bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of neoadjuvant immunotherapy and chemotherapy for muscle-invasive bladder cancer in a national registry.
Authors: Klein Matthew Nicholas , Xu Vincent Eric , Gordon Olivia French , Antar Ryan Michael , Whalen Michael Joseph 
Published: January 2024

611 Background: Neoadjuvant immunotherapy (NIO) is an exciting new treatment option for muscle-invasive bladder cancer (MIBC). Early-phase trials are encouraging however increased evidence is needed to support its use over Neoadjuvant chemotherapy (NAC). In this study, we sought to assess factors associated with NIO use in MIBC and survival outcomes. Methods: The National Cancer Database was used to identify 8,267 patients between 2006 and 2019. Patients were included based on urothelial bladder cancer diagnosis, clinical staging (T2-4N0-3M0), and receipt of NIO or NAC prior to radical cystectomy. NAC and NIO patient groups with similar clinical and demographic characteristics were defined using a 1:1 propensity score matching method. Categorical and continuous were assessed with chi-square test and independent sample T-test, respectively. Survival outcomes were compared using Kaplan-Meier analyses. Results: Mean age at diagnosis was significantly higher in NIO patients (70.5 years, SD 8.93) compared to NAC patients (65.64 years, SD 8.99) (p<.001). NIO patients were associated with higher Charlson-Dayo scores (p=.028), high income (p=.027), treatment at an academic facility (p<.001), and at a facility greater than 30 miles away (p=.002) when compared to NAC patients. In the matched analysis, these characteristics were all similar. NAC use was associated with increased rates of T down-staging to pT0-1 compared to NIO (47/118, 39.8% vs 20/109, 18.3%; p<0.001). Conversely, NIO use was associated with increased rates of T up-staging to pT3-4 compared to NAC (38/109, 34.9% vs 23/118, 19.5%; p=0.009). Kaplan-Meier analysis demonstrated no difference in overall survival when comparing patients who received NIO and NAC (p=.477). Conclusions: In this study use of NIO was associated with older and more comorbid patients compared to NAC. We found NIO less effective at achieving pathologic down-staging than NAC. Furthermore, increased rates of pathologic up-staging were observed with NIO use compared to NAC. These findings suggest the clinical benefit of neoadjuvant immunotherapy remains unclear. [Table: see text]
Extended follow-up report of a randomized phase II trial comparing gemcitabine and cisplatin with or without berzosertib in patients with advanced urothelial carcinoma.
Authors: Parikh Mamta , Pal Sumanta Kumar , Frankel Paul Henry , Ruel Christopher , Mortazavi Amir , Milowsky Matthew I. , Vaishampayan Ulka N. , Lyou Yung , Wang Peng , Parikh Rahul Atul , Teply Benjamin A. , Dreicer Robert , Emamekhoo Hamid , Michaelson Dror Dror , Hoimes Christopher J. , Zhang Tian , Srinivas Sandy , Kim William Y. , Liu Glenn , Lara Primo N 
Published: January 2024

614 Background: Gemcitabine with cisplatin (GC) remains a frontline treatment option for patients (pts) with metastatic urothelial cancer (mUC). Preclinical synergy has been noted when combining cisplatin with berzosertib, a selective ATR inhibitor. This trial sought to determine the effect of addition of berzosertib to GC on clinical outcomes in mUC; here we present final study results with extended follow-up. Methods: This open-label, randomized study enrolled pts with confirmed mUC, no prior cytotoxic therapy for metastatic disease, > 12 months since perioperative chemotherapy and eligible for cisplatin based on standard criteria. Pts were randomized to receive either GC plus berzosertib (Arm A) or GC alone (Arm B). In Arm A, cisplatin 60 mg/m2 IV was given on D1, gemcitabine 875 mg/m2 IV on D1 & 8, and berzosertib 90 mg/m2 IV on D2 & 9 of a 21-day cycle. In Arm B, cisplatin 70 mg/m2 IV was given on Day 1 (D1) and gemcitabine 1000 mg/m2 IV on D1 & 8 of a 21-day cycle. The primary endpoint of the study was progression-free survival (PFS), with secondary endpoints including response rate (RR), overall survival (OS) and toxicity. Results: A total of 87 pts (median age 67; M:F 68:19) were randomized, 46 pts to Arm A and 41 pts to Arm B. With a median follow-up of 37.7 months (95% CI: 28.3, 39.3), median PFS in Arm A was 6.2 month and 7.1 months in Arm B (HR: 1.3 [95% CI: 0.8-2.2], p=0.1). RR was 54% in Arm A and 63% in Arm B. Median OS was 10.9 months in Arm A and 19.8 months in Arm B (HR: 1.2 [95% CI: 0.7-2.1], p=0.2). Common > Grade 3 adverse events included anemia (Arm A: 57%, Arm B: 24%), neutropenia (Arm A: 36.9%, Arm B: 26.8%), thrombocytopenia (Arm A: 58.7%, Arm B: 39%). Conclusions: With >18 months of extended follow-up, there remained no PFS or OS benefit with the addition of berzosertib to GC, compared to GC alone in a biomarker unselected population. Myelosuppression was common despite reduced dosing of cisplatin and gemcitabine suggesting that combining ATR inhibition with platinum-based chemotherapy may not be feasible in pts with mUC. Clinical trial information: NCT02567409 .
