bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term outcome and safety in patients treated with immune checkpoint blockade therapies for urothelial carcinoma: Experience from real-world clinical practice.
Authors: Tural Deniz , Arslan Cagatay , Selcukbiricik Fatih , Olmez Omer Fatih , Erman Mustafa , Ürün Yüksel , Karadurmus Nuri , Akar Emre , Kilickap Saadettin 
Published: February 2022

474 Background: Anti-tumor activity and manageable safety profile of immune checkpoint blockade therapies (ICT) have been demonstrated in previous clinical trials in patients with metastatic urothelial carcinoma. To the best of our knowledge, very limited real-life data is available with the long follow-up time that confirms the durable antitumor activity and safety of ICT. In this study, we reported the real-life results of 56 months follow-up data of urothelial carcinoma patients who were treated with ICT. Methods: Metastatic urothelial carcinoma patients treated with at least one course of ICT included in the study. The primary endpoint was the overall response rate (ORR); secondary endpoints were overall survival (OS), progression-free survival (PFS), duration of the ICT treatment, and safety. Median follow-up, PFS, and OS were estimated by using the Kaplan-Meier method. Results: Data of 185 eligible patients were analyzed, 11.9% of these patients received the ICT as the first line, 76.8 % as the second line, and 11.3 % as the third or more line of treatment. The median age of the patients was 66 years, and 156 (84.3%) were male (37-86). The majority of patients (93.5%) had ECOG PS scores of 0–1 and primary tumor in the bladder was predominant (86.7%). The median follow-up time was 47(1.15-56) months. The complete response rate to ICT, partial response rate, and ORR were 10.3% (n = 19), 19.5% (n = 36), and 29.8% (n = 55), respectively. The median duration of response was 33.1 months (95% CI, 16.5–49.7). Of the fifty-five patients who responded to treatment, 28 (51%) had an ongoing response at the time of the analysis. Median PFS and OS was 3.8 (2.6–5.1) months and 8.9 (6.8–11.1) months, respectively. 56-month PFS and OS rate was 9.2% and 11.4%, respectively. 56-month PFS and OS rate for CR and PR was 56.2% and 20%, respectively. Fifty-nine percent of patients experienced a treatment-related adverse event of any grade, and 32 (17.3%) of patients had a grade 3–4 treatment-related adverse event. Because of treatment-related side effects, treatment was discontinued in 8 (4.3%) patients and adverse event that required systemic steroid use was reported in only 13 (7%) patients. Four patients (2.2%) died due to treatment-related causes. Conclusions: This 56-month analysis of real-world data confirms the durable response and long-term survival with ICT in metastatic urothelial carcinoma patients. The safety profile was consistent with prior reports, and no new safety signals emerged.
Survival outcomes comparing radical nephroureterectomy versus endoscopic treatment in solitary kidney patients diagnosed with upper tract urothelial carcinoma.
Authors: Alam Ridwan , Cheaib Joseph G. , Biles Michael J. , Winoker Jared S. , Singla Nirmish , Bivalacqua Trinity , Pierorazio Phillip M. , Kates Max R. , Patel Sunil H. 
