Virtual Library

Background:
NSCLC patients with ALK rearrangement (2-7%) are usually young, non-smokers and benefit from targeted first and second lines tyrosine kinase inhibitor e.g. Crizotinib. The gold standard test for ALK in patients with proven metastatic or locally advanced NSCLC is fluorescence in situ hybridisation (FISH), however, immunohistochemistry (IHC) for ALK protein overexpression such as the VENTANA anti-ALK (D5F3) antibody is a useful screening test for ALK status in NSCLC patients as it has a high negative predictive value. Positive or equivocal cases can be confirmed by FISH.

Method:
Accreditation standards require laboratories to verify equipment and reagent performance before adopting into routine practice. We tested cytology and histology NSCLC samples of primary lung origin using anti-ALK (D5F3) antibody for ALK status using the VENTANA IHC platform and compared the findings against the gold standard FISH methodology. We tested 50 consecutive NSCLC samples of which 3 were excluded as FISH failed.

Result:
Of the remaining 47 samples, one was ALK positive by IHC and FISH and the remaining 46 were negative by both methods. As there were no false positive or negative cases by IHC, sensitivity, specificity, PPV and NPV were all 100%. We then proceeded to adopt reflex ALK testing by IHC as verification was achieved and confirmed equivocal and positive cases by FISH. In total we have tested 213 cases with ALK IHC equivocal in only 4 instances and one false positive (PPV = 85.7%). All 5 cases were negative by FISH (table below). Figure 1



Conclusion:
ALK by IHC can be implemented to identify patients’ ALK status with confirmatory reflex testing by FISH for equivocal or positive cases in a cost effective and efficient process so that ALK positive patients can receive targeted TKI. Established cutting protocol to maximise tissue use is essential for tissue preservation and turn around times.

Background:
Crizotinib is an oral small-molecule inhibitor of anaplastic lymphoma kinase (ALK) tyrosine-kinase that has been approved for treating patients with advanced echinoderm microtubule associated protein like 4-anaplasitic lymphoma kinase (EML4-ALK) rearranged non-small-cell lung cancer (NSCLC). Toxic epidermal necrolysis (TEN) is a rare adverse event related to crizotinib.

Method:
We report a case of 75-year-old Chinese male patient of advanced NSCLC harboring with ALK fusion, who developed TEN after 56 days of crizotinib treatment

Result:
the patient demised due to this dermatological adverse event

Conclusion:
The occurrence of severe cutaneous necrolysis that predominantly involve skin and mucous membranes during crizotinib treatment should alert clinicians to be aware of TEN and take prompt actions.

Background:
Dexamethasone is a systemic corticosteroid often used in non-small cell lung cancer (NSCLC) patients to treat disease and treatment-related complications. It is a known weak-to-moderate cytochrome P-450 (CYP) 3A inducer that may decrease exposure of CYP3A substrate tyrosine kinase inhibitors (TKIs). Crizotinib (Xalkori®) is a selective inhibitor of anaplastic lymphoma kinase (ALK) and ROS1 and is approved for treating ALK-positive and ROS1-positive NSCLC. Crizotinib is a substrate and time-dependent inhibitor of CYP3A. Co-administration of crizotinib 250 mg BID with a strong CYP3A inducer, rifampin 600 mg QD, resulted in an 84% decrease in steady-state crizotinib exposure. In this analysis, we evaluated the effect of dexamethasone on steady-state crizotinib exposure from clinical studies in patients with ALK-positive and ROS1-positive NSCLC.

Method:
Data were from 4 clinical studies (PROFILE 1001, 1005, 1007, and 1014) with 1669 ALK-positive and 53 ROS1-positive NSCLC patients treated with crizotinib at the recommended starting dose of 250 mg BID. For each patient, multiple steady-state trough concentrations (C~trough, ss~) of crizotinib were measured after ≥ 14 days of consecutive crizotinib 250 mg BID dosing. Within‑patient comparison of crizotinib C~trough, ss~ between crizotinib dosing alone and crizotinib co‑administered with dexamethasone consecutively for ≥ 21 days was performed using a linear mixed effects model.

Result:
There were a total of 514 (29.8%) patients who received dexamethasone from the 4 PROFILE studies. Other less commonly used (< 10%) weak-to-moderate CYP3A inducers included: methylprednisolone, prednisone, ginkgo/ginseng and efavirenz. In this analysis, a total of 15 patients had crizotinib C~trough,ss~ for both crizotinib dosing alone and crizotinib co-administered with dexamethasone consecutively for ≥ 21 days. The adjusted geometric mean of crizotinib C~trough,ss~ following co-administration with dexamethasone was 98.2% (90% CI: 79.1%-122.0%) relative to crizotinib dosing alone, with the lower limit just below the typical bioequivalence limits of 80%-125%.

Conclusion:
Dexamethasone was the most commonly used CYP3A inducer across the 4 PROFILE studies. Long-term (≥ 21 days) use of dexamethasone in NSCLC patients treated with crizotinib had no statistically significant effect on crizotinib exposure and thus would not compromise treatment efficacy. Other weak-to-moderate CYP3A inducers are not expected to have an effect on crizotinib, similar to the findings with dexamethasone. The framework of this analysis can be applied when dexamethasone or other weak-to-moderate CYP3A inducers are concomitantly used with CYP3A substrate TKIs.

Background:
Alectinib is a potent and highly selective inhibitor of the tyrosine kinase ALK and has shown marked efficacy and safety in patients with ALK rearrangement–positive non–small cell lung cancer (NSCLC) and a good performance status (PS). It has remained unclear whether alectinib might also be beneficial for such patients with a poor PS.

Method:
Eligible patients with advanced ALK rearrangement–positive NSCLC and a PS of 2 to 4 received alectinib orally at 300 mg twice daily. The primary end point of the study was objective response rate (ORR), and the most informative secondary end point was rate of PS improvement. Plasma concentrations of alectinib were measured by liquid chromatography-mass spectrometry (LC-MS/MS).

Result:
Between September 2014 and December 2015, 18 patients were enrolled in this phase II study (Lung Oncology Group in Kyushu 1401). Twelve, five, and one patients had a PS of 2, 3, or 4, respectively, whereas four patients had received prior crizotinib treatment. The median follow-up time for all patients was 9.8 months (range, 5.6 to 18.0 months) at the time of the primary analysis. The ORR was 72.2% (90% confidence interval [CI], 52.9–85.8%), and the disease control rate was 77.8% (90% CI, 58.7–89.6%). The ORR did not differ significantly between patients with a PS of 2 and those with a PS of ≥3 (58.8% and 100%, respectively, P = 0.114). The PS improvement rate was 83.3% (90% CI, 64.8–93.1%, P < 0.0001), with the frequency of improvement to a PS of 0 or 1 being 72.2%. The median progression-free survival (PFS) was 10.1 months (95% CI, 7.1 to17.8 months), with no difference between the patients with a PS of 2 and those with a PS of ≥3 (median PFS, 10.1 and 17.8 months, respectively, P = 0.24). Toxicity was mild, with the frequency of adverse events of grade ≥3 being low. Neither dose reduction nor withdrawal of alectinib because of toxicity was necessary. The trough concentration of alectinib in plasma was 235 ± 65 ng/mL (mean ± SD), which is slightly lower than that previously reported in patients with a good PS, supporting the tolerability of alectinib administration in those with a poor PS.

Conclusion:
Alectinib is a treatment option for patients with ALK rearrangement–positive NSCLC and a poor PS. Updated data and that for overall survival will be available at presentation.

Background:
ALK inhibitors are a standard of care for ALK-positive metastatic NSCLC and several ALK inhibitors are currently available. Alectinib is one of the recommended therapies as 1[st] line treatment for ALK-positive metastatic NSCLC in Japan based on robust progression-free survival (PFS) prolongation and favorable safety profile. However, even with treatment with alectinib, these cancers eventually progress after acquiring resistance against alectinib. Therefore, which drug should be chosen after alectinib is relevant clinical question. Recently, ceritinib, which is a highly selective oral ALK inhibitor, has demonstrated superior activity compared to chemotherapy in the 1[st] line setting for patients with ALK-positive metastatic NSCLC (ASCEND-4, Soria et al. Lancet 2017). It also showed clinically meaningful benefit in patients who failed to prior ALK inhibitor treatment including alectinib (Nishio et al. J Thorac Oncol 2015). In this study, we tried to evaluate efficacy and safety of ceritinib in ALK-positive metastatic NSCLC patients who progressed on alectinib treatment.

Method:
ASCEND-9 (NCT02450903) is a single-arm, open-label, multicenter, phase 2 study of ceritinib 750 mg/day (fasted) in adult patients with ALK+ (Vysis ALK Break Apart FISH Probe kit test), stage IIIB/IV NSCLC previously treated with alectinib and had subsequent disease progression. Other key inclusion criteria are ≥ 1 measurable lesion per RECIST 1.1 and WHO PS 0-1. Patients must have received previous treatment with alectinib, but prior crizotinib and/or up to 1 chemotherapy regimen are allowed. Patients with asymptomatic CNS metastases are eligible. Ceritinib may be continued beyond RECIST-defined PD. Primary endpoint is investigator assessed-overall response rate (ORR) per RECIST 1.1. Secondary endpoints include disease control rate (DCR), time to response (TTR), duration of response (DOR), PFS and safety. Biomarkers are evaluated for exploratory purpose.

Result:
Twenty patients were enrolled at 10 centers in Japan from Aug 2015 to Feb 2017. At present, the study is underway, and the results including ORR, DCR, TTR, DOR, PFS, safety and exploratory biomarker data will be presented at the 2017 WCLC.

Conclusion:
Section not applicable.

Background:
Anaplastic lymphoma kinase (ALK)-rearrangements are mainly encountered in 5% of adenocarcinomas lung cancer (Ad-LC) patients and anti-ALK targeted therapy dramatically improves therapeutic responses. The prevalence of ALK rearrangement in squamous cell lung carcinomas (Sq-LC) is extremely rare and thus, clinicopathological features and clinical outcomes for ALK inhibitors of ALK-rearranged Sq-LC were still unknown. Accordingly, in this study, we compared clinical features and clinical outcomes in patients with Sq-LC and Ad-LC.

Method:
We retrospectively analysed the clinical features of five patients with ALK-rearranged Sq-LCs including two ALK-rearranged adenosquamous cell lung carcinomas (AdSq-LC) and compared the results with ALK-rearranged Ad-LC. We also evaluated representative cases of both responder and nonresponder to ALK inhibitors.

Result:
The prevalence of ALK rearrangement in Sq-LCs was 1.36%. The population in ALK rearrangement NSCLC with smoking history was higher in ALK-rearranged Sq-LC than in ALK-rearranged Ad-LCs (80.0% and 68.0%). Progression-free survival (PFS) after initial treatment with the ALK inhibitor crizotinib was significantly shorter in ALK-rearranged Sq-LC than in ALK-rearranged Ad-LC (6.4±4.7 months and 13.4±12.8 months: p=0.033). Notably, two ALK fluorescence in situ hybridization (FISH)-positive/immunohistochemistry-negative cases did not respond to crizotinb, and PFS following alectinib treatment of ALK-rearranged Sq-LC was short (p = 0.045). The responder to ceritinib showed the presence of the L1196M mutation, which causes other ALK inhibitor resistance, by rebiopsy and successes to maintain CR response, even if detected off-target resistance marker of both EGFR and vimentin, a marker of EMT, for ALK inhibitors. However, the nonresponder did not respond to all ALK inhibitors, despite the presence of ALK FISH-positive circulating tumor cells and circulating free DNA without the mutation for ALK inhibitors resistance by liquid-biopsy.

Conclusion:
ALK-rearranged Sq-LC was associated with poor outcomes in ALK inhibitor-treated patients, suggesting that complexity of resistance mechanisms including off-target mechanisms for ALK inhibitors may exist. Oncologists should be aware of the possibility of ALK-rearranged Sq-LC based on clinicopathological features and plan the next therapeutic strategy by as much of re-biopsy accordingly to improve clinical outcomes.

Background:
Crizotinib has resulted in substantial benefits for advanced non-small- cell lung cancer (NSCLC) patients harboring anaplastic lymphoma kinase (ALK) rearrangement. With limited real-world data available, the present work aimed to explore the clinicopathological characteristics and survival outcome of patients with advanced ALK+ NSCLC in a single center in China.

Method:
Data of 83 advanced ALK-rearranged NSCLC patients treated in Zhejiang Cancer Hospital were collected and analyzed retrospectively. Survivals were analyzed using the Kaplan-Meier method and were compared using the log-rank test. Multivariate analysis were performed by the Cox proportional hazard model.

Result:
Of the 83 patients enrolled, 33(39.8%) patients received crizotinib, and the other 50(60.2%) patients received chemotherapy as the initial treatment. The first-line use of crizotinib prolonged PFS compared with chemotherapy (median PFS 19.0 m vs. 5.7 m, P < 0.001), but not OS (46.0 m vs. 30.6 m, P=0.797). Till the last follow up, 71(85.5%) patients had received crizotinib, and 12(14.5%) patients were crizotinib-naïve. Patients who had received crizotinib had significantly longer OS than those who did not (48.9 m vs. 19.8 m, P < 0.05). Among the 71 patients who had received crizotinib,33(46.5%) used in first-line therapy, 22(31.0%) used in second-line therapy, and 16(22.5%) used after second-line therapy. There were not significant difference of OS among the three groups (30.6 m vs. 57.7 m vs. 40.8 m, P=0.583). The Cox multivariate analysis identified the following independent negative prognostic factors for OS: smoking (HR=4.725), liver metastasis(HR=4.570), bone metastasis (HR=2.651), and use of crizotinib (HR=0.295).

Conclusion:
Our real-world study showed that the use of crizotinib improved long-term survival of patients with advanced ALK-rearrangement NSCLC. There were no difference in survival outcome between patients with initial crizotinib and those with non-initial crizotinib.

Background:
Incidence and potential risk factors of interstitial lung disease (ILD) were evaluated in patients with ALK-positive non-small cell lung cancer (NSCLC) enrolled for all-case surveillance of Xalkori.

Method:
The survey was conducted on all patients treated with XALKORI[®] 200mg/250mg capsules. The observation period was 52 weeks from the initiation of treatment with Xalkori, or time from treatment commencement until treatment discontinuation in patients who discontinued treatment prematurely. Investigator-reported cases of ILD were assessed by the ILD independent review committee consisting of external experts to evaluate background risk factors potentially associated with the onset of ILD.

Result:
Among 2059 patients enrolled for this survey from May 2012 to October 2014, 1972 were included in a safety analysis. Among 139 reported cases of patients developing ILD following Xalkori treatment, 116 patients were confirmed to have ILD (incidence rate of 5.9%). The breakdown of these cases was mainly as follows: 63 (54%) patients were male, 52 (45%) were female, 57 (49%) were aged at least 65 years, 3 (2.6%) had a previous history of ILD, and 63 (54%) had smoking history, including former smokers. Giving the breakdown by Grade, 46 patients had Grade 2 or lower ILD, and 70 patients had Grade 3 or higher, including 22 with Grade 5 (mortality rate of 1.1%). Ninety-one patients (78.4%) developed ILD within 12 weeks after treatment commencement. The background factors with statistically significant differences among patients included age, body surface area, Eastern Cooperative Oncology Group Performance Status (ECOG PS) and smoking history. Also the multivariate analysis revealed that aging, poor ECOG PS, former smokers and previous history or complications of ILD were correlated with the occurrence of ILD.

Conclusion:
The onset time, the incidence of ILD and risk factors obtained from this surveillance didn’t seem to be significant difference with those of EGFR TKIs reported previously.

Background:
Patients with advanced-stage non-small cell lung cancer (NSCLC) can receive benefits from treatment with anaplastic lymphoma kinase (ALK) inhibitors, if the tumor harbors a rearrangement of the ALK-encoding gene. Alectinib, a second-generation ALK inhibitor, is generally an effective therapy for ALK-rearranged NSCLC, but not all patients are responsive to Alectinib treatment. The aim of the present study was to assess the clinical and genetic characteristics of ALK-positive lung adenocarcinoma (ADC) that showed poor response to Alectinib treatment.

Method:
Patients with ALK-rearranged NSCLC, who received Alectinib treatment at Nihon University Itabashi Hospital (Tokyo, Japan) between 2015 and 2017, were included in the study. Demographic and clinical data including year, sex, stage, smoking history, treatment response, and survival were collected. Pleural effusion from a poorly responsive patient was further examined for secondary ALK mutations and ALK fusion partners. Secondary ALK mutations were analyzed using Sanger sequencing, and ALK fusion partners were identified by RNA sequencing. Furthermore, p-glycoprotein (p-gp)/ATP binding cassette subfamily B member 1 (ABCB1) mRNA levels were quantified by quantitative RT-PCR. The study was approved by the institutional review board.

Result:
Five patients (three men and two women; median age, 51 years) with adenocarcinoma were studied. Two patients received first-line treatment, two received second-line treatment, and one received fourth-line treatment. Four patients achieved partial response, and one patient did not respond to the treatment. The median progression-free survival (PFS) rate was 204 days. In the poorly responsive patient, PFS rate was 92 days, which was much shorter than previously reported. No secondary gatekeeper mutations in the ALK tyrosine kinase domain was detected in carcinoma cells obtained from pleural effusion of one poorly responsive patient. However, Striatin (STRN)/ALK, a rare fusion of the aggressive rearranged ALK, was identified, it was confirmed that one end of STRN exon3 was fused with the beginning of ALK exon 20. ABCB1 overexpression was also detected.

Conclusion:
A rare ALK rearrangement, STRN/ALK, and overexpression of the multidrug-resistant ABCB1 are possible candidates for predictive factors for poor response to Alectinib treatment.

Background:
Anaplastic lymphoma kinase (ALK) gene rearrangements occur in 3-5% of non-small cell lung cancer (NSCLC) cases. ALK tyrosine kinase inhibitors (ALK-TKIs), such as crizotinib and alectinib, are recommended for the treatment of ALK-positive NSCLC. However, acquired resistance to the ALK-TKIs develops after treatment with these agents. Therefore, it is necessary to consider the alteration of the therapeutic approach against ALK-positive NSCLC. This investigation, reviewed patients with ALK-positive NSCLC treated at Hiratsuka Kyosai Hospital in 2016, to determine the efficacy and safety of ALK-TKIs in this setting.

Method:
The medical data of 11 patients who had been diagnosed with ALK-positive advanced NSCLC and treated with ALK-TKIs at Hiratsuka Kyosai Hospital in 2016 were reviewed retrospectively.

Result:
A total of 11 patients (3 males and 8 females; mean age: 62 years) with ALK-positive NSCLC were investigated. All the pathological types were adenocarcinomas. Eight patients were treated with crizotinib as first-line therapy, and 3 out of those patients were treated with alectinib as second-line therapy. The remaining 3 patients were treated with alectinib as first-line therapy. The overall response rate was 87.5%, and the median progression-free survival was not reached. Four patients had developed PD while receiving crizotinib. Two out of those patients have developed brain metastasis, and were administered local radiotherapy to the brain. Patients who progressed following treatment with ALK-TKIs, were treated with pemetrexed-based chemotherapy. Although adverse events (AEs) of crizotinib were more than those of alectinib, most of them were of Grade 1 to 2 severity. Most common AEs of crizotinib included vision disorder (62.5%), diarrhea (50%), elevated aminotransferases (50%), and nausea (37.5%). Grade 3 to 4 adverse events were reported in 4 cases. However, all of them were controlled by withdrawal of treatment or reduction of dosage.

Conclusion:
ALK-TKIs demonstrate good efficacy and safety in patients with ALK-positive NSCLC.

Background:
Testing for Anaplastic Lymphoma Kinase (ALK) rearrangement in patients diagnosed with Non-Small Cell lung Cancer (NSCLC) is the standard of care in the UK. 2-7% of tumours are positive and subsequently patients may be eligible for treatment with Tyrosine Kinase Inhibitors (TKIs). Response rates to TKIs range from 65-75% with a median PFS of 7.7-10.7 Months. We investigated the relationship between the percentage of ALK positive cells and clinical outcomes in a local patient cohort.

Method:
All patients found to have an ALK rearrangement between 1/1/13 - 1/4/17 in the Leeds Cancer Centre, UK were included. ALK analysis was performed using Fluorescent in situ Hybridisation (FISH) and the percentage of positive abnormal cells was recorded. Retrospective review of the medical notes was performed and outcomes documented including, whether the patient received a TKI, response to TKI, duration of response and overall survival. Chi-squared, Kaplan-Meier survival curves and log-rank test were used to assess survival outcomes.

Result:
75 patients were found to have an ALK rearrangement in total. Median age was 66 (range 51-92). Only 23 patients received a TKI. Until 2016 TKIs were not available in the first line setting in the UK and many patients were unable to receive a TKI either because first line chemotherapy was contra-indicated or because their performance status had deteriorated during first line chemotherapy making them unsuitable for a TKI. Some patients had early stage disease and therefore a TKI was not indicated (n=7). Median percentage of ALK positive cells was 27% and this was used as a cut off for further statistical analysis. Patients with > 26% of cells positive for ALK had a significantly higher chance of response (91.67% Vs. 42.86% p= 0.025). There was a trend towards improved PFS (107 vs 70 days) for those patients with >26% positivity. This was not statistically significant (PFS p=0.102) and no difference in overall survival was observed (OS p=0.421).

Conclusion:
In this small cohort, patients whose tumours had a higher proportion of tumour cells with an ALK rearrangement, were more likely to respond to TKI. They also had better PFS, though this was not significant. This study was limited by small numbers. TKIs are now available in the first-line setting, allowing more patients to access them. Future investigations will benefit from these increased numbers and if confirmed prospective studies, assessing more targeted use of TKIs on the basis of cellular positivity, could be considered.

Background:
Chromosomal inverse translocation of anaplastic lymphoma kinase ( ALK ) have induced constitutively active ALK fusion proteins. Lung cancers with ALK rearrangements are highly sensitive to ALK tyrosine kinase inhibition(TKI). The multi-targeted TKI crizotinib, ceritinib and alectinib were approved by the FDA in 2011 , 2014 and 2015 to treat patients with advanced ALK positive NSCLC. However, most patients develop resistance within 1 to 2 years. The purpose of current study is to utilize computational modeling to simulate clinical response of ALK inhibitors and to investigate possible resistant mechanisms.

Method:
The X-ray crystal structure of ALK complexed with crizotinib (PDB code 2xp2) was used for the simulations. The residue G1202 was mutated into R1202 by using the SWISS-MODEL software. iGEMDOCK v2.1 was used to generate the docked conformation of ligands and to rank the conformations according to their docking scores. We used its molecular docking platform to dock the crizotinib or ceritinib or alectinib to the active cavity of the ALK models (wild type and mutation type). Molecular dynamic (MD) simulations were performed using the GROMACS package.

Result:
The trajectories of ligands binding with ALK protein were analyzed for : (a) the root mean square deviation (RMSD) of the activation sites; (b) the pocket distances between the mass center of residues DFG of activation site and the mass center of ligands. The RMSD was found to increase for R1202 ALK protein with three compounds when compared with G1202 ALK protein with crizotinib. By monitoring the pocket distances between the center of residues DFG and the mass center of ligands, we found that the G1202R ALK protein was more open than that of the wild type. Table 1 show docking score using iGEMDOCK v2.1 for three ligands with G1202R ALK protein. Figure 1



Conclusion:
Computation modeling may simulate the clinical response but need further investigation.

Background:
Co-isolated exosomal RNA and cfDNA from plasma can be used for detection of genomic alteration such as EML4-ALK fusion RNA and ALK resistance mutations in NSCLC patients. The clinical utility of this liquid biopsy for response monitoring is under investigation. The aim of this study was to evaluate liquid biopsy as tool for monitoring response to treatment in a prospective cohort of ALK-positive NSCLC patients.

Method:
Consecutive ALK positive NSCLC patients treated with systemic therapies in our institution were enrolled. After informed consent, blood samples were prospectively collected for longitudinal analysis during treatment and at progression. Exosomal RNA and cfDNA co-isolated from plasma was used for detection of EML4-ALK fusion RNAs by the qPCR-based ExoDx Lung(ALK)™-test as well as for analysis of ALK-resistance mutations by ExoDx NGS sequencing.

Result:
From Aug 2016 to date, 23 patients were enrolled in the study, 14 (61%) were females, 15 (65%) non-smokers, median age of 50 years (23-76). All patients had adenocarcinoma and were tissue positive for ALK by immunohistochemistry 14 (61%) and/or FISH 16 (70%). Nineteen patients (83%) had stage IV disease at diagnosis, with brain involvement in 7 patients (37%), bone in 11 (48%) and liver in 2 (11%). The median number of ALK inhibitors received was 2 (0-4). Twenty-one patients (91%) received ALK inhibitors (5 crizotinib, 3 ceritinib, 13 next-generation inhibitors) and 2 chemotherapy, with an objective response rate of 48%. Five out of 8 patients (63%) that were treatment naïve (baseline) or progressive disease (PD) at the time of collection, were positive for EML4-ALK by liquid biopsy, 1 of 4 samples (25%) at baseline, and 4 of 4 samples (100%) at PD, were positive by liquid biopsy. EML4-ALK variant 1 was detected in two (40%) and variant 3 in three patients (60%). All 26 samples collected during objective response or stable disease (100%) were negative for EML4-ALK by liquid biopsy. The ALK resistance mutation panel was performed on 2 samples from patients with PD, and both were detected positive for ALK resistance mutations, L1196M (variant 1) and G1202R (variant 3), respectively.

Conclusion:
The monitoring of ALK fusions on exosomal RNA by liquid biopsy is applicable in the clinic and closely correlated to disease control. ALK mutations detection using liquid biopsy can be an accurate tool for assessing the resistance to ALK inhibitors. Updated results from up to 30 patients will be available for the final presentation.

Background:
Cisplatin is widely used as an effective chemotherapy in diverse neoplasms and is associated with renal toxicity. Several studies suggest that pre-hydration plus mannitol prior to chemotherapy with cisplatin prevents nephrotoxicity. The aim of this study is to determine the acute effects of hydration plus mannitol on renal function in patients receiving cisplatin.

Method:
Fifty patients who were eligible to receive chemotherapy with cisplatin alone or in combination with other chemotherapy were randomized to receive 1L saline alone (A) or saline plus mannitol before and after chemotherapy. The mannitol group received 12.5 g of mannitol in saline solution. Serum Creatinine (Ser Cr), BUN, and GFR were measured at baseline (no more than 3 days prior to therapy) and on Day 1, 5, and 14. Baseline characteristics were analyzed using t-tests or chi-squared tests. Repeated Measures (RM) ANOVA was used to compare the change in BUN, creatinine, GFR, and BUN to Creatinine ratio.

Result:
Data for 48 patients (36 male and 12 female) were collected. The median age is 57 (range 18 to 78); 23 received saline alone and 25 received mannitol. There are no difference between randomized groups between Age, Gender, and Race. The mean BUN and BUN to creatinine ratio significantly increased by 46% and 37% respectively (p <0.001), while the corresponding mean Serum Cr did not significantly change over time and mean GFR peaked at day 1 then decreased by day 5 (p=0.001). All variables returned to baseline by Day 15. Twenty patients (42%) had grade 1 increase in Ser Cr (25% in A and 17% in B, p=0.078). No patients had grade 2 or greater in the mannitol group, while 2 patients had grade 2 or grade 3 in saline only group. RM ANOVA analysis show no difference between randomized groups from baseline through Day 1, Day 5, and Day 14 for BUN, creatinine, GFR, and BUN to Creatinine ratio.

Conclusion:
Cisplatin caused acute decline in renal function as determined by BUN, BUN to Ser Cr ratio and GFR, however, addition of mannitol to pre-hydration fluid did not change the outcome.

Background:
Genetic polymorphisms in the UDP-glucuronosyltransferase 1A1 (UGT1A1), UGT1A7, and UGT1A9 genes are associated with interindividual differences in irinotecan toxicities. Purpose: To evaluate the effects of gene polymorphisms, including UGT1A1*7, *27, and *29, on the safety of irinotecan therapy.

Method:
The eligibility criteria were as follows: lung cancer patients who were scheduled to undergo irinotecan therapy, aged ≥20 years, and had a performance status of 0-2. After informed consent had been obtained, patients were enrolled, and their blood was collected and used to examine the frequency of the UGT1A1*6, *7, *27, *28, and *29 polymorphisms and the drug concentrations of irinotecan, SN-38, and SN-38G after irinotecan therapy.

Result:
Thirty-one patients were enrolled. The patients’ characteristics were as follows: male/female = 25/6, median age (range) = 71 (55-84), stage IIB/IIIA/IIIB/IV = 2/6/11/12, and Ad/Sq/Sm/Oth = 14/10/3/4. The -/-, *6/-, *7/-, *27/-, *28/-, and *29/- UGT1A1 gene polymorphisms were observed in 10 (32%), 10 (32%), 2 (6%), 2 (6%), 7 (23%), and 0 (0%) cases, respectively. There were no homozygous or complex heterozygous polymorphisms. The UGT1A1*27 polymorphism occurred separately from the UGT1A1*28 polymorphism. The lowest leukocyte counts of the patients with the UGT1A1*27 and UGT1A1*6 gene polymorphisms were lower than those seen in the wild-type patients. SN-38 tended to remain in the blood for a prolonged period after the infusion of irinotecan in patients with the UGT1A1*27 or UGT1A1*28 polymorphism. No severe myelotoxicity was seen in the patients with UGT1A1*7.

Conclusion:
UGT1A1*27 and UGT1A1*7 are both rare gene polymorphisms. UGT1A1*27 can occur separately from UGT1A1*28 in some circumstances and is related to leukopenia during irinotecan treatment. UGT1A1*7 is less relevant to irinotecan-induced toxicities, and UGT1A1*29 seems to have little clinical impact.

Background:
Adjuvant chemotherapy compliance and the full dose delivery of agents are believed to be superior after video-thoracoscopic lobectomy (VATS-L) for operable non-small cell lung carcinoma (NSCLC), compared with thoracotomy. The purpose of this study was to determine the role of minimally invasive lobectomy on when to start and the percentage of provided planned regimen.

Method:
All patients undergoing pulmonary resection for NSCLC between January 2010 and May 2016 were reviewed retrospectively. For comparison, analyses were performed only on patients receiving sole adjuvant chemotherapy, after the final pathology. Chemotherapy was planned according to Adjuvant Navelbine International Trialist Association (ANITA) trial. The analyzed variables were the duration between the discharged day form surgical unit and the initial chemotherapy day, the planned and the received chemotherapy doses.

Result:
Total of 74 patients were subsequently underwent adjuvant chemotherapy for NSCLC either after thoracoscopic surgery (n=26) or thoracotomy (n=48). Patients undergoing VATS-L had a shorter median length of hospital stay (4.4 versus 7.3 days; P<0.001), that leads significantly reduced time delay on chemotherapy commencement (29.4 versus 37.0 days; P=0.002). VATS-L group received 83.0% of planned Cisplatin and 81.7% of Navelbine dose. In the thoracotomy group, the compliance to planned doses of Cisplatin and Navelbine was 77.6% and 75.0%, respectively. Both of the drug regime tolerance was significantly (Cisplatin P=0.005; Navelbine P=0.020) increased in the VATS-L group (Table 1).

Table 1. Comparison of different variables between groups
		n		Median	SD	P*
Hospital LOS (days)	VATS	26		4.35	1.77	<0.001
	T	48		7.33	3.00
%C	VATS	26		82.96	4.56	0.005
	T	48		77.63	8.64
%N	VATS	26		81.65	7.85	0.020
	T	48		75.00	13.03
Time to chemotherapy (days)	VATS	26		29.38	9.41	0.002
	T	48		36.98	9.74
C: Cisplatin, N: Navelbine, LOS: length of stay, SD: standard deviation, T: thoracotomy, VATS: video-assisted thoracoscopic surgery

Conclusion:
It is known that VATS-L has several advantages over conventional open surgery. Moreover, our data presented that it also allows more accurate and rapid adjuvant chemotherapy in terms of treatment initiation timing and compliance, by enabling quick postoperative recovery.

Background:
Benzyl isothiocyanate (BITC) inhibits the growth of various human cancer cells, however, the mechanism underlying growth inhibitory effect of BITC is not fully understood. In the present study, we investigated the effect of BITC on autophagy induction in human lung cancer cells in vitro and in vivo.

Method:
Autophagy was characterized by detection of the formation of acidic vesicular organelles (AVOs), the accumulation of microtubule-associated protein 1 light chain 3-II (LC3-II), the punctuate pattern of LC3, and expression of Atg5. Endoplasmic reticulum (ER) stress was determined by measurement of cytosolic calcium level, and phorphorylation of ER stress marker proteins PERK and eIF2α. The effect of BITC on lung tumor growth was examined by lung cancer cell xenograft experiments.

Result:
Our data showed that BITC inhibited the growth of human lung cancer cells. BITC induced autophagy in lung cancer cells, pretreatment with autophagy inhibitor 3-MA enhanced the inhibitory effect of BITC. ER stress was also caused by BITC, suppression of ER stress by ER stress inhibitor 4-PBA attenuated autophagy induction, and further potentiated the cell growth inhibition by BITC. Xenograft experiments showed that BITC inhibited lung tumor growth in vivo, and induced both autophagy and ER stress in lung tumor cells.

Conclusion:
Our results indicated that BITC inhibits lung cancer cell growth both in vitro and in vivo. BITC induces autophagy in lung cancer cells, and autophagy plays a protective role in the inhibition effect of BITC. The autophagy induction is mediated by ER stress response.

Background:
Lung cancer(LC) chemotherapy is associated with several adverse effects(AEs). Data regarding supportive care medications(SCMs) offered to prevent/treat chemotherapy-related AEs in resource-limited settings and compliance to these therapies is lacking. A prospective observational study was therefore carried out in an attempt to ascertain effectiveness of SCMs in real life setting.

Method:
Consecutive patients with newly-diagnosed LC initiated on first-line chemotherapy at a tertiary referral centre in North India (from July 2014-September 2015) were enrolled. Details of chemotherapy-related AEs including incidence, timing of onset, duration and grades were recorded. Compliance with use of mandatory SCMs prescribed after each chemotherapy cycle was assessed by a structured questionnaire. Patients were also instructed to maintain a symptom diary to record various symptoms, frequency of use of need-based SCMs, visits to local health-care providers and hospitalization(if any) during the inter-cycle period.

Result:
Of 112 patients enrolled, majority were males(83.9%,n=94), current/ex-smokers(82.1%,n=92), had advanced stage [IIIB=33.9%(n=38), IV=46.4%(n=52)] and of non-small-cell type (NSCLC; 72.3%,n=81). A total of 602 chemotherapy cycles were administered with AEs being reported in 580 cycles(96.3%). Diarrhea was the commonest AE(180 cycles,29.9%) developing after a mean (SD) duration of 3.6(2.5) days and lasting for 4(3.3) days. Vomiting(138 cycles,22.9%) beginning after a mean (SD) of 3.5(2.7) days, lasting for 3.8(3.1) days; and constipation(121 cycles,20.1% mean[SD] onset after 2.9[1.7]days, lasting for mean[SD] of 6.5[6 .1]) were the other common AEs. Grade3/4 AEs occurred in 6.7%(39/580) cycles. Compliance to dexamethasone and proton-pump inhibitors prescribed as part of mandatory SCMs was 98.2% and 98.3% respectively. Need based SCMs were required in 479 of the 580 cycles(82.6%) reporting AEs. Need-based SCMs were effective in relieving most symptoms (100% episodes of pain, cough and epigastric pain). Local physician consultation was sought in 18.1% and 15.8% episodes of vomiting and pain respectively. Proportion of patients with grade 3/4 AEs and requiring hospitalization was highest for mucositis(16.1% grade 3/4 and 9.7% hospitalized); followed by vomiting(10.1% grade3/4 and 8.7% hospitalized) and diarrhea(10.6% grade 3/4 and6.7% hospitalized). Hiccups, despite occurring in only 5 chemotherapy cycles(0.9%) did not improve with need based SCMs in 40%. Anemia was observed in 441(73.3% prevalence) chemotherapy cycles and was treated with blood transfusions, erythropoiesis-stimulating agents and intravenous iron supplementation in 47(10.7%), 30(6.8%) and four(0.9%) cycles respectively.

