bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quality of life in QUILT 3.032 study: Patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) receiving IL-15RαFc superagonist N-803 plus BCG.
Authors: Chamie Karim , Chang Sam S. , Kramolowsky Eugene V. , Gonzalgo Mark L. , Lechpammer Stanislav , Reddy Sandeep K. , Soon-Shiong Patrick 
Published: March 2023

495 Background: Patients (pts) with BCG-unresponsive NMIBC have limited treatment options and are at an increased risk for cystectomy. Nogapendekin alfa inbakicept (NAI, also known as N-803), is an interleukin-15 superagonist (IL-15RαFc), which synergizes with BCG to elicit innate immune memory resulting in durable complete responses (CRs) in this patient population. In an open-label, 3-cohort, multicenter Phase 2/3 study of intravesical BCG plus NAI in BCG-unresponsive high-grade NMIBC (QUILT 3.032; NCT03022825), pts with carcinoma in situ (CIS; Cohort A) have a CR rate of 71% (median duration 26.6 months), 89.2% cystectomy avoidance and 100% bladder cancer specific survival at 24 months. We submit here the first quality of life (QOL) data report in the same pts cohort. Methods: Cohort A: 86 pts (median age 73 years; 87% male) with histologically confirmed BCG-unresponsive CIS with or without Ta/T1 disease, treated with intravesical BCG 50 mg plus NAI 400 μg. Mean baseline ECOG score was 0.183, with 82% of pts having score = 0. QOL was measured by the EORTC QOL Questionnaire Core 30 (QLQ-C30) and QOL NIMBC-Specific 24 Questionnaire (QLQ-NMIBC24). Results: Multivariate analyses have shown no significant changes over time for any of the measured QOL domains. Mild worsening vs. baseline in feeling ill was reported by 6% and 3% of pts by week 27 and 52, while 4% and 6% reported improvement. By week 78 and 104, 7% and 9% of pts reported improvement vs. baseline in their wellbeing with the majority being stable (non-significant). No statistically significant variations were detected in the physical function (PF) score (baseline vs. week 27, 52, 78 and 104). Higher PF scores were observed in pts responding to the therapy vs. non-responders; however, baseline value of PF was also higher in responders vs. non-responders. In contrast to historical results of BCG alone, week 27 physical function scores were numerically higher than baseline, with a subsequent nadir at week 78 and recovery to baseline by week 104 (non-significant). Hospitalizations for any reason remained low (0% - 6% per assessments) during the study. Conclusions: QOL measurement supports good tolerability of the intravesical NAI plus BCG in BCG-unresponsive, high-grade NMIBC pts with CIS. These results further strengthen the evidence of a favorable benefit: risk ratio of this novel combination immunotherapy, in a challenging disease. Clinical trial information: NCT03022825 .
Enfortumab vedotin (EV) alone or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer (la/mUC): Subgroup analyses of confirmed objective response rate (cORR) from EV-103 cohort K.
Authors: O'Donnell Peter H. , Rosenberg Jonathan E. , Hoimes Christopher J. , Petrylak Daniel P. , Milowsky Matthew I. , McKay Rana R. , Srinivas Sandy , Friedlander Terence W. , Ramamurthy Chethan , Bilen Mehmet Asim , Burgess Earle F , Mar Nataliya , Moon Helen , Geynisman Daniel M. , George Saby , Carret Anne-Sophie , Yu Yao , Guseva Maria , Homet Moreno Blanca , Flaig Thomas W. 
