bluuebunny/crossref_metadata_2025_split huggingface dataset:
The prognostic value of body fat components in metastasis renal cell carcinoma patients treated with TKIs.
Authors: Dai Jindong , Zhang Xingming , Liu Zhenhua , Song Tingni , Zhu Xudong , Zhang Haoran , Zeng Hao , Shen Pengfei 
Published: February 2020

668 Background: To assess the association between body fat components and survival status and tumor response for metastatic renal cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors (TKIs). Methods: Patients with pathologically diagnosed and radiologically indicated mRCC were enrolled into the retrospective study. Three body fat components: total fat accumulation (TFA), visceral fat accumulation (VFA) and subcutaneous fat accumulation (SFA) were measured using standard CT scans. The clinical outcomes included progression-free survival (PFS), overall survival (OS), and tumor response rates. Univariate analysis and multivariate Cox proportion hazard regression models were used to find associated parameters and to calculate the adjusted hazard ratio (HR). Results: A total of 146 patients were enrolled. The median follow-up time was 22 months. According to the univariate analysis, patients with an increased SFA and TFA had a longer PFS and OS. A similar phenomenon was observed among patients with ≥2 increasing body fat components about PFS and OS. As for multivariate analysis, SFA change (p=0.014) or the number of increasing body fat components (p=0.040) were independent indicators to predict PFS. In addition, SFA change (p=0.022) or the number of increasing body fat components (p=0.008) could independently predict OS. Moreover, a better disease control rate (p=0.028) was founded in patients with ≥2 increasing components. In the subgroup of patients with ≥2 metastasis sites, improved OS (p=0.017) and PFS (p=0.027) were found compared to those with <2 increasing components. Further multivariate analysis identified the number of increasing body fat components was an independent factor in predicting PFS (p=0.018) and OS (p=0.029). Conclusions: Body fat accumulation, such as high SFA or TFA at progression, could improve the survival of patients with mRCC treated with TKIs, especially patients with higher tumor burden. It should be considered as an important parameter to predict the survival status of patients with mRCC.
A randomized phase II trial comparing switch to nivolumab with TKI continuation after 12 weeks of TKI induction therapy in metastatic renal cell carcinoma patients (NIVOSWITCH).
Authors: Grünwald Viktor , Grüllich Carsten , Ivanyi Philipp , Wirth Manfred , Staib Peter , Schostak Martin , Dargatz Philip , Müller Lothar , Metz Michael , Bergmann Lothar , Steiner Thomas , Welslau Manfred , Lorch Anja , RAFIYAN Mohammad-Reza , Hellmis Eva , Hinke Axel , Meiler Johannes , Kretz Thomas , Loidl Wolfgang C. , Flörcken Anne 
Published: February 2020

678 Background: Tyrosine kinase inhibitors (TKI) and Nivolumab (NIVO) are standard treatment options for mRCC. We tested whether TKI followed by early switch to NIVO improved outcome in mRCC patients (pts). Methods: Main inclusion criteria: measurable advanced or metastatic clear cell RCC, ECOG PS 0-2, adequate organ function, PR or SD to induction therapy with sunitinib (50 mg, 4-2 regime) or pazopanib (800 mg OD). 1:1 randomization at 12 wks.: TKI continuation vs. switch to NIVO (240 or 480 mg IV q2-4wks). Strata were MSKCC risk, TKI used and response to TKI. Imaging was performed q12w. 49 of 244 planned pts were randomized between Dec 2016 and Aug 2018, which led to premature closure of the trial. We report the second interim analysis with data base lock on 31.07.19. ORR was assessed according to RECIST 1.1. Efficacy and safety analyses were performed in ITT and safety population, respectively. Log-Rank analyses were used for survival analyses. Results: 25 and 24 pts received NIVO or TKI, respectively. Median age was 65 y (range: 35-79), 82% were male and 4% had ECOG PS 2. Metastases occurred predominantly in lung (47%), lymph nodes (27%) and liver (24%). MSKCC risks were: favorable (31%), intermediate (65%), and poor (4%), which were balanced between arms. 55% received sunitinib. ORR for NIVO vs. TKI differed when assessed from start of induction therapy (64 vs. 70%, P=0.76) or from time of randomization (16 vs. 48%; P=0.032). Accordingly, PFS from randomization was 3.0 vs. 11.9 mo. (HR = 1.72 [95% CI: 1.19 – 2.48]; P=0.0026) in favor of TKI continuation. At a median follow-up of 12.9 mo. median OS was not reached, but HR = 1.86 (95% CI: 0.85 – 4.07) P=0.10 showed a trend for TKI continuation. All grades AE for NIVO vs. TKI occurred in 96% vs. 100%, grade 3-5 48% vs. 71% and serious AE 40% vs. 46%. Conclusions: In TKI-sensitive pts, continuation of TKI is more efficacious than early switch to NIVO. The major limitation of our trial is the premature closure and its limited sample size. Clinical trial information: NCT02959554.