Conclusion:
This study highlights a high prevalence of AEs during LC chemotherapy. However, majority of episodes were grade 1-2 and were controlled with need-based SCMs, without requiring hospitalization or local physician consultation.

Background:
Lung cancer is regarded as the most commonly diagnosed malignant disease with the leading cause of cancer-associated death. Sophoridine is a quinolizidine alkaloid extracted from Sophora alopecuroides L, a traditional Chinese medicine, which was found to have diverse pharmacological properties such as anti-inflammatory and anti-cancer. In our current research, we evaluated the effect of sophoridine alone and in combination with cisplatin on various human lung cancer cell lines and also explored the possible anti-cancer mechanisms underlie.

Method:
Colony formation assay, CCK-8 assay as well as transwell invasion and migration assay were adopted to investigate the anti-cancer effects of Sophoridine through a series of human lung cancer cell lines. Western-blot and Quantitative Real-time PCR were used to explore the possible underlying mechanisms of the inhibitory effect of Sophoridine on lung cancer progress.

Result:
We confirmed that Sophoridine can inhibit lung cancer cell proliferation, invasion and migration significantly. In addition, the Hippo-YAP pathway and p53 signaling might be involved in the inhibitory effect of Sophoridine in NCI-H446, NCI-H460 and A549 cell lines but not in the p53-deficient NCI-H1299 cells. Quantitative Real-time PCR showed that Sophoridine can dramatically suppress the downstream targets of Hippo-YAP1 pathway such as CYR61, CDX2, FOXM1, c-Myc and VEGF.

Conclusion:
In conclusion, our study first suggested that sophoridine might be used as a novel agent for lung cancer.

Background:
Hypoxia is associated with increased resistance to radiation and chemotherapy treatments and may be an important prognostic factor in non-small cell lung cancer (NSCLC). Antiangiogenic drugs such as bevacizumab can have the paradoxical effect of transiently improving perfusion by normalizing blood vessels and reducing interstitial pressure, which may improve chemotherapy delivery and tumor cell killing. The aim of this study was to non-invasively assess tumor hypoxia with [18]F-EF5 PET/CT imaging in patients with advanced-stage NSCLC prior to systemic therapy and to compare changes during and after chemotherapy treatments with and without bevacizumab. [18]F-EF5 is a 2-nitroimidazole-based PET tracer reported as a good surrogate for hypoxia.

Method:
Eligibility included patients with incurable stage III/IV NSCLC who were to receive first-line platinum-based doublet chemotherapy alone or in combination with bevacizumab; prior radiation therapy was not allowed. 10 patients completed the study; 5 were treated with standard chemotherapy alone and 5 with chemotherapy plus bevacizumab. Each patient had three [18]F-EF5 PET/CT studies: one baseline pre-treatment, one at day 15 after the first cycle and one post-treatment study after 4-6 cycles of therapy. The investigators reading the PET/CT studies were blinded as to whether patients were treated with bevacizumab or not and no clinical information was available. [18]F-EF5 PET/CT images were acquired from shoulders to upper abdomen and analyzed by calculating tumor-to-muscle (T/M) uptake ratios. A ratio ≥1.50 was considered positive for hypoxia.

Result:
A total of 64 lesions were analyzed on baseline [18]F-EF5 PET/CT scans: 42 in the bevacizumab group and 22 in the control group. 51 of these lesions were positive for hypoxia (79.7%): 37 in the bevacizumab group (88.1%) and 14 in the control group (63.6%). Using a Dunn’s multiple comparisons test, there was a significant decrease in [18]F-EF5 uptake only on post-treatment study versus baseline in the group treated with chemotherapy alone (p=0.009). On the other hand, in the group treated with chemotherapy plus bevacizumab, T/M ratios obtained after one cycle of chemotherapy and after treatment completion were statistically lower when compared to baseline (p<0.0001).

Conclusion:
Preliminary data suggest that many advanced NSCLC are hypoxic and that the combination of bevacizumab and chemotherapy leads to a greater decrease in [18]F-EF5 accumulation compared to chemotherapy alone in primary tumors and metastatic lymph nodes. Further studies are necessary to understand the clinical significance of this finding and to explore this as a potential predictive marker for the use of bevacizumab.

Background:
Lung Cancer is a prothrombotic state with its treatment frequently complicated by thromboembolism leading to shorter life expectancy, worsening of the quality of life and may delay, interrupt, or completely halt the cancer therapy. Based on many retrospectives and prospective analyses in patients with lung cancer, thromboembolic complications are a common event with incidences ranging from 10-17 %. It is possible to identify those with the highest risk of venous thromboembolism suitable for antithrombotic prophylaxis, which could favorably affect their morbidity and mortality

Method:
All patients with advanced lung cancer who were started on platinum-based chemotherapy were included. Those patients who had prior TEs or inherited coagulopathy or those on therapeutic anticoagulation, regular NSAIDs / aspirin or those on bevacizumab were excluded.A thromboembolic event was considered associated with chemotherapy if it occurred between the time of the first dose and 4 weeks after the last dose

Result:
A total 188 patients were screened for the study and 167 patients were enrolled in the study. Since 2 patients were lost to follow-up after accrual, 165 patients were included in the final analysis. Of the 165 patients, 67.8% (112/165) received chemotherapy regimen of carboplatin with gemcitabine, 30.3% (50/167) received carboplatin with pemetrexed, 1.2 % (2/165) received cisplatin with pemetrexed and 0.6 % (1/165) received carboplatin with paclitaxel. A median number of days on platinum were 94 (range 10-478). The median number of chemotherapy cycles administered was 4 (range 1–6). Thromboembolic events occurred in 4.8% of patients (8 out of 165 patients) which were related to the platinum chemotherapy. Among 8 patients with thromboembolic events, 3 patients developed venous pulmonary thromboembolism and 5 patients developed cerebral infarction, out of which 4 had arterial cerebral infarction and one patient had a superior sagittal sinus thrombosis. All eight patients were symptomatic and one patient with cerebral infarction died because of the infarction. The majority of events (7 out of 8) occurred within the first 100 days of starting platinum chemotherapy. Overall, the median time until occurrence of a thromboembolic event was 24 days (range, 8 to 129days). None of the presumed risk factors associated with thrombosis were found be related to the occurrence of TEs on univariate analysis.

Conclusion:
The incidence of thromboembolic events were 4.8 % in our study was low due to the use of carboplatin-based regimens in the majority of patients. The majority of thromboembolic events occurred within 3 months from the initiation of chemotherapy.

Background:
Given the modest/transitory benefit of bevacizumab(B)/chemotherapy(CT) in advanced non-small cell lung cancer (NSCLC) and the tendency of tumors to develop escape pathways of angiogenesis,investigation of dual anti-angiogenic therapy may result in more effective angiogenesis inhibition. TRC105 is an antibody to endoglin,an essential angiogenic target expressed on proliferating endothelial cells,and overexpresed in response to VEFG inhibition.This phase 1b study of TRC105 in combination with standard (STD) dose of B with paclitaxel/carboplatin(P/Crb) in advanced non-squamous (NSQ) NSCLC had the primary objectives of safety/tolerability and to determine a recommended phase 2 dose.Secondary objectives included preliminary evidence of antitumor activity and pharmacokinetic(Pks) profile of TRC105.

Method:
A dose finding study (3+3 design) of TRC105 with B(15mg/kg), P(200mg/m2),and Crb(AUC6), given iv on day 1 of each 21 day cycle.Two dose levels of TRC105 were evaluated: 8mg/kg (cohort 1) and 10mg/kg (cohort 2), administered iv weekly. An expanded cohort at dose level 2 is being evaluated. A maintenance phase with TRC105 + B was considered after of induction therapy in those pts without evidence of progressive disease. Safety and efficacy assessments were determined by the NCI-CTCAE (v 4),and RECIST 1.1,respectively. Eligible pts had PS 0-1, chemotherapy naive stage 4 NSQ-NSCLC,measurable disease, and no significant cardiovascular comorbidities. Pts with asymptomatic treated CNS metastases were allowed.Other parameters assessed included Pks,immunogenicity,and angiogenic biomarkers in plasma.Descriptive statistics were used to summarize pt characteristics, safety, efficacy, Pks and biomarkers.

Result:
Overall safety population comprised 9 pts receiving ≥ 1 cycle of treatment . Median age was 65 years, 55% were women, and one pt had brain metastases. A total of 67 cycles of treatment were delivered (median of 8 cycles). The most frequent grade (G) 3 adverse events:anemia (55%),fatigue (55%),,and neuropathy (44%).There was a G3 epistaxis and a G5 neutropenic event. Responses shown below: Figure 1



Conclusion:
TRC105 with STD CT was associated with an acceptable safety profile.

Background:
Non- small-cell lung cancer (NSCLC) is the most frequent histologic type of lung cancer, and adenocarcinoma is the predominant subtype. The ECOG 4599 trial showed bevacizumab, carboplatin, and paclitaxel is regarded as a new standard regimen.[1] The AVAil study showed bevacizumab in combination with gemcitabine/cisplatin significantly increased PFS compared to chemotherapy alone, but did not demonstrate a statistically significant prolongation of overall survival.[2] A previous meta-analysis showed that bevacizumab plus first-line platinum-based chemotherapy was able to significantly prolong the overall survival (OS) and progression-free survival (PFS) of NSCLC patients.[3] However, bevacizumab is not covered by health Insurance in Taiwan, so the real-world efficacy of bevacizumab plus chemotherapy remains unclear.

Method:
We retrospectively reviewed lung cancer database at Kaohsiung Chang Gung Memorial Hospital between January 2015 and May 2017, and a total of 18 patients with lung adenocarcinoma receiving bevacizumab plus chemotherapy were identified.

Result:
Figure 1 All patients were stage IV disease, and most of them were female (67%), epidermal growth factor receptor (EGFR) wild type (78%) and ALK wild type (94%). There were 15 patients receiving bevacizumab plus first-line chemotherapy, and the remaining 3 patients underwent second-line chemotherapy in combination with bevacizumab. In first-line chemotherapy group, the chemotherapy regimen included pemetrexed/platinum/bevacizumab (73%) and docetaxel/platinum/bevacizumab (27%); the response rate was 27%, and disease control rate was high to 94%. There were only three patients in second-line chemotherapy group, including one patient treating with pemetrexed/bevacizumab and two patients treating with docetaxel/bevacizumab; only one patient responded to treatment (response rate: 33%). The PFS was 16.6 and 4.7 months in first-line and second-line chemotherapy groups, respectively.



Conclusion:
Our data showed the chemotherapy plus bevacizumab as the first-line treatment, led to better response rates and disease control rates in stage IV lung adenocarcinoma patients. Bevacizumab combined with cytotoxic drugs was also suitable as the second-line treatment for such patients.

Background:
Combination of platinum-based and third generation drugs such as vinorelbine chemotherapy are frequently used as paliative chemotherapy for Non-small cell lung cancer (NSCLC) patients in Indonesia especially in Persahabatan Hospital. But there is still no data about the efficacy and tolerability of carboplatin-vinorelbine regimen. This study was conducted to evaluate the efficacy and toxicity of this regimen as first line chemotherapy for advanced NSCLC patients in Persahabatan Hospital.

Method:
This study was an observational study in advanced NSCLC patients who receive carboplatin-vinorelbine regimen as first line chemotherapy. subjects were recruited between 1[st] January 2015 to 30[th ]March 2017. Clinical data regarding the histological type, staging, side effect of chemotherapy, RECIST and survival were recorded.

Result:
Thirty eight subjects were recruited in this study of which carboplatin 5 AUC on day 1 and vinorelbine 30mg/m[2 ]on day 1 and 8 were administered as a combination therapy. This regimen has a good efficacy with overall response rate (ORR) 12,5% and clinical benefit rate (CBR) 87,5%. The overall survival (OS) 34,2% with median of survival time 387 days (12,9 moths) and progression free survival (PFS) 323 days (10,7 months). We found grade 1 anemia (38,4%) and grade 2 nausea vomiting (57,9%) as hematological and non-hematological toxicity that frequently occured in this study. Two cases of grade 2 gastrointestinal bleeding were observed but the subjects still be able to continue the chemotherapy soon after recovery. Mild phlebitis were observed in 65.7% cases ( 24 subjects) and moderate phlebitis in 2.6% (1 subject) as procedural complication of this chemotherapy regimen.

Conclusion:
Combination of carboplatin and vinorelbine as first line chemotherapy has a good efficacy and tolerability for advanced NSCLC subjects.

Background:
We explored the effects of intermittent normobaric hyperoxia alone or combined with chemotherapy on the growth, general morphology, oxidative stress, and apoptosis of benzo[a]pyrene (B[a]P)-induced lung tumors in mice.

Method:
Female A/J mice were given a single dose of B[a]P and randomized into four groups: (1) control, (2) carboplatin (50 mg/kg intraperitoneally), (3) hyperoxia (95% fraction of inspired oxygen), and (4) carboplatin and hyperoxia. Normobaric hyperoxia (95%) was applied for 3 h each day from weeks 21 to 28. Tumor load was determined as the average total tumor numbers and volumes. Several markers of oxidative stress and apoptosis were evaluated.

Result:
Intermittent normobaric hyperoxia combined with chemotherapy reduced the tumor number by 59% and the load by 72% compared with the control B[a]P group. Intermittent normobaric hyperoxia, either alone or combined with chemotherapy, decreased the levels of superoxide dismutase (SOD) and glutathione (GSH) and increased the levels of catalase and 8-hydroxydeoxyguanosine (8-OHdG). The Bax/Bcl-2 mRNA ratio, caspase-3 level, and number of transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells increased following treatment with hyperoxia with or without chemotherapy.

Conclusion:
Intermittent normobaric hyperoxia was found to be tumoricidal and thus may serve as an adjuvant therapy for lung cancer. Oxidative stress and its effects on DNA are increased following exposure to hyperoxia and even more with chemotherapy, and this may lead to apoptosis of lung tumors.

Background:
Chemotherapy, including taxanes, may augment the effects of immune checkpoint inhibitors through tumor cell lysis and subsequent antigen release. This phase I trial is evaluating safety and efficacy of nivolumab plus nab-paclitaxel in NSCLC (+ carboplatin), pancreatic cancer (± gemcitabine), and metastatic breast cancer. Interim results for Arm C, in which patients with NSCLC were treated with nivolumab starting in cycle 1, are presented.

Method:
Potential dose-limiting toxicities (DLTs) were evaluated in Part 1 before Part 2 expansion. Chemotherapy-naive patients with histologically/cytologically confirmed stage IIIB/IV NSCLC received 4 cycles of nab-paclitaxel 100 mg/m[2] days 1, 8, 15 plus carboplatin AUC 6 day 1 plus nivolumab 5 mg/kg day 15 of each 21-day cycle. In cycles ≥ 5, single-agent nivolumab was continued as maintenance therapy. Primary endpoints are number of patients with DLTs (Part 1) and percentage of patients with grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (Parts 1/2). DLT-evaluable patients were those who received ≥ 2 complete nivolumab cycles and remained on study for 14 days after the last nivolumab dose in cycle 2, received ≥ 1 nivolumab dose and discontinued due to DLT before completing 2 nivolumab cycles, or experienced an equivocal DLT after ≥ 1 nivolumab dose. Secondary endpoints included PFS, DCR, ORR, DOR (all by RECIST v1.1), OS, and safety.

Result:
All patients (N = 22) received nab-paclitaxel/carboplatin; results for those who received nab-paclitaxel/carboplatin plus nivolumab (n = 20) are presented. The median age was 65.5 years (55% ≥ 65 years), 70% had ECOG PS 1, 75% were female, and 80% were white. More patients had adenocarcinoma (50%) than squamous cell carcinoma (35%; adenosquamous carcinoma, atypical, and data pending, 5% each). No DLTs were reported among 6 DLT-evaluable patients (Part 1). The most common grade 3/4 TEAEs were neutropenia (45%) and anemia (40%). No grade 3/4 colitis or pneumonitis was reported. Best ORR was 50% (1 CR [5%] and 9 PRs [45%]; 10 patients [50%] had SD); ORR was 43% (3 PRs among 7 patients) and 54% (1 CR and 6 PRs among 13 patients) in those with squamous and nonsquamous histologies, respectively. Median PFS was 10.5 months (95% CI, 4.9-18.1 months); 10.5 and 10.2 months for those with squamous and nonsquamous histologies, respectively.

Conclusion:
These results suggest that nab-paclitaxel/carboplatin plus nivolumab is tolerable for patients with NSCLC. Preliminary efficacy findings indicate promising antitumor activity across histologies. (NCT02309177)

Background:
The study objective was to compare efficacy and safety of CBDCA+PTX+BEV and CDDP+PEM+BEV in non-squamous (non-Sq) NSCLC patients.

Method:
Treatment-naïve patients aged 20-74 with advanced or recurrent EGFR/ALK-negative non-Sq NSCLC were randomly assigned at 1:2 ratio to either treatment A (4 cycles of CBDCA [AUC 6] + PTX [200mg/m[2]] + BEV [15mg/kg] q3wk, and maintenance therapy with BEV q3wk until progression) or treatment B (4 cycles of CDDP [75mg/m[2]] + PEM [500mg/m[2]] + BEV q3wk, and maintenance therapy with PEM + BEV until progression). The primary endpoint was PFS by central review. The secondary endpoints included OS and safety profile. Target enrollment number was 210.

Result:
A total of 55 sites across Japan enrolled 199 patients: 67/132 (A/B). The median age was 67/66 years, 70%/74% were male, 54%/52% were PS 0, 75%/73% were stage IV and 93%/98% had adenocarcinomas. As of April 14, 2017, patients had completed a median of 7/8 treatment cycles, while 94%/80% had discontinued treatment. The most common ≥G3 adverse events were neutropenia (75%/24%), and hyponatraemia (6%/10%). The most common BEV-related adverse events (≥G1) were hypertension (44%/58%), proteinuria (52%/43%) and epistaxis (26%/14%). Dose reduction was necessary due to an adverse event in 31%/22% patients. Treatment-related death (pulmonary infection) was reported in 1 patient receiving treatment B.

Conclusion:
CBDCA+PTX+BEV and CDDP+PEM+BEV had different safety profiles. Efficacy results including the primary endpoints will be presented in 2018.

Background:
Therapeutic options for squamous cell lung cancer (SQCLC) patients remain limited. Platinum-based chemotherapies, which have been the standard first-line treatments for nearly 20 years, are associated with ORR=30-40%, median PFS=4-5.7mo, and median OS=9-11.5mo. We previously reported the results of a phase 1/2 trial of albumin-bound paclitaxel (ABP) in 40 patients with untreated stage IV NSCLC, noting an ORR of 30%, median PFS of 5mo, and median OS of 11mo (Rizvi JCO 2008). These data suggest that platinum adds little when coupled to ABP. Conversely, compelling evidence of anti-tumor synergy between gemcitabine and ABP was recently demonstrated by Frese et al. who showed that ABP downregulates cytidine deaminase (which inactivates gemcitabine), leading to increased intratumoral [gemcitabine] (Cancer Disc 2012). Based on these data, we sought to assess the efficacy of ABP + gemcitabine in patients with SQCLC.

Method:
This is a phase II trial of ABP (100mg/m[2]) + gemcitabine (1000mg/m[2]) given on D1, D8, D15 of an every 4 week cycle (A1) in patients with untreated stage IV SQCLC. Patients received up to 6 cycles and were followed thereafter (A1). The primary endpoint is best objective response (RECIST 1.1). The study utilizes a Simon two-stage design with H0=25% (6/17 responses) and H1=45% (16/41 responses). After clearing the first stage, the study was amended to a 3 week cycle (D1, D8 treatment); to allow ABP + gemcitabine until progression; and to allow maintenance ABP to begin after C4 for tolerability (A2). PFS, TTP, and OS were calculated using the Kaplan-Meier method. Patients underwent NGS by MSK-IMPACT for genotype-phenotype correlation.

Result:
N=17 patients (14 evaluable) were treated on A1 and, to date, N=3 patients (2 evaluable) have been treated on A2. Median age=70, female=30%, median KPS=90%, smokers=90%, median pack years=32. Median cycles of therapy in A1=4. Grade ≥3 related AEs included: peripheral neuropathy (5%); diarrhea (5%); elevated ALT (5%); anemia (15%); and decreased neutrophils (25%). Three patients (15%) experienced a related SAE including G3 decreased WBC, G3 diarrhea, and G3 lung infection. There was 1 unrelated death as a result of complications from a G3 mechanical fall. ORR in A1=50% (7/14 PRs). ORR in A2=100% (2/2 PRs). ORR in A1+A2=56% (9/16 PRs). SD=6 (38%) and PD=1 (6%). Median PFS=5.8mo; TTP=6.9mo; OS=13.3mo.

Conclusion:
ABP + gemcitabine has promising efficacy and is relatively well-tolerated, particularly when compared to platinum regimens. Accrual to the study is ongoing and updated data, including NGS correlates, will be presented.

Background:
Vitamin supplementation reduces pemetrexed toxicity. Raised plasma homocysteine levels reflect folate deficiency and are suppressed by supplementation. Depression is common in lung cancer patients. Elevated homocysteine levels are linked to neurotoxicity; its association with depression is less clear.

Method:
This prospective observational study of 112 lung cancer patients receiving pemetexed-based chemotherapy assessed homocysteine level after 3 weeks of vitamin B12 and folate supplementation, hypothesizing that high levels reflect an ongoing deficiency and would correlate with increased chemotherapy toxicity and depression. All patients received B12 and folate supplementation and had a homocysteine level checked 3 weeks later. The primary objective was proportion of patients with a treatment delay/ dose reduction/ drug change or hospitalisation during the first six weeks of chemotherapy, between patients showing normal plasma homocysteine (i.e. successfully supplemented, SS group) and patients showing high levels (i.e. unsuccessfully supplemented, US group). Secondary objectives included grade 3-4 toxicity, overall survival and exploratory analyses for depression.

Result:
100 patients were included in the primary end-point analysis. 84% of patients demonstrated appropriate supplementation (SS group). The proportion of patients undergoing a treatment delay/ dose reduction/ drug change or hospitalisation in the SS group was 44.0% (37/84) (95% confidence interval [CI] 33.2% to 55.3%) and in the US group was 18.8% (3/16) (95% CI 4.0% to 45.6%) (p=0.093). Proportion of patients experiencing grade 3-4 toxicity in SS group was 14.5% (95% CI 7.7% to 23.9%) and in US group was 18.8% (95% CI 4.0% to 45.6%) (p=0.705). The proportion of patients with a Hospital Anxiety and Depression (HAD) score >7 (indicative of depression) in the SS group was 63.9% (95% CI 46.2% to 79.2%) and in the US group was 75% (95% CI 34.9% to 96.8%) (p=0.695). Median overall survival was 11.8 months (95% CI 8.6 – 16.5 months) in the SS group and 8.8 months (95% CI 6.6 – 16.2 months) US group (Log Rank test; p-value = 0.484).

Conclusion:
Standard vitamin supplementation was adequate in the majority of patients and thus our US population was small. Homocysteine levels at 3 weeks did not correlate with increased toxicity or overall survival and is unlikely to be useful to identify patients at an increased risk of toxicity, though analysis was limited by the smaller than expected number of patients in the US group. Depression is very common in this population, and HAD score is a feasible assessment tool in this patient group.

Background:
Effects of the presence of COPD on clinical outcomes in patient with advanced stage NSCLC cancer were inconclusive. Aim of our study is to evaluate the effects of COPD on overall survival of NSCLC patients who undergo conventional chemotherapy as 1st line treatment.

Method:
Advanced NSCLC (stage IIIB and IV) received first-line chemotherapy from January of 2008 to December 2015 were enrolled from 6 university hospitals. Patients who underwent pretreatment pulmonary function test were selected in the analyses, and COPD was defined according to GOLD guideline: FEV1/ FVC < 0.7. Primary endpoint was the overall survival according to the patients’ clinicopathological characteristics.

Result:
A total of 197 patients comprised of 92 patients (46.7%) in the COPD group and 105 (53.3%) in the non-COPD group were enrolled in the analysis. The median duration of follow-up for survived patients was 23.9 months. The presence of COPD was a significant risk factor for mortality in the univariate analysis (HR, 1.402; p = 0.037), however not in the multivariate analysis (HR, 1.275; p = 0.144). The patients with COPD have poor clinical outcomes in subgroups of smokers and stage IV cancer, significantly.

Conclusion:
: COPD does not have clinical impact of overall survival of advanced NSCLC patients who undergo conventional chemotherapy. However COPD was a poor prognostic factor in terms of overall survival of in smokes and stage IV NSCLC patients. Further studies which evaluate clinical effects of airflow obstruction management on lung cancer patients can elucidate the clinical impact of COPD.

Background:
S-1 is one of the key-drugs as chemotherapy for the non-small cell lung cancer (NSCLC). We conducted a multicenter randomized study of adjuvant S-1 administration schedules for surgically treated pathological stage IB-IIIA NSCLC patients.

Method:
Patients receiving curative surgical resection were centrally randomized to arm A (4 weeks of oral S-1 and a 2-week rest over 12 months) or arm B (2 weeks of S-1 and a 1-week rest over 12 months). The primary endpoints were total days of administration, and the secondary endpoints were relative total administration dose (relative dose intensity), toxicity, and 3-year disease-free survival. Total days of administration were evaluated according to the cumulative rates of total S-1 administration days within 224 days, at the end of 12 months. Relative dose intensity was defined as (the actual total dose administered divided by the planned total administered dose) × 100.

Result:
From April 2005 to January 2012, 80 patients were enrolled, of whom 78 patients were eligible and assessable. The cumulative rates of total S-1 administration days at the end of 12 months, were 81.3% for arm A (38 cases) and 60.2% for arm B patients (40 cases, p = 0.04). The relative dose intensity was 77.2% for arm A and 58.4% for arm B (p = 0.01). Drug-related grade 3 adverse events were recorded for 11% of arm A and 5% of arm B (p = 0.43). The 3-year disease-free survival rate was 79.0% for arm A and 79.3% for arm B (p = 0.94). Toxicity showed no significant difference among the shorter schedule and the conventional schedule, except for grade 1-3 elevation of bilirubin.

Conclusion:
The superiority of feasibility of the shorter schedule was not recognized in the present study. The conventional schedule showed higher cumulative rates of total S-1 administration days at the end of 12 months (p = 0.04) and relative dose intensity of S-1 (p = 0.01).

Background:
To investigate the safety and efficacy of recombinant human endostatin (endostar) administrated by durative infusion combined with chemotherapy within the vascular normalization period in treating advanced non‐small cell lung cancer (NSCLC).

Method:
From February 2012 to December 2013, 34 cases of IIIB‐IV NSCLC patients were treated with endostar (15mg/m2) durative infusion combined with chemotherapy within vascular normalization time. Endostar was durative infusion every 24 hour for 7 days, and in the fourth day of the normalization time patients were received combined chemotherapy based on platinum, 21 days per cycle. All patients received 2‐6 cycles; efficacy was evaluated every two cycles, and side effects were recorded every cycle.

Result:
Every patient was received at least 2 cycles, one patient achieved CR, 14 patients were PR and 8 patients were SD. Eleven patients were PD. The overall response rate (ORR) of 34 patients was 44.1%, and non‐squamous NSCLC was 38.9%, squamous NSCLC was 50.0%. First‐line treatment of patient showed higher ORR, 53.9%. Major toxicities related to endostar were sinus tachycardia in one case, and one case hypertension. No serious side effects such as bleeding were observed.

Conclusion:
Endostar (15mg/m2) durative infusion combined with normalization period chemotherapy for NSCLC was an efficacy and safe regimen. A larger prospective randomized controlled clinical study is worth to carry out in future.

Background:
Histoculture Drug Response Assay (HDRA) is a representative in vitro drug response assay used for anticancer agents. Several papers reported that HDRA was useful to predict chemosensitivities in non-small cell lung cancer (NSCLC). However, it is unknown that whether HDRA truly predict clinical outcome and associate with other predictive markers, such as ERCC1 and class III beta-tubulin (TUBB3).

Method:
Between August 2007 to July 2009, 46 patients with non-small cell lung cancer who underwent surgical treatment were enrolled. HDRA technique was the same as we previously reported (JTCVS 133: 303-8, 2007). Chemosensitivities of cisplatin (CDDP), paclitaxel (PTX), docetaxel (DTX), and vinorelbine (VNR) were evaluated. Immunohistochemical staining for ERCC1 and TUBB3 were done using monoclonal antibody clone 8F1 and TUJ1. The H-score was adopted for the evaluation of ERCC1 and TUBB3 expression. Adjuvant therapy was selected for each patient based on HDRA within the standard treatment. Median follow up period was 117 months.

Result:
ERCC1 was positive in 38 specimens and negative 6 specimens. Inhibition rate for CDDP in HDRA was significantly lower (p=0.02) in ERCC1-positive specimens (41±16)% than in ERCC1-negative specimens (58±8%). TUBB3 was positive in 12 specimens and negative 32 specimens. Inhibition rate for VNR in HDRA was significantly higher (p=0.01) in TUBB3-positive specimens (38±17)% than in TUBB3-negative specimens (23±15%).However, inhibition rate for PTX and DTX were not significantly correlated with TUBB3 status (p=0.39, 0.94).Disease -free survival(DFS) in patients from IB to IIIA with HDRA guided therapy tended to be longer than those without HDRA (p=0.083). Overall survival (OS) in patients from IB to IIIA with HDRA guided therapy were not to be longer than those without HDRA (p=0.77).

Conclusion:
Tumors with low ERCC1 levels exhibited greater chemosensitivity to CDDP than tumors with high ERCC1 levels. Tumors with high TUBB3 levels exhibited greater chemosensitivity to VNR than tumors with low TUBB3 levels. HDRA-guided adjuvant chemotherapy may prolonged RFS, but not affect to OS.

Background:
Among the aminoacyl-tRNA synthetases (ARSs) which catalyze ligation of amino acids to their cognate tRNAs, leucyl-tRNA synthetase (LRS) involves in amino acid-induced mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activation by sensing intracellular leucine concentration. Because mTORC1 regulates cell growth and proliferation by coordination upstream signals such as growth factor and amino acid availability, we hypothesized that inhibition of LRS inhibits cell growth and proliferation and synergize in cell death when combined with cytotoxic agents.

Method:
Expression of LRS and pS6 was observed by immunochemical staining of NSCLC tissue from 117 patients. The effect of B1206 on mTORC1 signaling was analyzed by immunoblotting and confocal imaging and its cytotoxic effect was measured by flow cytometer after annexin V-propidium iodide staining. In vivo effect of B1206 was evaluated by microCT in LSL-Kras G12D mouse lung cancer model.

Result:
Among 117 human NSCLC tissues, LRS was overexpressed in the 52 (44.4%) cases of cytoplasm and 14 cases (11.2%) of nucleus and the expression of pS6(Ser235/236) in the serial tissue section from matched lung cancer patient showed significant correlation with that of LRS expression (Pearson’s correlation coefficiency=0.315, p-value<0.001). Treatment of B1206 inhibited phosphorylation of pp70S6K(T389), pS6(S235/236), and p4EBP1(T36/45) in a dose dependent manner, which is more prominent in 6 Hr after treatment. On the other hand, it did not influence phosphorylation of pAKT(S473) and pGSK(S9), which are signaling markers of mTORC2. There was a significant change in the cell size by treatment of sublethal dose of B1206, which is additional finding suggesting B1206 possesses mTORC1 inhibitory effect. Among the 10 cell lines tested, B1206 treatment could not induce cell death in 6 cell lines up to 30 uM of concentration. But H2009, H460, and H358 cells were sensitive to B1206 and most cell death occurred at concentrations below 10 uM and H1703 showed moderate sensitivity to B1206. Treatment of B1206, cisplatin, and combination of both drugs significantly reduced tumor size when compared with that of vehicle treated group and the anti-tumor effect of B1206 and cisplatin was comparable. However, combination of B1206 and cisplatin did not show significant difference in tumor size when compared with single drug treatment.

Conclusion:
This study suggests that B1206 could be used as a new concept of therapy for NSCLC by inhibiting the non-canonical function of LRS and that continuous efforts are required on exploring non-canonical function of ARS as well as its inherent function for protein synthesis.

Background:
Nintedanib is an orally administered, small-molecule triple angiokinase inhibitor of VEGF1–3, PDGFa and b, and FGFR1–3. The LUME-Lung 1 trial showed that nintedanib significantly extended progression-free survival (PFS) and overall survival (OS) in patients with NSCLC adenocarcinoma when added to docetaxel chemotherapy. The bioactive flavonolignan silibinin, the main component of standardized extracts from the seeds of the milk thistle herb Silybum marianum, has been shown to exert significant anti-cancer effects in pre-clinical models. The oral use of the silibinin-containing nutraceutical Legasil[®] could represent the first silibinin formulation with proven clinical benefit as an adjunct cancer treatment.

Method:
Patients with stage IV NSCLC who failed ≥1 prior treatment were eligible for nintedanib/docetaxel combination. We present data of patients that received nintedanib plus docetaxel with or without combination with up to 5 capsules/day of Legasil[®], which equated to a 630 mg/ day dose silibinin regimen, as complementary treatment. The nature of the interaction between nintedanib and silibinin was explored in a broad panel of human NSCLC cell lines.

Result:
Twenty-two patients were enrolled in the study: median age 63y (range: 44–74); male: 14. All the cases were non-squamous NSCLC. All patients had received first line therapy; 3 patients had ≥2 prior lines of treatment. The mean PFS was 1.82 months (95% confidence interval [CI] 1.39–2.26) for the nintedanib plus docetaxel combination (n=7) versus 4.97 (95%CI 2.87–7.07) for the nintedanib, docetaxel and Legasil[® ]triple combination (n=15) (p=0.02). No statistically significant differences in mean OS were observed between the two arms: 4.88 (95%CI 3.26–6.48) for nintedanib plus docetaxel versus 10.3 (95%CI 5.85–14.76) for nintedanib plus docetaxel plus Legasil[® ](p=0.534). At the data cutoff in June 2017, 9 (41%) patients remained alive. A significant inverse correlation was found between nintedanib and silibinin sensitivity among NSCLC cell lines. The combined treatment of nintedanib and silibinin produced unanticipated, synergistic cytotoxic effects in nintedanib-unresponsive NSCLC cells.

Conclusion:
There is a clinical and biological rationale for combining nintedanib and docetaxel with the silibinin-containing nutraceutical Legasil[®] in patients with advanced NSCLC, where few effective second-line treatment options are available.

Background:
The aim of this retrospective study was to investigate the efficacy of adjuvant chemotherapy for patients in pathological T1aN0M0 lung adenocarcinoma with lymphatic vessel invasion.

Method:
We retrospectively collected data on 72 consecutive patients with pathological T1aN0M0 (the 7th edition of the UICC TNM stating system) lung adenocarcinoma with lymphatic or/and vessel invasion from January 2001 to December 2013. Adjuvant uracil-tegafur group were compared with control group. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method and differences compared using log-rank test. Prognostic factors were evaluated using a Cox proportional hazard model.

