bluuebunny/crossref_metadata_2025_split huggingface dataset:
Datopotamab deruxtecan in locally advanced/metastatic urothelial cancer: Preliminary results from the phase 1 TROPION-PanTumor01 study.
Authors: Lisberg Aaron , Drakaki Alexandra , Meric-Bernstam Funda , Alhalabi Omar , Kojima Takahiro , Kato Manabu , Spira Alexander I. , Salkeni Mohamad Adham , Heist Rebecca , Gao Xin , Bhave Manali A. , Klauss Gunnar , Sakaki Hayato , Kakurai Yasuyuki , KOGAWA TAKAHIRO 
Published: January 2024

603 Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload via a plasma-stable, tumor-selective, tetrapeptide-based cleavable linker. Dato-DXd has shown encouraging antitumor activity and a manageable safety profile in patients (pts) with solid tumors. We report preliminary results in pts with advanced/metastatic (a/m) urothelial cancer from the ongoing phase 1 TROPION-PanTumor01 study (NCT03401385). Methods: Pts with unresectable a/m urothelial cancer treated with ≥1 prior line of therapy received intravenous Dato-DXd 6 mg/kg Q3W. Primary study objectives were safety and tolerability. Secondary endpoints were objective response rate (ORR; complete response [CR] + partial response [PR]), and disease control rate (DCR; CR + PR + stable disease) per RECIST 1.1 by BICR. This is the first data disclosure from this cohort in an ongoing expansion cohort study. Results: At data cutoff (May 18, 2023), 18 pts had received Dato-DXd. Median follow-up was 9.1 (range 5–17) months; 6 (33.3%) pts were receiving ongoing treatment. Median age was 63.5 (range 46–79) yrs. Pts were heavily pretreated, 15 (83.3%) had received ≥3 prior regimens. All pts received prior immunotherapy, 17 (94.4%) prior platinum-based chemotherapy, and 4 (22.2%) prior taxanes. Treatment-emergent adverse events (TEAEs) occurred in 100% (any grade [gr]) and 44.4% (gr ≥3) of pts, and drug-related TEAEs occurred in 94.4% (any gr) and 16.7% (gr ≥3) of pts. No drug-related serious AEs were reported, and no TEAEs associated with death were observed. Any gr TEAEs associated with reduction, interruption, and discontinuation of treatment were reported in 11.1%, 33.3%, and 5.6% of pts, respectively (Table). Adjudicated drug-related interstitial lung disease (gr 2) occurred in 1 (5.6%) pt. Confirmed ORR was 27.8% (95% CI 9.7–53.5); 1 pt achieved a CR and 4 achieved a PR. DCR was 77.8% (95% CI 52.4–93.6). Clinical evaluation of this cohort is ongoing and updated results will be presented. Conclusions: In heavily pretreated pts with a/m urothelial cancer, Dato-DXd demonstrated a tolerable and manageable safety profile with encouraging antitumor activity. Dato-DXd is being evaluated in pts with urothelial cancer as part of the phase 1/2 TROPION-PanTumor02 (NCT05460273) and the phase 2 TROPION-PanTumor03 (NCT05489211) studies. Clinical trial information: NCT03401385 . [Table: see text]
Performance of the OncoUrine test on predicting patients who can avoid Re-TURBT and prognosis: A prospective, multicenter clinical study.
