Virtual Library

Background:
The Chronic Respiratory Questionnaire short form (SF-CRQ) is frequently used in patients with obstructive pulmonary disease and it has demonstrated excellent psychometric properties. The CRQ (both in its original or short form) has not been previously used in the assessment of lung cancer patients’ HRQL. Therefore this study, being part of a larger therapeutic trial, aims to evaluate the psychometric properties of the SF-CRQ in patients diagnosed with thoracic malignancies.

Methods:
Forty-six patients were assessed at two time points (with a four-week interval) using the SF-CRQ, the modified Borg Scale, five numerical rating scales related to perceived severity of breathlessness, and the Hospital Anxiety & Depression Scale. Internal consistency reliability was investigated by Cronbach’s α reliability coefficient, test-retest reliability by Spearman-Brown reliability coefficient (p) and convergent validity by Pearson’s correlation coefficient between the SF-CRQ, and the conceptual similar scales mentioned above and content validity was also explored. A principal component factor analysis was performed.

Results:
The internal consistency was high, indicated by an α=0.88 (baseline) and 0.91 (after one month). The SF-CRQ had good stability with test-retest reliability ranging from r=0.64 to r=0.78, p<0.001. Factor analysis suggests a single construct in this population showing that the items of the SF-CRQ scale are strongly correlated and represent the conceptual meaning of the underlying construct, which is the quality of life of lung cancer patients as related to breathlessness.

Conclusion:
The data analyses supported the convergent, content, and construct validity of the SF-CRQ indicating this is a valid and reliable instrument for the assessment of quality of life related to breathlessness in lung cancer patients. This study is the first study that provides initial data of the psychometric properties of the SF-CRQ in lung cancer patients, and further validation with larger sample sizes and across different settings and dyspnea severity is needed.

Background:
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors such as gefitinib and erlotinib are dependent on gastric pH for absorption which may be affected by concomitant gastric acid suppressive therapy (AS) with proton pump inhibitors and histamine 2 antagonists. We sought to determine the effect of gastric acid suppressive therapy on overall survival (OS) in patients treated with EGFR tyrosine kinase inhibitors.

Methods:
Patients with advanced stage non-small cell lung cancer harboring EGFR mutations treated with EGFR tyrosine kinase inhibitors were retrospectively identified. Medical records in our single institution were reviewed from 1[st] January 2008 to 30[th] December 2013. Patient clinico-pathological characteristics,use of gastric acid suppressive therapy and the overall survival were obtained. Statistical analysis was performed using chi[2], log rank test and cox regression where indicated

Results:
We identified 191 patients. The median age of patients was 64 years (range: 30-89) ,109 (57.1%) were female, 117(61.3%) were never smokers, 91 (47.6%) harbored EGFR exon 19 deletion and 144 (75.4%) received EGFR tyrosine kinase inhibitors as first line treatment. 55 (28.8%) patients received gastric acid suppressive therapy The groups of patients who received gastric acid suppressive therapy and those who did not receive gastric acid suppressive therapy were similar with regards to gender, smoking status, and type of EGFR mutations, Charlson co-morbidity score and Kanorfsky performance status. Brain metastasis at the time of diagnosis was more frequent in the group who received gastric acid suppressive therapy compared with the group who did not receive gastric acid suppressive therapy (61.8% v 35.3% respectively, p= 0.001). The median overall survival in the total patient population was 13.1 months (95%CI 11.7-15.2 months). On multivariate analysis, presence of visceral metastasis at diagnosis was associated with a worse overall survival (HR: 1.53, 95% CI:1.10-2.13 p value: 0.012). However a Karnofsky performance score of 90-100 was associated with an improved overall survival (HR: 0.69, 95% CI; 0.49-0.97 p value: 0.031). The median overall survival OS in patients with gastric acid suppressive therapy was 11.9 months (95%CI: 9.90-16.94 months) and 14.5 months (95%CI: 11.74-15.95 months) in the group not receiving gastric acid suppressive therapy. (HR: 0.98, 95% CI: 0.69-1.40 p value: 0.934)

Conclusion:
Although the group of patients who were treated with gastric acid suppressive therapy had a numerically poorer overall survival compared to the group who did not receive gastric acid suppressive therapy, this difference was not statistically significant. Based on the our analysis, the use of gastric acid suppressive therapy concurrent with EGFR tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer harboring EGFR mutations did not affect overall survival.

Background:
Cancer cachexia (CC) is a wasting syndrome without durable palliative intervention observed in 50% of all solid tumors and responsible for 20-30% of all cancer-related deaths. Knowledge of prevalence and survival outcomes for lung CC patients by clinical and pathologic parameters is scarce due to limited series. We provide the largest, most detailed evaluation of lung cancer patients for cachexia, enabling new clinical and biologic insight.

Methods:
A retrospective review of 1627 patients with non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) treated at UT Southwestern Medical Center between 1/1/2006 and 12/31/2013 was performed. Patient demographics and tumor characteristics including histology, stage, grade, and size were collected. Each patient was assessed for CC at diagnosis, retrospectively identified by the presence of significant weight loss (>5% loss over 6 months in patients with BMI >= 20; >2% in patients with BMI <20). Overall Survival (OS) was evaluated, and clinicopathologic factors predicting for cachexia development were identified with stepwise logistic regression (SLR).

Results:
Overall, CC independently predicted reduced OS on stepwise Cox regression (1.21 OR). 419/1468 (28.5%) of all NSCLC and 57/159 (35.8%) of all SCLC patients had CC. Within NSCLC, CC was documented in 107/350 (30.6%) of squamous carcinomas and 208/761 (27.3%) of adenocarcinomas. CC significantly reduced NSCLC OS across all stages: 21.0 vs. 9.9 months (log-rank P<0.0001). However, CC did not significantly affect SCLC OS: 10.5 vs. 9.9 months (log-rank P=0.46). Prevalence of CC in NSCLC for stages 1, 2, 3, and 4 was 48/309 (15.5%), 16/124 (12.9%), 118/377 (31.3%), and 237/658 (36.0%), respectively. OS for NSCLC -/+ CC for stages 1, 2, 3, and 4 were 67.1 vs. 45.0, 35.4 vs. 37.2, 20.9 vs. 14.3, and 11.4 vs. 6.6 months, respectively (log-rank P=0.0427, =0.5803, =0.0155, <0.0001). OS for squamous histologies -/+ CC for stages 1, 2, 3, and 4 were 56.9 vs. 22.7, 19.3 vs. 19.5, 18.6 vs. 14.3, and 7.8 vs. 5.8 months, respectively. OS for adenocarcinoma histologies -/+ CC for stages 1, 2, 3, and 4 were 86.4 vs. 51.1, 43.9 vs. 23.3, 28.6 vs. 19.2, and 13.0 vs. 8.2 months, respectively. On univariate analysis, grade, stage, tumor size, and tobacco use were significant factors in the development of CC in adenocarcinomas, while stage alone was significant in squamous carcinomas. On SLR, stages 3+4 were associated with increased odds of CC development as compared to stages 1+2 (OR 2.6, P=0.0004) in squamous histologies. On SLR, tumor size >50mm was associated with increased odds of CC development when compared to 0-20 mm (OR 4.3, P<0.0001) in adenocarcinomas.

Conclusion:
Cachexia significantly impacts OS in lung cancer, primarily for NSCLC. Fundamental differences of CC prevalence and associated OS were observed for the first time between different histologies and stages. Though CC can manifest in all stages, increased stage and tumor size were independent, significant predictors for CC in squamous and adenocarcinoma populations, respectively. Understanding which clinicopathologic characteristics impact CC prevalence and OS may offer insight into the syndrome’s clinical and biologic underpinnings, providing impetus for novel therapeutics and prediction methods.

Background:
Family caregivers (FCGs) of lung cancer patients experience decreased quality of life (QOL) and psychological distress related to their caregiving role. Although there is extensive data about the significant impact of lung cancer surgery on patient QOL, little is known about the impact on FCGs. We describe QOL, psychological distress, and perceived caregiver burden outcomes among FCGs of patients undergoing lung cancer surgery.

Methods:
As part of a National Cancer Institute-supported Program Project (P01) testing the effect of a palliative care intervention in patients with non-small cell lung cancer, patients and their FCGs were sequentially enrolled into a usual care group or an intervention group, which received interdisciplinary care planning as well as a comprehensive assessment and education by an advanced practice nurse. For this subset analysis, we included only those patients who underwent surgery and their FCGs. Outcomes were assessed at baseline (pre-operatively), at 6-7 weeks, and 12 weeks after surgery. FCGs were assessed using the following validated measures: distress thermometer for psychological distress, family version of QOL scale in four domains (physical, psychological, social, and spiritual well being), and Caregiver Burden Scale. Patients were assessed using distress thermometer and FACT-L for QOL domains.

Results:
QOL data were available for 41 pairs of patients and FCGs (10 usual care and 31 intervention). Psychological distress levels were highest for patients (3.8/10) and FCGs (5.1/10) before surgery, then decreased six weeks after surgery for both groups respectively (2.9/10 and 4.2/10). Patients’ distress continued to decrease at 12 weeks (2.2/10, p = .001), but FCGs did not (4.4/10, p = .0.157). Although patients had improvements in all domains between 6 and 12 weeks, FCGs did not experience similar improvements in most domains (Figure 1). Likewise, there was no significant decrease in caregiver objective burden over the 12 weeks (21.1 vs. 21.3, p = 0.942). Patients in the intervention group had improved total QOL at 12 weeks compared to usual care (Total FACT-L 116 vs. 94, p <.001). In contrast, there were no significant differences between the usual care and intervention groups in QOL of FCGs.

Conclusion:
FCGs of lung cancer patients experience significant psychological distress. FCGs continue to have decreased QOL 3 months after lung cancer surgery. The trajectory of QOL for FCGs does not mirror that of patients. FCGs play an important role in patient recovery and greater research is needed to understand how they are impacted by thoracic surgery. Figure 1

Background:
Cancer cachexia (CC) and sarcopenia occur in up to 60% of patients with lung cancer. With better knowledge of the pathophysiology leading to cancer cachexia, multiple recent therapeutic trials have been directed at these mechanisms. Additionally, it is clear that cancer cachexia is associated with several negative outcomes. Inherent in all studies for this problem, is the ability to measure components of cancer cachexia, such as skeletal muscle mass (SMM). SMM assessment by CT scanning (SD <1.2kgs) is more accurate than either Dual X ray absorptiometry (DXA, SD 3kgs) or than bioelectrical impedance (SD 9.3kgs). A single slice on CT at the third lumbar vertebra (L3) correlates highly (r=0.924) with total body SMM in healthy individuals. While CT measurement at L3 is often used in cancer cachexia trials, the problem exists that routine chest CT scans rarely extend to L3; thus routine chest CTs will not allow inclusion of most patients. Importantly, prior studies in normal subjects demonstrated high correlation (r = 0.903) of SMM measurement at L1 with L3; however, the utility and feasibility of L1 measurement of SMM has not been assessed in patients with cancer.

Methods:
We enlisted patients with NSCLC and performed SMM measurements at L1 using Slice-O-Matic software for muscle mass in the Hounsfield unit range of -29 to +150. Patients were assessed for accuracy of using the L1 level for imaging quality and the ability to use the software properly.

Results:
56 patients with NSCLC (99 CT assessments) were enlisted at three institutions. Characteristics: 45% female; medians: age 60, KPS 80%; BMI 24.96, weight 72.38 kg, SMM index 58.89. Sarcopenia was detected in 29% of patients (58% of males <55.5 cm2/M2; 6% of females <38.5cm2/M2) with all having normal or overweight BMI. Overall, of the 99 CT images, 92.9% (95% CI = 88%-98%) included L1. 5 additional images (5%) were difficult to evaluate for SMM due to ascites or effusions; also, 1 patient was too obese for proper imaging; 2 had poor quality scans. Importantly, inclusion of L1 differed among the 3 institutions ranging from 80.6% to 97.2%. Also noted, as previously reported with assessment at L3 (r = 0.35), the correlation of BMI with SMM in this study at L1 was low (r = 0.36) as well.

Conclusion:
This study indicates that: 1) SMM assessment at L1 is achievable on routine chest CT in patients with lung cancer, with 93% of patients having images at this level, and 93% have acceptable quality for SMM evaluation; 2) although L1 is included in the majority of patients at all 3 institutions, this may vary by different radiologic protocols; 3) the low correlation and poor sensitivity of BMI to identify muscle mass loss is equally demonstrated at both L3 and L1, and 4) use of L1 enhances patient evaluation for SMM without needing additional testing or radiation exposure, and allows many more patients with NSCLC to have assessment of SMM in clinical trials and patient management. Funding in part: NIH/NCI 1 R01 CA157409-01A1

Background:
Cancer-related fatigue (CRF) is a common and persistent symptom experienced by patients with Non Small Cells Lung Cancer (NSCLC). It is produced by multifactorial factors including those associated to the disease itself, comorbidities, life style and/or treatment. Malnutrition is found in up to 80% of patients with advanced cancer and could be associated with the presence of CRF. Both, malnutrition and fatigue have a negative impact on many aspects of patients’ Health-related quality of life, treatment compliance and prognosis. The aim of this study was to associate nutritional status variables with the occurrence of CRF in patients with advanced NSCLC.

Methods:
Patients with advance stage NSCLC under different lines of treatment were prospectively evaluated. Fatigue was assessed by the FA-13 (EORTC) test; malnutrition and anorexia were diagnosed using Subjective Global Assessment (SGA) and (S/AC-12) FAACT, respectively. Weight loss in the last six months was calculated, albumin and hemoglobin levels were used as biochemical parameters of nutrition.

Results:
129 patients were included, 75 were female (58%), the mean age was 61.9±13.8 years, Adenocarcinoma histology was present in 92 patients (71.4%) and the rest were classified as other histology, 90 patients (69.8%) were in ≤2[nd ]line of treatment, 106 patients (83.5%) had a functional status between 0-1 and the rest between 2-3, according to SGA 79 patients (64.8%) had any grade of malnutrition, 94 patients (75.8%) had a weight loss ≥10kg in six months, 25 patients (19.4%) were diagnosed with anorexia, albumin mean was 3.8mg/dl and 55 patients (32%) had less than that, as well as Hemoglobin level mean was 12.7 mg/dl and 61 patients (35.5%) had a valor less than it. Nutritional variables associated with CRF are shown in Table 2. Nutritional variables as Malnutrition, weight loss ≥10% and albumin were related with higher presence of physical, emotional, cognitive and daily-life fatigue. Clinical variables as histology, line of treatment and functional status were analyzed and just poor functional status was associated with higher presence of physical, emotional, cognitive and daily-life fatigue (p≤0.01). Table 2.- Nutritional status variables related fatigue

n=129		Physic-FS	p	Emotional-FS	p	Cognitive-FS	p	Daily-life-FS	p	Social-FS	p
Nutritional-Status	Malnourished Wellnourished	42 25	<0.01	42 25	<0.01	42 25	0.001	33 33	0.001	0	0.224
Weight-loss (≥10% 6 months)	≥10 <10	50 33	0.003	50 33	0.001	42 25	0.002	67 33	0.006	0	0.273
Anorexia	Yes No	67 33	<0.01	58 33	<0.01	58 25	<0.01	67 33	<0.01	33 0	0.02
Albumin-(gr/dL)	<3.8 ≥3.8	42 33	0.004	42 25	0.003	42 25	0.004	33 33	0.002	0	0.212
Hemoglobin-(gr/dL)	<12.7 ≥12.7	42 33	0.077	42 25	0.04	42 25	0.012	33 33	0.227	0	0.023

FS: fatigue score

Conclusion:
Malnutrition, weight loss, anorexia, hypoalbuminemia and low hemoglobin are associated with CRF. Hence, timely nutritional evaluation should be considered in NSCLC patients. Early nutritional treatment could help to reduce treatment and disease related fatigue. Nutritional and psychological support might confer beneficial effects.

Background:
Depression is extremely common in elderly lung cancer patients. However, it is extremely difficult to predict or develop predicting tools. There is some early studies suggesting using psychosocial factors. Unfortunately there appears to be no data from developing countries, more so from India. This is an attempt to initiate the process.

Methods:
Design: A descriptive correlational study. Setting: Multispeciality Hospitao Oncology OPD Sample: Indian Lung Cancer Patients with cancer aged 50–88 years. Methods: Fisher’s exact and Wilcoxon rank-sum tests were used to evaluate differences between patients who were possibly depressed (Geriatric Depression Scale) or not.Multivariate linear regression statistics were used to identify the psychosocial factors that predicted higher depression scores. Education and gender were included as covariates. Main Research Variables: Religiosity, emotional support, collectivism, perceived stigma, and depression.

Results:
Participants (N = 67) had a mean age of 65 years (SD = 8.4), and a majority were well-educated, insured, religiously affiliated, and currently in treatment. Participants who were in the lowest income category, not married, or male had higher depression scores. The multivariable model consisting of organized religion, emotional support, collectivism, education, and gender explained 52% (adjusted R2) of the variation in depression scores. Stigma became insignificant in the multivariable model

Conclusion:
Psychosocial factors are important predictors of depression. Emotional support and organized religious activities may represent protective factors against depression, whereas collectivism may increase their risk Implications for Management : Care providers need to be particularly aware of the potential psychological strain for patients with collectivist values, experienced stigma, disruptions in church attendance, and lack of emotional support. In addition, the treatment plans for these patients should ensure that family members are knowledgeable about cancer, its treatment, and side effects so they are empowered to meet support needs. Knowledge Translation: Among Indian Lung Cancer Patients patients with cancer, emotional support and reassurance from family and friends that they will not abandon them decreases the likelihood of depressive symptoms and minimizes the impact of stigmatizing responses, but the perception that the illness is placing a strain on the family increases the likelihood of such symptoms. Emotional support likely is a stronger predictor of depressive symptoms than religious service attendance

Background:
The treatment of recurrent malignant pleural effusion (RMPE) has a palliative purpose. Pleurodesis is the most used method. However, not all the procedures are effective, in part because of the lung entrapment by the visceral pleura, preventing the contact between the pleural surfaces. The behavior of the pleural cavities submitted to pleurodesis has not been studied more objectively to date. Moreover, how evolve cases with good initial lung expansion and those with poor expansion?

Methods:
Prospective study including 131 patients with recurrent malignant pleural effusion candidates for treatment with bedside pleurodesis with silver nitrate or mineral talc. Each patient underwent two chest CT scans, one right after the drainage (CT1) and another 30 days after pleurodesis (CT30). A thoracic radiologist has calculated pleural volume using the software Aquarius Intuition Viewer® (Terarecon). The evaluation of lung expansion was based on residual pleural volume on CT1 and the radiological evolution on the difference between the pleural volumes on CT30 and CT1 (Delta volume). The pleural volumes on CT1 were arbitrarily classified into small cavity after the drainage (volume <500mL) and large cavity after the drainage (volume ≥500 mL). After that, the Delta volume was classified in unchanged (≥-268.77 and ≤254,49 mL), negative (<-268.77 mL) and positive (> 254.49 mL). For such we used the average of the numerical variable and half of the standard deviation upwards and downwards. The clinical effectiveness was evaluated as the need for additional procedures to control symptoms.

Results:
We evaluated 87 patients of a total of 131 recruited. The median pleural volume on CT1 was 377 (IR: 171-722) mL and 386 (IR: 164-726) mL on CT30, and has no significant difference between them (p= 0.753). The clinical effectiveness was observed in 86.2% of patients. We found 54 patients (62.06%) in the small cavity after the drainage group and 33 (37.93%) in the large cavity group. Clinical effectiveness was 92.6% and 75.8% respectively. There was significant difference (p= 0.051), with an odds ratio of 4.00 (CI: 1.098 to 14.570) in favor of the small cavity. Among patients with small pleural cavity, 27.77% progress with a significant accumulation of fluid, 66.66% did not show significant changes and 5.55% have decreased pleural volume. Clinical effectiveness was 86.7%, 94.4% and 100% respectively with no significant difference (p= 0.552). Among patients with large pleural cavity, 21.21% progress with an even greater volume of pleural cavity, 27.27% did not show significant changes and the majority (51.51%) evolves with a decrease in the pleural volume. Clinical effectiveness was 57.1%, 77.8% and 82.4% respectively with no significant difference (p= 0.418).

Conclusion:
Almost two third of the patients with RMPE treated with pleurodesis had good lung expansion, while just over one-third had a bad one. Those with good expansion had 4 times higher chances of clinical success. Among poor lung expansion patients, more than half had significant reduction of pleural volume in 30 days, while a fifth had a significant accumulation.

Background:
Pericardial effusion (PE) is a complication of late-stage cancer and operative pericardial drainage is its standard treatment. However, in many patients PE is an end-of-life event and some never leave the hospital despite the procedure. The main objective of this study was to identify predictors of hospital discharge in patients with cancer who coursed pericardial effusion and underwent operative pericardial drainage. We also looked at predictors of ICU discharge and overall survival and also factors that might be associated with paradoxical hemodynamic instability (PHI).

Methods:
Retrospective study carried out in a tertiary cancer center. We included all patients with known malignancy who coursed with PE and underwent surgical pericardial drainage from 2011 to 2014. Patients who underwent previous pericardial drainage or only needle pericardiocentesis were excluded from the study.

Results:
Out of the 90 patients included in this study, fifty one were discharged from hospital (56%). Renal failure and pulmonary embolism negatively influenced the chances of hospital discharge [OR 0,247; p=0,039 and OR 0,293; p=0.089, respectively]. On the other hand, patients who received recent chemotherapy were more likely to leave the hospital (OR 3,9; p=0,009). 55 patients (61%) were discharged from ICU. Renal failure was the main determinant of that (OR 0,284 (p=0,047)). Mean survival was 138.2 days (95% CI 84,48-189,90), influenced only by ECOG status (OR 1,258; p=0,047). PHI occurred in 6 patients and all of them died within 30 days after surgery. In our series, we could not identify predictors for PHI.

Conclusion:
In this study we demonstrated that almost half of cancer patients admitted with PE requiring drainage never leave the hospital. Renal failure and pulmonary embolism are strong predictors of in-hospital death. PHI remains a serious condition with causes unknown.

Background:
The current drug evaluation model is designed at primarily optimizing therapeutic outcomes. Measures of quality of life and patient reported outcomes are often relegated as secondary endpoints. Even with excellent outcome results, there are many aspects of the patient journey that need to be addressed and improved. It is possible to improve therapeutic outcomes by addressing these other aspects of patient care. This study was concerned with elucidating these areas of unmet therapeutic and supportive needs.

Methods:
An online survey tool was used to collect lung cancer patient responses to questions about treatments, quality of life, and supportive therapies during their lung cancer treatment regimens. The various measures of outcomes, disease progression, treatments, quality of life, and side effects and their management were stratified according to lung cancer stage at diagnosis and other patient factors.

Results:
Responses from 106 lung cancer (non-small cell and small cell) patients were collected and analyzed. The study population had a significantly better 5-year survival rate compared to the national average for lung cancer patients. Only 2% of patients reported financial difficulties as a result of lung cancer. The patient population was quite homogenous (89.3% females and 90.4% white). Eighty percent of patients reported experiencing side effects from chemotherapy and of those, 86% reported that taking chemotherapy was difficult because of the side effects. Patients diagnosed at Stage II and III experienced the most side effects and received the highest average number of treatment modalities. Patients who agreed/strongly agreed that side effects affected ability to take chemotherapy experienced a significantly higher number of side effects than those patients who reported that side effects were not as bothersome. The same was seen with patients who agreed/ strongly agreed that side effects caused lifestyle disturbance. A subset of side effects negatively affected quality of life to a greater extent than other (nausea, vomiting, diarrhea, loss of appetite, and fatigue). Neuropathy and loss of appetite were the most poorly managed side effects. When asked what changes to chemotherapy administration they would like, the most common responses were oral agents or no changes.

Conclusion:
Even with excellent therapeutic outcomes, there continue to be unmet needs that can improve patient experience and quality of life. Side effects continue to be troublesome and common in cancer therapy. Side effects had negative impact on lifestyle and ability to take chemotherapy. Certain side effects are poorly managed. Better supportive care for chemotherapy-related issues can enhance patient quality of life and may further improve quality of life.

Background:
Recent development of novel cancer treatments have enabled patients to have prolonged survival; however, some patients cannot receive benefits from those effective therapies because of severe adverse effects. One of the major adverse effects that are recognized by medical staff in patients who undergo chemotherapy is taste disorder, although little is known about how to treat it. To overcome this problem, accumulating fundamental data, such as incidence rate and timing of taste disorder in cancer patients who have undergone chemotherapy, is necessary. With this in mind, we attempted to collect the data regarding taste disorder in patients with thoracic malignancy after initiation of chemotherapy as a pilot study, in order to determine the primary endpoint for subsequent intervention studies.

Methods:
All eligible patients had treatment-naive non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC) or malignant pleural mesothelioma (MPM) with ECOG performance status (PS) 0-2, and underwent chemotherapy. Written informed consent was obtained from all participants. We prospectively investigated the incidence rate and timing of taste disorder in these patients using the following two methods: i) analysis of gustatory threshold for salty taste using a sodium-impregnated test strip (SALSAVE, Advantec Toyo Co. Ltd., Tokyo, Japan); and ii) analysis of responses of a questionnaire which asked about the patient’s appetite, the timing of each taste change (sweet, salty, sour, and bitter taste), the presence of a taste in the mouth without eating any food, changes in sense of smell, tolerability against taste disorder, and the condition of the mouth and stomach after each cycle (1-4 cycles) of chemotherapy. This study was registered with the University Hospital Medical Information Network Clinical Trials Registry, identification number UMIN00007879, and approved by the Institutional Review Board of our institution.

Results:
From June 2012 to August 2014, 36 pts were enrolled. The average age was 64.5 years (range: 37-83); male/female=29/7 (81/19%); ECOG PS 0/1/2=20/12/1 (56/33/3%); NSCLC/SCLC/MPM=25/8/3 (69/22/8%), clinical stage IIIA/IIIB/IV/adjuvant of lung cancer =2/6/23/2 (6/18/70/6%), and IMIG stage III/IV of MPM=2/1. Chemotherapy regimens were as follows; cisplatin/carboplatin/pemetrexed/etoposide/ paclitaxel/others=18/14/16/8/3/7. There was a trend of increased threshold for salty taste detected by a test strip after one or two cycles of chemotherapy (p=0.10, each). Questionnaire analysis demonstrated that patients felt changes in taste after two or three cycles of chemotherapy (p=0.04, 0.005, respectively), felt changes in their sense of smell after one to three cycles (p=0.04, 0.002, 0.001, respectively), and had a reduced sensitivity to salty tastes after three cycles (p=0.02).

Conclusion:
These results suggest that using a salt test strip may detect salty taste disorder earlier than analysis of the patient’s subjective symptoms as answered in a questionnaire. The questionnaire evidently demonstrated taste disorder from various aspects in patients with thoracic malignancy receiving chemotherapy, and thus intervention using novel drugs is necessary. Further accumulation of such data is definitely warranted for further studies.

Background:
Rapid tissue donation (RTD), also known as “warm autopsy,” is a novel method of tissue procurement for research purposes where tissues from the primary tumor and metastatic sites are collected within 24 hours of patient death. These tissues provide tremendous research possibilities and hope for new cancer treatments. However, recruiting for RTD has ethical challenges such as diminishing patients’ hope and causing distress to Next of Kin (NoK). Presently there is limited RTD education, training, or protocols for biomedical researchers and healthcare professionals (HCPs) to address the psychosocial and ethical aspects of the request for postmortem tissue donation. The purpose of this study was to: i) identify barriers and facilitators to RTD recruitment and tissue collection from key stakeholders; ii) identify the RTD processes used in other organizations and programs; and iii) establish a standardized process for RTD in a Thoracic Oncology Program at a Comprehensive Cancer Center.

Methods:
Mixed methods were used for each of the 3 purposes of the study: i) formative research (surveys and focus groups) was conducted to explore knowledge, perceptions, and barriers and facilitators to patient recruitment to RTD across key stakeholders including HCPs (n= 91), cancer patients/survivors and advocates, caregivers, physicians and clinic staff (n=42); ii) semi-structured interviews with hospice staff, morgue pathologists, funeral home directors, national organ/tissue donation programs (n= 27); and iii) conducted an extensive review of the literature regarding existing models of RTD.

Results:
Results from part 1 of the study identified several barriers including use of the word “autopsy”; discussing RTD during an initial appointment; approaching patients who attended visits alone; having staff discuss RTD with patients; and expecting all physicians would want to assist with recruitment. Facilitators included identifying enthusiastic physicians; establishing that the treating physician should identify who would be a good candidate (interest and willingness); use of the word “donation”; only approaching patients who have expressed interest and are coping well with their diagnosis; engaging family members in the consenting process; developing written educational materials about RTD; and allowing family members the authority to revoke consent after patient death. Results from part 2 identified the need to use a body map to indicate metastatic sites, developing a standardized operation procedure (SOP); restricting the geographic area where patients reside to facilitate quick retrieval; enlisting the help of Hospice, providing training to staff and physicians and developing a mechanism to provide study results to NoK and recognition for donors. Results from part 3 revealed that despite more than 300 publications using tissue collected via RTD, only 1 study actually described the process for obtaining the tissues and consent. Based on these results, a 12-step RTD SOP was developed.

Conclusion:
Ethical guidelines, an SOP, and training for HCPs is needed prior to initiation of an RTD program. A verbatim script is necessary for physicians’ comfort level and to ensure consistent messaging. Our study provides important information about knowledge, attitudes, and logistics related to RTD from all stakeholders and guided the development of a RTD at a Comprehensive Cancer Center.

Background:
Many patients with cancer die in an acute hospital bed, which has been frequently identified as the least preferred location, with psychological and financial implications. This study aims to look at place and cause of death in patients with lung cancer to identify which factors are associated with dying in an acute hospital bed versus at home.

Methods:
We used data from the National Lung Cancer Audit (NLCA) linked to Hospital Episode Statistics (HES) and Office of National Statistics (ONS) records to determine cause and place of death in those with lung cancer overall. England was divided into 28 cancer Networks at the time these data were collected so we used these to assess geographical variation in place of death. We used multivariate logistic regression to compare demographic, co-morbid and tumour-related factors between those who died in an acute hospital versus those who died at home.

Results:
Of 143627 patients identified 40% (57678) died in an acute hospital, 29% (41957) died at home and 17% (24108) died in a hospice. Individual factors strongly associated with death in an acute hospital bed compared to home were male sex, increasing age, poor performance status, social deprivation and diagnosis via an emergency route (table 1). There was marked variation between cancer Networks in place of death. The proportion of patients dying in an acute hospital ranged from 28% to 48%, with variation most notable in provision of hospice care (9% versus 33%). Cause of death in the majority was lung cancer (86%), with other malignancies, chronic obstructive pulmonary disease (COPD) and ischaemic heart disease (IHD) comprising 9% collectively.

Conclusion:
A substantial proportion of patients with lung cancer die in acute hospital beds and this is more likely with increasing age, male sex, social deprivation and in those with poor performance status. There is marked variation between Networks, suggesting a need to improve end-of-life planning in those at greatest risk, and to review the allocation of resources to provide more hospice beds, enhanced community support and ensure equal access. Figure 1

Background:
Pathologic examination of NSCLC resection specimens is vital to optimal treatment. In 2004, the College of American Pathologists (CAP) issued guidelines for NSCLC reporting, which were most recently updated in 2013. We evaluated the adoption of CAP reporting elements in a regional database.

Methods:
The Mid-South Quality of Surgical Resection (MS-QSR) database includes detailed information on 2,593 NSCLC resections in 11 institutions in 5 Dartmouth Hospital Referral Regions in Eastern Arkansas, North Mississippi and Western Tennessee from 2009-2014. In 2009, we started a multifaceted educational intervention: 1. Analyzed 2004-2008 pathology reports demonstrating the quality deficit in pathology reporting. 2. Recommended adoption of synoptic reporting of CAP checklist items. 3. Embedded a surgical intervention to improve mediastinal lymph node examination at some institutions. To allow for comparisons between eras and across the post-intervention era by intervention and type of hospital, we evaluated 4 groups: pre-intervention (pre-int), post-intervention participating hospital with surgical intervention (post-int/surg), post-intervention participating hospital without surgical intervention (post-int/non-surg), and non-participating non-surgical intervention hospital (post-int/non-part). We evaluated the inclusion of each CAP checklist item and the percent of cases with all items and 6 key items reported. We also evaluated the accuracy of T and N-stage categorization. Proportions reporting each item were compared between groups using Fisher’s Exact test.

Results:
Details of the completeness of pathology reporting are shown in Table 1 by group. The percent reporting the 6 key checklist items improved significantly from 63% pre-int to 76% post-int/non-part, 86% post-int/non-surg, and 95% post-int/surg (p-value<0.0001). A similar pattern of improvement was observed for N-stage (p-value<0.0001) and T-stage (p-value<0.0001) reporting. However, we observed significant decreases in the reporting of M-stage, and therefore all key items, post-intervention (p-value<0.0001). The accuracy of N-stage reporting improved significantly from 66% pre-int to 72% post-int/non-part, 86% post-int/non-surg, and 97% post-int/surg (p-value<0.0001). A similar trend was observed for T-stage accuracy (p-Value<0.0001).

%Reporting	Pre-Int (N=1390)	Post-Int/ Non-Part (N=271)	Post-Int/ No-Surg (N=645)	Post-Int/ With-Surg (N=310)	P-Value
Specimen*	98.4	100	100	100	<0.0001
TumorSize*	97.2	99.6	98.1	99.4	0.0094
Histology*	99.8	99.6	99.5	99.7	0.59
MarginStatus*	97.1	98.5	92.6	98.7	<0.0001
T-Stage*	67.8	76.4	92.1	97.1	<0.0001
N-Stage*	66.3	76.8	89.8	97.7	<0.0001
*All Key-Items	62.7	75.7	85.7	94.8	<0.0001
Laterality	99.8	100	99.5	100	0.56
HistologicGrade	99.9	100	99.5	100	0.18
M-Stage	75.8	31.4	25	21.6	<0.0001
VascularInvasion	28.6	10.7	25	11.9	<0.0001
All Items	10.7	4.1	6.2	3.2	<0.0001
%Accurate
N-Stage	66.2	71.6	86.2	96.8	<0.0001
T-Stage	55.3	61.6	83	84.8	<0.0001

Conclusion:
There was significant improvement in reporting of CAP checklist items and the accuracy of pT- and pN-categorization. After the introduction of synoptic reporting, we observed a secular trend of improvement, shown by our post-int/non-part external control. Direct educational intervention in 2009-2010 further improved the completeness and accuracy of reports in participating hospitals. The surgical intervention provided additional benefit. Interventions to improve the quality of reporting for NSCLC are impactful on accuracy and thoroughness of reporting, thereby improving the quality of care.

Background:
Practice guidelines in non-small-cell lung cancer (NSCLC) list multiple therapy choices based on levels of evidence but cannot account for variability in patient (pt)-tumor characteristics between individual patient cases. To provide oncologists with expert guidance and feedback on choice of treatment (Tx) for specific pt scenarios, we previously implemented an interactive Web-based decision support tool in 2012, in which oncologist users input specific pt characteristics and selected among treatment options, then compared their selection with that of an NSCLC expert panel for that scenario. (Chow JTO 2015). Here we report data from version 2.0 of this tool, capturing current Tx trends for advanced NSCLC and investigating the impact of this online tool on oncology practitioners.

Methods:
V2.0 was developed based on input from 6 international NSCLC experts who provided Tx recommendations for 1st-line treatment in 96 pt case variations based on histology (nonsquamous vs squamous), EGFR mutational status (positive [+] vs negative [-]), ALK rearrangement (+ vs -), age (< 70 vs ≥ 70 years), performance status (0, 1 vs 2), smoking history (never/former light vs former heavy/current), and pt primary Tx goal (response and survival vs quality of life and low adverse events). As in V1.0, oncologist users input specific pt scenarios, then were prompted for their treatment choice. Once completed, recommendations for that scenario from each of the experts were displayed, and users were prompted to indicate whether the expert recommendations changed their treatment choice. Statistical methods: as previously described (Chow JTO 2015).

Results:
V2.0 oncologist users (N = 218 unique users) contributing 314 unique cases were 87% non-USA, 13% USA. As in V1.0, experts agreed on selection of targeted therapies (TKIs) for cases with actionable EGFR mutations and ALK translocations. Choice of a specific EGFR inhibitor by experts varied depending on region and clinical factors. By comparison, among online users of V2.0, an EGFR inhibitor was selected for 67% of EGFR-mutated cases (n = 78), while an ALK inhibitor was selected for 61% of ALK cases (n = 31). For nonsquamous histology cases without actionable mutations, use of pemetrexed was more common among experts compared with oncologist users (91% vs 48% of case scenarios). In 182 cases entered by users who reported on the impact of expert recommendations, treatment choice was affected in 86% of cases (confirmed in 71%); 5.5% disagreed with expert recommendations and 8% indicated barriers to implementing the recommendations. In comparing overall results from V1.0 (2012) to V2.0 (2014), more oncologist users were likely to select TKIs in both EGFR mutation (49% vs 67%) and ALK translocation (35% vs 61%), with a corresponding decrease in use of chemotherapy. A detailed analysis of expert vs user data will be presented, comparing V1.0 (2012) and V2.0 (2014).

