bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of PD-L1 expression with hotspot mutations in non-small cell lung cancer (NSCLC).
Authors: Wan Renping , Zhang Xiaoni , Qu Hongyue , Li Hui , Li Yingmei , Xu Mingyan , Xiao Yun 
Published: May 2020

e21604 Background: PD-L1 is of great interest in many clinical trials on immunotherapy as a promising biomarker, however, its role in targeted therapy and correlation with hotspot mutations remains unclear. Methods: From May 6th 2019 to Jan 27th 2020, 609 NSCLC patients were prospectively enrolled. Targeted deep sequencing (~3000X) with a 605-gene panel was performed on tumor and blood sample from each patient. The expression of PD-L1 was tested by immunohistochemistry. PD-L1 expression level was defined as negative ( < 1%), low (1%~50%), and high (≥50%). Results: In the total 609 patients, the expression of PD-L1 was negative in 36.9% (n = 256), low in 51.7% (n = 315) and high in 11.3% (n = 69) of them. In 440 patients harboring hotspot mutations, 35.0% (n = 154) of them were identified as PD-L1 negative, 52.3% (n = 230) as PD-L1 low and 12.7% (56/440) as PD-L1 high. In 169 patients without hotspot mutations, there were 42.0% (71/169) of patients with negative PD-L1 expression, 50.3% (85/169) with low PD-L1 expression and 7.7% (13/169) with high PD-L1 expression. Mutation frequencies of several hotspot mutations were summarized in Table. Conclusions: This study showed that PD-L1 expression was associated with some hotspot mutations, such as BRAF_p.V600E, KRAS_p.G12/G13/Q61 and amplification of MET. Although the biological mechanism of this association is yet to be investigated, combination of hotspot mutations and PD-L1 expression could be a future direction in biomarker studies. [Table: see text]
Intergration of common clinical and laboratory parameters for predictive modeling of outcome with immune checkpoint inhibitors (ICIs) in patients (pts) with Nnon-small cell lung cancer (NSCLC).
Authors: Rounis Konstantinos , Makrakis Dimitrios , Papadaki Chara , Monastirioti Alexia A , Vamvakas Lampros , Kalbakis Kostas , Gourlia Krystallia , Xanthopoulos Iordanis , Mavroudis Dimitrios , Agelaki Sofia 
Published: May 2020

e21609 Background: We prospectively recorded common clinical and laboratory parameters of pts with metastatic NSCLC treated with 2nd line ICIs to evaluate their potential value in a clinical outcome prediction model. Methods: Data on patient (age, PS, BMI) and disease characteristics (histology, sites/number of metastases), smoking status, use/duration of co-medications [proton pump inhibitors (PPIs) inhalational/p.os steroids, antibiotics (ATB)], laboratory values [neutrophil/lymphocyte ratio (NLR), LDH] and response to previous therapy were prospectively collected. Pts were categorized as having steroids if they had received steroids > 10mg for ≥10d (starting from 15d before or within the first 3 months of treatment). Prolonged ATB administration was defined as ATBs ≥14d (30d before or within the first 3 months). JAD Bio (www.jadbio.com), an Automated Machine Learning service that analyzes biological data with emphasis on feature selection was used to create predictive models. Results: 66 pts were evaluated; median follow up time was 6.37 months. 15.2% of patients had PR, 34.8% SD and 50% PD. Median PFS and OS were 3.5 and 6.77 months, respectively. Steroids had negative impact on disease stabilization (PR+SD) rates (p = 0.042) and PFS (p = 0.013) but not OS (p = 0.051). ATBs negatively affected RR (p = 0.046) only, whereas, prolonged ATB exposure was associated with lower RR (p = 0.007), PFS (p = 0.0001) and OS (p = 0.001). In multivariate analysis, steroids [HR = 2.54 (CI:1.23-5.29, p = 0.012)], prolonged ATBs [HR = 3.46 (CI:1.72-6.95, p = 0.0001)], liver HR = 2.92 (CI:1.45-5.78, p = 0.003) and bone HR = 2.06 (CI:1.041-4.10, p = 0.038) metastases independently predicted for shorter PFS. Only prolonged ATBs [HR = 2.52 (CI: 1.39-4.54, p = 0.002)] and bone metastases [HR = 2.26 (CI: 1.23-4.17, p = 0.009)] independently predicted for shorter OS. Analysis of the investigated parameters by JAD Bio predicted disease stabilization with an accuracy of 71%. Importantly, PDL-1 status was not included due to high rates of missing data. Conclusions: Our results corroborate previous evidence on the detrimental role of prolonged ATB administration on ICIs efficacy, possibly related to perturbation of the gut microbiota. Modeling, including other significant parameters from larger patient cohorts, could result in a robust estimation of outcome.
