bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-effectiveness of pembrolizumab in combination with axitinib as first-line treatment for advanced renal cell carcinoma.
Authors: Bensimon Arielle G. , Zhong Yichen , Swami Umang , Briggs Allison , Young Joshua , Feng Yuan , Song Yan , Signorovitch James , Adejoro Oluwakayode , Chakravarty Abhiroop , Chen Mei , Perini Rodolfo F. , Geynisman Daniel M. 
Published: February 2020

716 Background: Pembrolizumab/axitinib significantly prolonged progression-free survival (PFS) and overall survival (OS) vs. sunitinib in a phase 3 trial KEYNOTE-426 among previously untreated patients with advanced renal cell carcinoma (RCC). This study assessed the cost-effectiveness of pembrolizumab/axitinib vs. other first-line treatments of advanced RCC from a US payer perspective. Methods: A partitioned survival model with 3 states (progression-free, progressed, death) evaluated costs and quality-adjusted life years (QALYs) for pembrolizumab/axitinib and other first-line regimens: sunitinib and pazopanib in the overall population; sunitinib, cabozantinib, and nivolumab/ipilimumab in the subgroup with poor/intermediate IMDC risk. Time on treatment, PFS, and OS were extrapolated using parametric models fitted to KEYNOTE-426 data (24 Aug 2018 cutoff) for pembrolizumab/axitinib and sunitinib, and hazard ratios from network meta-analyses for other comparators. Costs of first-line and subsequent treatment, adverse events, medical resources, and terminal care were estimated based on trial results, drug labels, and published sources. Utilities were derived through mixed-effects regressions of KEYNOTE-426 EQ-5D data. Results: Over a lifetime, the incremental cost-effectiveness ratios (ICERs) for pembrolizumab/axitinib were below willingness-to-pay thresholds of $150,000/QALY or $180,000/QALY (approx. 3 × gross domestic product per capita) vs. all comparators in the overall and intermediate/poor risk populations (table). Results were robust in deterministic and probabilistic sensitivity analyses. Conclusions: Pembrolizumab/axitinib is associated with higher QALYs and considered cost-effective vs. other first-line treatments of advanced RCC in the US.[Table: see text]
Prevention of docetaxel-associated febrile neutropenia with primary granulocyte colony-stimulating factors (GCSF) in Chinese metastatic hormonal-sensitive (mHSPC) and castration-resistant prostate cancer (mCRPC).
Authors: Poon Darren M.C. , Chan Kuen , Chan T.W. , Ng Bryan , Siu S Wai-kwan , Ng Joyce , Johnson David , Lee Ka Chai ,   Hong Kong Society of Uro-Oncology
Published: February 2020

72 Background: Plenty reports suggest Asian prostate cancer patients are more susceptible to docetaxel-related febrile neutropenia (FN). However, primary GCSF prophylaxis is currently not recommended by international guidelines for patients with mCRPC or mHSPC when docetaxel is administered. Therefore, we aim to evaluate the potential benefit of primary GCSF in preventing the potentially life-threatening FN for Chinese mHSPC and mCRPC treated with docetaxel. Methods: Two cohorts (2003-2012 & 2015-2018) that consisted of Chinese patients with mHSPC and mCRPC who had docetaxel at six public oncology centres in Hong Kong were grouped and analysed. Primary GCSF was defined as its administration within 5 days of beginning docetaxel, and its use was at the discretion of oncologists. The primary outcome was FN within 21 days of first cycle of docetaxel (1st FN). Multivariable regression analysis was used. Results: A total of 377 metastatic prostate cancer (mHSPC, n=100 (26%); mCRPC, n=277 (73%)) patients with docetaxel treatment was identified. Primary GCSF was given in 71 (18%) patients. The baseline characteristics were balanced between groups with and without primary GCSF. FN was happened in 61 patients (16%), with 37 (9%) of them at 1st cycle. Primary GCSF were administered in 2 and 69 patients with and without 1st FN, respectively (5.4% vs 20.3%, p=0.03). Primary GCSF was associated with reduced risk of 1st FN (odds ratio (OR), 0.22; 95% CI 0.05 - 0.96; p=0.04) in overall, and a similar trend was observed in both mHSPC (OR, 0.36; p=0.35) and mCRPC (OR, 0.16, p=0.08) subgroups. Besides, among various clinical parameters, poor performance status (ECOG 2-3) was associated with increased risk of 1st FN (OR, 3.90, 95% CI 1.66 – 9.13, p=0.002). Conclusions: Primary GCSF prophylaxis is suggested for Asian mCRPC and mHSPC patients, particularly those with poor performance status, to alleviate the risk of docetaxel-related febrile neutropenia.
