (WES) allows for hypothesis-free biomarker discovery, but may be technically challenging in the setting of limited tumor-derived DNA content in plasma cfDNA. In this study, we aim to develop a workflow to guide the selection of samples for targeted and whole exome sequencing for noninvasive molecular profiling.

Method:
Plasma samples were collected from 20 NSCLC patients receiving a variety of treatment (chemotherapy, targeted therapy, or immunotherapy). Most patients (>70%) had stage III or IV disease at the time of plasma collection. CfDNA was extracted from 3 mL of plasma, and analyzed using low-pass shallow whole genome sequencing (sWGS) and MSK-IMPACT, a hybridization capture-based assay targeting over 400 cancer-related genes. Analysis of matched normal was performed for somatic variant calling.

Result:
Median cfDNA yield per plasma sample was 28ng (range 7 - 236ng). We applied z-score statistics to estimate the levels of tumor-derived mutant allele fractions in cfDNA based on sWGS data. We trained the algorithm using a separate cohort of cfDNA data from >100 patients with metastatic solid tumors to classify samples by mutant allele fraction (MAF) as either low (<5% MAF) or high (>5% MAF) tumor-derived DNA. In the subset of 10 patients with unknown drivers, two were estimated to have MAF >5% in cfDNA, and WES recapture was performed. MSK-IMPACT targeted sequencing identified actionable alterations in a subset of patients who did not have sufficient materials for tissue profiling. WES in cases with high tumor-derived DNA content by sWGS identified alterations in genes outside of the MSK-IMPACT panel.

Conclusion:
Molecular profiling using cfDNA is feasible in lung cancer and may identify actionable alterations to inform treatment decisions in patients without sufficient tissue for molecular characterization. The application of sWGS to estimate the levels of tumor-derived mutant allele fractions in plasma cfDNA samples may help guide selection of the optimal downstream sequencing strategy.

Background:
Circulating tumor DNA (ctDNA) sequencing and analysis has the potential to transform clinical management of patients with advanced NSCLC. Non-invasive sampling of blood draws at different time points during treatment could potentially be used for routine monitoring of disease progression and detection of therapy resistant mutations by using next generation sequencing (NGS).

Method:
448 longitudinal plasma samples (mean 6.3 per subject) collected from 71 subjects with advanced NSCLC during 1[st] line treatment were analyzed by NGS. Of these 71 subjects, 47 also had matched baseline tumor tissue samples. The AVENIO ctDNA Surveillance kit and AVENIO FFPET Analysis kit (RUO, Roche, Pleasanton, CA, USA) were used for sequencing analysis. The Surveillance kit contains 17 cancer driver genes and additional 180 frequently mutated genes mainly selected for NSCLC and colorectal cancer. This kit is capable of detecting four mutation classes: SNVs, fusions, CNVs and InDels. CT images were reviewed centrally using RECIST v1.1.

Result:
Somatic, disease-associated mutations were detected with allele frequency (AF) of >5% in 94% of baseline tumor samples (44/47), and in 100% of plasma samples with AF in ctDNA ranging from ≥0.5% to ≤30%. The most commonly mutated genes in tumors were TP53 (22/47 subjects), KRAS (14/47), BRAF (7/47), STK11 (5/47), and ERBB2 (5/47). Tracking the AF’s of key tumor mutations by the Surveillance panel in the paired longitudinal plasma samples allowed the monitoring of treatment response at the molecular level. We identified a number of subjects in which the AF of cfDNA mutations increased three to four months before clinical evidence of progression of disease detected by CT scans that were centrally reviewed according to RECIST v1.1. Cases were also observed where the AF’s of key mutations decreased in 1[st] line chemotherapy to nearly zero which correlated with clinical partial response and stable disease. . Additionally, first post treatment plasma samples collected during first line treatment showed a difference of 96 days in median survival times of ctDNA- vs ctDNA+ groups (logrank p value =0.0371).

Conclusion:
ctDNA testing with molecular bar coded duplex sequencing and digital background error suppression of a large 197 gene panel offers high sensitivity for tumor variant detection. The study demonstrated that the presence of tumor variants detected in blood at the beginning and end of 1[st] line treatment is a risk factor for early disease progression. Longitudinal mutation monitoring has the potential to predict disease progression earlier than regular CT imaging.

Background:
The detection of driver gene mutation based on tumor tissue can instruct target therapy and conduct molecular monitoring after drug-resistance in advanced NSCLC, but many patients have no access to this kind of test because of inadequate tumor tissue or inability to tolerate the invasive test. Some studies have explored the value of EGFR mutation test in body fluids such as plasma，urine and sputum from NSCLC patients. But the sensitivity based on individual liquid specimen is poor compared with gold standard---tissue. We detect multi-genes in multi-liquid samples in parallel to investigate the Consistency and complementarity of genetic profile in different liquid samples and it’s correlation with efficacy of the real world therapy in advanced NSCLC.

Method:
The patients newly diagnosed with NSCLC and first-generation EGFR-TKI acquired drug-resistance were enrolled into our research (NCT:02778854) prospectively, the pre-treatment samples including tumor tissue, plasma, urine and sputum were collected. We conducted capture-based NGS (next generation sequencing) on all of these samples from 50 patients with a ctDNA panel covering significant exons and introns from 400 human genes including EGFR, KRAS, ALK, ROS1, c-MET and other important genes in the tumor related singling pathways such as PI3K-AKT-mTOR, JAK-STAT, Notch, Wnt and so on. Patients recruited in our experiment have been given unique treatment such as targeted treatment or chemotherapy according to the clinical examination. The final molecular diagnostic results of all clinical liquid or tissue specimen are supposed to be correlated with clinical response data.

Result:
（Applied for Late-Breaking Abstract） This section is not applicable now because the sequencing and complex data analysis is in progress. Therefore, we will submit the final results as late-breaking abstract.

Conclusion:
Section not applicable. We expect to figure out the molecular diagnostic value of different body fluid compared with tumor tissue. we are able to analyze for correlation of the genomic profile derived from liquid samples and respective tissue results and clinical response of each patient.

Abstract not provided

Background:
Tobacco smoking has a negative impact on the prognosis of A-NSCLC. It is less well known how smoking impacts the burden of disease. As such, an analysis was conducted to evaluate the impact of a current tobacco smoking habit and/or history of smoking on the burden of A-NSCLC.

Method:
Data were collected between May 2015 and June 2016 from adult patients with Stage IIIB or IV NSCLC via medical chart reviews and patient self-completion forms as part of a multicentre, cross-sectional study conducted in France, Germany and Italy. Health status was measured using the EQ-5D-3L (including the visual analogue scale, EQ-VAS), quality of life (QoL) using the EORTC QLQ-C30 and work/activity impairment using the WPAI:GH questionnaire. Costs of NSCLC-related productivity losses and out-of-pocket expenses were also collected. Outcomes were stratified by smoking status (current/former smoker vs never smoked); no adjustments were made for possible confounding factors. Statistical significance was assessed using Mann–Whitney U tests.

Result:
1030 patients were recruited: mean patient age, 64.5 years; male, 65.9%; Stage IV NSCLC, 88.4%; non-squamous histology, 70.3%; receiving first-line therapy, 70.5%. Patients were largely receiving chemotherapy, regardless of line of therapy. In total, 1010 patients had smoking status recorded; 787 (77.9%) were current/former smokers and 223 (22.1%) had never smoked. Significant differences were observed between current/former smokers and patients who had never smoked for health status, QoL, work- and activity-related impairments, and NSCLC-related costs (TABLE). Figure 1



Conclusion:
A significant deterioration in health status and QoL, along with greater work- and activity-related impairments, was observed in current/former smokers with A-NSCLC. Moreover, costs of NSCLC-related productivity losses and out-of-pocket expenses were also higher versus those who had never smoked. These findings suggest an association between tobacco smoking and the humanistic and financial burden incurred by patients with A-NSCLC.

Background:
Identifying key issues for patients with lung cancer is central to assessing quality of life (QOL). Gralla el al described in 2014 a five rated issues which were: maintaining independence, ability to perform normal daily activities, ability to sleep, not being a burden for caregivers and not being fatigued. Studies have shown that patients with advanced lung cancer have a decline in functional capacity from diagnosed and during treatment. Studies examining physical exercise in patients with lung cancer have indicated increased physical capacity, functional capacity and muscular capacity, but no unambiguously significant improvements in QOL. The aim of this study is to investigate the effect of an exercise intervention for patients with advanced stage lung cancer.

Method:
Eligible patients >18 years with a WHO performance status 0-2 with stage IIIb-IV NSCLC and SCLC-ED who were undergoing chemotherapy at the Department of Oncology University Hospital Copenhagen were randomized to standard care or a 12 week physical and psycho-social intervention. Aerobic capacity (VO2peak), functional capacity (6MWD) and QOL (FACT-L) were measured at baseline and 12 weeks.

Result:
A total of 218 patients met the inclusion criteria and were randomized. There were no significant differences in baseline characteristics between the groups. There was a significant improvement in 6MWD in both groups, improvement in intervention was 41.1 m and improvement in control was 16.5 m. There were no significant differences between-groups in overal QOL (FACT-L) although there was a significant improvement in groups in overall QOL (FACT-L), Physical wellbeing, Emotrional wellbeing,Trial Outcome Index for the intervention group. There was a significant difference between groups in the subscale Social Wellbeing (FACT-L) P=<0.04.

Conclusion:
Conclusion: The results of this study demonstrate that functional capacity (6MWD) improves during a 12 week period for patients with advanced stage lung cancer. The improvements in both groups indicate an effect of chemotherapy on functional capacity however the significantly higher improvement in the intervention group indicate a further effect of the exercise intervention. The in-group improvement in QOL in the intervention group indicate a link between an incline in functional capacity and the QOL.

Background:
Lung cancer is the leading cause of cancer death in the US. Only 15% are diagnosed at early stage, resulting in a 5-year survival of 17%. Disparities exist among racial/ethnic minorities and the medically underserved and regionally. High mortality is in part due to the prior absence of a lung cancer screening guideline. c-CARE aims to improve cancer health literacy and outcomes in disparate populations. The purpose of c-CARE project is to increase community awareness of lung cancer risk factors and screening criteria, and to connect high-risk individuals to lung cancer screening and tobacco cessation services.

