Virtual Library

Background:
Anlotinib hydrochloride, a novel multi-targeted tyrosine kinase inhibitor (TKI) was found to exhibit excellent inhibitory efficiency on a variety of receptor tyrosine kinases (RTK) involved in tumor progression, especially the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and stem cell-factor receptor (c-Kit). This ongoing trial aimed at evaluating the efficacy and safety of anlotinib hydrochloride comparing with placebo in advanced NSCLC patients who had received at least two previous chemotherapy and EGFR/ALK targeted therapy regimens.

Methods:
This Phase III, randomized, double-blind, placebo-controlled study (NCT 02388919) is ongoing in 31 centers in China under the supervision of Independent Data Monitoring Committee (IDMC). Pathological stage IIIB/IV adult advanced NSCLC patients (Pts) who had failed with at least two previous chemotherapy and EGFR/ALK targeted therapy regimens were eligible. The status of EGFR and ALK genes should be clear in all enrolled pts. Pts with sensitive EGFR or ALK mutations must had received and appeared intolerance to pervious targeted therapies. Pts were randomized (2:1) to receive Anlotinib hydrochloride or placebo once daily (12 mg) from day 1 to 14 of a 21-day cycle until progression. Dose reduction to 8 or 10 mg/day could be applied when grade 3 or 4 treatment-related toxicities were observed. The minimal sample size was estimated to 450 patients. The primary endpoint is overall survival (OS) and second endpoints are progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR) and quality of life (QoL). Quality of life was assessed via EORTC QLQ-C30, safety is determined using standard NCI-CTCAE v4.02, and responses are evaluated according to RECIST v1.1.

Results:
This study started in February 2015, up to early July 2016, a total of 420 pts have been enrolled (93.3 % of 450 pts). Among enrolled pts, about 80 % were diagnosed as adenocarcinoma, EGFR mutation or ALK rearrangement was found in 1/3 of the pts. The overall analyses will start after 300 OS events.

Conclusion:
Anti-angiogenesis is the main mechanism of Anlotinib hydrochloride for preventing the tumor progression. Results of randomized, placebo-controlled Phase II trial (NCT01924195) has been reported in WCLC 2015, however, advantages in PFS (4.8 vs. 1.2 months) and OS (9.3 vs. 6.3 months) were observed in Anlotinib arm from the renewed data. Based on these exciting data, we are looking forward for the results of the Phase III trial

Background:
Chemotherapy is standard of care for patients with metastatic SCC. There is limited information on the use and outcome of patients with metastatic SCC who receive chemotherapy. We used the National Cancer Data Base (NCDB) to investigate the use and survival of patients receiving chemotherapy for stage IV SCC.

Methods:
The NCDB was queried for patients≥ 18 years, diagnosed with stage IV SCC between 2004-2013 for whom chemotherapy data was available. The percentage of patients receiving chemotherapy within 2 months of diagnosis was calculated. Patients were stratified by age (<50, 50-70 and >70 years), Charlson-Deyo comorbidity score (0, 1 and 2), gender, and period of diagnosis (2004-2006, 2007-2009, 2010-2012) to evaluate patterns of chemotherapy use. Median, 1-year and 2-year OS were calculated for patients that received chemotherapy using Kaplan Meier method.

Results:
Among the 86,200 patients that met the eligibility criteria, 40,147 (46.6%) patients received chemotherapy, which included single agent (n=3,912; 9.7%) multiagent (n=32,737;81.5%) and number of agents unknown (n=3,498;8.7%). A total of 46,053 (53.43%) patients did not receive chemotherapy due to chemotherapy not recommended (n=5,397; 11.7%), patient refusal (n=6,119; 13.3%) and other/unknown reasons (n=34,537; 75%). Patients receiving multi-agent chemotherapy were younger than those receiving single agent chemotherapy (65.6 vs 71.5 years). Chemotherapy use declined with increase in comorbidity score (50.4% for score of 0, 44% for score of 1 and 36.2% for score of 2). The median, 1-year and 2-year OS for patients receiving chemotherapy were 7.5 months, 30.6% and 11.8% respectively (Table).

OS for patients receiving chemotherapy by risk factor

Risk factor		Median survival (months)	1 year OS	2 year OS
Age	<50	7.6	29.7%	11.5%
	50-70	7.8	32.0%	12.4%
	>70	7.0	28.5%	10.8%
Gender	Male	7.3	29.0%	10.7%
	Female	7.9	33.7%	13.8%
Year of diagnosis	2004-2006	7.3	28.8%	10.7%
	2007-2009	7.5	31.0%	11.8%
	2010-2013	7.7	31.6%	12.7%
Charlson-Deyo comorbidity score	0	8.0	32.6%	12.7%
	1	7.1	28.4%	10.6%
	2	6.3	24.9%	9.2%
All patients		7.5	30.6%	11.8%

Conclusion:
Most patients with metastatic SCC do not receive chemotherapy. The OS for patients with metastatic SCC remains poor, especially in patients over the age of 70, in men and those with multiple comorbidities.

Background:
Belinostat is a potent inhibitor of the enzyme histone deacetylase (HDAC), which influences chromatin accessibility through altering acetylation levels of histone and non-histone proteins. Belinostat may enhance the antitumor activity of carboplatin and paclitaxel. We conducted a phase 1 clinical trial of belinostat in combination with carboplatin and paclitaxel in chemotherapy-naive patients with stage IV NSCLC.

Methods:
This was a multicenter phase 1 open label study of belinostat in combination with carboplatin and paclitaxel in chemotherapy-naïve patients with histologically or cytologically confirmed Stage IV NSCLC, PS 0-1. A standard 3+3 dose escalation design was used to determine the primary endpoint of maximum tolerated dose (MTD) of belinostat administered intravenously on days 1-5 of a 21 day cycle in combination with carboplatin (AUC 6) and paclitaxel 200mg/m2 intravenously on day 3 of each cycle for up to 6 cycles. MTD was defined as the dose at which fewer than 2 of 6 patients experienced protocol defined dose-limiting toxicities (DLT) during cycle 1. Maintenance belinostat was allowed after sponsor approval. The starting dose of belinostat was 1000mg/m2. Secondary endpoints were safety and tolerability, progression free survival (PFS) and objective response rate (ORR) of the combination regimen.

Results:
Twenty three patients were enrolled and treated at the following belinostat levels: 1000 mg/m2 (n=5), 1200 mg/m2 (n=6), 1400 mg/m2 (n=6), 1600 mg/m2 (n=6). At the dose of 1600 mg/m2, 2 of 6 patients experienced DLTS (grade 3 syncope and grade 3 hypotension) and 1400 mg/m2 was determined as the belinostat MTD. Median cycles of belinostat: 10, 7, 5.5 and 4, median cycles of chemotherapy 6, 6, 5.5 and 4 in each of the four cohorts respectively. The most frequent adverse events (all grades) were fatigue (91%), nausea (78%), constipation (74%) anemia and diarrhea (65%) alopecia, arthralgia, decreased appetite, insomnia and neutropenia (61%) dizziness and vomiting (57%) and headache (52%). Median PFS was 5.7 months (95% CI: 2.8, 8.8). 13/23 patients had available response data at the end of cycle 6 with ORR of 35%. The responses observed were partial response in 8 patients (35%), stable disease in 4 patients (17%) and progressive disease in 1 patient (4%). Two patients with partial response at cycle 6 continued on belinostat maintenance and later achieved a complete response.

Conclusion:
The combination of belinostat and carboplatin and paclitaxel is feasible with observed toxicities consistent with expected side effect profile. Preliminary antitumor activity of this combination was also demonstrated.

Background:
The effect of palliative chemotherapy for non-small cell lung cancer (NSCLC) is well established. However, little is known on the efficacy of cytotoxic chemotherapy in patients whose tumors are refractory to first-line chemotherapy. We analyzed the outcome of all consecutive and unselected patients receiving palliative chemotherapy in a single institution to assess the efficacy of second-line chemotherapy in primary refractory NSCLC.

Methods:
462 consecutive patients with palliative treatment for NSCLC at the University Hospital Basel between 1990 and 2009 were analyzed. Measured outcomes were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Patients with progressive disease (PD) as best response to first-line treatment were compared to patients with stable disease (SD), partial (PR) or complete remission (CR). Chi-square test was used for discrete, and Mann Whitney U tests for continuous variables, respectively. Probabilities of survival were calculated using the Kaplan-Meier estimator. The log-rank test was used for comparing groups.

Results:
Median age was 63 years, 71% were male, 81% were smokers and 53% had adenocarcinoma. Median OS of the whole cohort was 11.3 months. 62.3% of patients were treated with a platinum-based (48.3% cisplatin-based) first-line therapy. Median PFS for first-line therapy was 3.0 months. 192 patients (41.6%) were primary refractory on first-line therapy. Median OS was significantly shorter for refractory patients compared to patients with CR, PR or SD (9.2 vs. 14.5 months, p<0.0001). Poorer initial performance status was significantly associated with primary refractory disease (p=0.015). All other baseline characteristics did not differ between refractory and responding patients. 67 (35%) primary refractory patients received a second-line therapy. The clinical benefit rate (CR+PR+SD) from second-line therapy was lower in primary refractory patients (33.9% vs. 43.5%, p=0.023). Median PFS for second-line therapy was shorter for primary refractory patients (2.2 vs. 4.6 months, p=0.26). Median OS was significantly longer for refractory patients receiving second-line chemotherapy vs. best supportive care (13.6 vs. 5.5 months, p<0.0001).

Conclusion:
More than 40% of patients are primary refractory to palliative first-line therapy. These patients have a poor prognosis. However, active second-line chemotherapy can significantly improve the outcome compared to best supportive care. Median OS for patients receiving second-line chemotherapy was close to patients with initial response or stable disease. Patients with primary refractory NSCLC should be offered further active therapy. These real life data for primary refractory patients form the basis against which immunotherapies, the current standard second line treatment, can be compared.

Background:
To observe the efficacy and safety of recombinant human endostatin (Endostar) combined with single-agent gemcitabine in the first-line treatment of the elderly patients with advanced non-small cell lung cancer (NSCLC)

Methods:
A total of 118 elderly patients with advanced NSCLC confirmed by pathology in Fuzhou Pulmonary Hospital ofFujian from Oct., 2007 to Sep., 2012 were randomly divided into treatment group and control group. Treatment group (n=62) was given the regimen of Endostar combined with single-agent gemcitabine, while control group only given the regimen of single-agent gemcitabine. After two cycles of chemotherapy, the efficacy was evaluated according to RECIST, and median time to tumor progression, median survival and 1-year survival rate in two groups were recorded. Besides, adverse reactions were evaluated every cycle based on NCICTC (version 3.0).

Results:
Sixty-two patients in treatment group completed more than two cycles of Endostar combined with chemotherapy.There were 11 cases with partial remission (PR), 36 with stable disease (SD)and 15 with progressive disease (PD). There was no statistical significance between two groups by comparison to the overall response rate (ORR) (17.7% vs.10.7%, P=0.278), but significant differences were presented by comparison to the disease control rate (DCR) (75.8% vs. 57.9%, P=0.031) and median progression-free survival (mPFS) (4.0 months vs. 3.7 months, P=0.027). Compared with the median overall survival (mOS), there was no statistical significance(9.1 months vs. 8.5 months, P=0.418). The incidence of myelosuppression among adverse reactions was higher, main in phase G~1/2~ and G~3/4~. In the aspect of hematotoxicity, non-hematotoxicity and biochemical indexes, there was also no statistical significance between two groups (P>0.05).

Conclusion:
Endostar combined withsingle-agent gemcitabine has certain anti-tumor activity, better DCR and highersafety as well as clinical benefit rate for elderly patients with advanced NSCLC, which may be a promising regimen for the elderly patients with advanced NSCLC.

Background:
Focusing on median progression free and overall survival does not fully inform us, or our patients, of the maximum achievable benefit found at the tail end of the survival curve (Hellman M, JAMA Oncology 2016). Milestone metrics in this context may be more informative; however, mature data are scarce. Our anecdotal observations suggested that some of our non-squamous NSCLC pts treated with pemetrexed continuation maintenance had long-term disease control beyond the reported median PFS. The objective of our single institution retrospective study was to determine the % of patients who reach the 2 year PFS milestone in patients whose treatment plan included continuation pemetrexed maintenance. Evaluation of the potential predictive value of clinical parameters was a secondary objective.

Methods:
Pts with stage IV NSCLC who received at least once cycle of pemetrexed/platinum with planned pemetrexed maintenance (N = 241) between May 2010 and December, 2013 were included in this retrospective analysis. Minimum follow up for every patient was > 24 months. Patient demographics, routine laboratory values, first and last dates of pemetrexed therapy, and date of progression were collected. Pts were grouped according to duration of disease control ≥24 months vs < 24 months. Potential associations between patient demographics and comparison of laboratory values for the two groups were assessed using a Mann-Whitney-Wilcoxon test.

Results:
Median age 66, male/female 40.25%/59.75%, 21% never smoker. The median progression free survival was 6.2 months. 34 pts (14.1%) had no progression of disease at ≥24 months since starting treatment with pemetrexed/platinum followed by pemetrexed maintenance. A PFS ≥24 months was associated with a lower baseline neutrophil/lymphocyte ratio (NLR) (median 3.3 vs 4.55; 25-75 percentile 2.32-3.94 vs 2.8-7.89; p=0.0011). PS at baseline was also significantly associated with a PFS≥24 months (p=0.02). Long term PFS was not significantly related to gender, age, sites of metastases, or number of disease sites.

Conclusion:
Considering that the two year OS rate for first line chemotherapy in clinical trials is approximately 25%, the 2 year PFS milestone rate of 14.1% patients is encouraging. Significantly lower baseline NLR, was observed in patients who reached the two year PFS milestone. Studies evaluating the potential predictive value of other clinical and molecular parameters are ongoing.

Background:
To evaluate the efficacy and safety of pemetrexed, carboplatin and bevacizumab (PCB) followed by maintenance pemetrexed and bevacizumab (PB) in chemotherapy-naïve patients with stage IV non-squamous non-small cell lung cancer (NSCLC) through the influence of thymidylate synthase (TS), ERCC1 and VEGF mRNA expression on several outcomes. The primary endpoints were the overall response rate (ORR), progression-free survival (PFS) and overall survival (OS).

Methods:
Patients were administered pemetrexed (500 mg/m2), carboplatin (AUC, 5.0 mg/ml/min) and bevacizumab (7.5 mg/kg) intravenously every three weeks for up to four cycles. Maintenance pemetrexed and bevacizumab was administered until disease progression or unacceptable toxicity.

Results:
One hundred forty-four Hispanic patients with a median follow-up of 13.8 months and a median number of maintenance cycles of 6 (range, 1- 32) were assessed. The ORR among the patients was 66% (95% CI, 47% to 79%). The median progression-free and overall survival (OS) rates were 7.9 months (95% CI, 5.9-10.0 months) and 21.4 months (95% CI, 18.3 to 24.4 months), respectively. Median TS, ERCC1 and VEGF mRNA levels were 1.45 (range, 0.17–2.52), 0.58 (range, 0.44-1.20), and 2.72 (range, 1.84-3.21), respectively. OS was significantly higher in patients with the lowest TS mRNA levels [29.6 months (95%CI 26.2-32.9) compared with those with higher levels 9.3 months (95%CI 6.6-12.0); p=0.0001]. ERCC1 mRNA levels also influenced the OS [median for ERCC1 mRNA˂0.58 28.7 months (95%CI 26.3-31.2) vs. ERCC1 mRNA˃0.58 11.1 months (95%CI 9.6-12.7); p=0.0001] as well as VEGF mRNA levels [median OS for VEGF mRNA˂2.72 26.4 months (95%CI 22.8-30.0) vs. VEGF mRNA˃2.72 18.2 months (95%CI 8.4-27.9); p=0.009]. TS mRNA did not influence treatment response, however the ORR was significantly higher in patients with low levels of ERCC1 (p = 0.003) and elevated VEGF (p = 0.005). Multivariate analysis found that TS mRNA levels (p=0.0001), VEGF mRNA levels (p=0.007) and PS (p=0.014) were independent prognostic factors.

Conclusion:
Overall, PCB followed by maintenance pemetrexed and bevacizumab was in Hispanic patients with non-squamous NSCLC. This regimen was associated with prolonged OS, particularly in patients with low TS, ERCC1 and VEGF mRNA expression. These biomarkers alone or in combination may be useful to assess the prognosis of patients with NSCLC treated with CBP/Pem/Bev.

Background:
For patients with advanced NSCLC, chemotherapy dose reductions/delays are commonly used to manage toxicities. However, there is limited information on the relationship between relative dose intensity (RDI) and survival in metastatic NSCLC. Objective: Describe the relationship between RDI and survival in patients with NSCLC in a US community oncology practice setting.

Methods:
This was a retrospective study using the McKesson Specialty Health/US Oncology iKnowMed[SM] electronic health record database. Inclusion criteria: Patients with advanced (stage III/IV) NSCLC who initiated first-line, intravenous, myelosuppressive chemotherapy between January 2007 and December 2010. Endpoints: Mean RDI (a composite measure including both dose delays and dose reductions), RDI <85%, and incidences of dose delays ≥7 days and dose reductions ≥15% in any chemotherapy cycle. Dosing analysis covered a period up to 6 months after chemotherapy initiation. Univariable and multivariable analyses for survival were conducted using Cox proportional hazard regression.

Results:
Overall, 3866 patients with NSCLC were included; the most common chemotherapy regimens included carboplatin/taxol (n=1733), pemetrexed/carboplatin (n=789), and bevacizumab/carboplatin/taxol (n=734). 709 (18.3%) received colony-stimulating factor primary prophylaxis. The mean (SD) RDI was 83.9% (28.5%), the incidence of RDI <85% was 40.4%, and the incidence of dose delays ≥7 days and dose reductions ≥15% were 32.4% and 50.1%, respectively. Univariable analysis suggested that dose delay ≥7 days was associated with a 22.4% reduction in the risk of death (P<0.0001). Multivariable analysis suggested that RDI and dose delay were significant predictors of survival after controlling for covariates. RDI <85% and dose delay ≥7 days were associated with a 17.6% increase and a 29.0% reduction in risk of death, respectively (Table).

Conclusion:
Reduced RDI and chemotherapy dose delays were common in advanced NSCLC and significantly associated with survival in a multivariable analysis. Understanding the complex effect of dose intensity on outcomes will be important for managing toxicities and improving survival.

Table. Multivariable Cox Regression Analysis for Overall Survival for Patients with Lung Cancer
Variable		HR (95%CI)		P Value
RDI <85% (reference: ≥85%)		1.176 (1.047–1.320)		0.0062
Dose delay ≥7 days (reference: <7 days)		0.710 (0.630–0.800)		<0.0001
ECOG performance status (reference: status of 0)
1		1.316 (1.192–1.453)		<0.0001
2		1.654 (1.350–2.027)		<0.0001
Hemoglobin <12 g/dL (reference: ≥12 g/dL)		1.098 (0.993–1.213)		0.0686
Tumor subgroups (reference: squamous)
Adenocarcinoma		0.783 (0.698–0.877)		<0.0001
Other		0.932 (0.725–1.199)		0.5855
ECOG=Eastern Cooperative Oncology Group; HR=hazard ratio; RDI=relative dose intensity.

Background:
The concept of “oligometastasis” has emerged as a basis on which to identify patients with stage IV non–small cell lung cancer (NSCLC) who might be most amenable to curative treatment. Although such patients without regional lymph node metastases tend to have a longer overall survival (OS) than those with regional lymph node involvement, limited data have been available regarding the survival of patients with node-negative oligometastatic NSCLC. We have therefore now evaluated the clinical outcome of stage IV node-negative oligometastatic NSCLC.

Methods:
Consecutive patients with advanced NSCLC who attended Kindai University Hospital between January 2007 and January 2016 were recruited to this retrospective study. Patients with regional lymph node–negative disease and a limited number of metastatic lesions (≤5) per organ site and a limited number of affected organ sites (1 or 2) were eligible.

Results:
Eighteen patients were identified for analysis during the study period. The most frequent metastatic site was the central nervous system (CNS, 72%). Most patients (83%) received systemic chemotherapy, with only three (17%) undergoing aggressive surgery, for the primary lung tumor. The CNS failure sites for patients with CNS metastases were located outside of the surgery or radiosurgery field. The median OS for all patients was 15.9 months, with that for EGFR mutation–positive patients tending to be longer than that for EGFR mutation–negative patients.

Conclusion:
Our results indicate that a cure is difficult to achieve with current treatment strategies for NSCLC patients with synchronous oligometastases, although a few long-term survivors and a smaller number of patients alive at last follow-up were present among the study cohort. There is an urgent clinical need for prospective evaluation of surgical resection as a treatment for oligometastatic NSCLC negative for driver mutations.

Background:
Lung cancer is the number one cause of cancer-related death. 80% of patients present with advanced disease, and first line standard of care is multi-agent chemotherapy; however, overall 2-year survival is only 15%. Metformin, a well-tolerated oral biguanide used in diabetes, is thought to have anti-cancer effects via a variety of proposed mechanisms.

Methods:
This is a single-arm study with a randomized control arm for reference to expected 1-year progression-free survival (PFS), the primary endpoint, defined as the proportion of patients alive without disease progression at 1 year of treatment. Non-diabetic, chemotherapy-naïve patients with advanced non-squamous NSCLC were randomized 3:1 to Arm A:Arm B. (NCT01578551) Arm A consisted of standard doses of paclitaxel, carboplatin, bevacizumab (PCB) and metformin (M; 1,000 mg PO BID) x 4-6 cycles, followed by bevacizumab (B) + M until disease progression. Arm B consisted of standard doses of PCB x 4-6 cycles, followed by B until disease progression.

Results:
The study enrolled 19 patients to Arm A and 6 patients to Arm B. 37% of Arm A patients and 33% of Arm B patients were male. Median age was 58 years (range: 37-64) in Arm A and 64 years (range: 55-70) in Arm B. One-year PFS for Arm A was 0.47 (95% CI: 0.25, 0.88). The 95% CI lower bound exceeded 15%, the hypothesized 1-year PFS without metformin. All Arm B patients either progressed or were off study treatment prior to 1 year. Median PFS (Figure) was statistically significantly better for Arm A patients (9.6 months; 95% CI: 7.3 months, Not Reached (NR)) than Arm B patients (6.7 months; 95% CI: 4.4 months, NR). Figure 1



Conclusion:
The addition of metformin to standard first-line PCB was well-tolerated and significantly improves PFS in chemotherapy-naïve advanced non-squamous NSCLC patients. Further study of the addition of metformin to treatment in NSCLC patients is needed.

Background:
A major challenge in advanced non-small cell lung cancer (NSCLC) remains the identification of predictors of clinical benefit from pemetrexed. Total systemic exposure to pemetrexed and its metabolites could be predictive for progression-free and overall survival (PFS/OS). However, sampling times in population pharmacokinetic (PK) analyses of pemetrexed are limited. We performed population PK modeling of pemetrexed during total treatment period and evaluated total systemic exposure as a predictor.

Methods:
In a prospective observational multi-center study, treatment-naive patients with stage IIIB or IV NSCLC receiving pemetrexed/platinum treatment were enrolled. Pemetrexed, dosed based on body surface area (500mg/m[2]), was administered as a 10-minute intravenous infusion every 21 days. Prior to and weekly after each pemetrexed administration, plasma sampling was performed (cycle-PK). Simultaneously, glomerular filtration rate (GFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboriation (CKD-EPI) formula. In a subgroup, blood samples were collected at 10, 30 minutes and 1,2,4, 8, 24 hours after start of pemetrexed infusion (24-hour-PK). We used a recently validated assay to quantify plasma pemetrexed concentrations (Stoop et al, J Pharm Biomed Anal 2016;128:1-8). Population PK analyses were performed using nonlinear mixed effects modeling (NONMEM version 7.2). The final model, based on both cycle-PK and 24-hour-PK, was used to estimate the area under the plasma concentration versus time curve during cycle 1 (AUC~cycle~). With a Cox-regression analysis we examined the relation between AUC~cycle~ and OS/PFS, adjusted for known prognostic factors (sex, disease stage, WHO performance-score).

Results:
For 97 of the 151 patients, concentrations of pemetrexed were quantified (24-hour-PK, n=15; cycle-PK, n=82). A two-compartment model parametrized (population estimate (%standard error of the estimate) in terms of clearance (CL; 5.44L/h (14.9%)), central distribution volume (V~1~; 19.6L (11.3%)), peripheral distribution volume (V~2~; 173L (32.7%)), intercompartimental clearance (Q; 0.19L/h (31.6%)) and incorporated between-patient variability of CL (10.7%), estimated cycle-PK appropriately. GFR and other covariates did not improve the estimation of the parameters. The AUC~cylce ~was significantly different between males (190.8±64.9mg·h/L) and females (165.4±47.2mg·h/L). When we stratified for sex, the highest quartile of AUC independently predicted worse OS (HR=3.06, 95%CI: 1.43-6.57) and PFS (HR=2.79 95%CI: 1.36-5.70), adjusted for the remaining prognostic factors, GFR and pemetrexed dosage.

Conclusion:
Paradoxically worse OS and PFS in patients with high plasma pemetrexed AUC may suggest lower intracellular levels of pemetrexed. Another possibility is that these patients poorly metabolize pemetrexed into its more effective metabolites, which inhibit tumor growth more strongly by prolonged intracellular retention and higher affinity to target enzymes.

Background:
In patients with advanced non-small cell lung cancer (NSCLC) pemetrexed (PEM) is increasingly used as maintenance therapy after induction PEM/platinum treatment. Despite the extensive use of PEM, the incidence of nephrotoxicity during (maintenance) PEM therapy has not been systematically evaluated. Knowledge about nephrotoxicity during PEM-based treatment could determine the need for adapted renal protective strategies. We assessed the occurrence of nephrotoxicity and its influence on treatment continuation in NSCLC patients receiving PEM-based therapy.

Methods:
In a prospective observational multi-center study, treatment-naive patients with stage IIIB or IV NSCLC were enrolled. Patients were treated with PEM-cisplatin (PEMCIS; PEM 500mg/m[2] and CIS 75mg/m[2]) or PEM-carboplatin (PEMCAR; CAR AUC=5). Patients with at least disease stabilization after four cycles and a favorable toxicity profile were eligible for PEM maintenance therapy. Prior to the initial PEM/platinum cycle, baseline serum creatinine (μmol/l) was obtained. Subsequently, prior to and weekly after each administration of PEM(/platinum) serum creatinine was measured. Glomerular filtration rate (GFR) was estimated by the Chronic Kidney Disease Epidemiology Collaboriation (CKD-EPI) formula. Acute kidney disease (AKD) was defined as >1.5-fold increase of serum creatinine and/or decrease in GFR >35% or GFR<60mL/min within 3 months (KDIGO).

Results:
Of the 151 patients starting PEM-based therapy, the majority of patients had stage IV disease (86.8%) and they were treated with PEMCIS (64.2%) or PEMCAR (35.8%). During the first four cycles, treatment was discontinued in four patients (2.6%) due to AKD. Patients starting maintenance therapy (n=44, 29.1%) received a median number of 4 PEM cycles. During maintenance treatment with PEM, 12 patients developed AKD (27.3%): three patients could continue treatment after recovery of renal function and in one patient AKD was a part of septic shock. The remaining eight patients (18.2%) stopped treatment due to renal impairment. From patients with a decreased renal function at baseline (eGFR<90mL/min) a significantly higher proportion of patients stopped maintenance therapy due to renal impairment compared to patients with an eGFR≥90mL/min at baseline (6/11 vs. 2/33, p<0.05).

Conclusion:
Patients have a significant risk of developing nephrotoxicity leading to treatment discontinuation during maintenance therapy, especially if the renal clearance is impaired at the start of induction PEM/platinum therapy. In those patients a cumulative systemic dose of PEM or increased susceptibility may play a role in the development of nephrotoxicity. Patients might benefit from altered renal protective strategies, like continuation of hydration during maintenance therapy or dose-adjustment based on renal function. This study was funded by ZonMw, the Netherlands.

Background:
In Sweden, almost half of the patients diagnosed with lung cancer diagnosis are more than 70 years old and indeed14% were 80 years and older. Treatment of the elderly with lung cancer has, therefore, become an important issue. In the Stockholm county, almost all patients with lung cancer are preferred to Karolinska University Hospital. We performed a retrospective study of our patients to demonstrate how octogenarians with non-small cell lung cancer (NSCLC) treated with chemotherapy responded in real-life clinical practice

Methods:
A retrospective observational study of all elderly (>80 years) patients with NSCLC referred to Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Sweden, 2003-2010 and followed until June, 2016

Results:
In total, 2350 patients were newly diagnosed with lung cancer during this period. 453 (19.2%) were 80 years or older and had NSCLC. Of these 51(11 %) received chemotherapy. In that group, mean and median age was 82 years (range 80-89). 86% were current- och ex-smokers. 70% had PS 0-1, 27% PS 2, and 2% PS 3. 92% had stage III-IV. Adenocarcinoma was the most prevalent histology type (59%) and squamous cell carcinoma was second (24%). 61% received carboplatin/gemcitabine, 8% carboplatin/vinorelbine, 12% gemcitabine only, and 16% vinorelbine only. Most patients (47%) received at least four cycles and another 6% three cycles. Chemotherapy dose reduction/ termination occurred in 12% due to hematologic toxicity, in 18% to non-hematologic toxicities, and in 4% because of progressive disease. In total, therefore, 53% completed their treatment. 59% hade stable disease, 33% partial response, and 9% progressive disease. 22% received second line, 10% third line, but only one patient (2%) 4[th] line treatment. The median overall survival was 281days in male patients and 332 days in females (NS).

Conclusion:
Treatment of elderly NSCLC patients with good PS with chemotherapy is feasible and appears to prolong survival.

Background:
Dysregulation of the JAK/STAT pathway contributes to abnormal inflammatory responses, oncogenesis, treatment resistance, and poor prognosis in NSCLC. This phase 2 clinical trial evaluated the JAK1/JAK2 inhibitor ruxolitinib+pemetrexed/cisplatin as first-line treatment for patients with stage IIIB/IV or recurrent nonsquamous NSCLC and systemic inflammation (per modified Glasgow Prognostic Score [mGPS]).

Methods:
Key inclusion criteria were mGPS of 1/2 and ECOG performance status ≤1. Part 1, an open-label, 21-day safety run-in, assessed ruxolitinib (15 mg BID [chosen dose for Part 2]) plus pemetrexed (500 mg/m[2] IV on Day 1) and cisplatin (75 mg/m[2] IV on Day 1). Ruxolitinib dose selection for Part 2 required <3 dose-limiting toxicities (DLTs) for 9 evaluable patients. Part 2 randomized patients to ruxolitinib+pemetrexed/cisplatin or placebo+pemetrexed/cisplatin. The trial was terminated early for lack of efficacy in other solid tumor programs in patients with high systemic inflammation.

Results:
All 15 patients enrolled in Part 1 received ruxolitinib 15 mg BID plus pemetrexed/cisplatin. Median age was 64 years; male, 80%; mGPS 1, 80%. Median treatment duration was 140 days. The Table reports Part 1 safety data. Four patients were inevaluable for DLTs (<80% compliance, n=2; disease progression, n=2). No DLTs occurred in 11 evaluable patients. The Part 1 overall response rate (ORR) was 53% (8/15; all partial responses). At study termination, 39 and 37 patients were randomized in Part 2 to ruxolitinib and placebo, respectively. Median treatment duration was 43 days. ORR was 31% (12/39) with ruxolitinib+pemetrexed/cisplatin versus 35% (13/37) with placebo+pemetrexed/cisplatin (all partial responses). The short follow-up duration may limit interpretation of Part 2 efficacy. The Part 2 safety profile was consistent with Part 1 (data to be presented).

Table. The Most Common Treatment-Emergent Adverse Events in Part 1
	Ruxolitinib+Pemetrexed/Cisplatin (N=15)
Event, n (%)	All-Grade	Grade 3/4
Nonhematologic*
Nausea	11(73)	1(7)
Fatigue	8(53)	3(20)
Vomiting	8(53)	1(7)
Constipation	7(47)	0
Diarrhea	7(47)	0
Dizziness	7(47)	0
Peripheral edema	7(47)	0
Decreased appetite	6(40)	0
Pyrexia	6(40)	0
Dyspnea	5(33)	1(7)
Pneumonia	4(27)	3(20)
Pulmonary embolism	2(13)	2(13)
Sepsis	2(13)	2(13)
New/worsening hematologic laboratory abnormalities
Anemia	13(87)	5(33)
Lymphopenia	11(73)	2(13)
Leukopenia	9(60)	1(7)
Neutropenia	9(60)	5(33)
Thrombocytopenia	9(60)	1(7)

*Common all-grade (≥30%) or grade 3/4 (≥10%) events.

Conclusion:
Ruxolitinib 15 mg BID had an acceptable safety profile in combination with pemetrexed/cisplatin as first-line treatment of patients with stage IIIB/IV or recurrent nonsquamous NSCLC.

Background:
Advanced cancer patients with elevated systemic inflammatory markers have significantly poorer chemotherapy response and shorter overall survival compared to patients without inflammation. However, mechanisms underlying this association are unclear. There is an urgent need to identify these mechanisms as a high proportion of advanced cancer patients present with systemic inflammation (~25%). This study aimed to determine the impact of inflammatory status, as determined by the neutrophil-to-lymphocyte ratio (NLR), on drug pharmacokinetics and clinical outcomes, including patient toxicity, chemotherapy cycles received, response and survival, in patients with advanced non-small cell lung cancer (NSCLC).

Methods:
Seventy-two advanced NSCLC patients were recruited for a planned 6 cycles of carboplatin (target AUC 6 mg/mL•min) and paclitaxel (175mg/m[2]) chemotherapy. Drug concentrations from the first chemotherapy cycle were measured and analysed using population pharmacokinetic modelling. Clinical data and pharmacodynamic endpoints were also collected. Univariate analysis and multivariable regression analysis was used to identify relationship between NLR status (NLR ≤ 5 and NLR > 5) to pharmacokinetic parameters and clinical outcomes.

Results:
Patient demographics were not different between low and high NLR groups except for nutritional status. Patients with NLR > 5 had increased carboplatin exposure but no associations were found with paclitaxel pharmacokinetics. Increased carboplatin exposure associated with increased toxicities. Patients with elevated inflammation had serious clinical consequences including dose-limiting toxicities leading to reduced cycles of first-line chemotherapy, poor response and shorter overall survival.

Conclusion:
Advanced NSCLC patients with elevated inflammation have alterations in drug pharmacokinetics that may be negatively impacting their clinical outcomes. This under-appreciated inflammatory-mediated change in pharmacokinetics is a potential source of inter-individual variability that may be reduced by dose individualisation according to inflammatory status. Future trials of this approach need to be investigated to assess the impact on survival in advanced cancer populations treated with platinum-based chemotherapy.

Background:
Progress has been made in the treatment of non-small cell lung cancer (NSCLC) over past 40 years. Chemotherapy can prolong survival in the patients with advanced NSCLC with newer supportive care availability. Newer advances include Histology, targeted therapy with the help of next generation sequencing (NGS) and Immunotherapy. Immunotherapy is not feasible in most of our patients in India after failure to first two line chemotherapy; hence this study was conducted to evaluate the efficacy and toxicity of weekly paclitaxel and 4 weekly Carboplatin as salvage regimen.

Methods:
The NSCLC patients(42) failure to previous 2 lines of chemotherapy including targeted agents were treated with salvage regimen weekly Paclitaxel 70- 80 mg/m2 3 weeks / 1 week gap and 4 weekly Carboplatin- AUC 5 with Growth factor support at HCG, Bangalore from Jan 2014 to june 2015. The efficacy and toxicity of above regimen were analyzed

Results:
Of 42 patients male: Female ratio 2.5:1, median age-59, 66.6%, were Adenocarcinoma, 19% had EGFR mutations. Objective response: Partial Response (PR)) was seen in 14.28%, Stable disease (SD) in 28.57% and progressive disease (PD) in 57.14%. Median progression free survival (PFS) 3.5 months, mean overall Survival (OS) 9.5 months.