Real-world effectiveness of nab-paclitaxel plus carboplatin as first-line therapy for patients with advanced NSCLC: Results of the second interim analysis of the NEPTUN study.
Authors: Dechow Tobias Nicolaas , Riera-Knorrenschild Jorge , Hackanson Björn , Fischer von Weikersthal Ludwig , Schulz Holger , Chiabudini Marco , Timm Barbara , Zerbes Ralf , Potthoff Karin 
Published: May 2020

e21611 Background: Collecting real-world evidence is required not only to evaluate effectiveness and safety in routine clinical practice, but to improve clinical cancer outcomes. Methods: NEPTUN is a prospective, multicenter, non-interventional study designed to evaluate effectiveness, safety and quality of life (QoL) of first-line nab-Paclitaxel plus carboplatin in patients (pts) with advanced or metastatic non-small cell lung carcinoma (NSCLC) in the real-world setting in Germany. The primary endpoint was 6-months progression free survival rate (PFSR). Descriptive statistics were used to analyze data. Results: Between August 2016 and June 2019, 408 pts were enrolled at 75 active sites, 373 pts started treatment according to label. The cut-off date for this interim analysis (07 Dec 2019) was after all pts were observed for at least 6 months. The 6-months PFSR was 40.8% (95% CI, 35.3-46.2), median PFS 5.2 months (95% CI, 4.5-5.7). Overall response rate was 41.5% (95% CI, 36.3-46.8) with a complete response documented in 6 pts (1.7%) and a partial response in 142 pts (39.8%). Disease control rate was 61.6% (95% CI, 56.4-66.7). Employing a multivariable cox regression model for PFS adjusted for ECOG, histology, age group, renal impairment, and smoking status, elderly patients and patients with squamous histology were identified as being of favorable risk (HR squamous vs. non-squamous histology 0.76 (95% CI, 0.58-1.01); HR for ≥70 vs. < 70 years of age 0.80 (95% CI, 0.59-1.08)). Median overall survival (OS) was 10.5 months (95% CI, 9.2-11.6) with 9.6 months (95% CI, 7.7-11.2) for non-squamous and 11.8 months (95% CI, 9.2-13.8) for squamous histology. 12-months OS rate was 43.1% (95% CI, 37.3-48.7). The most common treatment-emergent AEs (TEAEs) were anemia (26.5%), leukopenia (25.7%) and thrombocytopenia (16.6%). Polyneuropathy was documented for 11.3% of pts. 54.2% of pts developed TEAE grade 3/4 including leukopenia (10.2%), anemia (8.6%) and pneumonia (5.1%). 9.9% pts discontinued nab-paclitaxel due to nab-paclitaxel-related TEAEs. EQ-5D-5L visual analogue scale and FACT-L total score remained stable during therapy. Conclusions: nab-Paclitaxel plus carboplatin given first-line according to German SmPC in advanced NSCLC patients in a real-world clinical setting is an effective and safe therapy commonly applied. These results were similar to those reported in the phase iii clinical trial setting. QoL scores remained stable during first-line treatment. No new safety signals emerged. Clinical trial information: NCT02799862.
The predictive values of mutation patterns, concurrent mutations and efficacy of different generations of EGFR-TKIs in advanced non-small cell lung cancer harboring non-resistant uncommon EGFR mutations.