Published: March 2023

499 Background: In EV-103 Cohort K (NCT03288545), EV and P in combination (EV+P) showed encouraging antitumor activity and a manageable safety profile when used as 1L therapy in patients (pts) w/ la/mUC who are ineligible for cisplatin, a population w/ high unmet need. Here we report results of an analysis of prespecified Cohort K subgroups known to be associated w/ poor outcomes. Methods: Pts who are cisplatin-ineligible w/ previously untreated la/mUC were randomized 1:1 to EV (1.25 mg/kg) as monotherapy on Days 1 and 8 or in combination w/ P (200 mg) on Day 1 of 3-week cycles. Primary endpoint is cORR per RECIST v1.1 by blinded independent central review w/ no formal statistical comparison between arms. Secondary endpoints included duration of response and safety (e.g. treatment-related adverse events, TRAEs). The cORR analysis was performed in prespecified subgroups including age, ECOG PS, liver metastasis, PD-L1 expression status, metastatic disease site at baseline, and primary disease site of origin. Results: 149 pts were treated: EV+P n=76; EV n=73; cORRs across key subgroups for both EV+P and EV monotherapy are shown in the table. For EV+P overall cohort, cORR (95%CI): 64.5% (52.7, 75.1); median DOR was not reached. cORRs were consistent across subgroups for EV+P including those w/ ECOG PS score of 1-2: 62.8% (46.7, 77.0) and presence of liver metastasis: 53.8% (25.1, 80.8). Among TRAEs of special interest in the EV+P arm, skin reactions occurred in n=51 (67.1%); peripheral neuropathy occurred in n=46 (60.5%). For EV+P, 68.4% of pts had TRAEs leading to interruption of either EV or P; 48.7% of pts had TRAEs leading to EV dose reduction. Median duration of EV+P treatment was 11 cycles. Conclusions: EV+P showed promising cORR in 1L cisplatin-ineligible pts w/ la/mUC; activity was consistently observed across a range of pre-specified subgroups including those with poor prognosis. EV+P TRAEs were manageable w/ close monitoring and appropriate dose modifications w/ a meaningful duration of treatment. EV+P has the potential to address high unmet needs in 1L la/mUC and MIBC and is being further evaluated in 3 Phase 3 trials (NCT04223856, NCT04700124, NCT03924895). Clinical trial information: NCT03288545 . [Table: see text]
Updated experience on PSMA PET/CT for recurrent prostate cancer in a high-volume Brazilian center.
Authors: Lages Dr. Paulo Sergio , Monteiro do Prado Junior Luciano , Fonseca Monteiro do Prado Leonardo , Carvalho Oliveira Bruno , Ramos Barra Renato , Silva Barbosa Michelle , Vargas Pivato de Almeida Daniel ,   Latin American Cooperative Oncology Group Genitourinary Tumors Division, LACOG-GU
Published: March 2023

50 Background: PSMA PET/CT scan (68Ga-PSMA PET/CT) has emerged as a highly accurate tool when assessing disease staging both for newly diagnosed localized high-risk prostate cancer and for recurrent disease, with treatment plan modification in up to two-thirds of patients. Methods: We retrospectively reviewed the PSMA PET/CT scans results of patients undergoing the exam in all disease stages in a single institution in Brasilia, Brazil, between October 2015 and July 2022 and correlated clinicopathological information with test results for those in the recurrent disease setting. Results: Overall, more than 2,500 PSMA PET-CT scans were performed during the selected time interval. Any clinicopathological information was available for 648 patients, of whom 586 underwent the test in the setting of recurrent disease following treatment of primary disease. Positive results were found in 400 studies, with a median PSA level of 1.035 ng/mL (IQR 0.3–3.5) and most prevalent Gleason score of 7 (3+4). Metastatic disease was found in 26.2% of patients with a median PSA level of 4.61 ng/mL. Conclusions: A positive correlation between both PSA level and Gleason grade and the positivity rate of PSMA PET/CT was found in this large dataset, confirming the findings previously demonstrated in a prior presentation of our database. This result reinforces the importance of including more sensitive image methods when staging recurrent prostate cancer for the early detection of metastatic disease and adequate treatment planning. [Table: see text]
Neoadjuvant pembrolizumab for cisplatin-ineligible muscle-invasive bladder cancer prior to radical cystectomy.
