bluuebunny/crossref_metadata_2025_split huggingface dataset:
The genomic characterization of different progression patterns in advanced lung cancer (LC) patients upon immune checkpoint inhibitor (ICI) treatment.
Authors: Zhong Hua , Li Jingwen , Xiang Chan , Wang Yue , Zhou Yan , Cao Shuhui , Ling Xuxinyi , Ye Junyi , Zheng Jingjing , Shao Lin , Han Yuchen 
Published: May 2020

e21653 Background: Hyperprogressive disease (HPD), characterized by a rapid increase in tumor growth rate (TGR), has been reported in 13.8% NSCLC patients (pts) treated with ICI. Besides, 10.4% of NSCLC pts experience FP (fast progression) and/or early dearth (ED) upon atezolizumab. Although defined differentially, it has been shown that these progression patterns have overlapped portions. The molecular characteristics in different progression patterns have not been well elucidated and compared. Methods: 117 advanced LC pts treated with ICI were recruited, whose progression pattern was assessed according to the following criteria: FP was defined as ≥ 50% increase in the sum of long diameters within 6 weeks (wks) of ICI start; ED was defined as deaths within 12 wks. HPD was defined as the change in TGR greater than 50% compared with that prior to the initiation of ICI (TGR2/TGR1 > 1.5). There were 14, 8 and 9 ED, FP and HPD patients respectively. 5 patients were qualified for than one definition and 1 patient qualified for all 3 definitions. Tissue samples from 36 pts (18 FP/ED/HPD patients) were subjected to genomic profiling using a panel of 520 cancer-related genes. For genomic comparison, additional 693 non-HPD, non-ED and non-FP LC samples with matched TMB and histology were retrieved from our internal database. Results: The FP, HPD and ED occurred in 7.21%, 9.38% and 11.97% pts, respectively. The PFS was comparable among the 3 groups (P = 0.541). The median OS for FP, HPD and ED was 3.19, 11.2 and 1.84 months, respectively (P < 0.001). The genomic landscape of 18 FP/ED/HPD pts revealed 1 EGFR amp, 1 ALK fusion, 6 KRAS mutations, 1 ERBB2 amp, 1 MET amp and 1 RET fusion. Two ED pts harbored concomitant STK11 and KRAS mutations. MDM2 and MDM4 mutations co-occurred in 1 ED patient. 1 patient with ED and HPD had MDM4 mutation. Genomic comparison analysis revealed that ED pts had higher mutation frequency in KRAS (P < 0.01) and CDKN1B (P < 0.01) comparing with the 693 controls. Furthermore, FP pts were more likely to have RAD54L (p = 0.018) an MYC (p = 0.04) mutations. HPD pts showed higher rate of RAD54L (P < 0.001) and ARID1A (p = 0.04) than controls. Conclusions: We revealed FP, HPD and ED have comparable PFS but significant difference is OS. We also demonstrated different genomic characteristics associated with different progression patterns upon ICI treatment, which might further facilitate clinicians to stratify pts for ICI therapy.
Immune-related adverse events and outcomes during treatment with immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) patients.
Authors: López Gallego Javier , Ayala de Miguel Pablo , Gorospe García Itziar , Rivera Vargas Pablo René , Posada Restrepo Andrea , Aires Machado Jonathan , Alonso Calderón Rubén , Rodríguez García José Manuel , Ceballos Barbancho Eduardo , Acero Caballero Alfonso , Illán Varella Andrea , Quintana Cortés Laura , Borrega Garcia Pablo 
Published: May 2020

