bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of immunotherapy in non-small cell lung cancer patients with poor performance status.
Authors: Lobefaro Riccardo , Viscardi Giuseppe , Di Liello Raimondo , Massa Giacomo , Iacovino Maria Lucia , Sparano Francesca , Ferrara Roberto , Signorelli Diego , Proto Claudia , Prelaj Arsela , Galli Giulia , De Toma Alessandro , Brambilla Marta , Ganzinelli Monica , Trevisan Benedetta , Bottiglieri Achille , De Braud Filippo G. , Morgillo Floriana , Garassino Marina Chiara , Lo Russo Giuseppe 
Published: May 2020

e21601 Background: The introduction of Immunotherapy (IO) has dramatically improved the prognosis of patients (pts) with advanced Non-Small Cell Lung Cancer (NSCLC). However, data regarding the role of IO in ECOG Performance Status (PS) 2 pts are generally limited in randomized trials, and real-world evidences could support clinical decision-making. Methods: We retrospectively analyzed data about pts with stage IV NSCLC treated with IO between April 2013 and December 2019 in two Italian Centers. The aim of our study was to assess the impact of PS status (0-1 vs 2) on disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Response was classified according to RECIST v1.1 criteria. PFS and OS were estimated by the Kaplan-Meier method. Chi-square test was used to compare clinical-pathological variables: gender, age ( < 70, 70-79, ≥80 years-old), smoking status, histology (squamous, non-squamous), PDL1 expression ( < 1%, ≥1%), IO line (1°, ≥2°), number (N) of metastatic sites (1, ≥2), presence of liver and/or brain metastasis. Their impact on survival was evaluated through Cox proportional hazard models. Results: Four-hundred-one pts (35.7% female) with median age of 65.4 years (range 27-88) were studied. Baseline PS was 0 in 134 pts (33.4%), 1 in 209 pts (52.1%) and 2 in 58 pts (14.5%). 312 pts had non-squamous NSCLC, 89 squamous NSCLC. Clinical-pathological variables were uniformly distributed across PS groups except for a higher rate of liver metastasis in PS2 pts ( p= 0.046). Response evaluation was available for 386 pts. DCR was 49.7% in PS0-1 pts and 25.9% in PS2 pts ( p= 0.006). At a median follow-up of 29 months (mos), median PFS was 3.0 mos (95% CI 2.63-4.00) and 2.04 mos (95% CI 1.84-3.00) in pts with PS0-1 and 2 ( p< 0.0001). Median OS was 13.2 mos (95% CI 11.18-15.78) and 4.0 mos (95% CI 2.66-5.62) in pts with PS 0-1 and 2 respectively ( p< 0.0001). Univariate analysis showed significant correlation of PS2 status, negative PDL1, IO line ≥2, N of metastatic sites ≥2 and liver metastasis, for both PFS and OS. Multivariate analysis confirmed an independent association of PS ( p= 0.0013 for PFS, p< 0.0001 for OS), PDL1 ( p= 0.0002 for PFS, p= 0.02 for OS) and liver metastasis ( p= 0.017 for PFS, p= 0.02 for OS). The incidence of Grade 3/4 adverse events was 10.5% in PS 0-1 pts and 13.7% in PS 2 pts ( p= 0.41). Conclusions: Our data confirm reduced efficacy of IO in pts with poor PS, regardless of the N of prior therapy lines or PDL1 expression. Despite IO appears to be safe and tolerable its role remains uncertain in PS2 pts based on worse survival outcomes.
Molecular subtyping reveals stage-specific mutational landscape and prognostic predicting factors of stage IV NSCLC.
