bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical predictive markers of response to immune checkpoint inhibitor therapy in advanced non-small cell lung cancer.
Authors: Rhone Raena , Dumais Katerine , Powery Herman W. , Gentile Frank , Raez Luis E. 
Published: June 2021

e21044 Background: Overweight and obesity have been associated with improved overall survival (OS) and progression-free survival (PFS) in patients treated with immune checkpoint inhibitors (ICI). EPSILoN score (EPSILoN), comprised of five clinical variables (smoking, Eastern Cooperative Oncology Group performance status, liver metastases, lactate dehydrogenase (LDH), and neutrophil-lymphocyte ratio), is a known predictive marker of response to ICI. This study aims to validate body mass index (BMI) and EPSILoN as predictive markers of response in frontline treatment of advanced non-small cell lung cancer (NSCLC) with ICI with or without concomitant chemotherapy. Methods: Patients with advanced NSCLC who received frontline ICI were identified using the electronic medical record. PFS and OS were retrospectively evaluated and stratified based on baseline BMI and EPSILoN. Due to lack of routine LDH testing, a modified EPSILoN (mEPSILoN) was used. For statistical analysis, log-rank tests were used to compare PFS and OS between groups, and Kaplan-Meier survival curves were used to report PFS and OS. Results: Thirty-six normal weight (NW) and 25 overweight and obese (OWO) patients were studied. Median PFS (mPFS) for OWO vs NW patients was 8.90 months vs 5.53 months (HR 0.54; 95% CI, 0.30-0.96; p = 0.04). mPFS at 12 months was 45% for OWO patients vs 23% for NW patients. Of the patients with PD-L1 ≥ 50%, 14 patients were NW and 11 patients were OWO. Among patients with PD-L1 ≥ 50%, mPFS for OWO was not reached (NR) vs 6.73 months in NW patients (HR 0.23; 95% CI, 0.09-0.60; p = 0.003), and the percent of patients that were PF at 12 months was 71% vs 15%. Of 56 patients with a calculable mEPSILoN, 29 patients had baseline mEPSILoN 1 and 27 patients had mEPSILoN 2-3. Median OS for patients with mEPSILoN 1 vs 2-3 was NR vs 11.13 months (HR 0.32; 95% CI, 0.14-0.76; p = 0.01) and 78% vs 49% survived at 12 months. Conclusions: OWO and lower mEPSILoN were associated with longer PFS and OS, respectively, in patients with advanced NSCLC who were treated with frontline ICI with or without concomitant chemotherapy, regardless of PD-L1 expression. These findings are consistent with recent studies that have reported these parameters as predictive markers of response in patients with NSCLC. However, this is the first study to our knowledge to evaluate these markers in frontline ICI treatment with or without chemotherapy.[Table: see text]
Financial impact of tepotinib for the treatment of adult patients with metastatic non-small cell lung cancer bearing METex14 skipping in the United States.
Authors: Stargardter Matthew , Yang Mo , Tosh Jon , Ambavane Apoorva , Mittal Madhav , Vioix Helene , Liu Frank Xiaoqing , McBride Ali 
Published: June 2021

e21108 Background: MET exon 14 ( METex14) skipping is found in approximately 3% of the non-small cell lung cancer (NSCLC) population and is associated with poor prognoses. We estimated the financial impact to US Medicare and commercial plans of reimbursing the receptor tyrosine kinase inhibitor (TKI) tepotinib for adult patients with metastatic NSCLC bearing METex14 skipping. Methods: We developed an Excel-based economic model to project plan financial outlays with or without tepotinib from 2021-2023. The number of patients eligible for treatment with MET TKIs was estimated from epidemiological data, real-world evidence, and forecasted biomarker testing rates. It was assumed this population has access to other TKIs (capmatinib and crizotinib) and non-targeted standards of care, including immune checkpoint inhibitors, anti–vascular endothelial growth factor (VEGF) medications, and chemotherapy. It was also assumed most patients receiving tepotinib would otherwise be treated with another TKI. Efficacy and safety inputs were obtained from the Phase II VISION study (July 2020 data cut-off), published literature and prescribing information. Resource utilization and costs (2020 US dollars) were informed by online pricing databases, CMS fee schedules, Healthcare Cost and Utilization Project (HCUP) and trial data, expert opinion, and publicly available sources. Results: In hypothetical Medicare and commercial plans with one million members each, an estimated 160 and 32 adult patients with metastatic NSCLC would test positive for METex14 skipping between 2021-2023, respectively. Of these, 26 Medicare and 5 commercial plan members would receive tepotinib. Introducing tepotinib reduced cumulative financial outlays by $661,379 and $151,700 for Medicare and commercial payers respectively, or $0.0061 and $0.0014 per patient per month, primarily due to lower overall drug acquisition and disease management costs relative to a treatment mix without tepotinib. Results are most sensitive to the clinical efficacy of tepotinib and capmatinib. Conclusions: Using tepotinib in adult patients with metastatic NSCLC bearing METex14 skipping is expected to have minimal financial impact on Medicare and commercial payers in the US.[Table: see text]
Associations between interaction effects of mutational events and efficient immunotherapy in squamous NSCLC: Results from 373 patients.
Authors: Zhang Fan , Zhao Lei , Li Tao , Xu Yu , Wang Guoqiang , Li Chengcheng , Cai Shangli , Liu Hao , Hu Yi , Wang Jinliang 
Published: June 2021