Method:
The study approach was Community-engaged Research. Formative development involved vetting the study design with the Community Advisory Board (CAB) to ensure community priorities and concerns were addressed. Curriculum development and intervention evaluation were guided by the Health Belief Model. Community members and Community Health Workers unassociated with the current project were recruited to participate in focus groups and semi-structured interviews to review the curriculum and guide refinement of the survey instruments. Thirteen community sites were enrolled: 9 African- American churches; 3 community clinics that serve the medically underserved, and a community recreation center. Researchers trained four Community Health Workers from within each community site to deliver four education sessions. High-risk individuals were connected to lung cancer screening programs and tobacco cessation. Pre- and post-intervention outcome measures were collected on enrolled participants (n=481) to assess changes in participant knowledge, attitudes and beliefs regarding cancer, perceived barriers and self-efficacy to obtain lung cancer screening and tobacco cessation services.

Result:
Participants were majority African American, (n= 481);mean age 58.3 years; 16% were tobacco users. Post intervention knowledge, attitudes and beliefs regarding cancer had significant change (p= 001). Health Belief Model constructs post intervention were significant for Perceived Benefits and Self Efficacy subscales. Spearman correlations were significant between smoking status and Perceived Susceptibility, Perceived Barriers post intervention, Self Efficacy at baseline, Attitude post intervention and Belief at baseline.

Conclusion:
Community engaged methods engendered community buy-in of the project, enhanced the study design and development of a culturally acceptable curriculum. The data derived from the focus groups and interviews facilitated the refinement of the curriculum and data collection instruments. Training Community Health Workers to recruit participants and deliver the curriculum facilitates access to a hard-to-reach population, builds community capacity,and ensures curriculum delivery within the social context of the setting.Brief community interventions can increase cancer knowledge and sreening self-efficacy.

Background:
Aggressive care and chemotherapy worsens quality of life (QoL) of dying cancer patients. Early palliative care (EPC) in patients with metastatic non small cell lung cancer (NSCLC) is associated with improvements in QoL. Thus, we aimed to explore an impact of EPC on the aggressiveness of care at the end of life (EOL).

Method:
An observational cohort enrolled newly diagnosed metastasis NSCLC at Ramathibodi hospital from 31[st] August 2015 to 1[st] September 2016. In EPC group, the consultation of specialized palliative team was performed ≤ 4 weeks of diagnosis and before start chemotherapy treatment, then monthly visits until death and the last visit for bereavement. The palliative consultation in standard of care (SOC) patients performed as their routine practices. The cutoff date for survival analysis was on 31[st] December 2016. The aggressiveness of care in EOL was defined as the composite outcome as any of the followings: last dose of chemotherapy received < 14 days of death, a new chemotherapy regimen starting < 30 days before death, ≥ 1 hospital admissions or emergency room visits or hospitalizations > 14 days in 30 days of death, or an ICU admission in 30 days of death.

Result:
105 patients were enrolled, 38 out of 70 patients (54%) in SOC group and 17 out of 35 patients (48%) in EPC group died. More aggressiveness of care at the EOL (97.3% vs 64.7%, p=0.003), more in-patient death (89.5% vs 58.8%; p=0.009) and longer hospitalization before death were observed in the SOC group (12 days vs 4 days, p=0.028). The cost analysis of patients who died at the hospital showed higher hospitalized cost in the SOC group (p=0.005). The EPC group received less aggressive treatments such as using less than 3 regimens of chemotherapy (77.1% vs 94.3%; p=0.028), but the survival rate was not different (11.3 months vs 6.6 months; p=0.08).

Conclusion:
Early palliative care reduced the aggressiveness of care at the end of life, shortened hospitalization and covered less cost of treatment.

Abstract not provided

Background:
Lung cancer continues to have a high mortality in Canada, with many patients presenting with advanced stage disease. The Ottawa Hospital (TOH) used a learning health systems (LHS) approach to redesign regional diagnostic processes to reduce the overall time from presentation with a suspicious lung mass to diagnosis and treatment. As previously published by our group, an LHS approach is driven by feedback utilizing operational and clinical information to drive system optimization and innovation. TOH is the only provider of cancer services for a population of 1.3 million people in eastern Ontario and hence the need for an integrated patient journey from regional health facility to tertiary care centre was identified. Patient advocates have been incorporated as key members of the LHS from inception to implementation to post-implementation review.

Method:
The Ottawa Health Transformation model (OHTM) was developed as a means of operationalizing a LHS. A kick off meeting brought together cancer patients and their families to map out existing processes and document the patient experience. A regional lung cancer Community of Practice (CoP) of clinical and non-clinical stakeholders was then established to guide and approve the work of a core transformation team. The team had patient and family advocates as key members and they were tasked with identifying appropriate wait time targets and vetting proposed processes. A consensus approach was used to address process barriers, resistance to change and conflicting priorities in regular meetings spanning over two years. Commercially available software was used to track patient progress through the diagnostic process and to report real time metrics to the transformation team.

Result:
The project operationalized lung cancer diagnostic pathway guidance and optimized patient flow from referral to initiation of treatment. Twelve major processes in referral, review, diagnostics, assessment, triage and consult were redesigned. TOH now provides a diagnosis to 80% of referrals within the provincial target of 28 days and leads all other jurisdictions in Ontario in this metric by a wide margin. The median patient journey from referral to initial treatment decreased 48% from 92 to 47 days. In 2016 this work was recognized by a provincial cancer agency with a quality award.

Conclusion:
A learning health system has significantly reduced the time from referral with suspicion of lung cancer to diagnosis to treatment. Achievements require a multi-disciplinary approach with a regional perspective. Patient and family advocates have an important voice in re-designing health care systems.

Background:
The Addario Lung Cancer Foundation’s community hospital COE Program seeks to improve LC outcomes by catalyzing the dissemination of coordinated, evidence-based multidisciplinary care incorporating institutional performance benchmarks across the LC care continuum. The COE program is a network of community-level institutions committed to objectively-measured quality improvement through annual cycles of data collection, comparative analysis and feedback. We analyzed 2016 benchmarks, comparing COE and non-COE programs.

Method:
The annual COE Impact Survey instrument includes an 81-item questionnaire administered by ZoomRx, an independent survey company. Respondents were key institutional representatives of COE- and community-level non-COE institutions. The survey measured the care continuum from screening to end-of-life care. Patient- and institutional-level data for 2016 were analyzed.

Result:
Cohort- 15 COE v 15 non-COE, mean number of annual patients per site 264 v 279; % stage III/IV patients 62 v 74; Medicare-enrolled patients, 54% v 40%; patients 61-80 years 61% v 46%; % patients who encountered financial difficulty in 2016, 42% v 34%. Institutional screening/nodule management programs: 71% of COE v 60% of non-COE programs had a low-dose CT (LDCT) screening program; 86% v 80% used a standard protocol to follow patients with suspicious nodules; 35% v 28% LDCT patients were requested to follow up on suspicious findings; 76% v 67% patients actually followed up. Diagnostic biopsy of LC was by minimally invasive endobronchial approaches in 47% v 15%. Programmatic management of patients with stage III/IV disease: 75% v 49% of patients with stage III/IV disease were reviewed at a Tumor Board and 74% v 62% had a palliative care discussion. Molecular testing was used in 51% v 81%. In patients undergoing molecular testing, institutional use of blood-based ‘liquid biopsies’ was 86% v 18% and next generation sequencing of tissue 67% v 58%. Clinical trials enrollment rates were 20% v 13%, but 18% v 31% of patients were not screened for clinical trials. In weighting factors driving treatment selection on a 100-point relative scale, COE programs weighted ‘quality of life’ (39% v 26%) and ‘patient expense’ (22% v 11%) more than non-COE programs. Non-COE programs weighted ‘product attributes’ (efficacy and safety) 48% (v 14% in COE) more.

Conclusion:
Differences exist in the approach to LC care between COE and non-COE programs. Future iterations of the COE Impact Survey will enable a data-driven approach to disseminating high quality LC care at community-level institutions, where the majority of patients seek care for lung cancer.

Abstract not provided

Background:
Approximately 10% of EGFR mutant NSCLCs have an insertion/mutation in exon 20 of EGFR resulting in primary resistance to currently available tyrosine kinase inhibitors (TKIs). We previously reported that the structural features of poziotinib could potentially enable it to circumvent the steric hindrance induced by exon 20 mutations. Here we further characterize the preclinical activity of poziotinib and report on initial clinical activity of poziotinib in patients with EGFR exon 20 mutations from an ongoing phase II study.

Method:
We evaluated poziotinib activity in vitro using human NSCLC cell lines and the BAF3 model as well as several patient-derived xenograft (PDX) models and genetically engineered mouse models (GEMMs) of exon 20 insertion. We launched a phase 2 investigator-initiated trial of poziotinib in patients with metastatic NSCLC with EGFR exon 20 insertions (NCT03066206).

Result:
In vitro poziotinib was approximately 100x more potent than osimertinib and 40x more potent than afatinib against a common panel of EGFR exon 20 insertions. Furthermore, it had ~65-fold greater potency against common exon 20 insertions compared with EGFR T790M mutations; 3[rd] generation inhibitors osimertinib, EGF816, and rociletinib were all significantly less potent for exon 20 mutations/insertions compared with T790M. in vivo poziotinib led to >85% reduction in tumor burden in GEM models of EGFR exon 20 insertion (D770insNPG) NSCLC and the PDX model LU0387 (H773insNPH). To date, 8 platinum-refractory patients with EGFR exon 20 insertion mutation metastatic NSCLC have been enrolled in the clinical trial and treated with poziotinib at a dose of 16 mg PO daily. Two patients have reached the first interval-imaging time point (at 8 weeks of therapy per protocol). Both patients exhibited dramatic partial response, with one patient reporting improvement in dyspnea and cough at one week of therapy. In this early stage of the study, one case of grade 3 paronchycia was observed. One additional platinum- and erlotinib-refractory patient with EGFR exon 20 insertion was treated with poziotinib on compassionate basis. The patient achieved partial response after three weeks of treatment.

Conclusion:
Poziotinib has selective activity against EGFR exon 20 mutations and potent activity in cell lines, PDX, and GEM models. Three platinum-refractory patients with EGFR exon 20 mutations have been treated thus far and are evaluable for response; all three had partial responses at the time of the initial scan. Updated data from the ongoing phase 2 clinical trial of poziotinib will be presented at the meeting.

Background:
EGFR exon 20 insertions (ins20) comprise 4-10% of EGFR mutations in NSCLC and are refractory to 1[st]/2[nd] generation EGFR TKIs. No effective targeted therapies exist for patients with EGFR ins20. EGFR is a client protein of the molecular chaperone Heat Shock Protein 90 (hsp90). Here, we present the final results of a phase II investigator-initiated trial to assess the activity of the Hsp90 inhibitor luminespib (AUY922) in NSCLC patients with EGFR ins20 (NCT01854034).