Authors: Huang Yuqing , Yang Yingshun , Yao Jianfei , Liu Qiang , Wang Bingzhi , Min Xianjun , Pei Guotian , Wang Shuai , Wang Xiaoyu , Liu Jun , Dang Shiying , Huang Tanxiao , Xu Mingyan , Song Lele 
Published: May 2020

e21607 Background: The mutational profile of non-small cell lung cancer (NSCLC) has been widely studied. However, the correlation between mutational profile and the prognosis of various molecular subtypes of NSCLC has not been fully investigated. Methods: We established the mutational landscape from 244 stage I-IV NSCLC patients using a 605-gene next generation sequencing panel. Molecular subtyping was performance based on the mutational status of EGFR, TP53, KRAS and STK11 genes according to reported methods. Sequencing data were analyzed with R packages and statistics analysis was performed with Graphpad PRISM 5.0 software. P ≤ 0.05 was regarded as statistically significant. Results: Differential SNV/INDEL mutation frequency across stage I-IV was found in EGFR, TP53, ATM, CDKN2A and NF1 (P < 0.05), differential CNV frequency was found in EGFR, RB1, PIK3CA, TERT, KRAS, FGFR1 and ERBB2 (P < 0.05), and differential SV frequency was found in ROS1 (P < 0.05). TMB of stage III-IV patients was higher than those of stage I (P < 0.05). TMB was higher in patients with TP53 but without EGFR mutations (P < 0.05). The association between prognosis and mutational status was further investigated in stage IV NSCLC. Patients with EGFR SNV/INDEL mutations exhibited better PFS and OS time, while patients with KRAS and/or STK11 SNV/INDEL mutations, or without mutations in EGFR, TP53, KRAS and STK11 exhibited worse PFS and OS time. However, no significant difference was observed in PFS and OS between patients with or without TP53 SNV/INDEL, EGFR CNV, ERBB2 CNV or TERT CNV variations. Further analysis showed that male or age≥62 exhibited worse OS time (P < 0.05), while smoking history, palliative surgery and palliative radiotherapy did not affect the PFS and OS time of stage IV patients. Conclusions: We found differential frequency in SNV/INDEL, CNV and SV variations across stage I-IV NSCLC. EGFR SNV/INDEL, KRAS SNV/INDEL, STK11 SNV/INDEL mutation, gender and age were found to be prognostic predicting factors for stage IV NSCLC.
Real-world evidence: Molecular subtype and its prognostic implications of Lung-molGPA in EGFR-mutated adenocarcinoma.
Authors: Kuan Feng-Che , Shi Chung-Sheng , Yang Wei-Hsun , Lai Hung-Yi , Huang Chun-Chieh , Yang Cheng-Ta 
Published: May 2020

e21621 Background: EGFR mutations are heterogenous but all carry the same weight in the Lung-molGPA. The aim of this study was to elucidate the different prognostic implications of molecular subtypes and frontline TKIs in EGFR-mutated lung adenocarcinoma with synchronous brain metastases (BM) using the Lung-molGPA. Methods: Medical records were searched in hospital databases from 2011 to 2015. Patients with EGFR-mutated adenocarcinoma and brain metastases who received TKIs were included. The Kaplan-Meier method was used to estimate survival, and multivariate Cox proportional hazard models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results: A total of 256 patients were included with a median overall survival (OS) of 17.2months. Patients with Lung-molGPA scores of 1, 1.5-2.0, 2.5-3.0, and 3.5-4.0 had median OS of 5.9,11.5, 17.2, and 23.4months, respectively (p < 0.001). In multivariate analysis of OS, only age (³70 versus < 70 years, HR:1.71, 95% CI:1.25-2.35, p < 0.001), KPS ( < 70 versus ³70, HR:1.71, 95% CI:1.26-2.31, p < 0.001), and rare mutations (other versus exon 19 deletions, HR:1.78, 95% CI:1.04-3.05, p = 0.037) remained statistically significant. In patients with a Lung-molGPA score £2.5, EGFR molecular subtypes had different median OS (exon 19 deletions versus Leu858Arg versus other, 18.9vs 12.8vs 4.5months, p = 0.021) and prognostic implications (Leu858Arg versus exon 19 deletions, HR: 1.85, 95% CI: 1.20-2.84, p = 0.005; other versus exon 19 deletions, HR:2.18, 95% CI:1.11-4.26, p = 0.023). Conclusions: Different molecular subtypes treated with frontline TKIs have different prognostic implications in the Lung-molGPA. Further prospective studies are warranted to validate these findings.