Preliminary efficacy and safety results from ReBirth: A phase II study of risk-based bladder-sparing therapy for MIBC.
Authors: Shen Yijun , Lu Xiaolin , Ma Xuejun , Liu Wei , Ye Dingwei 
Published: January 2024

615 Background: Trimodal therapy (TMT) has achieved long-term survival and persistent oncologic control in selected MIBC patients, however, tailored treatment using biomarkers based on chemotherapy plus PD-1 inhibitor responses is currently absent. Furthermore, the safety and efficacy of hypo-fractionated radiation in combination with PD-1 inhibitors and concurrent chemotherapy is worth exploring. Methods: This is a two-stage, single-arm, phase II trial recruiting cT2-4aN0-1M0 MIBC pts. Based on results of cystoscopy, urine cytology, imaging and MRD detection after first stage (Tislelizumab (T) 200 mg on D1, Cisplatin (C) 70 mg/m2 on D1 and Gemcitabine (G) 1000 mg/m2 on D1 and D8 Q3W for 3-4 cycles), pts achieving cCR (cT0, cTa) are treated with T, while the other pts receive T and chemoradiotherapy (whole bladder 44Gy/16 fractionation combined with C as radiosensitizer). 1-year BIDFS rate is the primary endpoint. Secondary endpoints include 2-year MFS rate, 2-year BIDFS rate and safety. Tissue and urine samples will be obtained for genetic profiling and biomarker research. Results: The preliminary efficacy and safety are reported this time. As of September 20, 2023 (median follow up: 258 (49-415) days, 25 pts with a median age of 64 (36-77) years were enrolled and 96% are male. 19 pts with cT2 (57.14%), cT3 (33.33%) and cT4 (9.52%) tumors were evaluable. 2 pts were assessed as N1. 14/19 pts (73.68%) achieved cCR and maintained a sustained response. Based on positive urine cytology and MRD, 5 pts were classified as non-cCR (2 pts in cT3N0M0, 2 pts in cT4N0M0 and 1 pt in cT2N0M0). Due to RC (2 pts achieving ypT0N0 and 1 pt achieving ypT2N0) and incomplete treatment cycles, 6 pts were excluded from the efficacy analysis set. BFS rate at 1 yr is evaluated in 6 pts (2 pts received hypo-fractionated on the second stage) and the rate is 100%. TRAEs were found in 19 of 25 pts (76%). The grade 3-4 TRAEs observed (8%) was adrenal cortical insufficiency and immuno-therapy related colonitis. Hematological AEs (32%), renal insufficiency (24%), pruritus (20%), and fatigue (20%) are the most common AEs. During hypo-fractionated radiation, no new safety signs were discovered. Conclusions: The preliminary findings indicate a potential efficacy and manageable toxicity during the two-stage treatment. Enrollment is still ongoing, and long-term efficacy will be proved. Clinical trial information: NCT05531123 .
Pemetrexed (PEM) maintenance versus observation (OBS) in patients (pts) with advanced urothelial carcinoma (aUC) who completed first-line (1L) platinum-based chemotherapy (CTx) without disease progression (PREMIER, KCSG GU16-05).