Investigating the role of the gastrointestinal microbiome in response to immune checkpoint inhibitors (ICIs) among patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Agarwal Anika , Modliszewski Jennifer , Davey Lauren , Reyes-Martinez Marco , Runyambo Daniella , Corcoran David , Dressman Holly , George Daniel J. , Valdivia Raphael , Armstrong Andrew J. , Zhang Tian 
Published: February 2020

730 Background: ICIs are effective in mRCC, but one pertinent clinical need is to identify predictive biomarkers for response. The PD-1 receptor has been implicated in regulating gastrointestinal commensal bacteria, with varied immune interactions, thereby impacting response to ICIs. We evaluated bacterial taxa and ICI outcomes in mRCC pts. Methods: Fecal samples from 22 mRCC pts were collected at baseline, week (wk)-4 on ICI, and upon disease progression. Pts were grouped as responders (R, complete or partial response) or non-responders (NR, stable or progressive disease). Microbial DNA was isolated by next generation DNA sequencing. The V4 region of bacterial 16S ribosomal RNA was amplified from extracted DNA and analyzed for bacterial abundance, as well as alpha diversity indices (number of amplicon sequence variants [ASVs], Shannon’s Index, Faith’s Phylogenetic Diversity, and Pielou’s evenness) and beta diversity indices on ASVs (Bray-Curtis, Jaccard, and unweighted/weighted UniFrac dissimilarity measures). Results: Beta diversity analysis at baseline showed no difference in microbial composition between Rs and NRs. However, beta diversity analysis did show a significant change in composition from baseline to wk 4 in R vs NR pts (Bray Curtis p-value=0.03). Among mRCC pts with CR to ICIs, counts of bacteria in the phylum Verrucomicrobia had an upward trend from baseline to wk 4. All mRCC pts with CR (n=3) had Akkermansia at wk 4. However, Akkermansia colonization was not sufficient for response, present in 7/9 Rs and 6/11 NRs. Conclusions: Baseline microbiome differences between ICI Rs and NRs are not enough to predict outcomes. Diversity changes between baseline and wk-4 on treatment could be an early predictor of response. Factors other than presence of Akkermansia (tumor or host-specific, Akkermansia strain variation, or other bacteria in the microenvironment) may contribute to response. Further species and strain-level profiling of the microbiota, tumor-specific genomic alterations, host immune response, and increasing sample size of ICI-treated patients may improve detection of significant differences between Rs and NRs.
Association of modified Glasgow Prognostic Score (mGPS) with survival outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (CPI).