Advanced Lung Cancer Inflammation Index: Prognostic value in a retrospective lung cancer cohort.
Authors: Syrigos Konstantinos N. , Patsilinakou Stavroula , Grapsa Dimitra , Chrysanthopoulou Evangelia , Gkiozos Ioannis , Kavantzas Nikolaos , Politi Ekaterini 
Published: May 2020

e21624 Background: As shown in recent studies, inflammation plays a key role in lung cancer (LC) pathogenesis and evolution, while the potential prognostic and predictive value of various inflammation markers in different disease stages is being extensively studied. We herein aimed to further evaluate the potential prognostic value of a new inflammation marker (ALI, Advanced Lung Cancer Inflammation Index = BMI x Alb / NLR), which combines previous markers of systematic inflammation with markers of nutrition or cachexia at the time of LC diagnosis. Methods: The medical records of 67 patients, diagnosed with LC in Sismanoglio Athens General hospital, within a two-year period (January 2016-January 2017) were retrospectively studied. Demographic, clinicopathological and laboratory features of patients, including pre-treatment ALI, were recorded and correlated with prognosis (overall survival, OS). Results: A total of 67 patients were included with a mean age of 60 (± 8) years. The majority of cases were men (39/67,58.2 %), with positive smoking history (62/67, 92.5%), performance status (PS) 1-2 (43/67, 64.2%) and disease stage IV (54/67, 80.6%). Adenocarcinoma was the commonest histological type observed (19/67, 28.5%). Values of ALI ranged from 7.8 to 37.2 (mean: 21±6). The cut-off point of ALI was 19 (based on ROC curve analysis) and patients were divided into two groups: those with ALI < 19 and those with ALI ≥ 19. In univariate analysis, PS and the presence of metastatic disease, as well as ALI values < 19, were all correlated with reduced survival (p = 0.002, p = 0.028 and p = 0.018, respectively). In multivariate analysis, PS was the only parameter that retained its statistically significant correlation with an adverse prognosis (p = 0.048), although its prognostic significance was increased when combined with ALI. Conclusions: Although failing to confirm an independent prognostic value for ALI, the results of our study suggest that combination of ALI with standard prognostic predictors such as PS may improve prediction of patients’ survival. Additional prospective studies are warranted to validate the prognostic significance of this promising biomarker and expand its use in routine practice.
Association of baseline characteristics and survival in patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (CPIs): Real-world evidence.
Authors: Crawley Danielle , Beckmann Kerri , Ravindra Saranya , Josephs Debra Hannah , Spicer James F. , Montes Ana , Karapanagiotou Eleni , Ghosh Sharmistha 
Published: May 2020

e21625 Background: CPIs including antibodies to programmed death-1 (PD-1) and its ligand anti PD-L1 are associated with superior overall survival (OS) in NSCLC. PDL1 is an imperfect predictive biomarker. We have examined real world data to identify additional factors associated with clinical benefit. Methods: 96 consecutive NSCLC patients (pts) were treated with CPIs at our institution. Multivariate cox proportional hazard regression models were used to examine the associations between OS and baseline characteristics including age, sex, histology, PDL1 status, performance status (PS), steroid use and brain metastases. Results: 93% (89/96) of pts received pembroluzimab, 6 (6%) nivolumab, and 1 (1%) atezoluzimab. All pts had metastatic disease (68% adenocarcinoma). 15% had PS 0, and 70% PS1. 11 of the 96 pts had brain metastases prior to CPI, 4 (37%) had whole brain radiotherapy, 2 (18%) targeted radiotherapy, 2 (18%) resection with radiotherapy and 3 (27%) had no definitive treatment for brain metastases. After multivariate analysis those with PS 1-2 had an increased risk of death (PS = 1 HR 2.74, 95% CI 1.11-6.72; PS = 2 3.61, 95% CI 1.28-10.15) compared with PS 0. Outcomes for pts receiving corticosteroids at the time of initiation of CPI were also inferior (HR 2.29, 95% CI 1.10-4.74) compared to those who were not. Conversely those who had brain metastasis diagnosed prior to commencing CPI had superior OS (HR 0.29 95% CI: 0.11-0.76). No statistically significant association was seen with age, gender, histology, stage at diagnosis, smoking or mutational status. PDL < 50% compared to > 50% was associated with an increased risk of death (HR 1.53 95% CI: 0.90-2.60) though it was not statistically significant. Conclusions: Here we show, using real world data, that PS and use at baseline of oral corticosteroids are associated with inferior OS with CPI treatment for NSCLC, in line with reports from large clinical trials. We show that baseline brain metastases are associated with improved outcomes. This may be explained by survivor bias, in that those who are successfully treated for brain disease, remain PS ≤2 and are able to commence CPI represent a highly selected group.