Result:
Among the 72 patients, 21 patients (29.1%) were treated with adjuvant chemotherapy with uracil–tegafur. No significant difference was found in patient characteristics between the two groups. In the 21 adjuvant chemotherapy and 51 control groups, the 5-year OS rates were 100% versus 80.8%, respectively; and the 5-year DFS rates were 88.2% versus 65.1% (p=0.0138), respectively. Multivariate analysis revealed that adjuvant chemotherapy was only independent predictor of OS and DFS (p = 0.014, 0.013, respectively).

Conclusion:
Adjuvant chemotherapy with uracil–tegafur improves survival among patients with completely resected pathological T1aN0M0 lung adenocarcinoma with lymphatic vessel invasion. Our study suggests that pathological T1aN0M0 lung adenocarcinoma with lymphatic vessel invasion potentially benefits from adjuvant chemotherapy.

Background:
Nedaplatin, a cisplatin derivative, has similar activity to cisplatin for non-small-cell lung cancer (NSCLC). We previous reported that the combination chemotherapy of docetaxel plus nedaplatin was well tolerated in patients with advanced NSCLC. The purpose of this phase II study was to evaluate the feasibility of combination chemotherapy of docetaxel plus nedaplatin as an adjuvant chemotherapy in patients with completely resected stage IB-IIIA NSCLC.

Method:
Following a radical surgery, patients were treated with docetaxel (60 mg/m[2]) and nedaplatin (80 mg/m[2]) on day 1 every four weeks up to four cycles. The primary endpoint was feasibility, determined by the proportion of patients who completed four cycles of the combination chemotherapy. Adverse events were graded according to National Cancer Institute Common Toxicity Criteria (version 4.0). Median relapse-free survival time after surgery was calculated by analyzed by Kaplan-Meier analysis.

Result:
From December 2010 and April 2016, 34 patients with median age of 64.5 years (range, 36–77 years) were enrolled in this study. The patients consisted of 30 males and four females. Histological types were adenocarcinomas in 20 patients, squamous cell carcinomas in 12, and others in 2. Pathological stages were IB in 2 patients, II in 21, and IIIA in 11. Concerning the feasibility of the combination adjuvant chemotherapy, twenty-six patients (76.5%) completed four cycles of the combination chemotherapy. In 11 of those patients (42.3%), doses of the agents were decreased from the initial doses due to toxicities. Grade 3 or 4 toxicities included leukopenia (36.4%), neutropenia (69.5), anemia (1.7%), thrombocytopenia (0.8%), anorexia (7.6%), and nausea (3.4%). There were no treatment-related deaths. Median relapse-free survival time after the surgery was not reached, and 5-year survival rate was 65.8%.

Conclusion:
Given high completion rate of adjuvant chemotherapy with docetaxel plus nedaplatin, we conclude that the adjuvant chemotherapy is feasible and tolerable in patients with completely resected NSCLC.

Background:
In advanced EGFR-mutant NSCLC, afatinib, a second-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) has demonstrated a significant survival benefit over platinum-based chemotherapy (Lancet Oncol. 2015) and the combination therapies of EGFR-TKI and bevacizumab showed favorable PFS data (J Thorac Oncol. 2015 and Lancet Oncol. 2014). Also, our preclinical study revealed the synergistic effect of afatinib and bevacizumab (Mol Cancer Ther. 2013). We hypothesized afatinib and bevacizumab potentially yields further efficacy and conducted a phase I trial.

Method:
Untreated patients with advanced EGFR-mutant NSCLC were enrolled. The primary endpoint was set as safety. The first 6 patients received afatinib at 40 mg/body daily and bevacizumab intravenously at 15 mg/kg every 3 weeks until PD or unacceptable toxicity (level 0). If 2 or fewer patients experienced DLT, we repeated at the same dose to additional 6 patients. When 2 or fewer patients experienced DLT in the both sets, we concluded this dose was feasible. Otherwise, we repeated the same method at the level -1 (afatinib 30 mg/body, bevacizumab 15 mg/kg). If the dose was feasible, the level was recommended.

Result:
Nineteen patients were enrolled (level 0: 5 and level -1: 14). Three patients at level 0 experienced DLT, which concluded level 0 was unfeasible. At level -1, 3 patients developed DLT. All of the DLT soon recovered. Severe adverse events were shown in Table. Three patients at level 0 and 5 at level -1 required dose reduction for toxicity, respectively. Two patients at level 0 stopped protocol therapy for toxicity, whereas 2 at level -1 for wish of patients. Among 16 evaluable patients, the best response was CR / PR (81.3%) and SD (18.8%).

Conclusion:
Dose level -1 was well tolerated and had evidence of disease control. There was no refractory patient as well as other trials of EGFR-TKI plus bevacizumab.

		Level 0 (n=5)	Level -1 (n=14)
Grade 4		0	0
Grade 3		5	4
Grade 3 (* DLT)	Diarrhea	2[*]	2[*]
	Skin rash	1	1
	Hypoxia	1[*]	0
	Anorexia	0	1[*]
	Paronychia	1	0

Background:
Cisplatin remains the cornerstone of current chemotherapeutic combination startegies in the treatment of NSCLC. Despite initial cisplatin sensitivity tumours develop resistance, which in turn undermines the efficacy of cisplatin as a therapuetic agent. Numerous mechanisms, signalling pathways and theories have been suggested and elucidated in terms of cisplatin resistance and in the development of it, however, to date the clinical issue of resistance has not been overcome. A current avenue of interest is the cancer stem cell (CSC) hypothesis, in which the survival and expansion of highly resistant CSCs during chemotherapeutic treatment are thought to be a contributing factor of resistance and recurrence. Specific inhibition of key CSC markers in combination with chemotherapy may undermine the inherent resistance of the CSC population and sensitise these cells to the cytotoxic effects of therapy. One such CSC marker observed across numerous tumours is aldehyde dehydrogenase 1 (ALDH1), our hypothesis suggests that inhibition of the ALDH1-positive CSC population within cisplatin resistant NSCLC will resensitise the cellls to the cytotoxic effects of cisplatin.

Method:
Using an isogenic panel of matched parent (PT) and cisplatin resistant (CisR) NSCLC cell lines ALDH1 was identified as a CSC marker present within the CisR sublines of each NSCLC histology and characterised as CSCs. ALDH1 was inhibited using two pharmacological ALDH1 inhibitors, diethlylaminobenzaldehyde (DEAB) and disulfiram (commercially known as Antabuse used in the treatment of alcoholism). ALDH1 inhibition was confirmed by flow cytometry. PT and CisR cell lines were treated with inhibitor alone and in combination with cisplatin and assessed in terms of proliferation, clonogenic survival and apoptosis relative to cisplatin-only treatment.

Result:
Both DEAB and the FDA-approved disulfiram significantly decreased the presence of the ALDH1-positive CSC subpopulation across all CisR cell lines. DEAB and disulfiram in combination with cisplatin induced a significant decrease in proliferation and clonogenic survival as well as significant increases in cisplatin-induced apoptosis across CisR sublines when compared to cisplatin alone.

Conclusion:
DEAB and disulfiram significantly reduced the presence of the highly resistant ALDH1-positive CSC subpopulation. This pharmacological CSC depletion in conjunction with cisplatin was associated with the resensitisation of cisplatin resistant cells to the cytotoxic effects of cisplatin, thus restoring cytotoxic efficacy. The resensitisation effect of the disulfiram-based combination strategy, as well as its FDA-approval and extentsive safety profile highlights this strategy as one of great promise. In summary, these data suggest a role for ALDH1 inhibition in the resensitisation and possible circumvention of cisplatin resistance.

Background:
Epidermal growth factor receptor (EGFR) mutation is seen 15-20% in non-small cell lung carcinomas (NSCLC), more common in non-smokers, female sex and Asian population. Treating NSCLC patients having activating EGFR mutations with tyrosine kinase inhibitor (TKI) significantly prolongs progression-free survival compared to standard chemotherapy and is a more tolerable. Our aim is to evaluate clinicopathologic features of patients using EGFR directed therapies (erlotinib or gefitinib) longer than 1 year.

Method:
Files of 46 patients with metastatic NSCLC having activating EGFR mutations and treated with EGFR TKI between 2012-2017 were retrospectively evaluated. Statistical analysis was done by SPSS 16.

Result:
Median age was 61 (30-80), and 56.5% (26/46) was female. Mean follow-up was 38 months.The rate of smoking was 41% (19/46). LDH elevation was found in 67% and CEA elevation was found in 50% of the patients at presentation. Median progression-free survival time (mPFS) was 21 months (range 2-58). mPFS is 21 months (2-35) for patients using erlotinib in first line (35 patients), and 13 months (5-30) in second line setting (11 patients). Sixty four percent of patients had exon 19 deletion, 28% had exon 21 mutation, and 8% had activating exon 18 mutations. There were 27 patients with PFS 12 months or more and 9 patients with less than 12 months. No statistically significant difference was found for PFS when clinicopathologic features (age, gender, 1st or 2nd line usage, LDH or CEA levels, ECOG PS, smoking, weight loss, mutation status) of these patients were compared. Median overall survival time (mOS) for metastatic disease was 39 months (range 4-65). The negative effect of ECOG-PS on OS was shown by univariate and multivariate analysis. Skin toxicity was observed in 18 patients (43%), while treatment was interupted and dose was reduced in 6 patients (14%) due to side effects.

Conclusion:
Activating mutation in EGFR is the most important marker that predicts response to EGFR-TKIs in NSCLC. Smokers should be tested for EGFR mutations, as some patients may benefit from EGFR-TKI treatment for longer than reported in the literature.

Background:
Despite significant advances in personalised medicine in recent decades, cisplatin remains the mainstay chemotherapy in the treatment of NSCLC. The major clinical challenge facing NSCLC today is the development of pan-resistance to platinum agents. Novel drug design, preclinical and clinical trials working toward the approval of new drugs is a lengthy and costly process and in the interim of the drug indentifcation and commercialisation research has turned its focus to two avenues of interest; overcoming cisplatin resistance and the repurposing of approved therapeutics with new indications. Cancer stem cells (CSCs) have been hypothesised to be the initiating cells of therapeutic resistance and tumour recurrence. An ALDH1-positive cell subset has been identified as a key CSC subpopulation present within cisplatin resistant NSCLC sublines. ALDH1 is involved in the metabolism of retinol (vitamin A) and the catalytic conversion of retinal to retinoic acid, where retinoic acid induces cell differentiation. All-trans retinoic acid (ATRA) is a well-established chemotherapeutic agent in the treatment of acute promyelocytic leukaemia; it induces the terminal differentiation of immature cells. We hypothesise that treatment of the cisplatin resistant NSCLC sublines with retinol or ATRA will deplete the ALDH1-positive population and subsequently increase or restore cisplatin sensitivity.

Method:
Flow cytometry on a panel of matched parent (PT) and cisplatin resistant (CisR) NSCLC cell lines revealed the greater presence of ALDH1-positive CSC subpopulations within the CisR sublines of each NSCLC histology relative to PT lines. Cells were treated with retinol (substrate of the retinoic acid pathway) or ATRA (product of the retinoic acid pathway) and the presence of the ALDH1-positive CSC subset reanalysed by flow cytometry. Following treatment of the PT and CisR cells with retinol or ATRA alone and in combination with cisplatin the functional parameters of proliferation, clonogenic survival and apoptosis were reassessed relative to cisplatin alone.

Result:
Treatment of the CisR sublines with retinol (1μM) or ATRA (5μM) significantly reduced the presence of the ALDH1-positive CSC subset across CisR sublines. Both retinol and ATRA when used in combination with cisplatin significantly reduced the proliferative and survival capacity of each CisR subline while significantly increasing apoptotic cell death compared to cisplatin alone.

Conclusion:
Exploitation of the vitamin A/retinoic acid pathway in combination with cisplatin re-sensitised resistant cells to the cytotoxic effects of cisplatin. These data suggest vitamin A supplementation or the addition of FDA-approved ATRA to the cisplatin-based chemotherapeutic regimen may be of clinical benefit in overcoming tumour recurrence and cisplatin resistance.

Background:
The cancer stem cell (CSC) hypothesis is now a well-established and widely investigated field within oncology. It hypothesises that there is a robustly resistant stem-like population of cells that survive and thrive 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. Following initial in vitro and in vivo preclinical promise of BBI608 reported in the literature, phase II and III clinical trials are underway and are at various stages of recruitment, progress and completion to investigate BBI608 across a number of advanced malignancies and in combination with numerous chemotherapeutic agents.

Method:
Aldefluor (Stemcell Technologies) staining and flow cytometry analysis of a panel of matched parent (PT) and cisplatin resistant (CisR) NSCLC cell lines identified the ALDH1-positive (ALDH1+ve) subpopulation of cells as an omnipresent CSC subset across cisplatin resistant NSCLC sublines. PT and CisR cell lines were treated with BBI608 (1μM) and 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 in the presence and absence of 1μM BBI608.

Result:
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 ALDH1+ve 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 in various stages of completion to further investigate BBI608. These data suggest a promising role for BBI608 in the treatment of non-responsive or recurrent NSCLC.

Background:
Systemic Anti-Cancer Therapies (SACT) are frequently employed as either curative or palliative treatments in patients with lung cancer, but the benefits of SACT take time and may not always render immediate benefit. Death within 30 days of receiving SACT suggests that treatments were futile since these patients did not live long enough to derive direct therapeutic benefit. This study aimed to identify clinical factors associated with the risk of 30-day mortality among patients with advanced non-small cell lung cancer (NSCLC) at the Tom Baker Cancer Center (TBCC) in Calgary, Canada.

Method:
A retrospective review of NSCLC patients receiving SACT between January 2010 and December 2014, and captured in the Glans-Look Lung Cancer Database was conducted. We identified patients with a regimen start or change of SACT in the last 30 days of life. Mortality rates were calculated, and multivariable logistic regression was used to identify demographic, tumor or treatment-related factors that correlated with 30-day mortality risk.

Result:
Of 573 NSCLC patients receiving SACT between January 2010 and December 2014, 119 patients were identified as dying ≤ 30 days following SACT, yielding a 22% 30-day mortality rate. Of these 119 patients, 47% had a change or initiation of SACT within the last 30 days of life, and 54% received treatment within the last 14 days of life. Of patients dying within 30 days, 50% received cytotoxic chemotherapy, and 48% received anaplastic lymphoma kinase/tyrosine kinase inhibitors (ALK/TKI) as compared to 79% and 20% of surviving patients, respectively. This resulted in a 30-day mortality rate of 10.6% for cytotoxic chemotherapy and 10.3% for ALK/TKI therapy. Ongoing analysis will elucidate predictive factors that are associated with increased risk of 30-day post-SACT mortality.

Conclusion:
A number of NSCLC patients are at increased risk of dying within 30 days of SACT receipt. Efforts to determine the clinical characteristics of patients dying within 30 days of SACT, and to ascertain potential indicators of poor outcome following SACT can reduce avoidable harm. Data from a diverse and representative patient population such as this can provide real world evidence and serve as a means of informing best practices in palliative and end-of-life care for cancer patients.

Background:
NC-6004 is a polymeric micelle exhibiting sustained release of cisplatin and selective distribution to tumors, reducing plasma C~max~ and increasing AUC. Preclinical data showed less neuro- and nephrotoxicity with greater anti-tumor activity versus cisplatin. A previous trial evaluated NC-6004 and gemcitabine defining a recommended phase 2 dose of 90 mg/m[2]. A Bayesian continual reassessment method (N-CRM) design evaluated escalating doses of NC-6004 in combination with gemcitabine at 1250 mg/m[2].

Method:
Patients with refractory solid tumors were enrolled at four US sites. NC-6004 was administered intravenously (IV) at 60-180 mg/m[2] over 1 hour on Day 1 with gemcitabine at 1250 mg/m[2] IV over 30 mins on Day 1 and Day 8 every 3 weeks. All patients were administered a hydration regimen. Escalation of NC-6004 began with a single patient run-in, escalating by 15 mg/m[2] until a dose limiting toxicity (DLT) occurred at 180 mg/m[2]. Cohorts of four patients were then enrolled at each dose predicted by the N-CRM design. The maximum tolerated dose (MTD) was defined as the dose with the greatest posterior probability of target toxicity < 25%.

Result:
Among 22 patients enrolled in Phase 1b, 11 patients (six male, five female) had lung cancer. Non-squamous non-small cell lung cancer (NSCLC) was the most common subtype in 8/11 (72%) followed by squamous NSCLC, SCLC and large cell neuroendocrine histology in 1/11 (9%) of each type. Patients received a mean of 1.7 (range, 1-5) prior lines of therapy with 82% receiving a prior platinum agent. Common Grade 3/4 hematologic adverse events (AEs) among all patients were leukopenia (27%), thrombocytopenia (27%), anemia (18%) and neutropenia (18%). All AEs/DLTs were manageable and resolved. Of the four lung cancer patients treated at the MTD (135 mg/m[2]), the mean number of cycles received was 6 (range, 2-17). The total cumulative doses were 120-2340 mg/m[2]. Of ten patients evaluable, partial response was observed in 2/10 and stable disease in 7/10. Tumor shrinkage was observed in 6/10.

Conclusion:
The nanoparticle formulation allowed greater cisplatin equivalent doses with no clinically significant neuro-, oto- or nephrotoxicity allowing patients to receive treatment for a longer duration. Activity was observed in heavily pretreated platinum exposed lung cancer patients with a majority of patients exhibiting tumor regression or stable disease. NC-6004 with gemcitabine demonstrated promising activity and tolerability in heavily pretreated lung cancer patients in this trial and warrants further investigation.

Background:
Human epidermal growth fator2 (HER-2) is a driver gene in non-small cell lung cancer (NSCLC), however, the effect of chemotherapy in patients with HER-2 mutation has not been studied.

Method:
HER-2 mutation was detected in 1041 EGFR/ALK/ROS1/KRAS/BRAF wild type NSCLC patient samples in Shanghai Pulmonary Hospital using ARMS method, and the mutation positive samples were confirmed by DNA sequencing. The clinicopathologic features and prognosis of the HER-2 mutation patients were analyzed.

Result:
63 samples (6.1%) were HER-2 mutation positive, and 53 samples (84.1%) were confirmed by DNA sequencing. 5(7.9%) were point mutation and 58(92.1%) were insertion mutations with 33 (52.4%) A775_G776insYVMA. Patients with A775_G776insYVMA mutation had no association with other mutations in sex, age, smoking status, and pathological types, as well as in objective response rate (ORR, 40.0% vs 28.6%, p=1.000) and progression-free survival (PFS, p=0.069). Patients with six gene wild type were matched with the 63 HER-2 mutation patients in clinicopathologic features. We found that there was no significant difference between HER-2 mutation and wild type patients in ORR (30.4% vs 29.3%, p=0.157) and PFS (7.0month vs 4.5month, p=0.086), although the PFS was longer in HER-2 mutation patients.

Conclusion:
HER-2 mutation was 6.1% in EGFR/ALK/ROS1/KRAS/BRAF wild type NSCLC patients. There was no significant difference between HER-2 mutation and wild type patients in ORR and PFS treated with first-line chemotherapy. Target therapy maybe needed to treat these patients.

Background:
Chemotherapy plays an important role in the treatment of lung cancer in the world as well as in China. Studies showed that chemotherapeutic drugs may change the interactions of cancer cells and TME. A number of international studies have changed the treatment paradigm of advanced lung cancer. Since we already entered into a new era of immunotherapy, positive reactions of immunotherapy usually related to the changes of TME. This retrospective study was designed to evaluate relationship between immune-related cytokines in TME and chemotherapy in advanced lung cancer.

Method:
A total of 728 patients with advanced lung carcinoma diagnosed and treated in Shanghai pulmonary hospital from June 2010 to June 2015 were included. IL-1, IL-2R, IL-5, IL-6, IFN-γ,TNF and different cut off values of the 6 cytokines (25%, 50%, 75%, 90%, median level) as well as proportion and ratio of CD4+T lymphocytes and CD8+T lymphocytes were analyzed by Flow Cytometry before and after chemotherapy.

Result:
Median age at diagnosis was 61 (19-83 years), and median OS was 435 days. Our results suggested that IFN-γ(cut off value 25%) had significant correlation with OS after first-line chemotherapy (OS:below25% vs above25% 406 vs 463 days, log-rank p=0.049). Other factors ,such as IL-1, IL-2R, IL-5, IL-6, TNF, did not showed statistically significant with the chemotherapy and PFS or OS (log-rank p>0.05 for all).

Conclusion:
IFN-γ is a predictive and prognostic factor of advanced NSCLC independent of chemotherapy. The results of our study may be expected to serve as useful information of influence by chemotherapy on TME and may indicate treatment sequence in the near future.

Background:
This multicenter, single-arm, open-label, phase 2 study assessed the efficacy and safety of carboplatin plus weekly nanoparticle albumin-bound paclitaxel in elderly patients with previously untreated advanced squamous non-small-cell lung cancer, selected based on the Mini Nutritional Assessment short-form scores (MNA-SF).

Method:
Patients received carboplatin (area under the curve: 6) on Day 1, and nanoparticle albumin-bound paclitaxel (100 mg/m[2]) on Days 1, 8, and 15, every 28 days for ≤4 cycles. Eligibility criteria included an MNA-SF score of ≥8 points. The primary endpoint was the objective response rate.

Result:
Thirty patients with a median age of 76 (range, 70–83) years were enrolled. The objective response rate was 50.0% (95% confidence interval: 31.3–68.7%), which met the primary objective of this study. The disease control rate was 73.3% (95% confidence interval: 54.1–87.7%). At a median follow-up of 15.0 months, the median progression-free and overall survival was 7.1 and 19.1 months, respectively. The most common treatment-related adverse event of Grade ≥3 was neutropenia (66.7%). Non-hematological adverse events of Grade ≥3 were minor. Well-nourished patients, based on the MNA-SF, experienced fewer adverse events of Grade ≥3 compared to patients at risk of malnutrition. All treatment-related adverse events were tolerable and reversible. There were no treatment-related deaths.

Conclusion:
Carboplatin plus weekly nanoparticle albumin-bound paclitaxel is effective and well tolerated as a first-line treatment for elderly patients with advanced squamous non-small-cell lung cancer. Eligibility based on MNA-SF screening may be useful in determining acceptable toxicity.

Background:
The capacity of microRNAs to post-transcriptionally regulate a myriad of genes has extended their remit into the realm of stemness and furthermore cancer stemness regulation. Disruption of Dicer-1, a crucial component of microRNA biogenesis, has been shown to completely deplete the stem cell pool in early development, indicating a potential role for microRNAs in the maintenance of stem cells. Such logic has led microRNAs to be investigated in the context of cancer stem cells (CSCs). Studies have revealed that microRNAs play a role in CSC self-renewal, differentiation, drug resistance and metastasis. With this, our hypothesis suggests that microRNAs associated with cisplatin resistance and CSC maintenance may be a key target by which the CSC root of cisplatin resistance could be overcome.

Method:
MicroRNA expression within a panel of age-matched parent (PT) and cisplatin resistant (CisR) NSCLC sublines was profiled using the 7[th] generation miRCURY LNA arrays (Exiqon) and validated by qPCR. Cell lines were stained for the presence of the CSC marker, aldehyde dehydrogenase 1 (ALDH1) and FACS was used to isolate the ALDH1-positive CSC population from the ALDH1-negative bulk cell population. Expression of the panel of cisplatin resistance-associated microRNAs was investigated within the ALDH1-positive CSC population relative to their negative counterparts by qPCR. Significantly altered miRNAs were inhibited in the CisR subline using antagomirs (Exiqon) and the presence of the ALDH1-positive subset reassessed by flow cytometry and expression of stemness genes (Nanog, Oct-4, Sox-2, Klf4, cMyc) determined. The presence of the cisplatin-associated miRNAs was investigated in FFPE murine tumours within a xenograft model of CSCs, in which 1x10[3] ALDH1-positive and negative subsets were injected into NOD/SCID mice.

Result:
Upon validation, a 5-miR signature was identified across NSCLC histologies to be associated with cisplatin resistance. When this panel was further investigated within the ALDH1-positive CSC subpopulation, it was observed that there was a significant up-regulation of miR-34a-5p relative to corresponding ALDH1-negative populations. Interestingly, the ALDH1-positive subpopulations showed significantly greater miR-34a-5p expression when compared to the CisR sublines from which they were isolated. This up-regulation was also observed within the FFPE xenograft tumours. However, inhibition of miR-34a-5p with antagomiRs did not significantly alter the presence of the ALDH1-positive CSC population, or the expression of stemness-associated genes.

Conclusion:
These data suggest that miR-34a-5p while significantly up-regulated in cisplatin resistance and CSCs may not play a functional role in CSC maintenance and further investigation is required to fully elucidate the role of miR-34a-5p in cancer stemness.

Background:
The combination of platinum plus third-generation cytotoxic drugs has been the gold standard first-line chemotherapy for patients with advanced NSCLC. However, most patients experience disease progression during or after first-line treatment. The survival benefit of S-1 monotherapy as second-line therapy is not satisfactory. Bevacizumab conferred a survival benefit when combined with carboplatin and paclitaxel as first-line treatment in non-squamous NSCLC. The benefit of adding bevacizumab to non-platinum cytotoxic monotherapy such as S-1 is not clear as subsequent treatment. Therefore, we conducted a multi-center, a single-arm phase II study to evaluate the safety and efficacy of combination therapy of tailored-dose S-1 plus bevacizumab in patients with recurrent non-squamous NSCLC.

Method:
This was a prospective, multi-center, single-arm phase II study. Patients with non-squamous NSCLC who had experienced progression after cytotoxic chemotherapy were enrolled. Oral S-1 was administered on days 1–14 of a 21-day cycle, and bevacizumab (15 mg/kg) was given intravenously on day 1. Patients received S-1 adjusted on the basis of their creatinine clearance and body surface area. The primary endpoint was response rate (RR); secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety.

Result:
We enrolled 30 patients. One patient had never received platinum-based therapy. Five patients had activating mutations of the epidermal growth factor receptor gene, of whom four had received tyrosine kinase inhibitors before this study. The RR was 6.7% (95% confidence interval (CI) 1.8–21.3%), and the disease control rate (DCR) was 80% (95% CI 62.7–90.5%). Median PFS was 4.8 months (95% CI 2.7–6.4 months], and median OS was 13.8 months (95% CI 8.4 months – not applicable). Patients did not experience any Grade 4 toxicity or treatment-related death. Grade 3 hematologic toxicity (anemia) occurred in one patient (3.3%). The main Grade 3 non-hematologic toxicities were anorexia (10%), infection (10%), and diarrhea (6.7%).

Conclusion:
The addition of bevacizumab to S-1 was tolerable, but not beneficial for patients with previously treated non-squamous NSCLC. We do not recommend further study of this regimen.

Background:
Ramucirumab is a human IgG1 monoclonal antibody antagonist of VEGFR-2 approved as a post-platinum progression therapy in non-small cell lung cancer (NSCLC). Chemotherapy-induced neutropenia is a major risk during cancer treatment and can be potentially dose-limiting, as well as play a significant role in infection-related morbidity and mortality. In the REVEL phase 3 global, placebo-controlled study of Stage IV NSCLC patients (NCT01168973), ramucirumab plus docetaxel treatment improved patient survival versus docetaxel monotherapy independent of histology; however, all grade and high-grade (Grade ≥3) neutropenia was numerically increased with ramucirumab versus placebo (Table 1). A post-hoc analysis was performed on the REVEL data to characterize neutropenia: clinical consequences, quality of life (QoL), and clinical management.

Method:
The duration of neutropenia, as well as the course and incidence of complications and their severity and related consequences associated with neutropenia were summarized. Time to deterioration in ECOG performance status (PS) was analyzed using Kaplan-Meier method, and stratified hazard ratios and 95% confidence intervals (CI, Wald) were estimated for average symptom burden index and lung cancer symptom scale items using Cox model. Clinical management summary data will be presented at the meeting.

Result:
Neutropenia events from the REVEL trial are summarized in terms of duration, course, incidence of complications, severity and resolution status in Table 1. All-grade neutropenia risk ratio is 1.197 (95% CI 1.072, 1.338) and Grade ≥3 is 1.226 (95% CI 1.081, 1.390). Figure 1



Conclusion:
Despite numerically increased rates of neutropenia observed in the ramucirumab plus docetaxel arm of the REVEL trial, the clinical consequences (resolution) of neutropenia, rate of hospitalization, and duration/incidence of Grade ≥3 infection were similar to placebo. In addition, the quality of life results do not indicate any significant differences between placebo and ramucirumab. Therefore, neutropenia in the NSCLC population is considered to be manageable during ramucirumab treatment.

Background:
The increasing prevalence of cancer cases worldwide and shortcomings of existing treatment methods including chemotherapy, radiation therapy, surgery and transplantation call for the immediate development of novel cancer therapies. Due to the non-specificity of current therapies, recognition between cancer cells and normal cells is a challenging dilemma in cancer therapeutics. Bacterial-mediated cancer therapy is a novel alternative treatment currently under intensive study. However, the exact mechanism of tumor degradation in bacterial-mediated cancer therapy is not fully understood and remains a challenging question for cancer therapeutics.

Method:
To characterize the mechanism of bacterial chemotactic preference towards cancer cells, we developed a novel microfluidic device for in vitro applications. The device, when used as model for lung cancer, provides simultaneous three-dimensional co-culture of multiple cell lines in separate culturing chambers and establishes constant concentration gradients of biochemical compounds in a central channel by diffusion through micro-channels. The quantification of preferential accumulation of bacteria towards a particular cell type was determined against established chemotactic gradient. Bacterial taxis behavior towards cancer and normal cells was measured in the two-chamber system using the fluorescence intensity of green fluorescence protein (GFP)-encoding bacteria. Furthermore, secretome and bioinformatic analysis of the cancer cells determined significant factors in bacterial cancer targeting. Figure 1



Result:
Using the microfluidic platform, E. coli clearly illustrated the preference for lung cancer cells (NCI-H460) which was attributed to biochemical factors secreted by carcinoma cells. Furthermore, secretome and bioinformatic analysis of the cancer cells determined CLU, SRGN and TGFβ2 as significant factors in bacterial cancer targeting. By validation test, clusterin (CLU) was found as a key chemo attractants for E. coli to target lung cancer.

Conclusion:
CLU, which released by lung cancer cells, was found as a key regulator for the chemotaxis of E. coli in targeting lung cancer.

Background:
Not all advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) activating mutations could get benefit from 1[st] line treatment of EGFR tyrosine kinase inhibitors (TKIs). Our previous study indicated that B-cell chronic lymphocytic leukemia/lymphoma-like 11 (Bim) deletion polymorphism was about 10% and was significantly associated with a poor clinical response to EGFR-TKIs in EGFR mutation-positive NSCLC. This retrospective study compared efficacy and tolerability of the EGFR-TKI alone versus EGFR-TKI plus chemotherapy as the 1[st] line treatment in advanced NSCLC patients with both activated EGFR mutation and Bim polymorphism.

Method:
Main included criterias were patients older than 18 years, histologically confirmed stage IIIB or IV NSCLC, EGFR mutation-positive (exon 19 deletion or 21 L858R mutation) and Bim polymorphism. Patients received gefitinib 250mg orally a day or gefitinib together with up to 4 cycles of pemetrexed/gemcitabine and platinum until disease progression or unacceptable toxic effects. The primary endpoint was progression-free survival (PFS); the second endpoint included objective response rate (ORR), overall survival (OS) and toxicity.

Result:
From June 2014 to September 2016, 65 patients were enrolled into this trial. 36 of them received gefitinib, and 29 received gefitinib plus pemetrexed/gemcitabine and platinum. Median PFS was significantly longer in EGFR-TKI plus chemotherapy-treated patients than in EGFR-TKI (7.2 [95% CI 5.35-9.05] vs 4.6 [4.01-5.19] months; p=0.008). The ORR was significantly lower in EGFR-TKI than in EGFR-TKI plus chemotherapy-treated patients (38.9% vs. 65.5% p=0.046). EGFR-TKI plus chemotherapy was associated with more grade 3 or 4 hematological toxic effects than EGFR-TKI (8 neutropenia, 4 thrombocytopenia vs. no any event). Figure 1



Conclusion:
Compared with EGFR-TKI, EGFR-TKI plus chemotherapy conferred a significant higher ORR and longer PFS in advanced NSCLC patients with both activated EGFR mutation and Bim polymorphism. An open-label, multicenter, randomized, phase 2 study is ongoing to validate these results in our institute ( NCT03002844).

Background:
Previous studies have shown EGFR TKIs provided superior 1[st] line efficacy to chemotherapy for advanced non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutation. LUX-Lung7, a phase IIB randomized head-to-head study, showed afatinib significantly improved PFS, TTF, and ORR compared with gefitinib. However, it is still unclear how to choose among these three EGFR TKIs in clinical setting, especially for uncommon mutation, which was excluded in most studies. This retrospective study is aimed to evaluate the treatment pattern in our hospital and efficacy of three EGFR TKI for patients with common mutations and uncommon mutations.

Method:
Patients with advanced NSCLC were retrospectively reviewed in a university hospital in central Taiwan from Jan 2013 to Mar 2017. In this population, patients with EGFR mutations and have to be taking EGFR TKIs as 1[st] line treatment more than 30 days were recorded for analysis.

Result:
1,951 patients with advanced lung cancer were reviewed. About 75% of lung cancer were adenocarcinomas and 55% were EGFR mutation rate. Clinical data of 467 patients with advanced EGFR mutation lung adenocarcinomas were extracted, 95.7% of them used EGFR TKI as 1[st] line therapy including gefitinib (n=210), erlotinib (n=147), and afatinib (n=110). The median age was 64 years old. More female was included in the gefitinib cohort and afatinib cohort tended to have higher component of uncommon mutations. The TTF among gefitinib (G), erlotinib (E) and afatinib (A) were 9.8 vs 11.4 vs 12.2 months (p = 0.094). Patients treated with afatinib had improved TTF compared with gefitinib (HR= 0.72, 95% CI: 0.54-0.97, p = 0.035) and showed a trend compared with erlotinib without significantly difference. In del 19, TTF among G, E and A were 9.4 vs 12.0 vs 12.2 months ( p = 0.074). In L858R, TTF among G, E and A were 10.4 vs 10.9 vs 11.7 months ( p = 0.721). Intriguingly, afatinib showed excellent TTF in uncommon mutations (median TTF G vs E vs A: 7.5 vs 7.0 vs 19.7 months, p = 0.506). Afatinib dose reduction didn’t have impact TTF (median TTF 30 mg vs 40 mg: 16.1 vs 10.3 months. p = 0.923)

Conclusion:
Consistently, our findings supported improved efficacy as observed from LUX-Lung7. In more resistance mutation type such as uncommon mutation, afatinib tended to have better efficacies. Due to insufficient sample size and the retrospective study design, further confirmatory study is warranted.

Background:
Combination studies of a first- or second-generation EGFR tyrosine kinase inhibitor (TKI) and either a VEGF or EGFR-targeting monoclonal antibody have recently shown promising clinical results in EGFR-mutant non-small cell lung cancer (NSCLC) patients. The preliminary safety results from the phase 1 study JVDL (NCT02789345), combining third-generation EGFR TKI osimertinib (Osi) with human IgG1 monoclonal antibodies ramucirumab (Ram) or necitumumab (Neci), are reported.