Prior therapy for NSCLC	Prior EGFR inhibitor +1 line Chemo(N-8)	Prior 2 lines of Chemo (n-27)	Prior 3 lines of chemo (n-7)
PR	37.5%	11.1%	-
SD	37.%	29.62%	14.2%
PD	25%	59.25%	85.7%
Median PFS in months	7	4	3
Median OS in months	15	10	8

Hematological toxicity: anemia (38% grade 1-2), neutropenia (28.57% grade 1-2), Febrile neutropenia (9.5%), thrombocytopenia (31%-Gr-1-2). Nonhematological toxicity: peripheral neuropathy (38% grade 1-2), Alopecia 88%, Mucositis 23.8%(Gr 1-2), Nausea/vomiting 16.6%, Diarrhea 9.52% and discontinuation due to severe peripheral neuropathy -7.1%

Conclusion:
Weekly Paclitaxel with 4 weekly Carboplatin is feasible, active and tolerable salvage regimen in previously treated NSCLC.

Background:
Despite therapeutic advances, CINV still represents a common side-effect of chemotherapy and often its perception is not equal between patients and healthcare professionals. Aims of this study were to evaluate the agreement degree among clinicians, patients and nurses about CINV and other relevant items, and to understand whether anxiety, as well as other demographical and treatment-related factors, could play a role in CINV development.

Methods:
A dedicated survey was designed in agreement with a psychologist: 11 aspects (anxiety, mood, weakness, appetite, nausea, vomiting, pain, somnolence, breath, general status, and trust in treatments) were investigated through Numerical Rating Scale in four consecutive evaluations (T0, T1, T2 and T3) during first-line chemotherapy. From August 2015 to February 2016, the survey was administered in 11 Oncologic Institutions to 188 stage III/IV lung cancer patients and to their oncologists and nurses. Clinician versus patient (CvP), nurse versus patient (NvP) and clinician versus nurse (CvN) agreements were estimated in relation with the investigated items, applying Weighted Cohen's kappa and the grid of Landis and Koch. A multivariate logistic model was applied to evaluate factors possibly influencing anticipatory CINV development as perceived by patients before initiating chemotherapy (T0). Generalized Equation Estimates (GEE) for repeated measures were used to evaluate factors possibly influencing CINV development overall at T1, T2 and T3.

Results:
The incidence of CINV as reported by patients varied from 40.3% at T0 to 71.3% at T3. Both CvP and NvP concordances on the investigated items were mainly moderate, slightly increasing over time and becoming substantial for some items, in particular when evaluating NvP concordances. Pre-chemotherapy anxiety in all its mild (Odds Ratio [OR]: 4.99; 95% Confidence Interval [CI]: 1.26 – 19.81), moderate (OR: 4.89; 95% CI: 1.29; 18.50) and severe (OR: 4.70; 95% CI: 1.10; 19.98) manifestations, as well as mild (OR: 10.02; 95% CI: 3.27; 30.64), moderate (OR: 11.23; 95% CI: 3.54; 35.67) and severe (OR: 12.86; 95% CI: 2.83; 58.48) anxiety experienced after chemotherapy start, exposed patients to a higher risk of anticipatory CINV and of acute/delayed CINV respectively, as confirmed by the multivariate logistic model at T0 and by GEE overtime.

Conclusion:
Even if clinical staff revealed to be aware and sensitive about patients status and perceptions, CINV still represents a problem among patients undergoing chemotherapy, with this study further confirming that particular attention should be given to anxiety due to its key role in CINV development.

Background:
Erlotinib (E) is an oral reversible tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR), known to have efficacy in NSCLC. The aurora kinases are necessary for cell cycle regulation and may have altered function in certain cancers; alisertib (A) is an oral selective aurora kinase A inhibitor. Preclinical data suggested that the combination of an EGFR inhibitor and aurora kinase inhibitor may have synergistic effects in wild-type EGFR NSCLC patients, leading to this phase I/II trial.

Methods:
Using a 3 + 3 dose escalation design, A was increased over four dose levels from 30 mg - 50 mg twice daily. E was given daily at 100 mg in DL1 and 150 mg in DL2-4. A was given on days 1-7 of a 21 day cycle along with daily E. Key eligibility criteria: age > 18, histologically confirmed NSCLC, ECOG PS 0-1, prior appropriate first line therapy, acceptable organ function. Key exclusion criteria: EGFR mutation, prior treatment with an EGFR pathway inhibitor or aurora kinase inhibitor.

Results:
We report our experience with the phase I portion of this study and plans for the phase II portion. Eighteen patients were treated on four dose levels. Patient characteristics: Median age 61, M/F (8/10), 10/18 had received RT in addition to systemic therapy. 14/18 patients completed at least 2 cycles. Median number of cycles completed was 4.6. Common drug-related AEs of any grade were fatigue (89%), anemia (83%), leukopenia (78%), dyspnea (78%), diarrhea and anorexia (61% respectively). Drug-related Grade 3/4 AE included neutropenia and leukopenia (33% each), febrile neutropenia, lymphopenia and anemia (11% each). Two DLT occurred at DL4 (febrile neutropenia, neutropenia delaying a cycle by > 7 days, both in cycle 1). Disease responses were noted, including one patient with a PR who completed 10 cycles, and 5 patients who achieved SD.

Conclusion:
In patients with recurrent/metastatic NSCLC, the combination of A and E was tolerable. However, the maximum administered dose (E 150 mg daily + E 50 mg BID) led to two DLT, thus the MTD was declared at DL3 (E 150 mg + A 40 mg BID); anti-tumor activity was noted. Updated preclinical data from KRAS mutated and WT cell lines indicate activity of this combination in KRAS mutants whereas either drug alone is ineffective. Based on this data, a protocol amendment was submitted to allow only patients with KRAS mutations to be treated in the phase II portion of the study.

Background:
This is the first report describing the safety and short-term efficacy of nanoparticle albumin bound paclitaxel (Nab-PTX) as monotherapy administered weekly in the treatment of Chinese patients with recurrent advanced non-small cell lung cancer (NSCLC), and analyzing potential factors that may affect prognosis.

Methods:
Patients with recurrent advanced NSCLC who received an weekly nab-paclitaxel regimen (130 mg/m2/week) treatment were eligible.Toxicity and response according to the RECIST criteria were summarized in the study. Classification and regression tree (CART) analysis was performed to estimate the effect of variables (age, gender, performance score, smoking, clinic stage, pathological type, previous line of therapy, treatment cycles, EGFR status, EGFR-/ALK-TKIs, SPARC expression) on PFS. The Kaplan–Meier analysis was used to estimate the effect of terminal tree notes.

Results:
A total of 104 patients were included in the study from June 2010 to March 2014 in the Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences,. The median follow-up period was 9.56 months (0.92-34.00 months). The overall response rate was 21.4%, and the disease control rate was 73.8%. The median PFS was 4.53 months (95% CI: 3.518- 5.542), and the median OS was 12.53 months (95% CI: 10.502- 14.558). Grade 3 adverse events were neutropenia (8.8%), peripheral neuropathy (4.8%), myalgia/arthralgia (4.0%), and fatigue (1.9%), respectively. Grade 4 toxicities rarely occured except neutropenia (1.0%). CART analysis identified 4 terminal nodes based on therapy cycles, age and therapy line. In the four subsets, those with ＜ 4 therapy cycles had the lowest PFS (Median: 1.80 months). Those with ≥ 4 cycles and age ≥70 years had the longest PFS (Median: 8.83 months). The median PFS was significantly different between the four subgroups (P =0.000). In addition, PFS in the ≥ 4 therapy cycles group was better than the without group (Median: 6.23 vs. 1.80 months, P=0.000). No PFS significant differences were observed for both age (≥70 years vs ＜70 years; Median: 8.83vs. 5.87 months, P=0.06) and lines of therapy (＞third-line vs ≤ third-line; Median: 6.37 vs 4.60, P=0.063). A trend of a benefit in PFS in favor of ≥70 years age and ＞third-line groups was found in our treatment.

Conclusion:
The weekly Nab-PTX regimen was effective and well-tolerated in patients with recurrent advanced NSCLC. Treatment cycles factors may be used to predict the therapeutic efficacy of Nab-PTX. Nab-PTX was also found the favourable survival benefit in older population (aged ≥70 years) and patients with ＞third-line therapy.

Background:
Metronomic chemotherapy involves chronic administration of low-dose chemotherapy at regular short intervals, with the aim to induce prolonged cancer control without significant side effects.Aim: was to evaluate metronomic oral vinorelbine in elderly patients with advanced NSCLC.

Methods:
Chemotherapy naïve patients with a mean age of 72.8 yrs with NSCLC stage IIIB-IV and PS 0-2 were enrolled in this trial. Vinorelbine was administered orally at a dose of 40mg three times a week, until disease progression or unacceptable toxicities occurred.

Results:
Thirty-four patients were enrolled (19 adenoca -14 squamous -1 NSCLC). Thirty were eligible for evaluation.10 pts 33.3% had PS 2 and 7 (23.3%) had comorbidities( COPD and/or Heart failure). A partial response was observed in 6 patients (20%) and 12 (40%) had stable disease. After a median follow up period of 24.2 months, the median progression-free survival period ( PFS) was 7.00 months ( 95%CI 4.9- 9.1 months). No significant difference was found in in PFS between patients with adenoca and squamous (5.00 vs 6.39 months p>0.05) Four patients(13.3%) showed a clinical improvement changing their PS from 2 to 1. Most adverse events were grade 1- 2 (peripheral neuropathy, diarrhea and nephrotoxicity) and there was no need for dose reduction or discontinuation of vinorelbine.

Conclusion:
Considering the PFS period and the negligible toxicity metronomic oral vinorelbine seems to be a useful and safe therapeutic option for elderly patients with adnanced NSCLC.

Background:
Scc accounts for about 30-40% of lung cancer cases, and the majority presents with locally advanced or metastatic disease. Vinorelbine/carboplatin (VC) and gemcitabine/carboplatin (GC) are both third-generation combinations used in the treatment of NSCLC. VC and GC were similar with respect to efficacy, healthrelated quality of life (HRQOL) and toxicity in stage IIIB/IV NSCLC patients.The aim is to compare VC and GC with respect to efficacy , DFS, hematologic toxicity in stage IIIB/IV Scc lung cancer patients.

Methods:
Chemonaive patients with SCC lung cancer stage IIIB/IV and WHO performance status 0–2 were eligible. No upper age limit was defined. Patients received vinorelbine 25 mg m[2] or gemcitabine 1000 mg m[2 ]on days 1 and 8 and carboplatin AUC 4 on day 1 and six courses with 3-week cycles. During 13 months, 103 patients were included (VC, n=53; GC, n=50).

Results:
median DFS was 22 vs 24.5 weeks (p=0.42 ), ORR (3cycle) 49.05% vs 58% and ORR(6cycle) % 16.89 vs %16 in the VC and GC arm, respectively (P=0.48). nausea/vomiting showed no significant differences. More grade 3–4 anemia (P=0.009), thrombocytopenia (P = 0.004) in GC arm . There was more grade 3–4 leucopoenia (P=0.28) in the VC arm, but the rate of neutropenic infections was the same (P=0.87).

Conclusion:
VC and GC are similar in treating advanced SCC lung cancer when regarding ORR and DFS, while grade 3–4 toxicity requiring interventions were less frequent when VC is compared to GC in advanced squamous cell lung cancer.

Background:
Febrile neutropenia (FN) is one of the serious complications associated with cancer chemotherapy and often leads to dose reduction and change of administration schedule which may affect treatment outcomes. This post hoc analysis explored the association between FN and patient reported outcomes (PRO).

Methods:
PROs were collected in the trial JVCG with Lung Cancer Symptom Scale (LCSS) and EQ-5D-3L. LCSS includes 6 symptom questions (loss of appetite, fatigue, cough, dyspnea, hemoptysis, pain) and 3 global QOL items (symptom distress, difficulties with daily activities, QOL) measured on a 0-100 mm scale, with higher scores representing greater symptom burden. PROs were collected at baseline (BL, during 14days till randomization), around Day 21 in every cycle, at the timing of discontinuation and at 30-day follow up (FU). LCSS total score, global QOL total score, each global QOL item score, EQ-5D utility index and VAS score were calculated. Time to deterioration (TtD) of the LCSS and EQ-5D defined as increase from BL by ≥15 mm for LCSS and ≥15% drop for EQ-5D, respectively, was analysed using the Kaplan-Meier method stratified by treatment-emergent FN status.

Results:
Of 192 patients randomized to receive ramucirumab+docetaxel or placebo+docetaxel, 80.0% were male, median age was 64.6 and 54.0% had performance status1 at BL. FN occurred in 26.0% (50/192). Patients compliance with LCSS and EQ-5D were approximately 97.4% and 97.9%, respectively. Patients without FN showed longer TtD than patients with FN in LCSS total score and EQ-5D VAS score. Hazard ratio (HR) (95% CI) for LCSS total score were 0.731 (0.469, 1.141), p=0.0945 (stratified) with censoring rate of 44.0% (with FN) and 54.9% (without FN). For EQ-5D VAS score, HR were 0.802 (0.537, 1.199), p=0.5956 with censoring rate of 32.0% (with FN) and 43.0% (without FN). No significant difference was found.

Conclusion:
Prevailing clinical opinion suggests that FN negatively impacts QOL. In trial JVCG, a tendency was shown that QOL of patients with FN deteriorates more rapidly than in patients without FN, consistent with current beliefs. Additional investigation is needed but prevention and management of FN may contribute to maintaining QOL.

Background:
Non-squamous non-small cell lung cancer (neNSCLC) is the most frequent lung cancer subtype. Prognosis of advanced disease is poor, but in recent years, the treat-to-progression strategy has emerged, demonstrating significant improvement in overall survival (OS) of maintenance regimen with pemetrexed (Pem). There are limited head-to-head clinical trial data of various treat-to-progression strategies, and a Pem-based platin doublet induction strategy has never been directly compared to vinorelbine (VNR)-based one.

Methods:
We reviewed retrospectively patients diagnosed of advanced neNSCLC from 2006 to 2015 who were treated with Pem-based and VNR-based platinum doublet as induction chemotherapy, followed by Pem maintenance if they had not progressed. We evaluated clinicopathological features and clinical outcomes. The main objective was to assess if there were survival differences between both induction strategies in terms of progression free survival (PFS) and OS.

Results:
51 patients were reviewed, 74.5% men and 25.5% women. Mean diagnosis age was 64 (range 37-78). 15.7% never smoked and 84.3% had ever smoked. 70.6% received Pem-platin doublet and 29.4% VNR-platin doublet. Initial PS was 0 in 35%, 1 in 63%, 2 in 2%. In Pem group 69.4%. did not progress during induction and in VNR group 46.7%. 55,6% received maintenance Pem in Pem group and 33,3% in VNR group (p=0,08).More treatment delays were done in VNR doublet (53,3% vs 30,6%, p=0,047). Objective response rate (ORR) and disease control rate (DCR) were better with Pem-doublet. Pem: partial response (PR) 35.3%; stable disease (SD) 44.1%, disease progression (DP) 20.6%; VNR: PR 38.5%, SD 23.1%, DP 38.5%. Median PFS was slightly better in Pem group than in VNR one (6,2 vs 4,5 months; p=0,28) and median OS was also better with Pem (16,1 vs 11,2 months; p=0,39), but there were no significant statistical differences. More patients in VNR group needed hospitalization during induction (42,9 vs 25%; p=0,06). Most frequent adverse effects (AEs) were asthenia, anemia and neutropenia. Grade 3-4 asthenia, anemia and neutropenia were more frequent in VNR group.

Conclusion:
No big differences were found between both induction-maintenance strategies. Os and PFS were similar in both groups but Pem group presented a trend to better OS and PFS. More patients presented DP during induction treatment in VNR group. Pem group had better toxicity profile and less hospitalizations during treatment.

Background:
This study was conducted to extract a specific conclusion about the clinical efficacy of paclitaxel liposome in non-small cell lung cancer (NSCLC).

Methods:
Pubmed, Embase and Chinese National Knowledge Infrastructure (CNKI) databases were searched for potential relevant articles. Relative risks (RRs) with 95% confidence intervals (CIs) represented the influences of paclitaxel liposome on the objective response rate (ORR), disease control rate (DCR) and adverse events. I2＞50% and P＜0.05 indicate significant heterogeneity. If there existed heterogeneity, then the random-effects model was used. Otherwise, the fixed-effects model was adopted. Sensitivity analysis was performed to test the robustness of overall results. Begg’s funnel plot and Egger’s linear regression test were used to evaluate the potential publication bias.

Results:
The results indicated that paclitaxel liposome could improve the ORR of NSCLC patients (RR=1.22, 95%CI=1.03-1.44). Moreover, we observed that paclitaxel liposome was related with enhanced DCR as well (RR=1.08, 95%CI=1.01-1.16). The influences of paclitaxel liposome on the occurrences of adverse events were analyzed. The outcome suggested that paclitaxel liposome could inhibit the occurrences of muscle pain during the therapy (RR=0.34, 95%CI=0.26-0.45). Besides, onset of rash could also be inhibit by paclitaxel liposome (RR=0.17, 95%CI=0.08-0.35). Sensitivity analysis indicated that the overall results were robust. The funnel plot seemed to be symmetry (P=0.669).

Conclusion:
Paclitaxel liposome is an effective anti-cancer drugs for NSCLC patients.

Background:
ABP 215 is a biosimilar candidate that is similar to bevacizumab, a VEGF inhibitor, in analytical and functional comparisons. Pharmacokinetic similarity between ABP 215 and bevacizumab has been demonstrated in a phase 1 study. Here we present results from a pivotal phase 3 clinical study in non–small-cell lung cancer (NSCLC).

Methods:
In this double-blind, active-controlled study in adults with non-squamous NSCLC receiving first-line chemotherapy with carboplatin and paclitaxel, subjects were randomized (1:1) to receive investigational product (IP; ABP 215 or bevacizumab 15 mg/kg) Q3W for 6 cycles as an IV infusion. Clinical equivalence was demonstrated by comparing the 2-sided 90% confidence interval (CI) of the risk ratio (RR) of the objective response rate (ORR; primary endpoint) with pre-specified margin of (0.67, 1.5) Secondary endpoints were risk difference (RD) of the ORR, duration of response (DOR), progression-free survival (PFS), treatment-emergent adverse events, and overall survival (OS).

Results:
A total of 642 subjects (ABP 215 [Arm 1], n=328; bevacizumab [Arm 2], n=314) were randomized. Demographic and baseline characteristics were balanced between arms. There were 128 (39.0%) responders in Arm 1 and 131 (41.7%) responders in Arm 2. The RR for ORR was 0.93 (90%CI, 0.80–1.09). The RD for ORR was −2.90% (90%CI, −9.26%–3.45%). Among the responders the estimated median DOR was 5.8 months in Arm 1 versus 5.6 months in Arm 2. The estimated median PFS in Arm 1 was 6.6 months versus 7.9 months in Arm 2; the analysis included all 256 PFS events, 131 (39.9%) in Arm 1 and 125 (39.8%) in Arm 2. The safety population included 324 treated subjects in Arm 1 and 309 in Arm 2; 139 (42.9%) subjects in Arm 1 and 137 (44.3%) in Arm 2 experienced grade ≥3 TEAEs. TEAEs leading to IP discontinuation affected 61 (18.8%) subjects in Arm 1 and 53 (17.2%) in Arm 2; 85 (26.2%) subjects in Arm 1 and 71 (23.0%) in Arm 2 experienced at least one serious AE; 13 (4.0%) in Arm 1 and 11 (3.6%) in Arm 2 had a fatal TEAE. OS analysis included 79 deaths, 43 (13.3%) in Arm 1 and 36 (11.7%) in Arm 2. Binding antibodies developed during the study in 4 (1.4%) subjects in Arm 1 versus 7 (2.5%) in Arm 2; no subject tested positive for neutralizing antibodies.

Conclusion:
The study met the primary and secondary objectives demonstrating that ABP 215 and bevacizumab are clinically equivalent.

Background:
The effectiveness and safety of continuation maintenance therapy with pemetrexed versus the watch-and-wait approach was proved by a large randomised phase III trial (Paz-Ares et al., 2013). We focused on continuance maintenance therapy with pemetrexed (Alimta) in routine clinical practice in the Czech Republic.

Methods:
The primary objective of our analysis was to evaluate the overall survival, defined as the length of time from the start of maintenance therapy to the date of death. Data was summarised using the standard descriptive statistics, absolute and relative rates for categorial variables, averages for continuous variables, 95% confidence intervals, as well as median, minimum and maximum values. Kaplan-Meier survival curves were used to display the patient survival. All analyses and graphical outputs were performed in the SAS 9.4 Software.

Results:
The analysed cohort of NSCLC patients treated with pemetrexed maintenance therapy in the Czech Republic as on March 2016 involved 194 patients. The median age was 64,0 years; stage IV was the predominant clinical stage (84,5%), 52.6% of patients were men, and 47,4% women. Adenocarcinoma was in 190 patients. From a total of 194 patients, treatment response was assessed in 173 patients. Among the assessed patients one showed complete regression (CR), 34 of them (19.7%) showed partial regression (PR), stable disease (SD) was the most frequent response, reported in 95 patients (54,9%); progression occurred in 36 patients (20.8%). Adverse events led to the termination of treatment in only 6 (3.5%) patients. The median number of cycles of maintenance therapy in our study was 5.0 (1.0; 24.0), and the median duration of maintenance therapy was 13.0 weeks. In the registration trial, the median number of cycles was 4.0 (1.0; 44.0). Median overall survival (median OS), was 15.4 months (95% CI: (12,7-18.18).

Conclusion:
The continuation maintenance therapy with pemetrexed (Alimta) has been shown to be effective and well tolerated in the Czech population. Treatment had to be terminated only in 6 (3.5%) patients due to adverse events. In the registration trial involving 359 patients (Paz-Ares et al., 2013), the continuation maintenance therapy with pemetrexed led to the median OS of 13.9 months, whereas in the Czech Republic, the median OS has been 15,4 months so far. However, a lower number of patients treated in the Czech Republic must be taken into account, and therefore this result is considered as preliminary.

Background:
The combination of cytotoxic chemotherapy with Src signaling pathway inhibitors represents a potential novel strategy to improve tumor response. Preclinical data suggests that thymidylate synthase (TS) and Src act via a common pathway and their overexpression has prognostic significance. Ceppi et al, explored the concept that Src inhibitors could be synergistic in combination with pemetrexed. Using immunohistochemical detection, Src kinase activation, evaluated by a phosphospecific antibody, was associated with higher TS expression in tumor specimens. Src-inhibition synergistically enhanced pemetrexed-cytotoxicity in human A549 lung cancer cells. Treatment with a Src inhibitor prevented up-regulation of TS mRNA and protein levels induced by pemetrexed that increased resistance to treatment. This suggests that Src represents a potential target to improve the efficacy of TS-inhibiting agents mainly in treatment of metastatic adenocarcinoma of the lung and malignant mesothelioma. Bosutinib is a NKI that inhibits the Abelson and Src kinases approved to treat CML. Hypothesis. Bosutinib can be safely administered in combination with pemetrexed with the MTD determined. Objectives. 1) Determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of bosutinib combined with pemetrexed, 2) Estimate the tumor response rate (RR), progression-free survival (PFS) and overall survival (OS) for patients with selected advanced cancers treated with this combination, 3) Explore potential biomarkers for treatment selection and response, including expression of Src kinase, phosphorylated Src kinase, and expression of potential modifying genes including K-ras, and 4) Determine the effect on the pharmacokinetics of each drug.

Methods:
This is a single institution phase I dose-escalation study for patients with selected advanced solid malignancies eligible to receive pemetrexed and ECOG performance status 0-2. Sequential dose cohorts of 3-6 patients will be treated. The starting dose of bosutinib is 200 mg daily in addition to pemetrexed 500 mg/m2 (Table 1).

Dose level (cohort)	number of patients	Bosutinib dose (mg)	Pemetexed dose (mg/m2)
-2	3-6	100	400
-1	3-6	100	500
1	3-6	200	500
2	3-6	300	500
3	3-6	400	500
4	3-6	500	500
Expansion cohort	10-12	MTD	500

Results:
not applicable

Conclusion:
not applicable

Background:
Nanoparticle albumin-bound paclitaxel (nab-PTX) is a new formulation of paclitaxel and has demonstrated efficacy when combined with carboplatin (Cb), resulting in one of the standard platinum-containing chemotherapy regimens for patients (pts) with chemo-naïve advanced non-small cell lung cancer (NSCLC). The addition of anti-vascular endothelial growth factor antibody bevacizumab (BEV) to chemotherapy has been known an effective treatment option for non-squamous NSCLC. The efficacy and safety of the new triplet regimen: Cb + nab-PTX + BEV has not yet been assessed.

Methods:
We planned multicenter, open-label, phase I/II trial of Cb + nab-PTX + BEV (CARNAVAL study; TORG1424 / OLCSG1402). Eligible pts were chemo-naïve, aged ≥20 years, ECOG PS 0/1 with advanced non-squamous NSCLC. Pts received 4 to 6 cycles of Cb (AUC = 6, day1) + nab-PTX (dose level 1; 100mg/m[2] on days 1, 8 or dose level 2; 100mg/m[2] on days 1, 8, and 15) + BEV (15mg/kg, day1) followed by maintenance nab-PTX + BEV every 3 weeks until disease progression. The phase I part of the study used a 6+6 dose-escalation design to determine the maximum tolerated dose. Major dose-limiting toxicity (DLT) was defined as grade 4 neutropenia for at least 4 consecutive days, febrile neutropenia, grade 4 thrombocytopenia, grade ≥3 non-hematologic toxicity (excluding nausea, vomiting, loss of appetite, fatigue, diarrhea, constipation, disorder of electrolyte, hypertension and hypersensitivity, if they are manageable), and grade 4 hypertension. DLT was assessed during 1st cycle. This study was registered at UMIN (ID: 000014560).

Results:
From October 2014 to July 2015, 4 and 12 pts were enrolled at dose level 1 and 2 cohorts respectively. No DLT was observed at either level and recommended phase II dose (RP2D) was determined at dose level 2. Grade ≥3 adverse events (AEs) during the overall treatment period were as follows; neutropenia (13 pts), thrombocytopenia (4 pts), nausea, vomiting, anorexia (3 pts each), anemia, fatigue, hypertension (2 pts each), pneumonitis, liver disorder, hyponatremia, febrile neutropenia, skin ulcer, esophageal perforation (1 pt each). All AEs were manageable.

Conclusion:
RP2D of Cb + nab-PTX + BEV was determined at dose level 2 (nab-PTX; 100mg/m[2] on days 1, 8 and 15 every 3 weeks). We have started phase 2 part of the trial at dose level 2 since November 2015.

Background:
The majority of patients (pts) with non-squamous non small cell lung cancer (NSq/NSCLC) present inoperable disease for which no curative disease exists. The combination of Carboplatin(CBDCA), Paclitaxel(PTX) and Bevacizumab(BEV) is one of the standards 1st line treatment for this group of pts without EGFR sensitizing mutation or ALK gene rearrangement. The aim of the study was to evaluate the effectiveness and safety of the combination of CBDCA, PTX and BEV in pts with NSq/NSCLC consecutively admitted and treated in our Dept between 03/2010 and 12/2015.

Methods:
In a total of 50 pts,37 men(74%),13 women(26%), median age 68 (47-82) and ECOG 1 (0-4), heavy smokers 42/50(84%), with no mutation of EGFR and ALK, were treated with CBDCA (AUC =5), PTX 175mg/m2, BEV 7.5 mg/Kg, every 3 weeks, and primary prophylaxis with G-CSFs d 1-10. The chemotherapy was repeated for a median of 4(1-11) cycles

Results:
The objective response was 36% (18/50), 27% for men and 61% for women (0.05 68 years (p = N.S.) respectively. The median PFS was 6+ (1-10+) months for women and 4(2-13) for men. The median OS was 9+ (3-30) months for women and 6(1-24) for men. One out of 50 pts experienced CR for 25 months. The toxicity of the treatment was estimated in a total of 210 cycles of chemotherapy. The most frequent adverse events grade III and IV were neutropenia 2/210 (0.95%), febrile neutropenia 1/210 (0.47%), anaemia 5/210 (2.38%) and thrombocytopenia 3/210 (1.43%). Reduction of doses were required only in 6 (12%) pts, in all cases after the 1st or the 2[nd] cycle of chemotherapy. Hospitalization was required for 4/50 (8%) of the pts., while 1/50 died during a toxic episode.

Conclusion:
In our unselected NSq NSCLC pts stages IIIb or IV: 1. The combination of CBDCA, PTX and BEV with G-CSF prophylaxis , was proved effective and very well tolerated independent of ECOG and age. 2. Women seemed to response better than men in this combination.

Background:
Despite a high symptom burden in many patients with advanced NSCLC, limited data exist on QoL with first-line chemotherapy. Here we report results of an interim QoL analysis in patients with SCC NSCLC treated with nab-paclitaxel/carboplatin in the induction part of the ongoing ABOUND.sqm study.

Methods:
Chemotherapy-naive patients with advanced SCC NSCLC received 4 cycles of induction therapy with nab-paclitaxel 100 mg/m[2] on days 1, 8, and 15 + carboplatin AUC 6 on day 1 (21-day cycles). Patients without progression after induction received (2:1) maintenance nab-paclitaxel 100 mg/m[2] on days 1 and 8 (21-day cycles) + best supportive care (BSC) or BSC alone until progression/unacceptable toxicity. The primary endpoint is progression-free survival (randomization to maintenance). Patient-reported QoL (exploratory endpoint) was assessed on day 1 of each cycle using the Lung Cancer Symptom Scale (LCSS) and Euro-QoL-5 Dimensions-5 Levels (EQ-5D-5L).

Results:
207 patients were treated in the induction phase. Median age was 68 years; 66% of patients were male, and 99% had an ECOG PS 0-1. Out of 200 patients treated for ≥ 2 cycles, 180 (90%) completed baseline + ≥ 1 postbaseline QoL assessments. The mean change from baseline in LCSS symptom burden index and total score ranged from 6.6%-10.3% and 5.5%-9.5%, respectively. Clinically meaningful improvements (≥ 10 mm [visual analog scale]) from baseline were observed in composite LCSS pulmonary symptom items of cough, shortness of breath, and hemoptysis in 46% of patients. For individual EQ-5D-5L dimensions, ≥ 82% of patients maintained/improved from baseline and ≥ 33% reported complete resolution (Table).Figure 1



Conclusion:
In this interim analysis, 4 cycles of nab-paclitaxel/carboplatin treatment led to clinically meaningful improvements in LCSS pulmonary symptom items. Complete resolution of problems reported at baseline in EQ-5D-5L dimensions was observed in ≥ 33% of patients at least once during treatment. NCT02027428

Background:
Non-small cell lung cancer (NSCLC) is one of the most frequent malignancies, and the majority of diagnosis are made at an advanced stage (IIIB/IV), with unsatisfactory results. Vinorelbine is a microtubule-targeting agent, with a favorable safety profile, and is currently available also as oral chemotherapeutic agent. Metronomic chemotherapy (MCT) is an attractive strategy for treating cancer, which has been shown to reduce toxicities and to extend duration of treatment, resulting in lower resistances and prolonged survival rates. The aim of our study was to evaluate the role of oral metronomic vinorelbine (mVNR) as first-line treatment in population of elderly unfit-platin patients with advanced NSCLC.

Methods:
Twenty patients (13 men and 7 women, median age 78 years, range 66-88) with advanced NSCLC (3 patients stage IIIb, 17 patients stage IV) and a median of 4 major co-morbidities, non-oncogenic addicted and unfit for platin, were treated with oral mVNR as first-line treatment, at a dose of 40 mg (Group 1, 9 patients) or 50 mg (Group 2, 11 patients) as MCT on days Monday, Wednesday and Friday. The ECOG performance status was 1 (PS1) in 11 patients and 2 or 3 (PS2-3) in 9.

Results:
The median overall survival (OS) was 7.80 months (PS1: 11.27 months; PS2-3: 4.3 months) and time-to-progression (TTP) was 3.07 months (PS1: 3.0 months; PS2-3: 3.5 months). The median OS in Group 1 was 4.5 months and 9.4 months in Group 2. Best response showed stable disease in 5 cases, partial response in 4, progression disease in 7. Low toxicity was reported because grade 1-2 asthenia was the most frequently reported symptom.

Conclusion:
Metronomic chemotherapy is a new approach that combines good tolerability and acceptable activity. Our preliminary data suggest that oral mVNR in advanced NSCLC may be an effective first-line treatment, even in elderly and unfit patients with major co-morbidities.

Background:
Approximately one-third to one-half of all patients with advanced NSCLC presents with a disease that is unsuitable for conventional chemotherapy, both at the first or subsequent lines of treatment. This is mostly due to their very elderly age, poor performance status (PS), to the extent of the disease and/or comorbidities. The prognosis of this patients is extremely poor and no active treatment is often offered.

Methods:
In a prospective phase II not randomised study, patients with advanced stage IV histologically confirmed NSCLC who were deemed not eligible to standard chemotherapy because of elderly age (= or > 70 years), and/or poor ECOG PS (= or > 2), and/or extensive brain or bone disease, and/or active comorbidities (= or > 2) requiring pharmacological treatment, were treated with oral metronomic vinorelbine at the fixed dose of 30 mg three times a week until disease progression. Primary endpoint was feasibility, including toxicity and disease control rate (DCR=CR+PR+SD); secondary endpoints included duration of treatment, progression-free survival (PFS) and overall survival (OS) since the start of treatment.

Results:
37 patients, 29 males, 8 females, with a median age of 73 years (range, 50-86), PS=1/2/3 in 1/28/8 (3/76/22%), stage IVA/IVB in 11/26 (30/70%), brain/bone disease in 8/13 (22/35%) and a median of 3 (range, 0-5) active comorbidities were treated. Twenty-five patients had an adenocarcinoma (68%), 12 (32%) a squamous cell carcinoma; 2 patients had an active mutation of the EGFR gene and were previously treated with a TKI. Fourteen patients (38%) received the treatment as first line, 8 (22%) as second line, and 15 (41%) as third or subsequent line. The median cycle of chemotherapy administered was 2 (range, 1-8). G1/G2 toxicities were: asthenia in 20 (54%) patients, constipation in 13 (35%), nausea in 9 (26%), anemia in 5 (14%). G3 toxicities were: anemia in 2 (5%) patients, neutropenia and fatigue each in one patient (3%). None patient had G4 toxicity and required dose reduction. Out of the 36 assessable patients, DCR was 25% (in 9 patients). The median duration of treatment was 2.8 months (range, 0.3-8.4). With a median follow-up of 22.1 months, 3 patients (8%) are still alive; median OS was 5.5 months (range, 5.2-6.1) and median PFS 2.5 months (range, 2.4-2.8).

Conclusion:
In patients with very poor prognosis advanced NSCLC unsuitable for chemotherapy, oral metronomic vinorelbine may lead to a disease control in a quarter of patients with acceptable toxicities.

Background:
Non-small cell lung cancer (NSCLC) is a worldwide problem and usually presents at an advanced stage. Despite widespread availability of multiple chemotherapies for stage IV NSCLC, response rates are generally low. We tried to identify pretreatment factors that may predict response to treatment, particularly relevant in countries with limited laboratory and imaging facilities and drug availability.

Methods:
we conducted a retrospective analysis of patients with stage IV NSCLC receiving systemic treatment from 2002 to 2012 at the University of Alabama at Birmingham (UAB), which is a NCCN member institute. Pretreatment risk factors including age, race, gender, presenting symptoms, and laboratory values, were evaluated. Patients who originally received adjuvant therapy and no further treatment upon recurrence and those receiving first line treatment on a clinical trial with no further therapy were excluded.

Results:
409 patients received more than 10 different regimens as first line treatment in metastatic non-small-cell lung cancer. The most commonly used regimens were paclitaxel and carboplatin with or without bevacizumab; Carboplatin and pemetrexed with or without bevacizumab; pemetrexed single agent; Carboplatin and Gemcitabine; and a tyrosine kinase inhibitor. 76.4%of patients had a performance status of 0-1 and 21.6% of them has a performance status of 2. More than 50 pretreatment factors were analysed, of which smoking (p = 0.049), pleural metastases or effusion (p = 0.004), abdominal metastases (p = 0.033), hypoalbuminemia (p = 0.043) and hyponatremia (p = 0.002) are associated with poor responses to treatment.

