bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final results from SAUL, a single-arm international real-world study of atezolizumab (atezo) in 1004 patients (pts) with pretreated locally advanced/metastatic urinary tract carcinoma (UTC).
Authors: Sternberg Cora N. , Loriot Yohann , Choy Ernest , Castellano Daniel , Lopez-Rios Moreno Fernando , Banna Giuseppe Luigi , De Giorgi Ugo , Masini Cristina , Bamias Aristotelis , Garcia del Muro Xavier , Duran Ignacio , Powles Thomas , Gamulin Marija , Zengerling Friedemann , Geczi Lajos , Gedye Craig , Huddart Robert A , Kandula Geetha , Skamnioti Pari , Merseburger Axel S. 
Published: June 2023

4569 Background: In the SAUL study (NCT02928406), clinical outcomes in a broad population were similar to findings from phase 3 trials of anti-PD-(L)1 in highly selected pts. We report the final analysis 4 y after enrolling the last pt. Methods: Eligible pts had locally advanced/metastatic urothelial or non-urothelial UTC that had progressed during or after 1–3 prior lines of therapy for advanced UTC (or within 12 months of [neo]adjuvant therapy). Unlike most phase 3 immunotherapy trials, pts with autoimmune disease (AID), ECOG PS 2, creatinine clearance (CrCl) ≥15–30 mL/min, and/or stable CNS metastases were eligible. Pts took atezo 1200 mg q3w until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included overall survival (OS) and duration of response (DoR). Results: Among 997 treated pts, 10% had ECOG PS 2, 5% had CrCl <30 mL/min, 4% had a history of AID, and 7% had 2–3 prior lines of therapy. At data cutoff (Dec 20, 2022; median follow-up 55 mo), 78% of pts had died. Median treatment duration was 2.8 mo (range 0–62 mo; mean 9.5 mo), 96 pts (10%) took atezo for >3 y, and 68 (7%) for >4 y. Grade ≥3 adverse events (AEs) occurred in 51%; AEs led to atezo discontinuation in 8%. We show outcomes overall and in key subgroups. OS was >4 y in 136 pts (14%); 132 responders had OS >2 y. Conclusions: After 55 mo median follow-up, median OS was 8.6 mo and 3-y OS was 21% in a real-world population including important understudied subgroups. Long-term safety data continue to support the tolerability of atezo in pts with complex comorbidities. AESIs were not increased in pts typically considered to be at increased risk of immune-related AEs. OS was similar to trials in highly selected pts. Ongoing analyses are characterizing pts with exceptional long-term outcomes. Clinical trial information: NCT02928406 . [Table: see text]
Biomarkers of response to sacituzumab govitecan (SG) and efficacy after treatment with enfortumab vedotin (EV) in advanced urothelial carcinoma (aUC): Analysis of the UNITE study.
Authors: Jindal Tanya , Jiang Cindy , Alhalabi Omar , Bakaloudi Dimitra Rafailia , Talukder Rafee , Davidsohn Matthew , Nizam Amanda , Taylor Amy K , Nguyen Charles B , Kilari Deepak , Pywell Cameron , Davis Nancy B. , Emamekhoo Hamid , Sonpavde Guru P. , Gupta Shilpa , Bellmunt Joaquim , Grivas Petros , Campbell Matthew T , Alva Ajjai Shivaram , Koshkin Vadim S 
Published: June 2023

4572 Background: SG is an antibody-drug conjugate (ADC) with accelerated FDA approval for aUC refractory to platinum-based chemotherapy and immune checkpoint inhibitor (ICI). SG activity following treatment with EV, the most commonly used ADC in the post-platinum/ICI setting, and biomarkers of response to SG are not well described. We hypothesized that SG would be active after EV in aUC. Methods: Patients (pts) treated with SG monotherapy who had next-generation sequencing (NGS), were identified in the retrospective UNITE study. Observed response rate (ORR) was determined for evaluable pts with scans after ≥1 SG cycle. All pts were assessed for baseline clinical characteristics, as well as molecular biomarkers including tumor mutational burden, somatic gene alterations (alt) in ≥ 10% of pts and presence of ≥1 DNA damage response (DDR) mutations. ORRs were compared with Chi-squared test. Kaplan Meier method and cox proportional hazard (cph) models were used to assess progression-free survival (PFS) and overall survival (OS) from SG start. Pt characteristics and molecular biomarkers were evaluated in univariate analyses (UVA), followed by evaluation of biomarkers in separate multivariate