bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of a national database to evaluate place-of-death preferences among patients with bladder cancer in the United States of America from 2003 to 2020.
Authors: Jatwani Karan , Sukaina Mahnoor , Khosla Atulya Aman , Patel Riya Jayesh , Muthusamy Kumarasamy Vasanthan , Singh Rohit , Gopalakrishnan Dharmesh
Published: January 2024

580

Background: Bladder Cancer (BC) is associated with significant treatment related morbidity and mortality risk. End of life care (EOL) and advance care planning are crucial in oncology care of BC patients. Place of Death (PoD) is an important determinant of patient and caregiver preference, access to home-based supportive care, and cost of caregiving at EOL. We evaluate trends in PoD for patients and hospice utilization with BC in the U.S. from 2003 to 2020 based on the CDC WONDER (Centers for Disease Control and Prevention for Wide-ranging Online Data for Epidemiologic Research) database. Methods: We analyzed data using the CDC WONDER database from January 01, 2003, to December 31, 2020. The data for deaths due to bladder cancer was pooled using the International Classification of Diseases-10th (ICD-10) Revision code as C67, C67.1, C67.2, C67.3, C67.4, C67.5, C67.8, C67.9. The inclusion criteria included patients aged >18. The demographic data was obtained to calculate descriptive statistics using age, gender, PoD, census region, and utilization of hospice mortality accordingly over the past two decades. Results: The analysis demonstrated that overall mortality due to BC were 319,229 from 2003-2020. Of these deaths, 27,990 (8.8%) were recorded in hospice facilities. The hospice mortality has steadily increased from 0.3% in 2003 to the highest of 9.10% in 2019, with a sharp decline to 7.3% in 2020. We noticed the PoD differed based on racial subgroups. More than half of African American (AA) population mortality was observed in a medical facility (57.01%) compared to Whites (50.27%). Hospice or death at home in AA were (42.99%) compared to whites (49.73%). Age stratified mortality analysis showed decreased hospice utilization in 25-44 yrs (9.61%) vs 65+ yrs (10.15%). Stratifying the results by the state census showed highest hospice utilization in Florida (25.23%) vs the lowest in Virginia (2.51%). Conclusions: To our knowledge this is the first study utilizing CDC WONDER database to demonstrate PoD preferences in BC related deaths. We observed a steady increase in hospice utilization from 2003-2020 throughout the US with a decline in 2020 possibly related to COVID pandemic. AA had higher mortality in medical facilities compared to whites, whereas the white population has utilized more hospice services or died at home. This study highlights the need for further efforts and policy changes needed to improve hospice utilization across the US with a focus on improved access to EOL care in BC patients.
Analysis of therapy attrition and changes in outcomes over time for patients (pts) with advanced urothelial cancer (aUC) treated at an academic center.
Authors: Reyes Kevin R , Jindal Tanya , Deshmukh Prianka , Zhu Xiaolin , Ding Chien-Kuang Cornelia , Wong Anthony C. , Chu Carissa E , Porten Sima P. , Chou Jonathan , Friedlander Terence W. , Koshkin Vadim S
Published: January 2024

590

Background: Despite recent advances in treatment (Tx) options for pts with aUC, real world data suggest that <50% of pts starting Tx receive 2nd line Tx and <15% receive 3rd line Tx. We hypothesized that aUC pts treated at an academic center would have lower Tx attrition rates which would translate into improved outcomes for pts treated more recently. Methods: We identified pts with aUC treated since 2011 and analyzed pts who received systemic Tx for metastatic disease, including baseline characteristics, Tx lines and outcomes. Date of 1/1/2019 for Tx start was used to divide pts into earlier vs later Tx groups. Overall survival (OS) from Tx start was assessed using Kaplan Meier Method in pts who started Tx >1 year before censor date of 12/31/2022 for survival. Chi-square test and Wilcoxon rank sum test were used to compare proportions and numerical data, respectively. Results: Among 360 pts with aUC, 237 received 1st line Tx from 09/2011-08/2022. Of 237 pts, 133 (56%) received 2nd line Tx, 61 (26%) 3rd line Tx, 30 (13%) 4th line Tx, and 10 (4%) > 4 Tx. Pts with Tx in the later group (start after 1/2019) had higher ORR with 1st and 2nd line Tx (Table) and more NGS testing (87% vs 54%, p<0.001) relative to earlier group. With median follow-up of 29.5 mos, median OS was 24.2 mos (95% CI: 17.4 – 29.7) for all pts. Pts in the later group (Tx started 1/2019-12/2021, n=94) had improved mOS relative to the 134 pts in the earlier group (30.6 vs 17.4 mos, p=0.02) despite similar number of average Tx lines (2.4 vs 2.5). Conclusions: During a decade when significant changes occurred in the aUC Tx landscape, pts treated at an academic center had lower Tx attrition rates than those described in real world settings during a similar timeframe. Notably, pts who started Tx after 1/2019 had improved OS relative to pts who started Tx earlier, despite similar number of average Tx lines. This finding may be driven by higher ORR to 1st and 2nd Tx lines in pts treated more recently. Validation in other academic centers and larger cohorts is needed. [Table: see text]
A phase II study of tislelizumab (T) monotherapy as neoadjuvant treatment for cisplatin-ineligible high risk upper tract urothelial carcinoma (UTUC).
Authors: Huang Jiwei , Cai Xinyun , Kong Wen , Zhang Jin , Chen Yonghui , Chen Haige , Xue Wei
Published: January 2024