e21662 Background: Immunotherapy of cancer has changed the paradigm of treatment of many tumours, specially non-small cell lung cancer (NSCLC). The use of immune-checkpoint inhibitors (ICI) is associated in some patients with the development of new immune-related adverse events (irAEs). Our aim was to study if there is any correlation between the appearence of irAEs and the efficacy of ICI. Methods: We collected data of 104 patients diagnosed of advanced NSCLC and treated with ICI in monotherapy at our institution between December 2015 and December 2019. Several variables as clinical, tumour-related and therapeutical were included and univariate and multivariate Cox regression analysis were performed. Results: Cohort of 84 men and 20 women, median age of 67 years and 86% with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 89% were active or ex-smokers and 11% had never smoked. 60% of patients had adenocarcinoma histology, 39% scamous and 1% had not otherwise specified (NOS) carcinoma histology. 3% of patients had III-B stage at the moment of start of immunotherapy, 37% M1a, 30% M1b and 30% M1c. 2 patients had driver mutations in EGFR gene. 41% of patients had unknown PDL1 status; 14% had no PDL1 expression, 14% low expression and 31% high expression. 78% of patients had progressed to prior line of treatment, while 22% were treatment-naive. irAEs occured in 65% of patients; 12% developed grade 3 to 4 toxicities. More frequent irAEs were fatigue (54%) and rash (27%). Significant statistical variables in univariate analysis were included in multivariate analysis by Cox regression. The appearence of any grade of iRAE was associated with improved progression-free survival (PFS) (median 17.9 months vs 5.1 months; HR 7.12; p = 0.008). Those patients who experimented any grade of irAE were more likely to achieve stabilization or response than those who suffered progression of disease (HR 13.00; p < 0.001; 95% CI [3.47-48.78]. The use of corticosteroids during treatment with ICI was not related to the benefit of treatment. Conclusions: Appearence of immune-related adverse effects during treatment with ICI was associated with better outcomes in our population. The use of corticosteroids during immunotherapy didn´t have any deleterious effect on the efficacy of treatment.
Radiogenomics for the prognosis in advanced non-small cell lung cancer patients receiving bevacizumab.
Authors: Li Butuo , Jiang Chao , Pang Linlin , Fan Bingjie , Ding Mingjun , Sun Xindong , Yu Jinming , Wang Linlin 
Published: May 2020

e21669 Background: In the new era of immunotherapy, the regimen based on bevacizumab is still one of the standard options for treatment of advanced non-small cell lung cancer (NSCLC) patients without driver mutations. However, the prognostic factors for bevacizumab are still missing. We aimed to determine the integrative value of computed tomography (CT), epigenetic modifications, clinicopathological and systemic inflammatory factors for predicting the survival of advanced NSCLC patients with bevacizumab. Methods: Clinicopathological parameters, dynamic systemic inflammatory factors, radiomics features, and DNA methylation profiling in advanced non-squamous NSCLC patients receiving first- or second- line bevacizumab plus chemotherapy were included in this study. The prognostic radiomics signature were constructed by least absolute shrinkage and selection operator (LASSO) Cox analysis. A multi-omics prediction nomogram for progression-free survival (PFS) based on radiomics, clinicopathological and systemic inflammatory features was established and independently validated. Furthermore, radiomics signature-related DNA methylation were submitted to functional enrichment analysis. Results: Total of 272 patients were included in analysis, 224 in training cohort and 48 in validation cohort. Five radiomics features, including Information Measure Corr1, Inverse Variance, Local Std Max, Gauss Area, Spherical Disproportion, were finally selected to construct radiomics signature with the AUC of 0.71. Smoking history, anatomical feature, liver metastasis, LDH4, NLR2 and radiomics signature were found to be independent prognostic factors for PFS. A multi-omics nomogram was developed based on these features in training cohort with the C-index of 0.76, and external validated with the C-index of 0.75. The tissue slices of 20 patients receiving bevacizumab were used for DNA methylation profiling. Functional enrichment analysis indicated widespread and statistically significant associations between radiomics features and DNA methylation changes which involved in several pathways related to angiogenesis and immune system, such as Notch signaling pathway, small GTPase Rho signal transduction, TGFβ signal transduction. Conclusions: This multi-omics nomogram integrating radiomics, clinicopathological, systemics inflammatory features improved the prediction of PFS in advanced NSCLC patients receiving bevacizumab. And the radiomics signature were found to be related to angiogenesis and immune status.
The potential of a CLIA-certified prognostic/predictive molecular test to address the rising costs of non-small cell lung cancer.
Authors: Mann Michael J , Jablons David , O'Day Ken , Su Wayne , Sundar Padma 
Published: May 2020