cph analyses (MVA), while accounting for clinical features. Results: Among 90 pts treated with SG at 9 US sites, 78 had NGS data. Median age at SG start was 68, 65 (72%) men, 73 (81%) Caucasian, 56 (62%) with pure urothelial histology, 60 (67%) primary bladder tumor and 67 (74%) ECOG PS 0/1. Most (n=84, 93%) received SG after EV, and 33 (37%) had ≥4 prior therapies for aUC. ORR with SG was 23% (15/66); 24% in pts with prior CR/PR/SD on EV and 14% after primary PD on EV. Median follow-up from SG start was 8.7 mos, PFS and OS were 3.5 mos and 7.1 mos. In pts with NGS, ORRs to SG were higher in MTAP altered pts (50% vs 19%; p = 0.05). In UVA, low neutrophil to lymphocyte ratio (NLR), high Hgb, no prior smoking history, < 3 prior therapies, as well as BRCA2 and DDR alts were associated with longer OS (p<0.05 for all). In MVA, pts with alt in either TP53 or MDM2 had longer OS. Conclusions: SG has notable activity after EV in heavily pretreated pts with aUC, with ORR consistent with SG phase 2 trial data in post-platinum/ICI only pts. We identified several clinical and genomic biomarkers, including TP53/MDM2 alt, that are potentially associated with improved outcomes with SG treatment. [Table: see text]
Evaluating the use of circulating tumor DNA (ctDNA) in patients with urothelial cancer in the context of FGFR-targeted therapy.
Authors: Schönlau Elena , Müller David Christian , Vandekerkhove Gillian , Murtha Andrew , Bacon Jack V.W. , Wells Connor , Rostin Kimia , Parimi Sunil , Noonan Krista , Basappa Naveen S. , Ko Jenny J. , Finch Daygen L. , Alimohamed Nimira S. , Bismar Tarek A. , Nappi Lucia , Annala Matti , Bernales Cecily Q. , Chi Kim N. , Wyatt Alexander William , Eigl Bernhard J. 
Published: June 2023

4577 Background: Fibroblast growth factor receptor (FGFR) inhibitors (e.g., erdafitinib) are increasingly important in the management of FGFR-mutated urothelial carcinoma. FDA-approved archival tissue testing for specific FGFR alterations was implemented as a companion diagnostic for erdafitinib. However, longitudinal sequencing studies indicate variable tumor FGFR status over time, and erdafitinib resistance mechanisms in metastatic urothelial carcinoma (mUC) are underreported. This ongoing study aims to evaluate the accuracy of cell-free DNA (cfDNA) compared to archival tissue testing in mUC for FGFR alterations detection, and to evaluate genomic mechanisms of erdafitinib resistance in cfDNA at progression. Methods: Patients with progressing mUC who were undergoing archival tissue testing for FGFR1-3 mutations and/or fusions and who had blood samples drawn during the management of their metastatic disease were eligible. Plasma cfDNA and matched leukocyte DNA were subjected to deep targeted sequencing with a custom panel including UC-specific gene loci and all clinically approved hotspots in FGFR1+2 and all exons and introns of FGFR3. Results: As of January 2023, 109 patients from 6 sites were enrolled. Median age at diagnosis was 71, 33% had upper urinary tract primaries, and 76% were male. Tissue and cfDNA results for comparison were available for 69 patients to date. Actionable somatic FGFR alterations were found in the tissue of 15 patients (31%); the most common alteration was the FGFR3 p.S249C mutation (67%). 50 of the analyzed cfDNA samples had detectable somatic circulating tumor DNA (ctDNA) variant allele fraction of 0.5% (72%). Of those, 49 had an evaluable tissue test result. Analysis of this subset revealed high concordance (92%) between the two test methods. With the assumption that archival tissue testing is considered the ‘gold standard’, sensitivity is 93% and specificity is 91%. The four discordant results comprised one cfDNA test with undetectable FGFR3-TACC3 fusion, which was detected in tissue and three positive ctDNA test results in patients with FGFR wild-type tissue tests. In one case at erdafitinib progression, ctDNA revealed multiple subclonal populations with distinct FGFR3 gatekeeper mutations suggesting polyclonal resistance. Conclusions: This ongoing study suggests cfDNA is a valuable minimally invasive adjunct to tissue-based assays for the detection of FGFR alterations to identify patients for FGFR inhibitor therapy and to monitor for mechanisms of resistance.