Published: February 2022

477 Background: Solitary kidney patients who develop upper tract urothelial carcinoma (UTUC) present a significant management challenge. Radical nephroureterectomy (RNU) renders these patients anephric with a need for dialysis, which is associated with lower life expectancy and decreased quality of life. However, organ-sparing endoscopic treatment may result in undertreatment of the cancer process. We sought to compare survival outcomes between RNU and endoscopy in solitary kidney patients diagnosed with clinically localized UTUC. Methods: The Surveillance, Epidemiology, and End Results database was linked to Medicare records to identify patients diagnosed with UTUC through 2017. This data was then linked to the Medicare Provider Analysis and Review and National Claims History databases to identify patients with a solitary kidney. Only patients with an established diagnosis of solitary kidney prior to developing clinically node-negative and non-metastatic disease (cN0M0) UTUC were included. Patients were stratified by treatment with RNU versus endoscopy. Kaplan-Meier analysis was performed to estimate survival between the two groups. Results: A total of 2108 solitary kidney patients with cN0M0 UTUC were identified, with a median age of 75.3 years at diagnosis [IQR 69.3-81.1]. Median follow-up time was 2.8 years [IQR 1.7-4.4]. High-grade disease was present in 1531 patients (72.6%), of whom 1344 underwent RNU and 195 underwent endoscopy. Between the two treatments, there was no difference in either cancer-specific survival ( P=0.18) or overall survival ( P=0.10). When combining high- and low-grade UTUC patients, 1839 underwent RNU and 269 underwent endoscopy. Again, no difference was observed in cancer-specific survival ( P=0.31) or overall survival ( P=0.17). Patients with high-grade disease demonstrated higher rates of cancer-specific and overall mortality than those with low-grade disease (both P<0.001). Conclusions: Solitary kidney patients diagnosed with clinically localized UTUC demonstrate no difference in survival outcomes when comparing RNU to endoscopic treatment. This potentially suggests that, when weighed against the option of endoscopic treatment, the benefits of RNU in these patients may not outweigh the risks of becoming anephric and therefore dependent on dialysis.
Association of changes in albumin levels with survival and toxicities in patients (pts) with metastatic urothelial carcinoma (mUC) receiving enfortumab vedotin (EV).
Authors: El Zarif Talal , Riaz Irbaz Bin , Adib Elio , Freeman Dory , Madueke Ikenna C. , Davidsohn Matthew , McClure Heather , Nuzzo Pier Vitale , McGregor Bradley Alexander , Mantia Charlene , Ravi Praful , Sonpavde Guru P. 
Published: February 2022

481 Background: EV is an anti-Nectin-4 antibody-drug conjugate that has been approved by the US FDA for mUC progressing on platinum and PD1/L1 inhibitor therapy and in cisplatin-ineligible pts following prior therapy. However, prognostic and predictive biomarkers in the setting of EV therapy are unclear. We aimed to investigate baseline and early changes in commonly available clinical and laboratory tests that could help predict survival and toxicities in patients with mUC treated with EV. Methods: Data from patients with mUC who were treated with EV at Dana Farber Cancer Institute between 2017 and 2021 were reviewed retrospectively. We assessed the association of demographic (age, sex), clinical (ECOG-performance status [PS], sites of metastasis) and laboratory variables (hemoglobin, RDW, neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio, platelet count and serum albumin) at baseline as well as after 4-7 weeks of treatment with Overall Survival (OS) by constructing univariate and multivariable Cox proportional-hazards models. Any variables significantly associated with OS at the univariate level (using an alpha-level of 0.1 to determine statistical significance) were then entered into the multivariable model. Predictors were eliminated from the final multivariable models by a backward selection process, retaining only those with a p-value of ≤ 0.05. Results: A total of 49 patients who received EV were included in the analysis. The median age was 72 years (range 48-88) and 36 (73.5%) were male. The median OS was 13.3 months (range: 2.7-38.7) and grade 3-4 toxicities were seen in 11 pts (22.4%). In the final multivariable models, lower serum albumin at 4-7 weeks (HR = 0.18; 95% CI = 0.05-0.71; p = 0.015), and baseline ECOG-PS of 1 vs. 0 (HR = 2.56; 95% CI = 1.05-6.21; p = 0.038) were significantly associated with worse OS (Table). Patients with higher serum albumin levels at 4-7 weeks also had significantly lower odds of experiencing grade 3-4 adverse events on EV (OR = 0.05; 95% CI = 0.002-0.52; p = 0.02). Conclusions: Lower serum albumin appeared to predict worse survival and severe toxicities in mUC pts receiving EV. This information may guide therapy and assist in the prevention of toxicities. Additionally, ECOG-PS was prognostic while the location of metastatic disease was not prognostic in the setting of EV.[Table: see text]
Phase Ib study of avelumab and taxane based chemotherapy in platinum-refractory or ineligible metastatic urothelial cancer (AVETAX study).