e21136 Background: Predictive biomarkers might not be similarly predictive in every single subpopulation, and they might be merely valid under certain circumstances, which is termed by “interaction effect”. Here, we proposed to investigate the interaction effect of mutational events on predicting efficacy of immune checkpoint inhibitors (ICIs), and to explore whether adding these interaction terms could optimize the prediction model based on genomic alterations. Methods: In total, 373 patients with squamous NSCLC were included. 191 patients with both PFS and OS data receiving monotherapy from the MSKCC, DFCI, SNCC, and POPLAR/OAK cohorts were included in the training set. 130 patients from the POPLAR/OAK cohort treated with docetaxel were included in the control set. Validation set-1 consists of 34 patients receiving monotherapy from the NCC and MSKCC cohorts, and validation set-2 comprises 18 patients treated with combination therapy from the MSKCC cohort. Risk models using single mutations (uni-model) and both single mutations and interactions (inter-model) were developed via multivariable Cox proportional hazards regression model. Results: Four single mutational events, including mutations of NOTCH1/2/3, LRP1B, RB1, and members in PI3K pathway, and two interactions ( TP53* NFE2L2 and TP53*HRR pathway) were identified as predictive biomarkers. The score of inter-model exhibited higher correlation with immunotherapeutic PFS in the training sets, compared to the uni-model ( Dxy: 0.196 vs. 0.175). Uni-score low was barely associated with the PFS (HR=0.32, 95% CI 0.07-1.50, P=0.15) and OS (HR=1.20, 95% CI 0.45-3.17, P=0.71) in the validation set-1, and the PFS in the validation set-2 (HR=0.96, 95% CI 0.31-2.95, P=0.94). Inter-score low showed better association with longer PFS (HR=0.17, 95% CI 0.03-0.84, P=0.029) and OS (HR=0.33, 95% CI 0.12-0.92, P=0.033) in the validation set-1, and longer PFS in the validation set-2 (HR=0.50, 95% CI 0.13-1.85, P=0.30). In addition, no association was observed between inter-score low and the PFS and OS in the control set, indicating that inter-score low might not be a prognostic biomarker, but a positive predictive biomarker to efficacious immunotherapy. Conclusions: Two interaction effects of mutational events on predicting efficacious immunotherapy in squamous NSCLC ( TP53* NFE2L2 and TP53*HRR pathway) were identified. Adding these interaction terms to the prediction model could optimize the predictive utility. Deeper understanding of these inter-relations might provide insights for basic research on anti-tumor immunity.
Machine learning based biomarkers to predict CD8 infiltration in non-small cell lung cancers using CT imaging.
Authors: Liu Yan , Francis Danny , Groza Vladimir , Voyton Charles , Baili-Laya Afef , Huet Benoit , Boujemaa Nozha 
Published: June 2021