Method:
Eligible pts naïve to third-generation EGFR TKI therapy with advanced EGFR T790M-positive NSCLC who progressed after initial EGFR TKI therapy were enrolled. In the dose-finding portion, following a dose de-escalation 3+3 design, patients received daily oral Osi (80 mg) and either 10 mg/kg intravenous (IV) Ram on day 1 (D1) every two weeks (Q2W), or 800 mg (IV) Neci on D1 and D8 Q3W. Primary objective of the study is to assess the safety and tolerability of Ram or Neci combined with Osi, and secondary objectives include preliminary evaluation of efficacy.

Result:
As of data cutoff on 09-May-2017, 7 pts were treated in the completed dose-finding portion: 3 pts with Ram+Osi (Arm A) and 4 pts (1 non-evaluable and replaced) with Neci+Osi (Arm B). No DLTs were observed in either arm, and the initial dose level became the recommended dose for expansion cohort. After the DLT observation period was complete, the only Grade ≥3 (Gr≥3) treatment-related adverse event (TRAE) was dermatitis acneiform (Arm B), with one unrelated Gr≥3 treatment-emergent AE (TEAE) of increased lipase (Arm B) and one serious AE of Gr2 diverticulitis (unrelated to study treatment) (Arm A). Expansion cohort A of Ram+Osi is fully enrolled with 22 pts. Safety data were available for 18 out of 22 cohort A patients. Gr≥3 TEAEs were reported in 4 patients, including dyspnea (unrelated [n=1]), decreased appetite (unrelated [n=1]), and hypertension (related [n=2]). Three patients reported serious adverse events (none related to study treatment): Gr3 dyspnea and Gr2 pyrexia, Gr2 dyspnea, and Gr2 urinary tract infection. No death was reported in patients in the dose-finding portion, and one death unrelated to study treatment was reported in the expansion cohort.

Conclusion:
No DLTs were observed and no unexpected safety signals were seen to date. The recommended dose for expansion cohort was the initial dose level of 10 mg/kg ramucirumab IV Q2W with oral 80 mg osimertinib. Additional safety and efficacy observation for the combination of Ram+Osi is ongoing, and will be presented at the meeting.

Background:
Osimertinib is a potent Epidermal Growth Factor Receptor (EGFR) inhibitor, conferring a longer survival if compared to platinum-pemetrexed chemotherapy in Non-Small Cell Lung Cancer (NSCLC) EGFR mutated patients who have progressed after first-line Tyrosine Kinase Inhibitor (TKI), with the aquired resistance mutation T790M. The ARPA study is a phase II, single institution observational study aiming to evaluate the tolerability of Osimertinib in a real world population of EGFR-T790M+ NSCLC patients, with special attention to patients' perception of symptomatic Adverse Events (AEs), their impact on health-related quality of life (HRQoL) and psychological issues.

Method:
Before entry into the study, patients have been requested to perform a new tissue or liquid biopsy to confirm the T790M+ status of their tumours. Multiple previous oncologic treatments and asymptomatic brain metastases at baseline were allowed. Patients' perception of symptomatic AEs and the matched medical evaluation were performed every 21 days under continuous treatment with dedicated questionnaires which mainly evaluated the HRQoL, until discontinuation. The psychological assessments include changes in domains related to physical, mental, emotional and social functioning, depression, sleep quality and distress. In case of documented clinical benefit, the study allows to patients to remain on treatment beyond progression.

Result:
From February 2016, a total of 34 patients have been evaluated: 2 of them were registered as screening failures for symptomatic brain metastases and lack of compliance, respectively. The 32 patients enrolled have a median age of 67,6 years (range 40-84 years), are predominantly female (65,6%), with ECOG performance status 0 (68,7%) and a non-smoking history (75,0%). Activating EGFR mutation at diagnosis have been described on exon 19 and 21 in 62,5% and 28,1% of cases, respectively. Only four patients had brain metastases at study entry. Osimertinib has been used as second-line treatment, after failure of first-line TKI, in 78,1% of cases. On the date of 1 June 2017, ten patients have interrupted the treatment for disease progression, with a median duration of therapy equal to 6,69 months (range 2,80-11,20 months).

Conclusion:
Data concerning the tolerability of treatment with Osimertinib in EGFR-T790M+ NSCLC patients, their perception of symptomatic AEs together with the psychological issues evaluated in the ARPA study, are not mature. Great expectations come from this study which reflects a real world population, and the hope of the investigators is to highlight the critical aspects for patients in order to better manage their treatment and the psychological issues.

Background:
There remain important knowledge gaps surrounding the optimal selection criteria of high-risk individuals for low-dose CT (LDCT) screening for lung cancer and the optimal management of screening-detected pulmonary nodules. The International Lung Screen Trial (ILST) is an international, multi-centre prospective cohort study with recruitment sites in Canada and Australia. The rationale and design for the study are presented here. The PLCO~m2012~ risk prediction model[1] may have higher sensitivity and positive predictive value in identifying individuals who develop lung cancer compared to the United States Preventive Services Task Force (USPSTF) criteria. The PanCan model[2] calculates malignancy probability in screen-detected nodules and provides a risk-based approach to managing pulmonary nodules. Both models will be prospectively tested in this study. Primary aims: (a) to define the optimal selection criteria for LDCT screening, (b) to evaluate pulmonary nodule management using the PanCan nodule risk calculator.

Method:
We aim to recruit 4,000 high-risk individuals with 5 years follow up. Eligible participants are current or former smokers, aged 55-80 years, with a PLCO~m2012~ lung cancer risk of ≥1.51% over 6 years or USPSTF criteria (age as above, plus ≥30 pack year history of smoking and smoking cessation <15 years ago). Exclusion criteria include: symptoms suspicious of lung cancer, severe co-morbidity, previous lung cancer and chest CT within the last 2 years. Baseline assessment includes interview, smoking status assessment and pulmonary function testing. Eligible individuals are offered a baseline screening LDCT and subsequent interval surveillance LDCTs dependent on the PanCan risk score. Participants with no nodules or nodule risk score of <1.5% will have biennial LDCT screening. Participants with nodule malignancy risk score ≥10%, or significant growth in subsequent scan will be considered suspicious for lung cancer and undergo clinical review for further investigation. The primary outcome is the proportion of lung cancers detected by either selection criteria. Secondary outcomes include: number needed to screen, cancer detection rate, lung cancer mortality, cancer stage distribution, resection rate, number of interval cancers, recall rate, invasive procedure rate, benign biopsy/surgery rate, screening-related adverse events and comprehensive healthcare economic evaluation.

Result:
This study is currently in its recruitment phase. Results will be reported in future conferences and peer-reviewed publications.

Conclusion:
The ILST trial will provide a clearer understanding on the optimum selection criteria for LDCT screening for lung cancer and prospective validation of the PanCan model. ClinicalTrials.gov number: NCT02871856 References: Tammemägi MC et al (2013). NEJM; 368:728-736. McWilliams A et al (2013). NEJM; 369:910-919.

Background:
Inhibition of the PD-1/PD-L1 axis with nivolumab has been a successful treatment strategy in a minority of patients with many different tumor histologies (non-small cell lung cancer, squamous cell head and neck cancer, melanoma, Hodgkin lymphoma, renal cell carcinoma, urothelial carcinoma). An increase in the proportion of patients that benefit from this emerging mechanism is needed. Veliparib is an inhibitor of poly (ADP-ribose) polymerase (PARP), and it has been shown in preclinical models and in patients with BRCA mutant ovarian cancer to exert anti-tumor effects through lethal exacerbation of DNA repair defects. Extensive genomic sequencing of tumors of varying histologies has revealed that approximately 5% of all tumors harbor defects in DNA repair genes such as BRCA1/2, RAD51, CHEK1, ATM, ATR, CHEK2, FANCD2, FANCA. We propose combining PD-1 inhibition with nivolumab with PARP inhibition with veliparib in patients with DNA repair gene defects in order to maximize the proportion of patients with clinical responses to these novel treatment strategies.

Method:
We are currently enrolling patients on this phase I/Ib clinical trial at the Northwestern Medicine Developmental Therapeutics Institute. The study schema is shown below. Figure 1



Result:
Section not applicable

Conclusion:
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Background:
Inhibition of the PD-1/PD-L1 axis with nivolumab has been proven to be a successful treatment strategy in a minority of patients with non-small cell lung cancer. An increase in the proportion of patients that benefit from this emerging mechanism is needed, and many novel combination therapies are being tested. Furthermore, many patients with non-small cell lung cancer are excluded from further clinical trials if they have received prior checkpoint inhibitor therapy, so this trial provides for this additional unmet need. Epidemiologic studies have consistently demonstrated an association between decreased cancer incidence and mortality in patient treated with metformin. Preclinical models have demonstrated that this anti-cancer effect is potentially mediated by inhibition of insulin like growth factor-1 (IGF-1) and mTOR, as well as activation of AMPK and tuberous sclerosis complex (TSC1, TSC2). Also, metformin has recently been found to exert immunomodulatory functions, inhibiting the exhaustion of CD8+ tumor infiltrating lymphocyte (TIL) function, thereby upregulating tumor-specific immune function. It accomplishes this by preventing apoptosis of CD8+ TILs and converting CD8+ TILs from quiescient central memory T cells to effector memory T cells with active anti-tumor effects. In vivo, the addition of metformin to vaccination enhances the generation of effector memory T cells, congruent with the overall hypothesis. We propose a proof-of-concept parallel phase 2 trial using the combination regimen of nivolumab and metformin. We hypothesize that the combination of nivolumab and metformin will be synergistic and can overcome resistance to single agent PD-1/PD-L1 inhibitors.

Method:
We are currently enrolling patients in this phase II clinical trial at the Northwestern Medicine Developmental Therapeutics Institute. Figure 1



Result:
Section not applicable

Conclusion:
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Background:
Small cell lung cancer (SCLC) represents ~15% of lung cancers. Patients (pts) are staged with limited or extensive stage disease (ES). ES standard therapy consists of a platinum-based therapy + a second agent (etoposide). Initial response rates are high but not durable. Treatment for relapsed pts is limited, but includes topotecan. However, efficacy of topotecan is suboptimal and there is a high unmet need in this population. Delta-like protein 3 (DLL3) is an atypical Notch receptor family ligand identified as a target in SCLC and neuroendocrine carcinomas (NECs). DLL3 is highly expressed in SCLC and NECs but not normal tissue. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate composed of a DLL3-targeting IgG1 monoclonal antibody tethered to a toxic DNA crosslinker. Rova-T has antitumor activity in relapsed ES SCLC pts, and was well-tolerated[1]. Thus, we are investigating Rova-T vs topotecan as a 2[nd] line therapy in advanced SCLC.

Method:
This is a Phase 3, randomized, open-label, multicenter study (NCT03061812) to assess efficacy, safety, and tolerability of Rova-T vs topotecan. Approximately 411 pts will be enrolled and randomized 2:1 between 2 arms. Arm A regimen: 0.3 mg/kg Rova-T intravenous (IV) on Day 1 + 8 mg dexamethasone orally, twice daily on Day -1, 1 and 2 of a 42-day cycle; administered for 2 cycles with up to 2 additional cycles permitted. Arm B: 1.5 mg/m[2] topotecan (or per local label) IV on Days 1-5 of each 21-day cycle; administered until disease progression. Pt eligibility: ≥ 18 years; confirmed, advanced/metastatic SCLC with first disease progression following frontline standard therapy; DLL3-high tumor expression; ECOG 0-1; no prior exposure to a pyrrolobenzodiazepine-based drug or topotecan, irinotecan, or other topoisomerase I inhibitor. Primary objectives: to determine if Rova-T improves objective response rate and overall survival vs topotecan. Secondary objectives: to assess if Rova-T improves progression-free survival vs topotecan; to compare duration of objective response between arms; and to assess effect on patient-reported outcomes. 1. Rudin et al., Lancet Oncol, 2016.

Result:
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Conclusion:
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Background:
SCLC embodies 15-20% of lung cancers. Patients (pts) are staged with either limited or extensive disease; the standard front-line treatment for the latter is chemotherapy with carbo- or cisplatin combined with etoposide or irinotecan. Response rates are high with limited duration. Recurrence may be attributable to chemo-resistant tumor initiating cells (TICs). Delta-like protein 3 (DLL3) is an inhibitory Notch receptor ligand identified as a novel target in SCLC TICs. DLL3 is highly expressed in SCLC but not normal tissue. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate composed of a DLL3-targeting IgG1 monoclonal antibody tethered to a DNA cross-linking toxin. Rova-T has shown activity in recurrent/relapsed ED SCLC patients[1]. Given DLL3 expression in TICs, exploration of Rova-T front-line maintenance strategies in ED SCLC is warranted. The postulated mechanism of action of Rova-T and its clinical activity indicate potential to improve progression-free and overall survival in this setting.

Method:
This is a Phase 3, randomized, double-blind, placebo-controlled, international study (NCT03033511, no pts enrolled yet as of 7 February 2017). Approximately 740 ED SCLC pts will be enrolled to include ~480 pts with high DLL3 expression. Eligibility: pts ≥ 18 years; histologically or cytologically confirmed ED SCLC with ongoing clinical benefit (complete/partial response or stable disease) after 4 cycles of 1[st] line platinum-based therapy; definitively treated CNS metastases allowed; > 3 but ≤ 9 wks between the administration of the last cycle of platinum-based chemotherapy and randomization; available tumor tissue for DLL3 expression testing; ECOG performance score 0-1. Pts will be randomly assigned 1:1 to receive 0.3 mg/kg Rova-T or placebo on Day 1 of each 6-wk cycle, omitting every 3[rd] cycle. Primary objectives: determine if Rova-T improves progression-free and overall survival. Secondary objectives: assess Rova-T antitumor activity by determining objective response rate, clinical benefit rate, duration of response, and changes in pt reported outcomes. 1. Rudin et al., Lancet Oncol, 2016.

Result:
Section not applicable

Conclusion:
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Background:
Immunotherapy is an important new treatment modality for NSCLC. Dual blockade of the non-redundant PD-1/PD-L1 and CTLA-4 pathways may provide additive or synergistic effects. Durvalumab is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab is a selective human IgG2 mAb against CTLA-4. A combination regimen of immunotherapy with chemotherapy may further enhance clinical benefit. In a Phase 1b study (NCT02537418), durvalumab ± tremelimumab combined with chemotherapy demonstrated manageable tolerability and preliminary signs of clinical activity in patients with solid tumors, including NSCLC.

Method:
POSEIDON (NCT03164616) is a Phase 3, randomized, multicenter, open-label, global study to investigate durvalumab ± tremelimumab + platinum-based chemotherapy vs platinum-based chemotherapy alone as first-line treatment in metastatic NSCLC. Patients must be immunotherapy- and chemotherapy-naïve with EGFR/ALK wild-type metastatic NSCLC, and have confirmed tumor PD-L1 expression status, and a WHO/ECOG performance status of 0/1. Approximately 801 patients will be randomized 1:1:1 to receive durvalumab + tremelimumab + chemotherapy (Arm 1); durvalumab + chemotherapy (Arm 2); or chemotherapy alone (Arm 3). After induction, patients in the immunotherapy arms will receive durvalumab monotherapy, and non-squamous patients who initially received pemetrexed during induction will receive it as maintenance therapy if eligible. Treatment will continue until disease progression or another discontinuation criterion has been met. The primary endpoint is PFS according to blinded independent central review (RECIST v1.1). Secondary endpoints include OS; ORR; duration of response; best overall response; proportion of patients alive and progression-free at 12 months; disease-related symptoms and HRQoL; and safety and tolerability. Recruitment is ongoing.Figure 1



Result:
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Conclusion:
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Background:
Thioredoxin reductase plays a critical role in cell metabolism. According to our previous study, The expression of TrxR1 was significantly higher in serum of tumor patients than in heathy volunteers and approximately 50% of non-small cell lung cancer patients harbored high thioredoxin reductase expression. EGFR and ALK negative patients with high expression of TrxR1 responded poorer to chemotherapy. Ethaselen, a potent mammalian thioredoxin reductase 1 inhibitor was applied to address the heavy treated EGFR and ALK negative NSCLC with high thioredoxin reductase expression.

Method:
We plan to recruit 40 EGFR wild type and ALK negative metastatic non small cell lung cancer patients who have received at least 2 lines of standard therapy, performance status as 0-2 and with high TrxR1 IHC expression. It is a single arm project and all patients receive the treatment of BBSKE 1200mg PO QD until disease progression according the Response Evaluation Criteria in Solid Tumor 1.1(RECIST 1.1) or intolerable toxicity or withdraw from the study. The primary endpoint is 8 weeks Disease Control Rate and the anticipated rate is over 20%. Test of TrxR1 Serum activity is mandatory and performed by a central laboratory at the Medical Center of Casis. There will be several times of dynamic testing, from baseline to parallelly go along with each RECIST Evaluation, so as to draw some correlation between the change of TrxR1 expression and imaging. This program has been registered at clinicaltrials.gov and the number is NCT02166242.

Result:
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Conclusion:
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Background:
Programmed death-1 (PD-1) is an immune checkpoint receptor that attenuates T-cell activation by binding to its ligands, PD-L1 and PD-L2, which are expressed on tumor cells. Nivolumab, an anti–PD-1 antibody, showed durable antitumor activity and a favorable safety profile compared with docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC) in 2 global phase 3 studies (CheckMate 017 and CheckMate 057). Data from these trials led to the approval of weight-based nivolumab 3 mg/kg administered as a 60-minute infusion every 2 weeks (Q2W) in previously treated patients with NSCLC. Data from exposure-response simulations indicated that flat-dose nivolumab 240 mg Q2W has comparable pharmacokinetic, safety, and efficacy profiles to the weight-based dose, and data from CheckMate 153 demonstrated that nivolumab 3 mg/kg can be safely infused over 30 minutes. CheckMate 078 is an ongoing phase 3 registrational trial evaluating second-line nivolumab 3 mg/kg as 60-minute infusions Q2W versus docetaxel in patients with advanced NSCLC in a predominantly Chinese population. CheckMate 078 excludes patients with hepatitis B virus (HBV) infection, which represent a clinically relevant subgroup of patients in Asia; approximately 15% of patients with lung cancer in China are seropositive for HBV surface antigens. CheckMate 870 is an open-label, single-arm phase 3b study evaluating the safety and tolerability of flat-dose nivolumab 240 mg infused over 30 minutes Q2W in Asian patients with advanced or metastatic NSCLC, with or without HBV infection.

Method:
Approximately 400 patients in Asia with advanced or metastatic NSCLC and disease progression during or after 1 prior systemic platinum-based therapy will be enrolled; those with EGFR mutations (maximum of 40 patients) or ALK translocations should have received 2 prior systemic treatments including a tyrosine kinase inhibitor and chemotherapy. Nivolumab will be administered 240 mg over 30 minutes Q2W until disease progression or unacceptable toxicity, for a maximum of 24 months. Nivolumab may be reinitiated for subsequent disease progression and administered for up to 1 additional year. The primary objective is to evaluate the safety and tolerability of nivolumab in non–HBV-infected patients with NSCLC. The secondary objective is to assess safety and tolerability in all patients and in HBV-infected patients. Exploratory objectives include efficacy, patient-reported outcomes, health care resource utilization and direct medical costs, biomarker characterization in all patients, and viral load change and HBV reactivation rate in HBV-infected patients.

Result:
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Conclusion:
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Background:
Worldwide it is estimated that 20%-30% of advanced NSCLC patients do not receive a complete molecular diagnosis at baseline and are ineligible for targeted therapies due to tissue biopsy limitations. Blood-based, multiplex testing that analyzes circulating tumor DNA (ctDNA) by targeted next-generation sequencing offers a minimally invasive testing method, but clinical utility has yet to be established. High tumor mutational burden (TMB) measured in tissue is associated with atezolizumab (anti–PD-L1) clinical activity in several tumor types, including NSCLC. Alectinib, a potent, selective ALK/RET kinase inhibitor, has shown activity in 1L and is approved as 2L therapy in patients with ALK- or RET-positive advanced NSCLC but requires tissue for analysis. Here we present an umbrella trial that aims to clinically validate novel blood-based diagnostic assays that measure TMB in the blood (bTMB) and somatic mutations (e.g., ALK/RET), and to determine the efficacy and safety of 1L atezolizumab or alectinib in biomarker-selected NSCLC patients.

Method:
BFAST is a Phase II/III global, multicenter, open-label, multi-cohort screening and interventional umbrella trial designed to evaluate the safety and efficacy of targeted therapies in patients with unresectable, advanced or metastatic NSCLC selected based on the presence of oncogenic somatic mutations or a positive bTMB score. Key eligibility criteria include previously untreated, stage IIIB-IVB NSCLC of any histology and measurable disease per RECIST v1.1. Pre-enrollment blood-based screening will identify patients whose tumors harbor oncogenic somatic mutations (ALK/RET) or a positive bTMB score (above a pre-specified cutoff); patients will be assigned to the appropriate cohort based on the screening results. Study treatment will continue until disease progression (all cohorts) or loss of clinical benefit (atezolizumab only) (Table). The modular trial design allows for additional biomarker-driven BFAST cohorts with distinct screening and treatment requirements, and endpoints such as ORR with highly active drugs.

Table. BFAST Study Details
Cohort	Treatment	Planned Enrollment, n	Primary Endpoints	Key Secondary Endpoints
Cohort AALK+	Alectinib 600 mg PO bid	78	ORR per RECIST v1.1 (INV-assessed)	DOR, CBR[c] and PFS per RECIST v1.1 (INV-assessed) ORR, DOR, CBR and PFS per RECIST v1.1 (IRF-assessed) OS
Cohort B RET+	Alectinib 900 and 1200 mg dose escalation	52-62	ORR per RECIST v1.1 (INV-assessed)	DOR, CBR and PFS per RECIST v1.1 (INV-assessed) ORR, DOR, CBR and PFS per RECIST v1.1 (IRF-assessed) OS
Cohort C bTMB+	Atezolizumab 1200 mg IV q3w or platinum-based chemotherapy[a]	≈440 (R, 1:1)[b]	PFS per RECIST v1.1 (INV-assessed)	OS PFS, ORR and DOR per RECIST v1.1 (IRF-assessed) ORR and DOR per RECIST v1.1 (INV-assessed) 6- and 12-month PFS rates
[a ]Cisplatin or carboplatin + pemetrexed for non-squamous histology, and cisplatin or carboplatin + gemcitabine for squamous histology. Administered per standard of care. [b ]Stratification factors include tissue availability, ECOG performance status, bTMB level and tumor histology. [c ]CBR is defined as the rate of patients with confirmed CR or PR or stable disease that has been maintained for ≥ 24 weeks. bid, twice a day; bTMB, blood tumor mutational burden; CBR, clinical benefit rate; INV, investigator; IRF, independent review facility; IV, intravenously; PO, orally; q3w, every 3 weeks; R, randomized.

Result:
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Conclusion:
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Background:
Nivolumab (N) has demonstrated clinical benefit in advanced non-small cell lung cancer (NSCLC) patients (PTS) who have progressed to platinum-based chemotherapy: improved overall survival (OS) versus (Vs) docetaxel in squamous NSCLC (median OS of 9.2 months [mo} Vs 6 mo) and in non-squamous NSCLC (median OS of 12.2 mo Vs 9.4 mo). TRC105 is an antibody to endoglin, a receptor expressed on proliferating endothelial cells and myeloid derived suppressor cell (MDSCs). MDSCs also inhibit anti-cancer immunity, but by a mechanism of action that is distinct from that inhibited by N. TRC105 inhibits tumor growth in preclinical models and complements the activity of antibodies that target the programmed death receptor (PD-1). Its toxicity profile is distinct from that of N. By targeting MDSCs, TRC105 has the potential to complement N and improve clinical efficacy over that seen with single agent N.

Method:
This is a phase 1b,dose-finding (3+3 design) study of TRC105 in combination with standard dose (240mg) of N in pts with advanced NSCLC with disease progression to platinum-containig doublet chemotherapy.The primary objective is to evaluate safety and tolerability and determine a recommended phase 2 dose of TRC105 in combination with standard dose of N. Secondary objectives include: preliminary evidence of antitumor activity by assessing response rate and progression-free survival; characterize the pharmacokinetic profile of TRC105 when given in combination with N; and to explore biologic effects of TRC105 and N on circulating immune cells. Two dose levels of TRC105 are initially considered: Dose Level I: 8mg/kg intravenously (IV) weekly for 4 weeks → 15mg/kg every 2 weeks; Level II: 10mg/kg (iv) for 4 weeks → 15mg/kg every 2 weeks. N will be administered IV every 2 weeks in both cohorts of pts.Toxicity and efficacy assessments will be determine using NCI-CTCAE(V 4) and RECIST (V 1.1),respectively. The dose-limiting toxicity (DLT) evaluation period will be the first 4 weeks of the first cycle of treatment. It is anticipated that up to 18 pts will be enrolled in the study,and up to 12 pts at the maximum tolerated dose(MTD).. Main criteria for inclusion are: confirmed stage 4 NSCLC,prior platinum-based doublets,measurable disease,ECOG PS 0-1,PD-L1 expression >/ 1%,adequate organ function,and no prior therapy with an immuno check point inhibitor. Descriptive statistics will be used to summarize pt characteristics,safety/efficacy/pharmacokinetic parameters ,and immunologic biomarkers.

Result:
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Conclusion:
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Background:
Mesothelin is expressed in a wide variety of tumors, including mesothelioma, ovarian, pancreatic, gastric/GEJ, NSCLC, triple-negative breast cancer, cholangiocarcinoma, and thymic carcinomas. Anetumab ravtansine (BAY 94-9343), is a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DM4 and has shown encouraging anti-tumor activity in mesothelioma and ovarian cancer patients in a phase I study. We will therefore conduct a signal generating study with anetumab ravtansine in six additional high unmet medical need malignancies with mesothelin expression (NCT03102320).

Method:
Eligibility criteria include: ≥18 years, unresectable locally advanced or metastatic recurrent or relapsing disease, one or more prior lines of therapy, and availability of tumor tissue for mesothelin expression testing. Mesothelin-positive patients with selected adenocarcinomas (NSCLC, triple negative breast, gastric including gastroesophageal junction) and thymic carcinoma will receive anetumab ravtansine as monotherapy at 6.5 mg/kg IV on a 21-day cycle. Patients with cholangiocarcinoma will receive anetumab ravtansine in combination with cisplatin (25 mg/m2 IV day 1 and 8 on a 21-day cycle for up to 6 cycles) and patients with pancreatic adenocarcinoma will receive anetumab ravtansine in combination with gemcitabine (1000 mg/m2 IV day 1 and 8 on a 21-day cycle). A safety run-in phase (18-24 patients each) will be conducted for the combination regimens prior to enrolling patients in the main study phase. The primary objective of the main phase of the study is objective response rate (ORR) of anetumab ravtansine as monotherapy or combination therapy in patients with either of two mesothelin expression levels: high (≥30% positive tumor cells with moderate and stronger membrane staining intensity) and low-mid (≥5% all intensities and <30% positive tumor cells with moderate and stronger membrane staining intensity). Secondary objectives include safety, disease control rate, duration of response, durable response rate, and progression-free survival. Approximately 348 patients will be enrolled.

Result:
Section not applicable

Conclusion:
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Background:
Previous studies showed that inoperable stage I non small cell lung cancer (NSCLC) benefited from microwave ablation (MWA) alone. This prospective, randomized, control, single-center clinical trial aimed to determining the survival benefit of MWA plus recombinant human endostatin (endostar) compared with MWA alone.

Method:
Patients with untreated, inoperable, stage I NSCLC were recruited. They were divided into MWA/ endostar group and MWA group, the former received MWA in the primary tumor sites, followed by 2 to 4 cycles of endostar and the latter treated with MWA only. The primary endpoint was overall survival (OS), the second endpoint included disease-free survival (DFS) , and adverse events (AE).

Result:
A total of 183 patients were enrolled, involved 92 cases in the MWA/ endostar group and 91 cases in the MWA group. Up to the latest follow-up , there were 24 cases of disease progression and 6 deaths in the MWA/ endostar group, versus 49 cases of disease progression and 9 deaths in the MWA group. DFS in the MWA/ endostar group (30.0 months, 95% CI, 27.1-32.9) was significantly better than MWA group (21.3 months, 95% CI, 19.5-23.1, p = 0.000). But there was no significant difference (p = 0.471) in OS between the MWA/ endostar group (31.6 months ,95% CI, 28.3-35.0) and MWA group (30.0 months, 95% CI, 27.2-36.5). The 1, 2 and 3 year survival rates in the MWA/ endostar group were 94%, 82% and 82%, respectively, while those in the MWA group were 94%, 89% and 89%, respectively. There was no significant difference between the two groups (p=0.982, p=0.924, p=0.924). AEs of MWA were observed in 63.7 % patients. Endostar -associated AEs were not observed in the MWA/ endostar group.

Conclusion:
MWA was a safe and effective alternative treatment for patients with inoperable stage I non small cell lung cancer. MWA combined with endostar significantly improved DFS compared to MWA alone, while not increased the MWA-related complications.

Background:
The solid component size of lung cancer showing ground glass opacity (GGO) on thin-section computed tomography (TSCT) has been regarded as a more important preoperative prognostic indicator than the whole tumor size. Moreover, previous study revealed that radiological early lung adenocarcinoma which has an excellent prognosis could be defined as an adenocarcinoma 3.0 cm or less with consolidation to tumor ratio (CTR) of 0.5 or less on TSCT. However, the characteristics and the prognosis of lung cancer larger than 3.0 cm showing GGO remain unclear.

Method:
From January 2002 through June 2012, we retrospectively reviewed 3,735 consecutive patients with primary lung cancer, which underwent complete resection at our institution. We extracted 686 (18.4%) patients with lung cancer larger than 3.0 cm in diameter and evaluated their preoperative TSCT findings. In total, 160 (4.3%) lung cancers larger than 3.0 cm showing GGO were eligible for this analysis. We divided the 160 lesions into three types based on CTR; type A: 0
Result:
Type A, type B, and type C were found in 16 (10%), 37 (23%), and 107 (67%) lesions, respectively. Regarding the operative mode, all patients except for two patients underwent lobectomy. All patients except for one patient was diagnosed as having adenocarcinoma. Lymph node metastasis was seen in none of types A and B, in 34 (32%) lesions of type C. Lymphovascular invasion was seen in 73(68%) lesions of type C, 6 (16%) lesions of type B but not in type A. The median follow-up period was 68 (2-162) months. Recurrence was not observed in patients with type A and type B. The 5-year overall survival (OS) and disease free survival (DFS) rates were both 100% in type A, both 97.2% in type B, and 88.4%, 66.7% in type C, respectively. Patients with type C had a significantly worse prognosis than did those with the other types with respect to OS (p = 0.033) and DFS (p < 0.001).

Conclusion:
Tumors with type A and type B on TSCT showed an excellent prognosis with no lymph node metastasis. Therefore, GGO predominant lung cancer could be considered “early” lung cancer even if tumor size was larger than 3.0 cm in diameter.

Background:
Cigarette smoking is a well-known cause of interstitial lung diseases (ILDs), pulmonary emphysema, and lung cancer. Coexisting pulmonary diseases can affect outcomes of patients with early-stage lung cancer. The aim of this study was to analyze the influence of pulmonary diseases upon oncological outcomes of patients with smoking history who underwent surgery for pStage I non-small cell lung cancer (NSCLC).

Method:
Medical records of a total of 227 patients with smoking history (current/former) who underwent anatomical lung resections (200 lobectomies and 27 segmentectomies) for pStage I NSCLC between June 2009 and December 2014 were reviewed. Coexisting ILDs were evaluated on high-resolution computed-tomography (HRCT). The degree of pulmonary emphysema was determined using image analysis software, applying Goddard classification. The impact of clinicopathologic factors including pulmonary diseases on oncological outcome was evaluated.

Result:
Among the 227 patients, ILDs on HRCT were detected in 47 (20.7%) patients; of those, UIP pattern and non-UIP pattern were seen in 19 (8.4%) and 28 (12.3%) patients, respectively. The degree of pulmonary emphysema was classified into normal, mild and moderate, including 44 (19.4%), 146 (64.3%) and 37 (16.3%) patients, respectively. Pathological stages were IA in 131 patients and IB in 96. The 5-year overall survival (OS) and cancer-specific survival (CSS) were 81.2% and 88.2%, respectively. Univariate analysis showed that UIP-pattern on HRCT, moderate pulmonary emphysema, vascular invasion, visceral pleural invasion (VPI), and pStage IB were correlated with poor CSS. Cox proportional hazards models revealed that the presence of UIP-pattern and VPI were independent risk factors for poor CSS. During a median follow-up period of 42.7 months, recurrent diseases were seen in 41 (18.1%) patients. Multiple logistic regression analysis showed that the presence of UIP-pattern and VPI were significantly related with tumor recurrence.

Conclusion:
The coexistence of UIP-pattern ILD on HRCT was shown to negatively affect the oncological outcome of patients with smoking history who underwent surgery for pStage I NSCLC.

Background:
The incidence of lung cancer in Denmark is approximately 4600/year. Adenocarcinoma is the most common histologic subtype, and standard treatment for early stage disease is radical surgical resection. According to the latest World Health Organisation (WHO) classification the histological subtyping of adenocarcinomas as well as visceral pleural invasion (VPI) are prognostic factors. Vascular invasion (VI) have also been associated with poor survival. This study aimed to validate the revised WHO classification on completely resected stage-I lung adenocarcinomas and investigate the prognostic significance of VPI and VI.

Method:
During a 9-year period (2004-2012) 367 consecutive patients with stage-I adenocarcinoma underwent surgical resection at a university based thoracic surgical centre. An average of 4 HE slides of tumour per case (range 2-10) were analysed microscopically by two dedicated pathology specialists. The predominant growth pattern was classified according to the revised WHO-classification and presences of subtypes. VPI and VI were included when evident from the primary pathology records and clinical data were retrieved from recorded electronic patient files. Survival was recorded from the National Civil Registry. We used a Cox proportional hazard regression model for all statistical analysis.

Result:
The 5-year overall survival (OS) for stage-I lung adenocarcinomas was 67%. Stratified by predominant histological subtypes univariate analysis showed OS was 72,7% for lepidic, 71,5% for acinar, 51,9% for papillary, 54,5% for solid, and 52,5% for micropapillary. However, multivariate analysis did not show any significant correlation between OS and predominant subtype (p=0.127). VI was highly predictive of OS (p=0.002) but VPI involvement was not (p=1,020). When analysing data for presence of subtypes we found that the papillary subtype was the only significant predictor (p=0.002). Age (p<0.001) and gender (p<0.001) were significant predictors for survival.

Conclusion:
Data from a consecutive Danish cohort of stage-I adenocarcinoma could not confirm the prognostic significance of the adenocarcinoma subtyping suggested by the WHO, but papillary subtype was associated with poor survival. Our data confirm that VI is a poor prognostic factor suggesting that VI should be included in the TNM classification.

Background:
Lung cancer patients concomitant with interstitial pulmonary fibrosis (IPF) sometimes develop a life-threatening acute exacerbation after surgery or radiotherapy. Percutaneous cryoablation is evolving as a potentially less invasive local treatment for lung cancer. The purpose of this study is to retrospectively analyze the outcomes of cryoablation for clinical T1N0M0 non-small cell lung cancer (NSCLC) patients for whom surgery or radiotherapy is contraindicated because of IPF.

Method:
Between December 2003 and June 2017, 215 patients underwent computer tomography guided percutaneous cryoablation for lung tumors at our institution. Of these, 11 histologically proven clinical T1N0M0 NSCLC patients, for whom surgery or radiotherapy was considered contraindicated because of severe IPF, were retrospectively reviewed. Complications, local progression-free survival and clinicopathological factors were evaluated.