Conclusion:
Expert opinions were largely unchanged between V1.0 and V2.0, while oncologist users increased use of TKIs. Most oncologist users of V2.0 either confirmed or changed treatment choices based on expert recommendations. This online tool can aid decision making, serve an educational purpose, and capture practice trends.

Background:
Electromagnetic Navigational Bronchoscopy (ENB) is an emerging technology to assist in obtaining a tissue diagnosis from suspicious lung nodules or masses. Despite the recognized advantages of having access to ENB technology, there are barriers to procure such expensive technology and effectively implement it. Acquiring and leveraging ENB technology is dependent on diverse considerations for community need, financial feasibility, patient / referral work flow and synergy with complimentary diagnostics and programs, proper coding and revenue cycle management and associated service development and marketing. There are many elements to implementing and achieving acceptable results which include the initial capital planning and service optimization, maximizing utilization, learning the techniques with enhanced competency and the handling and management of the specimens once obtained. Herein, we describe our approach to procuring the technology and early clinical results.

Methods:
ENB technology was purchased after partnering with the parent company (Covidien) and our health system's business development department, to perform a market analysis as well as a return on investment that integrated multiple service lines and hospital costs centers. From these data, a business plan was created and ultimately approved by the Foundation Board. All ENBs (SuperDimension®) were performed under general anesthesia by a single thoracic surgeon in the operating room, using a therapeutic bronchoscope inserted through a 9 endotracheal tube. Almost all procedures utilized fine needle aspiration, brushings, biopsies and washings. The biopsy phase of the procedure was done under fluoroscopy. Cytologic slide review via Rapid Onsite Evaluation (ROSE) was performed by a pathologist in the operating room in 100% of the cases. Results were obtained by retrospective review of a prospective database. Time period of study was 12/11/13-03/30/14.

Results:
72 total ENB cases were performed in the time period of which 52 were for suspected malignancy. There were no pneumothoraces or bleeding complications. Two patients had to be admitted for 23 hours secondary to poor respiratory function following procedure. Of the 52 suspected malignancies, 33 (64%) were found to be a primary lung cancer, 7 were atypical and 12 benign or non-diagnostic. 5 of the patients with atypia went on to surgical resection and were found to have lung adenocarcinoma.

Conclusion:
ENB is an emerging technology with promising results for tissue diagnosis of lung nodules suspected of being malignant. Implementing new and costly technologies in smaller healthcare systems, such as a regional hospital, can be challenging. Some of the barriers to implementation are finding the capital and justification for procuring the technology, perfecting the technique and securing support from pathology, anesthesiology and operating room time. By partnering with industry and our business department, we were able to justify procurement of ENB technology. In our first 72 cases, 52 were for suspected malignancy. A diagnosis of lung cancer was achieved in 64% of lung lesions, with a low complication rate (2/72). Our results compare favorably to published results of trans thoracic needle biopsies as well as within our own health system. Initiating and implementing an ENB program in a community setting is feasible with acceptable results.

Background:
Endobronchial Ultrasound (EBUS) has become an established modality for pathological mediastinal staging for lung cancer and in some centers, is used at the exclusion of mediastinoscopy, the traditional gold standard. Herein, we describe our early results of EBUS, in a community setting, for mediastinal pathologic staging for lung cancer and compare it to concomitant mediastinoscopy.

Methods:
All EBUS procedures were performed in the operating room under general anesthesia, with a Pentax scope introduced through a 9 endotracheal tube, by a single thoracic surgeon. The Pentax needle was used early in the series and the Cook needle later. Rapid Onsite Evaluation (ROSE) for immediate cytologic evaluation of specimens was performed in 100% of the cases. For lung cancer staging patients, mediastinoscopy was performed immediately after the EBUS under the same anesthetic. This was an outpatient procedure. Study period was 04/21/14-04/13/15. Data was collected from a retrospective review of a prospective database.

Results:
There were 40 EBUS cases performed during the study period. There were no complications. 36 were performed for cancer diagnosis/staging and 21 for lung cancer staging specifically. 27 cases had EBUS and mediastinoscopy performed concomitantly under one anesthetic and thus could be directly compared. 46 total # of lymph node stations were evaulated with EBUS and 16 (35%) resulted in no lymphocytes or diagnosis. Regarding the 21 lung cancer patients who were being evaluated for pre-treatment pathologic mediastinal staging, the average # of lymph node stations was 1.1 for EBUS vs. 3.4 for mediastinoscopy. Using mediastinoscopy as the reference for pathologic staging, the sensitivity of EBUS was 80% and specificity 100%. If the EBUS stations that yielded no lymphocytes or diagnosis were eliminated from the analysis, the sensitivity was 89% and specificity 100%.

Conclusion:
EBUS has become an established technique to pathologically stage mediastinal nodes for lung cancer. In some centers, it is used at the exclusion of mediastinoscopy (the gold standard) and in others, selectively. Our early results with the adoption of this technique and comparing it to mediastinoscopy performed concommitantly, has an acceptable sensitivity and specificity. However, we experienced a relatively high rate of absence of lymphocytes/non-diagnostic (35%), compared to mediastinoscopy (0%), and fewer nodal stations biopsied per procedure (avg. 1.1) compared to mediastinoscopy (avg. 3.4). This does represent an early experience and likely not beyond the learning curve. We will continue to utilize EBUS for lung cancer staging but will be liberal to employ concomitant mediastinoscopy until we can approach the results of our mediastinoscopy with respect to yield of lymphocytes/diagnosis and # of stations biopsied per procedure.

Background:
Delays in lung cancer diagnosis and adequate staging can both delay and affect appropriate care. It is not uncommon to take months from the time of the first suspicion of lung cancer on imaging to diagnosis, staging and treatment. We have recently adopted both electromagnetic navigational bronchoscopy (ENB) and endobronchial ultrasound (EBUS) technologies as part of our comprehensive lung cancer program. By cultivating an early referral system, within the primary care network, of suspected lung cancer and with the understanding of which patients should have pathologic mediastinal staging, we are able to both diagnose a primary lung cancer and pathologically stage the mediastinal nodes in one setting under the same anesthetic. This combined approach by a lung cancer expert, saves many potential delays of separate serial procedures often ordered by those not as familiar with lung cancer evaluation and staging. Herein, we describe our early results with this approach.

Methods:
Criteria for patient selection was a lung nodule/mass suspicious for lung cancer and either clinically positive hilar or mediastinal lymph nodes (>1cm on short axis or > 2.5 SUV on PET) or central primary, >4 cm primary or >10 SUV of suspected primary lung cancer. All procedures were performed by a single thoracic surgeon, in the operating room with the patient under general anesthesia. The Superdimension® ENB system was utilized and the Pentax® EBUS system. Rapid Onsite Evaluation (ROSE) for immediate cytologic evaluation of specimens was performed in 100% of the cases. The study period was 04/21/14-04/13/15. Data was evaluated retrospectively from a prospective collected database.

Results:
21 patients had a combination of ENB and EBUS and/or mediastinoscopy or both. 19 patients had lung cancer and constitute this analysis. A diagnosis of lung cancer was achieved in 16 patients (84%). EBUS/Mediastinoscopy was negative for cancer in 11 (59%) patients and positive for cancer in 8. (41%). There were no complications and all procedures were outpatient. The subsequent treatment of the patients were as follows: 5 definitive chemoradiation, 3 lobectomy followed by chemotherapy, 1 lobectomy followed by radiation to chest wall, 1 lobectomy, 2 clinical trials, 1 neoadjuvant chemotherapy followed by lobectomy (intent), 2 chemoradiation followed by lobectomy (intent), 1 radiation, 2 chemotherapy, 1 hospice.

Conclusion:
The ability to both diagnose lung cancer and pathologically stage the mediastinum under one anesthetic with utilization of ROSE, has several potential advantages. It allows an efficient and expeditious diagnosis and staging in select patients so they move expeditiously to the appropriate treatment and potentially skip several serial appointments and tests. Like most centers, we selectively pathologically stage the mediastinum for lung cancer patients and this is likely why in this series there is a relatively high percentage of pathologic N2 nodes (41%) found on pre-treatment pathologic staging and relatively high percentage of patients having adjuvant treatment after lobectomy. We believe this is an efficient approach for patients with a suspected lung cancer and meet criteria for pathologic mediastinal staging. Future studies will focus on quantifying the time savings differential between this approach and the more traditional approaches.

Background:
The majority of smokers start smoking at a very early age. Many teenagers, who start smoking at school age, are at increased risk of becoming adult smokers. The purpose of this study was to evaluate family and social factors that might contribute to the acquisition of smoking in Portuguese adolescents.

Methods:
A cross-sectional study was conducted in 285 healthy adolescents (15–19 years old) of both sex attending 3 high schools (public and private) from northern Portugal. The smoking habits of teenagers were evaluated according to a protocol adapted from the Global Youth Survey (GYTS), Center of Disease Control and Prevention (2001). The questionnaire consisted of 34 questions related to tobacco consumption, knowledge and attitudes towards smoking, smoking cessation, school regulation and the family role in preventing smoking. Participants were classified as: 1 - never having tried smoking; 2 - have just tried smoking (not smoked in the previous month); 3 - occasional smokers (smoked at least 1 day during the previous month); 4 - current smokers (smoked at least 20 days in the previous month). The protocol was approved by the School Direction and statistical analysis was performed with SPSS ® for the entire sample and by gender.

Results:
Of the total sample (n=285), 46% were males and 54% females with an average age of 16.6±1.2 years (minimum:15; maximum:19). About 59.6% of adolescents have experienced smoking at least once, 54% of whom were female. Although the average age of tobacco onset was between 12-15 years (64%), we found that 21% of subjects experienced smoking before 11 years of age. Regarding parents tobacco use, there is a higher percentage of smoking fathers (30.2%) versus 15.2% of mothers. 38% (n=170) of smoking adolescents do it in public places, mainly in social events (65%) and with friends (91%). It is noteworthy that the major causes referred by the adolescents to smoke were: have many smoking friends [girls: OR=44,0 (9,932- 194,92)] (p<0,001); boys: OR=33,21 (6,14-179,65)] (p<0,001) and a smoking mother [girls: OR=4,39 (1,417-13,637)] (p=0,010); boys: OR=2,627 (0,824-8,378)] (p=0,103).

Conclusion:
It should be noted that in addition to early initiation, a high percentage of adolescents smoke regularly. Having parents and/or friends who smoke are the highest prediction factors for adolescent smoking. This study highlights the importance for an effective intervention in respect to tobacco harmful effects, with strong family involvement, in order to reduce consumption and prevent its negative health consequences, as well as the morbidity and mortality associated.

Background:
Previous data suggests quality of Internet information regarding surgical conditions and their treatments is variable. However, no comprehensive analysis exists for Thoracic surgery.

Methods:
World Health Organization Health on the NET (HON) principles may be applied to websites using an automated toolbar function. We used the English, French, Spanish and German Google search engines to identify 12,000 websites using keywords related to Thoracic conditions and procedures. The first 150 websites returned by each keyword in each language had HON principles examined. We compared website quality to assess for tertile (thirds) and language differences. A further evaluation of the English site types was undertaken, with a comparative analysis of website provider types.

Results:
‘Lung Cancer’ returned over 150 million websites, whereas ‘Ravitch Procedure’ returned less than 250 thousand. Less than 10% of websites are HON accredited with differences by search term (p<0.05) and tertiles (p<0.05) of the first 150 websites but, in contrast to earlier work in other tumour streams, not between languages. Oncological keywords regarding conditions and procedures were found to return a higher percentage of HON-accreditation than cosmetic search terms. The percentage of HON-accredited sites was similar across all four languages (p<0.05). In general, the first tertile contained a higher percentage of HON-accredited sites for every keyword. Figure 1 Figure 2





Conclusion:
Clinicians should appreciate the lack of validation of the majority of thoracic websites, with discrepancies in quality and number of websites across conditions and procedures. These differences appear similar regardless of language. An opportunity exists for clinicians to participate in the development of informative, ethical and reliable health websites on the Internet and direct patients to them.

Background:
Many communities do not have a comprehensive, evidence based approach to lung cancer diagnosis, staging and treatment. This is often secondary to lack of providers in the area with expertise in lung cancer as well as lack of appropriate diagnostic and treatment modalities. Herein we describe the creation and implementation of a comprehensive lung cancer program in a community setting.

Methods:
A regional health system that serves a population with a relatively high incidence of lung cancer, recruited an experienced general thoracic surgeon, with expertise in the diagnosis, staging and treatment of lung cancer. The community had a pre-existing cardiac surgery program, a cancer center that provided chemotherapy and traditional radiation, a PET scanner and 2 CT scanners.

Results:
The study period was 9/1-2012 to 4/1/2015 which spans the time after the introduction of the general thoracic surgeon in the community to present. Under the leadership of the thoracic surgeon, the following was accomplished: 1. An extensive outreach campaign to primary care physicians as well as directly to the community regarding lung cancer awareness, modern diagnostic, staging and treatment modalities. 2. Establishment of a pulmonary nodule clinic to provide expertise and continuity in the evaluation of pulmonary nodules. 3. The establishment of a lung cancer CT screening program, 4. Evolution of the tumor board from a once a month meeting, reviewing an average of 3.1 patients retrospectively and an average attendance of 3.6 attendees to currently meeting weekly, prospectively reviewing an average of 8.6 cases per meeting (>90% lung cancer) and an average attendance of 9.3 attendees including thoracic surgery, medical and radiation oncology, pathology, social work and a rotation of surgeons, pulmonologists and primary care physicians. 5. The procurement and implementation of Electromagnetic Navigational Bronchoscopy to the community to obtain tissue diagnosis of suspected lung lesions. 6. The procurement and implementation of Endobronchial Ultrasound for the minimally invasive pathologic staging of appropriate lung cancer patients. 7. The procurement and participation in the Society of Thoracic Surgery (STS) General Thoracic Surgery Database for registration of patient outcomes and national comparison. 8. The introduction of VATS lobectomies and complex open resections. 9 400 new thoracic surgical cases to the Regional Medical Center. 10. 54 cases of multimodallity therapy for lung cancer patients compared with 4 the previous two years. 11. The establishment of stereotactic body radiation therapy (SBRT) as a treatment alternative to surgery for medically inoperable stage I lung cancer patients.

Conclusion:
It is possible to create a de novo comprehensive lung cancer program in a community setting with the appropriate expertise and leadership. General thoracic surgeons with expertise in current lung cancer diagnostics, staging and treatment options are uniquely positioned to provide the expertise and leadership to create a comprehensive lung cancer program as they are integrally part of assessing pulmonary nodules, establishing diagnosis, rigorously staging lung cancer and treatments including surgery, radiation chemotherapy and multimodality regimens. This approach could serve as a paradigm for similar communities to bring current, evidence based lung cancer diagnostics and treatment to their region.

Background:
Octogenarian patients with lung cancer are underestimated in the scientific literature. Since in our institution, the median age of patients with lung cancer is 71 years old, we decide to conduct a study to get specific data of our population over 80 years

Methods:
Retrospective observational cohort study of patients with lung cancer referred to Medical Oncology at our institution, during 4 years (2010-2013) and follow-up until April 2015. Inclusion criteria were age (80 years or older) and lung cancer diagnosis. The cohort was 41 patients

Results:
Our octogenarian patients were a 6.1% of our 672 patients seen in 2010-2013 interval. Of our 41 patients, 78% were male, and the median age is 81 years (80-87). Histologies are 88% NSCLC and 12% SCLC; in the NSCLC group, squamous carcinomas are most common (50%), followed by adenocarcinoma (26.8%). 51% patients were diagnosed in stages I-III, but only 3 patients were under radical treatment (2 surgery, 1 radiation therapy). 34% patients did not receive any oncologic treatment, only palliative care. Of the patients with active cancer treatment, 92% received first-line therapy. In the first-line group, 68% were under chemotherapy, 48% platinum doublet (more used schedules were carboplatin-vinorelbine, carboplatin-pemetrexed and carboplatin-paclitaxel), and 20% monotherapy (vinorelbine, pemetrexed and carboplatin) and 24% TKi (all EGFR mutated, with gefitinib and erlotinib). 26.8% (11) of patients received second-line treatment (10 erlotinib and 1 pemetrexed), and only 2 patients received 3 or more lines (1 patient up to 7 lines). 39 of 41 patients died (95%), and most patients die at home (95%). The median survival time is 11.19 months (CI 95% 7.84-14.53) and median overall survival is 8 months (CI 95% 4.51-11.48). In male patients, median survival time expected is 9.97 months, and in female patients, 14.88 months. Depending on the stage, stage IV patients had a expected survival of 9.94 months and stage I-III patients, 11.40 months, with no statistically significant diference. Depending on smoking status, survival is 8.95 months for ever-smokers, and 18.44 months for never-smokers (p-value: 0.035). Depending on therapy, survival in active cancer treatment group is 14.56 months, and in palliative care only group is 5.28 months (p-value: 0.001)

Conclusion:
In our cohort of elderly patients, with a small number of patients (a 6% of all the patients, maybe underreferred), we found some differences with our global lung cancer patients group. The ratio SCLC-NSCLC is quite similar (12-88% in elderly vs 14-86% in all our patients), but there is a different pattern according histological subtypes, with more squamous carcinomas in this cohort (44% vs 29.6%), and more EGFR mutations (24% vs 18%). We see that survival was better in patients receiving active cancer treatment plus best supportive care vs only palliative care. Factors influencing survival are smoking status (ever vs never-smokers) and sex. Although is essential a joint management with Palliative Care, in this particular group of patients, that are believed that cancer treatment is less useful, active cancer treatment is beneficial, if we always individualize decisions in each patient.

Background:
Conventional therapeutic solutions in NSCLC are not effective to treat the disease. Despite of all developments in understanding of the disease, mortality of lung cancer patients remains high. Recent developments of personalized therapy have given promising results in terms of improved survival of NSCLC patients. Thus, we were keen to develop a cost effective and sensitive diagnostic lung cancer panel assay for targetable mutation detection by using SNaPShot PCR technique on FFPE samples.

Methods:
Method: Multiplexed (SNaPShot) PCR was optimized to amplify hotspot regions from 9 targetable genes followed by single base extension reaction using fragment analysis on ABI 3500 Sequencer. Gene Mapper software was used for analysis

Results:
The successfully developed mutation profiling assay was divided into 3 multiplexed reactions, covering 23 actionable genotypes of EGFR, KRAS, BRAF, PIK3CA, Her2, AKT1, NRAS, MEK1 and PTEN genes. The assay was standardized and validated on 20 blood samples, 10 cell lines and 20 FFPE samples expressing good sensitivity and specificity for wild type and mutant genotypes.

Conclusion:
This In house developed SNaPShot PCR technology is robust, economical, specific and sensitive to detect actionable mutations in FFPE Adeno as well as in Squamous Carcinoma samples. Because these variants have differing genetic, biological, and clinical properties, including response to treatment, this Bench to Bedside research will lead us to correct classification of lung cancer cases and will assure that lung cancer patients receive optimum management.

Background:
While clinical guidelines provide clinical decision support for selection of agent, combination, and order of administration, there are few studies that provide a comprehensive description of contemporary advanced NSCLC treatment patterns in patients following platinum therapy over time; there are limited recent US data on practice patterns and outcomes for advanced NSCLC patients following chemotherapy. The purpose of this study is (1) to describe patient flow from advanced NSCLC diagnosis to anti-cancer treatment following completion of a platinum regimen, and if EGFR mutation or ALK translocation positive, an appropriate TKI; (2) to describe the characteristics of advanced NSCLC patients treated with anti-cancer therapy following platinum therapy and, if EGFR mutation or ALK translocation positive, an appropriate TKI; to describe anti-cancer treatment patterns following completion of platinum therapy and, if EGFR mutation or ALK translocation positive, an appropriate TKI.

Methods:
Retrospective EMR database cohort study using data from a cloud-based Oncology Electronic Medical Record (EMR) system with 220 cancer clinics, 700 community-based cancer treatment clinics, 1750 clinicians, and 725,000 active cancer patients, representing 17% of incident cases in the United States. The data represents lab values and physician notes from both structured and unstructured data. Variables of interest include demographic, disease-related, biomarker testing-related, anti-cancer treatment. Treatment patterns include regimens by line of therapy, agents and number of doses administered or prescribed, and distribution of dosage strengths. Analyses will be conducted by histology and EGFR/ALK status (among non-squamous cell carcinoma patients). Data will be analyzed descriptively. Overall survival, if data are available, will be estimated using a series of Kaplan Meier curves, with median OS (95% confidence interval) reported.

Results:
Approximately 1598 patients with advanced NSCLC initiating a line of therapy after completing a platinum regimen and, if EGFR mutation or ALK translocation positive, an appropriate TKI between January 1, 2013 and October 31, 2014 will be followed until April 30, 2015. Preliminary results identified 6536 patients with advanced NSCLC; of these, 5048 (77.2%) received any 1L treatment after advanced NSCLC diagnosis with 3786 (57.9%) receiving platinum-based chemotherapy as 1L treatment. Among the final cohort of patients (n=1598), the majority were men (54.0%) initially diagnosed with stage IV disease (68.5%) at age 66. The distribution of histological subtypes in the sample included non-squamous (74.4%), squamous (21.0%), and NOS (4.6%). Treatment patterns will be described according to histology and biomarker status at index date. Patient characteristics and overall survival will be reported by histology, biomarker status at index date, and regimen type.

Conclusion:
Results from this study will describe treatment patterns in the second-line setting, prior to the introduction of newer therapies, such as anti-PD1/PD-L1 inhibitors and angiogenesis inhibitors. Additionally, it will advance current understanding of the specific patterns of 2L care for patients being treated with anti-cancer therapy in the real world of community settings.

Background:
Cancer has been associated with immuno-surveillance dysfunction resulting to failure in identification and removal of malignant cells, followed by subsequent proliferation. Immune cell therapy aims to restore this immuno-surveillance function and manages micro-metastasis. DC/CIK (dendritic cell/cytokine-induced killer cells) an immune-based-maintenance therapy for advanced non-small cell lung cancer has been reported to improve progression free survival in several studies. Our early study suggested limited advantage of autologous DC vaccination in advanced NSCLC, hence, we proceeded to evaluate the response of a patient with Stage IV NSCLC to DC/CIK.

Methods:
The patient, 43-year-old nonsmoker male with family history of maternal breast cancer signed an informed consent to undergo the cell therapy protocol institutionally approved by Ethics Review Board of Lung Center of the Philippines. The patient earlier diagnosed with Stage IV NSCLC in November 2013, underwent chemotherapy of two cycles of Paclitaxel and Carboplatin and subsequently Erlotinib following partial remission. Patient had no severe existing medical condition that affected protocol compliance. The patient enrolled in November 17, 2014, and underwent hematology clearance, hematopoietic stem cell (HSC) mobilization with GCSF injection and leukapheresis. HSC’s recovered from the buffy coat were propagated in-vitro using standard procedures to produce dendritic cells and cytokine induced killer cells. Three DC/CIK treatments were given at three-week intervals consisting of 25-28x10[6] DC primed with mixed peptide antigens based on personalized circulating tumor cell (CTC) RT-PCR profile and 10-20x10[6] CIK. The blood IFN-Y level, CTC count, RT-PCR profile and PET-CT data were obtained.

Results:
DC/CIK treatment resulted to initial decline in IFN-Y levels relative to baseline which recovered in levels on the second and third treatment. The CTC count showed reduction in number (i.e., from 229 to 699 and down to one cell/ml) while the RT-PCR profile indicated downregulated expression of three tumor markers (MUC1, Recoverin and p53), obliteration of one marker (KRT19) and emergence of four markers (Brachury, NFYC, S100A14 and MAGE-A3). Meanwhile, the PET-CT results indicated significant regression of bilateral pulmonary nodules and masses; interval resolution of some hypermetabolic lymph nodes and interval increase in others consistent with metastatic lymphadenopathy; osseous metastasis with interval decrease in metabolic activity of bone lesions; and occurrence of patchy reticular and ground glass opacities in right upper and lower lobe with possible infectious or inflammatory nature; and right atrium and pulmonary artery thrombosis. Few days post-PET-CT, patient manifested difficulty of breathing, cough and back pain; initially managed for pneumonia and pulmonary embolism, but showed progressive deterioration. Repeat CT-scan imaging of chest with angiography revealed drastic size increase of right lung mass relative to previous PET-CT scan; while sample biopsy revealed poorly differentiated carcinoma of lung primary. In 28 days post-PET-CT, patient yielded to Acute Respiratory Distress secondary to aggressive tumor in right lung of primary origin.

Conclusion:
DC/CIK treatment can be a promising immunobiological maintenance therapy for advanced NSCLC with recognizable molecular and clinical benefit to patients. Optimization of protocol towards anticipative strategies addressing aggressive primary tumor relapse may have to be considered in order to realize its complimentary therapeutic potential.

Background:
Lung cancer is the leading cause of cancer death globally. Important survival benefit has been recently obtained with targeted therapies against driver mutations. Immunotherapy approach under development will probably represent a new standard option of care in pretreated patients: clinical and/or pathological prognostic factors will further be needed to select the maximum benefit treated population.

Methods:
We reviewed retrospectively clinical, pathological and efficacy data from 28 patients with metastatic NSCLC treated with anti-PD1 (programmed cell death 1) and anti-PDL1 (programmed cell death-ligand 1) check-point inhibitors in our Institution between 2013 and 2015.

Results:
28 metastatic NSCLC patients were treated: 2 (7,14%) in first line, 14 (50%) in second line and 12 (40%) patients beyond third line. 82% were males, median age was 61 years old, and 71,4% adenocarcinomas. Mutation profile was defined as 1 patient (3,5%) EGFR positive and 1 patient ROS-1 positive (3,5%). PDL-1 resulted positive by immunohistochemistry on 43% of total population. 75% of patients received anti-PDL-1 therapy versus 25% anti-PD1 check point inhibitors. With a median follow up time of 22 months, overall response rate (ORR) was 10,7% and disease control rate (DCR) was 64,3%: no differences were seen by immunotherapy strategy. ORR, DCR, and median time for treatment (MTT) were analysed according to the line of therapy and type of immunotherapy. ORR 0%, DCR 100% and MTT 104 days at first line setting; ORR 7,14%, DCR 64,28% and MTT 98 days at second line; and finally, ORR 18,18%, DCR 63,63% and MTT 67 days at third line or beyond. Most of patients remain on treatment so survival data were not reached. The most common grade III-IV adverse events related with treatment were pneumonitis (14,3%), fatigue (3,6%), hyperamylasemia (3,6%), hypertransaminasemia (3,6%) and neurologic disorders (7%).

Conclusion:
Our retrospective and local analysis confirmed immunotherapy as a safe and effective therapy option with high rate of DCR and longer MTT than standard chemotherapy, independently PD-1 or PDL-1 inhibition or line of therapy used.

Background:
Brain metastases (BM) come with poor prognosis (median survival 3 to 6 months) and data are lacking as patients are often excluded from clinical trials.

Methods:
We present the results of a subgroup of NSCLC patients with BM treated with OSE-2101 (T-cytotoxic specific immunotherapy combining 9 epitopes targeting 5 tumor associated antigens and 1 pan-DR epitope) during a phase IIb study of OSE-2101 (1 injection per 3 week for 6 injections followed by 1 injection every 2 to 3 months) in advanced stage IIIB and IV NSCLC (Barve et al. 2008. J Clin Oncol 26:4418-4425). Patients were eligible whatever the number of prior chemotherapy (chemo) lines (65.5% entering 3rd line) and patients with stable BM for 2 months could be included. Six out of 64 treated patients had BM prior to inclusion and are reviewed.

Results:

Table 1: NSCLC patients included with BM

Patient	108	150	169	132	133	135
Gender	F	M	M	M	M	M
Ethnic origin	CAU	CAU	CAU	CAU	AA	CAU
Age (years)	46	61	58	79	46	57
ECOG performance status	1	1	1	1	1	1
Previous treatment	RT 30 Gy Chemo 2 lines	WBRT 30 Gy Chemo 2 lines	RT 30 Gy Chemo 2 lines	WBRT 30 Gy Chemo 3 lines	RT 30 Gy Chemo 1 line	WBRT 30 Gy Chemo 3 lines

AA: African-American, CAU: Caucasian, Chemo: chemotherapy, F: female, Gy: Gray, M: male, RT: radiotherapy, WBRT: whole brain radiotherapy Table 2: Response to therapy

Patient	108	150	169	132	133	135
OS	30.16 mo	41 mo*	16.5 mo	9.6 mo	11 mo	7 mo**
Time without progression	11.57 mo	24.39 mo	11.9 mo	4.53 mo	6.2 mo	2 mo*[2]
CTL response (positive epitopes out of 5 tested)	3	2	5	2	1	Not tested
HTL response	+	+	+	-	-	Not tested

* Patient still alive at the time of the last follow up, ** treatment stopped after 2 injections for progressive disease. CTL: cytotoxic T lymphocytes, HTL: helper T lymphocytes, mo: months, OS: Overall survival, The 6 BM patients present long survival (median 13 mo, range 7-41) considering the advanced stage and the poor prognosis of these heavily pretreated patients. All patients had received from 1 to 3 previous chemo lines. Evaluation of CTL responses to 5 epitopes of OSE-2101 in 5 patients shows that each patient had a CTL response to at least one and up to 5 epitopes. Surprisingly patients with positive HTL response (patient 108, 150, 169) achieve the longest OS when compared with negative HTL patients (132 and 133).

Conclusion:
Long OS has been documented in NSCLC patients with BM treated with T-specific immunotherapy following RT and 1 to 3 previous chemo lines.

Background:
Advanced NSCLC is now recognized as an immune-modifiable disease, and with the approval of the first PD-1 inhibitor, immune checkpoint inhibitors represent a new standard of care for patients with previously treated squamous cell lung cancer. The objective of this study was to evaluate oncologists’ familiarity with cancer immunotherapy in the context of advanced NSCLC and the impact of an educational curriculum on narrowing gaps in clinical practices.

Methods:
An expert panel of oncologists identified educational gaps in the area of cancer immunotherapy. A series of 9 CME online activities were developed, 2 of which centered on advanced NSCLC and are the focus of this study. Interactivity questions allowed learners to self-report their familiarity with immunotherapy concepts in the management of advanced NSCLC, while case vignette and knowledge-based questions were constructed around evidence-based medicine. Confidentiality of survey respondents was maintained and responses were de-identified and aggregated prior to all analyses.

Results:
1368 oncologists participated in the 2 activities on advanced NSCLC. As seen in the table below participation in the education activities resulted in numerous improvements in knowledge and competence as seen in the table below. Despite improvements, several important gaps remained. Only70% of oncologists comprehend that a tumor may increase in size or new lesions appear during initial therapy with an immune checkpoint inhibitor. In addition, about half of oncologists still had difficulty grasping how immune checkpoints downregulate T cell responses. Finally, oncologists still had difficulty identifying the unique side effect profile associated with immune checkpoint inhibitors. In addition, 55% of oncologists reported they were not comfortable with managing side effects associated with these agents.

Table

	% answered correctly	% answered correctly
	Pre-Activity	Post-Activity
Comprehension of Basic Immunology
Interaction of TCR with MHC-peptide complex and co-stimulatory receptors CD28/CD80 and CD86	52%	69%
Which does not represent a role of an immune checkpoint in the adaptive immune response: CTLA-4 binds to CD28, augmenting T-cell activation	50%	57%
Knowledge of Immune System’s Role in Response to Cancer
T cell infiltration and decreased risk of recurrence	69%	76%
Disease progression on an immune checkpoint inhibitor	65%	71%
Efficacy, Safety, Limitations of Immune Checkpoint Inhibitors
Limitations PD-L1 as a biomarker	26%	70%
Durability of response	5%	30%
Unique side effect profile	41%	59%

Conclusion:
The study evaluated oncologists’ familiarity with cancer immunotherapy in advanced NSCLC and demonstrated the necessity of developing targeted educational interventions for improving the knowledge and practice patterns of oncologists. Additional education is needed to continue to improve clinicians’ competence in the use of cancer immunotherapies in the management of NSCLC.

Background:
The icotinib hydrochloride tablets (Conmana) is a novel orally administered EGFR-TKI agent, which is the first homegrown anticancer drug designed, synthesizedand screened by Betapharma (Zhejiang, China) . The preclinical animal experiments showed that the agent had an anticancer activity in vitro and in vivo whose mechanism is that icotinib can inhibit EGFR activity specifically and competitively through binding to the tyrosine of the EGFR. A head-to-head Phase III clinical trial (ICOGEN) comparing the roles of icotinib and gefitinib in treating NSCLC in China has suggested that icotinib has similar (and even better) efficacy with gefitinib in treating Chinese NSCLC patients, with much better safety profiles; furthermore, it is superior to gefitinib in terms of treatment cost. Recently, a retrospective study demostrated that icotinib is active in the treatment of patients with NSCLC both in first or second/third line. Up to date, Icotinib has completed phase I、 II and III trials, Pharmacokinetic study in Phase I clinical trial data displayde that non-linear character with saturated absorption and first-order elimination. But whether the exposure of icotinib would influence the therapeutic effects is cofused us.So Beta Pharma (China) and Peking Union Medical College Hospital (PUMCH) jointly conducted this single-center open-label Phase I clinical trial, from August 2007 to April 2009, to explore the relationship between icotinib exposure and clinical outcomes of a single dose or administration for 31 consecutive days among Chinese NSCLC patients. In this article, by analysing the clinical efficacies and pharmacokinetic characteristics of iconitib in 30 subjects, we tried to elucidate the relationship between the iconitib exposure and therapeutic effects.

Methods:
In this single-center open-label phase I clinical trial, a dose-escalation method was applied until disease progression or unacceptable toxicities. Different doses of icotinib were orally administered for 31 consecutive days in different groups until disease progression or unacceptable toxicities. Blood samples were collected in the first treatment cycle (day 1 - day 28) for the pharmacokinetic analysis. Tumor responses were assessed by using the Response Evaluation Criteria in Solid Tumors(RECIST). The plasma concentrations of icotinib were assessed by liquid chromatography–mass spectrometry (LC-MS).

Results:
Univariate analysis showed that the time to maximum (Tmax) after a single dose of icotinib was significantly correlated with the overall survival (OS) (Spearman correlation coefficient=0.441, P=0.021). Patients with higher Clast were independently associated with PFS (p=0.012). Multivariate analysis showed that the AUC0-last and AUC0-∞ after a single dose of icotinib were significantly correlated with OS (P=0.037, P=0.042, respectively).. Stratification of these subjects according to smoking status indicated significant correlation between OS and AUC0-last (Spearman correlation coefficient = -0.709, P=0.015).

Conclusion:
Iconitib is a novel EGFR TKI developed by Chinese scientists. For advanced NSCLC patients who have failed prior treatment(s), the exposure of a single dose of iconitib was significantly correlated with the treatment efficacy. This finding may provide a simple and feasible clinical indicator for predicting the survivals.

Background:
Local therapy showed promising results for the patient who had an oligo-metastasis after acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).Our study is to evaluate the efficacy and safety of continuing EGFR-TKI treatment in combination with regional chemotherapy beyond RECIST progression disease (PD) of EGFR-TKI in advanced patients with EGFR mutation-positive NSCLC.

Methods:
Advanced NSCLC patients with EGFR mutation who got a locally progressed in central lung lesion after the treatment of EGFR-TKI were included.Patients received EGFR-TKI continually in combination with super-selectedsystemicarterial infusionwith docetaxel (75 mg/m2) every 21 days until disease progression again or unacceptable side effect.Response to treatment, progression-free survival (PFS) 1 (time to RECIST PD), PFS 2(time to PD if EGFR-TKI was extended beyond RECIST PD) andtreatment-related adverse effects (AEs)were analyzed. Patient-reported outcomes were evaluated inall patients who had completed a baselineassessment and at least one post-baseline assessment based on the QLQ-LC13 scales.

Results:
A total of 6 patientswere recruited. Patients had the median age of 54.17 years (range, 40-68 years).Two patients achieved partial responses and four had stable disease. Median PFS1was 11.70±8.97 months. Median PFS2 was 5.36±1.47 months.There was one death (none treatment related). OS data are immature. No unexpected side effects were found in our study.Patients reported significantly greater reductions from baseline in the symptoms of cough, hemoptysis, chest pain and dyspnea (P<0.05 for all comparisons).

Conclusion:
Continuing EGFR-TKI in combination with super-selected systemic arterial infusion chemotherapybeyond progression for advanced NSCLC patients with EGFR mutation is feasible and warrent further investigation.