Method:
Between 8/2013 and 10/2016, the study enrolled 29 patients with stage IV NSCLC, EGFR ins20 identified on local testing, ECOG PS 0-2, at least one prior line of therapy and no untreated brain metastases. The study was closed on 2/28/17 when the available drug supply was exhausted. Luminespib was given at 70mg/m2 IV weekly. Response was assessed by RECIST 1.1 every 6 weeks; treatment beyond progression was allowed. Dose interruptions and dose reductions were allowed as needed for toxicity management. Primary endpoint was ORR with a target disease control rate (DCR; PR/CR plus SD lasting > 3 mos) of > 20%. Secondary endpoints were PFS, OS, safety and response by EGFR ins20 subtype.

Result:
29 patients (18 female/11 male, median age 60 (range, 31-79)) were enrolled. Median number of prior therapies = 1 (range, 1-5.) 4/29 achieved PR and 1 CR (ORR 5/29; 17%). 15 patients had SD and 9 had PD as their best response. mPFS was 2.9 mos (95% CI, 1.4-5.6,) mOS was 13 mos (95% CI, 4.9-19.5.) DCR was 11/29 (38%). Among 19 patients with baseline PS 0-1 and < 2 prior therapies, ORR = 21% and mPFS = 5.1 mos (95% CI, 2.1-11.8.) The most common luminespib-related toxicities were visual changes (22/29; 76%) diarrhea (21/29; 72%) and fatigue (13/29; 45%). Treatment-related grade 3 toxicities included ocular toxicity (1/29; 3%), hypertension (3/29; 10%) and hypophosphatemia (1/29; 3%). All study treatment was stopped on 2/28/17 due to lack of drug availability; 3 patients were on treatment without progression at study termination.

Conclusion:
The study met its primary endpoint and suggests that luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of luminespib and other Hsp90 inhibitors in this population is warranted, as are novel systems to continue drug supply for benefitting patients when availability of experimental compounds is limited.

Background:
HER2 is a potential driver oncogene. HER2-targeted precision therapy has been tested in NSCLC. However, the demographics of HER2-positive NSCLC have not been defined systematically.

Method:
Pts with advanced NSCLC were registered. HER2-IHC and FISH assays were performed with commercial kits. HER2 mutations were identified by the direct sequencing. The aim of this study was to clarify the frequency, characteristics and outcome of HER2-positive NSCLC.

Result:
Of 1,126 tumors screened (Table A), 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 EGFR wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775_G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female pts had HER2 mutant tumors more frequently, while IHC/FISH+ tumors were detected more often in males (Table B). HER2-positive tumors had similar survival outcome to triple negative tumors, but significantly worse prognoses than EGFR-mutant and ALK-positive tumors (p < 0.05 each). The treament info will be presented at the meeting.

A. The Genotype-Specific Subsets*
	HER2 (n = 88)	EGFR (n = 358)		ALK (n = 44)	Triple negative /unknown (n = 662)		Total (n = 1,126)
Age, median Sex (male) Smoking habit Non-Sq Stage III/IV	69 61 (69%) 58 (66%) 78 (89%) 51 (58%)	69 142 (40%) 142 (40%) 351 (98%) 220 (61%)		62 21 (48%) 19 (43%) 44 (100%) 35 (80%)	69 516 (78%) 544 (82%) 503 (76%) 423 (64%)		69 726 (64%) 754 (67%) 951 (84%) 714 (63%)
MST (mo) 1-yr OS rate	17.5 59%	NR 85%		NR 79%	15.1 59%		19.8 67%
B. The Subsets of HER2 aberrations**
	IHC3+ (n = 34)		IHC2+/FISH+ (n = 34)			Mutant (n = 21)
Age, median Sex (male) Smoking habit Non-Sq Stage III/IV	71 27 (79%) 24 (71%) 30 (88%) 17 (50%)		71 27 (79%) 26 (76%) 28 (82%) 21 (62%)			65 8 (38%) 9 (43%) 21 (100%) 14 (67%)
MST (mo) 1-yr OS rate	10.5 46%		16.0 70%			NR 59%

*including 22 pts with HER2-positive tumors with EGFR mutations, 2 with both HER2- and ALK-positive tumors, and 2 had ALK-positive tumors with EGFR-mutations. ** 1 had an IHC2+/FISH+ tumor with mutation.

Conclusion:
This is the first prospective study showing a small fraction of NSCLC possessed HER2 aberrations. HER2-positive tumors had relatively poor prognosis. NSCLCs with HER2 IHC3+ and mutation seem to be distinct subsets.

Abstract not provided

Background:
Somatic BRAF V600E is a National Comprehensive Cancer Network clinical therapeutic target in non-small cell lung cancer (NSCLC), occurring in 6% of tumors from patients with lung adenocarcinoma. However, approximately half of BRAF alterations are non-V600E that do not respond to FDA-approved vemurafenib or dabrafenib. Emerging evidence suggests some non-V600E mutations exhibit clinical response to novel therapeutic agents. We analyzed the landscape of BRAF mutations in a very large cohort of patients with NSCLC who underwent somatic genomic testing utilizing a CLIA-certified/CAP-accredited/NYSDOH-approved 73 gene cell-free circulating tumor DNA (cfDNA) panel which evaluates single nucleotide variants, and selected indels, fusions, and copy number amplifications.

Method:
The Guardant Health laboratory database was queried for cfDNA tests from patients with a diagnosis of NSCLC where a BRAF variant was identified. Literature was queried for a description of the known function of non-V600E BRAF mutations on serine-threonine kinase activity.

Result:
A total of 1,014 BRAF alterations were observed in 914 tests, with 234 unique alterations identified. The majority of variants were observed only once (75.6%; N=177). 43 alterations were synonymous and excluded from analysis. Plasma-detected BRAF amplification was the most common alteration, observed in 484 tests. Of the remaining variants, 33 of 190 had functional consequence reported in the literature (17.4%), 18 with gain of function or predicted gain of function, 13 with loss of function or predicted loss of function and 2 with no effect. BRAF V600E accounted for 51.1% of occurrences of variants with gain of function or predicted gain of function (N=95 occurrences). Recurrent (>10 occurrences) non-V600E gain of function mutations included G469A (13.4%; N=25 occurrences), K601E (8.0%: N = 15 occurrences), and N581S (7.0%; N=13 occurrences). Fourteen additional gain of function variants comprised the remaining 21% of occurrences. Recurrent loss of function BRAF mutations (>10 occurrences) included G466V and D594G.

Conclusion:
This is the largest reported cohort of somatic BRAF alterations in metastatic non-small cell lung cancer. Non-V600E alterations accounted for almost 50% of the gain of function variants. The spectrum of non-V600E alterations was consistent with reports from The Cancer Genome Atlas and prior published results from tissue genomic sequencing. The recurrent non-V600E variants identified in this cohort are emerging therapeutic targets with promising early clinical data. These findings advocate for more comprehensive BRAF genomic profiling and identification of patients eligible for clinical trials targeting these non-V600E classic mutations and demonstrate the ability of plasma-based cfDNA to detect these alterations.

Background:
MET exon 14 alterations occur in ~4% of non-squamous non-small cell lung cancers (NSCLCs). Treatment with the MET inhibitor, crizotinib, achieves confirmed and durable responses in patients with MET exon 14-altered NSCLCs, underscoring the need to test for these drivers (as of August 1, 2016, objective response rate was 39% and median duration of response was 9.1 months). Comprehensive molecular tumor profiling is required to detect MET exon 14 alterations that are highly heterogeneous. The utility of plasma profiling to detect these drivers has not previously been explored in a prospective trial.

Method:
Patients with advanced NSCLCs harboring MET exon 14 alterations by local tumor profiling performed in a CLIA-certified or equivalent environment were treated with crizotinib at 250 mg twice daily on an expansion cohort of the ongoing phase I PROFILE 1001 study (NCT00585195). Objective response was assessed by RECIST v1.0. Prospective plasma profiling of circulating tumor DNA (ctDNA) for MET exon 14 alterations was performed using the PlasmaSELECT64 targeted gene panel (sequencing and analysis output by Personal Genome Diagnostics, Boston MA).

Result:
Plasma samples were obtained for MET exon 14 alteration analysis after study amendment approval in 20 of 52 crizotinib-treated patients, of which 18 samples were deemed sufficient for analysis. MET exon 14 alterations were detected in ctDNA in 11 of 18 patients (61% agreement of plasma ctDNA testing with tumor testing) mapping to the same exon 14 splice site region in 10 of the 11 cases. Of the 11 patients with ctDNA-positive tumors, all were evaluable for response. Of these evaluable patients, a confirmed partial response and stable disease were observed in 2 and 4 patients, respectively.

Conclusion:
MET exon 14 alterations can be detected in plasma ctDNA in a subset of patients with advanced NSCLCs that harbor MET exon 14 alterations by tumor testing. Responses to crizotinib were observed in patients with ctDNA-positive testing for a MET exon 14 alteration. Plasma profiling should be considered as an adjunct to tumor profiling in screening patients for MET exon 14 alterations, pending further confirmation.

Background:
RET fusions are validated therapeutic targets in human lung cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity is limited by a narrow therapeutic index from off-target effects and poor pharmacokinetics (PK). Moreover, MKIs have limited RET inhibition in the central nervous system (CNS), and patients often experience disease progression in the brain. LOXO-292 is a potent and highly selective RET inhibitor, with >100-fold selectivity versus important off-targets, and anti-tumor activity in the brain and periphery in RET-dependent tumor models in vivo.

Method:
Two RET fusion-positive lung cancer patients were treated with LOXO-292: a patient with CCDC6-RET-rearranged lung cancer with acquired resistance to RXDX-105; and a patient with KIF5B-RET-rearranged lung cancer with progressive disease in the brain while on alectinib treated under a single patient protocol with real-time, PK- guided intra-patient dose titration.

Result:
The first patient was enrolled on cohort 1 of the Phase 1 trial (20 mg daily) and was the first lung cancer patient to receive LOXO-292. She achieved a rapid, confirmed partial response (PR) by RECIST 1.1, with a 44% reduction in target lesion size. The second patient, the first to receive LOXO-292 in the setting of brain metastases, achieved a PR with escalating doses of LOXO-292 (20-60-100 mg twice daily) that included target lesion responses in both the lungs and brain (Figure 1), and resolution of cancer-related CNS symptoms. Early clinical experience with LOXO-292 has already established drug exposures that are consistent with significant RET inhibition in vitro and RET-dependent tumor regression in vivo. Importantly, LOXO-292 has been well-tolerated, with the majority of treatment-emergent adverse events reported as Grade 1-2, and none attributed to LOXO-292.