Presence of CD8+ cytotoxic T-cells in proximity to tumor cells, TIM3, CTLA-4 and prognostic implications for muscle-invasive urothelial cancer.
Authors: Debatin Nicolaus F. , Plage Henning , Klatte Tobias , Elezkurtaj Sefer , Bruch Paul G. , De Santis Maria , Horst David , Marx Andreas H. , Fisch Margit , Slojewski Marcin , Kaczmarek Krystian , Ecke Thorsten , Hallmann Steffen , Koch Stefan , Adamini Nico , Lennartz Maximilian , Sauter Guido , Zecha Henrik , Schlomm Thorsten , Blessin Niclas C. 
Published: June 2023

4582 Background: Although it is well known that the quantity of specific immune cell types can provide prognostic information in bladder cancer, only little is known about the prognostic relevance of the localization of immune cells within the tumor microenvironment. Methods: To study the spatial interplay of different immune cell subpopulations and its prognostic role in bladder cancer, 2463 urothelial bladder carcinomas were immunostained with 21 antibodies (i.e., TIM-3, PD-L1, PD-1, CTLA4, CD3, CD8, CD4, FOXP3, CD20, CD68, CD163, CD11c, panCK, Ki67, CD31, Vimentin, HLA-DRa, Myosin-11, Desmoglein 3, PAX-8, and CDH16) using BLEACH&STAIN multiplex fluorescence immunohistochemistry in a tissue microarray format and analyzed using a framework of neuronal networks for image analysis. Thus, Spatial immune parameters were compared with histopathological parameters and overall survival data. Results: The identification of more than 300 different immune cell subpopulations and the characterization of their spatial relationship resulted in numerous spatial interaction patterns. 32 immune parameters showed prognostic significance in univariate analyses of which 16 were independent from pT, pN, and histologic grade in muscle-invasive bladder cancer. The strongest association to clinical outcome was identified for intraepithelial CD8+ cytotoxic T-cells (AUC: 0.70) while stromal CD8+ cells were less relevant (AUC: 0.64, p=0.016). A favorable prognosis of inflamed cancers with high levels of “exhaustion markers” suggests that TIM3, PD-L1, PD-1, and CTLA-4 on inflammatory cells do not hinder anti-tumoral immune response in tumors rich of tumor infiltrating tumor cells. Conclusions: The density of intraepithelial CD8+ T-cells was the strongest prognostic feature in muscle-invasive bladder cancer. Given that tumor cell killing by CD8+ cytotoxic T-lymphocytes through direct cell-to-cell-contacts represents the “terminal end route” of anti-tumor immunity, the quantity of “tumor-cell adjacent CD8+ T-cells” may constitute a surrogate for the efficiency of cancer recognition by the immune system that can be measured straightaway using conventional brightfield IHC in routine pathology as the CD8 labelling index.
Genome-wide aneuploidy detected in circulating cell-free DNA of patients with metastatic urothelial cancer as a predictive biomarker of response to pembrolizumab.
Authors: Salhi Youssra , Rijnders Maud , Mendelaar Pauline , de Weert Vania , Beaufort Corine , Head R , Westgeest Hans M. , Voortman Jens , Aarts Maureen J.B. , Martens John W.M. , Van Der Veldt Astrid Aplonia Maria , De Wit Ronald , Wilting Saskia M , Robbrecht Debbie 
Published: June 2023

4584 Background: Pembrolizumab is the standard of care second-line treatment of metastatic urothelial cancer patients. However, success rates are low and there is risk for significant toxicity. Therefore, reliable biomarkers to select patients who will or will not benefit from pembrolizumab are urgently needed. An earlier study showed that a high aneuploidy score (i.e. Z-score ≥ 5) at baseline in cell free DNA (cfDNA), based on the modified fast aneuploidy screening test-sequencing system (mFast-SeqS), associated with poor response to pembrolizumab. However, a low aneuploidy score (Z-score < 5) at baseline was not discriminative. The aim of this study was to evaluate early during treatment (after the first cycle pembrolizumab), whether the cfDNA based mFast-SeqS aneuploidy scores can discriminate patients with expected benefit from therapy from those who will not benefit. Methods: The mFast-SeqS to assess aneuploidy was performed on blood samples collected from 74 patients with metastatic urothelial cancer (mUC) at baseline and after cycle 1 of pembrolizumab. Responders were defined as patients with stable disease (SD) or partial/complete response (PR, CR) according to RECIST v1.1. and continued treatment beyond 6 months from initiation of pembrolizumab. Non-responders did not fulfil these criteria. Results: Paired samples were available in 60 out of 74 patients. At baseline 25% (n=15) of patients had a high aneuploidy score and 75% (n=45) had a low aneuploidy score. Two patients (13%) with a high baseline score were responders and 13 (87%) were non-responders. In all responders, there was a marked decrease in aneuploidy score after one cycle of pembrolizumab (p=0.005), irrespective of their baseline score. About half of patients (47%) with a low baseline score were non-responders and in those patients there was a significant increase of the aneuploidy score post cycle 1, when compared to the responders (p=0.039). Conclusions: The aneuploidy score based on mFast-SeqS may stratify mUC patients for expected lack of benefit early during treatment (after 1 cycle) with second line pembrolizumab, providing an opportunity to switch treatment and to spare patients from potential unnecessary toxicity. Clinical trial information: NCT03263039 .