Efficacy of adjuvant vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (VEGFRi) in renal cell carcinoma (RCC): A systematic review and meta-analysis.
Authors: Botrel Tobias Engel Ayer , Clark Otávio , Bretas Francisco Flávio Horta , Sadi Marcus V. , Ferreira Ubirajara , Paladini Luciano , Matheus Wagner , Duraes Ronilson Oliveira , Pompeu Antônio Carlos Lima 
Published: February 2020

680 Background: To perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) comparing the efficacy of adjuvant VEGFRi in locally advanced, non-metastatic clear renal-cell carcinoma (RCC). Methods:Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. We included studies that compared the addition of VEGFRi versus placebo, after nephrectomy. Analyzed endpoints were overall survival (OS) and disease-free survival (DFS). The data extracted from the studies were combined by using Hazard Ratio (HR) or Risk Ratio (RR) with their corresponding Confidence Intervals of 95% (CI95%). Results: Overall, 121 references were identified and screened. The final analysis included 5 trials (S-TRAC, ATLAS, ASSURE, PROTECT and SORCE) comprising 6,128 patients that underwent previous nephrectomy for RCC. The DFS was similar in patients who received VEGFRi (fixed effect: HR=0.94, CI95%=0.87 to 1.03; p=0.19), with no heterogeneity (Chi2 = 4.33, df = 5 (P=0.50); I2 = 0%). Overall survival also was not statistically better in patients who received VEGFR inhibitors (HR=1.01, CI95%=0.90 to 1.15; p=0.84), with no heterogeneity (Chi2= 3.57, df = 5 (P=0.61); I2 = 0%). In the final combined analysis of the higher-risk disease group (pT3, pT4, or N+ disease), patients who received VEGFRi had a longer DFS (fixed effect: HR=0.85, CI95%=0.74 to 0.97; p=0.02), with no heterogeneity (Chi2 = 2.46, df = 3 (P=0.48); I2 = 0%). Overall survival was not statistically different for these higher-risk disease patients (fixed effect: HR=0.93, CI95%=0.74 to 1.16; p=0.5). Conclusions: This is the first meta-analysis including the five available RCTs in the literature (the previous meta-analysis reviewed only four), comparing adjuvant VEGFRi versus placebo in patients submitted to nephrectomy with a locally advanced, non-metastatic RCC. Adjuvant VEGFRi did not increase the OS in this group of patients. Amodest benefit of DFS with the use of adjuvant VEGFR inhibitors was restricted to patients with the highest risk of relapse.
Genomic biomarkers of response to lenvatinib/pembrolizumab (Len/Pembro) in patients with advanced renal cell carcinoma.