Authors: Yang Xiao , Cai Lingkai , Zhen Bing , Yuan Lin , Qin Zhenqian , Chen Xinfeng , Han Jie , Jiang Xuping , Xin Yaqun , Yuan Hongling , Cao Dandan , Lu Qiang 
Published: January 2024

623 Background: According to European Association of Urology (EAU) guidelines, repeated transurethral resection of bladder tumor (re-TURBT) is recommended in a large percentage of non–muscle-invasive bladder cancers (NMIBC) due to possibility of incomplete initial TURBT. However, no reliable predictors have been developed to help select patient candidates who could avoid Re-TURBT in NMIBC. Methods: This was a blinded, observational, prospective multicenter study (NCT05112523). A total of 162 patients who underwent initial TURBT and were scheduled for Re-TURBT were enrolled in this study between June 2021 and August 2023 from four centers. Urine sample of each patient was collected prior to Re-TURBT. High-throughput sequencing of 17 genes and methylation analysis for ONECUT2 CpG sites were combined as a liquid biopsy test panel named OncoUrine. The OncoUrine test results were compared to pathological results at Re-TURBT to assess the performance in predicting residual tumor and predictive value of risk stratification. Patients who received intravesical infusion chemotherapy or BCG were followed up for recurrence analysis. Results: 151 patients were finally included for performance analysis. At Re-TURBT, 48 (31.8%) samples had residual tumor and 103 (68.2%) had no residual tumor. 1 Ta and 2 T1 patients were up staged to T2 at Re-TURBT. Overall, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of OncoUrine test were 77.1%, 77.7%, 61.7%, and 87.9%. Compared to OncoUrine, Cytology prior to Re-TURBT yielded a high specificity of 95.8% but lower sensitivity of 20% and combined with OncoUrine improved the sensitivity to 75.6%. In the overall OncoUrine test results, variants from 12 genes showed positive mutations. TERT, TP53, ERBB2, FGFR3, and PIK3CA were on the top 5 of the lists with other mutations from ERBB3, ERCC2, U2AF1, HRAS, KDM6A, KRAS, and ROHA. 132 were followed up with a median of 362 days (range 21 to 953). 19 patients were found recurred. The pathological results at Re-TURBT, OncoUrine, methylation and TERT results were risk stratification approaches for the recurrence analysis (positive vs. negative, p＜0.05). Conclusions: OncoUrine test after initial TURBT for NMIBC showed promise as to guide patient selection for Re-TURBT and risk stratification in the management of NMIBC. Clinical trial information: NCT05112523 .
Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma (mUC) with FGFR2/3 genetic alterations (GAs).
Authors: Jain Rohit K. , Heiligh Jazlyn , Kim Youngchul , Piekarz Richard , Pelosof Lorraine Cheryl , Yang Yuanquan (Aaron) , D'souza Anishka , Wong Risa Liang , Graham Laura , Gupta Sumati , Park Anna , Synold Timothy W. , Sonpavde Guru P. 
Published: January 2024

625 Background: Erdafitinib (E) is a treatment option in mUCpatients with somatic FGFR2/3 GAs after progression on platinum-based chemotherapy (PBC). Enfortumab Vedotin (EV) is approved as a single agent to treat mUC patients following prior PBC and PD1/L1 inhibitors or as second-line therapy for cisplatin-ineligible patients. Retrospective studies suggest that the activity of EV is not compromised by FGFR2/3 GAs. E and EV have different mechanisms of activity, and toxicities are mostly non-overlapping. Hence, there is rationale to evaluate the feasibility of combination E + EV, to overcome the difficulties of resistance and sequencing agents in mUC patients with FGFR2/3 GAs. Methods: This is an ongoing, single arm, multicenter, dose-escalation and expansion study of combination E + EV evaluating the safety, tolerability, pharmacokinetics (PK), and antitumor activity in patients with mUC harboring somatic FGFR2/3 GAs who have progressed after PBC and/or PD1/L1 inhibitor therapies. Dose escalation phase aims to identify the maximum tolerable dose and recommended phase 2 dose of EV at dose levels of 1 mg/kg and 1.25 mg/kg in combination with E at 8 mg/day as shown in the table. Preliminary safety, PK, and efficacy data for Dose Level (DL) 1 and 2 are presented in this abstract. Results: As of data cutoff, based on 3+3 design, total 8 patients are enrolled and finished dose limiting toxicity (DLT) period (1st cycle). Six patients were enrolled in DL1 with 1 DLT (skin rash) and 2 patients in DL2. The most common treatment-related adverse events (TRAE) included hyperphosphatemia (88%), mucositis (88%), hypercalcemia (75%), high AST (75%), hand foot syndrome (75%), peripheral neuropathy (75%), alopecia (63%), diarrhea (63%), hypoalbuminemia (63%) and hypomagnesemia (63%). Grade 3 TRAE included hand foot syndrome (50%), anemia (17%), rash (17%), anorexia (17%) and paronychia (17%). One patient developed grade 4 Stevens-Johnson syndrome related to EV which subsequently improved. PK data are available for all 6 subjects in DL1. The average steady-state Cmin of E and monomethyl auristatin E (MMAE) was 1430 ± 639 ng/mL and 1.4 ± 0.9 ng/mL, respectively, and the average Cmax of MMAE was 3.9 ± 0.9 ng/mL at DL1. All 8 patients are evaluable for response, and best response is partial response in all. Detailed safety and additional efficacy data will be presented. Conclusions: Combination E + EV is feasible and preliminarily exhibits antitumor activity. Dose escalation is ongoing to identify the MTD or recommended dose for expansion of the trial. Clinical trial information: NCT04963153 . [Table: see text]
Association of ARID1A deficiency with invasive transformation in metastatic bladder cancer.