Conclusion:
Smoking status, presence or absence of pleural metastases or effusion, abdominal metastases, presence of hypoalbuminemia or hyponatremia can help identify patients who are less likely to respond to treatment. We are developing a mathematical model incorporating these factors. This may help in the selection of patients for systemic therapy and may improve stratification in clinical trials

Background:
RRM1 is the regulatory subunit of ribonucleotide reductase. It has important role in DNA synthesis and damage repair as it is linked to G2 cell cycle arrest. Previous studies showed its prognostic significance in early stage NSCLC post-operatively (NEJM 356:800, 2007)

Methods:
We prospectively analyzed formalin fixed and paraffin-embedded (FFPE) tumor specimens to identify RRM1 mRNA expression (using Real-time quantitative PCR). Tumor cells isolated from male smoker with advanced NSCLC who will receive Cisplatin and Gemcitabin was measured in patients attending National Cancer Institute(NCI), Cairo between Jan2011-Jan2014

Results:
70 cases were involved, median age was 57years (35-76). 90% had ECOG-PS1 while 59(84.3%) had Stage IV and 55.7% had ≥4 chemotherapy cycles. 62.7% were responders(SD/PR), High RRM1 RNA was encountered in 33(37.1%) specimens. High RRM1 protein and IHC were encountered in 37(52.9%) and 33(47.1%) specimens respectively. RRM1 RNA was correlated and collinear with RRM1 protein and IHC (Kappa value 0.462 and 0.686, p<0.001 respectively) On Cox regression multivariate analysis (MVA) for predictors of overall survival; Advanced age (p=0.025, HR1.05, 95%CI:1.01-1.09), Non-responder(p=0.035, HR:1.95, 95%CI:1.05-3.63) and high RRM1.RNA(p=0.048, HR:1.93, 95%CI:1.01-3.70) adversely affect survival. Median OS in low RRM1.RNA was 11.6 vs 7.1 months in high group (Figure).Median PFS in low RRM1.RNA was 6.8 vs 5.1 months in high group. On logistic regression MVA for predictors of chemotherapy response; number of chemotherapy cycles was the only independent predictor (p<0.001).

Conclusion:
Low expression of RRM1 could be used to predict better survival in advanced NSCLC. The RRM1 could contribute to the future design of personalized cancer treatment in advanced NSCLC. Prospective multi-institutional clinical trials are warranted. Figure 1

Background:
Despite the success of taxol as an anti-tumor agent, the development of acquired resistance greatly limits its efficacy. A biomarker to predict sensitivity is greatly needed for this agent. The aim of this study was to explore the correlation between the expression of βIII -tubulin/bFGF and taxol chemosensitivity in non–small cell lung carcinoma (NSCLC) A549/Taxol cell lines.

Methods:
Small interfering RNA (siRNA) was utilized to down-regulate the expression of the two genes βIII-tubulin and bFGF in lung adenocarcinoma A549/Taxol cell lines. Interference effect was detected at mRNA level and protein level respectively by Real Time PCR (RT-PCR) and Western-blot. The cell sensitivity to taxol was examined using MTT assay. Furthermore, apoptosis and cell cycle of A549/ taxol cells were tested by flow cytometry.

Results:
βIII-tubulin and bFGF expression at mRNA level and protein level in NSCLC A549/Taxol cell lines after siRNA transfection were significantly lower than those before transfection. The sensitivity of A549/Taxol cells to taxol got a raise by down-regulating βIII-tubulin and bFGF expression. Moreover, it was also found that down-regulation of the two genes significantly increased cell apoptosis and G2/M phase cells percentage.

Conclusion:
Down-regulation of either βIII-tubulin or bFGF can sensitize A549/Taxol cells to taxol in vitro. It might be achieved through regulating cell apoptosis and cell cycle. It revealed that the two genes βIII-tubulin and bFGF play critical roles in mediating response to taxol and may serve as novel potential predictive factors for NSCLC therapy.

Background:
In advanced non-small cell lung cancer (NSCLC), main therapeutic modalities are chemotherapy and palliative radiotherapy. With the development of various chemotherapeutic options, the selection of chemotherapeutic agent in NSCLC subjects who showed progressive disease (PD) since 1st chemotherapy is crucial. Response of additional chemotherapy, since 1st-line chemotherapy is an important issue. The purpose of the study is the analysis of predictors on the survival of patients who received further chemotherapy since PD for 1st-line chemotherapy in NSCLC.

Methods:
It was reviewed retrospectively based on chart reviews for the 616 subjects of inoperable advanced NSCLC. Median values of overall survivals (OS) were analyzed according to gender, age, smoking history, BMI, pathology, hematologic parameters, TNM stage, response to 1st-line chemotherapy, initial chemotherapeutic regimen using univariate and multivariate analysis.

Results:
Age, sex, smoking history, pathologic type, T-stage, responsiveness to 1st-line chemotherapy, and first-line regimens were significant predictors in Log-rank test for median OS. In multivariate analysis, the patients over 65 year (hazard ratio: HR 1.53, 95% confidence interval: CI 1.02-2.30) and poor responder to initial chemotherapy (HR 1.53, 95% CI 1.06-2.20) have higher hazard ratio of death. In T stage, HR of T4 was higher than T1 (HR 2.27, 95% CI 1.01-5.11).

Conclusion:
Age less than 65 years old and responsiveness to initial chemotherapy were favorable prospecting factors for the following chemotherapy. Initial tumor stage seems to be more important than nodal status in responsiveness of chemotherapy. These factors might be helpful to prospect the outcome of following chemotherapy in advanced NSCLC.

Background:
Platinum based chemotherapy is a standard treatment for patients with advanced non-small cell lung cancer (NSCLC) without EGFR mutation or ALK translocation. However, some patients show no response to 1st line treatment. In this study we investigated characteristics and treatment outcome of salvage treatment in these population of advanced NSCLC primary refractory to 1st line chemotherapy including platinum.

Methods:
We investigated consecutive patients with NSCLC stage IIIB-IV who received platinum-doublet chemoherapy as a first line treatment between 2014-2015 in a single center. Primary refractory NSCLC was defined as progressive disease(PD) according to RECIST criteria at the first evaluation. Survival was estimated by Kaplan-meier method.

Results:
Among 102 patients without known EGFR mutation or ALK translocation who received platinum doublet as 1st line, 13 patients (12.7%) showed PD on the first evaluation of tumor response. Median age was 68 years (range 30 -84 years). Five patients had adenocarcinoma, one squamous cell carcinoma, one sarcomatoid carcinoma, and the other five had other histology. First chemotherapy regimen included pemetrexed (n=6), gemcitabine (n=6), and paclitaxel (n=1). Eight of 13 patients received subsequent salvage chemotherapy (gemcitabine based in four, taxane based in three, etoposide+ifosfamide+cisplatin in one) and no one had objective response. Three patients had stable disease, one patient showed PD to subsequent chemotherapy, and response could not be evaluated in the other four patients. Median overall survival of the 13 patients was 3.2 months (95% confidence interval 2.3 - 4.1 months).

Conclusion:
NSCLC which is primarily refractory to 1st line platinum based chemotherapy had poor survival. The efficacy of other cytotoxic chemotherapy regimen as a salvage treatment was limited. Studies to find an optimal salvage treatment strategy in this population are needed.

Background:
We aimed to compare pemetrexed/carboplatin doublet (PC) versus pemetrexed singlet (P) as induction therapy in chemotherapy-naïve elderly patients aged 70 or more with advanced non-squamous non–small-cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.

Methods:
In this open-label multicenter phase III randomized trial, elderly patients aged 70 or more with advanced non-squamous NSCLC, ECOG PS of 0-1, no prior chemotherapy, adequate organ function and measurable disease were assigned to PC doublet (P, 500 mg/m2; C, area under the curve of 5) or P singlet (500 mg/m2) after stratified randomization according to center, gender and Charson Comorbidity Index (CCI). The treatment was given every 3 weeks till disease progression, unacceptable toxicity or withdrawal of consent. However, carboplatin was given for only the first four cycles during induction therapy period. The primary end point was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, and safety.

Results:
A total of 267 eligible patients were enrolled from six centers between March 2012 and October 2015; median age was 74 years (70~86); 95% had PS of 1; 68% were men; and 61% had CCI of 1 or more. The median PFS was 5.4 months for PC doublet and 4.2 months for P singlet, respectively (hazard ratio [HR], 0.85; 95% CI, 0.65 to 1.11; P= 0.2353). The median survival time was 12.5 months for PC and 9.0 months for P, respectively (HR, 0.86; 95% CI, 0.62 to 1.21; P =0.4108). The objective response rates for PC doublet and P singlet were 34.7% and 25.9%, respectively (p=0.1387). The most common adverse events in PC doublet arm were anemia (9.6%), fatigue (8%) and pneumonia (6.4%) while those in P singlet arm were pneumonia (4.2%), fatique (3.3%) and anemia (2.5%) in descending of frequency.

Conclusion:
The addition of carboplatin to pemetrexed during induction therapy period did not show the improvement of survival time in elderly patients aged 70 or more with advanced non-squamous NSCLC and ECOG PS of 0-1 even though it increased the response rate numerically. Updated data will be presented.

Background:
QoL data in elderly patients with NSCLC receiving chemotherapy are limited, although these assessments can help inform treatment decisions. Interim QoL outcomes from the ongoing ABOUND.70+ study are reported here.

Methods:
Patients aged ≥ 70 years with locally advanced/metastatic NSCLC were randomized 1:1 to first-line nab-paclitaxel 100 mg/m[2] on days 1, 8, and 15 + carboplatin AUC 6 on day 1 every 21 days or the same nab-paclitaxel/carboplatin regimen with a 1-week break between cycles. The primary endpoint is the percentage of patients with grade ≥ 2 peripheral neuropathy or grade ≥ 3 myelosuppression adverse events. QoL (an exploratory endpoint) was assessed on day 1 of each cycle using the Lung Cancer Symptom Scale (LCSS) and EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L).

Results:
This analysis included 119 patients; 88 patients (74%) completed baseline + ≥ 1 postbaseline QoL assessments. The median age was 76 years (range, 70-93 years); 30% of patients were ≥ 80 years of age, 56% were male, and 99% had an ECOG PS 0-1. In general, LCSS symptom burden index and average total scores improved during cycles 1-4. The LCSS item of cough improved each cycle, with a mean change of 18.98 mm from baseline to end of cycle 4 on the visual analog scale (VAS; 95% CI, 8.42-29.54 mm). Fifty percent of patients had a clinically meaningful improvement (≥ 10 mm [VAS]) from baseline in the composite LCSS pulmonary symptom items of cough, shortness of breath, and hemoptysis. More than 80% of patients maintained/improved in each EQ-5D-5L dimension from baseline; complete resolution of baseline pain/discomfort, anxiety/depression, and self-care items was reported by ≥ 55% of patients (Table). Figure 1



Conclusion:
Clinically meaningful improvements in several QoL dimensions were observed in elderly patients with NSCLC treated with nab-paclitaxel/carboplatin. These data support the role of nab-paclitaxel/carboplatin in this patient population. NCT02151149

Background:
Retrospective analyses suggest benefit to 2[nd] line therapy in the fit elderly, but prospective data are lacking. Subgroup analysis of a phase III study of carboplatin and nab-paclitaxel for 1[st] line treatment of NSCLC showed superior survival in elderly patients.

Methods:
This is a phase II study for patients > 70 years of age with progression on a non-taxane 1[st] line doublet. Nab-paclitaxel 100mg/m[2] is administered intravenously, 3/4 weeks per cycle until progressive disease or intolerance. The primary endpoint is occurrence of ≥grade 3 treatment-related toxicities after 6 cycles or within 3 weeks if early treatment discontinuation occurred. Null hypothesis is a rate of 60% and alternative hypothesis is < 40%.

Results:
As of June 2016, 35/42 patients started treatment, and 31 completed. Median age is 75 (range 70 to 83). 51.4% are female. 8.6% have PS0, 68.6% PS1 and 22.9% PS2. 82.9% have adenocarcinoma, 14.3% SqCC, and 2.9% adenosquamous. 5.7% had EGFR, 28.6% kRAS. 33 patients had one prior treatment and 2 also received nivolumab. Of the 31 patients off treatment, median cycles received was 3 (range 1-22). 11/30 (37%) experienced the primary endpoint. When expanded to >=grade 3 toxicity at any time, this rose to 43% (13/30). The most common ≥G3 toxicities at any time point were fatigue (6/30), peripheral sensory neuropathy (4/30) and neutropenia (3/30). RR was 21% (1CR, 5PR, 16SD and 7PD of 29 patients evaluable). With a median FU of ongoing survivors (n=9) of 7.8 months, median progression free survival (PFS) was 5.2 months and median overall survival (OS) was 10.1 months. Figure 1



Conclusion:
These results demonstrate efficacy and safety of nab-paclitaxel for the 2[nd] line treatment of NSCLC in elderly patients and provide prospective data to support the treatment of fit elderly in 2[nd] line. Updated PFS, OS, geriatric assessment and quality of life data will be presented.

Background:
Despite the elderly patients represents the majority of lung cancer population, only 10~20% of study patients in clinical trials were elderly. Moreover, the studies examining combination versus single-agent therapy in an elderly with advanced non-small cell lung cancer (NSCLC) have showed conflicting results in terms of survival benefit. This population-based analyses aimed to assess the pattern of initial chemotherapeutic regimen and the survival benefit of combination chemotherapy compared with single-agent in elderly patients with advanced NSCLC.

Methods:
Patients ³ 70 years with advanced NSCLC incident from 2007 to 2012 were identified in the National Health Insurance Service database of Korea. Multivariate models examined the patient characteristics associated with receipt of combination compared with single-agent chemotherapy. Cox proportional-hazards regression model was used to examine the effect of treatment modality on survival. Propensity score analysis adjusted for confounding.

Results:
Among 41276 patients with de novo lung cancer, 8274 (20.0%) who received palliative chemotherapy were eligible for this study. Of 8274 patients with advanced NSCLC, 7298 (88.2%) who received cytotoxic chemotherapy were included in further analyses, except 976 (11.8%) who received first-line EGFR tyrosine kinase inhibitor. A total of 5636 (77.2%) patients received combination chemotherapy and 1662 (22.8%) received monotherapy. The most frequent regimen was gemcitabine + platinum doublet (44.7%) in combination group and gemcitabine single (46.7%) in monotherapy group. Multivariate analyses indicated that the lower use of combination chemotherapy with increasing age (odds ratio[OR] 0.73; 95% CI 0.67 to 0.79; P < .001) and female (OR 0.71; 95% CI 0.62 to 0.80; P < .001). Receipt of combination over single-agent chemotherapy was associated with reduction in the adjusted hazard of death (hazard ratio[HR] 0.91; 95% CI 0.86 to 0.96; P=0.001) and an increase in median overall survival from 9.7 to 10.8 months. In the propensity-matched cohort, survival was still significantly better in combination chemotherapy group (HR 0.89; 95% CI 0.80 to 0.98; P = .019 by stratified Log-rank test).

Conclusion:
In elderly patients with advanced NSCLC who are eligible for cytotoxic chemotherapy, there are clear survival benefit of combination chemotherapy compared with single-agent with controls for age, sex and comorbidity.

Background:
The number of elderly lung cancer patients rises due to prolonged life expectancy, therefore the larger is proportion of patients with more comorbid conditions. The aim of this study is to evaluate influence of comorbidity on 2-year survival of elderly patients with advanced stage of non-small cell lung cancer treated with platinum-based chemotherapy.

Methods:
In our study we observed 152 elderly patients with patohistologicaly confirmed non-small cell lung cancer in advanced stage (IIIB, IV), treated with platinum-based chemotherapy, retrospectively. We evaluate the prognostic value of pretreatment comorbidity status on the 2-year survival.

Results:
Our analysis showed that the number of comorbid conditions (0-without, 1, 2, 3 comorbid conditions) didn’t statistically influence 2-year survival (p=0,894), but patients with more comorbid diseases have shorter 2-year survival (12.5% / 10.5% / 8.5% / 6.3% respectivelly). There were no statistically significant differences in 2-year survival according the value of Charlson index of comorbidity (p=0.312). There were no statistically differences in 2-year survival relative to the presence or absence of comorbid condition of particular systemic organs: respiratory (p=0.692), cardiovascular (p=0.382), gastronitestinal (p=0.657), diabetes (p=0.676), previous malignancy (p=0.586). Patients without respiratory comorbidity had better 2-year survival, but not significantly (Mantell/Cox p=0.0782).

Conclusion:
CONSLUSION: In strictly, by criteria selected, fit, elderly lung cancer patient comorbidity doesn’t significantly influence survival. Comorbidity should be a stimulus for treatment design rather than an exclusion criteria for oncologic treatment.

Background:
The number of elderly patients with lung cancer is increasing, and it is becoming a public health problem in Japan. There is little data on the efficacy and safety of chemotherapy for patients aged 80 and older, even though they constitute 30% of all lung cancer incidence (80-84 years, 16%; 85years and older, 14.4%) reported by cancer information service, National Cancer Center, Japan in 2012.

Methods:
The objective of this study was to evaluate the efficacy and safety of chemotherapy in patients aged 80 and older with advanced lung cancer in our hospital, retrospectively. The medical records were analyzed from January 2010 to July 2016.

Results:
In total, 27 patients were analyzed. Patient characteristics were below; the median ages were 81 years (range, 80-84); female/ male: 8/19, PS 0-1/ 2: 22/5, adenocarcinoma/ squamous/ NOS (not otherwise specified) /SCLC: 7/8/1/11, stageⅢ/ Ⅳ/ recurrence : 3/19/5. Platinum-doublets, mono-chemotherapy were used in 15, 12 patients, respectively. In platinum-doublets, the median number of cycle was 4 (range 1-6) and dose reduction was conducted in 4 of 11 patients（36%）receiving at least 2 cycles. CBDCA+ETP was administered for 11 SCLC patients. The response rate was 45% and median PFS was 4.1months (95%CI: 1.2-4.9). Four patients with NSCLC used platinum-doublets; CBDCA+nab-PTX/ CBDCA+PEM: 1/3. There were no patients who achieved objective response and the median PFS was 3.0 months (95%CI: 2.2-6.5). Among 2 of 4 patients, treatment discontinuation due to the deterioration of depression and bone fracture arose. Treatment related death (TRD) was observed in 2 patients with PS-2（13%）. Mono-chemotherapy was administered in 12 patients; VNR/ DTX/ PEM: 7/ 4/ 1. The median number of cycle was 3.5 (range 1-13) and dose reduction was conducted in 2 patients　(20%). No TRD was observed. The response rate and disease control rate was 8% and 91%, and median PFS was 6.4months (95%CI: 1.8-12.2). Grade 3 or more hematological toxicities tended to be more frequent in platinum-doublets than mono-chemotherapy, but febrile neutropenia was frequent in both groups; neutropenia 93%/75%, thrombocytopenia 33%/0%, febrile neutropenia 20%/33%. After discontinuation of first line therapy, the subsequent chemotherapy was more frequently administered in mono-chemotherapy than platinum-doublets（58% vs 40%）.

Conclusion:
The chemotherapy for patients aged 80 and older could be well tolerated in most cases, but patient selection should be more carefully conducted than younger patients.

Background:
Among elderly patients with advanced non-small cell lung cancer (aNSCLC), treatment beyond first-line therapy may be associated with higher risk of adverse events (AEs) due to patients’ poorer performance status and higher disease burden and comorbidities. This study assessed the impact of severe AEs during second-line (2L) therapy on OS and cost of care in elderly with aNSCLC.

Methods:
Patients aged ≥65 years, diagnosed with aNSCLC between 2007-2011 and receiving 2L chemotherapy/targeted therapy, were identified in the SEER-Medicare database (2006-2013). 57 AEs were identified by literature review and consultation with an oncologist. Severe AEs were operationalized as hospitalizations during which a diagnosis for ≥1 AEs was recorded. OS and all-cause healthcare costs post-initiation of 2L chemotherapy/targeted therapy were compared between patients with and without severe AEs.

Results:
Among 3967 patients initiating 2L, 1624 (41%) had ≥1 severe AEs where hypertension (26%), anemia (24%), and pneumonia (23%) were most commonly reported. Patients with and without severe AEs were similar in demographic and cancer characteristics at diagnosis and 2L treatment regimens; although patients with severe AEs had more comorbidities, notably anemia (69% vs 60%). Median OS for patients with severe AEs was almost half of that for patients without severe AEs (6 vs 11 months). After adjustment for potential confounders, patients with severe AEs had more than double risk of death than patients without severe AEs. Cost of caring for patients with severe AEs was more than twice higher than those patients without severe AEs ($16,135 vs $7,559 per-patient-per-month).

OS	With severe AEs cohort N = 1,624	Without severe AEs cohort N = 2,343
Kaplan-Meier rates (95% CI)
1 year post 2L initiation	26% (24 - 28)	46% (44 - 48)
2 years post 2L initiation	11% (9-13)	23% (21-25)
Median survival time (in months)	6	11
Adjusted hazard ratio[1] (95% CI)	2.31 (2.16 - 2.47)
[1] Patients with vs without severe AEs
AE: adverse event; 2L: second line chemotherapy/targeted therapy; CI: confidence intervals

Conclusion:
Occurrence of severe AEs among elderly aNSCLC patients who are receiving 2L chemotherapy/targeted therapy is associated with worse clinical outcomes and a higher economic burden. Results of this analysis suggest that better tolerated therapies may improve outcomes for patients and reduce cost to the healthcare system.

Background:
The addition of B to platinum-doublet chemotherapy in first-line treatment for non-squamous NSCLC showed improvement of progression free survival (PFS) and overall survival (OS) (ECOG 4599). However, in a subset analysis of this trial, grade 3 to 5 toxicities occurred more frequently in elderly patients treated with CPB compared with patients treated with CP and in elderly patients compared with younger patients. Grade 3/4 neutropenia was 34% in elderly patients. GIDO1201 is the first trial addressed specifically to assess the safety of B in elderly patients. We hypothesized that an adjusted dose-regimen administered to elderly patients selected by an adapted geriatric assessment could decrease the rate of neutropenia to 20%.

Methods:
Elderly (≥70 years old) chemotherapy-naive stage IIIB/IV or recurrent non-squamous NSCLC patients, ECOG-PS 0-1, measurable target lesion, and adequate organ functions were eligible for this study. After an Adapted Geriatric Assessment, elderly patients with NSCLC received a modified regimen consisting on triweekly C AUC 4 + P 175 mg/m[2] + B 7.5 mg/kg

Results:
Twenty-six eligible patients (20 male, 6 female; median age, 76 years) were enrolled between August 2013 and June 2015. Six and 20 patients had ECOG-PS of 0 and 1, respectively. The median number of CPB treatment cycles received was 4 (2-6). 17 patients (66%) received B maintenance (median number of cycles 7). At the time of analysis, 3 patients are still on treatment. Grade 3/4 neutropenia was observed only in one patient (3.8%). Grade 3/4 non-haematological and haematological toxicities were observed in 10 (38.5%) and 4 (15.4%). pts, respectively. The most common grade 3/4 AEs included anaemia (11.5%) and hypertension (15.4%). One fatal AE was observed. At the time of this preliminary analysis, median PFS was 8.22 months (6.0-10.3) and median OS was 11.6 (8.0-15.1)

Conclusion:
CPB triweekly followed by BEV showed an acceptable toxicity profile with a favourable grade 3-4 neutropenia of 3.8% compared with previously reported. Efficacy of this first-line regimen for selected elderly non-squamous NSCLC patients was similar to younger patients. However, this study has the limitation of the small number of patients, although a simple size of 51 patients was needed to test this hypothesis, the study was halted after the inclusion of 26 patients due to the slow recruitment.

Background:
Treatment of elderly patients with NSCLC is challenging given comorbidities and reduced tolerability. First-line nab-paclitaxel/carboplatin significantly increased median OS vs paclitaxel/carboplatin in a subset of patients ≥70 years with advanced NSCLC in a phase III trial. Here we report pooled interim safety and efficacy results from the ongoing ABOUND.70+ trial evaluating 2 schedules of first-line nab-paclitaxel/carboplatin in elderly patients with advanced NSCLC.

Methods:
Patients ≥70 years with histologically/cytologically confirmed locally advanced/metastatic NSCLC received (1:1) first-line nab-paclitaxel 100 mg/m[2] qw + carboplatin AUC 6 q3w (arm A) or the same nab-paclitaxel/carboplatin dose q3w followed by a 1-week break (arm B). Stratification factors: ECOG PS (0 vs 1) and histology (squamous vs nonsquamous). Primary endpoint: percentage of patients with grade ≥2 peripheral neuropathy (PN) or grade ≥3 myelosuppression AEs. Key secondary endpoints: PFS, OS, and ORR.

Results:
As of 5/20/2016, 124/128 randomized patients were treated. Median age was 76 years, 30% were ≥80 years, 58% were male, and 86% were white. Majority of patients (70%) had ECOG PS 1, stage IV disease (82%), and nonsquamous histology (59%). Overall, 91 (73%) patients experienced grade ≥2 PN or grade ≥3 myelosuppression AEs (primary endpoint). Grade ≥2 PN was reported in 34%, and grade ≥3 neutropenia, anemia, thrombocytopenia in 52%, 21% and 21%, respectively. Interim efficacy analysis demonstrated a median PFS of 6.2 months and a median OS of 14.6 months. ORR (unconfirmed) was 43% (95% CI, 34.3-52.0), with 1 complete response; 32% had a best response of stable disease, 6% had progressive disease, and response data are pending for 19% of patients. QoL measured by LCSS and EQ-5D-5L remained stable or improved through 4 cycles.

Conclusion:
This interim analysis from ABOUND.70+ demonstrated promising activity and tolerability of nab-paclitaxel/carboplatin regimens in elderly patients with advanced NSCLC similar to prior phase III data. NCT02151149 Figure 1

Background:
There is some evidence that patients who participate in clinical trials have improved outcomes compared with patients receiving standard chemotherapy. We look forward if the outcome for patients with stage III and IV non-small cell lung cancer treated on a clinical trial was associated with a better outcome at our institution, a tertiary centre in Spain.

Methods:
Patients with NSCLC treated on standard chemotherapy/TKI between 2010 and 2015 were matched with individuals who received 1st line chemotherapy or TKI in a clinical trial in a ratio 2:1. Cases were matched for age (<65 years or >65 years), stage (III or IV), histology (adenocarcinoma, squamous), EGFR status (mutated vs wild-type) and therapy received in 1st line (platinum doublet, TKI). All patients were World Health Organisation (WHO) performance status 0 or 1.

Results:
Patients in each group were well matched for stage, histological sub type, surgery and treatment. The median follow up for patients treated on a trial was 3.2 years, compared with 2.8 years for matched patients who received standard 1st line therapy. The median overall survival for patients treated on a trial was 19.4 months, compared with 15.8 months for those in a matched control group. The difference between groups was not significant (Log rank test, HR 0.81, 95% CI: 0.42 to 1.35, p=0.5). The difference in overall survival between groups was not significant (Log Rank test, HR 0.87, 95%CI: 0.46 to1.64, p=0.7).

Conclusion:
Data from our institution, a tertiary centre active in clinical trials, shows a good outcome for patients with advanced NSCLC regardless of whether they received 1st line therapy on a clinical trial. There is a trend for a better outcome for those patients that are enrolled in a clinical trial, so this encourage our active participation in clinical research.

Background:
Small cell lung cancer (SCLC) is an aggressive form of lung cancer characterized by loss of the tumor suppressor Rb. Chemotherapy remains the standard of care for SCLC patients but produces severe myelosuppression that compromises patient outcomes. G1T28 is a potent and selective CDK4/6 inhibitor in development to reduce chemotherapy-induced myelosuppression and preserve immune system function in SCLC patients. Cyclin dependent kinases 4 and 6 (CDK4/6) phosphorylate Rb protein promoting proliferation of specific cell types such hematopoietic stem progenitor cells (HSPCs) by allowing cells to progress through G1 to S phase. HSPCs are exquisitely dependent upon CDK4/6 for proliferation and become arrested in the G1 phase of the cell cycle upon exposure to G1T28. We hypothesize that G1T28-mediated CDK4/6 inhibition may selectively protect immune cells (Rb intact) from chemotherapy without antagonizing the antitumor efficacy in Rb deficient tumors, such as SCLC. G1T28 preservation of adaptive immunity from cisplatin-induced cytotoxicity may enhance the efficacy of chemotherapy in SCLC tumors by allowing a more robust host-immune response.

Methods:
Syngeneic mouse models were established by flank injection of KP1 and TKOTmG murine cells derived from TP53 and RB1 or TP53, RB1 and P130 mutant mice respectively. When tumors reached 150mm[3], mice were randomized and treated with G1T28, cisplatin and combination of both. Tumor volumes were measured and immune populations from tumor, spleen and peripheral blood were analyzed by flow cytometry.

Results:
CDK4/6 inhibition by G1T28 protects peripheral white blood cells (lymphocytes, monocytes and eosinophils) from cisplatin-induced cytotoxicity in the syngeneic SCLC KP1 mouse model. Additionally, treatment with G1T28 prior to cisplatin inhibited tumor growth to a greater extent than cisplatin alone (46% versus 12%, respectively) in the syngeneic SCLC TKOTmG mouse model.

Conclusion:
G1T28-mediated CDK4/6 inhibition protects immune cells from chemotherapy and potentiates the reduction of tumor volume when combined with cisplatin in a syngeneic Rb deficient SCLC mouse model. Studies are ongoing to determine if the immune protection by G1T28 is enhancing the anti-tumor activity of cisplatin in this model, as well as to evaluate other potential mechanisms. Additionally, clinical trials testing the combination of G1T28 with chemotherapy in patients with extensive stage SCLC are currently in progress (1[st] line, carboplatin-etoposide, NCT02499770; 2[nd] line, topotecan, NCT02514447).

Background:
Programmed death-1 (PD-1) inhibitors are effective second line treatment in non-small cell lung cancer (NSCLC), however objective responses are seen in only 20-30% of patients. While a minority of patients achieve durable response to PD-1 inhibitors, those who progress or are refractory receive salvage chemotherapy. We evaluate response to salvage chemotherapy following exposure to PD-1 inhibitors.

Methods:
Eligible patients were adults with NSCLC followed at the Vanderbilt Cancer Center or the Winship Cancer Institute from 2011 to 2016 who received salvage chemotherapy following PD-1 inhibitors (cases) versus no PD-1 inhibitors (controls). CT-imaging of the chest/abdomen/pelvis was done within 4 weeks of initiation of salvage chemotherapy and every 6 weeks thereafter. Revised RECIST guidelines were used to define response to treatment. Clinical and imaging data were abstracted from review of electronic medical records. Multivariate logistic regression analysis was used to calculate probability of response.

Results:
Three hundred patients’ charts were reviewed and 56 patients met eligibility criteria. Among evaluable patients, 28 were males versus 28 females. Median age was 61.64 years (interquartile ranges (IQR): 55.33–69.36) in cases versus 67.82 (IQR: 54.08-72.24) in controls. Forty-one patients were classified as cases versus 15 controls. Thirty-six patients received nivolumab and 5 pembrolizumab. Forty-five (80%) patients had adenocarcinoma, 10 (18%) squamous cell carcinoma and 1 (2%) large cell carcinoma. The median number of chemotherapy regimens prior to salvage chemotherapy was 3 (IQR: 2-3) in cases versus 2 (IQR: 1-2) in control. The drugs most commonly used in salvage regimens included docetaxel, pemetrexed, paclitaxel, gemcitabine. Seven (17%) cases had partial response to chemotherapy versus 1(6.6%) controls. Eleven (27%) cases had progressive disease versus 6 (40%) controls. Twenty-three (56%) cases had stable disease versus 8 (53%) controls. The odd ratio for achieving a partial response was 0.16 (95% CI: 0.08 to 0.35, P=0.000). In multiple logistic regression model, age, gender, number of prior chemotherapy regimens, tumor histology, smoking status, different salvage chemotherapy regimens were not associated with the likelihood of achieving a partial response.

Conclusion:
The odds of achieving a partial response to salvage chemotherapy were 6 times higher in patients with prior exposure to PD-1 inhibitors. This observed difference however warrants confirmation in larger cohorts. If confirmed, this difference may represent an argument to promote immune PD-1 inhibitors as first line regimen for the treatment of NSCLC not amenable to targeted therapy.

Background:
A validated RNA molecular expression signature based on cell cycle progression (CCP) genes [CCP score] and a molecular Prognostic Score [(mPS) combination of CCP score and pathological stage] are significant prognostic markers of cancer-specific mortality in patients with early stage lung adenocarcinoma. Additionally, preliminary data suggest a significant association between CCP score and absolute benefit with platinum-based adjuvant chemotherapy in early stage lung adenocarcinoma patients. The aim of this study is to further demonstrate the effectiveness of CCP score and mPS in predicting platinum-based chemotherapy benefit in a large, multi-institutional cohort of stage IB and IIA lung adenocarcinoma patients who underwent definitive surgical resection with and without adjuvant chemotherapy.

Methods:
Formalin-fixed paraffin-embedded surgical tumor samples from approximately 1000 patients diagnosed with stage IB and II adenocarcinoma who underwent definitive surgical treatment with adjuvant platinum-based chemotherapy (n = 400) and without (n = 600) will be analyzed for 31 proliferation genes by quantitative RT-PCR. The associations of CCP score and mPS with absolute benefit from platinum-based chemotherapy will be separately examined using Cox proportional hazards regression with an outcome of 5-year lung cancer survival.

Results:
To date, lung tumor samples have been accrued from 388 patients treated with a platinum-based chemotherapy and 590 untreated patients. We hypothesized that the absolute treatment benefit will increase as CCP score or mPS increases. Results will be shown for continuous CCP score and mPS as well as pre-defined binary CCP score and binary mPS.

Conclusion:
This study will determine the abilities of CCP score and mPS as predictive tools for absolute chemotherapy benefit and 5-year lung cancer survival in patients with early stage lung adenocarcinoma thereby furthering the clinical utility for these signatures to identify patients with high risk disease who should receive adjuvant chemotherapy.

Background:
Despite a consistent rate of initial responses, chemotherapy treatment often results in the development of chemoresistance, leading to therapeutic failure in non-small cell lung cancer (NSCLC). CMTM1_v17 is highly expressed in human testis tissues and solid tumor tissues but relatively low expression was obtained in the corresponding normal tissues. This study aims to investigate the significance of CMTM1_v17 in NSCLC and its association with cisplatin-based neo-adjuvant chemotherapy (NAC) response

Methods:
31 pairs of tumor tissues before and after NAC and 78 resected tumor tissues after NAC were utilized for immunohistochemistry (IHC) staining of CMTM1_v17 protein. Flow cytometry was used to detect the change of CMTM1_v17 expression in NSCLC patient-derived xenografts (PDX models) with cisplatin treatment.

Results:
CMTM1_v17 expression was found to be significantly related to treatment effect and outcome in the tumor tissues after NAC but not in the tissues before NAC from the 31 cases of NSCLC. We identified that high CMTM1_v17 expression was associated with low objective remission rate (ORR) (p=0.008) and poor prognosis (the median OS: 35.1 months vs 65.6 months，p=0.0045；the median DFS: 17.27 months vs 35.54 months，p=0.0207) in the 31 patients. Next, we detected CMTM1_v17 expression to confirm correlation between this protein status and clinical characteristics in 78 NSCLC patients with NAC. The up-regulation of CMTM1_v17 had a higher SD rate (p=0.007) and worse outcome ( the median OS: 41.0 months vs 80.6 months, p=0.0028；the median DFS: 33.4 months vs 64.8 months，p=0.0032). COX multivariate analysis indicated that CMTM1_v17 is an independent prognostic risk factor on patients who received NAC (OS：HR=3.642，p=0.002；DFS：HR=2.867，p=0.003). Then, we tested CMTM1_v17 expression in the lung cancer PDX mice with different treatment, showing that this protein was up-regulated in the tumor tissues received cisplatin treatment, compared to the tumor tissues with saline stimulation of control group.

Conclusion:
CMTM_v17 expression was significantly associated with chemoresistance and poor prognosis of the early stage NSCLC patients who received NAC. Cisplatin could induce the expression of CMTM1_v17 in lung cancer cells from PDX model.

Background:
Paclitaxel micelle for injection is a Cremophor-free, nanoscale, polymer micelles loaded paclitaxel formulation. The absence of Cremophor EL may permit Paclitaxel Micelle to be administered without the premedications used for the prevention of hypersensitivity reactions. The objective of this Phase I trial were to determine the toxic effects, maximum tolerated dose (MTD), Dose-limiting toxicity (DLT), pharmacokinetics(PKs) profile and recommended phase II dose of Paclitaxel Micelle.