Authors: Lee Chung-Han , DiNatale Renzo G. , Chowell Diego , Krishna Chriag , Makarov Vladimir , Shapnik Natalie , Murray Samuel J. , Carlo Maria Isabel , Voss Martin H , Feldman Darren R. , Hakimi A. Ari , Adachi Yusuke , Minoshima Yukinori , Matsui Junji , Funahashi Yasuhiro , Perini Rodolfo F. , Nomoto Kenichi , Motzer Robert J. , Chan Timothy An-thy 
Published: February 2020

733 Background: A phase 1b/2 clinical trial indicated that len/pembro shows promise in the treatment of renal cell carcinoma (RCC) in both PD-1/PD-L1 immune checkpoint blockade (ICB)-naïve and pretreated patients (NCT02501096). The combination is being further investigated in a phase 3 clinical trial in RCC (NCT02811861). Tumor antigen presentation depends on multiple factors, including HLA diversity, which can be measured by HLA evolutionary divergence (HED). HED quantitates the capacity of a patient’s HLA genotype to present different peptide antigens. This study is investigating the genomic components of tumor antigen presentation in ICB-naïve patients who have RCC and are treated with len/pembro. Methods: Whole exome sequencing (WES) was performed on pretreatment tumor-derived DNA. Somatic mutations, tumor mutation burden (TMB), neoantigen (NA) load, germline HLA zygosity and somatic loss of heterozygosity (LOH), and HED were correlated with objective response rate (ORR) and progression-free survival (PFS). An updated clinical cutoff was March 29, 2019. Results: Twenty four (80%) of 30 ICB-naïve patients underwent WES. A top-quartile cutoff was used. Increased mean HED was associated with improved PFS, while HLA homozygosity or LOH trended toward worse PFS. Loss-of-function mutations in PBRM1 (PBRM1 LOF) trended toward improved PFS. However, TMB and NA load were not correlated to PFS. No genomic biomarkers were correlated to ORR. Conclusions: Increased HLA diversity was associated with improved PFS, while decreased HLA diversity may be associated with worse PFS. PBRM1 mutation may be associated with improved PFS; however, TMB and NA load were not correlated to outcomes. These findings warrant further examination in larger datasets to rule out possible artifacts from multiple testing in a small cohort. Clinical trial information: NCT02811861. [Table: see text]
Impact of metastasectomy on progression free and overall survival in metastatic renal cell carcinoma: Analysis of the REMARCC registry.
Authors: Meagher Margaret Frances , Autorino Ricardo , Kriegmair Maximilian , Mir Maria Carmen , Rubio Jose , Campi Riccardo , Mari Andrea , Heck Matthias , Porpiglia Francesco , Van Bruwaene Siska , Linares Espinos Estefania , Musquera Mireia , Ghali Fadi , Veccia Alessandro , Guruli Georgi , Rousel Eduard , Pavan Nicola , Antonelli Alessandro , Marchioni Michele , Derweesh Ithaar 
Published: February 2020

753 Background: The role of metastasectomy has been in flux as treatment paradigms for management of metastatic renal cell carcinoma (mRCC) have shifted. We examined outcomes of surgical metastasectomy stratified in the setting of different mRCC risk groups. Methods: Multicenter retrospective analysis of patients from the REMARCC (REgistry of MetAstatic RCC) database. The cohort was subdivided by Motzer RCC criteria (low, intermediate, and high risk), and impact of metastasectomy was analyzed via multivariable analysis (MVA) and Kaplan Meier analyses (KMA). Primary outcome was progression free survival (PFS) and secondary outcome was overall survival (OS). Results: 438 patients (46 low risk, 262 intermediate risk, 140 high risk) with median follow-up 16 months were analyzed. Metastasectomy was performed in 18 (39%), 63 (24%), and 32 (23%) of low, intermediate and high risk groups (p=0.04). Risk groups differed significantly with respect to ECOG performance status (p<0.001), metastases at diagnosis (low 1.72, intermediate 3.49, high 6.45, p<0.001), hemoglobin (p<0.001) and LDH (p<0.001). MVA for PFS revealed age (OR=1.03, p=0.05), BMI (OR=1.05, p=0.01), and higher risk category [vs. low (referent) intermediate OR=7.4, p<0.001, high OR=3.4, p=0.01] to be independent risk factors. MVA for OS revealed age (OR=1.03, p=0.02), BMI (OR=1.06, p=0.01), and higher risk category [low (referent) vs. intermediate OR=2.8, p=0.03, high OR=2.3, p=0.01] to be independent risk factors. KMA for PFS demonstrated that metastasectomy was associated with longer PFS in intermediate (24.0 vs. 6.7 months, p=0.01) but not high risk (4.2 vs. 4.0 months, p=0.58) and low risk (p=0.51) groups. KMA for OS demonstrated that metastasectomy was associated with longer median OS in the intermediate (56.9 vs. 29.3 months, p=0.01) and high risk (18.2 vs. 10.5, p=0.01), but not low risk (p=0.21) groups. Conclusions: Receipt of metastasectomy was associated with improved PFS in intermediate risk and improved OS in intermediate and high risk mRCC patients. These findings challenge prevailing assumptions about utility of metastasectomy. Further investigation is requisite to refine criteria for employment.