Authors: Deng Pengbo , Tan Jiarong , Hu Chengping , Cao Liming , Yang Huaping , Li Min , Gu Qihua , Li Yuanyuan , An Jian , Han-Zhang Han 
Published: May 2020

e21612 Background: The efficacy of EGFR-TKIs in patients with non-resistant uncommon EGFR mutations is controversial. The predictive values of mutation patterns, the presence of concurrent mutations and the choice of different generations of EGFR-TKI have not been well elucidated. Methods: We retrospectively enrolled 190 NSCLC patients with non-resistant uncommon EGFR mutations, defined as mutations other than single L858R, 19del, T790M or 20ins. Among them, 72 were advanced/recurrent patients who received 1st (N = 55) or 2nd generation (N = 17) EGFR-TKIs as first-line therapy and with retrievable PFS data; therefore, were enrolled for subsequent survival analyses. Results: Patients were categorized according mutation patterns: group1 patients harboring EGFR uncommon mutation in combination with EGFR 19 del/L858R; group 2 patients harboring single or complex EGFR uncommon mutations. Our analyses revealed that the median PFS (mPFS) of group 1 was significantly longer than those in groups 2 (14.65months vs 8.05 months; P = 0.004). Next, we investigated whether the presence of concurrent mutations in tumor suppressor genes or oncogenes would affect PFS. The mPFS of patients with no concurrent mutation, patients with concurrent tumor-suppressor genes mutations and patients with concurrent oncogenic driver mutations were 13.57m, 8.05m and 16.92m, respectively (p = 0.04). Patients with no concurrent mutation had a significantly longer mPFS than patients with concurrent tumor-suppressor genes mutations (p = 0.013). Collectively, multivariate analysis revealed that patients receiving 2nd generation TKI (p = 0.006, HR:0.277,95%CI:0.112-0.688) and coexist with 19del/L858R (p < 0.001, HR: 0.148,95% CI:0.065-0.333) were independently associated with favorable PFS; while concurrent TP53 mutation was independently associated with worse PFS (p = 0.008, HR: 2.530,95% CI:1.270-5.042). Conclusions: Our study revealed NSCLC patients harboring non-resistant uncommon EGFR mutations in combination with 19del/L858R were associated with favorable PFS. The presence of concurrent tumor-suppressor genes mutations especially TP53 is associated with worse prognosis. Patients treated with 2nd generation EGFR-TKI showed a longer PFS than those treated with 1st generation TKI.
Sputum supernatant as an alternative source for liquid biopsy in patients with advanced lung cancer.
Authors: Guo Ting , Hu Chengping , Qin Ling , Yang Huaping , Gu Qihua , Cao Liming , Deng Pengbo , Han-Zhang Han , Li Bing , Ye Junyi , Zhang Lu , Chen Zhiqiu 
Published: May 2020

e21617 Background: With the advancements in the development of targeted therapy, the detection of actionable genes has become routine practice in diagnosing lung cancer. Plasma-based mutation profiling is widely used in clinical settings. Profiling using other body fluids is actively explored. In this study, we investigated the potential of induced sputum obtained from non-small cell lung cancer (NSCLC) patients for mutation profiling. Methods: We performed targeted sequencing on matched FFPE, plasma and induced sputum samples of 41 treatment-naïve advanced NSCLC using a panel consisting of 168 lung cancer-related genes. 10ml of whole blood and 8 ml of induced sputum were obtained from each patient. Induced sputum samples were fractionated into supernatant (sup) and precipitates (ppt). The cohort had a median age of 65 with a majority (32/41) diagnosed with lung adenocarcinoma. 7 of them were diagnosed with squamous cell carcinoma and the remaining 2 patients were diagnosed with neuroendocrine tumor. All patients had advanced disease (stage III or IV). Results: First, we investigated the optimal sputum fraction for mutation profiling by comparing the detection rates and maximum allelic fraction (maxAF) between sputum sup and ppt samples using matched tissue and plasma as references. The detection rate was defined as any mutation detected from the panel used; while maxAF was defined as the highest mutation allelic fraction among all mutations detected. Tissue, plasma, sputum sup and ppt achieved a rate of detection of 100%, 76.9%, 72.4% and 65.7% respectively, revealing comparable detection rates between plasma and sputum sup (p = 0.89). Sup had a significantly higher average maxAF than plasma (p = 0.03) and ppt samples (p < 0.01). Using driver mutations detected from tissue samples as references, sup, ppt and plasma samples achieved a sensitivity of 63.2%, 50% and 67.8%, respectively. Next, we investigated whether induced sputum obtained from smokers would be more informative than non-smokers. Our analysis revealed that sup from smokers had a significantly higher average AF than sup from non-smokers (p < 0.001). Furthermore, there was a statistical significant difference in average AF between sup and ppt obtained from smoker (p < 0.001) but such difference was non-existent in non-smokers (p = 0.46). Conclusions: Our study demonstrated that sputum sup demonstrates a comparable performance as plasma samples and is as a better sampling source than its ppt. Induced sputum from advanced stage NSCLC patients is an alternative media for mutation profiling.
