bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pembrolizumab (pembro) monotherapy for patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette–Guérin (BCG): Results from cohort B of the phase 2 KEYNOTE-057 trial.
Authors: Necchi Andrea , Roumiguié Mathieu , Esen Ahmet Adil , Lebret Thierry , De Wit Ronald , Shore Neal D. , Bajorin Dean F. , Krieger Laurence E. M. , Kandori Shuya , Uchio Edward M. , Seo Ho Kyung , Boormans Joost , Kamat Ashish M. , Singer Eric A. , Grivas Petros , Nishiyama Hiroyuki , Nam Kijoeng , Kapadia Ekta , Van den Sigtenhorst-Fijlstra Margot , Kulkarni Girish S. 
Published: March 2023

LBA442 Background: Although most pts with HR NMIBC respond to BCG, pts whose cancer does not respond or who relapse within 12 mo have poor prognosis and require radical cystectomy (RC). The single-arm, multicohort phase 2 KEYNOTE-057 trial (NCT02625961) was designed to investigate the safety and efficacy of pembro monotherapy for pts with BCG-unresponsive HR NMIBC (per FDA) who were ineligible or declined to undergo RC. Results from cohort A (carcinoma in situ [CIS] ± papillary tumors) showed a clinical complete response rate of 41% at 3 mo and led to approval of pembro monotherapy for such pts in the United States. We describe the results from cohort B (papillary tumors without CIS). Methods: Pts were aged ≥18 y with BCG-unresponsive HR NMIBC with papillary tumors only (high-grade Ta or any-grade T1) at baseline and ECOG PS 0-2. Pts received pembro 200 mg every 3 wk (Q3W) for ≤35 cycles (~2 y). Cancer was assessed at 12 wk and Q12W thereafter if no recurrent HR NMIBC or progression was observed; CT urography was done Q24W. Primary end points for cohort B were 12-mo disease-free survival (DFS) rate of HR NMIBC as assessed by central pathology/radiology review and safety, assuming a 12-mo DFS of >20% for HR NMIBC. Secondary efficacy end points were 12-mo DFS rate of any disease; progression-free survival (PFS) to worsening of grade, stage, or death; PFS to muscle invasion, metastasis, or death; and overall survival (OS). Results: Overall, 132 pts received pembro for a median of 9.5 cycles (range, 1.0-35.0). Median age was 72 y (range, 37-87); 57 pts (43.2%) had T1 stage; all pts (100%) had urothelial histology; 104 pts (78.8%) were male; pts received a median of 10 (range, 6-33) prior BCG instillations. Median follow-up was 45.4 mo (range, 14.9-77.1). Efficacy data are shown in Table. Thirty-one pts (23.5%) had RC after stopping pembro. Treatment-related AEs occurred in 97 pts (73.5%); 19 (14.4%) had a grade 3/4 treatment-related AE and 14 pts (10.6%) discontinued due to a treatment-related AE. No deaths from treatment-related AEs occurred. Conclusions: Pembro showed notable antitumor activity in pts with BCG-unresponsive non-CIS papillary HR NMIBC after ~45 mo of follow-up. Toxicity was manageable and consistent with that in cohort A, with no new safety signals. Results suggest pts with non-CIS papillary HR NMIBC unresponsive to BCG who declined or were ineligible to undergo RC may also benefit from pembro monotherapy. Clinical trial information: NCT02625961 . [Table: see text]
Extended follow-up results from the CheckMate 274 trial.
Authors: Galsky Matt D. , Witjes Alfred Alfred , Gschwend Jürgen E. , Schenker Michael , Valderrama Begoña Pérez , Tomita Yoshihiko , Bamias Aristotelis , Lebret Thierry , Shariat Shahrokh F. , Park Se Hoon , Agerbaek Mads , Jha Gautam Gopalji , Stenner Frank , Dutta Santanu , Nasroulah Federico , Zhang Joshua , Brophy Lynne , Bajorin Dean F. 
Published: March 2023