Apalutamide (APA) for metastatic castration-sensitive prostate cancer (mCSPC) in TITAN: Outcomes in patients (pts) with low- and high-risk disease.
Authors: Ozguroglu Mustafa , Chowdhury Simon , Bjartell Anders , Uemura Hirotsugu , Chung Byung Ha , Agarwal Neeraj , Merseburger Axel Stuart , Juárez Soto Álvaro , Lopez-Gitlitz Angela , Bhaumik Amitabha , Larsen Julie S. , McCarthy Sharon Anne , Chi Kim N. 
Published: February 2020

87 Background: TITAN showed that APA + androgen deprivation therapy (ADT) improves radiographic progression-free survival (rPFS) and overall survival (OS) in a broad group of pts with mCSPC (Chi et al. NEJM 2019). This post hoc analysis evaluates APA + ADT based on baseline (BL) prognostic risk as defined in LATITUDE (Fizazi et al. Lancet Oncol 2019). Methods: 1052 pts with mCSPC receiving ADT were randomized 1:1 to APA (240 mg/d; n = 525) or placebo (PBO; n = 527). Treatment cycles were 28 days. Risk included Gleason score ≥ 8, ≥ 3 bone lesions, or visceral metastasis. High risk was ≥ 2 risk factors, low risk was ≤ 1. Cox proportional hazards model was used to estimate HR and 95% CI for rPFS and OS. Results: Pt demographic and BL disease characteristics were similar between treatment groups (high risk: APA n = 289, PBO n = 286; low risk: APA n = 236, PBO n = 241). Median treatment duration was similar in the low-risk group with APA or PBO (21.8 mo and 20.3 mo, respectively). For the high-risk groups, treatment duration was longer with APA (APA 19.5 mo, PBO 14.7 mo). APA significantly reduced the risk of radiographic progression relative to PBO in both groups (Table). Risk of death (OS) was reduced by 38% in high-risk pts and 26% in low-risk pts with APA (Table). 24-mo survival rates: high risk, 76% APA, 63% PBO; low risk, 90% APA, 85% PBO. There were few deaths (≤ 33) in low-risk groups. Second PFS in APA pts: high risk, HR 1.9 (95% CI 1.2-3.0), p = 0.004; low risk, HR 2.2 (95% CI 1.5-3.2), p < 0.0001. Regardless of risk category, the safety profile of APA remained consistent with previously reported overall results. Conclusions: Addition of APA to ADT for pts with mCSPC prolonged rPFS and OS with a consistent safety profile compared with PBO + ADT regardless of BL risk. Clinical trial information: NCT02489318. [Table: see text]
Randomized phase II study of docetaxel (D) + abiraterone acetate (AA) versus D after disease progression to first-line AA in metastatic castration-resistant prostate cancer (mCRPC): ABIDO-SOGUG Trial.