Background:
Disease stage and performance status (PS) are the most widely accepted prognostic factors of non-small cell lung carcinoma. Several other features such as sex, age, histology, and health related quality of life (HRQOL) have also been reported as prognostic factors. Adenocarcinoma, especially EGFR mutation status, influences therapeutic strategy and prognosis. However, there have been few studies evaluating prognostic factors including activating EGFR mutation status focused on lung adenocarcinoma. This study aimed to clarify prognostic factors including EGFR status in advanced lung adenocarcinoma.

Methods:
From April 2010 to December 2014, patients diagnosed with lung adenocarcinoma were identified retrospectively. Stage ⅢB, StageⅣ and recurrent post-operative patients were included. A total of 95 patients with adenocarcinoma who was measured EGFR mutation status and completed the overall health related quality of life (HRQOL) item before receiving initial cytotoxic chemotherapy were included in the analysis. We evaluated HRQOL using EORTC QOL-C30 and LC-13 (European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire). The activating EGFR mutations consist of a deletion in exon 19 and a point mutation involving the replacement of leucine with arginine at codon 858 (L858R) in exon 21. EGFR mutation status, HRQOL scales, PS, age, sex, stage, data on Charlson comorbidity index, pulmonary function testing, and serum levels of white blood cells, haemoglobin, fibrinogen, calcium, alkaline phosphatases, lactate dehydrogenase were included in univariate and multivariate Cox proportional hazard analyses.

Results:
The median age was 67 years. Sixty one patients were men. Five patients had stage ⅢB , 76 had stage Ⅳand 14 were recurrent post-operative cases. Thirty two patients had activating EGFR mutation. Median survival time was 556 days. Global health status, Physical functioning, Role functioning, Social functioning, Fatigue scales of EORTC QOL-C30, Coughing scales of LC-13, EGFR mutation status, PS, Stage and serum levels of white blood cells, fibrinogen and albumin were associated with poor prognosis in univariate analyses. On multivariate analysis, Role functioning (HR: 0.988, 95% CI: 0.979-0.997), activating EGFR mutation (HR: 2.621, 95% CI: 1.401-4.906), female sex (HR: 2.158, 95% CI: 1.118-4.163) and stage (HR: 0.213, 95% CI: 0.090-0.501) were significantly predictors of survival.

Conclusion:
EGFR mutation status, Role functioning, sex and stage are significant and independent prognostic factors for survival in patients with advanced lung adenocarcinoma.

Background:
The phase III clinical study (ICOGEN) showed that Icotinib has a similar efficacy and tolerability in Asian patients with advanced non-small cell lung cancer (NSCLC) compared with Gefitinib. This retrospective study aims to evaluate the efficacy and tolerability of the EGFR-TKI Icotinib in first-month effective (unknown EGFR mutation type) and EGFR mutation positive (exon 19 deletion or exon 21 L858R point mutation) advanced non-small-cell lung cancer patients group from Eastern Coastal China .

Methods:
In this retrospective, observational, and multicentric study, 342 Eastern Coastal Chinese patients from 5 centers in China with histologically confirmed stage IIIB/IV non-small-cell lung cancer were treated in Qingdao, China. The patients with performance status from 0 to 3 wrote informed consent, and then received the standard dose of Icotinib (125 mg three times daily) until disease progression or unacceptable toxicity between Aug, 2012 and Dec, 2013. The patients were divided into EGFR mutation positive group and First-month effective group. First-month effective group refers to those patients whose tissue sample was difficult to obtain for EGFR measure and were responsive to Icotinib for one month trial. The primary outcome was progression-free survival among patients who received at least first dose of study treatment and the patients are still in follow-up.

Results:
The disease control rate (DCR) at 4[th] month was 81.6% in first-month effective group (n=170) and 89.41% in EGFR mutation positive group (n=174). The median progression-free survival (PFS) is 13.0 months (95% CI 1.0-22.8m) in first-month effective group (n=170) and 13.9 months (95% CI 1.8-24.6m) in EGFR mutation positive group (n=174), respectively (P>0.05). The 1-year survival rate of overall patients is 65.5%, 54.70% in these groups. It is impressive that PFS from first-month effective group is similar with from EGFR mutation positive group. The characteristics of non-smoker, female gender, performance status 0 or 1 are associated with a significantly better prognosis in terms of disease control rate.The median overall survival (OS) was not reached in EGFR mutation positive patients and the first-month effective group patients. The most common treatment-related adverse events are rash (n=154[45.0%]), diarrhea (n=78[22.8%]) and increase in AST and ALT (n=61[18.12%]). Most of the drug-related adverse events are mild (grade I or II) and reversible with no grade IV toxicity.

Conclusion:
Icotinib is effective and well tolerated in advanced NSCLC patients. For those patients with unknown EGFR mutation status, Icotinib first-month effective regimen may be an optical treatment rather than standard first-line chemotherapy in the future.

Background:
It has been demonstrated that lung cancer is the most common cause of brain metastases(BM). This study was designed to analyse the association of timing and survival of BM according to histology and epidermal growth factor receptor (EGFR) mutation status in patients with metastatic nonsmall cell lung cancer (NSLCL).

Methods:
We retrospectively analysed the medical records of 268 patients with NSCLC in single center in Incheon, Korea who were tested for EGFR mutation analysis from January 2010 to August 2013. We analysed the cumulative incidence of BM regard to EGFR mutation status, the time from the diagnosis to the development of BM, the time from BM to death and median survival. Survival was estimated by the Kaplan-Meier method and compared with the log-rank test.

Results:
Out of 268 patients, 74 (28%) had BM, 54(73%) patients already at the time of diagnosis. Synchronous BM was more frequent in patient with EGFR mutation than WT EGFR patient (79% vs. 69%). But patients with metachronous BM, time to BM diagnosis was not significantly different according to EGFR status. (p=0.298) Among the 67 patients with BM, 25(37%) had mutations in EGFR, including 13 exon 19 deletions and 12 L858R mutations and 40 had WT (60%). The time from diagnosis of first brain metastases to death(BM-OS) was significantly longer in patient with EGFR mutation than WT (22.28 vs. 7.55 month, p<0.005). The BM-OS in EGFR mutated patients with synchronous BM was longer than in EGFR WT patients (25.42 vs. 8.86 month, p<0.005). But the BM-OS in EGFR mutated patients with metachronous BM was not significant different from WT EGFR patients. (p=0.16).

Conclusion:
NSCLC patients with EGFR mutations were more prevalent with synchronous BM than those with EGFR WT patients. EGFR mutation was associated with significantly longer survival from BM diagnosis, especially in those with synchronous BM.

Background:
EGFR mutations have become an important target to choose a treatment for non-small cell lung cancer (NSCLC) patients. The response to chemotherapy is evaluated after the patient completes the second-third course of treatment. The response to tyrosine Kinase Inhibitor (TKI) could be observed in few days, the time for response evaluation is not well-defined.

Methods:
From January 2009 to November 2014, EGFR mutation status was analysed in 360 NSCLC patients’ samples. 55 patients (15,3%) were EGFR mutation positive. Among the 55 patients, 40 patients who were stage IIIB-IV and had received treatment with either gefitinib 250 mg, erlotinib 150 mg or afatinib 40 mg once daily were included in this analysis. The principal aim was to correlate the early radiological response (ERR) to TKI by computed tomography (TC) with progression‑free survival (PFS) and overall surviv­al (OS) in NSCLC patients with EGFR mutations and stage IIIB-IV disease. Secondary objectives were to correlate the TKI response with different EGFR mutations and to evaluate the safety and efficacy of TKI treatment. The PFS and OS were estimated by the Kaplan–Meier method with (SPSSv.19). The log‑rank test was used to assess significant differences between‑groups (p<0.05).

Results:
The clinic-pathologic characteristics of the 40 eligible patients are listed in table 1. The EGFR mutations identified were mainly exon 19 deletions (12 patients) and L858R point mutations (16 patients). Twenty‑six patients (65%) had ERR. Four patients with a partial response (PR) on early CT achieved a complete response (CR). The median follow‑up time was 17 months (range 2-66 months). Among the 26 patients with ERR the median PFS was 11.8 months. The median PFS for patients with stable disease (SD) and progressive disease (PD) was 7.5 months. The overall log‑rank test for PFS, when comparing the groups of patients (ERR vs SD and PD) showed a sig­nificant difference (p<0.034). For patients with ERR the median OS was 20.1 months. The median OS for patients with SD and PD was 11.9 months. The overall log‑rank test for OS, when comparing the groups showed a sig­nificant difference (p<0.017).

Table 1: The clinic-pathologic characteristics

VARIABLES	NUMBER	%
Patients	40	100
Gender Male Female	19 21	47.5 52.5
Age (years) Median (range)	62 (40-85)
Race European Others	38 2	95 5
Smoking Yes No Former smokers	9 22 9	22.5 55 22.5
Packs-year Median (range)	35.5 (5-185)
PS 0 1 >2	14 22 4	35 55 10
Pathology diagnosis Adenocarcinoma Squamous Others	37 2 1	82.5 5 2.5
Stage IIIB IV	2 38	5 95
Number of prior chemotherapies 0 1-2 >2	17 20 3	42.5 50 7.5
TKI Erlotinib Gefitinib Afatinib	30 8 2	75 20 5

Conclusion:
The ERR to TKI could be a predictive factor of PFS and OS in NSCLC with activating EGFR mutation. Patients with SD at the first evaluation should be followed closely because of the risk of early progression.

Background:
The purpose of this study was to investigate whether outcomes with various chemotherapy regimens were affected by the specific epidermal growth factor receptor (EGFR) mutations in patients with stage IV non-small cell lung cancer (NSCLC).

Methods:
We retrospectively analyzed the association between the different EGFR mutations (exon 19 deletion, exon 21, and 18 mutations) and their response to chemotherapy. A total of 17 patients with stage IV NSCLC treated at Winship Cancer Institute of Emory University between January 2007 and February 2015 who received chemotherapy were investigated retrospectively, and their clinical date were assessed according to EFGR mutation.

Results:
14 (82.4%) females and 3 (17.6%) males were identified harboring EGFR mutations. Median age at the time of diagnosis was 66 years (SD 14.08). 12 patients (70.6%) were never smokers, and 5 (29.4%) were former or current smokers. EGFR exon 19 deletion was present in 7 patients (41.2%), exon 21 mutation in 8 (47.1%), and exon 18 in 2 (11.8%). 15 (88.2%) received chemotherapy, and 11 (64.7%) received pemetrexed-based treatment. Four patients had partial response (PR) as the best response to pemetrexed-based chemotherapy, and all of them harbored exon 21 mutation. Among patients that received other types of chemotherapies (paclitaxel, gemcitabine, navelbine and platinum), 6 with exon 21 mutation, and 2 with exon 19 deletion experienced PR. Progression-free survival (PFS) was not significantly different among the groups of mutation (p=0.3645) that received paclitaxel, gemcitabine, navelbine and platinum as chemotherapies, and PFS was also not different for pemetrexed-based regimen (p=0.4569).

Conclusion:
We did not find differential sensitivity to various chemotherapy agents based on mutation type in advanced NSCLC patients harboring an EGFR mutation.

Background:
Bone metastasis and skeletal-related events (SREs) such as pathologic fracture and spinal cord compression are common in advanced lung cancer. This study was aimed to investigate the characteristics of disease progression focused on SREs during EGFR-TKI treatment.

Methods:
We retrospectively reviewed the medical records of 3,085 Korean patients with advanced non-small cell lung cancer who were treated with gefitinib or erlotinib between 2004 and 2014. SRE associated with aggravation of bone metastasis was termed ‘bone failure (BF)’. BFs were classified into 2 categories according to the presence of accompanying disease progression of preexisting cancer lesions in extra-skeletal organs; isolated bone failure (IBF) versus non-IBF.

Results:
The incidence of SREs during EGFR-TKI treatment was 4.7% (146/3085). Among them, 60 patients experienced IBF without aggravation of disease in extra-skeletal organs. IBF was more frequent in clinical benefit group (responders and stable ≥ 6 months) than in non-clinical benefit group (53.5% vs 13.3%; P < 0.001). Adenocarcinoma histology and clinical benefit from EGFR-TKI were independent risk factors for IBF (adenocarcinoma: adjusted hazard ratio [HR] 10.283; 95% confidence interval [CI] 1.148 – 92.121; P= 0.037, clinical benefit from TKI: adjusted HR 9.463; 95% CI 3.027 – 29.584; P < 0.001). The time from the start of EGFR-TKI to the occurrence of SRE was significantly longer in IBF than that in non-IBF (9.8 vs 5.2 months; P= 0.054). Moreover, patients with IBF exhibited longer survival time from the initiation of TKI (20.1 vs 7.7 months; P = 0.008) and from the occurrence of SRE (9.2 vs 1.9 months; P = 0.006). Multivariate analysis showed that IBF was one of independent prognostic factors for better survival although the statistical significance was marginal (adjusted HR 0.492; 95% CI 0.237 – 1.021; P = 0.057).

Conclusion:
IBF without systemic disease progression frequently occurs in patients with clinical benefits from EGFR-TKI treatment and shows the better survival requiring more active treatment.

Background:
Gefitinib is a potent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and is a key drug for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutation. The orally administered gefitinib showed large interindividual variability in its pharmacokinetics. Some phase I studies have suggested there is a relationship between gefitinib plasma concentration and skin toxicity, diarrhea, and liver toxicity. The aim of this study was to evaluate the association of pharmacokinetics or pharmacogenomics with toxicity or effectiveness of gefitinib in patients with advanced NSCLC.

Methods:
The evaluation of pharmacokinetics was performed using sample obtained on day 1 at 0, 1, 3, 5, 8, 24 hour and day 8 and day 15 after start of gefitinib 250mg administration. Plasma concentration of gefitinib was analyzed by high-performance liquid chromatography. The genotypes of ABCG2, ABCB1, ABCC2, CYP3A4, CYP3A5, CYP2D6 were analyzed by direct sequencing.

Results:
Thirty-five patients with advanced NSCLC (14 men and 21 women; median age, 72 years; range, 53 to 90 years) were enrolled. All patients were stage IV adenocarcinoma harboring EGFR mutation: 18 had exon 19 deletions, 16 had exon 21 L858R, and 1 had exon 18 G719A. The overall response rate was 82.9% (95% confidence interval 66.4-93.4%). The median survival time was 21.2 months, and the median progression-free survival time was 10 months. The common adverse events were rash or acne (68%), diarrhea (46%), and liver injury (63%). One patient died of drug induced interstitial lung disease (ILD). The median area under the plasma concentration-time curve of gefitinib estimated from 0 to 24 hour (AUC0-24) was 10.9 (1.5-31.3) µM·h. The peak plasma concentrations (Cmax) was achieved 5 hour after dosing, and the median was 0.84 (0.38-1.74) µM. There were no statistically significant association of pharmacokinetics or pharmacogenomics with response rate, survival, and toxicity, such as skin toxicity, diarrhea, liver injury, and ILD of gefitinib. However, one patient died of drug induced ILD showed the highest AUC and Cmax.

Conclusion:
The elevated gefitinib exposure could be associated with drug-induced ILD. Further studies of the association of pharmacokinetics or pharmacogenomics with toxicity of EGFR-TKI are needed.

Background:
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are recommended in the first-line setting for patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). However, it remains unclear whether frontline EGFR TKIs are better strategy than first-line chemotherapy in EGFR-mutant patients. Generally, EGFR-TKIs had no significant benefits in overall survival (OS) compared with chemotherapy in both first-line and second-line setting. This retrospective study compared survival benefits in patients treated with post-TKI chemotherapy and first-line chemotherapy controls.

Methods:
This retrospective study included 442 EGFR-mutant patients in our institute. We examined EGFR gene status from 2007 to 2015. The patients treated from 1999 to 2015. The study group contained 173 patients treated with first-line EGFR-TKI and the control group contained 109 patients who received EGFR-TKI after first-line chemotherapy. The overall survival (OS) was assessed.

Results:
There was no significant difference between first-line chemotherapy and EGFR-TKI in OS for patients with mutation-positive NSCLC (median OS; 43 vs. 38 months, P = 1.645). There was substantial difference in OS between patients with postoperative recurrence and those with III/IV stage disease. Among patients with III/IV stage NSCLC, median OS was 40.8 months in first-line chemotherapy group, 30.5 months in chemotherapy after frontline EGFR-TKI group and 21.1 months in only EGFR-TKI group.

Conclusion:
In EGFR-mutant patients, both EGFR-TKI and chemotherapy improve the survival. Among patients with advanced NSCLC, EGFR-TKI after first-line chemotherapy may improve survival than frontline EGFR-TKI. These findings need to be validated in further randomized trials.

Background:
Brain metastases (BM) are common in non-small cell lung cancer (NSCLC). They are often associated with significant impairment of quality of life and a poor prognosis. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have proven superior to chemotherapy in patients with advanced NSCLC that harbour an EGFR mutation.​They are now standard of care as first line treatment. Many studies, however, have excluded patients with BM. Therefore the best treatment modality for these patients remains unknown. Different treatment options include: surgery, whole brain radiotherapy (WBRT), radiosurgery, chemotherapy and TKIs. This report looks at the outcomes of patients with EGFR mutated lung cancer and BM who have undergone different treatment modalities.

Methods:
The West of Scotland Network for Lung Cancer supports over 2,000 lung cancer patients per year. We collected data on patients diagnosed with EGFR mutated lung cancer between 2012 and 2014. Patients had to have radiological evidence of BM either at time of diagnosis or subsequently. Patient demographics were recorded alongside response to different treatment modalities. Outcomes included progression free survival and overall survival.

Results:
Between 2012 and 2014, 117 patients were diagnosed with EGFR mutated lung cancer. Eleven patients had confirmed BM: 10 women, 1 man, ages 48-83 years (median 62). Nine patients had BM at presentation, one developed BM while on erlotinib and another had BM on relapse post lobectomy. The median overall survival was 28 weeks (range 10-96). Three patients remain alive at 55, 64 and 139 weeks post diagnosis. Three patients were treated with erlotinib alone. Two remain alive 64 and 55 weeks from diagnosis. The first has controlled intra and extra cranial disease, whilst the other had extracranial progression at 49 weeks. The third patient only survived 22 weeks. Three patients had WBRT, two with erlotinib. Overall survival was 19 weeks without erlotinib and 34 and 42 weeks with erlotinib. A separate patient developed BM while on erlotinib and underwent WBRT. She survived a further 13 weeks from diagnosis of BM and had an overall survival of 96 weeks. One patient achieved stable extracranial disease for 81 weeks with erlotinib. At 16 weeks, however, there was progression of an isolated BM. She underwent radiosurgery with a single 20Gy fraction and on subsequent scans has stable intracranial disease 67 weeks post radiosurgery. She remains alive 139 weeks post diagnosis. Finally, two patients received no active treatment and died at 10 and 18 weeks post diagnosis.

Conclusion:
There is currently little trial data to guide our treatment decisions in patients with EGFR mutated lung cancer and BM. In our group only 9% of patients with EGFR mutated NSCLC had BM. They underwent a variety of treatment modalities, however, numbers are too small to draw firm conclusions. Without treatment, or with WBRT alone, survival is similar to patients with advanced non EGFR mutated NSCLC. The use of a TKI either with or without radiotherapy appears to have a prolonged survival and is probably the treatment of choice. Of note, no patient in this group had a change in TKI.

Background:
First generation EGFR TKIs, erlotinib, gefitinib and icotinib, have shown excellent clinical efficacy in non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations. However, patients eventually progress due to acquired resistance in the form of a T790M point mutation. This mutation occurs in about 50-60% of EGFR TKI treated patients. Second generation, irreversible EGFR TKIs, afatinib and dacomitinib, express even higher kinase potency in the activating mutation as well as potency against the acquired resistance mutation. Clinical efficacy of these TKIs is reduced due to the dose limiting toxicities of the drugs, attributed to wild type EGFR potency of the compounds. In order to improve clinical efficacy against the activating and double mutant EGFR tumor cells, it is important to build in selectivity against wild type EGFR to avoid dose-limiting toxicities. Here, we present BPI-7701, a novel EGFR inhibitor with high potency against the activating mutant EGFR and the T790M resistance mutation with good selectivity over wild type EGFR.

Methods:
BPI-7701 was evaluated in biochemical and in vitro assays against mutant EGFR (L858R, del ex19, del ex19/T790M) and WT EGFR. In vivo anti-tumor activity was evaluated in xenografts of HCC827 (del ex19) and H1975 (del ex19/T790M) NSCLC cells.

Results:
Biochemical assays showed that BPI-7701 inhibited del ex19 and L858R mutant EGFR, as well as the T790M resistance mutation of EGFR at IC~50 ~values lower than that of WT EGFR, showing an ~100-fold difference in activity. BPI-7701 showed growth inhibition of PC-9 (del ex19), HCC827 (L858R) and H1975 (del ex19/T790M) cells in vitro, with IC~50~ values of 11-160 nM. BPI-7701 showed an IC~50~ value of 1.25 μM against A431, wild type EGFR epithelial cells. In vivo, BPI-7701 showed greater than 90% inhibition of pEGFR at tested doses as low as 6.25 mpk in nude mice. pEGFR inhibition was dose-dependent and was maintained over the course of 24 hours. In mouse xenograft studies, BPI-7701 induced complete tumor regression in H1975 (del ex19/T790M) and HCC827 (L858R) NSCLC cell lines after 14-day repeat dose treatment. In an H1975 xenograft model, complete tumor regression occurred after 6 days of BPI-7701 treatment (14-day regimen), with 80% of mice remaining tumor-free 35 days after the completion of BPI-7701 dosing.

Conclusion:
BPI-7701 inhibits the growth of NSCLC cells with EGFR mutations and T790M resistance mutation, both in vitro and in vivo. BPI-7701 may be an excellent option for NSCLC patients with activating EGFR mutations. Clinical trials are planned to begin Q2 2016 in Asia.

Background:
Genetic variations in the epidermal growth factor receptor (EGFR) gene may alter protein expression or function and influence response to tyrosine kinase inhibitors. This study evaluates the role of genetic polymorphisms in the EGFR gene in advanced non-small cell lung cancer (NSCLC) patients treated with erlotinib. EGFR mutation status was known for all patients.

Methods:
Genotypes for -216G>T, -191C>A and 181946C>T in the EGFR gene were retrospectively evaluated by DNA sequencing and polymerase chain reaction in 354 Caucasian patients with advanced NSCLC. Hundred and seven of the patients had a somatic EGFR mutation, and all patients had been treated with erlotinib. Genotypes were correlated with clinical characteristics and outcome. A multivariate analysis was conducted adjusting for clinical relevant factors, including EGFR mutation status, using Cox proportional hazards model. A subgroup analysis was performed based on the EGFR mutation status.

Results:
Patients harboring at least one variant T allele (CT or TT) at position 181946 had a significantly longer median progression-free survival (PFS) (5.6 versus (vs.) 2.9 months; p =0.032) and overall survival (OS) (8.3 vs. 6.7 months; p=0.032) compared to patients with the CC genotype. The result remained significant in a multivariate analysis; PFS, adjusted hazard ratio (AHR)=0.73 (95% confidence interval (CI): 0.55-0.98); OS, AHR=0.72 (95%CI: 0.54-0.97). Patients carrying -216GT or TT genotypes showed a trend to a better clinical outcome compared to those with the GG genotype. The -216GT or TT and 181946CT or TT combined genotypes showed an even more pronounced association with clinical outcome compared to patients with the -216GG and 181946CC genotype (PFS, AHR=0.66 (95%CI: 0.44-0.98); OS, AHR=0.58 (95%CI: 0.38-0.87)). A subgroup analysis demonstrated that the association might be most relevant in EGFR mutation-positive patients; PFS, AHR=0.27 (95% CI: 0.11-0.68); OS, AHR=0.33 (95% CI: 0.13-0.83).

Conclusion:
A combination of 181946C>T and -216G>T polymorphisms in the EGFR gene seems to be a potential predictor of longer PFS and OS in advanced NSCLC patients treated with erlotinib; especially in EGFR mutation-positive patients. A prospective randomized study is wanted to confirm our data.

Background:
Patients with higher lymphocyte to monocyte ratio (LMR) has shown to have favorable prognostic in early stage lung cancer, non-metastatic renal cell carcinoma, gastric cancer, colon cancer, pancreatic cancer and breast cancer. However, prognostic significance of LMR in patients with advanced stage, epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer receiving first line EGFR tyrosine kinase inhibitors is not well known. We conducted a retrospective analysis to investigate the influence of baseline LMR on clinical outcomes including progression free survival (PFS) and overall survival (OS) in EGFR mutant NSCLC patients.

Methods:
This retrospective study evaluated 253 patients harboring EGFR mutation received TKIs as first line therapy for advanced NSCLC between January 2011 and October 2013. The cut- off value determined by Receiver operating characteristic (ROC) curves for LMR was 3.29. Patients were divided into high and low LMR ratio based on above cut-off level. Kaplan–Meier analysis was used for PFS and OS estimation; and the log-rank test was utilized to examine the significance of the differences of survival distributions between groups.

Results:
Among 253 patients mean age was 65.2 years, 41% were male, medium PFS was 10.3 months, medium OS was 22 months. Low baseline LMR patients had shorter PFS (low vs. high: 8.2 vs 11.6m, HR: 1.508, p=0.003), and OS (low vs. high: 14.3m vs. 32.1m HR: 2.23, p<0.001) Figure 1



Conclusion:
Our results suggest baseline LMR is a prognostic marker for EGFR mutant NSCLC patients receiving first line EGFR-TKIs.

Background:
The aim of this study is to refine the existing lung cancer graded prognostic assessment (GPA) index by analysing a cohort of patients with non-small cell lung cancer (NSCLC) tested for epidermal growth factor receptor (EGFR) mutation status and newly diagnosed brain metastases.

Methods:
We used the pathology registries of two institutions to identify 259 eligible patients diagnosed with brain metastases secondary to NSCLC between 2006 and 2014. We linked the electronic medical records of these patients to the National Death Registry. Survival is defined as from date of first treatment for brain metastases or date of brain metastases diagnosis for patients on best supportive care till death. We analysed the prognostic factors significant for survival by multivariate Cox regression and recursive partitioning analysis (RPA).

Results:
Significant prognostic factors identified by multivariate Cox regression and RPA were age, Karnofsky performance status (KPS), presence of extra-cranial metastases (ECM), number of brain metastases (BM) and presence of sensitizing EGFR mutations. Patients who were age 70 years old and above (Hazard ratio (HR) 1.47, 95% confidence interval (CI) 1.07-2.01, reference (ref) age < 70 years old); with KPS score 70-80 (HR 2.37, 95%CI 1.69-3.34, ref KPS 90-100); with KPS score < 70 (HR 4.34, 95%CI 2.90-6.51, ref KPS 90-100); ECM present (HR 1.82, 95%CI 1.27-2.62, ref no ECM); having two or more BM (HR 1.40, 95%CI 1.01-1.95, ref less than two BM) and absence of sensitizing EGFR mutations (HR 1.97, 95%CI 1.49-2.61, ref sensitizing EGFR mutations present) were poor prognostic factors. There was a robust separation of survival curves between GPA score 0-1.0 (median survival (MS) 2.1 months), GPA score 1.5-2.0 (MS 6.3 months) and GPA score 2.5-3.0 (MS 14.1 months). The proposed modified GPA index is shown in below table.

Proposed modified GPA index

Prognostic factors / score	0	0.5	1.0
Age Group	≥70 years old	<70 years old	-
KPS	<70	70-80	90-100
ECM	Present	-	Absent
No. of BM	≥2	0-1
Sensitising EGFR mutations	Absent	-	Present

Conclusion:
EGFR mutation status is a significant prognostic factor and should be considered in the design of lung-cancer GPA index. The proposed modified GPA index need to be validated with an independent dataset.

Background:
In patients with non -small cell lung cancer (NSCLC), mutations in the epidermal growth factor receptor (EGFR) have been associated with sensitivity to EGRF-tyrosin kinase inhibitors (TKIs). However, clinical course of EGFR mutation subtypes are still controvertial. The aim of this study was to analyze clinical features between EGFR mutation exon 19 and 21, including treatment with EGFR-TKIs

Methods:
In patients with NSCLC, EGFR exon 19 deletion mutations and EGFR L858R point mutations were analyzed by DNA sequencing method or pyrosequencing method from paraffin blocks of tissue obtained before treatment. We reviewed clinical characteristics of the patients, retrospectively.

Results:
One hundred and sixty seven patients displayed EGFR mutations in exon 19 and exon 21 from October 2002 to December 2013. 63.6% (n=100) had EGFR 19 deletion, whereas 36.3 % (n=67) had an EGFR L858R mutation. There were no differences in sex, smoking, ECOG status, stages, blood chemistry, tumor marker, and overall survivals (OS) between two groups. Overall survival was similar in both groups. However, OS was longer in non-smoker (p=0.000), female (p=0.007), and age ≥ 65 (p=0.031) only in 19 deletion group. After treatment with gefitinib (n=74), erlotinib (n=31), and afatinib (n=2), patients with EGFR mutations had a median overall survival of 47 month. Among the patients treated with gefitinib or erlotinib, gefitinib treated patients had significantly longer progression free survival (PFS) than erlotinib treated patients in EGFR exon 19 deletions (10.3 versus 5.1 months; p=0.002), but not in exon 21 mutation. The median PFS of the patients with higher body surface area (BSA, ≥1.5 m[2]) was worse than that of those with lower BSA (3.9 vs. 8.9 month; p=0.063) in exon 21 mutation group.

Conclusion:
There are different clinical course between types of EGFR exon 19 and 21 mutations. We need confirmation in a prospective study and have to more elucidation of the biological mechanisms of the differences between the two major EGFR mutations.

Background:
Preclinical data demonstrate that the T790M clone is associated with a growth disadvantage in the absence of TKI selection. With selection stress of standard dose of TKI, T790M cells may become a dominant population. In a mathematical model, high pulse dose combined with continuous low-dose of TKI could delay the emergence of resistant clone of T790M. Clinically, some patients use lower dose of EGFR TKI due to various reasons such as toxicity. The treatment outcome in terms of PFS in this group of patients has not been reported. Whether the PFS would be impaired due to dose adjustment or unaffected and even better to support above theory may need further clarification.

Methods:
A retrospective cohort study was conducted to recruit patients with advanced NSCLC from 1997/1 to 2014/12 in a regional teaching hospital. Inclusion criteria were patients whose tumors were either tested to have sensitizing mutations of EGFR using highly sensitive methods or clinically responsive to EGFR TKI using Jackman’s criteria. Patients having titrated dose of TKI to two-thirds or less for more than 6 months were assigned to low-dose (LD) group. The standard-dose (control) group includes patients receiving daily 250 mg of Gefitinib or 150 mg of Erlotinib during whole course of treatment, matched with sex and age to LD group. The primary outcome was PFS. Secondary outcome was overall survival (OS).

Results:
LD group includes 20 patients and control group 80 patients. Patients using LD treatment were mostly due to intolerable side effects with standard dose (n=18, 90%). The median PFS was 15.4 months in the LD group and 9.3 months in control (hazard ratio 0.45, 95% CI of 0.29-0.71; p=0.018). The median OS was 31.5 months in LD and 31.4 months in control (hazard ratio 0.99, 95% CI 0.49-1.98; p=0.98). In the subgroup of Gefitinib treatment, the median PFS was 17.9 months in LD and 8.1 months in control (hazard ratio 0.35, 95% CI 0.19-0.62; p=0.0037). In patients receiving Erlotinib, median PFS was 15.3 months in LD and 12.1 months in control (hazard ratio 0.67, 95% CI 0.33-1.37; p=0.2652). Median OS was similar in LD and control in either subgroup of Gefitinib or Erlotinib.

Conclusion:
This study showed that lower dose of EGFR-TKI treatment is a non-inferior strategy for patients sensitive to EGFR TKI. Better PFS in the LD group of Gefitinib-treated patients support the theory of delayed emergence of resistant clone. Since 150 mg of Erlotinib is at its maximum tolerated dose, a dose choice of no more than optimum biologic dose may be needed to gain such benefit as Gefitinib. Larger-scale studies would be needed to confirm this finding.

Background:
Many randomized clinical trials have demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are advantageous over standard chemotherapy either as front-line treatment or as further management of patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC). But which subgroup of patients with EGFR mutation-positive advanced NSCLC could benefit more from EGFR-TKIs needs to be further explored. In the present study, we attempted to explore predictive factors in such cohorts of patients who received gefitinib by classification and regression tree (CART) analysis.

Methods:
Included in this study were 95 patients with EGFR mutation-positive advanced NSCLC who received gefitinib treatment at the Cancer Institute (Hospital) of the Chinese Academy of Medical Sciences between February 2010 and October 2013. Multivariate analysis of progression-free survival (PFS) was performed using recursive partitioning referred to as CART analysis to assess the effect of specific variables on PFS in subgroups of patients with similar clinical features.

Results:
The median PFS in patients with EGFR mutation-positive advanced NSCLC who received gefitinib treatment was 13.3 months (95% CI 9.4-17.2). CART analysis showed an initial split on body mass index (BMI), based on which three terminal subgroups were formed. The median PFS in the three subsets ranged from 8.2 months to 15.2 months, in which the subgroup with a BMI less than or equal to 20.768Kg/m2 had the longest PFS (15.2 months). In addition, PFS in EGFR exon 19 mutation group was better than that in other mutation site group (10.3 vs. 8.2 months).

Conclusion:
BMI and exon 19 mutation are predictors of PFS in patients with EGFR mutation-positive advanced NSCLC who received gefitinib treatment. Both active EGFR mutation and patient’s own factors could be used to predict the therapeutic efficacy of EGFR-TKIs. Figure 1Figure 2

Background:
The biological rationale for intercalated therapy in EGFR mutated NSCLC is to derive benefit both from cytotoxic and from targeted therapy, avoid their mutual antagonism, and prevent tumor repopulation during intervals of cytotoxic treatment. After a promising report from a single-arm trial of intercalated treatment (Zwitter et al, Radiol Oncol 2014;48:361), we here present a comparison to treatment with TKI alone on a similar population of patients.

Methods:
All patients were treatment-naive with metastatic EGFR mutated NSCLC, were in fair general condition and fulfilled the standard criteria for platin-based chemotherapy. Patients in the intercalated group joined a prospective clinical trial and signed informed consent. Treatment consisted of gemcitabine at 1250 mg/m2 on days 1 and 4, cisplatin at 75 mg/m2 on day 2 and erlotinib 150 mg on days 5 – 15 of a 3-weekly cycle for 4 to 6 cycles, followed by continuous erlotinib as maintenance. Due to reluctance of their physicians to join the intercalated trial, patients in the TKI alone group were treated with erlotinib or gefitinib as the standard treatment.

Results:
Regarding demographics and main prognostic factors, there was a slight disbalance in favor of the TKI alone group (Table). The intercalated trial recruited 38 patients. Treatment was well tolerated, with 6 cases of grade 4 toxicity. Complete or partial response was seen in 16 and 17 patients, respectively, for response rate of 87%. For 21 patients on TKI alone as standard treatment, precise evaluation of response was not feasible. Median time to progression was 24.3 months and 9.6 months (p < 0.05), and median survival was 34.9 and 25.8 months for the intercalated and TKI alone group, respectively.

	TKI alone 21 patients	Intercalated schedule 38 patients
Gender, Female/Male	13/8	21/17
Age, median	63	61
Age, range	42 – 70	37 – 74
Performance status, 0 - 1	18	30
Performance status, 2 – 3	3	8
Brain metastases at diagnosis	5	13

Figure 1



Conclusion:
In advanced EGFR mutated NSCLC, intercalated schedule appears superior to TKI alone. These observations should be confirmed in a randomized trial.

Background:
ENSURE study shows that 1[st] line treatment with erlotinib provides longer PFS over gemcitabine/cisplatin (GP) for stage IIIB/IV NSCLC patients with EGFR mutations. Cross-over treatments after progression of disease (PD) was allowed in ENSURE study. However, post-study treatments might have significant impact on patient survival or other clinical benefits, which is insufficiently investigated. This trial in an extension of the ENSURE study, intended to evaluate PFS in 2[nd] line progression after cross-over treatments in ENSURE.

Methods:
Chinese patients who had PD after 1[st] line treatment in ENSURE were enrolled. Enrolled patients received cross-over treatment as 2[nd] line treatment after 1[st] line PD. The primary endpoint was PFS, defined as the time of randomization in ENSURE to disease progression or death while on 2[nd] line treatment. For patients who had already progressed after 2[nd] line therapy prior to entering this extension study, relevant information would be collected retrospectively. PFS from 1[st] line PD to 2[nd] line PD was also calculated. The study was approved by IRB and all patients signed informed consent. This study was registered in clinicalgrials.gov (NCT02000531). We also retrospectively analyzed the time to 2[nd] line treatment failure (TTF) defined as the time from randomization to discontinuation of 2[nd] line treatment for any reason.