Methods:
Dose escalation of paclitaxel micelle for injection followed the standard “3+3” rule, and started at does level 175 mg/m2. Eligible patients were treated with paclitaxel micelle given as a 3 h intravenous infusion on day 1 once every 3 weeks. Blood samples were collected to determine the PKs of paclitaxel micelle.

Results:
18 patients with advanced malignancies were enrolled and treated, including non-small cell lung cancer (NSCLC) 17 patients and breast cancer 1 patients. The dose of paclitaxel micelle for injection ranged from 175 mg/m2 (dose level 1) to 435 mg/m2 (dose level 5). All patients were evaluable for toxicity and antitumor response. The most common toxic reactions of paclitaxel micelles include neutropenia, peripheral nerve numbness and muscle pain, no acute hypersensitivity reactions were observed. DLT included grade 4 neutropenia, which occurred in 1 of 6 patients treated at 300 mg/m2 (level 3) and all of 3 patients at 435 mg/m2 (level 5), and grade 3 peripheral nerve numbness in 1 patient at 435 mg/m2 (level 5). The MTD was thus determined to be 390mg/m2 (level 4). Partial response was observed in 6 of 18 patients (33.3%), 3 of whom had prior exposure to paclitaxel chemotherapy. 9 patients (50%) had stable response and only 3 patients had disease progression. 18 patients completed 99 cycles of paclitaxel micelle chemotherapy (2~19 cycles), and now one patient at 390 mg/m2 (level 4) has been completed 19 cycles of chemotherapy and is still in treatment. The median PFS was 9.1months (95% CI,4.70-18.43). The paclitaxel Cmax and area under the curveinf values increased with escalating doses, which revealed paclitaxel micelles has linear PKs.

Conclusion:
In this study, Paclitaxel Micelles was administered safely without premedication for preventing hypersensitivity reactions and showed higher paclitaxel MTD without additional toxicity, which are more advantageous than conventional paclitaxel formulation in clinic treatment. Therefore, the recommended dose for the phase II study is 300 mg/m2.

Background:
The BEVA2007 study is a multistep phase I-II trial aimed to investigate in advanced NSCLC patients the safety, the immunobiological and the antitumor activity of the mPEBev, an original metronomic chemo-biological regimen whose results showed significant antiangiogenic and immune-modulating and antitumor activity.

Methods:
Eighty-six advanced NSCLC patients (76 males and 10 females; 53, adenocarcinoma; 13 squamous carcinoma; and 20 with different subtypes) were enrolled between September 2007 and September 2015. All of them received cisplatin (30mg/sqm, days 1-3q21), oral etoposide (50mg, days 1-15q21) and bevacizumab 5mg/kg on the day 3q21 (mPEBev regimen).

Results:
There were two cases of fatal bleeding after 3 and 4 treatment courses, and five cases of severe infections fully recovered with medical treatment. Hematological toxicity [grade 1-3 leukopenia (25%), anemia (25%)], g 1-2 gastroenteric toxicity (10%) and alopecia (50%) were the most common adverse events. There was a partial response in 54 cases ( 62,8%) and a stable disease in 9 cases (10,5%) with a mean progression free survival (PFS) and overall survival (OS) of 13.46 (8.39-18.54) and 20.57 (14.5-26.6) months, respectively. Log-rank tests, revealed a longer survival in patients with baseline levels of Neutrofil to lymphocyte ratio (NLR) [L vs. H= 24.9 vs. 8.9 months, P=0.033], IL17 [L vs. H= 32.9 vs 11 months, P=0.033], leptine [L vs. H= 30,5 vs 8,5 months, P=0,025] and T~reg~s [L vs. H= 35.37 vs 9.9 months, P=0.049] lower than median value of each specific parameter. A longer survival was also found in patients with a treatment related fold increase to baseline > 1 in CD4+/CD8+ t cell ratio and DCs expressing CD83 [L vs H 8.4 vs 20.85 months, P=0.05 ] and CD80 [L vs H = 8 vs 23 months, P=0.046].

Conclusion:
These results suggest that both systemic Inflammatory status and treatment-related immunomodulation may affect the outcome of these patients a finding that highlight a possible involvement of immunesystem in ultimate antitumor effect of this regimen, and offer a solid rationale to test our metronomic regimen in a module of sequential combination with anti-PD-1/PDL-1 inhibitors.

Background:
Background: Albumin-bound paclitaxel (nab-PTX) is a paclitaxel formulation in which nanoparticles of PTX are bound to human serum albumin. We conducted this study to evaluate the efficacy and safety of nab-PTX in patients with advanced non-small cell lung cancer (NSCLC) who failed previous chemotherapy.

Methods:
Methods: Eligible patients had refractory advanced NSCLC. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 and adequate organ function. Patients received nab-paclitaxel, 100 mg/m[2] i.v. on days 1, 8 and 15 every 4 weeks. The primary endpoint was the overall response rate (ORR).

Results:
Results: From July 2013 to July 2015, 31 patients enrolled, 14 patients received nab-paclitaxel as a second-line and 17 received it as an over third-line therapy. The median number of treatment cycles was 5 (range, 1-11). The overall response rate was 19.3% (95% confidence interval, 9.1%-36.2%) (compleate response (n = 0), partial response (n = 6), stable disease (n = 17), and progressive disease (n = 8)). The median progression-free survival time was 4.5 months (95% confidence interval 3.5- 6.3 months), median overall survival time was 15.7 months, and 1-year survival rate was 54.8%. Grade 3 or 4 hematological toxicities included neutropenia (38.6%), anemia (3.2%), and thrombocytopenia (0%). Grade 3 or 4 non-hematological toxicities were elevated aspartate transaminase level (3.2%) and sensory neuropathy (9.6%). Febrile neutropenia developed in 12.9% patients. No treatment-related deaths were observed in this study.

Conclusion:
Conclusions: Single agent nab-paclitaxel showed significant clinical activity with manageable toxicities for patients with chemorefractory advanced NSCLC. This study provides relevant data for routine practice and future prospective trials evaluating treatment strategies for patients with advanced NSCLC. Clinical trial information: UMIN000011696.

Background:
Neutropenia is the most serious hematologic toxicity associated with the use of chemotherapy. Severe neutropenia (SN) may result in dose delays and/or reductions, and the use of growth colony stimulating factors (CSFs) increases the cost of therapy. Lyman et al. (2011) published a risk model to predict individual risk of neutropenia in patients receiving chemotherapy for multiple types of cancer. The Lyman model (LM) has not been validated by external datasets. We investigated the LM with a large external lung cancer dataset based on clinical criteria of SN and investigated new risk prediction models for SN.

Methods:
Stage IIIA/IIIB/IV non-small cell lung cancer (NSCLC) and extensive small cell lung cancer (SCLC) chemotherapy phase II/III trials completed in 1990-2012 were assembled from U.S. cancer cooperative groups. SN was defined as any neutropenic complications grade ≥ 3 according to CTCAE. A risk score was calculated as a weighted sum of regression coefficients of the LM for all patients in the database. The performance of risk models was evaluated by the area under the ROC curve (AUC) with a good model defined as AUC ≥ 0.7. To develop new risk models, a random split was used to divide the database into training cohort (2/3) and testing cohort (1/3). Multivariable logistic regression models with stepwise selection and lasso selection (Tibshirani, 1996) were built in training cohort and validated in testing cohort. Candidate predictors included patient-level and treatment-level variables. The patients with complete data were used for validation and all patients, including those with imputed predictors, were used to develop new risk models.

Results:
Eighty seven trials with 14,829 patients were included. The LM had a good performance in SCLC patients (AUC=0.86), but it had poor performance in NSCLC patients (AUC=0.47), and an overall unsatisfactory performance in all patients (AUC=0.56). The stepwise model had superior performance than the lasso model (AUC: 0.84 vs. 0.76) in training, while the lasso model had smaller shrinkage in testing. A parsimonious model, based on histology, prior chemo, platinum-based, taxanes, gemcitabine, CSFs, age as continuous variable, relative dose intensity, and white blood cell (WBC), performed slightly worse (AUC=0.71) in testing than the stepwise model and the lasso model.

Conclusion:
The U.S. cooperative group data failed to validate the LM in predicting the risk for severe neutropenia in lung cancer patients receiving chemotherapy. The parsimonious model involving nine predictors showed good performance in predicting severe neutropenia. Prospective validation is warranted.

Background:
We performed an open-label, multicenter, single-arm phase II study (UMIN ID 000010532) to prospectively evaluate the efficacy and safety of nab-paclitaxel for previously treated patients with advanced non–small cell lung cancer (NSCLC).

Methods:
Patients with advanced NSCLC who experienced failure of prior platinum-doublet chemotherapy received weekly nab-paclitaxel (100 mg/m[2]) on days 1, 8, and 15 of a 21-day cycle until disease progression or the development of unacceptable toxicity. The primary end point of the study was objective response rate (ORR).

Results:
Forty-one patients were enrolled between September 2013 and April 2015. The ORR was 31.7 % (90% confidence interval, 19.3% to 44.1%), which met the primary objective of the study. Median progression-free survival was 4.9 months (95% confidence interval, 2.4 to 7.4 months) and median overall survival was 13.0 (95% confidence interval, 8.0 to 18.0 months) months. The median number of treatment cycles was four (range, 1 to 17) over the entire study period, and the median dose intensity was 89.1 mg/m[2] per week. Hematologic toxicities of grade 3 or 4 included neutropenia (19.5%) and leukopenia (17.1%), with no cases of febrile neutropenia being observed. Individual nonhematologic toxicities of grade 3 or higher occurred with a frequency of <5%.

Conclusion:
Weekly nab-paclitaxel was associated with acceptable toxicity and a favorable ORR in previously treated patients with advanced NSCLC. Our results justify the undertaking of a phase III trial comparing nab-paclitaxel with docetaxel in this patient population.

Background:
Lung cancer is a disease of uncontrolled cell growth in tissues of lung. It is most common cause of cancer-related deaths in men and second most common in women. It is responsible for 1.3 million deaths worldwide annually. Most common cause is long term exposure to tobacco smoke. The occurrence of lung cancer in nonsmokers, who accounts 15% cases, attributed to combination of genetic factors, radon gases, and asbestos and air pollution including second hand smoke.

Methods:
The treatment and management of diseases associated with lung is difficult with presently available therapeutic systems, as insufficient drug reaches to lung due to mucocilliary clearance of the medicament. The proposed drug delivery system was used to determine targeting efficiency of optimized formulation via conjugation of ligand ie Solid Lipid Nanoparticles (SLNs) bearing paclitaxel anchored with lactoferrin molecules. These systems may enhance the drug delivery to lung via receptor mediated endocytosis mechanism

Results:
The SLNs were prepared by modified Solvent Injection Method, and then sonicated and finally ligand anchored. The nanoparticles were characterized in-vitro for their shape and size by Scanning (SEM) & Transmission Electron Microscopic (TEM), drug entrapment, in-vitro drug release and stability. The in-vivo study comprised of biodistribution studies in various organs and fluorescence microscopy was performed. The Sulforhodamine Blue (Srb) Colorimetric Assay was performed on human lung cancer cell line (BEAS-2B) For Cytotoxicity Screening.

Conclusion:
The in-vitro & in-vivo studies result shows a more specific delivery of the Paclitaxel to the Lung. The cell cytotoxicity studies states that Lactoferrin coupled SLN deliver the drug more specifically and have lowtoxicity effect over the unconjugated SLN and plain drug solution.This study suggests that loading another drug will open new and exciting gateways in the management of other lung diseases. Our finding should be helpful for possible exploitation of lactoferrin as future ligand for the delivery of the drugs for treatments of other lungs diseases.

Background:
There is a lot of lung cancer patients progressing beyond the third or fourth line of treatment still suitable for further therapy .And some patients choose to receive previous chemotherapy rechallenge,particularly in patients who had previously responded.So the role of chemotherapy rechallenge is worth discussing.Pemetrexed is known to be a potent chemotherapeutic agent with high efficacy and low toxicity in the treatment of advanced lung adenocarcinoma.In clinical practice,it is used to rechallenge by certain patients,according to previous efficacy and tolerance, as long as it was stopped for reasons other than progression. Therefore, the aim of this retrospective study is to evaluate the efficacy and safety of pemetrexed rechallenge strategy in lung adenocarcinoma.

Methods:
We retrospectively identified patients with the following criteria:(i) clinical benefit (stable disease(SD) or partial response(PR)) from previous line of pemetrexed-based chemotherapy (ii) discontinuation for a reason other than progression (iii) rechallenge with pemetrexed after a minimal pemetrexed-based chemotherapy-free interval of 3 months.The main objectives were to evaluate disease control rate (DCR),progression-free survival (PFS), overall survival (OS) and toxicity of pemetrexed rechallenge .

Results:
62 patients were enrolled into this study. Initial pemetrexed-based therapy was used as 1[st] or 2[nd] line of chemotherapy in 46(74.2%), and 16(25.8%)of cases. 43(69.4%) patients achieved SD, 19 (30.6%) achieved PR. Pemetrexed was rechallenged as a 2nd, 3rd,or further line of chemotherapy in 43.5%, 37.1% and 19.4% of cases.4 patients (6.5%) achieved PR ,41 (66.1%) achieved SD and 17 (27.4%) experienced progressive disease.The median PFS was 3.9 months with the pemetrexed rechallenge.The median OS from the beginning of pemetrexed rechallenge was 8.2 months (95% CI: 5.0-11.3months).38(61.3%) patients had chance to receive further therapy after pemetrexed challenge failure.Next,we associated DCR,PFS,OS of pemetrexed rechallenge with the cllicial outcomes of initial pemetrexed treatment. We found that patients who had longer PFS (P=0.036)or achieved PR response(P=0.022) to initial pemetrexed were more likely to get benefit from rechallenge.The patients with longer PFS of initial treatment exhibited longer PFS of rechallenge (P=0.008). However, the interval time between initial and rechallenge treatment did not affect efficacy of pemetrexed rechallenge.25 patients (40%) reported grade 1/2 toxicity, 4 patients (6%) experienced grade3/4 toxicity, mostly neutropenia (65%) and hepatobiliary disorder (24%).

Conclusion:
It is a pragmatic strategy to retreat patients with pemetrexed when this drug has shown previous activity.The rechallenge treatment is generally well tolerated.

Background:
LCL161, a novel Smac mimetic, is known to have anti-tumor activity and improve chemosensitivity in various cancers. However, the function and mechanisms of the combination of LCL161 and paclitaxel in non-small cell lung cancer (NSCLC) remain unknown.

Methods:
Cellular inhibitor of apoptotic protein 1 and 2 (cIAP1 and cIAP2) expression in NSCLC tissues and adjacent non-tumor tissues were assessed by immunohistochemistry. The correlations between cIAP1,2 expression and clinicopathological characteristics, prognosis were analyzed. Cell viability and apoptosis were measured by MTT assays and Flow cytometry. Western blot and co-immunoprecipitation assay were performed to measure the protein expression and interaction in NF-κB pathway. siRNA-mediated gene silencing and caspases activity assays were applied to demonstrate the role and mechanisms of cIAP1,2 and RIP1 in lung cancer cell apoptosis. Mouse xenograft NSCLC models were used in vivo to determine the therapeutic efficacy of LCL161 alone or in combination with paclitaxel.

Results:
The expression of cIAP1 and cIAP2 in Non-small cell lung cancer (NSCLC) tumors was significantly higher than that in adjacent normal tissues. cIAP1 was highly expressed in patients with late TNM stage NSCLC and a poor prognosis. Positivity for cIAP1 and cIAP2 was an independent prognostic factor that indicated a poorer prognosis in NSCLC patients. LCL161, an IAP inhibitor, cooperated with paclitaxel to reduce cell viability and induce apoptosis in NSCLC cells. Molecular studies revealed that paclitaxel increased TNFα expression, thereby leading to the recruitment of various factors and the formation of the TRADD-TRAF2-RIP1-cIAP complex. LCL161 degraded cIAP1 and cIAP2, releasing RIP1 from the complex. Subsequently, RIP1 was stabilized and bound to caspase-8 and FADD, thereby forming the caspase-8/RIP1/FADD complex, which activated caspase-8, caspase-3 and ultimately lead to apoptosis. In nude mouse xenograft experiments, the combination of LCL161 and paclitaxel degraded cIAP1,2, activated caspase-3 and inhibited tumor growth with few toxic effects.

Conclusion:
Thus, LCL161 could be a useful agent for the treatment of NSCLC in combination with paclitaxel.

Background:
The translational research analysis of the Pointbreak study could demonstrate superior overall survival (OS) for TTF-1 expressing NSCLC in comparison to TTF1-1 negatives treated with Pemetrexed based chemotherapy. The aim of this study was to prove retrospectively whether this finding can be reproduced in patients from the daily clinical practice in three different german hospitals.

Methods:
323 patients (pts), 182m, 141f, median age 64 years (34-84) with non-sqamous NSCLC stage UICC IIIB/IV undergoing pemetrexed based palliative chemotherapy were analyzed for TTF- 1 expression by immunohistochemistry and outcome.

Results:
246 pts (76%) were TTF-1 positive, well balanced for for age and gender. Median number of administered chemotherapy cycles was 4 in both groups; 19 pts (5.9%) received maintenance therapy. Response was superior in TTF-1 expressing (vs non-expressing) patients (CR 2% vs. 6%, PR 58% vs. 39%, NC 21% vs. 16%, PD 19% vs. 39%, X[2]=14.4, p<0.002) as well as OS (MST 14.5m vs. 8.3m, HR=0.44, CI 0.33-0.58, p<0.0001) and progression free survival (PFS: MST 7.7m vs. 4.8m, HR 0.51, CI 0.35-0.74, p<0.001). 1-y and 2-y OS were 59% and 23% for TTF-1 expressing pts compared to 34% and 0%, respectively In multivariate analysis TTF-1 expression (HR= 0.43, CI 0.30 - 0.63, p<0.0001) and 4 vs. 6 cycles of chemotherapy (HR=0.81, CI 0.70 - 0.95, p=0.009) were the only independent factors for OS. For PFS TTF-1 expression was the only independent predictive factor (HR=0.49, CI 0.31-0.77, p=0.002).

Conclusion:
These results confirm the relevance of TTF-1 expression on outcome in pemetrexed based chemotherapy with TTF-1 being of significant independent prognostic relevance. Further analyses with TTF-1 in non pemetrexed treated patients are ongoing to evaluate its predictive value.

Background:
The combination of pemetrexed and erlotinib was synergistic in non-small cell lung cancer in vitro, if erlotinib exposure was avoided before pemetrexed. To enhance the efficacy of 2[nd]-line pemetrexed, we designed to test the sequential administration of afatinib followed by pemetrexed (pem+afa) compared with pemetraxed (pem) monotherapy.

Methods:
We performed randomized phase II trial in Asan Medical Center, Seoul, Korea. Patients with histologically or cytologically confirmed as non-squamous lung cancer were enrolled. Patients were stratified by response to 1[st] line treatment and smoking history, and randomly assigned in a 2:1 ratio to receive intravenous pemetrexed (500 mg/m2) on D1 followed by afatinib 40 mg/day on D2-15 or pemetrexed (500 mg/m2) on D1 every 3 weeks. The treatment was continued until disease progression. Primary end point was objective response rate (ORR), and secondary end points were progression-free survival (PFS) and overall survival (OS).

Results:
From August 2012 to July 2016, a total 87 patients (male, 71.3%; never smoker 31.0%; sensitive to 1[st]-line chemotherapy (PR+SD) 65.5%; median age 59 years) were randomized to pem (n=30) or pem+afa (n=57). Median follow-up duration was 12.4 months (range, 0.4-46.6 months). Median cycles administered were both 4 cycles in each groups (range, 1-37 in pem group; 1-62 in pem+afa group). Among 57 patients in pem+afa group, 26 patients (45.6%) underwent dose reduction (30 mg/day in 18 patients; 20 mg/day in 8 patients). By July, 2016, among 81 evaluable patients, 22 responses were noticed (4 in pem group; 18 in pem+afa group). ORR were 13.3% (4/30) and 31.6% (18/57) in pem and pem+afa, respectively (2-sided p value=0.074). Median PFS were 2.9 months and 5.7 months in pem and pem+afa, respectively (HR 0.718; 95% CI, 0.427-1.148; p=0.163). Median OS were 15.6 months and 12.1 months in pem and pem+afa, respectively (HR 1.393; 95% CI, 0.794-2.445; p=0.245).

Conclusion:
Intercalation of afatinib to pemetrexed looks better in numerically but statistically insignificant over pemetrexed monotherapy in 2[nd]-line treatment in EGFR unselected population with non-squamous lung cancer.

Background:
In the absence of specific treatable mutations, platinum-based doublet chemotherapy remains the gold standard treatment for NSCLC patients. However, its clinical efficacy is hindered in many patients due to intrinsic and acquired resistance to these agents, in particular cisplatin. Alterations in the DNA repair capacity of damaged cells is now recognised as an important factor in mediating this phenomenon.

Methods:
DNA Repair Pathway RT[2 ]Profiler Arrays were used to elucidate key DNA repair genes implicated in chemoresistant NSCLC cells using cisplatin resistant (CisR) and corresponding parental (PT) H460 cells previously established in our laboratory. DNA repair genes significantly altered in CisR cells were validated at the mRNA and protein level, using RT-PCR and Western blot analysis, respectively. The translational relevance of differentially expressed genes was examined in a cohort of chemo-naïve matched normal and tumour lung tissues from NSCLC patients. Loss of function studies were carried out using siRNA technology. The effect of XRCC6BP1 gene knockdown on apoptosis was assessed by FACS using Annexin-V/PI staining. Cellular expression and localisation of XRCC6BP1 protein and γH2AX foci in response to cisplatin were examined by immunofluorescence using the Cytell™ Imaging System. To investigate a role for XRCC6BP1 in lung cancer stem cells, Side Population (SP) studies were used to characterise stem-like cells in chemoresistant cells. XRCC6BP1 mRNA analysis was also examined in ALDH1[+] and ALDH1[- ]subpopulations.

Results:
We identified a number of critical DNA repair genes that were differentially regulated between H460 PT and CisR NSCLC cells, where XRCC6BP1 mRNA and protein expression was significantly increased (mRNA; 19.4-fold) in H460 CisR cells relative to their PT counterparts. Relative to matched normal lung tissues, XRCC6BP1 mRNA was significantly increased in lung adenocarcinoma patients. Gene silencing of XRCC6BP1 induced significant apoptosis of CisR cells and reduced the DNA repair capacity of these cells relative to scrambled (negative) controls. Immunofluorescence studies showed an increase in XRCC6BP1 protein expression and γH2AX foci in CisR cells relative to their PT counterparts. SP analysis revealed a significantly higher stem cell population in CisR cells, while XRCC6BP1 mRNA expression was considerably increased in SKMES-1, H460 and H1299 ALDH1[+] CisR cells compared to ALDH1[-] cells.

Conclusion:
We identified XRCC6BP1 as key DNA repair gene implicated in cisplatin resistant NSCLC. Our data highlight the potential of targeting components of the DNA repair pathway in chemoresistant lung cancer, in particular, XRCC6BP1, either alone or in combination with conventional cytotoxic therapies.

Background:
The cancer stem cell (CSC) hypothesis is now a well-established and widely investigated field within oncology. It hypothesizes that there is a robustly resistant stem-like population of cells that survive initial chemotherapeutic treatment. These surviving CSCs contribute to the recapitulation of a heterogeneous tumour via a combination of asymmetric and symmetric cell division, subsequently resulting in relapse and therapeutic resistance. BBI608 is a small molecule inhibitor of cancer stemness; it targets STAT3, leading to the inhibition of critical genes required for the maintenance of cancer stemness. To date, preclinical studies investigating BBI608 in in vitro and in vivo models of pancreatic and prostate cancer have shown promise.

Methods:
Aldefluor (Stemcell Technologies) staining and flow cytometry analysis of an isogenic panel of matched parent (PT) and cisplatin resistant (CisR) NSCLC cell lines identified the ALDH1-positive (ALDH1+ve) subpopulation of cells as a key CSC subset across cisplatin resistant NSCLC cell lines. PT and CisR cell lines were treated with BBI608 (1μM) and stemness factors investigated, the presence of the ALDH1+ve CSC population was reassessed by flow cytometry and expression of stemness factors (Nanog, Oct-4, Sox-2, Klf4 and cMyc) were examined by reverse transcriptase PCR. The functional parameters of proliferation, clonogenic survival and apoptosis were investigated with increasing concentrations of cisplatin (0-100μM) in the presence and absence of 1μM BBI608.

Results:
The NSCLC CisR sublines showed a significantly greater ALDH1+ve CSC population relative to their PT counterparts. Treatment of the CisR sublines with 1μM BBI608 significantly depleted the ALDH1+ve CSC population and decreased gene expression of stemness markers. BBI608 significantly decreased the proliferative capacity and clonogenic survival of the CisR sublines when in combination with cisplatin relative to cisplatin alone. Cisplatin in combination with BBI608 significantly increased cisplatin-induced apoptosis in the CisR sublines indicating restoration of cisplatin sensitivity.

Conclusion:
To date, BBI608 has not been investigated in terms of a cisplatin resistant CSC population in lung cancer. BBI608, via the inhibition of STAT3, pharmacologically depleted the CSC subpopulation and stemness expression while simultaneously restoring cisplatin sensitivity. There are currently a number of clinical trials recruiting patients to further investigate BBI608. These data suggest a promising role for BBI608 in the treatment of non-responsive or recurrent NSCLC.

Background:
The root of therapeutic resistance is hypothesized to be the presence a rare CSC population within the tumour population which survives chemotherapeutic treatment and has the potential to recapitulate a heterogenic tumour. Aldehyde dehydrogenase 1 (ALDH1) is involved the catalytic conversion of vitamin A (retinol) to retinoic acid and has been identified as a CSC marker in a number of solid malignancies.

Methods:
FACS analysis of an isogenic panel of matched parent (PT) and cisplatin resistant (CisR) NSCLC cell lines identified ALDH1 as a promising CSC-marker associated with cisplatin resistance across NSCLC histologies. The H460 CisR subline was separated by FACS into ALDH1-positive and negative subpopulations and subcutaneously injected into NOD/SCID mice to assess tumour initiation and growth. ALDH1 was inhibited in vitro within the cell lines using two pharmacological ALDH1 inhibitors, DEAB and disulfiram, alone and in combination with cisplatin. Cell lines were treated in vitro with retinol and all-trans retinoic acid (ATRA) to exploit the vitamin A/retinoic acid axis in which ALDH1 is involved.

Results:
The CisR sublines showed significantly greater ALDH1 activity relative to their PT counterparts. In vivo subcutaneous injection of ALDH1-positive and negative subpopulations revealed no significant difference in tumour initiation or growth rate. ALDH1 inhibition in combination with cisplatin significantly decreased clonogenic and proliferative competencies and increased apoptosis cell death compared to cisplatin alone. Vitamin A supplementation and ATRA treatment in combination with cisplatin showed similar re-sensitising effects.

Conclusion:
This pharmacological CSC depletion in conjunction with cisplatin treatment resulted in re-sensitisation of cisplatin resistant cells to the cytotoxic effects of cisplatin. These data suggest vitamin A supplementation or the addition of ATRA or an ALDH1 inhibitor to the cisplatin-based chemotherapeutic regimen may be of clinical benefit in overcoming tumour recurrence and cisplatin resistance.

Background:
Necitumumab is a recombinant human immunoglobulin G1 monoclonal antibody that blocks the ligand-binding site of EGFR. This study evaluated the effects of necitumumab on the pharmacokinetics (PK) of gemcitabine and cisplatin, and compared the PK of 2 necitumumab drug products manufactured by 2 different processes: Process C and Process D.

Methods:
Study participants included adult patients with advanced or metastatic malignant solid tumors (except colorectal tumors with KRAS mutation) that were resistant to standard therapy or for which no standard therapy was available. Patients enrolled in 2 cohorts received intravenous (IV) infusions of necitumumab 800 mg (cohort 1: Process C drug product; cohort 2: Process D drug product) on Day 3 of the PK run-in period following IV infusions of gemcitabine 1250 mg/m[2] and cisplatin 75 mg/m[2] on Day 1 of the PK run-in period, and subsequent infusions (same doses) of gemcitabine on Days 1 and 8, cisplatin on Day 1, and necitumumab on Days 1 and 8 of each 3‑week cycle. The effect of necitumumab on the PK of gemcitabine and cisplatin was evaluated in the PK run-in period and cycle 1 of cohort 1, and the PK of Process C and D necitumumab drug products were compared in PK run-in periods of cohorts 1 and 2. Blood was drawn immediately before and at regular intervals after each infusion in the PK run-in period to determine concentrations of necitumumab, gemcitabine, and cisplatin for PK parameter computation. Study treatment could continue up to 6 cycles and was discontinued for disease progression, unacceptable toxicity, or other withdrawal criteria. Patients who had not progressed had an option to continue necitumumab monotherapy until withdrawal criteria were met.

Results:
Eighteen and 20 patients were enrolled in cohort 1 and cohort 2, respectively. Coadministration of necitumumab did not alter dose-normalized area under the plasma concentration curves (AUCs) of gemcitabine and cisplatin (geometric least squares mean [GLSM] ratios: 90% CI;1.184: 0.960‑1.459 and 1.105: 1.063-1.148, respectively). Similarly, coadministration of gemcitabine and cisplatin with necitumumab did not alter AUC of necitumumab (GLSM ratio:90% CI; 1.077: 0.988-1.174). PK exposure parameters for both Process C and Process D drug products were similar, with GLSM ratios for AUC close to 1 and 90% CIs within the range of 80‑125%. No new safety signals were reported.

Conclusion:
No clinically relevant DDIs between necitumumab and gemcitabine or cisplatin were observed. Process C and Process D drug products had similar PK profiles. ClinicalTrials.gov Identifier:NCT01606748; Funding: Eli Lilly.

Background:
Platinum-based chemotherapy remains the standard first-line treatment for a NSCLC. A standard for second-line chemotherapy could be docetaxel or pemetrexed. Third and fourth line of chemotherapy is poor defined.

Methods:
42 patients (Pt.) were included in the study. Pt. were enrolled successively by the date of coming into the clinic All Pt. had assessment of response after 2-3 cycles of chemotherapy. First line consisted of: P plus carboplatin. P in mono-therapy was used in second, third and fourth line. 26 Pt. (Group A) were evaluated after first and second line of treatment. 16 Pt. (group B) were evaluated after third and fourth line. Overall survival was calculated for patients included in each line of therapy using Kaplan Meier curve.

Results:
Group A: 13 men and 13 women, median age 57 years (37-81), 3 patients in stage IIIB and 23 stage IV, ECOG performance status=I for 20 Pt. and 2for Pt.=2, for 6Pt.Hystopathology: 25 adenocarcinomas and 1 large cell carcinoma; 12 smokers and 14 nonsmokers. First line consisted of: Paclitaxel + Carboplatin 11 (42%) Docetaxel + Carboplatin four (15%), Carboplatin + Vinorelbine 3 (12%), Pemetrexed + Cisplatin 2 (8%), Gem + Cys 2 (8%) other 4 (15%). The median number of cycles in first line was 4 (2-4), in second line 7 (2-24). Overall survival in first line: 12 month; in second line: 10 month. In group B group: 12 men and 4 women, median age 62 years (31-80) .4 patients had stage IIIB and 12 stages IV, the histopathology was adenocarcinoma for all. ECOG performance status for all Pt. in first line of chemotherapy was I. First line chemotherapy was similar to group A except 3 Pt. treated in second line with Erlotinib and 2 cases treated with bevacizumab+paclitaxel and carboplatin. Median overall survival in this group was 6.5 months. Toxicity was no more than 2 on the WHO toxicity scale.

Conclusion:
In selected Pt. with aNSCLCns namely those who responded to the first and second line chemotherapy or erlotinib, P can be administered in third and fourth line with survival benefits and acceptable toxicity. A large studio is necessary to confirm the data obtained in this study. Once again highlighting the need of a marker of response to chemotherapy.

Background:
Therapy-related leukemia defined by the World health Organization 2008 classification scheme of hematolymphoid tumors including therapy-related acute myeloid neoplasms (t-AML), myelodysplastic syndrome (t-MDS). They occur as late complication of cytotoxic chemotherapy, radiation therapy and molecular target agents therapy against primary neoplasms. Recently, for lung cancer chemotherapy, new anti-cancer agent and molecurar target agents are increased and more intensification chemotherapy performed.We report that we reviewed t-AML cases who survived from lung cancer and suffered t-AML.

Methods:
We intended for multiple neoplasms 339 cases including hematological malignancy. We reviewed 55 multiple neoplasms including the lung cancer. In 55 cases, second neoplasms that were t-AML cases were 4 cases, t-MDS case was 1 case. All patients were followed up until death or untile December 2015. Survival was measured from the diagnosis of multiple cancer to time of death or last contact. We investigated cytogenetic abnormality, therapy, clinical outcome, prognosis, and cause of death.

Results:
In 5 cases, 4 cases were diagnosed t-AML, 1 case was t-MDS. 5 of cases were 4 male and 1 femal, primaly diagnosis were small cell carcinoma 2 cases, squamous carcinoma adenocarcinoma 3 cases. 1 case, One case(male case) was t-APL, he treated by all-trans retinoic acid and he reached complete response. T-M2 type, hshe treated by chemotherapy included daunorbicin and Ara-C(DC3-7), she did not achieve complete response. About prognosis, t-APL case, he lived 1 month after complete response, he died by lung cancer, t-AML cases, one female case, she lived 25 months after partial response, she died by t-AML relapse and refractory for salvage CTx. Other 3 cases, 1 case death by t-MDS, 2 cases death by t-AML.

Conclusion:
As the number of lung cancer survivors increased due to improvement in chemotherapy, clinician must more take attention of therapy-related leukemia and myelodysplastic syndrome by previous treatments.

Background:
Adjuvant chemotherapy improves the survival for completely resected non-small cell lung cancer (NSCLC) patients. Platinum/pemetrexed is known to be less toxicity, better compliance and longer survival in advanced non-squamous NSCLC, but the survival outcome compared with other regimens in adjuvant setting is still unknown. This report described the survival in adjuvant chemotherapy for lung adenocarcinoma with platinum/pemetrexed versus other platinum-based doublets.

Methods:
389 completely radical surgery lung adenocarcinoma patients who received adjuvant chemotherapy with platinum/pemetrexed regimen (Group A, n=143) and non-pemetrexed platinum-based regimens (Group B, n=246) were analyzed retrospectively. Primary end point was disease-free survival (DFS). Propensity score matching (PSM) allowed best matched pairs for platinum/pemetrexed versus other platinum-based doublets for comparison of survival and adverse events.

Results:
PSM created treatment groups for platinum/pemetrexed versus non-pemetrexed regimen (125 pairs), docetaxel and paclitaxel (107 pairs), gemcitabine (56 pairs), and vinorelbine (24 pairs)-contained doublets, respectively. Although DFS was not significantly different between Group A and B (P=0.1643)(Figure A), in 125 PSM pairs, DFS was considerably better in patients who received platinum/pemetrexed regimen (P=0.0079)(Figure B). From the subgroup analysis, Pemetrexed benefit is consistent across different subgroups, and especially aging(>65) was associated with the decision to use platinum/pemetrexed (HR=0.25,95%CI 0.09-0.73, P=0,011). Furthermore, platinum/pemetrexed was associated with several significantly lower hematological and non-hematological AE rates, such as versus gemcitabine (Leukopenia: RR 0.514, p=0.001; Neutropenia: RR 0.688, p=0.002) and paclitaxel- and docetaxel-based chemotherapy (Leukopenia： RR 0.685, p=0.019; Neutropenia: RR 0.805, p=0.032).Figure 1



Conclusion:
Adjuvant chemotherapy with platinum/pemetrexed shows both better disease-free survival and less clinical toxicity than other non-pemetrexed based doublets in completely resected adenocarcinoma lung cancer.

Background:
Cisplatin and vinorelbine given intravenously is a well-established adjuvant chemotherapy regimen after surgery for early NSCLC. However, few validated alternative exist when cisplatin is not indicated or tolerated. Carboplatin is frequently used in this setting. We evaluated the 5 years overall survival (OS), progression-free survival (PFS) and toxicity in patients treated for stage IB to IIIB resected NSCLC receiving adjuvant carboplatin based chemotherapy compared to cisplatin in association with vinorelbine.

