bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two-year survival with nivolumab in previously treated, advanced non-small cell lung cancer: A pooled analysis of real-world patients from France, Germany and Canada.
Authors: Sebastian Martin , Audigier-Valette Clarisse , Butts Charles Andrew , Debieuvre Didier , Dixmier Adrien , Gröschel Andreas , Gutz Sylvia , Juergens Rosalyn A. , Labbe Catherine , Moro-Sibilot Denis , Perol Maurice , Schumann Christian , Juarez-Garcia Ariadna , Lakhdari Khalid , Penrod John R. , Pettersson Filippa , Reynaud Dorothee , Waldenberger Daniela , Allan Victoria , Barlesi Fabrice 
Published: May 2020

e21714 Background: Data from clinical studies demonstrate a long-term survival benefit of nivolumab in previously treated advanced non-small cell lung cancer (NSCLC) patients with overall survival (OS) at two-years of 27%, however real-world data are limited. We report OS in patients pooled from two prospective multi-centre observational cohort studies in France (EVIDENS, NCT03382496) and Germany (ENLARGE, NCT02910999) and a third retrospective registry of patients treated through expanded access to nivolumab in Canada. Methods: Individual patient data from each cohort were pooled and harmonised in eligibility criteria and variable definitions. Included patients had locally advanced or metastatic (stage IIIB/IV) NSCLC, received nivolumab after at least one prior systemic therapy and had no other concurrent primary cancers. OS was estimated from nivolumab initiation until death or censoring using Kaplan-Meier method. Equality of survival distributions across cohorts was measured using log-rank test. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated from unstratified Cox proportional hazards regression models to explore survival among subgroups. Data on bone and liver metastases, PD-L1 and safety were available and analysed for France and Germany only. Results: Data from 2582 patients (48% France; 34% Germany; 18% Canada) were pooled. Baseline characteristics were: median age 66 years, 64% male, 82% ECOG 0-1, 69% 1 prior line of therapy, 68% non-squamous histology, and 18% with brain metastases (treated or untreated). Median follow-up was 8 months. No difference in OS was observed between countries. The 2-year OS was 28% (95%CI 25-31) for all patients, 26% (95%CI 21-31) for squamous histology and 29% (95%CI 26-33) for non-squamous histology. Bone metastases (HR 1.42; 95%CI 1.26-1.60; P= < .0001) and liver metastases (HR 1.60; 95%CI 1.39-1.85; P= < .0001) were associated with shorter survival, while ECOG PS 0-1 (HR 0.61; 95%CI 0.52-0.71; P= < .0001) and PD-L1 positivity (HR 0.75; 95%CI 0.60-0.93; P= < .0001) were associated with prolonged survival. Rates of any grade and grade 3/4 treatment-related adverse events (TRAE) were 32% and 7% respectively. Conclusions: In this three-country pooled analysis of nivolumab in previously treated advanced NSCLC, real-world overall survival at 2-years was consistent with pivotal nivolumab trials overall and in subgroups. Rates of grade 3/4 TRAEs were comparable, but events of lower grade may be underreported in the real world.
Peripheral blood biomarkers associated with outcome in non-small cell lung cancer patients treated with nivolumab and durvalumab monotherapy.