LBA443 Background: The 2 primary endpoints of the CheckMate 274 trial were met as nivolumab (NIVO) improved disease-free survival (DFS) versus placebo (PBO) in the intent-to-treat (ITT) population and in patients with tumor programmed death ligand 1 (PD-L1) expression ≥ 1%. We report extended follow-up data. Methods: CheckMate 274 is a phase 3, double-blind trial of adjuvant NIVO versus PBO for high-risk muscle-invasive urothelial carcinoma (MIUC) (bladder, ureter, or renal pelvis) after radical resection. Patients were randomly assigned 1:1 to NIVO 240 mg every 2 wk or PBO for ≤ 1 year of treatment. Patients had pathologic evidence of UC at high risk of recurrence and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1. Primary endpoints were DFS in ITT patients and in patients with PD-L1 ≥ 1%. DFS was also analyzed in prespecified subgroups. Overall survival and non–urothelial tract recurrence-free survival (NUTRFS) in ITT patients and in patients with PD-L1 ≥ 1% were secondary endpoints. Distant metastasis-free survival (DMFS) and safety were exploratory endpoints. Results: There were 353 patients randomly assigned to NIVO (PD-L1 ≥ 1%, n = 140) and 356 to PBO (PD-L1 ≥ 1%, n = 142). With median follow-up of 36.1 months (minimum follow-up, 31.6 months), median DFS was 22.0 months with NIVO versus 10.9 months with PBO in ITT patients and 52.6 months with NIVO versus 8.4 months with PBO in patients with PD-L1 ≥ 1% (Table). DFS benefit was seen in most subgroups analyzed including age, sex, ECOG PS, nodal status, prior cisplatin-based chemotherapy, and PD-L1 status. NUTRFS and DMFS benefits with NIVO versus PBO were also observed in both populations (Table). Grade 3–4 treatment-related adverse events occurred in 18.2% and 7.2% of patients in the NIVO and PBO arms, consistent with the primary analysis. Overall survival will be assessed at a future database lock. Conclusions: With extended follow-up, NIVO continued to show DFS, NUTRFS, and DMFS benefits versus PBO. The hazard ratio (HR) for DFS and NUTRFS in PD-L1 ≥ 1% patients and for DMFS in both ITT and PD-L1 ≥ 1% patients also continued to improve versus the primary analysis. No new safety signals were identified. These results further support adjuvant NIVO as a standard of care for high-risk MIUC after radical resection. Clinical trial information: NCT02632409 . [Table: see text]
Cell-free urinary tumor DNA to detect minimal residual disease prior to repeat-transurethral resection of bladder tumor in non–muscle-invasive bladder cancer: A prospective study.
Authors: Rose Kyle M. , Murthy Prithvi , Gould Billie , Huelster Heather L , Davaro Facundo , Du Pan , Jia Shidong , Li Roger 
Published: March 2023

LBA445 Background: Cell-free urinary tumor DNA (utDNA) generated from tumor genomic sequencing is an emerging biomarker showing tremendous potential for detecting minimal residual disease (MRD) in muscle-invasive and metastatic bladder cancer. We performed a prospective study to assess utDNA’s ability to measure MRD at the time of standard-of-care repeat transurethral resection of bladder tumor (rTURBT) in non-muscle invasive bladder cancer (NMIBC). Methods: Patients with high-risk NMIBC were enrolled prior to rTURBT. Index tumor and rTURBT mutational profile was performed via PredicineWES whole exome sequencing across 20,000 genes. Genes with non-synonymous (NS) mutations observed in index and rTURBT specimens identified in a minimum of two samples are reported. Urine samples were taken immediately prior to r-TURBT. utDNA detection was performed by ultra-deep sequencing of urinary cfDNA using a custom panel of up to 50-baseline mutations per patient together with a fixed core panel covering hotspot regions and actionable variants via PredicineBEACON. Urinary tumor fraction was used to call utDNA positivity. The primary endpoint was the detection of utDNA to predict MRD at the time of repeat-TURBT. Results: Eleven patients underwent rTURBT for high-risk NMIBC. Residual tumor was detected at rTURBT in 8/11 (73%) patients. Fifty genes with NS mutations found in at least two samples were identified including TP53, PIK3CA, RB1, MYC, CDKN1A and ARID1A. A median of 146 (range 39-418) and 91 NS (range 2-312) mutations were identified in the index and re-TUR specimens, respectively. Concordance rates were 83% on average between index and rTURBT, highest for patients upstaged to T2 disease, and lowest for patients harboring CIS. New somatic variants not observed in the index tissue were detected in rTURBT for 4/6 patients and 7/14 were also detected in the pre-operative urine. Overall, 50% of utDNA mutations were concordant with index tumor tissue, 39% were concordant with rTURBT tissue, and 33% were concordant with both. The tumor fraction of utDNA was higher in patients with residual disease (mean 2.5% vs. 0.2%, p=0.10). Using tumor-fraction to predict MRD, the area under the receiver-operator curve was 0.85. Using an optimal threshold of ≥3.3% tumor-fraction to define utDNA positivity, the test had a sensitivity of 75% at 100% specificity. Conclusions: Urinary tumor DNA shows promise as a surrogate for minimal residual disease and may predict TURBT pathology for NMIBC. Genomic alterations between index and rTURBT tumors are highly concordant in papillary tumors even in the setting of upstaging, which may aid in targeted intravesical or systemic therapy selection. Larger cohorts and long-term follow up is needed to determine if utDNA can risk-stratify patients prior to rTURBT and predict long-term recurrence.
A multi-center, open-label, randomized dose expansion study of PF-06821497, a potent and selective inhibitor of enhancer of zeste homolog 2 (EZH2), in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Calvo Mariona , Penkov Konstantin , Spira Alexander I. , Moreno Candilejo Irene , Shore Neal D. , Zhang Tian , Mellado-Gonzalez Begoña , Alonso Gordoa Teresa , Paz-Ares Rodriguez Luis , Tarantolo Stefano R. , Soto Juan José , Alter Robert S. , Andreu-Vieyra Claudia , Bowler Timothy , Maity Arnab K , Hariharan Subramanian , Schweizer Michael Thomas 
Published: March 2023