e21145 Background: Immune-checkpoint inhibitors (ICIs), specifically monoclonal antibodies targeting the programmed cell death protein-1 and programmed death-ligand 1 (PD-1 and PD-L1) have shown promise in the treatment of non-small cell lung cancer (NSCLC). Unfortunately, patients response to ICI is difficult to predict, with cancer stage, treatment line and regimen all affecting response rates. Identification of patients who will be “responsive” to ICI is of great importance to increase treatment efficacy. Current techniques used to identify responsive patients rely on PD-L1/PD-1 expression, microsatellite instability, tumor mutagenic burden and less commonly CD8+ infiltration, all of which are invasive and costly procedures. In this study we aim to develop a machine learning derived CT imaging biomarker that predicts CD8 status of tumors, allowing for non-invasive determination of ICI treatment efficacy. Methods: To study CD8 infiltration we extracted patients that included CT scans and CD8 transcript data from publicly available cohorts (TCGA-LUSC, TCGA-LUAD, NSCLC-Radiogenomics) to produce the Lung3 cohort (104 patients). Using this cohort, we trained (80 patients) and tested (24 patients) an AI model to predict tumor CD8 infiltration using patient CT scans as the sole input. CD8 expression (high and low) was characterized using transcriptomic quantification and served as surrogate for CD8+ infiltration, following previously described methods. Supervised and unsupervised models previously trained to identify lung features were trained to identify CD8 status using the CD8 expression data provided in the Lung3 dataset. Algorithm performance was tested on a randomly chosen subset of the cohort (24 patients) and compared against transcriptomic confirmed CD8 expression. AUC were calculated for supervised and unsupervised models. Results: AUC for the supervised and unsupervised models generated using the Lung3 cohort are shown below. Our results suggest that the derived supervised and unsupervised models could identify the CD8 infiltration status using only patient CT scans in the test dataset. Conclusions: The machine learning based models described here show encouraging results suggesting that CT imaging of NSCLC lung cancers contain sufficient information to predict the CD8 infiltration status of tumors. Although these results are just a proof of concept, the promise of a CT based non-invasive marker for tumor immune status is encouraging to help advance treatment efficacy in the ever-growing field of ICI therapy. References: (1)Wu, X. et al. (2019). (2) Schulze, A. B. et al. (2020). (3) Sun, R. et al. (2018).[Table: see text]
Impact of age and frailty markers on overall survival among hospitalized patients with lung cancer treated with immunotherapy.
Authors: Olson Eric , Russell Gregory , Lantz Jeffrey , Roberts Nathan , Dothard Andy Shipe , Lycan Thomas , Klepin Heidi D. 
Published: June 2021

e21151 Background: Although predictive of chemotherapy toxicity, geriatric assessment measures are not systematically collected in clinical practice and may or may not be predictive for immune-related adverse events. Furthermore, hospitalization during immune checkpoint inhibitor (ICI) treatment for advanced lung cancer has variable prognostic significance. This study aimed to evaluate whether age and documented patient characteristics mapped to geriatric assessment domains (frailty markers, FM) predict survival in this setting. Methods: A single-center retrospective cohort of advanced stage lung cancer patients who received >1 dose of an ICI from 6/1/18 to 2/1/20, were later hospitalized, and received ≥ 1 dose of systemic corticosteroids (n=97) was analyzed. Chart review ascertained documentation of any of the following FMs prior to ICI initiation: inability to walk one block, unintentional weight loss, decreased social activities, recent falls, need for assistance with medications, visual or hearing impairments, living alone, and concern regarding social support. Patients were stratified according to age and three FM categories (0 FM [low risk], ≥1 FMs [at risk], and ≥2 FMs [high risk]). Overall survival (OS) analysis was calculated from first dose of ICI to date of death or last follow-up. Cox’s proportional hazards models were used to assess the relationship between FMs and age on OS; hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Results: Analysis of < 75 and ≥ 75 yo revealed a median OS of 15.1 and 5.4 months respectively (HR 2.76, CI 1.62-4.72). Controlled for performance status (PS), older age (≥75 yo) was associated with a higher risk of death (HR 2.39, CI 1.32-4.31). FMs were associated with higher mortality, adjusted for PS and age (at risk patients HR 1.81, CI 1.03-3.16; high risk patients HR 2.02, CI 1.07-3.78). PS prior to starting ICI was not associated with OS. Conclusions: Age ≥ 75 yo is associated with short survival among lung cancer patients hospitalized while receiving ICI. Pre-treatment FMs documented as part of usual care were associated with worse OS, even after controlling for PS and age. This study shows promise for use of machine learning algorithms to stratify risk in hospitalized patients undergoing treatment for lung cancer with ICIs. These data would allow providers to better target serious illness conversations and end-of-life resources.[Table: see text]
Patterns of lung cancer in people living with human immunodeficiency virus (HIV): A retrospective, single-center study in Washington, D.C.
Authors: Pruitt Margaret , Janapala Rajesh Naidu , Haroun Faysal 
Published: June 2021

