bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of ADXS-503 alone and in combination with pembrolizumab in subjects with metastatic squamous or non-squamous non-small cell lung cancer (NSCLC).
Authors: Ramalingam Suresh S. , Stinchcombe Tom , Gerstner Gregory James , Haigentz Missak , Vangala Surya , Parsi Megan , Heyburn John W. , Kabala Victor , Prasad Tuhina , Gutierrez Andres A. , Goldman Jonathan Wade ,   ADXS-503 Author's Group
Published: May 2020

e21682 Background: ADXS-503 (A503) is an off-the-shelf, attenuated Listeria monocytogenes (Lm)-based immunotherapy bioengineered to elicit potent T cell responses against 22 tumor antigens commonly found in NSCLC (i.e., 11 hotspot mutations and 11 tumor-associated antigens, TAAs). Pembrolizumab (Pembro) is a programed death receptor-1 (PD-1)- blocking antibody with proven efficacy in NSCLC. A503 and Pembro have complementary mechanisms of immune activation and reversal of immune tolerance. Methods: This is a phase I study of A503 ± Pembro in patients (pts) with metastatic squamous or non-squamous NSCLC. Dose escalation with A503 alone has been tested at two dose levels (i.e., 1 and 5 x108 CFU) in Part A in pts refractory or intolerant to prior systemic therapy. In dose escalation Part B, A503 is being evaluated at the same dose levels (DLs) in combination with Pembro in pts with disease progression on Pembro. Part C will be a dose expansion cohort with A503 + Pembro as first-line treatment in the metastatic setting. A503 ± Pembro (200 mg) will be infused intravenously every 3 weeks until disease progression or limiting toxicity. Main endpoints include safety, tolerability and immune-correlative data. Results: Nine patients have been treated: 7 with A503-alone in Part A and two pts with A503+ Pembro in Part B-DL1. No pts in Part A experienced dose-limiting toxicities at the 2 DLs tested. Two Grade 3 adverse events occurred in one pt related to the infusion: hypertension and flu-like syndrome. A transient and manageable SAE (Grade 2 acute kidney injury) was possibly related to A503 alone at 5 x108 CFU. A503+ Pembro have been well tolerated in 2 pts in Part B-DL1. Four pts achieved a best overall response of stable disease, three in Part A and one in Part B. A503 alone induced immune responses in pts so far evaluated in Part A. Conclusions: ADXS-503 alone has demonstrated a manageable safety profile and immune responses in Part A. The 1x108 CFU was identified as the recommended phase II dose. Dose escalation with A503+ Pembro is ongoing and dose expansion in first line treatment is due to start shortly. Clinical trial information: NCT03847519.
Efficacy of immune checkpoint inhibitors in non-small cell lung cancer patients with different metastatic sites: A systematic review and meta-analysis.
Authors: Yang Kaili , Zhao Lin , Li Jiarui , Bai Chunmei 
Published: May 2020

e21684 Background: Previous studies have demonstrated that bone, brain and liver metastases are poor prognosis factors of immune checkpoint inhibitors (ICIs) therapy in patients with non-small-cell lung cancer (NSCLC). This study aims to compare the efficacy of ICIs with conventional therapy in NSCLC patients with bone, brain or liver metastases. Methods: MEDLINE, Embase and CENTRAL were searched for prospective studies comparing ICIs with conventional therapy in NSCLC patients with bone, brain or liver metastases. Quality assessment was performed using the Newcastle-Ottawa Scale. The pooled hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS) among included studies was analyzed using the random-effects model. Results: From 1,195 relevant articles, eight studies with high methodological quality consisting of 988 patients were included in the analysis. ICIs significantly improved OS for patients with brain metastases (HR = 0.57; 95%CI: 0.37-0.86; P = 0.007). Among patients with liver metastases, OS (HR = 0.72; 95%CI: 0.57-0.91; P = 0.006) and PFS (HR = 0.72; 95%CI: 0.49-0.87; P = 0.004) improvement was observed in the ICI treatment arm. No available study with bone metastases information was identified. Subgroup analysis revealed that PD-1 inhibitors could benefit patients on OS and PFS regardless of metastatic sites. Sensitivity analysis indicated good stability of this analysis. No obvious heterogeneity or publication bias was detected. Conclusions: ICIs could significantly improve OS in patients with brain metastases and both OS and PFS in patients with liver metastases. Although brain and liver metastases are generally regarded as poor prognostic factors for immunotherapy, this study still indicates ICIs are effective therapeutic options for NSCLC patients with these metastatic sites.
Dynamic changes in circulating PD-1+CD8+ T lymphocytes for predicting treatment response to PD-1 blockade in patients with non-small cell lung cancer.
Authors: Kim Chang Gon , Hong Min Hee , Kim Kyung Hwan , Pyo Kyoung-Ho , Xin Chun-Feng , Cho Byoung Chul , Shin Eui-Cheol , Kim Hye Ryun 
Published: May 2020