Thyroid dysfunction in lung cancer patients treated with immune checkpoint inhibitors (ICI): Role of race, gender, and concurrent chemotherapy in a multiethnic urban cohort.
Authors: D'Aiello Angelica , Gucalp Rasim A. , Tabatabaie Vafa , Cheng Haiying , Bloomgarden Noah A. , Halmos Balazs 
Published: May 2020

e21622 Background: Immune-related adverse events (irAE) associated with ICI have been reported, but remain poorly understood. We sought to characterize patterns of thyroid dysfunction—one of the most common irAE—in a large cohort of ethnically-diverse lung cancer patients treated with ICI. Methods: A retrospective chart review of lung cancer patients receiving an anti-PD1 or PD-L1 agent from January 2016 to July 2019 was performed. Subjects included had normal baseline thyroid function. Thyrotoxicosis and hypothyroidism was defined as thyroid-stimulating hormone level less than 0.4 and greater than 4.6, respectively. Time to event analysis with inverted Kaplan Meier curves and log-rank tests were used to compare thyroid dysfunction among race, gender, and treatment subgroups. Results: We identified 256 subjects: 206 had normal baseline thyroid function and 76 went on to develop thyroid dysfunction. Rates of thyroid dysfunction by one year occurred at similar frequencies among all races. Thyrotoxicosis occurred at significantly higher rates in Black (25, 31.7%) than in White (8, 12.9%) and Hispanic (7, 16.7%) subjects. In contrast, hypothyroidism occurred more often in White (13, 21.0%) and Hispanic (18, 42.9%) than in Black (12, 15.2%) subjects. Gender and concurrent chemotherapy showed no significant association with thyroid dysfunction. Of subjects with thyrotoxicosis (N = 42), hypothyroidism followed in 33.3% (N = 14) with 1 subject receiving methimazole and 13 levothyroxine. In those subjects, median time to thyrotoxicosis and hypothyroidism was 4.0 and 7.2 weeks, respectively. Conclusions: Despite the higher prevalence of non-ICI-related thyroid disease among females and the anticipated immunosuppressive effect of chemotherapy, neither gender nor chemotherapy correlated with thyroid dysfunction; however, race did. Black subjects exhibited significantly higher rates of thyrotoxicosis. Our findings are consistent with prior research showing that thyrotoxicosis, including Graves’ disease, occurs more often in Blacks. While the pathogenesis of ICI-related thyroid dysfunction is unclear, the early onset of thyrotoxicosis demonstrated by our study calls for careful monitoring, especially for particular races. [Table: see text]
Safety and efficacy of atezolizumab (atezo) in patients (pts) with autoimmune disease (AID): Subgroup analysis of the TAIL study.