Authors: Wu Lin , Jiang Meilin , Peng Wenying , Pu Xingxiang , Chen Bolin , Li Jia , Xu Fang , Xu Li , Xu Yan , Wang Jingyi 
Published: May 2020

e21732 Background: Selecting patients that potentially benefit from immune checkpoint inhibitors (ICIs) is critical. Programmed death ligand-1 (PD-L1) protein immunohistochemical expression on cancer cells or immune cells and Next generation sequencing based tumor mutational burden (TMB) are the hot spots in studies on ICIs, but there is still confusion in the testing methods. Due to blood samples are much easier for clinical application, many potential peripheral biomarkers have been proposed. This study identify blood parameters that associated with outcome of non-small cell lung cancer (NSCLC) patients with ICIs monotherapy. Methods: Data of 76 NSCLC patients were analyzed retrospectively. To assess the connection between survival and peripheral blood markers measured before and after treatment, we utilized COX regression model survival analysis and receiver operating characteristic (ROC) curve to assess the markers. Results: In the nivolumab cohort, the optimal cutoff for predicting 11 month overall survival (OS) were 168.13 and 43g/L in Plateletto-lymphocyte ratio (PLR) and albumin, respectively. When patients are grouped with PLR and albumin the cut-offs, a significant difference in SD-PR vursus PD rate were found between high and low groups, separately. which was not found when grouped by PD-L1 expression. Patients with high PLR ( > 168.13) or low albumin ( < = 43g/L) before ICI had a significantly raised hazard of progression, separately (for PLR, P = 0.006; for albumin, P = 0.033) and of death (for PLR, P = 0.014; for albumin, P = 0.009) compared with those patients who had low PLR or albumin level. More importantly, we found that higher PLR ( > 168.13) after the fourth cycle of ICIs was also an prognostic biomarker, which significantly correlated with shorter OS in both Nivolumab (P = 0.046) and durvalumab cohort (P = 0.028). Conclusions: PLR and albumin may help the stratification of high progression and death risk group in advanced NSCLC patients treated with nivolumab and durvalumab monotherapy.
Efficacy and safety of apatinib plus docetaxel for non-squamous non-small cell lung cancer with bone metastases.
Authors: Zang Aimin , Sun Guoguo ,   ASCO Authors' Group
Published: May 2020

e21741 Background: The skeletal system is one of the most common distant sites of metastatic non-small cell lung cancer (NSCLC) which may lead to skeletal-related events (SREs). Bone metastasis can reduced quality of life. Vascular endothelial growth factor receptor (VEGFR)-targeted therapy is effective against bone metastasis in animal models. Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR2), which is inhibits tumor angiogenesis. Therefore, we aimed to investigate the efficacy and safety of apatinib plus docetaxel for NSCLC with bone metastases. Methods: Eligible patients of NSCLC with bone metastases who received first-line platinum-based chemotherapy. Treated with apatinib (500 mg, qd, orally) plus docetaxel (60mg/m2, q3w, iv) and zoledronic acid (4mg, q3w, iv). Treatment was continued until disease progression or unacceptable toxic effects. Results: Between July 2017 and June 2019, 10 patients were enrolled. All patients available for efficacy and safety evaluation. the objective response rate (ORR) was 50% and the disease control rate (DCR) was 80%. The median progression-free survival (PFS) was 6.5 months, The proportions of patients with SREs were 20%. The most common Grade 1 or 2 adverse events included hypertension (30%, 3/10), fatigue (30%, 3/10), digestive tract reaction (30%, 3/10), leukopenia (20%, 2/10). Conclusions: Apatinib plus docetaxel prolonged PFS and reduced the incidence of SREs, with acceptable toxic effects. The therapeutic regime may be an option for NSCLC with bone metastases. Clinical trial information: NCT03127319.
Randomized phase II study of nivolumab (N) alone versus with pegilodecakin (PEG) in combination with N in patients (pts) with post-platinum immunotherapy-naive stage IV non-small cell lung cancer (NSCLC) and no or low PD-L1 expression (CYPRESS 2).
Authors: Jotte Robert M. , Goldschmidt Jerome H. , Schneider Jeffrey Gary , Shum Merrill Kingman , Berz David , Seneviratne Lasika C. , Socoteanu Matei P. , Hung Annie , Hozak Rebecca R. , Chao Bo H. , Nemunaitis John J. 