e21690 Background: The predictive value of dynamic changes in the expression of programmed cell death-1 (PD-1) among circulating CD8+ T lymphocytes for treatment response to PD-1 inhibitors has not been explored in non-small-cell lung cancer (NSCLC). This study aimed to investigate whether dynamic changes in PD-1+CD8+ T lymphocytes have predictive value with respect to durable clinical benefit (DCB) and survival after PD-1 blockade. Methods: Patients with recurrent and/or metastatic NSCLC treated with PD-1 inhibitors were enrolled between March 2016 and August 2018 (discovery cohort; n = 94). Peripheral blood was obtained immediately before and after one cycle of treatment with PD-1 blockade. Phenotyping of circulating CD8+ T lymphocytes was conducted using multi-color flow cytometry. Predictive values of dynamic changes in circulating PD-1+CD8+ T lymphocytes during the first cycle were validated in an independent cohort (validation cohort; n = 54) of a prospective trial with PD-1 inhibitor (NCT03486119). Results: Circulating PD-1+CD8+ T lymphocytes were enriched with effector/memory populations with elevated expression of activation- and exhaustion-related markers. Reduction in the frequency of PD-1+ cells among CD8+ T lymphocytes after one cycle of treatment was associated with a higher probability of DCB and superior survival outcomes in the discovery cohort. Similar results were obtained in analysis of tumor antigen NY-ESO-1-specific CD8+ T lymphocytes and in the validation cohort. Conclusions: Dynamic changes in circulating PD-1+CD8+ T lymphocytes predict clinical and survival benefit from PD-1 blockade treatment in NSCLC. Thus, tracking these changes may be useful for identifying NSCLC patients who will optimally benefit from the treatment.
Detection of ALK and ROS1 fusion transcripts in FFPE samples of non-small cell lung cancer patients using a novel RT-PCR based assay and targeted RNA sequencing.
Authors: Denis Marc G. , Vallee Audrey , Sagan Christine , Herbreteau Guillaume , Theoleyre Sandrine , Rajamani Jaya , Lee Michael , Ordinario Ellen 
Published: May 2020

e21695 Background: Detection of genomic rearrangements like ALK and ROS1 fusions are mandatory in non-small cell lung cancer (NSCLC) as those alterations can be targeted by an increasing number of drugs. Fluorescence in-situ hybridization (FISH) has been so far the gold standard but multiplexed technologies would allow analysis of many potential targets simultaneously. We have evaluated a novel RT-PCR based assay and a targeted RNA sequencing solution for the detection of ALK and ROS1 rearrangement in NSCLC patients. Methods: 41 patients with late stage NSCLC were included in the study. ALK and ROS1 status were screened on FFPE tissue sections using immunohistochemistry and confirmed with FISH. Total nucleic acids were extracted from tissue sections using the Maxwell RSC RNA FFPE kit (Promega). Detection of rearrangements was performed by RT-PCR using the prototype ALK/RET/ROS1 Fusion Panel assay (Roche), which detects 7 ALK fusion variants, 13 ROS1 variants and 6 RET variants. For RNA sequencing, the libraries were prepared with the QIAseq Targeted RNAscan Lung Cancer Panel (Qiagen). Sequencing was performed on a MiSeq instrument (Illumina). Results: We tested 16 ALK FISH+ tumors, 4 ROS1 FISH+ tumors, and 21 samples that were either IHC- or IHC+/FISH-. The RT-PCR assay detected 15 of the 16 ALK FISH+ tumors, and 3 of the 4 ROS1 FISH+ tumors. In the 21 IHC- or IHC+/FISH- samples, 1 additional ROS1 fusion and 1 RET fusion were detected. The remaining 19 assays samples were negative. 2 fusions were missed by RT-PCR because the assay design does not cover these rearrangements (KLC1-ALK and CTNND1-ROS1). With targeted RNA sequencing, we were able to detect 14 of the 16 ALK FISH+ tumors and all 4 of the ROS1 FISH+ tumors. We also identified 1 additional ROS1 fusion and 1 RET fusion in the 21 IHC- or IHC+/FISH- samples. 17 patients were negative and 2 tests were not contributive. Overall, using FISH as a reference, the sensitivity of both assays was 90% (18/20). Conclusions: Using limited amount of biological material, both RT-PCR and targeted RNA sequencing were able in one assay to detect the overwhelming majority of ALK and ROS1 fusions identified with FISH. These approaches also allowed us to detect gene rearrangements that were missed by the initial IHC/FISH screening. The RT-PCR assay requires less RNA (as little as 3 ng) and has a much faster turn-around time. The RNA sequencing approach allowed us to identify the fusion partners, but it requires much more RNA and is rather difficult to implement in routine practice.
Using real world data to examine outcomes in immunotherapy-treated patients with metastatic non-small cell lung cancer.
Authors: Luciano Sierra , Haudenschild Christian , Kuranz Seth 
Published: May 2020