Authors: Rose Kyle M , Bandini Marco , Huelster Heather L , Basile Giuseppe , Naidu Shreyas U , Spiess Philippe E. , Necchi Andrea , Li Roger 
Published: March 2023

513 Background: There is an unmet need for systemic treatment options in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based neoadjuvant chemotherapy. The PURE-01 trial has also demonstrated preliminary efficacy when pembrolizumab is used in the neoadjuvant setting. We aimed to compare pathologic response and survival outcomes in cisplatin-ineligible patients receiving neoadjuvant pembrolizumab (NAP) vs. immediate radical cystectomy (IRC). Methods: Cisplatin-ineligible MIBC patients were identified from the PURE-01 trial and compared against cisplatin-ineligible MIBC patients treated with immediate radical cystectomy (IRC). Overall survival was analyzed using Kaplan-Meier and Cox Proportional Hazards Modelling. IRC patients were matched via nearest neighbor propensity technique to cisplatin-ineligible patients from PURE-01 by ECOG status, GFR, age, sex, and clinical T stage. Results: Thirty-nine cisplatin-ineligible patients treated with NAP were identified from PURE-01, and compared against 313 cisplatin-ineligible patients undergoing IRC (Figure 1A). OS was prolonged in the NAP patients, with median survival of 19 months in the IRC vs. not reached (NR) in the NAP group (p=<0.01). Following nearest neighbor matching, 39 patients were identified from the IRC cohort, with comparable baseline clinicopathologic variables as listed in the table. Patients receiving NAP experienced a higher complete response rate on final pathology (pT0: 33% vs. 13%, p=0.03). Median OS was prolonged in the propensity score matched analysis (NAP NR vs. IRC 21.0mo, p<0.01), specifically at 12mo (89% vs. 57%), 24mo (64% vs. 28%), and 36 months after surgery (33% vs. 13% ) (p<0.01). Compared to NAP, cisplatin-ineligible patients undergoing IRC experienced worse OS, with a Hazard Ratio of 2.0 (95% CI 1.1 - 3.89). Conclusions: Cisplatin-ineligible patients receiving NAP for muscle invasive bladder cancer had a higher rate of downstaging and a survival advantage over patients who underwent IRC. Although this study suggests promising systemic options for cisplatin-ineligible patients in the neoadjuvant setting, results of ongoing prospective randomized trials will help validate these findings and provide therapeutic options to cisplatin-ineligible patients. [Table: see text]
Sequential enfortumab vedotin (EV) after platinum-based chemotherapy in metastatic or locally advanced urothelial cancer: Complete response, bladder preservation and survival.
Authors: Cen Putao , Chan Kok Hoe , Canfield Steven , Shu Tung , Maithel Neha , Tammisetti Varaha 
Published: March 2023

529 Background: For metastatic or unresectable invasive urothelial cancer (UC), standard first-line platinum-based chemotherapy achieved progression-free survival (PFS) of 4–7 months. Complete response (CR) rate is <10%. The minority of patients downstaged after chemotherapy followed by cystectomy still suffer from loss of bladder function and a high risk of recurrence. To improve PFS, CR, and bladder preservation, we explored the use of EV after platinum-based chemotherapy in patients with metastatic or locally advanced UC who desired bladder preservation. Methods: Patients with metastatic or locally advanced unresectable UC who desired bladder preservation and received EV after platinum-based chemotherapy were identified. CR was defined as no evidence of disease identified on both radiology (MRI+CT) and cystoscopy; PFS were calculated from the date of initial treatment (first-line chemotherapy) to the date of last follow-up/death or recurrence via Kaplan-Meier analysis. Results: A total of 12 patients were identified: median age was 69.5 years (range, 52–83); 10 (83%) were men; 9 (75%) partial response and 3 (25%) disease progression were observed from platinum-based chemotherapy. EV was given after platinum-based chemotherapy to all 12 patients who subsequently achieved 100% of response: CR was achieved in 7 (58%) patients, and 4 (33%) remained disease free without ongoing treatment, their disease-free survival (DFS) was 9 months (range, 4–18); 2 patients who achieved CR then recurred as carcinoma in situ (CIS), one of whom had a cystectomy with TisN0 confirmed on final pathology. 2 (17%) patients received radiation to bladder and nodal area. Eleven (92%) patients retained their bladders and no patients died. Median follow-up was 19 months (range, 3.4–53.6). The median duration of EV was 7.5 months (range, 2–20). One-year PFS with bladder intact was 83%. Detailed clinical characteristics and outcome listed on Table. Conclusions: For patients with locally advanced or metastatic UC who desired bladder preservation, platinum-based chemotherapy followed by EV with or without pembrolizumab showed encouraging CR and PFS and deserves to be explored further. [Table: see text]
Pathologic response with neoadjuvant chemotherapy, immunotherapy, and chemo-immunotherapy for muscle-invasive bladder cancer (MIBC): A systematic review and meta-analysis.