591

Background: Platinum-based chemotherapy is standard of care after radical nephroureterectomy for patients with high risk UTUC. However, more than half of UTUC patients may suffer from severe renal function loss which limits the use of cisplatin. Here we report the efficacy and safety results of T in the neoadjuvant treatment of patients with high risk UTUC who are ineligible for cisplatin-based chemotherapy. Methods: Eligible patients had high risk UTUC defined as pathological high-grade UTUC (either by endoscopic biopsy or urinary cytology) and/or invasive aspect on radiological examination(cT2-T4a N0/X M0) and/or hydronephrosis, ECOG PS 0-2, no prior systemic therapy and ineligible for cisplatin. Patients with variant histology on biopsy were included. Patients were given T 200mg IV every 3 weeks for at most 4 cycles followed by surgery (radical nephroureterectomy or ureteral resection or endoscopic ablation). CTU or contrast enhanced MRI examination was performed before the third dose and another before the surgery. The primary endpoint was pCR(pT0N0). The secondary endpoint included PaR(＜pT2N0) and safety. Results: 16 patients were recruited between Mar 2021 and Sep 2022: median age was 65 years(46-71), 13(81.3%) male, 14(87.5%) cT3-cT4, 4(25%) cN+. All patients received at least 2 doses of T but 7 patients didn't accept all 4 doses as planned. 9 patients received radical nephroureterectomy, 1 patient received endoscopic ablation, 3 patients received segmental ureteral resection. 3 patients declined surgery due to disease progression or adverse events. Best radiological tumor response before surgery were 6(37.5%) cPR, 7(43.8%) cSD and 3(18.7%) cPD. Overall, 4 patients achieved pCR(25%) after surgery, among which 3 patients received radical nephroureterectomy. 1 patient received endoscopic ablation with no residual disease observed in specimens and was assessed as pCR after surgery with no recurrence observed 1 year after surgery. 7 patients were evaluated as ＜pT2N0. Grade 3/4 TRAE was 18.8%. No new safety signals were observed. Conclusions: The trial demonstrated a promising pCR rate of neoadjuvant tislelizumab in patients with high risk UTUC who were ineligible for cisplatin-based chemotherapy. Further exploratory analysis is ongoing to investigate underlying correlation between tumor immune microenvironment and treatment response. Clinical trial information: NCT04672330 .
Impact of HIV-HPV co-infection on inpatient penile cancer outcomes.
Authors: Olafimihan Ayobami Gbenga , Deenadayalan Vaishali , Fawehinmi Praise , Gupta Shweta
Published: January 2024