Authors: Brown Jacqueline T , Liu Yuan , Martini Dylan J. , Shabto Julie M. , Hitron Elise , Russler Greta , Caulfield Sarah , Yantorni Lauren Beth , Joshi Shreyas S. , Kissick Haydn , Ogan Kenneth , Carthon Bradley Curtis , Kucuk Omer , Harris Wayne , Master Viraj A. , Bilen Mehmet Asim 
Published: February 2020

738 Background: The current risk models for mRCC were developed for patients treated with targeted therapy. The mGPS incorporates albumin and C-reactive protein and may serve as a composite prognostic biomarker in mRCC in the era of CPI. Methods: We conducted a retrospective analysis of patients with mRCC treated with CPI (anti-PD1 or PD-L1 agents) at Winship Cancer Institute between 2015-2018. Overall survival (OS) and progression-free survival (PFS) were defined as months from CPI initiation to death or clinical/radiographic progression, respectively. mGPS was defined as a summary score with one point given for CRP > 10 mg/L and/or albumin < 3.5 g/dL. Univariate (UVA) and multivariate (MVA) analyses were carried out for OS and PFS using Cox proportional hazard model. Results: A total of 78 eligible patients were included with a median follow up of 30.7 months. Median age was 66 years (range = 38-82), 64% were male, 78% had clear cell histology, and 76% received anti-PD-1 monotherapy. Higher mGPS at baseline was significantly associated with worse OS while at week 6 was associated with worse OS and PFS (Table). Conclusions: A higher mGPS score in the early course of CPI treatment was associated with worse survival in patients with mRCC. These results should be validated in a larger, prospective study.[Table: see text]
Prognostic value of epithelial-mesenchymal transition markers in clear cell renal cell carcinoma.
Authors: Qu Yuan-Yuan , Tian Xi , Xu Wenhao , Anwaier Aihemutaijiang , Ye Dingwei , Zhang Hailiang 
Published: February 2020

739 Background: Epithelial-to-mesenchymal transition (EMT) in important in tumor invasiveness and metastasis. We aimed to determine prognostic value of six key EMT markers (CDH1, CDH2, SNAI1, SNAI2, VIM, TWIST1) in clear cell renal cell carcinoma (ccRCC). Methods: A total of 533 ccRCC patients with RNASeq data from The Cancer Genome Atlas (TCGA) cohort were included for analysis. Gene expression of these EMT markers was compared between tumor and normal tissues based on Oncomine database and TCGA cohort. Their correlations with progression-free survival (PFS) and overall survival (OS) were also examined in both TCGA cohort and FUSCC (Fudan University Shanghai Cancer Center) cohort. Cox proportional hazards regression model and Kaplan-Meier plot were used to assess the relative factors. Functional enrichment analyses were utilized to describe biologic function annotations and significantly involved hallmarks pathways of each gene. Results: We found that Epithelial marker, CDH1 expression was lower, while mesenchymal markers (CDH2, SNAI1, VIM, TWIST1) expression was higher in ccRCC primary tumors. In the TCGA cohort, we found that patients with higher expression of VIM, TWIST1 or lower expression of CDH1 had worse prognosis. Further, in the FUSCC cohort, we confirmed the predictive ability of mesenchymal markers and epithelial marker expression in PFS and OS of ccRCC patients. After generating Cox regression models, EMT markers (CDH1, SNAI1, VIM, and TWIST1) were independent prognostic factors of both PFS and OS in ccRCC patients. Conclusions: Our preliminary EMT prediction model can facilitate further screening of EMT biomarkers and cast a better understanding of EMT gene function in ccRCC.
Association of De Ritis Ratio and Neutrophil Lymphocyte Ratio with renal functional decline and all-cause mortality in renal cell carcinoma.