Authors: Park Inkeun , Yoon Shinkyo , Kim Il Hwan , Park Kwonoh , Lee Suee , Keam Bhumsuk , Park Joo-Hwan , Kim Jin Young , Choi Yoon Ji , Sohn Byeong Seok , Lee Jae-Lyun 
Published: January 2024

621 Background: Four-to-six cycles ofplatinum-based CTx have been a standard treatment for aUC. However, disease progresses within several months after completion of 1L CTx. Switch maintenance after 1L with effective and safe regimen is an attractive approach to delay disease progression. PEM showed modest response as a salvage CTx in aUC with mild toxicities, which are good candidate for maintenance therapy. We evaluated PEM as switch maintenance therapy versus OBS in pts with aUC whose disease had not progressed. Methods: Eligible pts with aUC without disease progression after 4-6 cycles of either cisplatin or carboplatin-based regimen were randomized 1:1 to receive maintenance PEM (500 mg/m2 IV q3 weeks, up to 16 cycles) or OBS until disease progression, stratified by Galsky et al.’s post-treatment prognostic nomogram for pts with mUC completing 1L cisplatin-based CTx. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival (OS), response rate, and safety. Results: This trial was closed early due to poor accrual after avelumab maintenance approval. From Oct 2016 to Dec 2022, a total of 97 pts was randomly assigned to maintenance PEM (n=49) or OBS (n=48). Median age (range) was 69 years (43-90) and 66 (33-82), and male was 63% and 73%, respectively. 1L regimen included gemcitabine plus cisplatin (84% and 83%, respectively), gemcitabine plus carboplatin (12% and 6%, respectively), and MVAC (4% and 10%, respectively). Response to 1L were CR (8% vs. 19%), PR (69% vs. 67%), and SD (22% vs. 15%). Most common metastatic site was abdominopelvic lymph nodes (61% and 65%) and lung (37% and 29%). For PEM group, median administered cycle was 6 (range 1-16), and most common reason for discontinuation was disease progression (53%), followed by completion of planned cycles (20%). With a median follow-up of 19.1 months, median PFS was 6.0 months (mo) [95% confidence interval (CI) 3.4-8.5] for PEM vs. 2.3 mo (1.8-2.7) with a log rank p=0.027, with a hazard ratio (HR) of 0.61 (95% CI 0.40-0.95). Median OS was 25.5 mo (95% CI 11.9-30.1) vs. 26.8 (11.9-41.7) (p=0.607, HR 1.18, 95% CI 0.62-2.26). Anemia (29%), fatigue (18%), and neutropenia (12%) were the most frequent adverse events, and these adverse events were mostly grade 1 or 2, and manageable. Conclusions: PREMIER trial showed that switch maintenance PEM prolonged PFS with statistical significance in aUC after 1L platinum-based CTx and had very favorable safety profile. Combination maintenance therapy including PEM needs further investigation. Clinical trial information: NCT03193788 .
Oral APL-1202 in combination with tislelizumab as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC): Interim analysis of ANTICIPATE phase II trial.
Authors: Galsky Matt D. , Sfakianos John P. , Ye Dingwei , He Dalin , Hu Hailong , Song Xiaodong , Jiang Haowen , Li Hanzhong , Jiang Shusuan , Wang Bin , Wang Gongxian , Wang Yujie , Yang Yong , Zhang Mingming 
Published: January 2024

632 Background: APL-1202 (nitroxoline) is a reversible and orally available MetAP2 inhibitor with anti-angiogenic and anti-tumor activities. Single-agent neoadjuvant programmed death 1 (PD-1) antibodies achieve pathological complete responses in a subset of patients (pts) with MIBC. APL-1202 and PD-1 antibody combination therapy demonstrates synergistic effects in several model systems of cancer, including bladder cancer. We hypothesized that APL-1202, in combination with tislelizumab, a humanized IgG4 anti-PD-1 antibody, may be an effective neoadjuvant therapy in MIBC. Methods: This is a prospective multicenter randomized phase II trial for pts with newly diagnosed MIBC for whom radical cystectomy (RC) is planned, and who are cisplatin ineligible or refuse cisplatin based neoadjuvant chemotherapy. Eligible pts are randomly assigned to group 1 (APL-1202 plus tislelizumab) or group 2 (tislelizumab), with randomization stratified by PD-L1 expression. Neoadjuvant treatment is administered every 3 weeks for 3 cycles. The primary endpoint is pathological complete response (pCR, pT0N0) rate. A Simon’s 2-stage design is employed with planned interim analyses after 18 evaluable pts in group 1 and 14 evaluable pts in group 2. Results: 42 pts have enrolled and results for 32 evaluable pts for stage 1 of the 2-stage design are reported. Radical cystectomy was completed in 18/18 pts in