Exploratory analysis of factors associated with hyperprogression in advanced non-small cell lung cancer (NSCLC) treated with PD1/PDL1 inhibitors.
Authors: Decatris Marios P. , Thomas Joy A , Hayes Mark , Ryan Philip , Phillips Aled , ElBatrawy Sherouk , Bowden Caitlin , Du Rand Ingrid 
Published: May 2020

e21634 Background: Hyperprogressive disease(HPD) is a recently recognized type of accelerated tumor progression with immune checkpoint inhibitor(ICI) therapy. A recent meta-analysis identified serum lactate dehydrogenase(LDH) above upper limit of normal(ULN), liver metastases and > 2 metastatic sites to be associated with increased likelihood of HPD. Methods: We performed a single-center retrospective analysis of NSCLC patients treated with ICI from 2/2017-1/2020. We defined HPD using combined criteria of failure to complete > 4 cycles of ICI and radiological progression with development of new lesions or marked clinical progression where restaging was not achievable because of rapid decline in performance status. Treatment discontinuation/interruption because of toxicity alone, was not designated as HPD. Results: HPD was seen in 9/41(22%) patients treated with at least 1 cycle of ICI. In 6/9 there was marked radiological progression (new lesions/significant progression of existing lesions); in the remaining 3 restaging was not possible because of rapid decline which mandated treatment cessation. Patients with HPD were more likely to have a raised LDH, liver metastases or > 2 metastatic sites but these differences were not statistically significant. 9/9 versus 5/32 patients in the HPD/non-HPD cohorts respectively progressed within 10 weeks of treatment (p < 0.001) and 7/9 versus 12/32 respectively did not survive beyond 6months (p = 0.057). Conclusions: This small study has shown a non-statistically significant trend for association between HPD, raised LDH, liver metastases and presence of > 2 metastatic sites. A better understanding of risk/predictive factors for HPD is essential for improved patient selection for treatment with ICI. [Table: see text]
C-reactive protein (CRP) as a predictive biomarker in lung cancer patients receiving immune checkpoint inhibitors (ICI).
Authors: Ananthula Aneesha , Konda Manojna , Bimali Milan , Safar Ahmad Mazen , Govindarajan Rangaswamy 
Published: May 2020

e21645 Background: C-Reactive Protein (CRP) is an acute phase reactant which is elevated in inflammatory conditions and malignancy. Elevated CRP levels are associated with poor prognosis in many cancers and has been reported in patients with melanoma treated with ICI. We examined the association between CRP levels during therapy with ICI in patients with advanced lung cancer and radiological response. Methods: A retrospective study of patients with metastatic lung cancer (stage IV) who were treated with immunotherapy from 2016 to 2019 was conducted. CRP levels were checked at or soon after initiation of therapy and at frequent intervals thereafter. Association between CRP levels and response was determined. Results: 36 patients had initial (at the beginning of therapy, baseline) and subsequent CRP levels recorded during the first course of immunotherapy. Among the 36 patients, 16 (44%) had radiological response or stable disease, and 20 (55%) had radiological progression. The median age was 69 years (range 50 – 89 years); male/female 35/1, Caucasian/African American/other 26/9/1. There was no significant difference in distribution of initial CRP levels between patients with response vs progression as assessed by Kruskal-Wallis test (P-val: 0.20). Logistic regression modeling was employed to examine the association between final CRP level, the last measurement while on ICI therapy (adjusted for baseline CRP level) and odds of observing a response. A unit increase in final CRP level was associated with 4% decrease in odds of observing a response (Odds Ratio, 95% CI: 0.96, 0.92-1.00, P-val: 0.05). Conclusions: Baseline-adjusted final CRP levels were inversely associated with likelihood of observing a response in advanced lung cancer subjects treated with ICI. Further validation in prospective studies is warranted.