Result:
The cohort was composed of 11 men with a mean age of 74 years (range: 68 to 82). The median follow-up time was 24 months (range: 15 to 65 months). The mean Krebs von den Lungen-6 (KL-6) level was 1608 ±1025 U/mL. The mean tumor size was 24 ± 7mm. The mean percentage of predicted diffusing capacity for carbon monoxide (DLCO) was 37±27%. Thirty and 90-day mortality was 0 and 18%, respectively. Two patients required chest tube drainage because of severe pneumothorax. Acute exacerbation of IPF occurred in two patients (18%). The use of oral steroids and need for chest tube drainage were predictors of higher mortality (p < 0.05) and higher incidence of acute exacerbation of IPF (p < 0.05). However, higher level of KL-6 and low percentage of DLCO were not significant risk factors of mortality or acute exacerbation of IPF. Local progression-free survival at 1, 2 and 3 year was 51, 41 and 31%, respectively.

Conclusion:
Percutaneous cryoablation for lung cancer patients with IPF provoked acute exacerbation of IPF in 18% of patients. The use of oral steroids and need for chest tube drainage were predictors of higher mortality and higher incidence of acute exacerbation of IPF.

Background:
Recent advances in imaging technology have enhanced the detection rate of small-sized peripheral lung cancers. While squamous cell carcinoma (SCC) had previously been regarded as a representative histological type of centrally-located lung cancer, recent studies have reported an increase in peripheral SCC. In order to reveal the malignancy of such peripheral lung cancer, we retrospectively compared the clinicopathological features of small-sized peripheral SCC with that of adenocarcinoma (ADC) in surgically resected cases.

Method:
We retrospectively analyzed lung cancer patients who underwent radical surgical resections at Gunma University Hospital between July 2007 and October 2011. We included all 26 patients diagnosed with SCC and 214 patients diagnosed with ADC who had tumors smaller than 2 cm in pathological size.

Result:
Patients with SCC were significantly older than those with ADC. In SCC patients, 80% of patients were male and almost all patients were smoker, whereas in ADC patients, only half of patients were male and smoker. For pathological stage, only 62% of SCC were staged IA whereas 85% of ADC were staged IA. On the other hand, 16% of SCC were staged IIA to IIIA whereas only 8% of ADC were staged IIA to IIIA. SCC patients tended to have higher rate of lymph node metastasis compared to ADC patients, although there was no significant difference (16% vs. 8%; p = 0.25). The incidences of pleural invasion (31% vs. 12%; p < 0.01), vascular invasion (50% vs. 19%; p < 0.01), and lymphatic invasion (50% vs. 15%; p < 0.01) were significantly higher in SCC than in ADC. Rate of postoperative recurrence was higher in SCC patients compared to ADC patients (23% vs. 10%; p = 0.04), although there was no significant difference in pattern of recurrence. Five-year survival rate of SCC was significantly shorter compared to that of ADC (60% vs. 94%; p < 0.01).

Conclusion:
SCC patients had worse prognosis compared to ADC patients, although there was no difference in lymph node metastasis. Adjuvant chemotherapy should be considered in SCC patients in order to improve treatment outcome.

Background:
Multidisciplinary team (MDT) has emerged as the standard of care for lung cancer management in the past two decades.Lung cancer MDT Hospital Umum Sarawak was established in June 2013. It is a collaboration of healthcare professionals involving in lung cancer management comprising of oncologists, cardiothoracic surgeons, pulmonologists, radiologists and pathologists. Although MDT approach is widely accepted, it is poorly evaluated with limited observational data available especially in developing countries. While some studies had proven a significant benefit from MDT approach to the management of inoperable non small-cell lung carcinoma (NSCLC), comparison of resection rate in operable NSCLC is scarcely done.

Method:
Data was retrieved from Hospital Umum Sarawak lung cancer registry and individual patient’s case note. Subjects were recruited according to inclusion criteria: operable newly diagnosed histologically proven Stage I to III NSCLC, from July 2012 to June 2013 (non-MDT group), January to December 2014 and 2015 (MDT group).

Result:

Table 1 illustrates the patients’ characteristics before and after introduction of MDT

	Non-MDT Group	MDT Group
Variables	July 2012 to June 2013, n (%)	January to December 2014, n (%)	January to December 2015, n (%)
Age at Diagnosis <40 41 – 50 51 – 60 61 – 70 71 – 80 >80	0 (0.00) 4 (13.33) 6 (20.00) 10 (33.33) 6 (20.00 4 (13.33)	1 (6.67) 1 (6.67) 3 (20.00) 7 (46.67) 3 (20.0) 0 (0.00)	0 (0.00) 3 (13.00) 4 (17.40) 7 (30.40) 8 (34.80) 1 (4.40)
Gender Male Female	11 (36.67) 19 (63.33)	6 (40.00) 9 (60.00)	5 (21.74) 18 (78.26)
Histology Adenocarcinoma Squamous Cell Carcinoma Adeno-squamous Carcinoma Large Cell Carcinoma Others Unsure	17 (56.67) 8 (26.67) 0 (0.00) 1 (3.33) 0 (0.00) 4 (13.33)	10 (66.67) 2 (13.33) 0 (0.00) 1 (6.67) 2 (13.33) 0 (0.00)	15 (62.22) 7 (30.43) 1 (4.35) 0 (0.00) 0 (0.00) 0 (0.00)
Stage I II III Unsure	2 (6.67) 3 (10.00) 21 (70.00) 4 (13.33)	2 (13.33) 3 (20.00) 7 (46.67) 3 (20.00)	3 (13.04) 2 (8.70) 14 (60.87) 4 (17.39)

Table 2 illustrates the comparison of resection rates and 2-year survival rates before and after introduction of MDT

	Non-MDT Group	MDT Group
	July 2012 to June 2013	January to December 2014	January to December 2015
Number of patients with Stage I to III NSCLC (n)	30	15	23
Number of patients with resection done (n)	10	7	9
Resection rate (%)	33.3	46.7	39.1
Total number of traceable patients (n)	30	15	18
Missing data (n)	0	0	5
Number of patients survived ≥2 years (n)	10	9	12
Two-year survival rate (%)	33.3	60.0	66.7

Conclusion:
This single-centre study demonstrates a marked increase of resection rates and two-year survival rates in operable stage I to III NSCLC after introduction of lung cancer MDT. More quality evidence is yet to be explored to confirm the asso­ciation between MDT approach and improvement in lung cancer outcomes.

Background:
Stereotactic Ablative Radiotherapy (SABR) and percutaneous microwave ablation (PMWA) are now being performed in patients deemed “medically inoperable” with non-small cell lung cancer (NSCLC). The majority of these patients are treated without ground truth histology, relying on imaging to establish the diagnosis. The purpose of this study was to investigate whether there were differences in the visible imaging features including CT Texture Analysis (CTTA) between patients referred for surgery, SABR and PMWA, which might suggest differences in underlying diagnosis.

Method:
A retrospective analysis of 92 patients with one pulmonary nodule (PN) suspected as T1N0M0 to T2AN0M0 NSCLC on imaging were treated either with SABR (22 patients), PMWA (25) or Video-assisted thorascopic surgery (45) of which 23 had NSCLC (SURG M) and 22 had benign disease (SURG B). Patient characteristics, CT nodule morphology, presence of emphysema and percentage emphysema score, FDG avidity and CT textural features were compared. Twenty texture features previously used in combination to predict nodule probability of malignancy were extracted from each automatic contoured region surrounding the PN. The Kruskal-Wallis test was used to compare texture features between the 4 patient groups (SABR, PMWA, SURG M and SURG B).

Result:
There was no significant difference in nodule morphology, volume at presentation (p=0.280) or nodule volume doubling times (p=0.149), and presence of emphysema (p= 0.348) or emphysema score (p= 0.367) between the 4 groups. There was no statistical difference in CTTA malignancy prediction score between the SABR, PMWA and SURG M groups (p>0.05). The probability of malignancy score was significantly lower (p-value < 0.01) for SURG B (0.58 mean ± 0.19 sd) vs. SABR (0.79 ± 0.15) treatment groups. In post-hoc analysis, 6 out of 20 texture features showed significant differences that were driven by the SURG B group.

Conclusion:
This is the first study to our knowledge to evaluate the radiological differences between patient groups referred for surgical and non-surgical treatments for NSCLC. On this small study, the results support the hypothesis that the non-operative patient groups comprise the same proportion of benign and malignant as those in the operative group. The results also demonstrate the potential clinical utility of CTTA in patient selection when histology is not obtainable. CTTA does not require volumetry detectable growth to detect change, and therefore may be a useful biomarker of malignancy at first diagnosis.

Background:
In the 8[th] edition of the TNM classification of lung cancer, the T descriptor reflects the invasive growth area, which is not always equal to the total tumor diameter. In this study, we analyzed the difference in postoperative prognosis between tumors for which the invasive growth area was equal to the total tumor diameter and those for which the invasive growth area was smaller than the total tumor diameter.

Method:
One hundred forty-two patients with pathological stage I lung adenocarcinoma that was completely resected in our institute were enrolled. Adenocarcinoma in situ and minimally invasive adenocarcinoma were excluded. The average age at operation was 67.8±9.7 years, 87 patients were male, the average total tumor diameter was 1.9±0.6 cm, and the average invasive growth area was 1.6±0.6 cm. In 61 patients, the invasive growth area was smaller than the total tumor diameter (Group A), and in the remaining 81, the invasive growth area was equal to the total tumor diameter (Group B). The postoperative prognosis was compared between Groups A and B.

Result:
The estimated 5-year recurrence-free survival (RFS) probabilities by the Kaplan-Meier method in Groups A and B were 94.4% and 70.1%, respectively (p = 0.002, log-rank test). By a log-rank test, T factor (p < 0.001) and lymphatic permeation (p = 0.031) were also significantly associated with RFS. By a multivariate COX proportional hazards model, Group B (p = 0.045) and a pathological T descriptor of T1c or more (p = 0.001) were independently associated with RFS. Group B had a higher percentage of smokers (p = 0.004) and a higher percentage of cases in which the predominant histological subtype was other than a lepidic pattern (p < 0.001).

Conclusion:
Tumors for which the invasive growth area is equal to the total tumor diameter are associated with smoking and a predominant subtype of other than a lepidic pattern, and have a worse prognosis than tumors for which the invasive growth area is smaller than the total tumor diameter.

Background:
Overall survival for lung cancer in England has previously been shown to be improving year on year and to correlate with surgical resection rates (National Lung Cancer Audit (NLCA) 2016 report). Recently the NLCA switched to use anonymised data collected and processed by the National Cancer Registration and Analysis Service (NCRAS) which has allowed linkage of the dataset to other national datasets including the radiotherapy dataset (RTDS), not previously reported. The main aim of this study was to identify a national curative treatment rate for early stage NSCLC and to identify which patient features influence whether a patient receives surgery, radical radiotherapy (RT) or no active treatment.

Method:
A cross-sectional analysis was conducted on all English patients diagnosed with stage I-II lung cancer between January 2015 and December 2015. Types of surgery and radical radiotherapy were identified from NCRAS databases including Cancer Outcomes and Services Dataset (COSD), Hospital Episode Statistics (HES) and RTDS databases. Survival was defined from time from treatment until death and Cox regression analysis was used to determine factors associated with survival.

Result:
36025 cases of lung cancer were identified in 2015 with 8841 (28%) cases of stage IA-IIB proven or presumed NSCLC. 4560 (51.6%) cases received surgery and 1437 (16.2%) received radical RT creating a combined total of 5997 (67.8%) cases receiving treatment with curative intent. Curative intent treatment varied across cancer networks from 61.6% to 74.4%. Stereotactic Ablative Radiotherapy (SABR) was delivered in 750/1437 (52.2%) radical RT cases, generally for stage I disease, 60/1437 (4.1%) cases received Continuous Hyper-fractionated Accelerated RT (CHART) and 486/1437 (33.8%) cases received 55Gy/20 fractions, a commonly prescribed hypo-fractionated radical RT regime in England. Notably, 2844 (32.2%) patients did not receive treatment with curative intent, receiving either palliative therapy or supportive care only. Lack of treatment with curative intent was associated with increasing age and worsening performance status and varied across networks (25.6% - 38.4%). Updated survival data will be presented.

Conclusion:
In England for 2015, the curative treatment rate for stage I and II NSCLC was 67.8%. This means that almost one third of patients did not receive definitive treatment for their early stage lung cancer, ranging from 25.6% to 38.4 % across networks. A NLCA deep dive spotlight audit to identify more details about why these patients did not receive definitive treatment is planned for later this year.

Background:
The consolidation size of tumor in early lung cancer is related to prognosis. However, the tumor area and volume can show the amount of tumor more precisely. The purpose of this study was to compare the prognostic impact of the tumor size, the area, and the volume in whole tumor and consolidation of it.

Method:
We retrospectively reviewed the clinicopathological characteristics of 160 patients with clinical stage IA NSCLC who received curative pulmonary lobectomy and mediastinal lymph node dissection between January 2008 and June 2011. We measured the size, the area and the volume in whole tumor and consolidation part respectively by using the volume analyzer SYNAPSE VINCENT by Fujifilm. We evaluated the relationships between these measurement methods and pathological upstage, tumor recurrence with receiver operating characteristics curve.

Result:
The median duration of follow up was 64.9 months. Thirty four percent of patients (n=55) were pathologically upstaged. Twenty three patients developed recurrence (14%). The mean whole tumor size, the area and the volume were 21 mm, 264 mm[2], 3741 mm[3], respectively. The mean consolidation tumor size, the area and the volume were 17 mm, 156 mm[2], 1861 mm[3], respectively. The receiver operating area under the curve for the consolidation tumor size, the area, and the volume used to predicting pathological upstage were 0.686, 0.692 and 0.687 respectively, and they all had significant correlations. The receiver operating area under the curve for the consolidation tumor size, the area, and the volume used to predicting tumor recurrence were 0.626, 0.649 and 0.623 respectively. The tumor area had significant correlation and the others had marginally significant correlations. On the other hand, there was no significant correlation between the whole tumor measurements and either pathological upstage or tumor recurrence.

Conclusion:
Each measurement method in consolidation of the tumor can be useful for predicting prognosis.

Background:
With competing treatment options for early stage non-small cell lung cancer (NSCLC), and controversies over patient selection and management of later stage disease, multidisciplinary tumor board (MDTB) is a critical decision-making forum for management plans. Studies encompassing several cancer domains have shown the benefit of MDTBs on operative mortality, 5-year survival, and patient satisfaction. We aimed to determine the timing and utilization of MDTBs, relative to the initiation of treatment, for patients with NSCLC within a large community healthcare system.

Method:
We reviewed cI-III patients who underwent work-up for primary NSCLC during 6/2013-6/2015 in a hospital network of 7 institutions. This network offers mature multidisciplinary care with dedicated thoracic oncologic services collaborating for formal, weekly MDTBs. Only patients who underwent oncologic treatment were included, and were stratified based on initial treatment type: surgical versus chemotherapy (CHT) and/or radiation therapy (RT). Stage was defined as clinical stage established prior to MDTB, or treatment initiation.

Result:
We identified 203 patients; the figure depicts MDTB timing and utilization stratified by stage for each initial treatment type. Sixty seven percent (24/36) of cI patients did not have a MDTB prior to receiving stereotactic ablative radiotherapy (SABR). In addition, 33% (2/6) of the cIII patients did not receive a MDTB prior to surgical resection. Figure 1



Conclusion:
Variable utilization of MDTB was demonstrated for all clinical stages of NSCLC. In cI NSCLC where competing treatment options of surgery and SABR exist, less than half of the patients received multidisciplinary discussion. MDTB was also underutilized in cIII where treatment controversy exists. Although time constraints, referral patterns and provider bias challenge clinical practice, greater study and quality initiatives are necessary to ensure patients have access to MDTB discussion in the rapidly evolving landscape of NSCLC care.

Background:
Induction chemo-radiation therapy has shown an increase in 5-year survival in patients with superior sulcus tumors and complete surgical resection. We hypothesized that induction chemo-radiation therapy followed by surgical resection is associated with improved survival in patients with non-superior sulcus lung cancer with chest wall invasion.

Method:
We performed a retrospective review of a single institution database (1/1/1992-1/31/17) of T3 (chest wall invasion) N0/N1 patients with non-small cell lung cancer who underwent surgical resection. Exclusion criteria included 1) superior sulcus tumors and 2) resection performed for palliation or recurrence. Statistical analysis was performed using Kruskal-Wallis test (disease free times), and Kaplan-Meier curves.

Result:
Thirty-four patients were included in the analysis. Median age was 63.5 (range 37-84). By clinical stage, 31(91%) were IIB(T3N0) and 3(9%) were IIIA(T3N1). By histology, 15 were adenocarcinomas, 11 squamous and 8 large cell. Five-year overall survival (OS) was 30% for the entire cohort. Of the 34 patients, 16(47%) received induction chemo-radiation (platinum-based doublet and radiation dose 59-61 Gy) before surgery, and the remaining 18(53%) underwent surgery as the first treatment. Three patients belonging to the no-induction group died within 30 days after initial surgical treatment and were excluded from analysis. In the remaining 31 patients, induction chemo-radiation was associated with improved 5-year OS (53% for induction group vs 7% for no-induction group; p<0.01; Figure). Disease recurrence was evident in 10 cases, 3 in the induction group and 7 in the no-induction group (median disease-free time 94.6 months vs. 14.0 among the no-induction group; p<0.01). R1 resection status was observed in 6 patients, 5 of them in the no-induction group. Figure 1



Conclusion:
In patients with non-superior sulcus lung cancers with chest wall invasion, induction chemo-radiation therapy followed by surgical resection is associated with decreased recurrence. More importantly, induction chemo-radiation is associated with improved overall survival in this population.

Background:
This study aimed to identify the predictive factors for prognosis of stage IB NSCLC and determine the efficacy of adjuvant chemotherapy on recurrence and survival.

Method:
This is a retrospective study with reviewing the electronic medical records. We enrolled 89 patients with stage IB NSCLC who underwent complete resection surgery at Gangnam Severance Hospital from Jan 2008 to Dec 2014. As per the National Comprehensive Cancer Network guidelines, patients were considered to be at high risk when they showed poorly differentiated tumors, lymphovascular invasion, tumor size > 4 cm, and visceral pleural invasion (VPI). We evaluated disease-free survival and overall survival.

Result:
Among the 89 patients, 62 underwent adjuvant chemotherapy. Young patients or patients with squamous cell lung cancer received adjuvant chemotherapy frequently. Adjuvant chemotherapy was not a significant factor for disease-free survival and overall survival. Adjuvant chemotherapy did not show a significant protective effect for survival, even for high-risk patients. However, VPI was a significant risk factor for disease-free survival (hazard ratio [HR]: 7.051; 95% confidence interval [CI]: 1.570–31.659; P-value = 0.011) and overall survival (HR: 8.289; 95% CI: 1.036–66.307; P-value = 0.046), even after adjustment for various factors.

Conclusion:
Adjuvant chemotherapy does not affect the prognosis of stage IB NSCLC, even in high-risk patients. Additionally, VPI is a strong prognostic factor of stage IB NSCLC.

Background:
In early-stage non-small cell lung cancer (NSCLC) patients, randomized phase III NATCH trial reported no statistically differences in disease-free survival (DFS) or overall survival (OS) with the addition of preoperative or adjuvant chemotherapy to surgery. In pre-operative arm, those patients who achieved a complete response obtained a benefit in 5-year DFS rate (59% vs. 38%). Recently, major pathological response (MPR) to preoperative therapy (10% or less of residual viable tumor after preoperative chemotherapy) has reported as surrogate marker of OS. We assess to validate this prognostic factor in a cohort of patients included the NATCH trial.

Method:
Retrospectively MPR was collected in a cohort of 57 early-stage NSCLC patients treated in the preoperative arm into NATCH trial from 2 institutions. OS according to MPR was analysed (long-rank test) in the whole population and by histologic subtype

Result:
In this cohort, median age was 67 years (47-78), 48 (84%) were males, 26 (46%) squamous subtype. By stage according to 6[th] TNM: 9 (16%) stage IA, 35 (61%) stage IB, 12 (21%) stage IIB and 1 (2%) stage IIIA. All except 3 completed 3 cycles of preoperative treatment. Surgical procedures: 81% lobectomies or bi-lobectomies, 14% pneumonectomies, 5% no surgery. In the whole population, there was a trend toward 5-year OS benefit among those patients with MPR (84.6% vs. 58.5%, p=0.106). According to histologic subtype, squamous tumours with MPR had significantly better 5-year OS (100% vs. 47.1%, p=0.026), but not in adenocarcinoma subtype (66.7% vs. 66.7%, p=0.586).

Conclusion:
MPR is a prognostic value in squamous NSCLC patients who receive preoperative chemotherapy. Validation in extended cohort merits further evaluation.

Background:
Synchronous multiple primary lung cancers (sMPLC) demonstrate good outcome if metastatic disease was absent. However, the prognostic factors vary across published reports.

Method:
Patients who met Martini & Melamed criteria of sMPLC were included for this study. Patients with small cell lung cancer, carcinoid tumor, neuroendocrine, incomplete resection or insufficient follow-up were excluded. Overall survival (OS) was estimated using the Kaplan-Meier method, cause-specific mortality analysis was performed with competing risks analysis; factors associated with survival outcome were evaluated using log-rank test and Cox proportional hazards models. Propensity score was taken to match the variables between sMPLC and sPLC with a ratio of 1:4.

Result:
A total of 438 patients met inclusion criteria for the study. The mean follow-up time was 6.3 years (1-22.9), with a 5-year OS rate of 59.48%. Squamous cell carcinoma (SQC) was a sole histology in 50 patients (Pure SQC group); SQC with other cell type in 59 patients (SQC-other group); no SQC in 329 patients (Non-SQC group). The 5-year OS rate of pure SQC group, SQC-other groups and Non-SQC group were 44.7%, 33.0% and 66.8% (p<0. 001) in univariate analyses. In multivariable analyses the SQC present as an independent poor predictor, the hazard ratio (HR) for pure SQC group was 1.39 (95% CI, 0.97-2.0, P=0.004) and SQC-other group was 1.82, (95% CI, 1.27-2.61, P=0.004) compared to Non-SQC group. Pure SQC group and SQC-other group were both with poorer survival than Non-SQC group in cause-specific mortality analysis. The sublobe resection (n=233) and pneumonectomy (n=14) shows worse outcome than pure lobectomy (n=174) with 5-year OS rate were 53.8%, 45.9% and 70.5%. The HR for sublobe resection and pneumonectomy in multivariate analyses were 1.41 (95% CI, 1.07-1.89, P=0.002) and 1.91 (95% CI, 1.0-3.7). The outcome of surgical T1-4N0M0 sMPLC with solo cell type (n=339) was worse than well-matched sPLC (n=1356), with a 5-year OS rate were 65% and 68.2% (P=0.05); the 5-year OS rate of sMPLC with different cell type and well-matched sPLC (cell type match to more aggressive one) were similar (41.7 vs. 52.7, P=0.36). The other significant prognostic factors include sex, age, highest tumor stage, highest lymph node stage and smoke status.

Conclusion:
The presence of SQC in sMPLC represents the poor outcome; The sublobe resection and pneumonectomy decease the survival of sMPLC patients; For those surgical T1-4N0M0 patients, the outcome was similar with well-matched sPLC; Studies with bigger size were needed to further confirm the findings.

Background:
The plasma D-dimer (D-dimer) level, a marker of hypercoagulation, has been reported to be associated with survival in several types of cancers. The aim of this study was to evaluate the prognostic significance of the preoperative D-dimer level in patients with surgically resected clinical stage I non-small cell lung cancer (NSCLC).

Method:
A total of 237 surgically resected NSCLC patients were included in this study. In addition to age, sex, the smoking status, etc., the association between the preoperative D-dimer level and survival was explored.

Result:
The patients were divided into two groups according to the D-dimer level: group A (≤ 1.0 µg/ml, n = 170) and group B (> 1.0 µg/ml, n = 67). The 5-year overall survival rate was 89.0 % (95 % confidence interval [CI] 77.7–95.3) for group A, 78.2 % (95 % CI 62.3–83.6) for group B (p = 0.015). A multivariate survival analysis showed that the D-dimer level was an independent significant prognostic factor, in addition to age and SUVmax of the tumor.

Conclusion:
The preoperative D-dimer level is an independent prognostic factor in patients with surgically resected clinical stage I NSCLC.

Background:
The aim of this study was to clarify whether tumor shadow disappearance rate (TDR) or consolidation to tumor diameter ratio (CTR) predict outcomes in patients with clinical stage IA lung adenocarcinoma.

Method:
We reviewed 250 patients with completely resected clinical stage IA lung adenocarcinoma between 2007 and 2014 and examined the prognostic impact of TDR and CTR. We classified all tumors into each two groups based on the TDR and CTR on high-resolution computed tomography: TDR >50% (Group A, n=77), TDR ≤50% (Group B, n=173), CTR <0.5 (Group C, n=33), and CTR ≥0.5 (Group D, n=217). TDR and CTR were calculated using the following formulas: TDR = 100 – (tumor size on mediastinal window/tumor size on lung window) ´ 100 and CTR = maximum diameter of consolidation/maximum tumor diameter.

Result:
The study group comprised 117 men (47%) and 133 women (53%), with a median age of 66 years (range, 36-83 years). The median follow-up was 50 months (range, 1 to 110 months). The disease-free survival rate at 5 years was 100%, 78.2%, 100%, and 82.5% in Groups A, B, C, and D, respectively. The lung cancer-specific survival rate at 5 years was 100%, 94.8%, 100%, and 95.9% in Groups A, B, C, and D, respectively. Multivariate analysis showed that the following factors were significant predictors of recurrence: lymph-node metastasis, lymphatic vessel invasion, blood vessel invasion, and TDR (TDR: hazard ratio=3.61, 95% confidence interval: 1.01-12.8, p=0.048). On the other hand, multivariate analysis revealed that lymph-node metastasis and TDR were significant predictors of lung cancer-specific mortality (TDR: hazard ratio=23.85, 95% confidence interval: 1.22-466.5, p=0.037).

Conclusion:
TDR is a significant predictor of not only recurrence but also lung cancer-specific mortality in patients with clinical stage IA lung adenocarcinoma.

Background:
In lung cancer (LC) TNM classification allows an estimation of patient prognosis, but a third of patients with initial stages will relapse within three years. Molecular markers may increase prognostic accuracy and identify subgroups with high risk of progression.

Method:
Stromal (fibrous stroma and α-actin) and inflammation markers (IL1β, TNF-α and COX-2) were examined by immunohistochemistry in tumor tissue from a cohort of 222 patients with early-stage (I-IIp) LC recruited in Spain for the International Association for the Study of Lung Cancer TNM-16 staging project.

Result:
The diagnosis was non-small cell lung carcinoma (NSCLC) in 199 patients (106 adenocarcinoma and 93 squamous cell carcinoma) who were the target for this study. The participants had a mean age of 69 (SD 9) years, frequent respiratory (108, 54.3%) and cardiac (84, 42.2%) comorbidities, and were staged as IA (53, 26.5%); IB (56, 28.1%); IIA (41, 20.6%); IIB (40, 20.1%) or ≥III (9, 4.5%). After three years 94 patients had died (47.2%). In the bivariate analysis, 3-year mortality showed statistically significant associations with more advanced stage (p <0.001) and a higher proportion of fibrous stroma in the tumor (p = 0.014); and a marginal relationship with cardiac comorbidity (p= 0.07) and higher IL1β levels (p = 0.098). Sensitivity and specificity of fibrous stroma and IL1β were calculated and optimal cut-off points established according to Youden’s index. Using these cut-offs, fibrous stroma in >8% of the tumor sample and IL1β H-score levels above 1356 were significantly related to mortality. In Cox proportional hazards models, adjusting by stage and cardiac morbidity, patients with fibrous stroma levels above 8% had higher 3 year-mortality [HR= 2.03, 95% CI (1.1-3.7), p= 0.021]; and similar results were obtained in patients with IL1β levels above 1356 [HR= 2.05, 95% CI (1.1-3.7), p= 0.019]. Combining both markers, patients with both markers above their established cut-offs had a significantly higher risk of 3 year mortality [HR= 2.95% CI (1.1-3.6), p= 0.022].

Conclusion:
An overrepresentation of fibrous stroma and IL1β in the tumor sample is independently associated with 3 year mortality in NSCLC, confirming that the tumor stroma influences survival in LC. Funded by PII Oncology SEPAR and FIS 12-02040

Background:
To investigate whether a cicatricial change of adenocarcinoma appearing as pure ground glass opacity nodule (GGN) on CT correlate with stromal invasion.

Method:
From June 2013 to December 2016, 425 adenocarcinomas were pathologically confirmed in our institution. With a retrospective investigation of CT images and pathologic reports, we found 37 surgically resected pure GGNs. Then, we analyzed the statistical difference of the presence of cicatricial changes (traction bronchiectasis and cystic airspace dilatation) on CT between two groups according to the presence of stromal invasion (Adenocarcinoma in situ vs Invasive pulmonary adenocarcinoma).

Result:
Among the 37 pure GGNs, there were 17 adenocarcinoma in situ and 20 invasive pulmonary adenocarcinomas (13 minimally invasive adenocarcinomas and 7 adenocarcinomas). The frequencies of traction bronchiectasis (12 % vs 70 %, p<0.001) and cystic airspace dilatation (24% vs 55%, p=0.052) were higher in invasive pulmonary adenocarcinoma with or without statistical significance. The presence of either traction bronchiectasis or cystic airspace dilatation (35% vs 80%, p=0.006) was also more frequently found in the invasive pulmonary adenocarcinoma. Figure 1



Conclusion:
Cicatricial changes in adenocarcinoma presenting pure GGN may be a finding suggesting stromal invasion.

Background:
The 5-year survival rate of pathologic stage IB stage lung adenocarcinoma is reported to be 73%, and adjuvant chemotherapy is expected to improve prognosis about 10%. In Japan, UFT is the standard regimen as adjuvant chemotherapy for completely resected pathological stage IB. In addition to conventional clinicopathological factors, adenocarcinoma tissue subtype, EGFR mutation status and maxSUV of primary tumor like have also been found to have a large Impact as a recurrence / prognostic predictor. The purpose of this study is to investigate the factors which affect recurrence and prognosis in stage IB lung adenocarcinoma．

Method:
From 2008 to 2015 lung, completely resected 218 cases that undergo lobectomy with mediastinal lymph node dissection and diagnosed as pathological stage IB (7th UICC) . We examined the relationship between clinical pathologic factors including postoperative adjuvant therapy and, recurrence and prognosis.

Result:
Median follow-up period was 45.4 months. There were 122 male and 96 female. Mean age was 69.4 years old, BMI 22.2, smoking 122 cases (56.0%). CEA elevation was noted in 63 cases (28.9%). Median value of max SUV was 2.96. Median operative time was 166 minutes and blood loss was 45.7 g. Histological adenocarcinoma subtypes were followed; MIA 6, Lepidic 62, Acinar 79,　Papillary 27,　Solid 40　and Micopapillary 4. Lymph vessel invasion was noted in 35 (16.0%) and vascular vessel invasion was in 72 (33.0%) and pleural invasion was in102(46.8%), EGFR mutation was noted in 62 among 150 examined cases (41.3%)． Mean tumor diameter was 3.33 cm, collapse-fibrosis size was 2.18 cm. Adjuvant chemotherapy was performed in 90 cases (41.3%). The relapse-free survival rate (RFS) at 5-year was 77.1%, the factors influencing RFS were lymph vessel invasion, vascular vessel invasion, pleural invasion, histological adenocarcinoma subtypes, blood loss and maxSUV. In multivariate analysis, RFS was significantly affected by pleural invasion (HR=3.141 (95% CI 1.122 - 8.798)), blood loss (HR = 1.004 (1.000 - 1.007)) and maxSUV (HR = 1.083 (1.004 - 1.169)). However, the presence or absence of EGFR mutation did not contribute to relapse (p = 0.208). The overall survival rate (OS) at 5-year was 88.3%, the histological subtype and BMI statistically affected OS. In multivariate analysis, only histological subtype (lepidic vs. non-lepidic) (HR = 4.710 (95% CI = 1.097-20.218) was left, it was an independent prognostic factor. After matching the distribution of histological subtype to examine the effect of adjuvant chemotherapy, but no significant difference was observed. On the other hand, when focusing on prognosis based on the presence or absence of EGRF mutation in recurred cases (35 cases), the 5-year OS was 58.8% in wild type and 90.0% in mutant; it was not statistically significant difference (p = 0.165), but the mutant case seemed to have a high probability of long-term survival after relapse.

Conclusion:
Factors that contribute to recurrence were pathological malignancy (vascular invasion, histological subtype) and biological malignancy (high value of maxSUV). On the other hand, only histological subtypes contributed to prognosis. In addition, lepidic predominant was almost free from relapse and survived. Even if lepidic subtype was excluded, the effect of adjuvant UFT administration was not observed. Cytotoxic agent or EGFR-TKI should be examined in the future. On the other hand, the presence or absence of EGFR mutation seems to be an important OS predictor after recurrence.

Background:
Tumor recurrence after surgical resection is the main obstacle for long term survival in patients with NSCLC. The identification of factors related to recurrence may help to determine new risk predictors and guide different forms of treatment. An elevated neutrophil to lymphocyte ratio (NLR) and a low lymphocyte to monocyte ratio (MNR) have been reported to be poor predictors of disease free survival (DFS) in patients with NSCLC. There is a lack of evidence on the association of these ratios in early stages of lung cancer.

Method:
Data of NSCLC patients who were lobectomized at Edgardo Rebagliati Hospital between years 2008-2014 were retrospectively reviewed. Patients with incomplete data were excluded. NLR and LMR were calculated before surgery. DFS was determinate according to Kaplan-Meier method, the comparison of the survival curves was made by Logrank test or Cox model.

Result:
Forty patients were included. The median age was 68.5 years old, 52.5% were men and 92% had an ECOG scale 1. The 32.5% were asymptomatic at the time of diagnosis and 22.5% were in pre-surgical evaluation for different diseases. The 57.5%, 32.5% and 10% of patients had clinical stage I, II and IIIA, respectively. The 80% of patients had adenocarcinoma and the 20% had a squamous subtype. The 36.1% and 63.9% of the patients had NLR < 1.5 and >1.5, meanwhile 8.6% and 91.4% of the patients had LMR < 2.3 and >2.3, respectively. The median follow-up was 4.4 years, in which the 40% of patients died. The DFS rate at 4-years was 40.5%. Three patients had LMR < 2.3, all of them have died during follow up. The variables associated to DFS were lymphatic permeation (HR: 3.2, p=0.011), tumor size > 5 cm (HR: 1.2, p=0.028) and NLR (HR: 3.5, p=0.136). DFS rate at 4-years was 75% in patients with NLR < 1.5 and 28.5% in those with NLR >1.5.

Conclusion:
A NLR > 1.5 before surgery is associated with a worse DFS than patients who had a NLR < 1.5. Studies with a bigger number of patients are needed to determine the importance of NLR and LMR as recurrence predictors in operated patients with NSCLC. This result encourages further investigation about available and inexpensive biomarkers as predictors of disease recurrence in early stages of lung cancer.

Abstract not provided

Background:
In NSCLC, loss-of-function (LOF) mutations are found in tumour suppressors, highlighting the importance of these genes in the aetiology of lung cancer. The major tumour suppressors (TS) associated with the development of lung cancer are p53 and the kinase LKB1. Unlike oncogenes that have been successfully exploited therapeutically, LOF alterations in TS are difficult to exploit therapeutically. The goal of our research is to understand how the loss of TS function allows for metabolic and epigenetic adaptation that favour conditions for tumour growth.