Methods:
Single-center retrospective study of patients having received adjuvant chemotherapy between January 2004 and December 2013 at the oncology clinic at Institut de Cardiologie et de Pneumologie de Québec (Canada). Three sub-groups were studied: cisplatin / vinorelbine (CISV), carboplatin / vinorelbine (CBV) and the substitution of cisplatin /vinorelbine for carboplatin /vinorelbine during treatment.

Results:
A total of 127 patients were included in this study. The overall survival (OS) at 5 years and the median progression-free survival (PFS) did not differ significantly between groups. The 5 years OS is respectively 66 %, 55 % and 70 % (p = 0, 95). The PFS is respectively 50,4 and 57,3 months for the CISV and CISV/CBV groups and was not achieved for the CBV group (p = 0,80). No differences were noted between groups concerning grade 3 or 4 hematologic toxicity.

Conclusion:
The effectiveness and hematologic toxicity are comparable between cisplatin and carboplatin in the adjuvant treatment of resected non-small cell lung cancer. The results obtained corroborate the practice used at our oncology clinic. Nevertheless, more prospective studies would be needed to confirm these results.

Background:
Albumin-bound paclitaxel (nab-paclitaxel) has been demonstrated to improve outcomes with lesser neuropathy compared to that with paclitaxel in patients with advanced non-small cell lung cancer (NSCLC). However, the feasibility of adjuvant chemotherapy setting is still uncertain. This phase II trial assessed the feasibility of adjuvant chemotherapy with nab-paclitaxel and carboplatin in patients who underwent complete resection of pathological stage IB/II/IIIA NSCLC (UMIN000011225).

Methods:
Patients with completely resected pathological stage IB/II/IIIA NSCLC were recruited from July, 2013. Patients were administered adjuvant chemotherapy with 4 cycles of carboplatin (AUC 5) on day 1 and nab-paclitaxel (100 mg/m2) on days 1 and 8 every 3 weeks. The primary endpoint was the completion of 3 cycles of chemotherapy. The sample size was set at 30 patients, and the treatment was considered feasible if the 80% CI of the completion rate of 3 cycles of chemotherapy was ⩾60%, α=0.05 and β=0.2.

Results:
The study enrolled 30 patients including 2 pilot patients. The median relative dose intensities of modified weekly carboplatin and nab-paclitaxel were 80% and 70%, respectively. First two pilot patients were required dose reduction in conventional weekly carboplatin (AUC5) on day1 and nab-paclitaxel (100 mg/m2) on days 1, 8 and 15 every 3 weeks, therefore we modified this setting. Among the treated patients, grade 3 adverse event listed neutropenia (60%) and thrombocytopenia (10%). Dose delays were observed in 20% of patients owing to neutropenia (85%). In this interim result analysis, all 10 patients completed 3 cycles of chemotherapy. Conversely, neuropathy did not develop in any patients. Neither febrile neutropenia nor treatment-related mortality was observed in this study.

Conclusion:
Based on the results, modified adjuvant chemotherapy with weekly nab-paclitaxel and carboplatin is feasible, with acceptable hematologic and non-hematologic toxicity, in patients who underwent complete resection of pathological stage IB/II/IIIA NSCLC.

Background:
A number of meta-analyses have shown post-operative chemotherapy is beneficial following curative surgery for NSCLC, with the LACE meta-analysis demonstrating a 5 year survival improvement of 5.4%. NICE guidance states that cisplatin based combination chemotherapy should be offered to all patients of good PS with T1-3, N1-2, M0 disease, and should be considered in T2-3 N0 disease if > 4cm. The primary outcome of this audit was to review 5 years of practice; to assess adherence to guidelines in offering post-operative chemotherapy, and overall survival.

Methods:
Data was collected retrospectively from electronic records of patients who underwent surgery for lung cancer across Abertawe Bro Morganwg University Health Board and Hywel Dda Health Board between 2009 and 2014 Data collected included; demographics, date of diagnostic CT scan, date and type of surgery, histology, pathological stage, PET SUV max of primary tumour, date adjuvant chemotherapy started, regimen received, date of recurrence and overall survival. SPSS and Excel software was used to collate results and statistical analysis.

Results:
Of the 281 patients, 241 had a histological diagnosis of NSCLC. Median age was 69 years. By stage; 31.9% IA, 40.3% IB, 9.2% IIA, 10.1% IIB, 7.5% IIIA, 0.4% IIIB, 0.4% IV. 88.8% underwent lobectomy, 4.9% excision of segment and 2.9% pneumonectomy. 62.5% of patients with stage IIA, IIB or IIIA disease had adjuvant chemotherapy (n=40/64), 70% of these received a cisplatin based combination (cisplatin/vinorelbine), 84% completed 4 cycles of treatment. 9.45% stage IA patients underwent chemotherapy which is not in accordance with guidance. The mean time from diagnostic CT to surgery was 109 days, and from surgery to post-operative chemotherapy 62 days. The one year overall survival (OS) was 89.6%, 80.1% and 82.6%, and the three year OS was 70.7%, 59% and 32.4%, for stage I, II and III respectively. 213 (88.4%) patients underwent PET scan with mean maximum SUV of 12.1 (range 1.0-76.3). There was no statistically significant relationship between SUV max and OS.

Conclusion:
Our data shows good compliance with national guidance in offering postoperative chemotherapy, and survival rates better than published UK survival data.

Background:
Improving tolerability of chemotherapy for patients with SCC NSCLC remains an important aspect of care. Induction therapy with nab-paclitaxel/carboplatin followed by nab-paclitaxel maintenance therapy could be an effective treatment option for this patient population. Interim safety results from the induction part of the ongoing ABOUND.sqm study are reported here.

Methods:
Patients with advanced SCC NSCLC who had no prior chemotherapy for metastatic disease received induction therapy with nab-paclitaxel 100 mg/m[2] on days 1, 8, and 15 + carboplatin AUC 6 on day 1 (21-day cycles) for 4 cycles. Patients not progressing after 4 cycles were randomized 2:1 to maintenance nab-paclitaxel 100 mg/m[2] on days 1 and 8 of each 21-day cycle + best supportive care (BSC) or BSC alone until progression/unacceptable toxicity. Progression-free survival from randomization into the maintenance part of the study is the primary endpoint. Secondary endpoints include safety (analyzed as treatment-emergent adverse events [TEAEs], overall survival, overall response rate, and disease control rate.

Results:
212 patients receiving induction treatment were evaluable in this analysis. Median age was 68 years; 66% of patients were male, 87% were white, and 99% had an Eastern Cooperative Oncology Group performance status of 0-1. Discontinuations were observed in 94/212 patients (44%) during induction. Of these, 35/94 (37%) discontinued due to disease progression, 23/94 (24%) due to AEs, 11/94 (12%) due to other reasons, 10/94 (11%) due to death, 9/94 (10%) due to patient decision, and 6/94 (6%) due to symptomatic deterioration. The median percentage of per-protocol dose of nab-paclitaxel was 75%, and median dose intensity was 74.87 mg/m[2]/week. At least 1 nab-paclitaxel dose reduction, missed dose, or dose delay occurred in 41%, 51%, and 58% of treated patients, respectively. Grade 3/4 TEAEs were mainly hematologic and included neutropenia (86/212; 41%), anemia (52/212; 25%), and thrombocytopenia (33/212; 16%). Grade 3/4 peripheral neuropathy occurred in 8/212 patients (4%).

Conclusion:
This interim report from the ABOUND.sqm study demonstrates that the tolerability profile of nab-paclitaxel/carboplatin was consistent with that reported in the phase III study, and no new safety signals were observed. Updated results will be presented at the meeting. NCT02027428

Background:
A significant portion of patients with non-small cell lung cancer (NSCLC) develop brain metastasis. Patients with brain metastasis suffer from poor prognosis with a median survival of less than 6 months and low quality of life with limited treatment options. First generation EGFR tyrosine kinase inhibitors (EGFR TKIs) have demonstrated significant clinical benefit for patients with EGFR-mutant NSCLC. However, their effect on brain metastasis is limited due to poor drug penetration into the brain. Epitinib is an EGFR TKI designed to improve brain penetration. A Phase I dose escalation study on epitinib has been completed and the recommended Phase 2 dose (RP2D) determined (Y-L Wu, 2016 ASCO). This Phase I dose expansion study was designed to evaluate the efficacy and safety of epitinib in EGFR-mutant NSCLC patients with brain metastasis.

Methods:
This is an ongoing open label, multi-center Phase I dose expansion study. EGFR-mutant NSCLC patients with confirmed brain metastasis, either prior EGFR TKI treated or EGFR TKI treatment naïve, were enrolled to receive oral epitinib 160 mg per day. Patients with extra-cranial disease progression while on treatment with an EGFR TKI were excluded. Tumor response was assessed per RECIST 1.1.

Results:
As of 31 May, 2016, 27 patients (13 EGFR TKI pretreated, 14 EGFR TKI treatment naïve) have been enrolled and treated with epitinib. The most frequent adverse events (AEs) were skin rash (89%), elevated ALT (41%)/AST (37%), hyper-pigmentation (41%) and diarrhea (30%). The most frequent Grade 3/4 AEs were elevations in ALT (19%), gamma-GGT (11%), AST (7%), hyperbilirubinemia (7%) and skin rash (4%). There have been no Grade 5 AEs to date. Among the 24 efficacy evaluable patients (11 TKI pretreated, 13 TKI naïve), 7 (7/24, 29%) achieved a partial response (PR), including 1 unconfirmed PR. All PRs occurred in EGFR TKI treatment naïve patients (7/13, 53.8%). Of the 24 evaluable patients, 8 (5 EGFR TKI treatment naïve, 3 EGFR TKI pretreated) had measurable brain metastasis (lesion diameter>10 mm per RECIST 1.1) with 2 PRs (both EGFR TKI treatment naïve patients, 2/5, 40%).

Conclusion:
Epitinib 160mg per day treatment in EGFR-mutant NSCLC patients with brain metastasis demonstrated clinical activity both extra- and intra-cranial. Epitinib was well tolerated. The data to date appears encouraging and warrants further development of epitinib.

Background:
We aimed to identify the optimal regimen of endostar combined with whole brain irradiation(WBRT) for BM for evaluation and provide preliminary efficacy data.

Methods:
The 30 cases of advanced NSCLC patients with symptomatic unresectable BM were randomly divided into two groups, experimental group (15 cases): the Endostar (15 mg/m[2], intravenous infusion, d1-7) synchronization of WBRT (40 Gy/20 fractions/4 weeks); control group (15 cases): WBRT alone. Cerebral blood volume (CBV), blood flow (CBF) and mean perfusion time (MTT) and lymphocyte analysis were observed by magnetic resonance perfusion imaging before and 4 weeks after WBRT.

Results:
In experimental group, CBF, CBV and MTT at baseline were 582.12±161.42, 524.00±428.64 and 235.00±149.36. Four weeks after treatment, those perfusion values were 260.00±356.6, 336.00±480.82 and 509.00±44.34 respectively, which showed obvious decreasing trends compared with baseline data in CBF and CBV, while increased in MTT(Fig 1). Figure 1 Figure 1 The measurement of MR perfusion imaging of brain. Figure 2 Figure 2: Immune function related indicators. All the ten cases showed a partial response (PR) to therapy in experimental group, while in the control group the response rate was 40%.Endostar in combination with WBRT was generally well tolerated.





Conclusion:
Endostar combined with WBRT appears to be a efficacy and tolerable treatment of BM.

Background:
Brain-metastases (BM) are a common metastatic site in non-small-cell lung cancer (NSCLC). We studied the impact of genetic alterations (EGFR, ALK and KRAS) in relation to objective response rate (ORR), intracranial-progression-free survival (IPFS) and overall-survival (OS) after whole-brain irradiation (WBI) in patients at recently diagnosis with NSCLC and BM.

Methods:
From 2009-2015, 231 NSCLC patients with BM were reviewed for eligibility. Among them, 121 patients with recently diagnosis of NSCLC, were treated with WBI and have available genotyping status.

Results:
EGFR, KRAS, ALK and WT patients were found in 38.0%, 6.6%, 5.8% and 49.6%, respectively. Overall, ORR and disease control rate (DCR) were 62.0% and 76.8%, respectively. ORR for EGFR, KRAS, ALK and WT patients were 82.6%, 25.0%, 71.4% and 50.0%, respectively (p=0.001). Female gender (OR 2.22 [95% CI: 1.01 – 4.89] P=0.047) and EGFR were associated to better response to WBI (OR 5.67 [95% CI 2.0-15.8], P = 0.001). A high architectural histological grade was independently associated with resistance to WBI. Median IPFS was 9.06 months [95% CI 6.5 -11.4]. IPFS for EGFR, K-RAS,ALK and WT patients were 11.9, 4.6,12.5 and 6.6 months, respectively (P <0.0001). EGFR mutation status (HR 0.54 [95%CI 0.3-0.9], P = 0.030) was the only factor associated with higher IPFS in the multivariate Cox-regression analysis. Median OS was 16.6 months [95% CI 11.6-22.6]. OS for EGFR, ALK, KRAS and WT patients were 26.8, 13.5, 4.9 and 13.6 months, respectively (P < 0.001). Intracranial OR was associated with a higher OS (HR 0.28 [95%CI 0.2-0.5], P < 0.001), while KRAS mutation positive status (HR 3.45 [95%CI 1.4-8.4], P = 0.006) was independently associated with worse OS. Figure 1



Conclusion:
EGFR mutation is an independent predictive factor for OR to WBI for BM in patients with NSCLC. KRAS mutation is an independent predictive factor for worse OS after BM.

Background:
The aim of the study is to demonstrate the relationship between clinicopathological variables and brain metastasis in patients with resected lung adenocarcinoma.

Methods:
The clinicopathological characteristics of 748 patients of resected lung adenocarcinoma at Taipei Veterans General Hospital between 2004 and 2012 were retrospectively reviewed. Comprehensive histological subtyping was performed according to the percentage of each invasive histologic component. The prognostic value of clinicopathological variables for brain metastasis-free survival was demonstrated.

Results:
Among the 182 patients with distant metastasis, 93 (51.1%) patients developed contralateral lung metastasis, 81 (44.5%) had brain metastasis, 71 (39.0%) had bone metastasis, and 18 (8.9%) had liver metastasis during follow-up. Greater tumor size (Hazard ratio [HR], 1.276; 95% confidence interval [CI], 1.045 to 1.559; P = 0.017), stage II or III (vs. stage I) (HR, 2.469; 95% CI, 1.201 to 5.076; P = 0.014), angiolymphatic invasion (HR, 1.818; 95% CI, 1.037 to 3.189; P = 0.037), and micropapillary predominant (HR, 2.686; 95% CI, 1.270 to 5.683; P = 0.010) were significantly associated with more brain metastasis in multivariate analysis. Angiolymphatic invasion (HR, 2.632; 95% CI, 1.420 to 4.879; P = 0.002) and micropapillary predominant (HR, 2.186; 95% CI, 1.148 to 4.163; P = 0.017) were significant prognostic factors for worse brain metastasis-free survival in multivariate analysis.

Conclusion:
Angiolymphatic invasion and micropapillary predominant pattern are significantly associated with brain metastasis in patients with resected lung adenocarcinoma. This information is important for patient follow-up strategy and further study of the mechanisms leading to brain metastasis.

Background:
In lung cancer overall survival and quality of life are affected adversely by brain metastases, while peritumoral brain edema is responsible for life-threatening complications.

Methods:
The clinicopathological and cerebral radiological data of 575 consecutive lung cancer patients with brain metastases were analyzed retrospectively.

Results:
In squamous cell carcinoma (SCC) and adenocarcinoma (ADC) peritumoral brain edema was more pronounced as compared with small cell lung cancer (SCLC) (p<0.001, p˂0.001, respectively). There was positive correlation between size of metastasis and thickness of peritumoral brain edema (p<0.001). It was thicker in supratentorial tumors (p=0.019), in younger patients (≤50 years) (p=0.042), and in females (p=0.016). The interval time to brain metastasis was shorter in case of central as compared with peripheral lung cancer (5.3 vs. 9.0 months, p=0.035). Early brain metastasis was characteristic for ADCs. A total of 135 patients had brain only metastases (N0 disease) characterized by peripheral lung cancer predominance (p<0.001), and longer time-to-metastasis interval (9.2 vs. 4.4 months, p<0.001). Overall survival was longer in the brain only subgroup than in patients with N1-3 diseases (p˂0.001).

Conclusion:
According to our results, clinicopathological characteristics of lung cancer are related to the development and radiographic features of brain metastases, and these findings might be helpful in selecting patients who could benefit from prophylactic cranial irradiation.

Background:
It is often difficult to evaluate the status of EGFR mutation in non-small cell lung cancer (NSCLC) patients with brain metastases either from primary or metastatic lesions. Is it possible to ascertain the EGFR status and to guide the usefulness of TKI according to the MR imaging features of metastatic lesions in brain?

Methods:
Patients diagnosed with NSCLC from June 2014 through May 2015 were identified synchronous brain metastases based on enhanced magnetic resonance imaging (MRI). The variables of metastatic brain tumor included the numbers and the size of the brain lesions, the size of the associated peritumoral brain edema (PTBE) measured with brain MRI. The information was obtained mainly by transbronchial lung biopsy, percutaneous needle lung biopsy or cervical lymph nodes biopsy about EGFR mutation status.

Results:
Among 156 patients, 41 had the exon 19 deletion, 48 had the exon 21 L858R point mutation, and 67 had the wild-type EGFR. The exon 19 deletion group and exon 21 point mutation group had smaller peritumoral brain edema than did the wild-type group (P = 0.002 and P = 0.010, respectively). Different from the wild-type group, the exon 21 point mutation group showed more multiple brain tumors (P = 0.020). There was no significant difference about the size of the largest brain tumors in either exon 19 deletion group or exon 21 point mutation group when compared with the wild-type group (P = 0.077 and P = 0.051, respectively), but the metastatic brain lesions were inclined to smaller in EGFR mutation groups.

Conclusion:
Specific features of MRI in brain metastatic lesions were found in NSCLC with EGFR mutation，including smaller peritumoral brain edema and more lesions than did those with wild-type EGFR. Meanwhile, there was the trend that the size of the largest brain lesion was smaller in EGFR mutation groups. Accumulation of more knowledge was needed to depend on radiomics to make a quantifying analysis of EGFR mutation status.

Background:
Brain metastases occur in 30-40% of patients with Non-Small Cell Lung Cancer (NSCLC) [(1)]. Whole Brain Radiotherapy (WBRT) has been standard treatment in those with multiple metastases although this has been challenged by the Quartz trial. This suggested there was no advantage over supportive care in terms of survival (median 66 days in the RT arm) or quality of life. [(1) (2)] In our centre Quartz has divided opinions and practice. We thus decided to review our data of 163 patients who were treated with WBRT in the context of advanced NSCLC.

Methods:
Radiotherapy database information was used to identify patients receiving WBRT for metastatic NSCLC between 2007 and 2015. Patients with completely resected brain metastasis were excluded. Notes were reviewed retrospectively. Data were collected on demographics, performance status (PS), histology, disease status, further treatment following WBRT and survival.

Results:
163 patients were identified of which 153 had complete follow up data to review. The demographics are presented in the table below. The median survival across all patients was 104 days. Longer survival was seen in those with PS0/1(median=225 days) vs. PS3 (median =44 days) Of the 19 patients surviving longer than 1 year, 95% were PS 1 and all went on to receive further treatment for NSCLC upon completion of WBRT. Conversely 26 patients had a survival of less than 30 days. 70% were PS2 or 3. None of them received further treatment following WBRT.

N=163	Number	%	Median Survival (days)
Female	72	44%
Male	91	56%
Median Age	65
HISTOLOGY
Adenocarcinoma EGFR WT	104	64%
Adenocarcinoma EGFR Mutant	10	6%
Adenocarcinoma ALK rearrangement	1	<1%
Squamous cell Carcinoma	20	12%
Other Inc. NSCLC NOS	28	17%
PERFORMANCE STATUS
PS0/1	72	44%	225
PS2	56	34%	80
PS3	28	17%	44
DISEASE STATUS
Brain metastasis as 1[st] presentation of NSCLC	77	47%	146
Brain metastasis in known NSCLC	86	53%	85
Extracranial metastasis	125	78%	89
No Extracranial metastasis	35	22%	160
Further treatment following WBRT	55	34%	313
OVERALL SURVIVAL			104 days

Conclusion:
In our series survival was seen to be favourable when compared to the radiotherapy arm of Quartz. Performance status and the option for further treatment seemed to improve outcome. Whilst lacking QOL data and a supportive care control group, our data would suggest that for selected patients, especially those of good PS there remains a role for WBRT in NSCLC.

Background:
New therapies, particularly in advanced patients with EGFR-mutated and ALK-rearranged tumors, result in prolonged survival. Brain metastases and/or their treatment, may have a negative impact on health-related quality of life. Technological assessment of the cost-effectiveness of various treatments for brain metastases will benefit from measurements of health-related qualify of life and health utility scores (HUS). This study evaluated the impact of brain metastases on HUS across multiple health states defined on the basis on disease stability, brain-specific therapies, and molecularly-defined subsets of NSCLC.

Methods:
A longitudinal cohort study at Princess Margaret Cancer Centre evaluated 1571 EQ5D-3L-derived HUS in 476 Stage IV lung cancer outpatients, from Dec, 2014 through May, 2016: EGFR+ (n=183), ALK+ (n=38), wild-type (WT) non-squamous (n=171), squamous (n=29), and small cell lung cancer (SCLC) (n=30). Patients were stratified according to presence or absence of brain metastases at the time of assessment; mean HUS (± standard error of the mean, SEM) by presence of brain metastases and various health states and disease subtypes were reported. For patients with repeated measures, only the earliest time point was analyzed.

Results:
172 patients had brain metastases, median age 62, (range 32-86) years and 304 patients did not have brain metastases, median age 66 (29-96) years. Overall HUS was related to disease subtype but not presence of brain metastases: EGFR/ALK+ patients with (0.78±0.02) or without brain metastases (0.79±0.01) versus WT/SCC/SCLC with (0.74±0.02) and without brain metastases (0.73±0.01) (p=0.01 by subtype; p>0.10 by presence of brain metastases). However, symptomatic CNS disease (0.69±0.04) had lower HUS (versus asymptomatic disease (0.77±0.02)) (p=0.03). Patients achieving intracranial stability or response to treatment had significantly higher HUS (0.81±0.05) than patients with progressive CNS metastases (0.72±0.02) (p=0.03). Extra-cranial control also correlated with higher HUS (0.81±0.02 versus 0.69±0.03, p<0.0001). When local treatment for brain metastases was delivered within 6 months, HUS was lower (0.71±0.02 versus 0.82±0.02, p=0.0005). CNS disease treated only with systemic therapy or on no active therapy had mean HUS of 0.81±0.03, while patients treated only with stereotactic radiosurgery (SRS) had values of 0.80±0.04; there was a trend for lower HUS with whole brain radiation (WBRT) only (0.72±0.03) or WBRT+SRS (0.74±0.03) (p=0.11).

Conclusion:
Brain metastasis stability has significant impact on HUS in lung cancer patients. Treatment modalities of brain metastases may also impact HUS. Data collection is ongoing; updated HUS data including longitudinal assessments and multivariable analyses will be presented.

Background:
The brain is a common site of metastasis in non-small cell lung cancer (NSCLC). The aim of this study was two-fold: 1) to determine the incidence of brain metastasis (BM) in Caucasian lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutations and 2) to evaluate the frequencies and potential relationship of the different EGFR mutations with BM.

Methods:
A retrospective cohort study was conducted at a Croatian tertiary hospital (Clinic for Respiratory Diseases “Jordanovac”) using data collected from medical records. Caucasian patients with primary NSCLC who were tested for EGFR mutation status between January 2014 and October 2015 were included.

Results:
Of 1040 NSCLC samples tested, 122 (11.7%) patients with lung adenocarcinoma harboured EGFR mutations; six EGFR positive (+) patients (four with BM) had repeat EGFR testing. The majority of EGFR mutants were females (n= 90, 77.6%), non-smokers (including never-smokers and former-smokers; n= 95, 92.2%), diagnosed with advanced disease (stage IIIB/IV) at first presentation (n= 75, 68.8%), and median age at initial diagnosis of primary lung cancer was 65 years (35 - 90). Twenty-three (19.8%) of 116 EGFR+ patients were diagnosed with BM; for six EGFR+ patients, data about BM was missing. Most were 64 years of age or younger (n= 15, 65.2%) at diagnosis of BM (median age: 62 years, 48 - 72). Synchronous BM disease at initial diagnosis of lung cancer was found in 43.5% of EGFR+ patients with BM (n= 10). There were more EGFR+ women with BM (n= 20, 87%) than men. Single exon 19 deletion and exon 21 L858R mutations were the most common subtypes in both EGFR+ patients without BM (n= 44, 47.3% and n= 27, 27.8%, respectively) and with BM (n= 13, 56.5% and n= 5, 21.7%, respectively). One BM patient (4.3%) had a double mutation (exon 19 and 21), while six non-BM patients (6.2%) had simultaneous pairings, most commonly between exon 19 and 20 (n=3, 3.1%). Although exon 18 mutations were seen in six patients without BM (6.2%), none were found in BM+EGFR+ patients. Exon 20 T790M mutation occurred in 17.4% of BM patients (n= 4) versus 15.3% of non-BM patients (n= 15). Rare EGFR double mutations (exon 18 and 20) were found in two non-BM patients (2.2%).

Conclusion:
Larger long-term prospective studies to explore and confirm these results in BM+EGFR+ patients are warranted. In the era of precision oncology, molecular testing of EGFR mutations may further clarify the pathogenesis of lung cancer-associated BM.

Background:
We aimed to investigate the feasibility of droplet digital PCR (ddPCR) for the detection of epidermal growth factor receptor (EGFR) mutations in circulating free DNA (cfDNA) from cerebrospinal fluid (CSF) and plasma of advanced Lung Adenocarcinoma (ADC) with brain metastases (BM).

Methods:
Fourteen advanced ADC patients with BM carrying activating EGFR mutations in tumour tissues were enrolled in this study, and their matched CSF and plasma samples were collected. EGFR mutations were detected by the Amplification Refractory Mutation System (ARMS) in tumour tissues. EGFR mutations, including 19del, L858R, and T790M were examined in cfDNA isolated from 2 milliliter CSF or plasma by ddPCR assay. The clinical response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. Overall survival (OS) and progression free survival (PFS) after the diagnosis of BM were also evaluated.

Results:
Out of 14 patients, eleven were females and three males aged from 34 to 74 years old (median age of 55 years old). In all of cases, CSF cytology were negative. In ddPCR assays, EGFR mutations were detected in CSF of three patients (21.4%; one of 19del and two of L858R), and in plasma of six patients (42.9%; one of 19del, one of L858R, one of T790M, two of L858R&T790M, and one of 19del&T790M). All EGFR T790M mutations were found during or after EGFR-TKIs treatments. The three patients with activating EGFR mutations in CSF achieved partial response (PR) of BM after treated with combination of WBRT and EGFR-TKIs. The median OS and PFS after the diagnosis of BM were 18.0 months and 9.0 months, respectively.

Patient	Tissue EGFR	CSF EGFR	Plasma EGFR	Systematic Treatment	BM Treatment
1	19del	WT	T790M	Erotinib+Chemotherapy	WBRT+Gamma knife
2	19del	WT	19del	Erotinib+Chemotherapy	WBRT
3	L858R	L858R	L858R	Gefitinib+Chemotherapy	WBRT
4	L858R	WT	WT	Gefitinib+Chemotherapy	WBRT
5	19del	WT	WT	Gefitinib+Chemotherapy	WBRT
6	L858R	WT	L858R/T790M	Erotinib+Chemotherapy	WBRT
7	L858R	WT	WT	Gefitinib	WBRT
8	19del	19Del	19Del/T790M	Gefitinib	WBRT
9	L858R	WT	WT	Erotinib+Chemotherapy	NONE
10	19del	WT	WT	Erotinib+Chemotherapy	WBRT
11	19del	WT	WT	Icotinib+Chemotherapy	WBRT
12	L858R	WT	L858R/T790M	Chemotherapy	WBRT
13	L858R	L858R	WT	Icotinib	WBRT
14	19del	WT	WT	Gefitinib+Chemotherapy	WBRT

Conclusion:
It was feasible to test EGFR mutation in CSF. CSF may serve as liquid biopsy of advanced ADC with BM by enabling measurement of cfDNA within CSF to characterize EGFR mutations.

Background:
Anaplastic lymphoma kinase (ALK) gene rearrangement was reported in 3-7% of primary non-small-cell lung cancer (NSCLC) and its presence is commonly associated with adenocarcinoma (AD) type and non-smoking history. ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, alectinib and ceritinib showed efficiency in patients with primary NSCLC harboring ALK gene rearrangement. Moreover, response to ALK TKIs was observed in central nervous system (CNS) metastatic lesions of NSCLC. Till date there is limited data ALK rearrangement incidence in CNS metastases of NSCLC, which could be considered as a regiment for targeted treatment. For this reason we undertook the present retrospective study to determine the frequency of ALK abnormalities in CNS metastases of NSCLC.

Methods:
The studied group included 145 patients (45 females, 100 males, median age 60 years ±8) with CNS metastases of NSCLC. The studied group was heterogeneous in terms of histology (80 adenocarcinoma, 29 squamous-cell carcinoma, 22 large-cell carcinoma, 14 not otherwise specific) and smoking status. ALK abnormalities were screened in sections obtained from formalin fixed paraffin embedded (FFPE) tissue samples. NSCLC using immunohistochemical (IHC) automated staining (BenchMark GX, Ventana, USA) and fluorescence in situ hybridization (FISH) technique (Abbot Molecular, USA).

Results:
ALK abnormalities were detected in 4.8% (7/145) of CNS metastases of NSCLC. ALK abnormalities were observed in AD and squamous-cell carcinoma (SqCC) patients (7.5%; 6/80 vs. 3.4%; 1/29, respectively). Analysis of clinical and demographic factors indicated that expression of abnormal ALK was significantly more frequently observed (p=0.0002; χ[2]=16.783) in former-smokers. Comparison of IHC and FISH results showed some discrepancies, which were caused by unspecific staining of macrophages and glial/nerve cells, which constitute the background of CNS tissues.

Conclusion:
In this retrospective study we evaluated the expression of ALK abnormal protein and ALK gene rearrangement in extremely unique material which are CNS metastatic lesions of NSCLC. The frequency of ALK abnormalities in this material could be higher or comparable to frequency of ALK gene rearrangement in primary NSCLC tumors. However, the comparison of IHC and FISH results showed discrepancies that arose from unspecific background, which was made by cells with nonmalignant origin. For this reason assessment of ALK gene rearrangement in CNS tissues require additional standardizations.

Background:
Up to 40% of lung cancer patients develop brain metastases. As brain metastases often progress following radiotherapy, chemotherapeutics with central nervous system (CNS) activity are needed. Etirinotecan pegol (NKTR-102) is a PEG-conjugate prodrug of irinotecan, resulting in a half-life of 37 days and accumulation in tumors with permeable vasculature. This phase II trial evaluated the CNS activity of etirinotecan pegol in patients with lung cancer and refractory brain metastases.

Methods:
Patients with lung cancer and brain metastases were eligible who had received prior systemic therapy and prior brain-directed neurosurgery, radiation/radiosurgery, or refused whole brain radiotherapy (WBRT). Measurable brain metastases were defined as one >= 10 mm; or one 5-9 mm with others >= 3 mm, totaling >= 10 mm. Etirinotecan pegol was administered at 145 mg/m2 IV every 3 weeks. Response (modified RECIST 1.1) was assessed with brain MRI and systemic CT every 6 weeks. The primary endpoint was a 25% or greater 12-week CNS disease control rate (CNS-DCR; defined as unconfirmed response or stable disease with systemic non-progression) in a non-small cell lung cancer (NSCLC) cohort. Another exploratory cohort enrolled small cell lung cancer (SCLC) patients.

Results:
In the NSCLC cohort, twelve patients were enrolled, all with adenocarcinoma. Genomic alterations included six (50%) with EGFR mutation, and one each with HER2, KRAS, ROS1, and NRAS. Patients received a median of 2.5 prior systemic treatments. Two (17%) patients had prior neurosurgery, ten patients (83%) had irradiation - 3 WBRT, 9 radiosurgery. Common related toxicities were nausea and diarrhea (each in 50%), vomiting (22%) and blurred vision (22%). One patient died after developing diarrhea and dehydration. CNS responses lasting 24, 8, and 6 weeks were observed in 25% (3/12) - all EGFR mutation positive. The 6-week CNS-DCR was 50% (6/12), but 12-week CNS-DCR was 17% (2/12). Median progression-free survival was 11.4 weeks (95% CI 5.3-11.7) and median overall survival from study entry was 29.6 weeks (95% CI 22.3-38.2). In the SCLC cohort, two patients were enrolled. One patient with prior PCI had CNS response at 5 weeks but died of neutropenic infection; one who refused prior WBRT had CNS progression at 6 weeks.

Conclusion:
Radiographic responses of brain metastases were observed in patients following administration of etirinotecan pegol, but the study did not meet the primary endpoint because the 12-week CNS-DCR was 17%. Further study of etirinotecan pegol is ongoing in patients with breast cancer and brain metastases.

Background:
The management of ALK+ NSCLC patients with CNS metastases represents a clinical challenge. We conducted this single institution retrospective analysis in order to evaluate the frequency of CNS metastases in this patient group and explore clinical features associated with survival

Methods:
Between 2011 and 2016, 70 patients with advanced ALK+ adenocarcinoma were treated at our institution. Data on CNS imaging modality, treatment strategy and outcome was collected by chart review

Results:
CNS imaging was performed with either MRI(36%) or CECT(64%) in 59 cases, and CNS metastases were diagnosed in 56% of examined subjects. The characteristics of these 33 patients were as follows: gender male/female 45%/54%; median age 60y (IQR 50-65); # of CNS metastases 1-3/4-10/>10 21%/36%/42% (including 3 subjects with leptomeningeal involvement); timing for diagnosis of CNS metastases: at primary cancer diagnosis (21%), at PD on chemotherapy (33%), at PD on crizotinib (39%), at PD on 2[nd] generation ALKi (6%). Radiotherapy was administered as either SRS(42%) or WBRT(58%) in 66% of cases. Overall medical treatment was chemotherapy (n=32); crizotinib (n=28); 2[nd] generation ALKi, either alectinib, ceritinib or brigatinib (n=22). The first treatment strategy upon diagnosis of CNS metastases was radiotherapy alone, crizotinib or a 2[nd] gen ALKi in 42%, 24% and 33% of subjects, respectively. In 4 cases, the 2[nd] generation ALKi was started directly after completion of radiotherapy. Median OS from the diagnosis of CNS metastasis was 18 months (95% CI 9-50). 1- and 2-year survival rates were 59% and 44%, respectively. Cox proportional hazard analysis showed that neither gender, age, timing for diagnosis of CNS metastasis nor the use of radiotherapy were significant prognostic factors for OS in this patient cohort. Survival analysis stratified by Number of CNS metastasis showed a trend favoring 1-3 met (median OS 59 months) vs 4-10 and >10 lesions (median OS of 25 and 9 months, respectively), with the three survival curves crossing each other (p=0.1). On the other hand, the first treatment strategy after the diagnosis of CNS metastases was shown to be indeed a significant prognostic factor for OS. Median OS for patients treated with crizotinib, radiotherapy alone or a 2[nd] ALKi (with or without RT) was 9 months, 29 months and Not reached, respectively (p=0.03).

Conclusion:
This retrospective study confirms the high incidence of CNS metastases in Caucasian patients with advanced ALK+ NSCLC. The wider implementation of 2[nd] generation ALKi in clinical practice may change the prognosis of these subjects

Background:
Brain metastases, occurring in 20% to 40% of patients with advanced NSCLC, are associated with poor survival. Atezolizumab (anti-PDL1) inhibits PD-L1/PD-1 signaling and restores tumor-specific T-cell immunity. Clinical benefits have been observed in patients with NSCLC across PD-L1 expression levels following atezolizumab monotherapy, but the safety profile in NSCLC patients with brain metastases has not previously been explored.