Authors: Garje Rohan , Packiam Vignesh T. , Koski Amy , Milhem Mohammed M. , O'Donnell Michael A. , Zakharia Yousef 
Published: February 2022

503 Background: Metastatic urothelial cancer is aggressive and associated with dismal 5-yr overall survival. Platinum-based chemotherapy and checkpoint inhibitors are standard first-line options with enfortumab vedotin, sacituzumab govitecan, and erdafitinib (in select FGFR altered tumors) subsequently utilized upon disease progression. However, despite these options, long-term outcomes remain poor, and novel strategies are needed to improve oncologic outcomes. We hypothesized that combining avelumab (anti-PD-L1 immunotherapy) with docetaxel is safe and will enhance cancer cell death by releasing neoantigens and potentiating anti-tumor immune-mediated cytotoxicity. Methods: This is a phase 1b, single-arm, open-label prospective clinical trial evaluating the combination of avelumab with docetaxel in adult subjects with locally advanced or metastatic urothelial carcinoma with disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. There are two phases. In Phase 1b, dose de-escalation of docetaxel (Level 0: 75, Level -1: 60 or Level -2: 45 mg/m2) with standard dose avelumab (10 mg/kg) aimed to establish the phase 2 dose in a standard 3+3 design. In dose-expansion, avelumab with the RP2D of docetaxel was evaluated for efficacy. The combination therapy is administered every 3 weeks for 6 cycles, and then avelumab alone is continued every 2 weeks. The primary endpoint is safety. Efficacy endpoints include objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: At the cutoff date of 10/8/2021, 21 patients were enrolled in the study. Only one of the 6 patients treated with level 0 dose of docetaxel had dose-limiting toxicity (neutropenic fever). Docetaxel at 75 mg/m2 along the avelumab was deemed safe for dose expansion cohort. An additional 15 patients were enrolled in the dose-expansion cohort. Of the 20 evaluable patients, ORR (CR+PR) was seen in 70% of subjects. (CR: 30%, PR: 40%, SD: 5%, PD: 25%, and 1 patient was not evaluable). The median PFS was 9.2 months (range: 1.5 – 25.8 months), and median OS was not reached. The most common Grade 3 or 4 AEs were febrile neutropenia, transaminitis, diarrhea, anemia, and neutropenia. No treatment-related deaths were noted. Conclusions: The combination of avelumab with docetaxel is safe with promising efficacy that is worth further studying in patients with platinum-refractory or ineligible metastatic urothelial cancer. Clinical trial information: NCT03575013.
Post hoc analysis of the efficacy of pembrolizumab retreatment after progression of advanced urothelial carcinoma (UC) in KEYNOTE-045 and KEYNOTE-052.