Authors: Keiner Cathrine , Meagher Margaret , Patil Dattatraya , Saito Kazutaka , Patel Devin , Ghali Fady , Dutt Raksha , Miller Nathan , Bradshaw Aaron , Wan Fang , Yasuda Yosuke , Fuji Yasuhisa , Master Viraj A. , Derweesh Ithaar 
Published: February 2020

741 Background: We sought to investigate utility of pre-operative neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and De Ritis Ratio as predictors of all-cause mortality (ACM) and renal functional decline renal cell carcinoma (RCC). Methods: Multi-institutional retrospective analysis of patients undergoing surgery for RCC. Multivariable analysis (MVA) was conducted to elucidate independent risk factors for ACM, de novo estimated glomerular filtration rate (eGFR)<45 ml/min/1.73m2 and eGFR<30 ml/min/1.73m2. Kaplan-Meier analysis (KMA) was used to investigate ACM, and de novo CKD. Results: 2928 patients were analyzed [1850 Male/1078 Female, median follow up 30.5 months, median tumor size 4.5 cm, 1741 partial nephrectomy (PN)/1187 radical nephrectomy (RN)]. 690 patients had NLR ≥ 3, while 208 patients had NLR ≥ 6; 110 patients had PLR ≥ 3; and 474 patients had De Ritis Ratio ≥ 3. MVA for risk factors associated with worsened ACM showed male sex (OR 1.6, p=0.02), HTN (OR 2.1, p=0.001), increasing tumor size (OR 1.12, p<0.001), clear cell RCC (OR 2.0, p=0.001), RN (OR 1.6, p=0.048), NLR≥ 6 (OR=2.4, p=0.001), Di Ritis Ratio≥3 (OR 2.4, p<0.001), and de novo eGFR<45 (OR=1.6, p=0.015) to be independent risk factors. MVA for factors associated with development of eGFR<45 included increasing age (OR 1.03, p<0.001), male (OR 1.5, p=0.01), HTN (OR 2.3, p<0.001), clear cell RCC (OR 2.2, p<0.001), RN (OR 6.8, p=0.03), NLR≥6 (OR 2.0, p=0.002), and Di Ritis Ratio≥3 (OR 2.3, p<0.001) to be independently associated. Variables associated with development of eGFR<30 included age (OR 1.05, p<0.001), DM (OR=3.01, p<0.001), black race (OR 1.9, p=0.005), Di Ritis Ratio≥3 (OR 2.0, p=0.001), and NLR≥6 (OR 2.1, p=0.002). PLR was not associated with OS, de novo eGFR<45, or de novo eGFR<30. On KMA, NLR≥6 was associated with worse OS (p<0.001). Di Ritis ratio ≥1.5 was associated with worse OS p<0.001 and Di Ritis ratio (≥3) was associated decreased freedom from of de novo eGFR<45 (p=0.026). Conclusions: Elevated NLR and De Ritis Ratio were associated with functional decline and worsened OS, while PLR was not predictive. These markers may be helpful in identifying high-risk patients.
PRINT: Prostate cancer intensive, non-cross reactive therapy for CRP—Early observations of efficacy.
Authors: Liaw Bobby Chi-Hung , Tsao Che-Kai , Galsky Matt D. , Bakst Richard Lorne , Stewart Robert , Stock Richard , Oh William K. 
Published: February 2020

89 Background: Optimal sequencing of therapeutic agents in mCRPC remains debated, but the standard approach is to treat with one agent until resistance is met before switching. PRINT explores the efficacy of treating mCRPC with a rapidly-cycling, non-cross reactive regimen as a way to more effectively treat intrinsic heterogeneity, delay/prevent drug resistance, and minimize toxicity. Methods: Enrolled patients all received 3 consecutive treatment modules, each 12 weeks: 1. abiraterone acetate 1000 mg PO daily + prednisone 5 mg PO BID; 2. cabazitaxel 20 mg/m2 IV + carboplatin AUC 4 IV q3 weeks; 3. enzalutamide 160 mg PO daily + radium-223 55 kBq/kg IV q4 weeks (in those with bone metastases). Upon completion of the 9-month regimen, patients are followed on ADT alone. Primary endpoint for the study is PSA or radiographic time to progression (TTP). Results: From 3/2017 to 10/2019, 35 of 40 planned men with mCRPC were enrolled, 25 patients have completed the 9-month study regimen and evaluable for TTP analysis. With median follow up of 52 weeks, median time to PSA progression after therapy completion is 15.5 weeks (95%CI; 5-26.1+ weeks). PSA response rates show successive improvements with each sequential treatment module (Table). Six (24%) patients continue on post-study surveillance with ADT alone, two of which have remained off any mCRPC agents for over a year (64+ weeks, 54+ weeks). In patients needing to restart therapy, experience with efficacy and tolerability of each agent while on the study, has helped inform subsequent mCRPC drug selection. The study regimen is well-tolerated, with few grade 3/4 AE’s: hyperglycemia (14.3%), diarrhea (5.7%), anemia (2.9%), fatigue (2.9%), neutropenia (2.9%), and thrombocytopenia (2.9%). Conclusions: Treatment of mCRPC with a rapidly-cycling non-cross reactive regimen demonstrates significant antitumor benefits, with potential for long-term suppression of disease. Further longitudinal follow up will determine if PRINT delays progression compared with standard approaches. Clinical trial information: NCT02903160. [Table: see text]
A prospective phase II/III multicenter study of PSMA-targeted 18F-DCFPyL PET/CT imaging in patients with prostate cancer (OSPREY): A sub-analysis of regional and distant metastases detection rates at initial staging by 18F-DCFPyL PET/CT.