Authors: Ayaz Ahsan , Naqvi Syed Arsalan Ahmed , Tripathi Nikita , Ijaz Hafsah , Mir Sajid Ahmad , Singh Parminder , Hussain Syed A. , Sonpavde Guru P. , McGregor Bradley Alexander , Bryce Alan Haruo , Riaz Irbaz Bin , Ravi Praful 
Published: March 2023

531 Background: Neoadjuvant cisplatin-based chemotherapy (NAC) is established in the management of MIBC. Pathologic complete response (pCR, ypT0N0) and downstaging (<ypT2N0) are associated with long term survival in patients with MIBC. Several trials have evaluated neoadjuvant immunotherapy (NAI) and chemoimmunotherapy (NACI) for MIBC. We aimed to conduct a meta-analysis of available trials to compare the incidence of pathological response with NAC, NAI and NACI in MIBC patients undergoing radical cystectomy. Methods: Phase II/III clinical trials assessing neoadjuvant systemic therapies (NAC, NAI, or NACI) in patients with MIBC undergoing radical cystectomy were identified through a systematic search of MEDLINE and EMBASE. Outcomes of interest included pCR and pathological downstaging. A DerSimonian and Laird random-effect meta-analysis was conducted to estimate pooled incidence of events using the Freeman-Tukey transformation. Clopper-Pearson method was used to estimate the associated 95% confidence intervals (CI). Results: Of the 5357 records initially identified, 28 trials with a total of 2138 patients were considered eligible for inclusion. Neoadjuvant chemotherapy was assessed in 15 trials (1535 patients), NAI in 5 (288 patients), and NACI in 8 (315 patients). The pooled incidence of patients experiencing a pCR was 30.91% (95% CI: 26.54%-35.45%) with NAC, 30.92% (23.22%-39.14%) with NAI, and 42.25% (36.6%-48.0%) with NACI. The difference in pCR among these therapies was statistically significant (p <0.05). Similarly, the pooled incidence of achieving pathological downstaging was 40.91% (34.26%-47.72%) with NAC, 38.84% (26.73%-51.64%) with NAI, and 62.88% (57.22%-68.39%) with NACI. Consistently, there was statistically significant effect modification by the choice of neoadjuvant systemic therapy (p <0.01). The results were consistent across different clinically important subgroups (Table). Conclusions: NACI may achieve better pCR and pathological downstaging than NAC and NAI alone in MIBC patients which may potentially be associated with long-term survival. Definitive data from phase III trials are pending. [Table: see text]
Association of liver metastases, tumor microenvironment, and treatment outcomes in patients with urothelial bladder cancer treated with tislelizumab.