Authors: D'Andrea Vincent , Hanlon Timothy , Chroneos Rea , Bekele Raie , Clinton Timothy , Carvalho Filipe L.F. , Mouw Kent William 
Published: January 2024

656 Background: ARID1A is an essential component of the BAF complex, a large SWI/SNF chromatin-remodeling complex which is implicated in bladder cancer (BC) pathogenesis. While ARID1A mutations are more highly represented in metastatic rather than localized tumors, the biological consequences of ARID1A loss in BC remain to be elucidated. We hypothesize that ARID1A deficiency primes an invasive transformation in BC, thus increasing the likelihood of disease progression and metastases. We used CRISPR/Cas9-mediated gene editing to knockout (KO) the ARID1A gene in several BC cell lines, thus providing a platform for cellular function assays. We show that ARIDA1 loss potentiates an invasive phenotype in these cell lines, giving evidence for its transformative role in the development of higher stage and metastatic BC. Methods: A CRISPR-Cas9 KO was performed with three cell lines with wild-type (WT) ARID1A (T24, SW1710, and 5637). This was accomplished by developing sgRNAs against ARID1A with a GFP marker and carrying out single-cell fluorescence-activated cell sorting (FACS) following nucleofection to identify ARID1A-deficient clones. Western blot analysis was performed on the resulting clones to confirm complete loss of ARID1A. Baseline proliferation studies were performed on the KO and WT cell lines. Finally, invasion studies were performed on the KO and WT cells with a scratch assay. Results: CRISPR-Cas9 directed KO of ARID1A yielded ARID1A-deficient clones for SW1710, T24, and 5637. The proliferation rates for each cell line were analyzed and compared which showed no significant differences. A scratch assay was performed with the cell lines in triplicate, with each ARID1A-deficient cell line showing a trend towards more rapid wound closure than its matched WT cell line (WT=31.5% vs. KO=53.5% for SW1710, p=0.15; WT=17.2% vs. KO=52.0% for T24, p=0.07; WT=10.4% vs. KO=13.9% for 5637, p=0.59). Conclusions: To explore the increased frequency of ARID1A alterations in metastatic BC compared to non-invasive tumors, we developed a model of ARID1A-deficient BC using CRISPR-Cas9. We compared the relative invasiveness of the lines using a scratch assay. All lines trended towards a more invasive phenotype following ARID1A KO, which was especially pronounced in T24. Taken together, these data suggest that ARID1A deficiency in BC may prime tumors for a more invasive phenotype, which may help to explain the higher frequency of ARID1A alterations in higher stage and metastatic samples.
The role of androgen response pathway in association with tumor biology and response to neoadjuvant immune-checkpoint inhibitors (ICI) in muscle-invasive urothelial bladder carcinoma (MIBC).
Authors: Tateo Valentina , Gibb Ewan , Mercinelli Chiara , Raggi Daniele , Cigliola Antonio , Patanè Damiano Alfio , Crupi Emanuele , Giannatempo Patrizia , Colecchia Maurizio , Moschini Marco , Avesani Giulio , Briganti Alberto , Montorsi Francesco , Santini Daniele , Necchi Andrea 
Published: January 2024

662 Background: Emerging findings from ICI trials are suggestive of differential outcomes in females compared with males. Sex-specific differences in tumor biology, microbiome, and outcomes in MIBC are well-established. Conversely, limited data are available regarding the role of the androgen response pathway in explaining subtype differences between males and females and, most importantly, response to ICI. Methods: We retrospectively evaluated the biomarker findings of the transurethral resection of the bladder tumors (TURBT) and baseline clinical characteristics of patients (pts) with cT2-4N0M0 MIBC who received neoadjuvant pembrolizumab and radical cystectomy (RC) in the PURE-01 study. Transcriptome-wide expression profiling was performed on 102 TURBT samples. We focused on androgen receptor (AR) gene expression and the hallmark androgen response pathway expression quantifying 117 different genes related to the androgen response pathway as previously reported (PMID: 26771021). Pt and tumor characteristics were compared between subgroups using χ2 tests and two-sided Wilcoxon rank-sum tests. Kaplan-Meier curves and log rank tests evaluated gene expression and signature scores in association with the event-free survival (EFS), calculated from start of pembrolizumab treatment. Signature scores were analyzed as continuous values and were split by median and quartile values. Results: Pts received pembrolizumab and RC from 2017 to 2022. There were 87 (85.3%) males and 15 (14.7%) females. AR gene expression was not significantly different between males and females (p = 0.5), whereas androgen response signature was significantly higher in male (p = 0.03). The AR gene expression and androgen response signature scores were more highly expressed in luminal tumors vs rest of molecular subtypes (p = 0.005 and p < 0.001). Despite AR gene expression was not associated with ypT0N0 response (p = 0.425), hallmark androgen response signature scores were significantly lower in ypT0N0 responders (p = 0.033). Higher hallmark androgen response signature scores were statistically significantly associated with shorter EFS (p = 0.028), whereas AR gene expression was not (p = 0.152). Conclusions: For the first time to our knowledge, we reported the androgen response pathway expression to be a potential biomarker of ICI benefit in MIBC. This signature was also associated with a luminal subtype, linked to inferior responsiveness to ICI. If confirmed at a larger scale these analyses will strengthen the need for sex-specific approaches and potentially new combination therapies in MIBC.