Authors: Pouliot Frederic , Carroll Peter , Probst Stephan , Pienta Kenneth J. , Rowe Steven P. , Saperstein Lawrence , Siegel Barry , Patnaik Akash , Preston Mark A. , Alva Ajjai Shivaram , Gorin Michael A. , Morris Michael J. 
Published: February 2020

9 Background: Current imaging modalities are suboptimal for the initial staging of men at risk of harboring occult metastatic prostate cancer (PCa). PSMA-based imaging is considered highly promising for PCa detection. 18F-DCFPyL is a novel PSMA-targeted radiopharmaceutical for positron emission tomography (PET) that may be useful in staging of pts with high risk PCa. The diagnostic performance of 18F-DCFPyL regarding regional and distant metastases has been previously reported. Here we report on detection rates and the resulting impact 18F-DCFPyL may have on staging of pts with high risk PCa. Methods: 18F-DCFPyL PET/CT was evaluated in 252 men with high-risk PCa who were planned for radical prostatectomy with lymphadenectomy (RP-PLND). 9 mCi (333 MBq) of 18F-DCFPyL was administered 1-2 hours prior to PET/CT. Based on TNM staging, 18F-DCFPyL PET/CT detection rates including lesion counts were systematically analyzed: prostatic (T), pelvic LN (N), extra-pelvic LN (M1a), bone (M1b) & other visceral organs/soft tissue (M1c). Three central, blinded, and independent readers evaluated the 18F-DCFPyL scans. Results: At study entry, 97% and 99% of all evaluable pts had no known nodal or metastatic disease, respectively, based on standard cross-sectional imaging. Of these, 18F-DCFPyL PET/CT staged 37 (14.7%) pts with N1 disease and 27 (10.7%) pts with M1 disease (1 [0.4%] M1a, 23 [9.1%] M1b, and 3 [1.2%] M1c). In total, 56 (22%) of patients were upstaged to N1 or M1 disease by 18F-DCFPyL. The positive predictive value of 18F-DCFPyL based on histopathologic validation for pelvic LNs was 86.7% (95% CI: 70, 95). Only one patient in Cohort A underwent a biopsy of their 18F-DCFPyL detected M1 finding; histopathology confirmed the metastatic lesion in the spine to be a true positive. Conclusions: A total of 22% of pts with high-risk PCa planned for RP-PLND had regional or distant metastatic lesions detected on 18F-DCFPyL PET/CT. These results suggest the potential utility of 18F-DCFPyL PET/CT in the staging of men with newly diagnosed high risk PCa to develop optimized treatment paradigms. Clinical trial information: NCT02981368.