TPS282 Background: Enhancer of zeste homolog 2 (EZH2) encodes the histone methyltransferase component of the polycomb repressive complex-2, inducing transcriptional silencing of target genes, and is altered in cancers such as follicular lymphoma (FL), small cell lung cancer (SCLC), and metastatic castration-resistant prostate cancer (mCRPC). We evaluated the pharmacokinetics (PK), safety, and antitumor activity of PF-06821497, a potent and selective inhibitor of EZH2, in an ongoing phase I trial (NCT03460977 ) in patients (pts) with SCLC, CRPC, and FL as monotherapy and in combination with standard of care therapies. For pts with CRPC, the PF-06821497 recommended dose for expansion (RDE) is 1250 mg BID, in combination with enzalutamide plus androgen deprivation therapy (E). Part 2B of this trial further explores outcomes for pts dosed with PF-06821497 and E compared with E monotherapy. Methods: Part 2B compares the safety and efficacy of twice-daily PF-06821497 in combination with E (160 mg daily) (treatment arm) versus E monotherapy (control arm) administered continuously in patients with mCRPC previously treated with abiraterone. At trial entry, all pts will have evidence of prostate cancer progression per the modified Prostate Cancer Working Group 3 Criteria. Prior treatment with E is not allowed. Approximately 80 participants will be randomized in a 1:1 fashion into two arms, in US, Spain, and other countries. Approximately 40 participants are required in each arm to have 80% power in the study in order to detect a hazard ratio of 0.5 (E plus PF-06821497: E alone). Patients randomized to E alone have the option to add PF-06821497 to their regimen upon confirmed radiographic disease progression. The primary objectives are to confirm the safety and tolerability of PF-06821497 in combination with E in pts with mCRPC, and to assess the effect of PF-06821497 in combination with E versus E monotherapy on radiographic progression free survival. Secondary objectives include further evaluation of anti-tumor activity of PF-06821497, and assessment of single and multiple dose PK when given in combination with E. The impact of PF-06821497 in combination with E and of E alone in men with mCRPC on patient reported outcomes will also be assessed. Clinical trial information: NCT03460977 .
DASL-HiCaP: A randomized, phase 3, double-blind trial of darolutamide with androgen-deprivation therapy and definitive or salvage radiation for localized very high-risk prostate cancer.
Authors: Niazi Tamim , McBride Sean Matthew , Williams Scott , Davis Ian D. , Stockler Martin R. , Martin Andrew James , Chung Hans T. , Roncolato Felicia , Ebacher Annie , Khoo Eric , Martin Jarad , Lim Tee Sin , Hughes Simon , Pryor David , Catto James W.F. , Kelly Paul , Gholam Rezaei Leily , Morgan Scott C. , Rendon Ricardo A. , Sweeney Christopher ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: March 2023