Results:
Forty-five patients (21 from erlotinib arm and 24 from GP arm) were enrolled in the final analysis in this ENSURE extension study. Limited recruitment was mainly due to later initiation of this study (from January to December of 2014), many deaths at the beginning of this study, or unwillingness to sign informed consent by some patients. Age, sex, and ECOG at baseline in erlotinib group and GP group were balanced. Among 45 enrolled subjects, 33 (73.3%) subjects completed the study. There was no significant difference in median PFS from the date of randomization in ENSURE study to 2[nd] line PD for both arms 26.3 (95%CI: 19.8 , 34.0 ) months vs 23.4 (95%CI: 17.8, 39.0 ) months, HR=1.26 (95%CI: 0.61, 2.62), p=0.529). For 2[nd] line cross-over treatment, ORR in erlotinib and GP arms was 33.3% (7PR/21) and 66.7% (16PR/24) respectively (p=0.0377). In a retrospective analysis of 175 patients from the whole ENSURE study, 63.2% patients in erlotinib arm (n=87) received 2[nd] line chemotherapy and 86.4% patients in GP arm (n=88) received 2[nd] line targeted therapy. The median TTF in erlotinib and GP arm were 29.4 (95%CI: 24.7, 34.2) and 24.7 (95%CI: 21.9, 28.4) months respectively (HR=0.74(95%CI: 0.47, 1.17), p=0.192).The subgroup analysis (mutation type, ECOG performance status, gender) for TTF between erlotinib and GP arm showed similar trend to the primary analysis.

Conclusion:
Despite limitations, both median PFS (in prospective analysis) and TTF (in retrospective analysis) for erlotinib patients were numerically larger than that in GP arm. This first cross-over treatment ENSURE extension study further confirms benefits of erlotinib as standard 1[st] line treatment for EGFR mutant NSCLC. It also supports the importance of 1[st] and 2[nd] line treatment sequence of erlotinib and platinum-based chemotherapy for the treatment of EGFR mutant NSCLC.

Background:
Crizotinib has been available in Slovakia since October 2012 for the treatment of adults with previously treated ALK-positive advanced non-small cell lung cancer (NSCLC), based on the therapeutic indication approved by the European Medicines Agency. Purpose of this study was to assess the results achieved with crizotinib in the treatment of advanced NSCLC in clinical practice in Slovakia.

Methods:
In this multicenter retrospective study, approved by the Ethical Committee of the Specialized Hospital of St Zoerardus Zobor, the data of 30 ALK-positive patients were reviewed. FISH with break-apart probes was used for the confirmation of ALK rearrangement in all cases. MedCalc[®] was used for the statistical analyses.

Results:
Between October 2012 and August 2014, 20 out of 30 ALK-positive patients were treated with crizotinib. Ten patients did not receive crizotinib: five due to on-going first-line chemotherapy, five due to other reasons. Characteristics of the treated patients: M/W: 6/14, age (years) median 56, range 23-77, PS (ECOG/WHO): 0/1/2/3: 1/10/4/5, Histology: 19 patients adenocarcinoma, 1 NSCLC, NOS. Treatment results: RR was evaluated in 20 patients: PR + CR: 13 (12+1), 65% (95% CI: 41-85), SD: 3, 15% (95% CI: 3-38), PD: 3, 15% (95% CI: 3-38), NS: 1, 5%, DCR: 16, 80% (95% CI: 56-94), PFS: Kaplan-Meier estimate: 13 months (95% CI: 7 -18), 0S (with 60% of patients censored): 19 months (95%CI: 12 - NR), PS: significant improvement within 2 months (mean dif. –0.95, P=0.0021), toxicities grade 3/4 occurred in 11 of 20 patients (55%), hematologic: 0, non-hematologic: hepatotoxicity 3/1, pneumonitis: 1/0, diarrhea 1/0, nausea: 3/0, vomiting: 1/1, vision disorder: 1/0, peripheral edema: 1/0, QT-interval prolongation: 1/0. Crizotinib was permanently discontinued due to toxicity in only two patients.

Conclusion:
Treatment results seen in this retrospective study are encouraging and consistent with the published data from the prospective trials.

Background:
Anaplastic lymphoma kinase (ALK) gene fusions are implicated in the pathogenesis of non-small cell lung cancer (NSCLC), occurring in 3–7% of cases. Crizotinib, a first-in-class ALK inhibitor, was granted US FDA approval in 2011 to treat metastatic ALK-positive (ALK+) NSCLC. However, intrinsic and acquired resistance limits its duration of use. Ceritinib, an ALK inhibitor with activity against crizotinib-resistant NSCLC and brain metastases, was granted accelerated approval by the US FDA in 2014 for treating crizotinib-resistant ALK+ NSCLC. Adverse events (AEs), particularly gastrointestinal (GI) AEs, are commonly experienced at the recommended dose of 750 mg/day (Shaw A et al. NEJM 2014;370:1189–1197) and around 60% of patients require dose interruption or reduction. This report details our experience with the use of proactive GI AE management regimens with ceritinib.

Methods:
Proactive regimens A and B were implemented in patients with metastatic ALK+ NSCLC treated with ceritinib to manage drug-related GI AEs. Regimen A comprised ondansetron and diphenoxylate/atropine or loperamide, taken 30 minutes prior to dosage. Regimen B included dicyclomine, taken with the first ceritinib dose, ondansetron, taken 30 minutes prior to dosage for the first 7 doses, and loperamide, taken as needed with the onset of diarrhea. The proactive medications were tapered off depending on patient tolerability to ceritinib. We report a case series comprising 9 patients treated at two sites with ceritinib (750 mg/day) for whom these proactive GI AE management programs were successfully implemented.

Results:
The 9 patients presented had discontinued crizotinib due to disease progression or intolerance, and received ceritinib as their 2[nd]–5[th] line of treatment (Table). Rapidly starting regimens A or B before the first dose of ceritinib, or as soon as GI symptoms were encountered, prevented the need for dose reduction due to GI toxicity in 8/9 patients. One patient discontinued therapy due to GI toxicities despite prophylaxis. One patient required dose reduction to 600 mg/day due to Grade 3 transaminitis. Using these regimens, 78% of patients were able to remain on 750 mg/day fasting. Two patients have completed 16 and 12 months of therapy, and remain on ceritinib 750 and 600 mg/day, respectively. Figure 1



Conclusion:
Although not currently recommended or implemented in clinical studies, based on the patients evaluated here, upfront or proactive treatment plans that address AEs early on can allow the majority of patients to remain on the approved 750-mg/day ceritinib dose.

Background:
The anaplastic large cell kinase gene (ALK)-positive is a special type of non-small cell lung carcinomas (NSCLC). Although Ventana IHC (D5F3) and FISH showed high coincidence for detecting ALK rearrangement, discordant results exist in some cases. Treatment strategy as well as efficacy of crizotinib in these cases is such an issue. We studied and reported the efficacy of crizotinib in six lung adenocarcinomas patients with ALK IHC positive and FISH negative.

Methods:
All histologic and cytologic specimens were stained by IHC with an anti-ALK monoclonal antibody (D5F3, Roche) with the OptiView DAB IHC Detection Kit (Roche) and OptiView Amplification kit (Ventana Medical Systems, Inc., Tucson, AZ). All histologic and cytologic samples were also tested by FISH, which was carried out using the Vysis ALK Break Apart FISH probe kit. Three samples [one histologic (patient 1) and two cytologic samples (patients 2 and 6), patients’ numbers were listed in Table 1] were still enough to further perform for EML4-ALK fusion by qRT-PCR. Two samples [one histologic(patient 1) and one cytologic sample(patient 6)] were still enough to further perform for next generation sequencing (NGS) analysis (using modified circulating single molecule amplification and resequencing technology, cSMART). The follow up data from 6 lung adenocarcinoma patients with ALK IHC-positive and FISH-negative who received crizotinib treatment were collected.

Results:
Table 1 showed the clinicopathological characteristics and the therapeutic efficacy of crozitinib for 6 patients in the study. The patients have achieved a response rate of 66.7% (4/6). Pathologically, for patient 1, the 3 unique DNA templates with EML4->EXOC6B->ALK fusion were identified in 710 DNA copies in tumor tissue. The fusion ratio is only 0.42%. For patient 6, we detected 75 unique DNA templates in total 495 DNA copies with 15.15% fusion ration in cytologic specimen. The fusion types of patient 1 and 6 were confirmed by sanger sequencing. Some unknown mechanisms caused the 3 gene fragments fusion of patient 1, the complex fusion type and low fusion ratio cause FISH negative.

Table 1：Patient Characteristics, pathologic characteristics and molecular tests in 6 cases

Patient NO.	Gender	Age	Smoking history	ALK IHC	ALK FISH	NGS-ALK	PFS (month)	Assessment
P1	Female	31	Never smoked	+	6%	E13:EXOC6B :A20	7.46+	Partial response
P2	Male	48	Ever smoker	+	10%	-	11.96+	Stable disease
P3	Female	49	Never smoked	+	6%	-	19.94+	Partial response
P4	Male	59	Ever smoker	+	6%	-	6.60+	Partial response
P5	Male	69	Ever smoker	+	10%	-	15.08+	Partial response
P6	Female	65	Never smoked	+	12%	E13:A2	3.58	Stable disease

ALK FISH: % of split signals by FISH; NGS: Next generation sequencing; +: No progressive disease was observed at the time of analyse.

Conclusion:
Lung adenocarcinoma patients with ALK IHC-positive and FISH-negative may also response to crizotinib. Ventana IHC is another candidate method for detecting ALK. One new fusion type EML4->EXOC6B->ALK fusion was verified and the patient with this fusion type showed partial response to crozitinib.

Background:
Neoadjuvant therapy is also known as induction therapy or preoperative therapy. For lung cancer, the neoadjuvant medication includes chemotherapy and targeted medication. Neoadjuvant chemotherapy is widely used in clinical practices, but targeted therapy is still rare in the preoperative applications. To our knowledge, this is the first report of neoadjuvant crizotinib and following surgery of pulmonary adenocarcinoma.

Methods:
Crizotinib had already been recommend as the standard treatment for advanced lung adenocarcinoma with anaplastic lymphoma kinase gene rearrangement. First-line therapy with crizotinib prolonged progression-free survival and improved qulity of life among selected patients. The possibility of using crizotinib as neoadjuvant therapy is interesting because of low toxicity of tyrosine kinase inhibitors. Here we report two cases affected by locally advanced lung adenocarcinoma, in whom one-month crizotinib treatment rendered the tumors reduction to surgical removal.

Results:
These two patients with ALK-positive stage IIIA received oral crizotinib 250mg twice daily in thirty days, and crizotinib was well tolerated with rapid, prominent responses following by surgery in a week. The sequential therapy of case 1 showed the less adverse events in crizotinib than chemotherapy, while case 2 revealed more obvious responses.

Conclusion:
For pulmonary adenocarcinoma patients with ALK rearrangement, crizotinib could achieve a higher remission rate and less adverse events as compared with the chemotherapy, suggesting that crizotinib may be better option for neoadjuvant therapy. A propositional clinical trial exploring the ability of preoperative crizotinib to achieve better results than can be obtained with chemotherapy in patients selected on the basis of ALK gene rearrangement is urgently needed.

Background:
Crizotinib has been commercially available since August 2011 for the treatment of locally-advanced or metastatic ALK+ non-small cell lung cancer (NSCLC). In April 2014, a second-generation ALK inhibitor, ceritinib, was approved in the US for use after intolerance to or progression on crizotinib. Tumor progression, which varies by anatomical site and extent, is complex and evolves over time, often with insidious onset. Considering this heterogeneity, it is currently unclear at which point physicians may decide to change therapy. The objective of this study was to evaluate physicians’ decision-making with regard to determining progression during crizotinib treatment of locally-advanced or metastatic ALK+ NSCLC. This research question is particularly relevant with the introduction of new, effective treatment options available to patients who progress on first-line ALK inhibitor therapy.

Methods:
In July-November 2014, US oncologists were invited to respond to a survey regarding their decision-making with regard to treatment changes following progression on crizotinib for patients with locally-advanced or metastatic ALK+ NSCLC. Information was also collected on the characteristics of their practice.

Results:
Of the 34 oncologists who responded to the survey, 59% were from private practice, 26% were from an academic practice, and 15% were from an institutional practice. In terms of practice size, 53% were from small/intermediate practices of 2-9 oncologists, and the rest were from larger practices. Half (50%) of physicians had their practice in an urban setting; 35% were in a suburban and 15% were in a rural setting. Responding physicians had been in practice for an average of 12 years. When asked to indicate all of the clinical scenarios for which they would modify or discontinue crizotinib therapy, 62% of the physicians indicated that they would do so following disease progression detected on scan; 53% following either new or worsening symptoms; 29% following the development of new metastases in the brain; 35% following the development of new metastases elsewhere; 29% following onset of a paraneoplastic neurological disorder; and 26% following lack of improvement of patient's symptoms.

Conclusion:
The study suggests there is substantial heterogeneity in the clinical scenarios physicians would consider for modifying or discontinuing therapy after progression on crizotinib. These findings highlight the need for further clinical guidance with regard to the early identification of progression on crizotinib, and in particular, for a better understanding of the optimal point to switch from crizotinib when patients present with different manifestations of disease progression.

Background:
Lung cancer is the leading cause of cancer related deaths worldwide, with approximately 1.8 million new cases diagnosed in 2012 resulting in an estimated 1.6 million deaths (Torre 2015). The basic tools of diagnosis include the assessment of clinical status (Rivera 2013), imaging to determine the size and location of tumors as well as the presence of metastases (Liam 2015), and tissue biopsies for establishing tumor histology and molecular subtype (Ofiara 2012). Correct characterization of the primary tumor can be particularly challenging when presentation includes confounding elements such as multiple lesions and/or no definite mass at the primary site. The accuracy and timing of molecular testing can play a vital role in compressing the diagnostic window for adenocarcinoma of the lung, allowing for timely treatment and a broader range of therapeutic options.

Methods:
Local research ethics board approval was obtained for this study. A standard diagnostic work up was undertaken, then supplemented by both internal and external pathological review of the available tissue sample, including EGFR and ALK mutation testing to clarify the diagnosis.

Results:
The patient, a 49 year old male smoker, initially presented with nausea, vomiting, weight loss and shortness of breath. Imaging revealed an anterior mediastinal mass with hilar, mediastinal, bilateral neck and left supraclavicular region lymphadenopathy. Ultrasound confirmed bilateral adrenal lesions and a solid lesion in the right testicle, but no definitive lung mass was identified. Presentation characteristics were initially thought to indicate a lymphoma or germ cell tumour, however, additional analysis of tissue from a biopsy of the supraclavicular node was more consistent with a poorly differentiated carcinoma suggestive of lung adenocarcinoma, with positive staining for TTF-1 and EMA and negative staining for CK20, CK45, CK30, melanoma markers and thyroglobulin. Molecular testing for EGFR and ALK mutations was then requested, along with external pathology review. Findings from external review confirmed the aforementioned molecular profile and revealed that the tumour was also negative for CDX2, CK5, P63, PAX8, OCT3/4, SALL4 and synaptophysin expression, suggestive of thymic cancer, a teratoma, a germ cell tumour, or metastases from upper gastrointestinal origin. Molecular testing results identified an EGFR exon 21 point mutation, confirming the diagnosis of primary lung cancer. Treatment with afatinib was considered; however, due to the protracted diagnostic window, the patient was ultimately too debilitated to receive therapy.

Conclusion:
The absence of a definite lung mass and the unusual clinical and molecular presentation of this case made primary tumour site identification very challenging. The differential diagnosis was ultimately achieved through molecular testing. It is now well-established that early (reflexive testing) knowledge of EGFR and ALK mutation status, accomplished through molecular profiling, is essential for the appropriate management of patients with adenocarcinoma of the lung. However, this case also highlights the importance of this type molecular characterization in achieving a timely diagnosis.

Background:
During 1998 and 2013 the “Colombian Coffee Zone” (conformed by Caldas, Quindio, and Risaralda states) had an increase of 105 mortality cases of Bronchi and lung malignant tumors, as reported in death certificates.

Methods:
This is an observational and descriptive study that was made in patients at Clinica Oncologos del Occidente in the year 2014 and the Information was taken from the Clinical History Administration System (SAHICO). Thereafter, pending data was collected, by phone calls to patients or patient’s family, according to every case. Patients were interviewed to know their actual performance status and, in case of death, date and basic cause of death was asked.

Results:
SAHICO reported 178 patients with lung cancer. From these patients, 33 did not have a correct diagnosis. Basically they did not have histology report. There were 130 patients with Non-Small Cell Lung Cancer and Small Cell Lung Cancer. The frequency of lung cancer was slightly more common in men; most of the patients were from Risaralda, followed by Caldas. 50% of the patients were 60.7 to 74 years old. The median age for men was 69.1 years old, and 64.1 years old for women. These median ages differences were statistically significant (F=9,121 p value=0,003). And 90.8% of the patients were from urban areas. 85.3% of tumors treated in 2014 correspond to NSCLC, meanwhile 10% were Small Cell lung cancer. Patients who received radiation therapy had a longer survival than patients without any radiations treatment. The survival media in the radiotherapy group was 180.4 days, and 113.2 days for the group without radiation therapy. This difference was significant (Log Rank test: 4.74, p value 0.029). Only 2 patients had both surgery and radiotherapy and had the major survival time, with a media of 331 days. The mean age of the squamous cellular carcinoma patients was 69.8 years old in 64 patients. It was reported a median survival of 120 days with a confidence interval between 78 and 162 days. Only 8 patients with squamous cellular carcinoma had surgery and reported an increase in their survival time. The time median of survival for the surgical patients was 270 days. Meanwhile, this indicator decreased in the non-surgical patients to 109.9 days.

Conclusion:
In general, characteristics of lung squamous cellular carcinoma patients in the Coffee area of Colombia are similar than other regions of the world; incidence in men is only slightly greater than in women, presumably by the early age to start of smoke of the female population and the expose since childhood to others risk factors like biomass combustion smoke. Is clear that patients are detected in an advance stage of disease which has strong influence in prognosis and outcome. Highlights the importance of an integral treatment including all management alternatives and a multidisciplinary equipment of attention for modification of prognosis and survival.

Background:
Long term survivors ( >3years) in advanced NSCLC is steadily increasing from 5 - 10% to 15 - 20%. It is related with the more effective and better treatment given in an individualised manner along with better understanding of the tumour biology. Many factors are also associated with the improved outcome. Our Institute’s 3 years data is analysed in an attempt to find out the favourable factors.

Methods:
Data mining of Stage III & IV non small cell lung cancers treated at RCC, RIMS during 2010 to 2012 are carried out from the patient’s departmental records. Only patients diagnosed and treated at RIMS who survive more than 3 years are included for analysis. Patient characteristics, disease profile & treatment pattern are analysed.

Results:
Out of 196 patients records available- Stage III & IV comprise 160 patients of these 30 patients survived more than 3 years. The analysis shows Male: Female ratio 5:4, mean age 55 years (range 36 to 90 yrs) stage III is 18(60%) stage IV 12(40%). Histologically, Squamous cell Ca. 60% Adeno ca. 24% and small cell 12% and rest others. KPS range from 60% to 90%. Treatment given: 80% received intent to cure with Chemo ± RT. And 20% palliative care only. Long survivors (>3years) 24 patients (16F + 8M) who received intent to treat chemo or chemo+ RT compared to none in supportive care only

Conclusion:
The result shows that females with Histo type adenocarcinoma who received therapy with Chemo + RT +/- targeted therapy with intent to treat are the long survivors according to this study. The study indicates that treatment should be given in a sub set of patients with advanced disease who are responders for increasing meaningful survival.

Background:
Most newly diagnosed advanced lung cancer patients have an initial medical oncology consult as an outpatient. However, occasionally the initial referral occurs as an inpatient. We explored the characteristics of advanced NSCLC patients whose first medical oncology consultation occurred while hospitalized.

Methods:
With ethics approval, we performed a retrospective analysis of all advanced NSCLC patients at our institution whose initial consult occurred while hospitalized, from 2007 to 2012. Demographics, treatment and survival data were collected. This was an exploratory analysis. Multivariate survival analysis was performed using Cox regression models.

Results:
In total, 223 patients were included (baseline characteristics in Table 1). Overall, only 24% received chemotherapy while 72% received some palliative radiotherapy. Median time from diagnosis to chemotherapy was 43 days. Reasons for not receiving chemotherapy included poor performance status (PS) (72%), patient choice (9%), clinical deterioration (6%) or co-morbidities (4%). Factors associated with receiving chemotherapy were good PS (OR 11.11 [95% CI 5.56-25.00], p<0.001), no constitutional symptoms (OR 2.86 [95% CI 1.41-5.88], p=0.004), no leukocytosis (OR 2.38 [95% CI 1.23-4.55], p=0.01), fewer co-morbidities (OR 1.54 [95% CI 1.27-1.89], p<0.001) and younger age (OR 1.09 [95% CI 1.05-1.12], p<0.001). Median OS was shorter in those not receiving chemotherapy (1.7 v 7.1 months, HR 2.76 [95% CI 1.72-4.41], p-value<0.001). Figure 1 shows Kaplan-Meier survival curves. In multivariate analysis, in addition to not receiving chemotherapy, factors associated with shorter OS were PS 3-4, (HR 1.55 [CI 1.03-2.33, p=0.04]), leukocytosis (HR 2.23 [95% CI 1.51-3.28], p-value <0.001) and thrombocytosis (HR 1.52 [1.06-2.18], p=0.02).

Conclusion:
Patients whose first consultation with medical oncologists occurs while hospitalized are an inherently sick population and only a minority receive chemotherapy. The lung cancer community must advocate for earlier diagnosis and referral, so more patients have access to treatment options before a terminal functional decline.

Table 1: Baseline Characteristics

Demographic (N=223)	%
Age in years, median (range)	65 (23-89)
Gender
Male	48
Female	52
Charlson Comorbidity Index total score, median (range)	10 (6-18)
Performance status
0-2	24
3-4	69
Unknown	7
Smoking status
Current	49
Ex	34
Never	9
Unknown	8
Stage at diagnosis
IIIB	10
IV	89
Unknown	1
NSCLC subtype
Adenocarcinoma	45
Squamous cell	23
Large cell	8
Other	23
Dominant presenting symptom
Dyspnea	34
Pain	23
Constitutional symptoms	9
Pneumonia	7
Cough	5
Hemoptysis	3
Other	18
Weight loss
<5%	22
>5%	52
Unknown	25

Figure 1

Background:
Brain metastases are evidenced in 10 to 30 % of NSCLC patients sometime during the disease. The purpose of our research is to identify the clinical pathological characteristics in patients with stage IIIB-IV in relation to the development of brain metastases.

Methods:
590 patients with lung cancer at our institution were analyzed between 2000 and 2013, of which 190 (32,3%) were stage EIIIB and 400 (67,7%) EIV. 76 (12.8%) had brain metastases. The variables included in the analysis of patients with and without brain metastases were: gender, age, histology, smoking status and ECOG. The multivariate logistic regression model was used to identify factors related to brain metastases.

Results:
64 patients out of the total 76 had brain metastases at initial diagnosis and 11 EIIIB developed brain metastasis in relapses. The development of brain metastasis was higher in men compared to women (77.7% vs 22.2%). Over 80% of patients presented ECOG of 0-1. Regarding histology, 60.32% were adenocarcinomas; 30% squamous, and 9.5% undifferentiated. 65% of patients were under 65 years old. 66.6% of patients were former smokers. Patients under 65 years old were at increased risk of developing brain metastases than older patients (HR=0,5-IC95%= 0,6-1,16- p=0,045). Adenocarcinoma histology was associated with an increased number of brain metastases development (OR = 2.42 - 95% CI = 1.84 to 3.00 - p= 0.003).

Conclusion:
Patients who were younger than 65 years old and adenocarcinoma histology, had a statistically significant higher risk of developing brain metastases. Regarding gender, we observed an increased risk in men; however, the differences were not statistically significant.

Background:
The brain is one of the organs where lung cancer often metastasizes. At the time of diagnosis, the central nervous system metastases are present in approximately 10% of lung cancer cases. 80-85% of them are located supratentorially, and 10-15% of supratentorial lesions are located on cerebellar regions. Median survival is 1-2 months from the time of diagnosis without treatment. A general consensus about standard treatment could not be provided in lung cancer with a single brain metastasis; but distant metastases should necessarily be controlled with surgery or stereotactic radiation therapy.

Methods:
74 patients (65 men and 9 women) were included in the study and evaluated retrospectively. They were followed in the department of medical oncology, school of medicine, Uludag University. All the patients had cranial operations for cranial metastases between 2004 and 2012. The ages and the first symptoms of the patients at the time of diagnosis, tumor localizations, surgical procedures, chemotherapy and radiotherapy protocols and histologic subtypes of lung cancer were analyzed. Time from diagnosis of cranial metastases to death was estimated as overall survival.

Results:
The symptoms of the patients at the time of diagnosis were as follows: 21 (28%) headache, 17 (23%) hemiparesis, 18 (24%) more than one neurologic symptoms, 8 (10%) seizure, and 8 (10%) imbalance. The distrıbution of histologic subtypes of patients was as follows: 42 (56%) adenocarcinoma, 17 (23%) squamous cell carcinoma, 14 (14%) small cell carcinoma, and 1 (1%) large cell carcinoma. According to surgical procedures, patients are distributed as follows: 68 (92%) total resection, 4 (5%) subtotal resection, and 2 (3%) stereotactic biopsy. 55 (74%) patients received cranial radiotherapy postoperatively. 15 (20%) patients received radiotherapy for both cranium and lung. 3 (4%) patients did not received radiotherapy. 1 patient’s information about radiotherapy could not be reached. 70 (95%) patients received platinum-based chemotherapy. 4 ()patients did not receive any chemotherapy regimens. Median overall survival was 12 months (1-110 months) in patients with cranial metastases.

Conclusion:
In an article examining brain metastases that were developed postoperatively, 65 patients were evaluated. 5-year survival in this group of patients was 15%. In that study, factors that affect survival positively, were listed as: female gender, adenocarcinoma histologic subtype, presence of limited number of metastases (1-2), no other extra thoracic metastases except brain metastases, stereotactic, radiologic and/or surgical treatment for metastases. However, in the literature it was reported that three cases, whose brain metastases appeared after surgical resection of lung cancer, had overall survival over 12 years with stereotactic radiotherapy. On the other hand, it is obvious that systemic therapy is so important for metastatic patients. The benefits of the combined treatment with surgery were studied by many groups. Although the studies have not identified the prognostic factors for survival exactly and either responded which group of patients could see more benefit from aggressive treatment yet; good results have been taken by adding surgical resection of metastases to combined treatment in especially selected patients.

Background:
Several studies have shown that tyrosine kinase inhibitors and chemotherapy improve the short term and median survival of patients with metastatic adenocarcinoma of the lung (MAL), but the long term survival (LTS) of these patients has not been thoroughly investigated.

Methods:
We performed a univariate retrospective analysis on 174 patients with MAL diagnosed at our institution between 2009 and 2011, and with up to a 5-year follow-up. Most patients received multiple treatment modalities. Overall survival was estimated using the product-limit method and compared using the log-rank test (significant results listed in Table 1); patients alive at last follow-up were censored.

Results:
In our series, 19% (33) of all patients (174) received erlotinib as part of their treatment, and 39%(13) of those receiving erlotinib had epidermal growth factor receptor (EGFR) mutations. Although the 2-year and median survival were superior in patients receiving erlotinib and chemotherapy, neither improved the 5-year survival rate (LTS). Surprinsingly, the 60-months survival rate was higher in the no erlotinib arm (Figure 1). The only treatment modality that significantly improved LTS was surgery. For the patients treated with erlotinib and chemotherapy, regardless of EGFR mutations, all observed deaths occurred within 4 years. Factors associated with LTS were: sex, surgery, and presence of metastatic disease confined to the the lungs.

Conclusion:
In our univariate retrospective analysis, MAL patients who were treated with erlotinib and chemotherapy had improved 2-year and median survival rates compared to patients treated with chemotherapy alone, but had no improvement in LTS. Factors such as: surgery, metastases limited to the lungs only, female sex were associated with LTS in MAL patients, but larger prospective studies are needed to confirm our findings. Our study puts into question the long term survival benefit of tyrosine kinase inhibitors in MAL and suggests a prominent role of surgery in this clinical context. Figure 1 Figure 2

Background:
This study reviews the results of extensive genetic analysis in non-small cell lung cancer (NSCLC) patients from a University of Chicago database in order to: describe how actionable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially actionable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS. This study reviews the results of extensive genetic analysis in non-small cell lung cancer (NSCLC) patients from a University of Chicago database in order to: describe how actionable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially actionable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS.

Methods:
Thoracic Oncology Research Program (TORP) Databases at the University of Chicago provided patient demographics, pathology, and results of genetic testing. Three hundred and sixty four patients included in this analysis had advanced NSCLC and underwent genotype testing by FoundationOne, Caris Molecular Intelligence, and Response Genetics.

Results:
99.4% (159/160) of patients, whose samples were analyzed by next-generation sequencing (NGS), had genetic alterations identified with an average of 10.8 alterations/tumor throughout different tumor types. However, mutations were not mutually exclusive. For the entire cohort 28% of patients were African Americans; adenocarcinoma was the most commonly tested tumor subtype; 91% of KRAS mutations were detected in smokers; 46% of EGFR alterations and 50% of ALK translocations were detected in never smokers. The majority of ALK translocations were detected in adenocarcinomas.

Conclusion:
Personalized medicine is a significant step forward in the realm of lung cancer treatment. In conjunction with NGS to identify and characterize tumor specific molecular abnormalities, biomarker-driven therapies have improved patients’ overall survival. NGS in this study identified potentially actionable genetic alterations across various tumor histology subtypes, races and smoking status. NGS also provided additional information by uncovering targetable concurrent alterations or alterations of unknown significance at this point in time, but potentially targetable in the future.

Background:
Non-Small Cell Lung Cancer (NSCLC) patients tend to develop brain metastasis (BM) early in the course of the disease, usually within 2 years of diagnosis. BM are an important cause of morbidity and mortality, the study of prognostic factors for its development are invaluable in implementing measures to prevent or decrease the incidence of BM. The aim of this study was to evaluate the prognostic value of certain clinical characteristics in the development of BM in NSCLC patients.

Methods:
We retrospectively analyzed all patients diagnosed with NSCLC at our institution between 2000 and 2013. Demographics, tumor characteristics and metastatic patterns were studied. Median follow up was 45 months. Cox regression was used for multivariate analysis.

Results:
A total of 1062 patients were studied. Of these, 172 (16%) had BM at the time of analysis, with 61 (35%) patients having BM at diagnosis. Median age was 68 years (range, 18-91); median time from diagnosis to BM was 259 days. There were more females than males (64% vs. 36%, p < 0.0001). About NSCLC characteristics, patients with BM were more likely to have upper lobe tumors than all other tumor locations combined (63% vs. 37%, p < 0.0001). 32% of the lung tumors were 5-7cm in diameter and adenocarcinoma represented 68% of all the histologic subtypes. In regards to other distant metastases: 34% of the patients had bone metastasis, 23% adrenal and 17% hepatic. BM were most commonly located in the frontal (41%), parietal (17%) and occipital (14%) lobes. There was a significant survival difference between Stage IV patients with and without BM; patients with BM survived 6.1 months compared with 11.9 months in those without BM (p < 0.0001). In univariate analysis, female sex, histologic grade, upper lobe tumors and high LDH levels were associated with BM. Age < 65 years (HR: 0.60, 95%CI: 0.37-0.95, p < 0.03), T3-4 tumors (HR: 3.4, 95%CI: 2.04-5.64, p < 0.0001), adrenal metastasis (HR: 5.2 95%CI: 2.5-10.7, p < 0.0001) and liver metastasis (HR: 8.6, 95%CI: 4.3-17.2, p < 0.0001) were independent risk factors for the development BM.

Conclusion:
The results of this study pose female sex, tumor histologic grade, tumor location, and LDH levels as important prognosticators of future BM. In addition, younger age, T3-4 tumors, and the presence of adrenal/liver metastases are noted as independent risk factors for BM development. With this information, criteria for the selection of patients as suitable candidates for intra-cranial irradiation, periodic brain imaging studies, and close outpatient follow-up may aid in further prevention of BM, early identification, and timely management.

Background:
The bone is one of the most frequent sites for metastases from non-small cell lung cancer (NSCLC) and bone metastases are diagnosed in 30-40% of patients. They are resulted in skeletal-related events (SREs) that associate with an important morbidity and poor survival. In the current study, clinicopathological factors and SRE-free survival were evaluated for patients with NSCLC with bone metastases.

Methods:
Three-hundred and thirty-five NCSLC patients with bone metastases were retrospectively analyzed, between 2010 and 2013. The effect of clinicopathological factors on SRE and survival were evaluated for all patients with or without SREs.

Results:
Totally, 244 (72.8%) patients developed SREs at the diagnosis or during treatment of disease. Of these, 145 required radiotherapy to the bone or pathological fracture, 59 developed malignant hypercalcemia, 21 developed compression fracture of the vertebrae and 5 required surgical treatment of the bone. There were significant differences between the patients with respect to number of bone metastasis, the presence of palliative radiotherapy and the presence of bisphosphonate therapy. The association of histopathological subtypes and bone metastases was not detected. Patients with multiple bone metastasis had significantly increased SRE when compared to patients with single bone metastasis (p=0.002). Patients with single bone metastasis had a better median SRE-free survival compared with patients multiple bone metastasis (7 vs. 2 months, respectively, p<0.0001). Univariate analysis revealed that performance status (PS), the presence of bone metastasis at diagnosis, number of bone metastasis, SRE, the presence of palliative radiotherapy and bisphosphonate therapy were significant prognostic factors for overall survival (OS). Patients with bone metastasis at diagnosis had a shorter median OS compared with patients developed bone metastasis after diagnosis (8 vs. 18 months, respectively, p<0.0001). The presence of bone metastasis at diagnosis and number of bone metastasis were found to be an independent factors for predicting the occurrence of SRE (p<0.001 and p<0.001, respectively).

Conclusion:
Our results showed that the presence of multiple bone metastases was significantly associated with the development of SRE for NSCLC patients with bone metastases. In addition, bone metastasis at diagnosis is related with poor OS. The determining of additional factors affecting the occurrence of SREs may guide to best treatment for NSCLC patients with bone metastases.

Background:
Approximately 180,000 Americans are diagnosed with non-small cell lung cancer (NSCLC) annually, and more than half have advanced (Stage IIIB/IV) disease. Historically, survival for these patients has been poor. Moreover, even though standard systemic therapies (e.g. platinum-doublet chemotherapy) provide a modest survival advantage, a substantial proportion(~60%) of patients do not initiate or complete treatment. The advent of newer systemic therapies with more favorable effectiveness and toxicity profiles affords opportunities to improve NSCLC outcomes. The objectives of this study were: 1)to quantify survival gains from 1990-2015, ranging from a period when best supportive care(BSC) only was standard, to the present, where multiple cytotoxic and targeted therapies are available, and 2)to project the potential impact of increasing use of modern systemic therapies in clinically appropriate patients.

Methods:
We developed a simulation model to estimate observed and potential survival gains for patients diagnosed with advanced NSCLC in 1990 and 2015. Survival inputs were derived from Phase III clinical trials referenced in National Comprehensive Cancer Network guidelines, and extrapolated to a lifetime horizon by fitting Weibull curves. Proportions of patients receiving available therapies were derived from SEER (for % receiving BSC only) and a commercial treatment registry. Outcomes included one-year survival proportion, mean expected overall survival(OS), expected OS if the proportion receiving systemic therapy is increased by 10% (“Scenario 1”) and 30% (“Scenario 2”) relative to current use, and population-level estimates of total life years. Results were calibrated with SEER overall survival curves. Annual incidence of advanced NSCLC was assumed to be 92,000 in both years.

Results:
In the expected survival analysis, from 1990 to 2015, one-year survival proportion increased by 15.8% and mean per-patient survival improved by 4.3 months (33,412 population life years)(Table 1). In scenarios 1 and 2, the improvement in survival increased to 4.6 months (35,684 population life years) and 5.2 months (40,279 population life years), respectively. Considering the proportion receiving each treatment, and the size of overall survival treatment effects, the majority of the survival gains were attributable to the advent of platinum-doublet chemotherapy (49%), followed by EGFR (35%), VEGF (10%), and ALK (6%) targeted therapies.

Table 1: Advanced non-small cell lung cancer outcomes by year of diagnosis.

Diagnosis Year	Expected: One-Year Survival (%)	Expected: Mean Per-Patient Survival (Months)	Expected: Population Life Years	Scenario 1: Population Life Years with 10% Relative Increase in Proportion Treated	Scenario 2: Population Life Years with 30% Relative Increase in Proportion Treated
2015	29.3%	11.4	87,287	89,559	95,154
1990	13.5%	7.1	53,875	53,875	53,875
Difference	+15.8%	+4.3	+33,412	+35,684	+40,279

Conclusion:
Though survival remains poor in advanced NSCLC relative to other common cancers, meaningful progress in per-patient and population-level outcomes has been realized over the past 25 years. These advances can be improved even further by increasing use of systemic therapies in the substantial proportion of patients who are suitable for treatment, yet currently receive BSC only.