Phase I study of AMG 160, a half-life extended bispecific T-cell engager (HLE BiTE) immune therapy targeting prostate-specific membrane antigen (PSMA), in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Tran Ben , Horvath Lisa , Dorff Tanya B. , Greil Richard , Machiels Jean-Pascal H. , Roncolato Felicia , Autio Karen A. , Rettig Matthew , Fizazi Karim , Lolkema Martijn P. , Fermin Anthony C. , Salvati Mark , Kouros-Mehr Hosein 
Published: February 2020

TPS261 Background: AMG 160 is a novel HLE BiTE immune therapy that redirects T cells to kill tumor cells by binding to PSMA on tumor cells and CD3 on T cells. Methods: Primary objectives of this open-label, ascending, multiple-dose, phase 1 study (NCT03792841) are to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of AMG 160 in men with mCRPC; secondary objectives are to characterize pharmacokinetics (PK) and evaluate preliminary efficacy. The dose exploration will estimate the MTD or RP2D by Bayesian logistic regression modeling. The dose expansion will assess safety, efficacy, PK, and pharmacodynamics (PD) of the selected dose and provide further safety and efficacy data. PD biomarkers and potential patient selection biomarkers will be explored. Preliminary antitumor activity will be assessed by objective response per RECIST 1.1 with PCWG3 modifications, PSA response, duration of response, time to progression, PFS (radiographic and PSA)/OS, and circulating tumor cell (CTC) response (CTC0 and CTC conversion). Imaging will include CT/MRI, bone scan, 68Ga-PSMA-11 PET/CT, and 18F-FDG PET/CT. In cycle 1, patients will be pretreated with dexamethasone before short-term IV infusion of AMG 160 and will be hospitalized for 72 h after each AMG 160 dose. Key inclusion criteria: age ≥18 y; histologically/cytologically confirmed mCRPC that progressed after novel hormone therapy; failure of 1–2 taxane-based regimens or have refused a taxane regimen; bilateral orchiectomy or continuous androgen-deprivation therapy; evidence of progressive disease; total serum testosterone ≤50 ng/dL. Key exclusion criteria: active autoimmune disease or diseases requiring immunosuppressive therapy (low-dose prednisone permitted); CNS metastases, leptomeningeal disease, or spinal cord compression; prior PSMA-targeted therapy (177Lu-PSMA-617 may be allowed). The study will enroll 30–50 patients in the dose exploration and 50 patients in the dose expansion globally. The study opened in January 2019; dose exploration is ongoing. Clinical trial information: NCT03792841.
Prospective trial of nivolumab (Nivo) plus radium-223 (RA) in metastatic castration-resistant prostate cancer (mCRPC) evaluating circulating tumor DNA (ctDNA) levels as a biomarker of response.
Authors: Maughan Benjamin Louis , Nussenzveig Roberto , Swami Umang , Gupta Sumati , Agarwal Neeraj 
Published: February 2020

TPS267 Background: RA is a calcium-mimetic radiopharmaceutical emitter of alpha particles that has been approved for treatment of mCRPC. Radiation plus checkpoint inhibitors has demonstrated promising efficacy in previous clinical trials (PMID 27466265, 23535954). Alteration to PD-1 expression has been observed with radium-223, suggesting potential synergy with Nivo (PMID 29137877). ctDNA concentration may accurately reflect overall tumor burden and response to immune therapy. ctDNA testing after 6 weeks of therapy predicts efficacy of immunotherapy in patients with metastatic NSCLC and urothelial carcinoma (PMID 30093454) and metastatic gastric cancer (PMID 30013197). Reduction of ctDNA correlated with both radiographic progression free survival (rPFS) and overall survival. We hypothesize that RA + Nivo will be safe and decrease ctDNA, which may predict response to therapy earlier than conventional scans. Methods: This is a single-arm phase I/II investigator initiated trial (NCT04109729). Primary objectives: 1) Safety, 2) Change in ctDNA after 6 weeks treatment compared to baseline. Secondary objectives: 1) PSA-PFS; 2) PSA 50% response rate; 3) Time to skeletal related event; 4) Bone metabolism marker response. Inclusion criteria: symptomatic bone metastasis, mCRPC, adequate hematopoiesis. Exclusion criteria: visceral metastasis, history of autoimmune disease and current use of immune suppression therapy. A total of 36 patients will be enrolled. Cycles are 28 days. ctDNA concentration will be measured using GuardantOMNI research platform which evaluates 500 genes. Treatment: RA (55 kBq/kg IV) monotherapy lead in for two cycles followed by RA plus Nivo (480mg IV) for an additional 4 cycles. Nivo monotherapy then continues for up to 2 years. ctDNA collected prior to combination therapy and 6 weeks after. Restaging scans done every 2 cycles while on radium-223 and every 3 cycles while on nivolumab. Clinical trial information: NCT04109729.