Conclusion:
LOXO-292 has demonstrated proof-of-concept tolerability, significant exposure, and efficacy in two patients with MKI-resistant, RET-dependent cancers, including a patient with progressive brain metastases after alectinib.Figure 1

Background:
MET amplification (METamp) is a known driver and a mechanism of resistance in EGFR-mutated lung cancers treated with targeted therapy. However, development of therapies targeting METamp has been hampered in part due to poor genomic stratification of patients. We investigated the natural distribution of the size of the MET amplicon and associated genomic characteristics.

Method:
Hybrid-capture based comprehensive genomic profiling (CGP) was performed prospectively on DNA isolated from FFPE samples from NSCLC. Tumor mutational burden (TMB) was calculated from 1.1 Mbp of sequenced DNA and reported as mutations/Mb, as previously described (PMID: 28420421).

Result:
We identified 545 NSCLC cases with focal, defined as <20 Mbp (n = 457, 84%), or non-focal (n = 88, 16%) amplification of the MET gene using CGP. Within this set, the size of the MET amplicon ranged from 0.095 – 158 Mbp; 25[th], 50[th] and 75[th] quartiles were 1.63 Mbp, 3.46 Mbp, and 11.66 Mbp, respectively. In cases with focal METamp the median MET copy number was 11, compared to a median of 7 copies for cases with non-focal METamp (P <0.001). Median TMB in cases with focal vs. non-focal METamp was 10.8 and 9.0, respectively (P=0.47). MET exon 14 splice site alterations co-occurred with METamp in 45 cases (8%), of which 80% had focal METamp (median amplicon size of 2.02 Mbp). EGFR mutations co-occurred with METamp in 93 cases (17%) in this dataset, of which 78% had focal METamp (median amplicon size: 3.77 Mbp). In contrast, cases with other co-occurring alterations described in the NSCLC NCCN guidelines (ALK, ROS1 or RET rearrangements, BRAF V600E, or ERBB2 mutations) METamp was more commonly non-focal (3 focal and 6 non-focal cases), with a median amplicon size of 25.5 Mbp. Clinical outcomes will be presented, including a subset of cases in the setting of resistance to EGFR inhibitors.

Conclusion:
The size of the MET amplicon in MET-amplified NSCLCs is largely variable. Focal amplification is associated with a higher estimate of MET copy number. Neither TMB or co-occurring MET or EGFR mutations significantly correlated with size of the MET amplicon; however, other co-occurring known drivers were associated with non-focal METamp. Additional investigation is warranted to determine the clinical significance of the size of the MET amplicon in NSCLC.

Abstract not provided

Background:
Although immune checkpoint inhibitors of the PD-1/PD-L1 axis provide significant clinical benefit for patients with lung cancer, effective use of these agents is encumbered by a high rate of primary or acquired resistance. Strategies for optimal therapeutic application of immunotherapy require a thorough understanding of resistance mechanisms. To date, there have been only a few studies reporting potential mechanisms of resistance to PD-1/PD-L1 blockade.

Method:
In multiple immunocompetent syngeneic and spontaneous animal models of K-ras/p53 mutant lung cancer, we explored the resistance mechanisms to PD-1/PD-L1 blockade using both pharmacologic and genetic approaches (therapeutic antibody treatment and CRISPR/Cas9-mediated editing). The molecular and immune profiles of the tumor microenvironment were evaluated. Additionally, to determine the applicability to patients with lung cancer, we analyzed 259 tumor specimens with IHC staining and mRNA expression, and further confirmed the analyses in publically-available TCGA datasets.

Result:
In multiple models of antibody blockade and genetic knockout of PD-L1, we identified the up-regulation of CD38 on tumor cells as a marker of treatment resistance. Furthermore, by manipulating CD38 on a panel of lung cancer cell lines we demonstrated in vitro and in vivo that CD38 expression inhibits CD8[+] T cell proliferation, anti-tumor cytokine secretion, and tumor cell killing capability. The T cell suppressive effect is dependent upon the ectoenzyme activity of CD38 that regulates the extracellular levels of adenosine. To test whether CD38 blockade might be therapeutically efficacious to prevent anti-PD-L1/PD-1 resistance, we applied combination therapy with anti-CD38 and anti-PD-L1 and demonstrated dramatic therapeutic benefit on primary tumor growth and metastasis. Additionally, in a set of 259 resected lung cancer specimens, ~15% exhibited positive staining for CD38 on tumor cells, and the expression correlated with cytolytic T cell score and an immune/inflammatory signature across multiple large datasets.

Conclusion:
CD38 was found to be a novel mechanism for tumor escape from immune checkpoint PD-1/PD-L1 inhibitor therapy. Targeting this resistance pathway may broaden the benefit of PD-L1/PD-1 axis blockade for lung cancer treatment.

Background:
Pembrolizumab was initially approved as a single agent by the US FDA on October 2, 2015, for treating patients with mNSCLC who have disease progression on or after platinum-containing chemotherapy and PD-L1 tumor expression ≥50%, as determined by the FDA-approved test (Dako 22C3). Subsequent approvals for first-line therapy and expanded second-line therapy followed in October 2016. Our aim was to study PD-L1 testing patterns in US oncology practices from October 2015 through March 2017 and the potential impact of the PD-L1 IHC assay type on measurement of PD-L1 tumor expression.

Method:
This retrospective, observational study drew on de-identified, longitudinal data from a large electronic medical record database (Flatiron Health) representing 17% of incident oncology cases in the US. Eligible patients were adults (≥18 years) with histologically/cytologically confirmed initial diagnosis of mNSCLC (stage IV) or metastatic recurrence from October 2015 through March 2017. We determined the rate of PD-L1 testing (test date defined as the result date) and distribution of PD-L1 tumor expression (percentage of tumor cells staining for PD-L1) by IHC assay type.

Result:
The 7879 eligible patients included 4111/3768 (52%/48%) men/women; 5123 (65%) were >65 years old, and 6706 (85%) had a history of smoking. The rate of PD-L1 testing increased consistently over time from 15% in Q4/2015 to 70% in Q1/2017. Of 1728 patients with mNSCLC tested for PD-L1, 77%, 5%, 4%, and 19% were tested using Dako 22C3, Dako 28-8, Ventana SP142, and laboratory-developed tests (LDTs), respectively. Measured PD-L1 expression varied significantly (χ[2] p<0.0001) across the four assay types, although there was no significant difference (p=0.053) among the remaining three assays when the SP142 assay was excluded (Table).Figure 1



Conclusion:
We found no significant differences in measuring PD-L1 tumor expression using Dako 22C3, Dako 28-8, and LDTs; however, results of the SP142 assay appeared discordant.

Background:
Immunotherapy targeting the PD-1/PD-L1 pathway has dramatically changed the treatment landscape of non-small-cell lung carcinoma (NSCLC). We previously demonstrated that HHLA2, a recently identified B7 family immune inhibitory molecule, was widely expressed in NSCLC. To better understand the immune evasion mechanisms within the tumor microenvironment, we compared the expression profiles and functional roles of PD-L1 with potential alternative immune checkpoints, B7x and HHLA2.

Method:
Expression was assessed by immunohistochemistry using tissue microarrays consisting of 392 NSCLC tumor tissues (mostly resected stage I to III), including 195 tumors in the discovery (D) set and 197 cases in the validation (V) set. Positive PD-L1 cases were defined as samples with percentage of tumor cells revealing membranous staining of PD-L1 ≥ 1% with SP142 antibody. Human T cells were purified from eleven donors. Control human IgG, human PD-L1-Ig, human B7x-Ig and human HHLA2-Ig were used to determine the effects of PD-L1, B7x and HHLA2 on T cell proliferation and cytokine production [Human Th Cytokine Panel: IL-5, IL-13, IL-2, IL-6, IL-9, IL-10, IFN-γ, TNF-α, IL-17F, IL-17A, IL-4, IL-21 and IL-22].

Result:
PD-L1 expression was detected in 25% and 31% of tumors in the D and V sets respectively, and was associated with higher stage and lymph node involvement in both cohorts. Multivariate analysis further showed that stage, TIL status and lymph node involvement were independently associated with PD-L1 expression. B7x was expressed in 69% and 68% of cases, while HHLA2 was positive in 61% and 64% of tumors in the two sets. Triple positive expression was detected in 13% whereas triple negative in 15% of cases. The double-expression of PD-L1 with B7x or HHLA2 was rare, 6% and 3% respectively. Interestingly, the majority (78%) of PD-L1 negative cases expressed B7x, HHLA2 or both. Moreover, the triple positive group correlated with more TIL infiltration as compared to the triple negative group (P = 0.0175). At the same concentration, B7x-Ig and HHLA2-Ig inhibited TCR-mediated proliferation of both CD4 and CD8 T cells significantly more robustly than PD-L1-Ig. All three significantly suppressed a variety of cytokine production by T cells.

Conclusion:
The majority of PD-L1 negative lung cancer cases express alternative immune checkpoint molecules (B7x, HHLA2 or both). The potential role of the B7x/HHLA2 pathway in mediating immune evasion in PDL1 negative tumors deserves to be explored to provide the rationale for an effective immunotherapy strategy in these tumors.

Abstract not provided

Background:
Non-small cell lung cancer (NSCLC) is characterized by a high mutational load. Accordingly, it is also among the tumor types responding to immune checkpoint blockade, likely through harnessing of the anti-tumor T cell response. However, the lung is continuously exposed to the outside environment, which may result in a continuous state of inflammation against outside pathogens unrelated to the tumor microenvironment. Therefore, further investigation into the T cell repertoire and T cell phenotypes across normal lung and tumor is warranted.

Method:
We performed T cell receptor (TCR) sequencing on peripheral blood mononuclear cells (PBMC), normal lung, and tumor from 225 NSCLC patients, among which, 96 patients were also subjected to whole exome sequencing (WES) of PBMC, tumor and normal lung tissues. We further performed Cytometry by Time-of-Flight (CyTOF) on 10 NSCLC tumors and paired normal lung tissues to phenotype immune and T cell subsets.

Result:
Comparison of the T cell repertoire showed 9% (from 4% to 15%) of T cell clones were shared between normal lung and paired tumor. Furthermore, among the top 100 clones identified in the tumor, on average 57 (from 0 to 95) were shared with paired normal lung tissue. Interestingly, T cell clonality was higher in the normal lung in 89% of patients suggesting potential differences in the immune response and immunogenicity. A substantial number of somatic mutations were also identified not only in NSCLC tumors (average 566; from 147 to 2819), but also in morphologically normal lung tissues (average 156; from 50 to 2481). CyTOF demonstrated striking differences in the immune infiltrate between normal lung and tumor, namely a lower frequency of PD-1+CD28+ T cells (both CD4+ and CD8+) in the normal lung (2.7% versus 3.0% in tumor). In addition, a unique GITR+ T cell subset (0.96%) was entirely restricted to the normal lung. Conversely, increases in regulatory T cell frequency (CD4+FoxP3+) were observed in the tumor (10.4% vs 1.7% in normal lung), further highlighting the differences in T cell phenotype and response across normal lung and tumor.