Methods:
Pooled safety analyses were conducted in 843 patients who received atezolizumab as 2L+ treatment in 4 studies (PCD4989g: NCT01375842 [N = 76]; BIRCH: NCT02031458 [N = 520]; FIR: NCT01846416 [N = 105]; POPLAR: NCT01903993 [N = 142]). Patients had asymptomatic untreated brain metastases or stable previously treated brain metastases at baseline.

Results:
27 (3%) of 843 patients in the pooled cohort had baseline brain metastases; 23 of whom were previously treated with radiation to the brain. Among the 27 patients, mean age was 60 years, 41% were male, 85% had non-squamous NSCLC, and 70% had received 3L+ therapy. Median number of atezolizumab cycles (21d/cycle) was 4 (range, 1-39). Neurological AEs occurred in 12 (44%) patients with and 229 (28%) patients without baseline brain metastases (Table). The incidence of treatment-related neurological AEs was 4 (15%) in patients with and 77 (9%) in patients without baseline brain metastases, including the most common treatment-related AE of headache in 2 (7%) and 27 (3%) patients, respectively. The most common all-cause AEs in patients with baseline brain metastases were fatigue, nausea, and vomiting (7 [26%] each); 3 (11%) patients developed new brain lesions on study, none during treatment. No treatment discontinuations occurred due to AEs.

Conclusion:
The current analyses indicate that atezolizumab has an acceptable safety profile in patients with NSCLC who have asymptomatic or previously treated stable brain metastases. Further investigation is needed to fully assess the efficacy of atezolizumab in this patient population.

Summary of safety data in patients with advanced NSCLC with and without baseline brain metastases following atezolizumab as 2L+ treatment
	Pooled Cohort (N = 843)
	Patients Without Baseline Brain Metastases (n = 816) n (%)	Patients With Baseline Brain Metastases (n = 27) n (%)
Any AE	779 (96%)	26 (96%)
Any neurological AE	229 (28%)	12 (44%)
Treatment-related AEs	548 (67%)	16 (59%)
Treatment-related neurological AEs	77 (9%)	4 (15%)
Serious AE	311 (38%)	9 (33%)
Serious neurological AEs	21 (3%)	1 (4%)
Treatment-related SAEs	78 (10%)	1 (4%)
Discontinued treatment due to AE	47 (6%)	0 (0%)

Background:
The prognosis of brain metastases (BM) from lung cancer is extremely poor. Some studies showed patients with BM responded well to afatinib, while little was known on detail mechanism. This study aimed to evaluate the efficacy of afatinib for BM and address whether it could actively penetrate brain-blood barrier (BBB) and hit its target.

Methods:
Tumor burden was evaluated weekly after administration of afatinib and vehicle, and pharmacokinetic and pharmacodynamics characteristics were measured in both normal mice and BM model mice.

Results:
Administration of 15mg/kg afatinib inhibited in vivo PC-9 tumor growth in brain with tumor growth inhibitory rate (TGI) of 79.8% and 90.2% on day 7 and 14, respectively. 30mg/kg afatinib exhibited the tumor regression on day 7 and 14 with TGI of 124.7% and 105%. The plasma concentration was 91.4±31.2 nM/L at 0.5h after afatinib administration, reached the peak (417.1±119.9 nM/L) at 1h, and still be detected at 24h. The CSF concentrations followed a similar pattern. A good correlation (R[2]=0.732) between plasma and CSF concentrations was demonstrated. Immunohistochemistry showed the signal of pEGFR was reduce by 90% at 1 hour after administration of 30mg/kg afatinib. A positive correlation between afatinib concentrations in CSF and pEGFR modulation was observed.

Conclusion:
Afatinib could penetrate into BBB contributing to brain tumor response. The exposure in CSF correlated with that in plasma, which was correlated with modulations of pEGFR in the tumor tissues. Our findings provide implication of potential application of afatinib in NSCLC patients with brain metastases.

Background:
Tesevatinib is a potent reversible EGFR inhibitor with strong preclinical evidence of brain penetration: brain:plasma ratios of 1-4 and brain:meninges ratios of 10-15 in rodents (AACR 2015 Abstract 2590). Tesevatinib was previously shown to have significant clinical activity in patients presenting with EGFR mutant NSCLC, but not in patients with T790M mutation. Approximately 25% of patients with EGFR activating mutations progress in the CNS, and metastases there have a low rate (10%) of T790M mutations.

Methods:
Patients with NSCLC driven by activating EGFR mutations who had BM or LM occurring or progressing while receiving erlotinib, gefitinib, or afatinib were treated with 300 mg of tesevatinib daily. Patients with BM had RECIST 1.1 measurable disease in the brain, and RECIST 1.1 evaluated response. Patients with symptomatic LM were diagnosed by either CSF cytology or MRI findings. Response was measured by improvement in symptoms, CSF cytology, and MRI. Patients with both BM and symptomatic LM were enrolled in the LM cohort. Target accrual is 20 patients in each cohort.

Results:
To date, 7 patients have been enrolled [2M:5F; median age 61 (36-66); 1 Asian], all with CNS symptoms. Four were in the BM cohort and 3 in the LM cohort. All had prior CNS radiotherapy, either WBRT or SRS or both. All had prior systemic therapy (median 3; range 1-6). Three patients had EGFR del 19, 3 had L858R, and 1 had L861Q. Gr ≥ 3 adverse events, regardless of relationship to study drug, have included Gr 3 prolonged QTc, Grade 3 hypokalemia, Gr 3 dehydration, Gr 3 UTI, and Gr 3 ALT elevation. Three patients had dose reductions due to asymptomatic QTc interval prolongation. Six out of the 7 patients had CNS symptom improvement, often occurring within 14 days of tesevatinib initiation. Two patients decreased steroids. One BM patient had marked improvement in right leg strength and a 19% reduction in the target BM on Study Day 23. One patient with BM and LM had resolution of LM symptoms, a 57% reduction in BM target lesion, and clearance of LM enhancement on MRI at Study Day 41.

Conclusion:
Early data from the first 7 patents in this ongoing clinical trial indicate that tesevatinib has clinical activity in the CNS in EGFR mutant disease manifesting as BM or LM in patients previously treated with erlotinib, gefitinib, or afatinib. An additional cohort of 20 treatment-naïve patients who have initial presentation with brain metastases is being added.

Background:
A few reports have suggested a difference in the incidences of new metastasis to the central nerve system (CNS) during gefitinib and erlotinib therapy. However, a direct comparison of these two therapies has not yet been reported. We planned a retrospective study to investigate the incidences of CNS metastasis progression (new CNS metastasis or progression of existing CNS metastasis) during gefitinib and erlotinib therapy in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutation.

Methods:
We retrospectively analyzed the incidences of CNS metastasis progression and the outcomes of NSCLC patients harboring EGFR mutation who received gefitinib or erlotinib as a first-line EGFR-TKI treatment at the National Cancer Center Hospital between 2008 and 2014.

Results:
A total of 175 patients were analyzed; 148 patients had received gefitinib, and 27 had received erlotinib. The median (range) ages were 64.5 (32-81) years and 62.0 (27-68) years, respectively; exon 19 deletion/L858R point mutations were present in 84/64 (56.7%/43.3%) and 17/10 (63.0%/37.0%) cases, respectively. The status of CNS metastasis before EGFR-TKI therapy was negative/positive in 105/43 (71.0%/29.0%) cases in the gefitinib group and 21/6 (77.8%/22.2%) cases in the erlotinib group, respectively. The incidence of CNS metastasis progression in the gefitinib group tended to be higher than that in the erlotinib group (29.0% vs. 11.1%; P = 0.051). In patients without CNS metastasis before EGFR-TKI therapy, the incidence of new CNS metastasis during EGFR-TKI treatment was significantly higher in the gefitinib group than in the erlotinib group (24.7% vs. 4.8%, P = 0.04). The progression-free survival (PFS) and overall survival (OS) periods of the patients who presented with CNS progression were shorter than those of the patients who presented without CNS progression (median PFS, 9.5 vs. 12.6 months, P = 0.034; median OS, 23.8 vs. 34.1 months, P = 0.002). Fifty-six patients underwent re-biopsy after the failure of EGFR-TKI therapy, but no difference in the incidences of EGFR T790M mutation was seen between patients with and those without CNS metastasis progression (40.0% for patients without CNS progression vs. 63.6% for patients with CNS metastasis progression, P = 0.19).

Conclusion:
The incidence of the progression of CNS metastasis during gefitinib therapy was higher than that during erlotinib therapy. In addition, the difference in this incidence was more remarkable among patients who had not developed CNS metastasis prior to the start of EGFR-TKI therapy.

Background:
Brain metastasis in NSCLC patients is often considered as a terminal stage of advanced disease. Crizotinib is a small-molecule tyrosine kinase inhibitor (TKI) for ALK-rearranged NSCLC patients that can improve systemic outcomes. Herein, a retrospective analysis of Crizotinib was performed in advanced ALK-rearranged NSCLC patients with brain metastases, to explore how Crizotinib affects the control of brain metastases and the overall prognosis in Chinese population in the real world.

Methods:
Advanced NSCLC patients with brain metastases who underwent Crizotinib treatment at the Cancer Hospital of the Chinese Academy of Medical Sciences between April 2013 and April 2015 were included. ALK translocation was determined by FISH, Ventana IHC test or RT-PCR. Brain metastases were diagnosed by CT or MRI.

Results:
A total of 34 patients were enrolled, of whom 20 patients had baseline brain metastases at the initiation of Crizotinib treatment. For patients with baseline metastases, overall survival (OS) after brain metastases was significantly longer, compared with those developing brain metastases during Crizotinib treatment (median OS, not reached vs. 10.3 months, p = 0.001). Among all the patients treated with chemotherapy at the first line, OS after brain metastases in patients with baseline brain metastases was significantly superior than those without (p = 0.023). Whereas, patients receiving Crizotinib at the first line with baseline brain metastases didn’t demonstrate such superior (p = 0.089). Among patients who developed brain metastases during Crizotinib treatment, for those receiving chemotherapy at the first line, though the result was not significant by the cut-off date, time to brain metastases was longer, compared with patients receiving Crizotinib at the first line (median time to brain metastases, 17.1 months vs. 10.5 months, p = 0.072).Figure 1



Conclusion:
Chinese ALK-rearranged NSCLC patients with baseline brain metastases may benefit more from Crizotinib than those developing brain metastases during Crizotinib treatment.

Background:
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are more effective in patients with advanced non-small-cell lung cancer (NSCLC) with EGFR mutations, compared with standard chemotherapy. In Japan, gefitinib, erlotinib, afatinib, and osimertinib have been approved so far. However, data comparing the efficacies of different EGFR-TKIs, especially in brain metastasis, are lacking.

Methods:
EGFR-TKI-naive patients with recurrent or stage IIIB/IV NSCLC with EGFR mutations, excluding resistance mutations, were enrolled in this study. We retrospectively analyzed the time to progression of brain metastasis in patients who received either gefitinib or erlotinib using the Kaplan-Meier method with the log-rank test.

Results:
Seventy-eight EGFR-TKI-naive patients received either gefitinib (n = 56) or erlotinib (n = 22) from April 2010 to April 2016 in our hospital. During EGFR-TKI treatment, brain metastasis progression was observed in 10 of the 56 patients (17.8%) in the gefitinib group and in 1 of the 22 patients (4.5%) in the erlotinib group. Prior to EGFR-TKI treatment, 15 patients in the gefitinib group and 12 in the erlotinib group had brain metastasis. Among these patients, brain metastasis progression was observed in 7/15 (46.7%) in the gefitinib group and 0/12 (0%) in the erlotinib group. Although event (brain metastasis progression)-free survival was marginally better in the erlotinib group, erlotinib significantly reduced brain metastasis progression in patients who had brain metastasis prior to EGFR-TKI treatment compared with gefitinib (P = 0.011, Figure). Figure 1



Conclusion:
Although this was a retrospective analysis involving a small sample size, erlotinib is potentially more promising than is gefitinib for brain metastasis in patients with EGFR-mutant NSCLC, especially those with brain metastasis prior to EGFR TKI treatment.

Background:
Lung cancer is characterized by the highest incidence of solid tumor-related brain metastases. This is also one of the reasons why it can cause significant mortality. Molecular targeted therapy plays a major role in the management of brain metastases in lung cancer, which has become the novel methods for treatment of lung cancer with brain matastases. Our study aims to explore the efficacy of the EGFR targeted treatments in NSCLC brain metastases, specially according to EGFR mutation sub-types.

Methods:
We collected 116 patients with NSCLC brain metastases who underwent EGFR-TKIs therapy from 2011-2015 of Zhejiang cancer hospital. The data were analysed to get progression-free survival for intracranial disease(MPFSI)、median progression-free survival for extracranial disease(MPFSE)、median overall median progression-free survival(MPFS)、median overall survival (MOS), which were evaluated by Kaplan-Meier and multivariate analysis were performed by Cox model.

Results:
The overall response rate for 116 patients with Icotinib treatment was 61%. No increase in neurotoxicity was detected. The overall response rate was significant higher with EGFR exon 19 deletion mutation than with EGFR exon 21 mutation, other type EGFR mutations or EGFR-wildtype (68% VS 42%). MPFSI, MPFSE and MOS was also significantly longer with EGFR exon 19 deletion mutation than with EGFR exon 21 mutation, other type EGFR mutations or EGFR-wildtype (P<0.05).

Conclusion:
Icotinib was well tolerated with a favorable objective response. In sub-group analysis, the NSCLC with brain metastases patients with EGFR exon 19 deletion mutation obtain better survival than those patients with EGFR exon 21 mutation, other type EGFR mutations or EGFR-wildtype.

Background:
Despite progress in personalized lung adenocarcinoma treatment, development of efficacious molecular targeted therapies for adenosquamous cell carcinoma (ASC) of the lung has made little progress because of limited knowledge concerning gene mutation status and the rarity of this type of tumor.

Methods:
We examined the frequency of EGFR, K-Ras, B-Raf, PIK3CA, DDR2, ALK, and PDGFRA gene mutation using NGS, PCR, and Sanger sequencing methods in ASC samples. Macrodissection or laser microdissection was performed in 37 cases to separate adenomatous and squamous components of ASC for further sequencing. Fifty-six patients who underwent operations in Peking Union Medical College Hospital between January 2010 and December 2014 were enrolled in the study.

Results:
The overall mutation rate was 64.29%, including 55.36%, 7.14%, and 1.79% for EGFR, K-Ras, and B-Raf mutations, respectively. PIK3CA mutation was detected in three cases; all involved coexisting EGFR mutations. Of the 37 cases, 34 were convergent in two components, while three showed EGFR mutations in the glandular components and three showed PIK3CA mutations in the squamous components. With respect to EGFR mutations, the number of young female patients, nonsmokers, and those with positive pleural invasion was higher in the mutation-positive group than that in the mutation-negative. K-Ras mutation was significantly associated with smoking. Overall survival in the different EGFR mutation groups differed significantly.Figure 1



Conclusion:
The frequency and clinicopathological characteristics of EGFR- and KRAS-mutated adenosquamous lung carcinoma were similar to that noted in Asian adenocarcinomas patients. The high convergence mutation rate in both adenomatous and squamous components suggests monoclonality in ASC.

Background:
Available clinical research data shows that early mutation testing for patients with NSCLC stage IV could lead to an effective choice of therapy for patients with a proved mutation. Targeted therapies achieve a better quality of life, a higher PFS and ORR and in some cases increased OS. The aim of the study was therefore to systematically analyze retrospective data from three cancer centers in the north of Germany. The study compares these three cancer centers in reference to the test rate and the therapeutic success of targeted therapy.

Methods:
1383 patients from the three cancer centers diagnosed with non-small lung cancer stage IV (UICC 7) were examined. Methods for the detection of mutations included Sanger Sequencing, hybridization based COBAS testing as well as hybrid cage next generation sequencing. Clinical characteristics including smoking status were available for more than 92% of the patients.

Results:
880 consecutive patients from the three cancer centers were studied for the presence of tumor mutations, especially for EGFR and ALK mutations. The overall mutation testing rate was 63.6% (880/1383). EGFR mutations were found in 18.4% (86/467)/ 13.1% (38/289)/ 11.3% (14/124) in the Pius-Hospital, Bremen-Ost or Hamburg Harburg respectively, ALK in 3.9% (18/467)/ 1.7% (5/289)/1.6% (2/124) yielding an overall EGFR M+ rate of 15.7% (138/880) and overall ALK M+ rate of 2.9% (25/880). Median OS was 43 (n=86) vs. 25 (n=38) vs. 16 (n=14) months (Pius vs. Bremen vs. Hamburg) (p<0.035). PFS on the 1[st] line TKI therapy was 25 (n=77) vs. 22 (n=31) vs. 10 (n=13) months respectively. Pts receiving 3[rd] generation TKI (Osimertinib n=12) had a significantly longer OS than pts not receiving 3[rd] gen. TKI (n=134). PFS on 3[rd] gen TKI was significantly longer than for other therapies (p<0.020). Median OS in ALK mutated patients was 31 (n=18) vs. 17 (n=5) vs. 10 (n=2) months (Pius vs. Bremen vs. Hamburg). Median OS of pts treated with Crizo alone (n=14) was 18 months, pts treated sequentially with Crizo and Ceritinib (n=6) 31 months, median OS without Crizotinib (n=4) was 17 months.

Conclusion:
The results illustrate differences between the three Lung Cancer Centers in the north of Germany. Significant differences in OS were observed, depending on the center and a significant difference in PFS between the therapy with Osimertinib and other therapies could be established. The differences mentioned could depend on the selection of the patients and their clinical characteristics. The clinical characteristics should be observed in detail.

Background:
Next-generation sequencing (NGS) of ctDNA is increasingly used for non-invasive genomic profiling of human cancers. However, studies to date have not detailed the ctDNA genomic landscape in LUSC.

Methods:
From June 2014 to June 2016, ctDNA from 467 patients with stage 3 or 4 (AJCC 7[th] edition) LUSC (60% male, 40% female; median age of 69 [range 27-96]) were tested with Guardant 360[TM], a ctDNA NGS assay that detects single nucleotide variants (SNVs) of 54-70 cancer genes and certain copy number amplifications (CNAs), indels, and fusions. The median time between diagnosis and ctDNA testing was 238 days. Somatic alterations were compared with those in the 2016 LUSC TCGA dataset.

Results:
426 patients (92.2%) had at least one somatic alteration detected. The most commonly observed SNVs (> 5% frequency) were TP53 (64.8%), PIK3CA (7.8%), CDKN2A (6.1%), and KRAS (5.9%). Frequencies of SNVs known to be significant in LUSC correlated well between our cohort and the TCGA (Spearman r = 0.93) but were generally lower in our cohort (Table 1). Several of our most frequently observed CNAs are strongly associated with LUSC (EGFR, CDK6, MYC, ERBB2, PDGFRA, KIT, CCND1). In addition, MET exon 14 skipping (1.3%), EGFR exon 19 deletion (1.9%), EGFR exon 20 insertion (0.5%), ERBB2 exon 20 insertion (0.3%) and EML4-ALK fusion (0.7%) were detected. These alterations have rarely been reported in LUSC.

Conclusion:
Patterns of SNVs and CNAs in LUSC obtained by ctDNA profiling are largely consistent with those from TCGA tissue profiling, although the frequency of key SNVs is lower. The presence of actionable alterations atypical for LUSC in 4.7% of this clinical cohort may represent underappreciated treatment options. Further investigation is warranted to evaluate whether these findings reflect a distinct mutational landscape in heavily treated advanced disease (which is under-represented in the TCGA) and/or challenges in histopathological classification. Figure 1

Background:
Brain metastasis (BM) is associated with poor prognosis, recurrence, and death in patients with non-small cell lung cancer (NSCLC). MicroRNAs (miRNAs) play an essential role in the development of NSCLC. We investigated miRNAs that serve as biomarkers to differentiate NSCLC patients with and without BM, and explored the underlying mechanism.

Methods:
The significant association for BM of NSCLC was analysed by univariate and multivariable logistic regression analysis of the clinical features of NSCLC patients with BM and without BM. The effects of miR-330-3p on NSCLC cells (A549 and HCC827) were investigated using assays of cell viability, migration, invasion, cell cycle, Western blot, and a tumor xenograft and brain metastatic xenografts models. The miR-330-3p targets were identified using microarray analysis and verified by luciferase reporter assay.

Results:
Female gender (OR = 3.15，P = .003), age under 60 (OR = 4.54, P < .001), adenocarcinoma (OR = 3.57, P = .01), EGFR19 exon mutation (OR = 3.76, P = .05), N2 (OR = 8.23, P = .01) or N3 (OR = 29.38, P < .001) were highly associated with BM in NSCLC patients. The miR-330-3p was expressed at a higher level in BM+ than in BM- NSCLC serum samples, and also higher in NSCLC cell lines than the normal human bronchial epithelial cell line. Cell proliferation, migration and invasiveness of 2 representative NSCLC cell lines (A549 and HCC827) were increased by over-expressing miR-330-3p using a lentivirus carrying a sequence of miR-330-3p, and decreased by knockdown of miR-330-3p. In nude mice receiving subcutaneous A549 and HCC827 cell inoculation, tumor growth were significantly faster in mice receiving A549 and HCC827 cell permanently expressing exogenous miR-330-3p, and slower in cells permanently expressing an anti- miR-330-3p sequence. The mice receiving cancer cells stably expressing exogenous miR-330-3p injection directly into the brain almostly developed multiple metastatic foci, while developed a smaller orthotopic tumor in mice receiving injection of cells expressing an anti- miR-330-3p sequence. GRIA3 was identified as a direct target of miR-330-3p using luciferase reporter assays. Real-time PCR and Western blot confirmed that miR-330-3p downregulated GRIA3 expression. MEK inhibition suggested that GRIA3 was regulated by miR-330-3p via MAPK/MEK/ERK signaling pathway.

Conclusion:
These results support the oncogenic role of miR-330-3p in NSCLC brain metastasis, providing a rationale for miRNA-targeted therapeutic strategies.

Background:
Brain metastases (BM) are common among patients with adenocarcinoma, affecting treatment response, quality of life and overall survival(OS). We examine the impact of the main histological pattern and the genetic alterations in EGFR and ALK on the incidence of BM in patients with advanced non-small cell lung cancer (NSCLC).

Methods:
From January 2004 through December 2014 the medical records of 991 patients with NSCLC were reviewed for eligibility, among them 711 had adenocarcinoma histology. We describe the factors associated with the overall incidence of BM as well as the incidence of BM stratified on the histological grade pattern according to the ERS/ATC/IASLC classification (lepidic vs acinar+papilar vs micropapilar+solid).

Results:
Among 711 patients, 53.6% were female, 47.1% were less than 60 years-old at the time of diagnosis, exposure to tobacco, wood-smoke and asbestos were found in 52.0%, 40.5% and 13.8%, respectively. Seventy-six percent had a good performance status, and nearly sixty percent (59.8%) had oligometastatic disease. Most of the patients had a stage IV disease at the time of diagnosis (79.3%). Regarding histological grade classification, male patients were more likely to have a poorly differentiated adenocarcinoma in comparison with women (61.2% vs. 51.2%, p=0.027), as well as ever-smokers compared with non-smokers (61.4% vs. 49.9%). Likewise, patients harboring an ALK rearrangement were more likely to have a highly- or moderate differentiated adenocarcinoma (100% vs. 43.6%, p=0.008). A total of 122 patients (17.1 %) had a brain metastasis at diagnosis and 37.4% had baseline carcinoembryonic levels above 20 pg/ml.By Kaplan-Meier method 6.45% and 12.10% of patients developed BM at 12 and 24 months. The factors associated with a high incidence of BM were: female gender (40.9% vs. 34.4%; p=0.036), age < 60 years (44.4% vs. 32.1%, p=<0.001), EGFR activating mutation (53.9% vs. 39.3%; p=0.001), advanced metastatic disease (IIIB vs IV 42.8% vs. 20.3%; p=<0.0001), serological carcinoembryonic level >20pg/ml (47.2% vs. 32.8%; p=<0.0001) Finally, brain metastases were more likely to be found among patients with moderate and poorly-differentiated adenocarcinomas in comparison with highly differentiated adenocarcinomas (54.2, and 48.1% vs. 7.7%; p=0.050). In the multivariate analysis EGFR (HR:0.63;95%CI 0.44-0.92, p=0.017) and highly differentiated adenocarcinomas EGFR (HR:1.59;95%CI 1.03-2.44, p=0.034) were found to be independent factors for the development of BM.

Conclusion:
Adenocarcinoma histological-architectural-grade differentiation according to ERS/ATC/IASCL classification was found to be a predictive factor for development of BM like other previously described clinically characteristics (e.g. gender, age, EGFR activating mutations and carcinoembryonic-antigen).

Background:
Molecular driven therapy of advanced lung adenocarcinoma implies the detection of specific genetic alterations predictive of response to agents targeting specific pathways. Next Generation Sequencing provides simultaneous analysis of hundreds of genes in samples with low DNA quantity with a fast, sensitive technology, even in the presence of low frequency alleles.

Methods:
In this study, the enrichment strategy used was the Ion Ampliseq Colon and Lung panel for tumour biopsies. All amplified products were used to prepare libraries and sequenced using the Ion PGM or S5xl system. The QuantStudio 3D Digital PCR System was used to confirm selected results. 92 patients with advanced lung adenocarcinoma previously tested for EGFR mutation by PCR and for ALK by FISH were included. Significant genetic alterations obtained by NGS are described and compared with those identified by standard techniques.

Results:
NGS was applied to 92 diagnostic samples, corresponding to 63 (68.5%) wild type (WT) patients, 21 (22.8%) with EGFR mutations and 8 (8.7%) with ALK-EML4 translocation. The Ion Torrent PGM confirmed the presence of the EGFR mutation in 20 (95.2%) patients and detected a new case with p.L858R. Among patients classified as WT, 18 had a KRAS mutation, 3 BRAF V600E and 1 STK11; among ALK patients, 2 had a KRAS mutation. Other significant concurrent genetic alterations were found: 2 patients with EGFR and PIK3CA mutations, 2 with EGFR and KRAS and sporadic cases with STK11 and TP53. Only 40 patients remained classified as WT (43,5%).

Conclusion:
NGS is useful for detection of actionable mutations in small tumour biopsies and cytology specimens of lung adenocarcinoma. It allows the identification of more candidates to targeted therapies and the detection of concurrent mutations that can impact prognosis and treatment efficacy.

Background:
Circulating tumour free DNA (cfDNA) is a noninvasive assessment that can be used as an alternative method for gene mutations detection in lung cancer patients and for real time therapeutic monitoring. Detection and quantification of such mutations is difficult and next generation sequencing (NGS) is a promising technology. Concordance between tumour tissue DNA (tDNA) and plasma cfDNA need to be studied and changes in cfDNA correlated with clinical evolution.

Methods:
Ion Ampliseq Colon and Lung panel was used for tissue biopsies and the new Oncomine Lung cfDNA assay for cfDNA samples. All amplified products were used to prepare libraries and sequenced using the Ion PGM or S5xl system. Selected results were confirmed with the QuantStudio 3D Digital PCR. Plasma cfDNA collected at the diagnosis and during disease´s evolution of patients with advanced adenocarcinoma was analysed. cfDNA mutations were compared with tDNA.

Results:
56 patients were included. In the tumour samples 24 activating EGFR mutations, 16 KRAS, 3 BRAF-V600E, 3 TP53, 1 STK11 and 1 PIK3CA were identified. 16 patients were classified as “wild type” (WT). Tumour derived genetic alterations could be identified in cfDNA with allelic frequencies as low as 0.01%. Among the 48 alterations detected on tDNA, 39 (81.3%) were found in cfDNA. Plasma detection failed in 6 EGFR and 3 KRAS. In 3 EGFR patients, concurrent alterations not identified in the tumour were detected: 1 combination with EGFR p.Glu746_Ala750del; 2 with T790M and 1 with ALK p.I1171N. A KRAS mutation was identified in 1 WT patient. cfDNA longitudinal variations are being studied and will be updated.

Conclusion:
Profiling cfDNA with Ion NSG technology is feasible, allowing the detection of molecular alterations associated with targeted therapy or valuable for disease´s monitoring. cfDNA has a good correlation with tumour DNA alterations, representing a true “liquid biopsy”. The application of NGS to tumour and plasma samples hold a large spectrum of clinical potentialities.

Background:
Broad implementation of molecular diagnostics and personalized cancer care is hampered by insufficient molecular screening, missing reimbursement for comprehensive molecular testing and lack of access to appropriate drugs. The Network Genomic Medicine (NGM) Lung Cancer is a health care provider network offering comprehensive next generation sequencing (NGS)-based multiplex genotyping on a central diagnostics platform in Cologne for all inoperable lung cancer patients (pts) in Germany.

Methods:
The NGS panel used in NGM consists of 14 genes and 102 amplicons to cover potentially targetable aberrations. Mutation analyses were run on an Illumina (MySeq) platform, while FISH analyses were performed separately. In 2015, we have started the second outcome evaluation for all NGM pts who had received NGS-based molecular diagnostics. In particular, we have focused on molecular subgroups of EGFR, ALK, BRAF-V600E, HER2 and ROS1 positive pts and especially on NGM pts treated in clinical trials.

Results:
From 2013-2015 6210 lung cancer pts (n=4244 non-squamous NSCLC) were genotyped. Preliminary data show the overall survival (OS) of 934 NSCLC pts including of 110 NSCLC pts treated in clinical trials. For 108 EGFR+ pts, the OS of clinical trials pts treated with so called 3[rd] generation EGFR-TKIs was 55 months (n=25) vs 22 months in control group (n=83) (p=0,002; mean OS: 29 months; 95%CI: 36-83 months). For 85 ALK+ pts, the OS of pts treated in clinical trials was 35 months (n=19) compared to OS of 23 months for 45 pts treated with one ALK inhibitor and 8 months for 19 pts treated with no ALK inhibitors (P<0,0001; mean OS: 22 months; 95%CI: 22-33 months).

Conclusion:
While the first NGM evaluation in 2013 already showed a survival benefit of 2 years in EGFR-TKI treated EGFR+ pts compared to chemotherapy, our current evaluation in pts treated with 3[rd] generation EGFR-TKIs after acquired resistance to 1[st] gen. EGFR-TKIs shows the significant increasing of the OS. Similarly, we show a significant longer OS for ALK+ pts treated with 2 ALK inhibitors compared to treatment with one or no ALK inhibitor. Further results of this ongoing NGM evaluation will be provided.

Background:
Pulmonary adenoid cystic carcinoma (PACC) is one of the rare malignancies, that primary from glandular tissues of lung. Currently, the treatment of PACC relies on surgery and local radiotherapy. However the therapy for advanced PACC patients is limited. A larger number of studies demonstrated that advanced PACC patients obtained little benefit from chemotherapy. Moreover, only a few case reports revealed PACC patients were appropriate for target therapy. Using high-flux and high-resolution techniques to detect the genomic alterations of PACC could provide theoretical foundation for the precision therapy of PACC.

Methods:
8 PACC patients who received surgical resection between January 2013 to December 2015 were enrolled. The tumor tissues from different locations and blood samples were collected. The oncoscreen[TM] panel by Illumina platform, which utilizing probe hybridization to gathering 287 exon regions and 22 intron regions, were used to detect the gene mutation status of PACC. And the embryonal system mutations were filtered by contrasting the gene mutation status of the leukocytes. The tumor heterogeneity was revealed by comparing the gene mutation status in different areas of the same PACC, and the phylogenetic relationships were analyzed to disclose the evolving and developing progression of PACC.

Results:
There were 69 gene mutations together among 8 patients including 29 samples. Each patient has 8.6 mutations averagely. The high-frequency mutations were PAK3-D219E, FBXW7-D112E, TET2-T418I, KAT6A-E796A, and MET-R1005Q. However, the common mutations in other NSCLC, like EGFR, KRAS, ALK, etc., weren’t happened in this group of PACC. In this study, the spatial heterogeneity was discovered in PACC, not only in the mutation site, but also in the mutant abundance. Moreover, the phylogenetic relationships revealed that the clonal evolution and development existed in PACC.

Conclusion:
The status of genomic alterations in PACC was different from the other non-small cell lung cancer (NSCLC). PACC showed obvious spatial heterogeneity and clonal evolution.

Background:
The availability of tumor genomic information from simple, minimally invasive blood collection may lead to significant impact in patient(pt) care. We report a retrospective review the clinical utility of a CLIA-certified cell-free DNA (cfDNA) next generation sequencing (NGS) blood test in our pts with lung cancers.

Methods:
From April 2015 to May 2016, blood samples from 250 consecutive pts were collected and sent for molecular profiling at a CLIA-certified lab (Guardant360, Guardant Health, Redwood City, CA) using cfDNA NGS with a panel of 70 cancer-related genes with reported high sensitivity (able to detect mutations of < 0.1% mutant allele fraction) with high specificity (> 99.9999%) (PLoS One, 10(10), 2015).

Results:
254 Guardant360 tests were completed in 250 pts (144/F:106/M); histology: adenocarcinoma(200), squamous(7), sarcomatoid(5), small cell(4) and others(34). Rationale for blood tests: addition to tissue analysis(39%), alternative to tissue biopsy(25%), treatment evaluation/resistant(18%), insufficient tissue(11%), no documentation(7%). Based on Guardant360 results, 77 pt samples (30.3%) demonstrated targetable alterations with FDA-approved agents; concordance with at least 1 genomic alteration (targetable with FDA-approved agent) from paired tissue analysis in 21pts; and in another 29 pts, new genomic alterations provided evaluation for potential change in therapies pts: EGFR T790M(n=21), EML4-ALK fusion(n=4), MET Exon 14 Skipping (3), EGFR ex19del(n=2), EGFR L858R(n=2), other targets(n=6). Significantly, detection of EGFR T790M in cfDNA lead to change in therapy with osimertinib 19 cases and eligibility to clinical studies in 2 cases with alterations in KIF5B-RET and NOTCH1,respectively. Additional clinical outcomes are pending and will be updated.

Conclusion:
Molecular testing of cfDNA is a simple, minimally invasive test. It has utility to obviate a repeat invasive tissue biopsy when the initial tissue sample is not available or inadequate for molecular analysis. It is particularly useful in the long-term management of patients at progression for detection of emergent resistance-associated molecular alterations; such as EGFR T790M.

Background:
Anti-PD-1/PD-L1 immunotherapy has delivered clinical benefit for patients with NSCLC, and PD-L1 has emerged as a predictive biomarker. In the Phase III SELECT-1 trial (NCT01933932), selumetinib (AZD6244, ARRY-142886), an oral, potent and selective, allosteric MEK1/2 inhibitor with a short half-life, plus second-line docetaxel did not provide clinical benefit for patients with KRAS-mutant (KRASm) NSCLC compared with placebo plus docetaxel (PBO+DOC). Although no incremental benefit was observed, it is important to evaluate biomarkers, such as PD-L1, to understand more about the biology of patients with KRASm NSCLC.

Methods:
In total, 510 patients with a prospectively, centrally confirmed KRAS mutation (cobas® KRAS Mutation Test, Roche Molecular Systems) were randomised 1:1 to selumetinib 75 mg BID, plus docetaxel 75 mg/m[2] q21d (SEL+DOC), or PBO+DOC. Evaluations included progression-free survival (PFS) by investigator assessment (RECIST 1.1; primary endpoint), and overall survival (OS). Association of tumour PD-L1 status with clinical responses was assessed as an exploratory objective. PD-L1 status was centrally determined using the PD-L1 IHC 28-8 pharmDx test (Dako) for all patients with sufficient tumour sample. Samples with a pre-specified cut-off of ≥5% tumour cell staining were considered PD-L1 positive.

Results:
SEL+DOC did not improve PFS or OS compared with PBO+DOC. PD-L1 status was determined for 385 (75%) patients: 224 (58%) samples were PD-L1 <5%, and 161 (42%) samples were PD-L1 ≥5%; the remaining 125 patients had unknown PD-L1 status due to insufficient tumour sample. Subgroups were balanced across treatments. PD-L1 subgroup analysis of PFS and OS is presented below.