Survival outcomes of sarcomatoid versus classic urothelial carcinoma of bladder.
Authors: Garje Rohan , Ozair Ahmad , Manoharan Meenakkshy , Prabhakar Pushan , Rubens Muni B. , Roy Mukesh , Saxena Anshul , Khosla Atulya Aman , Bastos Bruno R. , Ahluwalia Manmeet Singh 
Published: June 2023

4588 Background: Sarcomatoid urothelial carcinoma (SUC), a rare bladder cancer variant, has both epithelial and mesenchymal differentiation along with frequent TERT C228T promoter mutations and has poorer prognosis. In this study, we compared survival outcomes of SUC with classic urothelial carcinoma (CUC) in patients with T2-T4, N0-N1 bladder cancer after definitive therapy. Methods: All cases meeting our inclusion criteria for SUC and CUC during 2004-2019 were identified from National Cancer Database. Sociodemographic and clinicopathological characteristics were analyzed via descriptive and comparative statistics. Propensity-score matching was performed to adjust for baseline differences between SUC and CUC. Overall survival (OS) was compared using Cox proportional-hazards modelling and visualized through Kaplan-Meier curves. Results: 30072 cases of CUC and 480 of SUC were identified. Propensity-score matching resulted in N = 478 patients in both groups. Matched cohorts had no baseline differences in age, sex, race, comorbidities, insurance status, income, distance to hospital, hospital location, rural versus urban residence, histological grade, and proportion getting regional lymph node surgery. Overall, there were 675 males and 281 females, 435 underwent surgery (Sx), and 521 surgery plus chemotherapy (Sx+Cx). For SUC, median survival with Sx vs Sx+Cx was 29.5 months (95%CI 20.0-50.6) vs 43.1 months (95%CI 25.3-64.4) respectively. For CUC, median survival was 56.1 (95%CI 53.7-58.6) vs 78.0 (95%CI 75.1-81.1) months with Sx vs Sx+Cx respectively. Conclusions: SUC has poorer prognosis than CUC. Perioperative chemotherapy along with surgery was associated with improved survival outcomes compared to surgery alone in patients with SUC. Further studies investigating novel immunotherapy agents are warranted to improve oncologic outcomes. [Table: see text]
Survival outcomes of micropapillary versus classic variant, loco-regional bladder cancer: A 2004-2019 National Cancer Database analysis.