Authors: Castellano Daniel E. , Balar Arjun Vasant , O'Donnell Peter H. , Grivas Petros , Vaughn David J. , Powles Thomas , Vuky Jacqueline , Lee Jae-Lyun , Fradet Yves , Bellmunt Joaquim , Climent Miguel Ángel , Vogelzang Nicholas J. , Plimack Elizabeth R. , Gurney Howard , Hahn Noah M. , Sternberg Cora N. , Xu Jin Zhi , Imai Kentaro , Homet Moreno Blanca , De Wit Ronald 
Published: February 2022

512 Background: Pembrolizumab (pembro) has shown efficacy in advanced/unresectable and metastatic UC (mUC). There is interest in determining whether pts should be treated subsequently with checkpoint inhibitors such as anti–PD-1 therapy if mUC responds then later progresses. Pembro retreatment after disease progression has shown efficacy in melanoma and NSCLC. This post hoc exploratory analysis investigated the efficacy of pembro retreatment for pts with advanced UC or mUC enrolled in KEYNOTE-045 and KEYNOTE-052 with a best overall response (BOR) of SD or better and whose disease progressed after discontinuation or completion of 2 y of therapy. Methods: The phase 3 KEYNOTE-045 trial (NCT02256436) was designed to compare the efficacy and safety of pembro vs chemotherapy (chemo) in pts with mUC that recurred/progressed on platinum containing chemo; ≤2 prior lines of systemic chemo for mUC were permitted. The phase 2 KEYNOTE-052 trial (NCT02335424) was designed to evaluate the efficacy and safety of first-line pembro in cisplatin-ineligible pts with advanced UC. In both studies, pembro was administered for up to 2 y; pts were eligible for retreatment if they stopped pembro after CR or had a BOR of CR, PR, or SD and completed 2 y of treatment. Pts must have investigator-confirmed radiographic PD after therapy cessation, have ECOG PS score 0-1, and not have received anticancer treatment after the last pembro dose. BOR to retreatment is reported. Results: At data cutoff for KEYNOTE-045 (Oct 1, 2020), 11 pts were retreated: 5 (45%) achieved objective response to retreatment (3 CR; 2 PR; Table) and 6 had SD, for a disease control rate (DCR; CR+PR+SD) of 100%. Median treatment-free interval was 7.7 mo (IQR, 3.6-16.5); median duration of retreatment was 11.4 mo (IQR, 7.6-12.0). Seven pts (64%) were alive at cutoff. At data cutoff for KEYNOTE-052 (Sep 26, 2020), 10 pts were retreated; 5 (50%) had objective response to retreatment (1 CR; 4 PR) and 4 had SD, for a DCR of 90%. Retreatment BOR was PD for 1 pt (10%). Median treatment-free interval was 13.0 mo (9.2-16.6); median duration of retreatment was 6.0 mo (IQR, 4.9-9.2). Four pts (40%) were alive at cutoff. Conclusions: Although the number of pts who received retreatment was small, objective responses were observed. The findings are generally consistent with observations from retreatment in other tumor types (e.g., melanoma). Clinical trial information: NCT02256436 and NCT02335424. [Table: see text]
Study RC48-C014: Preliminary results of RC48-ADC combined with toripalimab in patients with locally advanced or metastatic urothelial carcinoma.
Authors: Zhou Li , Xu Huayan , Li Siming , Yan Xieqiao , Li Juan , Wu Xiaowen , Chi Zhihong , Si Lu , Cui Chuanliang , Kong Yan , Tang Bixia , Mao Lili , Lian Bin , Bai Xue , Wang Xuan , Guo Hongqian , He Zhisong , Guo Jun , Sheng Xinan 
Published: February 2022

515 Background: RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC), which showed promising data in HER2-positive and even negative patients (pts) with metastatic urothelial carcinoma (mUC). Toripalimab is an anti-PD-1 antibody with a durable antitumor effect for mUC. The combination may have a synergistic antitumor effect. Initial RC48-C014 data was previously presented (ASCO 2021); here we reported an update on safety and ORR. Methods: In dose-escalation cohort, pts received 1.5 or 2 mg/kg RC48-ADC + 3mg/kg toripalimab with the traditional 3+3 escalation design. In the expansion cohort, patients received the recommended dose of RC48-ADC + toripalimab every 2 weeks. The primary endpoints were safety/tolerability and recommended RC48-ADC dose; secondary endpoints included pharmacokinetics, ORR per RECIST 1.1, PFS, and OS, stratified by HER2 and PD-L1 expression. Results: As of 23 Sep 2021 (data cutoff), 32 mUC pts (18 males; median age 67 y [52-76]) were enrolled since 20 Aug 2020. Fifty-three percent