6

Background: HPV (human papillomavirus) and HIV (Human Immunodeﬁciency Virus) are risk factors for Penile cancer (PC); HIV-HPV co-infection heightens the risk of anogenital dysplasia (PMID: 19706632, 19082746, 35630489). However, there is paucity of data on the impact of HIV-HPV co-infections on PC outcomes. We evaluated the characteristics, outcomes, and healthcare utilization of patients with PC with and without HIV-HPV co-infection (HHC) from a national sample. Methods: Healthcare Cost and Utilization Project-Nationwide Inpatient Sample database was queried to identify all PC patients with (HIV-HPV-PC) and without HIV-HPV co-infection (non-HIV-HPV-PC) from 2016-2020. The groups were compared for socio-demographic differences, medical comorbidities, inpatient mortality, length of stay (LOS), and total hospital charges (THC). Secondary outcomes included rates of sepsis, septic shock, and UTI. Statistics were performed using t-test, univariate and multivariate logistic regression. Results: Out of 11,320 PC admissions, 255 had HIV, 205 had HPV, and 30 had HIV-HPV co-infection. Patients without the co-infection were older with a mean age of 65.6 years as compared to those with HIV-HPV co-infection, who had a mean age of 52.7 years (p = 0.002). Compared to non-HIV-HPV-PC, HIV-HPV-PC patients were more likely to be Black (66.7% vs 11.3%, p<0.001). The prevalence of comorbidities was similar between both groups. HIV-HPV co-infection in penile cancer patients was associated with a ten-fold higher adjusted all-cause mortality compared to those without the co-infection (adjusted odd ratio (aOR) = 10.2, p = 0.035). Mean LOS (6.0 vs 5.7 days, p = 0.8) and THC ($65,472 vs $64,627, p = 0.32) were similar between cohorts. Conclusions: HIV-HPV co-infection in penile cancer is associated with younger age, black race, and a ten-times higher adjusted all-cause inpatient mortality. [Table: see text]
Trends over time in the proportion of sequential treatment and overall survival in patients with metastatic urothelial carcinoma in real-world practice.
Authors: Yamamoto Shoma , Kato MInoru , Matsue Taisuke , Yukimatsu Nao , Takeyama Yuji , Otoshi Taiyo , Yamasaki Takeshi , Kuratsukuri Katsuyuki , Uchida Junji
Published: January 2024

606

Background: New approaches involving immune checkpoint inhibitors (ICIs) and antibody-drug conjugates prolong overall survival (OS) in patients with metastatic urothelial carcinoma (mUC). However, the access to such systemic therapy in clinical practice is suboptimal, and whether these agents improve OS in patients with mUC over time remains unclear. In the present study, we investigated the OS trend from the initiation of first-line therapy with these agents to identify changes due to the medication and time of treatment initiation. Methods: We retrospectively evaluated 195 patients who received platinum-based chemotherapy as a first line treatment. The patients were treated with chemotherapy, pembrolizumab, avelumab, or enfortumab vedotin (EV) sequentially and were divided into the following three groups: chemotherapy period (April 2009–June 2017; P1), pembrolizumab period (July 2017–December 2020; P2), and avelumab and EV period (January 2021–August 2022; P3) based on the regulatory approval. Data cutoff was set at July 31, 2023. Results: OS was prolonged over time by the new therapeutic agents, and median OS was 11, 25, not reached, and 35.5 months for patients who were treated with chemotherapy, pembrolizumab, avelumab, or EV, respectively. However, median OS was 14, 18 months, and not reached in P1, P2 and P3, respectively. Analysis by periods showed that OS was significantly longer in P2 than in P1 (HR = 0.62, 95% CI: 0.43–0.89, P = 0.009) and in P3 than in P1 (HR = 0.47, 95% CI: 0.28–0.78, P = 0.015). No difference was observed in OS between P2 and P3 (HR = 0.66, 95% CI: 0.36–1.20, P = 0.21). Overall, the proportion of patients who received ICIs increased over time, as indicated by the fact that 77 and 95 patients received ICIs (pembrolizumab or avelumab) in P2 and P3, respectively. However, the prevalence of the treatment with EV was only 24%, and 43% of patients who received pembrolizumab received best supportive care. Conclusions: This study showed an improvement in OS over time in patients with mUC in real-world practice and may indicate the importance of not missing the appropriate opportunity to receive sequential treatments.
Comparative outcomes of radical nephroureterectomy and kidney-sparing surgery in the treatment of high-grade upper tract urothelial carcinoma.
Authors: Gao Helen , Moore Kyle , Delgado Jennifer , Kulkarni Anirudh , Lichtbroun Benjamin , Chua Kevin J. , Pfail John , Packiam Vignesh T. , Golombos David , Jang Thomas L. , Ghodoussipour Saum
Published: January 2024