Conclusion:
These results suggest that a substantial proportion of infiltrating T cells in NSCLC tumors may be residential T cells associated with response to environmental factors. However, normal lung and NSCLC tumors carry T cells of distinct phenotypes including increases in immunosuppressive T cells within the tumor which may further highlight the differences in the anti-tumor immune response.

Background:
Indoleamine 2, 3-dioxygenase 1 (IDO1) serves as an immunosuppressive effector and it is closely related to the prognosis in several types of cancer. We herein aim to elucidate the clinicopathological features and prognoses in patients with IDO1-expressing lung adenocarcinoma, and especially, show its correlation with the expression of programmed cell death-ligand 1 (PD-L1).

Method:
The expressions of IDO1 and PD-L1 proteins in 427 patients with surgically resected primary lung adenocarcinoma were evaluated by immunohistochemical analyses and any associations identified between IDO1 and the clinicopathological features, the prognosis and co-expression of IDO1 with PD-L1 were investigated. The expressions of IDO1 and PD-L1 at the protein and mRNA levels in lung adenocarcinoma cell lines were examined by an Enzyme-Linked Immuno Sorbent Assay, flow cytometry, and reverse transcription and real-time PCR analysis, respectively.

Result:
IDO1 was expressed in 260 patients (60.9%) at a 1% cut-off and in 63 patients (14.8%) at a 50% cut-off, respectively. PD-L1 was positive for 145 patients (34.0%). A ultivariate analysis showed IDO1 positivity (1% cut-off) to be significantly associated with a higher tumor grade, the presence of vascular invasion, and the expression of PD-L1. IDO1 and PD-L1 proteins were co-expressed in 123 patients (28.8%), and the patients whose tumor expressed both proteins exhibited significantly higher malignant traits than those whose tumor expressed only one protein or none. According to a multivariate analysis, the co-expression of both proteins was significantly associated with a shorter disease-free survival and overall survival. The expressions of IDO1 and PD-L1 in lung adenocarcinoma cell lines were elevated by treating them with interferon-γ and transforming growth factor-β.Figure 1



Conclusion:
The findings of this study suggest that the co-expression of IDO1 and PD-L1 may indicate more aggressive features of lung adenocarcinoma. Combination therapy targeting both of these proteins may therefore improve the clinical outcomes in patients with lung adenocarcinoma.

Background:
Clonal evolution and the heterogeneity of non-small cell lung cancer (NSCLC) may affect patient outcomes through variations in treatment planning, response to therapy, and drug resistance. Even less is known about the diversity of the adaptive immune response to primary and metastatic lesions in this disease. We sought to characterize the richness, abundance and overlap of T cell clones between paired primary NSCLC lesions and brain metastases.

Method:
We identified 20 patients with NSCLC with paired, fully resected primary lesions and brain metastases with sufficient tissue available in our clinical archives. DNA was purified from formalin-fixed paraffin-embedded specimens. The complementarity determining region 3 of T-cell receptor β was profiled by next generation sequencing to identify unique T cell clones. Sample richness (including iChao1 and Efron-Thisted Estimator), and clonal abundance (Simpson’s diversity index) were compared between paired lesions with the paired t test. Overlap in clonality was measured with the Morisita index.

Result:
There was a significant contraction of T cell clonality in paired metastases compared to primary lesions (mean of differences -2803, 95% CI -4202 to -1405; p=0.0005). The decreased richness in clonality in brain metastases was also supported by significant differences in iChao1 (mean of differences -20355, 95% CI -29561 to -11149; p=0.0002) and the Efron-Thisted Estimator (95% CI -21331 to -7216; p=0.0004). Simpson’s diversity index was higher in brain metastases than primary lesions (mean of differences 0.002, 95% CI 0.001 to 0.004; p=0.05), but low overall. Only a fraction of T cell clones in primary lesions were also found in brain metastases (mean Morisita Index 0.23).

Conclusion:
There is greater richness but less abundance of T cell clones in primary NSCLC lesions compared to paired brain metastases. Although the blood brain barrier may restrict T cell trafficking to tumors, the minimal overlap in T cell clones may reflect the genetic divergence of metastatic tumor clones.

Abstract not provided

Background:
Radiologic assessments of the baseline and post-treatment tumor burden are subject to measurement variability, but the impact of this variability on response categorization and the resulting overall response rate (ORR) in a specific trial has been practically unpredictable.

Method:
We built up a hierarchical model of measurement variability using a clinical trial dataset of CT scans. Simulations were then performed using the model 1) to establish the behaviour of differences between the first and the hypothetical second assessments of percent change of tumor burden in various scenarios, 2) to elaborate on the probabilistic nature of decisions about categorization, and 3) to estimate the variation in the ORR due to measurement variability.

Result:
The extent of the discrepancies between assessments of the percent change depended on the baseline burden. Smaller differences were associated with larger shrinkage of tumor burdens. The simulated probability for a specific categorization (-30% or 20%) to result from reassessment had a sigmoid shape depending on the percent change in the first set of readings, inflecting at the cutoff point for the categorization. In 3 virtual trials having the same baseline burden and the same ORR of 50%, the presence of fewer percent changes around the cutoff in a trial resulted in a more reproducible ORR (95% central range, 35%-65% vs. 40%-60% vs. 45%-60%). Figure 1



Conclusion:
Since determinations of partial response or progression are probabilistic outcomes due to measurement variability, quantification of the variation in the ORR by potential measurement variability is essential and will help inform decisions made on the basis of trial data.

Background:
►►OS assessment requires high follow-up times and patient numbers and is impacted by crossover (CO). OS hazard ratios (HRs) are generally inferior to PS HRs due to impact of post-progression survival (PPS) and CO. Some authors propose that absolute OS gains (ΔOS) should be similar to those in PFS (ΔPFS). Hence, ΔPFS might be a useful OS surrogate (Clin Cancer Res 2013;19:2646; Ann Oncol 2016;27:373).

Method:
To assess this further, we reviewed Journal of Clinical Oncology and New England Journal of Medicine 01/01/2012-06/12/2017 for randomized drug trials in incurable solid tumors. We extracted data for PFS and OS medians and HRs, calculated ΔPFS and ΔOS (experimental medians minus control medians), and did paired comparisons between 2-6 different arms in each study (245 comparisons across 201 trials).

Result:
Mean ΔOS across studies (1.03 months) was similar to mean ΔPFS (1.06 months) (n=201 evaluable, p=0.88). ΔOS correlated with ΔPFS (r=0.50, p<0.0001). With CO in <20% of patients or unstated %CO (n=144), mean ΔOS and ΔPFS were 0.93 and 0.92 months, respectively. With CO in >20% of patients (n=57), mean ΔOS and ΔPFS were 1.29 and 1.41 months, while with CO>50% (n=20), they were 1.4 and 1.9 months. OS HRs (mean=0.92) were inferior to PFS HRs (mean=0.82, n=196, p<0.0001), although OS and PFS HRs correlated with each other (r=0.64, p<0.0001). With CO<20% or unstated (n=135), mean OS and PFS HRs were 0.93 and 0.83, while with CO>20% (n=61), they were 0.90 and 0.80, and with CO>50% (n=20), they were 0.94 and 0.71.

Conclusion:
OS HRs were inferior to PFS HRs, probably due to PPS, competing causes of death and CO. The better mean gains and HRs in high vs low CO trials may be due to more frequently allowing CO in trials with more effective therapies. This increases risk of false-negative OS results with effective therapies if CO is permitted, but it is potentially unethical to withhold CO of effective therapies. With PFS, clinically insignificant gains may be statistically significant. Since ΔOS and ΔPFS are similar, an alternate approach would be a primary study outcome requiring PFS HR to be statistically significant and ΔPFS 95% CIs in a range considered clinically relevant for OS gains. To better understand the limitations of this approach, we are analyzing examples with minimal OS gains despite ΔPFS>2 months and examples of ΔOS>2 months but no gain in PFS, and have formulated a potential biological/statistical explanation for the latter.

Background:
Clinical trials (CTs) are recognized as a key component of a quality cancer care system. When funding for systemic therapy (ST) services in Ontario transitioned in 2014/15 from a one-time payment for new cases to bundled payments for specific evidence-informed regimens, stakeholders expressed concern that the funding model could exclude patients from participation in CTs as treatment facilities would only receive funding when evidence-informed regimens were used.

Method:
A CT policy was implemented to enable public funding through the ST funding model for older and inexpensive drugs and their administration within randomized CTs at the level of the standard of care. Non-randomized CTs were to be funded at the level of best supportive care or other appropriate funding level. New and expensive drugs in a CT could be funded through a separate provincial drug reimbursement program if used according to public funding criteria with administration costs covered by the ST funding model. Each new CT is now assessed to determine the level of public funding possible. The funding model can now capture data on phase of trial, disease type, treatment regimen, trial purpose (adjuvant, palliative) and patient accrual by treatment facility

Result:
During 2015/16 and 2016/17, 43 and 44 lung CTs, respectively, were assessed and activated in Ontario. Trial accrual increased by 33% (from 311 to 413 patients) over the two years since the introduction of the funding model. Accrual varied by facility. In 2016/17, it ranged from a low of 0.25% to 37.5% of the new lung cancer (LC) patients seen at individual facilities. For the five largest cancer centres in Ontario, the percentage of patients recruited ranged from 5% to 18.3% and total accruals from these centres (n=257) comprised 63% of provincial LC trial recruitment. Five immuno-oncology trials accrued 183 patients and made up 44% of total LC trial accruals. Public funding through the ST funding model amounted to $415,000 in 2015/16 and increased to $815,000 in 2016/17.

Conclusion:
The new bundled payment system for ST and the CT policy have enabled public funding to support lung CTs. The ST funding model has facilitated the capture of CT data and trends not previously available for LC and other tumours. The new provincial CT policy and payment system do not appear to have negatively impacted participation in lung cancer CTs. The variance in trial accrual between centres warrants further study.

Abstract not provided

Background:
Human epidermal growth factor receptor 2 (HER2, ERBB2) mutation and amplification each occurs in 2% of lung cancers, resulting in receptor dimerization and oncogenic signaling with in vitro sensitivity to trastuzumab. Ado-trastuzumab emtansine is a HER2 targeted antibody drug conjugate linking trastuzumab with the anti-microtubule agent emtansine.