Published: May 2020

e21744 Background: Nivolumab (N) is an immune checkpoint inhibitor (CPI) approved to treat post-platinum NSCLC as monotherapy. PEG in combination with N has demonstrated promising efficacy in NSCLC pts in a phase I trial (IVY; NCT02009449; Naing et al., 2019 Lancet Oncol), providing rationale for this randomized phase II trial (CYPRESS 2). Methods: CYPRESS 2 was an open label phase II trial, for ECOG 0-1, PD-L1 negative or low (TPS 0-49%), Stage IV NSCLC pts, without known EGFR/ALK mutations. Pts were randomized 1:1 to arm N (240 mg every 14-days or 480 mg every 28-days as decided by investigator) v. arm PEG+N (received N as above + PEG daily of 0.8 mg if weight ≤80kg and 1.6mg if weight > 80 kg). Pts were stratified by tumor histology and smoking history and must have no prior history of cancer or CPI therapy. Primary endpoint was ORR (per RECIST v 1.1 per investigator). Secondary endpoints included PFS, OS, and safety. Exploratory endpoints included immune activation biomarkers (baseline and change from baseline), assessed by immunoassay. Results: As of Aug 28, 2019, 52 pts were randomized to PEG+N (n=27) or N (n=25). Median follow-up time was 11.6 months. The following results were found for PEG+N versus N: ORR 14.8% v. 12.0%, mPFS 1.9 v. 1.9 months with HR = 1.01 (95% CI [0.52, 1.95]), mOS 6.7 v. 10.7 months with HR = 1.87 (95% CI [0.77, 4.53]). Gr ≥3 treatment related adverse events (TRAEs) for PEG+N versus N were 70.4% vs. 16.7%. Gr 3 TRAEs of ≥10% incidence included anemia (40.7% v. 0%), fatigue (18.5% v. 0%), and thrombocytopenia (14.8% v. 0%). In PEG+N arm, increased circulating IL-18, Granzyme B, FasL, and IFNg levels and decreased TGFb levels were observed on treatment. Conclusions: Exploratory pharmacodynamic results were consistent with immunostimulatory signals of the IL-10R pathway. Despite evidence of biological effect, adding PEG to N did not lead to improvement in ORR, PFS, or OS in post-platinum advanced NSCLC with no or low PD-L1 expression. PEG+N arm demonstrated expected safety profile but overall higher toxicity compared to nivolumab alone. Clinical trial information: NCT03382912.
A phase I trial of nab-paclitaxel/bevacizumab (AB160) nano-immunoconjugate therapy for unresectable stage IV malignant melanoma (MM): MC1371 (NCT02020707).
Authors: Block Matthew Stephen , Suman Vera J. , Nevala Wendy Kay , Finnes Heidi Diann , Schimke Jill , Strand Carrie , Dimou Anastasios , Kottschade Lisa A. , Yan Yiyi , Reid Joel M. , Hocum Craig , Markovic Svetomir , McWilliams Robert R. 