Authors: Garje Rohan , Ozair Ahmad , Saxena Anshul , Roy Mukesh , Prabhakar Pushan , Rubens Muni B. , Khosla Atulya Aman , Muina Antonio F. , Millado Kristen F. , Bastos Bruno R. , Ahluwalia Manmeet Singh 
Published: June 2023

4592 Background: Micropapillary (MP) is a rare histologic variant of urothelial cancer (UC) with luminal-type characteristics and p53-like gene expression, leading to chemotherapy resistance and poor prognosis. However, contemporary outcomes of MP variant T2-T4, N0-N1 loco-regional bladder UC after definitive therapy are underreported, which this work sought to determine. Methods: A retrospective review was performed of all eligible cases of MP and classic UC (CUC) available during 2004-2019 from National Cancer Database. Socio-demographic, pathological, and clinical attributes were analyzed via descriptive and comparative statistics. Propensity-score matching was performed to adjust for baseline differences between MP and CUC. Overall survival, being the primary outcome, was compared using multivariable Cox proportional-hazards modeling and visualized through Kaplan-Meier curves. Results: 30072 cases of CUC and 397 of MP were identified. After propensity-score matching, 395 patients remained in both groups, with matched cohorts having no baseline differences in age, sex, race, Charlson-Deyo comorbidity index (CCI), insurance status, income, distance to hospital, hospital location, rural versus urban residence, tumor pathological grade, proportion receiving radiotherapy, and proportion getting regional lymph node surgery. In both matched cohorts there were 313 males (79%) and 82 females (21%). Both cohorts had 334 (85%) T2 cases, 41 (10%) T3 cases, and 20 (5%) T4 cases. Both cohorts had 375 (95%) N0 cases and 20 (5%) N1 cases. MP variant was associated with inferior survival compared to CUC (HR 1.26, 95%CI 1.03-1.54, P=0.024). Older age (≥65 years) and higher CCI were also associated with inferior survival. Irrespective of histology, patients undergoing surgery (S) plus chemotherapy (C) had better survival compared to S alone (HR 0.77, 95%CI 0.62-0.94, P=0.012). Regional lymph node surgery resulted in improved survival (HR 0.59, 95%CI 0.42-0.83, P=0.002). Sex, race, insurance, income, and hospital type did not impact survival. Median and two-year OS are summarized. Conclusions: Survival outcomes of MP are poorer than CUC of bladder. Surgery combined with perioperative chemotherapy was associated with better survival compared to surgery alone in patients with MP and CUC. Studies evaluating novel immunotherapies and antibody drug conjugates in perioperative setting are needed to improve outcomes. [Table: see text]
CABOSUN II: Results from a phase 2, open-label, multi-center randomized study of cabozantinib (CABO) vs. sunitinib (SUN) for non-clear cell renal cell carcinoma (NCCRCC).
Authors: Johns Andrew , Campbell Matthew T , Msaouel Pavlos , Jonasch Eric , Hahn Andrew Warren , Gao Jianjun , Shah Amishi Yogesh , Goswami Sangeeta , Zurita Amado J. , Pagliaro Lance C. , Bilen Mehmet Asim , Venkatesan Aradhana M. , Rao Priya , Tamboli Pheroze , Sircar Kanishka , Slack Tidwell Rebecca , Tannir Nizar M. 
Published: June 2023

4597 Background: NCCRCC are a diverse group of rare diseases with limited data to guide treatment. CABO is highly effective in clear cell RCC, but it is unknown whether it is superior to SUN, the historic standard of care for metastatic NCCRCC. Methods: CABOSUN II (NCT03541902) was a randomized phase II study at 3 centers for patients (pts) with metastatic NCCRCC. Sixty pts were planned to detect CABO as better than SUN with a 1-sided test. Pts were randomized 1:1 to CABO 60mg daily or SUN 50mg daily (4 weeks on, 2 weeks off). SUN dose modification to 2 weeks on, 1 week off was allowed for toxicity. Stratification was by papillary RCC (PRCC) vs. non-PRCC (NPRCC), good/intermediate vs. poor risk disease by IMDC criteria, and prior TKI use. The primary outcome was progression-free survival (PFS) by RECIST v1.1 compared between the 2 arms using the log-rank test. Secondary outcomes were objective response rate (ORR), overall survival (OS), and adverse event (AE) rates (2-sided tests). Results: 32 pts were randomized to CABO (N=15) or SUN (N=17) between 9/2018 and 6/2021. The trial stopped early due to a change in standard therapy for PRCC not based on these pts’ outcomes. Age range was 22-88 years with medians 57 and 61 for CABO and SUN. Pts were primarily white (84%) and male (72%), with good/intermediate risk (88%), and these were balanced between arms. More pts on the CABO arm had bone metastases (62% vs. 24%). NPRCC were chromophobe (N=6; 5 randomized to SUN), unclassified (N=5), and MiT family translocation (N=3; all randomized to CABO). With median follow-up of 33.3 months and 20 PFS events, median PFS for CABO vs. SUN was 8.2 vs. 13.8 months (1-sided p=0.96). There were no statistically significant differences in ORR or OS between the arms. AEs were in line with previous studies. Conclusions: CABO was not superior to SUN for metastatic NCCRCC in this study. Both arms had high rates of stable disease or better. Despite stratification by PRCC or NPRCC, there were major differences in NPRCC subtypes between the arms that may have impacted the results. More pts with chromophobe histology, an often indolent subtype, received SUN while all pts with MiT family translocation, a relatively aggressive subtype, received CABO. Permitted SUN dose modifications may have also influenced outcomes. While the PAPMET study showed CABO to be superior to SUN for PRCC, optimal treatments for rare, NPRCC remain a pressing need. Clinical trial information: NCT03541902 . [Table: see text]