e21671 Background: Treating recurrences of non-small cell lung cancer (NSCLC) is increasingly expensive but still rarely curative. Disease free survival (DFS) among resected stage I-IIA patients remains only 50-70%. Guidelines advocate adjuvant therapy in “high-risk” patients in this population to reduce these costly and deadly recurrences, but recognize that conventional criteria have not been validated to stratify risk or predict benefit. A CLIA-certified, commercially available 14-gene expression risk profile (DetermaRx) has been extensively validated among stage I-IIA non-squamous NSCLC patients; prospective data now suggest that the test predicts improved DFS with adjuvant therapy. We therefore studied the potential economic impact of this molecular test on early stage NSCLC. Methods: Model variables included: relative increase in DFS with adjuvant treatment of molecular intermediate- and high-risk patients (25.5%; range 12.3-41.3%); cost of adjuvant ($8,760; $8,144-$9,376) or late-stage ($284,500; $224,900-345,200) treatment; and compliance with recommendations for adjuvant therapy (75%; 60-90%). Ranges were based on: historical trials and recent prospective data, published cost literature, and published survey data, respectively. Parameters were varied in a multifactorial, one-way sensitivity analysis to assess the impact of parameter uncertainty. Results: Reduction of recurrences with implementation of the 14-gene assay resulted in an average cost savings of $11,608/patient (potential systems savings of ~$450 million), even when including the cost of molecular risk stratification ($4000/patient) and of cisplatin-based adjuvant chemotherapy for molecular high- and intermediate-risk patients. Lower bound assumptions for relative improvement, cost of care, and compliance yielded persistent savings of $3,699, $8,091 and $8,486, respectively. Conclusions: Utilization of this predictive molecular risk stratification assay in the management of stage I-IIA non-squamous NSCLC has the potential to significantly reduce lung cancer costs in an era of targeted therapy and immunotherapy, while at the same time improving DFS and saving lives.
A pilot study of nintedanib in molecularly selected patients with advanced non-small cell lung cancer (NSCLC) (NCT02299141).
Authors: Waqar Saiama Naheed , Rawat Usha , Morgensztern Daniel , Shah Sanjana , Ward Jeffrey P. , Devarakonda Siddhartha Hk , Rearden Timothy Patrick , Gao Feng , Govindan Ramaswamy 
Published: May 2020

e21694 Background: Nintedanib is a small molecule tyrosine kinase inhibitor targeting VEGFR1-3, PDGFR and FGFR. The purpose of the study was to evaluate the response rate for patients with advanced non-small cell lung cancer (NSCLC) with mutations in TP53, VEGFR1-3, PDGFR-A, PDGFR-B, and FGFR1-3 treated with nintedanib as part of an open label, single arm pilot study. Methods: Patients with advanced NSCLC previously treated with platinum-doublet chemotherapy with ECOG PS≤1 and adequate organ function were enrolled. Exclusion criteria included cavitary or necrotic tumors with invasion of major blood vessels, history of recent thromboembolic events, predisposition to bleeding or thrombosis, myocardial infarction and weight loss > 10% within past 6 months. Nintedanib was administered at a dose of 200 mg orally twice daily during each 28-day cycle until disease progression or unacceptable toxicity. Response assessments were performed every 8 weeks. The primary endpoint was overall response (ORR) by RECIST 1.1. Secondary endpoints included progression-free survival (PFS) and correlating outcomes with specific mutations. Results: Between 5/7/2015 and 11/15/2019, 20 patients were enrolled to study. The median age was 66 years, 15/20 (75% were females), 17/20 (85%) had received prior immunotherapy and 11/20 (55%) had received at least three prior lines of systemic therapy. The ORR was 15% with 3/20 partial responses (PR), while 12 patients had stable disease (SD), with disease control (PR+SD≥16 weeks) rate of 60% (12/20). The median progression-free survival and median overall survival were 18 weeks (95% CI: 8-31) and 48 weeks (95% CI:15-56) respectively. All three responders had a TP53 mutation and had received prior immunotherapy. There were nine grade 3 events including transaminitis in 20%, while one patient each (5%) experienced hyperbilirubinemia, anorexia, fatigue, hypertension, and nausea. Grade 4 events included transaminitis (10%) and cerebral edema (5%). There was one grade 5 cardiac event, which was unrelated to nintedanib. Conclusions: In this pilot study in heavily pretreated and molecularly selected patients with metastatic NSCLC, nintedanib showed modest activity. Clinical trial information: NCT02299141.
Clinical outcome of local treatment in synchronous oligometastatic non-small cell lung cancer (NSCLC): A preliminary analysis of prospective data.
Authors: Li Shangbiao , Zhu Xiaoxia , Zheng Zhihao 
Published: May 2020