Published: May 2020

e22020 Background: The combination of nab-paclitaxel (NP) and bevacizumab (BEV) in patients with MM has shown promising clinical activity. AB160 is a 160 nm nano-immunoconjugate of NP nanoparticles non-covalently coated with BEV for targeted delivery into high VEGF expressing tissues. Preclinical data showed that AB160 improved tumor targeting/ tumor inhibition more than NP followed by BEV. Methods: A 3+3 phase I trial was conducted in patients (pts) with MM who had prior systemic treatment for metastatic disease to determine the maximum tolerated dose of AB160 administered intravenously on days 1, 8 and 15 of a 28-day cycle. Dose level 1 (DL1) was 125 mg/m2 NP /50 mg/m2 BEV. Dose limiting toxicities (DLT) included grade (G) 4 neutropenia or anemia, PLT < 25,000, serum creatinine ≥ 2 times baseline, G2-4 neurologic toxicity or G3-4 non-hematologic toxicities. Tumor evaluations (RECIST) were conducted every 8 weeks. Treatment continued until progression or intolerability. Results: 21 pts (11 ♀) aged 36-78 years old were enrolled. One of the first 3 pts on DL1 developed a G2 colonic perforation; this was considered a DLT. One of the next 3 pts on DL1 had a DLT: G4 neutropenia. Of the 3 pts on DL-1 (100 mg/m2 NP/40 mg/m2 BEV), 2 had no DLTs and 1 died of sepsis after C1D1 dose. Enrollment was suspended until an amendment modifying the eligibility criteria was approved by the IRB. The trial reopened. One of the 4 pts on DL-1 and 1 of the 5 pts on DL1 had a DLT: G3 pain and G3 fatigue, respectively. Enrollment ended after 2 of the 3 pts on DL2 (150 mg/m2 NP/ 60 mg/m2 BEV) developed G4 neutropenia. Thus, MTD is DL1. A median of 3 cycles was administered. Treatment ended due to progression (9), intolerability (9), refusal (2) and death (1). There were no objective tumor responses. Common G3-4 toxicities were: neutropenia (33%) and thromboembolic events (19%). Conclusions: AB160 was found to have insufficient clinical benefit in patients with previously treated MM to justify further development. However, parallel phase I testing in gynecologic cancers suggests clinical benefit (abstract #300225). Clinical trial information: NCT02020707.
Methylated DNA marker panel for metastatic melanoma: Discovery and tissue validation.
Authors: Meves Alexander , Taylor William R. , Bamlet William R , Mahoney Douglas W. , Doering Karen A , Burger Kelli , Foote Patrick H. , Quattrocchi Enrica , Lehman Julia S. , Ahlquist David A. , Kisiel John B. 
Published: May 2020

e22024 Background: Disease surveillance in high risk melanoma patients using PET/CT is recommended every 6 months, an algorithm that is extremely expensive and often difficult to access. Biomarkers capable of detecting recurrence and low volume metastasis have application in tools to improve the cost effectiveness of surveillance. Towards this long term goal, our aim was to discover melanoma-specific methylated DNA markers (MDMs). Methods: Candidate MDMs were identified by reduced representation bisulfite sequencing of selected age- and sex-balanced snap frozen metastatic melanoma, benign control skin and white blood cells. Sequences were filtered for highest methylation difference, lowest control methylation background ( < 1%), and highest discrimination by variance inflated logistic regression. Using formalin-fixed tissues, the top 32 MDMs were further evaluated in metastatic melanoma from 35 patients, primary melanoma from 26 patients, and 73 control samples (47 benign precursor lesions or normal skin, and 26 healthy buffy coat samples to assess for background DNA in circulation). Candidate markers were blindly assayed by quantitative methylation specific PCR. After normalization by within sample ACTB level, random forest modeling with cross-validation identified marker combinations with greatest predictive accuracy. Results: On receiver operator characteristics analyses of individual marker candidates, areas under the curve (AUCs) ranged from 0.43 to 0.97. Median AUC was 0.835. At 100% specificity, a cross-validated panel of five MDMs (see Table), yielded a sensitivity of 33/35 cases (94.3%; 95% CI, 86.6-100%) for metastatic melanoma and 22/26 cases (84.6%; 95% CI, 70.7-98.5%) for primary melanoma. Furthermore, none of the 5 markers were detected in normal buffy coat samples. Conclusions: A panel of five novel MDMs assayed on tissue and undetectable in normal buffy coat achieves very high discrimination between melanoma and benign control tissues. This panel can be assessed in blood or other bodily fluids for application in melanoma surveillance. [Table: see text]
Efficacy and safety of apatinib in patients with recurrent or refractory melanoma.