Background:
The OEA[TM] is a clinical support system with a continuous improvement capability. Its objectives are to enable/empower evidence-based decisions/care by disseminating knowledge and expertise to physicians/users tailored to meet the clinical needs of individual patients as if consulting with an expert. Cognitive computing platforms have the potential to disseminate expert knowledge and tertiary level care to patients. This objective is made possible by making available to physicians/providers cognitive computing generated expert recommendations in diagnosis, staging and treatment. The cognitive computing software was trained by MD Anderson experts using currently available consensus guidelines and an iterative feedback process. Here we test the capability of this cognitive computing software program developed at MD Anderson to generate expert recommendations when patients with advanced-stage NSCLC have a targetable molecular aberration.

Methods:
We developed a web based prototype of MD Anderson’s Oncology Expert Advisor (OEA[TM]), a cognitive clinical decision support tool powered by IBM Watson. The Watson technology is IBM’s third generation cognitive computing system based on its unique capabilities in natural language processing and deep QA (question-answer). We trained OEA[TM] by loading historical patient cases and assessed the accuracy of targeted treatment suggestions using MD Anderson’s physicians’ decisions as benchmark. A false positive result was defined as a treatment recommendation rendered with high confidence that was non-correct (less optimal), whereas false negative was defined as a correct or more optimal treatment suggestion listed as a low confidence recommendation.

Results:
In our preliminary analyses, OEA[TM] demonstrated four core capabilities: 1) Patient Evaluation through interpretation of structured and unstructured clinical data to create a dynamic case summary with longitudinal view of the pertinent events 2) Treatment and management suggestions based on patient profile weighed against consensus guidelines, relevant literature, and MD Anderson expertise, which included approved therapies, genomic based therapies as well as automated matching to appropriate clinical trials at MD Anderson, 3) Care pathway advisory that alerts the user for anticipated toxicities and its early identification and proactive management, and 4) Patient-oriented research functionalities for identification of patient cohorts and hypothesis generation for future potential clinical investigations. Detailed testing continues and the accuracy of standard-of-care (SOC) treatment recommendations of OEA[TM], as well as false positivity and negativity rates will be presented in detail at the meeting.

Conclusion:
OEA[TM] is able to generate dynamic patient case summary by interpreting structured and unstructured clinical data and suggest personalized treatment options. Live system evaluation of OEA[TM] is ongoing and the application of OEA[TM] in clinical practice is expected to be piloted at our institution.

Background:
EGFR mutation-positive (EGFR M+) NSCLC is a specific lung cancer subtype characterized by presence of EGFR mutations and sensitivity to treatment with EGFR tyrosine kinase inhibitors (TKIs). Common activating mutations (Del19, L858R) account for ~90% of EGFR M+ NSCLC cases. Afatinib, an oral, irreversible ErbB family blocker, improved progression-free survival (PFS) versus standard platinum-based chemotherapy in 1st-line EGFR M+ NSCLC. Afatinib also significantly prolonged overall survival (OS) in the EGFR Del19 mutation subgroup. Erlotinib, a reversible EGFR TKI licensed in the US has also improved PFS in EGFR Del19 mutation subgroup, but not OS. The objective of this study was to assess the cost-effectiveness of afatinib versus erlotinib in the 1st-line treatment of patients with metastatic EGFR Del19 M+ NSCLC in the US healthcare setting.

Methods:
A partitioned survival model was developed consisting of “progression-free”, “progressive disease”, and “death” health states. Patients entered the model in the progression-free state and advanced to progressive disease and death based on the progression-free survival and overall survival curves. The survival curves for afatinib were estimated by fitting parametric models to the empirical data from the LUX-Lung 3 clinical trial. For erlotinib the survival curves were estimated based on hazard ratios that were applied to the afatinib curves. The hazard ratios were derived via a network meta-analysis. Patients incurred treatment-specific drug costs for afatinib and erlotinib until disease progression. Costs to treat grade 3/4 adverse events were applied to each treatment. Resource use from the LUX-Lung 3 trial data and unit costs from published literature and from standard U.S. sources were used to derive the additional, monthly costs of being progression free. Monthly continuing care costs and one-time, end-of-life costs for patients with progressive disease were obtained from published literature. The utility of progression-free disease was obtained from LUX-Lung 3, and the disutility of progressive disease was obtained from the published literature. Disutilities associated with adverse events were also obtained from the literature. The model calculated patient survival (life years) and quality of life adjusted years (QALYs), and total costs per patient. Incremental cost-effectiveness ratios (ICERs) were calculated as the ratio of the difference in cost to the difference in LYs and QALYs. Costs and outcomes were calculated over a 20-year time horizon and discounted at an annual rate of 3%.

Results:
Based on the model, the patients taking afatinib accrued more life years (3.09 vs. 2.46) and QALYs (2.17 vs. 1.72) than patients taking erlotinib. Although the wholesale acquisition cost (WAC) of afatinib was lower than that of erlotinib, the incremental per patient cost was higher with afatinib ($ 32,961) owing to patients spending more time in “progression-free”, and “post-progression” health states in the afatinib group. At an accepted US ICER threshold of $100,000/QALY, afatinib vs. erlotinib had an ICER/QALY gained of $74,345 and cost per LY gained was $52,401.

Conclusion:
Afatinib as a 1st-line therapy for locally advanced or metastatic NSCLC with EGFR exon 19 deletion mutations is a cost-effective alternative to erlotinib according to the commonly accepted cost-effectiveness threshold in the US.

Background:
The RANZCR Faculty of Radiation Oncology Lung Interest Cooperative (FROLIC) surveyed patterns of lung cancer radiotherapy practice in Australasia for both non-small cell (NSCLC)and small cell lung (SCLC) cancer to evaluate current patterns of care and define gaps in optimal care requiring improvement.

Methods:
Radiation Oncologists were surveyed at all 62 departments in Australasia using a web-based survey targeting those treating lung cancer. Questions covered current radiotherapy practice as well as measures of quality

Results:
Of 62 responses received, 57 did treat lung cancer and were eligible for analysis. All Australian states and New Zealand were represented. Sixty-two percent of respondents worked at metropolitan centres, 58% were subspecialists in lung cancer and 60% participate in lung cancer trials. Ninety-four percent discuss lung cancer patients at a tumour board, 74% peer review contours for conventional fractionation and 50% for SABR. Fifty percent used a department protocol for contouring and/or prescription, 39%, an external protocol and 11% had no protocol. For radical conventional radiotherapy, 58% use 4DCT to assess tumour motion, 44% utilise breath hold or respiratory gating, 44% use PET Fusion, 35%, free-breathing CT and 23% PET-CT simulation. In palliative settings, free-breathing CT was most common (81%). For conventional treatment, 98% use 3DCRT, 34% IMRT and 18% VMAT. Image verification was primarily with cone beam CT (86%), KV imaging (72%) and MV imaging (30%). The commonest dose fractionation regime in NSCLC was 60Gy in 30 fractions used in 95% of node-positive and 82% of node-negative disease. 66Gy in 33 fractions and 50-55Gy in 20 had been used by 32% and 30%of respondents respectively. 30Gy/10 fractions was the most frequent palliative regime that had been used (by 76%), followed by 36Gy/12 (72%) . For limited stage SCLC, the majority (61%) treated with 45-50.4Gy in 25-28 fractions while 45Gy/30 twice daily had been used by 48%. In extensive stage SCLC, consolidation chest radiotherapy was used by 63% in complete response, 48% for partial response and 24% would not treat. 46% of departments provided SABR but only half treated central tumours. For peripheral tumours, 80% used 54Gy in 3 fractions and if close to chest wall, 70% used 48Gy in 4 fractions. In fit patients with synchronous solitary brain metastasis and controlled extra-thoracic disease, 37% of respondents would treat both chest and brain definitively, 43% would do so only if chest disease was equivalent to Stage I/II, and 9% would never treat radically. If three brain metastases were present, just 46% would treat definitively. In the setting of an isolated systemic metastasis only, 35% would treat definitively while 61% do not offer definitive treatment in the setting of systemic oligo-metastases.

Conclusion:
A significant proportion of radiation oncologists did not have access to 4DCT for simulation. The majority used 3D image verification and consistently prescribed evidence-based doses. Although protocols were widely used, a significant number did not participate in peer review of contours. The treatment of synchronous oligo-metastatic disease was variable, likely due to a lack of high quality evidence and should be an area of future research.

Background:
Although TAILOR phase 3 trial showed superiority of docetaxel versus erlotinib as second line treatment in NSCLC with wild type EGFR as assessed by direct sequencing, second-line treatment of patients with wild-type status is controversial and EGFR-TKIs are still used as second line treatment.

Methods:
We retrospectively analyzed the results of 2[nd] line treatment with EGFR-TKIs in 25 patients with activating EGFR mutations and 68 patients with wild-type EGFR as assessed by PNA clamping (Panagene®, South Korea), which is more sensitive than direct sequencing.

Results:
There was no significant difference in age, sex, smoking history and histologic subtypes of NSCLC between the two groups. Erlotinib was more frequently used in EGFR wild group (48/68, 71%), while use of gefitinib was significantly higher in EGFR mutation group (15/25, 60%, p=0.003). Progression-free survival (PFS) was significantly longer in EGFR mutation group than EGFR wild group: median PFS was 11.6 months (95% CI 6.2~17.1) in mutation group versus 1.8 months (1.5~2.1) in wild group (log rank p<0.001). PFS was numerically shorter than the 2.4 months (2.1~2.6) of TAILOR trial. Figure 1



Conclusion:
This results show that possibility of survival benefit using second-line EGFR-TKI is very low in patients with NSCLC with wild-type EGFR status, when tested with sensitive EGFR mutation detection technique. Thus chemotherapy should be favored for the second line treatment of patients with NSCLC with wild-type EGFR status.

Background:
Limited data are available on treatment experience in patients with advanced lung adenocarcinoma with unknown EGFR gene status (UN-EGFR-GS). We studied the demographic profile and treatment outcomes of advanced NSCLC patients with adenocarcinoma, which the EGFR gene status was unknown.

Methods:
Retrospective study of patients with UN-EGFR-GS advanced lung adenocarcinoma over a 4-year period at a tertiary care institute in China. Patients diagnosed with stage IIIb or IV were included for analysis during 2009 and 2012.

Results:
In total, 113 patients were included, females and males constituted 46.9% (n=53) and 53.1% (n=60), respectively. Among the 113 patients, 53 were non-smokers and 60 were smokers. The median age was 57.5y(35y-85y). The performance score was 2 in only 12 patients, otherwise was 0 or 1. Majority of patients had stage IV disease (95.6%). Seventy-five patients were advanced stage when diagnosed, and 38 patients were relapsed disease once received surgical resection. Nine patients received adjuvant chemotherapy, which were not relapsed in 6 months after finishing last cycle. The common regimens of first-line treatment were gemcitabine plus platinum (n=36) and pemetrexed plus platinum (n=32). Eleven patients received EGFR-TKIs as first-line treatment. Other drugs included docetaxel, paclitaxel, novelbine and etc. The commonest second-line treatment was oral EGFR-TKIs (n=44). Fifty patients received third-line treatment and 19 received fourth-line treatment. At the end of follow-up (2015-3-30), 91 patients were dead and 22 patients were alive or lost follow up. The median survival of this whole cohort was 20.0m (16.1m-24.0m, 95%CI). The overall survival was not associated with sex (p=0.441), performance status (p=0.809) and smoking (p=0.677). Those patients (29.9m, 95%CI; 18.6m-41.1m) who received surgical resection lived longer than the patients (17.8m, 95%CI; 13.8m-21.8m) who were advanced stage when diagnosed (p=0.01). The overall survival was also not associated with the chemotherapy drugs used in the first-line treatment. The patients (19.0m, 95%CI; 11.4m-26.5m) used pemetrexed plus platinum lived no longer than other regimens (20.5m, 95%CI; 13.4m-27.4m) (p=0.272). In the gemcitabine plus platinum group, the median survival was 19.9m (95%CI; 9.2m-30.6m), which was not longer than other regimens (20.0m, 95%CI; 15.4m-27.4m). The p value was 0.404. We also analyzed the influence of oral EGFR-TKIs on overall survival. Those who had a chance taken EGFR-TKIs lived numerically longer than never; the median survival was 24.8m (19.1m-30.5m, 95%CI) and 16.3m (12.7m-19.9m, 95%CI), respectively. However, the overall difference was not significant (p=0.184).

Conclusion:
The median survival of patients with advanced lung adenocarcinoma with UN-EGFR-GS was 20m. Oral EGFR-TKIs appear to be useful for this group of patients.

Background:
Malignant pericardial effusions are common in lung cancer (LC) and can produce cardiac tamponade (CT). This oncologic emergency requires a high index of suspicion for accurate, prompt diagnosis. To study how CT is diagnosed in LC, we reviewed symptoms, signs and differential diagnoses recorded, and tests obtained, at a tertiary teaching hospital.

Methods:
Records of patients hospitalized with a diagnosis of CT between April 1999 and September 2011 were reviewed, focusing on LC related CT. Extent of disease, treatment history and response, symptoms, vital signs, physical exam and EKG findings recorded by the initial and admitting physicians were recorded, together with differential diagnoses mentioned in the physician notes before radiologic testing. Finally, the radiologic tests used to make or confirm the diagnosis were recorded.

Results:
Of 770 patients with a diagnosis of CT, 57 had malignant CT and 26 had LC. Of these, 7 (27%) were newly diagnosed with cancer at the time of diagnosis of CT. The most common symptom, shortness of breath, was present in 24 (92%) cases. Physical exam findings recorded by physicians are listed in Table 1. EKG findings of low QRS voltage/electrical alternans were present in 3, absent in 3 and were not documented in 20 patients. In only 8 cases (31%) CT was included in the differential diagnosis based on the signs, symptoms and EKG findings at initial presentation. Of these, 3 had a known prior history of pericardial effusion and 3 were newly diagnosed with LC at the time of presentation. Two of these diagnoses were made by oncologists and the other 6 were made by Emergency physicians (ED)/internists. In the remaining 18 cases, the diagnosis was made serendipitously with imaging studies obtained for other reasons. Of these, 5 patients had a known history of malignant pericardial disease and 6 were newly diagnosed with LC. The physician seeing the patient initially was an oncologist in 5 cases and an ED /internist in 13 cases.

	Jugular venous distention	Distant heart sounds	Pulsus paradoxus	Tachycardia	Hypotension
Present	7 (27%)	5 (19.2%)	3 (11.5%)	22 (84.6%)	6 (23%)
Absent	10 (38.4%)	-	4 (15.3%)	4 (15.3%)	20 (77%)
Not recorded	9 (34.6%)	21 (80.7%)	19 (73%)	-	-

Conclusion:
Not including CT in the differential diagnosis of LC patients presenting with dyspnea is common among physicians of all types, including oncologists, internists, and ED. Physicians should include CT in the differential diagnosis of LC patients presenting with dyspnea and tachycardia, especially those with advanced disease, and a careful physical examination will elicit the classic signs in a substantial proportion of patients. Without a high index of clinical suspicion the diagnosis may be delayed or missed.

Background:
Most patients with secondary malignant tracheobronchial tumors have distressing symptoms due to major airway obstruction. However, they are always too frail for curative surgical resection. We choose fibrobronchoscopic cryorecanalization to improve their life quality and analyzed the long time survival outcome.Most patients with secondary malignant tracheobronchial tumors have distressing symptoms due to major airway obstruction. However, they are always too frail for curative surgical resection. We choose fibrobronchoscopic cryorecanalization to improve their life quality and analyzed the long time survival outcome. file://localhost/Users/app/Documents/2014下半年/11122014%20JTO/冷冻/Figures/Figure%202.tif file://localhost/Users/app/Documents/2014下半年/11122014%20JTO/冷冻/Figures/Figure%201.tif file://localhost/Users/app/Documents/2014下半年/11122014%20JTO/冷冻/Figures/Figure%203.tif

Methods:
Clinical records of 14 patients were reviewed retrospectively from December 2005 to January 2013. A temperature from -50℃ to -70℃ was delivered to the central part of the tumor by cryo-probe for 4 to 6 minutes causing destruction of the tumor mass (Cryo-melt method). Subsequently, the edge of tumor was froze for 0.5 to 2 minutes and then tore the lesion piece by piece immediately with the advantage of concretion between the frozen probe tip and the tumor tissue (Cryo-resection method). file://localhost/Users/app/Documents/2014下半年/11122014%20JTO/冷冻/Figures/Figure%204.tif

Results:
The rates of dramatic and partial symptomatic alleviation were 57.1% and 28.6% respectively. There were no intraoperative deaths. The median survival was 16.0 months. Overall survival was 64.3% at half year, and 50.0% at 2 years. 2-year survival was significantly correlated to age (less than 60 years 22.2% versus more than 60 years 100%, p=0.011), tumor location (main bronchi 0% versus trachea 77.8%, p=0.003), and cryorecanalization times (one time 33.3% versus two or more times 80.0%, p=0.037). file://localhost/Users/app/Documents/2014下半年/11122014%20JTO/冷冻/Figures/Figure%205.tif file://localhost/Users/app/Documents/2014下半年/11122014%20JTO/冷冻/Figures/Figure%206.tif file://localhost/Users/app/Documents/2014下半年/11122014%20JTO/冷冻/Figures/Figure%207.tif

Conclusion:
Fibrobronchoscopic cryorecanalization is a safe, easily repeatable and effective minimally invasive choice for releasing the airway obstructive symptoms. In addition to high local-regional control rates, a rewarding result of prolonged survive time can also be obtained.

Background:
In the last years, new drugs and strategies have emerged in the management of lung cancer (LC). The French College of General Hospital Respiratory Physicians therefore promoted a prospective multicenter epidemiological study: the ESCAP study. This study was aimed to describe the therapeutic strategies implemented during the first 2-year after diagnosis in patients with LC followed in French General Hospital chest departments. We report below descriptive results for metastatic non-small-cell lung cancer (mNSCLC).

Methods:
For each patient with a LC diagnosed in 2010, a standardized form was completed at diagnosis and following each change in treatment strategy up to at least 2 years after diagnosis.

Results:
53 centers participated in the ESCAP study and included 3,943 patients. Among them, 3,418 patients had a NSCLC. NSCLC was metastatic in 2,003 patients. In patients with mNSCLC, the first therapeutic strategy was chemotherapy alone (56%) followed by palliative chemotherapy plus incidental radiotherapy (35%); 4% of patients died without any implemented therapeutic strategy (see figure). 29% of patients with chemotherapy alone as first strategy died without undergoing any other strategy and 70% had a second strategy (72% chemotherapy alone). 35% of patients with radiochemotherapy died without undergoing any other strategy and 64% had a 2[nd] strategy (73% chemotherapy alone). Figure 1 The most frequent chemotherapy during the first strategy was platinum salts doublet with pemetrexed (39%), followed by platinum salts doublet with paclitaxel (15%). Chemotherapy during the second strategy was second line chemotherapy (67%) or maintenance therapy (25%). EGFR-TKi (34%) and docetaxel (26%) alone were the most frequently prescribed drugs for second line chemotherapy, and pemetrexed (44%) and EGFR-TKi (26%) alone for maintenance therapy.



Conclusion:
The ESCAP study describes the 2-year management of metastatic NSCLC on real-life settings in France. Its preliminary results are consistent with the guidelines of the French National Cancer Institute.

Background:
Inoperable cases are common in T4 lung cancer patients, and their prognoses are mostly poor. Nevertheless, among those who undergo resection, some can achieve long-term survival. We reviewed the validity of surgical treatment for T4 lung cancer at our department.

Methods:
Fifty-six cases of pathologically confirmed T4 lung cancer resection between January 1989 and December 2013 were selected for this study. Cases of nodules in different lobes of the same lung were ineligible. The relationships among the number of infiltrated organs, pN factor, presence or absence of preoperative treatment, histological effect (Ef), and surgical curative rate and prognosis were assessed using statistical techniques.

Results:
The subjects consisted of 53 males and 3 females with an average age of 62.2 years. Depending on the histological types, they were classified as squamous cell cancer (29 cases), adenocarcinoma (16 cases), adenosquamous cancer (7 cases), large cell cancer (1 case), and other cancers (2 cases). Also, there were 37 single and 19 multiple organ infiltration cases, which were classified by infiltrated organ as 16 in the trachea and tracheal bifurcation, 11 in the vertebral body, 10 in the aorta, 10 in the superior vena cava, 9 in the mediastinum, 6 in the left atrium, 6 in the pulmonary artery, 5 in the esophagus, and 2 in the subclavian artery, including duplicated cases. Preoperative treatment was carried out in 22 cases (chemoradiotherapy, 14; chemotherapy, 8), whose histological effect was Ef0-1 in 13 and Ef2-3 in 9. The surgical curative rate was complete resection in 27 and incomplete resection in 29; complete resection was common in those receiving preoperative treatment. There were no death cases within 30 days after the surgery. In all cases, the five-year survival rate was 21.7% and median survival time (MST) was 16.5 months. The five-year survival rate was 27.5% in single organ infiltration compared with 15.8% in multiple organ infiltration (P = 0.08), 27.5% in n0-1 versus 13.8% in n2-3 (P = 0.30), 36.8% with preoperative treatment in contrast to 11.2% without preoperative treatment (P = 0.06), 9.4% in Ef0-1 as opposed to 76.2% in Ef2-3 (P = 0.05), and 37.7% in complete resection in comparison with 7.8% in incomplete resection (P = 0.003). Long-term survival over 5 years was noted in 7 cases (12.5%), 4 of which involved single organ infiltration, n0-1, preoperative treatment, and Ef2-3.

Conclusion:
Single organ infiltration and n0-1 are good surgical indications for T4 lung cancer, and a favorable prognosis can be expected if preoperative treatment and complete resection are performed.

Background:
One of the strongest rationale for maintenance therapy in NSCLC is the fact that exposure to 2nd line therapy is only 40-60% in clinical trials in specialized treatment centers. Even with follow-up intervals of 6 weeks, the 2nd line treatment rate does not seem to increase. We analyzed the exposure of 2nd line therapy as well as OS and PFS in patients with stage IV NSCLC in the subgroups no 2nd line, 2nd line after maintenance and 2nd line without maintenance therapy.

Methods:
All primary lung cancer cases stage IV in the lung cancer center were analyzed based on the documentation files between 2009 and 2013. Patients were followed-up between 1st and 2nd line therapy every 6-8 weeks according to S3 guidelines. Patients with EGFR+, ALK+ or ROS1+ were excluded from the analysis.

Results:
221 patients were diagnosed with NSCLC IV (UICC7), or had systemic relapse of localized disease and were treated with 1st line therapy for metastatic disease. Of these, 160 (72%) received 1st line combination therapy with Carboplatin, 50 (23%) with Cisplatin and 11 (5%) with platin-free single agent therapy. 45 (19%) of all patients received maintenance therapy, most of them with bevacizumab. Of 221 patients, 203 (92%) progressed after 1st line therapy or 1st line and maintenance therapy. 106/163 (65%) of non-maintenance therapy patients received 2nd line therapy, 57 patients (36%) did not. Of 40 patients receiving maintenance therapy and requiring 2nd line therapy, 31 (78%) received 2nd line therapy. Reasons for not obtaining 2nd line therapy were captured and were manifold. Survival analyses showed significant differences regarding overall survival (median survival 21 (maintenance and 2nd line) vs. 13 (1st and 2nd line) months) but no relevant differences regarding progression free survival on 2nd line (median 2 months).

Conclusion:
In a certified lung cancer center and stringent follow-up every 6 to 8 weeks, 1/3 of patients do not receive 2nd line therapy because of various reasons. The application of maintenance therapy raises the chances of receiving 2nd line therapy and increases overall survival whereas progression free survival is not affected.

Background:
Concurrent chemoradiotherapy (CCRT) is considered the standard treatment regimen in patients with inoperable stage III non-small cell lung cancer (NSCLC). Sequential chemoradiotherapy (SCRT) is recommended in patients who are deemed unfit to receive CCRT. As this selection criterion is not very explicit, the ‘personalized’ choice for either CCRT or SCRT is mainly dependent on the multidisciplinary team and treating physician’s judgment. Consequently, this may result in a variation of treatment policies across hospitals/radiotherapy (RT) departments. In this study, we investigated the ratio CCRT/SCRT in eight RT departments in the Netherlands. Furthermore, we explored which patient and disease characteristics determined the choice for SCRT compared to CCRT.

Methods:
Data were derived from the Dutch Lung Radiotherapy Audit (DLRA). Within the DLRA, lung cancer patients undergoing a curative intent treatment are prospectively registered with respect to patient and disease characteristics, diagnostics and treatment. For this study, from eight out of 21 Dutch RT departments, patients with stage III NSCLC undergoing chemoradiotherapy in 2014 were selected. CCRT was defined as ≤ 50 days between the start of chemotherapy and the start of radiotherapy. Furthermore, RT had to start before the end of the last chemotherapy in CCRT. Patients with < 150 days between treatments were scored as undergoing SCRT. Differences in patient and disease characteristics between CCRT and SCRT were tested with independent samples t-tests (for continuous variables) and with chi-square tests (for categorical variables). A multivariate logistic regression model was constructed to determine patient and disease characteristics associated with the choice for SCRT, using a backward selection procedure. Odds ratios (OR) with 95% confidence intervals (CI) are reported.

Results:
In total, 453 stage III NSCLC patients (mean age 65.4 years, 56.5% male) were registered. Of those, 351 (77.5%) patients underwent CCRT and 102 (22.5%) patients received SCRT. The proportion of patients treated with CCRT ranged from 51% to 89% across RT departments. Gender, smoking, gross target volume (GTV), performance score (PS), lung function, Charlson comorbidity index and tumor location were not significantly associated with SCRT in the multivariate model. Conversely, older age (OR 1.05 [95%CI 1.03-1.09]), histology (large cell carcinoma vs adenocarcinoma [OR 0.42 CI 0.19 to 0.97]) and cN-stage (N3 vs N0-1 [OR 5.71 {95%CI 2.10-15.50}]) were significantly associated with SCRT.

Conclusion:
In this selected group of registered NSCLC patients, a large variation was observed in the proportion of stage III NSCLC patients treated with CCRT, ranging from 51% to 89% across RT departments. Surprisingly, PS and comorbidity index (as indicators of a patients’ physical fitness) were not significantly different in CCRT or SCRT patients while age and cN-stage were. Based on the analyzed patient and disease characteristics, it is currently unclear why patients treated with SCRT were not eligible for CCRT.

Background:
Cisplatin [cis-diaminedichloroplatinum-II] is an extensively used chemotherapeutic agent, and one of its most adverse effects is ototoxicity. A number of studies have demonstrated that these effects are related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD[+]) has emerged as a key regulator of cellular energy metabolism and homeostasis. Although a link between NAD[+]-dependent molecular events and cellular metabolism is evident, it remains unclear whether modulation of NAD[+] levels has an impact on cisplatin-induced hearing impairment.

Methods:
To investigate whether augmentation of NAD[+] by NQO1 activation using b-Lapachone (b-Lap) attenuates cisplatin-mediated hearing impairment, male C57BL/6 mice and NQO1 knockout mice on a C57BL/6 background were used. For analysis of the auditory threshold, auditory brainstem response (ABR) was recorded. For biochemical analysis, we measured the enzymatic activity of SIRT1, PARP1, ROS production, NAD+/NADH ratio, mRNA levels of miR-34a and pro-inflammatory cytokines. Immunohistochemistry and western blot analysis were also performed.

Results:
We have demonstrated for the first time that both the protein expression level and the activity of SIRT1 were suppressed by the reduction of intracellular NAD[+] levels in cisplatin-treated cochlear tissue. We also found that the decrease in SIRT1 protein expression and its activity after cisplatin exposure were mediated by the increase in transcriptional activity of p53 for miR-34a expression and PARP-1 activation causing NAD[+]-depletion, respectively. However, the increase in cellular NAD[+] levels by NQO1 activation using b-Lap prevented mice from cisplatin-induced cochlear damage and hearing impairment through the modulation of PARP-1, SIRT1, p53, and NF-kB.

Conclusion:
Considering that b-Lap itself did not attenuate the tumoricidal effect of cisplatin, these results suggest that the direct modulation of the cellular NAD[+] level by pharmacological agents could be a promising therapeutic strategy for enhancing the efficacy of cisplatin chemotherapy without its adverse effects.

Background:
Primary sarcomatoid carcinoma (PSC) accounts for 2% to 3% of all lung cancers. Stage-for-stage, PSC carries a poorer prognosis compared to the more common types of lung cancer. It typically occurs in older heavy smoking men and has a predilection for upper lobe involvement. PSC of the lung was initially described by Virchow in 1865 as a “biphasic” lesion of adenocarcinomatous or squamous cell components along with spindle cell or giant cell elements forming at least 10% of the tumor mass. This description fulfills the current WHO criteria for the diagnosis of PSC. Mutational analysis has revealed a common origin of both elements and it is thought that epithelial-mesenchymal transition (EMT) is the mechanism of that gives rise to this tumor, with the epithelial elements (adenocarcinoma or squamous component) that has undergone a transition to a poorly-differentiated mesenchymal type (sarcomatoid) with the expression of mesenchymal proteins such as vimentin. Efforts to study PSC has been hindered by the rarity of this variant. Aim of the study: To assess the impact of surgery and various systemic therapies on patients with PSC of the lung at the University of Cincinnati Medical Center (UCMC).

Methods:
This retrospective study included all patients identified with a pathologically confirmed diagnosis of PSC of the lung treated at UCMC between the years 2000-2014. Death was considered as the study endpoint. Kaplan-Meier analysis was used to calculate median overall survival (OS) and 95% confidence intervals (CI). Cox model was used to test the chemotherapy effect adjusted for age, sex and surgery, and determine hazard ratios (HR). Data was analyzed using SAS® Version 9.4.

Results:
We identified 21 patients with a diagnosis of PSC of the lung that were eligible for chart review and analysis. The 14 men and 7 women had a median age of 59 (range, 31-84 years). Treatment with systemic chemotherapy showed a trend in improvement in outcome among all stages of disease (p=0.08 and HR 0.04) but chemotherapy was most often used in advanced stages. Female gender demonstrated a trend for improved OS (p=0.1), and older patients demonstrated a better OS (HR=0.849; p=0.041) by a one-year increase in age. The median OS of the patients with PSC treated with systemic chemotherapy was 375 days (95% CI 114-600 days). Patients with early stage disease who were eligible for surgical resection, with or without the addition of systemic chemotherapy had a median survival of 457.5 days (95% CI 206.-1187 days), only slightly different from patients with advanced disease that received systemic chemotherapy. Patients who did not receive systemic chemotherapy had a lower median OS of 256 days (95% CI 98-999 days). Two patients demonstrated EML-4/ALK translocations. The patient with the longest OS of about three years was treated with systemic therapies including cisplatin, gemcitabine, docetaxel and crizotinib.

Conclusion:
Patients with PSC of the lung may benefit from systemic therapy. Larger prospective studies are needed to confirm this benefit especially if used as an adjuvant therapy in early stage disease.

Background:
Pemetrexed is a multitargeted antifolate agent approved for use in the treatment of pleural mesothelioma and non-small cell lung cancer. A recent phase III PARAMOUNT trial has shown that pemetrexed continuation maintenance therapy reduced the risk of disease progression and death compared with a placebo. However, renal toxicities of maintenance therapy of pemetrexed has not been clarified.

Methods:
We retrospectively evaluated a total of 30 patients who had received 4 cycles of induction therapy with pemetrexed with platinum (cisplatin or carboplatin) regimens with or without bevacizumab followed by more than 4 cycles of pemetrexed (± bevacizumab) maintenance therapy. Estimated creatinine clearance at three different time points (before the induction therapy, after the induction therapy, and after the 4 cycles of maintenance therapy) were analyzed. We also investigated factors significantly associated with deterioration in renal function during pemetrexed maintenance therapy using univariate and multivariate logistic regression analyses.

Results:
Significant decrease in the mean value of eCcr could be observed during pemetrexed maintenance therapy in both cisplatin and carboplatin groups. Multivariate analysis revealed that cisplatin administration and poor performance status (PS ≥1) were risk factors significantly associated with eCcr decrease.

Conclusion:
Continuance maintenance therapy of pemetrexed generally could cause renal dysfunction. More attention should be paid to the patients receiving a cisplatin based induction therapy and patients with poor performance status.

Background:
UGT1A1*27 is known that exist together with UGT1A1*28 as linkage disequilibrium and impair the effect of UDP-glucuronosyltransferase (UGT) in basic research, however, poor clinical investigation because of the rare frequency. The aim of this study is to evaluate the effect of UGT1A1*27 gene polymorphism for safety and efficacy in irinotecan therapy.

Methods:
Eligibility criteria were: lung cancer patients; scheduled the dose of irinotecan therapy as single ≥ 80 mg/m[2], combination ≥ 50 mg/m[2], radiation with single ≥ 50 mg/m[2], radiation with combination ≥ 40 mg/m[2]; age ≥ 20 years; performance status 0-2. After informed consents, patients were enrolled and collected the blood to examine UGT1A1*28 and UGT1A1*6 polymorphism and received irinotecan therapy. Examination of UGT1A1*27 were added when founding UGT1A1*28 polymorphism. We planned 111 enrollment for an accrual of 10 patients with UGT1A1*27 gene polymorphism.

Results:
Fifty patients were enrolled in this trial between October 2011 and December 2013. Two patients judged protocol violation. Remaining 48 were evaluated. UGT1A1 gene polymorphisms *28/*28, *6/*6, *28/*6, *28/-, *6/-, -/- observed 0, 1, 1, 7, 17 and 22, respectively. UGT1A1*27 were analyzed in 9 patients including ineligible one patients with *28/*28, however, no UGT1A1*27 gene polymorphism was found and the study was stopped. A total of 153 times of irinotecan therapy were administered with a median of 3 times per one patient: 1 time in 7 patients (15%), 2 times in 9 (19%), 3 in 19 (40%), 4 in 3 (6%), 5 in 1 (2%), and 6 in 9 (19%). Irinotecan were used as combination chemotherapy in 32 (67%) patients, with cisplatin in 12 (25%), carboplatin in 10 (21%), gemcitabine in 9 (19%), paclitaxel in 1 (2%). In remaining 16 patients (33%), only irinotecan single therapy were administered. Radiotherapies were administered concurrently in 23 (48%) patients with median 60 (range 40-61.4) Gy. Febrile neutropenia were observed higher tendency in patients with UGT1A1*6 (32%) and UGT1A1*28 (25%) gene polymorphism compare with wild type (14%) but had no significant difference. Grade 3/ 4 leukopenia and neutropenia were observed in 6 out of 8 patients with UGT1A1*28 gene polymorphism and significant higher compare with wild type (75% vs. 32%, p=0.049; 75% vs. 36%, p=0.039, respectively). The other toxicities have no difference between UGT1A1 gene polymorphism and wild type. There was no pneumonitis and treatment-related death. Tumor response was not evaluated because not included endpoints. Median PFS of 48 patients was 6.8 months and the 1- and 2-year survival rates were 20.8%. Median PFS separated by UGT1A1 gene polymorphisms were 10.1 months in UGT1A1*28 heterozygous, 8.5 months in UGT1A1*6 heterozygous, and 6.8 months in both wild type, respectively. Median OS of 48 patients was 15.7 months and the 1- and 2-year survival rates were 57.7% and 40.3%, respectively. Median OS separated by UGT1A1 gene polymorphisms were not reached in in UGT1A1*28 heterozygous, 16.4 months in UGT1A1*6 heterozygous, and 12.3 months in wild type, respectively.

Conclusion:
UGT1A1*27 gene polymorphism was not found in our methods. Further investigation might be warranted in patients with UGT1A1*28 wild type.

Background:
There are no demonstrated predictive molecular markers for pemetrexed. The aim of this study is to explore and evaluate whether thyroid transcription factor 1 (TTF1) protein expression can be a predictive biomarker of clinical activity for pemetrexed-based chemotherapy in patients with nonsquamous non-small cell lung cancer (NSCLC).

Methods:
123 patients with advanced nonsquamous NSCLC treated with pemetrexed-based chemotherapy as first-line, maintenance, second or later-line therapy were retrospectively reviewed. Then we chosen patients who had undergone assay of immunohistochemical expression of TTF1 in their tumor tissue sample, and we analyzed for their clinicopathological features, expression of TTF1 and clinical outcomes. Analysis of TTF1 expression was done according to the routine clinical practice of our center.