e21715 Background: Important questions have been raised about whether real world data (RWD) can be relied upon to support clinical and regulatory decision-making. The aims of this study were to assess overall survival (OS), time-to-treatment (TTT), follow-up time, and treatment pathways in metastatic non-small cell lung cancer (mNSCLC) patients treated with programmed cell death protein 1 inhibitors (PD-1i). Methods: Two mNSCLC cohorts were identified in a US based EMR network. To explore treatment pathways, patients had to have an advanced (stage 3/4) diagnosis of NSCLC confirmed by a tumor registry record. A line of treatment (LOT) was defined as a PD-1i or chemotherapy taken within 30 days. OS, time to treatment, and follow-up time were also calculated. In another cohort patients had to have at least one PD-1i (pembrolizumab, nivolumab, durvalumab, or atezolizmab) and an oncology treatment within 3 months of an advanced stage diagnosis. OS was calculated using Kaplan-Meier analysis and stratified by time after nivolumab approval, quarter of PD-1i initiation, and line of therapy of first PD-1i. Patient characteristics were defined by ICD, CPT, LOINC, and RxNorm terminology. Results: Median overall survival was found to be 213 days (IQR 109, 425.25). In the treatment pathways analysis, 58.3% of patients started on a non-PD-1i chemotherapy as an initial line of treatment for mNSCLC. PD-1i was the most common second line treatment and 41.4% of patients who started on a non-PD-1i therapy switched to a PD-1i as their second line therapy. Median time from advanced diagnosis to PD-1i inhibitor initiation (9.6 months (IQR 3.45, 21.45)) and median structured follow-up times from advanced diagnosis (21.87 months (IQR 11.94, 38.97)) and from inhibitor initiation (8.71 months (3.06, 17.26)) were comparable to results found in other RWD. Conclusions: Overall survival, time to treatment, and other outcomes were consistent with comparable RWD sources, (Stewart M, 2019; Sean K 2018) regardless of treatment timeframe. We demonstrated that our real world evidence based approach provides a robust method for analyzing clinical outcomes, supporting the validity of real world data to complement clinical trials and inform clinical decisions.
Real-world outcomes of pembrolizumab plus carboplatin plus paclitaxel or nab-paclitaxel in non-small cell lung cancer (NSCLC).
Authors: Tabah Ashley , Huggar David , Kish Jonathan , Bapat Bela , Liassou Djibril , Gajra Ajeet , Miller Talia , Copher Ronda , Patel Manali I. 
Published: May 2020