e21154 Background: Lung cancer is the leading cause of cancer death and the most common non-acquired immune deficiency syndrome defining malignancy in people living with HIV (PLWH). Disparities in outcomes have been observed despite lung cancer mortality reportedly decreasing in the general population over the last decade due to lower rates of smoking and the advent of novel therapies. To better understand the current trend in lung cancer in PLWH, we explored demographic characteristics, comorbidities, and lung cancer pathology and molecular data in this population. Methods: A retrospective search of patient charts was conducted from 2004 to January 2021 using billing codes for HIV and primary lung cancer. Patients who had incorrect HIV or primary lung cancer diagnoses were excluded. Results: The search yielded 45 patients, of which 11 were excluded as described above: 66% were males, 82% African American, and 18% Caucasian. About two-thirds of patients were living in zip codes with predominantly low to medium household incomes. The median pack years of patients diagnosed with Stage I or II non-small cell lung cancer (NSCLC) was 40, Stage III or IV NSCLC was 20, early stage small cell lung cancer (SCLC) was 30, and late stage SCLC was 60. The median time between HIV and lung cancer diagnoses was 21.7 years for Stage I or II NSCLC, 17.1 years for Stage III or IV NSCLC, 15.2 for early stage SCLC, and 13.3 for late stage SCLC. Of 26 patients with viral load (VL) data, 21 (80.7%) had VL less than 500 when lung cancer was diagnosed. Of the 33 charts with available pathology data, there were 16 adenocarcinomas, 6 squamous carcinomas, 3 adenosquamous carcinomas, 1 large cell neuroendocrine cancer, 4 SCLCs, 1 mesothelioma, and 2 unspecified NSCLCs. Of 19 patients with a histologic grade, 11 had a high-grade tumor (57.9%). For the NSCLCs, 8 were Stage I (28.5%), 2 Stage II (7.1%), 8 Stage III (28.5%), 9 Stage IV (32.1%), and 1 with an unspecified stage. One SCLC was early stage and the remaining 3 were late stage. Five patients had brain metastasis. Molecular data or PDL-1 expression was available for 10 adenocarcinomas (62.5%), 1 adenosquamous (33%), 3 squamous carcinomas (50%), and the large cell neuroendocrine cancer. An EGFR mutation was detected in 2 cancers. ALK rearrangement was found in 1. Other mutations were detected. Two cancers were in each PDL1 expression category: < 1%, 1-50%, and > 50%. Conclusions: Our study suggests that PLWH with lung cancer continue to have high rates of smoking. Viral load was well controlled. A range in stages of lung cancer was observed including earlier stages. Although molecular data was limited, available EGFR and ALK gene alterations, and PD-L1 expression prevalence were on par with that of the general population. With advancements in lung cancer treatment, additional research is needed in the PLWH population to better understand and mitigate disparities.
An investigation on acquired mutations after TKI treatment in Chinese lung cancer patients.
Authors: Jiang Yong , Li Yingmei , Zha Jiandong , Liu Danni , Kong Feng-Ming Spring 
Published: June 2021

e21162 Background: Targeted therapy has greatly extended the survival of certain molecular selected cancer patients. However, lots of them would eventually develop drug resistance and required alternative treatment. Research on the genomic changes before and after treatment allows us to understand the mechanism of drug resistance and to develop new treatment strategies. Methods: A total of 143 patients were enrolled and their specimens were sequenced with a panel of 680 cancer-related genes in this study. Briefly, tumor FFPE samples before treatment (T1) were collected and underwent deep sequencing (2000X), and blood samples after treatment (T2) were collected, cell-free DNA (cfDNA) was isolated and sequenced (20000X). Patients with positive EGFR mutations at T1 received TKIs afterwards. Results: A total of 160 mutations were identified in T1 and 206 mutations were found in T2 samples, while 90 of them were shared in both time points. EGFR mutations were found in 95 (66.4%) patients at T1 and 101 (70.6%) patients at T2. ERBB2 mutations were found in 9 (6.3%) patients at T1 and 19 (13.3%) patients at T2. Among them, one patient had ERBB2 amplification at T1, and new ERBB2 amplifications were found in 11 patients at T2. Conclusions: ERBB2 amplifications are associated with TKI treatment, and are likely to be involved with disease progression and TKI drug resistance.
Upfront thoracic radiotherapy to primary lession improve outcomes in patients with stage IV non-small cell lung cancer harboring EGFR mutations.
Authors: Kotek Sedef Ayse , Sümbül Ahmet Taner , Akkus Yildrim Berna , Topkan Erkan 
Published: June 2021