Clinical and molecular characteristics of TSC1/2 mutant lung cancer.
Authors: Wang Yanye , Xu Song , Zhao Shikang , Zhu Shuai , Li Xiongfei , Lei Xi , Chen Jun , Chen Gang 
Published: May 2020

e21647 Background: Tumor suppressor genes TSC1 and TSC2 inhibit cell growth through inactivation the function of mTORC1. Previous studies have demonstrated that loss of function mutation of either TSC1 or TSC2 gene result in formation of neoplasm in multiple tissues. However, the clinical significance of TSC1 and TSC2 in non-small-cell lung cancer (NSCLC) remains unknown. This study aimed to investigate the clinical and molecular characteristics of TSC1 and TSC2 mutation in NSCLC patients. Methods: We retrieved the clinical and genomic information of 1144 NSCLC from the Pan-Lung cancer dataset through the cBioportal ( www.cbioportal.org) . The cohorts of TSC1 and TSC2 mutant patients were identified. We compared baseline characteristics of patients with the Fisher exact test for categorical data and the Mann-Whitney U test for continuous variables. Overall survival (OS) was estimated with Kaplan-Meier curves, and differences were compared with the log-rank test. Results: Among 1144 patients, 27(2.36%) of them had TSC1 mutation and 40 (3.50%) had TSC2 mutation. Most patients with TSC1 and TSC2 mutations coexisted with other oncogenic gene alterations. TP53 was the most frequent concurrent gene (n = 53), followed with ERBB family genes (n = 24) and KRAS (n = 15). Compared to squamous cell carcinoma, TSC1/2 mutation was slightly more common in adenocarcinoma (53.7% vs 46.3%). 61.2% TSC1/2 mutant patients were male and 88.1% patients had former/current smoking history. Kaplan–Meier analysis showed that the patients harboring TSC1 mutation had a median OS of 14.1 months, whereas patients with TSC2 mutation had a median OS 110.6 months. However, there was not a statistically difference (P = 0.201). Conclusions: TSC1/2 mutation may define a unique population of NSCLC, which often coexists with other oncogenic gene alterations such as TP53 mutation. The function of TSC1/2 mutation and the value of TSC1/2 as therapeutic target in NSCLC are under investigation.
A randomized phase II trial of olaparib maintenance versus placebo monotherapy in patients with chemosensitive advanced non-small cell lung cancer.