Authors: Climent Duran Miguel Angel , Font Albert , Duran Ignacio , Puente Javier , Castellano Daniel , Sáez M Isabel , Mendez Vidal Maria Jose José , Santander Carmen , Arranz Arija Jose Angel , Gonzalez del Alba Aranzazu , Sanchez-Hernandez Alfredo , Esteban Emilio , Alonso Gordoa Teresa , Maroto Pablo , Lázaro Quintela Martín Emilio , Cassinello Javier , Perez Valderrama Begona , Juan Fita María José , Mellado Begona ,   Spanish Oncology Genitourinary Group
Published: February 2020

95 Background: Abiraterone acetate (AA) improves OS and rPFS in first line mCRPC patients (pts). After AA progression D is commonly used as standard second line therapy. However, the value of maintaining AA in combination with D despite progression has not been tested beyond small exploratory studies (Tagawa ST, Eur Urol 2016) ABIDO is a randomized-phase II trial that evaluates efficacy and safety of D + AA vs D after first-line AA progression in mCRPC. Methods: Asymptomatic or minimally symptomatic mCRPC pts with no visceral metastases, ECOG PS 0-1, and adequate organ functions were included. The study has two stages: In stage I pts receive AA (1000 mg/d + prednisone (P) 10 mg qd) until radiological or unequivocal clinical progression. In stage II pts were randomized to D 75 mg/m2 q3wk in combination with AA 1000 mg/d (arm A) or without AA (arm B) The primary endpoint was rPFS and the secondary endpoints radiological response (RR), OS, PSA-response, PSA-PFS and safety. Results: 88 pts were randomized, (46 arm A, 42 Arm B). Median age was 69 y/o, 43% had ECOG 0 and 91%/11%/5% had bone, liver and lung metastases. Median rPFS was 11.4 months (m) in arm A vs 10.5 m in ARM B; 12-m rPFS was 43% vs 45%; Median PSA PFS was 6.2 vs 5.5 m and median OS was 17.3 vs 16.9 m. Twenty four pts (52%) in arm A and 19 (46%) in arm B achieve ≥50% PSA response. RR was achieved in 15% vs 7% of pts and disease control rate in 74% in both arms. No statistically significant differences were found in efficacy parameters. Half of pts received 10 cycles of D (median 7 and 8). D median dose intensity was 86% and 90% for each arm and 91% for AA. Eleven pts discontinued treatment due to non-hematological toxicity, 5 in arm A and 6 in arm B. Most frequent G3-4 toxicities per arm (A/B) were: neutropenia (57%/29%; P=0.027), febrile neutropenia (17%/10%), diarrhea (9%/7%), and asthenia (11%/10%). Conclusions: ABIDO trial was unable to demonstrate the significant clinical benefit of maintenance AA approach + D after AA first-line therapy. No differences were observed in RR, PSA PFS, rPFS and OS. In AA + D cohort, more frequent and severe hematological toxicity (neutropenia and febrile neutropenia) were reported. Clinical trial information: NCT02036060.
An open-label phase Ib study of ORIC-101 in combination with enzalutamide in patients with metastatic prostate cancer progressing on enzalutamide.