Authors: Xu Linlin , Liu Mo , Huang Ruiqi , Ma Xiaopeng , Wu Xikun , Ramakrishnan Vanitha , Zhang Lilin , Zhang Yun 
Published: March 2023

537 Background: Tislelizumab, a humanized monoclonal antibody that targets programmed cell death protein 1 (PD-1), has shown promising activity in the treatment of advanced urothelial bladder cancer (UBC). Recent studies suggest that liver metastases (LM) are associated with reduced effectiveness of PD-1/PD-L1 therapies (Yu, et al. Nat Med. 2021;27[1]:152-164). We evaluated how LM correlate with survival outcomes and the tumor immune microenvironment in UBC patients treated with tislelizumab in the BGB-A317-204 trial (NCT04004221). Methods: Cox regression was used to evaluate the effect of LM on overall survival (OS). Other key baseline characteristics were further included as covariates in the model to investigate the adjusted effect of LM and the interactions of LM with them. Gene expression profiling and multiplex immunohistochemistry (mIHC) analysis were performed on baseline tumor samples. Gene expression differences between LM positive (LM+) and LM negative (LM–) patients were compared by Wilcoxon rank-sum test for continuous biomarkers, and Fisher’s exact test for categorical biomarkers. All P-values reported in this post-hoc exploratory analysis were descriptive, without multiplicity adjustment. A result of P<0.05 was considered statistically significant. Results: A total of 113 patients were included in the analysis. LM were present in 27/113 (23.9%) of them. Cox regression analysis showed the presence of LM was a negative prognostic factor for overall survival (OS) in UBC patients treated with tislelizumab, OS (hazard ratio (HR), 3.7; 95% CI, 2.3-6.2; P<0.001). The LM negative prognostic value remained unaffected after adjustment for other baseline covariates. Next, we investigated immune cell infiltration and gene expression as potential indicators of impaired response in LM+ patients included in this analysis. Significantly fewer circulating lymphocytes at baseline were found in LM+ compared to LM– patients ( P<0.05), while no differences were observed in other immune cell types. Reduced expression of gene signatures of CD4 Th1 ( P<0.05), CD8+T cells ( P<0.05) and NK cells functions ( P<0.05) within tumor tissues was observed in samples from LM+ patients. Reduced CD8+ T-cell infiltration within the tumor and the intra-tumor stroma was also observed in LM+ patients based on mIHC analysis. No significant differences were observed in tumor mutational burden level between LM+ and LM– patients. Conclusions: LM were associated with worse outcomes of UBC patients treated with tislelizumab in the A317-204 study. Diminished number and impaired function of CD8+ T cells and NK cells in the tumor microenvironment of LM+ patients may have contributed to the worse survival observed in this subset of patients. Clinical trial information: NCT04004221 .
Spatial immunophenotypes of distant metastases and response to immune checkpoint inhibition.
Authors: Erlmeier Franziska , Klümper Niklas , Strissel Pamela , Strick Reiner , Sikic Danijel , Bahlinger Veronika , Breyer Johannes , Ritter Manuel , Bolenz Christian , Roghmann Florian , Erben Philipp , Schwamborn Kristina , Wirtz Ralph M. , Horn Thomas , Wullich Bernd , Hölzel Michael , Hartmann Arndt , Gschwend Jürgen E. , Weichert Wilko , Eckstein Markus ,   BRIDGE Consortium e.V., Mannheim, Germany
Published: March 2023

538 Background: The value of PD-L1 to predict durable responses to immune checkpoint inhibition (ICI) in metastatic urothelial carcinoma (mUC) is inconsistent. We hypothesize that the use of archived primary tumor material (PRIM) for PD-L1 testing in clinical trials not properly reflecting the metastatic disease status (MET) contributes to this clinical issue. Objective: To analyze the predictive and prognostic value of PD-L1, spatial immunephenotypes and MHC-I determined in patient-matched PRIM/MET. Methods: PD-L1 (Ventana IC-Score, combined positivity score), spatial immunephenotypes (midi-plex digital spatial immuneprofiling) and MHC-I were examined in 154 mUC patients with at least one available pretreatment MET (138 patient-matched PRIM/MET pairs). 