Results:
Immunohistochemical analysis of TTF1 expression was only performed in 51 of the 123 patients reviewed. Of these 51 patients, 36 were men and 15 women, 7 (13,7%) had never smoked and 44 (86,3%) were former or current smokers. Median age was 65 (range 39-79). Performance status (PS) distribution: 0 (25,4%), 1 (62,7%), 2 (7,8%), 3 (3,9%). Predominant histology type was adenocarcinoma (78,4%), followed by large cell carcinoma (13,7%) and not otherwhise specified-NOS (7,8%). 36 patientes had TTF1-positive tumors (70,5%), and 15 TTF1-negative ones (29,5%). The types of tumor tissue sample in which TTF1 assay was undergone were the following: endobronquial biopsy (43,1%), percutaneous biopsy (33,3%), fine needle aspiration puncture (17,6%), citology (0,5%). TTF1 positive tumors shown a higher disease control rate (DCR) for pemetrexed-based chemotherapy (60,5% vs 39,5%, p=0,05). Median progresión free survival (PFS) and overall survival (OS) in the whole group was 5,55 and 23,95 months respectively. TTF1-positive tumors had significant longer PFS (6,96 vs 3,64 months; p=0,0156) and a nonsignificant trend of longer OS (24,27 vs 13,66 months; p=0,581) to pemetrexed-based chemotherapy than patients with TTF1-negative tumors.

Conclusion:
TTF1 protein expression was associated with better clinical outcomes. TTF1 positive tumors shown a significant association with better PFS and a nonsignificant trend of better DCR and OS in nonsquamous NSCLC patients who were treated with pemetrexed-based chemotherapy. The predictive role of TTF1 expression should be further studied.

Background:
The mass-spectrometry based serum test VeriStrat® (VS) was developed using samples from non-small cell lung cancer (NSCLC) patients (pts) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs); VS was shown to be prognostic in several tumors and predictive of differential overall survival (OS) benefit for erlotinib vs. chemotherapy (CT) in 2[nd] line for NSCLC. We investigated the role of VS in pts receiving Cisplatin (CDDP) or Carboplatin (CBDCA) plus Pemetrexed (P) as 1[st] line for advanced, non-squamous NSCLC.

Methods:
VeriStrat classification was available for 55 eligible pts, who were classified as VS Good (VSG) or VS Poor (VSP); VS testing was done blinded to clinical data. Progression-free survival (PFS) and OS were analyzed by Kaplan-Meier method and compared using log-rank p-values; Cox models were used in multivariate analysis. Association with categorical variables was analyzed by Fisher’s exact test.

Results:
36 (65%) pts were classified as VSG and 19 (35%) as VSP. In the overall population, median PFS was 6.1 months (mo) for VSG vs.1.3 mo for VSP (hazard ratio (HR) 0.39 [0.21-0.70], p=0.001 ); adjusted HR (AHR) 0.43 [0.21-0.91], p=0.026). Median OS was 10.6 mo for VSG vs. 3.1 mo for VSP (HR 0.26 [0.14-0.50], p<0.001; AHR 0.20 [0.09-0.47], p<0.001). A similar relationship was found in both treatments: In CBDCA-P median PFS in VSG and VSP was 3.9 mo and 1.6 mo respectively (HR 0.34 [0.14-0.81], p=0.011); median OS was 10.0 mo in VSG and 2.0 mo in VSP (HR 0.26 [0.11-0.61], p=0.001). In CDDP-P median PFS was 6.6 mo in VSG and 1.2 mo in VSP (HR 0.52 [0.20-1.33], p=0.161), median OS was 12.3 mo in VSG, 3.5 mo in VSP (HR 0.25 [0.09-0.70], p=0.005).When compared within VS groups, no statistically significant differences between CBDCA-P and CDDP-P was found either for PFS (VSG: p=0.471, VSP: p=0.493) or OS (VSG: p=0.319, VSP: p=0.429). VS was significantly associated with disease control rate (p=0.003) and objective response (p=0.021).

Population (N°)	Median PFS (months)		Hazard ratio, p	Median OS (months)		Hazard ratio, p
	VSG	VSP		VSG	VSP
Overall (55)	6.1	1.3	0.39 [0.21-0.70] p=0.001	10.6	3.1	0.26 [0.14-0.50] p<0.001
CBDCA-P (30)	3.9	1.6	0.34 [0.14-0.84] p=0.011	10.0	2.0	0.26 [0.11-0.61] p=0.001
CDDP-P (25)	6.6	1.2	0.52 [0.20-1.33] p=0.161	12.3	3.5	0.25 [0.09-0.70] p=0.005

Conclusion:
VeriStrat has prognostic significance in platinum-based CT: overall, VSP pts have significantly shorter PFS and OS than VSG pts. In each VS group, CDDP-P and CBDCA-P showed similar behavior. Further research is needed to find alternative treatments to improve outcomes for VSP pts. ClinicalTrials.gov Identifier: NCT02055144.

Background:
BACKGROUND: The Paramount trial demonstrated a significant survival benefit with pemetrexed continuation maintenance therapy for non-squamous NSCLC. This retrospective work aims to study predictive factors for a long duration of maintenance therapy and its toxicities.

Methods:
METHOD: All patients who received pemetrexed maintenance between 1st January 2009 and 1st July 2013 in Centre Léon Bérard (France) were included. Patients were classified in two groups: “long maintenance” if they received ≥ 5 cycles of maintenance with pemetrexed and “short maintenance” if they received ≤ 4 cycles. We retrospectively collected data about patients (age, gender, smoking status, PS), histological subtype, number of metastatic sites, number of induction and maintenance cycles, response to induction chemotherapy, bevacizumab use, reason for discontinuation, and toxicities. Proportions of patients or disease characteristics in each group were compared with univariate test (Fisher exact and Wilcoxon).

Results:
RESULTS: 65 patients were included, 33 in “short maintenance” group and 32 in “long maintenance” group, with 60% male and a mean age of 61.13 (±7,78). 55% of patients had ≥ 2 metastatic sites with PS 0, 1 or 2 in 21%, 67%, and 13% out of patients, respectively. Induction cycles were initiated with cisplatin in 71% and carboplatin in 29% of patients; median number of induction cycles was 4 [3-6]. 39% of patients achieved partial response to induction chemotherapy and 61% stable disease. Median number of maintenance cycles was 4 [1-28]. 19 patients (29%) received bevacizumab in combination to pemetrexed during induction and maintenance therapy. Maintenance discontinuation was due to progressive disease in 61%, toxicity in 19% and local treatment in 16% of patients, respectively. Significant predictive factors of a long duration of maintenance therapy were female gender (27% vs 53%; p=0.044) and ≥ 2 metastatic sites (42% vs 70%; p=0,046). Age, smoking status, histological subtype, response to induction therapy, bevacizumab use, and PS were not significantly related to maintenance duration. Grade 3-5 adverse events occurred in 20 patients (31%) including 5 treatment-related deaths (8%) (including 4 infectious-related deaths). There was a similar rate of grade 3-5 toxicities in both groups. Toxicities were mainly infectious (n= 13; 65%) including 4 febrile neutropenia. Predictive factors of grade 3-5 toxicities were age > 70 years (35% vs 9%; p=0.026) and carboplatin use (50% vs 20%; p=0,020). At the end of the study, maintenance therapy was ongoing in 3 patients. Among the 62 other patients, 81% received subsequent systemic therapy with a similar duration of treatment between “short” and “long” maintenance groups.

Conclusion:
CONCLUSION: Univariate analysis identified female gender and ≥2 metastatic sites as only predictive factors for a long duration of pemetrexed maintenance therapy. Patients with single metastasis frequently stopped maintenance treatment for administration of local therapy. Predictive factors for severe toxicities were age > 70 years and carboplatin use whereas addition of bevacizumab to pemetrexed did not result in an increase of toxicity.

Background:
Pemetrexed/platinum is one of the standard treatment regimens for patients with advanced non-squamous non-small cell lung cancer(NSCLC). The aim of this study was to examine the association between survival of lung cancer patients treated with pemetrexed/platinum and clinical factors.

Methods:
The medical records of advanced or relapsed non-squamous NSCLC patients treated with pemetrexed/platinum at our hospital between January 2010 and December 2013 were reviewed. Basic characteristics, histological subtypes of NSCLC, driver mutation status, TTF1 staining status and status of treatment with taxane were evaluated for association with the survival from pemetrexed/platinum started day to deaths.

Results:
Two hundreds nine records were reviewed. The median age was 62 (28-79), 60% were male, 40% were never smoker, 89% had an ECOG PS0-1 and 11% had a PS 2-3. The median value of CEA and CYFRA were 10.5 ng/ml and 3.0 ng/ml, respectively. 93% were diagnosed as adenocarcinoma and 7% were diagnosed as other subtypes (large, adenosquamous, sarcomatoid and not otherwise specified). 79% (81/102) had a positive TTF1 staining. 26% had EGFR mutation, 7% had ALK fusion and 11% had KRAS mutation. 36% of patients were received bevacizumab with pemetrexed/platinum. 35% of patients were treated with cisplatin. The response rate of pemetrexed/platinum was 34.8%. Median overall survival was 537days. 65% of patients were treated with taxane and the response rate was 15.0%. In multivariate analysis, poor PS(HR 1.33; p=0.027), others in histological subtypes (HR2.00; p=0.047) and K-RAS mutation(HR 2.74; p=0.021) correlated significantly with a shorter overall survival and low CYFRA(≤3.0ng/ml, HR 0.55; p=0.002) correlated significantly with a longer overall survival.

Conclusion:
High CYFRA, KRAS mutation and others in histological subtypes may be associated with shorter overall survival treated with pemetrexed/platinum in non-squamous NSCLC. The development of effective treatment regimens for such patients is needed to improve their outcomes.

Background:
Irinotecan and bevacizumab are effective against non-small cell lung cancer (NSCLC) and synergism with non-cross-resistance has been demonstrated in preclinical studies. Tissue inhibitor of metalloproteinases 1 (TIMP1) and EGFR regulates extracellular matrix catabolism and promotion of cell growth and anti-apoptotic activity in NSCLC.

Methods:
Forty nine patients with heavily treated metastatic NSCLC were enrolled from March 2011 to November 2014. Thirty-three (67%) had never been exposed to bevacizumab and 16 had received antiangiogenic therapy as part of their first-line (all had achieved a previous response for more than 6 months). Treatment consisted of a 90-min intravenous infusion of 125 mg/m[2] irinotecan on day 1 and 8 plus 7.5 mg/kg bevacizumab on day 1 (treatment was repeated every 3 weeks). In all patients the mutational status of KRAS and EGFR, as well as TIMP1 and EGFR expression was evaluated.

Results:
The median age was 60 years (range, 44-78 years), 57% was male and 75% had ECOG 0-1. The median follow-up was 13.2 months and twenty-three patients had received >3 prior lines. The ORR was 32% (95%CI 22% to 39%) and thirteen patients (26%) achieve stable disease. Median progression-free survival (PFS) rate was 4.4 months (95%CI 2.8-8.3) and median overall survival (OS) rate was 18.0 months (95%CI 16.2-30.7). Nine patients harbouring EGFR mutations had a long-lasting, partial response (>5 months after at least 4 prior lines). Major toxicity was myelosuppression (grade 3 neutropenia occurred in 32% of patients and thrombocytopenia in 8.3%). Three patients experienced febrile neutropenia, one patient suffered grade 4 diarrhoea, and non-haematological toxicity was usually mild. Shorter OS was found in patients with a higher expression of TIMP1 mRNA (P=0.0001) but not according to the expression of EGFR (P=0.14).

Conclusion:
Irinotecan plus bevacizumab resulted in favourable activity and manageable toxicity profiles as third or fourth line for patients with advanced NSCLC. Our results suggested that such regimen can represent a reasonable chemotherapeutic option, especially for subjects having EGFR mutations and low expression of TIMP1.

Background:
Increased expression of cyclooxygenase-2 (COX-2) is common in non-small cell lung cancer (NSCLC), and is therefore a potential target for treatment. However, phase III trials have failed to demonstrate beneficial survival effects of adding COX-2 inhibitors to standard chemotherapy. We investigated whether COX-2 expression in tumor and stromal cells had any predictive impact on the effects of celecoxib, a selective COX-2 inhibitor.

Methods:
In a previously published multicenter phase III trial, 316 patients with NSCLC stage IIIB or IV and WHO performance status 0-2 were randomized to receive celecoxib 400 mg b.i.d. or placebo up to one year in addition to a two-drug platinum-based chemotherapy regimen. In a subset of 122 patients, archive tumor tissue was available for further analyses. Immune stainings for COX-2 expression were undertaken. Intensity and extent of positively stained cells in tumor and stroma cells were scored on a 0 to 3 scale, and the product of these scores was used as a co-variable in the predictive analysis.

Results:
An updated analysis of all 316 patients included in the original trial, and of the 122 patients with available tumor tissue showed no survival differences between the celecoxib or placebo arms (HR 0.99; 95% CI 0.79-1.24 and HR 0.89; 95% CI 0.62-1.28, respectively). Similarly, in patients with high COX-2 expression in tumor cells (n=71) or stroma cells (n=55), survival did not differ significantly between patients who received celecoxib or placebo (HR 0.96; 95% CI 0.60-1.54 and HR 0.66; 95% CI 0.38-1.16). The p-value for interaction effect between COX-2 score in tumor or stroma cells and celecoxib effect on survival was 0.48 and 0.25, respectively.

Conclusion:
In this subgroup analysis of patients with advanced NSCLC treated in a randomized trial, we could not detect any significant interaction between COX-2 expression in tumor or stroma cells and outcome of celecoxib treatment in addition to standard chemotherapy.

Background:
To evaluate the efficacy and safety of weekly intravenous Nanoparticle albumin-bound paclitaxel (NAB-paclitaxel) for the patients with advanced non-small-cell lung cancer (NSCLC) who have failed prior multilines treatments, and to investigate the association of status of secreted protein, acidic and rich in cysteine (SPARC) expression and clinipathological factors with clinical outcome.

Methods:
We retrospectively analyzed the efficacy and toxicities of NAB-paclitaxel monotherapy in treating 84 patients who had progression disease after at least two lines standard chemotherapy from May 1, 2011 to June 31, 2014. All patients were treated with NAB-paclitaxel 130mg/m2 on days 1 and 8 of a 21-day cycle. Radiologic tumor assessment was performed every 6 weeks or when the patient’s symptoms deteriorated obviously. We also detected the SPARC status expression (by immunohistochemistry) in 35 patients who had tumor tissue available. 76 of 84 patients had EGFR mutation status. The date of last follow-up was March 31, 2015.

Results:
Of these 84 patients, 76 patients had complete follow-up data, 5 patients lost of follow-up for overall survival, and 3 patients couldn’t tolerate the continuous NAB-paclitaxel therapy due to serious adverse events and had only the evaluation of safety data.. EGFR mutation were found in 22 of 76 patients and their median PFS and OS were 4.4 months and 11.5months. The median treatment line of weekly NAB-paclitaxel therapy was 4 line (range: 2~7 line). The median follow-up interval time was 11.2 months. The objective response rate (ORR) and disease control rate (DCR) (N=81) were 14.8% (12/81) and 67.9% (55/81), respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.9 months (95% CI: 2.8~5.0 months) and 11.0 months (95%CI: 7.6~14.4 months), respectively. Pearson’s correlation analysis showed that previous treatment with Solvent-based Paclitaxel or Docetaxel didn’t affect the response to NAB-paclitaxel. However, the patients who reached disease control after previous Solvent-based Paclitaxel or Docetaxel presented better DCR than the patients who failed to previous Solvent-based Paclitaxel or Docetaxel (DCR: 77.1% vs 47.6%, p=0.040) (by Fisher’s Exact Test). Cox regression analysis showed that ORR was related with both PFS and OS. The common adverse events (N=84) included leukopenia (36.1%), neutropenia (29.2%), peripheral neurotoxicity (23.6%), et al. The main grade 3/4 toxicities included neutropenia (9.7%) and leukopenia (6.9%). 3 patients had discontinued chemotherapy due to drug induced lung injury, serious fatigue and serious anorexia, separately. In this study, no association between SPARC expression and efficacy was observed.

Conclusion:
Advanced NSCLC patients who have experienced multiline chemotherapy with disease progression could benefit from weekly NAB-paclitaxel therapy with good safety and clinical outcome. It seemed that SPARC expression could not predict efficacy to NAB-paclitaxel.

Background:
In the JMEN trial (Ciuleanu et al., Lancet 374:1432-1440, 2009), patients with advanced non-squamous non-small cell lung cancer (NSCLC) derived a benefit from pemetrexed maintenance therapy after platinum-based initial therapy by extending survival, delaying disease progression, and maintaining overall quality of life (QoL). However, fatigue was the most common physician-reported toxic effect in the pemetrexed treated group. We conducted a post-hoc analysis to investigate the dynamic change of fatigue in overall population and East-Asian (EA) patients treated on the JMEN trial.

Methods:
This analysis was performed in the overall safety population (N=656) and the EA subgroup safety population (N=152) mainly from China, Taiwan, and Korea including squamous and non-squamous NSCLC patients. The Common Terminology Criteria for Adverse Events (version 3.0) was used for summary of the AE incidence rates by cycle and AE severity reported by investigator. The Lung Cancer Symptom Scale (LCSS) was used to evaluate patients’ QoL. Worsening of fatigue was defined as an increase of 15 mm or more from baseline on a 100 mm scale in LCSS reported by the patients. The percentage of patients with worsening fatigue was also summarized by cycle. The time to worsening of fatigue symptom was analyzed using Kaplan-Meier method and Cox proportional model.

Results:
In the EA population drug-related fatigue (grade 1-4) occurred more frequently in pemetrexed arm compared with placebo arm (30.4% vs 16.0%, p=0.075). The grade 3/4 drug-related fatigue was rare in both arms (1 event reported in each arm). For both overall and EA populations, the fatigue incidence by cycle during the maintenance treatment with pemetrexed did not increase during subsequent cycles (Figure 1A, B). The percentage of patients who experienced worsening of fatigue based on the patients-reported LCSS scores was also comparable between the two arms in the overall and EA populations (Figure 1C, D). EA Patients in the pemetrexed arm experienced a numerically longer median time to worsening of fatigue compared to EA patients in the placebo arm, although the difference is not statistically significant (5.95 months vs. 3.91 months, HR= 0.84, 95% confidence interval [CI]: 0.51-1.37, p= 0.471). Figure 1



Conclusion:
These analyses suggest that despite a higher incidence of grade 1/2 drug-related fatigue compared with placebo, pemetrexed maintenance treatment for EA patients with advanced NSCLC will not impair patient-reported QoL.

Background:
Platinum-based doublet chemotherapy is still mainstay in treatment of advanced non-small-cell lung cancer (NSCLC). There was no molecular determinant for guiding platinum-based chemotherapy. Excision repair cross-complementing group 1 gene (ERCC1) is important for platinum-induced DNA adduct repair and ribonucleotide reductase subunit 1 (RRM1) is crucial for nucleotide metabolism and has been known for the dominant molecular determinant of gemcitabine efficacy. We assessed whether selection of first-line chemotherapy based on ERCC1 and RRM1 mRNA expression levels would improve clinical outcomes in patients with advanced NSCLC.

Methods:
Eligible patients were randomly assigned 1:1 to experimental arm and control arm. The experimental arm consisted of gemcitabine/carboplatin (GC) if ERCC1 and RRM1 were low, gemcitabine/vinorelbine (GV) if ERCC1 was high and RRM1 was low, docetaxel/carboplatin (DC) if ERCC1 was low and RRM1 was high, and docetaxel/vinorelbine (DV) if both were high. In the control arm, patients received docetaxel/carboplatin (DC). All chemotherapy regimens were to be continued for maximum 4 cycles every 3 weeks or unacceptable toxicity. ERCC1 and RRM1 mRNA expression were measured by quantitative real-time PCR in formalin-fixed paraffin-embedded (FFPE) tissue. The trial was powered for an 80% improvement in overall response rate (ORR, P0=0.25, P1=0.45, α=0.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. The study was prematurely terminated after the futility analysis of 42 PFS events, which showed a low conditional probability (conditional power=0.14) of a statistically significant outcome.

Results:
A total of 56 patients (n=26 in experimental arm, n=30 in control arm) were evaluable for efficacy and toxicity. Patient characteristics were well balanced in both groups. Majority of patients had adenocarcinoma histology (64.3%) and ECOG performance status 0 to 1 (96.4%). EGFR mutation was documented in 8 patients (4 in experimental arm, 4 in control arm). Among 26 patients in the experimental arm, mRNA expression of ERCC1 and RRM1 ranged from 0.18 to 2.81 (median, 0.69) and 0.22 to 16.65 (median, 0.66), respectively. Based on mRNA expression levels, 19 (73.1%) patients were assigned to GC, 0 (0.0%) to GV, 4 (15.4%) to DC, and 3 (11.5%) to VD. The median number of chemotherapy cycles delivered was 3.7 in experimental arm and 3.5 in control arm. The ORRs were 26.9% in experimental arm and 40.0% in control arm, which were not statistically significant (P=0.58). With a median follow-up of 30.1 months, median PFS was 4.6 months in experimental arm and 5.1 months in control arm (hazard ratio [HR] 1.27; 95% CI 0.69-2.31; P=0.43). Median OS was 18.2 months in experimental arm and was 12.6 months in control arm (HR 0.71; 95% CI 0.32-1.53; P=0.38). The occurrence of grade 3 or higher neutropenia (69.2% vs. 93.4%, P=0.02) and febrile neutropenia (3.8% vs. 23.3%, P=0.04) was significantly more common in control arm. There was no treatment-related death.

Conclusion:
ERCC1 and RRM1 expression-based chemotherapy did not improve clinical outcomes in advanced NSCLC (NCT01648517).

Background:
Renal impairment increases with age and can impact treatment decisions. In a phase III trial, first-line treatment with nab-paclitaxel plus carboplatin (nab-P/C) significantly improved the overall response rate (ORR; primary endpoint) compared with solvent-based paclitaxel plus C (sb-P/C) in patients with advanced NSCLC (Socinski et al. J Clin Oncol. 2012;30:2055-2062). In a subgroup analysis of this phase III trial, nab-P/C demonstrated promising efficacy and was well tolerated in patients with or without renal impairment (Langer et al. Clin Lung Cancer. 2015;16:112-120). This analysis examined outcomes of patients in the phase III trial stratified by age and renal function.

Methods:
Patients with histologically or cytologically confirmed stage IIIB/IV NSCLC and no prior chemotherapy for metastatic disease received either nab-P 100 mg/m[2] on days 1, 8, and 15 or sb-P 200 mg/m[2] on day 1 in combination with C AUC 6 on day 1 every 21 days (randomized 1:1). Treatment continued until disease progression. Baseline renal function (creatinine clearance [CrCl]) was assessed in a central lab. ORR and progression-free survival (PFS) were assessed by blinded, centralized review. P values for ORR were based on the chi-square test, and those for overall survival (OS) and PFS were based on the log-rank test.

Results:
Treatment with nab-P/C resulted in improved outcomes compared with sb-P/C in patients with mild renal impairment, regardless of age (Table). nab-P/C also consistently demonstrated greater treatment effect compared with sb-P/C for ORR and similar or better PFS and OS in patients ≥ 60 years, regardless of renal function. In patients with either mild renal impairment or normal renal function, the toxicity profiles in each treatment arm were similar to those of the intent-to-treat population.

Conclusion:
These results suggest that, in general, clinical outcomes in patients with advanced NSCLC and mild renal impairment are better with nab-P/C vs sb-P/C, regardless of age. It should be noted that these were small subset analyses and results should be interpreted with caution. Figure 1

Background:
Chemotherapy-induced thrombocytopenia (CIT) has seriously hindered the application of anti-cancer drugs. Thrombopoietic factors such as recombinant human interleukin-11(rhIL-11), thrombopoietin and its derivative(recombinant human thrombopoietin, rhTPO) are routinely administrated for CIT. But there is no randomized study to compare rhTPO with rhIL-11 on efficacy and safety of thrombocytopenia prophylactic treatment before. This is the first randomized, open-label, multicenter, phase Ⅲ study to compare them in China. We tried to investigate the efficacy and safety of prophylactic administration with rhTPO or rhIL-11 to prevent CIT in advanced non-small-cell lung cancer(NSCLC) patients.

Methods:
From June 2009 to February 2015, 71 patients with advanced NSCLC who were receiving the first-line platinum-based chemotherapy suffered severe thrombocytopenia(the nadir of platelet counts＜50×10[9]/L, confirmed by two times of blood routine in different days) during prior chemotherapy cycle. They were randomized to rhTPO arm or rhIL-11 arm in the following chemotherapy cycle, and the chemotherapy regimens and drug doses were consistent in the prior and following cycle (GC Gemcitabine 1000-1250 mg/m[2], D1 and D8; Carboplatin dosing by AUC value=5, D1; Q3W) or GP (Gemcitabine 1000-1250 mg/m[2], D1 and D8; Cisplatin 75 mg/m[2], D1; Q3W). 49 patients (34 males, 15 females) were enrolled rhTPO arm and 22 patients (14 males, 8 females) were enrolled rhIL-11 arm. There were no statistical difference between two arms in terms of gender[34 males(69.4%) vs.14 males(63.6%),P＞0.05], age(58.5±9.3 yrs vs. 60.3±7.5 yrs, P＞0.05), and the nadir of platelet counts during prior chemotherapy cycle(31.4±13.1×10[9]/L vs. 28.6±12.8×10[9]/L, P＞0.05). rhTPO (15000U/d) was injected subcutaneously on the 2[nd], 4[th], 6[th], 9[th ]Day after the initiation of chemotherapy, and IL-11(3mg/d) was injected subcutaneously per day from Day 9 to Day15 after the initiation of chemotherapy. Blood routines were conducted to test before chemotherapy initiation and the 3[th], 5[th], 7[th], 9[th], 11[th], 13[th], 15[th], 17[th], and 21[th] day after chemotherapy. Toxicity and efficacy were monitored.

Results:
In the following chemotherapy cycle there were no statistical difference between rhTPO arm and rhIL-11 arm on the following indexes: the nadir of platelet counts(66.6±43.1×10[9]/L vs. 53.8±40.6×10[9]/L, P＞0.05) , the maximum platelet counts (219±132×10[9]/L vs. 240±151×10[9]/L, P＞0.05) , duration of platelet counts less than 50×10[9]/L[Median (95%CI): 4.0(3.0-5.0) days vs. 4.5(3.0-6.0) days, P＞0.05], time of platelet count recovered to 75×10[9]/L [Median(95%CI): 2(2-3) days vs. 3(0-4) days, P＞0.05] and to 100×10[9]/L[median(95%CI): 4(3-6) days vs. 4.5(3-8) days, P＞0.05]. Drug-related adverse events in rhTPO arm were less than that of rhIL-11 arm (5 cases(10.2%) in rhTPO arm, 7 cases(31.8%) in rhIL-11 arm, P<0.05).

Conclusion:
Although there is no statistical difference on efficacies, prophylactic administration of rhTPO is safer and more convenient than that of rhIL-11 in advanced NSCLC patients. This is an interim analysis. More data is still waiting.

Background:
The Victorian Lung Cancer Registry is a clinical quality registry designed with the aim of improving the quality of care delivered to Victorians with lung cancer by collecting and assessing management, treatment and outcome data on all new cases of lung cancer.

Methods:
The establishment of the Victorian Lung Cancer Registry Pilot Project commenced with the appointment of a Steering Committee to provide project governance. Review of current literature and evidence-based national and international clinical practice guidelines was undertaken by an expert working group. Included data items were epidemiologically sound, reproducible and valid. The data set enables the capture of identified quality indicators designed to describe the structural quality, process quality and indicators of outcome in lung cancer management. Case ascertainment is derived from institutional ICD-10 coding and participant consent occurs via an “opt-off” system. Follow up and outcome measures are collected at baseline, 6 and 12 months after diagnosis capturing survival, treatment and quality of life. Institutional recruitment was designed to sample from metropolitan public, metropolitan private and regional hospitals.

Results:
Data was collected on 690 patients from 1 July 2012 to 31 June 2013 from 8 Victorian Hospitals (3 public and 3 private metropolitan and 2 regional). Evidence of distress screening was available for 27% of subjects. Diagnosis was confirmed < 28 days from referral in 66% of cases across institutions. A statement of ECOG status was available in 45% of cases and clinical TNM staging in 49% prior to treatment. A record of multidisciplinary team meeting presentation was available in 59% of cases. First treatment was initiated < 42 days from diagnosis in 76% of cases. Curative surgery was provided for 28% of subjects, curative chemotherapy <5% and curative radiotherapy < 5%.

Conclusion:
The evaluation of registry outcomes at governance, administrative and clinical levels may identify targets for quality and service improvement and further define safety measures. The comparison of performance outcomes across institutions and sectors may drive competitive recruitment to improve measures on a longitudinal basis.

Background:
Cancer of the prostate and lung are most commonly diagnosed in the elderly. Aberrant female sex hormone signaling has been well-described in NSCLC. The impact of androgen deprivation therapy (ADT) on non-small cell lung cancer (NSCLC) outcome has, however, not been well studied.

Methods:
We employed the linked SEER-MEDICARE database to assess the potential impact of ADT on NSCLC. We analyzed data from patients diagnosed with NSCLC between 1985 and 2005 and registered in the SEER-MEDICARE database. Patients were categorized into three groups: prostate cancer diagnosis followed by NSCLC (PL), NSCLC followed by prostate cancer (LP) and NSCLC only (L). Demographic and survival outcomes were compared between these groups. The impact of sequence of cancer diagnosis and ADT on survival post NSCLC diagnosis was assessed within the PL group using logistic regression model. Cox proportional hazards models were employed to estimate the effect of ADT and stage of prostate cancer on survival with adjustment for significant prognostic factors.

Results:
A total of 417630 patients were included in this analysis; male/female (56.4%/43.6%); Race: White (84.0%), Black (9.0%), Asian (2.1%), Hispanic (1.0%), others (3.0%); Stage: I (17.4%), II (2.9%), III (33.6%) and IV (46.1%). The majority of the patients were in the L group (96.3%), followed by PL (2.9%) and LP (0.8%). Patients in the LP group had the best 12-month survival rates (84.5%), followed by L (44.4%) and PL (40.1%). Analysis within the PL group showed an inverse correlation between stage of prostate cancer diagnosis and interval of time to NSCLC diagnosis: 54.8, 54.1, 62.1 and 59.3 months for stage I, II, III and IV prostate cancer, respectively. Prostate cancer patients exposed to ADT had a shorter interval to lung cancer diagnosis (48.3 vs. 52.7 months; p < 0.001). On multivariate analysis, patients exposed to ADT had a higher median survival (10 months vs. 9 months; p < 0.001) and reduced risk of death (HR:1.11; 95%CI:1.05-1.18), p <0.001).

Conclusion:
ADT therapy for prostate cancer was associated with improved survival for subsequent NSCLC diagnosis. Our result supports systematic exploration of ADT as a treatment strategy for NSCLC.

Background:
Metastatic non-small cell lung cancer (NSCLC) remains an incurable disease. Sacher et al reviewed phase III studies in first-line advanced/metastatic NSCLC conducted from 1981 to 2010. Although trends in study outcomes were assessed, design and stratification factors have never been analyzed.

Methods:
The recently published list of phase III trials by Sacher et al (JCO 2014;32:1407-11) was reviewed thoroughly. Eligible trials for this study must have been published in the English literature between 1981 and 2010. Trials that included a substantial number of previously treated NSCLC patients were excluded. Maintenance studies after first-line chemotherapy were also excluded. Characteristics in each decade were determined for sample size, number of trials, region, rate of meeting accrual goal, primary endpoint, type of phase III, interim analysis, allocation method, and stratification factors (SFs). Any p-value of less than 0.05 was considered significant for statistical analysis.

Results:
A total of 162 studies were considered to meet the criteria. The number of studies and median sample size increased from 29 and 133 in 1980s to 46 and 181 in 1990s to 87 and 407 in 2000s, respectively. Primary endpoint was reported more frequently in recent decades; 24% of studies in 1980s, 83% in 1990s, 99% in 2000s. Non-overall survival endpoints were frequently chosen in European and Asian studies. Interim analysis was planned for 3% in 1980s, 20% in 1990s, 33% in 2000s. Allocation method was rarely reported throughout the three decades (0% in 1980s, 22% in 1990s, 28% in 2000s). The median number of SFs increased significantly from one in 1980s to three in 2000s (see Table). Performance status (PS), stage, and institution have been most frequently selected, and at least one of the three factors was used in most of the studies (84%) in 2000s. There are many other SFs that were used infrequently. More details will be presented. Table: SFs in first-line phase III NSCLC trials. All others; stratification factors other than PS, stage, and institution. The median number of SFs increased significantly (one way ANOVA, p=0.003).

	1981-1990	1991-2000	2001-2010	Total
No. of studies	29	46	87	162
Median no. of SFs	1	2	3	2
PS	14(48%)	21(46)	48(55)	83(51)
Stage	2(7)	22(48)	63(72)	86(53)
Institution	2(7)	17(37)	37(43)	56(35)
PS or Stage	15(52)	29(63)	6(7)	113(70)
PS, Stage, or Institution	16(55)	32(70)	73(84)	121(75)
Not reported or None	12(41)	13(28)	13(15)	38(23)
All others	1(3)	1(2)	1(1)	3(2)

Conclusion:
This study reports extensive details in design of phase III trials for first-line NSCLC that have been published over three decades. We found increases in sample size and reporting primary endpoint, whereas allocation method remains underreported. Although PS, stage, and institution are the most frequently selected, choice of SFs remains inconsistent across studies. Our report provides researchers with valuable information for future studies.

Background:
Molecular targeted therapy based on tyrozine kinase inhibitors (TKI), directed at epidermal growth factor receptor (EGFR) is one of the novel effective agents in management of advanced-stage NSCLC. However several candidate predictors have been extensively studied, apart from activating EGFR gene mutations, no reliable biochemical or molecular predictors of response to erlotinib have been validated. The aim of our retrospective study was to evaluate the association of baseline serum albumin with outcomes in a large cohort of patients with advanced-stage NSCLC treated with erlotinib.

Methods:
Clinical data of 457 patients with locally-advanced (IIIB) or metastatic stage (IV) NSCLC treated with erlotinib were analysed. Serum samples were collected and the measurement was performed one day before the initiation of erlotinib treatment.

Results:
Before the treatment initiation, low albumin was (<35 g/l) measured in 37 (8.1%) patients and normal albumin (≥ 35 g/l) was measured in 420 (91.9%). The median PFS and OS for patients with low serum albumin was 0.9 and 1.9 months compared to 1.9 and 11.4 months for patients with normal serum albumin (p=0.001 and p<0.001). The multivariate Cox proportional hazards model revealed that EGFR mutation status (HR=2.50; CI: 1.59-3.92; p<0.001) and pretreatment serum albumin (HR=1.73; CI: 1.21-2.47; p=0.003) were significant independent predictive factors for PFS, whereas EGFR mutation status (HR=3.14; CI: 1.70-5.81; p<0.001), stage (HR=1.48; CI: 1.09-2.02; p=0.013), ECOG PS (HR=1.77; CI: 1.37-2.29; p<0.001) and pretreatment serum albumin (HR=4.60; CI: 2.98-7.10; p<0.001) were significant independent predictive factors for OS.

Conclusion:
The results of the present retrospective study indicate that pretreatment hypoalbuminemia is associated with poor outcome of NSCLC patients treated with erlotinib. Based on the present study results, measuement of serum albumin is an objective laboratory method feasible for estimation of prognosis of patients with advanced-stage NSCLC. This study is supported by Ministry of Health, Czech Republic - conceptual development of research organization Faculty Hospital in Pilsen - FNPl, 00669806 and by the project CZ.1.05/2.1.00/03.0076 from European Regional Development Fund.

Background:
We conducted a systematic review of data from patients reported in the TULUNG registry (data cut-off 26-Jan-15). The TULUNG registry is Czech national oncology registry which prospectively collects data from all NSCLC patients treated with new targeted therapies in Czech Republic since 2008.

Methods:
Analysis was performed on a group of patients with non-squamous NSCLC with good performance status (PS 0-2), treated with bevacizumab. Since 2008 bevacizumab has been used for treatment in 193 patients (full record criteria met). 10 patients with incomplete records were not included to the review

Results:
In this group of patients 35.8% were female; the median age at bevacizumab treatment initiation was 60 years (range 29-83). The majority of patients were smokers and ex-smokers (37.8% and 34.7% respectively) and 91.7% of tumors were adenocarcinomas by histology. 91.7% patients were at the metastatic stage at the initiation of bevacizumab treatment, 6.2% of patients were in stage IIIb and only 2.1% of patients in stage IIIa (UICC6). The performance status was distributed between ECOG PS0 and PS1 mainly (40.9% PS0 and 58% PS1)at the initiation of the bevacizumab treatment. Majority of patients received bevacizumab treatment in the first line (96.4%). Two main chemotherapy regimens were used; carboplatin+paclitaxel (68.4%) and cisplatin+gemcitabine (9.8%). In this group of 193 patients analyzed, bevacizumab therapy was terminated in 152 (78.8%) patients at data cut-off. The most frequent reasons for termination were disease progression, in 55.9%, termination of treatment according to plan in 8.6% and death, in 7.9% of patients. Treatment with bevacizumab is ongoing in 41 (21.2%) patients. In 152 of patients with terminated treatment, the median duration of treatment was 15.6 weeks (95% CI 0.3 – 51.3). Response assessment showed CR in 0.7%, PR in 40.8% and SD in 35.5% of patients. Median progression free survival was 6.9 months (95% CI 5.8 – 8.1), median overall survival 16.7 months (95% CI 11.7 – 21.7). 1-year survival from bevacizumab treatment initiation was 67.9%. Adverse events were reported in 9.8% of patients, the most frequently reported adverse events were thromboembolic events (5.2%) and neutropenia (1.6%). Tromboembolic events were observed in 10 patients, none of these was fatal. We didn´t observe any severe episode of bleeding event.