607

Background: Patients with upper tract urothelial carcinoma (UTUC) can be managed with either radical nephroureterectomy (RNU) or kidney sparing surgery (KSS) depending on the pathology and patient specific characteristics. Due to the rarity of this disease, high-level evidence is lacking with regard to clinical and oncologic outcomes after surgery. This study aims to compare outcomes of RNU with KSS for patients with high-grade (HG) UTUC. Methods: We retrospectively reviewed patients with >1 year follow-up who were treated for HG UTUC at our institution from 2015-2021. Oncologic and clinical outcomes were recorded. Procedure-related burdens, including total number of procedures under anesthesia, anesthesia time, and days hospitalized were collected. Results: 65 patients were analyzed, with 46 patients treated via RNU and 19 treated via KSS. There were no differences in the ASA or CCI between patients in the two groups. The 5-year overall survival (OS) was 65.2% (95% CI, 52.8%-80.5%) for RNU and 44.4% (95% CI, 26.5%-74.5%) for KSS. The 3-year metastasis-free survival was 78.3% for RNU and 78.9% for KSS. The 3-year recurrence-free survival, including recurrences in the bladder, was 47.8% (95% CI, 35.4%-64.7%) for RNU and 43.8% (95% CI, 25.1%-76.3%) for KSS. A decline of GFR <10 2 years after surgery occurred in 97.1% of patients treated with RNU and 100.0% of those treated with KSS. The total number of procedures under anesthesia was higher for KSS than RNU at 3.4 +/- 1.7 vs 2.1 +/- 1.7, respectively (p = 0.0155). The total number of TURBTs for KSS and RNU was similar at 0.6 +/- 0.7 vs 1.1 +/- 1.7, respectively (p = 0.9538). The total number of days hospitalized for KSS was similar to RNU at 5.5 +/- 4.3 vs 6.8 +/- 4.6, respectively (p = 0.3579). The total anesthesia time for KSS was 400 +/- 218 min and was 474 +/- 185 min for RNU (p = 0.2561). Conclusions: There were similar oncologic and clinical outcomes in patients with HG UTUC treated with either KSS or RNU. Patients treated with KSS saw a higher procedural load. There was a trend towards lower OS for patients treated with KSS but this was not statistically significant, likely due to the small sample size. Larger datasets are needed to further evaluate outcome and treatment burdens of RNU vs KSS as treatment options for patients with HG UTUC. [Table: see text]
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.
A meta-analysis assessing objective response rates with first-line systemic treatment options in locally advanced/metastatic urothelial carcinoma.
Authors: Saxena Akshat , Naqvi Syed Arsalan Ahmed , Tripathi Nikita , Khan Muhammad Ali , Bibi Arifa , Ballouz Tara , Abdul-Muhsin Haidar , Tyson Mark , Riaz Irbaz Bin , Bryce Alan Haruo , Singh Parminder
Published: January 2024

639

Background: Immunotherapy combined with chemotherapy (IO/C) as the first-line management of locally advanced or metastatic urothelial carcinoma (LA/mUC) has been investigated in multiple trials with conflicting outcomes. Therefore, we conducted a meta-analysis of available trials to compare objective response rates (ORR) of this combination regimen, both in overall and in cisplatin-ineligible populations. Methods: EMABSE and MEDLINE were searched from 2000 through July 20th, 2023, to identify phase II and III clinical trials assessing IO, C or both in LA/mUC. Main outcome of interest was objective response rates (ORR) as defined in the included trials. An inverse variance random-effects meta-analysis was performed to estimate pooled ORR using the restricted maximum likelihood estimation method. Subgroup differences were assessed among IO/C, IO alone, and C alone. The threshold for statistical significance was established at 0.1. Results: Of 5975 citations identified, a total of 26 trials with a total of 4,628 participants were included in this systematic review. In the overall group, the ORR in IO/C trials (5 trials, 1,236 patients) was 44.70% (95% CI: 21.88%- 70.0%). In IO trials (7 trials, 2,189 patients), ORR was 23.68% (19.55%- 28.36%) and in C trials (26 trials, 4,628 patients) was 43.46% (37.43%-49.68%]). In the cisplatin-ineligible group, the ORR in IO/C trials (2 trials, 240 patients) was 60.06% (33.38%-81.86%), in IO trials (6 trials, 1,103 patients) was 26.15% (23.01%; 29.56%), and in C trials (8 trials, 767 patients) was 42.45% (35.67%-49.52%). In terms of subgroup differences, the difference in ORR was statistically significant between IO/C and IO trials (p= 0.0844) and between IO and chemotherapy trials (p< 0.0001) in the overall population. Similarly, we found a statistically significant difference in ORR between IO/C and IO (p= 0.0108) and between IO and chemotherapy trials (p< 0.0001) in the cisplatin-ineligible population. No statistically significant differences were observed between IO/C and C alone. Conclusions: First-line IO/C may achieve a better objective response compared to IO alone in patients diagnosed with locally advanced/metastatic UC. Although, there appears to be a trend of greater benefit with IO/C compared to C alone, the difference was not statistically significant. The results will be updated as soon data from new trials (CheckMate 901 and EV 302) becomes available which could offer new insights. [Table: see text]
Effect of type of antibiotics (Abx) on outcomes with immune checkpoint inhibitors (ICIs) in patients (pts) with metastatic urothelial carcinoma (mUC) in a real-world setting.
Authors: Hobeika Charbel , Dawsey Scott , Patgunarajah Ubenthira , Lynn David , Pramod Nikhil , Wei Wei , Nair Monica , Maroli Kimberly , Martin Allison , Ornstein Moshe Chaim , Wee Christopher Eing , Gilligan Timothy D. , Nizam Amanda , Bonham Amanda , Mian Omar Y. , Pavicic Paul G. , Diaz-Montero C. Marcela , Gupta Shilpa
Published: January 2024