e21698 Background: Advanced NSCLC is a heterogeneous disease, a large number of retrospective studies suggested that patients with oligometastases may achieve long-term survival from aggressive local treatment. However, relevant prospective studies were limited. Therefore, we prospectively evaluated the role of local treatment in synchronous oligometastatic NSCLC. Methods: We prospectively identified 50 NSCLC patients newly diagnosed with synchronous oligometastases (≤5)in two centers between 11/2017 and 12/2019, among whom there were 24 patients from a randomized clinical trial NCT03119519. Patients were given first-line systemic therapy according to the latest NCCN guidelines with either local radiotherapy or surgery to thoracic primary tumor and/or radiotherapy to metastases. They were divided into combined therapies (Tx), systemic Tx and untreated groups. Kaplan Meier Survival analysis was used to compare progression free survival (PFS) and overall survival (OS) among the groups. Results: Median age of all patients was 61 years old (range: 27-80 years) and median follow up was 5.7 months (range: 0.5-23.3 months). A total of 10 deaths were observed. In the combined Tx group, 23 patients received radiotherapy, and 2 patients received primary surgical resection. The median OS of the combined Tx group (n = 25), the systemic Tx group (n = 19) and the untreated group (n = 6) was 18.47 months, not reached, 3.27 months, respectively. Compared with the untreated group, the combined group and the systemic Tx group had better OS (hazard ratio [HR] = 0.1047, p = 0.0001; HR = 0.1125, p= 0.0006). However, the patients in the combined group did not show significant OS advantage compared with those in the systemic Tx group (HR = 1.376, p= 0.667). In addition, we conducted an ITT analysis in clinical trial NCT03119519, in which 8 progression events were observed. There was no significant difference in PFS between the combined group (n = 13) and the systemic Tx group (n = 11) (13.2 months vs. not reached, HR = 1.317, p= 0.7015; 1-year PFS: 74% vs. 54%, p = 0.7015, respectively). Conclusions: Current analysis shows that the addition of local treatment to first-line systemic Tx does not improve PFS and OS. More samples, further updated data and selection of potential beneficer are necessary. Funding: 81972853, 81572279, 2016J004, LC2019ZD009, 2018CR033. Clinical trial information: NCT03119519.
Immunotherapy efficacy of strong positive PD-L1 expression non-small cell lung cancer (NSCLC) patients: A systematic review and meta-analysis.
Authors: Lu Hongmin , Cui Longgang , Bai Yuezong , Zhang Yuzi , Zhao Zhengyi 
Published: May 2020

e21701 Background: Immune-checkpoint inhibitors (ICIs) based therapy has been approved as the new 1L standard of care in advanced PD-L1 strong positive (>=50%) non-small cell lung cancer (NSCLC). However, little is known about the differences of efficacy between monotherapy and combined therapy of checkpoint inhibitors. We did a systematic review and meta-analysis to assess the heterogeneity of efficacy between monotherapy and combined therapy in 1L PD-L1 strong positive NSCLC patients. Methods: We systematically searched PubMed, Cochrane library, Embase and and major conference proceedings from January 2000 to November 2019 for randomized controlled trials that had available hazard ratios (HRs) for death according to PD-L1 expression (>=50%). The primary outcome was the difference in overall survival (OS). We calculated the pooled overall survival HR and 95% CI in monotherapy and combined therapy in 1L PD-L1 strong positive NSCLC patients using a random-effects model. Results: A total of 2211 publications were retrieved through initial literature search, 10 randomized controlled trials were included for this meta-analysis. No statistical differences were found between ICIs monotherapy and combined therapy (HR 1.09, 95% CI 0.88- 1.35). Subgroup analysis showed that immune monotherapy has similar effects to immune combined chemotherapy (HR 1.24, 95% CI 0.90-1.71) and immune combined immunotherapy (HR 1.01, 95% CI 0.81-1.27). Conclusions: For PD-L1 strong positive (>=50%) NSCLC patients, ICIs monotherapy had similar efficacy when compared with ICIs combination therapy.
A randomized phase II multi-institutional trial of anlotinib plus docetaxel versus docetaxel in EGFR-wild-type non-small cell lung cancer (NSCLC) patients after progression on first-line platinum-base chemotherapy: ALTER-L018.
Authors: Wu Lin , Wu Zhijun , Xiao Zemin , Weng Jie , Ma Zhongsha , Chen Yanhua , Xiao Maoliang , Cao Yongqing , Duan Huaxin , Cao Peiguo , Zhang Hui , Wang Qianzhi , Li Jia , Xu Yan , Pu Xingxiang , Li Kang 
Published: May 2020