Authors: Shore Neal D. , Efstathiou Eleni , Patel Rupal , Xu Rongda , Johnson Ann , Multani Pratik S. , Morris Michael J. , Abida Wassim 
Published: February 2020

TPS253 Background: The glucocorticoid receptor (GR) has been identified as a potential antiandrogen bypass mechanism of resistance to enzalutamide treatment in prostate cancer. In an in vivo enzalutamide resistant prostate cancer model, GR activates a transcriptional program that is similar but distinguishable from AR and maintains the resistant phenotype (Arora et al 2013). In human prostate cancer cells, GR expression increases upon exposure to AR antagonists, and higher GR expression is associated with treatment resistance. These findings suggest that combined inhibition of both GR and AR may prolong the duration of response or restore sensitivity to AR antagonists such as enzalutamide or apalutamide. ORIC-101 is an oral small molecule GR antagonist that fully inhibits GR transcriptional activity and blocks proliferative and survival signals mediated by GR. Methods: This is an open-label, single arm, multicenter, dose escalation followed by dose expansion study to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of ORIC-101 in combination with enzalutamide in patients with PSA progression on enzalutamide (NCT04033328). Escalating dose levels of ORIC-101 will be administered orally, once daily in combination with enzalutamide 160 mg on a 28-day cycle following a modified interval (i) 3+3 design. Parallel enrollment of up to 3 additional patients presenting with GR overexpressing tumors (determined in tissue via immunohistochemistry) may be performed at each dose level. Based on the i3+3 design, the target toxicity rate for the maximum tolerated dose (MTD) is set at 25% (midpoint between 1 out of 3 and 1 out of 6) and any values between 20% and 30% can be considered as acceptable toxicity rates for the MTD. During dose expansion, patients will be stratified into 3 cohorts based on GR expression in tumor tissue: GR-high, GR-moderate, and GR-low. A Simon’s Two-Stage Optimal design will allow for early enrollment stopping in any cohort if PSA response rate is not sufficiently promising to warrant further development. Patients will continue treatment until disease progression or unacceptable toxicity. Clinical trial information: NCT04033328.
A phase I clinical trial of PSMA-directed/TGFβ-insensitive CAR-T cells in metastatic castration-resistant prostate cancer.
Authors: Narayan Vivek , Gladney Whitney , Plesa Gabriela , Vapiwala Neha , Carpenter Erica L. , Maude Shannon L. , Lal Priti , Lacey Simon F. , Melenhorst Jan J. , Fraietta Joseph , Sebro Ronnie , Farwell Michael , Moniak Michael , Gilmore Joan , Lledo Lester , Dengel Karen , Marshall Amy , Coughlin Christina Marie , June Carl H. , Haas Naomi B. 
Published: February 2020

TPS269 Background: Adoptive immunotherapy with Chimeric Antigen Receptor (CAR)-T cells is a novel approach for the treatment of prostate cancer. However, the prostate cancer immunosuppressive microenvironment, including high levels of TGFβ, may limit the therapeutic potential of re-directed T cells upon tumor infiltration. The inhibition of TGFβ signaling via co-expression of a dominant negative TGFβ receptor (TGFβRdn) can enhance antitumor immunity. Co-expression of TGFβRdn on PSMA-redirected CAR-T cells in in vivo disseminated tumor models led to increased T cell proliferation, enhanced cytokine secretion, resistance to exhaustion, long-term persistence, and greater induction of tumor eradication. Methods: We are conducting a first-in-human phase 1 clinical trial evaluating the safety and preliminary efficacy of lentivirally-transduced PSMA-redirected/TGFβ-insensitive CAR-T cells (CART-PSMA-TGFβRdn) in metastatic CRPC (NCT03089203). In a 3+3 dose-escalation design, patients received a single dose of 1-3 x 107/m2 (Cohort 1) or 1-3 x 108/m2 (Cohort 2) CART-PSMA-TGFβRdn cells without lymphodepleting chemotherapy. In Cohort 3, 1-3 x 108/m2 CART-PSMA-TGFβRdn cells are administered following a lymphodepleting chemotherapy regimen of cyclophosphamide and fludarabine (cy/flu). A currently accruing modified protocol seeks to optimize the therapeutic window with CART-PSMA-TGFβRdn (CAR-T dose of 1-3 x 107/m2 following lymphodepleting cy/flu). Eight patients have received a single dose of CART-PSMA-TGFβRdn. CAR-T expansion and persistence in peripheral blood and trafficking to target tissues is evaluated via quantitative PCR of CART-PSMA-TGFβRdn DNA. Bioactivity of CAR-T cells in peripheral blood is evaluated via multiplex immunoassays. Additional correlative analyses will interrogate the therapeutic contribution of TGFβRdn, as well as early markers of response and resistance to CART-PSMA-TGFβRdn therapy. Clinical trial information: NCT03089203.