Enfortumab vedotin (EV) in combination with pembrolizumab (P) versus chemotherapy in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC): Subgroup analyses results from EV-302, a phase 3 global study.
Authors: Van Der Heijden Michiel Simon , Powles Thomas , Gupta Shilpa , Bedke Jens , Kikuchi Eiji , De Wit Ronald , Galsky Matt D. , Duran Ignacio , Necchi Andrea , Retz Margitta , Yu Evan Y. , Hoffman-Censits Jean H. , Iyer Gopa , Park Se Hoon , Su Wen-Pin , Parmar Hema , Guan Xuesong , Gorla Seema Rao , Homet Moreno Blanca , Valderrama Begoña Pérez 
Published: January 2024

LBA530 Background: EV-302/KEYNOTE-A39 (NCT04223856) is a phase 3, open-label, randomized, global study comparing EV+P with platinum-based chemotherapy for first-line (1L) treatment of patients (pts) with la/mUC regardless of cisplatin eligibility or PD-L1 expression status. In EV-302, EV+P demonstrated a statistically significant and clinically meaningful benefit compared with platinum-based chemotherapy for the dual primary endpoints of progression-free survival (PFS) (hazard ratio [HR]: 0.45; P<0.00001) and overall survival (OS) (HR: 0.47; P<0.00001) in the overall pt population (Powles ESMO 2023). Here we present results not previously presented of prespecified subgroup analyses. Methods: Pts with previously untreated la/mUC were randomized 1:1 to receive 3-week cycles of EV (1.25 mg/kg; Days 1 and 8; IV) and P (200 mg; Day 1; IV) or gemcitabine with cisplatin or carboplatin. Select secondary endpoints included confirmed objective response rate (cORR), duration of response, and safety. For PFS and OS, an HR between treatment arms was estimated using a stratified Cox proportional hazards regression model controlling for the stratification factors (cisplatin eligibility, PD-L1 status [high/low], liver metastases [yes/no]) for each predefined subgroup. Results: 886 pts (EV+P: 442, chemotherapy: 444) were randomized; baseline pt and disease characteristics were balanced between groups. PFS and OS were prolonged for EV+P among prespecified subgroups, including race, cisplatin eligibility, PD-L1 expression, metastatic site, liver involvement, and renal function. Select subgroup data not previously presented for OS are presented in the Table. Kaplan-Meier curves for PFS (liver metastases, cisplatin eligibility, and PD-L1 status) and OS (liver metastases) will also be presented. Conclusions: EV+P significantly improved outcomes in pts with previously untreated la/mUC compared with chemotherapy; OS benefit was consistently observed across select prespecified subgroups, including those historically associated with poor prognosis. The results of these subgroup analyses support the findings of the primary analysis, which indicate that EV+P is a potential new standard of care for 1L la/mUC. Clinical trial information: NCT04223856 . [Table: see text]
Phase II trial of ArtemiCoffee for men with biochemical recurrence of prostate cancer after local therapy.