Subgroup	Events (%) in SEL+DOC group	Events (%) in PBO+DOC group	HR (95% CI)
PFS
PD-L1 <5%	94/112 (84%)	101/112 (90%)	0.89 (0.67, 1.18)
PD-L1 ≥5%	65/79 (82%)	71/82 (87%)	0.70 (0.50, 0.99)
PD-L1 unknown	59/63 (94%)	57/62 (92%)	1.24 (0.86, 1.79)
OS
PD-L1 <5%	73/112 (65%)	74/112 (66%)	0.94 (0.68, 1.30)
PD-L1 ≥5%	55/79 (70%)	58/82 (71%)	0.89 (0.61, 1.28)
PD-L1 unknown	48/63 (76%)	38/62 (61%)	1.57 (1.02, 2.41)

Conclusion:
Prevalence of PD-L1 positive status in this KRASm cohort was similar to that reported for a pan-NSCLC cohort (Borghaei, NEJM 2015). No significant PFS or OS differences were observed between treatments in either PD-L1 positive or negative tumours. Additional biomarker analyses are planned for different KRAS codon mutations, and LKB1 and TP53 status.

Background:
Cytophenotypic transformation from adenocarcinoma to SCLC raises much attention as a mechanism of drug resistance in NSCLC patients treated with EGFR-TKI therapy. However, there’s no noninvasive way to predict and monitor the occurrence of cell transformation.

Methods:
We collected 362 cases of transformation from adenocarcinoma to SCLC to analyze the relationship among cancer development, tumor cell transformation and specific serum tumor marker of SCLC (NSE). The associations among the tumor medications, therapeutic effect and serum NSE were analyzed by chi-square test and Kaplan-Meier survival analysis was conducted by log-rank analysis in adenocarcinoma patients.

Results:
All 362 adenocarcinoma patients were collected from 2013 to 2015 in Shanghai Pulmonary Hospital and accepted EGFR mutation test. 79 patients accepted the repeat biopsy and 4 patients showed the cytophenotypic transformation. In the cytophenotypic transformation cases, NSE was normal at first and increased remarkably during the treatment. The peculiar rising pattern of serum NSE matched the SCLC pathological confirmation in repeat biopsy. Then we further found that in 362 cases, 66 (18.2%) patients experienced the peculiar rising pattern of serum NSE. Notably, this kind of NSE changing pattern is associated with drug resistance (p=0.026), but has no relationship with EGFR mutation or targeted therapy. What’s more, the peculiar rising pattern of serum NSE during the first-line treatment led to a shortened PFS of the second-line treatment (p=0.042). Figure 1



Conclusion:
Cytophenotypic transformation from adenocarcinoma to SCLC develops no matter the EGFR mutation positive or not, targeted therapy taken or not. For adenocarcinoma patients, serum tumor markers, especially NSE, need highly attention in clinical practice. A repeat biopsy is strongly recommended when adenocarcinoma patients’ NSE level shows the remarkable rise in case of cytophenotypic transformation to SCLC.

Background:
Personalized medicine significantly increases survival of lung adenocarcinoma patients. Currently, existing diagnostic guidelines include only EGFR and ALK testing, although other oncogenic drivers can be detected and targeted as well. Massive parallel sequencing (MPS) detects a wider spectrum of actionable genomic alterations (GAs) compared to regular molecular diagnostic procedures. Studies on the influence of hybrid capture-based (HC-based) MPS on therapeutic strategy are limited. In this study, we explored its impact on therapy management and clinical outcomes.

Methods:
A retrospective cohort of patients who were diagnosed with advanced stage lung cancer, and performed HC-based MPS between 11/2011 and 10/2015. Two platforms of HC-based MPS were included: a tissue based assay, and a blood based assay of circulating free DNA (cfDNA, "liquid biopsy") for tissue-exhausted cases. Demographic and clinico-pathologic characteristics, treatments, and outcome data were collected and analyzed.

Results:
One hundred and one patients were analyzed in this study: median age, 63 years; 53% females; 45% never smokers; 85% with adenocarcinoma, 19/101 performed a blood-based assay of cfDNA. HC-based MPS was carried-out upfront and after EGFR/ALK testing yielding negative or uncertain results in 15% and 85% of cases, respectively. HC-based MPS was performed before 1[st]-line therapy in 51.5% cases, and in 48.5%, after treatment failure. HC-based MPS recognized clinically actionable, National Comprehensive Cancer Network (NCCN) recommended drivers in 50% of cases, most commonly in EGFR (18%), RET (9%), ALK (8%), MET (6%) and ERBB2 (5%). EGFR/ALK aberrations were identified in 16 patients by HC-based MPS after negative prior regular testing. Therapeutic strategy was changed for 43 patients (42.6%). A higher fraction of tissue-based assays changed therapeutic strategies (n=37/82, 45%) compared to blood-based cfDNA assays (n=6/19, 32%), although not significantly. The overall response rate after treatment change to targeted therapy was 65% (complete response, 14.7%; partial response, 50%), and 62% if excluding not-previously tested patients. Median duration of targeted treatment was 26 weeks (range: 1-227). Median survival was not reached. Immunotherapy was administered in 33 patients, mostly without a detected actionable driver, presenting disease control rate of 32% and an association to tumor mutational burden.

Conclusion:
HC-based MPS changed therapeutic strategy in close to half of the patients with lung cancer, and was associated with high overall response rate, which may translate into a survival benefit.

Background:
The mutation profile in the brazilian population with advanced lung adenocarcinoma remains largely unexplored and also their relationship to many other genes. Next Generation Sequencing(NGS) allows higher sensitivity and multiplexing for several genes for translational research

Methods:
80 lung adenocarcinoma patients were collected. DNA concentration and quality was determined by Qubit2.0fluorometer and Agilent2100Bioanalyzer. Genomic libraries were constructed using the TruSeq®Custom Amplicon v1.5) comprising 764 amplicons of 38genes on the Illumina-MiSeq®sequencing plataform.

Results:
The 7362 genetic mutation were observed with 78% of single-nuclotide variants (SNVs) and 22% insertions and deletions. The majority of the SNVs were located in inter-genic regions or introns. EGFR were mutated in 21(6%) of patients with 19 (57%) of mean expression. The most frequent EGFR-mutation was exon 19deletions, followed by L858R amino acid substitution in exon 21. KRAS was mutated in 26 (4%) of patients. ALK rearrangement was detected in 6 patients (4.8%). The stop gained mutation was present in PIK3CA,TP53,AXL,EGFR,RAB25,CDH1,CD276 and TGFB1. The AXL receptor tyrosine kinase gene showed 11 missense-mutations, of which 7 are considered possibly damaging (Polyphen)/deleterious(SIFT)(74/79) and 14 intronSNVs(49/80). CD44 showed 50 variants, however most of them have an undetermined significance. The clustering analysis demonstrated that a select group of AXL-related gene alterations was highlighted(Fig 1). Figure 1



Conclusion:
The results suggest that genomic variants in lung adenocarcinoma tissues are complex and show that NGS is an effective way to detect novel mutations in lung cancer. 58% of patients wild type by standard testing for EGFR/KRAS/ALK have genomic changes identifiable by CGP that suggest benefit from target therapy. The AXL and CD44 genes remain a relatively unexplored target, thus we intend to increase the available data for the true translational potential of target AXLand CD44 therapy in lung cancer. CGP used when standard molecular testing for adenocarcinoma is negative can reveal additional avenues of benefit from targeted therapy.

Background:
Necitumumab (Neci) is a monoclonal antibody directed against the human epidermal growth factor receptor (EGFR). In the SQUIRE trial (NCT00981058), the addition of Neci to gemcitabine plus cisplatin (Gem-Cis) in squamous cell lung cancer resulted in a significant advantage in terms of overall survival (OS), but the expression of EGFR assessed by immunohistochemistry was not able to robustly predict the benefit from Neci. In a post-hoc analysis of SQUIRE, EGFR gene copy number gain determined by fluorescence in situ hybridization (FISH) showed a trend towards improved OS (HR=0.70) and progression-free survival (PFS) (HR=0.71) with the addition of Neci. We present the analysis of granular EGFR-FISH data from SQUIRE to examine the potential predictive role of high polysomy (HP) vs gene amplification (GA) as both were included in the “FISH-positive” category.

Methods:
Suitable specimens from SQUIRE patients underwent FISH analysis. Probe hybridization was performed in a central laboratory and each sample was analyzed using the Colorado EGFR scoring criteria. FISH was considered positive in cases of HP (≥40% cells with ≥4 EGFR copies) or GA (EGFR/CEP7 ≥2 or ≥10% cells with ≥15 EGFR copies). The correlation of granular FISH parameters with clinical outcomes was assessed.

Results:
FISH analysis was available for 557 patients (out of 1093); 208 patients (37.3%) were FISH+, including 167 (30.0%) with HP and 41 (7.4%) with GA. The outcome data for HP and GA are reported below:

	HIGH POLYSOMY		GENE AMPLIFICATION
	Neci+Gem-Cis (N=89)	Gem-Cis (N=78)	Neci+Gem-Cis (N=22)	Gem-Cis (N=19)
Median OS in months (95% CI)	12.58 (11.04-16.00)	9.53 (7.16-12.48)	14.78 (10.02-31.51)	7.62 (4.99-16.10)
Hazard ratio within subgroup (interaction model)	0.77 (0.55-1.08) p = 0.133		0.45 (0.21-0.93) p = 0.033
Interaction p value	0.189
Median PFS in months(95% CI)	6.08 (5.59-7.59)	5.13 (4.24-5.72)	7.36 (4.27-11.40)	5.55 (2.79-8.34)
Hazard ratio within subgroup (interaction model)	0.70 (0.50-0.99) p = 0.044		0.69 (0.33-1.45) p = 0.334
Interaction p value	0.980

Conclusion:
The OS benefit from the addition of Neci to Gem-Cis appeared to be more pronounced in the small subset of patients with GA when compared to HP, but the same trend was not observed for PFS. The potential predictive value of different EGFR FISH parameters should be evaluated in future studies.

Background:
Molecular multiplex diagnostics is increasingly integrated now in routine diagnostics of lung adenocarcinoma (LAD). Although targetable aberrations are predominantly found in LAD, they have also been reported in squamouscell lung carcinoma (SQLC). We here present results of routine molecular multiplex diagnostics of advanced stage SQLC obtained within the German Network Genomic Medicine (NGM) and compare them with results reported previously in early stage SQLC in The Cancer Genome Atlas (TCGA) LUSC cohort.

Methods:
Tumor biopsies of 821 patients consecutively diagnosed within NGM were analyzed with next-generation parallel sequencing (NGS). The panel consisted of 102 amplicons and 14 genes: KRAS, PIK3CA, BRAF, EGFR, ERBB2, NRAS, DDR2, TP53, ALK, CTNNB1, MET, AKT1, PTEN and MAP2K1. In subsets of patients, fluorescence in-situ hybridization (FISH) was performed for amplification detection of FGFR1 and MET. We queried the TCGA dataset with respect to the panel used and compared the findings. For NGM patients, therapy and outcome are also reported..

Results:
In addition to the expected frequencies of TP53, DDR2, PTEN and PIK3CA mutations, we detected EGFR mutations in 3.2% and BRAF mutations in 1.8%. Unlike the TCGA dataset, where the frequencies were 2.8% and 3.9%, respectively, the detected mutations in the NGM cohort included also activating targetable mutations (i. e., EGFR del19 and L858R, and BRAF V600E). FISH data revealed presence of MET amplification in 14.2% and of FGFR1 amplification in 20.0%. The association and correlation of these aberrations with clinical findings and prognosis as well as with PD-L1 expression status and mutational load will be presented.

Conclusion:
Our data give an overview on the presence and clinical characteristics of targetable mutations in advanced SQLC and show, that such mutations occur in a substantial amount of patients. Thus, molecular multiplex diagnostics might be indicated also in SQLC in order to use all therapeutic options available in these patients.

Background:
In 2013, recommendations for 1st line treatment in advanced NSCLC included a platinum based chemotherapy (pCT) with or without bevacizumab (BEV-pCT), an EGFR-TKI, or a non-platinum based CT (non-pCT) depending on clinical, pathological and molecular characteristics. Molecular testing for KRAS, EGFR and ALK, is routinely performed in France for advanced non-squamous NSCLC. However, the prognostic impact of the molecular status knowledge before beginning 1st line treatment is unknown.

Methods:
After a cross-validation study, KRAS, EGFR and ALK molecular status were assessed in 843 consecutive patients (pts) with previously untreated advanced NSCLC (all histologic subtypes) and categorized as: EGFR/ALK+, KRAS+, wild-type (WT), undetermined (UD) and not done (ND). Treatments from the 1st to 3rd line were separated into 4 groups: p-CT, BEVA-pCT, EGFR/ALK TKI and non-pCT. Demographic, clinical and pathological characteristics were collected and pts were followed-up until death. Overall survival (OS) and progression-free survival (PFS) for each line were determined. Prognostic factors including treatment categories (p-CT as reference) and biomarkers status (WT as reference) were studied by Cox model.

Results:
Treatments were analyzed in 767 (91.0%) of the 843 pts enrolled between 01/2013 and 02/2014. Pts were 93.1% Caucasians, 66.2% males. Median age was 62.4 yr (28-92). 13.4% were never smokers. PS ≥2 were 21.4% and 90.3% were stage IV. 76.5% had adenocarcinoma, 14.5% squamous cell carcinoma and 9% others with WT=40.4%, KRAS+=23.1%, EGFR/ALK+=10.2%, UD=5.1%, ND=21.2%. 1st line treatments were: p-CT=75.9%, BEVA-pCT=14.2%, EGFR/ALK TKI=7.8% and non-pCT=2.1%. With a 30.3 months (mo) median of follow-up, median OS and PFS were 10.7 mo and 5.3 mo, respectively. Factors independently associated with shorter OS were PS≥2 (HR=2.08, p<.0001), KRAS+, UD and ND mutation status (HR=1.40, p=.002; 1.53, p=.02; 1.29, p=.02), and non-pCT as 1st line treatment (HR=1.92, p=.01), while EGFR/ALK+ (HR=.38, p<.0001) and BEVA-pCT (HR=.54, p<.001) were associated with better survival. There was no interaction effect between biomarkers status and OS treatment groups. However, BEVA-pCT in 1st line therapy in KRAS+ and WT NSCLC (p<.0001 and <.0003, respectively) was associated with longer survival compared to p-CT, while giving a TKI or p-CT in 1st line therapy in EGFR/ALK+ NSCLC did not affect OS.

Conclusion:
Results from the IFCT-PREDICT.amm study suggest that prognosis of advanced NSCLC might be optimized in 1st line setting by the knowledge of EGFR/ALK molecular status and the opportunity to give a BEVA-pCT regimen, especially in patients with KRAS+ and WT tumor.

Background:
Cyfra 21-1, belonging to the intermediate filament protein, is responsible for the mechanical integrity of the cell and celluar processes such as cell division. Cyfra 21-1 in cerebrospinal fluid (CSF) has been proposed as a diagnostic and prognostic marker in patients with leptomeningeal carcinomatosis. We aimed to evaluate the diagnostic and prognostic value of CSF cyfra 21-1 in patients with leptomeningeal metastasis (LM) of non-small cell lung cancer (NSCLC).

Methods:
CSF cyfra 21-1 was measured by chemiluminescence immunoassay in cerebrospinal fluid (CSF) samples of LM patients with NSCLC (n = 36) and other neurological diseases (n=209, OND, multiple sclerosis, neuromyelitis optica spectrum disorder, Guillain-Barre syndrome, headache) from National Cancer Center in Korea. Diagnosis of LM was made via positive CSF cytology and/or MRI scans showing LM. Upper normal limit (UNL) was calculated by two times of mean value plus two standard deviation (3.46 ng/ml). Overall survival was defined as the time elapsed from the start of intra-thecal chemotherapy to death and survival curves were analyzed according to the Kaplan-Meier method.

Results:
CSF cyfra 21-1 (22 ± 83 vs. 1.4 ± 0.1 ng/ml, p<0.001) was significantly higher in LM patients with NSCLC than patients with OND. Diagnostic sensitivity, specificity, positive and negative predictive values for LM with NSCLC were estimated 41%, 100%, 100% 91% in CSF cyfra 21-1 and 67%, 100%, 100%, 95% in CSF cytology, respectively. Two of 12 cytology-negative patients showed high CSF cyfra 21-1 (over 3.46 ng/ml). CSF cyfra 21-1 was significantly higher in cytology-positive LM patients than cytology-negative LM patients (31.4 ± 101 vs. 3.1 ± 3.5 ng/ml, p=0.004). The median overall survival was longer in LM patients with low CSF cyfra 21-1 than those with high CSF cyfra 21-1, although it did not reach statistical significance (median 5 vs. 2 months, p=0.163).

Conclusion:
These findings suggested that CSF cyfra 21-1 could be used as an additional diagnostic and prognostic biomarker for LM of NSCLC.

Background:
Cell-free circulating tumor DNA (ctDNA) and RNA (ctRNA) can be extracted from plasma of cancer patients (pts). Measuring dynamic changes in gene expression, allele-fractions of mutations and levels of nucleic acids per ml of plasma in metastatic patients has shown great potential for monitoring disease state and predicting outcome to antitumoral therapy in advance of imaging.

Methods:
We designed a clinical trial to measure gene levels of plasma ctDNA and ctRNA in metastatic pts with NSCLC, breast, and GI malignancies under treatment and correlate the levels with CT scans done assessing response for one-year clinical trial. CtDNA/ctRNA were extracted from plasma separated from patient whole-blood draws shipped at ambient temperature. CtRNA was reverse transcribed with random primers to cDNA. Levels of ctDNA/ctRNA were determined by real-time qPCR. Results of ctDNA/ctRNA tests were compared with responses (CR, PR, SD or PD) as determined by the CT scans. Levels of PD-L1 expression relative to β–actin were determined by qPCR.

Results:
We have enrolled 39 pts and we are presenting data from 15 pts with NSCLC. The first-line treatments were Carboplatin (40%, 6/15), Opdivo (26.7%, 4/15), Afatinib (13.3%, 2/15), Ceritinib (6.7%, 1/15), Crizotinib (6.7%, 1/15), and Taxotere/Cyramza (6.7%, 1/15). Histological subtypes were 73.3% (11/15) adeno, 20% (3/15) squamous, and 6.7% (1/15) other. The majority of patients were Caucasian (66.7%, 10/15), Hispanic (26.7%, 4/15), and African American (6.7%, 1/15). Levels of ctDNA and ctRNA were significantly correlated with one another across patient blood draws (r = 0.5781, p < 0.0001). After the first 2 cycles of therapy, 9 of the 15 patients achieved SD, of whom 8 were analyzed for ctDNA/ctRNA levels. In 7/8 of pts who had SD indicated by CT scan, CtDNA/ctRNA levels were stable, while the 2 PD pts showed significant increases in levels of ctDNA/ctRNA 4.8 weeks prior to progression. In the 2 SD pts treated with Opdivo, PD-L1 expression was stable during the cycles when CT scans also indicated an SD status.

Conclusion:
In almost 90% of the pts, constant ctDNA/ctRNA levels correlated with stable disease status as seen by CT; moreover, in 2 pts changes in the levels of both ct nucleic acids predicted progression about 5 weeks before CT scans. Importantly, the concordance between cDNA and cfRNA suggest that cfRNA can just as effective as cfDNA as a prognostic tool, while adding the extra dimension of gene expression.

Background:
NANOG is a master transcription factor that regulates embryonic stem cell pluripotency and cell-fate specification though complex interaction with a myriad of factors in signaling pathways. Cumulating evidence suggests that it has oncogenic potential correlating with cell proliferation, clonogenic growth, tumorigenicity and invasiveness. Increased NANOG expression has been reported to be related with poor survival in several human malignancies including hepatic, breast, ovarian and colorectal cancers. However, clinical significance of NANOG overexpression in lung cancer has been scarcely evaluated, and correlation between NANOG expression and prognosis in advanced non-small cell lung cancer (NSCLC) has not been studied. The aim of this study is to investigate whether NANOG expression is associated with clinical outcomes of patients who were treated with platinum-based chemotherapy for advanced NSCLC.

Methods:
To prove NANOG overexpression in lung cancer, we initially assessed the expression of NANOG using Western blotting in lung cancer tissue from NSCLC patients who underwent surgical resection. Then, NANOG expression was examined by immunohistochemistry and evaluated by a semiquantitative histologic score (H score) in tumor tissues from NSCLC patients treated with platinum-based doublet. We performed survival analyses and evaluated the association between NANOG expression and clinical parameters.

Results:
NANOG expression in lung cancer tissues was significantly increased compared with non-tumorous tissues (p < 0.001). Survival analyses using 110 tumor specimens showed that, at the cutoff value of H score 200, high NANOG expression was significantly associated with short progression-free survival (hazard ratio [HR] = 2.40, 95% confidence interval [CI]: 1.14 –5.62), and with short overall survival (HR = 2.89, 95% CI: 2.18–4.62). In addition, similar results were shown in the subgroup analyses for adenocarcinoma and squamous cell carcinoma. NANOG expression was not associated with any clinical parameter including age, gender, smoking status, stage, differentiation, or tumor histology.

Conclusion:
Increased NANOG expression was associated with poor response and short overall survival in advanced NSCLC patients treated with platinum-based chemotherapy. NANOG overexpression could be a potential adverse predictive marker in this setting.

Background:
The diagnosis of leptomeningeal metastases (LM) relied on tumor cells found in cerebrospinal fluid (CSF) and/or typical magnetic resonance imaging (MRI) findings, but both lack sensitivity. The CellSearch Assay™ had been validated to detect CTCs for follow-ups of cancer patients, and we adapted it to identify CSF tumor cells (CSFTCs) in non-small cell lung cancer (NSCLC) with suspected LM, and moreover detected their gene statuses of epidermal growth factor receptor (EGFR).

Methods:
Twenty-one NSCLC patients with suspicious LM had CSF analyzed through both traditional Thinprep cytologic test (TCT) and CellSearch, and peripheral blood were detected for circulating tumor cells (CTCs) in fourteen patients. The statuses of EGFR were tested in primary tissues of all twenty-one patients and in CSFTCs of eight patients.

Results:
All twenty-one patients were identified as LM, CSFTCs were captured by CellSearch in twenty patients (median 969 CSFTCs/ 7.5 mL, range: 27-14888), while CTCs were captured in only five patients (median 2 CTCs/7.5 mL, range: 2-4), which were much lower than CSFTCs. The sensitivity of CellSearch was 95.2%, while that of TCT from the same CSF puncture was 57.1%, and that of MRI was 52.4%, and that of combined MRI and TCT was 90.5%. Moreover, the specificity of CSFTCs was 100%. Among eight patients with EGFR tested in CSFTCs, six patients matched with primary tissues and resistant gene T790M was identified in two cases.Figure 1



Conclusion:
Cerebrospinal fluid tumor cells could be more sensitive and effective to diagnose LM, and may serve as the potential way of liquid biopsy for EGFR mutation in NSCLC with LM.

Background:
Activation of the MET tyrosine kinase receptor can drive oncogenesis and metastasis in certain cancer types. Somatic mutations at or around the splice junctions for MET exon 14 (METΔ14) are a recurrent mechanism of MET activation. METΔ14 mutations lead to aberrant messenger RNA (mRNA) splicing resulting in a METΔ14 protein lacking the juxtamembrane domain.

Methods:
We analyzed RNAseq data across 12 cancer types to define the prevalence of METΔ14 in solid tumors. We explored the driver role of METΔ14 both in vitro and in vivo. Finally, we explored acquired resistance mechanisms in a patient treated with crizotinib.

Results:
The METΔ14 mutation and aberrant mRNA transcript are most common in lung adenocarcinoma and also identified in other cancers. Endogenous levels of METΔ14 transcript transform human epithelial lung cells in an HGF-dependent manner. This allele also induces lung cancer in mice that is responsive to a clinically available MET inhibitor. Finally, we document clinical response to crizotinib in a patient with a METΔ14-driven NSCLC lung cancer. Upon clinical progression on crizotinib, indicating acquired resistance, we detected acquired MET mutations in cell-free DNA from the patient that converge on critical drug-binding residues in the MET activation loop.

Conclusion:
These findings qualify METΔ14 mutations as drivers of lung adenocarcinoma, deomstrate the utility of a new animal model of MET-driven disease and identify a subpopulation of patients who may benefit from further development of targeted MET/HGF therapies.

Background:
CD45RA+ CCR7+ naive T cells were reported to generate effectors possessed the high potent cytotoxic activity and low level of "exhaustion" T cells in vitro. However the relationship between frequency of naïve T cells in peripheral blood and prognosis in non-small cell lung cancer (NSCLC) is not clear. In order to elucidate this relationship, we first analyzed the frequency of CD45RA+ CCR7+ naïve T cell in peripheral blood of healthy population and patients with NSCLC.

Methods:
The frequency of CD45RA+ CCR7+ naïve T cells was calculated by flow cytometry from healthy volunteers and NSCLC patients. The correlation of naive T cell frequency and overall survival (OS) of NSCLC patients who were treated with tyrosine kinase inhibitors (TKIs) or chemotherapy was statistically analyzed.

Results:
105 healthy volunteers (age rank 23-85year-old) and 137 NSCLC patients (age rank 33-86year-old) were enrolled in our study from 2013 October 1st to 2015 December 1st. Our results showed that the frequency of peripheral blood naïve T cells in NSCLC patients’ (Mean=17.8±5.7%) was significantly lower than that in healthy subjects’ (Mean=31.2±5.2%) (p<0.05). The frequency of naïve T cell was negatively correlated with the frequency of PD-1+CD8+ T cells (R[2]=0.1111, p<0.001) in peripheral blood of NSCLC patients, whereas, which was positively associated with the immune activity of CD8+ T cells and with the frequency of lymphoid stem cells or lymphoid progenitor cells in peripheral bloods (R[2]=0.1521, p<0.001). In the patients who were treated with TKIs，mOS in the group of high frequency of naïve T cells (>17.8%) was not reached, while that of group with low frequency (17.8%) was 19.0m (HR=0.3057, 95% CI 0.1127- 0.8291, p=0.0199). In patients who were administered chemotherapy, the mOS in the naïve T cells low frequency group was 12.0m, but in the high frequency group the median OS was undefined (HR=0.3286, 95% CI 0.1100 0.9817, p=0.0463).

Conclusion:
Our study shows that the CD45RA+ CCR7+ naïve T cells in peripheral blood closely related with immune response, and the frequency of naïve T cells in peripheral blood is positively associated with prognosis of NSCLC, which can be worked as a valuable prognostic factor for NSCLC patients.

Background:
Although long-term survival was observed in selected patients (pts) with oligometastatic non-small cell lung cancer, the current treatment for those pts remains controversial. This retrospective study aimed to determine the characteristics and the outcome of pts with synchronous oligometastatic NSCLC (SOM-NSCLC) treated in a single center.

Methods:
SOM was defined as thoracic disease along with ≤3 metastatic lesions. We identified 90 pts in our database that qualified as SOM-NSCLC treated from 2007-2015 at the Catalan Institute of Oncology. Overall Survival (OS) was plotted using Kaplan Meier method, and multivariate Cox model for prognostic factors was developed.

Results:
Pts’ characteristics are shown in Table 1. Most pts received chemotherapy (91%): 85% platinum doublet and 56% ≥4 cycles. 57 of 90 pts (63%) received thoracic radical therapy (TRT): surgical resection (16%), SBRT (3.5%), concurrent chemoradiotherapy (CRT; 70%) and sequential CRT (10.5%). Median OS for all patients was 17.4m (95% CI 9.6 – 25.2). In the multivariate Cox analysis of OS, T extension, histology, smoking history and TRT were independent prognostic factors. As TRT was a highly favourable prognostic factor (HR=0.39, 95% CI 0.20 - 0.80), we looked at the characteristic of pts according to whether they received TRT. Pts treated with TRT had significantly lower number of metastases and metastatic organs involved. 70 of 90 pts (78%) received local therapy (LT) in the metastatic sites: surgery (10%), radiotherapy (61%) or both (29%). Interestingly, pts treated with TRT and LT had significantly longer median OS (32.8; 95% CI 10.8 – 54.9) as compared with other pts (9.3; 95% CI 4.3 – 14.2; p=0.006). Figure 1



Conclusion:
In this retrospective cohort of SOM-NSCLC pts, TRT combined with LT provided a remarkable median OS of 33 months. These data support radical treatment of the primary tumor including definitive chemoradiation in the setting of SOM-NSCLC.

Background:
Background: Due to their pathophysiological role and stability in biological samples, microRNAs have the potential to become valuable predictive markers for non-small cell lung cancer (NSCLC). Samples of biopsy tissue constitute suitable material for microRNA profiling with the aim of predicting the effect of palliative chemotherapy.

Methods:
Patients and Methods: Our study group consisted of 81 patients (74 males, 7 females, all of them smokers or former smokers) with late stage (3B, 4) of squamous cell carcinoma (SCC) histological subtype of NSCLC. All patients underwent palliative chemotherapy based on platinum derivatives in combination with paclitaxel or gemcitabin. The expression of 17 selected microRNAs was measured by quantitative RT PCR in tumor tissue macrodissected from formalin-fixed paraffin-embedded (FFPE) tissue samples. To predict the effect of palliative chemotherapy, the relationship between gene expression levels and overall survival (OS) was analysed.

Results:
Results: From the set of the 17 microRNAs of interest, we found relation of high expression levels of miR-34a and miR-224 to shorter OS.

Conclusion:
Conclusions: In routinely available FFPE tissue samples, we found microRNAs with a relation to OS, which may be candidate predictors of the effectiveness of palliative treatment in SCC lung cancer patients. Such microRNAs could help in decision about the type of palliative chemotherapy - patients with predicted poor treatment effect could be candidates to available clinical trials.

Background:
RET fusion gene is identified as a novel oncogene in a subset of non-small cell lung cancer (NSCLC). However, few data are available about the prevalence, clinicopathologic characteristics, genetic variability and therapeutic options in RET-positive lung adenocarcinoma patients.

Methods:
For 615 patients with lung adenocarcinoma, RET status was detected by reverse transcription-polymerase chain reaction (RT-PCR). Next-generation sequencing (NGS) and FISH were performed in positive cases. Thymidylate synthetase (TS) mRNA level was assayed by RT-PCR. Overall survival (OS) was evaluated by Kaplan-Meier method and compared with log-rank test.

Results:
Twelve RET-positive patients were identified by RT-PCR. However, one patient failed the detection of RET arrangement by FISH and NGS. Totally, 11 patients (1.8%) confirmed with RET rearrangements by three methods , including six females and five males with a median age of 54 years. The presence of RET rearrangement was associated with lepidic predominant lung adenocarcinoma subtype in five of 11 patients. RET rearrangements comprised of nine KIF5B–RET and two CCDC6–RET fusions. Four patients had concurrent gene variability by NGS detection,including EGFR(n=1),MAP2K1 (n=1), CTNNB1 (n=1) and AKT1 (n=1) . No survival difference existed between RET-positive and negative patients (58.1 vs. 52.0 months, P=0.504) . The median progression-free survival of first-line pemetrexed/platinum regimen was 7.5 months for four recurrent cases,and longer than RET-negative patients(7.5 vs.5.0 months, P=0.026). . The level of TS mRNA was lower in RET-positive patients than that in those RET-negative counterparts (239±188×10[-4] vs. 394±457×10[-4], P=0.019) .

Conclusion:
The prevalence of RET fusion is approximately 1.8% in Chinese patients with lung adenocarcinoma. RET arrangement is characterized by lepidic predominance and a lower TS level. RET-rearranged patients may benefit more from pemetrexed-based regimen.

Background:
Next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) enables a non-invasive option for comprehensive genomic analysis of lung cancer patients. Currently there is insufficient data in regard to the impact of ctDNA analysis on clinical decision making. In this study, we evaluated the clinical utility of ctDNA sequencing on treatment strategy and progression-free survival.

Methods:
In this retrospective study, data was collected from files of 90 NSCLC patients monitored between the years 2011-2016 at the Thoracic Center Unit at Davidoff Cancer Center, Rabin Medical Center, Israel. The patients performed liquid biopsy NGS analysis by a commercial test (Guardant 360), in which ctDNA was extracted from plasma and analyzed by massively parallel paired end synthesis by digital NGS. This test allows the detection of somatic alterations such as point mutations, indels, fusions and copy number amplifications.

Results:
Age at diagnosis ranged between 31 and 89 years, with median age of 63 years. Sex ratio was 1:2.2. Out of 90 patients, 38 consecutive patient files have already been reviewed for clinical impact. 82% (31/38) were diagnosed with Adenocarcinoma. 5% (2/38) performed ctDNA at initial diagnosis, 48% (17/38) performed ctDNA after 1[st] line therapy due to progressive disease and the remaining 50% performed the test after multiple lines of treatment. Liquid biopsy NGS analysis allowed the detection of actionable mutations, according to NCCN guidelines, in 68% (26/38). Treatment decision was changed subsequent to NGS analysis in 34% (13/38) which received tailored targeted therapy. Interestingly, 13% (5/38) were detected with EGFR activating mutation following wild type result by standard local molecular testing based on RT-PCR from tissue biopsy. Based on the RECIST criteria of response evaluation, 30% of the patients had partial response after switching to targeted therapy, 15% had stable disease, 15% experienced progressive disease and ~40% were not evaluated yet. Survival rates will be calculated further in the study based on data availability.

Conclusion:
Our interim results analysis showed that liquid biopsy ctDNA testing revealed possible treatment options for more than two-thirds of patients analyzed, including FDA-approved drugs as well as eligibility for clinical trials. Most of the patients that were evaluated showed a positive response to treatment. Although this topic needs to be further assessed in large randomized controlled trials, these positive results emphasize the utility of liquid biopsy analysis to guide clinicians to select the right therapy for the right patient.

Background:
Access to biomarker testing is critical for selecting appropriate treatment for patients with advanced non-small cell lung cancer (aNSCLC). This study assessed rates and patterns of biomarker testing among patients with aNSCLC.

Methods:
Patients aged ≥65 years diagnosed with aNSCLC between 2007-2011 were identified in the SEER-Medicare database and were followed for ≥4 months post-diagnosis (n = 9,651). Patients’ first biopsy within ±8 weeks of diagnosis was defined as the index date. Biomarker tests included procedure codes for gene analyses to test for EGFR, ALK, and other mutations. IHC tests, which are mostly used for diagnosis, were excluded. The use of biomarker tests was assessed from the index date until the end of data availability (12/31/2013) or end of Medicare Parts A, B and D eligibility. Analyses were replicated in the subgroup with cancer stages IIIB-T4 or IV and adenocarcinoma, adenosquamous or unknown type of NSCLC histology (n = 6,193).

Results:
Of 9,651 patients observed for a median of 11 months, 18% had a biomarker test during the follow-up. The use of biomarker testing increased from 5% in 2007 to 35% in 2011, and was higher among patients who saw a cancer specialist as compared to those who did not see a cancer specialist. When comparing the patients with and without a biomarker test diagnosed in 2011 (i.e., the most recent year in the data) in the full study sample, a higher proportion of patients without a biomarker test were males (51 vs 43%), non-Hispanic Blacks (13 vs 5%), resided in areas with higher poverty (27 vs 15%) and lower education levels (26 vs 17%), and had larger tumors at diagnosis (median 41 vs 38 mm; p <.05 for all). In addition, a lower proportion of them were married (44 vs. 52%), resided in big metropolitan areas (51 vs 57%), had stage IV cancer (64 vs 69%), and adenocarcinoma histology at diagnosis (43 vs. 77%; p <.05 for all). Among tested, >40% of the patients had their first biomarker test >8 weeks after biopsy. Results were similar in the subgroup, but the rate of biomarker testing was slightly higher and with slightly shorter delays.

Conclusion:
Among patients with aNSCLC diagnosed in 2007-2011 a substantial proportion did not undergo biomarker testing or had their biomarker test delayed by >8 weeks post-biopsy. Significant differences exist in demographic and cancer characteristics between patients with and without a biomarker test.

Background:
Lung cancer treatment has taken a paradigm shift with advent of molecular therapy. This study evaluates lung adenocarcinoma cases for molecular markers EGFR, ALK, ROS-1 and MET testing.

Methods:
A total of 4485 cases of lung carcinomas were enrolled from the period of October 2010 to June 2016 in a North Indian tertiary Cancer Centre. Amongst these 815 cases after workup were found to be stage IV adenocarcinoma. Molecular mutation analysis was done for EGFR, ALK, ROS1 and C-MET amplification in 778, 522, 51 and 50 cases respectively. EGFR mutation testing was done using Qiagen Therascreen EGFR kit and Sanger sequencing, ALK testing was done using ALK IHC (clone anti-ALK D5F3) ,ROS1 gene rearrangement and MET gene amplification using Zytolight DNA FISH probes. The incidence of these biomarkers and its association with the age, sex, smoking history, histological subtype, site of biopsy, treatment history and survival outcome would be analyzed.