Method:
We developed a CRISPR/Cas9 mouse model of lung cancer representative of tumour suppressors lost in NSCLC that has allowed for temporal evaluation of tumourigenesis. Here, we evaluated the role metabolism, epigenetics and the immune system plays in promoting tumour growth. Since LKB1 and p53 are the most common LOF tumour suppressors found in NSCLC, and KRas is the most commonly abundant of oncogene, using the Cre-dependent Cas9 mouse model developed by the Zhang Lab at the Broad Institute, mice were treated by inhalation with CRISPR-directed viruses that target the excision of Lkb1, p53 and activation of KRas compared to mice treated with control virus. Post-treatment, lungs were analyzed for metabolic, immunologic and epigenetic profiles.

Result:
Lung tumours were harvested from mice, followed by analysis of global epigenetic modifications, immunological markers and for metabolic enzymes. The metabolic profile of lung tumours harvested from CRISPR/Cas9 mice that lack expression of Lkb1, p53 and express enhanced KRas, was significantly different from the metabolic profile of lungs harvested from control mice, favouring a switch from glycolysis to mitochondrial metabolism. Acetylation and methylation modifications to histones 3 (H3) and H4 were significantly different compared to control mice, as was the macrophage activation profiles.

Conclusion:
The goal of our study was to identify and characterize the molecular profile of early stage lung cancers. We conclude from our study that patients with lung cancers that lack expression of LKB1 are likely to respond favourably to interventions that simultaneously target aberrant metabolism with modifiers of tumour epigenetic landscape. Our findings suggest that loss of LKB1 expression serves as a marker for lung cancers that are metabolically and epigenetically challenged.

Background:
Objective: The evaluation of supportive care needs in lung cancer patients may be enhanced by engaging systematic screening using a validated distress screening tool, the distress thermometer (DT). We aimed to identify the extent of use of the screening tool, levels of distress and psychosocial problems identified by the tool and to determine associations with distress and the impacts of distress screening on patient outcomes in an Australian university teaching hospital.

Method:
We recruited all new lung cancer diagnoses recruited via the Victorian Lung Cancer Registry at the Alfred Hospital, Melbourne, Australia, during the period 14 July 2011 to 24 September 2016. We evaluated the presence of documented supportive care screening using the distress thermometer and demographic, clinical, treatment and outcome measures.

Result:
Levels of screening were very low (15.2%) amongst this cohort and yet 49.2% respondents described high levels of distress (median DT 3.5; IQR 1-6). High levels of distress (DT≥4) were associated with higher levels of practical, family, emotional and physical problems. Patients reporting higher levels of distress experienced an accelerated rate of decline in physical component of quality of life and had increased risk of death.

Conclusion:
The identification of the supportive care needs for lung cancer patients may be augmented by the use of a systematic screening tool. This study identifies significant gap in supportive care screening, high levels of distress amongst screened subjects and poorer patient related outcomes for distressed patients. This study provides an important platform for institutional supportive care screening strategy planning.

Background:
Do never-smokers who develop non–small-cell lung cancer catch a break as innocent bystanders? This study seeks to understand differences in presentation and outcome after resection of lung cancer in never-smokers vs. smokers.

Method:
From 2006 to 2013, 652 patients underwent lung resection for clinical stage I-III (p I-II or yp I-II) non–small-cell lung cancer (NSCLC)—584 smokers (90%) and 68 never-smokers. Propensity matching yielded comparable pairs of smokers and never-smokers to assess cancer recurrence, overall survival, and recurrence-free survival.

Result:
Never-smokers presented with somewhat more advanced disease than smokers (59% pT2 vs. 48%, 34% pN1 or pN2 vs. 27%), were more likely to have had preoperative chemotherapy or radiotherapy (26% vs. 17%), and more often were female (66% vs. 45%) and of Asian descent (10% vs. 0.34%). Among matched patients (including for cancer stage), 5-year freedom from cancer recurrence was 57% vs. 49% (Figure) in never-smokers vs. smokers. However, not surprisingly, non-cancer death was lower in never-smokers than smokers (6.3% vs. 16% at 5 years; Figure). Thus, when this competing risk of death without recurrence is accounted for, the proportion of never-smokers experiencing recurrence was 40% vs. 37% for smokers, and recurrence-free survival was 54% vs. 46%.Figure 1



Conclusion:
Because disease presentation and response to therapy are unexpectedly and surprisingly similar in never-smokers and smokers, the effect of lung cancer on survival is magnified in never-smokers by fewer non–cancer-related deaths. Moreover, since never-smokers present with fewer comorbidities and singular disease, they are optimal candidates for the most aggressive therapies and tightest long-term surveillance.

Background:
Numerous studies show a link between poor socioeconomic status (SES) and late stage cancer diagnosis. This however has not been consistently shown looking at non-small cell lung cancer (NSCLC) in isolation. Despite the extremely high prevalence of lung cancer as well as disparities in access to healthcare based on health insurance in South Africa, there is a paucity of data looking at the influence of health insurance (as a surrogate for SES) on stage at presentation of NSCLC. We aimed to study the relationship between health insurance status (and invariably SES) and staging of patients (and by virtue, resectability) with primary non-small cell lung carcinoma at the time of initial presentation.

Method:
We retrospectively compared privately health insured patients (n=55) to those with no health insurance (n=610) with regard to demographics, tumour node metastasis staging and cell type at initial presentation.

Result:
Those with no health insurance were younger (59.9±10.1 years) than those with private health insurance (64.15±9.6 years, p = 0.03). Poorly differentiated NSCLC was significantly more common in the privately health insured group (23.6%) compared to those with no health insurance (4.6%; p < 0.01). Six of 51 NSCLC patients (11.8%) with private health insurance presented with early stage, potentially curable disease (up to stage IIIA) compared to 55 patients (10.3%) in the uninsured group (p = 0.75).

Conclusion:
We found that access to private health insurance did not have a significant impact on stage at initial presentation. The only significant differences were the relatively advanced age at presentation and relatively higher percentage of poorly differentiated NSCLC seen in private practice.

Background:
Coexisting disease constitutes a challenge for the provision of optimal cancer care. The influence of comorbidity on lung cancer management and prognosis remains incompletely understood. We assessed the influence of comorbidity on treatment intensity and prognosis in a population-based setting in patients with nonsmall cell lung cancer.

Method:
Our study was based on information available in Lung Cancer Data Base Sweden (LcBaSe), a database generated by record linkage between the National Lung Cancer Register (NLCR) and several other population-based registers in Sweden. The NLCR includes data on clinical characteristics on 95% of all patients with lung cancer in Sweden since 2002. Comorbidity was assessed using the Charlson Comorbidity Index. Logistic regression and time to event analysis was used to address the association between comorbidity and treatment and prognosis.

Result:
In adjusted analyses encompassing 19,587 patients with a NSCLC diagnosis and WHO Performance Status 0-2 between 2002 and 2011, those with stage-IA-IIB disease and severe comorbidity were less likely to be offered surgery (OR: 0.45; 95% CI: 0.36-0.57). In late-stage disease (IIIB-IV), severe comorbidity was also associated with lower chemotherapy treatment intensity (OR: 0.76; 95% CI: 0.65-0.89). In patients with early, but not late-stage disease, severe comorbidity in adjusted analyses was associated with an increased all-cause mortality, while lung cancer-specific mortality was largely unaffected by comorbidity burden.

Conclusion:
Comorbidity contributes to the poor prognosis in NSCLC patients. Routinely published lung cancer survival statistics not considering coexisting disease conveys a too pessimistic picture of prognosis. Optimized management of comorbid conditions pre- and post-NSCLC-specific treatment is likely to improve outcomes.

Background:
An increasing interest is seen in the role of preoperative physical function and activity in enhancing postoperative recovery. But, the short-term effect of preoperative physical activity (PA) on recovery after lung cancer surgery is unknown. The purpose of this study was to compare the difference of physical function and activity between General elderly and lung cancer patients before surgery. Also, we compared post-operative Cardiorespiratory fitness (CRF) according to preoperative PA level.

Method:
Lung cancer patients of this study consisted of patients who were registered for lung cancer cohort. Patients of cohort included were those scheduled to undergo lung cancer surgery, at participating hospitals in the Seoul of South Korea. We are selected a total 69 elderly lung cancer patients in cohort patients. Exclusion criteria of a cohorts of lung cancer study included ECOG PS >1 and neoadjuvant therapy, Multiple cancer, recurrent lung cancer. Patients planned for lung cancer surgery filled out a questionnaire and perform before, as well as at 3 weeks after the operation. Also, we selected 69 general elderly by matching the gender and age, at users of Seniors Welfare Center in Seoul of South Korea. The physical function test included muscle strength, gait ability, and cardiorespiratory fitness (6-minute walk test). PA was assessed using the self-reported short form IPAQ questionnaires.

Result:
Preoperatively, No difference was seen CRF and PA between General elderly and lung cancer patients before surgery. More active lung cancer patients (MVPA>150min) had higher CRF at 3 weeks after surgery (p<.002*) than inactivity lung cancer patients. Table 1. Differences of physical function and activity by PA level

	General elderly (n=69)		P	Elderly Lung Cancer Patientsn(n=69)		P
	Inactive	active		Inactive	active
6MWT(m)	466.7±2.9	508.2±3.1	0.350	484.5±10.6	544±28.3	0.144
Hand grip strength (kg)	27.2±0.1	27.1±0.1	0.971	24.4±0.7	30.1±1.4	0.000*
10m gait maximum speed (sec)	6.7±0.0	6.4±0.0	0.853	5.9±0.1	5.4±0.1	0.049*
Rate of MVPA>150min/week	55.1%	44.9%		85.3 %	14.7 %	-

Conclusion:
The preoperative physical function of elderly lung cancer patients is not different from general elderly, but physical activity is very low. Also, Regular and increase physical activity before surgery with elderly lung cancer has been associated with CRF after surgery.

Background:
Lung cancer is the leading cause of death worldwide in both women and men. According to the guidelines of the Polish National Cancer Registry in 2013, it is estimated that lung cancer had first place in oncological morbidity of men and third of women. The aim of the study was to evaluate the occurrence of lung cancer retrospective analysis in a group of patients before the age of 50. Patients had confirmed lung cancer diagnosis and were hospitalized in Center for Pulmonary Disease in Olsztyn between October 2014 and March 2017.

Method:
A retrospective analysis of 1,622 medical history patients who were hospitalized in the center at that time with histopathologically confirmed diagnosis of lung cancer. We selected only the patients who were diagnosed before the age of 50. The inclusion criteria were met by 23 patients: 7 women and 16 men. We analyzed: age, gender, symptoms, risk factors, including family history and additional diseases, type, stage, and survival.

Result:
We identified 23 cases of lung cancer before the age of 50, which was 1.41% of all patients diagnosed with lung cancer. There were 12 cases of small cell carcinoma, 6 cases of adenocarcinoma, 4 cases of squamous cell carcinoma and 1 case of NOS (Not Otherwise Specified). The majority (78%) of the respondents had a positive history of smoking - 2 of them quit smoking, the average pack-years was 31 (SD 13.72). A positive family history was reported in 11 individuals, while exposure to harmful environmental factors at work in 12 subjects. Prior to the diagnosis of cancer, 15 out of 24 patients had reported respiratory symptoms such as dyspnoea, cough, hemoptysis, or weight loss. Out of these 23 patients: 12 have died - their average lifetime from the moment of diagnosis till death was 6.45 months (SD 2.98)

Conclusion:
1. The incidence of lung cancer below the age of 50 years is 1.41% of all patients hospitalized with the diagnosed of lung cancer at that time. 2. Most common, in patients diagnosed with lung cancer below the age of 50, is small cell carcinoma 52.17%. 3. Most of the patients had a positive history of smoking (78%) and often additional factors such as family history (47%) or workplace exposure (52%); the total percentage was 91%. 4. Most (78%) of lung cancers were diagnosed in an advanced non-operative stage. 5. The average lifetime from the moment of diagnosis till death was 6.45 months.

Background:
Previous studies report intrinsic sex differences among lung cancer patients; however, current epidemiological data remains inconclusive as to the existence and impact of inherent sex differences. This study aimed to perform a descriptive evidence-based study of the literature to identify and quantify sex-associated characteristics among non-small lung cancer (NSCLC) patients.

Method:
We retrieved all potentially relevant articles published in English by searching Medline between 1996 and 2016, worldwide. Using a systematic review protocol, all abstracts were reviewed for eligibility, and studies meeting inclusion criteria retained. We identified eligible studies on NSCLC and its subtypes, with the inclusion of both men and women of age over 45 in the study population. Pooled data was analyzed using a semi-parametric longitudinal regression model and an ANOVA Two-way test. A data-visualization tool was used to demonstrate global NSCLC incidence distribution and sex-based disparities.

Result:
Of 1405 articles identified on Medline, 46 studies met eligibility requirements; 36 were included in statistical analyses, and 10 underwent descriptive-systematic review. We found that disparities between the sexes are significant (p=0.01). Among men, we found a significant effect of race on age-standardized incidence rates (ASR) in this subset (p <0.001). Among women, the incidence of NSCLC was found to increase over time, irrespective of race. For adenocarcinoma (ADC), a significant interaction between sex and race was found (p=0.02), with women showing higher rates of ADC than men. Asians, however, had the highest rates of ADC among other races. For squamous cell histology (SCC), no interaction between sex and race was found (p=0.7); however, a significant difference in SCC incidence rates was found between the sexes (p= 0.01). Analyzing SCC data shows significant effect over time by gender (p=0.02), with ASR values in males decreasing by -0.31 units per year. Conversely, the data-visualizing tool showed an increase in incidence rates of SCC among Canadian women.

Conclusion:
Our findings demonstrate that NSCLC trends vary by sex, and both race and sex have a significant affect on incidence rates. However, the inclusion of women in clinical studies is increasing over time, and women often express ADC. This histology is also predominant among all Asians. Findings also illustrated that global trends do not always align with regional trends. Our study serve as a basis to begin to resolve the inherent controversies in the research, and highlight the importance of the inclusion of sex as a risk modifier in the development of screening initiatives and therapies in NSCLC.

Background:
Lung cancer is rare in young patients. The aim of this study was to determine the incidence of non-small cell lung cancer (NSCLC) among young patients (YP) versus older patients (OP) at our tertiary cancer centre. Additionally, associated prognostic factors, survival outcomes, and adherence to guideline-recommended treatment based on age were described.

Method:
All NSCLC patients initially diagnosed through the Tom Baker Cancer Centre (TBCC), in Calgary, Alberta, Canada between January 1999 and December 2013 were included. Patient data was retrospectively collected from electronic and paper charts as part of an institutional research program (Glans-Look Lung Cancer Database). YP were defined as ≤47 years, or two standard deviations below the mean. Chi-square tests were used to analyze categorical clinical and demographic factors among the age groups (≤47 versus >47), and overall survival (OS) was determined using Kaplan-Meier. The Cox proportional hazard model was applied to calculate the hazard ratio (HR) and its 95% confidence intervals (CI).

Result:
A total of 6,899 cases were examined. YP represented 3% (n=197) of incident NSCLC from 1999-2013: 1999-2004 (4.1%), 2005-2009 (2.8%), and 2010-2013 (1.8%). Compared to OP, YP tend to be female (54.8% vs. 47.9%, p=0.062) and never-smokers (25.4% vs. 7.7%, p<0.001). Additionally, most present with stage IV disease (61.4% vs. 54.1%, p=0.279), and adenocarcinoma (57.4% vs. 42.4%, p<0.001). YP demonstrated better median OS (13.5 months, 95% CI: 10.8-16.2) compared to OP (9.4 months, 95% CI: 9.0-9.9, p<0.001). Positive independent prognostic factors were early stage disease (IB-IIIA) (HR, 0.544; CI: 0.392-0.753, p=0.002), female sex (HR, 0.880; CI: 0.836-0.927, p<0.001), never-smoker (HR, 0.714, CI: 0.654-0.779, p<0.001), and former smoker (HR, 0.735; CI: 0.671-0.806, p<0.001). Non-adenocarcinoma subtypes were negative prognostic predictors of survival (HR, 1.648; CI: 1.416-1.919, p<0.001). Compared to OP, YP were more likely to receive guideline treatment according to disease stage. Among stage IV patients, YP were 30% more likely to receive chemotherapy (p<0.001). YP with stage III were twice as likely to receive concurrent chemo-radiation (p=0.007). Lastly, 90% of YP with stage I and II (A and B) received surgery, compared to half of OP (p<0.001).

Conclusion:
The incidence of NSCLC diagnoses among YP has been decreasing at the TBCC since 1999. In our cohort of NSCLC patients, YP demonstrated better overall survival; possibly due to a higher likelihood of receiving guideline-recommended therapy. Additionally, clinical characteristics of YP NSCLC patients differ from those observed in OP.

Background:
Therapies targeting genetic alterations have improved response rates and overall survival for some patients with NSCLC (non small cell lung cancer) as agents against EGFR (epidermal growth factor receptor) actionable mutations. Is recommended to test all patients with advanced/metastatic non squamous NSCLC, but the rates of patients actually tested vary in different institiutions.The prevalence of EGFR mutations in non-squamous NSCLC population range from 15% to 40%. There is few data about EGFR mutations in the Brazilian population, which is known for ethnic heterogeneity. This study intends to report the rates of EGFR evaluation in advanced non-squamous NSCLC, as the prevalence and the profile of such mutations in a south brazilian public health instituition.

Method:
We performed an observational retrospective study including patients diagnosed with advanced non-squamous NSCLC between january 2011 to december 2016 at CEPON (Centro de Pesquisas Oncológicas). Their medical record have been reviewed and information regarding epidemiological profile as well as EGFR testing was retrieved.

Result:
345 patients were accrued. Targetable genetic alterations in EGFR were assessed in 74% (255/345) along the years and has a incremental pattern rising from only 22% of patients tested in 2011, 60% in 2012, 72% in 2013, 85% in 2014, to 100% of patients tested in 2015 and 2016. EGFR mutations were found in 18,03% (46/255) using the PCR COBAS method in tumoral tissue. EGFR mutations were more prevalent in women (30.09% vs. 9.60%; p < 0.001); and in never-smokers (49.12 vs. 9.58%; p < 0.001), but no significant difference was found regarding age under 50 year-old (27.66 vs. 17.28%; p = 0.159). The mean age of the mutated patients was 59 years (SD 11.82) with female predominance (74% vs. 26%). The most frequent genetic alteration detected was exon 19 deletion (50%), followed by L858R mutation (36%). Among the 46 patients with targetable EGFR mutation, 32 received getitinib or erlotinib in first or second line.

Conclusion:
Our findings shows that nowadays we have a good rate of screening of EGFR in advanced NSCLC. This improved over the years, reflecting the test availability, medical education with subespecialization, and easier acess to TKIs in CEPON. The prevalence of EGFR mutations in our population (18,03%) is slightly lower than the prevalence founded in other studies with brazilian patients (around 20%), maybe reflecting the european immigration in south of Brazil. Epidemiological profile is similar to previous studies showing EGFR mutation rates higher in female and non smokers patients.

Background:
Lung cancer epidemiology related to interstitial lung disease (ILD) with or without connective tissue disease (CTD) and idiopathic pulmonary fibrosis (IPF) is not yet established. ILD potentially develops into scar lung cancer. We aimed to explore lung cancer prevalence in ILD patients with or without CTD and IPF in comparison with chronic obstructive pulmonary disorder (COPD).

Method:
We evaluated lung cancer prevalence associated with ILD and IPF using Korean Health Insurance Review and Assessment Service (HIRA) data from January to December 2011. This database (HIRA-NPS-2011-0001) was created using random sampling of outpatients; 1,375,842 sample cases were collected, and 670,258 (age ³ 40) were evaluated. Patients with ILDs, IPF, CTD, or COPD were identified using the International Classification of Disease-10 diagnostic codes.

Result:
Lung cancer prevalence rates per 100,000 person for the study population and those with ILD, IPF, CTD-ILD, and COPD were 420, 7334, 7404, 7272, and 4721, respectively. Lung cancer prevalence was significantly higher in those with ILD than in those with COPD.

Conclusion:
More attention must be paid to lung cancer development in those with ILD as well as COPD.

Background:
Multiple previous studies have revealed disparities in clinical trial (CT) participation among oncology patients. In this study, we examined the factors that affect CT participation for lung cancer (LC) patients at the University of Washington (UW). Specifically, we hypothesized that patients who spoke a primary language other than English had significantly lower CT participation.

Method:
We analyzed data from patients with stage IV LC evaluated at UW from 2004-2015. We examined patient and disease characteristics such as histologic subtype, molecular status, ECOG performance status (PS) and total lines of therapy. We analyzed multiple demographic factors including age, self-reported race, primary language and gender, as well as socioeconomic factors including marital status, employment, insurance status, zip code, distance to clinic, and presence of email address and phone number. We performed multiple logistic regression analyses to evaluate the association between the primary language and CT participation and also examined other factors independently affecting CT enrollment in this patient population.

Result:
654 patients were included in our study. 73% did not participate in clinical trials, while 27% enrolled in at least one trial. The median age was 63 and 50% were female. 69% patients self-identified as Caucasian, 11% Asian, 5% African-American and the remainder as other or unknown. 94% of patients named English as their primary language. 90% had non-small cell histology, 73% had ECOG PS score of 0 or 1 and patients had received a median of 2 prior lines of therapy. In the multiple logistic regression model, we did not observe an association between the primary language and CT participation (OR 0.96, 95% CI 0.43 – 2.14). However, factors independently associated with a greater likelihood of CT participation were: an active email address (p = 0.01), better ECOG PS at diagnosis (0-1) (p=0.001), non-adenocarcinoma histology (p = 0.02), and increased number of lines of therapy (p<0.0001).

Conclusion:
We did not find that patients with non-English primary language had lower rates of CT participation. Our findings replicate the nationally low level of CT participation and identified surrogates for socioeconomic status as being important. Continued efforts to understand the barriers and factors affecting CT participation will be necessary to help increase access and enrollment.

Background:
Objective: The aim of this study is to evaluate the effect on the mortality of a delay of more than 2 months in treatment delivery after the diagnosis of non small cell lung cancer (NSCLC).

Method:
We performed a retrospective review of records form patients registered in a prospectively keep database on lung câncer.. patients with malignant lung neoplasms, admitted at a single reference oncology center of public-system health between July 2008 and December 2014. Patients were considered eligible for this study if they were older than 18 years and had not undergone any previous oncology treatment when they were admitted at the institution. The following data were collected from all patients: age, gender, smoking status, histological type, surgical treatment, tumor staging and time from the date when the patient was diagnosed with cancer to the starting date of effective treatment.

Result:
We identified 359 elegible patients. Of these, 278 (77.4%) died during follow-up while 81 (22.6%) were censored. Age, sex and smoking status were not statistically significant predictors of mortality and were not considered for multivariate analysis. Stage of disease, surgical treatment and histological type of lung cancer were predictor of mortality (p< 0.05)). Besides that, in both the crude and adjusted analysis, delayed delivery of treatment was protective for the risk of death, with a crude HR= .75 (.59 - .97; p= .02) and an adjusted HR= .59 (.46 - .77; p<.001). A statistically significant interaction for mortality was observed between timely delivery of treatment and tumor stage (p=.01). The HR for mortality of getting delayed access to treatment according to stage are described: stages I and III, mortality was not significantly different between those that got treatment before or after 2 months from diagnosis (Stage I: HR= 1.24 (.39 – 3.98; p=.71); Stage III: HR= .65 (.38 – 1.1; p=.11)). However, patients with stage II disease who received delayed treatment had a mortality 3 times higher than those that received timely treatment delivery (HR= 3.08 (1.05 – 9.0; p=.04)). On the other hand, stage IV patients that received delayed treatment had a 52% reduction in mortality.

Conclusion:
There was influence of stage at the association between time to start treatment and mortality. About this influence, only the subgroup of stage II NSCLC patients appears to benefit of early treatment.

Background:
Hyponatremia is an underestimated hazardous complication; which goes side by side since diagnosis till terminal outcome of carcinoma lung patients. The aim of study is to evaluate the prevalence of hyponatremia in hospitalized lung cancer patients and influence of hyponatremia on prognosis in same group of patients.

Method:
Observational study was conducted between July, 2015 to November, 2016 in United Hospital Cancer Care Centre. A total 200 hospitalized patients were analyzed with diagnosed carcinoma lung. These subjects were free from gross liver diseases; kidney diseases and brain metastasis. Prevalence of hyponatremia including severity (mild, moderate and severe) was evaluated. The role of hyponatremia with lung cancer was also evaluated in hospital mortality. Hyponatremia was treated with oral salt, NaCl tablets along with fluid restriction to 500 mL per day. In some cases hypertonic saline was also used. In the present study we were not assessing the prevalence of SIADH but only hyponatraemia.

Result:
Among 200 patients; NSCLC were 79.5 %( n=159) and SCLC were 20.5% (n=41). Various degree of hyponatremia was found in 63.52 % ( n=101) NSCLC patients and 56.09 %( n=23) SCLC patients. There was no statistical significance in prevalence of hyponatremia between histological types of lung cancer. Out of 200 patients, 124 patients had mild, moderate and sever hyponatremia which was 61.29 %( n=76), 27.42 %( n=34) and 11.29 %( n=14) respectively. Among 124 hyponatremic patients 23.38% (n=29) died and 76.61 %( n=95) survived. And remaining 76 normo-natremic patients 10.53% (n=8) died of their illness and 89.47 %( n=68) survived. In patients with lung cancer with hyponatremia compared to patient with lung cancer without hyponatremia; a significant increase in hospital mortality was found. (23.38% Vs 10.53%) (p <0.001)

Conclusion:
Hyponatremia is common abnormality found in approximately 62% of lung cancer patients. It is also considered as a significant prognostic factor associated with mortality of lung cancer patient. In future large prospective multicenter study is needed to better understand the relation of hyponatremia in lung cancer patient for both management and outcome.

Background:
Understanding non-small cell lung cancer (NSCLC) epidemiology and outcomes is fundamental for clinical decision-making. SCAN-LEAF is a retrospective longitudinal cohort study that aims to describe NSCLC epidemiology, clinical care, and outcomes of patients in Scandinavia. The present analyses examine clinical characteristics and disease management of a subset of these patients.

Method:
Cohort 2 (EMR data from Uppsala, Stockholm sites, extracted using the Pygargus Customized Extraction Platform (CXP 3.0) and linked to registry data) consisted of NSCLC patients diagnosed 2005-2013 (follow-up until 2014). Co-morbidity burden was calculated with the Charlson Co-morbidity Index (CCI). Descriptive statistics were calculated, stratified by disease stage at diagnosis [resectable: I-IIIA; locally advanced: IIIA-B (radiation therapy within 3 months); advanced: IIIB (no radiation therapy within 3 months)-IV].

Result:
48.4% of the 3984 patients were male. At diagnosis, mean age was 68.4 years with disease stage distribution: resectable (30.4%), locally advanced (10.5%), advanced (56.3%), not specified (2.7%). CCI distribution was similar between stages, as was BMI. Smoking status: never (7.4%), former smoker (34.7%), current smoker (25.6%), unknown (32.4%). Histology: adenocarcinoma (63.3%), squamous (20.5%), NSCLC NOS (Not Otherwise Specified) (16.2%). ECOG: 0/1 (48.4%), 2/3 (13.2%), 4 (2.2%), unknown (36.2%). Metastases at diagnosis were reported for 42.4% patients. 829 patients were tested for molecular sub-type EGFR (of which 751 had a valid test result, of which 14.6% were positive for the mutation) and 267 for ALK (of which 247 had a valid test result, of which 14.6% were positive for the rearrangement). More patients with locally advanced disease were treated with radiation than patients with resectable or advanced disease [(68.8%, n=289) vs (35.9%, n=436) and (47.4%, n=1064), respectively], and a greater proportion of locally advanced patients received systemic therapy [(72.1%, n=303) vs (39.4%, n=478) and (67.1%, n=1505), respectively]. The proportion of patients not treated with surgery, radiation, or systemic therapy (based on pre-selected procedure lists) was higher for advanced (22.3%, n=500) vs resectable (6.5%, n=79) and locally advanced disease (11.9%, n=50).

Conclusion:
SCAN-LEAF EMR data provides unique insights into Scandinavian NSCLC patient populations and treatments. These data suggest unmet medical need based on majority of patients being diagnosed at advanced stage and low numbers tested for molecular subtype mutation but we expect these dynamics to change over time. Additionally, our data suggest unmet treatment need in patients with advanced disease based on a high proportion receiving no surgery, radiation, or systemic therapy, whilst acknowledging potential for misclassification and/or missing treatment data.

Background:
Lung cancer and tuberculosis (TB) share common risk factors and are associated with high morbidity and mortality. Coexistence of lung cancer and TB were reported in previous studies, with uncertain pathogenesis. The association between lung cancer and latent TB infection (LTBI) remains to be explored. In Spain the prevalence is higher compared to other European countries and there are a high emigration rates. The key objetive is to place value on the need to detect LTBI for assesment for prophylaxis in patients at risk of reactivation due to cancer and cancer treatments.

Method:
Newly diagnosed , treatment-naïve advanced lung cancer patients from October-December 2015 and from October-December 2016 were prospectively enrolled .The presence of LTBI was determined by QuantiFERON-TB Gold In-Tube (QFT-GIT). Demographic characteristics and cancer-related factors associated with LTBI were investigated.

Result:
A total of 67 lung cancer patients were enrolled. The patients demographics were: median age 64 years, 10 (15%) female and 58 (85%) male. Adenocarcinoma 50% (n=34) , 23% (n=16) squamous-cell carcinoma and small cell lung cancer 26% ( n= 18) The stage was IV in 71%(n=53) and III in 29% (n=20) These patients come from urban area in 16% of cases and rural areas in the 83% and the 82% (n=56) had history of smoking. The 79,4% % ( n= 54) of patients received chemotherapy and 16% ( n= 11) inunotherapy with Nivolumab. Among these patients including 23 % (n=16) LTBI,65% (n=44) non-LTBI, and 12% (n=8 ) QFT-GIT results-indeterminate cases. Out of these LTBI patients received Isoniazid chemoprophylaxis only 60% because of poor performance status. Adenocarcinoma had higher proportion of LTBI 64% vs 18 % for epidermoid and 18% for oat-cell At the time of database lock, the median of overall survival was only 6 months.

Conclusion:
Nearly a quarter of newly diagnosed advanced lung cancer patients in Toledo ( Spain) have LTBI. There is a lack of widely acceptable and established standards for screening for latent TB in patients undergoing treatment for active solid-organ malignancy. Perhaps is recommended screening all patients born in countries with endemic TB before beginning radiotherapy or chemotherapy to avoid TB reactivation.

Background:
Obesity is the accumulation of body fat that has a harmful effect on health and has been increased the risk and mortality of multiple diseases, such as cardiovascular diseases and diabetes. Obesity has been associated with increased risk and mortality of most cancers. On the other hand, obesity is associated with decreased risk of a part of lung cancer. The mechanism to decrease risk of lung cancer in obese individuals is not clear.

Method:
In our hospital, we retrospectively assessed 675 lung cancer patients who were hospitalized for the first time from April 2012 to July 2015. We collected patient data of baseline characteristics, histology, performance status (PS), body mass index (BMI), stage, smoking history, molecular profiling for EGFR, ALK. Patients were stratified into 3 BMI groups based on the WHO classification: underweight (< 18.5 kg/m[2]), normal weight (18.5 to < 25 kg/m[2]), and overweight (≥ 25 kg/m[2]). The classification of obese (≥ 30 kg/m[2]) was included in the overweight group in this study. Overall survival was calculated using the Kaplan-Meier method. We compared overall survival between BMI groups using log rank test.

Result:
In this retrospective cohort study, we assessed 566 patients with non-small cell lung cancer (NSCLC) and 109 patients with small cell lung cancer (SCLC). There were no significant differences in patient characteristics except for smoking history. In SCLC patients, there was no significant difference in overall survival by each BMI group (good PS [0 – 1] group, p = 0.186; poor PS [2 – 4] group, p = 0.809). In NSCLC patients with good PS, overall survival was prolonged in the order of the standard group and the overweight group, in comparison with the underweight group (p = 0.031). In NSCLC patients with poor PS, there was no significant difference in overall survival by each BMI group (p = 0.401). In NSCLC patients with good PS, higher BMI and activating EGFR mutation were associated with longer overall survival in a multivariate analysis (BMI: hazard ratio 0.468, 95% CI 0.253 – 0.855, p = 0.0136; EGFR mutation: hazard ratio 0.476, 95% CI 0.279 – 0.796, p = 0.0044). In SCLC patients with good PS, there was a tendency of longer overall survival in the overweight group than in the underweight group.

Conclusion:
Overweight in NSCLC patients with good PS had significantly improved overall survival.

Background:
Approximately 80% of non-small cell lung cancers (NSCLC) are related to smoking, and smokers are 10-20 times more likely to have NSCLC than non-smokers. Nicotine has a 1.5 times higher rate of post-exposure dependence than other drugs, making it very difficult to stop. Thus, the aim of this study is to clarify the association between NSCLC and nicotine dependence.Approximately 80% of non-small cell lung cancers (NSCLC) are related to smoking, and smokers are 10-20 times more likely to have NSCLC than non-smokers. Nicotine has a 1.5 times higher rate of post-exposure dependence than other drugs, making it very difficult to stop. Thus, the aim of this study is to clarify the association between NSCLC and nicotine dependence.

Method:
We investigated the prevalence of nicotine dependence in NSCLC patients and analyzed the clinical characteristics of nicotine dependent NSCLC patients. Smoking information was assessed via questionnaires and personal interview in a cohort of 120 patients from four hospitals of the Catholic Medical Center between 2016 and 2017. Tobacco Use Disorder criteria of DSM-V, DSM-IV nicotine dependence criteria, and Fagerstrom Test for Nicotine Dependence (FNTD) were used to define nicotine dependence. Urine cotinine test was also performed to validate tobacco use.

Result:
Most of them were male (93.3%) and the average smoking amount was 40 pack years. At the time of diagnosis of NSCLC, 71.7% were current smoking status. The prevalence of nicotine dependence was 77-92% according to the diagnostic tool, DSM-V (92%), DSM-IV (78%) and FNTD (77%), which is expected to be higher in the NSCLC group compared to the general smoking population. Based on FTND scores, patients were divided into mild, moderate, and severe groups. Smoking amount was significantly higher in severe group than the others. In addition, although drinking habit scores were higher in the severe nicotine dependent group, there were no significant differences among the groups in the other parameters, such as number of attempts to quit smoking, smoking cessation success, urine cotinine test results, depression, anxiety, and quality of life.

Conclusion:
These preliminary results of the prevalence of nicotine dependence in NSCLC patients may provide medical evidence for development of intensive smoking-cessation program in NSCLC patients.

Background:
The commonest route to lung cancer diagnosis in the United Kingdom (UK) is via emergency presentations (EP), with 35% of lung cancer diagnoses being made via this route. We aim to study the outcome of patients diagnosed with lung cancer via all routes of presentation and its contributing factors in a UK district general hospital.