119 patients received first-line platinum-based chemotherapy, and 50 patients received second-line immunecheckpoint inhibition. PD-L1 expression, spatial immunephenotypes and MHC-I status of (patient-matched PRIM and) pretreatment MET were correlated to chemotherapy and ICI response and outcomes. Results: Discordance rates in patient-matched PRIM/MET amounted 25/30%, 36% and 49% for PD-L1 (CPS10/IC5%), immunephenotypes and MHC-I (loss versus preserved), respectively. Correlations with chemotherapy and ICI responses were observed for immunephenotypes and MHC-I status determined in MET (not for PD-L1 alone), but not in PRIM. In case of ICI, patients with cytotoxic tumor immune microenvironments (TIME) showed durable responses with disease control rates of 90% and a hazard ratio for disease progression/death of 0.05 (95%-CI:0.01-0.65) versus patients with immunedepleted MET (DCR 29%). MET MHC-I status added incremental value to predict durable ICI responses: Combination of MHC-I based (auto-)antigen expression of tumor cells with spatial immunepehnotypes in pre-treatment MET improved predictive and prognostic impact for response and outcome prediction of mUC patients undergoing first-line platinum-based chemotherapy and second-line immunecheckpoint inhibition. Limitations include the partly retrospective design and the lack of MET multisampling on individual patient level. Conclusions: The TIME is subject to substantial dynamics during metastatic evolution. MET immunephenotypes and MHC-I statuses show promising potential to predict chemotherapy and durable ICI responses, while the PRIM TIME does not. Thus, future clinical trials should rather rely on pre-treatment MET-biopsies reflecting the current immunological disease state than on PRIM.
Association of peripheral blood neutrophil-lymphocyte ratio (NLR) and red cell distribution width (RDW) with immune checkpoint inhibitors (ICIs) for metastatic urothelial carcinoma (mUC).
Authors: El Zarif Talal , Thomas Jonathan , Riaz Irbaz Bin , Freeman Dory , Epstein Ilana , Nuzzo Pier Vitale , Davidsohn Matthew , McClure Heather , Matar Ayah , Kalluri Uttam , Yadav Ritu , Mantia Charlene , Ravi Praful , McGregor Bradley Alexander , Sonpavde Guru P. 
Published: March 2023

540 Background: Determining a benefit from ICIs radiographically may take months and may be confounded by pseudoprogression. The NLR & RDW are readily accessible inflammatory markers from routine peripheral blood analysis and have been associated with outcomes in malignancies. We evaluated the association of early changes in NLR and RDW within 4 weeks after initiating ICI with any regression of tumor (ART) and overall survival (OS) in mUC. Methods: This study included de-identified data from Dana-Farber Cancer Institute in pts with mUC who were treated with ICIs from 2015 to 2020. Age, gender, setting (untreated vs. post-platinum), sites of metastasis (mets), performance status (PS), platelet count, RDW, and NLR at baseline and 3-4 weeks after initiating the ICI were collected. The primary objective was to assess the association of early increase in NLR by ≥1.0 from baseline or RDW at 3-4 weeks (as a continuous variable) post-ICI therapy with ART and OS. ART was assessed via subsequent imaging at any time point while on ICI. A multivariable logistic regression model and Cox proportional-hazards model were employed to identify the association of NLR changes with ART and OS, respectively, using backward selection. Results: A total of 330 pts were evaluable. The median age was 70 years, 72.1% (n = 298) were male and 69.4% (n= 227) received post-platinum ICI (remaining were platinum naïve). 46.5% (n = 146) experienced ART and the median OS was 13 months (11.14-16.14). An increase in NLR ≥ 1 in 3-4 weeks was associated with a lower rate of ART (OR: 0.41, 95% CI 0.24-0.70; p: 0.001) and worse OS (hazard ratio [HR]: 1.84, 95% CI 1.37-2.46; p < 0.0001) on multivariable analysis (Table). Higher RDW values at 3-4 weeks were associated with worse OS (HR: 1.08, 95% CI 1.03-1.14; p: 0.0004) but were not associated with ART. Conclusions: In pts with mUC initiating ICI, an early increase in NLR ≥ 1 and higher RDW in 3-4 weeks were associated with poor outcomes. Early changes in these readily available variables may enable early modification or intensification of therapy to improve outcomes. External validation of these findings is warranted. [Table: see text]