e21167 Background: The role of thoracic radiotherapy in the treatment of metastatic EGFR mutant non-small cell lung cancer patients in literature datas are insufficient.The aim of this study was to examine the effectiveness of upfront thoracic radiotherapy in metastatic EGFR mutant NSCLC patients treated with chemotherapy or TKI. Methods: This study was designed as a hospital-based retrospective observational case-series study. A total of 141 patients with metastatic EGFR mutant non-small cell lung cancer who has followed in two different oncology centers at Turkey between 2014 and 2020. have been included to this study. Results: The median age of the patients was 63 (range 35-91) years. EGFR mutation results of exon 19 deletion, exon 21 mutation and exon 18 mutation were found in 82 (58.2%), 56 (39.7%) and 3 (2.1%) patients, respectively. The median follow-up time was 22 months and 94 (33.3%) patients died during follow-up. Median overall survival (OS) was 26 months and progression free survival (for first line treatment) (PFS) was 10 months for whole patients, respectively. Radiotherapy was given to the primary tumor site in 32 (22,6%) patients. Patients receiving radiotherapy to primary tumor site had better overall survival than those not (31 versus 23 months respectively and p = 0,02) The survival advantage was also seen for patients group taking TKI at upfront setting (33 versus 23 months respectively and p = 0.05). Conclusions: In this study, we have showed that upfront thoracic radiotherapy to primary lession as combination with EGFR-TKI treatment may improve the outcome in advanced stage IV NSCLC patients harboring EGFR mutations.
Effectiveness of osimertinib plus chemotherapy and avastin for untreated EGFR-mutated advanced non-small cell lung cancer.
Authors: Wang Fang , Liu Hui , Zeng Zhen , Wang Shasha , Qin Haifeng 
Published: June 2021

e21178 Background: Osimertinib is recommended as a novel first-line standard treatment for advanced Non-Small-Cell Lung Cancer (NSCLC) patients with EGFR mutation. However, there are also patients with concurrent mutation or/and metastases have limited benefits. According to the current remission rate, regression depth and PFS data, the main mechanism of the benefit of combined anti-angiogenesis or chemotherapy is to reduce tumor load and heterogeneous reserve to a greater extent, so as to extend the remission time, that is, to delay the occurrence of drug resistance to extend PFS. This prospective study aims to investigate the efficacy and safety of Osimertinib plus chemotherapy and Avastin for Untreated EGFR-Mutated advanced NSCLC. Methods: The study enrolled 22 patients diagnosed with untreated advanced NSCLC and tested with EGFR mutation, who received osimertinib ( 80mg QD) plus pemetrexed (500mg/m2), cisplatin (75mg/m2) and bevacizumab (7.5mg/kg) for 6 cycles, then maintained with osimertinib/pemetrexed/bevacizumab. The primary endpoint was progression free survival (PFS). The secondary endpoint was objective response rate (ORR). Treatment was continued until disease progression and the tumor response was determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. The toxicity was determined according to CTCAE 4.0. Results: From February, 2018 to July, 2020, 22 patients enrolled. All the patients were evaluated and showed partial response(PR) when make efficacy evaluation at the first time. The target lesions reduction were shown. The average reduction is 48%, ranged from 32% of Pt12 to 71% of Pt11. Up to January, 2021, all the patients are still under the treatment. Especially for Pt7 who has already benefited from the treatment protocol by 35months. The toxicities associated with this protocols were manageable. Only 1 patient was 3/4-grade Anemia, 1 patient was 3/4-grade Diarrhea and 3 patients was 3/4-grade Lymphopenia. Conclusions: Osimertinib in combination with chemotherapy and Bevacizumab. exhibits superior activity and generally manageable toxicities for the naive advanced NSCLC patients with EGFR mutant, especially for the patients with concurrent mutation or/and metastases. It may provide a new and effective therapy strategy for them, but large sample and additional clinical trials are also needed.