pts were systemic treatment naïve in the locally advanced or metastatic setting. The primary site was in upper tract UC in 56%; 53% had visceral metastases (mets), including 28% with liver mets; HER2 expression was positive (IHC 3+ or 2+ ISH+) in 19% pts, and PD-L1 CPS≥1 in 56%. No dose-limiting toxicity was reported, and the recommended dose for RC48-ADC was 2mg/kg. At data cutoff, confirmed investigator-assessed ORR was 75% (95%CI: 50.9, 91.3), including 15% CRs; DCR was 95% (95%CI: 75.1, 99.9). The ORR for 1L previously untreated mUC pts was 80% and 75% for pts with liver mets. The ORR was 100% for pts with HER2 (3+), 77.8% for HER2 (2+), 66.7% for HER2 (1+), and 50% for HER2 (0) respectively. The ORR was 97.1% in pts with PD-L1 CPS≥1 and 50% in CPS < 1. Follow-up continues for PFS and OS. Most common treatment-related AEs were anorexia (72%), asthenia (56%, 8%≥G3), aminotransferase level increased (56%, 4%≥G3), peripheral sensory neuropathy (56%), alopecia (52%), nausea (36%), and anemia (32%). The most common immune-related AE was pneumonitis (20%). Conclusions: RC48-ADC in combination with toripalimab demonstrated promising efficacy in pts with mUC and a manageable safety profile. Further evaluation of RC48 + toripalimab in mUC is ongoing. Clinical trial information: NCT04264936.
Impact of primary tumor location on efficacy and safety of pembrolizumab (pembro) in patients (pts) with locally advanced or metastatic urothelial carcinoma (UC) enrolled in the phase 2 KEYNOTE-052 and phase 3 KEYNOTE-045 trials.
Authors: O'Donnell Peter H. , Balar Arjun Vasant , Castellano Daniel E. , De Wit Ronald , Vaughn David J. , Powles Thomas , Vuky Jacqueline , Lee Jae-Lyun , Fradet Yves , Bellmunt Joaquim , Fong Lawrence , Petrylak Daniel P. , Gerritsen Winald R. , Quinn David I. , Culine Stephane , Bajorin Dean F. , Xu Jin Zhi , Imai Kentaro , Homet Moreno Blanca , Grivas Petros 
Published: February 2022

516 Background: Pembro showed antitumor activity in 1L and 2L for pts with UC in the single-arm, phase 2 KEYNOTE-052 study (NCT02335424) and the randomized phase 3 KEYNOTE-045 (NCT02256436) study, respectively. This post hoc exploratory analysis evaluated whether primary tumor location affected efficacy and safety of pembro (KEYNOTE-052; KEYNOTE-045) and chemotherapy (chemo; KEYNOTE-045). Methods: KEYNOTE-052 enrolled cisplatin-ineligible pts with advanced/metastatic UC who had not previously received systemic therapy; they received pembro (200 mg IV Q3W). KEYNOTE-045 enrolled pts with advanced/metastatic UC who had received platinum-containing chemo; pts were randomly assigned 1:1 to receive pembro (200 mg IV Q3W) or investigator’s choice of chemo (paclitaxel, docetaxel, or vinflunine). Both studies required pts to have measurable disease per RECIST v1.1. Upper tract (UT) UC included primary tumors in the renal pelvis or ureter; lower tract (LT) UC included primary tumors in the bladder or urethra. Pts with UT and LT disease (UT/LT) were classified as LT. Pts receiving pembro were treated until disease progression, unacceptable toxicity, or withdrawal of consent, for up to 2y. End points were PFS, ORR, and DOR per RECIST v1.1 by central radiology assessment and OS. Results: A total of 369 pembro-treated pts (68 UT; 301 LT [79 UT/LT]) from KEYNOTE-052 plus 270 pembro-treated pts (93 UT; 177 LT [33 UT/LT]) and 272 chemo-treated pts (94 UT; 178 LT) from KEYNOTE-045 were evaluated. Median follow-up from randomization to data cutoff (09/26/20 and 10/1/20, respectively) was ≥56 mo. Both studies enrolled a similar percentage of pts with PD-L1–positive tumors (25%-30%). PFS, ORR, DOR, and OS for pembro were consistent regardless of tumor location, although ORR for KEYNOTE-045 was lower for the UT group (Table). In the chemo arm of KEYNOTE-045, similar efficacy was observed regardless of tumor location or regimen. Grade 3-5 TRAEs occurred at similar rates in KEYNOTE-052 (19.1% UT; 21.6% LT) and KEYNOTE-045 (17.2% UT; 16.8% LT). Conclusions: In this exploratory analysis, pembro showed similar clinical activity and manageable safety regardless of primary UC tumor location. Clinical trial information: NCT02256436 and NCT02335424. [Table: see text]
Defining hereditary upper tract urothelial carcinoma: Implications for genetic testing and clinical management.