TPS396 Background: Radiation therapy (RT), plus androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone analogue (LHRHA), is a standard of care for patients with very high-risk localized prostate cancer (PC), or with very high-risk features and persistent PSA after radical prostatectomy (RP). Despite this, incurable distant metastases develop within 5 years in 15% of patients with very high-risk features. Darolutamide is a structurally distinct oral androgen receptor antagonist with low blood-brain-barrier penetration, a demonstrated favorable safety profile, and low potential for drug-drug interactions. Our aim is to determine the efficacy of adding darolutamide to ADT and RT used either as primary definitive therapy, or as salvage therapy, for very high-risk PC. Methods: This study is a randomized (1:1), phase 3, placebo-controlled, double-blind, international trial for patients planned for RT who have very high-risk localized PC on conventional imaging; or very high-risk features with PSA persistence or rise within one year following RP. The trial is stratified by previous RP; planned use of adjuvant docetaxel; clinical or pathological pelvic nodal involvement. 1100 participants will be randomized to receive darolutamide 600 mg or placebo twice daily for 96 weeks in combination with SOC (LHRHA for 96 weeks, plus RT starting week 8-24 from randomization). Participants are allowed nonsteroidal antiandrogen in addition to LHRHA for up to 90 days prior to randomization. Early treatment with up to 6 cycles of docetaxel completed at least 4 weeks prior to RT is permitted. The primary endpoint is metastasis-free survival, with secondary endpoints of overall survival, PC-specific survival, PSA-progression free survival, time to subsequent hormonal therapy, time to castration-resistance, frequency and severity of adverse events, health related quality of life, fear of recurrence. Tertiary endpoints include incremental cost-effectiveness, and identification of prognostic and/or predictive biomarkers of treatment response, safety, and resistance to study treatment. Clinical trial information: NCT04136353 .
A multi-center, prospective, observational study of patients with prostate cancer being treated with relugolix: OPTYX.
Authors: Spratt Daniel Eidelberg , McKay Rana R. , Dorff Tanya B. , Lowentritt Benjamin H , Fallick Mark , Hanson Sarah , Ross Ashley 
Published: March 2023

TPS398 Background: Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) receptor agonists or antagonists are the foundation of advanced prostate cancer (aPC) treatment. Relugolix is an oral non-peptide GnRH receptor antagonist approved in the US for the treatment of aPC. In the phase 3 HERO trial, relugolix maintained suppression of testosterone to castration levels in 96.7% of men from Day 29 to 48 weeks, with superiority to leuprolide acetate. Relugolix was well tolerated and associated with a 54% lower risk of major adverse cardiovascular events relative to leuprolide acetate (Shore N, NEJM 2020;382;23). The goal of this current study (OPTYX) is to generate real-world evidence about the safety and effectiveness of relugolix in patients with prostate cancer during routine clinical care. Methods: This prospective observational cohort study (registry) is enrolling patients who have planned initiation with relugolix within 1 month prior to the time of study enrollment. The study is designed to prospectively understand the actual experience of patients with prostate cancer treated with relugolix through data collection on patients selected for treatment, treatment patterns, adherence, patient reported quality of life (QoL) and safety data. Additionally, a better understanding of the trajectory of patients with prostate cancer following cessation of relugolix therapy will be gained by observing the clinical course of the disease, health outcomes, and health-related quality-of-life (HRQoL) in these patients. Inclusion criteria include patients > 18 years old with prostate cancer and planned total treatment with relugolix of at least 4 months. Estimated enrollment is 1000 patients, and patients will be followed for up to 5 years. In addition to assessing routine clinical care and disease progression, patient reported outcomes will be assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) for HRQoL and Simplified Medication Adherence Questionnaire (SMAQ) for adherence at 3 and 6 months then every 6 months. Clinical trial information: NCT05467176 .
Phase II trial of lurbinectedin combined with avelumab as maintenance therapy for metastatic urothelial carcinoma with stable or responding disease following platinum-based chemotherapy.
Authors: Sonpavde Guru P. , Alemany Carlos A. , Mchayleh Wassim , Pepe Julie W. , Coakley Susan , Young Ashley , Jain Rohit K. 
Published: March 2023