Authors: Myint Zin , St. Clair William H , Strup Stephen , Hensley Patrick J. , Yan Donglin , Ellis Carleton Scott , Kolesar Jill 
Published: January 2024

TPS350 Background: The optimal timing for initiating androgen deprivation therapy (ADT) in biochemical recurrent (BCR) prostate cancer (PC) patients, specifically those with PSA doubling time > 10 months, remains uncertain. Therefore, there is a compelling need for clinical trials exploring alternatives to ADT. Artesunate, derived from Artemisinin which is extracted from Artemisia annua (Aa), shows anti-cancer effects. Aa comprises several active constituents including dihydroartemisinic acid, artemisinic acid, and artemisinin. Our research group assessed the sensitivity of prostate cancer cells to Artesunate using established PC cell lines such as LNCaP, C4-2, CWR-22Rv1 and PC-3. Two cell lines, LNCaP (PSA and AR positive, hormone naïve) with an IC50 of 3.30 µM (95% CI 2.28-4.79) and C4-2 (PSA and AR positive, castration resistant) with an IC50 of 3.99 µM (3.13-5.10 µM) demonstrated sensitivity to Artesunate. Wang et. al (2017) reported that Artesunate, administered at varying doses, effectively suppressed tumor growth, inhibited cell viability and enhanced apoptosis in a mouse xenograft model using the 22rv1 PC cell line. Based on these promising preclinical findings, we hypothesize that Aa decaf coffee has the potential to decrease rising PSA levels in patients with BCR PC. Our research group previously conducted a phase I dose escalation of ArtemiCoffee in ovarian cancer (NCT04805333) and preliminary results indicated no grade ≥3 toxicities at the proposed dose (unpublished data). In this study, we aim to conduct a phase II study of Aa decaf coffee in men with BCR PC. Methods: An open-label, single center, phase II study targets men with BCR PC following primary definitive local therapy and a PSA doubling time > 10 months. Commercially available Aa decaf coffee pods supplied by ArtemiLife Inc. will be utilized. These decaf coffee pods adhere to FDA food-grade quality standards and Aa plants used for ArtemiLife coffee are cultivated in Kentucky, USA. Aa decaf coffee will be self-administered three times daily (total of 1,350mg Aa) on an outpatient basis for 24 weeks. The primary endpoint is to determine the proportion of patients achieving a ≥50% decline in PSA levels within 24 weeks of Aa decaf coffee treatment in BCR population. A total of 30 patients will be enrolled in this study, ensuring a maximum margin of error of approximately 16% in the 95% confidence interval for the primary endpoint. Secondary endpoints include safety and tolerability. Correlative endpoints include 1) changes in downstream biomarkers of the NRF2/KEAP1 signaling pathway and 2) changes in plasma concentrations of artemisinin and dihydroartemisinin by comparing pre- and post-treatment with Aa decaf coffee using non-parametric paired test. The study commenced accrual in August 2023. Clinical trial information: NCT05478239 .
Phase II study of axitinib intensification compared to nivolumab alone after induction with ipilimumab plus nivolumab in patients with mRCC without previous complete response (AxIn study).
Authors: Ciccarese Chiara , Verzoni Elena , Bimbatti Davide , Buti Sebastiano , Calabrò Fabio , Galli Luca , Scagliarini Sarah , Fornarini Giuseppe , Baldessari Cinzia , Bilancia Domenico , Facchini Gaetano , Cattrini Carlo , Masini Cristina , Giganti Maria Olga , Scandurra Giuseppa , Nole Franco , Berruti Alfredo , Milella Michele , Antonuzzo Lorenzo , Iacovelli Roberto 
Published: January 2024

TPS494 Background: The combination of nivolumab plus ipilimumab (N+I) is able to increase the overall survival (OS), progression free survival (PFS) and overall response rate (ORR) compared to sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC) at intermediate or poor prognosis. However, the rate of pts with partial response to N+I (32%) is lower of that reported with the combination of axitinib plus pembrolizumab (51%). Moreover, analysis of outcome based on the depth of response strongly suggests a connection between response and survival. This study aims at investigating the efficacy of an intensified strategy with axitinib added to nivolumab in mRCC pts without complete response at the end of N+I induction. Methods: AxIn study (NCT05817903) is a randomized, open-label, multicenter, phase 2 trial evaluating in mRCC pts who completed induction with N+I without complete response or progressive disease, whether the intensification of therapy by adding axitinib to the standard nivolumab can increase the response rate and improve the survival compared to nivolumab alone. Eligible pts with partial response or stable disease after completion of N+I induction as first-line therapy, without any toxicity ≥ G2, and candidates to maintenance nivolumab as per standard clinical practice will be randomized 1:1 to intensification of therapy with axitinib in addition to nivolumab (Arm A) or nivolumab alone (Arm B). The primary endpoint is to assess the ORR of pts treated with the intensification of axitinib plus nivolumab compared to the standard of care of nivolumab monotherapy. Secondary endpoints include PFS, OS, depth of response, duration of response, quality of life, and safety. Exploratory biomarkers analysis will be performed. The trial is actively recruiting. Clinical trial information: NCT05817903 .