e21703 Background: Anlotinib is an oral VEGFR, FGFR, PDGFR and c-Kit tyrosine kinase inhibitor, which can prolong both PFS and OS of refractory advanced NSCLC patients in phase III trial: ALTER0303. The combination of docetaxel and ramucirumab/nintedanib had been demonstrated activity in the second line therapy setting for NSCLC. We performed ALTER-L018 to assessed the safety and efficacy of anlotinib with docetaxel in EGFR-wild type refractory advanced NSCLC (NCT03624309). Methods: Patients (pts) with EGFR-wild type refractory advanced NSCLC, who failed to first-line platinum-based chemotherapy, were randomized to group A(anlotinib: 12mg QD from day 1 to 14 of a 21-day cycle +docetaxel: 75mg/m2 Q3W) and group B(docetaxel: 75mg/m2 Q3W). The primary end points is PFS, and secondary end points include OS, ORR, DCR and safety. Results: Between January and December 2019, 36 pts were enrolled at 10 institutions in Hunan China, with 31(15 in group A, 16 in group B) of these individuals being evaluable for treatment efficacy and safety. Pt characteristics(group A/ group B): median age: 55(39-70)/57(44-67); male: 73%/81%; non-squamous NSCLC: 86%/75%. Median PFS were 5.3 months (95%CI:2.76-7.85) in group A and 2.3 months (95%CI, 1.14-3.46) in group B (HR 0.42; 95% CI:0.16-1.13; p = 0.047); In group A and B, ORR and DCR were 26.67% versus 0%(p = 0.043), 60.00% versus 31.25%(p = 0.16), respectively. Among 31 pts, 89% of treatment-related AEs (TRAEs) were grade 1 or 2, and the most common TRAEs in group A were hand-foot syndrome, pruritus and insomnia of 13%(2/15) each; in group B were alopecia, constipation and anemia of 12%(1/16) each. Toxicities≥grade 3(TRAEs) included: neutropenia, leukopenia, diarrhea and hrombocytopenia, 6.6%(1/15) each in group A. There was 1 grade 5 AE in group A. Conclusions: This combination of anlotinib and docetaxel with significant difference PFS prolonging and manageable safety profile, is a viable option in relapsed NSCLC, should be considered following progression on platinum-based chemotherapy. It will be further explored in a randomized phase III trial. Clinical trial information: NCT03624309.
Impact of chemoradiotherapy (CRT) on immune-related tumor microenvironment and the efficacy of anti-PD-1 therapy after the recurrence of CRT in unresectable locally advanced NSCLC patients.
Authors: Shirasawa Masayuki , Yoshida Tatsuya , Motoi Noriko , Matsumoto Yuji , Shinno Yuki , Okuma Yusuke , Goto Yasushi , Horinouchi Hidehito , Yamamoto Noboru , Watanabe Shun-ichi , Ohe Yuichiro 
Published: May 2020

e21719 Background: Chemoradiotherapy (CRT) followed by durvalumab as maintenance therapy prolonged progression-free survival (PFS) and overall survival (OS) in unresectable locally advanced NSCLC (LA-NSCLC). Additionally, the history of radiotherapy and CRT has been reported to increase the efficacy of PD-1 blockade in advanced NSCLC patients. We evaluated the efficacy of anti-PD-(L)1 antibody therapy after CRT failure, and how CRT changes the status of PD-L1 expression on tumors and tumor infiltrated lymphocytes (TILs) in tumor microenvironment (TME) in unresectable LA-NSCLC patients. Methods: We retrospectively reviewed unresectable LA-NSCLC patients treated with CRT between December 2007 and December 2018, and evaluated the efficacy of PD-1 blockade after CRT failure. We also analyzed PD-L1 (clone: 22C3) expression on tumor cells, and CD8 positive TILs using the paired specimens that had been obtained pre-CRT and post-CRT failure. Results: We identified 422 patients who received CRT. Median follow-up was 36.1 months (range 2.7–138.1 months). Among these patients, sixty-five patients who had progressed post-CRT received anti-PD- (L)1 therapy (PD-1 therapy: 61 patients, PD-L1 therapy: 4 patients). Response rate (RR) and PFS of anti-PD-(L)1 therapy were 48% (95% CI, 35–60) and 8.7 (95% CI, 4.5–13.0) months. The RR and PFS did not differ according to PD-L1 expression levels (Table). Of the 18 patients, 9, 7, and 2 showed upregulation in PD-L1 expression or down- or no change, respectively, post-CRT. In contrast, the density of CD8 positive TILs in TME increased by CRT treatment ([pre-CRT]: median, 110 ± 239 /mm2 vs. [post-CRT]: median, 470 ± 533 /mm2, p = 0.025). Conclusions: The clinical outcome of anti-PD-(L)1 therapy after CRT failure in LA-NSCLC patients could be better than advanced NSCLC patients, but did not differ according to PD-L1 expression levels. The efficacy of PD-(L)1 therapy enhanced by CRT treatment could be due to the infiltration of CD8 T-cells into TME. [Table: see text]