Authors: Truong Hong , Sheikh Rania , Kemel Yelena , De Jesus Escano Manuel , Khurram Aliya , Reisz Peter , Lenis Andrew Thomas , Goh Alvin C. , Cha Eugene K. , Bochner Bernard H. , Iyer Gopa , Rosenberg Jonathan E. , Bajorin Dean F. , Solit David B. , Stadler Zsofia Kinga , Latham Alicia , Offit Kenneth , Carlo Maria Isabel , Coleman Jonathan , Al-Ahmadie Hikmat A. 
Published: February 2022

523 Background: Despite being a rare cancer, upper tract urothelial carcinoma (UTUC) is the third most common core cancer associated with Lynch syndrome (LS) after colorectal and endometrial cancers. Yet, there is no established guideline to identify patients with UTUC who are at risk of carrying germline mutations in LS-associated genes. The objective of this study is to define selection criteria for patients with UTUC for LS screening. Methods: We retrospectively identified patients with UTUC who underwent germline sequencing of ≥77 cancer susceptibility genes using next generation sequencing (NGS) as part of a prospective matched tumor-normal genomic profiling initiative from 04/2015 to 04/2021. Mismatch repair protein status was evaluated by immunohistochemical (IHC) staining for MMR genes MSH2, MSH6, MLH1, and PMS2. Microsatellite instability (MSI) status was determined using NGS. Diagnostic performance of clinical and tumor-based screening criteria was assessed by the presence of germline pathogenic/likely pathogenic variants (PGVs) in MMR genes. Results: A total of 232 patients with UTUC underwent germline testing; median age of diagnosis was 67 years (interquartile range 59 – 73). Of these patients, 70% were male, 43% had UTUC diagnosed before the age of 65, 85% had high grade UTUC,12% had bilateral UTUC, 11% had metastasis at diagnosis, 10% and 31% had personal and family history of LS-associated cancers, respectively. PGVs in moderate or high-penetrance genes were identified in 31 (13%) patients including 6 (3%) in BRCA1/ 2 and 21 (9%) in MMR genes (13 MSH2, 4 MSH6, 4 MLH1). A total of 10/21 (48%) patients with MMR PGVs developed UTUC as their first cancer diagnosis. Of patients with MMR PVGs, 15/16 (94%) had MMR-deficient tumors and 12/18 (67%) had MSI-high tumors. Personal and family history of LS core cancers (p < 0.001), age of diagnosis < 65 (p = 0.008), MSI-high (p < 0.001), and MMR-deficiency (p < 0.001) were associated with MMR carrier status. Female gender (p = 0.7), HG UTUC (p = 0.5), and bilateral UTUC (p = 0.7) were not associated with MMR PGVs. Current NCCN genetic referral criteria for Lynch syndrome has high specificity in identifying patients with LS (100%) but missed 11/21 (52%) patients with UTUC and MMR PGVs. Conclusions: Current genetic referral guidelines for Lynch syndrome may miss a significant portion of patients with LS-associated UTUC. UTUC tumor should be investigated for MMR protein and MSI status with IHC or next generation sequencing methods to augment LS-screening of patients with UTUC and inform systemic treatment selection.