Authors: Newsom-Davis Thomas , Rubio Viqueira Belen , Rodriguez-Abreu Delvys , Alatorre-Alexander Jorge , Smit Hans J.M. , Yu Jinming , Syrigos Konstantinos N. , Patel Hina , Tolson Jonathan , Cardona Andrés , Vollan Hans Kristian , Azevedo Sergio Jobim , Choy Ernest , Ardizzoni Andrea 
Published: May 2020

e21628 Background: Atezo showed improved survival and a manageable safety profile in advanced NSCLC. The Phase III/IV TAIL study (NCT03285763) evaluated atezo in pts with previously treated advanced NSCLC, including pts often excluded from pivotal trials. We analyzed outcomes in pts with a history of AID in TAIL. Methods: Pts had stage IIIb/IV NSCLC that progressed after 1-2 lines of chemo and ECOG PS ≤ 2. Eligible pts included those with preexisting AID. Pts received atezo 1200 mg IV q3w. The primary endpoint was safety as measured by the incidence of treatment-related (TR) serious AEs (SAEs) and TR immune-related AEs (irAEs). Secondary endpoints included OS, PFS, ORR and other safety measures. Results: Of the 619 pts enrolled, 615 received atezo, including 30 pts with AID. In AID pts, the median age was 67 y, 43.3% were male and 86.7% had ECOG PS 0-1; common preexisting conditions included psoriasis (n = 7) and rheumatoid arthritis (n = 5). 23 pts had active AID at baseline. At data cutoff (Jun 4 2019), median follow-up was 12.7 mo. TR SAEs occurred in 6.7% and 7.9% of AID vs non-AID pts, respectively; TR irAEs occurred in 10.0% and 8.2% (table). AEs occurring in AID pts at a ≥ 10% difference vs non-AID pts were decreased appetite (26.7%), nausea (26.7%), dyspnea (23.3%) and pneumonitis (13.3%). G3-4 AE incidences were similar between groups (30.0% vs 29.9%). AEs leading to treatment discontinuation occurred in 16.7% and 4.3% of AID vs non-AID pts and included G1-2 pneumonitis (6.7%), G3-4 pleural infection (3.3%) and G3-4 pneumonia (3.3%). AEs of special interest (AESI) occurred more frequently in AID (40.0%) vs non-AID (34.2%) pts, with pneumonitis (13.3% vs 3.1%), rash (13.3% vs 10.6%) and hypothyroidism (6.7% vs 9.6%) as the most common AESIs in either group. Exploratory efficacy analyses in AID vs non-AID pts showed an mOS of 10.1 vs 11.1 mo, an mPFS of 2.9 vs 2.7 mo and ORRs of 10.0% vs 11.1%. Conclusions: Despite the small number of AID pts, safety and efficacy outcomes of atezo in TAIL pts with a history of AID were similar to those of pts with no history of AID. Moderate AE increases seen in AID pts tended to be respiratory in nature or GI disorders. These data may inform treatment decisions in pts with advanced NSCLC and AID. Clinical trial information: NCT03285763. [Table: see text]
Osimertinib in previously EGFR-TKI treated non-small cell lung cancer (NSCLC) patients without T790M mutation: Real-world evidence.