Authors: Wang Zibing , Yuan Shumin , Zhang Xiaojie , Huang Hao , Gao Quanli 
Published: May 2020

e22026 Background: The prognosis of patients with metastatic malignant melanoma is very poor, a fact that is partly due to its high resistance to conventional chemotherapies. The objectives of this phase II trial were to assess the activity and tolerability of apatinib, an oral small molecule anti-angiogenesis inhibitor, in patients with recurrent advanced melanoma. Methods: This was a single arm, single center phase II trial. The primary endpoint was progression free survival (PFS), and the second endpoints was objective response rate (ORR), disease control rate (DCR) and overall survival (OS). Eligible patients received at least one prior line of therapy for advanced melanoma and experienced recurrence. Apatinib was given daily at a dose of 500 mg orally. This study was registered at ClinicalTrials.gov , number NCT03383237 . Results: A total of 17 patients were included in the final analysis. The median PFS was 4.5 months. There were two major objective responses, for a response rate of 11.8%. Thirteen patients had a stable disease, for a DCR of 88.2%. The median OS was 11.5 months. The most common clinically significant grade 3 or 4 toxicities included hypertension (n = 1) and canker sore (n = 1). No treatment-related death occurred. Conclusions: Apatinib showed antitumor activity as a second or above line therapy in patients with malignant melanoma. The toxicity was manageable. Clinical trial information: NCT03383237.
Cyclooxygenase inhibitor use during checkpoint immunotherapy and effect on time to progression and overall survival for metastatic melanoma and non-small cell lung cancer patients.
Authors: Wang Shang-Jui , Khullar Karishma , Kim Sinae , Crayton Samuel H , Yegya-Raman Nikhil , Groisberg Roman , Silk Ann W. , Nosher John L , Malhotra Jyoti , Gentile Michael A. , Mehnert Janice M. , Jabbour Salma K. 
Published: May 2020

e22034 Background: Immune checkpoint inhibitors (ICIs) improve survival outcomes in metastatic melanoma and non-small cell lung cancer (NSCLC). Preclinical evidence suggests that overexpression of cyclooxygenase-2 (COX2) in tumors facilitates immune evasion through prostaglandin E2 production and that COX inhibition synergizes with ICIs to promote antitumor T-cell activation. This study investigates whether concurrent COX inhibitor (COXi) use during ICI treatment is associated with improved time-to-progression (TTP), objective response rate (ORR) and overall survival (OS) in metastatic melanoma and NSCLC patients. Methods: We retrospectively reviewed 90 metastatic melanoma and 37 metastatic NSCLC patients, treated only with ICI between 2011 and 2019. Differences in TTP and OS by COXi use were compared using Kaplan-Meier and Cox regression. Interaction between COXi use and neutrophil-lymphocyte ratio (NLR) was examined. Independent radiology review per RECIST v1.1 was performed. Results: For melanoma patients, median TTP was significantly prolonged in COXi users (245 v 100.5 days, p = .0002). On multivariate analysis (MVA), COXi use associated with increased TTP (HR 0.36, 95% CI: 0.2 – 0.66, p = 0.001) when adjusted for age, pretreatment NLR, and gender. For NSCLC patients, COXi use also associated with increased TTP on MVA (HR 0.45; 95% CI: 0.21 – 0.97; p = 0.042) adjusted for age. ORR at 6-months was significantly higher in patients who received concurrent COXi compared to those that did not in both melanoma (58.6% v 19.2%, p = 0.0005) and NSCLC (73.7% v 33.3%, p = 0.036) cohorts. COXi use was associated with improved OS in NSCLC patients on MVA (HR 0.3; 95% CI: 0.12 – 0.78; p = 0.013), but not in melanoma patients. In the melanoma cohort, high pretreatment NLR of > 5 associated with decreased TTP on MVA (HR 3.21, 95% CI: 1.64 – 6.3; p = 0.0007). However, for melanoma patients with high NLR > 5, COXi use significantly associated with increased TTP (HR 0.08, 95% CI: 0.03 – 0.25); but in melanoma patients with low NLR ≤5, there was no effect on TTP (HR 0.65, 95% CI: 0.32-1.32). Similar outcomes were found in an adjusted melanoma cohort after RECIST review. Conclusions: Our study suggests that use of COXi concurrent with ICI is significantly associated with longer TTP and improved ORR at 6-months in metastatic melanoma and NSCLC patients. NSCLC patients using COXi had prolonged OS. Furthermore, COXi use appears to reverse the negative prognostic effect of a high NLR by prolonging TTP in melanoma patients.