Authors: Fennell Dean A. , Lester Jason Francis , Danson Sarah , Blackhall Fiona Helen , Nicolson Marianne , Nixon Lisette Sheena , Porter Catharine , Gardner Georgina Mary , White Ann , Griffiths Gareth Owen , Casbard Angela Claire 
Published: May 2020

e21649 Background: Impaired DNA damage response (DDR) is a common feature of cancer, however therapeutic exploitation has been limited to cancers harbouring somatic inactivation of BRCA1/2 which causes homologous recombination deficiency (HRD). We hypothesized that patients (pts) with metastatic non-small cell lung cancer responding to platinum doublet based chemotherapy, might enrich for impaired DDR encompassing HRD, rendering these tumours more sensitive to inhibition of poly-ADP ribose polymerase (PARP) inhibition by olaparib. Methods: PIN was a multicentre double-blind placebo controlled randomised phase II screening trial (alpha and beta = 0.2). Chemonaive pts had advanced (stage IIB/IV) squamous (Sq) or non-sq (NS) NSCLC, ECOG performance status 0-1, no EGFR nor ALK mutation. Prior immunotherapy with a PD1/ PDL1 inhibitor was allowed. If tumour shrinkage was observed after 3 cycles of platinum chemotherapy, pts were randomised 1:1 to olaparib (O, 300mg po bd q21) or placebo (P), which was continued until disease progression or withdrawal. Primary end point was progression free survival (PFS), with a one-sided test for significance. Secondary endpoints were overall survival (OS), response (RECIST v1.1) and safety (CTCAE4.0). Results: 70 pts were randomised to O (32) or P (38) between Aug 2014 and Nov 2017. There was no difference in median dose intensity (% (IQR), O vs P) was 86.4 (64.3-95.7) vs 93.3 (80.2-97.6). Pts receiving O had a longer, but not statistically significant median PFS (weeks (IQR) was O 16.6 (7.1-21.7) vs P 12 (5.6-18.7)); and hazard ratio (HR) was 0.83 (80% CI 0.6-1.15, p = 0.23), using intention to treat (ITT) unadjusted analysis. However, the ITT Cox model, adjusted for smoking history and histology, showed a significantly longer PFS for pts receiving O (HR 0.73 (80% CI 0.52-1.02, p = 0.11)). Pts receiving O also had greater, but not statistically significant OS: median (weeks (IQR) was O 59.4 (38.7-67.9) vs P 31.3 (22.4-58.6)). OS HR was 0.68 (95% CI 0.37-1.26; two-sided p = 0.22). 3 patients were completely withdrawn prior to progression. No complete responses were observed and treatment was well tolerated. Conclusions: Design parameters justifying a Phase III trial (p < 0.2) were met in the adjusted, but not unadjusted PFS analysis, with a trend towards longer PFS and OS in the O arm. We speculate that this signal may be driven by a DDR deficient molecular subgroup. Translational studies are warranted to investigate these possibilities. Clinical trial information: NCT01788332.
Clinical activity and safety profile of dacomitinib in advanced epidermal growth factor receptor-positive non-small cell lung cancer patients with brain metastases.
Authors: Zhang Jinyao , Wang Shouzheng , Yang Ke , Xing Puyuan , Junling Li 
Published: May 2020

e21656 Background: Dacomitinib is a second-generation epidermal growth factor receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) which has been shown to be superior to first-generation EGFR TKI, gefitinib in both progression- free survival and overall survival outcomes in EGFR+, non-small cell lung cancer (NSCLC) patients in a Phase III, randomized study, ARCHER 1050. However, the activity of dacomitinib in the central nervous system (CNS) is not known as ARCHER 1050 did not include patients with baseline brain metastases (BM). To our knowledge, this is the first chart review which describes dacomitinib’s activity in the CNS in a real-world setting. Methods: 24 patients who were receiving dacomitinib (30 mg daily) for advanced NSCLC harboring EGFR sensitive mutations, either Exon 19 deletion or Exon 21 L858R substitutions were included in this study. Hospital chart was retrospectively reviewed to identify patients with baseline brain metastases (n = 6). Treatment outcomes of these patients who were presented with baseline brain metastasis were analyzed. Results: Among the 6 patients, median age was 54.5 years (range, 41-74), 4 were male, ECOG PS 0 and 1 were 1 and 5, respectively. All of them had non-squamous NSCLC with asymptomatic BM and 5 with no measurable BM lesion. One patient had dose reduction due to drug-related adverse events. One patient has not reached the 4-week RECIST assessment at data cut-off. The intracranial ORR and DCR among 5 response- evaluable patients with at least one follow-up disease assessment were 40% and 100% (2/5 complete response, 3/5 stable disease). All patients are having ongoing treatment (median follow-up:3-months). Patients experienced low-grade (G1/2) toxicities which are reversible, including diarrhea, rash, paronychia and stomatitis. Conclusions: This chart review suggests, for the first-time, that dacomitinib may have CNS efficacy in patients with untreated EGFR+ NSCLC in the real-world setting. Due to the small number of patients included in this chart review, the findings need to be confirmed in future studies.