Method:
Patients with advanced HER2 mutant or amplified lung cancers were enrolled into separate cohorts in a basket trial of ado-trastuzumab emtansine, treated at 3.6mg/kg IV every 3 weeks. The primary endpoint was overall response rate (ORR) using RECIST v1.1. A separate cohort included patients with HER2 mutant lung cancers assessed using PERCIST, with pre-treatment 89Zr-trastuzumab PET as correlative imaging. A Simon two stage optimal design was used with type I error rate under 2.7% (and a family wise error rate across baskets under 10%), power of 89%, H0 10%, H1 40%. Other endpoints include progression-free survival (PFS) and toxicity. HER2 testing was performed on tumor tissue by next generation sequencing (NGS), fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC).

Result:
A total of 33 patients were identified by NGS and enrolled. The first HER2 mutant cohort completed accrual of 18 patients with ORR of 44% (8/18 confirmed, 95% CI 22-69%), rejecting null hypothesis. The median PFS was 4 months, and median PFS for responders was 6 months (range 4-11 months). The PERCIST measured HER2 mutant cohort accrued 9 patients, there were 2 confirmed partial responses (PR) in 5 patients evaluated. The HER2 amplified cohort accrued 6 patients, with 3 confirmed PR observed including 1 with concurrent EGFR sensitizing mutation and resistance to erlotinib. Toxicities included grade 1 or 2 including infusion reaction, thrombocytopenia and transaminitis, there were no treatment related deaths. Of the 27 patients in the HER2 mutant cohorts, there were 18 (67%) exon 20 insertions and 9 (33%) point mutations; responders were seen across mutation subtypes (A775_G776insYVMA, G776delinsVC, V659E, S310F, L755P). Concurrent HER2 amplification was observed in 4 of 27 patients by either NGS or FISH. IHC ranged from 0 to 3+ and did not predict response. Of the 6 patients in the HER2 amplified cohort, 2 had concurrent HER2 mutation and 1 had concurrent EGFR L858R mutation.

Conclusion:
Ado-trastuzumab emtansine is active and well tolerated in patients with advanced HER2 mutant or amplified lung cancers as identified by NGS. While cohort expansion is ongoing, this study has met its primary endpoint in patients with HER2 activating mutations. Further development is warranted.

Background:
Entrectinib is a potent, investigational, CNS-active, oral inhibitor of ROS1 with a biochemical IC~50~ (0.2 nM) ~30 times more potent than crizotinib, the only agent approved for the treatment of ROS1-positive NSCLC. Previously, we reported an objective response rate of 85% in 13 ROS1 inhibitor-naïve NSCLC patients who were treated in Phase 1 studies (Drilon and Siena et al, Cancer Discov 2017), including 2 of 3 (67%) patients with CNS disease. Responses were durable, with 1 patient remaining on study for more than 3 years. Entrectinib was well tolerated, with predominantly Grades 1 or 2 adverse events that were reversible with dose modification.

Method:
Patients with ROS1 inhibitor-naïve NSCLC were enrolled across Phase 1 and 2 studies of entrectinib. Patients were screened for ROS1 gene fusions either locally or centrally at Ignyta’s diagnostic laboratory using next generation sequencing. Entrectinib was administered orally at 600 mg once-daily in 4-week cycles. Safety was assessed by monitoring adverse events, laboratory tests, and clinic visits. Tumor assessments were performed at the end of Cycle 1 and every 8 weeks thereafter. All scans were read locally (INV) and by blinded independent central review (BICR) using RECIST v1.1. INV results will be presented except where noted.

Result:
As of 24 May 2017, a total of 32 patients were evaluable for response (median age 52 years, 72% female). At a median follow-up of 12 months, objective responses were observed in 24 of 32 (75% [95% CI: 56.6, 88.5]; 3 complete responses) patients, including 7 of 11 (64% [95% CI: 30.8, 89.1]) patients with CNS disease at baseline. Five of 7 patients with evaluable CNS lesions by BICR experienced confirmed RECIST intracranial responses, for a CNS response rate of 71% (95% CI: 29.0, 96.3). With 19 (59%) patients remaining on study, the median duration of response was 17.2 months (95% CI: 6.5, 36.0) and progression-free survival was 19.1 months (95% CI: 6.5, 36.6). The most common (>15%) treatment-related adverse events were fatigue/asthenia (34%), dysgeusia (34%), dizziness (24%), weight increase (21%), paresthesia (19%), nausea (18%), constipation (18%), and diarrhea (16%). All data will be updated at the time of presentation.

Conclusion:
Entrectinib is well tolerated and has shown promising antitumor activity in ROS1 inhibitor-naïve NSCLC, including patients with CNS disease. Patients with ROS1+ NSCLC and other tumor types continue to be enrolled in STARTRK-2 (NCT02568267) in order to support a potential regulatory filing for entrectinib in this population.

Background:
Lung-MAP (S1400) is a master umbrella protocol designed to establish genomic screening for previously treated squamous cell lung cancer patients (SqCCA), and independently evaluate targeted therapies with matching biomarkers and alternative therapies (designated non-match therapy) in patients without putative markers. The protocol opened June 16, 2014 with four biomarker-driven sub-studies and one non-match sub-study.

Method:
Eligibility stipulated advanced SqCCA, progressing after at least one prior platinum-based chemotherapy, PS 0–2, and EGFR/ALK wild-type. Tumor samples were required and analyzed for gene alterations by FoundationOne NGS assay (Foundation Medicine). The original biomarker and non-match studies were: S1400B evaluating taselisib for PI3K mutations, S1400C evaluating palbociclib for cell cycle gene alterations (CCGA), S1400D evaluating AZD4547 for FGFR mutations, S1400E evaluating rilotumumab and erlotinib for c-MET positive tumors, and S1400A evaluating durvalumab in patients with no matching biomarkers. The original design included randomization to a control arm, but was amended to a single-arm phase 2 design. The primary endpoint for each modified sub-study was response.

Result:
As of June 16, 2017 all original sub-studies have been closed to accrual; 1298 patients registered to the screening component of the trial and 486 patients have registered to a sub-study. Two new sub-studies have been launched and are currently accruing. Details of the completed sub-studies are included in the table.

Sub-study	Final Accrual	Biomarker prevalence/% of sub-study registrations	Closure Date	Response to investigational therapy N (%)	Status
S1400A (non-match)	Total: 116 Durvalumab: 78 Docetaxel: 38	NA/59%	12/18/15 Docetaxel arm closed: 4/22/15	11 (16%)	Administratively closed to enable activation of new non-match study.
S1400B PI3K	Total: 39 taselisib: 31 Docetaxel: 8	8%/9%	12/12/16 Docetaxel arm closed: 12/18/15	1 (4%)	Closed at interim futility analysis.
S1400C (CCGA+)	Total: 54 Palbociclib: 37 Docetaxel: 17	19%/15%	09/01/16 Docetaxel arm closed: 12/18/15	2 (6%)	Closed at interim futility analysis.
S1400D (FGFR+)	Total: 45 AZD4547: 35 Docetaxel: 10	16%/12%	10/31/16 Docetaxel arm closed: 12/18/15	2 (7%)	Closed at interim futility analysis.
S1400E (MET+)	Total: 9 R+E: 4 E: 5	N/A (closed too early)	11/26/2014	N/A	Closed d/t discontinuation of development of rilotumumab

Conclusion:
Lung-MAP as a master genomic screening protocol has demonstrated feasibility with respect to accrual and evaluation of targeted therapies in lower prevalence patient populations. This dynamic, centralized, single-IRB platform is well positioned to efficiently assess multiple novel therapeutics for advanced SqCCA patients.

Abstract not provided

Abstract:
Crizotinib is the first ALK TKI that has demonstrated statistically superior progression-free survival over standard of platinum-based chemotherapy in treatment-naïve ALK+ NSCLC patients (PROFILE1014, PROFILE 1029). Since then next generation ALK TKI such as ceritinib (ASCEND-4) has also demonstrated statistically improved PFS over platinum-base chemotherapy (ASCEND-4) and alectinib has demonstrated statistically improved PFS over crizotinib (J-ALEX, ALEX). In ALEX, a global randomized phase 3 study comparing alectinib to crizotnib demonstrated that alectinib achieved an median PFS of 25.7 months compared to median PFS of 10.4 months for crizotinib. Additionally, the cumulative incidence of CNS metastasis was significantly lower over for patients treated with alectinib than patients treated with crizotinib the duration of study period. Crizotinib did achieve higher than expected confirmed overall response rate in patients with CNS metastasis in the ALEX trial than has previously published. In fact the median PFS achieved by patients without CNS metastasis at study enrollment and treated by crizotinib was 14.8 months. There is a retrospective study that demonstrated two-third of the patients treated with crizotinib would continue to benefit from continuation of crizotinib beyond disease progression with local ablative therapy with a median overall survival of additional 16 months from the time of disease progression. Next generation ALK inhibitor such as brigatinib has achieved a median PFS of > 15 months in patients who are crizotinib-refractory or intolerant. Furthermore, “third-generation” ALK inhibitor, lorlatinib, achieved clinically meaningful overall response rate presented at this conference. Thus sequencing crizotinib to brigatinib could potentially achieve the additional 15.3 months of additional PFS achieved by using alectinib first. Finally, one of the major resistance mechanism of alectinib is the generation of ALK G1202R solvent front mutation while the incidence of ALK G1202R resistance mutation in crizotinib-refractory cases are much lower. Currently only lorlatinib and TPX-0005 (next generation ALK inhibitors presented at this WCLC) have shown reliably in vitro inhibitory against solvent front mutation. Thus the up-front use of alectinib could potential generate resistance mechanisms that allow limited further treatment options.