Conclusion:
Therapy with bevacizumab in non-squamous NSCLC was active and very well tolerated. In eligible patients, only 7 patients (4.6%) had to discontinue bevacizumab therapy due to safety reasons. In patients with completed bevacizumab therapy 77.0% disease control rate was reached with a median survival of approximately 16.7 months from initiation of first line therapy with bevacizumab.

Background:
Maintenance therapy (MT) after platinum doublet chemotherapy has been shown to improve progression-free survival (PFS) and overall survival (OS) in advanced non-small-cell lung cancer (NSCLC), whereas optimal strategies for MT, such as continuation or switch maintenance, have yet to be determined. ATLAS trial adopted a combination maintenance strategy design in which both EGFR-positive and -negative NSCLC patients received platinum doublet chemotherapy at the choice of investigators plus bevacizumab (Bev) followed by Bev with either erlotinib (Erl) or a placebo as a maintenance therapy. The trial demonstrated that Erl plus Bev was favorable for PFS, but not for either OS or toxicity, when compared with placebo plus Bev. The aim of this phase II study was to clarify the effects and safety of a fixed induction regimen: carboplatin (Cb)/pemetrexed (PEM)/Bev followed by Bev plus Erl as a maintenance therapy in non-squamous (nonSq)-NSCLC patients with wild-type (WT) EGFR.

Methods:
All eligible patients (pts) had treatment-naive nonSq-NSCLC (stage IIIB, IV, or postoperative recurrent) with WT EGFR. Cb (AUC 5), PEM (500 mg/m[2]) and Bev (15mg/kg) were administered on Day 1 every three weeks for four-to-six cycles and maintenance therapy with Bev (15mg/kg) once every three weeks plus continuous Erl (150mg/body) was administered until occurrence of either disease progression or unacceptable toxicity. The primary endpoint was PFS at 6 months (mo). The secondary endpoints included OS, tumor response, toxicity, and quality of life (QOL).

Results:
From September 2011 to June 2014, 51 pts were enrolled. Fifty pts were evaluated for the efficacy and safety of the treatment. The median follow-up duration was 14.3 months (range: 1.1-30.7). The median age was 64 years (range: 36-74); male/female=27/23 (54/46%); ECOG PS 0/1=28/22 (56/44%); Stage IIIB/IV/recurrent=5/41/4 (10/82/8%); adenocarcinoma/NSCLC=48/2 (96/4%). The median cycles of the induction/maintenance therapy were 4 (range: 1-6)/4 (range: 1-20). Twenty-nine pts (58%) received the MT. Overall response rate was 48.0% (95% CI: 34.8-61.5%), and disease control rate was 86% (95% CI: 73.8-93.0%). Six-month PFS rate was 59.5% (95% CI: 45.0-72.6%). Median OS and PFS were 18.4 mo (95% CI: 11.9-24.9 mo) and 6.5 mo (95% CI: 5.8-7.2 mo), respectively. CTCAE Grade (Gr) 3/4 hematological toxicities were neutropenia (48%/3.4%), anemia (18%/3.4%) and thrombocytopenia (22%/0%). The most frequent Gr 3/4 non-hematological toxicities were anorexia (14%/3.4%), hypertension (10%/3.4%), malaise (6%/3.4%), nausea (6%/0%) and rash (0%/10%). There were two interstitial lung diseases (Gr1), one gastrointestinal perforation (Gr4), and one treatment-related death due to ventricular fibrillation. QOL results are still under analysis.

Conclusion:
Cb/PEM/Bev followed by maintenance Bev/Erl was effective and well tolerated in NS-NSCLC pts with WT EGFR.

Background:
ARCHER 1042 (NCT01465802) was a randomized patient (pt) blinded trial that explored prophylactic interventions to minimize select dermatologic adverse events of interest (SDAEI) and diarrhea associated with D, an irreversible small molecule PanHER inhibitor.

Methods:
In Cohorts I (CI) and II (CII) pts with advanced NSCLC, ≥1 prior chemo, ECOG 0–2, were randomized (pt blinded) in CI to (a) D 45 mg daily (QD) plus placebo (pbo) (D+pbo) or (b) D 45 mg QD plus doxy 100 mg twice daily x 4 wks (D+doxy) and in CII assigned to D 45 mg QD plus probiotic (prob) and topical alclometasone (alclo) (D+prob+alclo). Primary endpoints in first 8 wks included: all grade (G) and G≥2 SDAEI and PRO (Skindex-16) (CI, CII) and CII G and G≥2 diarrhea and PRO (modified Mucositis Daily Questionnaire). Plasma samples were collected to confirm that exposure of D is not altered with doxy treatment.

Results:
As of August 25, 2014, 112 pts randomized to Cohort I D+pbo vs. D+doxy (median age 66 years, 53% male) and 59 pts to CII D+prob+alclo (median age 66 years, 66% male) were evaluable (>6 wks treatment). Median relative dose intensity (RDI) of D in the first 8 wks was 82.74% for D+doxy compared with 79.76% for D+pbo and 75.00% for D+prob+alclo. Figure 1 PRO Skindex scores improved with prophylactic doxy, but not alclo; prophylactic probiotic was not associated with improved CTCAE or PRO. Plasma exposure of D was similar when administered either with pbo or doxy.



Conclusion:
These preliminary data suggest prophylactic doxy improves ≥G2 Select Dermatologic AEs with improved D RDI and less need for dose discontinuations. The prophylactic effect observed with doxy cannot be attributed to altered exposure of D. In contrast, prophylactic topical corticosteroids had no effect on rash or diarrhea.

Background:
In industrialized countries, the age of approximately 50% of patients at diagnosis of non-small cell lung cancer (NSCLC) is >70 years old. Exploration of an optimal treatment strategy for elderly patients with NSCLC as either a first-line or second-line therapy is required. Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that is an effective treatment for patients with NSCLC, especially those harboring activating EGFR mutations. A previous phase III trial suggested that patients with EGFR wild-type (EGFR-wt) NSCLC or elderly patients with disease progression after cytotoxic chemotherapy might benefit from erlotinib monotherapy. However, few studies have prospectively evaluated the efficacy and safety of second or third-line erlotinib monotherapy in elderly patients with EGFR-wt advanced or recurrent NSCLC.

Methods:
Eligibility criteria included: patients aged ≥70 years with pathologically or cytologically proven NSCLC; measurable tumor sites according to the Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1; an Eastern Cooperative Oncology Group performance status of 0–2; no activating EGFR gene mutations (exon 18, 19, 20 and 21); history of 1–2 regimens of systemic chemotherapy; stage IIIB or IV NSCLC, or postoperative recurrence; treatment naïve to EGFR-TKI; and appropriate organ function. EGFR gene mutation analysis was performed by using invasive signal amplification reaction with a structure-specific 5’ nuclease and a polymerase chain reaction (PCR) product (PCR-invader). Patients received oral erlotinib at a dose of 150 mg/day until disease progression. Primary outcome was the objective response rate (ORR). Secondary end points included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and toxicity profile.

Results:
This study was terminated early because of the results from a Japanese phase III trial (DELTA trial). Sixteen patients were enrolled between April 2010 and May 2013. The median age was 78 years (range, 70–84 years), and six patients were female. Five patients had an Eastern Cooperative Oncology Group performance status of 0, and 11 (69%) patients had adenocarcinoma. Fifteen (94%) patients were treated with erlotinib as a second-line therapy. The ORR was 0% (95% confidence interval [CI]: 0–17.1) and DCR was 56.3% (95% CI: 33.2–76.9). The median PFS and OS were 1.7 months (95% CI: 1.3–2.2) and 7.2 months (95% CI: 5.6-8.7), respectively. The most commonly occurring adverse events included acneiform eruption (31.3%) and skin rash (25.0%). One patient developed grade 3 interstitial lung disease, which was improved by following steroid therapy.

Conclusion:
In pretreated elderly patients with advanced or recurrent EGFR-wt NSCLC, daily oral erlotinib was well tolerated; however, administration of the drug should not be considered as a second-line therapy.

Background:
This multicenter, randomized phase II trial investigated the efficacy and safety of docetaxel plus bevacizumab and S-1 plus bevacizumab in the second-line treatment of non-squamous (non-Sq) non-small-cell lung cancer (NSCLC).

Methods:
Patients with non-Sq NSCLC who experienced disease progression after prior platinum-based chemotherapy with or without bevacizumab were randomly assigned (1:1) to receive docetaxel 60 mg/m[2] plus bevacizumab 15 mg/kg (DB) once every 3 weeks or S-1 40 mg/m[2] orally twice daily on days 1–14 plus bevacizumab 15 mg/kg (SB) on day 1 every 3 weeks until disease progression. The primary endpoint was progression-free survival (PFS).

Results:
Ninety patients were randomized. The median PFS was 3.9 months (95% confidence interval [CI] = 3.0–6.5) in the DB arm and 3.5 months (95% CI = 2.9–5.9) in the SB arm. The objective response rate was significantly higher in the DB arm than in the SB arm (22.2% vs. 2.2%; P = 0.004), whereas the disease control rates of the arms were identical (62.2% vs. 62.2%; P = 1.00). Patients receiving DB were more likely to have ≥grade 3 neutropenia (93.4% vs. 4.4%) and febrile neutropenia (33.3% vs. 0%) than SB-treated patients. In the DB arm, PFS and overall survival were significantly longer among bevacizumab-naïve patients than among bevacizumab-experienced patients (median PFS: 7.4 months vs. 2.8 months; P < 0.001; and median OS: 27.4 months vs. 11.7 months; P = 0.002).

Conclusion:
DB and SB produced modest PFS benefits in the second-line treatment of patients with advanced non-Sq NSCLC. Because of the toxicity of DB and the low response rate of SB, neither regimen warrants further investigation, excluding DB in bevacizumab-naïve patients with advanced non-Sq NSCLC.

Background:
This study aimed to explore the safety and effectiveness of anti-angiogenesis agent Endostar combined with neo-adjuvant chemotherapeutic therapy in the treatment of non-small cell lung cancer (NSCLC) patients in phase ⅢA (N2).

Methods:
From April, 2011 to December, 2013, a total of 30 patients diagnosed as NSCLC in phase ⅢA (N2) by pathology or assistant examinations were selected in the randomized, control and open clinical study treated with NP combined with Endostar or single NP neo-adjuvant chemotherapeutic therapy. Control group was treated with neo-adjuvant NP chemotherapy for 2 weeks, on which basis trial group was added with Endostar for 2 weeks. Clinical efficacy was evaluated 3 weeks and surgery was performed within 4 weeks after 2-cycle treatment. The primary end points were response rate (RR), clinical benefit rate (CBR) and tumor regression rate (TRR) as well as peri-operative clinical indexes and safety. The secondary end points included disease-free survival time (DFS) and overall survival time (OS).

Results:
In the 26 patients with evaluable efficacy, trial group and control group were 50.0% and 40.0% in RR (P＝1.0), 87.5% and 64.0% in CBR (P＝0.76), 19.7% and 7.1% in TRR (P＝0.036), 12.0 months and 10.0 months in total DFS (P＝0.44) and 16.0 months and 14.0 months in OS (P＝0.39), respectively. however, there was no significant difference between two groups in all clinical indexes and hematological and non-hematological toxicities in all degrees (P＞0.05).

Conclusion:
Endostar combined with NP chemotherapy are markedly higher than single NP neo-adjuvant chemotherapy in RR, CBR, TRR, DFS and OS without increasing the therapeutic toxicities. In addition, there is no significant difference between two groups in peri-operative clinical indexes, indicating that Endostar combined with NP chemotherapy are safe and effective in treating patients with NSCLC in ⅢA (N2).

Background:
Erlotinib is active in tumors with an EGFR mutation. Capecitabine, a thymidylate synthetase inhibitor, has shown some activity in advanced lung cancer (ALC). The combination of erlotinib and capecitabine has not been studied in ALC.

Methods:
We conducted a phase 1b trial, using a standard 3+3 dose escalation design to define the maximum tolerated dose (MTD) and safety of the combination of erlotinib and capecitabine, given on a 3-weekly cycle in 2[nd] line patients unselected for EGFR status. DLT was any grade≥2 toxicity. After MTD was defined in the 2[nd] line patients, we planned expansion of the trial to 1[st] line patients for further dose escalation. Dosing levels are listed in Table 1. Toxicity was assessed using CTCAE v3.0, response rate was assessed using RECIST 1.1, and survival assessed using Kaplan-Meier method.

Results:
We recruited 40 patients with adenocarcinoma. 55% were male, with median age of 67 years (range 38-84). 65% were ex-smokers and 28% were current smokers. Performance status was ECOG 1 in 65% and 2 in 35% of patients. 85% of patients had received platinum-doublet chemotherapy for 1[st] line ALC, with 10% having maintenance pemetrexed. One patient had an EGFR mutation. Dose escalation stopped at level 3 in 2[nd] line patients with expansion to 6 patients due to dose limiting toxicities (DLTs) of grade (G) 2 creatinine rise, G2 anemia, G3 atrial fibrillation, and G3 pneumonia in 2/6 patients. The MTD was thus at level 2 that was also expanded to 6 patients, confirming safety. First line patients were then recruited at MTD but resulted in DLTs in 3/4 patients with G3 troponin rise, G2 rash, and G2 bilirubin rise in 2 patients. Hence the 1[st] line approach was abandoned. The MTD in 2[nd] line patients was further expanded for toxicity and activity. The overall response rate was 3% with a disease control rate of 34%. A partial response was seen in 1 patient with EGFR mutation of 11.3 months duration. The median progressive free survival was 1.6 months (95%CI 1.4 – 3.5) and the median overall survival was 6.1 months (95%CI 5.1 – 12.5).

Conclusion:
The MTD for capecitabine is 750mg/m[2] bd days 1–14 and erlotinib 100mg od on a 3-weekly cycle. The addition of capecitabine does not improve the efficacy of erlotinib in unselected ALC. This combination could be explored further in ALC selected for EGFR mutation. Table 1: Patient disposition.

Dose escalation	No. of pts	No. of pts with DLTs
Level 1 - Erlotinib 100mg od, Capecitabine 500mg/m[2], bd, days 1-14	3
Level 2 - Erlotinib 100mg od, Capecitabine 750mg/m[2], bd, days 1-14	3 + 3
Level 3 - Erlotinib 100mg, od, Capecitabine 1000mg/m[2] bd, days 1-14	3 + 3	2
1[st] line ALC at level 2	4	3
Dose Expansion
2[nd] line ALC	21

Background:
Concurrent chemoradiotheray is the standard of care for patients with locally advanced non-small cell lung cancer (NSCLC), but often accompanying with high toxicities and poor tolerability. Radiosensitization of EGFR tyrosine kinase inhibitors (TKI) has been proved in preclinical studies, and the safety of TKI combined with thoracic radiotherapy has also been evaluated in several phase II trials.

Methods:
Patients with previously untreated, non-metastasis NSCLC, EGFR wild-type, Easter Cooperative Oncology Group performance status of 0-2 and acceptable organ function were eligible. The prescribed radiation dose was 60-70Gy, and both three dimensional conformal and intensity-modulated radiation therapies were allowed. TKI was administrated concurrently with thoracic radiotherapy. The primary endpoint was local-regional control; second endpoints included progression-free survival, overall survival and treatment-related toxicities.

Results:
Between 2012.1 and 2015.3, 12 eligible patients were recruited into this study, with an median age of 65 years (range 47 ~ 82 years)， 1 female and 11 males. One of them was stage Ⅳ, two of them were stage Ⅱ and nine of them were stage Ⅲ. During the process of treatment, 2 (16.7%) of patients developed grade Ⅱ radiation pneumonitis and 9 (75.0%) developed level Ⅰ~Ⅱ hematological toxicity. Patients were followed up with a median follow-up time of 13 months (6~35months) and the last follow-up time was 2015.3. The results showed that 1-year and 2-year overall survival rates were 76.2% and 57.1%, respectively. 1-year and 2-year local recurrence-free survival rates (LRFS) were 62.2% and 62.2%, respectively. 1-year and 2-years PFS rates were 55.0% and 55.0% (see table), respectively.

Conclusion:
The preliminary results showed that concurrent thoracic radiotherapy and EGFR-TKI were safe and effective in NSCLC patients with wild-type EGFR. This trial is on going.

Background:
PF-06439535, a potential biosimilar to bevacizumab, is a humanized monoclonal IgG1 antibody that targets the vascular endothelial growth factor. This study (B7391001) compared the pharmacokinetics (PK) of PF-06439535 to bevacizumab sourced from the US (bevacizumab-US) and EU (bevacizumab–EU), and the PK of bevacizumab-EU to bevacizumab–US in healthy male volunteers.

Methods:
In this double-blind study, 102 healthy males, aged 21-55 years, were randomized 1:1:1 to receive a single 5 mg/kg intravenous dose of PF-06439535, bevacizumab-US, or bevacizumab-EU. One subject discontinued before dosing. Assessments for PK were conducted for 71 days, with extended safety and immunogenicity assessments up to 100 days postdose. PK similarity was achieved if 90% confidence intervals (CIs) for the test-to-reference ratios of the maximum concentration (C~max~), the area under the concentration-time curve (AUC) from time 0 to the last quantifiable time point (AUC~T~), and AUC from time 0 extrapolated to infinity (AUC~0-∞~) were within 80.00%–125.00%.

Results:
Ninety-seven subjects were eligible and included in the PK analysis. The demographics of the PK eligible subjects were comparable among the 3 treatment groups. The 3 study drugs exhibited similar PK parameters (Table 1). For the comparisons of PF-06439535 to bevacizumab-EU or bevacizumab-US, and of bevacizumab-EU to bevacizumab-US, the 90% CIs for the ratios of C~max~, AUC~T~, and AUC~0-∞~ were all within 80.00%–125.00% (Table 2). Treatment-related adverse events were reported in 15.2%, 25.7%, and 18.2% of subjects in the PF-06439535, bevacizumab-EU, and bevacizumab-US treatment arms, respectively. Table 1: Mean (±SD) PK Parameter Estimates

Parameters (units)	PF-06439535	Bevacizumab-EU	Bevacizumab-US
N	32	33	32
C~max~ (µg/mL)	142.9 ± 20.3	137.0 ± 20.5	130.0 ± 18.2
AUC~T~ (µg•hr/mL)[a]	40840 ± 6411	41010 ± 6711	38920 ± 4566
AUC~0-∞~ (µg•hr/mL)	43080 ± 7103	43830 ± 8326	41450 ± 5350

[a]AUC~T~ was ≥80% of the corresponding AUC~0-∞~ in all 97 PK eligible subjects. Table 2: Comparisons of Pharmacokinetic Exposure Parameters between Test and Reference Products

Comparison (Test to Reference)	Parameters, units	Test[a]	Reference[a]	Test/Reference Ratio (%)	90% CI for Ratio
PF-06439535 to bevacizumab-EU	C~max~, µg/mL	141.5	135.5	104.42	98.36–110.84
	AUC~T~, µg•hr/mL	40330	40490	99.62	93.69–105.93
	AUC~0-∞~, µg•hr/mL	42490	43100	98.58	92.16–105.44
PF-06439535 to bevacizumab-US	C~max~, µg/mL	141.5	128.9	109.79	103.38–116.60
	AUC~T~, µg•hr/mL	40330	38660	104.32	98.06–110.97
	AUC~0-∞~, µg•hr/mL	42490	41120	103.33	96.55–110.58
Bevacizumab-EU to bevacizumab-US	C~max~, µg/mL	135.5	128.9	105.15	99.05–111.62
	AUC~T~, µg•hr/mL	40490	38660	104.71	98.48–111.34
	AUC~0-∞~, µg•hr/mL	43100	41120	104.82	98.00–112.12

[a]Adjusted geometric means

Conclusion:
This study demonstrates PK similarity of PF-06439535 to both bevacizumab-US and bevacizumab-EU, and of bevacizumab-EU to bevacizumab-US. The safety profile was similar in the 3 treatment groups with no significant safety findings reported.

Background:
Treatment strategies for advanced non-squamous (sq) non-small cell lung cancer (NSCLC) are divided by EGFR mutations. However, there has been no previous report about efficacy of cytotoxic agents separated by EGFR mutations. In addition, the influence of the EGFR mutations on the maintenance therapy with pemetrexed (Pem) or bevacizumab (Bev) has not been elucidated. We planned two studies designed to evaluate the efficacy and safety of combination therapy with Pem, carboplatin (Cb) and Bev followed by Pem and Bev maintenance therapy for non-sq NSCLC patients without or with activating EGFR mutation.

Methods:
We undertook two multicenter, open-label, single-arm, phase II studies. Patients with wild type EGFR or with EGFR mutation (exon 19 deletions or exon 21 point mutation) entered CJLSG0909 or 0910, respectively. Patients received Pem 500mg/m[2], Cb AUC 6, and Bev 15mg/kg day1, every 3 weeks, 4 to 6 cycles (induction therapy). Patients who had achieved disease control received Pem+Bev maintenance therapy until progressive disease or unacceptable adverse event. Key inclusion criteria were stage IIIB, IV, or recurrent disease after surgery, no prior chemotherapy, age 20 to 74. The primary endpoint was the objective response rate (ORR), and the secondary endpoints were the disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. (Unique trial Number; UMIN000003736/UMIN000003737)

Results:
In CJLSG0909, 50 patients received induction treatment. They had a median age of 64 years and were predominantly men (40 [80%]) with adenocarcinoma (47 [94%]), stage IV (40 [80%]), and a performance status (PS) of 1 (40 [80%]). The median of induction therapy was 5 cycles. Thirty-five (70%) patients received maintenance therapy, and the median of maintenance therapy was 5 cycles. Partial response was observed in 25 patients with a ORR of 50.0% (95% confidence interval, 33.7–62.6%). Stable disease was observed in 21 patients and the DCR was 92%. Median PFS was 6.8 months and median OS was 19.4 months. Grade 3/4 toxicities during induction therapy included neutropenia (40 [80%]), thrombocytopenia (12 [24%]), anemia (8 [16%]), nausea (4 [8%]), anorexia (3 [6%]), ALT elevation (3 [6%]), AST elevation (2 [4%]), vomiting, periodontal, hemoptysis, thrombosis and proteinuria (1 [2%]) respectively. In CJLSG0910, 30 patients received induction treatment. They had a median age of 65.5 years and were predominantly women (17 [57%]) with adenocarcinoma (29 [97%]), stage IV (27 [90%]), and a PS of 0 (23 [77%]). The median of induction therapy was 6 cycles. Twenty-five (83%) patients received maintenance therapy, and the median of maintenance therapy was 8.5 cycles. Partial response was observed in 15 patients with a ORR of 50.0% (95% confidence interval, 33.9–66.1%). Stable disease was observed in 15 patients and the DCR was 100%. Median PFS was 10.0 months and median OS was 41.4 months. Grade 3/4 toxicities during induction therapy included neutropenia (14 [47%]), thrombocytopenia (6 [20%]), anemia (6 [20%]), diarrhea (2 [7%]), nausea, anorexia, amylase elevation (1 [3%]) respectively.

Conclusion:
These studies suggested that chemotherapy with Pem+Cb+Bev, including Pem+Bev maintenance therapy is candidate for first line therapy in non-sq NSCLC patients regardless of the activating EGFR mutations.

Background:
HER2 has long been recognized as an oncogenic driver in some breast and gastro-esophageal cancers. More recently, somatic mutations in HER2 have been reported in 1-2% of patients with lung adenocarcinoma, and the promise of HER2 as a treatment target in lung cancer has been suggested using anti-HER2 small molecules and antibodies.

Methods:
Here we report the outcomes of three patients with metastatic lung adenocarcinoma with HER2 mutations being treated with HER2 targeted therapies at a single institution.

Results:
The first patient is a 65yo Caucasian woman, minimal smoking history, with stage IIIA lung adenocarcinoma who then developed recurrent metastatic disease mainly in the liver after completing definitive chemoradiotherapy. She progressed through three lines of chemotherapies, with near replacement of liver with tumor. At that time she was found to have HER2 exon 20 insertion mutation (A775_G776 insSVMA) and was started on vinorelbine and trastuzumab. The main side effect was fatigue, which was tolerable. She achieved radiographic stable disease with 13% reduction of her liver metastasis as her best response by RECIST v1.1 for 6 months and significant clinical improvement before progression of disease in all sites. The second patient is a 60yo Caucasian woman, former smoker, diagnosed with stage IV lung adenocarcinoma with HER2 exon 20 insertion mutation (unknown exact sequence) with extensive bony disease. She was treated with carboplatin, paclitaxel, bevacizumab, and an investigational anti-Met therapy with initial mild decrease in lung mass and nodules after one month, then mild progression for 14 months. She was taken off trial then and started on vinorelbine and trastuzumab, and so far shows no measurable growth after 5 months on therapy. The third patient is a 35yo Asian woman, non-smoker, diagnosed with stage IV lung adenocarcinoma with HER2 exon 20 insertion mutation (unknown exact sequence) with malignant pleural effusions, bilateral lung and brain lesions, and extensive lymph node involvement. She was treated with carboplatin, pemetrexed, and bevacizumab first followed by pemetrexed and bevacizumab maintenance, with initial mild improvement then progression after 4.5 months. She was then treated with erlotinib with rapid progression within 1 month. She was then treated with afatinib 40mg daily based on the HER2 mutation, improved disease after 2 months with best response 21% reduction, then progression after 3 more months (5 months total of clinical benefit). She was then started on vinorelbine and trastuzumab. Treatment was interrupted due to one new brain lesion requiring stereotactic radiation treatment. She has shown partial response with best response of 31% on the latest imaging done 4 months after starting therapy.

Conclusion:
From our single institution experience, HER2 targeted therapy can provide disease control for patients with metastatic HER-2 mutated NSCLC that has progressed on previous therapies. Our results are consistent with the study by Mazières et al. Vinorelbine was dosed as 25 mg/m2 and trastuzumab as 2 mg/kg every 1 week (with 4mg/kg first loading dose) or 6 mg/kg every 3 weeks. All three patients were able to tolerate therapies well with no significant toxicities nor cardiac toxicity.

Background:
Angiotensin converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) are among the most common medications in the treatment of hypertension and diabetes. These drugs are under evaluation as a means to mitigate radiation pneumonitis/fibrosis likely mediated by anti-inflammatory and endothelial effects. Their collateral impact on oncological outcomes is unknown. We retrospectively evaluate the effect of ACEi and ARB usage on pathological response during preoperative platinum-based concurrent chemoradiotherapy (CCRT) with high-dose radiotherapy (≥59.4 Gy) in a cohort of patients with stage III non-small cell lung cancer (NSCLC).

Methods:
Between June 2000 and December 2009, 79 patients with stage III NSCLC (AJCC 7[th] ed.) were treated with preoperative CCRT at our institution. Data on ACEi/ARB usage during CCRT and pathological response was available for 72 patients. The primary end-point was pathological complete response (pCR), in both the primary site and involved lymph nodes. X[2] analysis was to assess distribution of categorical variables, Kaplan-Meier survival analysis with log rank test for univariate and Cox regression multivariate (age, gender, race, stage, RT dose and chemotherapy regimen) analysis of overall survival (OS) and freedom-from recurrence (FFR) was performed.

Results:
The median age at diagnosis was 56 years (range, 38-78) with 56% males, 74% Caucasians and 96% smokers. Stage distribution was IIIA (72%), IIIB (28%), T1/2 (54%), T3/4 (46%), N0/1 (14%) and N2/3 (86%). The median radiation dose was 66.6 Gy (range 59.4-69.6 Gy) with the most common CCRT regimen being carboplatin-paclitaxel (54%). At a median follow up of 3.8 years for all patients and 6.8 years for surviving patients, the median OS and FFR of the entire cohort were 4.9 years (95% Confidence Interval (CI): 3.5-6.5) and 3.1 years (95% CI: 1.3-4.9), respectively with overall pCR rate of 44%. During CCRT, 11 patients (15%) were taking ACEi/ARB and 61 patients (85%) were not taking ACEi/ARB. No statistical differences were seen in the distribution of baseline variables between the two cohorts. None of the patients developed acute radiation pneumonitis in the time interval between radiotherapy completion and surgery (median 55 days; range, 33-105 days). The pCR rate without and with ACEi/ARB was 46% vs 36% (p=0.56). The median FFR without and with concurrent ACEi/ARB use was 3.1 years vs. not reached, p = 0.35, while the corresponding median OS values were 4.8 years and 5.5 years, p = 0.59, respectively. On multivariate analysis, an improved OS was associated with younger age (HR: 0.39, 95%CI: 0.2-0.8, p<0.01), an improved FFR was associated with lower stage (HR: 0.3, 95%CI: 0.15-0.76, p<0.01) and Caucasian race (HR=0.37, 95% CI: 0.15-0.88, p=0.02), with no impact of ACEi/ARB use on either outcome.

Conclusion:
The use of ACEi/ARB did not have any apparent influence the rates of pCR in this small cohort of advanced stage NSCLC patients treated with trimodality therapy following preoperative platinum-based CCRT with high-dose radiotherapy. As the role of these drugs in mitigating radiation pneumonitis continues to be evaluated, simultaneous assessment of lack of a negative impact on disease outcomes needs to be validated in larger, prospective analyses.

Background:
Circulating Tumor Cells (CTCs) have been shown to be a useful prognostic tool in several cancers. Non-small-cell-lung cancer (NSCLC) lacks validated prognostic biomarkers and, thus, this study aimed to explore the sensitivity and clinical significance of the detection of CK19mRNA (+) CTCs in NSCLC patients.

Methods:
Peripheral blood was obtained from 642 patients with previously untreated stage IIIB/IV NSCLC and from 455 patients after the completion of 1[st] line chemotherapy. RNA extracted from the Calu-3 and ARH-77 cell lines was used as positive and negative controls, respectively. The detection of CK19mRNA-positive cells was performed using an RT-qPCR assay.

Results:
The analytical detection limit of the method was found to correspond to 0.42 Calu-3 cell equivalents/5μg RNA. One hundred and sixty seven (26.0%) patients had detectable CK19mRNA (+) CTCs at baseline; the detection of CK19mRNA (+) CTCs post chemotherapy was associated with significantly decreased PFS and OS (PFS: 2.6 vs 3.8 months, p=0.008; OS: 5.7 vs 10.0 months, p=0.006). Multivariate analysis revealed that gender, performance status and the detection of CK19mRNA (+) CTCs post chemotherapy emerged as independent factors associated with reduced PFS (HR=1.350, p=0.010) and OS (HR=1.608; p=0.001).

Conclusion:
Detection of peripheral blood CK19mRNA (+) CTCs post chemotherapy is an adverse prognostic factor correlated with poor clinical outcome in patients with stage IIIB/IV NSCLC.

Background:
The median overall survival time for patients with stage IV non-small cell lung cancer (NSCLC) is 4 months, and 1- and 5-year survival is less than 16% and 2%, respectively. NSCLC is usually treated with surgery followed by radiation and treatment with platinum-based regimens or in some cases Tyrosine Kinase Inhibitors (TKIs). Unfortunately, long-term prognosis with platinum-based therapies is poor, and TKI resistance has emerged as a significant unmet medical need. Dianhydrogalactitol (VAL-083) is a structurally unique bi-functional alkylating agent mediating interstrand DNA crosslinks at N[7] of guanine. It has previously demonstrated activity against NSCLC in NCI-sponsored preclinical and clinical trials and is approved for treatment of lung cancer in China (Approval No. Guoyao Zhunzi H45021133); however, it is currently not widely known or used for the treatment of NSCLC.

Methods:
not applicable

Results:
Recent preclinical data suggest that VAL-083 may be a therapeutic option for drug-resistant NSCLC. VAL-083 has superior activity to cisplatin in both in vitro and in vivo models of NSCLC, including TKI-resistant NSCLC. When combined with either cisplatin or oxaliplatin in vitro, VAL-083 demonstrates significant superadditivity (p<0.05) and synergism (CI < 1) for both combinations in NSCLC cell lines A549, H1975 and H460. When tested in a standard syngeneic mouse fibrosarcoma model (RIF-1 cell-line in C3H mice), VAL-083 (10 mg/kg) was superior to cisplatin (4 mg/kg) in tumor growth delay. Mice were treated with a single IP injection of either cisplatin, VAL-083 or VAL-083 followed immediately by cisplatin. Combination treatment of with cisplatin produced a more than additive effect by delaying growth 8.65 days. In another in vivo model using NSCLC cell-line A549 in Rag2mice, VAL-083 was given as part of a combination treatment with cisplatin. Tumour growth delays of 11, 18 and 25 days were observed for 2 mg/kg cisplatin in combination with 2, 2.5 or 3 mg/kg VAL-083, respectively, while no significant tumour growth delay was observed between untreated and Cisplatin (2 mg/kg). The median survival time was increased by 2 days for cisplatin alone, while the combination of VAL-083 (2 mg/kg, 2.5 mg/kg and 3 mg/kg) with cisplatin (2 mg/kg) increased survival by 17 days, 17 days, and 14 days, respectively.

Conclusion:
The preclinical data strongly suggest VAL-083 as a potential treatment for drug-resistant NSCLC. A planned open-label phase IV (post market) clinical trial will investigate the activity of VAL-083 in relapsed or refractory NSCLC assessed by objective response rates, complete and partial response rates and stable disease. VAL-083 will be dosed in accordance with the approved label (40 mg/day) and the results will provide guidance to treating physicians under the context of VAL-083’s current approval in China, as well as serve as proof of concept for expanded development in the rest of the world.

Background:
Abemaciclib, a cell cycle inhibitor selective for CDK4/6, demonstrated acceptable safety and early clinical activity in metastatic NSCLC, given orally as monotherapy on a continuous schedule. Combinations of abemaciclib showed greater activity compared with monotherapy in KRAS-mutant NSCLC preclinical models. Primary aim of study NCT02079636 was safety/tolerability of combination therapy with abemaciclib; secondary aims included pharmacokinetics and antitumor activity.

Methods:
In this open-label 3+3 dose-escalation study with expansion cohorts, eligibility included stage IV NSCLC, measurable or nonmeasurable disease (RECISTv1.1), ECOG PS ≤1, and 1-3 prior therapies. Abemaciclib was combined with pemetrexed (Part A, nonsquamous, 500 mg/m[2] IV day 1), gemcitabine (Part B, 1250 mg/m[2] IV days 1 and 8), ramucirumab (Part C, 10 mg/kg IV day 1, or 8 or 10 mg/kg IV days 1 and 8) (Q21), or LY3023414 (dual PI3K-mTOR inhibitor) (Part D, 100 mg, 150 mg or 200 mg orally Q12H). In escalation, patients were dosed continuously until progression with abemaciclib at 100 mg (Part D), 150 mg or 200 mg orally Q12H.

Results:
As of February 27, 2015, 70 patients (Parts A-C) received ≥1 dose; 15 patients at 150 mg and 55 patients (including all 39 patients in expansion) at 200 mg Q12H abemaciclib. The MTD was established at 200 mg Q12H abemaciclib for Parts A-C. See Table 1 for treatment-emergent adverse events (TEAEs). Stable disease was observed in 13/23 patients in Part A; 7 unknown, 4/24 patients in Part B; 10 unknown, and 7/23 patients in Part C; 12 unknown. In Parts A-C, 18/70 (26%) patients started ≥4 cycles (Part A=9, Part B=3, Part C=6). Three confirmed PRs were observed: Part B, 1 patient with squamous histology (unknown mutation status), Part C, 1 patient with nonsquamous histology (KRAS mutation positive; EGFR mutation negative), and 1 patient with squamous histology (unknown mutation status). Updated analyses will be presented including Part D and longer term follow-up for Parts A-C through approximately June 2015. Table 1. TEAEs related to treatment (≥20% in ≥1 part)

% All grades (% Gr3/4)	Part A (n=23)	Part B (n=24)	Part C (n=23)
Diarrhea	65 (4)	50 (17)	52 (9)
Fatigue	57 (9)	63 (8)	17 (4)
Nausea	35 (0)	50 (4)	48 (9)
Neutropenia	61 (61)	50 (33)	17 (4)
Anemia	57 (26)	33 (17)	9 (0)
Thrombocytopenia	39 (9)	38 (8)	17 (13)
Decreased appetite	30 (0)	25 (0)	22 (0)
Vomiting	9 (0)	21 (0)	35 (0)
Blood creatinine increased	30 (0)	8 (0)	17 (4)
Leukopenia	30 (22)	17 (8)	9 (4)

Conclusion:
Abemaciclib combined with single-agents with acceptable toxicity. Safety findings observed in Parts A and B are consistent with AEs expected when combining myelosuppressive compounds with abemaciclib, resulting in an increased myelosuppressive effect. In Part C, safety findings are consistent with those of single-agents. Tumor responses were observed in Parts B and C.