e21717 Background: Pem+carbo+pac or nab-pac are approved first-line (1L) treatments for metastatic squamous NSCLC since 10/30/2018. Difference in real-world outcomes of these triplet combinations are unknown. Methods: Providers from community oncology practices in the USA reviewed the charts of consecutive NSCLC patients initiating 1L treatment with either pem+carbo+pac (“pac”) or pem+carbor+nab-pac (“nab-pac”) from 06/01/18-12/31/18; data were collected 11/22/2019-12/23/2019. Patient characteristics, treatment patterns, grade 3/4 toxicities, disease response, date of progression/death were retrospectively abstracted into an electronic case report form (eCRF). Univariate statistics were used to compare demographics, clinical characteristics and treatment patterns between cohorts. Overall survival (OS) from 1L was calculated using the Kaplan-Meier method. A Cox proportional hazards model was used to compare the risk of death between the two cohorts adjusted for multiple variables. Results: eCRFs were completed for 254 patients: nab-pac = 115, pac = 139. Median follow-up was 13.1 mos in both cohorts. No differences in demographics/clinical characteristics were noted (table). Median duration of therapy was 3.9 mos (nab-pac) and 3.8 mos (pac) (p = 0.58). Objective response rate: nab-pac = 69.6%, pac = 69.8% (p = 0.96). Receipt of maintenance therapy: nab-pac = 44.4%, pac = 48.9% (p = 0.47) . Median time to progression was 6.4 mos for nab-pac (n = 32) and 3.5 mos for pac (n = 29) (p = 0.10). 13.9% of nab-pac and 7.9% of pac patients had grade 3/4 toxicities (p = 0.16). At data cut-off, 18 nab-pac (15.7%) and 30 pac (21.6%) patients were deceased. Median OS from initiation of 1L was not reached. 12-month OS: nab-pac = 87.8% (95% CI: 81.8-93.8), pac = 79.3% (95% CI: 72.5-86.2). Adjusting for sex, age, race, PD-1 expression level, charlson comorbidity index (CCI) and ECOG-PS patients treated with nab-pac had a 40% reduction in mortality risk (HR = 0.55, 95% CI: 0.30-1.01, p = 0.05). Conclusions: No significant differences in demographics and clinical characteristics between patients treated with nab-pac or pac were observed. Median duration of treatment was equivalent with a marginally longer 12-month survival rate, and a lower adjusted mortality risk, among patients treated with nab-pac. [Table: see text]
Prognostic role of filgrastim and derived neutrophil-to-lymphocyte ratio (dNLR) in the effectiveness of PD1/PDL1 inhibitors in previously treated non-small cell lung cancer.
Authors: Marin Pozo Juan Francisco , Muñoz Cid Carmen Lucia , Merino Almazán Macarena , Claramunt García Raquel , Marin Caba Elvira , Pérez Cano Encarnación , Ortega Granados Ana Laura 
Published: May 2020

e21729 Background: A neutrophil/lymphocyte ratio (NLR)> 5 or its derivative (dNLR)> 3 have been proposed as a prognostic factor for non-effectiveness of nivolumab in non-small-cell lung cancer (NSCLC). Filgrastim (GSGF) increases the absolute counts of neutrophils in patients (pts) with neutropenia. The aim of this study is to determine whether the use of GSGF, during the first line therapy of nSCLC, influences the effectiveness of the anti-PD1/PDL1 inhibitors (aPD1-i) used in subsequent line. Methods: We designed a single center, observational and retrospective study. We included NSCLC pts treated with Nivolumab (NIV), Pembrolizumab (PEM) or Atezolizumab (ATE) between January-16 and November-19 after primary platinum-based chemotherapy at one hospital from south Spain. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Results were assessed using Kaplan-Meier method for GSGF-use stratified by NLR, dNLR, or aPD1-i. Results: 79 pts were enrolled (91% men), mean age was 66.7 years, 78.8% of pts had ECOG = 0-1. NIV was used at 55.7%, ATE 25.3% and PEM 19.0% of pts. 50.6 % of tumors were squamous histology. GSGF was used at 19 pts (24.1%). The mean WBC at the start of therapy with aPD1-I was 9300 cell/µL (sd=3900), range 3600-25800 cell/µL. NLR was less than 5 in 46 pts (58.2%) and dNLR was less than 3 in 51 pts (64.6%). The mean time from the start of line previously to start the treatment with aPD1-i was 9.7 months (sd=8.6). The median for treatment duration was 4.1 months [IC 95%; 2.3-5.8].OS was 7.3 months [IC 95%:3.4-11.3] and PFS was 4.4 months [IC95%:2.3-6.5]. We found statistically significant difference in OS between patients with dNLR <3, median 13.9 months [IC95%; 5.4-22.4] vs patients with dNLR> 3, median 3.6 months [IC95%; 2.4-4.7], p=0.037. The median OS was higher in pts GSGF-treated (6.1 months) vs pts no GSGF-treated (3.3 months), p=0.347, no reaching statistical significance. No difference was found in OS by NLR. The analysis for OS by GSGF use stratified by dNLR is shown in the table. Conclusions: The effectiveness of aPD1-i in nSCLC patients previously treated and with dNLR>3, a priori poor prognosis, is greater in the group of patients treated with GSGF, reaching OS like pts with dNLR <3. [Table: see text]
Cause of mortality in patients with lung cancer and brain metastasis.
Authors: Thawani Rajat , Fakhoury Kareem , Becker Kevin Douglas 
Published: May 2020