640

Background: Use of Abx was associated with worse overall survival (OS) and progression-free survival (PFS) in our real-world cohort of mUC pts treated with ICI. (ASCO 2023). We now report the effect of type of Abx on ICI outcomes. Methods: In our cohort of 335 pts with mUC treated with ≥2 cycles of ICI with atezolizumab (A) or pembrolizumab (P) at CCF between 2015 and 2023, Abx class used in at least 20 pts was included. PFS and OS were calculated using Kaplan-Meier method, outcomes compared using log-rank testing and multivariate (MVA) Cox regression method. Results: Of 335 pts, 26.27% received A and 73.73% received P. Median follow-up was 26.8 mos. Details of type of Abx (cephalosporins (CPH), fluoroquinolones (FQ), penicillins (PCN) and trimethoprim-sulfamethoxazole (TMP-SMX), timing (30 or 60 (d) pre or post ICI start) and OS/PFS are shown in the Table. On MVA Cox regression analysis, Abx use within 60 (d) before ICI start was associated with worse OS (10.97 vs 16.03 mos.; (HR) 1.6 [1.2 -2.1], p=0.0004). Abx use within 30 (d) post ICI was associated with worse OS (6.9 vs 14.39 mos, p=0.008). Individual Abx and effect on OS and PFS are shown in Table. On MVA Cox regression analysis, Abx use within 60 (d) post ICI start was associated with worse PFS (3.12 vs 5.67 mos., HR 1.4; p=0.015). Conclusions: In our large cohort of pts with mUC treated with ICI, Abx PCN, CPH and FQ, within 30 and 60 (d) prior to starting ICIs demonstrated worse OS, Abx used after 30 and 60 (d) of ICI demonstrated worse OS and PFS, especially with CPH and PCN but not FQ. These findings have the potential to influence clinical practice, including using a higher threshold for prescribing antibiotics to pts with mUC when planned for or on ICI and the choice of Abx used. [Table: see text]
Real world experience of FGFR gene alterations and clinical outcomes in advanced/metastatic urothelial cancer in Japan: MONSTAR-SCREEN database study.
Authors: Matsubara Nobuaki , Osawa Takahiro , Abe Takashige , Oya Mototsugu , Nishimoto Koshiro , Iwahori Toshiyuki , Tsuchiya Hiroaki , Murota Maiko , Yoshida Masaki , Tatematsu Yohei , Nakano Yosuke , Eto Masatoshi , Nonomura Norio
Published: January 2024