Results:
Late breaking. Will complete information later

Conclusion:
Late breaking abstract. Will be completed later

Background:
The class I human leucocyte antigen (HLA) molecules play a critical role as escape mechanism of antitumoral immunity. Indeed, novel immune-targeting cancer vaccines are currently developped in HLA-A2 positive patients for modulating the T cells response. The HLA-A2 status has been proposed as prognostic factor in lung cancer, but previous evidence is inconsistent. The aim of this study is to evaluate the role of HLA-A2 status as prognostic factor in a large cohort of advanced NSCLC patients.

Methods:
Advanced NSCLC patients eligible to platinum based chemotherapy (CT) were included from Oct. 2009 to July 2015 in the prospective MSN study (IDRCB A2008-A00373-52) in our institute. HLA-A2 status was analysed by flow cytometry. Clinical and pathological data were collected in a Case Report Form (CRF). Statistical analysis was performed with software SAS version 9.3.

Results:
Five hundred forty-five advanced NSCLC patients were included. Three hundred forty-four patients (63%) were male, median age was 61 years (21-84); 466 (85%) were smokers. Four hundred seven (75%) were adenocarcinoma, 69 (13%) squamous and 69 (13%) others histologies. Among 259 patients with known molecular profile, 113 (43.6%) NSCLC were KRASmut, 50 (19.3%) EGFRmut, 30 (11.6%) ALK positive, 9 (3.5%) BRAFmut and 8 (3.1%) FGFR1amp. Four hundred forty-seven (83%) patients had performance status 0-1 at diagnosis. Five hundred eight patients (93%) were stage IV, and 37 (7%) stage IIIB. All received platinum-based CT (49% cisplatine, 42% carboplatin and 9% both). No association was observed between HLA-A2 status and patient or tumor characteristics. The median progression free survival to platinum-based CT (PFS) was 5.6 months [confidence interval (CI) 95% 5.20-6.10]. In HLA-A2 positive patients, the median PFS was 5.6 months [CI 95% 5.1-6.4] vs. 5.7 months [CI 95% 4.9-6.2] in HLA-A2 negative patients (HR 1, Wald test, p=0.8).The median overall survival (OS) was 12.6 months [CI 95% 11.3-14.3]. The median OS was 12.8 months [CI 95% 11-14.6] in HLA-A2 positive vs. 12.5 months [CI 95% 10.4- 15.3] in HLA-A2 negative patients (HR 1, Wald test p=0.61). No significant differences were found between HLA-A2 status and PFS and OS in advanced NSCLC patients.

Conclusion:
Our study has observed no prognostic role of HLA-A2 status in advanced NSCLC patients.

Background:
Figure 1Deregulating cellular energetics is one promising hallmark of cancer and Thioredoxin reductases 1 (TrxR1) plays a key role in cell metabolism [1-4]. It was found in our previous study that the activity of TrxR1 in serum is significantly higher in cancer patients than volunteers (table1, based on 1122 cancer patients VS 84 volunteers). However, the role of TrxR1 in prognosis and evaluation of treatment in EGFR wildtype non-small cell lung cancer need to be investigated.



Methods:
In cohort one, serum level of TrxR1 in 127 metastatic EGFR wide type NSCLC patients was measured by ELISA assay before receiving first line standard doublet chemotherapy( wiht PP and GP included). In cohort two, a phase IC clinical trial was conducted to compare the TrxR1 inhibitor (BBSKE) and placebo in advanced NSCLC patients with EGFR wild type mutation and high activity level of TrxR1 after second line treatment. Patients in cohorts one and two were from NCT01980212, NCT01991418 and NCT02166242. Survival data were collected in cohort one and two.

Results:
Survival data analysis in cohort one showed that the PFS of lower TrxR1 activity group was significantly long compared to the higher in the total (mPFS:5.0m vs 3.1m, p=0.029), and also in adeno subtype and squamous subtype. The same tendency was observed in OS(mOS:15.0m vs 12.5m),but the date were not mature yet. Results in cohorts two show that patients with high level activity of TrxR1 can benefit more from BBSKE( data were not matue).

Conclusion:
Human with high level TrxR1 may have the high risk to suffer from NSCLC. High level of TrxR1 may suggest poor prognosis in metastatic EGFR wild-type non-small-cell lung cancer patients. Further clinical studies are warranted to profile TrxR1 inhibitors from bench to bedside.

Background:
XRCC1 and Rad51 are proteins involved in DNA base excision repair and DNA homologous recombination/double-stranded-break repair mechanisms respectively. In non-small cell lung cancer, XRCC1 Arg399Gln polymorphism (disrupts protein-protein interactions), and Rad51 G135C polymorphism (enhances Rad51 promoter activity), have been proposed as factors that influence the overall and progression-free survival (OS and PFS) of patients treated with platinum-based chemotherapy. This study aimed to evaluate the influence of XRCC1 Arg399Gln and Rad51 G135C polymorphisms on the toxicity of chemotherapy and clinical outcome (OS, PFS) of advanced adenocarcinoma patients in Serbia.

Methods:
The study included 94 advanced lung adenocarcinoma patients, EGFR wild type, stage IIIB or IV (TNM7), performance status 0, 1 or 2, of Caucasian descent, who recieved standard platinum-based chemotherapy. XRCC1 and Rad51 genotyping was done by PCR-RFLP. Statistical analysis was performed using Chi-square, Fisher’s exact, Wilcoxon rank sum test, Breslow-Day test. Survival methodology was used for OS and PFS (Kaplan-Meier product limit method and Log-Rank test, Cox regression for HR). Statistical significance was considered for p<0.05.

Results:
The group consisted of 62 males (66%) and 32 females (34%), median age at diagnosis 61 years (range 37-84), with 77 (82 %) of current or ex-smokers, and 65 (66%) of which presented with metastases at diagnosis. Follow up period was 1-55 months (median 11 months), during which 76 patients (81%) progressed, and 24 (19%) experienced chemotherapy-related toxicity of grade 3 and 4. Median (95%CI) PFS was 8,1 months (7.1-9.1), and median OS was 10 months (8.2-11.7). Genotype frequencies for XRCC1 Arg399Gln were 39.4% for Arg/Arg, 25.5% for Arg/Gln and 3.2% for Gln/Gln genotype. For Rad51 G135C frequencies were 61.7% for G/G, 26.6% for G/C and 1.1% for C/C genotype. Carriers of the XRCC1 Gln allele had a significantly shorter PFS (7.2m vs 9.5m, Breslow p=0.023) and OS (6.4m vs 15.7m, Breslow p=0.04), and were more susceptable to progression during chemotherapy. Although Rad51 genotypes alone had no statistically significant effect on PFS and OS, carriers of both XRCC1 Gln allele and Rad51 C allele had a 4 months shorter OS, the difference was not statistically significant. There were no statistically significant differences in the occurence of high grade chemotherapy-induced toxicity according to the patients' XRCC1 and Rad51 genotypes.

Conclusion:
These results suggest that in the Serbian population XRCC1 and Rad51 genotyping could be a useful tool for predicting the clinical outcome with platinum-based chemotherapy in advanced EGFR wild-type adenocarcinoma patients.

Background:
The S0819 phase III study of chemotherapy and bevacizumab (by patient/physician choice) with or without cetuximab in NSCLC showed no benefit from the addition of cetuximab, either overall or within the EGFR FISH-positive subset. Secondary analysis suggested an overall survival benefit in EGFR FISH-positive squamous cell carcinoma (SCC) (Herbst WCLC 2015, Hirsch ASCO 2016). In colorectal cancer (CRC), benefit from EGFR monoclonal antibodies such as cetuximab is limited to patients with RAS wild type (WT) tumors; however, in NSCLC, previous studies have not been sufficiently powered to make this determination. We prospectively incorporated KRAS mutation testing in S0819 to determine whether it predicts cetuximab efficacy. Since KRAS mutations are rare in SCC, we focused this analysis on nonSCC.

Methods:
KRAS mutation status was determined using the Therascreen KRAS test (Qiagen), conducted in a CLIA-certified diagnostic laboratory at the UC Davis Comprehensive Cancer Center. This test is FDA-approved for KRAS diagnostics in metastatic CRC, and identifies 6 mutations at codon 12 (G12A,D,R,C,S,V) plus G13D.

Results:
KRAS mutation status was available for 448 nonSCC patients, and mutations were identified in 150 cases (33%). Amino acid substitutions matched the expected distribution for a NSCLC population, with 52% harboring G12C and 17% with G12V. No significant differences were observed between KRAS-mut and WT populations for PFS (HR=1.15 (0.94-1.42); p=0.18) or OS HR=1.10 (0.89-1.37); p=0.39). Furthermore, no differences in outcomes between arms were observed based on KRAS mutation status (Table). The KRAS WT, EGFR FISH+ molecular subset (hypothetically the most likely subgroup to benefit from cetuximab) showed no statistical differences in outcomes between arms. Figure 1



Conclusion:
Determination of KRAS mutation status did not identify a subgroup of nonSCC patients with differential outcome from addition of cetuximab to front-line chemotherapy. In contrast to CRC, cetuximab does not appear to confer benefit to patients with KRAS-WT nonSCC NSCLC.

Background:
Among the major challenges in the chemotherapeutic regimens is lacking of effective biomarkers for drug response and sensitivity. Our current study reviewed two promising biomarkers, ERCC1 (excision repair cross-complementing group 1) and RRM1 (ribonucleotide reductase group 1) to identify their potentiality to predict responder to Cisplatin and Gemcitabine among NSCLC (Non Small Cell Lung Cancer) patients.

Methods:
Prospectively, this study was conducted in National Cancer Institute (NCI) Cairo, Egypt. We measured the mRNA expression level of ERCC1 and RRM1 in tumor cells (using Real-time quantitative PCR) isolated from Stage IIIB/IV NSCLC patients planned to receive Cisplatin and Gemcitabine. Patients were divided into two groups, either both low ERCC1 and RRM1 (group 1)or both are high (group 2).Our objectives were the correlation between both groups and clinical response (CR), Progression free survival(PFS) and Overall Survival(OS).

Results:
Figure 1 55 patients were enrolled and followed from Jan 2011 to Jan 2014, Median age was 57(30-75years), 87% had ECOG-PS1, 86% had stage IV, responder(SD/PR) represented 56%. 30 patients had both low ERCC1 and RRM1 (group 1) while the rest 25 patients had high ERCC1 and RRM1 (group 2). There was no significant differences between different clinical response in both groups(P= 0.239), however multivariate Cox regression analysis revealed responders(p=0.007,HR0.33) and high ERCC1/RRM1 RNA (p=0.032, HR;2.51)to be the only predictors of overall survival. Patients in group 1 had longer median PFS (9.8 ms vs 4.9 ms, P= 0.001) and longer median OS (12.5 ms vs 6.2 ms, P<0.001) than patients in group 2.



Conclusion:
Low ERCC and RRM1 RNA levels serve as a guidance to predict chemosensitivity to cisplatin and Gemcitabine, with longer survival. Combination of ERCC1 and RRM1 RNA has a prognostic and predictive significance in Stage IIIB/IV NSCLC patients receiving Cisplatin and Gemcitabine. Large cohort studies are warranted.

Background:
The administration of tyrosine kinase inhibitors (TKI) has changed the treatment of NSCLC pts with driver mutations. In the Lung Cancer Mutation Consortium study, survival was significantly better for those with an oncogenic driver which received a TKI compared to those who did not.

Methods:
Retrospective records review was performed on NSCLC pts treated at Sandton Oncology Centre (SOC), between 1/1/2010 and 31/12/2015.

Results:
There were 176 lung cancer pts in total, of which 25 were small cell and 151 NSCLC. 129 pts (85%) had non-squamous histology. 85 pts (all non-squamous) had EGFR and/or ALK mutations tested. Driver mutations (n=25) were detected in adenocarcinoma pts, with 22 EGFR mutations (EGFR mutation rate = 26%), 2 ALK re-arrangements, and 1 ROS1 mutation. Among 20 known EGFR mutations, 13 were Exon 19 deletions, 6 were L858R mutation, and 1 had dual G719X & S768I mutations. Median age for pts with driver mutations was 62.5 years (39-77). There were 16 females and 8 males (17 Caucasians, 5 Africans, 1 Chinese, and 1 Indian). Both ALK and ROS1 mutations were detected in adenocarcinoma, in Caucasians and in never smokers. 82 of the 85 pts tested for mutations had documented smoking status. Driver mutation rates were higher in never (17/25, 68%) and former smokers (6/32, 19%), than current smokers (2/25, 8%). 21 pts with driver mutations were evaluable for survival. 19 pts received TKI at least once in their lifetime (TKI ever), and 2 pts never received TKI (TKI never). First-line TKI was given in 11 pts and was associated with higher response rate (50%) than platinum-based chemotherapy (38%). Median PFS was not different between first-line treatment received (274 days in platinum-based chemotherapy, versus 291 days with TKI, p=0.58). Median OS was significantly longer in TKI ever group compared to TKI never group (809 days and 81 days, respectively, p=0.0235). OS was not influenced by smoking status, sex, race, first-line treatment received or specific EGFR mutations.

Conclusion:
Based on our retrospective analysis, we recommend that driver mutations be tested in all pts with non-squamous histology. NSCLC pts with driver mutations should receive a TKI at some point in the course of their treatment. Although we could not demonstrate improvement in PFS associated with first-line TKI therapy, the overall survival documented at our centre for the TKI ever group was consistent with international published data.

Background:
Previously we and others proposed the Neutrophil-Lymphocyte Ratio (NLR) was a prognostic marker in the patients with advanced NSCLC. But whether its prognostic value was influenced by other factors was never discussed before. The aim of this study was to evaluate the influence of albumin level on the prognostic value of the baseline NLR.

Methods:
A total of 325 patients were retrospectively enrolled from October 2007 to October 2014. The baseline NLR and demographic features were recorded, together with the overall survival (OS). Survival analysis was performed by the Kaplan-Meier method.

Results:
The cut-off value of NLR (3.19) was determined by the receiver operator characteristics analysis. The patients were dichotomized into high (≥3.19) and low (<3.19) NLR groups. Both groups had similar demographic features. However, the low group had longer OS (22.3 m) than the higher one (13.1 m, P<0.001). Interestingly, it was also found that the albumin level had an impact on its prognostic value. For patient with compromised albumin level (<35 g/L), NLR had no relationship with the OS (P=0.380). However in patients with normal albumin level (= or >35 g/L), high NLR strongly indicated poor OS (13.6 m vs 24.5 m, P<0.001).

Conclusion:
This study argued the NLR was a convenient prognostic marker, but its prognostic value was influenced by albumin level.

Background:
Cytology fails to detect neoplastic cells in 40–50% of malignant pleural effusions (PEs), which commonly accompany lung adenocarcinomas.

Methods:
PE samples were collected from 74 lung adenocarcinoma patients with associated cytologically positive (41) and negative (33) effusions, and from 99 patients with benign conditions including tuberculosis, pneumonia, congestive heart failure, and liver cirrhosis. We evaluated the diagnostic sensitivity and optimal cutoff points for tumor markers Her-2/neu, Cyfra 21-1, and carcinoembryonic antigen (CEA) to distinguish lung adenocarcinoma-associated cytologically negative pleural effusions (LAC-CNPEs) from benign PEs.

Results:
Mean levels of Her-2/neu, Cyfra 21-1, and CEA were significantly higher in LAC-CNPEs than in benign pleural effusions (P = 0.0050, = 0.0039, and < 0.0001, respectively). The cutoff points for Her-2/neu, Cyfra 21-1, and CEA were optimally set at 3.6 ng/mL, 60 ng/mL, and 6.0 ng/mL. Their sensitivities ranged from 12.1%, to 30.3%, to 63.6%, respectively. CEA combined with Cyfra 21-1 increased diagnostic sensitivity to 66.7%.

Conclusion:
Combining CEA with Cyfra 21-1 will provide the best differentiation between LAC-CNPEs and benign PEs with two tumor markers to date, and allows early diagnosis and early treatment for two-thirds of affected patients.

Background:
Systemic inflammation has been linked with cancer development and outcome. Several biomarkers reflect this inflammatory response, notably, the neutrophil (NLR), monocyte (MLR) or platelet (PLR) to lymphocyte blood count ratio. It has also been shown that inflammatory/immune cells (IC) in tumor microenvironment have an importantrole in tumor development and behavior. The aim of this study is to investigate the clinical significance of NLR,MLR, PLR and IC infiltration as prognostic factors in mNSCLC.

Methods:
We retrospectively collected clinical, pathological and demographical data from the medical charts of mNSCLCpatients, diagnosed between Jan 1st 2011 and July 30th 2014, from a single Brazilian institution. When available,archival tissue samples were evaluated for tumor IC intensity and pattern (hematoxylin-eosin stain)and CD8 and FOXP3 positive cell counts by immunohistochemistry (IHC).NLR, MLR and PLR were defined as the ratio between the absolute neutrophil, monocyte or platelet to lymphocyte blood counts. Overall survival (OS) was calculated from the time of CT start for metastatic disease till death by any cause. Association between clinical variables and NLR/MLR/PLR was tested with Chi-square or Fisher´s exact test. OS curves were generated by Kaplan–Meier method and compared using log-rank test. Multivariate analysis was performed using Cox regression (backward stepwise method) to assess variables independently associated with OS. P values <0.05 were considered statistically significant.

Results:
A total of 170 patients were included in the study.Median age was 63.4 years, 54.1% were male, 80.6% had adenocarcinoma, 17.1% had mutated EGFR, 73.3% were current/former smokers, and 78.2% had ECOG≤1. Median values for NLR, MLR and PLR were 4.6, 0.419 and 215, respectively. 114 (67.1%) patients had samples available for IC analysis and 88 for IHC, 39% had moderate to strong IC(IC2/3) infiltrate and 91.2% had a monuclear predominant infiltration pattern. Median follow-up time was 19.64 months (mo) and median overall survival was 13.6 mo. NLR>4.6 (6.89 vs. 19.05 mo, p<0.001) and PLR>215 (6.89 vs. 8.7 mo, p<0.014) were associated with poor OS. IC2/3 was associated with shorter OS (IC1 13.63mo vs. 4.6mo IC2/3, p=0.006), while mononuclear IC pattern was associated with improved survival (13.6 vs. 4.6 mo, p=0.023). CD8 and FOXP3 positive cells were not associated with OS. In multivariate analysis, the NLR remained as an independent prognostic factor for worse OS (HR 2.71 IC95% 1.39-5.25, p=0.003).

Conclusion:
Elevated NLR is an independent predictor of poor OS in patients with advanced NSCLC.

Background:
Peripheral blood circulating tumor cells (CTCs) are involved in tumor distant metastasis. According to different cell surface markers, CTCs can be divided into epithelial phenotype (EP), hybrid epithelial/mesenchymal phenotype (EMP) and mesenchymal phenotype (MP). An epithelial to mesenchymal transition (EMT) is a process which epithelial cells lose their polarized organization and acquire migratory and invasive capabilities. Emerging evidences have indicated that CTCs with mesenchymal phenotype play important role on cancer metastasis. This study aimed to evaluate the the ability of CTCs to detect distant metastases in non-small cell lung cancer (NSCLC).

Methods:
This study was performed between September 2014 and December 2015. Patients were considered eligible and were enrolled in this study if they met the following criteria: 1) histologically confirmed NSCLC; 2) patients who did not undergo any treatment; 3) patients at 18 to 85 years old. Blood samples were collected within 14 days before or after radiographic evaluation. CTCs detection was proceeded by multiple mRNA in situ hybridization. The ability of CTCs in detection of distant metastasis was compared with radiographic results. The counts of different CTCs phenotype were applied by Logistic regression equation, distant metastasis was determined with P≥ 0.5, when 0
Results:
In total, fifty-nine patients were enrolled. 15 were females and 44 were males. There are 6, 11, and 22 patients diagnosed as stage I-II, stage III, and stage IV, respectively. Adenocarcinoma accounts for 49.2% (29 cases), 22% (13 cases) for squamous, and 5.1% (3 cases) for adenosquamous. The median of total CTCs detected was 5 counts (0 to 57), 2 counts (0 to 14) for EP, 2 counts (0 to 45) for EMP, and 0 count (0 to 10) for MP. The counts of different CTCs phenotype showed no significant difference in gender, age and pathological type. In patients with stage IV, the detection rate of MP was much higher. Compared with radiographic examination, CTCs detection showed a sensitivity of 75.00%, and the specificity of 71.43%. The overall concordance was 72.41%, indicating well ability of CTCs in detection of tumor distant metastasis.

Conclusion:
CTCs detected by multiple mRNA in situ hybridization has well ability in detection of tumor distant metastasis. It might have clinical potential in the future application.

Background:
The aim of this project was to correlate pretreatment levels of circulating biomarkers of insulin resistance with computed tomography measured evidence of sarcopenia in stage IV NSCLC patients receiving platinum doublet chemotherapy.

Methods:
Pretreatment serum from 93 patients with frontline stage IV NSCLC was evaluated for 13 metabolism biomarkers with the Bio-Plex Pro Human Diabetes Assay Panel and 20 inflammation-related biomarkers using the Milliplex Human High Sensitivity T Cell Panel. All patients were treated with standard platinum doublet based chemotherapy. All patients had skeletal muscle index (SMI) calculated from baseline CT images using the Slice-O-Matic software package (Tomovision); where SMI = (muscle cross sectional area in cm2) / height in m2. Associations of biomarkers with SMI were assessed using a Spearman’s Rank Correlation Coefficient. The Log-Rank test was performed to evaluate the association of individual biomarkers with overall survival (OS).

Results:
High levels of adiponectin (with low levels of adiponectin being correlating with obesity in the literature) were associated with good OS (p=0.036) and low baseline SMI value specifically for males (p=0.00029). High levels adipsin was associated with favorable OS (p=0.015) and a higher baseline SMI specifically for females (p=0.66 x10-5). Low levels of ghrelin were associated with favorable OS (p=0.005) and were inversely associated with SMI values for both genders (p=0.021).

Conclusion:
Altered values of several biomarkers of insulin resistance were associated with inferior survival and a greater degree of sarcopenia in frontline NSCLC patients receiving platinum double therapy. These findings suggest a certain subset of patients that may have improvements in cancer cachexia by targeting insulin resistance.

Background:
We examine the predictive value of neutrophil–lymphocyte ratio (NLR) by examining their association with baseline presence and subsequent development of brain metastases in patients with stage IV non-small-cell lung cancer (NSCLC).

Methods:
We examined the predictive value of NLR for brain metastasis in 263 stage IV NSCLC using the receiver operating characteristic (ROC) curve analysis for optimal cut-off value. Logistic regression models were used to determine the association of NLR with the baseline presence of brain metastases. For patients without brain metastases at diagnosis, a competing risk analysis was performed, calculating the probability of brain metastasis in the presence of the competing risk of mortality by other causes using Gray’s test.

Results:
The median follow-up time was 11 months (range: 1–95 months). Univariate analysis reveals that patients with high NLR(≥4.95) had significantly more brain metastases at diagnosis than those with low NLR (P = 0.038), multivariate analysis was not performed because there was no significant risk factor for predicting brain metastases at diagnosis, except NLR. In patients who did not have baseline brain metastasis, competing risks analysis reveals that patients with high NLR showed higher cumulative incidence of subsequent brain metastases, compared to those with patients with low NLR (P = 0.02). A high NLR was associated with the baseline presence or the subsequent development of brain metastases, particularly in the group with adenocarcinoma (P = 0.006 and P = 0.04, respectively). Furthermore, an increase in NLR during treatment was associated with subsequent brain metastases (P = 0.003)

Conclusion:
The NLR is a predictive factor for the baseline presence of brain metastases and subsequent brain metastases in stage IV NSCLC. The NLR can be used to identify a subgroup of adenocarcinoma who is at a high risk for brain metastasis, and who may benefit from prophylactic treatment.

Background:
Survival of lung cancer (LC) patients has increased and it is important to assess disease and treatment related symptoms that could negatively impact on prognosis and health-related quality of life (HRQL). The FAACT questionnaires have been proposed as a useful tool to measure HRQL, it includes 5 subscales: physical (PWB), emotional (EWB), functional (FWB) and social well-being (SWB), and AC/S-12 which is used to diagnose anorexia cachexia syndrome (CACS). The aim of this study was to associate the FAACT total score and subscales with clinical outcomes and survival.

Methods:
A cohort of patients with LC completed the FAACT instrument; regardless of age, gender, line of treatment, number of cycle, performance status, or histopathology subtype. Clinical and biochemical variables were collected. Survival was estimated from the day of questionnaire application until death or last follow-up.

Results:
The study included 200 patients. FAACT subscales had association with several clinical and biochemical data that are show in Table 1. PWB, FWB, AC/S-12 and FAACT total score were strongly associated to overall survival (Figure 1). Figure 1 Figure 2





Conclusion:
The FAACT questionnaire is reliable and valid for the assessment of HRQL and CACS in patients with LC and can be used liberally in clinical trials.

Background:
Molecular profiling of advanced non-small-cell lung cancer (NSCLC) is recommended according to patients’ histological and clinical features. Despite the existence of national guidelines, routine care is still heterogeneous. Aim of this observational study was to obtain prospectively a clinical practice picture of molecular testing and therapeutic choices in advanced NSCLC patients.

Methods:
Newly diagnosed metastatic or recurrent NSCLC patients enrolled in 38 Italian centres, from November 2014 to November 2015, have been included in the study. Baseline information were collected about molecular profiling performed and therapies.

Results:
A total of 1787 patients were enrolled (64% males, 36% females; median age 67 years-old; 22% never smokers, 31% current smokers, 47% former smokers; 75% adenocarcinoma, and 73% with PS ECOG 0 or 1). The 73.9% of diagnosis was histological, while 26.1% was cytological. 1382 (77%) patients were tested for one or more molecular analysis during the history of disease, for a total of 3532 molecular tests. Only 405 patients did not receive any molecular test. 32.3% of patients presented a genetic alteration: EGFR mutation was reported in 17.8% of cases (319/1787), ALK translocation in 8.8% (82/926), KRAS mutation in 31.9% (154/482), MET amplifications in 15.8% (10/63), BRAF mutations in 3.7% (9/241), ROS1 translocation in 4% (11/269), HER2 mutation in 3.3% (3/89) of cases and FGFR alteration was found in 3 cases (only 15 tested). Considering patients younger than 45 years, never smokers and females, an EGFR mutation was detected in 25.4%, 43.5% and 30.6%, respectively. While 15.6%, 9.5% and 6.3% were ALK rearranged, respectively. For patients receiving an EGFR tyrosine-kinase inhibitor as first-line treatment, among those whose data are evaluable (79.2%), the median interval from diagnosis to first-line was 35 days. EGFR mutated patients received first-line erlotinib, gefitinib and afatinib in 9.4%, 39.1% and 33.8% of cases, respectively. At time of analysis, ALK-rearranged patients received an ALK inhibitor (crizotinib, alectinib or ceritinib) as first and/or second-line in 71.9% of cases. 29.3% of all patients received a maintenance therapy, mainly with pemetrexed (91.2% of cases).

Conclusion:
Routine molecular assessing is properly performed according to the national guidelines. A selection bias in including only those patients performing molecular tests, may explain the high proportion of patients with a molecular alteration. The low number of patients tested for ALK could be partially related to the impossibility to prescribe Crizotinib in first- line. In more than 70% of cases EGFR mutated patients received gefitinib or afatinib as first-line treatment.

Background:
Lung cancer is rich in molecular complexities and spurred by different molecular pathways. Personalized medicine has begun to bring new hope to people with lung cancer, especially non-small cell lung cancer (NSCLC). Personalized medicine involves looking at the cells obtained from a biopsy to see if there are any genetic mutations able to exploit these unique pathways to develop targeted therapies. Very few publications are there from India related to lung cancer and genomics by Next generation Sequencing (NGS).

Methods:
The patients with NSCLC with initially negative for EGFR by PCR and ALK by IHC or FISH method treated at HCG Hospital from Jan-2013 to April -2016 are subjected for Gene profiling. The patients were consented to be profiled by targeted deep sequencing for hotspot mutations in 48 cancer-related genes using Illumina’s TSCAP panel and MiSeq technology. The average coverage across 220 hot spots was greater than 1000X. Data was processed using Strand Avadis NGS™. Mutations identified in the tumor were assessed for ‘actionability’ i.e. response to therapy and impact on prognosis.

Results:
. A total of 65 patients were analyzed. Male: Female ratio- 2.6:1. In 11 patients NGS were rejected due to poor quality DNA tumor availability in paraffin blocks. In 19 patients didn’t find any actionable mutation. The pathogenic mutations were identified in remaining 35 patients. The following mutations were found. (table)

Types of mutations	Number of cases
TP 53	18
EGFR	7
EGFR , T790M	3
PIK3CA	4
K-RAS	4
N-RAS	1
KDR	2
RET	2
PTEN	3
MPL	1
HER2	1
MET	1
CTNNB1	1
ATM	1

Out of 35positive patients, 13 had two mutations and 43.75% could offer targeted therapy. 38% of them responded to therapies who were treated with targeted drugs.

Conclusion:
There is a potential role for PIK3CA, EGFR +/- T790M, KDR, RET and PTEN as therapeutic targets as personalized therapy in NSCLC. Present study helps us in understanding the diversity of molecular drivers in lung cancer and its clinical management for these patients, along with understanding of prognosis.

Background:
Adiponectin (APN) is a major adipokine systhesized by the adipose tissue. A significant body of preclinical evidence has documented the involvement of APN in molecular pathways with a key role in carcinogenesis, while some, but not all, previous clinical studies have suggested the potential value of this molecule as a biomarker of diagnosis and/or prognosis in various malignancies, mainly including obesity-related solid tumors. The main objective of this study was to further explore the prognostic implications of APN levels in the serum and bronchoalveolar lavage of patients with advanced non-small cell lung cancer (NSCLC).

Methods:
Twenty-nine (29) consecutive newly diagnosed NSCLC patients with stage IV disease were prospectively enrolled. Serum and BAL levels of APN were obtained at baseline (before initiation of any therapeutic intervention) and assayed by enzyme-linked immunoassay (ELISA). Serum and BAL levels of APN were correlated with standard clinicopathologic parameters, including gender, age, body mass index (BMI), weight loss, size, histology and grade of the primary tumor, pathologic nodal status and performance status (PS). The association of each study variable with overall survival (OS) was assessed by univariate and multivariate Cox regression analyses.

Results:
Mean age of patients was 65.6 years (SD=10.1 years), while the majority were male (24/29 cases, 82.8%). The predominant histological type was adenocarcinoma (18/29 cases, 62.1% ). PS was 0 and ≥1 in 17/29 (58.6%) and 12/29 (41.4%) patients, respectively. Weight loss more than 10% was noted in 10/29 patients (34.5%). Median serum and BAL APN levels were 911.5 ng/ml and 17710 ng/ml, respectively. No statistically significant correlations were observed between the serum or BAL levels of APN and the clinicopathologic parameters evaluated. Univariate Cox regression analysis showed that APN levels were not significantly associated with survival. The only prognostic factor identified, both by univariate and multivariate survival analysis, was PS.

Conclusion:
The results of our prospective cohort failed to reveal any significant associations between serum or BAL levels of APN and several prognostic parameters (including OS) in stage IV NSCLC, thus confirming most previous observations.

Background:
Pleural effusion (PE) is common in patients with advanced non-small cell lung cancer (NSCLC) and lung metastases from breast cancer, accounting for at least 20-30% of cases. Unfortunately, many patients with malignant PE exhibit a negative pleural cytology (PC), and thus further invasive diagnostic procedures, including VAT-guided biopsy, are required. The aim of this study was to evaluate the diagnostic value of PC together with pleural carcinoembryonic antigen (pCEA) and vascular endothelial growth factor (pVEGF) assay in cancer patients with PE.

Methods:
Thirty-six patients with suspicious PE scheduled to undergo VAT-guided biopsy underwent both PC and pCEA and pVEGF measurement before surgery. There were 20 (55.6%) males and 16 (44.4%) females, with an overall median age of 67 (range 40-82 years). Patients with non-diagnostic cytology were excluded from the study. pCEA was measured with automated method of immuno-chemiluminescence (LOCI, Dimension Vista, Siemens HD, Camberley, UK), while pVEGF with an enzyme-linked immunosorbent assay (ELISA) commercially available kit. According to previously obtained data from laboratory archival information, the optimum cutoff levels were 5 ng/mL and 6 ng/mL for pCEA and pVEGF, respectively.

Results:
Final pathology showed 10 (27.8%) patients with NSCLC, 13 (36.1%) with lung metastases, and 13 (36.1%) with benign PE. The age did not differ between groups (p=0.59). The sensitivity, specificity and accuracy of PC, and pleural CEA and VEGF are reported in the Table. The area under the curve (AUC) of the ROC curve of PC+pCEA+pVEGF in combination was 0.921 (95% CI: 0.513-0.973), and the diagnostic accuracy was 97.2%.

RESULTS	Cytology	pCEA	pVEGF	Cytology+pCEA+pVEGF
Sensitivity	65.2% (45.7-84.7)	73.9% (56.0-91.9)	78.3% (61.4-95.1)	95.6% (87.3-99.9)
Specificity	92.3% (77.7-99.9)	92.3% (77.8-99.9)	92.3% (77.8-99.9)	100%
Negative predictive value	93.7% (81.9-99.9)	66.7% (44.9-88.4)	70.6% (48.9-92.2)	92.9% (79.4-99.9)
False negative rate (α)	34.8%	26.1%	21.7%	4.35%
Accuracy	75.0%	80.5%	83.3%	97.2%

Conclusion:
In patients with PE, according to our results, the measurement of pleural CEA and VEGF, and PC evaluation together reached a very good accuracy and 100% specificity, and should be suggested in all cancer patients when a noninvasive evaluation of a PE is required as non-invasive procedure.

Background:
Squamous cell lung cancer(SqCLC)has a unique clinico-pathologic criteria in comparison to other non-small cell lung cancer(NSCLC).SqCLC is infrequently reported in depth as a separate category in the literature.This study aims to identify patients with SqCLC prior to biopsy and understand clinico-pathologic criteria of SqCLC vs others.

Methods:
Among enrolled NSCLC cases attending National Cancer Institute(NCI)–Cairo University(2012-2014), we retrospectively reviewed those who had SqCLC. Data regarding demographics,ECOG-performance status(PS),tumor histology,grade and stage, chemotherapy type,response to chemotherapy, overall and progression free survival(OS,PFS)were retrieved. Pearson’s(X[2])test, Cox and logistic regression and Kaplan-Meier survival curves were used in statistical analysis.Outcomes and other clinical characteristics of SqCLC were analyzed and compared with of other NSCLC.

Results:
Among 99 NSCLC cases, we identified SqCLC(35.4%),adenocarcinoma(29.3%),undifferentiated(20.2%),large cell carcinoma(12.1%)and adenosquamous carcinoma(3%). Predictors of SqCLC among the whole cohort in uni-and multi-variate analyses(MVA)was PS>1(p=0.033;Odd Ratio2.54(95%CI=1.08-5.99)). Among(35)SqCLC cases; median age was 54years(range;41-70 years), Male:Female was 4:1. Three-fifth of our cohort were PS >1, nearly 55% were stage III while stage IV represents the remaining. Progressive disease(PD)occurred in 57.1%. Median OS and PFS was 12 and 6months respectively. Nearly 90% of disease progression were found within 1 year after the chemotherapy onset. There was no difference in median OS or PFS in SqCLC vs other NSCLC(OS= 12 vs 18 months in other NSCLC(p=0.832)while PFS=6months in both groups(p= 0.452)).Also, no difference in age(p=0.795)or response to chemotherapy(p=0.689) in both groups. Among SqCLC cohort;poor PS and PD were associated with adverse PFS.However,on MVA,the only predictor was PD(p=0.006, HR=3.06, 95%CI 1.38-6.79).Median PFS for patients with PS =1 vs >1 was 9 vs 4months respectively.Median PFS for non-progressive versus PD was 11 vs 4 months respectively(p<0.001,See figure). No difference in survival between stage III and IV(p=0.209)

Conclusion:
Good PS and chemotherapy responder predict good PFS in SqCLC. In advanced stages; no difference in survival among SqCLC and indeed aggressive treatment is warranted. Figure 1