Method:
Data was collected retrospectively from a non-teaching hospital over the period of January to June 2015. Only patients with a confirmed diagnosis (clinical or histological) of lung cancer were included. The following categories were analysed: -Demographics -Histological subtype of lung carcinoma -Performance Status -Stage of disease at presentation -Proportion offered treatment -Survival data (overall and at 1-year)

Result:
94 patients were identified over this period. 35% (n = 33) presented via the EP route, while 51% (n=48) presented via the elective (2 week wait) route. The remaining 14% (n = 13) presented via other routes. Figure 1 A higher proportion of patients presenting via the EP route have more extensive disease and a poorer performance status. A significantly lower proportion of patients in the EP subgroup were offered treatment. A substantial difference in overall survival between the EP and elective subgroups was also noted.



Conclusion:
Patients diagnosed via the EP route have a poorer performance status at presentation and are less likely to receive treatment or be alive at 1-year. Non-small cell lung carcinomas form the majority subtype of lung carcinoma in all routes of presentation. The demographics between the three subgroups are comparable, with a significant proportion of patients from the most deprived areas in the UK. This study suggests earlier diagnosis of lung cancer is crucial to improve outcomes. Due to strong associations between smoking and social deprivation with lung cancer, this study supports a risk-based screening programme utilising low-dose computerised tomography (LDCT).

Background:
Lung cancer screening with LDCT scan is covered by private insurance and Medicare for current and former smokers quit within the last 15 years, age 55 to 77 (55-80 for private insurance), with a 30 or greater pack year smoking history. However, it is not covered for National Comprehensive Cancer Network (NCCN) Group 2; a group of slightly younger, lighter smokers with no limit on quit duration but at least one additional risk factor. Our previous study on 1328 patients demonstrated NCCN Group 2 (Cohort A) to be at equivalent risk for lung cancer as the covered group (Cohort B). The objective of this study is to statistically evaluate the potential difference in lung cancer prevalence between Cohorts A and B. Towards that end we are compiling a large sample set (1563 Cohort A, 4000 Cohort B) with 80% power that can detect a minimum of 1% difference in lung cancer prevalence between the two groups.

Method:
A REDCap data registry was created to retrospectively collect LDCT scan data on high-risk individuals from two historical cohorts who underwent lung cancer screening at three institutions between January 1, 2012 and May 31, 2017.

Result:
To date, 804 Cohort A and 2712 Cohort B individuals have been entered into the data registry. Data entry is expected to be complete by the end of 2017 with follow-up through end of May 2019 to ensure a minimum follow up period of two years for each patient. A preliminary analysis is planned with 3 month minimum follow-up. A separate analysis of overall cancer detection rates (CDR) with a smaller sample at one of the study institutions shows CDR are not statistically different between the two cohorts (Pearson’s Chi-Square). The CDR for Cohort A, the NCCN Group 2 patients, was 3.98% (28 lung cancers in 704 patients) and in Cohort B, the covered group, was 3.92% (91 lung cancers in 2319 patients; p=0.95). Average time in the program was 2.5 years for Cohort A and 2.4 years for the Cohort B (p=0.18). Maximum time in the program was 5.4 years for both groups; minimum follow-up time was 3 months.

Conclusion:
Using an expanded data set, NCCN Group 2 CDR continue to be the same as the group covered by Medicare and insurance. At this point, there is no statistical difference in lung cancer risks between the two groups.

Background:
Lung cancer is the leading cause of cancer death worldwide. In Brazil, cancer is the second most common cause of death and there were an estimated 27,330 new cases of lung cancer in 2014. Targeted therapies have changed disease prognosis and current clinical guidelines advocate for testing all patients with advanced disease for EGFR mutations and ALK gene rearrangements. Access to this testing is often limited in the developing world. In the case of Brazil, there is limited data regarding the frequency of testing and the changes in patterns of testing overtime.

Method:
Observational, retrospective study involving practice patterns of over 2000 cancer physicians in Brazil. We obtained de-identified data from a commercial database which included 11,684 patients with non-small cell lung cancer treated between 2011 and 2016. We analyzed the frequency of EGFR mutation testing and ALK rearrangement testing.

Result:
11,684 patients were analyzed, of which all had stage IV lung adenocarcinoma. In the years ranging from 2011 to 2016 there was a significant increase in the frequency of testing for EGFR mutations overtime; from 13% in 2011 (287/2228) to 34% in 2012 (738/2142), 39% in 2013 (822/2092), 44% in 2014 (866/1972) to 53% in 2015 (1165/2184) and 58% in 2016 (626/1066). Testing for ALK rearrangements over that same time period also increased noticeably from no patients tested in 2011 and 2012, to 0.9% in 2013 (19/2092) 3% in 2014 (59/1972), 5% in 2015 (121/2184), 5% in 2016 (52/1066).

Conclusion:
To our knowledge this is the largest data analysis regarding changing practice patterns of molecular testing for lung adenocarcinoma over time in Brazil and Latin America. The frequency of testing for EGFR mutations and ALK gene rearrangement has increased over the last 5 years but is still below the current guidelines recommending that all patients with advanced disease be tested. Further understanding of the barriers to testing, will hopefully lead to national strategies for universal implementation of molecular testing.

Background:
The etiology of non-smoking NSCLC remains largely unknown. It has been widely proved that human papillomavirus (HPV) participate in the development of various cancers unrelated to smoking. Epidermal growth factor receptor (EGFR) mutation patients represent a large part of non-smokers with NSCLC. We performed this meta-analysis to evaluate whether HPV infection in NSCLC tissue is associated with EGFR mutation compared with HPV negative controls.

Method:
MEDLINE, EMBASE, PubMed and Web of Science were searched through June 2017, using the search terms “lung cancer”, “human papillomavirus”, “HPV”, “epidermal growth factor receptor”, “EGFR” and their combinations. We included studies in which HPV detection was based on PCR methods. Association was tested using odds ratio (OR) with 95% confidence intervals (95%CI). Heterogeneity was assessed using Q and I[2] statistic.

Result:
Finally, three studies with a total of 288 patients from Asian countries were identified as eligible publications. The presence of EGFR mutation was significantly related to HPV DNA compared with HPV negative controls (57% vs. 27%，OR 3.91, 95% CI 1.85 to 5.50; p<0.001), with no statistical heterogeneity among studies (I[2]=0; p=0.525).

Conclusion:
Our results suggest that HPV may contribute in part to EGFR mutations in non-small cell lung cancer, at least in Asian population.

Background:
Lung cancer is the leading worldwide cancer related death. Recently, 8[th]edTNM lung cancer was published, changing prognosis. Brazil provides free public healthcare system(SUS); however, we believe access is unequal. 25% of population has private healthcare insurance(SHS). Our objective was to evaluate the impact of the new staging and overall survival comparing patients from SUS and SHS.

Method:
Restrospective analysis of primary lung cancer patients resected between 2011 and 2016. Pathological was classificated according to 8[th]ed TNM. Proportional odds model was used to compare staging and healthcare system,Kaplan-Meier and Log-Rank test for survival analysis.

Result:
267 patients underwent surgery for lung cancer. 52.6%(139)were females, 64.5yo(SD=10.06), adenocarcinoma(60.7%) and 61%(163)from SUS. The upgrade in staging for the current system(8[th]) was significantly higher for SUS(graphic 1)(OD1.55– 95%CI1.00-2.39). Overall median survival was 61months regardless staging, with SHS better survival(p=0.080),graphic 2.Figure 1Figure 2





Conclusion:
Lung cancer new staging is more precise predicting prognosis. An upstaging was expected with new TNM classification. However, a patient from SUS has a 55% higher chance than private care patients of being upstaged not only in T descriptor but also in final staging TNM. Also, SUS had a lower survival tendency. We need to review and address our unequal healthcare system in order better assist our patients.

Background:
Lung cancer remains the leading cause of cancer death worldwide and is responsible for 20,000 deaths yearly in Argentinean women. Despite prevention strategies the incidence of lung cancer in women in our population has not been decreasing. We described the clinicopathological and epidemiological profile of women diagnosed with lung cancer in our institution in the last seven years

Method:
A retrospective cohort of women with lung cancer diagnosis from the data base of the Thoracic Oncology Unit was reviewed

Result:
From 2010 to 2017, a total of 185 women with lung cancer were included. Median age was 61 (30-92). Distribution by age group was: ≤30: 1 (0.5%), 31-39:6 (3.2%), 40-49: 17 (9.2%), 50-64: 87 (47%), ≥65: 74 (40%).Histologic subtypes were: adenocarcinoma (77.3%, n=143), squamous cell carcinoma (13%, n=24), small cell lung cancer (5.9%,n=11), NOS (2.2%, n=4), large cell carcinoma (1.1%, n=2), and large cell neuroendocrine cancer ( 0.5%, n=1). Most women were smokers (70.8%, n=131)(mean 24.52±29.84 pack/year) and presented with and advanced disease (III-IV)(75%, n=139). Twenty eight women (15%) had history of other cancer (36% breast cancer and 21% cervix cancer).EGFR mutationand ALK rearrengements were identified in 26(14%) and 8 (4.3%)patients, respectively. Uncommon EGFR mutations like G719X in exon 18 (4/12, 33%) were observed in smokers (46%, 12/26). We also detected compound mutation patterns in 2 cases (1.9%)(G719X+L861Q and del19+T790M). Median OS for all patients was 25 months (95% CI 21.53-28.46), whereas for patients at stage III-IV was 20 months (95% CI 21.53-28.46). The independent factors associated with the OS were the ECOG PS, disease stage and the presence of symptoms at diagnosis.

Conclusion:
Women with lung cancer assisted in our institution showclinical and epidemiologic characteristics previously described in western population. However, we observed a relatively high proportion of EGFR mutations in smokers. Prospectively collected data will explore molecular and epidemiologic items in this subgroup of patients.

Background:
Lung cancer remains as the principal death cause in many regions around the world. Unfortunately, between 60-70% of patients are diagnosed with advanced disease (clinical stage IIIB-IV), that determinate the prognosis of patients. The high mortality rates of advanced lung cancer (ALC) are partly due to the lack of effective prognostic biomarkers. Recent investigations suggest that neutrophils-to-lymphocyte ratio (NLR) play an important role in the immune response to lung cancer, high value is considered as a prognostic indicator. We evaluated the prognostic value of NLR in overall survival (OS) of patients with ALC treated at a private institution (Oncosalud – AUNA).

Method:
We analyzed data of 75 patients with advanced lung cancer, treated at Oncosalud-AUNA between 2013 - 2014. The clinical-pathological data were collected from digital medical records. The laboratory data (hemoglobin, leukocytes, neutrophil, lymphocyte, and monocyte) were collected from blood routine test. Optimal cutoff value of NLR (<3.6 and >3.6) and LMR (<4.7 and >4.7) were calculated using the maximally selected rank statistics. OS was determinate using Kaplan-Meier method and survival curves comparison were performed using log-rank test or Breslow. Cox model was used to estimate the effect of NLR on overall survival.

Result:
The median age was 70 years (range: 39-91) and 49% of patients were women. The metastatic sites were brain (28%), osseous (18%), cervical and supraclavicular (14%). The 66.7% of patients received chemotherapy with/without radiotherapy, 9% radiotherapy only and 24% non-treatment. In patients previously treated with chemotherapy, 52% received targeted therapy. The median follow-up was 23 months (CI95%: 17-29), median survival was 9.6 months (CI95%. 5.6-13.5) and, 1 and 2 years survival rate were 38% and 23%, respectively. The survival rate at 1 and 2 years in those receiving targeted therapy were 65% and 43%, and those who did not receive were 35% and 10%. In univariate analysis, ECOG scale 2-4 (p = 0.001), leukocytes > 10,000 cell/uL (p = 0.031), neutrophil > 7500 cell/mL (p = 0.021), monocytes > 800 cell/mL (p = 0.027), NLR >3.6 (p = 0.001), LMR>4.7 (0.036) and CYFRA 21.2 > 3.3 ng/mL (p = 0.033) were associated with poor survival. However, in the Cox model only NLR was associated with poor prognosis (HR: 3.2, CI95%: 1.6-6.3)

Conclusion:
Overall survival for our patients is similar to other series. Patients under NLR e <3.6 had a relatively better prognostic.

Background:
Lung cancer still remains as the principal death cause in many regions around the world. Its mortality varies according to the regions and study periods. In Peru it represents the sixth most frequent malignant neoplasm and the fourth cause of cancer related death. We reported the spatial autocorrelation and the temporal variation in lung cancer mortality rate in Peru.

Method:
Data of lung cancer mortality in Peru between 2005-2014 was obtained from the Ministry of Health. Information on the number of inhabitants was obtained from National Institute of Statistics and Informatics. Age standardized mortality rate (ASMR) was calculated based on the 2011 world standard population. Spatial autocorrelation was determined according to Moran’s Index and the Local G Cluster Map to explore the cluster patterns between regions.

Result:
During the study period 16,839 deaths due to lung cancer were reported. The lung cancer mortality rate in Peru increased from an ASMR of 12.8 (95% CI: 11.9-13.7) by 100,000 persons in 2005 to 13.4 (95% CI: 12.5-14.3) in 2014. According to the quartiles, the ASMR was higher in the north, south and east, and lowest in others regions. The spatial distribution of the ASMR showed a significant spatial autocorrelation (Moran´s I: p = 0.025). Also, during the study period, the ASMR showed a significant increase and decrease in some regions and in others it was constant.

Conclusion:
In Peru, lung cancer mortality rate showed a spatial and temporal variation in different regions. The increase in mortality rate in some regions requires identification of risk factors in order to establish public measures to reduce the risk of lung cancer mortality.

Background:
Developing countries often present a dichotomous health care system, where patients may be treated in either public or private institutions that differ substantially in terms of level of access to diagnostic and therapeutics procedures. Herein, we present the first report of this comprehensive study to assess real-world data in non-small cell lung cancer (NSCLC) patients treated in the private health care in Brazil.

Method:
This is a prospective study of lung cancer patients treated in a private health care institution, comprising six unities in Rio de Janeiro and surroundings. Eligible patients were at least 18 years old and had a histology-proven diagnosis of lung cancer between July 2012 and February 2017. For this analysis, only NSCLC patients with an invasive component were included. Patients or relatives were contacted by telephone to ensure that all information was annotated. Data quality was certified by regular monitoring. This study was approved by the local Research Ethics Committee.

Result:
Six hundred twenty-eight patients were enrolled. Eighty-three were excluded in this analysis due to small-cell (57), carcinoid (5), in situ carcinoma (5), and other histological subtypes (16). The final report comprises 545 NSCLC patients, predominantly of non-squamous histology (76.5%). Median age was 68 years (range 21-93), and most cases were males (54.3%). Most patients were current (28.3%) or former (49.7%) smokers, diagnosed in advanced stages (stage III in 20.7% and stage IV in 57.2%). Treatment had a curative intent in 38.9% of times, and included surgery in 29.4%. Palliative chemotherapy was delivered in 64.5% of times, while adjuvant and neoadjuvant chemotherapy was used in 10.2% and 5.4%, respectively. Radiotherapy was used in 53.9% of cases. Molecular testing was available for 49.3% of cases, mostly in non-squamous histology (92.8%) and in advanced stages (stages III/IV in 74.8%). Median overall survival was 25.3 months (95% CI 22.0-28.6). Factors significantly correlated to OS were disease stage, performance status, tumor grade, gender, and weight loss (p<0.01 in all). Among patients with metastatic or recurrent disease, OS was significantly longer in those with a molecular testing (p<0.01).

Conclusion:
To our knowledge, this is the most comprehensive and best-annotated study in this scenario. Outcomes were favorably similar to the current literature from developed countries in all stages, which suggest that data generated from international clinical trials should be reproducible locally. Our dataset may serve as a foundation to guide resource allocation in the years to come.

Background:
The aim of this study was to classify non-small cell lung cancer (NSCLC) based on the tumor microenvironment (TME) immune status according to the expression of PD-L1(5H1) and infiltration of CD8+ T-cells. To provide effective guidance for patients with NSCLC to use immunotherapy.

Method:
Fifty-eight patients with NSCLC were enrolled, most of whom are stage I adenocarcinoma. Analyse the expression of PD-L1 and CD8 by immunohistochemistry. According to the tumor microenvironment immune status , we classify the patients into four types: type I (PD-L1+ CD8+), type II (PD-L1-CD8-), type III (PD-L1+CD8-), and type IV (PD-L1-CD8+). Analyze the relationship between the characteristics of patients and the immune status.

Result:
The positive rate of PD-L1 expressing on the tumor cell is 74.14%(43/58) in 58 cases of NSCLC patients. Whereas the rate of CD8 positive lightly is 60.34%(35/58), the rate of CD8 positive mediately is 29.31%(17/58), and the rate of CD8 positive heavely is 1.72%(1/58). And the rate of type I is 72.41%(42/58), the rate of type II is 6.90%(4/58), the rate of type III is 1.72%(1/58) ,and the rate of type IV is 18.97%(11/58) .

Conclusion:
The major type of the tumor microenvironment immune status is type I, while the slightest type is type III. Except for the pathological classification (adenocarcinoma, squamous carcinoma, or others) (P < 0.05), we cannot relate the expression of PD - L1 (especially the tumor cell surface expression) to patients' gender, age, and tumor stage (P > 0.05).We conclude the expression of PD-L1 in squamous cell carcinoma is more than that in adenocarinoma ; we also cannot relate tumor infiltration of CD8 + T lymphocytes (none, mild, moderate, severe) with patients' gender, age, pathological classification, and stage (P > 0.05). So we would better test the the expression of the immune bio-marker like PD-L1 which express in the early stage of NSCLC and CD8+ T cell infliction before PD-1 antibody curing in patients of NSCLC to promote the cure rate.

Background:
Programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway-targeted immunotherapy has become the standard option of care in the management of lung cancer. The expression of the PD-L1 protein in lung cancer is expected to be a prognostic factor or to predict the response to PD-1-blocking antibodies. However, the association between PD-L1 positivity and the clinicopathological features and patient outcomes in lung squamous cell carcinoma (SCC) remains unclear because the definitive cut-off value for the expression of PD-L1 protein remains to be established.

Method:
The expression of PD-L1 protein in 205 surgically resected primary lung SCC patients was evaluated by immunohistochemistry with the antibody clone SP142. We generated a histogram to show the proportion of PD-L1-positive carcinoma cells as described in the figure below, and set the cut-off values as 1%, 5%, 10% and 50%. Moreover, we examined the proliferative capacity of these tumors using Ki-67 immunohistochemistry.Figure 1



Result:
The samples from 106 (51.7%), 72 (35.1%), 61 (29.7%) and 37 (18.0%) patients were positive for the expression of PD-L1 protein at cut-off values of 1%, 5%, 10% and 50%, respectively. Fisher’s exact test showed that, for almost all of the factors, PD-L1 positivity was not associated with the clinicopathological features with any of the four cut-off values. Univariate and multivariate survival analyses revealed that the PD-L1-positive patients only had a poorer prognosis than the PD-L1-negative patients at the 1% cut-off value. The Ki-67 labeling index in the PD-L1-positive patients was higher than that in the PD-L1-negative patients.

Conclusion:
The expression of PD-L1 protein was associated with a poor prognosis in lung SCC patients. The 1% cut-off value for PD-L1 might become a better predictive marker than the other cut-off values, and notably, even minimal expression of PD-L1 protein may have a negative prognostic significance.

Background:
The preferential accumulation of NeuGcGm3 in a variety of malignant tumors, compared with healthy tissues, made this molecule as an attractive target for cancer immunotherapy . 14F7 monoclonal antibody is a highly specific IgG1 against NeuGcGM3 gangliosid. The immunohistochemical detection of NeuGcGM3 allow the potential selection of patients for specific therapy with anti-idiotype racotumomab cancer vaccine. Racotumomab is an anti-idiotype vaccine, mimics this ganglioside and triggers an immune response. Antibodies reactive to NeuGcGM3 ganglioside in the vaccinated patient’s sera have cytotoxic anti-tumor properties which can be assessed in L1210 cell line, expressing this ganglioside .

Method:
12 patients with advanced stage NSCLC, whose tumor tissue expressed NeuGcGM3 with 14F7 monoclonal antibody included in the study. Progressing patients, unresponsive to the 1.st line platinum doublets excluded from the study. 10 Patients received racotumomab as switch maintanance following the 1st.line chemotherapy, whereas 2 patients in Stage IIIA received Racotumomab as adjuvant. Antibodies to NeuGcGM3 have been detected with ELISA test,and cytotoxic tests was performed with hyperimmune patient’s sera in the L1210 cancer cell line expressing N-Glycol GM3, at the time of initiation, and at the 3rd,6th,9th, and 12th months of vaccination. Results of cytotoxic tests as a prognostic tool and clinical outcome of the patiens were compared. The assesment of the potential predictive value of NeuGcGM3 expressions in the tumor tissue for efficacy outcomes was also investigated.

Result:
Out of 12 patients, 11 patient's sera showed positive cytotoxic activity over cut off value, in NueGcGM expressing L1210 cell line. Mean PFS for these patients was 13.8(8-21) months. One patient’s PFS lasted as long as 21 months whose initial stage was IIIB. In 9 patients cytototoxic activity was progressively incresed at consecutive vaccinations on the 3rd, 6th, 9th and 12th months . There was no significant difference in between IHC staining intensities with 14F monoclonal antibody in terms of cytotoxicity results.

Conclusion:
As a result, we can assume that cytotoxic tests may predict prognosis in the vaccinated patients.When percentage of cytotoxicity progresivelly increase in consecutive assays, we can predict a better outcome, looking to the longer PFS of these patients.In this study we could not assess the potential predictive value of NeuGcGM3 expression in the tumor tissue for efficacy outcome, since there was no significant difference in between IHC staining intensities with 14F monoclonal antibody in terms of cytotoxicity results. However, the issue of NeuGcGM3 expression in the tumor tissue as a biomarker deserve further investigation.

Background:
It is important to seek predictive factors for the efficient use of immune check point inhibitors in non-small-cell lung cancer (NSCLC), because of the lack of a definitive predictive biomarker.

Method:
Study design for the analysis: A multicenter retrospective cohort study. Patient eligibility criteria: Consecutive patients treated with nivolumab between January 2016 and October 2016 after the second line systemic chemotherapy outside of a clinical trial. Definition of exposures: Variables were retrieved from the medical records before the administration of nivolumab. All variables were dichotomized based on previous study or median. Definition of study endpoint: Progression free survival (PFS) defined by response evaluation criteria in solid tumours (RECIST) 1.1. Two researchers evaluated the endpoint independently. Any disagreements were resolved by discussion. Statistical methods: Cox proportional hazards models were used to assess the impact of pretreatment markers on PFS. Missing values were imputed by multiple imputation.

Result:
A total of 189 patients were included in the study. Median follow-up time was 5.5 months. Fourty six (24%) patients were censored. Median age was 69 (range, 38–88); 26% were female. 64% had received ≧2 prior systemic therapies. In multivariate analyses, worse performance status, higher lactate dehydrogenase, and higher carcinoembryonic antigen,were independently associated with inferior PFS (Table 1). Figure 1



Conclusion:
Our study indicated that patients with NSCLC treated with nivolumab in routine practice, pretreatment performance status ≧2, carcinoembryonic antigen ≦13.8, and Lactate Dehydrogenase ≧217 were associated with inferior PFS. Another study is warranted to determine the precise utility of each marker take account of the programmed death-ligand 1.

Background:
Programmed cell death ligand 1(PD-L1) targeted immunotherapy is emerging as a promising therapeutic strategy for non-small-cell lung cancer (NSCLC). However, the association of PD-L1 and EGFR, KRAS, and ALK and other driver genes in NSCLC are not well known. To explore the potential association, we systematically integrated published articles and analyzed RNA-seq dataset from The Cancer Genome Atlas project (TCGA) in order to comprehensively investigate the association between PD-L1 and the mutation and expression of these common driver mutations.

Method:
The relevant articles published in English were searched by using the database of PubMed, Web of science and Embase up to September 2016. The effect sizes were estimated by odds ratio with a correspondent 95% confident interval (CI), which were pooled by random effect or fixed effect models. Subgroup and sensitivity analysis were performed and the Begg’s test was used to analysis the potential publication bias. We further applied the Pearson correlation analysis to investigate the association of PD-L1 and the expression of driver genes. Wilcoxon rank sum was used to evaluate the expression difference of PD-L1 among population.

Result:
A total of 9934 lung cancer cases were collected from 34 published studies. Patients with EGFR wild type (OR 0.68, 95% CI 0.48 to 0.96; P = 0.03), KRAS mutation positivity (OR 1.27, 95% CI 1.02 to 1.58; P=0.03) or non-adenocarcinoma histology (OR 0.68, 95% CI 0.47 to 0.98; P =0.04) were associated with high PD-L1 expression rate. However, PD-L1 expression was not associated with the status of ALK. Complementary to the findings of the meta-analysis, results from the TCGA project indicated that the expression of PD-L1 was significantly higher for patients with squamous cell carcinoma than adanocarcinoma (p=0.023) while the expression of common driver genes including EGFR, KRAS, ALK, MET, ROS1, PIK3CA, RET, HER2, NRAS and BRAF do not correlate with PD-L1 expression in NSCLC.

Conclusion:
High expression of PD-L1 was associated with the presence of EGFR wild-type, KRAS mutations or non-adenocarcinoma histology in NSCLC patients. Our results provide evidences for screening candidates for anti-PD-1/PD-L1 treatments.

Background:
Immunotherapy is a new research direction in the treatment of lung cancer. PD1/PD-L1, PD-L2 pathway as representative of the immune checkpoint, play critical roles in the development and progression of cancer. And the expression of PD-1, PD-L1, PD-L2 were associated with therapeutic effect. Many studys have shown that many factors may effect the expression of PD1, PD-L1, PD-L2, such as chemotherapy. The present study aims to examine the impact of neo-adjuvant chemotherapy (NAC) on PD-1, PD-L1, PD-L2 expression in lung cancer.

Method:
In this study, tumor samples were obtained from 26 patients who confirmed primary lung cancer prior to and after NAC（platinum-based）from June, 2009 to May, 2016 in the First Hospital of Jilin University. Expression of PD-1, PD-L1, PD-L2 in lung cancer tumor specimens were assessed by immunohistochemistry (IHC). Using 5%, 10%, 20%, 30%, 50% expression threshold to define PD-1, PD-L1, PD-L2 positive status, respectively. The variation of PD-1, PD-L1, PD-L2 in prior to and after NAC were evaluated by Matching chi-square test. Besides that, Spearman's rank correlation and non-parametric test were used to calculate the relationship between the changes of PD-1, PD-L1, PD-L2 and tumor shrinkage rate, interval from the end of NAC to operation, pathological type, gender, smoking or not. P value ＜ 0.05 was considered statistically significant.

Result:
Using 5%, 10%, 20% expression threshold to define PD-L1 positive status, 65.4%(17/26), 53.8%(14/26), 42.3%(11/26) were found to be PD-L1 positive prior to NAC, and 92.3% (24/26), 80.8%(21/26), 69.2%(18/26) expressed positively after NAC, PD-L1 was up-regulated after NAC（p=0.003, p=0.016, p=0.016）, however, there were no obviously statistical significance about the expression of PD-L1（p＞0.05）when using 30%, 50% expression threshold. The expression of PD1, PD-L2 were not show any statistical significance before and after NAC（p＞0.05）. Furthermore, there were no relationship between the changes of PD-1, PD-L1, PD-L2 and pathological type, interval from the end of NAC to operation, gender, smoking or not (p＞0.05）.Figure 1



Conclusion:
The expression of PD-L1 was up-regulated after NAC when using 5%, 10%, 20% expression threshold, there were obviously statistical significance. No correlations existed between the variation of PD-1, PD-L1, PD-L2 and tumor shrinkage rate, interval from the end of NAC to operation, pathological type, gender, smoking or not.

Background:
Proinflammatory cytokine Interleukin (IL)-17A (IL-17A) is the prototypical member of the IL-17 family of pro-inflammatory cytokines. It is produced by Th17 cells, CD8 T cells, γδT cells, and Natural Killer (NK) cells in the tumor microenvironment. The inflammatory milieu can contribute to lung cancer growth by further production of tumor promoting cytokines, reduction in cytotoxic T cells, and development of myeloid derived suppressor cells. IL-17A and its receptors are expressed across different tumor types; however, their exact role in tumor development, progression, and response to therapeutic regimens is unclear. IL-17A is overexpressed in a subset of patients with lung cancer. We hypothesized that IL-17A promotes a pro-tumorigenic inflammatory phenotype, and inhibits anti-tumor immune responses.

Method:
IL-17A is expressed at high levels in a subset of lung cancers. Interestingly, we observed that IL-17A could not be detected in Bronchoalveolar lavage fluids (BALFs) from immunocompetent mouse lung cancer models. To characterize the role of IL-17A in Kras mutant lung tumors, we developed a mouse model of chronic inflammation that more closely resembles human KRAS mutant lung cancer through expressing IL-17A constitutively in the lung epithelium and then introducing this allele into lox-stop-lox Kras G12D mutant mice. We performed immune phenotyping of mouse lungs, survival analysis, and treatment studies with antibodies either blocking PD-1 or IL6, or depleting neutrophils. To support preclinical findings, we analyzed human gene expression datasets and immune profiled patient lung tumors.

Result:
Tumors in IL-17:Kras G12D[]mice grew more rapidly, resulting in a significantly shorter survival as compared to Kras G12D. IL-6, G-CSF, MFG-E8, and CXCL1 were increased in the lungs of IL17:Kras mice. Time course analysis revealed that tumor-associated neutrophils were significantly elevated, and lymphocyte recruitment was significantly reduced in IL17:Kras G12D mice as compared to Kras G12D. In therapeutic studies PD-1 blockade was not effective in treating IL-17:Kras G12D tumors. In contrast, blocking IL-6 or depleting neutrophils with an anti-Ly-6G antibody in the IL17:Kras G12D tumors resulted in a clinical response associated with T cell activation. In tumors from lung cancer patients with KRAS mutation we found a correlation among higher levels of IL-17A and the colony stimulating factor (CSF3), and a significant correlation among high neutrophil and lower T cell numbers.

Conclusion:
Here we show that an increase in a single cytokine, IL-17A, without additional mutations, can promote lung cancer growth by promoting inflammation, which contributes to resistance to PD-1 blockade and sensitizes tumors to cytokine/neutrophil depletion.

Background:
Mounting evidence suggests the gut microbiome influences response to cancer immunotherapy. Antibiotic exposure (ATB+) alters the gut microbiome, and limited clinical data demonstrate ATB may negatively impact cancer immunotherapy response and survival outcomes. This study evaluates the impact of ATB+ on response and survival outcomes in patients with metastatic non-small-cell lung cancer (NSCLC) treated with programmed death-1 (PD-1) inhibitors.

Method:
We performed a retrospective review of all metastatic NSCLC patients treated with PD-1 inhibitors at our institution. A patient was considered to be in the ATB+ group if exposed to ATB within 6 weeks of initiating PD-1 inhibitors. All other patients were included in the antibiotic unexposed (ATB-) group. The primary outcome of interest was overall survival (OS), and secondary outcomes included overall response rate (ORR) and progression-free survival (PFS). ORR was compared between ATB+ and ATB- utilizing logistic regression modeling. The Kaplan-Meier method and Cox regression model were utilized to compare PFS and OS between ATB+ and ATB- groups.

Result:
A total of 74 patients met study eligibility criteria. The median age was 66 years old (range 33-88 years old). The majority of patients were male (55%), Caucasian (65%), and had adenocarcinoma histology (57%). A minority had brain metastases (15%) and radiation (38%) prior to receiving a PD-1 inhibitor. Most received nivolumab (95%). A total of 18 patients (24%) received antibiotics prior to initiating a PD-1 inhibitor, and most received fluoroquinolones (50%) for mild respiratory infections (72%). Antibiotic exposure did not impact ORR in our study. The ORR was 23% in ATB- and 25% in ATB+ patients (adjusted OR 1.2, p=0.20). ATB+ patients had inferior PFS compared to ATB- patients (median PFS 2.0 vs 3.8 months, p<0.001). Likewise, ATB+ patients had worse OS compared with ATB- (median OS 4.0 months vs 12.6 months, p=0.005). The association between ATB+ and inferior PFS (HR 2.5, p=0.02) and OS (HR 3.5, p=0.004) remained significant when controlling for age, sex, race, tobacco history, tumor histology, presence of brain metastases and previous radiation.

Conclusion:
To our knowledge, this is the first study evaluating the impact of ATB on survival outcomes with immunotherapy in metastatic NSCLC. ATB+ was associated with inferior PFS and OS, suggesting a link between antibiotic-induced alteration of the gut microbiome and efficacy of immunotherapy. While this is a relatively small retrospective study, it does generate justification for further investigation into the interaction between the gut microbiome and cancer immunotherapy.

Background:
Inhibitors of the immune checkpoint PD-1/PD-L1 (ICI) have become a standard of care in non-small cell lung cancer (NSCLC). The outcomes, although very promising, remain inconstant. Patient selection, currently based on PD-L1 expression in tumor tissue, must be improved, through more dynamic and non-invasive tests. PD-L1 staining of circulating tumor cells (CTCs) could represent such a valuable predictive biomarker.

Method:
Blood samples were prospectively collected from patients with advanced NSCLC before their first infusion of nivolumab. Ten ml of blood were collected and CTCs were isolated on cell size-based technology (ISET, Rarecells). PD-L1 expression was assessed by immunofluroescence (IF) on CTCs and immunochemistry (IHC).

Result:
60 advanced NSCLC patients were included. 45 tissue biopsies were available for PD-L1 expression analysis of: 31.4 (68.9%) and 9 (20%) of biopsies were positive, respectively, using a 5% and a 50% cut-off for tumor cell PD-L1 expression. 56 ISET filters were analyzed. The number of PD-L1(+) CTCs ranged from 1.5 to 47.5 per 7.5mL of blood (median 8.5, 12.5% of CTCs). No correlation between tissue and CTC staining of PD-L1 was observed. A optimal cutoff of 30/7.5mL number of CTCs was determined. Patients with elevated CTCs (>30/7.5mL) experienced a decrease of overall and progression-free survival (p=0.04 and p<0.0001 respectively). PD-L1 expression on CTCs at baseline was not predictive of outcome in the global population but significantly increased in “non-responders” group (PFS <6 months) in comparison with the “responder” group (PFS>6 months) (p=0.02).Figure 1



Conclusion:
We demonstrated the feasibility of PD-L1 detection in CTCs in patients with advanced NSCLC. In our cohort, PD-L1(+) CTCs are associated with a worse outcome. This can be partly explained by the pejorative impact of the number of CTCs that may outweigh its possible predictive value. The interest of PD-L1 assessment on CTC will be likely reinforced by integrating other biomarkers.

Background:
Targeting of the immune system has been found to confer clinical benefit for patients with some types of advanced solid tumor. Given that only a limited number of patients experience a durable response, whereas all those treated are at risk for specific immune side effects, the identification of individuals who are most likely to benefit from nivolumab and similar agents is an important clinical goal. We have now examined the possible impact of clinical parameters determined in the routine laboratory setting—including peripheral blood cell counts such as ANC, absolute lymphocyte count (ALC), absolute monocyte count (AMC), and absolute eosinophil count (AEC)—on outcome in patients with advanced or recurrent NSCLC treated with nivolumab.

Method:
A total of 134 patients with advanced or recurrent NSCLC treated with nivolumab was analyzed retrospectively. Univariable and multivariable analyses were performed to evaluate the relation between survival and peripheral blood parameters measured before treatment initiation, including absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count, and absolute eosinophil count (AEC) as well as serum C-reactive protein and lactate dehydrogenase levels. Progression-free survival (PFS), overall survival (OS), and response rate were determined. We further evaluated the association of these factors and the expression level of PD-L1 of tumor tissue.