group 1 and 13/14 pts in group 2; 1 patient who could not undergo surgery due to disease progression and 10 pts refused RC. The 32 evaluable pts consisted of 11/18 (61%) and 10/14 (72%) cT2, and 6/18 (33%) and 2/14 (14%) cT3, and 1/18 (6%) and 2/14 (14%) cT4a in group 1 and 2, respectively. PD-L1 expression was assessed using the VENTANA PD-L1 (SP263) Assay; 8/18 (44%) pts in group 1 and 7/14 (50%) in group 2 was positive. The pathological response was shown in the table. Treatment emergent adverse events (TEAEs) were reported in 17 (94.4%) pts in group 1 and 11 (78.6%) in group 2; most common (≥ 10%) TEAE of CTCAE grade ≥ 3 were anaemia (4, 22.2%), lymphocyte count decreased (3, 16.7%) in group 1 and intestinal obstruction (3, 21.4%) in group 2. AEs led to drug discontinuation in 3 (16.7%) pts in group 1 (acute kidney injury, anaemia, hepatic function abnormal) and 2 (14.3%) in group 2 (immune hyperthyroidism, COVID-19), and no treatment-related AEs led to death. Conclusions: The pCR rates in both group 1 (APL-1202 plus tislelizumab) and group 2 (tislelizumab) exceeded thresholds to trigger expansion to stage 2 of the 2-stage design. The activity and safety of neoadjuvant APL-1202 plus tislelizumab support further evaluation of this novel regimen (NCT04813107). Clinical trial information: NCT04813107 . [Table: see text]
Avelumab or pembrolizumab: Which is the better subsequent treatment in patients with advanced urothelial carcinoma who did not show progression after 4 cycles of first line chemotherapy?
Authors: Tomisaki Ikko , Harada Mirii , Minato Akinori , Higashijima Katsuyoshi , Takaba Tomohisa , Nagata Yujiro , Harada Kenichi , Fujimoto Naohiro 
Published: January 2024

633 Background: In platinum eligible patients with advanced urothelial carcinoma (UC), there are two treatment options if they did not show progression after 4 cycles of first line chemotherapy. One is switching to avelumab maintenance therapy and the other is pembrolizumab after the disease progression on first line chemotherapy. However, there is no data witch treatment strategy demonstrate better survival. This study aimed to compare the efficacy between avelumab and pembrolizumab after first line chemotherapy without disease progression. Methods: We retrospectively reviewed patients with advanced UC who received avelumab or pembrolizumab as subsequent therapy following first line platinum-based chemotherapy between March 2018 and Jun 2023. In patients who receive pembrolizumab, only patients who did not show progression after 4 cycles of first line chemotherapy were included in the study cohort. The oncological outcomes were compared between the patients who received avelumab and pembrolizumab. Results: Thirty-three and 100 patients received avelumab and pembrolizumab during study periods, respectively. Among 100 patients who received pembrolizumab, 14 patients did not show progression during 4 cycles of first line chemotherapy. Median 4 and 6 cycles of first line chemotherapy were performed in patient treated with avelumab and pembrolizumab, respectively. All patients treated with pembrolizumab showed disease progression after 1st line chemotherapy. With the median follow-up of 16.7 months, progression was observed in 19 (57%) and 12(86%) patients in avelumab and pembrolizumab group, respectively. Among the patients with progression, all patients had treated with avelumab received subsequent treatment mainly enfortumab vedotin. However, only 2 patients (17%) had treated with pembrolizumab received subsequent treatment and the other patients were not candidate of additional treatment due to poor PS or cachexia. Although median progression free survival from starting first line chemotherapy was shorter in patients with avelumab compared to pembrolizumab (9.7 vs. 19.9 months, P=0.06), median OS was longer in patients with avelumab (40.9 vs. 24.9 months, P=0.34). Conclusions: In patients who did not show progression after 4 cycles of first line chemotherapy, avelumab maintenance therapy might be a better treatment option with longer overall survival compared to pembrolizumab.
Urinary minimal residual disease detection predicts recurrence in BCG-unresponsive NIMBC and quantifies molecular response to nadofaragene firadenovec.
Authors: Narayan Vikram M , Tholomier Come , Mokkapati Sharada , Martini Alberto , Caruso Vincent M. , Mazzarella Brian C. , Phillips Kevin G. , Bicocca Vincent T. , Levin Trevor G. , Yla-Herttuala Seppo , Sawutz David , Parker Nigel , McConkey David James , Dinney Colin P.N. 