Abstract not provided

Abstract:
Tissue biopsy has been the gold standard in cancer diagnosis and molecular diagnosis of NSCLC for years. However, “liquid biopsy” is gaining in popularity as the sensitivity and availability of the assays increase. Plasma testing is now a standard approach for EGFR mutation testing with US FDA approved tests (Cobas), and much broader applications are available. Liquid biopsies are preferred, especially from the patient perspective. Would you prefer a simple blood draw or an invasive biopsy with high complication risk? The answer is obvious. As tumor cells die they shed DNA into peripheral blood. This circulating tumor DNA (ctDNA) is transient in nature, but can be detected in the plasma samples of patients. Plasma assays require simple phlebotomy compared to the risks of tissue biopsy. This technology can be applied to many malignancies, but is of particular interest in NSCLC given the number of known actionable driver mutations. Rapid detection of these mutations, and monitoring for development of resistance is already part of standard practice. Tissue biopsy strategies are significantly hampered by difficult to access tumors such as those in the brain or bone, and risks such as hemorrhage or pneumothorax. The issue of tumor heterogeneity is also of significance, as a biopsy in one lesion may not reflect the resistance biology of another location.[1] The application of ctDNA is best illustrated in the setting of EGFRmutant (EGFRmut) NSCLC. Though most patients have an EGFR activating mutation identified in the initial tumor biopsy, on June 1, 2016 the US FDA approved the cobas Mutation Test v2, a real-time PCR based assay for EGFR mutations, for use with plasma for detection of EGFR exon19del and L858R (and others in exons 18-21). ctDNA testing for the T790M EGFR resistance mutation is of greater practical utility as biopsy can be avoided in this setting with a positive liquid biopsy. AURA3 established the third generation EGFR TKI osimertinib as superior to chemotherapy for patients with T790M mutations, making T790M testing of high clinical significance.[2] In addition to tissue testing AURA3 was designed with an imbedded plasma assay. Based on the trial results the cobas EGFR Mutation Test v2 approval was expanded to include detection of T790M mutation in plasma samples. The Cobas assay established liquid biopsies as a standard approach for EGFRmut NSCLC, but has limited sensitivity and more sensitive liquid biopsy approaches exist including droplet digital PCR (ddPCR) and BEAMing (beads, emulsion, amplification, and magnetics), in addition to broader next generation sequencing (NGS) assays. Osimertinib activity has been demonstrated in T790M+ NSCLC patients regardless of how T790M is detected.[3] In a large analysis of hundreds of matched tissue, plasma and urine samples from EGFRmut NSCLC patients, both plasma and urine T790M detection sensitivity were 81% versus tissue testing. In the 181 patients with matched tissue, plasma and urine specimens there were 23 patients with T790M detected in plasma but not tissue, and 24 patients with T790M found in tissue but not plasma. The study utilized BEAMing technology, and a sensitive urine assay with quantitative NGS focused on EGFRdel 19, L585R and T790M.[4 ] One challenge for liquid biopsy is in the setting where there is limited ctDNA shedding, such as in lung only disease (M1a) in which case EGFRmut detection rates can be <50%,[5] but increasingly sensitive assays will ameliorate this issue. In a comparison across various platforms of Cobas (non-digital PCR), ARMS (therascreen EGFR amplification refractory mutation system (ARMS), digital detection droplet PCR (ddPCR) and BEAMing dPCR, the sensitivity ranged from 78-100% for the sensitizing mutations and 29-81% for T790M with specificity of 93-100% for the activating mutation and 58-100% for the T790M assays.[6] As outlined above, there is variability in the assays available for plasma analyses, however these assays correlate well with the tissue testing. In a meta-analysis of 26 studies comparing EGFR mutation detection in plasma versus tissue the specificity was 0.97 (95% CI 0.93-0.99) and sensitivity was 0.65 (95% CI 0.54-0.74).[7] Sensitivity is increased with more modern techniques such as BEAMing and droplet digital PCR. As this and other comparisons highlight, specificity is exceedingly high in all available assays, but sensitivity varies amongst the tests and thus a positive ctDNA test should be believed and can spare the patient a biopsy, but a negative test should be followed by further evaluation, bearing in mind that tissue testing can also result in false negatives. Another advantage of “liquid biopsy” is the speed of obtaining results. In a comparison of plasma ddPCR versus biopsy the median turnaround time was significantly faster for the plasma testing (3 days versus 12 days, not including time to arrange the biopsy).[8 ] Thus, for EGFRmut NSCLC it is clear that compared to tissue biopsy, liquid biopsy is highly sensitive and specific, faster, and much more convenient and safe for patients. There should be no debate on the utility of liquid biopsy at initial diagnosis and around development of resistance to 1[st]/2[nd] generation EGFR TKIs. We already have an FDA approved assay in these settings with many improved technologies available as well. EGFR testing lays the foundation for ctDNA testing in NSCLC, but the utility of ctDNA has already expanded to testing for BRAF and other actionable mutations, and tumor rearrangements such as ALK. As an example, a commercially available ctDNA NGS assay performed on 362 NSCLC patients with paired tissue samples identified 51 additional actionable driver mutations via ctDNA analysis compared to the tissue assay, demonstrating real world practicality of this approach and theoretically improved patient outcomes.[9] Other highly sensitive NSCLC platforms looking at panels of dozens to hundreds of genes are available and rapidly changing our ability to detect mutations in larger groups of actionable mutations.[10] Utilization of these technologies at the time of diagnosis and for identification of resistance mechanisms is no longer theoretical but practical. Use of these technologies to monitor treatment response may one day replace or at least supplement imaging, and of particular utility, ctDNA analysis is already showing promise as a measure of minimal residual disease after curative therapy in early stage disease and will likely help guide us in decisions regarding adjuvant therapy in the near future. Liquid biopsy is an established, approved standard for EGFR testing, widely available and practical for tumor genotyping for other actionable mutations, and poised to radically change our surveillance strategies and our management of earlier stages of disease and likely even screening, which is far beyond the scope of what can be done with tissue. The preference for liquid biopsy over tissue biopsy should be clear. REFERENCES: 1) Hata A, Katakami N, Yoshioka H, et al. Spatiotemporal T790M Heterogeneity in Individual Patients with EGFR-Mutant Non-Small-Cell Lung Cancer after Acquired Resistance to EGFR-TKI. J Thorac Oncol 10 (2015) 2) Mok TS, Wu YL, Ahn MJ, et al. AURA3 Investigators, Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med (2016) 3) Oxnard GR, Thress KS, Alden RS, et al. Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 34 (2016) 4) Wakelee HA, Gadgeel SM, Goldman JW, et al.. Epidermal growth factor receptor (EGFR) genotyping of matched urine, plasma and tumor tissue from non-small cell lung cancer (NSCLC) patients (pts) treated with rociletinib. J Clin Oncol 34, (abstr 9001) (2016) 5) Karlovich C, Goldman JW, Sun JM, et al. Assessment of EGFR mutation status in matched plasma and tumor tissue of NSCLC patients from a phase I study of rociletinib (CO-1686). Clin Cancer Res 22(10)(2016) 6) Thress KC, Brant R, Carr TH, et al. EGFR mutation detection in ctDNA from NSCLC patient plasma: A cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer (2015). 7) Wu Y, Liu H, Shi X, Song Y. Can EGFR mutations in plasma or serum be predictive markers of non-small-cell lung cancer? A meta-analysis, Lung Cancer Amst. Neth. 88 (2015) 8) Sacher AG, Paweletz C, Dahlberg SE, et al. Prospective validation of rapid plasma genotyping for detection of EGFR and KRAS mutations in advanced NSCLC. Jama Oncology (2016) 9) Zill O, Banks K, Mortimer S, et al. Somatic genomic landscape of over 15,000 advanced stage cancer patients from clinical NGS analysis of ctDNA. J Clin Oncol 34, (LBA11501) (2016) 10) Newman AM, Lovejoy AF, Klass DM, et al. Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol 34(5) (2016)

Abstract not provided

Abstract not provided

Abstract:
Untreated small-cell lung cancer (SCLC) is highly sensitive to both chemotherapy and radiotherapy, although its growth is very rapid. Clinically, SCLC is classified into limited-diseases (LD) and extensive-disease (ED). Although there is no distinct criteria, LD is generally accepted to be a disease which is confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes without malignant effusion, i.e., a disease that curative radiotherapy is applicable. Nearly 30% of SCLC is LD at initial diagnosis. LD-SCLC is potentially curable disease, and standard treatment is chemo-radiotherapy, especially concurrent use of chemotherapy and radiotherapy is chosen if performance status of patient is 2 or less and organ function is good. Cisplatin plus etoposide is usually administered together with radiotherapy, since the combination chemotherapy is one of the most effective regimens and also risk of radiation pneumonia is low when the combination is chosen. Median survival time of LD-SCLC is 16 to 24 months and 5-year survival is nearly 15%. On the other hand, median survival time of ED-SCLC is 6-12 months, and long-term disease-free survival is rare. Chemotherapy alone is chosen to ED-SCLC. Globally, combination of cisplatin/carboplatin plus etoposide is recognized as a standard chemotherapy. In Japanese guideline, a combination with cisplatin plus irinotecan is the first choice if tolerable. One of the reasons why standard therapy is different between western and eastern countries is based on distribution of uridine diphosphate glucuronosyltransferase (UGT) 1A1 gene polymorphisms. Although drug therapy with cytotoxic agents to SCLC used be the only successful treatment modality for metastatic lung cancer in the past century, its development now appears to slow down. To maximize the effect of cytotoxic agents, combination with immune checkpoint inhibitors or novel targeted drugs would be critical.