Baseline biomarkers correlated with outcome in advanced melanoma treated with pembrolizumab monotherapy.
Authors: Awada Gil , Schwarze Julia Katharina , Gondry Odrade , Jansen Yanina , Ong SuFey , Gorman Kara M. , Warren Sarah , Kockx Mark , Seremet Teofila , Keyaerts Marleen , Everaert Hendrik , Neyns Bart 
Published: May 2020

e22041 Background: Pembrolizumab (PEMBRO) improves survival in advanced melanoma (MEL). This research investigates baseline (BL) biomarkers that predict long-term benefit on PEMBRO monotherapy. Methods: Outcome data on patients (pts) with advanced cutaneous/mucosal MEL treated with PEMBRO in our institution were collected after pt consent. Responses were evaluated using the immune-related response criteria. Total metabolic tumor volume (TMTV), assessed by 18-fluorodeoxyglucose positron emission tomography/computed tomography, was calculated as the sum of all tumor-associated voxels with a standardized uptake value (SUV) above the mean SUV measured in a reference region in normal liver tissue plus 3 standard deviations using Syngo.via software (Siemens Healthcare). The NanoString PanCancer IO360 panel was used for gene expression profiling (GEP). Results: A total of 196 pts was included in this analysis (median age 60; cutaneous 86%, mucosal 3%, unknown primary 12%; stage III 14%, IV-M1a/b/c 60%, IV-M1d 26%; first-line 24%). Median progression-free survival (PFS) in the population was 20.4 w (95% CI 10.2-30.7); median overall survival (OS) was 143.6 w (95% CI NR-NR). BL WHO Performance Status (PS) > 0 (HR 1.63 [95% CI 1.13-2.37]), C-reactive protein (CRP) > ULN (HR 1.92 [95% CI 1.33-2.77]), absolute lymphocyte count (ALC) < 750/mm³ (HR 2.45 [95% CI 1.32-4.55]) and > 1 metastatic site (HR 1.84 [95% CI 1.23-2.77]) were associated (P≤0.01) with worse PFS in multivariate analysis (Cox regression); BL WHO PS > 0 (HR 2.77 [95% CI 1.82-4.24]), lactate dehydrogenase (LDH) > ULN (HR 1.80 [95% CI 1.16-2.79]) and > 1 metastatic site (HR 1.95 [95% CI 1.16-3.25]) were associated with worse OS (P≤0.011). BL TMTV data were available in 118 pts (60%): BL CRP > ULN (HR 1.83 [95% CI 1.13-2.96]), ALC < 750/mm³ (HR 2.49 [95% CI 1.02-6.08]), > 1 metastatic site (HR 1.71 [95% CI 1.04-2.82]) and BL corticosteroid use (HR 4.62 [95% CI 1.38-15.45]) were associated with worse PFS (P < 0.05). BL WHO PS > 0 (HR 2.82 [95% CI 1.57-5.08]), ALC < 750/mm³ (HR 2.62 [95% CI 1.06-6.51]), history of brain metastases (HR 2.59 [95% CI 1.37-4.91]) and TMTV > 80 mL (HR 3.56 [95% CI 1.82-6.95]) were all associated with worse OS (P≤0.038). GEP data on a representative BL tumor sample were available in 27 pts (14%). Higher apoptosis signature scores were associated with increased probability of OS (HR 0.45 [95% CI 0.33-0.73], P < 0.01). Conclusions: BL TMTV > 80 mL identifies a subgroup of advanced MEL pts with worse outcome on PEMBRO. Increased apoptosis gene signature scores in a subset of patients predict increased OS.