Published: January 2024

635 Background: Urinary minimal residual disease (uMRD) profiling uses next-generation sequencing to identify mutations associated with urothelial carcinoma and can be used to predict recurrence and assess response to therapy. Nadofaragene firadenovec is a novel intravesical therapy recently approved for BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC). We evaluate the utility of uMRD to identify molecular response to Nadofaragene in patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods: This was an open-label, multicenter, parallel-arm, phase II study (NCT01687244) of 43 patients with BCG-unresponsive NMIBC who received intravesical nadofaragene. The primary endpoint was 12-month HG-recurrence-free survival (RFS). All patients who received at least one dose were included in the uMRD analysis. Urine samples were collected prior to induction and at 3 months. uMRD testing was done using the UroAmp MRD assay, which identifies single-nucleotide variants, copy-number variants (CNVs), insertion-deletions, copy-neutral loss of heterozygosity, microsatellite instability, and aneuploidy. Results: Among evaluable patients (n=35), initial pathological stages were Ta (n=3), T1 (n=9), and Tis (n=23), with concomitant CIS in six patients. In pre-treatment urine (n=32), TP53, TERT, PIK3CA, ARID1A, PLEKHS1, ELF3, and ERBB2 were among the most prevalently mutated genes. Most CNVs occurred in SOX4 and NIT1. uMRD identified patients with high (72%) and low (28%) recurrence risk in both pre- and post-induction collections. At 12 months, post-induction RFS rate was 100% for low-risk and 38% for high-risk patients (P = 0.038, log-rank test). Pre-induction RFS was 56% for low-risk and 22% for high-risk (P = 0.097, log-rank test). Using matched pre- and post-induction urine (n=15), quantitative drug response was measured and patients categorized as MRD Negative (7%), MRD Complete Responder (13%), MRD Partial Responder (27%), MRD Stable (20%), or MRD Refractory (33%). Recurrence correlated broadly with response groups: MRD Negative and Complete Responder groups did not recur on study, while 7 of 12 patients in the other groups recurred. Conclusions: uMRD enables quantitative assessment of molecular response to drug treatment. uMRD-determined pre-treatment disease burden assessment can support stratification of control and intervention arms in future treatment trials.
Validity of renal function eligibility criteria for cisplatin-based chemotherapy for patients with urothelial carcinoma.
Authors: Hi Sai , Naito Yushi , Hattori Kyosuke 
Published: January 2024

638 Background: The eligibility criteria of renal function in cisplatin (CDDP) -based chemotherapy for urothelial carcinoma has generally been a creatinine clearance (CCr) ≥ 60 (mL/min) without adjusting for body surface area (BSA). While CDDP dosage is determined by body surface area, the use of CCr (mL/min) without correction for body surface area as a criterion for cisplatin eligibility may lead to CDDP overdose, especially in obese patients with borderline renal function. CCr with BSA modification (CCr mL/min/1.73 ㎡) may be more appropriate than without BSA modification for assessing renal function in patients with nonstandard body mass. Methods: This retrospective analysis included 82 patients who received CDDP-based chemotherapy as primary systemic treatment for urothelial carcinoma at Nagoya University in the past 10 years. For all patients, CDDP eligibility was determined by CCr mL/min by 24-hour urine collection, and the inclusion criteria for this study were CCr < 80 mL/min. To identify the possibility of a gap between CCr mL/min and CCr mL/min/1.73 ㎡ resulting in cisplatin overdose unit organ function, ΔCCr (difference between CCr mL/min and CCr mL/min/1.73 ㎡) and CDDP/CCr (actual dose of CDDP mg per unit CCr mL/min) were calculated and compared between the obese and standard-body groups. In addition, we compared the incidence of CTCAE Grade ≥3 adverse events (AEs) and the objective response rate (ORR) to chemotherapy in the two groups. In accordance with Japanese standards, BMI ≥ 25 was defined as obese patients. Results: There were no significant differences in patient background between the obese and standard groups in terms of age, gender, cancer type and status, and CDDP dose per unit BSA. CCr mL/min/1.73m2 was similar between the two groups, whereas CCr mL/min was significantly higher in the obese group, which resulted in a significantly higher ΔCCr in the obese group. In addition, CDDP/CCr was also greater in the obese group. Conclusions: The results of the current study suggest that the application of CCr mL/min to the assessment of renal function for CDDP eligibility may lead to CDDP overdosing, especially in obese patients with borderline renal function. Further larger studies are warranted to clarify whether or BSA correction should be applied to assess renal function for CDDP eligibility, since the method for assessing renal function may affect the occurrence of AEs and the efficacy of chemotherapy.