647

Background: Gene alterations (GA) in fibroblast growth factor receptors ( FGFR) may be oncogenic drivers in urothelial cancer (UC). However, the association between FGFR GA status and the prognosis with platinum-based chemotherapy has not been well investigated, especially in Asian patients. This study aims to elucidate the proportion and prognosis of FGFR2 or 3 (2/3) GA-positive advanced or metastatic UC (a/m UC). Methods: This study included patients registered during 2019 and 2022 in the “MONSTAR-SCREEN” database, where FoundationOneLiquid (F1L) was used for detecting 324 cancer-related genes, including FGFR. Analyzed FGFR2/3 GA variants included FGFR3 mutations (R248C, S249C, G370C, and Y373C) and FGFR2/3 fusions (FGFR2-BICC1, FGFR2-CASP7, FGFR3-TACC3, and FGFR3-BAIAP2L1). The positive ratio of FGFR2/3 GA and other gene alterations except FGFR was obtained at registration in eligible patients; besides, FGFR2/3 GA status was also evaluated after systemic treatment. Progression-free survival (PFS) in each treatment line was estimated, summarized by FGFR2/3 GA positive/negative. Results: Among the registered 2,224 cancer patients in this database, 138 eligible a/m UC patients were included (median age [SD] 72.0 [9.1] years for all; 95 males [68.8%]). The primary tumor site was the bladder in 70 patients (50.7%), renal pelvis in 50 patients (36.2%), and ureter in 18 patients (13.0%). FGFR2/3 GA was positive in 16 patients (11.6% [95% confidence interval: 6.8, 18.1]); the proportion of other typical gene alterations was 92.8%, 41.3%, 23.2%, and 23.2% in TP53, TERT, ARID1A and BRCA2, respectively. F1L was performed both before and after systemic treatment twice or more in 55 patients (39.9%). The FGFR concordance was analyzed in 55 patients available for both before and after treatment F1L results. Among them, 3 of the 6 FGFR2/3 GA-positive patients (50.0%) remained positive, and 1 of the 49 FGFR2/3 GA-negative patients (2.0%) before systemic treatment turned positive after treatment. The median PFS after first-line treatment was 6.8 months in FGFR GA-positive and 6.4 months in the negative patients. The estimated survival rate after first-line treatment was also similar between FGFR GA-positive and -negative patients at 12 months (68.8% vs. 81.0%). Conclusions: The results showed a similar trend to previous studies, where FGFR GA was reported in approximately 20% of metastatic UC patients. No difference was found in the PFS and the estimated survival rate by FGFR2/3 GA-positive or -negative patients. Our data showed that treatment pressure did not alter the FGFR status commonly.
Performance of a tumor-informed molecular residual disease (MRD) assay in resected bladder cancer with mixed or pure variant histology: Analysis of a real-world multicenter cohort.
Authors: Kommalapati Ajitha , Laliotis George , Rich Jordan , Cumarasamy Shivaram , Rivero Samuel , Sharma Shruti , Palsuledesai Charuta C , Malhotra Meenakshi , Galsky Matt D. , ElNaggar Adam , Liu Minetta C. , Sfakianos John P. , Peyton Charles , Ferguson James , Basu Arnab
Published: January 2024

649

Background: Circulating tumor DNA (ctDNA)-based MRD assays can detect clinically occult disease with high sensitivity and specificity in patients with solid tumors. Previous trials that evaluated MRD testing in bladder cancer, such as ABACUS and IMVigor010, enrolled patients with a predominant urothelial carcinoma component. Given the known histological and molecular heterogeneity in urothelial carcinoma, we examined the prognostic value of a tumor-informed MRD assay in bladder cancer patients with mixed or pure variant histologies (M/VH). Methods: This retrospective study analyzed the results of post-cystectomy longitudinal ctDNA testing from a multi-institutional database of patients with urothelial carcinoma (n=205). A personalized, tumor-informed assay (Signatera, Natera, Inc.) was used for the detection and quantification of ctDNA. Patients with M/VH and at least 3 months of postoperative follow-up data on relevant demographic, clinical, pathologic, and NGS variables were eligible for inclusion. Time-dependent Cox regression analyses were performed for disease-free survival (DFS) based on ctDNA during the MRD window (<12 weeks from surgery, N=29) and surveillance window (>12 weeks post-surgery or post-AT, N=29). Multivariable regression was performed to adjust hazards for clinicopathologic factors predicting DFS. Results: Of the 205 patients, 46 (74% male, median age: 69 years) met the inclusion criteria for analysis. Whole exome sequencing of tumor tissue revealed that TP53 (45.7%), ARID1A (32.6%), and KDM6A (30.4%) were the top three genes with somatic mutations. Twenty-seven (59%) patients received neoadjuvant therapy, 37% of whom (10/27) also received adjuvant therapy. ctDNA-positivity during the MRD window and during surveillance was strongly associated with poor DFS (MRD window: HR=4.93, 95%CI: 1.77-20.77, p=0.03; surveillance: HR=28.3, 95% CI: 3.52-3660, p<0.001). None of the serially ctDNA-negative patients (N=25) recurred, whereas 58.9% (10/17) of patients who were ctDNA-positive anytime post-surgery recurred at a median follow-up of 9 months from the date of surgery, range: 3.1-36.4 months). When adjusted for all other risk factors, ctDNA-positivity anytime post-surgery was the only significant predictor of recurrence (HR=55.26, 95%CI: 5.3-7648, p<0.00001). Conclusions: Personalized, tumor-informed ctDNA testing can identify patients with mixed or variant histology bladder cancer who are at high risk of recurrence. Further studies are warranted to evaluate the potential benefit of ctDNA-guided adjuvant therapy in this patient population.