Result:
Among variables selected by univariable analysis, a low ANC, high ALC, and high AEC were significantly and independently associated with both better PFS (P = 0.001, P = 0.04, and P = 0.02, respectively) and better OS (P = 0.02, P = 0.04, and P = 0.003, respectively) in multivariable analysis. Categorization of patients according to the number of favorable factors revealed that those with only one factor had a significantly worse outcome compared with those with two or three factors. Median PFS was 209, 87, and 42 days and the response rate was 43.5%, 27.1%, and 5.9% in patients with three, two, or one of the three favorable factors, respectively. The association between survival factors and the expresssion of PD-L1 in tumor tissue will be presented at the conference as well.

Conclusion:
A baseline signature of a low ANC, high ALC, and high AEC was associated with a better outcome of nivolumab treatment, with the number of favorable factors identifying subgroups of patients differing in survival and response rate.

Background:
For the past few years, the predictive role of programmed death-ligand 1 (PD-L1) for anti-PD1 immunotherapy in advance NSCLC has raised people’s attention. Tumor–infiltrating lymphocytes (TILs) are often observed in resected cancer tissue and anticipated in the host adaptive immune response against tumor cells as well. However, expression and the prognostic value of PD-L1 as well as CD8+ TILs in pulmonary neuroendocrine tumors (PNETs) have not been fully studied. The aim of our research is to investigate the status of PD-L1 expression and CD8+ TILs and to measure the prognostic value of PD-L1 and CD8+ TILs in different types of PNETs.

Method:
Totally 168 specimens of PNETs (36 TC, 7 AC, 100 SCLC, 25 LCNEC) were involved in this study. Immunohistochemistry (IHC) was used to detect the expression of PD-L1 on these cases. Cases demonstrating ≥ 5% tumor cell expression or any expression (>1%) of PD-L1 on TILs were considered positive. CD8+ TILs both within stroma and tumor areas of invasive carcinoma were analyzed using whole slide digital imaging. For each case, manual regional annotation and machine cell counts were taken. The number of positive cells has been evaluated by counting them in 4 peritumoral and 6 intratumoral non-overlapping fields using the fixed areas of 1.44 square milimeter.

Result:
PD-L1 was expressed on the membrane of tumor cells or immune cells of 72 cases (42.9%). Significant correlation was observed between CD8+ TILs and PD-L1 expression (P<0.001). For overall survival (OS) and progression free survival (PFS) analysis of PD-L1 as well as CD8+ TILs, there was no association between PD-L1 expression with OS and PFS, however, higher CD8+ TIL levels in stroma was demonstrated to have significant correlations with better OS (P=0.000) and PFS (P=0.020). Importantly, multivariate analysis revealed that CD8+ TILs in stroma was an independent prognostic factor for better OS (p=0.045) and PFS (p=0.006). In high grade NECs, similar analysis was performed and the result showed that positive expression of PD-L1 was associated with better OS (P=0.011) but not with PFS (P=0.383), in contrast, CD8+ TILs in stroma was proved to be an in­dependent prognostic factor for both of OS (p=0.035) and PFS (p=0.005) as well.

Conclusion:
We found that PD-L1 was expressed in about half of PNETs and correlated with better OS in NECs. Higher CD8+ TIL levels within stroma was positively associated with PD-L1 expression and proved to be an independent prognostic factor for favorable OS and PFS in PNETs and NECs.

Background:
Recent development of immune checkpoint blockade such as anti-PD-1 antibody brought great benefits to non-small cell lung cancer (NSCLC) patients. However, some population of NSCLC showed resistance and pseudo-progressions against anti-PD-1 checkpoint blockade. Thus, it is very important for developing biomarkers which predict of efficacy of PD-1 checkpoint blockade. In this background, we developed novel digital pathology system that predict for response to anti-PD-1 checkpoint blockade using H&E staining sections and technology of AI.

Method:
In this study, we extract 361 ROIs(Region of Interest) and 254,205 nuclei were measured from NSCLC cases that treated with anti-PD-1 antibody. We used ilastik for nuclei image segmentation, CellProfiler and our CFLCM tool for features measurement, 992 features are evaluated for each ROI. At first, we analyzed by step-wise discriminant analysis for select the effective features, and using canonical discriminant analysis and SVM (Support vector Machine) RBF kernel model discrimination, we analyzed morphological data based PD-1 blockade response on statistical platform R.

Result:
Except undeterminable cases, we got the more than 95% accuracy level discrimination results. The mapping the discriminant scores, SD cases were mapped in the middle of PR and PD. Only using the average and standard deviation of ROIs’ nuclei shape features (size, roundness, perimeter, etc.) and inside nuclei features (mainly chromatin texture) more than 90% discrimination results were obtained. This means the nuclei morphological data is more important than CFLCM (pleomorphism and heterogeneity measurement data). We challenged the prediction for undeterminable cases by using canonical discriminant and SVM.

Conclusion:
This time analysis is small number samples, so the results application robustness may be limited. But our results show the possibility for clinical response prediction even on the pre-treatment pathological tissues specimens.

Background:
Targeted exome sequencing (TES) using plasma ctDNA has been used in complementing tissue-based genomic assay for matching targeted molecular therapy for individuals with advanced solid tumors. However, concordance varies significantly in reported studies. Unlike tissue-based genomic assays, plasma ctDNA assays are more dependent on viable tumors producing sufficient ctDNA. The objective of this study was to explore successful detection of genomic alterations (GAs) and tumor metabolic activity by FDG PET/CT scan.

Method:
Plasma ctDNA samples extracted from frozen plasma (Group A) or fresh whole blood (Group B) samples were subjected to a 62-gene panel TES assay (FoundationACT™). The fraction of ctDNA in the blood was estimated using the maximum somatic allele frequency (MSAF) for each sample. Tumor load, assessed by RECIST V1.1, and tumor metabolic activity, assessed by SUVmax, were correlated with ctDNA GAs detected by FoundationACT™.

Result:
Patient characteristics are summarized in Table. MSAF was significantly higher in fresh blood than frozen plasma specimens. GAs (≥1) were detected in 50 cases (77%). Various tumor features contributing to undetectable GAs include low tumor burden, indolent growth, and tumor regression. Tumor metabolic activity (i.e., viable tumor burden) measured by SUVmax on FDG-PET scan correlated better with the detection of GAs in plasma ctDNA than tumor radiographic burden measured by RECIST V1.1 on CT scan (Table).

FoundationACT	Group A (N=14)	Group B (N=51)	Total (N=65)
Specimen Type	Frozen plasma	Fresh whole blood	All samples
Volume (mL)	~3.0	8.5 (6.0-11.0)	-
Age: median (range)	66 (44-74)	68 (50-93)	67 (44-93)
Gender: Female (N, %)	7 (50%)	32 (63%)	39 (60%)
Race/Ethnicity (N, %)
Hispanic	2 (14%)	6 (12%)	8 (12%)
Caucasian	10 (71%)	33(65%)	43 (66%)
Asian	2 (14%)	10 (20%)	12(18%)
African American	0	2(3%)	2 (4%)
Histology:
Lung adenocarcinoma	3 (21%)	40 (78%)	43 (66%)
Lung squamous cell carcinoma	11 (79%)	8 (16%)	19 (29%)
Others*	0	3 (6%)	63(5%)
GA ≥1	10 (71%)	40 (78%)	50 (77%)
MSAF (mean± SD); (GA ≥1 vs GA = 0)	0.122 ±0.250 vs 0.008±0.009 (P=0.185)	0.163±0.256 vs 0.002±0.004 (P=0.0003)	0.155±0.253 vs 0.004±0.006 (P=0.0001)
Tumor burden by RECIST V1.1 (GA ≥1 vs GA = 0) (mean ± SD)	7.1±6.2 vs 12.8±7.4 (P=0.182)	10.0±6.2 vs 6.9±3.6 (P=0.145)	9.4±6.2 vs 8.6±5.4 (P=0.682)
Tumor metabolic activity by SUVmax (GA ≥1 vs GA = 0) (mean ± SD)	47.6±30.9 vs 39.0±23.2 (P=0. 637)	48.3±30.9 vs 20.2±12.5 (P=0.003)	48.1±30.5 vs 25.6±17.6 (P=0.002)

*Other tumor types include lung small cell carcinoma (n=2); Lung large cell neuroendocrine (n=1). *P-values in abstract are calculated using unpaired t-test.

Conclusion:
Our study supports the clinical utility of plasma ctDNA genomic profiling in patients with metabolically active tumors that are measurable by SUVmax on PET/CT scan. Further study is needed to understand the biology of plasma ctDNA and to optimize imaging tools for quantifying tumor metabolism and guiding clinical use of plasma ctDNA assay.

Background:
Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have been approved as a standard therapy for metastatic non-small cell lung cancer (NSCLC). Although PD-L1 expression serves as a predictive biomarker for the efficacy of immunotherapy, there are no established biomarkers to predict the expression of PD-L1. The inflammatory markers C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) were recently shown to predict the efficacy of nivolumab for NSCLC patients. Therefore, here we investigated the potential association of PD-L1 expression with systemic inflammatory markers, including CRP, NLR, lymphocyte-monocyte ratio and platelet-lymphocyte ratio.

Method:
We retrospectively examined tumor PD-L1 expression in 508 surgically resected primary NSCLC cases by immunohistochemical analysis (cut-off value: 1%). The association of PD-L1 expression with preoperative systemic inflammatory markers was assessed by univariate and multivariate analyses. We generated a PD-L1 association score (A-score) from serum CRP level (cut-off value: 0.3 mg/dl) and smoking status to predict PD-L1 expression.

Result:
Among the total 508 patients, 188 (37.0%) patients were positive for PD-L1 expression at the 1% cut-off value and 90 (17.5%) had elevated serum CRP level. Multivariate logistic regression revealed that that PD-L1 positivity was significantly associated with advanced stage, the presence of vascular invasion and high serum CRP level (P=0.0336, 0.0106 and 0.0018, respectively). Though not significant, smoking history tended to be associated with PD-L1 protein expression (P=0.0717). There was no correlation with other inflammatory markers. Smoking history with elevated CRP level (A-score: 2) was strongly associated with PD-L1 protein expression (odds ratio: 5.18, P<0.0001), while it was inversely associated with EGFR mutation (odds ratio: 0.11, P<0.0001).

Conclusion:
Our results indicate that among all systemic inflammatory markers examined, serum CRP level could be a helpful biomarker for PD-L1 expression that is easily determined and available worldwide.

Background:
PD-L1 is induced by oncogenic signals or via INFG. STAT3, through DNMT1, epigenetically silences STAT1 and RIG-I and opposes INFG signaling. TET1 is a DNA demethylase. I kappa B kinase epsilon (IKBKE), a noncanonical I-kappa-B kinase, is essential for INFG induction, but can also promote NFATc1 phosphorylation and T cell response inhibition. Eomesodermin (Eomes) regulates T cell exhaustion. CCL5 (or Rantes), dependent on STAT3, causes myeloid-derived suppressor cell (MDSC) recruitment. YAP1 can also drive MDSC recruitment via CXCL5 signaling. We have explored whether the expression of genes related to INFG signaling, T cell exhaustion and MDSC recruitment is associated with response to ICB.

Method:
Total RNA from pre-treatment tissue samples of 17 NSCLC and 21 melanoma patients treated with nivolumab and pembrolizumab respectively, was analyzed by qRT-PCR. INFG, STAT3, IKBKE, STAT1, RIG-I and PD-L1 mRNA were examined. CCL5, YAP1, CXCL5, NFATC1, EOMES and TET1 expression was additionally assessed. Gene expression was categorized with respect to tertiles and patients were divided into two risk groups (low and intermediate/high). CD8[+ ]tumor-infiltrating lymphocytes (TILs) and PD-L1 protein expression in tumor and CD8[+ ]TILs were examined by immunohistochemistry (SP57 and SP142 assay, respectively). Progression free survival (PFS), overall survival (OS) and Disease Control Rate (DCR) were estimated.

Result:
Seventeen NSCLC patients, previously treated with one or more prior systemic therapies, received nivolumab. IKBKE was positively correlated with INFG (r=0.65, p=0.0124) and PD-L1 (r=0.58, p=0.0225) expression. RIG-I was loosely anticorrelated with NFATc1 (r=-0.55, p=0.0518). Among all biomarkers explored, only INFG was associated with PFS, OS and DCR. Specifically, PFS was significantly longer for nivolumab-treated patients with intermediate/high versus low INFG expression (5.1 versus 2.0 months, p=0.0124). OS was longer (though not statistically significant) for patients with intermediate/high versus low INFG expression (10.2 versus 4.9 months, p=0.0687). DCR to nivolumab was 71.43% for patients with intermediate/high INFG versus 0% for patients with low INFG expression. Neither PD-L1 immunohistochemistry expression nor CD8[+ ]TILs were related to nivolumab outcome. The same results were observed for 21 melanoma patients treated with pembrolizumab.

Conclusion:
IFNG production by T-cells plays critical roles in anti-cancer immune responses by augmentation of MHC Class I expression, growth arrest, post-proteasomal trimming of antigen epitopes, recruitment of effector cells, induction of T-regs fragility and PD-L1 expression. Further research is warranted in order to validate whether INFG is more accurate than PD-L1.

Background:
PD-L1 can be detected by immunohistochemical (IHC) analysis and has emerged as a biomarker that predicts which patients are more likely to respond to anti-PD-L1/PD-1 immunotherapies in non-small cell lung cancer (NSCLC)(1, 2). To date, there is no evidence to support or refute PD-L1 IHC staining on endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples. Our study aimed to establish the sensitivity, specificity, positive predictive value, and negative predictive value of PD-L1 IHC staining reliability on EBUS-TBNA samples, when compared to resected tumor specimens.

Method:
A retrospective review was performed on all patients who underwent an EBUS-TBNA of either a lymph node(s) or the tumor itself, who subsequently had surgical resection of their tumor between July 2006 through September 2016. Patients who had a concordant NSCLC EBUS-TBNA diagnosis with their resected tumor were included. Patients with small cell lung cancer were excluded. All EBUS-TBNA samples were obtained using Olympus EBUS bronchoscopes and a 22-gauge ViziShot needle (Olympus Medical Systems Corp., Tokyo, Japan). The Dako PD-L1 IHC 22C3 (Agilent Pathology Solutions) assay was used. A positive PD-L1 stain was defined as ≥1% of tumor cell positivity. EBUS-TBNA aspirates were compared with the surgically resected specimen to calculate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).

Result:
We performed 5448 EBUS-TBNA procedures for lung cancer. Seventy patients were included in our analysis. To date, 23 cases have been stained and reviewed (Table). The sensitivity and specificity was 71% and 100%, respectively. The PPV and NPV were 100% and 69%, respectively. We expect to complete our analysis of all patients prior to the IASLC World Conference.

Comparison of PD-L1 IHC stain between EBUS-TBNA samples and resected tumor specimen.

	Resected tumor PD-L1 positive	Resected tumor PD-L1 negative
EBUS-TBNA PD-L1 positive	10	0
EBUS-TBNA PD-L1 negative	4	9

Conclusion:
Positive PD-L1 IHC staining on EBUS-TBNA aspirates appears to have a strong correlation with resected tumor specimen. When EBUS-TBNA aspirates are negative for PD-L1 staining, additional tumor specimens are required to confirm the PD-L1 status.

Background:
For successful cancer immunotherapy, comprehensive profiling of cancer-immune system interaction is required for each individual patient. To this end, we developed an immunogram reflecting the cancer immunity cycle and applied it to real patients with lung cancer.

Method:
Whole-exome sequencing and RNA-Seq were performed in 25 non-small cell lung cancer patients (13 adenocarcinoma, 11 squamous cell carcinoma, and 1 large cell neuroendocrine carcinoma). The number of somatic mutations and the expression of genes related to cancer-immunity were assessed and normalized using TCGA-LUAD and LUSC data (n=1035). Immunogram of each patient was drawn in a radar chart composed of 9 axes reflecting 7 steps of cancer-immunity cycle.

Result:
Various patterns of immunogram were observed in all 25 lung cancer patients, suggesting that each patient has their own pattern of immunosuppressive microenvironment (Figure 1). The hierarchical clustering using each scores of immunogram showed four clusters of patients characterized by T cell phenotype (inflamed vs non-inflamed) and tumor antigenicity (high vs low) (Figure 2). T cell-inflamed tumors (Clusters 3&4) had gene signatures of abundant T cells and interferon gamma (IFNG) response, as well as inhibitory cells and checkpoint molecules, suggesting the presence of counter regulatory immunosuppressive microenvironment. Unleashing of counter regulations by checkpoint inhibitors, for example, may be indicated for these patients. Each scores of immunogram had no correlation with histology. This result was consistent with previous studies of checkpoint blockade that clinical responses were not easily predicted solely by the histology. Patient age, gender and TNM stage also did not correlate with each immunogram scores. Figure 1



Conclusion:
The landscape of the tumor microenvironment in each patient can be appreciated by utilizing immunogram. Immunogram for the cancer-immunity cycle can be used for the assessment and visualization of cancer immunity status in each patient, and thus may become a helpful resource toward optimal personalized immunotherapy.

Background:
The recognition of programmed cell death 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) as key therapeutic targets has led to the clinical development of several PD-1 and PD-L1 inhibitors as breakthrough treatments in advanced non small cell lung cancer. Although some patients experience durable tumour response, many do not derive any clinical benefit, therefore highlighting the importance of identifying methods to improve patient selection. PD-L1 expression on tumour cells with or without immune cells is the most reported association with anti-tumour activity of PD-1 blockade. Despite multiple publications, the use of different assays and cutpoints make it difficult to know if PD-L1 is a reliable biomarker for predicting outcomes to anti PD-1/PD-L1 treatment.

Method:
We performed a systematic search of MEDLINE, EMBASE, PubMed and conference proceedings up to 20 June 2017 and identified all clinical trials of anti PD-1 or PD-L1 monotherapy in advanced non-small cell lung cancer. We retrieved data regarding outcomes of 1 year overall survival (1yr OS), 1 year progression free survival (1yr PFS) and overall response rate (ORR), including 95% confidence intervals, in subgroups of varying PD-L1 tumour expression with cutpoints of 1%, 5%, 10%, 25%, 50% and 90%. Results were pooled and analysed based on different cutpoints. As PD-L1 expression is a continuum, we also tested for a correlation between outcomes and increasing cut-points of PD-L1 expression.

Result:
Of sixteen included studies with a total of 4,452 patients who received PD-1/PD-L1 inhibitor monotherapy, eight trials (n=821) reported on PD-1 blockade as first-line (1L) therapy and thirteen trials (n= 3,631) reported on treatment as second-line or beyond (>2L). Using 1% cutpoint, PD-L1 positivity was associated with higher ORR in 1L and >2L and 1yr PFS in >2L. Using a high cutpoint of 50%, PD-L1 positivity was associated with higher ORR in 1L and >2L, and higher PFS in 1L. Comparison of increasing cutpoints of PD-L1 expression and outcomes showed a positive correlation with 1yr PFS in 1L, a modest correlation with 1yr PFS in >2L and ORR in 1L and >2L, and little correlation with 1yr OS in 1L and >2L. Sensitivity analysis revealed no difference when excluding studies using the SP142 assay with weaker tumour staining.

Conclusion:
Within the limitations of current data, there is a positive correlation between increasing cutpoints of PD-L1 expression and ORR and 1yr PFS, but little correlation with 1yr OS in treatment naive and pretreated patients.

Background:
In non-small cell lung cancer (NSCLC) the TNM staging remains standard for prognostic assessment and therapy decisions. Nevertheless, stage-specific outcomes vary significantly, indicating a need for additional prognosticators.Lymphocytic infiltrates are found in 6-11% of NSCLC patients and associated with a significant increase in disease-free and overall survival (OS). We now want to assess T cells and PD-L1[+] cells in tissue microarrays (TMAs) cored at the invasive margin (IM) and tumor center (CT) via multispectral imaging. We asked the question of their link to interleukin-22 (IL-22). Furthermore, we want to elucidate the role of IL-22 in prognosis, therapy response and recurrence.

Method:
TMAs were generated from formalin-fixed paraffin embedded tissue of 89 curatively resected patients with stage IA-IIIA NSCLC. TMAs included each 3 cores from CT and IM, selected from areas with the most dense lymphocytic infiltrates. Immunolabelling followed mIHC technique for PD-L1, CD8, CD3, FoxP3, CD163 and Cytokeratin. IL-22 expression was analyzed by immunohistochemistry (double-staining: IL-22, CD3).

Result:
We could show that the ratio of CD8[+] cells in CT compared to IM is significantly higher in stage I than stage II/III NSCLC. A similar pattern was seen for CD3[+], but not for ratios of PD-L1[+], FoxP3[+] or CD163[+]. Based on the CT/IM ratios of CD8[+] and PD-L1[+] we established an 'Invasive Score' ranging from 0–2. A Score of 0 (low CD8, low PD-L1) had a median OS of 45 months. A score of 1 (high CD8 or PD-L1) had a median OS of 53 months. A score of 2 (high CD8 and PD-L1) had a 62% survival rate at 72-months: Combining the rate of CD8 T cell infiltrates with PD-L1 positivity in the tumor is a stronger predictor for survival than one based only on CD8 CT/IM ratio. We will now combine these results with the IL-22 expression and present the respective progression free and OS data.

Conclusion:
Multispectral assessment of CD8 and PD-L1 performed on “hot-spots” NSCLC does show a clear correlation with clinical outcome: A tumor-controlling immune response appears to be associated with the permeability of the tumor to CD8 cells. This is consistent with other reports that immune infiltrates are associated with improved outcome. Current studies are seeking to verify these findings in a larger cohort of patients with NSCLC. *Authors Stump and Reu contributed equally to this study. Supported by the Harder Family, Lynn and Jack Loacker, Robert W. Franz, Wes and Nancy Lematta, the Murdock Trust and Providence Medical Foundation.

Background:
Cancer testis (CT) genes are expressed in various types of cancer but otherwise restricted to normal tissues of testis and placenta. Several CT genes have shown to encode immunogenic proteins that are able to induce an anti-tumour response in cancer patients. The presence of autoantibodies towards expressed CT proteins could indicate which CT proteins that are more suitable for immunotherapeutic interventions, as these are recognized by the patient´s immune system.

Method:
Suspension bead arrays (Luminex) were used to analyse the presence of autoantibodies towards expressed CT proteins in plasma samples from patients with non-small cell lung cancer (NSCLC). The technology enables to screen for autoantibodies in minute amount of patient plasma. Protein fragments with an average length of 80 amino acids, produced within the Human Protein Atlas, were coupled to unique beads, allowing multiplex analysis of 244 different autoantibodies towards antigens representing 198 unique genes in each sample. The primary sample set included 51 samples from 34 individuals taken before radiation therapy and 17 samples taken after radiation therapy. Longitudinal plasma samples taken during radiation therapy were available for most individuals resulting in a total of 89 samples.

Result:
Of 198 analysed CT genes, autoantibodies against antigens representing 25 genes were detected in at least one of the 51 samples from the primary study set. The autoantibody detection ranged from five different autoantibodies in two individuals to no detected autoantibodies in seven individuals. Among those individuals with samples available both before and after radiation therapy (n=13), the autoantibody profiles were not altered by the treatment. Three individuals however showed autoantibodies towards one additional protein in the sample taken after radiation therapy compared to the sample before radiation. In two individuals, autoantibodies detected towards one protein in the sample taken before radiation were not detected in the sample taken after radiation. Unsupervised hierarchical clustering with 25 detected autoantibodies and all 89 samples showed that samples from the same individual cluster based on the autoantibodies´ profile. There was no apparent association of autoantibody profiles with clinical parameters (histology, gender, age, stage). However, patients with detected autoantibodies showed a longer overall survival than patients without autoantibodies.

Conclusion:
This study provides a first comprehensive analysis of autoantibody detection against antigens representing 198 CT genes. Among the identified autoantibodies only AKAP4 has been reported previously in NSCLC. The individual autoantibody profiles showed only minor differences between samples taken before, during and after radiation therapy.

Background:
There is an increasing impact of the immunotherapy in the treatment of NSCLC. The accurate characterization of immune cell infiltrates in the in situ environment of cancer is regarded to be of major importance to predict prognosis and to guide therapy. The aim of this study was to perform a multi-marker characterization of immune cells and to evaluate their spatial distribution patterns with regard to patient survival.

Method:
A tissue microarray including 55 cases of non-small cell lung cancer (NSCLC) was used to perform multiplex immuno-fluorescent staining with antibodies against CD8, CD20, CD4, FoxP3, CD45RO and pan-cytokeratin (Opal, Perkin Elmer). The staining was digitalized by a multispectral imaging system (Vectra 3, PerkinElmer). Single cell marker expression profiles and their tissue coordinates were used to evaluate cell quantity and spatial distribution patterns. The data were validated with conventional immunohistochemical staining on consecutive sections.

Result:
Based on the co-expression of single immune markers we determined eight different classes of immune cells. While CD8+ single positive cells are evenly distributed in the stroma and tumor cell compartment, CD20+ and CD4+ cells were predominantly located in the stroma. Based on the immune cell subtypes we could define patients with a predominant B-cell response and patient with dominating T-cell infiltrates. No statistically significant impact on survival was found with regard to the abundance of immune cell subpopulations. When the spatial relation of stromal CD8+ regulatory T cells (CD8+FoxP3+) was considered, the shorter distance (< 20 μm) between CD8+FoxP3+ cells and tumor cells was associated with shorter survival (median 34 vs. 76 month, HR=2.6, 95%CI 1.3-6.8, log-rank p<0.01).

Conclusion:
The fluorescence multiplexed IHC technique provides a multi-marker characterization and spatial information for single cell-level analysis of immune infiltration patterns. Spatial localization of CD8+ regulatory T lymphocytes in relation to cancer cells is associated with overall survival in NSCLC.

Background:
Immunohistochemical testing for PD-L1 expression is increasingly used as a predictive biomarker for anti PD-1/PD-L1 immunotherapies in non-small cell lung cancer (NSCLC). We report here the experience of population-based PD-L1 testing using the 22C3 antibody in the routine clinical practice of a large regional reference pathology laboratory.

Method:
PD-L1 testing was performed by the PD-L1 immunohistochemistry (IHC) 22C3 PharmDx assay (Agilent) using a Dako Link48 autostainer, according to the manufacturer’s instructions. Testing was performed on (1) all biopsies and resections for NSCLC performed at University Health Network (UHN) and partner hospitals between August 1, 2016 and March 31, 2017; (2) all cases of NSCLC referred from external sources for EGFR/ALK testing; and (3) cases of pulmonary squamous cell carcinoma referred in specifically for PD-L1 testing. PD-L1 IHC was also performed retroactively on archived UHN cases upon request by oncologists, dating from January 1, 2013. Tumour Proportion Scores (TPS) were reported in three categories (no expression, <1%; low expression, 1-49%; and high expression, ≥50%).

Result:
A total of 2027 PD-L1 IHC were performed on specimens from 1814 patients, of which 110 (5.4%) were reported as indeterminate, mostly due to insufficient tumor cellularity. Indeterminate results were more frequent in biopsy (6.4%) vs. resection (2.7%) specimens. For the remaining 1917 evaluable tests, proportions in each TPS category were: <1% (42.3%); 1-49% (28.5%); ≥50% (29.3%). In 1482 tests with known EGFR mutation status, EGFR-mutated tumors (n=296) demonstrated lower rates of PD-L1 expression [TPS <1% (51.7%); 1-49% (29.4%); ≥50% (18.9%); P<0.01]. No statistically significant difference in PD-L1 expression was detected in ALK-rearranged tumors (n=29). Of 100 patients with successful PD-L1 staining in both a biopsy and paired resection specimen, 57/100 (57%) demonstrated concordant TPS categories in both specimens. Only 22/49 (44.9%) biopsies with TPS<1% showed TPS<1% in the resection, while 26/49 (53.1%) and 1/49 (2.0%) showed TPS 1-49% and ≥50%, respectively. Of biopsies with TPS 1-49%, 17/29 (58.6%) were concordant in the resection, while 5/29 (17.2%) and 7/29 (24.1%) showed TPS <1% and ≥50%, respectively. Among biopsies with TPS≥50%, 18/22 (81.8%) were concordant in the resection, while 4/22 (18.2%) showed TPS 1-49% in the resection.

Conclusion:
In our population-based study, PD-L1 expression in NSCLC using the 22C3 antibody demonstrated similar prevalence as reported in clinical trials. EGFR mutated but not ALK rearranged tumors were associated with lower PD-L1 expression. Intra-tumoral heterogeneity of PD-L1 expression may result in its under-estimation in biopsy specimens compared to paired resection specimens.

Background:
In spite of the results achieved by nivolumab in advanced non-small cell lung cancer (NSCLC), reliable predictive factors are still needed, and even the expression of the programmed death protein 1 ligand (PD-L1) has a limited role in predicting benefit from this agent. Our aim was to determine whether the expression of other molecules involved in immune response might be associated with outcomes of NSCLC patients receiving nivolumab.

Method:
This retrospective study included patients treated with nivolumab for advanced NSCLC (Nivolumab Cohort). Response rate (RR) and progression-free survival (PFS) were assessed by response evaluation criteria in solid tumors (RECIST) v 1.1 and immune-related response criteria (irRC). Available tumor specimens were analyzed by immunohistochemistry (IHC) in order to determine the expression of PD-L1, PD-1 ligand 2 (PD-L2), PD-1, B7-H3, and B7-H4. The possible correlations between IHC findings and clinical outcomes were explored. Additionally, the meaningful biomarkers observed in the Nivolumab Cohort were assessed in a population of NSCLC patients treated with platinum-based chemotherapy (Chemotherapy Cohort) and the results from the two cohorts were compared in order to determine whether the administered treatment played a role in our observations.

Result:
The Nivolumab Cohort included 46 evaluable patients. The following proportions of positive IHC samples were observed: PD-L1=15.22%; PD-L2= 17.39; PD-1= 67.39%; B7-H3= 13.04%; B7-H4= 36.96%. At univariate analysis, patients expressing B7-H4 ≥1% had significantly lower PFS compared to those patients with B7-H4 <1% according to RECIST (1.67 vs. 2.00 months; p= 0.026) and irRC (1.73 vs. 2.17 months; p= 0.039), as well as a numerically lower overall survival (OS; 4.37 vs. 9.83 months; p= 0.064). At multivariate analysis for OS, PD-L1 ≥1% had favorable effect (HR= 0.29; p= 0.027), while B7-H4 ≥1% had unfavorable effect (HR= 2.98; p= 0.006). No other correlation was observed in this cohort. Within the Chemotherapy Cohort (n=27), no significant correlation between IHC findings and response or survival was observed. At the multivariate analysis including both cohorts, a statistically significant interaction was observed between OS and the combined effect of B7-H4 expression and treatment (p= 0.048), favoring nivolumab in B7-H4 <1% patients (HR= 0.60) and chemotherapy in B7-H4 ≥1% patients (HR= 0.67).

Conclusion:
A meaningful negative correlation between B7-H4 expression and outcomes was observed with nivolumab, but not with chemotherapy. In spite of a relatively small patient population, our results strongly encourage further studies exploring the potential role of B7-H4 as predictor of outcomes during treatment with nivolumab.

Background:
We have shown that the iSEND model may be predictive of clinical outcomes for advanced NSCLC (aNSCLC) patients receiving nivolumab but little is known of its potential performance for patients on other PD-1/PD-L1 inhibitors (PD-1/PD-L1i), chemotherapies (Chemo) or Targeted Kinase Inhibitors (TKIs).

Method:
We evaluated clinical outcomes of 325 aNSCLC patients who received second-line PD-1/PD-L1i (nivolumab, pembrolizumab, or atezolizumb, n=203), first-line platinum followed by maintenance (Chemo, n=81), and TKIs (erlotinib, afatinib, or crizotinib, n=41). As described in our previous reports, the iSEND model (Sex, ECOG [Performance status], NLR [Neutrophil-to-Lymphocyte Ratio] & DNLR [Delta NLR = NLR after treatment - pretreatment NLR]) was developed. We stratified each treatment group by iSEND and compared progression free survivals (PFS) and clinical benefit rates (CBR) at 12+/-2 weeks in the iSEND Good vs. the iSEND Others (Intermediate and Poor).

Result:
Median follow-up was 9.5 (95% CI: 7.1-11.9), 11.7 (95% CI: 4.5-18.9) and 9.3 months (95% CI: 4.5-14.2), respectively for PD-1/PD-L1i, Chemo, and TKIs groups. In the PD-1/PD-L1i group, PFS was better in the iSEND Good than the iSEND Others with a median of 17.4 vs. 5.1 months, (HR: 0.32, 95% CI, [0.20-0.50], p<0.0001) (Figure 1). In contrast, PFS was not better in the iSEND Good in Chemo (HR, 0.69, 95% CI, [0.42-1.20], p=0.19) or TKIs (HR, 0.89, 95% CI, [0.43-1.84], p=0.75). The area under the curves (AUC) of the iSEND for CBR at 12+/-2 weeks for aNSCLC patients treated with PD-1/PD-L1i was 0.72, (95% CI: 0.65-0.79, p<0.0001). The AUCs of iSEND for CBR in Chemo and TKIs were not significant. Figure 1. Kaplan-Meier curves for PFS in PD-1/PD-L1i, Chemo, and TKIs stratified by iSEND Good vs. Others Figure 1



Conclusion:
In our single-institution retrospective cohort, the iSEND model showed a predictive potential for advanced NSCLC patients treated with PD-1/PD-L1i but not for those treated with Chemo or TKIs

Background:
We developed an algorithmic model namely, the iSEND (Sex, ECOG performance status, NLR [Neutrophil-to-Lymphocyte Ratio] & DNLR [Delta NLR =NLR posttreatment - pretreatment NLR]) to predict the clinical outcomes of aNSCLC patients receiving nivolumab. Performance of the iSEND has not been compared with other potential immunotherapy biomarkers like TMB.

Method:
We identified 36 aNSCLC patients who received nivolumab after platinum with commercial TMB reports. As described in our previous reports, the iSEND was used to categorize patients into good, intermediate, and poor groups. 36 matched patients were also categorized into high TMB: ≥ 20 m/Mb (mutations per megabase), intermediate TMB: 6-19 m/Mb, and low TMB: ≤5 m/Mb. We evaluated progression free survival (PFS), and overall survival (OS). Performances of the iSEND and TMB were correlated with clinical benefit at 12+/-2 weeks by receiver operating characteristic (ROC) curves.

Result:
The median follow-up was 18.4 months (95% CI: 10.1-26.7). There were 16 deaths. The number of patients from iSEND good, intermediate, and poor groups were 12 (33%), 18 (50%), and 6 patients (16%), respectively. The median overall survivals of iSEND good, intermediate, and poor groups were 15.7 (10.8-20.58), 10.3 (4.8-15.7), and 3.7 (0-7.8) months, respectively (p=0.00006). The median overall survivals for high, intermediate, and low TMB groups were unreached, 10.3 (4.7-15.9), and 12.4 (7.1-17.7) months, respectively. (p=0.211, Figure1) The area under ROC curve of the iSEND for clinical benefit at 12+/-2 weeks was 0.733 (p=0.025, 95% C.I.: 0.56-0.90). Four intermediate iSEND patients who had OS less than 6 months had low TMBs. Figure 1. Kaplan-Meier curves for Overall Survival by iSEND model and TMBFigure 1



Conclusion:
From a limited retrospective single institutional database, iSEND characterized the clinical outcomes of aNSCLC patients on nivolumab well and high TMB correlated with better outcomes. A larger cohort validation is encouraged to explore the mutual supplementary benefit for improved performance.