Background:
Although the anaplastic lymphoma kinase inhibitor (ALKi), crizotinib achieves high responses in patients with ALK-rearranged (ALK+) non–small cell lung cancer (NSCLC), disease progression within 1 year can occur, with the brain/central nervous system (CNS) as a common site of progression and relapse. Ceritinib is a novel oral ALKi with 20-fold greater potency than crizotinib in enzymatic assays and crosses the blood-brain barrier with good CNS penetration in preclinical studies. In the pivotal phase 1 study (NCT01283516), ceritinib was highly active in ALK+ NSCLC patients (regardless of prior crizotinib exposure) and achieved intracranial responses in 7 of 14 patients with measurable baseline brain lesions. The adverse events profile in these patients was similar to that of the full study population.

Methods:
This international, prospective, phase 2, open-label study is designed to evaluate the antitumor activity of ceritinib in patients with ALK+ NSCLC metastatic to the brain or leptomeninges (ASCEND-7; CLDK378A2205). Eligible patients must have ALK+ (centrally assessed) NSCLC metastatic to the brain and ≥ 1 extracranial measurable lesion using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients must be neurologically stable ≥ 1 week prior to study drug administration and will be allocated to 1 of 5 arms depending on prior treatment:

Arms 1-4 (patients with active* brain metastases, without leptomeningeal carcinomatosis [LC])	Prior ALKi treatment	No prior ALKi treatment
Prior whole brain radiotherapy (WBRT)	Arm 1	Arm 3
No prior WBRT	Arm 2	Arm 4
Arm 5: patients with LC with or without evidence of active lesion at baseline

*Lesion free of local treatment (stereotactic or WBRT) or lesions in unequivocal progression after radiotherapy. Oral ceritinib 750 mg/d will be dosed on a continuous schedule and study assessments are consistent across arms. The primary and key secondary objectives are to evaluate overall response rate and disease control rate, respectively. Other secondary objectives include assessment of intracranial and extracranial responses for all patients and for each of arms 1–4; overall survival and safety for all patients and for each of arms 1–5; and ceritinib pharmacokinetics in all patients. Enrollment is ongoing.

Results:
This study is in the activation phase.

Conclusion:
This study will demonstrate the efficacy of ceritinib in ALK+ NSCLC brain metastases and leptomeningeal metastases, in both WBRT-naive patients and prior irradiated patients.

Background:
Plinabulin (P) is a microtubule-depolymerizing agent that inhibits tumor growth by targeting both angiogenesis and tumor vasculature as well as directly by inducing apoptosis via the Ras-JNK pathway. It also could activate anti-tumor immunity via inducing maturation of dendritic cells. Pinabulin at 30 mg/m2 given on days 1 and 8 was studied in a randomized phase 2 study in combination with docetaxel 75 mg/m2. Despite the fact that ITT overall survival (OS) was not statistically different between both arms, duration of response was notably longer in DP compared to D, 12.7 months vs 1.5 month in the 30 cohort ( p=0.049). Nivolumab (Nivo) is the first PD-1 inhibitor approved by the FDA in metastatic squamous NSCLC, based on results of a phase III trial showing that patients receiving Nivo lived, on average, 3.2 months longer than patients receiving standard ChRx. Microtubule-depolymerizing agents are known to induce dendritic cell maturation and synergize with immune checkpoint inhibitors in immune competent cancer models. Therefore we hypothesize that combining plinabulin with nivolumab will enhance the immune response which will in turn lead to a higher response rate (RR) and longer OS in patients with metastatic squamous NSCLC.

Methods:
This is a phase I open-label, dose escalation study of plinabulin in combination with nivolumab (PNivo) in patients with metastatic squamous NSCLC that have progressed through one line of platinum-containing ChRx. The primary objectives are safety and tolerability of combination therapy to define the maximum tolerated dose (MTD), dose limiting toxicities (DLT) and/or RP2D for PNivo. The secondary objective is the efficacy of PNivo in terms of RR, progression free survival and OS in the expanded cohort. Plinabulin will be escalated from the biologically active dose of 13.5 mg/m2 using a “3+3” design. At the MTD or highest dose level in this study, the cohort will be expanded as applicable to ensure a total of 9 subjects are treated at the RP2D. Correlative studies to investigate pharmacodynamical effects will be performed. Main inclusion criteria are histologically documented metastatic squamous NSCLC with measurable disease, EGFR/ALK and ROS-1 negativity, ECOG status 0 to 2, preserved organ and marrow function. Main exclusion criteria are untreated brain metastases, concurrent radiation and systemic therapy within 21 days of the first dose of study drug.

Results:
not applicable

Conclusion:
not applicable

Background:
Treatment of elderly patients with non-small cell lung cancer (NSCLC) is challenging due to comorbidities and reduced tolerability; as a result, these patients often receive suboptimal treatment. In addition, 5-year survival rates are lower in elderly than in younger patients with NSCLC. In a multicenter phase III trial, first-line treatment with nab-paclitaxel plus carboplatin (nab-P/C) significantly increased median overall survival (OS) vs solvent-based paclitaxel plus C in a subset of patients ≥ 70 years of age with advanced NSCLC (19.9 vs 10.4 months; HR 0.583; P = 0.009; Socinski et al. Ann Oncol. 2013;24:314-321). However, 55% of elderly patients treated with nab-P/C required dose reductions and 84% had dose delays, primarily due to adverse events, including myelosuppression. In the open-label, multicenter phase IV ABOUND.70+ trial, the safety and efficacy of 2 different schedules of first-line nab-P/C treatment will be evaluated prospectively in elderly patients with advanced NSCLC.

Methods:
Approximately 284 patients with NSCLC ≥ 70 years of age who are not candidates for curative surgery or radiation therapy will be randomized 1:1 to nab-P 100 mg/m[2] intravenously (IV; 30-minute infusion) on days 1, 8, and 15 plus C AUC 6 on day 1 every 21 days or the same nab-P/C dose every 21 days followed by a 1-week break. Key eligibility criteria include histologically/cytologically confirmed locally advanced or metastatic NSCLC, no prior chemotherapy for metastatic disease, ECOG performance status ≤ 1, adequate organ function, no active brain metastases, and absence of preexisting peripheral neuropathy (PN) grade > 2. Patients will be stratified by ECOG performance status (0 vs 1) and histology (squamous vs nonsquamous). ClinicalTrials.gov identifier NCT02151149.

Key Endpoints
Primary	Percentage of patients developing either PN grade ≥ 2 or myelosuppression grade ≥ 3
Secondary	Safety Progression-free survival OS Overall response rate
Exploratory[a]	Healthcare resource utilization throughout the study Changes in quality of life

[a] Additional exploratory endpoints may be defined in the statistical analysis plan if applicable.

Results:
TPS Abstract Section NA

Conclusion:
TPS Abstract Section NA

Background:
Patients with advanced non-small cell lung cancer (NSCLC) progressing after 1[st] line platinum containing doublet chemotherapy +/- targeted therapy for EGFR mutations and EML4-ALK fusion genes have limited therapeutic options. Extracellular components such as hyaluronan (HA) make up the tumor microenvironment (TME) and may limit access of chemotherapeutic agents to the cell as a result of increased interstitial pressure and decreased blood flow. PEGPH20 (PEG) decreases HA and restores blood flow. In animal models of NSCLC, PEG + docetaxel (Doc) significantly prolonged survival compared to Doc alone. These results are consistent with results in previous studies in pancreatic adenocarcinoma (PDA). In a Phase 1b trial of the combination of PEG + gemcitabine in Stage IV pts with PDA whose tumors were HA-high pts had higher ORR, PFS and OS compared to pts with HA-low tumors.

Methods:
This is an ongoing Phase 1b/2 open-label, randomized study of the addition of PEG to docetaxel (PDoc) compared to docetaxel (Doc) in pts with Stage IIIB/IV NSCLC having been treated with at least 1[st] line platinum containing chemotherapy. The Phase 1b portion of the study will determine the maximum tolerated dose (MTD), dose limiting toxicity and recommended Phase 2 dose for two schedules of PEG; one given every 21 days with Doc and the second dosed 2X per week with Doc. Up to 40 subjects are expected to be enrolled in the Phase 1b dose escalation. Once MTDs are determined the second portion of the Phase 1b will accrue approximately 10 patients whose tumors are HA-high to determine which schedule will go forward in Phase 2. The Phase 2 will randomize 188 patients in a 1:1 fashion to receive PDoc or Doc stratified by histology and prior targeted therapy. The primary endpoint of the Phase 2 portion is PFS. This is the first clinical trial evaluating PEGPH20 in NSCLC. The trial is currently accruing to the dose finding portion of the Phase 1b. ClinicalTrials.gov Identifier: NCT02346370

Results:
not applicable

Conclusion:
not applicable

Background:
Lucitanib is a potent, oral inhibitor of the tyrosine kinase activity of Fibroblast Growth Factor Receptors 1-3 (FGFR1-3), Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR1-3) and Platelet-Derived Growth Factor Receptors A/B (PDGFRA/B). Clinical activity was observed in a phase 1/2 study of lucitanib monotherapy in cancer patients with tumor amplification of FGF-related genes or in tumors with predicted sensitivity to VEGF inhibitors. Genomic evidence of FGF, VEGF or PDGF axis aberrancy is seen in up to 15% of patients with lung cancer, which provides a strong rationale to assess lucitanib in this setting.

Methods:
The current study evaluates daily oral lucitanib monotherapy in 40 patients with amplification or activating mutations in FGF, VEGF or PDGF-related genes. This is an international, multicenter, open-label, single-arm study. The primary endpoint is objective response rate (ORR; RECIST 1.1) with secondary endpoints of response duration, clinical benefit rate, progression-free survival, and safety. Exploratory objectives include volumetric assessment of tumor growth kinetics, serial circulating tumor DNA measurement, and identification of additional biomarkers of lucitanib activity. Key inclusion criteria include: patients with advanced/metastatic non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) or large cell lung cancer and tumor tissue evidence of relevant genomic aberrancies. Patients must have measurable disease and at least one previous treatment for advanced disease. Key exclusion criteria include: carcinoid histology, symptomatic CNS metastases, anti-cancer treatment for lung cancer within 28 days or 5 half-lives before first dose of lucitanib. This study is enrolling patients in the United States and Europe at centers skilled in the identification of patients with relatively uncommon genetic tumor alterations.

Results:
not applicable

Conclusion:
not applicable

Background:
Ramucirumab, a human IgG1 monoclonal antibody, binds to Vascular Endothelial Growth Factor (VEGF) Receptor 2, preventing binding of VEGF-A, C and D. Ramucirumab in combination with docetaxel has demonstrated improvement in overall survival, progression free survival (PFS), objective response rate and disease control rate in 2nd line treatment of NSCLC patients in the phase III REVEL study, which included non-squamous and squamous cell carcinoma patients. Although erlotinib is recognized as one of the standard of care options in the frontline treatment of patients whose tumors harbor an Epidermal Growth Factor Receptor (EGFR) mutation, it is hypothesized that the duration of disease control would be greater when an antiangiogenic agent such as ramucirumab is added to erlotinib. This global phase Ib/III trial will assess safety, tolerability and efficacy (phase III) of the combination of ramucirumab with erlotinib in previously untreated stage IV NSCLC patients harboring activating EGFR mutations. The trial is planned to be conducted in ~120 sites in the Americas, Europe, and Asia and is currently open for enrollment. (RELAY, NCT02411448)

Methods:
In part A (phase Ib) approximately 12 patients (6 Japan + 6 US/EU) will receive ramucirumab (10mg/kg on day 1) every two weeks + erlotinib (150 mg/day). DLT assessment will be performed after patients complete four weeks of treatment. In part B (phase III), approximately 450 patients will be randomized in a 1:1 ratio to receive ramucirumab or placebo every two weeks with erlotinib until disease progression, unacceptable toxicity, or other withdrawal criteria are met. The primary endpoint is PFS. There are 3 planned interim analyses that will evaluate safety, futility and efficacy, respectively. Other secondary endpoints include overall survival, objective response rate, disease control rate, duration of response, safety and quality of life.

Results:
Not applicable

Conclusion:
Not applicable

Background:
Despite advances in targeted therapy, treatment options for metastatic NSCLC progressing after initial therapy remains limited. HSP90 is an ATP-dependent molecular chaperone that plays a vital role in protein stabilization. Some HSP90 client proteins are key regulators in cell proliferation and survival. Many mutant oncoproteins are more dependent on HSP90 for proper folding and stability compared to their wildtype counterparts. AUY922 potently inhibits HSP90, showing preclinical activity in a wide range of cancer cell lines, including NSCLC (1). Phase I clinical trials established 70 mg/m[2] as the dose for further development (2). A single agent phase II trial demonstrated clinical activity of AUY922 in NSCLC, particularly molecular subsets with driver mutations in the known HSP90 client proteins, epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) (3). Pemetrexed is a folate antimetabolite chemotherapeutic approved for use in advanced non-squamous, NSCLC. In pre-clinical models, mRNA for dihydrofolate reductase (DHFR), a target of pemetrexed, reliably decreased in response to AUY922 exposure (1). These findings suggest that the combination of AUY922 and premetrexed in NSCLC is worthy of investigation.

Methods:
Adult patients with previously treated stage IV non-squamous, NSCLC, measureable disease per RECIST 1.1, ECOG performance status < 2, and life expectancy > 3 months are eligible for this open label phase Ib clinical trial (NCT01784640). A standard 3 x 3 design will evaluate 3 cohorts, all with pemetrexed at the standard 500 mg/m[2] dose, plus: AUY922 40 mg/m[2], 55 mg/m[2], and 70 mg/m[2] qwk. Enrollment of the 70 mg/m[2] qwk cohort has been open since November 2014 and is currently ongoing. After the optimal dose for further evaluation is determined, an additional 20 patients will be enrolled at that dose. This expansion phase will focus on patients with EGFR mutations and ALK gene rearrangements. The primary endpoint is safety and tolerability of AUY922 combined with pemetrexed in patients with previously treated non-squamous NSCLC. [Funding by Novartis, K23CA149079, Wolfen Family, One Ball Matt Memorial Golf Tournament]. References 1) Garon EB et. al. Mol Cancer Ther. 2013 2) Sessa C et. al. Clin Cancer Res. 2013 3) Garon EB et. al. ASCO 2012

Results:
Not applicable

Conclusion:
Not applicable

Background:
Tumor Treating Fields (TTFields) are a novel, non-invasive regional anti-mitotic treatment modality, based on low intensity alternating electric fields. Efficacy of TTFields in non-small cell lung cancer (NSCLC) has been demonstrated in multiple in vitro and in vivo models, and in a phase I/II clinical study. TTFields treatment to the brain was shown to be safe and effective in glioblastoma patients. Local treatment options for patient with brain metastases (BM) are limited to neuro-surgery (NS), stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT) or a combination thereof. In patients treated with NS or SRS, intracranial recurrence remains high, since the rest of the brain is not treated. The addition of WBRT, can improve intracranial control either alone or when added to SRS but at the risk of severe neurocognitive and other complications. Thus, new therapeutic options are needed, particularly ones that allow for greater intracranial control while minimizing the risk of neurocognitive and other adverse events.

Methods:
The METIS Clinical Trial 240 patients with 1-10 BM from NSCLC will be randomized in a ratio of 1:1 to receive SRS followed by either TTFields or supportive care alone. Patients are followed-up bimonthly until 2[nd] intracerebral progression. Patients in the control arm may cross over to receive TTFields at the time of 1[st] intracerebral progression. Objectives To test the efficacy, safety and neurocognitive outcomes of TTFields in this patient population. Endpoints Time to intracerebral progression (primary); time to first/second intracerebral progression for patients with 1-4 and 5-10 BM; 2, 4, 6, 8, 10, 12-month first/second intracerebral progression rate; intracerebral progression free survival; overall survival; time to neurocognitive failure; rate of decline in cognitive function; neurocognitive failure-free survival; radiological response; safety (secondary). Treatment Continuous TTFields at 150 kHz will be applied to the brain using the NovoTTF-100M System within 7 days of SRS. The System is a portable medical device allowing normal daily life activities. The device delivers alternating electric fields to the brain using 4 Transducer Arrays, which may be covered by a wig or a hat for cosmetic reasons. Patients will receive the best standard of care for their systemic disease. Statistical Considerations This is a prospective, randomized, multicenter study for 240 patients. The trial is designed to detect an increase in the time to intracerebral progression from 7.7 to 13.4 months (hazard ratio 0.57). This sample size assessment takes into consideration a competing risk (death prior to intracerebral progression) of 0.08252 per month in both treatment arms. The competing risk is based on a predicted median overall survival of 8.4 months mainly due to systemic disease progression. The trial has 80% power at a two sided alpha of 0.05. The sample size was calculated using a log-rank test (based on Lakatos 1988 and 2002) with the competing risk taken as loss to follow up (patients will be censored at time of death if it occurs prior to intracerebral progression).

Results:
not applicable

Conclusion:
not applicable

Background:
The recommended phase II dose of the highly selective c-Met inhibitor tepotinib (MSC2156119J) for use in combination with gefitinib was confirmed as 500 mg/day in the phase Ib part of the current trial, in which patients with gefitinib-resistant locally advanced/metastatic c-Met-positive NSCLC were treated with tepotinib plus gefitinib. This trial demonstrated that the combination regimen is well tolerated and has evidence of antitumor activity that may be associated with c-Met-positive tumor status. These observations suggest that c-Met inhibition may have a role in EGFR tyrosine kinase inhibitor-resistant NSCLC and that a phase II trial is warranted.

Methods:
The design of the phase II part of a phase Ib/II trial (NCT01982955) is described. Asian adults with histologically or cytologically confirmed, gefitinib-resistant locally advanced/metastatic NSCLC other than predominantly squamous histology and ECOG PS 0/1 are eligible. Patients must have tumors with documented activating mutations of EGFR. Tumor tissue obtained between documentation of acquired resistance to gefitinib and enrollment must be available. Tumors must be confirmed as being c-Met positive (2+/3+ c-Met protein overexpression by immunohistochemistry using CONFIRM anti-total c-MET [SP44] rabbit MAb [Ventana] or c-Met gene amplification on IQ FISH [Dako] [c-Met:CEP7 ratio ≥2 or <2.0 with >15 c-Met signals/cell in >10% of cells or clusters in >10% of tumor cell nuclei]). EGFR mutation status will be assessed centrally using the therascreen[®] EGFR RGQ PCR Kit (QIAGEN). Patients will be enrolled into different parts of the trial based on tumor T790M status. Patients with c-Met-positive, T790M-negative NSCLC (n=136) will be randomized to tepotinib 500 mg/day p.o. + gefitinib 250 mg/day q3w or cisplatin 75 mg/m[2] + pemetrexed 500 mg/m[2] q3w for up to 6 cycles. Patients with c-Met-positive, T790M-positive NSCLC (n=15) will be treated with tepotinib 500 mg/day p.o. + gefitinib 250 mg/day q3w. The primary objective is to determine whether progression-free survival (PFS) in patients treated with second-line tepotinib combined with gefitinib is superior to that of pemetrexed + cisplatin in patients with c-Met-positive, T790M-negative advanced NSCLC and acquired resistance to first-line gefitinib. The two T790M subgroups will be analyzed separately. An interim analysis of the randomized part of the study is planned when 50% of PFS events have occurred in both arms. Secondary objectives are to evaluate: the safety and tolerability tepotinib combined with gefitinib; the efficacy of tepotinib combined with gefitinib; the antitumor activity of tepotinib combined with gefitinib in patients with c-Met-positive, T790M-positive tumors; and patient-reported outcomes.

Results:
not applicable

Conclusion:
This randomized phase II trial will provide the first evidence regarding whether tepotinib has a role in the treatment of Asian patients with gefitinib-resistant, c-Met-positive, T790M-negative NSCLC.

Background:
Many patients with advanced non-small cell lung cancer (NSCLC) often present with poor performance status (PS), and there is no clear consensus on how best to treat these patients. Despite an increased risk of toxicity resulting from standard chemotherapy, patients with NSCLC and a poor PS can clinically benefit from platinum-doublet therapy. In a multicenter phase III trial, first-line treatment with nab-paclitaxel plus carboplatin (nab-P/C) in patients with NSCLC and an ECOG PS 0-1 significantly improved the overall response rate (ORR) compared with solvent-based paclitaxel plus C (33% vs 25%; P = 0.005; Socinski et al. J Clin Oncol. 2012;30:2055-2062). In the single-arm, open-label, multicenter phase II ABOUND.PS2 study, the safety and efficacy of first-line nab-P/C followed by nab-P monotherapy will be evaluated in patients with locally advanced/metastatic NSCLC and an ECOG PS of 2.

Methods:
During the induction part of the study, approximately 50 patients will be treated with 4 cycles of nab-P 100 mg/m[2] intravenously (IV; 30-minute infusion) on days 1 and 8 plus C AUC 5 IV on day 1 every 21 days. Patients without disease progression may proceed to the monotherapy part of the study in which they will continue to receive nab-P 100 mg/m[2] IV (30-minute infusion) on days 1 and 8 every 21 days until progression or unacceptable toxicity. Key eligibility criteria include histologically/cytologically confirmed stage IIIB/IV NSCLC, no prior chemotherapy for metastatic disease, ECOG PS of 2, adequate organ function, no active brain metastases, and preexisting peripheral neuropathy grade < 2. ClinicalTrials.gov number NCT02289456.

Key Endpoints
Primary	The percentage of patients who discontinue treatment during the induction part due to treatment-emergent adverse events
Secondary	Safety Progression-free survival Disease control rate Overall survival ORR
Exploratory	Healthcare resource utilization throughout the study Changes in physician-reported ECOG PS and patient-reported quality of life Summary of Charlson Co-Morbidity Index at baseline Correlation between patient- and physician-reported ECOG PS during treatment Correlation between patient- and physician-reported Karnofsky PS at baseline

Results:
This is a TPS abstract Results = NA

Conclusion:
This is a TPS abstract Results = NA

Background:
Tumor hypoxia is associated with chemo- and radioresistance and is a prevalent characteristic in tumors of patients with non-small cell lung cancer (NSCLC). Evofosfamide (previously known as TH-302) is a hypoxia-activated prodrug designed to release the bis-alkylating DNA crosslinker bromo-isophosphoramide mustard (Br-IPM) when reduced in severe hypoxia. In a Phase 1/2 study (NCT00743379) that included a single arm evofosfamide in combination with pemetrexed in 18 patients with relapsed/refractory non-squamous NSCLC, median PFS was 7.0 months and median OS was 14.9 months. Response in 15 evaluable patients: 6 partial responses (4 confirmed), 6 stable disease and 3 progressive disease. The most common adverse events were fatigue, anemia, stomatitis and nausea.

Methods:
An international, multicenter, randomized, double-blind, placebo-controlled trial was initiated to evaluate evofosfamide in combination with pemetrexed versus placebo and pemetrexed as a potential second-line treatment for patients with non-squamous NSCLC (NCT02093962). Approximately 440 patients will be enrolled with histologically confirmed stage IIIB or IV NSCLC with non-squamous histology, measurable disease according to RECIST 1.1, and ECOG performance status 0-1. Eligible patients have recurrent or progressive disease after one prior platinum-based non-pemetrexed chemotherapy treatment for advanced disease with or without maintenance. EGFR-activating and ALK rearrangements status must be known, and if identified, patients must have received a targeted kinase inhibitor. Evofosfamide (400 mg/m[2]) or matched placebo is administered by IV infusion over 30 - 60 minutes on Day 1 and Day 8 of a 21-day cycle. Pemetrexed (500 mg/m[2]) is administered by IV infusion 2 to 4 hours after evofosfamide administration on Day 1. Overall survival (OS) is the primary endpoint; secondary endpoints include safety, progression-free survival and RECIST response rate. The study design has 85% power to detect a 40% improvement in OS with a one-sided alpha of 0.025. The first patient was enrolled in June 2014; recruitment is ongoing.

Results:
not applicable

Conclusion:
not applicable

Background:
Platinum-based chemotherapy with or without maintenance therapy is the standard of care for treatment-naive non-small cell lung carcinoma (NSCLC) that lacks EGFR sensitizing mutations and ALK translocations. The PD-1 pathway is frequently used by tumors to evade an immune response. Pembrolizumab (MK-3475), an anti–PD-1 monoclonal antibody, has demonstrated manageable toxicity and promising antitumor activity in patients with treatment-naive NSCLC enrolled in the phase 1b KEYNOTE-001 study. In this study, a relationship between increased tumor PD-L1 expression and improved pembrolizumab antitumor activity was observed. KEYNOTE-042 (ClinicalTrials.gov identifier NCT02220894) is a randomized, open-label, international, phase 3 study designed to compare the efficacy and safety of pembrolizumab with those of platinum-doublet chemotherapy as first-line therapy for PD-L1–positive advanced NSCLC.

Methods:
Eligibility criteria include age ≥18 years, advanced NSCLC without EGFR sensitizing mutations or ALK translocation, no prior systemic chemotherapy, PD-L1 expression in ≥1% of tumor cells, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1. Patients are randomly assigned in a 1:1 ratio to a 200-mg fixed dose of pembrolizumab every 3 weeks (Q3W) or investigator’s choice of carboplatin AUC 5 or 6 plus paclitaxel 200 mg/m[2] Q3W or carboplatin AUC 5 or 6 plus pemetrexed 500 mg/m[2] Q3W. Randomization is stratified by ECOG PS (0 vs 1), histology (squamous vs nonsquamous), region (East Asia vs non-East Asia), and PD-L1 expression (strong [staining in ≥50% of tumor cells] vs weak [staining in 1%-49% of tumor cells], as assessed by immunohistochemistry at a central laboratory). Pembrolizumab will be continued for 35 cycles or until disease progression, intolerable toxicity, or investigator decision; treatment may be continued beyond initial radiographic disease progression in eligible patients. Discontinuation of pembrolizumab is permitted for patients who experience a complete response confirmed on a follow-up scan performed ≥4 weeks after initial observation. Chemotherapy will be given for a maximum of 6 cycles and may be followed by optional pemetrexed 500 mg/m[2] Q3W maintenance therapy in patients with nonsquamous histology. Adverse events will be collected throughout the study and for 30 days (90 days for serious adverse events) thereafter and graded per NCI CTCAE v4.0. Response will be assessed every 9 weeks per RECIST v1.1 by independent central review. Patients will be followed for survival every 2 months. Primary end point is overall survival in the PD-L1–strong-positive stratum; secondary end points are progression-free survival in the strong-positive stratum and progression-free and overall survival in all patients. Enrollment is ongoing and will continue until approximately 1240 patients have been allocated to study treatment.

Results:
Not applicable.

Conclusion:
Not applicable.

Background:
Treatments that improve overall survival (OS) in advanced NSCLC are urgently needed. Docetaxel (DOC) is recommended as 2[nd]-line chemotherapy for advanced NSCLC, with a median OS of 7-8 months. The chaperone protein clusterin (CLU) is upregulated in NSCLC and other cancers in response to anticancer therapies. Custirsen (OGX-011) is a second-generation antisense oligonucleotide that inhibits CLU expression, enhances chemotherapeutic activity, and in vivo has reversed DOC resistance. In early phase studies in metastatic castration resistant prostate cancer (mCRPC), custirsen plus DOC was well tolerated and showed encouraging results. In a phase 3 mCRPC study (SYNERGY), 50% of patients defined as poor prognosis had survival benefit from custirsen when added to 1[st]-line DOC.

Methods:
ENSPIRIT was initiated September 2012. Eligible patients in this phase 3, multinational, open-label trial have failed 1 prior line of platinum (PT)-based therapy, have an ECOG of 0-1, and adequate bone marrow, renal, and liver function. Randomization is 1:1, with stratification by gender, NSCLC histology, best response to 1[st]-line PT therapy (response/stable disease vs progression), and ECOG score. Patients receive 21-day cycles of DOC (75 mg/m[2] IV day 1) or DOC plus custirsen (640 mg IV/wk, preceded by 3 doses during a 9-day loading period) until progressive disease, unacceptable toxicity, or withdrawal. The primary efficacy measure is OS. Two interim analyses are planned for stopping the trial based on inadequate evidence of clinical benefit or futility; the first futility analysis was completed in August 2014. A recent amendment changed the hypothesized hazard ratio for the primary analysis from 0.80 to 0.75 (power remains at 90%), resulting in a required sample size of 700 patients (instead of original 1100). In addition, the second futility has a more rigorous criterion for stopping due to survival futility and is to occur earlier than originally planned. The study will not be stopped early for efficacy. The aim of the ENSPIRIT amendment is to assess for a more clinically relevant survival benefit when adding custirsen to 2[nd]-line DOC or terminate the trial early for survival futility.

Results:
Not applicable.

Conclusion:
Not applicable.

Background:
Patients with squamous cell (SCC) non-small cell lung cancer (NSCLC) may be at risk of poorer outcomes and have fewer treatment options than those with other histologies. Furthermore, no randomized studies have demonstrated the benefit of maintenance therapy in these patients. In a phase III trial, first-line treatment with nab-paclitaxel plus carboplatin (nab-P/C) demonstrated a 68% improvement in the overall response rate (ORR; 41% vs 24%; P < 0.001) and a trend toward improved overall survival (OS; median, 10.7 vs 9.5 months; HR 0.890; P = 0.310) compared with solvent-based paclitaxel plus C in a subset of patients with advanced SCC NSCLC (Socinski et al. Ann Oncol. 2013;24:2390-2396). An exploratory analysis of the phase III trial demonstrated that therapy with nab-P/C beyond 4 cycles of first-line treatment was effective in the subset of patients with SCC NSCLC who did not progress (from the time of randomization, median progression-free survival [PFS] and OS were 6.8 and 13.8 months, respectively), and no new safety signals were noted (Socinski et al. IASLC 2013 [abstract 3438]). In the open-label, multicenter phase III ABOUND.sqm trial, the efficacy and safety of nab-P maintenance therapy after nab-P/C induction therapy will be evaluated in patients with advanced SCC NSCLC.

Methods:
During the induction part of the study, approximately 540 patients will be treated with 4 cycles of nab-P 100 mg/m[2] intravenously (IV; 30-minute infusion) on days 1, 8, and 15 plus IV C AUC 6 on day 1 every 21 days. Patients with a complete response (CR), a partial response (PR), or stable disease (SD) will be eligible for maintenance. In the maintenance part of the study, approximately 260 patients will be randomized 2:1 to nab-P 100 mg/m[2] on days 1 and 8 every 21 days plus best supportive care (BSC) or BSC alone until disease progression. Patients will be stratified by disease stage (IIIB vs IV), response to induction therapy (CR/PR vs SD), and ECOG performance status at the end of induction (0 vs 1). Key eligibility criteria include histologically or cytologically confirmed stage IIIB/IV SCC NSCLC, no prior chemotherapy for metastatic disease, ECOG performance status ≤ 1, adequate organ function, no active brain metastases, and preexisting peripheral neuropathy grade < 2. ClinicalTrials.gov identifier NCT02027428.

Key Endpoints
Primary	PFS from randomization into the maintenance part of the study
Secondary	Safety OS from randomization into the maintenance part of the study ORR during the induction and maintenance parts of the study
Exploratory	Correlation between pretreatment tumor characteristics and response to treatment Association between changes in tumor characteristics and acquisition of resistance to therapy at the time of treatment failure during maintenance Correlation between genetic polymorphisms and treatment efficacy and/or toxicity Healthcare resource utilization during the maintenance part of the study Changes in quality of life

Results:
Not applicable.

Conclusion:
Not applicable.

Background:
Patients harboring epidermal growth factor receptor (EGFR)-mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) invariably develop acquired resistance (AR). The mechanisms of AR are unknown in 30–40% of patients. In pre-clinical studies, insulin-like growth factor (IGF) signaling has been implicated in AR to EGFR TKIs in the absence of other known mechanisms including T790M mutation. It is hypothesized that an EGFR TKI combined with an IGF inhibitor can overcome this resistance. BI 836845 is a fully human, affinity-optimized, IGF ligand-neutralizing antibody. BI 836845 binds to IGF-1 and IGF-2 and neutralizes growth-promoting signaling. Preliminary results from two Phase I studies have shown a tolerable safety profile. This trial was designed to evaluate the safety and anti-tumor activity of BI 836845 combined with afatinib in patients with EGFR-mutated NSCLC progressing following prior treatment with reversible or irreversible EGFR TKIs.

Methods:
This is an open-label, dose-escalation trial in Korea, Taiwan and Singapore (NCT02191891; Study 1280.16) consisting of a dose confirmation part (Part A) followed by an expansion part (Part B). Eligible patients are aged ≥18 years with advanced and/or metastatic NSCLC progressing during continuous treatment with single-agent EGFR TKI ≤30 days immediately prior to study treatment, with documented presence of an activating EGFR mutation and lacking an EGFR T790M mutation (confirmed by central testing in Part B). Patients with prior afatinib treatment at a dose below the assigned dose level (Part A only) or <30 mg/day (Parts A and B), or disease progression on an insufficient dose of EGFR TKI immediately prior to study in the investigator’s opinion, or >2 (Part A) or >1 (Part B) prior EGFR TKI treatment regimens for relapsed or metastatic NSCLC are excluded. Part A follows a 3+3 design to determine the MTD and/or recommended Phase 2 dose (RP2D) of BI 836845 combined with afatinib (starting dose: BI 836845 1000 mg/week intravenous infusion over 60 minutes plus oral afatinib 30 mg/day administered in 4-week courses). Patients receive continuous treatment until disease progression, intolerable adverse events (AEs), consent withdrawal or non-compliance with the study protocol. Patients are entered sequentially into escalating/de-escalating dose tiers to determine the MTD based on the occurrence of dose-limiting toxicities (DLTs) during Course 1 (3–6 patients per cohort); 6 additional patients will be enrolled in an extension cohort at the R2PD. Part B consists of two separate expansion cohorts of patients previously treated with irreversible EGFR TKIs (e.g. afatinib, dacomitinib; Cohort 1) and those previously treated with reversible EGFR TKIs (gefitinib or erlotinib; Cohort 2). In each cohort, 18 patients will be treated with the RP2D determined in Part A. Primary endpoints are the MTD and DLTs during Course 1 (Part A) and the objective response assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Part B). Secondary endpoints include disease control, time to objective response, duration of objective response, and pharmacokinetic parameters. AEs are evaluated according to Common Terminology Criteria for AEs (CTCAE) v4.03. All analyses will be descriptive and exploratory.

Results:
Not applicable.

Conclusion:
Not applicable.

Background:
Plinabulin (BPI-2358) is a marine derived tubulin binding agent, which inhibits existing tumor vasculature and directly induces cancer cell apoptosis via the Ras-JNK pathway. Additional effect of inducing dendritic cell maturation is also observed. Phase 1/2 randomized clinical trial of Docetaxel + Plinabulin (DP) compared to Docetaxel (D) alone failed to show improvement in OS in an ITT analysis. The median OS was 8.6 months in DP, and 7.5 months in D arm. (HR 0.97, P=0.90). However, post hoc subset analysis showed improvement in OS in patient with pulmonary tumors >3 cm regardless of number of prior therapy for metastatic disease. In this population, OS was 11.47 (7.13, 16.73) months vs. 7.10 (4.06, 10.60) in DP vs D arm (HR 0.76 and P=0.36). Mechanistically it is postulated that those patients are more dependent on angiogenesis. This phase 3 protocol is designed to test the hypothesis generated from the subset analysis.

Methods:
This is a randomized phase 3, open label clinical trial comparing DP at 75 mg/m2 of D on day1 and 30 mg/m2 of P on days 1 and 8 to D alone at 75 mg/m2 on day 1 in a 21-day cycle. Randomization stratified by ECOG performance status and region. Study population: patients with metastatic with non small cell lung cancer ( NSCLC), who has failed one line of chemotherapy and have at least one lung lesion larger than 3 cm. Primary endpoint of the study is to compare overall survival (OS) between two arms. Secondary endpoints are Progression free survival (PFS), overall response rate (ORR), duration of response (DOR), and adverse event profile. Planned number of subjects 550 (440 from China and 110 from the US). Primary outcome analysis is planned after 434 death events which will provide a 0.85 power to detect a statistically significant treatment effect using a two-sided log-rank test at a significance level of α = 0.05.

Results:
Not applicable, trial in progress.

Conclusion:
not applicable