Authors: Luo Yung-Hung , Liu Han , Wampfler Jason A. , Tazelaar Henry D. , Li Yalun , Peikert Tobias , Liu Dan , Leventakos Konstantinos , Chen Yuh-Min , Yang Yanan , Chiou Shih-Hwa , Yang Ping 
Published: May 2020

e21631 Background: The efficacy of osimertinib in previously EGFR-TKI treated NSCLC patients without T790M mutation remains unclear in real-world practice. We investigated whether osimertinib can provide survival benefit in EGFR-mutant patients without T790M mutation after 1st/2nd generation TKI treatment. Methods: Between January 1, 2009, and March 31, 2019, 417 patients had stage III-IV NSCLC harboring EGFR mutation and 154 out of 417 patients receiving osimertinib as≥2nd-line EGFR-TKI treatment were identified at Mayo Clinic. The time to treatment failure of osimertinib was analyzed by the Kaplan-Meier (KM) estimates. The risk of death post diagnosis was analyzed by Cox proportional hazard models. Results: Among 417 EGFR-mutant patients, higher risk of death was found in patients with age above 65 years, non-adenocarcinoma, no surgery treatment, no radiation treatment, non-exon 19 deletion/exon 21 L858R mutation, higher ECOG PS (2-4), PD-L1 expression of 50% or more, bone metastasis, live metastasis, and adrenal metastasis (all p < 0.05). Moreover, osimertinib as ≥2nd-line TKI treatment in patients with or without T790M revealed lower risk of death compared to 1st/2nd generation TKI treatment without subsequent osimertinib (HR = 0.33; 0.46, and p = 0.0002; 0.0232, respectively). However, among patients receiving osimertinib as ≥2nd-line TKI treatment, patients with T790M did not have superior survival than those without (p = 0.2803). Among 154 patients receiving osimertinib, a higher risk of treatment failure for osimertinib was found in male (HR = 1.72; p = 0.0327), patients with 1st-line TKI duration ≤12 months (HR = 2.16; p = 0.0019), BMI drop > 10% (HR = 1.85; p = 0.0207), PD-L1 levels of 50% or more (HR = 4.28; p = 0.0008), and 1st-line TKI with afatinib (HR = 2.19; p = 0.0136). Nonetheless, osimertinib as ≥2nd-line TKI in patients without 790M mutation did not have higher risk of treatment failure than those with T790M (p = 0.1236). Conclusions: This is the first study to demonstrate that osimertinib can provide similar survival benefit in previously EGFR-TKI treated NSCLC patients without T790M mutation as those with T790M in real-world practice. Additionally, EGFR-mutant patients with PD-L1 expression ≥50% had a higher risk of treatment failure for osimertinib and worse overall survival than those with PD-L1 expression < 50% and may potentially gain benefit from optimizing treatment strategies including immunotherapy.
Towards patient-centric drug discovery: Drug action in malignant pleural effusions and ascites using high content imaging and deep learning.
Authors: Krall Nikolaus , Sehlke Robert , Taubert Christina , Alt Isabella , Rohrer Florian , Fuchs Elisabeth , Vilagos Bojan , Schumacher Michael , Maurer Dominik , Hackner Klaus , Lafleur Judith , Hefler Lukas , Minichsdorfer Christoph , Fuereder Thorsten , Vladimer Gregory Ian 
Published: May 2020

e21633 Background: Many anticancer drugs found to be active in preclinical development later do not show desired effect clinically. This suggests that currently used preclinical models do not fully recapitulate the complexity of the disease. The study of drug activity in primary samples could provide a more immediate picture of a molecule’s activity in a patient. Factors that have so far hampered the use of primary tissue samples for drug discovery and development include access in sufficient quantity as well as robust analytical methods. We hypothesised that malignant pleural effusions and ascites (MPAs) of solid tumour patients are a promising model system to study preclinical drug activity. MPAs are easily accessible and contain cancer cells as well as recruited immune cells. Following previous successes in studying drug action in primary tissues of patients with haematological malignancies with automated microscopy (Snijder et al 2017, Lanc Haem, NCT03096821) we describe advances in using high content imaging and deep learning-based image analysis to study drug action in MPAs of solid tumour patients. Methods: MPAs from patients with metastatic breast, pancreatic and ovarian cancer (at least n = 10 of each) were collected. The response of EpCam+/CD45- and CD45+ cells against small molecule drugs was evaluated using high content microscopy. Drug response was quantified at single cell resolution using regional convolutional neural networks (R-CNNs) comprising object detection and single cell classification. Results: MPAs contain both cancer cells and recruited myeloid and lymphoid immune cells with varying activation. Ex vivo drug responses from each patient sample were measured and the EC50 of each molecule determined by curve fitting. Sensitivity mirrored drug approvals for some indications, and also revealed drugs with potential off label use. On target and off-target response curves, along with integrative scores are used to visualize the effects. Conclusions: Single-cell phenotypic analysis of MPAs enables the study of anticancer drug action in a setting that is one step closer to the clinic than cell line or outgrown organoid models of solid tumor. While initial response patterns can be observed that mirror current approvals, further biological and clinical validation must occur to understand in how far these data can be used for drug discovery and translational research purposes.