e21743 Background: Lung cancer is the most common cause of cancer-related mortality and most deaths are associated with metastatic disease, with brain being a common site. Historically, whole brain radiation therapy was the treatment of choice and resulted in median survivals in the range of 6 months. There is no consensus in management of patients who have brain metastasis with systemic disease.We aim to evaluate patients with brain metastasis from lung cancer for cause of death, to investigate whether patients died from central nervous system (CNS) progression or systemic disease or other/undetermined causes. Our hypothesis is that most deaths in contemporary patients with brain metastasis in lung cancer are due to systemic disease, and less commonly due to CNS progression. Methods: In this retrospective observational study, we did a chart review of all adult patients with non-small cell lung cancer and brain metastasis or leptomeningeal disease, who received treatment at Maimonides Cancer Center between 2010 and 2017. Patients with unavailable or incomplete medical records were excluded. Baseline characteristics, pathological factors of the tumor and cause of death was collected from the chart. The cause of death was categorized into systemic and brain causes, and difference in characteristics of patients and tumor were studied. Results: A total of 132 patients were included and their charts were reviewed. Out of 132, 96 could have a clear cause of death categorized into systemic or brain causes, the rest were either mixed or uncategorized. We found that 33% patients died of brain metastasis, and related causes, whereas 67% died of systemic disease progression. There were no different in the two groups in terms of gender, smoking status, histology, size of lung lesion, or number and size of brain lesion. The patients who died of brain metastasis had a significantly higher age, and worse Eastern Cooperative Oncology Group status. Interestingly, the patients who died of systemic causes more commonly had adrenal metastasis (12 vs 0) which was statistically significant, and liver (14 vs 3) metastasis which was not statistically significant. Conclusions: Two-thirds of patients with brain metastases died of systemic disease rather than CNS progression. This may reflect improvements in systemic and local therapies to forestall cancer progression in the CNS. This finding suggests that delaying systemic therapy for CNS treatment may negatively impact overall cancer control. More research needs to be done to answer this question with certainty, including prospective clinical trials.
Comparison of baseline patient characteristics in immunotherapy versus targeted therapy trials for advanced melanoma.
Authors: Handa Shivani , Petrone Giulia , Rutledge John R , Friedlander Philip Adam 
Published: May 2020

e22012 Background: Immune checkpoint inhibitors (ICI) or BRAF/MEK targeted therapy are both FDA approved first line options for BRAF mutant advanced melanoma. However, the optimal sequencing of these approaches and the profile of patients who benefit the most from one treatment over the other is suboptimally defined. Methods: We compared the baseline characteristics of the participants enrolled in the immunotherapy (IT) and targeted therapy (TT) trials quoted in the NCCN guidelines as the guidelines are used by many oncologists who do not subspecialize in melanoma to formulate treatment plans. Data was gathered about age, sex, race, ECOG score, LDH levels, stage, BRAF mutation status, PD-L1 expression and prior lines of therapy. Results: Median age range was younger in the TT population (48-57 y) as compared to the IT population (56-65 y); > 50% were males. 54-82% patients in the IT trials had an ECOG score of 0. Relatively more patients (pts) with ECOG score of 1 were included in Dabrafenib/ Trametinib and Vemurafenib/Cobimetinib trials (62-65%). Most pts had stage IV M1c disease. LDH levels were similar in IT and TT trials. V600E mutation was uniformly more common in the TT trials as expected. PD-L1 expression varied widely; from 23% to 81% patients with a high PD-L1 expression. Trials evaluating pembrolizumab included patients (7-26%) who were previously treated with BRAF/MEK inhibitor, however TT trials did not include as many pts exposed to ICI. Conclusions: Age range and sex ratio of the pts included in the trials were representative of the epidemiology of melanoma, but race was underreported. TT studies trended towards a younger median age range than patients treated in the IT studies. However optimal biomarkers for initial treatment choice cannot be determined by the patient demographics and characteristics presented in the studies discussed in the NCCN guidelines. Studies randomizing treatment sequence and identification of biomarkers prognostic of patient specific treatment efficacy are needed. Comparison of the IT and TT studies support the choice of either approach as initial treatment in pts with BRAF mutant melanoma lacking contraindications.