TPS590 Background: Maintenance avelumab following stable/responding disease after 4-6 cycles of platinum-based chemotherapy is a conventional first-line therapy for metastatic urothelial carcinoma (mUC). Given the attrition of patients between lines of systemic therapy, there is a role for extending the benefits of maintenance avelumab by combinations with tolerable and active agents. Lurbinectedin (Lurbi) is an alkylating agent and selective inhibitor of oncogenic transcription. Lurbi is approved by the US FDA for treating small cell lung cancer with progression on platinum-based chemotherapy with typical dosing as 3.2 mg/m2 intravenously (IV) every 3 weeks. The activity of lurbi in the presence of DNA damage repair (DDR) alterations, multiple transcriptomic drivers and preclinical synergism with and feasibility of co-administration with immune checkpoint inhibitors (ICI) suggests potential activity of combination lurbi and ICI in mUC. Patients with stable or responding disease following platinum-based chemotherapy are phenotypically selected for deficiencies in DDR. Lurbi may be tolerable in this setting given mostly reversible myelosuppression and no serious non-hematologic toxicities especially neurotoxicity. Thus, the combination of lurbi with maintenance avelumab may warrant evaluation in mUC. Methods: A non-randomized multicenter (Advent Health Cancer Institute, Moffitt Cancer Center) phase II trial (n=36) is designed to evaluate combination avelumab (800 mg IV every 2 weeks) and lurbi (3·2 mg/m2 IV as a 1-h infusion every 4 weeks) for those with stable or responding disease following 4-6 cycles of platinum-based first-line platinum-based chemotherapy for mUC. Therapy is continued till progression of disease, intolerable toxicities or patient decision. Patients are seen for a clinical examination every 4 weeks (1 cycle) with laboratory evaluation every 2 weeks. Radiographic imaging is performed every 8 weeks for 6 months and then every 12 weeks thereafter to assess disease. Premedication for lurbi includes corticosteroids (dexamethasone 8 mg or equivalent) and serotonin antagonists. Mandatory granulocyte-colony stimulating factor (G-CSF) prophylaxis will be administered to all patients. Baseline archival tumor tissue and periodic blood is collected for correlative studies (tumor genomics/PD-L1 expression, circulating tumor DNA and immune markers). Given a median progression-free survival (PFS) with avelumab alone of 3.7 months, an alternative median PFS of 6 months is of interest warranting further development. We will enroll 33 evaluable patients to achieve 90% power at a 1-sided alpha level 0.1 to detect hazard ratio of 0.62. Given ~10% of enrolled patients may be inevaluable, we may enroll up to 36 patients. Clinical trial ID: NCT05574504. Clinical trial information: NCT05574504 .
Vacancy-superlattice–induced higher-order topological corner states in a Chern insulator
Authors: Tu Wei , Wu Ya-Jie , Liu Chao-Chen , Li Ning 
Published: March 2023

Abstract
Recent studies have discovered local potentials can induce nontrivial eigenmodes responding to the bulk topology for the system. While previous studies focused on conventional first-order topological states emerging from vacancy superlattice, here we study higher-order topological properties of the vacancy superlattice on a two-dimensional Chern insulator with particle-hole symmetry. The vacancy superlattice with alternate lattice spacings exhibits an emergent second-order topological phase characterized by the nontrivial edge polarization. This topological phase is robust against particle-hole symmetry-preserved perturbations as long as the energy gap remains open for the mid-gap states. Our work generalizes the nontrivial higher-order topological properties to a Chern insulator with local defect vacancies and provides a controllable platform for engineering higher-order topological corner states.
The Prevalence of Metabolically Unhealthy Normal Weight and Its Influence on the Risk of Diabetes
Authors: Ye Jianan , Guo Keyu , Li Xia , Yang Lin , Zhou Zhiguang 
Published: March 2023

Abstract

Context
Diabetes is a major health problem and metabolically unhealthy is an important risk factor.

Objective
To conduct the first nationally representative study on epidemiological data of metabolically unhealthy normal weight (MUNW) focused only on nondiabetic subjects and determine the predictive effect on diabetes in China.

Methods
A longitudinal study was conducted using data from the Rich Healthcare Group in China. Metabolic status was determined by the revised National Cholesterol Education Program Adult Treatment Panel III criteria, and individuals with 2 or more criteria were categorized as MUNW and diagnosed with metabolic syndrome (MetS) if they met 3 or more.

Results
Of a total of 63 830 nondiabetic normal-weight individuals, 8935 (14.0%) were classified as MUNW and 1916 (3.00%) were diagnosed with MetS. After adjusting for potential confounders, individuals with MUNW had a greater diabetes risk (4.234, 95% CI 3.089-5.803) than those without MUNW during an average of 3.10 years of follow-up. Also, the multivariable-adjusted hazard ratios for developing diabetes were 3.069 (95% CI 1.790-5.263), 7.990 (95% CI 4.668-13.677), and 11.950 (95% CI 6.618-21.579) for participants with 1, 2, and 3 or more components, respectively, compared with those without any components. Further analyses suggested that the number of MetS components present is associated with the risk of diabetes, especially in metabolically unhealthy normal-weight young male adults. Multivariable-adjusted hazard ratios (95% CI) for incident diabetes among individuals with 1, 2, and at least 3 components were 4.45 (1.45-13.72), 9.82 (3.05-31.64), and 15.13 (3.70-61.84) for participants aged ≤44 years, and 3.55 (1.81-6.97), 8.52 (4.34-16.73), and 13.69 (6.51-28.77) for male participants, respectively.

Conclusions
The prevalence of MUNW is 14% in Chinese normal-weight nondiabetic individuals, and active intervention is necessary for this category of people. The presence of MUNW significantly increases the risk of diabetes, and the risk of diabetes is associated with the number of MetS components present in the patient.