Abstract:
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor which accounts for 10-15% of all lung cancers[1]. It is extremely lethal with rapid recurrence and dismal prognosis. Although it is sensitive to chemotherapy with 50%-80% overall response rate (ORR), it inevitably recurs within 6 months, especially those in extensive-stage (ES) SCLC[2, 3]. However, treatment options are limited for those who relapse after first-line chemotherapy and standard options have few improvements in SCLC for several decades. How to tackle the chemo-resistant SCLC patients with rapid recurrence after first-line chemotherapy? How to prolong the effective duration of standard chemotherapy? How to improve the prognosis after the second line treatment? These tough concerns need to be addressed. Immunotherapy, especially the inhibitors targeting immune checkpoints such as cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed death-1(PD-1) and programmed death ligand-1(PD-L1), achieved great success and durable anti-tumor response across multiple tumor types[4, 5]. In terms of SCLC, the high frequency of somatic mutations[6], along with the approximately 10% incidence rate of para-neoplastic and neoplastic triggered autoimmune disease, for instance, Lambert-Eaton myasthenia[7], prompts that the SCLC is a immunogenic type of cancer and possibly, responds to immunotherapy. Therefore, several clinical trials come up then. At present, in the context of high ORR of the first-line chemotherapy treatment, the purpose of the clinical studies based on the immune checkpoint inhibitors (ICI) in the treatment of SCLC can be divided into two categories: 1) integrating ICI into standard chemotherapy as first-line regimen or maintenance therapy 2) single ICI ( nivolumab/ipilimumab/atezolizumab)/ combined with chemotherapy/combined with multiple immune checkpoint inhibitors as compelling options as second or subsequent line regmen. In summary, these regimens could be subdivided into: 1) Ipilimumab plus chemotherapy 2) PD-1/PD-L1 inhibitors alone or together with chemotherapy 3) combination of CTLA-4 blockade and PD-1/PD-L1 inhibitors with or without chemotherapy. Since the outcome from a phase III trial regarding ipilimumab plus chemotherapy was dismal[8], the paradigm has been shifted from single CTLA-4 blockade plus chemotherapy to PD-1 inhibitor, and indeed, PD-1 inhibitor alone or combined with CTLA-4 blockade seem more promising in the treatment of SCLC. In 2017 ASCO, a phase II study evaluating the role of maintenance pembrolizumab in newly diagnosed SCLC patients demonstrated that this regimen didn’t improve the PFS (median PFS: 1.4 months). However, an exploratory analysis from this study suggested that patients with expression of PD-L1 in tumor stromal interface had better outcome( longer PFS: 5.5 months VS 1.3 months and OS: 10.1 VS 7.2 months)[9]. Multiple trials are ongoing to define the roles of this drug in SCLC patients, for instance, pembrolizumab plus chemotherapy in first-line settings (Keynote011), in second or subsequent settings. Additionally, a phase III study is ongoing to determine the effectiveness of nivolumab monotherapy compared to chemotherapy in relapsed SCLC (Checkmate 331). As for atezolizumab, a phase I/III study is underway to evaluate the efficacy of combination of atezolizumab and carboplatin/etoposide as first-line treatment of ES-SCLC (IMPOWER 133). In terms of combination of PD-1 inhibitors and CTLA-4 blockade, Checkmate 032, the first trial evaluating the combination of nivolumab and ipilimumab in the treatment of patients with SCLC who had progressed after one or more treatment regimens was reported in ASCO recently. Both nivolumab monotherapy and nivolumab plus ipilimumab showed promising anti-tumor activity with durable responses and manageable safety profiles[10]. These data prompted nivolumab alone or nivolumab-ipilimumab combination regimen to be incorporated into NCCN guidelines for SCLC as second line treatment recommendation. Moreover, in 2017 ASCO, the updated data from Checkmate032 was reported. With longer follow up in non-randomized cohort, the response remains encouraging. 2-year OS could be achieved 14% and 26%, respectively in monotherapy and combination therapy[11]. In this setting, a phase III trial, termed Checkmate451 assessing the role of nivolumab monotherapy, nivolumab-ipilimumab combination and placebo as maintenance therapy in ES-SCLC and a phase II trial, STIMULI, in LS-SCLC were initiated. Plus, a phase II trial regarding the tremelimumab and durvalumab with or without radiation in relapsed SCLC patients is ongoing and more data are warranted . However, many questions remain. The immune microenvironment in SCLC is distinct from other tumor types for SCLC cells express low levels PD-L1, though with high mutation burdens. In Checkmate032, there is no observation on clear association between tumor PD-L1 expression and clinical benefit. However, as mentioned above, patients with positive PD-L1 expression in the stromal interface had better PFS and OS observed in a phase II trial[9]. The prediction value of PD-L1 expression is supposed to be shifted from tumor cells to surrounding immune cells in SCLC. Thus, it is important to define a specific biomarker to predict the response to immunotherapy and explore the distinct tumor microenvironment in SCLC. Moreover, potential toxicity is not supposed to be underestimated, especially the immune-related adverse effects. Immune related side effects will happen in the course of the treatment. Close monitoring is essential and oncologists are suggested to balance the risks and benefits of immunotherapy in the clinical practice. References 1. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359:1367-1380. 2. Rossi A, Di Maio M, Chiodini P, et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol. 2012;30:1692-1698. 3. Lehman JM, Gwin ME, Massion PP. Immunotherapy and Targeted Therapy for Small Cell Lung Cancer: There Is Hope. Curr Oncol Rep. 2017;19:49. 4. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375:1823-1833. 5. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320-330. 6. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415-421. 7. Gozzard P, Woodhall M, Chapman C, et al. Paraneoplastic neurologic disorders in small cell lung carcinoma: A prospective study. Neurology. 2015;85:235-239. 8. Reck M, Luft A, Szczesna A, et al. Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol. 2016;10.1200/JCO.2016.67.6601. 9. Gadgeel SM, Ventimiglia J, Kalemkerian GP, et al. Phase II study of maintenance pembrolizumab (pembro) in extensive stage small cell lung cancer (ES-SCLC) patients (pts). Journal of Clinical Oncology. 2017;35:8504-8504. 10. Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17:883-895. 11. Hellmann MD, Ott PA, Zugazagoitia J, et al. Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): First report of a randomized expansion cohort from CheckMate 032. Journal of Clinical Oncology. 2017;35:8503-8503.

Abstract:
Small cell lung cancer (S.C.L.C.) represents approximately 15% of lung cancers and offers a unique profile of clinical and biological features) S.C.C.L. is a fast growing tumor with are estimated doubling time of 10 days, high propensity to metastatic diffusion since the early beginning of the disease, high sensitivity to chemoradiotherapy but early and common development of pleiotropic drug resistance. Unfortunately in the past 30 years very few advances have been realized in the treatment of S.C.L.C. which in most of the patients is a fatal disease with a median survival of 16-18 months in limited thoracic and 11 months in extensive disease. S.C.L.C. is the most common cancer associated with paraneoplastic syndromes because of it’s propensity to release endocrine peptides, ectopic hormones and neoantigens that can develop the para neoplastic syndromes.Paraneoplastic syndromes constitutes different and heterogeneous clinical conditions associated with cancer development, affecting various tissues at remote locations from theprimary tumour , with an unpredictable clinical behavior. In SCLC, a large number of paraneoplastic syndromes have been reported, involving different organ functions and complicating the clinical course of the disease, including endocrine, neurological and miscellaneous less frequent manifestations. The most common paraneoplastic syndromes in SCLC, can be divided in ectopic hormone-associated syndromes, and immunomediated neurologic syndromes. According to the S.C.L.C. produced hormones we can recognized among the ectopic hormone-associated syndromes, the Hyponatremia (10%) of S.C.L.C., the ectropic Cushing syndrome (5%) Hypertension reninrelated (1%), galactorrhea (1%) and hyperamylasemia (1%). S.C.L.C. has the unique feature to be often heralded or accompanied by a number of immune-mediated neurologic syndromes, the Lambert-Eaton myastemic syndrome 1%, the limbic encephalopaty and the encephalomyelitis, the sensory polyneuropathy, the cerebellar degeneration the opsoclonus myoclonus, all accounting for less than 1%. In most of the cases the neurological symptoms develop before the onset of clinical overt S.C.L.C manifestation and the stage seems not to be related to the presence of paraneoplastic neurological syndrome, whose evolution usually mirrors the behavior and the clinical manifestation. In most of the cases the starting of systemic chemoterapy can induce a dramatic improvement of neurological symptoms in advance to clinical response, and viceversa the worsening of the neurological condition can indicate progressive disease and resistance to the treatment.The study and the improved understanding of pathophisiolgy mechanisms of paraneoplasic syndromes in SCLC can contribute to elucidate the natural history of a fascinating and still largely unknown disease which was erroneously predicted to be a potential curable disease in the eighty years. From that time the treatment strategies and the therapeutic results have been only marginally improved and the undersanding and resolution of paraneoplastic syndromes can contribute substantially to the cure improvement of SCLC.

Abstract:
The worldwide toll in mortality due to small cell lung cancer (SCLC) is still unacceptable. Based on an analysis conducted by the National Cancer Institute US (NCI) in 2014, there are five priorities in SCLC that need to be addressed by scientists and clinicians: 1. Development of better research tools for the study of SCLC; 2. Conduct of comprehensive genomic profiling of SCLC; 3. Creation of new diagnostic and prevention approaches for SCLC; 4. Therapeutic development efforts; and 5. Study of mechanisms underlying both high rate of initial response and rapid emergence of drug and radiation resistance. These priorities are being currently addressed by the newly established NCIs SCLC Consortium, an effort to coordinate and network investigators focusing on pre-clinical studies of the disease. The SCLC Consortium currently includes a coordinating resource center, members with their individual projects, and associate members funded through other grant mechanisms. The Principal Investigator of the Coordinating Center is Dr. Charles Rudin from the Sloan Kettering Institute for Cancer Research in New York, NY and he is joined by Drs. John Minna (University of Texas South Western), Tyler Jacks (Broad Institute), You Shyr (Vanderbilt University), and Afshin Dowlati (Case Western Reserve University). The Coordinating Center provides administrative, meeting, and communication support, a bioinformatics database, centralized tissue banking and virtual biospecimen database, centralized biostatistics, cell line and animal model repository. The four Research Projects in the Consortium were selected by a standard peer review process and they focus on: 1) the use of extracellular vesicles for early detection of SCLC; 2) preclinical development of a DLL3-targeted theranostic for SCLC; 3) targeting the transcriptional and epigenetic landscape in chemo-refractory SCLC; and 4) novel therapeutic approaches for enhancing anti-tumor immunity in SCLC. The first project, led by Drs. Serge Nana-Sinkam from Virginia Commonwealth University and James Lee from Ohio State University attempts to carry out an analysis of nucleic acids found in exosomes using molecular beacons contained on biochips to detect specific mRNA and miRNA sequences. The hypothesis is that unique nucleic acid differences in exosomes exist that can differentiate among normal smokers and SCLC patients. The goal is to obtain a biochip that can be used as a biomarker for early stage SCLC that can be applied broadly to blood samples. The second project is conducted by Dr. John Thomas Poirer (Sloan Kettering Institute for Cancer Research) and it builds on the earlier clinical success of the antibody-drug conjugate against a ligand of the Notch pathway, DLL3, selectively expressed on the surface of SCLC cells. The new project will develop a radioimmunotherapy reagent targeted against DLL3, expressed in 70-80% of SCLC. If even moderately successful, this work may provide therapeutic options to some patients who currently have none. The third project designed by Drs. Kwok Kin Wong from New York University and Nathanael Schiander Gray from Dana-Farber Harvard Cancer Institute aims to define transcriptional and epigenetic factors that contribute to chemotherapy-resistance in both tumor cells and the surrounding microenvironment and assess the efficacy of transcriptional CDK inhibitors alone or in combination with novel investigational therapies, utilizing in vivo SCLC models. This is a compelling, well-rationalized, project that pursues an important new direction for both understanding the fundamental biology of SCLC tumor cells and exploiting that information for therapeutic development. The latest addition to the Consortium is project 4 by John Heymach, Lauren Byers (both from the University of Texas MD Anderson Cancer Center), and Julien Sage from Stanford University. The investigators seek to identify improved treatment strategies in SCLC using immunotherapeutic agents targeting the PD1 pathway. The overarching goals of this project are to exploit the intersection of DNA damage repair and immunotherapy in SCLC for new targets and therapies, and to enhance the benefit of existing therapeutic options or ongoing clinical studies. Besides the main Research Projects, the Consortium serves as a hub for Associate Members with additional SCLC projects funded through NCI grants. The topics of these projects include new determinants of acquired resistance, Notch signaling in SCLC, molecular and cellular mechanisms of metastasis, therapeutic strategies for targeting PARP1, kinase dependent chemotherapy resistance mechanisms, and investigating CREBBP as a tumor suppressor. The NCI accepts applications for membership in the SCLC Consortium through two program announcements PAR-16-049 and PAR-16-051. International teams are encouraged to apply.